Condensed heterocyclic derivatives as Bcl-2 inhibitors for the treatment of neonatal diseases
阅读说明：本技术 作为治疗新生性疾病的Bcl-2抑制剂的缩合杂环衍生物 (Condensed heterocyclic derivatives as Bcl-2 inhibitors for the treatment of neonatal diseases ) 是由 Y.陈 Y.娄 于 2018-08-22 设计创作，主要内容包括：本公开内容包括式(A)的化合物：<Image he="387" wi="700" file="DDA0002451631090000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中本文中限定R<Sub>1</Sub>、R<Sub>2</Sub>、R<Sub>3</Sub>、R<Sub>4</Sub>、R<Sub>5</Sub>、R<Sub>6</Sub>、R<Sub>7</Sub>、R<Sub>8</Sub>、R<Sub>9</Sub>、R<Sub>10</Sub>、R<Sub>11</Sub>和R<Sub>12</Sub>、j、k、m、n、Y、W、W<Sub>1</Sub>、W<Sub>2</Sub>、W<Sub>3</Sub>、V、L、Z<Sub>1</Sub>、Q<Sub>1</Sub>、Q<Sub>2</Sub>、Q<Sub>3</Sub>和Q<Sub>4</Sub>。还公开了使用这些化合物治疗新生性疾病、自身免疫性疾病或神经变性性疾病的方法。(In the present disclosureA compound comprising formula (A): wherein R is defined herein 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 And R 12 、j、k、m、n、Y、W、W 1 、W 2 、W 3 、V、L、Z 1 、Q 1 、Q 2 、Q 3 And Q 4 . Also disclosed are methods of using these compounds to treat neonatal, autoimmune or neurodegenerative diseases.)
1. A compound of formula (a) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof:
wherein
Q1Is 7-membered heterocycloalkyl, 7-membered heterocycloalkenyl or 7-membered heteroaryl;
Q2is aryl or heteroaryl;
Q3is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;
Q4is that
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11And R12Each independently H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halogen, nitro, oxo, cyano, ORa、SRaalkyl-Ra、NH(CH2)pRa、C(O)Ra、S(O)Ra、SO2Ra、C(O)ORa、OC(O)Ra、NRbRc、P(O)RbRcalkyl-P (O) RbRc、C(O)N(Rb)Rc、N(Rb)C(O)Rc、S(O)(＝N(Rb))Rc、-N＝S(O)RbRc、SO2N(Rb)RcOr N (R)b)SO2RcWherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are optionally substituted with one or more RdSubstitution;
Ra、Rb、Rcand RdIndependently H, D, alkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, ═ O, C (O) NHOH, C (O) OH, C (O) NH2Alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally substituted with one or more ReSubstitution;
Reh, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, ═ O, C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Z1is a bond, (CH)2)p、N(H)、O、S、C(O)、S(O2)、OC(O)、C(O)O、OSO2、S(O2)O、C(O)S、SC(O)、C(O)C(O)、C(O)N(H)、N(H)C(O)、S(O2)N(H)、N(H)S(O2)、OC(O)O、OC(O)S、OC(O)N(H)、N(H)C(O)O、N(H)C(O)S、N(H)C(O)N(H)、(CH2)pN(H)(CH2)q、(CH2)pN(H)C(O)(CH2)q、(CH2)pC(O)N(H)(CH2)q、OC(O)N(H)(CH2)p+1N(H)(CH2)qA divalent alkenyl group, or a divalent alkynyl group;
l is a bond, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more RdSubstitution;
Y、W、W1and W2Each independently is CH or N;
W3is O or N (R)a)；
V is N, C, or CH;
R9two of the groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, where R9Said cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more RdSubstitution;
R2two of the groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, where R2Said cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more RdSubstitution;
R10two of the groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, where R10Said cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more RdSubstitution;
R11and R12The groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, wherein R11Or R12Said cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more RdSubstitution;
R10and R2The groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, wherein R10Or R2Said cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more RdSubstitution;
R4and-Z1-L-R6The groups, together with the atoms to which they are attached, may optionally form a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl group, wherein R4Said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl of (a) is optionally substituted with one or more RdSubstitution;
Rband RcThe groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, wherein RbAnd RcSaid cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more ReSubstitution;
Rdtwo of the groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, where RdSaid cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more ReSubstitution;
Retwo of the groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, where ReSaid cycloalkyl or heterocycloalkyl group of (a) is optionally substituted with one or more groups selected from the group consisting of: H. d, alkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, c (o) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
j and k are each independently 0, 1,2, 3,4,5,6, 7, or 8; and is
m, n, p, q, and r are each independently 0, 1,2, 3, or 4.
2. A compound according to claim 1, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein the compound is represented by formula (B):
wherein
Z2is-O-, -CH2-、-C(O)-、-N(Ra)-、-S-、-S(O)-、-S(O2)-、-S(O)(＝N(Ra))-、-P(O)(Ra) -; wherein Z2R of (A) to (B)aIndependently H, D, C1-C6Alkyl radical, C2-C6Alkenyl radical, C1-C6Alkylcarbonyl group, C1-C6Alkoxycarbonyl group, C3-C6Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C6-C14Aryl, or 5-8 membered monocyclic heteroaryl, wherein said C1-C6Alkyl radical, C3-C6Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C6-C14Aryl, 5-8 membered monocyclic heteroaryl optionally substituted with one or more Re, and
a is- (CR)2R2)r-or-O-; wherein r is 0, 1,2, or 3;
R2each independently of the other being H, - (C)1-C4) Alkoxy, optionally with- (C)1-C4) Alkoxy substituted- (C)1-C4) Alkyl, or
R2Two of the radicals together with the same carbon atom to which they are attached form- (C)3-C6) Cycloalkyl or a 4-6 membered heterocyclic ring, wherein said- (C)3-C6) The cycloalkyl or 4-6 membered heterocyclic ring is optionally substituted with one or more groups selected from: - (C)1-C4) Alkyl, - (C)1-C4) Haloalkyl or oxetanyl.
3. A compound according to claim 2, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein the compound is represented by formula (C):
wherein R is1Is H, D, halogen or- (C)1-C4) An alkyl group.
4. A compound according to claim 3, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein the compound is represented by formula (D):
wherein
R5Independently is nitro, halogen, or-SO2RaWherein R is5R of (A) to (B)aIs- (C)1-C4) Alkyl or- (C)1-C4) A haloalkyl group; and is
Z1Is a bond, NH, N (H) (CH)2)qO, S, or- (C)1-C4) Alkylene, wherein q is 1,2, or 3;
l is absent or optionally substituted with- (C)3-C6) Cycloalkyl-substituted- (C)1-C4) An alkylene group; and is
R6Is H, D, -N (CH)3)-(C1-C4) alkylene-P (O) ((C)1-C4) Alkoxy group)2、-P(O)(N(CH3)2)(OEt)、-P(O)(O-(C1-C4) alkylene-O-CO- (C)1-C4) Alkyl radical)2、-(C3-C6) Cycloalkyl, phenyl, 5-7 membered heterocyclyl, 8-10 membered bicyclic ring, wherein said — (C)3-C6) Cycloalkyl, phenyl, 5-7 membered heterocyclyl, or 7-10 membered bicyclic ring optionally substituted with one or more groups selected from: halogen, -OH, ═ O, -CN, -COOH, -NH2、-N(CH3)2、-NS(＝O)(CH3)2、-SO2(C1-C4) Alkyl, - (C)1-C4) Alkyl, - (C)1-C4) Alkoxy, - (C)1-C4) Haloalkoxy, cyclopropyl, 4-6 membered heterocyclyl, -CH2P(O)(OH)2、-CH2P(O)((C1-C4) Alkoxy group)2、-P(O)((C1-C4) Alkyl radical)2or-N ═S(O)((C1-C4) Alkyl radical)2。
5. A compound according to claim 4 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein R9Independently of each other, D, halogen, -OH, CN, -NH2、＝O、-(C1-C4) Alkyl, - (C)1-C4) Alkoxy, - (C)1-C4) Haloalkyl, - (C)1-C4) Hydroxyalkyl, - (C)3-C6) Cycloalkyl, or 1, 3-dithiolyl; and k is 0, 1,2, 3, or 4.
6. A compound according to claim 4 or 5, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein a is-CH2-or-O-.
7. A compound according to any one of claims 4 to 6, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein each R is2Independently is-CH3(ii) a And n is 0 or 2.
8. A compound according to any one of claims 4 to 7, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein Z is2is-O-.
9. A compound according to any one of claims 4 to 8, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein R is1Is Cl.
10. A compound according to any one of claims 4 to 9 or N-oxidation thereofOr a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein R is5Is a nitro group.
11. A compound according to any one of claims 4 to 10, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein Z is1Is absent, NH or O.
12. A compound according to any one of claims 4 to 11, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein Z is2is-O-, -CH2-, -C (O) -, -NH-, -N- (oxetanyl) -, -S-, -S (O) -, -S (O)2)-、-S(O)(＝NH)-、-S(O)(＝NCH3) -, or-P (O) (CH)3)-。
13. The compound according to any one of claims 4 to 12, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein R is6Is H, D, - (C)3-C6) Cycloalkyl, phenyl, tetrahydro-2H-pyranyl, or 1, 4-dioxetane, wherein said- (C)3-C6) Cycloalkyl, phenyl, tetrahydro-2H-pyranyl or 1, 4-dioxanyl optionally substituted with 1 or 2 groups selected from: halogen, -OH, - (C)1-C4) Alkyl, or- (C)1-C4) An alkoxy group.
14. The compound according to any one of claims 4 to 13, or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein R is6Is tetrahydro-2H-pyranyl or 1, 4-dioxanyl, wherein said tetrahydro-2H-pyranyl or 1, 4-dioxanyl is optionally substituted with 1 or 2 groups selected from halogen.
15. A compound according to claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, wherein the compound is
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
n- ((4- ((((S) -1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- ((S) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
n- ((4- ((((R) -1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- ((S) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
n- ((4- ((((S) -1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- ((R) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
n- ((4- ((((R) -1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- ((R) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- (4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((((R) -2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((S) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((((S) -2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((S) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- (4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((((R) -2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((R) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((((S) -2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((R) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide, or
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide.
16. A pharmaceutical composition comprising a compound of formula (a) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of said compound of formula (a) or an N-oxide thereof, as defined in claim 1, and a pharmaceutically acceptable diluent or carrier.
17. A method of treating a neonatal disease, an autoimmune disease or a neurodegenerative disease, which comprises administering to a subject in need thereof an effective amount of a compound of formula (a) as defined in claim 1 or an N-oxide thereof or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of said compound of formula (a) or an N-oxide thereof.
18. The method of claim 16, wherein the neonatal disease, the autoimmune disease or the neurodegenerative disease is characterized by abnormal (e.g. enhanced or increased) Bcl-2 activity, such as hematological malignancy/cancer, class I diabetes, or schizophrenia.
19. The method of claim 16, wherein the neoplastic disease is myeloma, multiple myeloma, lymphoma, follicular lymphoma (F L), non-hodgkin's lymphoma, leukemia, acute lymphoblastic leukemia (a LL) (e.g., BC LL 0-2 dependent a LL 1L and paediatric a LL), chronic lymphoblastic leukemia (C LL) (e.g., relapsed/refractory C LL, del (17p) C LL), chronic myeloid leukemia (CM L) (e.g., primitive cell crisis CM L), Mantle Cell Lymphoma (MCL), diffuse large B-cell lymphoma, lung cancer such as Small Cell Lung Cancer (SCLC), melanoma, breast cancer or prostate cancer, including drug resistant cancers thereof.
20. The method of any one of claims 16-19, further comprising administering one or more further treatments effective to treat the neonatal disease, such as surgery, radiotherapy, chemotherapeutic agents (such as bendamustine, N L-101, cisplatin, carboplatin, etoposide, topotecan), targeted therapeutic agents (such as rituximab, ibrutinib, ACP-196, Idelalisib), antibody-drug conjugates or ADCs (such as brentuximab vedotin), immunotherapy (such as pembrolizumab), nivolumab, alemtuzumab (atezolizumab), delaviruzumab (avilumab), avilumab (avelumab), or CAR-T therapy (e.g., tisagenllecel, axicabecagene cilouucel).
Background
Apoptosis or programmed cell death is a conserved and regulated process which is a major mechanism for the clearance of senescent, damaged and unwanted cells the ability to block apoptotic signal transduction is a key marker for cancer and thus is important for tumorigenesis, tumor maintenance and chemical tolerance [ Hanahan, D. & Weinberg, r.a. the hallmarks of cancer. cell 100, 57-70 (2000) ]. pro-death (death) in the BC L-2 family (e.g. BC L-2 associated X protein (BAX), BC L-2 antagonist/killer 1(BAK), BC L-2 associated cell death agonist (BAD), BC L-2-like 11(BIM), NOXA and BC L-2 binding component 3(PUMA)) and pro-survival (BC 384-2, BC L-X L, BC L-2-like 2(BC L-2), the BC L-2 binding component 3(PUMA)) and pro-survival (BC L-2, BC L-X L, BC L-2-like 2, BC L-2 binding component 3(PUMA) and pro-survival (bcsipt) genes: [ 9. biotreatin) provide a balanced effects on apoptosis of these pro-9, b 9, t, b. 9, b 9, b. 7-7, 9, 3-2, 3, b 3-7, b. 7, b3, b 9, b. 7, b3, b.
BC L-2 (the first identified apoptosis regulator) was originally cloned from the breakpoint of T (14; 18) translocation present in human B-Cell lymphomas [ Tsujimoto, Y., et al science 228, 1440-1443 (1985); Cleary, M. L, et al Cell 47, 19-28 (1986); Boise, L. H.et al 74, 597-608 (1993) ], since then this protein has been shown to have a dominant effect in survival of various lymphoid malignancies [ Vaux, D. L., et al pre-Bcells.Nature 335, 440-442 (1988) ]. overexpression of Bcl-2 protein has been shown to be associated with resistance to chemotherapy in various cancers and immune system disorders, clinical results, disease progression, overall prognosis, or combinations thereof with Bcl-2 protein involved in bladder cancer, brain cancer, breast cancer, renal carcinoma, Bcl-2, leukemia-2-leukemia, leukemia-2, as disclosed in the publication No. PCT-A, No. 7, European publication No. 7, No. 5-9, No. 7, No. 4, No. 5, No. 4, No.
Over the past decade, several Bcl-2 inhibitors such as ABT-737, ABT-263, and ABT-199, shown below, have been identified and entered into human clinical trials for cancer treatment.
ABT-737[ Tillman Oltersdorf, et al, Nature, Vol 435,2005, p 677 ]. ABT-737 is a small molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X L and Bcl-w, with an affinity of 2 to 3 orders of magnitude stronger than previously reported compounds.
After extensive efforts by MedChem, the orally bioavailable Bcl-2 inhibitor ABT-263(Navitoclax) [ Cheol-Min Park, et al J. Med. chem.2008,51, 6902-]ABT-263 is a potent inhibitor of Bcl-x L, Bcl-2 and Bcl-w with a Ki ≦ 0.5nM, ≦ 1nM and ≦ 1nM ABT-263 IC 110nM against SC L C H146 cell line50. Significant antitumor efficacy was observed with 80% TGI and 20% treated tumors when ABT-263 was administered at 100 mg/kg/day in the H345 xenograft model, indicating at least a 50% reduction in tumor volume. ABT-263 alone administered orally resulted in complete tumor regression in xenograft models of small cell lung cancer and acute lymphoblastic leukemia [ Tse C, et al. cancer Res.2008,68(9),3421-]However, in clinical trials inhibition of BC L-X L by ABT-263(navitoclax) induced a rapid concentration-dependent decrease in the number of circulating platelets this mechanism-based thrombocytopenia is a dose-limiting toxicity of single agent navitoclax treatment in patients and limits the ability to drive drug concentrations to a high potency range.
Thus, BC L-2 selective (not against BC L-X L) inhibitors will ultimately result in substantially reduced thrombocytopenia with maintenance of efficacy in lymphoid malignancies the resulting increase in therapeutic window should allow greater BC L-2 inhibition and clinical efficacy in BC L-2 dependent tumor types after extensive Medchem, ABT-199(GDC-0199) [ Andrew J Souers, et al, Nature Medicine, Vol.19, 22, p202,2013]. ABT-199 is a Bcl-2 selective inhibitor with Ki<0.01nM, high selectivity relative to Bcl-x L and Bcl-w>4800 times, and has no activity on Mcl-1. ABT-199 with EC of 8nM50Potent suppression RS 4; 11 cells. In addition, ABT-199 induces RS4, 11 cells rapidly apoptosis, with cytochrome c release, caspase activation and sub-G0/G1 DNA accumulation quantitative immunoblotting revealed that sensitivity to ABT-199 was closely related to Bcl-2 expression, including NH L, D L BC L, MC L, AM L and A LL cell lines ABT-199 with an average EC of 3.0nM50ABT-199 also inhibited xenograft growth as a single agent or in combination with bendamustine and other agents (DoHH2, Granta-519). human data in stages I and II show that ABT-199 is highly potent against C LL with 17p deletion and is FDA approved in 2016.
WO/2017/132474 discloses a new class of BC L-2 inhibitors however, there is still a strong need to continue to search for more potent BC L-2 inhibitors in the art.
Summary of The Invention
In a first embodiment, the present invention provides a compound of formula (a) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of said compound of formula (a) or an N-oxide thereof:
wherein
Q1Is 7-membered heterocycloalkyl, 7-membered heterocycloalkenyl or 7-membered heteroaryl;
Q2is aryl or heteroaryl;
Q3is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl;
Q4is that
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11And R12Each independently H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halogen, nitro, oxo, cyano, ORa、SRaalkyl-Ra、NH(CH2)pRa、C(O)Ra、S(O)Ra、SO2Ra、C(O)ORa、OC(O)Ra、NRbRc、P(O)RbRcalkyl-P (O) RbRc、C(O)N(Rb)Rc、N(Rb)C(O)Rc、-S(O)(＝N(Rb))Rc、-N＝S(O)RbRc、SO2N(Rb)RcOr N (R)b)SO2RcWherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl are optionally substituted with one or more RdSubstitution;
Ra、Rb、Rcand RdIndependently H, D, alkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, ═ O, C (O) NHOH, C (O) OH, C (O) NH2Alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally substituted with one or more ReSubstitution;
Reh, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, ═ O, C (O) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, haloalkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
Z1is a bond, (CH)2)p、N(H)、O、S、C(O)、S(O2)、OC(O)、C(O)O、OSO2、S(O2)O、C(O)S、SC(O)、C(O)C(O)、C(O)N(H)、N(H)C(O)、S(O2)N(H)、N(H)S(O2)、OC(O)O、OC(O)S、OC(O)N(H)、N(H)C(O)O、N(H)C(O)S、N(H)C(O)N(H)、(CH2)pN(H)(CH2)q、(CH2)pN(H)C(O)(CH2)q、(CH2)pC(O)N(H)(CH2)q、OC(O)N(H)(CH2)p+1N(H)(CH2)qA divalent alkenyl group, or a divalent alkynyl group;
l is a bond, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more RdSubstitution;
Y、W、W1and W2Each independently is CH or N;
W3is O or N (R)a)；
V is N, C, or CH;
R9two of the groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, where R9Said cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more RdSubstitution;
R2two of the groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, where R2Said cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more RdSubstitution;
R10two of the groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, where R10Said cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more RdSubstitution;
R11and R12The groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, wherein R11Or R12Said cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more RdSubstitution;
R10and R2The groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, wherein R10Or R2Said cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more RdSubstitution;
R4and-Z1-L-R6The groups, together with the atoms to which they are attached, may optionally form a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl group, wherein R4Said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl of (a) is optionally substituted with one or more RdSubstitution;
Rband RcThe groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, wherein RbAnd RcSaid cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more ReSubstitution;
Rdtwo of the groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, where RdSaid cycloalkyl or heterocycloalkyl of (A) is optionally substituted with one or more ReSubstitution;
Retwo of the groups together with the atoms to which they are attached may optionally form a cycloalkyl or heterocycloalkyl group, where ReSaid cycloalkyl or heterocycloalkyl group of (a) is optionally substituted with one or more groups selected from the group consisting of: H. d, alkyl, alkenyl, alkynyl, halogen, cyano, amine, nitro, hydroxy, c (o) NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
j and k are each independently 0,1, 2,3,4,5,6, 7, or 8; and is
m, n, p, q, and r are each independently 0,1, 2,3, or 4.
In a second embodiment, the present invention provides a compound represented by formula (B):
or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of said compound of formula (B) or an N-oxide thereof, wherein
Z2is-O-, -CH2-、-C(O)-、-N(Ra)-、-S-、-S(O)-、-S(O2)-、-S(O)(＝N(Ra))-、-P(O)(Ra) -; wherein Z2R of (A) to (B)aIndependently H, D, C1-C6Alkyl radical, C2-C6Alkenyl radical, C1-C6Alkylcarbonyl group, C1-C6Alkoxycarbonyl group, C3-C6Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C6-C14Aryl, or 5-8 membered monocyclic heteroaryl, wherein said C1-C6Alkyl radical, C3-C6Cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C6-C14Aryl, 5-8 membered monocyclic heteroaryl optionally substituted with one or more Re, and
a is- (CR)2R2)r-or-O-; wherein r is 0,1, 2, or 3;
R2each independently of the other being H, - (C)1-C4) Alkoxy, optionally with- (C)1-C4) Alkoxy substituted- (C)1-C4) Alkyl, or
R2Two of the radicals together with the same carbon atom to which they are attached form- (C)3-C6) Cycloalkyl or a 4-6 membered heterocyclic ring, wherein said- (C)3-C6) The cycloalkyl or 4-6 membered heterocyclic ring is optionally substituted with one or more groups selected from: - (C)1-C4) Alkyl, - (C)1-C4) Haloalkyl or oxetanyl; and the remaining variables are as defined in the first embodiment.
In a third embodiment, the present invention provides a compound represented by formula (C)
Or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of said compound of formula (C) or an N-oxide thereof, wherein R is1Is H, D, halogen or- (C)1-C4) Alkyl, and the remaining variables are as defined in the first and/or second embodiments.
In a fourth embodiment, the present invention provides a compound represented by formula (D)
Or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, of said compound of formula (D) or an N-oxide thereof, wherein
R5Independently is nitro, halogen or-SO2RaWherein R is5R of (A) to (B)aIs- (C)1-C4) Alkyl or- (C)1-C4) Haloalkyl (e.g., -CF)3) (ii) a And
Z1is a bond, NH, N (H) (CH)2)qO, S or- (C)1-C4) Alkylene, wherein q is 1,2 or 3;
l is absent or optionally substituted with- (C)3-C6) Cycloalkyl-substituted- (C)1-C4) An alkylene group; and is
R6Is H, D, -N (CH)3)-(C1-C4) alkylene-P (O) ((C)1-C4) Alkoxy group)2、-P(O)(N(CH3)2)(OEt)、-P(O)(O-(C1-C4) alkylene-O-CO- (C)1-C4) Alkyl radical)2、-(C3-C6) Cycloalkyl, phenyl, 5-7 membered heterocyclyl, 8-10 membered bicyclic ring, wherein — (C)3-C6) Cycloalkyl, phenyl, 5-7 membered heterocyclyl or 7-10The bicyclic ring is optionally substituted with one or more groups selected from: halogen, -OH, ═ O, -CN, -COOH, -NH2、-N(CH3)2、-NS(＝O)(CH3)2、-SO2(C1-C4) Alkyl, - (C)1-C4) Alkyl, - (C)1-C4) Alkoxy, - (C)1-C4) Haloalkoxy, cyclopropyl, 4-6 membered heterocyclyl, -CH2P(O)(OH)2、-CH2P(O)((C1-C4) Alkoxy group)2、-P(O)((C1-C4) Alkyl radical)2or-N ═ s (o) ((C)1-C4) Alkyl radical)2And the remaining variables are as defined in the first, second and/or third embodiments.
In a fifth embodiment, the present invention provides a compound according to structural formula A, B, C or D or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of said compound according to formula (la) or an N-oxide thereof, wherein R is9Independently of each other, D, halogen, -OH, CN, -NH2、＝O、-(C1-C4) Alkyl, - (C)1-C4) Alkoxy, - (C)1-C4) Haloalkyl, - (C)1-C4) Hydroxyalkyl, - (C)3-C6) Cycloalkyl or 1, 3-dithiolyl; and k is 0,1, 2,3 or 4; and the remaining variables are as defined in the first, second, third and/or fourth embodiments.
In a sixth embodiment, the present invention provides a compound according to structural formula A, B, C or D or an N-oxide thereof, a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of a compound according to formula A, B, C or D or an N-oxide thereof, wherein a is-CH2-or-O-; and the remaining variables are as defined in the first, second, third, fourth and/or fifth embodiments.
In a seventh embodiment, the present invention provides a compound according to structural formula A, B, C or D, or an N-oxide thereof, according to formulaA. B, C or D, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof, of an N-oxide thereof, wherein each R is2Independently is-CH3(ii) a And n is 0 or 2; and the remaining variables are as defined in the first, second, third, fourth, fifth and/or sixth embodiments.
In an eighth embodiment, the present invention provides a compound according to structural formula A, B, C or D or an N-oxide thereof, a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of a compound according to formula A, B, C or D or an N-oxide thereof, wherein Z is2is-O-; and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth and/or seventh embodiments.
In a ninth embodiment, the present invention provides a compound according to structural formula A, B, C or D or an N-oxide thereof, a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of a compound according to formula A, B, C or D or an N-oxide thereof, wherein R is1Is halogen, such as Cl; and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh and/or eighth embodiments.
In a tenth embodiment, the present invention provides a compound according to structural formula A, B, C or D or an N-oxide thereof, a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of a compound according to formula A, B, C or D or an N-oxide thereof, wherein R is5Is a nitro group; and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth and/or ninth embodiments.
In an eleventh embodiment, the present invention provides a compound according to structural formula A, B, C or D or an N-oxide thereof, a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or N-oxide thereof, a compound according to formula A, B, C or D or an N-oxide thereofProdrug of, wherein Z1Is absent, NH or O; and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth and/or tenth embodiments.
In a twelfth embodiment, the present invention provides a compound according to structural formula A, B, C or D or an N-oxide thereof, a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of a compound according to formula A, B, C or D or an N-oxide thereof, wherein Z is2is-O-, -CH2-, -C (O) -, -NH-, -N- (oxetanyl) -, -S-, -S (O) -, -S (O)2)-、-S(O)(＝NH)-、-S(O)(＝NCH3) -or-P (O) (CH)3) -; and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth and/or eleventh embodiments.
In a thirteenth embodiment, the present invention provides a compound according to structural formula A, B, C or D or an N-oxide thereof, a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of a compound according to formula A, B, C or D or an N-oxide thereof, wherein R is6Is H, D, - (C)3-C6) Cycloalkyl, phenyl, tetrahydro-2H-pyranyl or 1, 4-dioxetane, in which — (C)3-C6) Cycloalkyl, phenyl, tetrahydro-2H-pyranyl or 1, 4-dioxetane optionally substituted with 1 or 2 groups selected from: halogen, -OH, - (C)1-C4) Alkyl, or- (C)1-C4) An alkoxy group; and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh and/or twelfth embodiments.
In a fourteenth embodiment, the present invention provides a compound according to structural formula A, B, C or D or an N-oxide thereof, a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of a compound according to formula A, B, C or D or an N-oxide thereof, wherein R is6Is tetrahydro-2H-pyranyl or 1, 4-dioxetane, wherein tetrahydro-2H-pyranyl or 1, 4-dioxetane is optionally substituted with 1 or 2 halogen; and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth and/or thirteenth embodiments.
For example, in a compound according to structural formula A, B, C or D or an N-oxide thereof, a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug of a compound according to formula A, B, C or D or an N-oxide thereof, Z is in the form of a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug1is-NH-and L is-CH2-，R6Is tetrahydro-2H-pyranyl or 1, 4-dioxetane, optionally substituted with 1 or 2 halogen radicals, and preferably, A is-CH2-or-O-, R1Is Cl, R5Is nitro, Z2is-O-each R2Independently is-CH3And n is 0 or 2, and R9Is methyl (and k is 1) or halogen (and k is 2, such as difluoro).
Modified compounds of any of such compounds are also contemplated, including modifications that have improved (e.g., enhanced, greater) drug solubility, stability, bioavailability, and/or therapeutic index as compared to the unmodified compound. Exemplary modifications include, but are not limited to, suitable prodrug derivatives and deuterium-enriched compounds.
Also within the scope of the invention are pharmaceutical compositions for the treatment of a neoplastic disease, therapeutic uses thereof, and the use of the compounds for the preparation of a medicament for the treatment of a disease/disorder, comprising one or more compounds described herein (e.g., any of those compounds of formulas (a) - (D) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof or an N-oxide thereof), modifications and/or salts thereof, and a pharmaceutically acceptable diluent or carrier.
The present invention also relates to methods of treating a neonatal, autoimmune or neurodegenerative disease comprising administering to a subject in need thereof an effective amount of one or more compounds of the invention described herein (e.g. any of those compounds of formulae (a) - (D) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, isotopic form or prodrug thereof or an N-oxide thereof), modifications and/or salts thereof, or a pharmaceutical composition comprising a compound of the invention.
In certain embodiments, the neonatal, autoimmune or neurodegenerative disease is characterized by abnormal (e.g., enhanced or increased) Bcl-2 activity. For example, the neoplastic disease may be a hematological malignancy or cancer, including solid tumors; the autoimmune disease may be type I diabetes; and the neurodegenerative disease may be schizophrenia.
In certain embodiments, the neoplastic disease is myeloma, multiple myeloma, lymphoma, follicular lymphoma (F L), non-hodgkin's lymphoma, leukemia, acute lymphoblastic leukemia (a LL) (e.g., BC LL 0-2 dependent a LL 1L and pediatric a LL), chronic lymphoblastic leukemia (C LL) (e.g., relapsed/refractory C LL, del (17p) C LL), chronic myeloid leukemia (CM L) (e.g., primitive cell crisis CM L), Mantle Cell Lymphoma (MCL), diffuse large B-cell lymphoma, lung cancer such as Small Cell Lung Cancer (SCLC), melanoma, breast cancer, or prostate cancer, including drug resistant cancers thereof.
In certain embodiments, the methods further comprise administering one or more additional therapies effective to treat the neoplastic disease, such as surgery, radiation therapy, chemotherapeutic agents (e.g., bendamustine, N L-101 (7- (bis (2-chloroethyl) amino) -1-methyl-1H-benzo [ d ] imidazol-2-yl) -N-hydroxyheptanamide), cisplatin, carboplatin, etoposide, topotecan), target therapies (e.g., anti-CD 20 antibodies, such as rituximab, Bruton tyrosine kinase inhibitors, such as ibrutinib and acalbutinib (ACP-196), PI3K inhibitors, such as idelalisib), antibody-drug conjugates or ADCs (e.g., anti-CD 30 ADC brentuximab vedotin), immunotherapies (e.g., anti-PD-1 antibodies including Pembrolizumab and nemuzumab or anti-nivolumab PD) or anti-PD-L1 antibodies including anti-zelizumab, e.g., Ducaleucitabib, or duloxetine (e.g., Ducalelcalizumab).
Also provided herein is the use of one or more compounds of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising one or more compounds of the invention for the manufacture of a medicament for the treatment of the diseases or conditions mentioned above.
In another embodiment provided herein, a compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising one or more of the disclosed compounds is used to treat a disease or condition mentioned above.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. It is to be understood that all embodiments/features of the invention (compounds, pharmaceutical compositions, methods of manufacture/use, etc.) described herein, including any particular features described in the examples and the original claims, may be combined with each other unless inapplicable or explicitly excluded.
Detailed Description
Exemplary compounds described herein include, but are not limited to, the following:
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
n- ((4- ((((S) -1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- ((S) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
n- ((4- ((((R) -1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- ((S) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
n- ((4- ((((S) -1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- ((R) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
n- ((4- ((((R) -1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- ((R) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(R) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 3-dimethyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (4- (trifluoromethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (4- (trifluoromethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (3- (trifluoromethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-cyano-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -2- (3-amino-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyrido [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-methoxy-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-hydroxy-3-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-methyl-3- (trifluoromethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-cyano-3-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (2-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (2- (trifluoromethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] thiazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 3-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] thiazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-hydroxy-3-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] thiazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-cyano-3-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] thiazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 3-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-cyano-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- (3-hydroxy-3-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl-3, 3-d2) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- (3-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-dimethyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- (2-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4' -chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (2H, 4H-spiro [ pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepine-3, 2' - [1,3] dithiolane ] -1(7H) -yl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 3-difluoro-4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (6,7,8, 9-tetrahydropyrrole [3',2':5,6] pyridine [3,2-b ] azepin-5 (1H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl-3, 3,4,4-d4) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (3,4,5, 7-tetrahydropyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] diazepin-1 (2H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (4-oxo-3, 4,5, 7-tetrahydropyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] diazepin-1 (2H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (5- (methylimino) -5-oxo-3, 4,5, 7-tetrahydro-5 l 4-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] thiazepin-1 (2H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4' -chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (2',3' -dihydrospiro [ cyclopropane-1, 4' -pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepine ] -1' (7' H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-3-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((2-morpholinoethyl) amino) -3-nitrophenyl) sulfonyl) benzamide
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-methylmorpholino-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((4- (oxetan-3-yl) morpholin-2-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-hydroxycyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((((1r,4r) -4-methoxycyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((((1s,4s) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((((1s,4s) -4-ethyl-4-hydroxycyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1s,4s) -4-morpholinocyclohexyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((4- (cyclopropylamino) cyclohexyl) amino) -3-nitrophenyl) sulfonyl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((4, 4-difluorocyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((tetrahydro-2H-pyran-4-yl) methoxy) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((tetrahydro-2H-pyran-3-yl) methoxy) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (2-morpholinoethoxy) -3-nitrophenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((4-methylmorpholino-2-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((4- (oxetan-3-yl) morpholin-2-yl) methoxy) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((4-hydroxycyclohexyl) methoxy) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1r,4r) -4-methoxycyclohexyl) methoxy) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1s,4s) -4-hydroxy-4-methylcyclohexyl) methoxy) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1s,4s) -4-ethyl-4-hydroxycyclohexyl) methoxy) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) oxy) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1s,4s) -4-morpholinocyclohexyl) oxy) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((4- (cyclopropylamino) cyclohexyl) oxy) -3-nitrophenyl) sulfonyl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((4, 4-difluorocyclohexyl) methoxy) -3-nitrophenyl) sulfonyl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((2- (4-chlorophenyl) cyclopent-1-en-1-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((2- (4-chlorophenyl) cyclohept-1-en-1-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4- (4-chlorophenyl) -6, 6-dimethyl-5, 6-dihydro-2H-pyran-3-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-4- (methoxymethyl) -4-methyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -5-fluoro-N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((5-nitro-6- (((tetrahydro-2H-pyran-4-yl) methyl) amino) pyridin-3-yl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (7, 8-dihydro-3H-imidazo [4',5':5,6] pyridine [2,3-b ] [1,4] oxazepin-9 (6H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((9- (4-chlorophenyl) -3-methyl-3-azaspiro [5.5] undec-8-en-8-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((9- (4-chlorophenyl) -3- (1, 3-difluoropropan-2-yl) -3-azaspiro [5.5] undec-8-en-8-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-difluoro-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((5- (4-chlorophenyl) spiro [2.5] oct-5-en-6-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((7- (4-chlorophenyl) spiro [3.5] non-6-en-6-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4' -chloro-3 ' -fluoro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -4- (4- ((4, 4-dimethyl-2- (pyridin-3-yl) cyclohex-1-en-1-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-fluoro-5-nitrophenyl) sulfonyl) -4- (4- ((6- (4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(R) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((6- (4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(R) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((6- (4-chlorophenyl) -2-oxaspiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(R) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-fluoro-5-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((6- (4-chlorophenyl) -2-oxaspiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((6- (4-chlorophenyl) -2-oxaspiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((6- (4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -6-fluorobenzamide,
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((6- (4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -5-fluorobenzamide,
4- (4- ((4 '-chloro-5, 5-bis (methyl-d 3) -3,4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2-methylpiperazin-1-yl-2, 3,3,5,5,6,6-d7) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyrido [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
((2- (((4- (N- (4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzoyl) sulfamoyl) -2-nitrophenyl) amino) methyl) morpholino) methyl) phosphonic acid diethyl ester,
((3- ((4- (N- (4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzoyl) sulfamoyl) -2-nitrophenyl) amino) propyl) (methyl) amino) methyl) phosphonic acid diethyl ester,
2- (((2- ((4- (N- (4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzoyl) sulfamoyl) -2-nitrophenyl) amino) ethyl) ((pivaloyloxy) methoxy) phosphoryl) oxy) pivalic acid ethyl ester,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1-methyl-1-phospha-cyclohex-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1-hydroxy-1-phospha-cyclohex-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
((4- (((4- (4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzoyl) sulfamoyl) -2-nitrophenyl) amino) methyl) -1-phosphahexacyclohex-1-yl) oxy) pivalic acid methyl ester,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((2-methyl-2-oxo-1, 3, 2-oxazepin-5-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((2- (2-methyl-2-oxo-1, 3, 2-oxazepin-3-yl) ethyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1- (dimethylphosphoryl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3- (dimethylphosphoryl) -4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
n- ((4- (((1, 4-dioxaspiro [4.5] decan-8-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
n- ((4- (((2-oxaspiro [3.5] non-7-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((2- (hexahydrofuro [3,4-c ] pyridin-5 (3H) -yl) ethyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((2- (3-oxooctahydro-7H-imidazo [1,5-d ] [1,4] diazepin-7-yl) ethyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyrido [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((2- (3-oxooctahydro-5H-pyrrolo [3,4-c ] pyridin-5-yl) ethyl) amino) phenyl) sulfonyl) benzamide,
n- ((4- ((2- (2-oxa-5-azabicyclo [2.2.2] oct-5-yl) ethyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((3-hydroxy-3-methylbicyclo [3.1.1] hept-6-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
n- ((4- ((2- (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) ethyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
2- ((3R) -8- (2- ((4- (N- (4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzoyl) sulfamoyl) -2-nitrophenyl) amino) ethyl) -6, 6-difluoro-8-azabicyclo [3.2.1] oct-3-yl) acetic acid,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((2- (6, 6-difluoro-8-azabicyclo [3.2.1] oct-8-yl) ethyl) amino) -3-nitrophenyl) sulfonyl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((2- (tetrahydro-2H-pyran-4-yl) -2-azaspiro [3.3] hept-6-yl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-thiopyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1-imino-1-oxahexahydro-1 l 6-thiopyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4- (methylsulfonyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4- ((dimethyl (oxy) -lambda 6-thioalkyl) amino) cyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((2- (4- ((dimethyl (oxy) -lambda 6-thioalkyl) amino) piperidin-1-yl) ethyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
n- ((4- (((4-aminotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((1- (tetrahydro-2H-pyran-4-yl) cyclopropyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((2- (5, 6-dihydroimidazo [1,2-a ] pyrazin-7 (8H) -yl) ethyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyrido [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-6-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((3- (difluoromethoxy) benzyl) amino) -3-nitrophenyl) sulfonyl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((3,4, 5-trihydroxytetrahydrofuran-2-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((3,4,5, 6-tetrahydroxytetrahydro-2H-pyran-2-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4, 5-dihydroxy-6, 6-dimethyltetrahydro-2H-pyran-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((2,3, 5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((2,3,4,5, 6-pentahydroxycyclohexyl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (1- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -1,2,3, 6-tetrahydropyridin-4-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (1- ((6- (4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) -1,2,3, 6-tetrahydropyridin-4-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -5- (4- ((6- (4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -3- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) picolinamide,
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (4- ((6- (4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) nicotinamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- (4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((((R) -2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((S) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((((S) -2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((S) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- (4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((((R) -2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((R) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((((S) -2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((R) -4-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((2-fluoro-1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (4, 4-dimethyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (3- (trifluoromethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (4- (trifluoromethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (3- (trifluoromethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-cyano-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(S) -2- (3-amino-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyrido [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-methoxy-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-hydroxy-3-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-methyl-3- (trifluoromethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-cyano-3-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (2-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (2- (trifluoromethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (5, 5-dioxido-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] thiazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (4- (trifluoromethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] thiazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-methoxy-3-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] thiazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-methyl-3- (trifluoromethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] thiazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 3-difluoro-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3-cyano-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- (3-hydroxy-3-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- (3-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 3-dimethyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- (2-methyl-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- (3- (hydroxymethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4' -chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (2' H,4' H-spiro [ cyclobutane-1, 3' -pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepine ] -1' (7' H) -yl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 3-dimethyl-4- (trifluoromethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3- (hydroxymethyl) -3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (9-oxo-6, 7,8, 9-tetrahydropyrrole [3',2':5,6] pyridine [3,2-b ] azepin-5 (1H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (5- (oxetan-3-yl) -3,4,5, 7-tetrahydropyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] diazepin-1 (2H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -2- (2-oxo-3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (5-imino-5-oxo-3, 4,5, 7-tetrahydro-5 l 4-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] thiazepin-1 (2H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (5-methyl-5-oxo-3, 4, 7-trihydropyrrole [3',2':5,6] pyridine [3,2-b ] [1,4] azaphosphoheptin (azaphosphopin) -1(2H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((3-fluorotetrahydro-2H-pyran-3-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((3-morpholinopropyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-methylmorpholino-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((4- (oxetan-3-yl) morpholin-2-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((((1s,4s) -4-methoxycyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((((1r,4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((((1r,4r) -4-ethyl-4-hydroxycyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((1- (oxetan-3-yl) piperidin-4-yl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1r,4r) -4-morpholinocyclohexyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((4- (methyl (oxetan-3-yl) amino) cyclohexyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((1,4, 4-trifluorocyclohexyl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((4-fluorotetrahydro-2H-pyran-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((3-fluorotetrahydro-2H-pyran-3-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (3-morpholinopropoxy) -3-nitrophenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((4-methylmorpholino-2-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide,
(R) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((4- (oxetan-3-yl) morpholin-2-yl) methoxy) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((4-hydroxy-4-methylcyclohexyl) methoxy) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1s,4s) -4-methoxycyclohexyl) methoxy) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1r,4r) -4-hydroxy-4-methylcyclohexyl) methoxy) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1r,4r) -4-ethyl-4-hydroxycyclohexyl) methoxy) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((1- (oxetan-3-yl) piperidin-4-yl) oxy) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1r,4r) -4-morpholinocyclohexyl) oxy) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((4- (methyl (oxetan-3-yl) amino) cyclohexyl) oxy) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((1,4, 4-trifluorocyclohexyl) methoxy) phenyl) sulfonyl) benzamide,
4- (4- ((4- (4-chlorophenyl) -5, 6-dihydro-2H-pyran-3-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(Z) -4- (4- ((2- (4-chlorophenyl) cyclooct-1-en-1-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-4-methoxy-4-methyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (5- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyrido [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- (3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenylsulfonamido) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((5-chloro-6- ((tetrahydro-2H-pyran-4-yl) methoxy) pyridin-3-yl) sulfonyl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) -3- (S- (trifluoromethyl) sulfonimidoyl) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H- [1,4] oxazepine [3,2-f ] indol-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((9- (4-chlorophenyl) -3-isopropyl-3-azaspiro [5.5] undec-8-en-8-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((9- (4-chlorophenyl) -3- (oxetan-3-yl) -3-azaspiro [5.5] undec-8-en-8-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-bis (fluoromethyl) -3,4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- (1- (4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) cyclopropyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((6- (4-chlorophenyl) spiro [2.5] oct-5-en-5-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4' -chloro-3 ',5, 5-trimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((2- (1H-indol-5-yl) -4, 4-dimethylcyclohex-1-en-1-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-fluoro-5-nitrophenyl) sulfonyl) -4- (4- ((6- (4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((6- (4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((6- (4-chlorophenyl) -2-oxaspiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-fluoro-5-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((6- (4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((6- (4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((6- (4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -3-fluorobenzamide,
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-fluoro-5-nitrophenyl) sulfonyl) -4- (4- ((6- (4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrole [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -6-fluorobenzamide,
4- (4- ((4 '-chloro-5, 5-bis (methyl-d 3) -3,4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl-2, 2,3,3,4,4-d6) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
((2- (((4- (N- (4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzoyl) sulfamoyl) -2-nitrophenyl) amino) methyl) morpholino) methyl) phosphonic acid,
(2- ((2- ((4- (N- (4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzoyl) sulfamoyl) -2-nitrophenyl) amino) ethyl) (methyl) amino) ethyl) phosphonic acid diethyl ester,
p- (2- ((4- (N- (4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzoyl) sulfamoyl) -2-nitrophenyl) amino) ethyl) -N, N-dimethylphosphamide ethyl ester,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1- (dimethylamino) -1-phospha-cyclohex-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1-ethoxy-1-phospha-cyclohex-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1-isopropoxy-1-phospha-cyclohexa (oxyphosphin) -4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((1,2, 3-trimethyl-2-oxo-1, 3, 2-diazaphosphorocyclohex-5-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((2- (2-methyl-2-oxo-1, 3, 2-diazaphosphocyclohex-1-yl) ethyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4- (dimethylphosphoryl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (dimethylphosphoryl) -3-nitrophenyl) sulfonyl) benzamide,
n- ((4- (((1, 4-dithiospiro [4.5] decan-8-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyrido [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
n- ((4- ((2- (6-azaspiro [2.5] oct-6-yl) ethyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((2- (2, 2-difluoro-7-azaspiro [3.5] nonan-7-yl) ethyl) amino) -3-nitrophenyl) sulfonyl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((2- (2- (oxetan-3-yl) octahydro-5H-pyrrolo [3,4-c ] pyridin-5-yl) ethyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyrido [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((2- (1-oxooctahydro-5H-pyrrolo [3,4-c ] pyridin-5-yl) ethyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((3-hydroxybicyclo [3.1.1] hept-6-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
n- ((4- (((3-amino-3-methylbicyclo [3.1.1] hept-6-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((2- (5- (oxetan-3-yl) -2, 5-diazabicyclo [2.2.1] hept-2-yl) ethyl) amino) phenyl) sulfonyl) benzamide,
2- ((3S) -8- (2- ((4- (N- (4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzoyl) sulfamoyl) -2-nitrophenyl) amino) ethyl) -6, 6-difluoro-8-azabicyclo [3.2.1] oct-3-yl) acetic acid,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((2- (6, 6-difluoro-8-azabicyclo [3.2.1] oct-8-yl) ethyl) amino) -3-nitrophenyl) sulfonyl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
n- ((4- ((7-oxaspiro [3.5] nonan-2-yl) amino) -3-nitrophenyl) sulfonyl) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1, 1-dioxotetrahydro-2H-thiopyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((1- (isopropylimino) -1-oxohexahydro-1. lambda.6-thiopyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((4- (S-methylsulphonimidoyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((4- ((1-oxotetrahydro-1. lamda.6-thiophen-1-ylidene) amino) cyclohexyl) methyl) amino) phenyl) sulfonyl) benzamide,
(S) -4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((1- (4- ((dimethyl (oxy) -lambda 6-sulfoalkyl (sulforylidene)) amino) piperidin-1-yl) propan-2-yl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((((4-cyanotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- ((2- (tetrahydro-2H-pyran-4-yl) propan-2-yl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- ((2- (5, 6-dihydro- [1,2,4] triazolo [1,5-a ] pyrazin-7 (8H) -yl) ethyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((1- (thiazol-2-yl) piperidin-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((4- (difluoromethoxy) benzyl) amino) -3-nitrophenyl) sulfonyl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((4- (((3, 5-dihydroxytetrahydrofuran-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((3,4, 5-trihydroxy-6, 6-dimethyltetrahydro-2H-pyran-2-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((2,3, 5-trihydroxytetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((3,4, 5-trihydroxy-6- (methylthio) tetrahydro-2H-pyran-2-yl) methyl) amino) phenyl) sulfonyl) benzamide,
4- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((3,4, 5-trihydroxy-6- (((4,5, 6-trihydroxy-2- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) methoxy) methyl) tetrahydro-2H-pyran-2-yl) methyl) amino) phenyl) sulfonyl) benzamide,
n- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (1- ((6- (4-chlorophenyl) -2-oxaspiro [3.5] non-6-en-7-yl) methyl) -1,2,3, 6-tetrahydropyridin-4-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) benzamide,
4- (1- ((6- (4-chlorophenyl) -2-oxaspiro [3.5] non-6-en-7-yl) methyl) -1,2,3, 6-tetrahydropyridin-4-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide,
(S) -6- (4- ((6- (4-chlorophenyl) -2-oxaspiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) -4- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridin [2,3-b ] [1,4] oxazepin-1 (7H) -yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-3-yl) methyl) amino) phenyl) sulfonyl) nicotinamide, or
(S) -N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -6- (4- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -2- (3, 4-dihydro-2H-pyrrolo [3',2':5,6] pyridine [2,3-b ] [1,4] oxazepin-1 (7H) -yl) nicotinamide.
The compounds of the present invention may contain one or more asymmetric carbon atoms. Thus, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may employ racemates, diastereomers or enantiomers as starting materials or intermediates. Diastereomeric compounds may be separated by chromatography or crystallization. Similarly, mixtures of enantiomers may be separated using the same techniques or other techniques known in the art. Each asymmetric carbon atom may be in either the R or S configuration, and both configurations are within the scope of the present invention.
Compounds having one or more chiral centers may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereoisomers, enantiomers and epimeric forms as well as racemates and mixtures thereof.
The term "geometric isomer" refers to a cyclic compound having at least two substituents, wherein both substituents are on the same side of the ring (cis) or wherein both substituents are on opposite sides of the ring (trans). When the disclosed compounds are named or depicted by structure without indicating stereochemistry, it is to be understood that the name or structure encompasses one or more possible stereoisomers or geometric isomers, or mixtures of the encompassed stereoisomers or geometric isomers.
When geometric isomers are delineated by name or structure, it is understood that the named or delineated isomer is present to a greater extent than the other isomer, that is, the geometric isomer purity of the named or delineated geometric isomer is greater than 50%, e.g., at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight. Geometric isomer purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.
A racemic mixture refers to 50% of one enantiomer and 50% of its corresponding enantiomer. When a compound having one chiral center is named or described without indicating the stereochemistry of the chiral center, it is to be understood that the name or structure encompasses both possible enantiomeric forms of the compound (e.g., enantiomerically pure, enantiomerically enriched, or racemic). When a compound having two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, it is to be understood that the name or structure encompasses all possible diastereomeric forms of the compound (e.g., diastereomerically pure, diastereomerically enriched, and equimolar mixtures (e.g., racemic mixtures) of one or more of the diastereomers).
Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallization of compounds as chiral salt complexes or crystallization of compounds as chiral salts in chiral solvents. Enantiomers and diastereomers can also be obtained from diastereomerically or enantiomerically pure intermediates, reagents and catalysts by well-known asymmetric synthesis methods.
When a compound is referred to by a name or structure indicating a single enantiomer, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as "enantiomerically pure"), unless otherwise indicated. Optical purity is the weight in the named or depicted enantiomer mixture divided by the total weight in the two enantiomer mixtures.
When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomer pair), it is to be understood to include one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers. It is further understood that the stereoisomers named or depicted have a stereoisomeric purity of at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. In this case, the stereoisomer purity is determined by dividing the total weight in the stereoisomer mixture covered by the name or structure by the total weight in all stereoisomer mixtures.
Modified compounds of any one of such compounds are also contemplated, including modifications having improved (e.g., enhanced, greater) pharmaceutical solubility, stability, bioavailability, and/or therapeutic index as compared to the unmodified compound. Examples of modifications include, but are not limited to, prodrug derivatives and deuterium enriched compounds. For example:
prodrug derivatives prodrugs will be converted in vivo to the active compounds of the invention when administered to a subject [ Nature Reviews of Drug Discovery,2008, Volume 7, p255] note that prodrugs themselves fall within the scope of compounds according to the invention.
Deuterium enriched compounds: deuterium (D or2H) Is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally as an isotopeXH (hydrogen or protium), D (2H or deuterium), and T: (3H or tritium). The natural abundance of deuterium is 0.015%. Those skilled in the art recognize that in all compounds having H atoms, the H atom is actually represented as a mixture of H and D, with about 0.015% being D. Thus, a compound having deuterium content that has been enriched to greater than 0.015% of its natural abundance should be considered unnatural and therefore new relative to its non-enriched counterpart.
It will be appreciated that the compounds of the invention may exist and optionally be administered in the form of salts and solvates. The present invention encompasses any pharmaceutically acceptable salts and solvates of the above compounds and modifications thereof. For example, it is within the scope of the present invention to convert and use the compounds of the present invention in their pharmaceutically acceptable forms derived from a variety of organic and inorganic acids and organic and inorganic bases, according to procedures well known in the art.
When the compound of the present invention possesses a free base form, the compound can be prepared as a pharmaceutically acceptable acid addition salt, for example, a hydrohalide salt such as a hydrochloride, hydrobromide, hydroiodide; other mineral acids such as sulfates, nitrates, phosphates, and the like; and alkyl and monoaryl sulfonates such as ethanesulfonate, methylbenzenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts, such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, and ascorbate. Other acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginine, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, hydrochloride, chlorobenzoate, cyclopentylpropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, hemi-lactobionate (from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, oxalate, butyrate, camphorate, camphorsulfonate, camphorate, digluconate, dig, Oleate, pamoate, pectate, persulfate, phenylacetate, 3-phenylpropionate, phosphonate and phthalate. It will be appreciated that the physical properties of the free base forms, such as solubility in polar solvents, typically differ to some extent from their respective salt forms, but that for the purposes of the present invention, the salts are equivalent to their respective free base forms.
When the compounds of the present invention possess the free acid form, pharmaceutically acceptable base addition salts can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Examples of such bases are alkali metal hydroxides including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N-methylglutamine. Also included are aluminum salts of the compounds of the present invention. Other base addition salts of the present invention include, but are not limited to: copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganous salt, potassium salt, sodium salt and zinc salt. Organic base addition salts include, but are not limited to, salts of primary, secondary, tertiary amines, salts of substituted amines including naturally occurring substituted amines, salts of cyclic amines, and salts of basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine (chloroprocaine), choline, N' -dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucamine (glucamine), glucosamine, histidine, hydrabamine (hydrabamine), isopropylamine, lidocaine (lidocaine), lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine (purine), purine, and the like, Theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris (hydroxymethyl) methylamine (tromethamine). It will be appreciated that the physical properties of the free acid forms, such as solubility in polar solvents, typically differ to some extent from their respective salt forms, but that the salts are equivalent to their respective free acid forms for the purposes of the present invention.
In one aspect, the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, mesylate, toluenesulfonate, acetate, fumarate, sulfate, bisulfate, succinate, citrate, phosphate, maleate, nitrate, tartrate, benzoate, bicarbonate, carbonate, sodium hydroxide salt, calcium hydroxide salt, potassium hydroxide salt, tromethamine salt, or a mixture thereof.
The compounds of the invention comprising a tertiary nitrogen containing group may be quaternized using, for example, the following reagents: (C)1-4) Alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chlorides, bromides and iodides; sulfuric acid di (C)1-4) Alkyl esters such as dimethyl sulfate, diethyl sulfate and diamyl sulfate; alkyl halides such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C)1-4) Alkyl halides such as benzyl chloride and phenethyl bromide. Such salts allow the preparation of both water-soluble and oil-soluble compounds of the invention.
The amino oxides, also known as ammonia-N-oxide and N-oxide, of anticancer agents having a tertiary nitrogen atom have been developed as prodrugs [ Mol Cancer therapy.2004mar; 3(3):233-44]. The compounds of the invention containing a tertiary nitrogen atom can be reacted with a reagent, for example hydrogen peroxide (H)2O2) Caro acid or peracids such as m-chloroperoxybenzoic acid (mCPBA) to form the ammoxidation oxide.
The compounds disclosed therein are bcl-2 inhibitors. The pharmaceutical compositions of the present invention comprise one or more bcl-2 inhibitors or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or diluent.
"pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to a substance that facilitates formulation and/or administration of an active agent to and/or absorption by a subject, and may be included in the compositions of the present disclosure without causing a significant adverse toxicological effect to the subject. Non-limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCl, physiological saline solution, ringer's lactate, physiological sucrose, physiological glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (e.g., ringer's solution), alcohols, oils, gelatin, carbohydrates, such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, pigments, and the like. Such formulations can be sterilized and, if desired, can be mixed with adjuvants, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants and/or aromatic substances, and the like, which do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds.
The pharmaceutical compositions of the invention optionally comprise one or more of their pharmaceutically acceptable carriers and/or diluents, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; a sweetener; and preservatives, such as methyl paraben, ethyl paraben, propyl paraben and butyl paraben. A more complete list of suitable Excipients can be found in Handbook of Pharmaceutical Excipients (5)thEd, Pharmaceutical Press (2005)). The skilled person will know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington's pharmaceutical Sciences (2003-20 edition) and The United states pharmaceutical: The National Formulary (USP 24NF19) published in 1999. Carriers, diluents, and/or excipients are "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.
The pharmaceutical compositions of the present invention may also contain other conventional pharmaceutically inactive agents. Any inert excipient that is generally used as a carrier or diluent, such as sugars, polyols, soluble polymers, salts and lipids, may be used in the compositions of the present invention. Sugars and polyols that may be used include, but are not limited to, lactose, sucrose, mannitol, and sorbitol. Exemplary soluble polymers that can be employed are polyoxyethylene, poloxamer (poloxamer), polyvinylpyrrolidone, and dextran. Useful salts include, but are not limited to, sodium chloride, magnesium chloride, and calcium chloride. Lipids that may be used include, but are not limited to, fatty acids, glycerol fatty acid esters, glycolipids, and phospholipids.
In addition, the pharmaceutical compositions of the present invention may further comprise binders (e.g., acacia, corn starch, gelatin, carbomer, ethylcellulose, guar gum, hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone), disintegrants (e.g., corn starch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers of various pH and ionic strength (e.g., tris-HC L, acetate, phosphate), additives to prevent absorption to surfaces such as albumin or gelatin, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), penetration enhancers, solubilizing agents (e.g., glycerol, polyethylene glycol, cyclodextrin), glidants (e.g., colloidal silicon dioxide), antioxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g., hydroxypropylcellulose, methylcellulose), viscosity enhancers (e.g., carbopol, ethyl cellulose, guar gum, colloidal silicon dioxide, polyethylene glycol, sodium stearate, citric acid, sodium stearate, citric acid, sodium stearate, citric acid, sodium stearate, citric acid, sodium stearate, citric.
In one embodiment, the pharmaceutical composition is prepared with a carrier that will protect the compound from rapid clearance from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid may be used. Methods of preparing such formulations will be apparent to those skilled in the art. Materials are also commercially available from Alza Corporation and Novapharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example as described in US patent No. 4,522,811.
In addition, the present invention encompasses pharmaceutical compositions comprising any solid or liquid physical form of a compound of the present invention. For example, the compound may be in a crystalline form or an amorphous form, and have any particle size. The particles may be micronized or may be agglomerated particles, powders, oils, oily suspensions or any other solid or liquid physical form.
Methods of solubilizing compounds can be used when the compounds according to the present invention exhibit insufficient solubility, such methods are known to those skilled in the art and include, but are not limited to, pH adjustment and salt formation, the use of co-solvents such as ethanol, propylene glycol, polyethylene glycol (PEG)300, PEG 400, DMA (10-30%), DMSO (10-20%), NMP (10-20%), the use of surfactants such as polysorbate 80, polysorbate 20 (1-10%), Cremophor E L, Cremophor RH40, Cremophor RH60 (5-10%), Pluronic F68/Poloxamer 188 (20-50%), Solutol HS15 (20-50%), vitamin ETS, and d- α -phenolic PEG 1000 succinate (20-50%), the use of complexation such as HP β CD and SBE β (10-40%), and the use of advanced approaches such as micelle, polymer addition, nanoparticle suspension, and tocopherol formation.
A wide variety of methods of administration can be used in conjunction with the compounds of the present invention. The compounds of the invention can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, liposomally, via inhalation, vaginally, intraocularly, via local delivery (e.g., by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally, or in combination. The compounds according to the invention can also be administered or co-administered in sustained release dosage forms. The compounds may be in gaseous, liquid, semi-liquid or solid form, formulated in a mode suitable for the route of administration to be used. For oral administration, suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets and effervescent, powders and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils, and the like. For parenteral administration, reconstitution of a lyophilized powder is typically used.
As used herein, "acyl" refers to a carbonyl-containing substituent represented by the formula-c (o) -R, wherein R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, wherein the alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl.
"aliphatic" refers to moieties characterized by a linear or branched arrangement of constituent carbon atoms, and can be saturated or partially unsaturated with one or more double or triple bonds.
The term "alkyl" refers to a straight or branched chain hydrocarbon containing 1 to 20 carbon atoms (e.g., C)1-C10,C1-C6). Examples of alkyl groups include, but are not limited to, methyl, methylene, ethyl, ethylene, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. Preferably, the alkyl group has 1 to 10 carbon atoms. More preferably, the alkyl group has 1 to 4 carbon atoms.
The term "alkenyl" refers to a group containing 2 to 20 carbon atoms (e.g., C)2-C10,C2-C6) And linear or branched hydrocarbons with one or more double bonds. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, and allyl. Preferably, the alkenyl group has 2 to 10 carbon atoms. More preferably, the alkenyl group has 2 to 4 carbon atoms.
The term "alkynyl" refers to a compound containing 2 to 20 carbon atoms (e.g., C)2-C10,C2-C6) And one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-and 2-butynyl, and 1-methyl-2-butynyl. Preferably, the alkynyl group has 2 to 10 carbon atoms. More preferably, the alkynyl group has 2 to 4 carbon atoms.
The term "alkylamino" refers to-n (R) -alkyl, where R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.
"alkoxy" refers to an oxygen moiety further bearing an alkyl substituent.
"alkoxycarbonyl" refers to an alkoxy group attached to a carbonyl group.
"Oxoalkyl" refers to an alkyl group further substituted with a carbonyl group. The carbonyl group can be an aldehyde, ketone, ester, amide, acid, or acid chloride.
The term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C)3-C12,C3-C8,C3-C6) The saturated hydrocarbon ring system of (1). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "cycloalkenyl" refers to groups having 3 to 30 carbon atoms (e.g., C)3-C12) And one or more double bonds. Examples include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
The term "heterocycloalkyl" refers to a saturated or unsaturated non-aromatic 5 to 8 membered monocyclic, 8 to 12 membered bicyclic, or 11 to 14 membered tricyclic ring system having 1-4 heteroatoms (e.g., O, N, S, B, P, Si, or Se), which may be the same or different. Examples of heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxethyl, morpholinyl, and tetrahydrofuranyl.
The term "heterocycloalkenyl" refers to a non-aromatic 5-to 8-membered monocyclic, 8-to 12-membered bicyclic, or 11-to 14-membered tricyclic ring system having one or more heteroatoms (e.g., O, N, S, P, B, Si or Se) and one or more double bonds.
The term "aryl" refers to a monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system of 6 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "heteroaryl" refers to a 5-to 8-membered monocyclic, 8-to 12-membered bicyclic, or 11-to 14-membered tricyclic aromatic ring system having one or more heteroatoms (e.g., O, N, S, P, or Se). Examples of heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl.
The above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkylamino, aryl, and heteroaryl groups include both substituted and unsubstituted moieties. Possible substituents on alkylamino, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl include, but are not limited to, C1-C10Alkyl radical, C2-C10Alkenyl radical, C2-C10Alkynyl, C3-C20Cycloalkyl radical, C3-C20Cycloalkenyl radical, C1-C20Heterocycloalkyl radical, C1-C20Heterocycloalkenyl, C1-C10Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C10Alkylamino, arylamino, hydroxy, halogen, oxo (O), thio (S), thio, silyl, C1-C10Alkylthio, arylthio, C1-C10Alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, mercapto, acylamino, thioureido, thiocyanate, sulfonamido, guanidine, ureido, cyano, nitro, acyl, thioacyl, acyloxy, ureido, carbamoyl, carboxyl and carboxylic ester. On the other hand, possible substituents on alkyl, alkenyl or alkynyl include other than C1-C10All substituents mentioned above other than alkyl. Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl groups may also be fused to one another.
"amino" refers to a nitrogen moiety further bearing two substituents, wherein each substituent has a hydrogen or carbon atom that is α bonded to the nitrogen.
"aromatic" refers to the moiety in which the building atoms constitute an unsaturated ring system in which all the atoms are hybridized sp2 and the total number of pi electrons is equal to 4n + 2. The aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon atoms and non-carbon atoms (see heteroaryl).
"carbamoyl" refers to the group-OC (O) NRaRbWherein R isaAnd RbEach independently being two further substituents wherein the hydrogen or carbon atom is at position α on the nitrogen note that the carbamoyl moiety may include protected derivatives thereof.
"carbonyl" means a radical-C (O) -. Note that the carbonyl group can be further substituted with a variety of substituents to form different carbonyl groups, including acids, acid halides, amides, esters, and ketones.
"carboxy" refers to the group-C (O) O-. Note that the compounds of the present invention containing a carboxyl moiety may include protected derivatives thereof, i.e., wherein the oxygen atom is substituted with a protecting group. Suitable protecting groups for the carboxyl moiety include benzyl, t-butyl, and the like.
"cyano" refers to the group-CN.
"formyl" refers to the group-CH ═ O.
"iminomethyl" refers to the group-HC ═ NH.
"halogen" means fluorine, chlorine, bromine or iodine.
As part of an isolated group or larger group, "halo-substituted alkyl" refers to an "alkyl" group substituted with one or more "halo" atoms, such terms being as defined herein. Halogen-substituted alkyl groups include haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, and the like.
"hydroxy" refers to the group-OH.
An "imine derivative" refers to a derivative comprising a-C (═ NR) -moiety, where R comprises a hydrogen or carbon atom at position α of the nitrogen.
"isomers" means any compound having the same molecular formula but differing in the nature or sequence of the bonding of its atoms or the arrangement of its atoms in space. Isomers in which the arrangement of atoms in space is different are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", while stereoisomers that are non-superimposable mirror images are referred to as "enantiomers" or sometimes "optical isomers". The carbon atom to which four different substituents are bonded is referred to as a "chiral center". Compounds with one chiral center have two enantiomeric forms of opposite chirality. The mixture of the two enantiomeric forms is referred to as a "racemic mixture".
"Nitro" means the radical-NO2。
"protected derivative" refers to a derivative of a compound in which the reactive site is blocked by a protecting group. The protected derivatives may be used in the preparation of medicaments or may themselves have inhibitor activity. A comprehensive list of suitable Protecting Groups can be found in T.W.Greene, Protecting Groups in Organic Synthesis, 3 rd edition, Wiley & Sons, 1999.
The term "substituted" means that an atom or group of atoms has replaced a hydrogen as a substituent attached to another group. For aryl and heteroaryl, the term "substituted" refers to any level of substitution, i.e., mono-, di-, tri-, tetra-, or penta-substitution, wherein such substitution is permitted. Substituents are independently selected and may be located at any chemically accessible position. The term "unsubstituted" means that a given moiety, through available valence states, may consist only of a hydrogen substituent (unsubstituted).
If a functional group is described as "optionally substituted," the functional group can be (1) unsubstituted or (2) substituted. If a carbon of a functional group is described as optionally substituted with one or more of a series of substituents, one or more hydrogen atoms (to any extent, if present) on that carbon may be replaced independently and/or together with independently selected optional substituents.
"sulfide" means-S-R, where R is H, alkyl, carbocyclic, heterocyclic, carbocycloalkyl, or heterocycloalkyl. Specific sulfide groups are mercapto; alkyl sulfides, such as methyl sulfur compounds (-S-Me); aryl sulfur compounds, such as phenyl sulfur compounds; aralkyl sulfur compounds, such as benzyl sulfur compounds.
"sulfinyl" means the radical-S (O) -. Note that the sulfinyl group can be further substituted with a variety of substituents to form different sulfinyl groups, including sulfinic acid, sulfinamide, sulfinate, and sulfoxide.
"Sulfonyl" means the radical-S (O) -. Note that the sulfonyl group can be further substituted with a variety of substituents to form different sulfonyl groups, including sulfonic acids, sulfonamides, sulfonates, and sulfones.
"Thiocarbonyl" means a group-C (S) -. Note that the thiocarbonyl group may be further substituted with a variety of substituents to form different thiocarbonyl groups, including thioacids, thioamides, thioesters, and thioketones.
"animals" include humans, non-human mammals (e.g., non-human primates, rodents, mice, rats, hamsters, dogs, cats, rabbits, cows, horses, sheep, goats, pigs, deer, etc.) and non-mammals (e.g., birds, etc.).
As used herein, "bioavailability" is the fraction or percentage of an administered dose of a drug or pharmaceutical composition that reaches the systemic circulation intact. Typically, the bioavailability is 100% when the drug is administered intravenously. But when administered via other routes (e.g., oral), the bioavailability decreases (e.g., due to incomplete absorption and first pass metabolism). Methods to improve bioavailability include prodrug approaches, salt synthesis, particle size reduction, complexation, modification of physical form, solid dispersion, spray drying, and hot melt extrusion.
"disease" specifically includes any unhealthy condition of an animal or a part thereof, and includes unhealthy conditions that may be caused by or accompanied by a medical or veterinary treatment applied to the animal, i.e., a "side effect" of such treatment.
"pharmaceutically acceptable" means that which is generally safe, non-toxic, and neither biologically nor otherwise undesirable for use in preparing a pharmaceutical composition, and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
"pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the invention, as defined above, which salt possesses the desired pharmacological activity. Such salts include acid addition salts formed with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts, which can be formed in the presence of an acidic proton capable of reacting with an inorganic or organic base. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, mesylate "deferoxamine", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1' -methylene-bis (2-hydroxy-3-naphthoate)), alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. Pharmaceutically acceptable salts may involve the inclusion of another molecule such as an acetate, succinate or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. For the example where the plurality of charged atoms is part of a pharmaceutically acceptable salt, the salt may have a plurality of counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.
As defined by The International Union of Pure and applied Chemistry, The "pharmacophore" is a collection of spatial and electronic features necessary to ensure optimal supramolecular interaction with a particular biological target and to trigger (or block) its biological response. For example, Camptothecin (Camptothecin) is a well-known pharmacophore of the drugs topotecan (topotecan) and irinotecan (irinotecan). Nitrogen mustards are a pharmacophore of a range of widely used nitrogen mustards such as melphalam (Melphalan), Cyclophosphamide (Cyclophosphamide), Bendamustine (Bendamustine) and the like.
By "prodrug" is meant a compound which is metabolically converted in vivo to the active drug according to the invention. For example, the inhibitor comprising a hydroxyl group may be administered in the form of an ester which is converted to a hydroxyl compound in vivo by hydrolysis.
"stability" generally refers to the length of time a drug retains its properties without losing potency. Sometimes this is referred to as shelf life. Factors that affect drug stability also include, inter alia, the chemical structure of the drug, impurities in the formulation, pH, water content, and environmental factors such as temperature, oxidation, light, and relative humidity. Stability can be improved by providing appropriate chemical and/or crystal modifications (e.g., surface modifications that alter the kinetics of hydration; different crystals that may have different properties), excipients (e.g., any substance other than the active substance in the dosage form), encapsulation conditions, storage conditions, and the like.
A "therapeutically effective amount" of a composition described herein refers to an amount of the composition that provides a therapeutic effect to the treated subject at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject exhibits signs or sensations of effect). An effective amount of the above-described composition may range from about 0.1mg/kg to about 500mg/kg, preferably from about 0.2 to about 50 mg/kg. Effective dosages will also vary depending upon the route of administration and the possibility of co-administration with other agents. It will be understood, however, that the total daily dosage of the compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for a particular patient will depend upon a variety of factors including the condition being treated and the severity of the condition; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors well known in the medical arts.
As used herein, the term "treating" refers to administering a compound to a subject having a neoplastic or immune disorder, or having a symptom or predisposition thereof, with the purpose of curing, healing, alleviating, relieving, altering, remedying, alleviating, ameliorating, or affecting the disorder, the symptoms of the disorder, or the predisposition of the disorder. The term "effective amount" refers to the amount of active agent required to impart the desired therapeutic effect in the subject. As will be appreciated by those skilled in the art, the effective amount may vary depending on the route of administration, the use of excipients, and the possibility of co-administration with other agents.
"subject" refers to both human and non-human animals. Examples of non-human animals include all vertebrates, such as mammals, such as non-human primates (particularly higher primates), dogs, rodents (e.g., mice or rats), guinea pigs, cats, and non-mammals such as birds, amphibians, reptiles, and the like. In a preferred embodiment, the subject is a human. In another embodiment, the subject is an experimental animal or an animal suitable as a model for a disease.
"combination therapy" includes administration of a test compound of the invention to a subject in combination with another biologically active ingredient (such as, but not limited to, a second and different anti-neobiological agent) and non-drug therapy (such as, but not limited to, surgery or radiation therapy) in further combination with the compound. For example, the compounds of the present invention may be used in combination with other pharmaceutically active compounds or non-pharmaceutical therapies, preferably compounds that enhance the effects of the compounds of the present invention. The compounds of the invention may be administered concurrently (as a single formulation or separate formulations) or sequentially with other therapies. In general, combination therapy contemplates administration of two or more drugs/treatments in a single treatment cycle or course.
In one embodiment, the compounds of the present invention are administered in combination with one or more conventional chemotherapeutic agents. Conventional chemotherapeutic agents include a variety of treatments in the oncology field. These agents are administered at various stages of the disease in order to shrink the tumor, destroy the remaining cancer cells remaining after surgery, induce remission, maintain remission and/or alleviate symptoms associated with the cancer or its treatment. Examples of such agents include, but are not limited to, alkylating agents such as nitrogen mustards (e.g., bendamustine, cyclophosphamide, melphalan, benzyl chlorobutyrate, ifosfamide), nitrosoureas (e.g., carmustine, lomustine, and streptozocin), ethyleneimines (e.g., thiotepa, hexamethyl melanin), alkylsulfonates (e.g., busulfan), hydrazines and triazines (e.g., altretamine, procarbazine, dacarbazine, and temozolomide) and platinum-based agents (e.g., carboplatin, cisplatin, and oxaliplatin); plant alkaloids, such as podophyllotoxins (e.g., etoposide and teniposide (Tenisopide)), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vincristine, vinblastine, and vinorelbine); antitumor antibiotics, such as chromomycins (e.g., actinomycin D and plicamycin), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, mitoxantrone, and idarubicin), and miscellaneous antibiotics such as mitomycin and bleomycin; antimetabolites, such as folate antagonists (e.g., methotrexate), pyrimidine antagonists (e.g., 5-fluorouracil, floxuridine (Foxuridine), cytarabine, capecitabine, and gemcitabine), purine antagonists (e.g., 6-mercaptopurine and 6-thioguanine), and adenosine deaminase inhibitors (e.g., cladribine, fludarabine, Nelarabine (Nelarabine), and pentostatin); topoisomerase inhibitors, such as topoisomerase I inhibitors (topotecan, irinotecan), topoisomerase II inhibitors (e.g. amsacrine, etoposide phosphate, teniposide), and heteroneodrugs, such as ribonucleotide reductase inhibitors (hydroxyurea), adrenocortical steroid inhibitors (mitotane), antimicrotubule agents (estramustine), and retinoids (bexarotene, isotretinoin, tretinoin (ATRA).
In one aspect of the invention, the compound may be administered in combination with one or more targeted anti-cancer agents that regulate protein KINASEs associated with a plurality of disease states, examples of such KINASEs include, but are not limited to, AB 1, AB 2/ARG, ACK, AKT, A0K/ACVR 21, A3K/ACVR, A4K/ACVR 1, A5K/TGFBR, A6K/BMPR 1, AMPK (A/B/G), AMPK (A/PKK) 7, PKK-K7, PKK-PKK 7, PKK-PKK 92, PKK-PKK 7, PKK-PKK 2, PKK-PKK 92, PKK-PKK 2, PKK-PKK, PKK 92, PKK-PKK, PKK-1, PKK-PKK, PKK-10, PKK-10, PKK-PKK, PKC, PKK-PKC, PKNo-10, PKK-1, PKK-PKNo-PKK-PKNo-7, PKNo-PKK-10, PKK-1, PKK-10, PKK-PKNo-1, PKK-1, PKNo-1, PKK-10, PKK-PKNo-PKK-PKNo-PKK-1, PKNo-PKK-PKNo-10, PKK-PKNo-1, PKNo-PKK-1, PKNo-1, PKK-PKNo-PKK-10, PKK-PKNo-PKK-PKNo-PKK-PKNo-10, PKK-PKNo-10, PKNo-PKK-PKNo-PKK-PKNo-PKK-PKNo-PKK-PKNo-PKK-1, PKK-PKNo-1, PKNo-PKK-PKNo-1, PKK-PKNo-PKK-PKNo-1, PKK-1, PKNo-PKK-PKNo-7, PKK-PKNo-PKK-PKNo-PKK-PKNo-10, PKK-PKNo-PKK-7, PKK-1, PKNo-PKK-PKNo-PKK-PKNo-7, PKNo-PKK-PKNo-PKK-PKNo-PKK-PKNo-1, PKK-7, PKK-PKNo-1, PKNo-7, PKK-10, PKK-PKNo-7, PKK-PKNo-PKK-PKNo-PKK-PKNo-7, PKNo-1, PKK-PKNo-10, PKNo-PKK-PKNo-PKK-1, PKNo-PKK-PKNo-7, PKNo-7, PKNo-7, PKNo-10, PKNo-7, PKNo-7, PKNo-1, PKNo-7, PKNo-1, PKNo-1, PKNo-7, PKNo-PKNo.
In another aspect of the invention, the compounds of the invention may be administered in combination with one or more targeted anti-cancer agents that modulate non-kinase biological targets, pathways or processes, including, but not limited to, heat shock proteins (e.g., HSP90), poly ADP (adenosine diphosphate) -ribose polymerase (PARP), Hypoxia Inducible Factor (HIF), proteasomes, Wnt/Hedgehog/Notch signaling proteins, TNF- α, matrix metalloproteinases, farnesyl transferase, apoptotic pathways (e.g., Bcl-x L, Bcl-2, Bcl-w), Histone Deacetylases (HDAC), Histone Acetyl Transferase (HAT) and methyltransferases (e.g., histone lysine methyltransferases, histone arginine methyltransferases, DNA methyltransferases, etc.) and other immunotherapies (e.g., anti-PD 1, anti-PD L1, anti-CT L A4, CAR-T, IDO, A2A antagonists, etc.).
In another aspect of the invention, the compounds of the invention are administered in combination with one or more other anti-cancer agents, including but not limited to gene therapy, RNAi cancer therapy, chemoprotectants (e.g., sulfamine (amfostine), mesna, dexrazoxane), antibody conjugates (e.g., brentuximab vedotin, ibritumometaxetan), cancer immunotherapy (e.g., interleukin-2), cancer vaccines (e.g., sipuleucel-T) or monoclonal antibodies (e.g., Bevacizumab (Bevacizumab), Alemtuzumab (Alemtuzumab), rituximab, trastuzumab, and the like).
In another aspect of the invention, the subject compounds are administered in combination with radiation therapy or surgery. Radiation is typically delivered internally (radioactive material implanted near the cancer site) or externally from equipment using photon (X-ray or gamma ray) or particle radiation. Where the combination therapy further includes radiation therapy, the radiation therapy can be administered at any suitable time so long as the beneficial effect resulting from the combined action of the therapeutic agent and the radiation therapy is achieved. For example, where appropriate, when radiation therapy is temporarily removed from administration of the therapeutic agent, beneficial effects may still be obtained, perhaps up to several days or even weeks.
In certain embodiments, the compounds of the invention are administered in combination with one or more of radiation therapy, surgery, or anti-cancer agents, including but not limited to DNA damaging agents, antimetabolites, topoisomerase inhibitors, anti-microtubule agents, kinase inhibitors, epigenetic agents, HSP90 inhibitors, PARP inhibitors, and antibodies targeting VEGF, HER2, EGFR, CD50, CD20, CD30, CD33, and the like.
In certain embodiments, the compounds of the present invention are administered in combination with one or more of the following: abarelix, abiraterone acetate, aldesleukin, alemtuzumab, altretamine, anastrozole, asparaginase, bendamustine, bevacizumab, bexarotene, bicalutamide, bleomycin, bortezomib (bortezombi), brentuximab vedotin, busulfan, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, clomiphene, crizotinib, cyclophosphamide, dasatinib, daunorubicin liposome, decitabine, degarelix (degarelix), dinil interleukin 2(denileukin difittox), dinil interleukin 2, dinolizumab (denosumab), docetaxel, doxorubicin liposome, epirubicin, eribulin mesylate (eribulin), erlotinib, valacitretin, etoposide, estramustine, etoposide, estramustin, estramustine, etoposide, estramustine, etoposide, flutemib, flutemsirolimus, doxepirubicin, doxycycline, and a, Fumonidine, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, ipilimumab, ixabepilone, lapatinib dibenzide, lenalidomide, letrozole, calcium folinate, leuprolide acetate, levamisole, lomustine, nitrogen mustard, melphalan, methotrexate, mitomycin C, mitoxantrone, nelarabine (nellabine), nilotinib (nilotinib), oxaliplatin, paclitaxel protein-binding particles, pamidronate (pamidron), Panitumumab (Panitumumab), pegamunase, interferon alfa-2, mellitinib, disodium griseofuracilostazol, mellitinib, doxin, mellitinib, temsirolimumab, and paclitaxel, pamidronate (pamidronate), panitumomab (panitumomab), pegamustin, doxorab, mellitorine, tretinib, mellitinib, doxin, temozolinicin, temsirolimumab, temsirolimus, and other, Teniposide, thalidomide, toremifene, tositumomab, trastuzumab, tretinoin, uramustine, Vandetanib (Vandetanib), vemurafenib, vinorelbine, zoledronic acid, Pembrolizumab (Pembrolizumab), nivolumab (nivolumab), atezumab (atezolizumab), dutvacizumab), avizumab (durvalumab), avizumab (avelumab), tisagenlecucercel, radiotherapy or surgery.
The invention further provides methods for preventing or treating a neonatal disease or an autoimmune disease. In one embodiment, the present invention relates to a method of treating a neonatal or autoimmune disease in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a compound of the present invention. In one embodiment, the invention further provides the use of a compound of the invention in the manufacture of a medicament for the cessation or reduction of a neoplastic or autoimmune disease.
In certain embodiments, the neoplastic disease is lung cancer, head and neck cancer, central nervous system cancer, prostate cancer, testicular cancer, colorectal cancer, pancreatic cancer, liver cancer, stomach cancer, biliary tract cancer, esophageal cancer, gastrointestinal stromal tumor, breast cancer, cervical cancer, ovarian cancer, uterine cancer, leukemia, lymphoma, multiple myeloma, melanoma, basal cell carcinoma, squamous cell carcinoma, bladder cancer, kidney cancer, sarcoma, mesothelioma, thymoma, myelodysplastic syndrome, or myeloproliferative disease.
Autoimmune diseases that can be affected using the compounds and compositions according to the invention include, but are not limited to, allergy, alzheimer's disease, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, celiac disease, chagas disease, chronic obstructive pulmonary disease, chronic Idiopathic Thrombocytopenic Purpura (ITP), churg-strauss syndrome, crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, Goodpasture's syndrome (and related glomerulonephritis and pneumorrhagia), ravesia (graves ' disease), guillain-barre syndrome (guillain-barre syndrome), Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, morphosis, multiple sclerosis, myasthenia gravis, narcolepsy, neuromuscular stiffness, parkinson's disease, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, septic shock, scleroderma, Sjogren's disease, systemic lupus erythematosus (and related glomerulonephritis), temporal arteritis, organ transplant rejection and hyperacute rejection of transplanted organs, vasculitis (vasculitis associated with ANCA (vasculitides) and other vasculitis diseases), vitiligo and wegener's granulomatosis.
It is to be understood that the invention is not limited to the particular embodiments shown and described herein, and that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the appended claims.
The compounds according to the invention can be synthesized according to various schemes. The necessary starting materials can be obtained by standard organic chemical processes. The compounds and processes of the present invention may be better understood in connection with the following representative synthetic schemes and examples, which are intended as an illustration only and not as a limitation on the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and changes and modifications, including but not limited to those relating to chemical structures, substituents, derivatives, and/or methods of the invention, may be made without departing from the spirit of the invention and the scope of the appended claims.
Synthesis of intermediatesA typical process of (a) is described in scheme 1 below: r in general scheme 11、R2M and n are the same as those described in the summary section above.
In scheme 1, a suitable ketone starting material 1-1 can be reacted with phosphorus tribromide (tribromophosphinothhine) to form an aldehyde intermediate 1-2, which can be coupled with Boc-protected piperazine to form an intermediate 1-3. Thereafter, 1-3 would be coupled via a Suzuki reaction with the appropriate phenylboronic acid to form intermediates 1-4, followed by a debo (de-boc) process to yield key intermediates 1-5.
Synthesis of intermediates(wherein R is5Is NO2) A typical process of (a) is set forth in scheme 2 below. R in general scheme 24、R5L and R6The same as those described in the summary section above.
In scheme 2, reaction of starting material 2-1 with a suitable alcohol or amine will yield 2-2.
Synthesis ofA typical method of (2) is described in scheme 4 below.
In scheme 4, protection of the free NH of the commercial starting material 3-6 yields 3-7, which can be reacted with 3, 3-diethoxypropan-1-ol in the presence of a base to form alkoxide (alkoxide) intermediate 4-2. Subsequently with NH2Buckwald coupling of Boc provided intermediate 4-3, which could be cyclized in a tandem reaction to tricyclic intermediate 4-4: deprotection of Boc groups, 7-membered cyclic imine formation and reduction.
Synthesis of(wherein Z is2、R9And k are the same as those described in the summary section of the invention above) are described in schemes 4-2 (method a), 4-3 (method B), 4-4 (method C) below.
Method A
Scheme 4-2
In scheme 4-2, the substitution reaction of intermediate 3-1-2 (which was synthesized from 3-1-1 in scheme 3) provides alkoxide intermediate 4-2-1. Subsequently with NH2Buchwald or Ullmann coupling of Boc provides intermediate 4-2-2, which can be cyclized in a one-pot series reaction to tricyclic intermediate 4-2-3: deprotection of the Boc group, 7-membered cyclic imine formation and reduction of the imine.
Method B
Schemes 4 to 3
In scheme 4-3, 3-1-2 is converted to alkoxide intermediate 4-3-1. Subsequent Buchwald or Ullmann reaction ring closure provides intermediate 4-3-2, followed by deprotection of the Ts group to yield intermediate 4-3-3.
Method C
Schemes 4 to 4
In scheme 4-4, 3-1-2 is converted to alkoxide intermediate 4-4-1. Subsequently with NH2Buchwald coupling or Ullmann reaction of-Ts affords intermediate 4-4-2. And subsequent Mitsunobu ring closure of 4-4-2 gives intermediate 4-4-3. Finally, deprotection of the Ts group yields intermediate 4-4-4.
Synthesis of(wherein Z is2、R9And k are the same as those described in the summary section of the invention above) are described in schemes 4-5 (method a), 4-6 (method B), 4-7 (method B) below.
Method A
Schemes 4 to 5
In scheme 4-5, the substitution reaction of intermediate 3-1-2 (which was synthesized from 3-1-1 in scheme 3) provides intermediate 4-5-1. Subsequently with NH2Buchwald or Ullmann coupling of Boc provided intermediate 4-5-2, which can be cyclized in a one-pot series reaction to tricyclic intermediate 4-5-3: deprotection of Boc groups, 7-membered cyclic imine formation and reduction.
Method B
Schemes 4 to 6
In scheme 4-6, 3-1-2 is converted to intermediate 4-6-1. Subsequent ring closure of the Buchwald or Ullmann reaction affords intermediate 4-6-2, and subsequent deprotection of the Ts group yields intermediate 4-6-3.
Method C
Schemes 4 to 7
In scheme 4-7, 3-1-2 is converted to intermediate 4-7-1 via nucleophilic aromatic substitution. Reduction of ester 4-7-1(R ═ Me, Et) formed intermediate 4-7-2. Subsequently with NH2Buchwald or Ullmann coupling of-Ts affords intermediate 4-7-3, which undergoes Mitsunobu ring closure to form 4-7-4, followed by deprotection of the Ts group to yield intermediate 4-7-5.
Synthesis of(wherein Z is2、R9And k is the same as those described in the summary section of the invention above) are described in schemes 4-8 below.
Schemes 4 to 8
In scheme 4-8, the thioether N-oxidation of 4-8-1 (which is synthesized from schemes 4-5, 4-6, 4-7) is reacted with m-CPBA to form intermediate 4-8-2.
(wherein Z is2、R9And k is the same as those described in the summary section of the invention above) can be prepared by a similar route to scheme 4, scheme 4-2, scheme 4-3, scheme 4-4, scheme 4-5, scheme 4-6, scheme 4-8.
(wherein Q is a 7-membered ring, R7、R8、R9、Y、W、W1And k is the same as those described in the summary section of the invention above) may be prepared by the same protocol4. Schemes 4-2, schemes 4-3, schemes 4-4, schemes 4-5, schemes 4-6, schemes 4-7, schemes 4-8.
Synthesis of a Compound of formula (D) (wherein Z2Is O) A typical process is set forth in scheme II:
in scheme II, intermediates 1-5 undergo nucleophilic aromatic substitution with selected p-fluoro-2-bromo-benzoate to give II-2. Buckwald coupling of II-2 with the appropriate amine intermediate gives II-3. Subsequent deprotection of II-3 with TFA to remove the SEM group and NaOH to remove the ester group yielded the free carboxylic acid intermediate II-5. Coupling of II-5 with 2-2 provides the final product having formula (D).
Compounds of formula (D) having different Z may be prepared by methods similar to general scheme II, using appropriate starting materials and intermediates.
The compounds of formulae (C), (B) and (a) may be prepared by methods analogous to general scheme II, using suitable starting materials and intermediates.
The compounds and processes of the present invention may be better understood by reference to the following examples, which are intended as illustrations only and not as a limitation on the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and changes and modifications, including but not limited to those relating to chemical structures, substituents, derivatives, and/or methods of the invention, may be made without departing from the spirit of the invention and the scope of the appended claims.
If NMR data are present, then1H spectra were obtained on X L400 (400MHz) and taken from Me4The ppm low magnetic field of Si is reported in parentheses indicating the number of protons, multiplicities, and coupling constants in Hertz the analysis was performed using the Agilent1100 system if HP L C data is presented, the analysis was performed using an Applied Biosystems API-100 mass spectrometer and Shimadzu SC L-10A L C column if L C/MS data is presented.
Example 1-1: preparation of 1- ((4 '-chloro-5, 5-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazine
Synthesis of 2-bromo-4,4-dimethylcyclohex-1-enecarbaldehyde 2. A solution of anhydrous chloroform (57ml) and anhydrous N, N-dimethylformamide (9M L) was cooled to about 3 deg.C (internal temperature) under nitrogen, after which phosphorus tribromide (10M L, 0.1mol) was introduced dropwise at a rate such that the reaction was maintained at about 3 deg.C. after the addition was complete, the reaction was allowed to warm slowly to about 10 deg.C, then the temperature was raised to 70 deg.C, where it was maintained for 30 min. the reaction was cooled to room temperature and 3, 3-dimethylcyclohexanone 1(5g,0.04mol) was added slowly over 20 minutes. after the reaction was complete, the reaction was brought to 70 deg.C and stirred for 1.5 h. then the mixture was cooled to 0 deg.C and 4M solution (53ml) was added slowly-the pH of the solution was adjusted to about 7 with 5M NaOH to obtain a solution, the sodium acetate solution was extracted with about 100 parts Na L parts of an organic heptane solution (3, dried)2SO4) Filtered and concentrated under reduced pressure to give 2-bromo-4,4-dimethylcyclohex-1-enecarbaldehyde 2(4g, 49%) as a yellow oil.
Synthesis of 2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enecarbaldehyde 3: to a degassed solution of 2-bromo-4, 4-dimethylcyclohex-1-eneformylimidazole 2(5g,0.023mol) and 4-chlorophenylboronic acid (3.6g,0.023mol) in 1, 4-dioxane at room temperature was added 2M Na2CO3Solution (20.4 ml). Nitrogen was bubbled through the mixture for 2min, then PdCl was added2(dppf) (0.5 g). The reaction flask was heated to 120 ℃ where it was maintained for 3 h. After this time, the suspension was cooled to room temperature and filtered through Celite. The collected solid was washed with additional dichloromethane and the combined filtrate and wash was concentrated under reduced pressure. Purification by column chromatography on silica with PE: EA ═ 20:1 gave 2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-enoylimidazole 3(3g, 53%) as a white solid. MS:249[ M + H ]]+
Synthesis of (2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-enyl) methanol 4A solution of 2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enecarbaldehyde 3(20g,80.6mmol) in MeOH (100m L) was cooled to 0 deg.C in a certain ratioAdd NaBH portion by portion to the reaction4(3.1g,80.6mmol) such that the reaction is maintained at 0-5 ℃ after addition, the mixture is stirred at 0 ℃ for 1h water is slowly added to the mixture and extracted with EA (200m L x3), the organic layer is washed with brine, Na is used2SO4Dried, filtered, and concentrated under reduced pressure to give (2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-enyl) methanol 4(15g, 75%) as a white solid. MS 233[ M + H-H2O]+
Synthesis of 1- (2- (bromomethyl) -5, 5-dimethylcyclohex-1-enyl) -4-chlorobenzene 5: adding Et2(2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-enyl) methanol in O4 (15g,0.060mol) solution (300ml) was added to 0 deg.C, after which phosphorus tribromide (7.5m L) was added dropwise to the mixture, after which the mixture was stirred for 1H at 0 deg.C for 90 min, H was added to the reaction mixture2O, followed by extraction with EA. The organic layer was washed with saturated NaHCO3Washing with solution and brine, and adding Na2SO4Drying, filtration and concentration under reduced pressure gave 1- (2- (bromomethyl) -5, 5-dimethylcyclohex-1-enyl) -4-chlorobenzene 5(18g, 96%) as a colorless oil.
Synthesis of tert-butyl 4- ((2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-enyl) methyl) piperazin-1-carboxylate: TEA (12.2g,0.12mol) was added to a solution (200ml) of 1-bromo-2- (bromomethyl) -5, 5-dimethylcyclohex-1-ene 5(21g,0.067mol) and tert-butylpiperazine-1-carboxylate (12.4g,0.067mol) in dichloromethane at room temperature. The reaction was stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. Purification by column chromatography on silica with PE: EA ═ 20:1 afforded tert-butyl 4- ((2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-enyl) methyl) piperazine-1-carboxylate 6(21g, 75%).
Synthesis of 1- ((2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-enyl) methyl) piperazine hydrochloride to a solution (20ml) of tert-butyl 4- ((2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-enyl) methyl) piperazine-1-carboxylate 6(30g,0.072mol) in MeOH concentrated HCl (50m L) was added and the reaction stirred for 24 hours then concentrated under reduced pressure saturated Na was added2CO3The solution was adjusted to pH about 8-9 and the mixture was extracted with dichloromethane (x 2). The combined extracts are washed with brine,drying (Na)2SO4) The oil product was treated with MeOH/HCl (g) (3M,500M L), stirred for 1 hour, then concentrated under reduced pressure to give the product 1- ((2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-enyl) methyl) piperazine hydrochloride IM-14-1(23g, 83%). MS:319[ M + H ]]+ 1H NMR(400MHz,DMSO)11.51(s,1H),9.60(s,1H),9.18(s,1H),7.45(d,J＝8.2Hz,2H),7.15(d,J＝8.0Hz,2H),3.43(s,8H),2.84(s,2H),2.39(s,2H),2.03(s,2H),1.45(t,J＝6.0Hz,2H),0.96(s,6H)。