Integrated stress pathway inhibitors
阅读说明：本技术 整合应激反应路径抑制剂 (Integrated stress pathway inhibitors ) 是由 S·伯纳勒斯 S·查克拉瓦蒂 B·普加拉 D·潘帕蒂尔 B·巴特 L·M·德尔加多·奥亚尔 于 2018-12-13 设计创作，主要内容包括：本公开大体上涉及可用作整合应激反应(ISR)路径抑制剂的治疗剂。(The present disclosure relates generally to therapeutic agents useful as inhibitors of the Integrated Stress Response (ISR) pathway.)
1. A compound of the formula (1-2),
or a pharmaceutically acceptable salt thereof;
wherein:
X2is CH;
RY1is hydrogen or C1-C6An alkyl group;
Y2selected from the group consisting of NRY2And O;
RY2Is hydrogen or C1-C6An alkyl group;
q2is 1;
r and s are independently of each other 0, 1 or 2;
A1is of the formula (A)1A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z1is selected from the group consisting ofThe group consisting of: CRZ1-1RZ1-2、NRZ1-2O, S and-CRZ1-1＝CRZ1-1-；
Wherein R isZ1-1Is H or R14(ii) a And R isZ1-2Is H or R14；
Z2Selected from the group consisting of: CRZ2-1RZ2-2、NRZ2-2O, S and-CRZ2-1＝CRZ2-1-；
Wherein R isZ2-1Is H or R14(ii) a And R isZ2-2Is H or R14；
Z3Independently at each occurrence is C or N, provided that at least one Z3Is C;
R13is hydrogen or R14Or R is13And RZ1-2Together form a ring with R13With Z1A double bond between, or R13And RZ2-2Together form a ring with R13With Z2A double bond between; and is
x1 is 1, 2, 3 or 4, and at least one R14Is halogen;
R14independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR14-aR14-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6HalogenatedAlkyl radical)2、-C(O)NR14-aR14-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical) 2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR14-aR14 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is14-aAnd R14-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A2is taken from at least one halogenSubstituted by radicals and optionally further substituted by one or more R16C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl;
R16independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical) 2、-N(C1-C6Haloalkyl groups)2、-NR16-aR16-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR16-aR16-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR16-aR16 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is16-aAnd R16-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R1aand R1bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
R2aand R2bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R3aAnd R3bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
When present, R4aAnd R4bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
or alternatively, R1aAnd R2aTogether form C1-C6An alkylene moiety;
or alternatively, R1aWith the presence of R3aAre formed in partC1-C6An alkylene moiety, and R1bAnd is located in said R3aGeminal R3bTogether with R1aTogether are both hydrogen;
or alternatively, R present3aMoiety and R present4aParts together forming C1-C6An alkylene moiety, and is located at said R3aGeminal R3bTogether with said R4aMoieties taken together and located in said R4aGeminal R4bTogether with said R3aAll moieties together are hydrogen;
R9aand R9bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent;
R10ais hydrogen; and is
R10bIs hydrogen.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein x1 is 1 and R14Is a halogen.
3. A compound of the formula (1-3),
or a pharmaceutically acceptable salt thereof;
wherein:
X2is CH or N;
RY1is hydrogen or C1-C6An alkyl group;
Y2selected from the group consisting of: chemical bond, NRY2And O; provided that when X is2When N is, then Y2Is a chemical bond;
RY2is hydrogen or C1-C6An alkyl group;
r and s are independently of each other 0, 1 or 2;
A1selected from the group consisting of:
formula (A)1A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z1selected from the group consisting of: CRZ1-1RZ1-2、NRZ1-2O, S and-CRZ1-1＝CRZ1-1-；
Wherein R isZ1-1Is H or R14(ii) a And R isZ1-2Is H or R14；
Z2Selected from the group consisting of: CRZ2-1RZ2-2、NRZ2-2O, S and-CRZ2-1＝CRZ2-1-；
Wherein R isZ2-1Is H or R14(ii) a And R isZ2-2Is H or R14；
Z3Independently at each occurrence is C or N, provided that at least one Z3Is C;
R13is hydrogen or R14Or R is13And RZ1-2Together form a ring with R13With Z1A double bond between, or R13And RZ2-2Together form a ring with R13With Z2A double bond between; and is
x1 is 1, 2, 3 or 4, and at least one R14Is halogen;
R14independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR14-aR14-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR14-aR14-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR14-aR14 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C) 1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is14-aAnd R14-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A2is substituted by at least one halogen substituent and optionally further by one or more R16C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl;
R16independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR16-aR16-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C) 1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR16-aR16-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR16-aR16 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is16-aAnd R16-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R1aand R1bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
R2aand R2bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R3aAnd R3bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R4aAnd R4bAt each occurrenceIndependently selected from the group consisting of: hydrogen, C 1-C6Alkyl and halogen;
or alternatively, R1aAnd R2aTogether form C1-C6An alkylene moiety;
or alternatively, R1aWith the presence of R3aParts together forming C1-C6An alkylene moiety, and R1bAnd is located in said R3aGeminal R3bTogether with R1aTogether are both hydrogen;
or alternatively, R present3aMoiety and R present4aParts together forming C1-C6An alkylene moiety, and is located at said R3aGeminal R3bTogether with said R4aMoieties taken together and located in said R4aGeminal R4bTogether with said R3aAll moieties together are hydrogen;
R9aand R9bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R9aAnd R9bAre all hydrogen;
R10aselected from the group consisting of: hydrogen, -OR10a-aand-NR10a-bR10a-c；
R10bIs hydrogen;
R12aand R12bTogether form an oxo (═ O) substituent, or alternatively, R12aAnd R12bAre all hydrogen;
R10a-aselected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group;
or R10a-aAnd RY2Can together form a carbonyl (C ═ O) moiety; and is
R10a-bAnd R10a-cIndependently of each other selected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group.
4. The compound of claim 3, or a pharmaceutically acceptable thereofSalt, wherein x1 is 1 and R14Is a halogen.
5. A compound of the formula (2-3),
or a pharmaceutically acceptable salt thereof;
Wherein:
X1and X2Independently of one another, is CH or N; provided that X is1And X2Is CH;
Y1selected from the group consisting of: chemical bond, NRY1And O; provided that when X is1When N is, then Y1Is a chemical bond;
RY1is hydrogen or C1-C6An alkyl group;
Y2selected from the group consisting of: chemical bond, NRY2And O; provided that when X is2When N is, then Y2Is a chemical bond;
RY2is hydrogen or C1-C6An alkyl group;
q1is 1;
r and s are independently of each other 0, 1 or 2;
A1is substituted by at least one halogen substituent and optionally further by one or more R14C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R14A substituent-substituted 5-10 membered heteroaryl;
R14independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR14-aR14-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR14-aR14-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups) 2、-S(O)2NR14-aR14 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl) and-N(C1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is14-aAnd R14-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A2is substituted by at least one halogen substituent and optionally further by one or more R16C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl;
R16independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups) 2、-NR16-aR16-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR16-aR16-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Halogenated alkyl) compoundsS(O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR16-aR16 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is16-aAnd R16-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R1aand R1bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
R2aand R2bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R3aAnd R3bIndependently at each occurrence is selected from the group consisting ofGroup consisting of: hydrogen, C1-C6Alkyl and halogen;
When present, R4aAnd R4bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
or alternatively, R1aAnd R2aTogether form C1-C6An alkylene moiety;
or alternatively, R1aWith the presence of R3aParts together forming C1-C6An alkylene moiety, and R1bAnd is located in said R3aGeminal R3bTogether with R1aTogether are both hydrogen;
or alternatively, R present3aMoiety and R present4aParts together forming C1-C6An alkylene moiety, and is located at said R3aGeminal R3bTogether with said R4aMoieties taken together and located in said R4aGeminal R4bTogether with said R3aAll moieties together are hydrogen;
R5aand R5bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively;
R6ais hydrogen;
R6bis hydrogen;
R9aand R9bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R9aAnd R9bAre all hydrogen;
R10aselected from the group consisting of: hydrogen, -OR10a-aand-NR10a-bR10a-c；
R10bIs hydrogen;
R12aand R12bTogether form an oxo (═ O) substituent, or alternatively, R12aAnd R12bAre all hydrogen;
R10a-aselected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group;
or R10a-aAnd RY2Can together form a carbonyl (C ═ O) moiety;
R10a-band R10a-cIndependently of each other selected from the group consisting of: hydrogen, C 1-C6Alkyl and C1-C6A haloalkyl group; and is
Provided that when X is2If N, then:
A1is substituted by at least two halogen substituents and optionally further by one or more R14C substituted by substituents6-C10Aryl, or substituted with at least two halogen substituents and optionally further substituted with one or more R14A substituent-substituted 5-10 membered heteroaryl; and is
A2Is substituted by at least two halogen substituents and optionally further by one or more R16C substituted by substituents6-C10Aryl, or substituted with at least two halogen substituents and optionally further substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl.
6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein X1Is CH and X2Is CH.
7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein X1Is N and X2Is CH.
8. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein:
X1is CH;
X2is N;
A1is substituted by at least two halogen substituents and optionally further by one or more R14C substituted by substituents6-C10Aryl, or substituted with at least two halogen substituents and optionally further substituted with one or more R14A substituent-substituted 5-10 membered heteroaryl; and is
A2Is a quiltAt least two halogen substituents and optionally further substituted by one or more R16C substituted by substituents6-C10Aryl, or substituted with at least two halogen substituents and optionally further substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl.
9. A compound of formula (XX),
or a pharmaceutically acceptable salt thereof;
wherein:
X5is CH or N;
Y5selected from the group consisting of: chemical bond, NRY5And O; provided that when X is5When N is, then Y5Is a chemical bond;
RY5is hydrogen or C1-C6An alkyl group;
RNis hydrogen or C1-C6An alkyl group;
m4、n5、p3and q is4Independently of one another, 0 or 1;
r3 and s3 are independently of each other 0, 1 or 2;
A13selected from the group consisting of:
optionally substituted by one or more R95C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R95A substituent-substituted 5-10 membered heteroaryl;
R95independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR95-aR95-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups) 2、-C(O)NR95-aR95-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR95-aR95 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is95-aAnd R95-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R84aand R84bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
R85aand R85bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R86aAnd R86bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R87aAnd R87bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
or, R 84aAnd R85aTogether form C1-C6An alkylene moiety;
or, R84aWith the presence of R86aParts together forming C1-C6An alkylene moiety;
or, R present86aMoiety and R present87aParts together forming C1-C6An alkylene moiety;
R88selected from the group consisting of: hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -C (O) (C)1-C6Alkyl), -C (O) (C)1-C6Haloalkyl), -C (O) OH, -C (O) O (C)1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR88-aR88-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2and-S (O)2NR88-aR88-b；
Wherein R is88-aAnd R88-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R89independently at each occurrence, selected from the group consisting of: hydrogen, halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR89-aR89-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR89-aR89-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical) 2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR89-aR89 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is89-aAnd R89-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
when present, R90aAnd R90bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R90aAnd R90bAre all hydrogen;
when present, R91aSelected from the group consisting of: hydrogen, -OR91a-aand-NR91a-bR91a-c；
When present, R91bIs hydrogen;
or alternatively, R91aAnd R91bTogether form a moiety selected from the group consisting of: -O-CH2-CH2-、-CH2-O-CH2-、-CH2-CH2-O-、-O-CH2-CH2-CH2-、-CH2-O-CH2-CH2-、-CH2-CH2-O-CH2-、-CH2-CH2-CH2-O-、-O-CH2-CH2-CH2-CH2-、-CH2-O-CH2-CH2-CH2-、-CH2-CH2-O-CH2-CH2-、-CH2-CH2-CH2-O-CH2-and-CH2-CH2-CH2-CH2-O-；
When present, R92aAnd R92bAre all hydrogen;
when present, R93aAnd R93bTogether form an oxo (═ O) substituent, or alternatively, R93aAnd R93bAre all hydrogen;
R91a-aselected from the group consisting of: hydrogen, C 1-C6Alkyl and C1-C6A haloalkyl group;
or R91a-aAnd RY5Can together form a carbonyl (C ═ O) moiety; and is
R91a-bAnd R91a-cIndependently of each other selected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group;
provided that when m is4Is 0, n5Is 0, and q4When is 0, then p3Is 1 and A13Is of the formula (A)13A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z14selected from the group consisting of: CRZ14-1RZ14-2、NRZ14-2、C(RZ14-1RZ14-2)N(RZ14-2)、O、C(RZ14-1RZ14-2)O、S、C(RZ14-1RZ14-2) S and-CRZ14-1＝CRZ14-1-；
Wherein R isZ14-1Is hydrogen or R16(ii) a And R isZ14-2Is hydrogen or R95；
Z15Selected from the group consisting of: CRZ15-1RZ15-2、NRZ15-2、C(RZ15-1RZ15-2)N(RZ15-2)、O、C(RZ15-1RZ15-2)O、S、C(RZ15-1RZ15-2) S and-CRZ15-1＝CRZ15-1-；
Wherein R isZ15-1Is hydrogen or R95(ii) a And R isZ15-2Is hydrogen or R95；
Z16Independently at each occurrence is CH, CR95Or N;
R94is hydrogen or R95Or R is94And RZ14-2Together form a ring with R94With Z14A double bond between, or R94And RZ15-2Together form a ring with R94With Z15A double bond between; and is
x23 is 0, 1, 2, 3 or 4.
10. The compound of claim 9, wherein the compound of formula (XX) is a compound of formula (XX-I):
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10, wherein the compound of formula (XX-I) is a compound of formula (XX-I-1):
or a pharmaceutically acceptable salt thereof;
wherein A is13Is of the formula (A)13A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z14Selected from the group consisting of: CRZ14-1RZ14-2、NRZ14-2、C(RZ14-1RZ14-2)N(RZ14-2)、O、C(RZ14-1RZ14-2)O、S、C(RZ14-1RZ14-2) S and-CRZ14-1＝CRZ14-1-；
Wherein R isZ14-1Is hydrogen or R16(ii) a And R isZ14-2Is hydrogen or R95；
Z15Selected from the group consisting of: CRZ15-1RZ15-2、NRZ15-2、C(RZ15-1RZ15-2)N(RZ15-2)、O、C(RZ15-1RZ15-2)O、S、C(RZ15-1RZ15-2) S and-CRZ15-1＝CRZ15-1-；
Wherein R isZ15-1Is hydrogen or R95(ii) a And R isZ15-2Is hydrogen or R95；
Z16Independently at each occurrence is CH, CR95Or N;
R94is hydrogen or R95Or R is94And RZ14-2Together form a ring with R94With Z14A double bond between, or R94And RZ15-2Together form a ring with R94With Z15A double bond between;
x23 is 0, 1, 2, 3 or 4; and is
R95Independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR95-aR95-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR95-aR95-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR95-aR95 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C) 1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl).
12. The compound of claim 10, wherein the compound of formula (XX-I) is a compound of formula (XX-I-2):
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 10, wherein the compound of formula (XX-I) is a compound of formula (XX-I-2 b):
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 10, wherein the compound of formula (XX-I) is a compound of formula (XX-I-3):
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 9, wherein the compound of formula (XX) is a compound of formula (XX-II):
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 15, wherein the compound of formula (XX-II) is a compound of formula (XX-II-3):
or a pharmaceutically acceptable salt thereof.
17. A compound selected from the group consisting of the compounds of table 1, or a pharmaceutically acceptable salt thereof.
18. A compound selected from the group consisting of compounds 1 to 144, or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20. A method of treating a disease or disorder mediated by an Integrated Stress Response (ISR) pathway in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition according to claim 19.
21. The method of claim 20, wherein the compound, the pharmaceutically acceptable salt, or the pharmaceutical composition is administered in combination with a therapeutically effective amount of one or more additional anti-cancer agents.
22. The method of claim 20, wherein the disease or disorder is mediated by eIF2 a phosphorylation and/or guanine nucleotide exchange factor (GEF) activity of eIF 2B.
23. The method of any one of claims 20-22, wherein the disease or disorder is mediated by reduced protein synthesis.
24. The method of any one of claims 20 to 23, wherein the disease or disorder is mediated by the expression of ATF4, CHOP, or BACE-1.
25. The method of any one of claims 20 to 24, wherein the disease or disorder is a neurodegenerative disease, an inflammatory disease, an autoimmune disease, a metabolic syndrome, cancer, a vascular disease, an ocular disease, a musculoskeletal disease, or a genetic disorder.
26. The method of claim 25, wherein the disease is a white matter ablative disease, childhood ataxia with reduced CNS myelination, intellectual impairment syndrome, alzheimer's disease, prion disease, creutzfeldt-jakob disease, parkinson's disease, Amyotrophic Lateral Sclerosis (ALS) disease, cognitive disorders, frontotemporal dementia (FTD), traumatic brain injury, post-operative cognitive dysfunction (PCD), neuro-otological syndrome, hearing loss, huntington's disease, stroke, chronic traumatic brain disorder, spinal cord injury, dementia or cognitive disorders, arthritis, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, asthma, allergic asthma, bronchial asthma, tuberculosis, chronic tracheal disorders, cystic fibrosis, glomerulonephritis, membranous nephropathy, sarcoidosis, vasculitis, ichthyosis, graft rejection reaction, psoriasis, cystic fibrosis, glomerulonephritis, membranous nephropathy, and the like, Interstitial cystitis, atopic dermatitis or inflammatory bowel disease, crohn's disease, ulcerative colitis, celiac disease, systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, alcoholic fatty liver, obesity, glucose intolerance, insulin resistance, hyperglycemia, fatty liver, dyslipidemia, hyperlipidemia, type 2 diabetes, pancreatic cancer, breast cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, urothelial cancer, endometrial cancer, ovarian cancer, cervical cancer, kidney cancer, esophageal cancer, gastrointestinal stromal tumor (GIST), multiple myeloma, secretory cell cancer, thyroid cancer, gastrointestinal cancer, chronic myelogenous leukemia, hepatocellular carcinoma, colon cancer, melanoma, malignant glioma, glioblastoma multiforme, astrocytoma, ganglioblastoma cerebellum, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, ductal adenocarcinoma, adenosquamous carcinoma, nephroblastoma, acinar cell carcinoma, lung cancer, non-Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, Monoclonal Gammopathy of Unknown Significance (MGUS), plasmacytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, Palmer's disease, atherosclerosis, abdominal aortic aneurysm, carotid artery disease, deep vein embolism, Berger's disease, chronic venous hypertension, vascular calcification, telangiectasia or lymphedema, glaucoma, age-related macular degeneration, inflammatory retinal disease, retinal vascular disease, diabetic retinopathy, uveitis, rosacea, Hugger's syndrome, or neovascularization in proliferative retinopathy, Hyperhomocysteinemia, skeletal muscle atrophy, myopathy, muscular dystrophy, muscle wasting, sarcopenia, Duchenne's Muscular Dystrophy (DMD), becker's disease, myotonic dystrophy, X-linked dilated cardiomyopathy, Spinal Muscular Atrophy (SMA), down's syndrome, MEHMO syndrome, schmidt's Metaphyseal Chondrodysplasia (MCDS), depression, or social behavior disorders.
27. A method of producing a protein, the method comprising contacting a eukaryotic cell comprising a nucleic acid encoding the protein with a compound or salt of any one of claims 1-18.
28. The method of claim 27, comprising culturing the cell in an in vitro culture medium comprising the compound or salt.
29. A method of culturing a eukaryotic cell comprising a nucleic acid encoding a protein, the method comprising contacting the eukaryotic cell with an in vitro culture medium comprising a compound or salt of any one of claims 1-18.
30. The method of any one of claims 27-29, wherein the nucleic acid encoding a protein is a recombinant nucleic acid.
31. The method of any one of claims 27-30, wherein the cell is a Human Embryonic Kidney (HEK) cell or a Chinese Hamster Ovary (CHO) cell.
32. The method of any one of claims 27 to 30, wherein the cell is a yeast cell, a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell, a baby hamster kidney cell, a murine myeloma cell, an HT-1080 cell, a per.c6 cell, a plant cell, a hybridoma cell, or a human blood-derived leukocyte.
33. A method of producing a protein, the method comprising contacting a cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2(eIF2) and a nucleic acid encoding a protein with a compound or salt of any one of claims 1 to 18.
34. The method of any one of claims 27 to 33, wherein the protein is an antibody or fragment thereof.
35. The method of any one of claims 27 to 33, wherein the protein is a recombinant protein, an enzyme, an allergic peptide, a cytokine, a peptide, a hormone, Erythropoietin (EPO), an interferon, granulocyte colony stimulating factor (G-CSF), an anticoagulant protein, or a coagulation factor.
36. The method of any one of claims 27 to 35, comprising purifying the protein.
37. An in vitro cell culture medium comprising a compound or salt according to any one of claims 1 to 18 and nutrients for cell growth.
38. The cell culture medium of claim 37, comprising eukaryotic cells comprising nucleic acids encoding proteins.
39. The cell culture medium of claim 37 or 38, further comprising a compound for inducing protein expression.
40. The cell culture medium of any one of claims 37-39, wherein the protein-encoding nucleic acid is a recombinant nucleic acid.
41. The cell culture medium of any one of claims 37-40, wherein the protein is an antibody or fragment thereof.
42. The cell culture medium of any one of claims 37-40, wherein the protein is a recombinant protein, an enzyme, an allergic peptide, a cytokine, a peptide, a hormone, Erythropoietin (EPO), an interferon, a granulocyte colony stimulating factor (G-CSF), an anticoagulant protein, or a clotting factor.
43. The cell culture medium of any one of claims 37-42, wherein the eukaryotic cell is a Human Embryonic Kidney (HEK) cell or a Chinese Hamster Ovary (CHO) cell.
44. The cell culture medium of any one of claims 37-42, wherein the cell is a yeast cell, a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell, a baby hamster kidney cell, a murine myeloma cell, an HT-1080 cell, a PER.C6 cell, a plant cell, a hybridoma cell, or a human blood-derived leukocyte.
45. A cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2(eIF2) and a nucleic acid encoding a protein, and a compound or salt according to any one of claims 1 to 18.
46. The CFPS system of claim 45, comprising a eukaryotic cell extract containing eIF 2.
47. The CFPS system of claim 45 or 46, further comprising eIF 2B.
48. The CFPS system of any one of claims 45-47, wherein the protein is an antibody or fragment thereof.
49. The CFPS system of any one of claims 45 to 48, wherein the protein is a recombinant protein, enzyme, allergic peptide, cytokine, peptide, hormone, Erythropoietin (EPO), interferon, granulocyte colony stimulating factor (G-CSF), anticoagulant protein, or coagulation factor.
Technical Field
The present disclosure relates generally to therapeutic agents useful as inhibitors of the Integrated Stress Response (ISR) pathway.
Background
Different cellular conditions and stresses will activate a more conserved signaling pathway known as the Integrated Stress Response (ISR) pathway. The ISR pathway is activated in response to intrinsic and extrinsic stresses such as viral infection, hypoxia, glucose and amino acid deficiencies, oncogene activation, UV radiation, and endoplasmic reticulum stress. When ISR is activated in the presence of one or more of these factors, the alpha subunit of eukaryotic initiation factor 2(eIF2, comprising three subunits, i.e., alpha, beta, and gamma) becomes phosphorylated and rapidly reduces overall protein translation by binding to the eIF2B complex. This phosphorylation inhibits eIF 2B-mediated GDP exchange to GTP (i.e., guanine nucleotide exchange factor (GEF) activity), thereby isolating eIF2B from eIF2 in the complex and reducing overall protein translation of most mRNA in the cell. Paradoxically, eIF2 a phosphorylation also increases translation of a small set of mrnas containing one or more upstream open reading frames (uorfs) in the 5' untranslated region (UTR). These transcripts include the transcriptional regulator protein transcriptional activator 4(ATF4), the transcription factor CHOP, the growth arrest and DNA damage inducing protein GADD34, and the β -secretase BACE-1.
In animals, ISRs regulate major translational and transcriptional processes involved in diverse processes such as learning memory, immunity, intermediary metabolism, insulin production, and resistance to unfolded protein stress in the endoplasmic reticulum. ISR pathway activation has also been associated with a variety of pathological conditions including cancer, neurodegenerative diseases, metabolic diseases (metabolic syndrome), autoimmune diseases, inflammatory diseases, musculoskeletal diseases (such as myopathy), vascular diseases, ocular diseases, and genetic disorders. Aberrant protein synthesis by eIF2 α phosphorylation is also characteristic of several other human genetic disorders, cystic fibrosis, amyotrophic lateral sclerosis, Huntington's disease, and prion diseases.
Disclosure of Invention
Integrated Stress Response (ISR) pathway inhibitors are described, as well as methods of making and using the compounds or salts thereof.
Drawings
Figure 1 shows the percent inhibition of ATF4 following induction with thapsigargin (Tg) in the presence of certain test compounds. Percent ATF4 inhibition was calculated as percent reduction normalized to Tg treatment (0% inhibition) and untreated cells (100% inhibition).
FIG. 2 shows the levels of protein synthesis in unstressed cells in the presence of medium alone or certain test compounds. The synthesis levels were normalized to the medium alone conditions, which corresponded to 100% protein synthesis.
FIGS. 3A and 3B show the percent recovery of protein synthesis in stressed cells in the presence of one of several test compounds at concentrations of 100nM (FIG. 3A) or 1 μ M (FIG. 3B). The recovery levels were normalized to medium-only conditions and to Tg-only conditions, which correspond to 100% and 0%, respectively. Figure 3C shows the percent inhibition of ATF4 versus the percent recovery of protein synthesis for selected compounds.
Fig. 4A shows representative ATF4 expression levels and β -actin expression levels in SH-SY5Y cells after treatment with conditioned cell culture medium using wild-type CHO cells (wtCM) or 7PA2CHO cells (7PA2CM) (control).
FIG. 4B shows the percent inhibition of ATF4 expression in SH-5Y5Y cells after incubation with conditioned medium of 7PA2CHO cells and one of several test compounds. The inhibition levels were normalized to medium alone and to the conditioned medium of 7PA2CHO cells alone, which corresponds to 100% and 0%, respectively.
FIG. 5A shows long-term enhancement (LTP) of stimulated hippocampal slices from WT C57BL/6 mice or transgenic APP/PS1 mice, with or without incubation with ISRIB. LTP is based on the measured slope of the zone field excitatory postsynaptic potential (fEPSP) from 20 minutes before Theta Burst Stimulation (TBS) to 60 minutes after TBS. Figure 5B shows responses recorded during the last 10 minutes following conditional stimulation of sections from WT C57BL/6 and APP/PS1 mice treated with ISRIB (APP + ISRIB) and APP/PS1 mice treated with compound 3(APP + Cmp3) or compound 152(APP + Cmp152) or vehicle (APP).
Figure 6A shows the results of an 8-arm radial water maze (RAWM) task to measure learning ability of aged mice treated with
Figure 7A shows the learning memory test results for mice that did not develop Traumatic Brain Injury (TBI), had TBI without treatment, and had TBI with
Figure 8A shows protein synthesis in muscle from fasting mice or fasting mice treated with
Fig. 9A and 9B show the weight of gastrocnemius muscle from a fed mouse, a fasting mouse, or a fasting mouse administered compound 3 (fig. 9A) or compound 152 (fig. 9B). Fig. 9C and 9D show the percent protein synthesis of fed mice, fasting mice, or fasting mice administered compound 3 (fig. 9C) or compound 152 (fig. 9D), normalized for β -actin expression and calculated as a percentage relative to the protein synthesis level of fed mice. Fig. 9E and 9F show the expression of dystrophin (Atrogin) -1 in gastrocnemius muscle from fed mice, fasting mice, or fasting mice treated with compound 3 (fig. 9E) or compound 152 (fig. 9F), normalized to β -actin expression and fold change calculated as a comparison of expression levels to that of fed mice. Figure 9G shows observations of muscle fiber cross-sectional area (CSA) from fed mice, fasted mice, and compound 152-treated fasted mice and stained for ATF 4.
Figures 10A-C show protein synthesis in gastrocnemius (figure 10A), tibialis anterior (figure 10B), and quadriceps (figure 10C) with unilateral hind limb immobilization and hind limb immobilization (causing immobilization-induced muscle atrophy) in mice treated with vehicle control or
Figures 11A-C show the muscle weights of gastrocnemius (figure 11A), quadriceps (figure 11B), and tibialis anterior (figure 11C) in control mice, mice with cachexia-induced muscle atrophy, and mice with cachexia-induced muscle atrophy and treated with
Fig. 12A-12C show tumor volume (fig. 12A), tumor weight (fig. 12B), and tumor density (fig. 12C) for CT26 colon cancer cell line tumors injected subcutaneously in untreated (vehicle) mice or mice treated with
Figure 13A shows the relative fluorescence intensity (RFU) of GFP produced by cell-free expression in
FIGS. 14A and 14B show SDS-PAGE gels of yeast cells engineered to express phospholipase C (PLC) under either methanol inducible promoter (pAOX-PLC; FIG. 14A) or constitutive promoter (pGAP-PLC; FIG. 14B) in the presence of
FIGS. 14C and 14D show the activity of PLC secreted by yeast cells engineered to express phospholipase C (PLC) under methanol inducible promoter (pAOX-PLC; FIG. 14C) or constitutive promoter (pGAP-PLC; FIG. 14D) cultured in the presence of
FIG. 15A shows an SDS-PAGE gel of secreted proteins in CHO cells cultured in the presence of 1 μm, 5 μm or 10
Detailed Description
Definition of
As used herein, the terms "a" and "an" and the like are used to refer to one or more than one unless clearly indicated otherwise.
Reference herein to "about" a value or parameter includes (and describes) embodiments relating to that value or parameter itself. For example, a description referring to "about X" includes a description about "X".
As used herein, unless otherwise specified, "alkyl" means having the specified number of carbon atoms (i.e., C)1-C10Meaning one to ten carbon atoms) or a branched monovalent hydrocarbon chain, or combinations thereof. Particular alkyl groups are those having from 1 to 20 carbon atoms ("C)1-C20Alkyl group ") having 1 to 10 carbon atoms (" C1-C10Alkyl groups ") having 6 to 10 carbon atoms (" C)6-C10Alkyl group ") having 1 to 6 carbon atoms (" C1-C6Alkyl group ") having 2 to 6 carbon atoms (" C)2-C6Alkyl group ") or having 1 to 4 carbon atoms (" C)1-C4Alkyl groups "). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
As used herein, "alkylene" refers to the same residue as alkyl but having a divalent radical. Particular alkylene radicals are those having from 1 to 20 carbon atoms ("C)1-C20Alkylene ") having 1 to 10 carbon atoms (" C1-C10Alkylene ") having 6 to 10 carbon atoms (" C)6-C10Alkylene ") having 1 to 6 carbon atoms (" C1-C6Alkylene ") having 1 to 5 carbon atoms (" C1-C5Alkylene ") having 1 to 4 carbon atoms (" C 1-C4Alkylene ") or having 1 to 3 carbon atoms (" C)1-C3Alkylene ") groups. Examples of alkylene groups include, but are not limited to, groups such as methylene (-CH)2-) ethylene (-CH2CH2-) propylene (-CH)2CH2CH2-) isopropylidene (-CH2CH(CH3) -) butylene (-CH)2(CH2)2CH2-) isobutylene (-CH)2CH(CH3)CH2-) pentylene (-CH)2(CH2)3CH2-) and hexylene (-CH2(CH2)4CH2-) heptylene (-CH2(CH2)5CH2-) octylene (-CH)2(CH2)6CH2-) and the like.
As used herein, unless otherwise specified, "alkenyl" means and includes having at least one site of ethylenic unsaturation (i.e., having at least one moiety of the formula C ═ C) and having the specified number of carbon atoms (i.e., C ═ C)2-C10Meaning two to ten carbon atoms) or a branched monovalent hydrocarbon chain, or combinations thereof. The alkenyl group may have the "cis" or "trans" configuration, or alternatively, the "E" or "Z" configuration. Particular alkenyl radicals are those having from 2 to 20 carbon atoms ("C)2-C20Alkenyl ") having 6 to 10 carbon atoms (" C)6-C10Alkenyl ") having 2 to 8 carbon atoms (" C)2-C8Alkenyl ") having 2 to 6 carbon atoms (" C)2-C6Alkenyl ") or having 2 to 4 carbon atoms (" C)2-C4Alkenyl ") groups. Examples of alkenyl groups include, but are not limited to, groups such as vinyl (ethenyl/vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-2-enyl, but-3-enyl, but-1, 3-dienyl, 2-methylbut-1, 3-dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, and the like.
As used herein, "alkenylene" refers to a residue that is the same as an alkenyl group but is divalent. Particular alkenylene radicals are those having from 2 to 20 carbon atoms ("C)2-C20Alkenylene ") having 2 to 10 carbon atoms (" C)2-C10Alkenylene ") having 6 to 10 carbon atoms (" C)6-C10Alkenylene radical ") Having 2 to 6 carbon atoms (' C)2-C6Alkenylene ") having 2 to 4 carbon atoms (" C)2-C4Alkenylene ") or having 2 to 3 carbon atoms (" C)2-C3Alkenylene "). Examples of alkenylene include, but are not limited to, for example, ethenylene (ethenylene/vinylene) (-CH ═ CH-), propenylene (-CH ═ CHCH)2-), 1, 4-buten-1-enyl (-CH-)2CH2-), 1, 4-buten-2-enyl (-CH)2CH＝CHCH2-), 1, 6-hex-1-enylidene (-CH- (CH)2)3CH2-) and the like.
As used herein, unless otherwise specified, "alkynyl" means and includes having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C ≡ C) and having the specified number of carbon atoms (i.e., C ≡ C)2-C10Meaning two to ten carbon atoms) or a branched monovalent hydrocarbon chain, or combinations thereof. Particular alkynyl radicals are those having from 2 to 20 carbon atoms ("C)2-C20Alkynyl "), having 6 to 10 carbon atoms (" C6-C10Alkynyl "), having 2 to 8 carbon atoms (" C 2-C8Alkynyl "), having 2 to 6 carbon atoms (" C2-C6Alkynyl ") or having 2 to 4 carbon atoms (" C)2-C4Alkynyl ") of a cyclic alkyl group. Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (ethyl/acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.
As used herein, "alkynylene" refers to a residue that is the same as an alkynyl group but that is divalent. Particular alkynylene radicals are those having from 2 to 20 carbon atoms ("C2-C20Alkynylene "), having 2 to 10 carbon atoms (" C2-C10Alkynylene "), having 6 to 10 carbon atoms (" C6-C10Alkynylene "), having 2 to 6 carbon atoms (" C2-C6Alkynylene "), having 2 to 4 carbon atoms (" C2-C4Alkynylene ") or having 2 to 3 carbon atoms (" C)2-C3Alkynylene ") are used. Examples of alkynylene groups include, but are not limited toNot limited to, for example, ethynylene (ethylene/ethylene) (-C.ident.C-), propynyl (-C.ident.CCH-)2-) and the like.
As used herein, "cycloalkyl" means and includes, unless otherwise specified, having the specified number of carbon atoms (i.e., C)3-C10Meaning three to ten carbon atoms) of a saturated cyclic monovalent hydrocarbon structure. Cycloalkyl groups may consist of one ring, such as cyclohexyl, or of multiple rings, such as adamantyl. Cycloalkyl groups containing multiple rings can be fused, spiro, or bridged cycloalkyl groups, or a combination thereof. Particular cycloalkyl groups are those having from 3 to 12 ring carbon atoms. Preferred cycloalkyl radicals are those having from 3 to 8 ring carbon atoms ("C) 3-C8Cycloalkyl "), having 3 to 6 carbon atoms (" C3-C6Cycloalkyl) or having 3 to 4 ring carbon atoms ("C)3-C4Cycloalkyl groups ") are used. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.
As used herein, "cycloalkylene" refers to the same residue as cycloalkyl, but having a divalent radical. Cycloalkylene groups may consist of one ring or multiple rings, which may be fused, spiro, or bridged rings, or combinations thereof. Particular cycloalkylene radicals are those having from 3 to 12 ring carbon atoms. Preferred cycloalkylene radicals are those having from 3 to 8 ring carbon atoms ("C3-C8Cycloalkylene "), having 3 to 6 carbon atoms (" C3-C6Cycloalkylene) or having 3 to 4 ring carbon atoms ("C)3-C4Cycloalkylene ") of cyclic hydrocarbons. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like. Cycloalkylene groups may be attached to the remaining structures through the same ring carbon atom or through different ring carbon atoms. When the cycloalkylene group is attached to the remaining structure through two different ring carbon atoms, the linkages may be cis or trans with respect to each other. For example, the cyclopropylene group may include 1, 1-cyclopropylene and 1, 2-cyclopropylene (e.g., cis-1, 2-cyclopropylene or trans-1, 2-cyclopropylene), or mixtures thereof.
Unless otherwise specified, "cycloalkenyl" refers to and includes moieties having at least one site of ethylenic unsaturation (i.e., having at least one moiety of the formula C ═ C) and having the specified number of carbon atoms (i.e., C2-C10Meaning two to ten carbon atoms) of unsaturated cyclic non-aromatic monovalent hydrocarbon structures. Cycloalkenyl groups can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. Preferred cycloalkenyl radicals are unsaturated cyclic hydrocarbons having from 3 to 8 ring carbon atoms ("C)3-C8Cycloalkenyl group "). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.
As used herein, "cycloalkenylene" refers to the same residue as cycloalkenyl, but having a valency.
As used herein, "aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl) which may or may not be aromatic. Particular aryl radicals are those having from 6 to 14 ring carbon atoms ("C)6-C14Aryl "). An aryl group having multiple rings with at least one ring being a non-aromatic ring may be attached to the parent structure at either the aromatic ring position or at the non-aromatic ring position. In one variation, an aryl group having multiple rings with at least one ring being a non-aromatic ring is attached to the parent structure at an aromatic ring position.
As used herein, "arylene" refers to a residue that is the same as aryl but has a divalent valence. Particular arylene radicals are those having from 6 to 14 ring carbon atoms ("C)6-C14Arylene ").
As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having from 1 to 14 ring carbon atoms and at least one ring heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen, and sulfur. Heteroaryl groups may have a single ring (e.g., pyridyl, furyl) or multiple fused rings (e.g., indolizinyl, benzothienyl) which may or may not be aromatic. A particular heteroaryl group is a 5-to 14-membered ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5 to 10 membered ring having 1 to 8 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-, 6-or 7-membered ring having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, a particular heteroaryl group is a monocyclic aromatic 5-, 6-or 7-membered ring having 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, a particular heteroaryl group is a polycyclic aromatic ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryl groups having multiple rings with at least one ring being a non-aromatic ring may be attached to the parent structure at an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl group having multiple rings with at least one ring being a non-aromatic ring is attached to the parent structure at an aromatic ring position. Heteroaryl groups may be attached to the parent structure at a ring carbon atom or a ring heteroatom.
As used herein, "heteroarylene" refers to a residue that is the same as heteroaryl but has a valency.
As used herein, "heterocycle", "heterocyclic" or "heterocyclyl" refers to a saturated or unsaturated non-aromatic cyclic group having a single ring or multiple fused rings and having from 1 to 14 ring carbon atoms and from 1 to 6 ring heteroatoms such as nitrogen, sulfur or oxygen. The heterocycle comprising multiple rings can be a fused heterocycle, a bridged heterocycle, or a spiroheterocycle, or any combination thereof, but excludes heteroaryl. The heterocyclyl group may be optionally substituted independently with one or more substituents described herein. A particular heterocyclyl group is a 3 to 14 membered ring having 1 to 13 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3 to 12 membered ring having 1 to 11 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3 to 10 membered ring having 1 to 9 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3 to 8 membered ring having 1 to 7 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3 to 6 membered ring having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, a heterocyclyl includes a monocyclic 3-, 4-, 5-, 6-or 7-membered ring having 1 to 2, 1 to 3, 1 to 4, 1 to 5 or 1 to 6 ring carbon atoms and 1 to 2, 1 to 3 or 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, the heterocyclic group includes a polycyclic non-aromatic ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
As used herein, "heterocyclylene" refers to a residue that is the same as a heterocyclyl but that has a divalent radical.
"halo" or "halogen" refers to elements of the
"carbonyl" refers to the group C ═ O.
"thiocarbonyl" refers to the group C ═ S.
"oxo" refers to the moiety ═ O.
Unless otherwise indicated, "optionally substituted" means that a group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, where the substituents may be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, the optionally substituted group is unsubstituted.
As used herein, "individual" is intended to refer to a mammal, including but not limited to a primate, human, bovine, equine, feline, canine, or rodent, unless clearly indicated otherwise. In one variation, the individual is a human.
As used herein, "treatment" is a method for obtaining beneficial or desired results, including clinical results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: reducing one or more symptoms caused by the disease; reducing the extent of disease; stabilizing the disease (e.g., preventing or delaying the worsening of the disease); preventing or delaying the spread of the disease; delay of onset or recurrence of disease; delay or slow down the progression of the disease; improving the disease state; remission (partial or complete remission) of the disease; reducing the dose of one or more other drugs required to treat the disease; enhancing the effect of another drug; delay of progression of the disease; the quality of life is improved; and/or prolonged survival. The methods of the present disclosure encompass any one or more of these therapeutic aspects.
As used herein, the term "effective amount" is intended to refer to such amount of a compound of the present invention that should be effective in a given therapeutic form. It will be appreciated in the art that an effective amount may be divided into one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. In the case of administration of one or more therapeutic agents (e.g., a compound or a pharmaceutically acceptable salt thereof), an effective amount is contemplated, and a single agent may be considered to be provided in an effective amount if the desired or beneficial result is achieved or achieved in combination with one or more other agents. Suitable dosages for any of the co-administered compounds may optionally be reduced by a combined effect (e.g., additive or synergistic) of the compounds.
"therapeutically effective amount" means an amount of a compound or salt thereof sufficient to produce the desired therapeutic result.
As used herein, a "unit dosage form" refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The unit dosage form may contain monotherapy or combination therapy.
As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" means that a material is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The pharmaceutically acceptable carrier or excipient preferably meets the criteria required for toxicological and manufacturing testing and/or is included in the inactive ingredient guidelines set by the U.S. food and Drug administration.
A "pharmaceutically acceptable salt" is a salt that retains at least some of the biological activity of the free (non-salt) compound and can be administered to an individual as a drug or medicine. For example, such salts include: (1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or an acid addition salt with an organic acid such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, etc.; (2) when the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or a salt formed when coordinated to an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ by manufacturing processes or by separately reacting a purified compound of the disclosure in free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.
As used herein, the term "excipient" means an inert or inactive substance that can be used in the manufacture of a medicament or medicine, such as a tablet containing the disclosed compound as an active ingredient. The term excipient may comprise a variety of substances including, but not limited to, any substance that acts as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, material for chewable tablets, sweetener or flavoring agent, suspending/gelling agent, or wet granulation agent. Binders include, for example, carbomers (carbomers), povidone, xanthan gum, and the like; coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, and the like; compression/encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc ═ directly compressible), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose or microcrystalline cellulose), starch dc, sucrose, and the like; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, and the like; creams or lotions include, for example, maltodextrin, carrageenan, and the like; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, and the like; materials for chewable tablets include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), and the like; suspending/gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, and the like; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, and the like; and wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, and the like.
It is understood that aspects and embodiments described herein as "comprising" include "consisting of and" consisting essentially of the embodiments.
When a composition is described as "consisting essentially of" the listed components, the composition contains the explicitly listed components, and may also contain other components that do not significantly affect the disease or condition being treated, such as trace impurities. However, the composition is free of any other components than those explicitly listed that would significantly affect the disease or condition being treated; or if the composition contains additional components other than those listed that significantly affect the disease or condition being treated, the composition does not contain concentrations or amounts of these additional components sufficient to significantly affect the disease or condition being treated. When a method is described as "consisting essentially of the listed steps," the method contains the listed steps, and may contain other steps that do not significantly affect the disease or condition being treated, but the method does not contain any other steps, other than the explicitly listed steps, that would significantly affect the disease or condition being treated.
When a moiety is indicated as being substituted with "at least one" substituent, it also covers the disclosure of exactly one substituent.
Compound (I)
In one aspect, there is provided a compound of formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
X1and X2Independently of one another, is CH or N;
Y1selected from the group consisting of: chemical bond, NRY1And O; provided that when X is1When N is, then Y1Is a chemical bond;
RY1is hydrogen or C1-C6An alkyl group;
Y2selected from the group consisting of: chemical bond, NRY2And O; provided that when X is2When N is, then Y2Is a chemical bond;
RY2is hydrogen or C1-C6An alkyl group;
m1、m2、n1、n2、p1、p2、q1and q is2Independently of one another, 0 or 1;
r and s are independently of each other 0, 1 or 2;
A1selected from the group consisting of:
formula (A)1A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z1selected from the group consisting of: CRZ1-1RZ1-2、NRZ1-2O, S and-CRZ1-1＝CRZ1-1-；
Wherein R isZ1-1Is H or R14(ii) a And R isZ1-2Is H or R14；
Z2Selected from the group consisting of: CRZ2-1RZ2-2、NRZ2-2(ii) a O, S and-CRZ2-1＝CRZ2-1-；
Wherein R isZ2-1Is H or R14(ii) a And R isZ2-2Is H or R14；
Z3Independently at each occurrence is C or N, provided that at least one Z3Is C;
R13is hydrogen or R14Or R is13And RZ1-2Together form a ring with R13With Z1A double bond between, or R13And RZ2-2Together form a ring with R13With Z2A double bond between; and is
x1 is 0, 1, 2, 3 or 4, provided that when one Z is3When N, then x1 is not 4;
optionally substituted by one or more R 14C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R14A substituent-substituted 5-10 membered heteroaryl;
R14independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Alkyl halidesRadical, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR14-aR14-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR14-aR14-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR14-aR14 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O) 2(C1-C6Haloalkyl);
wherein R is14-aAnd R14-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A2selected from the group consisting of:
formula (A)2A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z4selected from the group consisting of: CRZ4-1RZ4-2、NRZ4-2O, S and-CRZ4-1＝CRZ4-1-；
Wherein R isZ4-1Is H or R16(ii) a And R isZ4-2Is H or R16；
Z5Selected from the group consisting of: CRZ5-1RZ5-2、NRZ5-2O, S and-CRZ5-1＝CRZ5-1-；
Wherein R isZ5-1Is H or R16(ii) a And R isZ5-2Is H or R16；
Z6Independently at each occurrence is C or N, provided that at least one Z6Is C;
R15is hydrogen or R16Or R is15And RZ4-2Together form a ring with R15Carbon atom of (2)And Z4A double bond between, or R15And RZ5-2Together form a ring with R15With Z5A double bond between; and is
x2 is 0, 1, 2, 3 or 4, provided that when one Z is6When N, then x2 is not 4;
optionally substituted by one or more R16C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl;
R16independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups) 2、-NR16-aR16-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR16-aR16-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR16-aR16 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is16-aAnd R16-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R1aand R1bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
R2aand R2bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R3aAnd R3bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
When present, R4aAnd R4bIndependently at each occurrence selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
or alternatively, R1aAnd R2aTogether form C1-C6An alkylene moiety;
or alternatively, R1aWith the presence of R3aParts together forming C1-C6An alkylene moiety, and R1bAnd is located in said R3aGeminal R3bTogether with R1aTogether are both hydrogen;
or alternatively, R present3aMoiety and R present4aParts together forming C1-C6An alkylene moiety, and is located at said R3aGeminal R3bTogether with said R4aMoieties taken together and located in said R4aGeminal R4bTogether with said R3aAll moieties together are hydrogen;
when present, R5aAnd R5bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R5aAnd R5bAre all hydrogen;
when present, R6aSelected from the group consisting of: hydrogen, -OR6a-aand-NR6a-bR6a-c；
When present, R6bIs hydrogen;
or alternatively, R6aAnd R6bTogether form a moiety selected from the group consisting of: -O-CH2-CH2-、-CH2-O-CH2-、-CH2-CH2-O-、-O-CH2-CH2-CH2-、-CH2-O-CH2-CH2-、-CH2-CH2-O-CH2-、-CH2-CH2-CH2-O-、-O-CH2-CH2-CH2-CH2-、-CH2-O-CH2-CH2-CH2-、-CH2-CH2-O-CH2-CH2-、-CH2-CH2-CH2-O-CH2-and-CH2-CH2-CH2-CH2-O-；
When present, R7aAnd R7bAre all hydrogen;
when present, R8aAnd R8bTogether form an oxo (═ O) substituent, or alternatively, R8aAnd R8bAre all hydrogen;
when present, R9aAnd R9bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R 9aAnd R9bAre all hydrogen;
when present, R10aSelected from the group consisting of: hydrogen, -OR10a-aand-NR10a-bR10a-c；
When present, R10bIs hydrogen;
or alternatively, R10aAnd R10bTogether form a moiety selected from the group consisting of: -O-CH2-CH2-、-CH2-O-CH2-、-CH2-CH2-O-、-O-CH2-CH2-CH2-、-CH2-O-CH2-CH2-、-CH2-CH2-O-CH2-、-CH2-CH2-CH2-O-、-O-CH2-CH2-CH2-CH2-、-CH2-O-CH2-CH2-CH2-、-CH2-CH2-O-CH2-CH2-、-CH2-CH2-CH2-O-CH2-and-CH2-CH2-CH2-CH2-O-；
When present, R11aAnd R11bAre all hydrogen;
when present, R12aAnd R12bTogether form an oxo (═ O) substituent, or alternatively, R12aAnd R12bAre all hydrogen;
R6a-aselected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group;
R10a-aselected from the group consisting of: hydrogen, C1-C6Alkyl radicals andC1-C6a haloalkyl group;
or R6a-aAnd RY1May together form a carbonyl (C ═ O) moiety;
or R10a-aAnd RY2May together form a carbonyl (C ═ O) moiety;
R6a-band R6a-cIndependently of each other selected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group; and is
R10a-bAnd R10a-cIndependently of each other selected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group.
In some embodiments, the compound of formula (I) is a compound of formula (1-1):
or a pharmaceutically acceptable salt thereof;
wherein:
A1is of the formula (A)1A substituent of (a)
A2Is of the formula (A)2A substituent of (a)
And wherein RY1、RY2、r、s、Z1、RZ1-1、RZ1-2、Z2、RZ2-1、RZ2-2、Z3、x1、Z4、RZ4-1、RZ4-2、Z5、RZ5-1、RZ5-2、Z6、x2、R1a、R1b、R2a、R2b、R3a、R3b、R4a、R4b、R13、R14、R15And R16As defined for the compounds of formula (I).
In some embodiments of the compounds of formula (1-1), (A)1-a) is selected from the group consisting of:
In some embodiments of the compounds of formula (1-1), (A)1A) is (A)1-b)。
In some embodiments of the compounds of formula (1-1), (A)1A) is (A)1-c)。
In some embodiments of the compounds of formula (1-1), (A)1A) is (A)1-d)。
In some embodiments of the compounds of formula (1-1), (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments of the compounds of formula (1-1), (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments of the compounds of formula (1-1), (A)2-a) is selected from the group consisting of:
in some embodiments of the compounds of formula (1-1), (A) 2A) is (A)2-b)。
In some embodiments of the compounds of formula (1-1), (A)2A) is (A)2-c)。
In some embodiments of the compounds of formula (1-1), (A)2A) is (A)2-d)。
In some embodiments of the compounds of formula (1-1), (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (1-1), (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A) 2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, the compound of formula (I) is a compound of formula (1-2):
or a pharmaceutically acceptable salt thereof;
wherein:
A1is of the formula (A)1A substituent of (a)
A2Selected from the group consisting of:
formula (A)2A substituent of (a)
Optionally substituted by one or more R 16C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl;
and wherein X2、RY1、Y2、RY2、q2、r、s、Z1、RZ1-1、RZ1-2、Z2、RZ2-1、RZ2-2、Z3、x1、Z4、RZ4-1、RZ4-2、Z5、RZ5-1、RZ5-2、Z6、x2、R1a、R1b、R2a、R2b、R3a、R3b、R4a、R4b、R9a、R9b、R10a、R10a-a、R10a-b、R10a-c、R10b、R13、R14、R15And R16As defined for the compounds of formula (I).
In some embodiments of the compounds of formula (1-2), X2Is CH. In some embodiments, r is 1 and s is 1.
In some embodiments of the compounds of formula (1-2), X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formula (1-2), (A)1-a) is selected from the group consisting of:
in some embodiments of the compounds of formula (1-2), (A)1A) is (A)1-b)。
In some embodiments of the compounds of formula (1-2), (A)1A) is (A)1-c)。
In some embodiments of the compounds of formula (1-2), (A)1A) is (A)1-d)。
In some embodiments of the compounds of formula (1-2), (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A) 1A) or (A)1-b) is selected from the group consisting of:
In some embodiments of the compounds of formula (1-2), (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (1-2):
q2is 1;
R9aand R9bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R9aAnd R9bAre all hydrogen;
R10aselected from the group consisting of: hydrogen, -OR10a-aand-NR10a-bR10a-c；
R10bIs hydrogen;
or alternatively, R10aAnd R10bTogether form-CH2-O-CH2-a moiety; and is
A2Is optionally substituted by one or more R16C substituted by substituents6-C10Aryl, or optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of the compounds of formula (1-2):
R9aand R9bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent;
R10aselected from the group consisting of: hydrogen, -OR10a-aand-NR10a-bR10a-c；
R10bIs hydrogen; and is
A2Is optionally substituted by one or more R16C substituted by substituents6-C10Aryl, or optionally substituted by one or more R 16A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of the compounds of formula (1-2), R9aAnd R9bTogether form an oxo (═ O) substituent. In some embodiments of the compounds of formula (1-2), R9aAnd R9bTogether form an imide (═ NH) substituent. In some embodiments, R10aIs hydrogen.
In some embodiments of the compounds of formula (1-2):
R9aand R9bAre all hydrogen; and is
R10aAnd R10bTogether form-CH2-O-CH2-a moiety.
In some embodiments of the compounds of formula (1-2):
R9aand R9bAre all hydrogen; and is
R10aAnd R10bAre all hydrogen.
In some embodiments of the compounds of formula (1-2):
X2is CH;
RY1is hydrogen or C1-C6An alkyl group;
Y2selected from the group consisting of NRY2And O;
RY2is hydrogen or C1-C6An alkyl group;
q2is 1;
r and s are independently of each other 0, 1 or 2;
A1is of the formula (A)1A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z1selected from the group consisting of: CRZ1-1RZ1-2、NRZ1-2O, S and-CRZ1-1＝CRZ1-1-；
Wherein R isZ1-1Is H or R14(ii) a And R isZ1-2Is H or R14；
Z2Selected from the group consisting of: CRZ2-1RZ2-2、NRZ2-2O, S and-CRZ2-1＝CRZ2-1-；
Wherein R isZ2-1Is H or R14(ii) a And R isZ2-2Is H or R14；
Z3Independently at each occurrence is C or N, provided that at least one Z3Is C;
R13is hydrogen or R14Or R is13And RZ1-2Together form a ring with R13With Z1A double bond between, or R 13And RZ2-2Together form a ring with R13With Z2A double bond between; and is
x1 is 1, 2, 3 or 4, and at least one R14Is halogen;
R14independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR14-aR14-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR14-aR14-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR14-aR14 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6HalogenatedAlkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C) 1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is14-aAnd R14-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A2is substituted by at least one halogen substituent and optionally further by one or more R16C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl;
R16independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR16-aR16-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR16-aR16-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR16-aR16 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C 1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is16-aAnd R16-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R1aand R1bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
R2aand R2bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R3aAnd R3bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R4aAnd R4bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
or alternatively, R1aAnd R2aTogether form C1-C6An alkylene moiety;
or alternatively, R1aWith the presence of R3aParts together forming C1-C6An alkylene moiety, and R1bAnd is located in said R3aGeminal R3bTogether with R1aTogether are both hydrogen;
or alternatively, R present3aMoiety and R present4aParts together forming C1-C6An alkylene moiety, and is located at said R3aGeminal R3bTogether with said R4aMoieties taken together and located in said R4aGeminal R4bTogether with said R 3aAll moieties together are hydrogen;
R9aand R9bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R9aAnd R9bAre all hydrogen;
R10ais hydrogen; and is
R10bIs hydrogen.
In some embodiments of the compounds of formula (1-2), RY1Is hydrogen. In some embodiments of the compounds of formula (1-2), RY1Is C1-C6An alkyl group.
In some embodiments of the compounds of formula (1-2), Y2Is NRY2. In some embodiments of the compounds of formula (1-2), RY2Is hydrogen. In some embodiments of the compounds of formula (1-2), RY2Is C1-C6An alkyl group.
In some embodiments of the compounds of formula (1-2), Y2Is O.
In some embodiments of the compounds of formula (1-2), R1aAnd R1bIndependently selected from hydrogen and C1-C6Of alkyl groupsAnd (4) grouping. In some embodiments of the compounds of formula (1-2), R1aAnd R1bAre all hydrogen.
In some embodiments of the compounds of formula (1-2), R2aAnd R2bIndependently selected from hydrogen and C1-C6Alkyl groups. In some embodiments of the compounds of formula (1-2), R2aAnd R2bAre all hydrogen.
In some embodiments of the compounds of formula (1-2), R1aAnd R2aTogether form C1-C6An alkylene moiety.
In some embodiments of the compounds of formula (1-2), r is 1 and s is 1. In some embodiments, R 3aAnd R3bIndependently selected from hydrogen and C1-C6Alkyl groups. In some embodiments, R3aAnd R3bAre all hydrogen. In some embodiments, R4aAnd R4bIndependently selected from hydrogen and C1-C6Alkyl groups. In some embodiments, R4aAnd R4bAre all hydrogen. In some embodiments, R1aAnd R3aTogether form C1-C6An alkylene moiety, and R1bAnd R3bAre all hydrogen. In some embodiments, R3aAnd R4aTogether form C1-C6An alkylene moiety, and R3bAnd R4bAre all hydrogen.
In some embodiments of the compounds of formula (1-2), R9aAnd R9bTogether form an oxo (═ O) substituent. In some embodiments of the compounds of formula (1-2), R9aAnd R9bTogether form an imide (═ NH) substituent.
In some embodiments of the compounds of formula (1-2), (A)1-a) is selected from the group consisting of:
in some embodiments of the compounds of formula (1-2), (A)1A) is (A)1-b)。
In some embodiments of the compounds of formula (1-2), (A)1A) is (A)1-c)。
In some embodiments of the compounds of formula (1-2), (A)1A) is (A)1-d)。
In some embodiments of the compounds of formula (1-2), (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (1-2), (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A) 1A) or (A)1-c) is selected from the group consisting of:
In some embodiments of the compounds of formula (1-2), A2Is substituted by at least one halogen substituent and optionally further by one or more R16C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of the compounds of formula (1-2), A2Is optionally substituted by one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Is substituted by at least one halogenSubstituted with an aryl substituent and optionally further substituted with one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R16Phenyl substituted with a substituent. In some embodiments, A2Is substituted by at least one halogen substituent and optionally further by one or more R16Phenyl substituted with a substituent. In some embodiments, A2Selected from the group consisting of:
In some embodiments of the compounds of formula (1-2), A 2Is optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Is substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R16A substituent-substituted pyridyl group. In some embodiments, A2Is substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted pyridyl group. In some embodiments, A2Is thatWhereinShowing the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (1-2):
q2is 0;
R9aand R9bAre all hydrogen;
R10ais-OR10a-aor-NR10a-bR10a-c(ii) a And is
R10bIs hydrogen.
In some embodiments of the compounds of formula (1-2):
R10ais-OR10a-aor-NR10a-bR10a-c(ii) a And is
A2Is of the formula (A)2A substituent of (a)
In some embodiments of the compounds of formula (1-2), R10ais-OR10a-a。
In some embodiments of the compounds of formula (1-2), (A)2-a) is selected from the group consisting of:
in some embodiments of the compounds of formula (1-2), (A)2A) is (A)2-b)。
In some embodiments of the compounds of formula (1-2), (A) 2A) is (A)2-c)。
In some embodiments of the compounds of formula (1-2), (A)2A) is (A)2-d)。
In some embodiments of the compounds of formula (1-2), (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments of the compounds of formula (1-2), (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some casesIn the examples, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting ofGroup (2):
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, the compound of formula (I) is a compound of formulae (1-3):
or a pharmaceutically acceptable salt thereof;
wherein:
A1is of the formula (A)1A substituent of (a)
A2Is optionally substituted by one or more R16C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl;
and wherein X2、RY1、Y2、RY2、r、s、Z1、RZ1-1、RZ1-2、Z2、RZ2-1、RZ2-2、Z3、x1、R1a、R1b、R2a、R2b、R3a、R3b、R4a、R4b、R9a、R9b、R10a、R10a-a、R10a-b、R10a-c、R10b、R12a、R12b、R13、R14And R16As defined for the compounds of formula (I).
In some embodiments of the compounds of formulas (1-3), X2Is CH. In some embodiments, r is 1 and s is 1.
In some embodiments of the compounds of formulas (1-3), X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formulas (1-3), (A)1-a) is selected from the group consisting of:
in some embodiments of the compounds of formulas (1-3), (A)1A) is (A)1-b)。
In some embodiments of the compounds of formulas (1-3), (A)1A) is (A)1-c)。
In some embodiments of the compounds of formulas (1-3), (A)1A) is (A)1-d)。
In some embodiments of the compounds of formulas (1-3), (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A) 1A) or (A)1-b) is selected from the group consisting of: where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments of the compounds of formulas (1-3), (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting ofThe group consisting of:
In some embodiments of the compounds of formulae (1-3):
R9aand R9bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R9aAnd R9bAre all hydrogen;
R10aselected from the group consisting of: hydrogen, -OR10a-aand-NR10a-bR10a-c；
R10bIs hydrogen; and is
R12aAnd R12bAre all hydrogen.
In some embodiments of the compounds of formulas (1-3), R9aAnd R9bTogether form an oxo (═ O) substituent. In some embodiments, R10aIs hydrogen. In some embodiments, R10ais-OR10a-a. In some embodiments, R10ais-NR10a-bR10a-c。
In some embodiments of the compounds of formulas (1-3), R 9aAnd R9bTogether form an imide (═ NH) substituent. In some embodiments, R10aIs hydrogen. In some embodiments, R10ais-OR10a-a. In some embodiments, R10ais-NR10a- bR10a-c。
In some embodiments of the compounds of formulas (1-3), R9aAnd R9bAre all hydrogen. In some embodiments, R10aIs hydrogen. In some embodiments, R10ais-OR10a-a. In some embodiments, R10ais-NR10a-bR10a-c。
In some embodiments of the compounds of formulae (1-3):
X2is CH or N;
RY1is hydrogen or C1-C6An alkyl group;
Y2selected from the group consisting of: chemical bond, NRY2And O; provided that when X is2When N is, then Y2Is a chemical bond;
RY2is hydrogen or C1-C6An alkyl group;
r and s are independently of each other 0, 1 or 2;
A1selected from the group consisting of:
formula (A)1A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z1selected from the group consisting of: CRZ1-1RZ1-2、NRZ1-2O, S and-CRZ1-1＝CRZ1-1-；
Wherein R isZ1-1Is H or R14(ii) a And R isZ1-2Is H or R14；
Z2Selected from the group consisting of: CRZ2-1RZ2-2、NRZ2-2O, S and-CRZ2-1＝CRZ2-1-；
Wherein R isZ2-1Is H or R14(ii) a And R isZ2-2Is H or R14；
Z3Independently at each occurrence is C or N, provided that at least one Z3Is C;
R13is hydrogen or R14Or R is13And RZ1-2Together form a ring with R13With Z1A double bond between, or R13And RZ2-2Together form a ring with R13With Z 2A double bond between; and is
x1 is 1, 2, 3 or 4, and at least one R14Is halogen;
R14independently at each occurrenceSelected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR14-aR14-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR14-aR14-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR14-aR14 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C: (O)(C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
Wherein R is14-aAnd R14-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A2is substituted by at least one halogen substituent and optionally further by one or more R16C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl;
R16independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR16-aR16-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR16-aR16-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR16-aR16 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O) 2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is16-aAnd R16-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R1aand R1bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
R2aand R2bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R3aAnd R3bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R4aAnd R4bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
or alternatively, R1aAnd R2aTogether form C1-C6An alkylene moiety;
or alternatively, R1aWith the presence of R3aParts together forming C1-C6An alkylene moiety, and R1bAnd is located in said R3aGeminal R3bTogether with R1aTogether are both hydrogen;
or alternatively, R present3aMoiety and R present4aParts together forming C1-C6An alkylene moiety, and is located at said R3aGeminal R3bTogether with said R4aMoieties taken together and located in said R4aGeminal R4bTogether with said R3aAll moieties together are hydrogen;
R9aand R9bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R 9aAnd R9bAre all hydrogen;
R10aselected from the group consisting of: hydrogen, -OR10a-aand-NR10a-bR10a-c；
R10bIs hydrogen;
R12aand R12bTogether form an oxo (═ O) substituent, or alternatively, R12aAnd R12bAre all hydrogen;
R10a-ais selected from the group consisting ofThe group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group;
or R10a-aAnd RY2May together form a carbonyl (C ═ O) moiety; and is
R10a-bAnd R10a-cIndependently of each other selected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group.
In some embodiments of the compounds of formulas (1-3), RY1Is hydrogen. In some embodiments of the compounds of formulas (1-3), RY1Is C1-C6An alkyl group.
In some embodiments of the compounds of formulas (1-3), X2Is CH and Y2Is NRY2. In some embodiments of the compounds of formula (1-2), RY2Is hydrogen. In some embodiments of the compounds of formulas (1-3), RY2Is C1-C6An alkyl group.
In some embodiments of the compounds of formulas (1-3), X2Is CH and Y2Is O.
In some embodiments, X2Is N and Y2Is a chemical bond.
In some embodiments of the compounds of formulas (1-3), R1aAnd R1bIndependently selected from hydrogen and C1-C6Alkyl groups. In some embodiments of the compounds of formulas (1-3), R1aAnd R1bAre all hydrogen.
In some embodiments of the compounds of formulas (1-3), R2aAnd R2bIndependently selected from hydrogen and C 1-C6Alkyl groups. In some embodiments of the compounds of formulas (1-3), R2aAnd R2bAre all hydrogen.
In some embodiments of the compounds of formulas (1-3), R1aAnd R2aTogether form C1-C6An alkylene moiety.
In some embodiments of the compounds of formula (1-3), r is 1 and s is 1. In some embodiments, R3aAnd R3bIndependently selected from hydrogen and C1-C6Alkyl groups. In some embodiments, R3aAnd R3bAre all hydrogen. In some embodiments, R4aAnd R4bIndependently selected from hydrogen and C1-C6Alkyl groups. In some embodiments, R4aAnd R4bAre all hydrogen. In some embodiments, R1aAnd R3aTogether form C1-C6An alkylene moiety, and R1bAnd R3bAre all hydrogen. In some embodiments, R3aAnd R4aTogether form C1-C6An alkylene moiety, and R3bAnd R4bAre all hydrogen.
In some embodiments of the compounds of formulas (1-3), R9aAnd R9bTogether form an oxo (═ O) substituent. In some embodiments of the compounds of formulas (1-3), R9aAnd R9bTogether form an imide (═ NH) substituent. In some embodiments of the compounds of formulas (1-3), R9aAnd R9bAre all hydrogen.
In some embodiments of the compounds of formulas (1-3), R10aIs hydrogen and R10bIs hydrogen.
In some embodiments of the compounds of formulas (1-3), R 10ais-OR10a-aAnd R is10bIs hydrogen. In some embodiments, R10a-aSelected from hydrogen and C1-C6Alkyl groups. In some embodiments, R10a-aIs hydrogen. In some embodiments, R10a-aIs C1-C6An alkyl group. In some embodiments, R10a-aAnd RY2Together, may form a carbonyl (C ═ O) moiety.
In some embodiments of the compounds of formulas (1-3), R10ais-NR10a-bR10a-cAnd R is10bIs hydrogen. In some embodiments, R10a-bAnd R10a-cIndependently of one another, from hydrogen and C1-C6Alkyl groups. In some embodiments, R10a-bAnd R10a-cIs hydrogen. In some embodiments, R10a-bAnd R10a-cIs C1-C6An alkyl group.
In some embodiments of the compounds of formulae (1-3):
X2is CH;
RY1is hydrogen;
Y2is NRY2；
RY2Is hydrogen;
R9aand R9bAre all hydrogen;
R10ais-OR10a-a；
R10a-aIs hydrogen;
R10bis hydrogen; and is
R12aAnd R12bAre all hydrogen.
In some embodiments of the compounds of formulae (1-3):
X2is CH;
Y2is NRY2；
R9aAnd R9bAre all hydrogen;
R10ais-OR10a-a；
R12aAnd R12bAre all hydrogen; and is
R10a-aAnd RY2Together form a carbonyl (C ═ O) moiety.
In some embodiments of the compounds of formulae (1-3):
X2is CH;
RY1is hydrogen;
Y2is NRY2；
RY2Is hydrogen;
R9aand R9bAre all hydrogen;
R10ais-OR10a-a；
R10bIs hydrogen;
R12aand R12bAre all hydrogen; and is
R10a-aAnd RY2Together forming a carbonyl (C ═ O) moiety。
In some embodiments of the compounds of formulae (1-3):
X2is CH;
RY1is hydrogen;
Y2Is NRY2；
RY2Is hydrogen;
R9aand R9bAre all hydrogen;
R10ais hydrogen;
R10bis hydrogen; and is
R12aAnd R12bAre all hydrogen.
In some embodiments of the compounds of formulae (1-3):
X2is N;
RY1is hydrogen;
Y2is a chemical bond;
R9aand R9bAre all hydrogen;
R10ais-OR10a-a；
R10a-aIs hydrogen;
R10bis hydrogen; and is
R12aAnd R12bAre all hydrogen.
In some embodiments of the compounds of formulae (1-3):
X2is N;
RY1is hydrogen;
Y2is a chemical bond;
R9aand R9bAre all hydrogen;
R10ais hydrogen;
R10bis hydrogen; and is
R12aAnd R12bAre all hydrogen.
In some embodiments of the compounds of formulae (1-3):
X2is CH;
RY1is hydrogen;
Y2is NRY2；
RY2Is hydrogen;
r and s are both 1;
R9aand R9bAre all hydrogen;
R10ais-OR10a-a；
R10a-aIs hydrogen;
R10bis hydrogen; and is
R12aAnd R12bAre all hydrogen.
In some embodiments of the compounds of formulae (1-3):
X2is CH;
Y2is NRY2；
r and s are both 1;
R9aand R9bAre all hydrogen;
R10ais-OR10a-a；
R12aAnd R12bAre all hydrogen; and is
R10a-aAnd RY2Together form a carbonyl (C ═ O) moiety.
In some embodiments of the compounds of formulae (1-3):
X2is CH;
RY1is hydrogen;
Y2is NRY2；
RY2Is hydrogen;
r and s are both 1;
R9aand R9bAre all hydrogen;
R10ais-OR10a-a；
R10bIs hydrogen;
R12aand R12bAre all hydrogen; and is
R10a-aAnd RY2Together form a carbonyl (C ═ O) moiety.
In some embodiments of the compounds of formulae (1-3):
X2is CH;
RY1is hydrogen;
Y2is NRY2；
RY2Is hydrogen;
r and s are both 1;
R9aand R9bAre all hydrogen;
R10ais hydrogen;
R10bIs hydrogen; and is
R12aAnd R12bAre all hydrogen.
In some embodiments of the compounds of formulae (1-3):
X2is N;
RY1is hydrogen;
Y2is a chemical bond;
r and s are both 1;
R9aand R9bAre all hydrogen;
R10ais-OR10a-a；
R10a-aIs hydrogen;
R10bis hydrogen; and is
R12aAnd R12bAre all hydrogen.
In some embodiments of the compounds of formulae (1-3):
X2is N;
RY1is hydrogen;
Y2is a chemical bond;
r and s are both 1;
R9aand R9bAre all hydrogen;
R10ais hydrogen;
R10bis hydrogen; and is
R12aAnd R12bAre all hydrogen.
R12aAnd R12bAre all hydrogen. In some embodiments of the compounds of formulas (1-3), A2Is substituted by at least one halogen substituent and optionally further by one or more R16C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of the compounds of formulas (1-3), A2Is optionally substituted by one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Is substituted by at least one halogen substituent and optionally further by one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R 16Phenyl substituted with a substituent. In some embodiments, A2Is substituted by at least one halogen substituent and optionally further by one or more R16Phenyl substituted with a substituent. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A2Is optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Is substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A) 1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is 2Is that
In some embodiments, the compound of formula (I) is a compound of formulae (1-4):
or a pharmaceutically acceptable salt thereof;
wherein:
A1is of the formula (A)1A substituent of (a)
A2Is optionally substituted by one or more R16C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl;
R11aand R11bAre all hydrogen;
R12aand R12bAre all hydrogen;
and wherein X2、RY1、Y2、RY2、r、s、A1、Z1、RZ1-1、RZ1-2、Z2、RZ2-1、RZ2-2、Z3、x1、R1a、R1b、R2a、R2b、R3a、R3b、R4a、R4b、R13、R14And R16As defined for the compounds of formula (I).
In some embodiments of the compounds of formulas (1-4), X2Is CH. In some embodiments, r is 1 and s is 1.
In some embodiments of the compounds of formulas (1-4), X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formulas (1-4), (A)1-a) is selected from the group consisting of:
in some embodiments of the compounds of formulas (1-4), (A)1A) is (A)1-b)。
In some embodiments of the compounds of formulas (1-4), (A)1A) is (A)1-c)。
In some embodiments of the compounds of formulas (1-4), (A)1A) is (A)1-d)。
In some embodiments of the compounds of formulas (1-4), (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments of the compounds of the formulae (1-4)In the examples, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formulas (1-4), A2Is optionally substituted by one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Selected from the group consisting of:
In some embodiments of the compounds of formulas (1-4), A2Is optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R16A substituent-substituted pyridyl group. At one endIn some embodiments, A2Is that
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
Where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, the compound of formula (I) is a compound of formula (2-2):
or a pharmaceutically acceptable salt thereof;
wherein:
A1selected from the group consisting of:
formula (A)1A substituent of (a)
Optionally substituted by one or more R14C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R14A substituent-substituted 5-10 membered heteroaryl;
A2selected from the group consisting of:
formula (A)2A substituent of (a)
Optionally substituted by one or more R16C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R 16A substituent-substituted 5-10 membered heteroaryl;
and wherein X1、X2、Y1、RY1、Y2、RY2、q1、q2、r、s、Z1、RZ1-1、RZ1-2、Z2、RZ2-1、RZ2-2、Z3、x1、Z4、RZ4-1、RZ4-2、Z5、RZ5-1、RZ5-2、Z6、x2、R1a、R1b、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6a、R6a-a、R6a-b、R6a -c、R6b、R9a、R9b、R10a、R10a-a、R10a-b、R10a-c、R10b、R13、R14、R15And R16As defined for the compounds of formula (I).
Conversion to the formula (2-2)In some embodiments of the compound, X1Is CH and X2Is CH. In some embodiments, r is 1 and s is 1.
In some embodiments of the compounds of formula (2-2), X1Is CH, X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formula (2-2), X1Is N, Y1Is a chemical bond, and X2Is CH. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formula (2-2), X1Is N, Y1Is a chemical bond, X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compound of formula (2-2):
q1is 1;
A1is optionally substituted by one or more R14Selected C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R14A substituent-substituted 5-10 membered heteroaryl;
A2selected from the group consisting of:
formula (A)2A substituent of (a)
Optionally substituted by one or more R 16C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl;
R5aand R5bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R5aAnd R5bAre all hydrogen;
R6aselected from the group consisting of: hydrogen, -OR6a-aand-NR6a-bR6a-c；
R6bIs hydrogen;
or alternatively, R6aAnd R6bTogether form-CH2-O-CH2-a moiety;
R9aand R9bAre all hydrogen;
R10aselected from the group consisting of-OR10a-aand-NR10a-bR10a-cA group of (a); and is
R10bIs hydrogen;
or alternatively, R10aAnd R10bTogether form-CH2-O-CH2-a moiety.
In some embodiments of the compound of formula (2-2):
R5aand R5bTogether form an oxo (═ O) substituent;
R6ais hydrogen;
R6bis hydrogen;
R9aand R9bAre all hydrogen;
R10aselected from the group consisting of-OR10a-aand-NR10a-bR10a-cA group of (a); and is
R10bIs hydrogen;
or alternatively, R10aAnd R10bTogether form-CH2-O-CH2-a moiety.
In some embodiments of the compound of formula (2-2):
q2is 1;
A2is optionally substituted by one or more R16C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl; and is
R10aAnd R10bTogether form-CH2-O-CH2-a moiety.
In some embodiments of the compounds of formula (2-2), A2Is optionally one orPlural R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Selected from the group consisting of:
Where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R16Phenyl substituted with a substituent. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (2-2), A2Is optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R16A substituent-substituted pyridyl group. In some embodiments, A2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments of the compound of formula (2-2):
q2is 0;
A2is of the formula (A)2A substituent of (a)
R10ais-OR10a-a(ii) a And areAnd is
R10bIs hydrogen.
In some embodiments of the compound of formula (2-2), (A)2-a) is selected from the group consisting of:
in some embodiments of the compound of formula (2-2), (A)2A) is (A)2-b)。
In some embodiments of the compound of formula (2-2), (A)2A) is (A)2-c)。
In some embodiments of the compound of formula (2-2), (A)2A) is (A)2-d)。
In some embodiments of the compound of formula (2-2), (A) 2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments of the compound of formula (2-2), (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compound of formula (2-2):
R5aand R5bAre all hydrogen;
R6aand R6bTogether form-CH2-O-CH2-a moiety;
R10aselected from the group consisting of-OR10a-aand-NR10a-bR10a-cA group of (a); and is
R10bIs hydrogen;
or alternatively, R10aAnd R10bTogether form-CH2-O-CH2-a moiety.
In some embodiments of the compound of formula (2-2):
q2is 1;
A2is optionally substituted by one or more R16C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R 16A substituent-substituted 5-10 membered heteroaryl; and is
R10aAnd R10bTogether form-CH2-O-CH2-a moiety.
In some embodiments of the compounds of formula (2-2), A2Is optionally substituted by one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R16Phenyl substituted with a substituent. In some embodiments, A2Selected from the group consisting of:
In some embodiments of the compounds of formula (2-2), A2Is optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R16A substituent-substituted pyridyl group. In some embodiments, A2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments of the compound of formula (2-2):
q2is 0;
A2is of the formula (A)2A substituent of (a)
R10ais-OR10a-a(ii) a And is
R10bIs hydrogen.
In some embodiments of the compound of formula (2-2), (A) 2-a) is selected from the group consisting of:
in some embodiments of the compound of formula (2-2), (A)2A) is (A)2-b)。
In some embodiments of the compound of formula (2-2), (A)2A) is (A)2-c)。
In some embodiments of the compound of formula (2-2), (A)2A) is (A)2-d)。
In some embodiments of the compound of formula (2-2), (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments of the compound of formula (2-2), (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)2A) or (A)2-c) is selected from the group consisting of:
In some embodiments of the compounds of formula (2-2), A1Is optionally substituted by one or more R 14C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14Phenyl substituted with a substituent. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (2-2), A1Is optionally substituted by one or more R14A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14A substituent-substituted pyridyl group. In some embodiments, A1Is that
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A) 2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
and
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
Wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A) 1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
Wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWherein isThe point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A) 2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Is selected from the group consisting ofThe group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A) 2A) or (A)2-c) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
At one endIn some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
Wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; a. the2Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; a. the2Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, A1Is that
In some embodiments, the compound of formula (I) is a compound of formula (2-3):
or a pharmaceutically acceptable salt thereof;
wherein:
A1selected from the group consisting of:
formula (A)1A substituent of (a)
Optionally substituted by one or more R14C substituted by substituents 6-C10An aryl group; and
optionally substituted by one or more R14A substituent-substituted 5-10 membered heteroaryl;
A2is optionally substituted by one or more R16C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl;
and wherein X1、X2、Y1、RY1、Y2、RY2、q1、r、s、Z1、RZ1-1、RZ1-2、Z2、RZ2-1、RZ2-2、Z3、x1、R1a、R1b、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6a、R6a-a、R6a-b、R6a-c、R6b、R9a、R9b、R10a、R10a-a、R10a-b、R10a-c、R10b、R12a、R12b、R13、R14And R16As defined for the compounds of formula (I).
In some embodiments of the compounds of formula (2-3), X1Is CH and X2Is CH. In some embodiments, r is 1 and s is 1.
In some embodiments of the compounds of formula (2-3), X1Is CH, X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formula (2-3), X1Is N, Y1Is a chemical bond, and X2Is CH. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formula (2-3), X1Is N, Y1Is a chemical bond, X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formula (2-3):
q1is 1;
A1is optionally substituted by one or more R14Selected C substituted by substituents 6-C10An aryl group; or optionally substituted with one or more R14A substituent-substituted 5-10 membered heteroaryl;
A2is optionally substituted by one or more R16C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R165-10 membered substituted by substituentA heteroaryl group;
R5aand R5bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R5aAnd R5bAre all hydrogen;
R6aselected from the group consisting of: hydrogen, -OR6a-aand-NR6a-bR6a-c(ii) a And is
R6bIs hydrogen;
or alternatively, R6aAnd R6bTogether form-CH2-O-CH2-a moiety.
In some embodiments of the compounds of formula (2-3):
R5aand R5bTogether form an oxo (═ O) substituent;
R6ais hydrogen; and is
R6bIs hydrogen.
In some embodiments of the compounds of formula (2-3):
R5aand R5bAre all hydrogen; and is
R6aAnd R6bTogether form-CH2-O-CH2-a moiety.
In some embodiments of the compounds of formula (2-3):
X1and X2Independently of one another, is CH or N; provided that X is1And X2Is CH;
Y1selected from the group consisting of: chemical bond, NRY1And O; provided that when X is1When N is, then Y1Is a chemical bond;
RY1is hydrogen or C1-C6An alkyl group;
Y2selected from the group consisting of: chemical bond, NRY2And O; provided that when X is2When N is, then Y2Is a chemical bond;
RY2is hydrogen or C1-C6An alkyl group;
q1is 1;
r and s are independently of each other 0, 1 or 2;
A1is substituted by at least one halogen substituent and optionally further by one or more R14C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R14A substituent-substituted 5-10 membered heteroaryl;
R14independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR14-aR14-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR14-aR14-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR14-aR14 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O) 2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is14-aAnd R14-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A2is substituted by at least one halogen substituent and optionally further by one or more R16C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl;
R16independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR16-aR16-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR16-aR16-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR16-aR16 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C) 1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is16-aAnd R16-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R1aand R1bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
R2aand R2bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R3aAnd R3bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R4aAnd R4bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
or alternatively, R1aAnd R2aTogether form C1-C6An alkylene moiety;
or alternatively, R1aWith the presence of R3aParts together forming C1-C6An alkylene moiety, and R1bAnd is located in said R3aGeminal R3bTogether with R1aTogether are both hydrogen;
or alternatively, R present3aMoiety and R present 4aParts together forming C1-C6An alkylene moiety, and is located at said R3aGeminal R3bTogether with said R4aMoieties taken together and located in said R4aGeminal R4bTogether with said R3aAll moieties together are hydrogen;
R5aand R5bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent;
R6ais hydrogen;
R6bis hydrogen;
R9aand R9bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R9aAnd R9bAre all hydrogen;
R10aselected from the group consisting of: hydrogen, -OR10a-aand-NR10a-bR10a-c；
R10bIs hydrogen;
R12aand R12bTogether form an oxo (═ O) substituent, or alternatively, R12aAnd R12bAre all hydrogen;
R10a-aselected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group;
or R10a-aAnd RY2May together form a carbonyl (C ═ O) moiety;
R10a-band R10a-cIndependently of each other selected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group; and is
Provided that when X is2If N, then:
A1is substituted by at least two halogen substituents and optionally further by one or more R14C substituted by substituents6-C10Aryl, or substituted with at least two halogen substituents and optionally further substituted with one or more R14A substituent-substituted 5-10 membered heteroaryl; and is
A2Is substituted by at least two halogen substituents and optionally further by one or more R 16C substituted by substituents6-C10Aryl, or substituted with at least two halogen substituents and optionally further substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of compounds of formula (2-3), R1aAnd R1bIndependently selected from hydrogen and C1-C6Alkyl groups. In some embodiments of compounds of formula (2-3), R1aAnd R1bAre all hydrogen.
In some embodiments of compounds of formula (2-3), R2aAnd R2bIndependently selected from hydrogen and C1-C6Alkyl groups. In some embodiments of compounds of formula (2-3), R2aAnd R2bAre all hydrogen.
In some embodiments of compounds of formula (2-3), R1aAnd R2aTogether form C1-C6An alkylene moiety.
In some embodiments of the compounds of formula (2-3), r is 1 and s is 1. In some embodiments, R3aAnd R3bIndependently selected from hydrogen and C1-C6Alkyl groups. In some embodiments, R3aAnd R3bAre all hydrogen. In some embodiments, R4aAnd R4bIndependently selected from hydrogen and C1-C6Alkyl groups. In some embodiments, R4aAnd R4bAre all hydrogen. In some embodiments, R1aAnd R3aTogether form C1-C6An alkylene moiety, and R1bAnd R3bAre all hydrogen. In some embodiments, R3aAnd R4aTogether form C1-C6An alkylene moiety, and R 3bAnd R4bAre all hydrogen.
In some embodiments of the compounds of formula (2-3):
X1is CH;
X2is CH;
Y1selected from the group consisting of NRY1And O;
RY1is hydrogen or C1-C6An alkyl group;
Y2selected from the group consisting of NRY2And O;
RY2is hydrogen or C1-C6An alkyl group;
q1and q is2Each is 1; and is
r and s are both 1.
In some embodiments of the compounds of formula (2-3):
X1is CH;
X2is CH;
Y1is NRY1；
RY1Is hydrogen;
Y2is NRY2；
RY2Is hydrogen;
q1is 1; and is
r and s are both 1.
In some embodiments of compounds of formula (2-3), R9aAnd R9bTogether form an oxo (═ O) substituent. In some embodiments of compounds of formula (2-3), R9aAnd R9bTogether form an imide (═ NH) substituent. In some embodiments of compounds of formula (2-3), R9aAnd R9bAre all hydrogen.
In some embodiments of compounds of formula (2-3), R10aIs hydrogen and R10bIs hydrogen.
In some embodiments of compounds of formula (2-3), R10ais-OR10a-aAnd R is10bIs hydrogen. In some embodiments, R10a-aSelected from hydrogen and C1-C6Alkyl groups. In some embodiments, R10a-aIs hydrogen. In some embodiments, R10a-aIs C1-C6An alkyl group. In some embodiments, R10a-aAnd RY2Together, may form a carbonyl (C ═ O) moiety.
In some embodiments of compounds of formula (2-3), R10ais-NR10a-bR10a-cAnd R is 10bIs hydrogen. In some embodiments, R10a-bAnd R10a-cIndependently of one another, from hydrogen and C1-C6Alkyl groups. In some embodiments, R10a-bAnd R10a-cIs hydrogen. In some embodiments, R10a-bAnd R10a-cIs C1-C6An alkyl group.
In some embodiments of the compounds of formula (2-3), A1Is substituted by at least one halogen substituent and optionally further by one or more R14C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R14A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of the compounds of formula (2-3), A1Is optionally substituted by one or more R14C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A1Is substituted by at least one halogen substituent and optionally further by one or more R14C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14Phenyl substituted with a substituent. In some embodiments, A1Is substituted by at least one halogen substituent and optionally further by one or more R14Phenyl substituted with a substituent. In some embodiments, A 1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is optionally substituted by one or more R14A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A1Is substituted by at least one halogen substituent and optionally further by one or more R14A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14A substituent-substituted pyridyl group. In some embodiments, A1Is substituted by at least one halogen substituent and optionally further by one or more R14A substituent-substituted pyridyl group. In some embodiments, A1Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (2-3), A2Is substituted by at least one halogen substituent and optionally further by one or more R16C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of the compounds of formula (2-3), A 2Is optionally substituted by one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Is substituted by at least one halogen substituent and optionally further by one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R16Phenyl substituted with a substituent. In some embodiments, A2Is substituted by at least one halogen substituent and optionally further by one or more R16Phenyl substituted with a substituent. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A2Is optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Is substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Selected from the group consisting of:
In some embodiments of the compounds of formula (2-3):
X1is N;
X2is CH;
Y1is a chemical bond;
Y2selected from the group consisting of NRY2And O;
RY2is hydrogen or C1-C6An alkyl group;
q1is 1; and is
r and s are both 1.
In some embodiments of the compounds of formula (2-3):
X1is N;
X2is CH;
Y1is a chemical bond;
Y2is NRY2；
RY2Is hydrogen;
q1is 1; and is
r and s are both 1.
In some embodiments of compounds of formula (2-3), R9aAnd R9bTogether form an oxo (═ O) substituent. In some embodiments of compounds of formula (2-3), R9aAnd R9bTogether form an imide (═ NH) substituent. In some embodiments of compounds of formula (2-3), R9aAnd R9bAre all hydrogen.
In some embodiments of compounds of formula (2-3), R10aIs hydrogen and R10bIs hydrogen.
In some embodiments of compounds of formula (2-3), R10ais-OR10a-aAnd R is10bIs hydrogen. In some embodiments, R10a-aSelected from hydrogen and C1-C6Alkyl groups. In some embodiments, R10a-aIs hydrogen. In some embodiments, R10a-aIs C1-C6An alkyl group. In some embodiments, R 10a-aAnd RY2Together, may form a carbonyl (C ═ O) moiety.
In some embodiments of compounds of formula (2-3), R10ais-NR10a-bR10a-cAnd R is10bIs hydrogen. In some embodiments, R10a-bAnd R10a-cIndependently of one another, from hydrogen and C1-C6Alkyl groups. In some embodiments, R10a-bAnd R10a-cIs hydrogen. In some embodiments, R10a-bAnd R10a-cIs C1-C6An alkyl group.
In some embodiments of the compounds of formula (2-3), A1Is substituted by at least one halogen substituent and optionally further by one or more R14C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R14A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of the compounds of formula (2-3), A1Is optionally substituted by one or more R14C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A1Is C6-C10And (4) an aryl group. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14Phenyl substituted with a substituent. In some embodiments, A1Is substituted by at least one halogen substituent and optionally further by one or more R14Phenyl substituted with a substituent. In some embodiments, A 1Selected from the group consisting of:
In some embodiments, A1Is optionally substituted by one or more R14A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A1Is substituted by at least one halogen substituent and optionally further by one or more R14A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14A substituent-substituted pyridyl group. In some embodiments, A1Is substituted by at least one halogen substituent and optionally further by one or more R14A substituent-substituted pyridyl group. In some embodiments, A1Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (2-3), A2Is substituted by at least one halogen substituent and optionally further by one or more R16C substituted by substituents6-C10Aryl, or substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of the compounds of formula (2-3), A 2Is optionally substituted by one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Is substituted by at least one halogen substituent and optionally further by one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A2Is optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Is substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R16A substituent-substituted pyridyl group. In some embodiments, A 2Is substituted by at least one halogen substituent and optionally further by one or more R16A substituent-substituted pyridyl group. In some embodiments, A2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (2-3):
X1is CH;
X2is N;
Y1selected from the group consisting of NRY1And O;
RY1is hydrogen or C1-C6An alkyl group;
Y2is a chemical bond;
q1is 1;
r and s are both 1;
A1is substituted by at least two halogen substituents and optionally further by one or more R14C substituted by substituents6-C10Aryl, or substituted with at least two halogen substituents and optionally further substituted with one or more R14A substituent-substituted 5-10 membered heteroaryl; and is
A2Is substituted by at least two halogen substituents and optionally further by one or more R16C substituted by substituents6-C10Aryl, or substituted with at least two halogen substituents and optionally further substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of the compounds of formula (2-3):
X1is CH;
X2is N;
Y1is NRY1；
RY1Is hydrogen;
Y2is a chemical bond;
q1is 1;
r and s are both 1;
A1is substituted by at least two halogen substituents and optionally further by one or more R14C substituted by substituents6-C10Aryl, or substituted with at least two halogen substituents and optionally further substituted with one or more R 14A substituent-substituted 5-10 membered heteroaryl; and is
A2Is substituted by at least two halogen substituents and optionally further by one or more R16C substituted by substituents6-C10Aryl, or substituted with at least two halogen substituents and optionally further substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of compounds of formula (2-3), R9aAnd R9bAre all hydrogen.
In some embodiments of compounds of formula (2-3), R10aIs hydrogen and R10bIs hydrogen.
In some embodiments of compounds of formula (2-3), R10ais-OR10a-aAnd R is10bIs hydrogen. In some embodiments, R10a-aSelected from hydrogen and C1-C6Alkyl groups. In some embodiments, R10a-aIs hydrogen. In some embodiments, R10a-aIs C1-C6An alkyl group. In some embodiments, R10a-aAnd RY2Together, may form a carbonyl (C ═ O) moiety.
In some embodiments of compounds of formula (2-3), R10ais-NR10a-bR10a-cAnd R is10bIs hydrogen. In some embodiments, R10a-bAnd R10a-cIndependently of one another, from hydrogen and C1-C6Alkyl groups. In some embodiments, R10a-bAnd R10a-cIs hydrogen. In some embodiments, R10a-bAnd R10a-cIs C1-C6An alkyl group.
In some embodiments of the compounds of formula (2-3), A1Is substituted by at least two halogen substituents and optionally further by one or more R 14C substituted by substituents6-C10Aryl, or substituted with at least two halogen substituents and optionally further substituted with one or more R14A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of the compounds of formula (2-3), A1Is substituted by at least two halogen substituents and optionally further by one or more R14C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A1Is substituted by at least two halogen substituents and optionally further by one or more R14Phenyl substituted with a substituent. In some embodiments, A1Is thatWhere denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is substituted by at least two halogen substituents and optionally further by one or more R14A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of the compounds of formula (2-3), A2Is substituted by at least two halogen substituents and optionally further by one or more R16C substituted by substituents6-C10Aryl, or substituted with at least two halogen substituents and optionally further substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of the compounds of formula (2-3), A2Is substituted by at least two halogen substituents and optionally further by one or more R16C substituted by substituents 6-C10And (4) an aryl group. In some embodiments, A2Is substituted by at least two halogen substituents and optionally further by one or more R16Phenyl substituted with a substituent. In some embodiments, A2Is thatWhere denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is substituted by at least two halogen substituents and optionally further by one or more R16A substituent-substituted 5-10 membered heteroaryl.
In some embodiments of the compounds of formula (2-3), A1Is optionally substituted by one or more R14C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14Phenyl substituted with a substituent. In some embodiments, A1Selected from the group consisting of:
In some embodiments of the compounds of formula (2-3), A1Is optionally substituted by one or more R14A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R 14A substituent-substituted pyridyl group. In some embodiments, A1Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (2-3):
q1is 0;
A1is of the formula (A)1A substituent of (a)
R6ais-OR6a-a(ii) a And is
R6bIs hydrogen.
In some embodiments of the compounds of formula (2-3):
R5aand R5bTogether form an oxo (═ O) substituent;
R6ais hydrogen; and is
R6bIs hydrogen.
In some embodiments of the compounds of formula (2-3), (A)1-a) is selected from the group consisting of:
in some embodiments of the compounds of formula (2-3), (A)1A) is (A)1-b)。
In some embodiments of the compounds of formula (2-3), (A)1A) is (A)1-c)。
In some embodiments of the compounds of formula (2-3), (A)1A) is (A)1-d)。
In some embodiments of the compounds of formula (2-3), (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments of the compounds of formula (2-3), (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (2-3):
R9aand R9bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R9aAnd R9bAre all hydrogen;
R10aselected from the group consisting of: hydrogen, -OR10a-aand-NR10a-bR10a-c；
R10bIs hydrogen; and is
R12aAnd R12bAre all hydrogen.
In some embodiments of compounds of formula (2-3), R9aAnd R9bTogether form an oxo (═ O) substituent. In some embodiments, R10aIs hydrogen. In some embodiments, R10ais-OR10a-a. In some embodiments, R10ais-NR10a-bR10a-c。
In some embodiments of compounds of formula (2-3), R9aAnd R9bTogether form an imide (═ NH) substituent. In some embodiments, R10aIs hydrogen. In some embodiments, R10ais-OR10a-a. In some embodiments, R10ais-NR10a- bR10a-c。
In some embodiments of compounds of formula (2-3), R9aAnd R9bAre all hydrogen. In some embodiments, R 10aIs hydrogen. In some embodiments, R10ais-OR10a-a. In some embodiments, R10ais-NR10a-bR10a-c。
In some embodiments of the compounds of formula (2-3):
X2is CH;
Y2is NRY2；
R9aAnd R9bAre all hydrogen;
R10ais-OR10a-a；
R12aAnd R12bAre all hydrogen; and is
R10a-aAnd RY2Together form a carbonyl (C ═ O) moiety.
In-situ typeIn some embodiments of the compounds of (2-3), A2Is optionally substituted by one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R16Phenyl substituted with a substituent. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (2-3), A2Is optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is 2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, A 1Selected from the group consisting of:
wherein represents a molecule thereofThe connection point of the remaining portion; and (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
In some embodiments, A 1Is thatWherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; a. the2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is that
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
Wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is that
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, A1Is that
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A 1Is thatWherein denotes the point of attachment to the rest of the molecule; and A is2Is that
In some embodiments, the compound of formula (I) is a compound of formulae (2-4):
or a pharmaceutically acceptable salt thereof;
wherein:
A1selected from the group consisting of:
formula (A)1A substituent of (a)
Optionally substituted by one or more R14C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R14A substituent-substituted 5-10 membered heteroaryl;
A2is optionally substituted by one or more R16C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl;
R11aand R11bAre all hydrogen;
R12aand R12bAre all hydrogen;
and wherein X1、X2、Y1、RY1、Y2、RY2、q1、r、s、Z1、RZ1-1、RZ1-2、Z2、RZ2-1、RZ2-2、Z3、x1、R1a、R1b、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6a、R6a-a、R6a-b、R6a-c、R6b、R13、R14And R16As defined for the compounds of formula (I).
In some embodiments of compounds of formula (2-4), X1Is CH and X2Is CH. In some embodiments, r is 1 and s is 1.
In some embodiments of compounds of formula (2-4), X1Is CH, X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of compounds of formula (2-4), X1Is N, Y1Is a chemical bond, and X2Is CH. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of compounds of formula (2-4), X1Is N, Y1Is a chemical bond, X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formulae (2-4):
q1is 1;
A1is optionally substituted by one or more R14Selected C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R14A substituent-substituted 5-10 membered heteroaryl;
R5aand R5bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R5aAnd R5bAre all hydrogen;
R6aselected from the group consisting of: hydrogen, -OR6a-aand-NR6a-bR6a-c(ii) a And is
R6bIs hydrogen;
or alternatively, R6aAnd R6bTogether form-CH2-O-CH2-a moiety.
In some embodiments of compounds of formula (2-4), R5aAnd R5bAre all hydrogen; and R is6aAnd R6bTogether form-CH2-O-CH2-a moiety.
In some embodiments of the compounds of formulas (2-4), A1Is optionally substituted by one or more R14C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14Phenyl substituted with a substituent. In some embodiments, A 1Selected from the group consisting of:
In some embodiments of the compounds of formulas (2-4), A1Is optionally substituted by one or more R14A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14A substituent-substituted pyridyl group. In some embodiments, A1Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formulas (2-4), A2Is optionally substituted by one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formulas (2-4), A2Is optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A 2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or moreR16A substituent-substituted pyridyl group. In some embodiments, A2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
Wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected fromA group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting ofGroup (2):
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or(A2-b) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
Where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
In some embodiments, A1Is that
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of：
Where denotes the point of attachment to the rest of the molecule.
In some embodiments, A 1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is that
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of：
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; a. the2Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Is that
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and A is 2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is that
In some embodiments, the compound of formula (I) is a compound of formula (3-3):
or a pharmaceutically acceptable salt thereof;
wherein:
A1is optionally substituted by one or more R14C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R14A substituent-substituted 5-10 membered heteroaryl;
A2is optionally substituted by one or more R16C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl;
and wherein X1、X2、Y1、RY1、Y2、RY2、r、s、R1a、R1b、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6a、R6a -a、R6a-b、R6a-c、R6b、R8a、R8b、R9a、R9b、R10a、R10a-a、R10a-b、R10a-c、R10b、R12a、R12b、R14And R16As defined for the compounds of formula (I).
In some embodiments of the compounds of formula (3-3), X1Is CH and X2Is CH. In some embodiments, r is 1 and s is 1.
In some embodiments of the compounds of formula (3-3), X1Is CH, X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formula (3-3), X1Is N, Y1Is a chemical bond, and X2Is CH. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formula (3-3), X1Is N, Y1Is a chemical bond, X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formula (3-3):
R5aand R5bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R5aAnd R5bAre all hydrogen;
R6aselected from the group consisting of: hydrogen, -OR6a-aand-NR6a-bR6a-c；
R10bIs hydrogen; and is
R12aAnd R12bAre all hydrogen.
In some embodiments of compounds of formula (3-3), R9aAnd R9bTogether form an oxo (═ O) substituent. In some embodiments, R10aIs hydrogen. In some embodiments, R10ais-OR10a-a. In some embodiments, R10ais-NR10a-bR10a-c。
In some embodiments of compounds of formula (3-3), R9aAnd R9bTogether form an imide (═ NH) substituent. In some embodiments, R10aIs hydrogen. In some embodiments, R10ais-OR10a-a. In some embodiments, R10ais-NR10a- bR10a-c。
In some embodiments of compounds of formula (3-3), R 9aAnd R9bAre all hydrogen. In some embodiments, R10aIs hydrogen. In some embodiments, R10ais-OR10a-a. In some embodiments, R10ais-NR10a-bR10a-c。
In some embodiments of the compounds of formula (3-3), A1Is optionally substituted by one or more R14C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14Phenyl substituted with a substituent. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (3-3), A1Is optionally substituted by one or more R14A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A1Selected from the group consisting of:
In some embodiments of the compounds of formula (3-3):
X2is CH;
Y2is NRY2；
R9aAnd R9bAre all hydrogen;
R10ais-OR10a-a；
R12aAnd R12bAre all hydrogen; and is
R10a-aAnd RY2Together form a carbonyl (C ═ O) moiety.
In some embodiments of the compounds of formula (3-3), A2Is optionally covered byOne or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Selected from the group consisting of:
In some embodiments of the compounds of formula (3-3), A2Is optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R16A substituent-substituted pyridyl group. In some embodiments, A2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
Where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
In some embodiments, A1Is that
In some embodiments, A 1Is thatWherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is that
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
Where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
Wherein denotes the point of attachment to the rest of the molecule; a. the2Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Is that
In some embodiments, A1Is that
In some embodiments, A1Is that
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is that
In some embodiments, the compound of formula (I) is a compound of formulae (3-4):
or a pharmaceutically acceptable salt thereof;
Wherein:
A1is optionally substituted by one or more R14C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R14A substituent-substituted 5-10 membered heteroaryl;
A2is optionally substituted by one or more R16C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl;
R11aand R11bAre all hydrogen;
R12aand R12bAre all hydrogen;
and wherein X1、X2、Y1、RY1、Y2、RY2、r、s、R1a、R1b、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6a、R6a -a、R6a-b、R6a-c、R6b、R8a、R8b、R14And R16As defined for the compounds of formula (I).
In some embodiments of the compounds of formulas (3-4), X1Is CH and X2Is CH. In some embodiments, r is 1 and s is 1.
In some embodiments of the compounds of formulas (3-4), X1Is CH, X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formulas (3-4), X1Is N, Y1Is a chemical bond, and X2Is CH. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formulas (3-4), X1Is N, Y1Is a chemical bond, X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formulae (3-4):
R5aAnd R5bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R5aAnd R5bAre all hydrogen;
R6aselected from the group consisting of: hydrogen, -OR6a-aAnd NR6a-bR6a-c；
R10bIs hydrogen; and is
R12aAnd R12bAre all hydrogen.
In some embodiments of compounds of formula (3-4), R9aAnd R9bTogether form an oxo (═ O) substituent. In some embodiments, R10aIs hydrogen. In some embodiments, R10ais-OR10a-a. In some embodiments, R10ais-NR10a-bR10a-c。
In some embodiments of compounds of formula (3-4), R9aAnd R9bTogether form an imide (═ NH) substituent. In some embodiments, R10aIs hydrogen. In some embodiments, R10ais-OR10a-a. In some embodiments, R10ais-NR10a- bR10a-c。
In some embodiments of compounds of formula (3-4), R9aAnd R9bAre all hydrogen. In some embodiments, R10aIs hydrogen. In some embodiments, R10ais-OR10a-a. In some embodiments, R10ais-NR10a-bR10a-c。
In some embodiments of the compounds of formulae (3-4):
X1is CH;
Y1is NRY1；
R5aAnd R5bAre all hydrogen;
R6ais-OR6a-a；
R8aAnd R8bAre all hydrogen; and is
R6a-aAnd RY1Together form a carbonyl (C ═ O) moiety.
In some embodiments of the compounds of formula (3-4), A1Is optionally substituted by one or more R14C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A 1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14Substituent group is takenA substituted phenyl group. In some embodiments, A1Selected from the group consisting of:
In some embodiments of the compounds of formula (3-4), A1Is optionally substituted by one or more R14A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14A substituent-substituted pyridyl group. In some embodiments, A1Is that
In some embodiments of the compounds of formula (3-4), A2Is optionally substituted by one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R16Phenyl substituted with a substituent. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (3-4), A2Is optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein represents andthe point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
Where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, A1Is selected from the group consisting ofThe group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A 1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein isThe point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A 1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is that
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
wherein denotes the remainder of the moleculeAnd connecting points.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the remainder of the moleculeA connection point; and A is2Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; a. the2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A 1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is that
In some embodiments, A1Is selected from the group consisting ofThe group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; a. the2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Is that
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is that
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is that
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is that
In some embodiments, the compound of formula (I) is a compound of formula (4-4):
or a pharmaceutically acceptable salt thereof;
wherein:
A1is optionally substituted by one or more R14C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R14A substituent-substituted 5-10 membered heteroaryl;
A2is optionally substituted by one or more R16C substituted by substituents6-C10An aryl group; or optionally substituted with one or more R16A substituent-substituted 5-10 membered heteroaryl;
R7aand R7bAre all hydrogen;
R8aand R8bAre all hydrogen;
R11aand R11bAre all hydrogen;
R12aand R12bAre all hydrogen;
and wherein X1、X2、Y1、RY1、Y2、RY2、r、s、R1a、R1b、R2a、R2b、R3a、R3b、R4a、R4b、R14And R16As defined for the compounds of formula (I).
In some embodiments of compounds of formula (4-4), X 1Is CH and X2Is CH. In some embodiments, r is 1 and s is 1.
In some embodiments of compounds of formula (4-4), X1Is CH, X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is0 and s is 2.
In some embodiments of compounds of formula (4-4), X1Is N, Y1Is a chemical bond, and X2Is CH. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of compounds of formula (4-4), X1Is N, Y1Is a chemical bond, X2Is N and Y2Is a chemical bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.
In some embodiments of the compounds of formula (4-4), A1Is optionally substituted by one or more R14C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14Phenyl substituted with a substituent. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (4-4), A 1Is optionally substituted by one or more R14A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A1Is optionally substituted by one or more R14A substituent-substituted pyridyl group. In some embodiments, A1Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (4-4), A2Is optionally substituted by one or more R16C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, A2Is optionally substituted by one or more R16Phenyl substituted with a substituent. In some embodiments, A2Selected from the group consisting of:
In some embodiments of the compounds of formula (4-4), A2Is optionally substituted by one or more R16A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A) 1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A) 1A) or (A)1-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-b) is selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, (A)1A) or (A)1-c) is selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-c) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A) 2A) or (A)2-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A)2A) or (A)2-b) is selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and (A) 2A) or (A)2-c) is selected from the group consisting of:
In some embodiments, A1Is that
In some embodiments, A1Is that
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Is thatWhere denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein represents andthe point of attachment to the rest of the molecule; a. the2Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule; and A is 2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Selected from the group consisting of:
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and A is2Selected from the group consisting of:
In some embodiments, A1Is thatWherein denotes the point of attachment to the rest of the molecule; and A is 2Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments, A1Is that
In one aspect, there is provided a compound of formula (II):
or a pharmaceutically acceptable salt thereof;
wherein:
m3 is 0 or 1;
n3 is 0 or 1;
r2 is 0, 1 or 2;
s2 is 0, 1 or 2;
X3is CH or N;
X4is CH or N;
provided that X is3And X4Is CH;
Y3selected from the group consisting of: chemical bond, NRY3And O;
wherein R isY3Is hydrogen or C1-C6An alkyl group;
Y4selected from the group consisting of: chemical bond, NRY4And O;
wherein R isY4Is hydrogen or C1-C6An alkyl group;
with the following conditions:
when X is present3When N is, then Y3Is a chemical bond and m3 is 1;
when X is present4When N is, then Y4Is a chemical bond and n3 is 1;
A3selected from the group consisting of:
formula (A)3A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z7selected from the group consisting of: CRZ7-1RZ7-2、NRZ7-2O, S and-CRZ7-1＝CRZ7-1-；
Wherein
RZ7-1Is H or R27(ii) a And is
RZ7-2Is H or R27；
Z8Selected from the group consisting of: CRZ8-1RZ8-2、NRZ8-2(ii) a O, S and-CRZ8-1＝CRZ8-1-；
Wherein
RZ8-1Is H or R27(ii) a And is
RZ8-2Is H or R27；
Z9Independently at each occurrence is C or N, provided that at least one Z 9Is C;
R26is hydrogen or R27Or R is26And RZ7-2Together form a ring with R26With Z7A double bond between; and is
x3 is 0, 1, 2,3 or 4, with the proviso that when a Z is present9When N, then x3 is not 4;
optionally substituted by one or more R27C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R27A substituent-substituted 5-10 membered heteroaryl;
R27independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl groups)、-N(C1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O) 2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A4selected from the group consisting of:
formula (A)4A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z10selected from the group consisting of: CRZ10-1RZ10-2、NRZ10-2O, S and-CRZ10-1＝CRZ10-1-；
Wherein
RZ10-1Is H or R29(ii) a And is
RZ10-2Is H or R29；
Z11Selected from the group consisting of: CRZ11-1RZ11-2、NRZ11-2O, S and-CRZ11-1＝CRZ11-1-；
Wherein
RZ11-1Is H or R29(ii) a And is
RZ11-2Is H or R29；
Z12Independently at each occurrence is C or N, provided that at least one Z12Is C;
R28is hydrogen or R29Or R is28And RZ10-2Together form a ring with R28With Z10A double bond between; and is
x4 is 0, 1, 2, 3 or 4, provided that when one Z is12When N, then x4 is not 4;
optionally substituted by one or more R29C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R29A substituent-substituted 5-10 membered heteroaryl;
R29independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C) 1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R17aand R17bIndependently selected fromThe group consisting of: hydrogen, C1-C6Alkyl and halogen;
R18aand R18bIndependently selected from the group consisting of: hydrogen, C 1-C6Alkyl and halogen;
when present, R19aAnd R19bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R20aAnd R20bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
or alternatively, R17aAnd R18aTogether form C1-C6An alkylene moiety;
or alternatively, R17aWith the presence of R19aParts together forming C1-C6An alkylene moiety, and R17bAnd is located in said R19aGeminal R19bTogether with R17aTogether are both hydrogen;
or alternatively, R present19aMoiety and R present20aParts together forming C1-C6An alkylene moiety, and is located at said R19aGeminal R19bTogether with said R20aMoieties taken together and located in said R20aGeminal R20bTogether with said R19aAll moieties together are hydrogen;
R21aand R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R21aAnd R21bAre all hydrogen;
when present, R22aAnd R22bAre all hydrogen;
R23aand R23bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R23aAnd R23bAre all hydrogen;
when present, R24aSelected from the group consisting of: hydrogen, -OH and-NH2；
Or alternatively, R24aAnd RY4Together form a # -C (═ O) -O-group, where # denotes a group with RY4The point of attachment of the nitrogen atom of (a);
When present, R24bIs hydrogen; and is
When present, R25aAnd R25bAre all hydrogen;
or alternatively, R present25aAnd A4One R of29Together with the atoms to which they are attached form an optionally substituted R29A 5-6 membered heterocycloalkenyl group substituted with a substituent, and R25bIs H;
or alternatively, R present25aR present25bAnd A4One R of29Together with the atoms to which they are attached form an optionally substituted R29A substituent-substituted 5-6 membered heteroaryl;
and with the proviso that one of (i), (ii), (iii) and (iv) applies:
(i) when m3 is 0 and n3 is 0, then:
X3is CH and Y3Is NRY3；
X4Is CH and Y4Is NRY4；
R21aAnd R21bTogether form an oxo (═ O) substituent;
R23aand R23bTogether form an oxo (═ O) substituent;
A3is of the formula (A)3A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z7selected from the group consisting of: CRZ7-1RZ7-2、NRZ7-2O, S and-CRZ7-1＝CRZ7-1-；
Wherein
RZ7-1Is H or R27(ii) a And is
RZ7-2Is H or R27；
Z8Selected from the group consisting of: CRZ8-1RZ8-2、NRZ8-2O, S and-CRZ8-1＝CRZ8-1-；
Wherein
RZ8-1Is H or R27(ii) a And is
RZ8-2Is H or R27；
Z9Independently at each occurrence is C or N, provided that at least one Z9Is C;
R26is hydrogen or R27Or R is26And RZ7-2Together form a ring with R26With Z7A double bond between;
R27independently at each occurrence, selected from the group consisting of: halogen, C 1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
x3 is 0, 1, 2, 3 or 4, provided that when one Z is9When N, then x3 is not 4;
A4Is of the formula (A)4A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z10selected from the group consisting of: CRZ10-1RZ10-2、NRZ10-2O, S and-CRZ10-1＝CRZ10-1-；
Wherein
RZ10-1Is H or R29(ii) a And is
RZ10-2Is H or R29；
Z11Selected from the group consisting of: CRZ11-1RZ11-2、NRZ11-2O, S and-CRZ11-1＝CRZ11-1-；
Wherein
RZ11-1Is H or R29(ii) a And is
RZ11-2Is H or R29；
Z12Independently at each occurrence is C or N, provided that at least one Z12Is C;
R28is hydrogen or R29Or R is28And RZ10-2Together form a ring with R28With Z10A double bond between;
R29independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C) 1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
x4 is 0, 1, 2, 3 or 4, provided that when one Z is12When N, then x4 is not 4; and is
With the proviso that A3And A4Not both being a moiety selected from the group consisting of:
wherein denotes the point of attachment to the rest of the molecule;
(ii) when m3 is 0 and n3 is 1, then:
r2 is 1 or 2;
s2 is 1 or 2;
X3is CH and Y3Is NRY3；
R21aAnd R21bTogether form an oxo (═ O) substituent;
R24aselected from the group consisting of: hydrogen, -OH and-NH2；
A3Is of the formula (A)3A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z7selected from the group consisting of: CRZ7-1RZ7-2、NRZ7-2O, S and-CRZ7-1＝CRZ7-1-；
Wherein
RZ7-1Is H or R27(ii) a And is
RZ7-2Is H or R27；
Z8Selected from the group consisting of: CRZ8-1RZ8-2、NRZ8-2O, S and-CRZ8-1＝CRZ8-1-；
Wherein
RZ8-1Is H or R27(ii) a And is
RZ8-2Is H or R27；
Z9Independently at each occurrence is C or N, provided that at least one Z 9Is C;
R26is hydrogen or R27Or R is26And RZ7-2Together form a ring with R26With Z7A double bond between;
R27independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
Wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
x3 is 0, 1, 2, 3 or 4, provided that when one Z is9When N, then x3 is not 4;
A4is optionally substituted by one or more R29C substituted by substituents6-C10Aryl, or optionally substituted by one or more R29A substituent-substituted 5-10 membered heteroaryl;
R29independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Alkyl halidesRadical, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O) 2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
provided that when R is23aAnd R23bTogether form an oxo (═ O) substituent, then R24ais-OH or-NH2；
(iii) When m3 is 1 and n3 is 0, then:
X4is CH and Y4Is NRY4；
R21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent;
R23aand R23bTogether form an oxo (═ O) substituent;
A3is optionally substituted by one or more R27C substituted by substituents6-C10Aryl, or optionally substituted by one or more R27A substituent-substituted 5-10 membered heteroaryl;
R27independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O) 2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6HalogenatedAlkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A4is of the formula (A)4A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z10selected from the group consisting of: CRZ10-1RZ10-2、NRZ10-2O, S and-CRZ10-1＝CRZ10-1-；
Wherein
RZ10-1Is H or R29(ii) a And is
RZ10-2Is H or R29；
Z11Selected from the group consisting of: CRZ11-1RZ11-2、NRZ11-2O, S and-CRZ11-1＝CRZ11-1-；
Wherein
RZ11-1Is H or R29(ii) a And is
RZ11-2Is H or R29；
Z12Independently at each occurrence is C or N, provided that at least one Z12Is C;
R28is hydrogen or R29Or R is28And RZ10-2Together form a ring with R28With Z10A double bond between;
R29Independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
x4 is 0, 1, 2, 3 or 4, provided that when one Z is 12When N, then x4 is not 4;
(iv) when m3 is 1 and n3 is 1, then:
R21aand R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent;
A3is optionally substituted by one or more R27C substituted by substituents6-C10Aryl, or optionally substituted by one or more R27A substituent-substituted 5-10 membered heteroaryl;
R27independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O) 2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A4is optionally substituted by one or more R29C substituted by substituents6-C10Aryl, or optionally substituted by one or more R29A substituent-substituted 5-10 membered heteroaryl;
R29independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C) 1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
with the following conditions:
when X is present3Or X4Is N, then r2 is 1 or 2 and s2 is 1 or 2; and is
When R is23aAnd R23bTogether form an oxo (═ O) substituent, then R24ais-OH or-NH2。
In some embodiments of the compound of formula (II):
m3 is 0 or 1;
n3 is 0 or 1;
r2 is 0, 1 or 2;
s2 is 0, 1 or 2;
X3is CH or N;
X4is CH or N;
provided that X is3And X4Is CH;
Y3selected from the group consisting of: chemical bond, NRY3And O;
wherein R isY3Is hydrogen or C1-C6An alkyl group;
Y4selected from the group consisting of: chemical bond, NRY4And O;
wherein R isY4Is hydrogen or C1-C6An alkyl group;
with the following conditions:
when X is present3When N is, then Y3Is a chemical bond and m3 is 1;
when X is present4When N is, then Y4Is a chemical bond and n3 is 1;
A3selected from the group consisting of:
wherein
Denotes the point of attachment to the rest of the molecule;
Z7selected from the group consisting of: CRZ7-1RZ7-2、NRZ7-2O, S and-CRZ7-1＝CRZ7-1-；
Wherein
RZ7-1Is H or R27(ii) a And is
RZ7-2Is H or R27；
Z8Selected from the group consisting of: CRZ8-1RZ8-2、NRZ8-2O, S and-CRZ8-1＝CRZ8-1-；
Wherein
RZ8-1Is H or R27(ii) a And is
RZ8-2Is H or R27；
R26Is hydrogen or R27Or R is26And RZ7-2Together form a ring with R26With Z7A double bond between; and is
x3 is 0, 1, 2, 3 or 4;
optionally substituted by one or more R27C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R27A substituent-substituted 5-10 membered heteroaryl;
R27independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C) 1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A4selected from the group consisting of:
formula (A)4Substituents of-b)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z10selected from the group consisting of: CRZ10-1RZ10-2、NRZ10-2O, S and-CRZ10-1＝CRZ10-1-；
Wherein
RZ10-1Is H or R29(ii) a And is
RZ10-2Is H or R29；
Z11Selected from the group consisting of：CRZ11-1RZ11-2、NRZ11-2O, S and-CRZ11-1＝CRZ11-1-；
Wherein
RZ11-1Is H or R29(ii) a And is
RZ11-2Is H or R29；
R28Is hydrogen or R29Or R is28And RZ10-2Together form a ring with R28With Z10A double bond between; and is
x4 is 0, 1, 2, 3 or 4;
optionally substituted by one or more R29C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R29A substituent-substituted 5-10 membered heteroaryl;
R29independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C) 1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R17aand R17bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
R18aand R18bIndependently selected from the group consisting of: hydrogen, C 1-C6Alkyl and halogen;
when present, R19aAnd R19bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R20aAnd R20bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
or alternatively, R17aAnd R18aTogether form C1-C6An alkylene moiety;
or alternatively, R17aWith the presence of R19aParts together forming C1-C6An alkylene moiety, and R17bAnd is located in said R19aGeminal R19bTogether with R17aTogether are both hydrogen;
or alternatively, R present19aMoiety and R present20aParts together forming C1-C6An alkylene moiety, and is located at said R19aGeminal R19bTogether with said R20aMoieties taken together and located in said R20aGeminal R20bTogether with said R19aAll moieties together are hydrogen;
R21aand R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R21aAnd R21bAre all hydrogen;
when present, R22aAnd R22bAre all hydrogen;
R23aand R23bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R23aAnd R23bAre all hydrogen;
when present, R24aSelected from the group consisting of: hydrogen, -OH and-NH2；
Or alternatively, R24aAnd RY4Together form a # -C (═ O) -O-group, where # denotes a group with RY4The point of attachment of the nitrogen atom of (a);
When present, R24bIs hydrogen; and is
When present, R25aAnd R25bAre all hydrogen;
or alternatively, R present25aAnd A4One R of29Together with the atoms to which they are attached form an optionally substituted R29A 5-6 membered heterocycloalkenyl group substituted with a substituent, and R25bIs H;
or alternatively, R present25aR present25bAnd A4One R of29Together with the atoms to which they are attached form an optionally substituted R29A substituent-substituted 5-6 membered heteroaryl;
and with the proviso that one of (i), (ii), (iii) and (iv) applies:
(i) when m3 is 0 and n3 is 0, then:
X3is CH and Y3Is NRY3；
X4Is CH and Y4Is NRY4；
R21aAnd R21bTogether form an oxo (═ O) substituent;
R23aand R23bTogether form an oxo (═ O) substituent;
A3is of the formula (A)3Substituents of-b)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z7selected from the group consisting of: CRZ7-1RZ7-2、NRZ7-2O, S and-CRZ7-1＝CRZ7-1-；
Wherein
RZ7-1Is H or R27(ii) a And is
RZ7-2Is H or R27；
Z8Selected from the group consisting of: CRZ8-1RZ8-2、NRZ8-2O, S and-CRZ8-1＝CRZ8-1-；
Wherein
RZ8-1Is H or R27(ii) a And is
RZ8-2Is H or R27；
R26Is hydrogen or R27Or R is26And RZ7-2Together form a ring with R26With Z7A double bond between;
R27independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C 1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
x3 is 0, 1, 2, 3 or 4;
A4is of the formula (A)4Substituents of-b)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z10Selected from the group consisting of: CRZ10-1RZ10-2、NRZ10-2O, S and-CRZ10-1＝CRZ10-1-；
Wherein
RZ10-1Is H or R29(ii) a And is
RZ10-2Is H or R29；
Z11Selected from the group consisting of: CRZ11-1RZ11-2、NRZ11-2O, S and-CRZ11-1＝CRZ11-1-；
Wherein
RZ11-1Is H or R29(ii) a And is
RZ11-2Is H or R29；
R28Is hydrogen or R29Or R is28And RZ10-2Together form a ring with R28With Z10A double bond between;
R29independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O) 2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
x4 is 0, 1, 2, 3 or 4; and is
With the proviso that A3And A4Not both being a moiety selected from the group consisting of:
(ii) when m3 is 0 and n3 is 1, then:
r2 is 1 or 2;
s2 is 1 or 2;
X3is CH and Y3Is NRY3；
R21aAnd R21bTogether form an oxo (═ O) substituent;
R24aselected from the group consisting of: hydrogen, -OH and-NH2；
A3Is of the formula (A)3Substituents of-b)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z7selected from the group consisting of: CRZ7-1RZ7-2、NRZ7-2O, S and-CRZ7-1＝CRZ7-1-；
Wherein
RZ7-1Is H or R27(ii) a And is
RZ7-2Is H or R27；
Z8Selected from the group consisting of: CRZ8-1RZ8-2、NRZ8-2O, S and-CRZ8-1＝CRZ8-1-；
Wherein
RZ8-1Is H or R27(ii) a And is
RZ8-2Is H or R27；
R26Is hydrogen or R27Or R is26And RZ7-2Together form a ring with R26With Z7A double bond between;
R27independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical、C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C) 1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
x3 is 0, 1, 2, 3 or 4;
A4is optionally substituted by one or more R29C substituted by substituents6-C10Aryl, or optionally substituted by one or more R29A substituent-substituted 5-10 membered heteroaryl;
R29Independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
provided that when R is 23aAnd R23bTogether form an oxo (═ O) substituent, then R24ais-OH or-NH2；
(iii) When m3 is 1 and n3 is 0, then:
X4is CH and Y4Is NRY4；
R21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent;
R23aand R23bTogether form an oxo (═ O) substituent;
A3is optionally substituted by one or more R27C substituted by substituents6-C10Aryl, or optionally substituted by one or more R27A substituent-substituted 5-10 membered heteroaryl;
R27independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C) 1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A4is of the formula (A)4Substituents of-b)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z10selected from the group consisting of: CRZ10-1RZ10-2、NRZ10-2O, S and-CRZ10-1＝CRZ10-1-；
Wherein
RZ10-1Is H or R29(ii) a And is
RZ10-2Is H or R29；
Z11Selected from the group consisting of: CRZ11-1RZ11-2、NRZ11-2O, S and-CRZ11-1＝CRZ11-1-；
Wherein
RZ11-1Is H or R29(ii) a And is
RZ11-2Is H or R29；
R28Is hydrogen or R29Or R is28And RZ10-2Together form a ring with R28With Z10A double bond between;
R29independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups) 2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
x4 is 0, 1, 2, 3 or 4;
(iv) when m3 is 1 and n3 is 1, then:
R21aand R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent;
A3is optionally substituted by one or more R27C substituted by substituents6-C10Aryl, or optionally substituted by one or more R27A substituent-substituted 5-10 membered heteroaryl;
R27independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C) 1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl radical)、-N(C1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A4is optionally substituted by one or more R29C substituted by substituents6-C10Aryl, or optionally substituted by one or more R29A substituent-substituted 5-10 membered heteroaryl;
R29Independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl)-C(O)NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6HalogenatedAlkyl groups);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
with the following conditions:
When X is present3Or X4Is N, then r2 is 1 or 2 and s2 is 1 or 2; and
when R is23aAnd R23bTogether form an oxo (═ O) substituent, then R24ais-OH or-NH2。
In some embodiments, the compound of formula (II) is a compound of formula (III):
wherein Y is3、RY3、Y4、RY4、m3、n3、r2、s2、A3、Z7、RZ7-1、RZ7-2、Z8、RZ8-1、RZ8-2、Z9、x3、A4、Z10、RZ10-1、RZ10-2、Z11、RZ11-1、RZ11-2、Z12、x4、R17a、R17b、R18a、R18b、R19a、R19b、R20a、R20b、R21a、R21b、R22a、R22b、R23a、R23b、R24a、R24b、R25a、R25b、R26、R27、R28And R29As defined in the compound of formula (II);
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of formula (II) is a compound of formula (IV):
wherein Y is3、RY3、m3、r2、s2、A3、Z7、RZ7-1、RZ7-2、Z8、RZ8-1、RZ8-2、Z9、x3、A4、Z10、RZ10-1、RZ10-2、Z11、RZ11-1、RZ11-2、Z12、x4、R17a、R17b、R18a、R18b、R19a、R19b、R20a、R20b、R21a、R21b、R22a、R22b、R23a、R23b、R24a、R24b、R25a、R25b、R26、R27、R28And R29As defined in the compound of formula (II);
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of formula (II) is a compound of formula (V):
wherein Y is4、RY4、n3、r2、s2、A3、Z7、RZ7-1、RZ7-2、Z8、RZ8-1、RZ8-2、Z9、x3、A4、Z10、RZ10-1、RZ10-2、Z11、RZ11-1、RZ11-2、Z12、x4、R17a、R17b、R18a、R18b、R19a、R19b、R20a、R20b、R21a、R21b、R22a、R22b、R23a、R23b、R24a、R24b、R25a、R25b、R26、R27、R28And R29As defined in the compound of formula (II);
or a pharmaceutically acceptable salt thereof.
In some embodiments of compounds of formula (II), (III), (IV), or (V), R17aAnd R17bIndependently is hydrogen or C1-C6An alkyl group. In some embodiments, R17aAnd R17bAre all hydrogen. In some embodiments, R17aAnd R17bAre all C1-C6An alkyl group. In some embodiments, R17aAnd R17bAre both methyl groups. In some embodiments, R17aIs hydrogen and R17bIs C1-C6An alkyl group. In some embodiments, R17aIs hydrogen and R17bIs methyl.
In some embodiments of compounds of formula (II), (III), (IV), or (V), R 18aAnd R18bIndependently is hydrogen or C1-C6An alkyl group. In some embodiments, R18aAnd R18bAre all hydrogen. In some embodiments, R18aAnd R18bAre all C1-C6An alkyl group. In some embodiments, R18aAnd R18bAre both methyl groups. In some embodiments, R18aIs hydrogen and R18bIs C1-C6An alkyl group. In some embodiments, R18aIs hydrogen and R18bIs methyl.
In some embodiments of compounds of formula (II), (III), (IV), or (V), R17a、R17b、R18aAnd R18bIs hydrogen.
In some embodiments of compounds of formula (II), (III), (IV), or (V), R17a、R17b、R18aAnd R18bIndependently is C1-C6An alkyl group. In some embodiments, R17a、R17b、R18aAnd R18bIs methyl.
In some embodiments of compounds of formula (II), (III), (IV), or (V), R17aAnd R18aIndependently is C1-C6Alkyl, and R17bAnd R18bAre all hydrogen. R17aAnd R18aAre all methyl, and R17bAnd R18bAre all hydrogen.
Some of the compounds of formula (II), (III), (IV) or (V)In the examples, R17aAnd R18aTogether form C1-C6An alkylene moiety, and R17bAnd R18bAre all hydrogen. In some embodiments, R17aAnd R18aTogether forming an ethylene radical (-CH)2-CH2-) moiety, and R17bAnd R18bAre all hydrogen. In some embodiments, R17aAnd R18aTogether form a propylene (-CH)2-CH2-CH2-) moiety, and R17bAnd R18bAre all hydrogen.
In some embodiments of the compounds of formula (II), (III), (IV), or (V), r2 is 1 and s2 is 1. In some embodiments, R 17aAnd R17bIndependently is hydrogen or C1-C6An alkyl group. In some embodiments, R17aAnd R17bAre all hydrogen. In some embodiments, R17aAnd R17bAre all C1-C6An alkyl group. In some embodiments, R17aAnd R17bAre both methyl groups. In some embodiments, R17aIs hydrogen and R17bIs C1-C6An alkyl group. In some embodiments, R17aIs hydrogen and R17bIs methyl. In some embodiments, R18aAnd R18bIndependently is hydrogen or C1-C6An alkyl group. In some embodiments, R18aAnd R18bAre all hydrogen. In some embodiments, R18aAnd R18bAre all C1-C6An alkyl group. In some embodiments, R18aAnd R18bAre both methyl groups. In some embodiments, R18aIs hydrogen and R18bIs C1-C6An alkyl group. In some embodiments, R18aIs hydrogen and R18bIs methyl. In some embodiments, R17a、R17b、R18aAnd R18bIs hydrogen. In some embodiments, R17a、R17b、R18aAnd R18bIndependently is C1-C6An alkyl group. In some embodiments, R17a、R17b、R18aAnd R18bIs methyl. In some embodiments, R17aAnd R18aIndependently is C1-C6Alkyl, and R17bAnd R18bAre all hydrogen. R17aAnd R18aAre all methyl, and R17bAnd R18bAre all hydrogen. In some embodiments, R17aAnd R18aTogether form C1-C6An alkylene moiety, and R17bAnd R18bAre all hydrogen. In some embodiments, R17aAnd R18aTogether forming an ethylene radical (-CH)2-CH2-) moiety, and R17bAnd R18bAre all hydrogen. In some embodiments, R 17aAnd R18aTogether form a propylene (-CH)2-CH2-CH2-) moiety, and R17bAnd R18bAre all hydrogen. In some embodiments, R19aAnd R19bIndependently is hydrogen or C1-C6An alkyl group. In some embodiments, R19aAnd R19bAre all hydrogen. In some embodiments, R19aAnd R19bAre all C1-C6An alkyl group. In some embodiments, R19aAnd R19bAre both methyl groups. In some embodiments, R19aIs hydrogen and R19bIs C1-C6An alkyl group. In some embodiments, R19aIs hydrogen and R19bIs methyl. In some embodiments, R20aAnd R20bIndependently is hydrogen or C1-C6An alkyl group. In some embodiments, R20aAnd R20bAre all hydrogen. In some embodiments, R20aAnd R20bAre all C1-C6An alkyl group. In some embodiments, R20aAnd R20bAre both methyl groups. In some embodiments, R20aIs hydrogen and R20bIs C1-C6An alkyl group. In some embodiments, R20aIs hydrogen and R20bIs methyl. In some embodiments, R19a、R19b、R20aAnd R20bIs hydrogen. In some embodiments, R19a、R19b、R20aAnd R20bIndependent of each otherGround is C1-C6An alkyl group. In some embodiments, R19a、R19b、R20aAnd R20bIs methyl. In some embodiments, R19aAnd R20aIndependently is C1-C6Alkyl, and R19bAnd R20bAre all hydrogen. In some embodiments, R19aAnd R20aAre all methyl, and R19bAnd R20bAre all hydrogen. In some embodiments, R19aAnd R20aTogether form C1-C6An alkylene moiety, and R 19bAnd R20bAre all hydrogen. In some embodiments, R19aAnd R20aTogether forming an ethylene radical (-CH)2-CH2-) moiety, and R19bAnd R20bAre all hydrogen. In some embodiments, R19aAnd R20aTogether form a propylene (-CH)2-CH2-CH2-) moiety, and R19bAnd R20bAre all hydrogen. In some embodiments, R17aAnd R19aTogether form C1-C6An alkylene moiety, and R17bAnd R19bAre all hydrogen. In some embodiments, R17aAnd R19aTogether forming an ethylene radical (-CH)2-CH2-) moiety, and R17bAnd R19bAre all hydrogen. In some embodiments, R17aAnd R19aTogether form a propylene (-CH)2-CH2-CH2-) moiety, and R17bAnd R19bAre all hydrogen.
In some embodiments of the compounds of formula (II), (III), (IV), or (V), r2 is 2 and s2 is 0. In some embodiments, R17aAnd R17bIndependently is hydrogen or C1-C6An alkyl group. In some embodiments, R17aAnd R17bAre all hydrogen. In some embodiments, R17aAnd R17bAre all C1-C6An alkyl group. In some embodiments, R17aAnd R17bAre both methyl groups. In some embodiments, R17aIs hydrogen and R17bIs C1-C6An alkyl group.In some embodiments, R17aIs hydrogen and R17bIs methyl. In some embodiments, R18aAnd R18bIndependently is hydrogen or C1-C6An alkyl group. In some embodiments, R18aAnd R18bAre all hydrogen. In some embodiments, R18aAnd R18bAre all C1-C6An alkyl group. In some embodiments, R 18aAnd R18bAre both methyl groups. In some embodiments, R18aIs hydrogen and R18bIs C1-C6An alkyl group. In some embodiments, R18aIs hydrogen and R18bIs methyl. In some embodiments, R17a、R17b、R18aAnd R18bIs hydrogen. In some embodiments, R17a、R17b、R18aAnd R18bIndependently is C1-C6An alkyl group. In some embodiments, R17a、R17b、R18aAnd R18bIs methyl. In some embodiments, R17aAnd R18aIndependently is C1-C6Alkyl, and R17bAnd R18bAre all hydrogen. R17aAnd R18aAre all methyl, and R17bAnd R18bAre all hydrogen. In some embodiments, R17aAnd R18aTogether form C1-C6An alkylene moiety, and R17bAnd R18bAre all hydrogen. In some embodiments, R17aAnd R18aTogether forming an ethylene radical (-CH)2-CH2-) moiety, and R17bAnd R18bAre all hydrogen. In some embodiments, R17aAnd R18aTogether form a propylene (-CH)2-CH2-CH2-) moiety, and R17bAnd R18bAre all hydrogen. In some embodiments, R19aAnd R19bIndependently at each occurrence is hydrogen or C1-C6An alkyl group. In some embodiments, R19aAnd R19bIndependently at each occurrence is hydrogen or methyl. In some embodiments, R19aAnd R19bAt each occurrence isAnd (3) hydrogen. In some embodiments, R19aAnd R19bAt each occurrence is C1-C6An alkyl group. In some embodiments, R19aAnd R19bAt each occurrence is methyl. In some embodiments, R 19aIs hydrogen at each occurrence and R19bAt each occurrence is C1-C6An alkyl group. In some embodiments, R19aIs hydrogen at each occurrence and R19bAt each occurrence is methyl. In some embodiments, R19aIs hydrogen at each occurrence and R19bAt each occurrence is methyl. In some embodiments, one R19aIs hydrogen and the other R19aIs C1-C6Alkyl, and R19bAt each occurrence is hydrogen. In some embodiments, one R19aIs hydrogen and the other R19aIs methyl, and R19bAt each occurrence is hydrogen. In some embodiments, R19aAt each occurrence is hydrogen, one R19bIs hydrogen, and the other R19bIs C1-C6An alkyl group. In some embodiments, R19aAt each occurrence is hydrogen, one R19bIs hydrogen, and the other R19bIs methyl. In some embodiments, R17aAnd R19aParts together forming C1-C6An alkylene moiety, and R17bAnd is located in said R19aGeminal R19bTogether with R17aTogether are both hydrogen. In some embodiments, R17aAnd R19aThe moieties together forming an ethylene group (-CH)2-CH2-) moiety, and R17bAnd is located in said R19aGeminal R19bTogether with R17aTogether are both hydrogen. In some embodiments, R17aAnd R19aThe moieties together forming a propylene (-CH)2-CH2-CH2-) moiety, and R17bAnd is located in said R19aGeminal R19bTogether with R 17aTogether are both hydrogen.
In some embodiments of compounds of formula (II), (III), (IV), or (V), R27At each timeIndependently when present, is halogen. In some embodiments, R27Independently at each occurrence, is selected from the group consisting of fluoro and chloro.
In some embodiments of compounds of formula (II), (III), (IV), or (V), R29Independently at each occurrence is halogen. In some embodiments, R29Independently at each occurrence, is selected from the group consisting of fluoro and chloro.
In some embodiments of compounds of formula (II), (III), (IV), or (V):
m3 is 0 and n3 is 0;
X3is CH and Y3Is NRY3；
X4Is CH and Y4Is NRY4；
R21aAnd R21bTogether form an oxo (═ O) substituent;
R23aand R23bTogether form an oxo (═ O) substituent;
A3is of the formula (A)3Substituents of-b)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z7selected from the group consisting of: CRZ7-1RZ7-2、NRZ7-2O, S and-CRZ7-1＝CRZ7-1-；
Wherein
RZ7-1Is H or R27(ii) a And is
RZ7-2Is H or R27；
Z8Selected from the group consisting of: CRZ8-1RZ8-2、NRZ8-2O, S and-CRZ8-1＝CRZ8-1-；
Wherein
RZ8-1Is H or R27(ii) a And is
RZ8-2Is H or R27；
R26Is hydrogen or R27Or R is26And RZ7-2Together form a ring with R26With Z7A double bond between;
R27independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C 1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
x3 is 0, 1, 2, 3 or 4;
A4is of the formula (A)4Substituents of-b)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z10Selected from the group consisting of: CRZ10-1RZ10-2、NRZ10-2O, S and-CRZ10-1＝CRZ10-1-；
Wherein
RZ10-1Is H or R29(ii) a And is
RZ10-2Is H or R29；
Z11Selected from the group consisting of: CRZ11-1RZ11-2、NRZ11-2O, S and-CRZ11-1＝CRZ11-1-；
Wherein
RZ11-1Is H or R29(ii) a And is
RZ11-2Is H or R29；
R28Is hydrogen or R29Or R is28And RZ10-2Together form a ring with R28With Z10A double bond between;
R29independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O) 2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
x4 is 0, 1, 2, 3 or 4; and is
With the proviso that A3And A4Not both being a moiety selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 0 and n3 is 0, X3Is CH, Y3Is NRY3，X4Is CH, Y4Is NRY4，R21aAnd R21bTogether form an oxo (═ O) substituent, and R23aAnd R23bTogether form an oxo (═ O) substituent; (A)3-b) is selected from the group consisting of:
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 0 and n3 is 0, X3Is CH, Y3Is NRY3，X4Is CH, Y4Is NRY4，R21aAnd R21bTogether form an oxo (═ O) substituent, and R23aAnd R23bTogether form an oxo (═ O) substituent; (A)4-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)4-b) is selected from the group consisting of:
In some embodiments of compounds of formula (II), (III), (IV), or (V):
m3 is 0 and n3 is 1;
r2 is 1 or 2;
s2 is 1 or 2;
X3is CH and Y3Is NRY3；
R21aAnd R21bTogether form an oxo (═ O) substituent;
R24aselected from the group consisting of: hydrogen, -OH and-NH2；
R25aAnd R25bAre all hydrogen;
A3is of the formula (A)3Substituents of-b)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z7selected from the group consisting of: CRZ7-1RZ7-2、NRZ7-2O, S and-CRZ7-1＝CRZ7-1-；
Wherein
RZ7-1Is H or R27(ii) a And is
RZ7-2Is H or R27；
Z8Selected from the group consisting of: CRZ8-1RZ8-2、NRZ8-2O, S and-CRZ8-1＝CRZ8-1-；
Wherein
RZ8-1Is H or R27(ii) a And is
RZ8-2Is H or R27；
R26Is hydrogen or R27Or R is26And RZ7-2Together form a ring with R26With Z7A double bond between;
R27independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O) 2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
x3 is 0, 1, 2, 3 or 4; and is
A4Is optionally substituted by one or more R29C substituted by substituents6-C10Aryl, or optionally substituted by one or more R29A substituent-substituted 5-10 membered heteroaryl;
R29independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C 1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring.
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X3Is CH, Y3Is NRY3，R21aAnd R21bTogether form an oxo (═ O) substituent, R24aSelected from the group consisting of: hydrogen, -OH and-NH2And R is25aAnd R25bAre all hydrogen; x4Is CH. In some embodiments, Y4Is a chemical bond. In some embodiments, Y4Is NRY4. In some embodiments, RY4Is hydrogen. In some embodiments, RY4Is C1-C6An alkyl group. In some embodiments, RY4Is methyl. In some embodiments, RY4Is ethyl. In some embodiments, Y4Is O. In some embodiments, R23aAnd R23bTogether form an oxo (═ O) substituent, and R24ais-OH or-NH2. In some embodiments, R24ais-OH. In some embodiments, R24ais-NH2. In some embodiments, R23aAnd R23bTogether form an imide (═ NH) substituent. In some embodiments, R 24aIs hydrogen. In some embodiments, R24ais-OH. In some embodiments, R24ais-NH2。
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X3Is CH, Y3Is NRY3，R21aAnd R21bTogether form an oxo (═ O) substituent, R24aSelected from the group consisting of: hydrogen, -OH and-NH2And R is25aAnd R25bAre all hydrogen; x4Is N. In some embodiments, R23aAnd R23bTogether form an oxo (═ O) substituent, and R24ais-OH or-NH2. In some embodiments, R24ais-OH. In some embodiments, R24ais-NH2. In some embodiments, R23aAnd R23bTogether form an imide (═ NH) substituent. In some embodiments, R24aIs hydrogen. In some embodiments, R24ais-OH. In some embodiments, R24ais-NH2. In thatIn some embodiments, R23aAnd R23bAre all hydrogen. In some embodiments, R24aIs hydrogen. In some embodiments, R24ais-OH. In some embodiments, R24ais-NH2。
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X3Is CH, Y3Is NRY3，R21aAnd R21bTogether form an oxo (═ O) substituent, R24aSelected from the group consisting of: hydrogen, -OH and-NH 2And R is25aAnd R25bAre all hydrogen; (A)3-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)3-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X3Is CH, Y3Is NRY3，R21aAnd R21bTogether form an oxo (═ O) substituent, R24aSelected from the group consisting of: hydrogen, -OH and-NH2And R is25aAnd R25bAre all hydrogen; a. the4Is optionally substituted by one or more R29C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A4Selected from the group consisting of:
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X3Is CH, Y3Is NRY3，R21aAnd R21bTogether form an oxo (═ O) substituent, R 24aSelected from the group consisting of: hydrogen, -OH and-NH2And R is25aAnd R25bAre all hydrogen; a. the4Is optionally substituted by one or more R29A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A4Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of compounds of formula (II), (III), (IV), or (V):
m3 is 1 and n3 is 0;
X4is CH and Y4Is NRY4；
R21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent;
R23aand R23bTogether form an oxo (═ O) substituent;
A3is optionally substituted by one or more R27C substituted by substituents6-C10Aryl, or optionally substituted by one or more R27A substituent-substituted 5-10 membered heteroaryl;
R27independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O) 2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A4is of the formula (A)4Substituents of-b)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z10selected from the group consisting of: CRZ10-1RZ10-2、NRZ10-2O, S and-CRZ10-1＝CRZ10-1-；
Wherein
RZ10-1Is H or R29(ii) a And is
RZ10-2Is H or R29；
Z11Selected from the group consisting of: CRZ11-1RZ11-2、NRZ11-2O, S and-CRZ11-1＝CRZ11-1-；
Wherein
RZ11-1Is H or R29(ii) a And is
RZ11-2Is H or R29；
R28Is hydrogen or R29Or R is28And RZ10-2Together form a ring with R28With Z10A double bond between;
R29independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C) 1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
x4 is 0, 1, 2, 3 or 4.
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 0, X4Is CH, Y 4Is NRY4，R21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, and R23aAnd R23bTogether form an oxo (═ O) substituent; x3Is CH. In some embodiments, Y3Chemistry of Chinese scholarAnd (5) learning a bond. In some embodiments, Y3Is NRY3. In some embodiments, RY3Is hydrogen. In some embodiments, RY3Is C1-C6An alkyl group. In some embodiments, RY3Is methyl. In some embodiments, RY3Is ethyl. In some embodiments, Y3Is O. In some embodiments, X3Is N. In some embodiments, R21aAnd R21bTogether form an oxo (═ O) substituent. In some embodiments, R21aAnd R21bTogether form an imide (═ NH) substituent.
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 0, X4Is CH, Y4Is NRY4，R21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, and R23aAnd R23bTogether form an oxo (═ O) substituent; a. the3Is optionally substituted by one or more R27C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A3Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 0, X 4Is CH, Y4Is NRY4，R21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, and R23aAnd R23bTogether form an oxo (═ O) substituent; a. the3Is optionally substituted by one or more R27A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A3Selected from the group consisting of:
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 0, X4Is CH, Y4Is NRY4，R21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, and R23aAnd R23bTogether form an oxo (═ O) substituent; (A)4-b) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A)4-b) is selected from the group consisting of:
In some embodiments of compounds of formula (II), (III), (IV), or (V):
m3 is 1 and n3 is 1;
R21aand R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent;
A3is optionally substituted by one or more R27C substituted by substituents6-C10Aryl, or optionally substituted by one or more R27A substituent-substituted 5-10 membered heteroaryl;
R27independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR27-aR27-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR27-aR27-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR27-aR27 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O) 2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is27-aAnd R27-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
A4is optionally substituted by one or more R29C substituted by substituents6-C10Aryl, or optionally substituted by one or more R29A substituent-substituted 5-10 membered heteroaryl;
R29independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR29-aR29-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR29-aR29-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR29-aR29 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C 1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl) and-N(H)S(O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is29-aAnd R29-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
with the following conditions:
when X is present3Or X4Is N, then r2 is 1 or 2 and s2 is 1 or 2; and
when R is23aAnd R23bTogether form an oxo (═ O) substituent, then R24ais-OH or-NH2。
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 1, and R is21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent; x3Is CH. In some embodiments, Y3Is a chemical bond. In some embodiments, Y3Is NRY3. In some embodiments, RY3Is hydrogen. In some embodiments, RY3Is C1-C6An alkyl group. In some embodiments, RY3Is methyl. In some embodiments, RY3Is ethyl. In some embodiments, Y3Is O.
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 1, and R is21aAnd R 21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent; x3Is N. In some embodiments, R21aAnd R21bTogether form an oxo (═ O) substituent. In some embodiments, R21aAnd R21bTogether form an imide (═ NH) substituent.
In the formulae (II), (III),Some embodiments of the compounds of (IV) or (V), wherein m3 is 1, n3 is 1, and R is21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent; x4Is CH. In some embodiments, Y4Is a chemical bond. In some embodiments, Y4Is NRY4. In some embodiments, RY4Is hydrogen. In some embodiments, RY4Is C1-C6An alkyl group. In some embodiments, RY4Is methyl. In some embodiments, RY4Is ethyl. In some embodiments, Y4Is O. In some embodiments, R23aAnd R23bTogether form an oxo (═ O) substituent, and R24ais-OH or-NH2. In some embodiments, R24ais-OH. In some embodiments, R24ais-NH2. In some embodiments, R23aAnd R23bTogether form an imide (═ NH) substituent. In some embodiments, R24aIs hydrogen. In some embodiments, R24ais-OH. In some embodiments, R24ais-NH2. In some embodiments, R 23aAnd R23bAre all hydrogen. In some embodiments, R24aIs hydrogen. In some embodiments, R24ais-OH. In some embodiments, R24ais-NH2。
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 1, and R is21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent; x4Is N. In some embodiments, R23aAnd R23bTogether form an oxo (═ O) substituent, and R24ais-OH or-NH2. In some embodiments, R24ais-OH. In some embodiments, R24ais-NH2. In some embodiments, R23aAnd R23bTogether form an imide (═ NH) substituent. In some embodiments, R24aIs hydrogen. In some embodiments, R24ais-OH. In some embodiments, R24ais-NH2. In some embodiments, R23aAnd R23bAre all hydrogen. In some embodiments, R24aIs hydrogen. In some embodiments, R24ais-OH. In some embodiments, R24ais-NH2。
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 1, and R is21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent; a. the3Is optionally substituted by one or more R27C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A 3Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 1, and R is21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent; a. the3Is optionally substituted by one or more R27A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A3Selected from the group consisting of:
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 1, and R is21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent; a. the4Is optionally substituted by one or more R29C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A4Selected from the group consisting of:
In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 1, and R is21aAnd R21bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent; a. the4Is optionally substituted by one or more R29A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A 4Selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule.
In one aspect, there is provided a compound of formula (X-1):
or a pharmaceutically acceptable salt thereof;
wherein:
R30and R31Independently of each other and independently at each occurrence is halogen;
x5 and x6 are independently of each other 0, 1, 2, 3, 4 or 5;
Q1selected from the group consisting of:
wherein represents and
R32And R33Are all hydrogen, or R32And R33Together form an oxo (═ O) substituent.
In some embodiments of the compounds of formula (X-1), Q1Is thatAnd R is32And R33Are all hydrogen.
In some embodiments of the compounds of formula (X-1), Q1Is that
In some embodiments of the compounds of formula (X-1), Q1Is that
In some embodiments of the compounds of formula (X-1), Q1Is that
In some embodiments of the compounds of formula (X-1), Q1Is that
In some embodiments of the compounds of formula (X-1), Q1Is that
In some embodiments of the compounds of formula (X-1), R30And R31Independently of each other and independently at each occurrence, is selected from fluoro and chloro.
In some embodiments of the compound of formula (X-1), both X5 and X6 are 1. In some embodiments, x5 is 1 and x6 is 2. In some embodiments, x5 is 2 and x6 is 1. In some embodiments, x5 and x6 are both 2.
In one aspect, there is provided a compound of formula (X-2):
or a pharmaceutically acceptable salt thereof;
wherein:
R34and R35Independently of each other and independently at each occurrence is halogen;
x7 and x8 are independently of each other 0, 1, 2, 3, 4 or 5;
A5is a 5-12 membered heteroaryl;
Q2selected from the group consisting of:
wherein represents andthe connection point of the parts, and # denotesA connection point of the portion;
R36and R37Are all hydrogen, or R36And R37Together form an oxo (═ O) substituent;
R38and R39Are all hydrogen, or R38And R39Together form a propylene (-CH)2-CH2-CH2-) moiety; and is
T1is-CR40R41-or S (═ O)2-, wherein R40Selected from the group consisting of: hydrogen, -OH and-NH2(ii) a And R is41Is hydrogen.
In some embodiments of the compounds of formula (X-2), Q2Is thatAnd R is36And R37Are all hydrogen.
A compound of the formula (X-2)In some embodiments of (1), Q2Is thatAnd R is36And R37Together form an oxo (═ O) substituent.
In some embodiments of the compounds of formula (X-2), Q2Is thatAnd R is36And R37Are all hydrogen.
In some embodiments of the compounds of formula (X-2), Q2Is that
In some embodiments of the compounds of formula (X-2), Q2Is that
In some embodiments of the compounds of formula (X-2), Q2Is thatAnd R is38And R39Together form a propylene (-CH)2-CH2-CH2-) moiety. In some embodiments, T1is-CR40R41-. In some embodiments, T1is-CR40R41-, and R40Selected from the group consisting of: hydrogen, -OH and-NH2(ii) a And R is41Is hydrogen. In some embodiments, T1is-CR40R41-，R40Is hydrogen and R41Is hydrogen. In some embodiments, T1is-CR40R41-，R40is-OH, and R41Is hydrogen. In some embodiments, T1is-CR40R41-，R40is-NH2And R is41Is hydrogen. In other embodiments, T1Is S (═ O)2-。
In some embodiments of the compounds of formula (X-2), R34And R35Independently of each other and independently at each occurrence, is selected from fluoro and chloro.
In some embodiments of the compound of formula (X-1), both X7 and X8 are 1. In some embodiments, x7 is 1 and x8 is 2. In some embodiments, x7 is 2 and x8 is 1. In some embodiments, x7 and x8 are both 2.
In one aspect, there is provided a compound of formula (X-3):
or a pharmaceutically acceptable salt thereof;
wherein:
R42and R43Independently of each other and independently at each occurrence is halogen;
x9 and x10 are independently of each other 0, 1, 2, 3, 4 or 5;
R44and R45Are all hydrogen, or R44And R45Together forming an ethylene radical (-CH)2-CH2-) moiety;
A6is a 5-12 membered heteroaryl;
A7is C6-C10Aryl or 5-12 membered heteroaryl;
Q3selected from the group consisting of:
wherein represents and
Provided that one of (i) or (ii) applies:
(i) q3 is 0, Q3Is thatAnd A is7Is a 5-12 membered heteroaryl;
(ii) q3 is 1, Q3Is that
In some embodiments of the compounds of formula (X-3), Q3 is 0, Q3Is that
In some embodiments of the compounds of formula (X-3), Q3 is 1, Q3Is that
In some embodiments of the compounds of formula (X-3), R44And R 45Are all hydrogen. In some embodiments of the compounds of formula (X-3), R44And R45Together forming an ethylene radical (-CH)2-CH2-) moiety.
In some embodiments of the compounds of formula (X-3), R42And R43Independently of each other and independently at each occurrence, is selected from fluoro and chloro.
In some embodiments of the compound of formula (X-3), both X9 and X10 are 1. In some embodiments, x9 is 1 and x10 is 2. In some embodiments, x9 is 2 and x10 is 1. In some embodiments, x9 and x10 are both 2.
In one aspect, there is provided a compound of formula (X-4):
or a pharmaceutically acceptable salt thereof;
wherein:
R46and R47Independently of each other and independently at each occurrence is halogen;
x11 and x12 are independently of each other 0, 1, 2, 3, 4 or 5;
R48is hydrogen or-OH;
Q4selected from the group consisting of:
wherein represents andthe connection point of the parts, and # denotes
R49、R50、R51、R52、R53、R54、R55、R56、R57、R58、R59、R60、R61、R62、R63and R64Independently of one another, hydrogen or C1-C6An alkyl group.
In some embodiments of the compounds of formula (X-4), Q4Is that
In some embodiments of the compounds of formula (X-4), Q4Is that
In some embodiments of the compounds of formula (X-4), Q4Is thatIn some embodiments, R61、R62、R63And R64Are all C1-C6An alkyl group. In some embodiments, R61、R62、R63And R64Are both methyl groups. In some embodiments, R61And R63Are all C1-C6Alkyl, and R62And R64Are all hydrogen. In some embodiments, R61And R63Are all methyl, and R 62And R64Are all hydrogen. In some embodiments, R61、R62、R63And R64Are all hydrogen.
In some embodiments of the compounds of formula (X-4), R48Is hydrogen.
In some embodiments of the compounds of formula (X-4), R48is-OH.
In some embodiments of the compounds of formula (X-4), R46And R47Independently of each other and independently at each occurrence, is selected from fluoro and chloro.
In some embodiments of the compound of formula (X-4), both X11 and X12 are 1. In some embodiments, x11 is 1 and x12 is 2. In some embodiments, x11 is 2 and x12 is 1. In some embodiments, x11 and x12 are both 2.
In one aspect, there is provided a compound of formula (X-5):
or a pharmaceutically acceptable salt thereof;
wherein:
R65and R66Independently of each other and independently at each occurrence is halogen;
x13 and x14 are independently of each other 0, 1, 2, 3, 4 or 5;
Q5selected from the group consisting of:
wherein represents andthe connection point of the parts, and # denotes
R67and R68Are all hydrogen, or R67And R68Together form an imino (═ NH) substituent; and is
R69Is hydrogen or-NH2。
In some embodiments of the compounds of formula (X-5), Q5Is that
In some embodiments of the compounds of formula (X-5), Q 5Is that
In some embodiments of the compounds of formula (X-5), R65And R66Independently of each other and independently at each occurrence, is selected from fluoro and chloro.
In some embodiments of the compound of formula (X-5), both X13 and X14 are 1. In some embodiments, x13 is 1 and x14 is 2. In some embodiments, x13 is 2 and x14 is 1. In some embodiments, x13 and x14 are both 2.
In one aspect, there is provided a compound of formula (X-6):
or a pharmaceutically acceptable salt thereof;
wherein:
R70and R71Independently of each other and independently at each occurrence is halogen;
x15 and x16 are independently of each other 0, 1, 2, 3, 4 or 5;
n4 is 1 or 2;
T2Is O or NH; and is
A8Is a 5-12 membered heteroaryl.
In some embodiments of the compound of formula (X-6), n4 is 1.
In some embodiments of the compound of formula (X-6), n4 is 2.
In some embodiments of the compound of formula (X-6), T2Is O.
In some embodiments of the compound of formula (X-6), T2Is NH.
In some embodiments of the compounds of formula (X-5), R70And R71Independently of each other and independently at each occurrence, is selected from fluoro and chloro.
In some embodiments of the compound of formula (X-5), both X15 and X16 are 1. In some embodiments, x15 is 1 and x16 is 2. In some embodiments, x15 is 2 and x16 is 1. In some embodiments, x15 and x16 are both 2.
In one aspect, there is provided a compound of formula (X-7):
or a pharmaceutically acceptable salt thereof;
wherein:
R72and R73Independently of each other and independently at each occurrence is halogen;
x17 and x18 are independently of each other 0, 1, 2, 3, 4 or 5;
A9is a 5-12 membered heteroaryl; and is
A10Is a 5-12 membered heteroaryl;
with the proviso that A9And A10Not both being a moiety selected from the group consisting of:
In some embodiments of the compounds of formula (X-7), R 72And R73Independently of each other and independently at each occurrence, is selected from fluoro and chloro.
In some embodiments of the compound of formula (X-7), both X17 and X18 are 1. In some embodiments, x17 is 1 and x18 is 2. In some embodiments, x17 is 2 and x18 is 1. In some embodiments, x17 and x18 are both 2.
In one aspect, there is provided a compound of formula (X-8):
or a pharmaceutically acceptable salt thereof;
wherein:
R74and R75Independently of each other and independently at each occurrence is halogen;
x19 and x20 are independently of each other 0, 1, 2, 3, 4 or 5;
A11is C6-C10Aryl or 5-12 membered heteroaryl;
Q6selected from the group consisting of:
wherein represents and
T3is O or NH;
T4is O or NH;
R76selected from hydrogen, -OH and-NH2；
R77Selected from hydrogen, -OH and-NH2；
R78Is hydrogen or-OH; and is
Provided that one of (i) or (ii) applies:
(i) when A is11Is C6-C10Aryl radicals, Q6Selected from the group consisting of:
(ii) when A is11When it is a 5-to 12-membered heteroaryl group, Q6Is that
In some embodiments of the compounds of formula (X-8), A11Is C6-C10Aryl, and Q6Selected from the group consisting of:
in some embodiments of the compounds of formula (X-8), A 11Is C6-C10Aryl, and Q6Is thatIn some embodiments, A11Is phenyl.
In some embodiments of the compounds of formula (X-8), A11Is C6-C10Aryl, and Q6Is thatIn some embodiments, R76Is hydrogen. In some embodiments, R76is-OH. In some embodiments, R76is-NH2. In some embodiments, A11Is phenyl.
In some embodiments of the compounds of formula (X-8), A11Is C6-C10Aryl, and Q6Is that
In some embodiments of the compounds of formula (X-8), A11Is C6-C10Aryl, and Q6Is that
In some embodiments of the compounds of formula (X-8), A11Is C6-C10Aryl, and Q6Is thatIn some embodiments, A11Is phenyl.
In some embodiments of the compounds of formula (X-8), A11Is C6-C10Aryl, and Q6Is thatIn some embodiments, T3Is O. In some embodiments, T3Is NH. In some embodiments, A11Is phenyl.
In some embodiments of the compounds of formula (X-8), A11Is C6-C10Aryl, and Q6Is that
In some embodiments of the compounds of formula (X-8), A11Is 5-12 membered heteroaryl, and Q6Is that
In some embodiments of the compounds of formula (X-8), A11Is 5-12 membered heteroaryl, and Q6Is that
In some embodiments of the compounds of formula (X-8), A11Is 5-12 membered heteroaryl, and Q6Is that
In some embodiments of the compounds of formula (X-8), R74And R75Independently of each other and independently at each occurrence, is selected from fluoro and chloro.
In some embodiments of the compound of formula (X-8), both X19 and X20 are 1. In some embodiments, x19 is 1 and x20 is 2. In some embodiments, x19 is 2 and x20 is 1. In some embodiments, x19 and x20 are both 2.
In one aspect, there is provided a compound of formula (X-9):
or a pharmaceutically acceptable salt thereof;
wherein:
R79and R80Independently of each other and independently at each occurrence is halogen;
x21 and x22 are independently of each other 0, 1, 2, 3, 4 or 5;
A12is C6-C10Aryl or 5-12 membered heteroaryl;
Q7selected from the group consisting of:
wherein represents and
T5is O or NH;
T6is O or NH;
R81selected from hydrogen, -OH and-NH2；
R82Selected from hydrogen, -OH and-NH2；
R83Is hydrogen or-OH; and is
Provided that one of (i) or (ii) applies:
(i) when A is12Is C6-C10Aryl radicals, Q7Selected from the group consisting of:
(ii) when A is12When it is a 5-to 12-membered heteroaryl group, Q7Is that
In some embodiments of the compounds of formula (X-9), A12Is C6-C10Aryl, and Q7Selected from the group consisting of:
in some embodiments of the compounds of formula (X-9), A12Is C6-C10Aryl, and Q7Is thatIn some embodiments, R81Is hydrogen. In some embodiments, R81Is selected from-OH. In some embodiments, R81Is selected from-NH2. In some embodiments, A12Is phenyl.
In some embodiments of the compounds of formula (X-9), A12Is C6-C10Aryl, and Q7Is that
In some embodiments of the compounds of formula (X-9), A12Is C6-C10Aryl, and Q7Is that
In some embodiments of the compounds of formula (X-9), A12Is C6-C10Aryl, and Q7Is thatIn some embodiments, T 5Is O. In some embodiments, T5Is NH. In some embodiments, A12Is phenyl.
In some embodiments of the compounds of formula (X-9), A12Is C6-C10Aryl, and Q7Is thatIn some embodiments, T6Is O. In some embodiments, T6Is NH. In some embodiments, A12Is phenyl.
In some embodiments of the compounds of formula (X-9), A12Is 5-12 membered heteroaryl, and Q7Is that
In some embodiments of the compounds of formula (X-9), A12Is 5-12 membered heteroaryl, and Q7Is that
In some embodiments of the compounds of formula (X-9), A12Is 5-12 membered heteroaryl, and Q7Is that
In some embodiments of the compounds of formula (X-9), R79And R80Independently of each other and independently at each occurrence, is selected from fluoro and chloro.
In some embodiments of the compound of formula (X-9), both X21 and X22 are 1. In some embodiments, x21 is 1 and x22 is 2. In some embodiments, x21 is 2 and x22 is 1. In some embodiments, x21 and x22 are both 2.
In one aspect, there is provided a compound of formula (XX):
or a pharmaceutically acceptable salt thereof;
wherein:
X5is CH or N;
Y5Selected from the group consisting of: chemical bond, NRY5And O; provided that when X is5When N is, then Y5Is a chemical bond;
RY5is hydrogen or C1-C6An alkyl group;
RNis hydrogen or C1-C6An alkyl group;
m4、n5、p3and q is4Independently of one another, 0 or 1;
r3 and s3 are independently of each other 0, 1 or 2;
A13selected from the group consisting of:
optionally substituted by one or more R95C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R95A substituent-substituted 5-10 membered heteroaryl;
R95independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR95-aR95-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR95-aR95-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR95-aR95 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C) 1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is95-aAnd R95-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R84aand R84bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
R85aand R85bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R86aAnd R86bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R87aAnd R87bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
or, R84aAnd R85aTogether form C1-C6An alkylene moiety;
or, R84aWith the presence of R86aParts together forming C1-C6An alkylene moiety;
or, R present86aMoiety and R present87aParts together forming C1-C6An alkylene moiety;
R88selected from the group consisting of: hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -C (O) (C)1-C6Alkyl), -C (O) (C)1-C6Haloalkyl), -C (O) OH, -C (O) O (C)1-C6Alkyl), -C (O) O (C) 1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR88-aR88-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2and-S (O)2NR88-aR88-b；
Wherein R is88-aAnd R88-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R89independently at each occurrence, selected from the group consisting of: hydrogen, halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR89-aR89 -b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR89- aR89-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR89-aR89-b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O) 2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is89-aAnd R89-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
when present, R90aAnd R90bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R90aAnd R90bAre all hydrogen;
when present, R91aSelected from the group consisting of: hydrogen, -OR91a-aand-NR91a-bR91a-c；
When present, R91bIs hydrogen;
or alternatively, R91aAnd R91bTogether form a moiety selected from the group consisting of: -O-CH2-CH2-、-CH2-O-CH2-、-CH2-CH2-O-、-O-CH2-CH2-CH2-、-CH2-O-CH2-CH2-、-CH2-CH2-O-CH2-、-CH2-CH2-CH2-O-、-O-CH2-CH2-CH2-CH2-、-CH2-O-CH2-CH2-CH2-、-CH2-CH2-O-CH2-CH2-、-CH2-CH2-CH2-O-CH2-and-CH2-CH2-CH2-CH2-O-；
When present, R92aAnd R92bAre all hydrogen;
when present, R93aAnd R93bTogether form an oxo (═ O) substituent, or alternatively, R93aAnd R93bAre all hydrogen;
R91a-aselected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group;
or R91a-aAnd RY5May together form a carbonyl (C ═ O) moiety; and is
R91a-bAnd R91a-cIndependently of each other selected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group;
provided that when m is4Is 0, n5Is 0, and q4When it is 0, then A13Is of the formula (A)13A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z14Selected from the group consisting of: CRZ14-1RZ14-2、NRZ14-2、C(RZ14-1RZ14-2)N(RZ14-2)、O、C(RZ14- 1RZ14-2)O、S、C(RZ14-1RZ14-2) S and-CRZ14-1＝CRZ14-1-；
Wherein R isZ14-1Is hydrogen or R16(ii) a And R isZ14-2Is hydrogen or R95；
Z15Selected from the group consisting of: CRZ15-1RZ15-2、NRZ15-2、C(RZ15-1RZ15-2)N(RZ15-2)、O、C(RZ15- 1RZ15-2)O、S、C(RZ15-1RZ15-2) S and-CRZ15-1＝CRZ15-1-；
Wherein R isZ15-1Is hydrogen or R95(ii) a And R isZ15-2Is hydrogen or R95；
Z16Independently at each occurrence is CH, CR95Or N;
R94is hydrogen or R95Or R is94And RZ14-2Together form a ring with R94With Z14A double bond between, or R94And RZ15-2Together form a ring with R94With Z15A double bond between; and is
x23 is 0, 1, 2, 3 or 4.
In some embodiments of the compound of formula (XX):
X5is CH or N;
Y5selected from the group consisting of: chemical bond, NRY5And O; provided that when X is5When N is, then Y5Is a chemical bond;
RY5is hydrogen or C1-C6An alkyl group;
RNis hydrogen or C1-C6An alkyl group;
m4、n5、p3and q is4Independently of one another, 0 or 1;
r3 and s3 are independently of each other 0, 1 or 2;
A13selected from the group consisting of:
optionally substituted by one or more R95C substituted by substituents6-C10An aryl group; and
optionally substituted by one or more R95A substituent-substituted 5-10 membered heteroaryl;
R95independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C) 1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR95-aR95-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR95-aR95-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR95-aR95 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is95-aAnd R95-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R84aand R84bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
R85aand R85bIndependently selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
when present, R86aAnd R86bIndependently at each occurrence, selected from the group consisting of: hydrogen, C 1-C6Alkyl and halogen;
when present, R87aAnd R87bIndependently at each occurrence, selected from the group consisting of: hydrogen, C1-C6Alkyl and halogen;
or, R84aAnd R85aTogether form C1-C6An alkylene moiety;
or, R84aWith the presence of R86aParts together forming C1-C6An alkylene moiety;
or, R present86aMoiety and R present87aParts together forming C1-C6An alkylene moiety;
R88selected from the group consisting of: hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -C (O) (C)1-C6Alkyl), -C (O) (C)1-C6Haloalkyl), -C (O) OH, -C (O) O (C)1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR88-aR88-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2and-S (O)2NR88-aR88-b；
Wherein R is88-aAnd R88-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
R89independently at each occurrence, selected from the group consisting of: hydrogen, halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C)1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR89-aR89 -b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C) 1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR89- aR89-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Haloalkyl groups)2、-S(O)2NR89-aR89-b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl halidesRadical), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl);
wherein R is89-aAnd R89-bTogether with the nitrogen atom which carries it, form a 3-to 10-membered heterocyclic ring;
when present, R90aAnd R90bTogether form an oxo (═ O) substituent or an imido (═ NH) substituent, or alternatively, R90aAnd R90bAre all hydrogen;
when present, R91aSelected from the group consisting of: hydrogen, -OR91a-aand-NR91a-bR91a-c；
When present, R91bIs hydrogen;
or alternatively, R91aAnd R91bTogether form a moiety selected from the group consisting of: -O-CH2-CH2-、-CH2-O-CH2-、-CH2-CH2-O-、-O-CH2-CH2-CH2-、-CH2-O-CH2-CH2-、-CH2-CH2-O-CH2-、-CH2-CH2-CH2-O-、-O-CH2-CH2-CH2-CH2-、-CH2-O-CH2-CH2-CH2-、-CH2-CH2-O-CH2-CH2-、-CH2-CH2-CH2-O-CH2-and-CH2-CH2-CH2-CH2-O-；
When present, R 92aAnd R92bAre all hydrogen;
when present, R93aAnd R93bTogether form an oxo (═ O) substituent, or alternatively, R93aAnd R93bAre all hydrogen;
R91a-aselected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group;
or R91a-aAnd RY5May together form a carbonyl (C ═ O) moiety; and is
R91a-bAnd R91a-cIndependently of each other selected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group;
provided that when m is4Is 0, n5Is 0, and q4When is 0, then p3Is 1 and A13Is of the formula (A)13A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z14selected from the group consisting of: CRZ14-1RZ14-2、NRZ14-2、C(RZ14-1RZ14-2)N(RZ14-2)、O、C(RZ14- 1RZ14-2)O、S、C(RZ14-1RZ14-2) S and-CRZ14-1＝CRZ14-1-；
Wherein R isZ14-1Is hydrogen or R16(ii) a And R isZ14-2Is hydrogen or R95；
Z15Selected from the group consisting of: CRZ15-1RZ15-2、NRZ15-2、C(RZ15-1RZ15-2)N(RZ15-2)、O、C(RZ15- 1RZ15-2)O、S、C(RZ15-1RZ15-2) S and-CRZ15-1＝CRZ15-1-；
Wherein R isZ15-1Is hydrogen or R95(ii) a And R isZ15-2Is hydrogen or R95；
Z16Independently at each occurrence is CH, CR95Or N;
R94is hydrogen or R95Or R is94And RZ14-2Together form a ring with R94With Z14A double bond between, or R94And RZ15-2Together form a ring with R94With Z15A double bond between; and is
x23 is 0, 1, 2, 3 or 4.
In some embodiments, the compound of formula (XX) is a compound of formula (XX-I):
or a pharmaceutically acceptable salt thereof;
wherein R isN、RY5、m4、n5、p3、q4、r3、s3、A13、R84a、R84b、R85a、R85b、R86a、R86b、R87a、R87b、R88、R89、R90a、R90b、R91a、R91b、R92a、R92b、R93aAnd R93bAs defined for the compound of formula (XX).
In some embodiments, the compound of formula (XX) is a compound of formula (XX-II):
Or a pharmaceutically acceptable salt thereof;
wherein R isN、m4、n5、p3、q4、r3、s3、A13、R84a、R84b、R85a、R85b、R86a、R86b、R87a、R87b、R88、R89、R90a、R90b、R91a、R91b、R92a、R92b、R93aAnd R93bAs defined for the compound of formula (XX).
In some embodiments of the compounds of formulas (XX), (XX-I), and (XX-II), a moietyWherein # represents the point of attachment to the rest of the molecule and isWhere # indicates the point of attachment to the rest of the molecule.
In some embodiments, the compound of formula (XX) or the compound of formula (XX-I) is a compound of formula (XX-I-1):
or a pharmaceutically acceptable salt thereof;
wherein R isN、RY5、R88、R89、R93aAnd R93bAs defined in the compound of formula (XX), and wherein A13Is of the formula (A)13A substituent of (a)
Wherein
Denotes the point of attachment to the rest of the molecule;
Z14selected from the group consisting of: CRZ14-1RZ14-2、NRZ14-2、C(RZ14-1RZ14-2)N(RZ14-2)、O、C(RZ14- 1RZ14-2)O、S、C(RZ14-1RZ14-2) S and-CRZ14-1＝CRZ14-1-；
Wherein R isZ14-1Is hydrogen or R16(ii) a And R isZ14-2Is hydrogen or R95；
Z15Selected from the group consisting of: CRZ15-1RZ15-2、NRZ15-2、C(RZ15-1RZ15-2)N(RZ15-2)、O、C(RZ15- 1RZ15-2)O、S、C(RZ15-1RZ15-2) S and-CRZ15-1＝CRZ15-1-；
Wherein R isZ15-1Is hydrogen or R95(ii) a And R isZ15-2Is hydrogen or R95；
Z16Independently at each occurrence is CH, CR95Or N;
R94is hydrogen or R95Or R is94And RZ14-2Together form a ring with R94With Z14A double bond between, or R94And RZ15-2Together form a ring with R94With Z15A double bond between;
x23 is 0, 1, 2, 3 or 4; and is
R95Independently at each occurrence, selected from the group consisting of: halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OH, -O (C) 1-C6Alkyl), -O (C)1-C6Haloalkyl), -SH, -S (C)1-C6Alkyl), -S (C)1-C6Haloalkyl), -NH2、-NH(C1-C6Alkyl), -NH (C)1-C6Haloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Haloalkyl groups)2、-NR95-aR95-b、-CN、-C(O)OH、-C(O)O(C1-C6Alkyl), -C (O) O (C)1-C6Haloalkyl), -C (O) NH2、-C(O)NH(C1-C6Alkyl), -C (O) NH (C)1-C6Haloalkyl), -C (O) N (C)1-C6Alkyl radical)2、-C(O)N(C1-C6Haloalkyl groups)2、-C(O)NR95-aR95-b、-S(O)2OH、-S(O)2O(C1-C6Alkyl), -S (O)2O(C1-C6Haloalkyl), -S (O)2NH2、-S(O)2NH(C1-C6Alkyl), -S (O)2NH(C1-C6Haloalkyl), -S (O)2N(C1-C6Alkyl radical)2、-S(O)2N(C1-C6Alkyl halidesBase)2、-S(O)2NR95-aR95 -b、-OC(O)H、-OC(O)(C1-C6Alkyl), -OC (O) (C)1-C6Haloalkyl), -N (H) C (O) H, -N (H) C (O)1-C6Alkyl), -N (H) C (O) (C)1-C6Haloalkyl), -N (C)1-C6Alkyl group C (O) H, -N (C)1-C6Alkyl radical C (O) (C)1-C6Alkyl), -N (C)1-C6Alkyl radical C (O) (C)1-C6Haloalkyl), -N (C)1-C6Haloalkyl) C (O) H, -N (C)1-C6Haloalkyl) C (O) (C1-C6Alkyl), -N (C)1-C6Haloalkyl) C (O) (C1-C6Haloalkyl), -OS (O)2(C1-C6Alkyl), -OS (O)2(C1-C6Haloalkyl), -N (H) S (O)2(C1-C6Alkyl), -N (H) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Alkyl), -N (C)1-C6Alkyl) S (O)2(C1-C6Haloalkyl), -N (C)1-C6Haloalkyl) S (O)2(C1-C6Alkyl) and-N (C)1-C6Haloalkyl) S (O)2(C1-C6Haloalkyl).
In some embodiments of compounds of formula (XX-I-1), RNIs hydrogen or C1-C6An alkyl group. In some embodiments of compounds of formula (XX-I-1), RNIs hydrogen.
In some embodiments of compounds of formula (XX-I-1), R Y5Is hydrogen or C1-C6An alkyl group. In some embodiments of compounds of formula (XX-I-1), RY5Is hydrogen.
In some embodiments of compounds of formula (XX-I-1), R88Is hydrogen, C1-C6Alkyl or C1-C6A haloalkyl group. In some embodiments, R88Is hydrogen.
In some embodiments of compounds of formula (XX-I-1), R89Independently at each occurrence, selected from the group consisting of: hydrogen, halogen, C1-C6Alkyl and C1-C6A haloalkyl group. In some embodiments of compounds of formula (XX-I-1), R89Independently at each occurrence is hydrogen or halogen. In some embodiments, R89Independently at each occurrence is hydrogen, fluoro or chloro. In some embodiments, one R89Is chloro, and the remainder of R89The substituent is hydrogen.
In some embodiments of compounds of formula (XX-I-1), R93aAnd R93bTogether form an oxo (═ O) substituent. In some embodiments of compounds of formula (XX-I-1), R93aAnd R93bAre all hydrogen.
In some embodiments of compounds of formula (XX-I-1), (A)13-a) is selected from the group consisting of:
where denotes the point of attachment to the rest of the molecule. In some embodiments, (A) 13-a) is selected from the group consisting of:
In some embodiments of compounds of formula (XX-I-1), moietyWherein # represents the point of attachment to the rest of the molecule and isWhere # indicates the point of attachment to the rest of the molecule.
In some embodiments, the compound of formula (XX) or the compound of formula (XX-I) is a compound of formula (XX-I-2):
or a pharmaceutically acceptable salt thereof;
wherein R isN、RY5、A13、R88And R89As defined in the compound of formula (XX).
In some embodiments of compounds of formula (XX-I-2), RNIs hydrogen or C1-C6An alkyl group. In some embodiments of compounds of formula (XX-I-2), RNIs hydrogen.
In some embodiments of compounds of formula (XX-I-2), RY5Is hydrogen or C1-C6An alkyl group. In some embodiments of compounds of formula (XX-I-2), RY5Is hydrogen.
In some embodiments of compounds of formula (XX-I-2), R88Is hydrogen, C1-C6Alkyl or C1-C6A haloalkyl group. In some embodiments, R88Is hydrogen.
In some embodiments of compounds of formula (XX-I-2), R 89Independently at each occurrence is selected fromA group consisting of: hydrogen, halogen, C1-C6Alkyl and C1-C6A haloalkyl group. In some embodiments of compounds of formula (XX-I-2), R89Independently at each occurrence is hydrogen or halogen. In some embodiments, R89Independently at each occurrence is hydrogen, fluoro or chloro. In some embodiments, one R89Is chloro, and the remainder of R89The substituent is hydrogen.
In some embodiments of compounds of formula (XX-I-2), A13Selected from the group consisting of: optionally substituted by one or more R95C substituted by substituents6-C14An aryl group; and optionally substituted with one or more R95A substituent-substituted 5-14 membered heteroaryl. In some embodiments, A13Is optionally substituted by one or more R95C substituted by substituents6-C14And (4) an aryl group. In some embodiments, A13Is optionally substituted by one or more R95C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A13Selected from the group consisting of:
In some embodiments of compounds of formula (XX-I-2), A13Is optionally substituted by one or more R95A substituent-substituted 5-14 membered heteroaryl. In some embodiments, A13Is optionally substituted by one or more R95A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A13Selected from the group consisting of:
In some embodiments of compounds of formula (XX-I-2), moiety
In some embodiments, the compound of formula (XX) or the compound of formula (XX-I) is a compound of formula (XX-I-2 b):
or a pharmaceutically acceptable salt thereof;
wherein R isN、RY5、A13、R88And R89A compound of formula (XX)As defined in (a).
In some embodiments of compounds of formula (XX-I-2b), RNIs hydrogen or C1-C6An alkyl group. In some embodiments of compounds of formula (XX-I-2b), RNIs hydrogen.
In some embodiments of compounds of formula (XX-I-2b), RY5Is hydrogen or C1-C6An alkyl group. In some embodiments of compounds of formula (XX-I-2b), RY5Is hydrogen.
In some embodiments of compounds of formula (XX-I-2b), R88Is hydrogen, C1-C6Alkyl or C 1-C6A haloalkyl group. In some embodiments, R88Is hydrogen.
In some embodiments of compounds of formula (XX-I-2b), R89Independently at each occurrence, selected from the group consisting of: hydrogen, halogen, C1-C6Alkyl and C1-C6A haloalkyl group. In some embodiments of compounds of formula (XX-I-2b), R89Independently at each occurrence is hydrogen or halogen. In some embodiments, R89Independently at each occurrence is hydrogen, fluoro or chloro. In some embodiments, one R89Is chloro, and the remainder of R89The substituent is hydrogen.
In some embodiments of compounds of formula (XX-I-2b), A13Selected from the group consisting of: optionally substituted by one or more R95C substituted by substituents6-C14An aryl group; and optionally substituted with one or more R95A substituent-substituted 5-14 membered heteroaryl. In some embodiments, A13Is optionally substituted by one or more R95C substituted by substituents6-C14And (4) an aryl group. In some embodiments, A13Is optionally substituted by one or more R95C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A13Selected from the group consisting of:
In some embodiments of compounds of formula (XX-I-2b), A13Is optionally substituted by one or more R95A substituent-substituted 5-14 membered heteroaryl. In some embodiments, A13Is optionally substituted by one or more R95A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A13Selected from the group consisting of:
In some embodiments of compounds of formula (XX-I-2b), moietyWherein # represents the point of attachment to the rest of the molecule and is
In some embodiments, the compound of formula (XX) or the compound of formula (XX-I) is a compound of formula (XX-I-3):
or a pharmaceutically acceptable salt thereof;
wherein R isN、RY5、A13、R88And R89As defined in the compound of formula (XX);
R91aselected from the group consisting of: hydrogen, -OR91a-aand-NR91a-bR91a-c；
R91a-aSelected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group;
or R91a-aAnd RY5May together form a carbonyl (C ═ O) moiety; and is
R91a-bAnd R91a-cIndependently of each other selected from the group consisting of: hydrogen, C 1-C6Alkyl and C1-C6A haloalkyl group.
In some embodiments of compounds of formula (XX-I-3), RNIs hydrogen or C1-C6An alkyl group. In some embodiments of compounds of formula (XX-I-3), RNIs hydrogen.
In some embodiments of compounds of formula (XX-I-3), RY5Is hydrogen or C1-C6An alkyl group. In some embodiments of compounds of formula (XX-I-3), RY5Is hydrogen.
In some embodiments of compounds of formula (XX-I-3), R88Is hydrogen, C1-C6Alkyl or C1-C6A haloalkyl group. In some embodiments, R88Is hydrogen.
In some embodiments of compounds of formula (XX-I-3), R89Independently at each occurrence, selected from the group consisting of: hydrogen, halogen, C1-C6Alkyl and C1-C6A haloalkyl group. In some embodiments of compounds of formula (XX-I-3), R89Independently at each occurrence is hydrogen or halogen. In some embodiments, R89Independently at each occurrence is hydrogen, fluoro or chloro. In some embodiments, one R89Is chloro, and the remainder of R89The substituent is hydrogen.
In some embodiments of compounds of formula (XX-I-3), R91aIs hydrogen OR-OR91a-a. In some embodiments, R91aIs hydrogen. In some embodiments, R91ais-OR91a-aWherein R is91a-aSelected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group; or R 91a-aAnd RY5Together, may form a carbonyl (C ═ O) moiety. In some embodiments, R91ais-OR91a-aWherein R is91a-aIs hydrogen.
In some embodiments of compounds of formula (XX-I-3), A13Selected from the group consisting of: optionally substituted by one or more R95C substituted by substituents6-C14An aryl group; and optionally substituted with one or more R95A substituent-substituted 5-14 membered heteroaryl. In some embodiments, A13Is optionally substituted by one or more R95C substituted by substituents6-C14And (4) an aryl group. In some embodiments, A13Is optionally substituted by one or more R95C substituted by substituents6-C10And (4) an aryl group. In some embodiments, A13Selected from the group consisting of:
In some embodiments of compounds of formula (XX-I-3), A13Is optionally substituted by one or more R95A substituent-substituted 5-14 membered heteroaryl. In some embodiments, A13Is optionally substituted by one or more R95A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A13Selected from the group consisting of: where denotes the point of attachment to the rest of the molecule. In some embodiments, A13Is optionally substituted by one or more R95A substituent-substituted pyridyl group. In some embodiments, A13Is thatWhere denotes the point of attachment to the rest of the molecule. In some embodiments, A13Is optionally substituted by one or more A13A substituent-substituted quinolyl group. In some embodiments, A13Selected from the group consisting of:
In some embodiments of the compounds of formula (XX-I-3), moiety
In some embodiments, the compound of formula (XX) or the compound of formula (XX-I) is a compound of formula (XX-II-3):
or a pharmaceutically acceptable salt thereof;
wherein R isN、RY5、A13、R88And R89As defined in the compound of formula (XX);
R91aselected from the group consisting of: hydrogen, -OR91a-aand-NR91a-bR91a-c；
R91a-aSelected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group;
or R91a-aAnd RY5May together form a carbonyl (C ═ O) moiety; and is
R91a-bAnd R91a-cIndependently of each other selected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group.
In some embodiments of compounds of formula (XX-II-3), RNIs hydrogen or C1-C6An alkyl group. In some embodiments of compounds of formula (XX-II-3), RNIs hydrogen.
In some embodiments of compounds of formula (XX-II-3), R88Is hydrogen, C1-C6Alkyl or C1-C6A haloalkyl group. In some embodiments, R88Is hydrogen.
In some embodiments of compounds of formula (XX-II-3), R 89Independently at each occurrence selected from the group consisting ofGroup (2): hydrogen, halogen, C1-C6Alkyl and C1-C6A haloalkyl group. In some embodiments of compounds of formula (XX-II-3), R89Independently at each occurrence is hydrogen or halogen. In some embodiments, R89Independently at each occurrence is hydrogen, fluoro or chloro. In some embodiments, one R89Is chloro, and the remainder of R89The substituent is hydrogen.
In some embodiments of compounds of formula (XX-II-3), R91aIs hydrogen OR-OR91a-a. In some embodiments, R91aIs hydrogen. In some embodiments, R91ais-OR91a-aWherein R is91a-aSelected from the group consisting of: hydrogen, C1-C6Alkyl and C1-C6A haloalkyl group; or R91a-aAnd RY5Together, may form a carbonyl (C ═ O) moiety. In some embodiments, R91ais-OR91a-aWherein R is91a-aIs hydrogen.
In some embodiments of compounds of formula (XX-II-3), A13Selected from the group consisting of: optionally substituted by one or more R95C substituted by substituents6-C14An aryl group; and optionally substituted with one or more R95A substituent-substituted 5-14 membered heteroaryl. In some embodiments, A13Is optionally substituted by one or more R95C substituted by substituents6-C14And (4) an aryl group. In some embodiments, A13Is optionally substituted by one or more R95C substituted by substituents 6-C10And (4) an aryl group. In some embodiments, A13Selected from the group consisting of:
In some embodiments of compounds of formula (XX-II-3), A13Is optionally substituted by one or more R95A substituent-substituted 5-14 membered heteroaryl. In some embodiments, A 13Is optionally substituted by one or more R95A substituent-substituted 5-10 membered heteroaryl. In some embodiments, A13Selected from the group consisting of:
In some embodiments of compounds of formula (XX-II-3), moiety
In the description herein, it is to be understood that each description, variation, embodiment, or aspect for one section can be combined with each description, variation, embodiment, or aspect for the other section as if each combination of descriptions were specifically and individually listed. For example, provided herein with respect to X in formula (I) 1Each description, variation, embodiment or aspect of (a) may be related to m1、m2、n1、n2、p1、p2、q1、q2、r、s、X2、Y1、Y2、A1、A2、R1a、R1b、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6a、R6b、R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10b、R11a、R11b、R12aAnd R12bAs if each combination were specifically and individually listed, each description, variation, embodiment, or aspect combination of (a) and (b). It should also be understood that all descriptions, variations, embodiments, or aspects relating to formula (I) apply equally to the other formulas detailed herein, where applicable, and are described equally as if each description, variation, embodiment, or aspect relating to all of the formulas was individually and individually listed. For example, where applicable, all descriptions, variations, embodiments or aspects relating to formula (I) apply equally to any of formulae (1-1), (1-2), (1-3), (1-4), (2-2), (2-3), (2-4), (3-3), (3-4) and (4-4) detailed herein, and are described equally as if each description, variation, embodiment or aspect relating to all of the formulae were individually and individually listed. Similarly, provided herein with respect to X in formula (II)3Each description, variation, embodiment or aspect of (a) may be related to m3、n3、r2、s2、X4、Y3、Y4、A3、A4、R17a、R17b、R18a、R18b、R19a、R19b、R20a、R20b、R21a、R21b、R22a、R22b、R23a、R23b、R24a、R24b、R25aAnd R25bAs if each combination were specifically and individually listed, each description, variation, embodiment, or aspect combination of (a) and (b). It should also be understood that all descriptions, variations, embodiments, or aspects relating to formula (II), as applicable, apply equally to the other formulas detailed herein, and are described equally as if each description, variation, embodiment, or aspect relating to all of the formulas was individually and individually listed. For example, where applicable, all descriptions, variations, embodiments or aspects relating to formula (II) apply equally to any of formulae (III), (IV) and (V) detailed herein, and are described equally as if each description, variation, embodiment or aspect relating to all of the formulae were listed separately and individually. Similarly, provided herein with respect to X in formula (XX) 5Each description, variation, embodiment or aspect of (a) may relate to RN、Y5、RY5、m4、n5、p3、q4、r3、s3、A13、R84a、R84b、R85a、R85b、R86a、R86b、R87a、R87b、R88、R89、R90a、R90b、R91a、R91b、R92a、R92b、R93aAnd R93bAs if each combination were specifically and individually listed, each description, variation, embodiment, or aspect combination of (a) and (b). It should also be understood that all descriptions, variations, embodiments, or aspects relating to formula (XX) apply equally to the other formulas detailed herein, and are described equally, as if each description, variation, embodiment, or aspect relating to all of the formulas were individually and individually listed. For example, where applicable, all descriptions, variations, embodiments or aspects relating to formula (XX) apply equally to formulas (XX-I), (XX-II), (XX-I-1), (XX-Any of I-2), (XX-I-2b), (XX-I-3), and (XX-II-3), and are described equally as if each description, variation, embodiment, or aspect were individually and individually listed for all of the various formulas.
Also provided are salts, such as pharmaceutically acceptable salts, of the compounds mentioned herein. The present disclosure also includes any or all stereochemical forms of the compounds, including any enantiomeric or diastereomeric form, as well as any tautomeric or other form. Thus, if a particular stereochemical form, such as a particular enantiomeric or diastereomeric form, of a given compound is depicted, it is to be understood that any or all stereochemical forms, including any enantiomeric or diastereomeric form, of that compound, as well as any tautomer or any other form, are described herein and encompassed by the present invention.
The compounds detailed herein may be in purified form in one aspect and compositions comprising the compounds in purified form are detailed herein. Compositions, such as compositions comprising substantially pure compounds, comprising a compound or salt thereof as detailed herein are provided. In some embodiments, the composition containing a compound or salt thereof as detailed herein is in a substantially pure form. Unless otherwise specified, "substantially pure" is intended to mean that a composition contains no more than 35% of impurities, where the impurities represent compounds other than the compound or salt thereof that make up a substantial proportion of the composition. In some embodiments, a composition comprising a substantially pure compound or salt thereof is provided, wherein the composition contains no more than 25%, 20%, 15%, 10%, or 5% impurities. In some embodiments, a composition comprising a substantially pure compound or salt thereof is provided, wherein the composition contains or does not exceed 3%, 2%, 1%, or 0.5% impurities.
In some embodiments, a compound selected from the compounds in table 1, or a stereoisomer, tautomer, solvate, prodrug, or salt thereof, is provided. Although certain compounds described in table 1 are in specific stereoisomeric and/or non-stereochemical forms, it is to be understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomeric or other form of any one of the compounds in table 1 is also described herein.
TABLE 1
Pharmaceutical compositions and formulations
The present disclosure includes pharmaceutical compositions comprising any of the compounds detailed herein. Accordingly, the present disclosure includes pharmaceutical compositions comprising a compound or salt thereof as detailed herein and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt with an inorganic or organic acid. The pharmaceutical composition may be in a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or in a form suitable for administration by inhalation.
The compounds detailed herein may be in purified form in one aspect and compositions comprising the compounds in purified form are detailed herein. Compositions, such as compositions comprising substantially pure compounds, comprising a compound or salt thereof as detailed herein are provided. In some embodiments, the composition containing a compound or salt thereof as detailed herein is in a substantially pure form.
In one variation, the compounds herein are synthetic compounds prepared for administration to a subject. In another variation, a composition containing the compound in substantially pure form is provided. In another variation, the disclosure includes a pharmaceutical composition comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, a method of administering a compound is provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any of the compounds or forms thereof detailed herein.
The compounds or salts thereof detailed herein can be formulated for any useful delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compounds or salts thereof may be formulated in the presence of suitable carriers to provide delivery forms including, but not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, dragees, lozenges, gels, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (such as nasal sprays or inhalants), gels, suspensions (such as aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions, and elixirs.
One or several compounds or salts thereof as described herein can be used for the preparation of formulations, such as pharmaceutical formulations, by combining one or more compounds or salts thereof as active ingredient with a pharmaceutically acceptable carrier, such as the carriers mentioned above. The carrier can take a variety of forms depending on the therapeutic form of the system (e.g., transdermal patch versus oral tablet). In addition, the pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetters, emulsifiers, sweeteners, dyes, regulators and salts for adjusting the osmotic pressure, buffers, coating agents or antioxidants. Formulations containing the compounds may also contain other materials which have useful therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington's pharmaceutical sciences, Mack Publishing Company, Philadelphia, Pa., 20 th edition (2000), incorporated by reference herein.
The compounds described herein for administration to a subject may be in the form of recognized oral compositions such as tablets, coated tablets, and gel capsules, emulsions or suspensions in hard or soft shells. Examples of carriers that can be used in the preparation of such compositions are lactose, corn starch or derivatives thereof, talc, stearates or salts thereof and the like. Acceptable carriers for soft shell gel capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. In addition, the pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetters, emulsifiers, sweeteners, dyes, regulators and salts for adjusting the osmotic pressure, buffers, coating agents or antioxidants.
Any of the compounds described herein can be formulated into a tablet in any of the dosage forms described, for example, a compound described herein or a salt thereof can be formulated into a 10mg tablet.
Also described are compositions comprising the compounds provided herein. In one variation, the composition comprises the compound or salt thereof and a pharmaceutically acceptable carrier or excipient. In another variation, a composition comprising a substantially pure compound is provided. In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is used in the methods described herein. In some embodiments, the composition is used to treat a disease or disorder described herein.
Method of use and use
Compounds and compositions, as detailed herein, such as pharmaceutical compositions containing a compound of any formula provided herein or a salt thereof, and a pharmaceutically acceptable carrier or excipient, can be used in the administration and treatment methods provided herein. The compounds and compositions may also be used in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for performing quality control assays.
Provided herein is a method of treating a disease or disorder in a subject in need thereof, the method comprising administering a compound described herein, or any embodiment, variation, or aspect thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound, pharmaceutically acceptable salt or composition thereof is administered to the subject according to the dosages and/or methods of administration described herein.
It is believed that the compounds or salts thereof described herein and the compositions described herein are effective in treating a variety of diseases and disorders. In some embodiments, a compound described herein or a salt thereof or a composition described herein can be used in a method of treating a disease or disorder mediated by an Integrated Stress Response (ISR) pathway. In some embodiments, the disease or disorder is mediated by eukaryotic translation initiation factor 2 a (eIF2 a) or eukaryotic translation initiation factor 2B (eIF 2B). In some embodiments, the disease or disorder is mediated by phosphorylation of eIF2 a and/or guanine nucleotide exchange factor (GEF) activity of eIF 2B.
In some embodiments, a compound described herein or a salt thereof or a composition described herein may be used in a method of treating a disease or disorder, wherein the disease or disorder is a neurodegenerative disease, an inflammatory disease, an autoimmune disease, a metabolic syndrome, a cancer, a vascular disease, a musculoskeletal disease (such as myopathy), an ocular disease, or a genetic disorder.
In some embodiments, the disease or disorder is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is a white matter ablative disease, childhood ataxia with decreased CNS myelination, a dysnoesia syndrome, alzheimer's disease, a prion disease, Creutzfeldt-Jakob disease, parkinson's disease, an Amyotrophic Lateral Sclerosis (ALS) disease, pemphigus disease (Pelizaeus-Merzbacher disease), a cognitive disorder, traumatic brain injury, post-operative cognitive dysfunction (PCD), neurootological syndrome, hearing loss, huntington's disease, stroke, chronic traumatic brain disorder, spinal cord injury, dementia, frontotemporal dementia (FTD), depression, or a social behavior disorder. In some embodiments, the cognitive disorder is caused by aging, radiation, sepsis, a seizure, a heart attack, heart surgery, liver failure, hepatic encephalopathy, anesthesia, brain injury, brain surgery, ischemia, chemotherapy, cancer treatment, a major disease, concussion, fibromyalgia, or depression. In some embodiments, the neurodegenerative disease is alzheimer's disease. In some embodiments, the neurodegenerative disease is age-related cognitive disorder. In some embodiments, the neurodegenerative disease is traumatic brain injury.
In some embodiments, a compound described herein or a salt thereof or a composition described herein can be used in a method of treating alzheimer's disease. In some embodiments, neurodegeneration, cognitive disorders, and/or amyloidosis are reduced.
In some embodiments, the disease or disorder is an inflammatory disease. In some embodiments, the inflammatory disease is arthritis, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, asthma, allergic asthma, bronchial asthma, tuberculosis, chronic tracheal disorder, cystic fibrosis, glomerulonephritis, membranous nephropathy, sarcoidosis, vasculitis, ichthyosis, graft rejection, interstitial cystitis, atopic dermatitis, or inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn's disease, ulcerative colitis, or celiac disease.
In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the autoimmune disease is systemic lupus erythematosus,
In some embodiments, the disease or disorder is metabolic syndrome. In some embodiments, the metabolic syndrome is alcoholic fatty liver, obesity, glucose intolerance, insulin resistance, hyperglycemia, fatty liver, dyslipidemia, hyperlipidemia, hyperhomocysteinemia, or
In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is pancreatic cancer, breast cancer, renal cancer, bladder cancer, prostate cancer, testicular cancer, urothelial cancer, endometrial cancer, ovarian cancer, cervical cancer, renal cancer, esophageal cancer, gastrointestinal stromal tumor (GIST), multiple myeloma, secretory cell cancer, thyroid cancer, gastrointestinal cancer, chronic myelogenous leukemia, hepatocellular carcinoma, colon cancer, melanoma, malignant glioma, glioblastoma multiforme, astrocytoma, ganglioblastoma of cerebellar dysplasia, ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, ductal adenocarcinoma, adenosquamous carcinoma, nephroblastoma, acinar cell carcinoma, neuroblastoma, or lung cancer. In some embodiments, the secretory cell cancer is non-Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, Monoclonal Gammopathy of Unknown Significance (MGUS), plasmacytoma, lymphoplasmacytoma, or acute lymphoblastic leukemia.
In some embodiments, the disease or disorder is a musculoskeletal disease (e.g., myopathy). In some embodiments, the musculoskeletal disease is a myopathy, a muscular dystrophy, a muscular atrophy, a muscle wasting, or a sarcopenia. In some embodiments, the muscular dystrophy is Duchenne Muscular Dystrophy (DMD), Becker's disease, myotonic dystrophy, X-linked dilated cardiomyopathy, Spinal Muscular Atrophy (SMA), or schmidt type Metaphyseal Chondrodysplasia (MCDS). In some embodiments, the myopathy is skeletal muscle atrophy. In some embodiments, the musculoskeletal disease (e.g., skeletal muscle atrophy) is caused by aging, chronic disease, stroke, malnutrition, bed rest, orthopedic injury, bone fracture, cachexia, hunger, heart failure, obstructive pulmonary disease, renal failure, Acquired Immune Deficiency Syndrome (AIDS), sepsis, an immune disorder, cancer, ALS, burns, denervation, diabetes, muscle disuse, limb immobilization, mechanical unloading, myositis, or malnutrition.
In some embodiments, the disease or disorder is a genetic disorder, such as down's syndrome or MEHMO syndrome (mental retardation, seizures, hypogonadism, microcephaly, and obesity).
In some embodiments, a compound described herein or a salt thereof or a composition described herein may be used in a method of treating a musculoskeletal disease. In some embodiments, skeletal muscle mass, quality, and/or strength is increased. In some embodiments, muscle protein synthesis is increased. In some embodiments, skeletal muscle fiber atrophy is inhibited.
In some embodiments, the disease or disorder is a vascular disease. In some embodiments, the vascular disease is atherosclerosis, abdominal aortic aneurysm, carotid artery disease, deep vein thrombosis, Buerger's disease, chronic venous hypertension, vascular calcification, telangiectasia, or lymphedema.
In some embodiments, the disease or disorder is an ocular disease. In some embodiments, the ocular disease is glaucoma, age-related macular degeneration, inflammatory retinal disease, retinal vascular disease, diabetic retinopathy, uveitis, rosacea, Sjogren's syndrome, or neovascularization in proliferative retinopathy.
In some embodiments, a method of suppressing an ISR path is provided herein. It is believed that the compounds described herein or salts thereof and the compositions described herein are effective in inhibiting the ISR pathway. In some embodiments, the method of inhibiting an ISR pathway comprises inhibiting an ISR pathway in a cell by administering or delivering a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, to the cell. In some embodiments, the method of inhibiting an ISR pathway comprises inhibiting an ISR pathway in a subject by administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Inhibition of the ISR pathway can be determined by methods known in the art, such as western blotting, immunohistochemistry, or reporter cell line assays.
In some embodiments, inhibition of the ISR pathway comprises binding eIF 2B. In some embodiments, the inhibition of the ISR pathway comprises increasing protein translation, increasing guanine nucleotide exchange factor GEF) activity of eIF2B, delaying or preventing apoptosis of the cell, and/or inhibiting translation of one or more mrnas comprising a 5 'untranslated region (5' UTR) comprising at least one upstream open reading frame (uORF).
In some embodiments, provided herein are methods of increasing protein production using a compound or salt described herein. Protein production is increased relative to the same conditions without the compound or salt. Protein production can be increased in vivo or in vitro. For example, the production of proteins in vivo can be increased by administering the compound or salt to an individual. In some embodiments, the production of the protein is increased in vitro using the compound or salt with a cell-free protein synthesis system (CFPS) or a cell-based protein expression system. The protein produced may be a heterologous protein (e.g., a recombinant protein) or a native protein. Heterologous proteins can be produced using recombinant nucleic acids encoding the proteins. In some embodiments, the protein produced is an antibody or fragment thereof. Other exemplary proteins may include, but are not limited to, enzymes, allergic peptides or proteins (e.g., for use as vaccines), recombinant proteins, cytokines, peptides, hormones, Erythropoietin (EPO), interferons, granulocyte colony stimulating factor (G-CSF), anticoagulant proteins, and clotting factors. Increased protein production can be determined by methods known in the art, such as western blot immunohistochemistry.
Cell-free protein synthesis (CFPS) systems are generally known and include cellular machinery for expressing proteins in an in vitro environment. In some embodiments, the CFPS system comprises a cellular extract (e.g., a eukaryotic cell extract) that includes a protein expression machinery. In some embodiments, the cellular machinery in the CFPS system comprises eukaryotic cellular machinery, such as eukaryotic initiation factor 2(eIF2) and/or eukaryotic initiation factor 2B (eIF2B), or one or more subunits thereof.
In some embodiments, there is a cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2(eIF2) and a nucleic acid encoding a protein and a compound or salt as described herein. In some embodiments, the protein is an antibody or fragment thereof. Other exemplary proteins may include, but are not limited to, enzymes, allergic peptides or proteins (e.g., for use as vaccines), recombinant proteins, cytokines, peptides, hormones, Erythropoietin (EPO), interferons, granulocyte colony stimulating factor (G-CSF), anticoagulant proteins, and clotting factors. In some embodiments, the CFPS system comprises a cell
In some embodiments, there is a method of producing a protein, the method comprising contacting a cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2(eIF2) and a nucleic acid encoding the protein with a compound as described herein or a salt thereof. In some embodiments, the protein is an antibody or fragment thereof. Other exemplary proteins may include, but are not limited to, enzymes, allergic peptides or proteins (e.g., for use as vaccines), recombinant proteins, cytokines, peptides, hormones, Erythropoietin (EPO), interferons, granulocyte colony stimulating factor (G-CSF), anticoagulant proteins, and clotting factors. In some embodiments, the CFPS system comprises a cell
In some embodiments, there is a method of producing a protein, the method comprising contacting a eukaryotic cell comprising a nucleic acid encoding the protein with a compound or salt as described herein. In some embodiments, the method comprises culturing the cell in an in vitro medium comprising the compound or salt. In some embodiments, the nucleic acid encoding the protein is a recombinant nucleic acid. In some embodiments, the eukaryotic cell is a Human Embryonic Kidney (HEK) cell or a Chinese Hamster Ovary (CHO) cell. In other embodiments, the eukaryotic cell is a yeast cell (such as Saccharomyces cerevisiae (Saccharomyces cerevisiae) or Pichia pastoris (Pichia pastoris)), a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell (such as a HeLa cell), a baby hamster kidney cell (such as a BHK21 cell), a murine myeloma cell (such as NSO or Sp2/0 cells), an HT-1080 cell, a per.c6 cell, a plant cell, a hybridoma cell, or a human blood-derived leukocyte. In some embodiments, the protein is an antibody or fragment thereof. Other exemplary proteins may include, but are not limited to, enzymes, allergic peptides or proteins (e.g., for use as vaccines), recombinant proteins, cytokines, peptides, hormones, Erythropoietin (EPO), interferons, granulocyte colony stimulating factor (G-CSF), anticoagulant proteins, and clotting factors. In some embodiments, the method comprises purifying the protein.
In some embodiments, there is a method of culturing a eukaryotic cell containing a nucleic acid encoding a protein, the method comprising contacting the eukaryotic cell with an in vitro culture medium comprising a compound or salt as described herein. In some embodiments, the nucleic acid encoding the protein is a recombinant nucleic acid. In some embodiments, the eukaryotic cell is a Human Embryonic Kidney (HEK) cell or a Chinese Hamster Ovary (CHO) cell. In other embodiments, the eukaryotic cell is a yeast cell (e.g., saccharomyces cerevisiae or pichia pastoris), a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell (e.g., HeLa cell), a baby hamster kidney cell (e.g., BHK21 cell), a murine myeloma cell (e.g., NSO or Sp2/0 cell), an HT-1080 cell, a per.c6 cell, a plant cell, a hybridoma cell, or a human blood-derived leukocyte. In some embodiments, the protein is an antibody or fragment thereof. Other exemplary proteins may include, but are not limited to, enzymes, allergic peptides or proteins (e.g., for use as vaccines), recombinant proteins, cytokines, peptides, hormones, Erythropoietin (EPO), interferons, granulocyte colony stimulating factor (G-CSF), anticoagulant proteins, and clotting factors. In some embodiments, the method comprises purifying the protein.
In some embodiments, there is an in vitro cell culture medium comprising a compound or salt described herein and nutrients for cell growth. In some embodiments, the culture medium comprises a eukaryotic cell comprising a nucleic acid encoding a protein. In some embodiments, the medium further comprises a compound for inducing protein expression. In some embodiments, the nucleic acid encoding the protein is a recombinant nucleic acid. In some embodiments, the protein is an antibody or fragment thereof. Other exemplary proteins may include, but are not limited to, enzymes, allergic peptides or proteins (e.g., for use as vaccines), recombinant proteins, cytokines, peptides, hormones, Erythropoietin (EPO), interferons, granulocyte colony stimulating factor (G-CSF), anticoagulant proteins, and clotting factors. In some embodiments, the eukaryotic cell is a Human Embryonic Kidney (HEK) cell or a Chinese Hamster Ovary (CHO) cell. In other embodiments, the eukaryotic cell is a yeast cell (e.g., saccharomyces cerevisiae or pichia pastoris), a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell (e.g., HeLa cell), a baby hamster kidney cell (e.g., BHK21 cell), a murine myeloma cell (e.g., NSO or Sp2/0 cell), an HT-1080 cell, a per.c6 cell, a plant cell, a hybridoma cell, or a human blood-derived leukocyte.
In some embodiments, provided herein is a method of increasing protein translation in a cell or cell-free expression system. In some embodiments, the cells are subjected to stress prior to administration of the compound, salt, or composition. In some embodiments, protein translation is increased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 100%, 125%, 150%, 175%, 200%, 250%, or 300% or more. In some embodiments, protein translation is increased by about 10% to about 300% (such as about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 125%, about 125% to about 150%, about 150% to about 175%, about 175% to about 200%, about 200% to about 250%, or about 250% to about 300%). In some embodiments, protein translation is increased as compared to prior to administration of the compound, salt, or composition. In some embodiments, protein translation is increased compared to an unstressed cell, which is a fundamental condition for a cell that has not been subjected to a particular stress that activates ISR. In some embodiments, protein translation is increased compared to stress cells in which ISRs are active.
Some of the compounds described herein increase protein synthesis in cells under both ISR-stressed and non-ISR-stressed conditions without completely inhibiting ATF4 translation. Exemplary compounds include
In some embodiments, provided herein is a method of increasing protein translation in a cell. In some embodiments, the cells are subjected to stress prior to administration of the compound, salt, or composition. In some embodiments, protein translation is increased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 100%, 125%, 150%, 175%, 200%, 250%, or 300% or more. In some embodiments, protein translation is increased as compared to prior to administration of the compound, salt, or composition. In some embodiments, protein translation is increased compared to an unstressed cell, which is a fundamental condition for a cell that has not been subjected to a particular stress that activates ISR. In some embodiments, protein translation is increased compared to stress cells in which ISRs are active.
In some embodiments, provided herein is a method of increasing guanine nucleotide exchange factor (GEF) activity of eIF2B in a cell. In some embodiments, provided herein is a method of delaying or preventing apoptosis of a cell. In some embodiments, provided herein is a method of inhibiting translation of one or more mrnas comprising a 5 'untranslated region (5' UTR) comprising at least one upstream open reading frame (uORF) encoding a protein with translational preference, including but not limited to ATF4, ATF2, ATF5, CHOP, GADD34, BACE-1, C/ebpa, or MAP1LC 3B. In some embodiments, the mRNA encodes ATF4, BACE-1, GADD34, or CHOP. In some embodiments, the mRNA encodes ATF 4.
In some embodiments, the expression of ATF4, BACE-1, GADD34, or CHOP is inhibited. In some embodiments, expression of ATF4 is inhibited. In some embodiments, expression of a β is inhibited. ATF4 increased expression of GADD45A, CDKN1A and EIF4EBP1, among others, GADD45A, CDKN1A and EIF4EBP1 encode DDIT-1, p21 and 4E-BP1, respectively. These proteins induce musculoskeletal diseases (e.g., skeletal muscle atrophy) and can be regulated by inhibiting the expression of ATF 4. Thus, in some embodiments, expression of one or more of CDKN1A, GADD45A, or EIF4EBP1 is inhibited.
In some embodiments, the compound, salt or composition thereof inhibits translation of one or more mrnas, ICs thereof50Values of less than about 1 μ M, such as less than about 750nM, 600nM, 500nM, 300nM, 200nM, 100nM, 80nM, 60nM, 40nM, 25nM or less, the one or more mRNAs comprising a 5 'untranslated region (5' UTR) comprising at least one upstream open reading frame (uORF). In some embodiments, the compound, salt or composition thereof inhibits translation of one or more mrnas, ICs thereof50Values are between about 1nM and 1 μ M, such as between about 10nM and 600nM, between 15nM and 200nM, or between 20nM and 180nM, the one or more mRNAs comprising a 5 'untranslated region (5' UTR) comprising at least one upstream open reading frame (uORF).
In some embodiments, the compound, salt or composition thereof inhibits the expression of ATF4, its IC50Values are less than about 1 μ M, such as less than about 750nM, 600nM, 500nM, 300nM, 200nM, 100nM, 80nM, 60nM, 40nM, 25nM or less. In some embodiments, the compound, salt or composition thereof inhibits the expression of ATF4, its IC50Values are between about 1nM and 1 μ M, such as between about 2nM and 800nM, between 10nM and 600nM, between 15nM and 200nM, or between 20nM and 180 nM.
In some aspects, half maximal Inhibitory Concentration (IC)50) Is a measure of the effectiveness of a substance to inhibit a particular biological or biochemical function. In some aspects, the IC50Is an indication of a given biological process or component of a process such as an enzyme, cell receptorOr a quantitative measure of the amount of inhibitor required for half inhibition of the microorganism. Determination of IC in vitro and in vivo50Methods of (a) are known in the art.
In some embodiments, the subject is a mammal. In some embodiments, the subject is a primate, bovine, ovine, porcine, equine, canine, feline, rabbit, or rodent. In some embodiments, the individual is a human. In some embodiments, the subject has any of the diseases or disorders disclosed herein. In some embodiments, the subject is at risk of developing any of the diseases or disorders disclosed herein.
In some embodiments, the individual is a human. In some embodiments, the human is at least about or any of about 21 years, 25 years, 30 years, 35 years, 40 years, 45 years, 50 years, 55 years, 60 years, 65 years, 70 years, 75 years, 80 years, or 85 years old. In some embodiments, the person is a child. In some embodiments, the human is less than about or about any of 21 years, 18 years, 15 years, 12 years, 10 years, 8 years, 6 years, 5 years, 4 years, 3 years, 2, or 1 years of age.
Also provided herein is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament. In some embodiments, the manufacture of a medicament is for treating a disorder or disease described herein. In some embodiments, the manufacture of a medicament is for the prevention and/or treatment of a disorder or disease mediated by an ISR pathway. In some embodiments, the manufacture of a medicament is for the prevention and/or treatment of a disorder or disease mediated by eIF2 a or eIF 2B. In some embodiments, the medicament is for use in the prevention and/or treatment of a disorder or disease mediated by eIF2 α phosphorylation and/or GEF activity of eIF 2B.
Combination of
In certain aspects, a compound described herein is administered to an individual in combination with one or more additional agents that treat a disease. For example, in some embodiments, an effective amount of the compound is administered to an individual in combination with one or more additional anti-cancer agents to treat cancer.
In some embodiments, the activity of the additional agent (e.g., the additional anti-cancer agent) is inhibited by the activated ISR pathway. An ISR inhibitor, such as one of the compounds described herein, may inhibit the ISR pathway to enhance the function of additional agents. For example, certain BRAF inhibitors, such as vemurafenib (vemurafenib) or dabrafenib (dabrafenib), activate the ISR pathway in BRAF mutant melanoma cells, such as BRAF with the V600F mutation, through expression of ATF 4. In some embodiments, there is a method of treating cancer comprising administering to an individual having cancer an effective amount of a compound described herein and an effective amount of a BRAF inhibitor. In some embodiments, there is a method of treating BRAF mutant melanoma comprising administering to an individual having BRAF mutant melanoma an effective amount of a compound described herein and an effective amount of a BRAF inhibitor. In some embodiments, there is a method of treating BRAF mutant melanoma comprising administering to an individual having BRAF mutant melanoma an effective amount of a compound described herein and an effective amount of vemurafenib or dabrafenib.
As another example, cancers are treated with certain anti-cancer agents, such as ubiquitin-proteasome pathway inhibitors (e.g., bortezomib), Cox-2 inhibitors (e.g., celecoxib), platinum-based anti-neoplastic agents (e.g., cisplatin), anthracyclines (e.g., doxorubicin), or topoisomerase inhibitors (e.g., etoposide), although these anti-cancer agents may have limited function against solid tumors.
In some embodiments, there is a method of treating a refractory cancer (such as a solid tumor) in an individual, the method comprising administering to the individual an effective amount of a compound described herein and an effective amount of an anti-cancer agent. In some embodiments, there is a method of treating a refractory cancer (such as a solid tumor) in an individual, the method comprising administering to the individual an effective amount of a compound described herein and an effective amount of a ubiquitin-proteasome pathway inhibitor (e.g., bortezomib), a Cox-2 inhibitor (e.g., celecoxib), a platinum antineoplastic agent (e.g., cisplatin), an anthracycline (e.g., doxorubicin), or a topoisomerase inhibitor (e.g., etoposide). In some embodiments, the refractory cancer is breast cancer. In some embodiments, the refractory cancer is melanoma.
In some embodiments, the compounds described herein are used in combination with one or more anti-cancer agents, such as an anti-tumor agent, an immune checkpoint inhibitor, or any other suitable anti-cancer agent to treat cancer. Exemplary immune checkpoint inhibitors include anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-GITR antibodies, anti-OX-40 antibodies,
In addition, ATF 4-mediated CHOP expression was shown to regulate the function and accumulation of myeloid-derived suppressor cells (MDSCs) in tumors. MDSCs in tumors attenuate the ability to stimulate T cell function and reduce the anti-tumor or anti-cancer response. Certain immunotherapeutic agents (such as anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-GITR antibodies, anti-OX-40 antibodies,
Dosage and method of administration
The dosage of a compound administered to an individual (e.g., a human) can vary with the particular compound or salt thereof, the method of administration, and the particular disease being treated, e.g., the type and stage of cancer. In some embodiments, the amount of the compound or salt thereof is a therapeutically effective amount.
In one aspect, an effective amount of a compound can be a dose between about 0.01 and about 100 mg/kg. An effective amount or dose of a compound of the present disclosure can be determined by conventional methods, such as modeling, dose escalation, or clinical trials, taking into account conventional factors, such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the health, condition, and weight of the subject. Exemplary dosage ranges are about 0.7mg to 7g per day, or about 7mg to 350mg per day, or about 350mg to 1.75g per day, or about 1.75 to 7g per day.
In one aspect, any of the methods provided herein can comprise administering to the subject a pharmaceutical composition comprising an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.
The compounds or compositions provided herein can be administered to an individual according to an effective dosage regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, and in some variations, for a duration that can last the life of the individual. In one variation, the compound is administered on a daily or intermittent schedule. The compound may be administered to the individual continuously (e.g., at least once per day) over a period of time. The frequency of administration may also be less than once a day, for example about once a week. The frequency of administration may be more than once per day, for example two or three times per day. The frequency of administration may also be intermittent, including a 'drug holiday' (e.g., once daily for 7 days followed by 7 days off, repeated for any 14 day period, such as about 2 months, about 4 months, about 6 months, or longer). Any frequency of administration can be employed with any of the compounds described herein and any of the dosages described herein.
Article and kit
The present disclosure additionally provides an article of manufacture comprising a compound described herein or a salt thereof, a composition described herein, or one or more unit doses described herein in a suitable package. In certain embodiments, the article is used in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, and the like. The article may be further sterilized and/or sealed.
The present disclosure also provides kits for performing the methods of the present disclosure, the kits comprising one or more compounds described herein, or compositions comprising compounds described herein. The kit may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a salt thereof. The kit may be for any one or more of the uses described herein, and thus, may contain instructions for treating any of the diseases described herein, e.g., for treating cancer.
The kit will generally comprise suitable packaging. A kit may comprise one or more containers containing any of the compounds described herein. Each component (if multiple components are present) may be packaged in separate containers, or some components may be combined in one container, where cross-reactivity and shelf-life permits.
The kits may be in unit dosage form, in bulk packaging (e.g., multiple dose packaging), or in sub-unit dosage form. For example, provided kits may contain sufficient doses of the compounds disclosed herein and/or additional pharmaceutically active compounds useful for the diseases detailed herein to provide effective treatment to an individual for an extended period of time, such as any one of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months or longer. Kits may also include a plurality of unit doses of the compound and instructions for use, and packaged in amounts sufficient for storage and use in pharmacies (e.g., hospital pharmacies and brewing pharmacies).
The kit may optionally include a set of instructions, typically written, however, an electronic storage medium (e.g., a magnetic or optical disk) containing instructions relating to the use of the components of the disclosed methods is also acceptable. The instructions included in the kit generally include information about the components and their administration to the individual.
General synthetic method
The compounds of the present disclosure can be prepared by a variety of methods as generally described below and, more particularly, in the examples below (as provided in the schemes below). In the following description of the process, each symbol, when used in the various formulae depicted, is understood to represent the groups described herein above with respect to those formulae.
When it is desired to obtain a particular enantiomer of a compound, this may be achieved from the corresponding enantiomeric mixture using conventional procedures suitable for the separation or resolution of the enantiomers. Thus, for example, diastereomeric derivatives may be prepared by reacting a mixture of enantiomers, such as a racemate, with an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization, and the desired enantiomer recovered. In another resolution method, chiral high performance liquid chromatography can be used to separate the racemates. Alternatively, where necessary, specific enantiomers can be obtained in one of the described processes by using appropriate chiral intermediates.
Chromatography, recrystallization, and other conventional separation procedures may also be used for intermediates or final products where it is desired to obtain a particular isomer of a compound or otherwise purify the reaction product.
Solvates and/or polymorphs of the compounds provided herein, or salts thereof, are also contemplated. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are typically formed during the crystallization process. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include different crystal packing arrangements of compounds of the same elemental composition. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability and/or solubility. Various factors may cause a single crystal form to dominate, such as recrystallization solvent, crystallization rate, and storage temperature.
Chromatography, recrystallization, and other conventional separation procedures may also be used for intermediates or final products where it is desired to obtain a particular isomer of a compound or otherwise purify the reaction product.
The following schemes will depict general methods of making compounds according to the present disclosure.
The compounds disclosed herein, such as compounds of formulas (C-3), (C-4), (C-5), and (C-6), for example, can be synthesized according to the general methods described in the schemes above. The compound of formula (C-1) is reacted with a carboxylic acid (B-1a) or a carboxylic acid derivative (e.g., an acid chloride of formula (B-1B)) under suitable conditions to give a compound of formula (C-2). The compound of formula (C-2) may first be optionally deprotected and then reacted with a carboxylic acid (B-2a) or carboxylic acid derivative (e.g., acid chloride of formula (B-2B)) to give a compound of formula (C-3). The compound of formula (C-2) may be first optionally deprotected and then reacted with an oxetane derivative of formula (B-3) to give a compound of formula (C-4). The compound of formula (C-2) may be optionally deprotected first and then reacted with a haloalkyl derivative, such as a bromoalkyl compound of formula (B-4), to give a compound of formula (C-5). The compound of formula (C-2) may first be optionally deprotected and then reacted with a carboxylic acid (B-5a) or carboxylic acid derivative (e.g., acid chloride of formula (B-5B)) to give a compound of formula (C-6).
The compounds disclosed herein, such as compounds of formulas (D-3), (D-4), (D-5), and (D-6), can be synthesized, for example, according to the general methods described in the schemes above. The compound of formula (D-1) is reacted with a carboxylic acid (B-1a) or a carboxylic acid derivative (e.g., an acid chloride of formula (B-1B)) under suitable conditions to obtain a compound of formula (D-2). The compound of formula (D-2) may first be optionally deprotected and then reacted with a carboxylic acid (B-2a) or carboxylic acid derivative (e.g., acid chloride of formula (B-2B)) to give a compound of formula (D-3). The compound of formula (D-2) may be first optionally deprotected and then reacted with an oxetane derivative of formula (B-3) to give a compound of formula (D-4). The compound of formula (D-2) may be optionally deprotected first and then reacted with a haloalkyl derivative, such as a bromoalkyl compound of formula (B-4), to give a compound of formula (D-5). The compound of formula (D-2) may be first optionally deprotected and then reacted with a carboxylic acid (B-5a) or a carboxylic acid derivative (e.g., an acid chloride of formula (B-5B)) to give a compound of formula (D-6).
The compounds disclosed herein, such as compounds of formulas (E-3), (E-4), (E-5), and (E-6), for example, can be synthesized according to the general methods described in the schemes above. The compound of formula (E-1) is reacted with a carboxylic acid (B-1a) or a carboxylic acid derivative (e.g., an acid chloride of formula (B-1B)) under suitable conditions to obtain a compound of formula (E-2). The compound of formula (E-2) may be first optionally deprotected and then reacted with a carboxylic acid (B-2a) or a carboxylic acid derivative (e.g., an acid chloride of formula (B-2B)) to give a compound of formula (E-3). The compound of formula (E-2) may be first optionally deprotected and then reacted with an oxetane derivative of formula (B-3) to give a compound of formula (E-4). The compound of formula (E-2) may be optionally deprotected first and then reacted with a haloalkyl derivative, such as a bromoalkyl compound of formula (B-4), to give a compound of formula (E-5). The compound of formula (E-2) may be first optionally deprotected and then reacted with a carboxylic acid (B-5a) or a carboxylic acid derivative (e.g., an acid chloride of formula (B-5B)) to give a compound of formula (E-6).
The compounds disclosed herein, such as compounds of formulas (F-3), (F-4), (F-5), and (F-6), for example, can be synthesized according to the general methods described in the schemes above. The compound of formula (F-1) is reacted with a carboxylic acid (B-1a) or a carboxylic acid derivative (e.g., an acid chloride of formula (B-1B)) under suitable conditions to give a compound of formula (F-2). The compound of formula (F-2) may first be optionally deprotected and then reacted with a carboxylic acid (B-2a) or carboxylic acid derivative (e.g., acid chloride of formula (B-2B)) to give a compound of formula (F-3). The compound of formula (F-2) may be first optionally deprotected and then reacted with an oxetane derivative of formula (B-3) to give a compound of formula (F-4). The compound of formula (F-2) may first be optionally deprotected and then reacted with a haloalkyl derivative, such as a bromoalkyl compound of formula (B-4), to give a compound of formula (F-5). The compound of formula (F-2) may first be optionally deprotected and then reacted with a carboxylic acid (B-5a) or a carboxylic acid derivative (e.g., an acid chloride of formula (B-5B)) to give a compound of formula (F-6).
The compounds disclosed herein, such as compounds of formulas (G-3), (G-4), (G-5), and (G-6), for example, can be synthesized according to the general methods described in the schemes above. The compound of formula (G-1) is reacted with a carboxylic acid (B-1a) or a carboxylic acid derivative (e.g., an acid chloride of formula (B-1B)) under suitable conditions to give a compound of formula (G-2). The compound of formula (G-2) may first be optionally deprotected and then reacted with a carboxylic acid (B-2a) or a carboxylic acid derivative (e.g., an acid chloride of formula (B-2B)) to give a compound of formula (G-3). The compound of formula (G-2) may be first optionally deprotected and then reacted with an oxetane derivative of formula (B-3) to give a compound of formula (G-4). The compound of formula (G-2) may be optionally deprotected first and then reacted with a haloalkyl derivative, such as a bromoalkyl compound of formula (B-4), to give a compound of formula (G-5). The compound of formula (G-2) may be first optionally deprotected and then reacted with a carboxylic acid (B-5a) or a carboxylic acid derivative (e.g., an acid chloride of formula (B-5B)) to give a compound of formula (G-6).
Illustrative examples
The following examples are presented to represent some aspects of the invention.