Compound and use thereof
阅读说明：本技术 化合物及其用途 (Compound and use thereof ) 是由 S·M·范 J·堪卡纳拉 P·S·贾达瓦尔 B·M·穆利克 F·卡恩 S·A·拉马钱德兰 于 2020-01-17 设计创作，主要内容包括：提供了作为腺苷受体的调节剂的化合物。所述化合物可以用作用于治疗通过G蛋白偶联受体信号传导通路介导的疾病的治疗剂,并且可以特别用于肿瘤学。(Compounds that are modulators of adenosine receptors are provided. The compounds may be used as therapeutic agents for the treatment of diseases mediated by the G protein-coupled receptor signalling pathway, and may be of particular use in oncology.)
1. A compound of formula (I):
or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
R1is H or C1-C6Alkyl, wherein R is1C of (A)1-C6Alkyl is optionally substituted by oxo or RaSubstitution;
R2and R4Each independently is H, RbOr oxo, with the proviso that when R is2is-NR9R10When then R is9And R10Is not H;
R3is H or Rc；
Each Ra、RbAnd RcIndependently is C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C＝NH(OR8)、-C(O)R8、-OC(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-C(O)NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-P(O)(OR9)(OR10)、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, - (C)1-C3Alkylene) CN, - (C)1-C3Alkylene) OR8、-(C1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene) CF3、-(C1-C3Alkylene) NO2、-C＝NH(OR8)、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene) OC (O) R8、-(C1-C3Alkylene group) C (O) OR8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) OC (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)OR9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-C(O)(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene group P (O) (OR)9)(OR10)、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene radical)(3-12 membered heterocyclic group), - (C)1-C3Alkylene) (5-to 10-membered heteroaryl) or- (C)1-C3Alkylene) (C6-C14Aryl) in which each R isa、RbAnd RcIndependently optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group;
is a single or double bond, wherein when it is a double bond, R2Is an oxo group;
is a single or double bond, whereinWhen it is a double bond, R4Is an oxo group;
andone is a double bond and the other is a single bond;
a is C6-C12Aryl, 5-to 10-membered heteroaryl, 9-to 10-membered carbocyclic ring, or 9-to 10-membered heterocyclic ring, wherein C of A is6-C12Aryl, 5-to 10-membered heteroaryl, 9-to 10-membered carbocyclic ring, or 9-to 10-membered heterocyclic ring is optionally further defined by R6Substitution;
b is phenyl, 5-to 6-membered heteroaryl, 5-to 6-membered carbocycle, 5-to 6-membered heterocycle, or 9-to 10-membered heteroaryl, wherein said phenyl, 5-to 6-membered heteroaryl, 5-to 6-membered carbocycle, 5-to 6-membered heterocycle, or 9-to 10-membered heteroaryl of B is optionally further substituted with R7Substitution;
each R6And R7Independently is oxo, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C＝NH(OR8)、-C(O)R8、-OC(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-C(O)NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-P(O)(OR9)(OR10)、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, - (C)1-C3Alkylene) CN, - (C)1-C3Alkylene) OR8、-(C1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene) CF3、-(C1-C3Alkylene) NO2、-C＝NH(OR8)、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene) OC (O) R8、-(C1-C3Alkylene group) C (O) OR8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) OC (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)OR9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-C(O)(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene group P (O) (OR)9)(OR10)、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-12 membered heterocyclic group), - (C)1-C3Alkylene) (5-to 10-membered heteroaryl) or- (C)1-C3Alkylene) (C6-C14Aryl) in which each R is6And R7Independently optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group, a carboxyl group,
with the proviso that when R1Is C1-C6When alkyl is present, thenR6Is oxo, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C＝NH(OR8)、-C(O)R8、-OC(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-C(O)NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-P(O)(OR9)(OR10)、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, - (C)1-C3Alkylene) CN, - (C)1-C3Alkylene) OR8、-(C1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene) CF3、-(C1-C3Alkylene) NO2、-C＝NH(OR8)、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene) OC (O) R8、-(C1-C3Alkylene group) C (O) OR8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) OC (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)OR9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-C(O)(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene group P (O) (OR)9)(OR10)、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-12 membered heterocyclic group), - (C)1-C3Alkylene) (5-to 10-membered heteroaryl) or- (C)1-C3Alkylene) (C6-C14Aryl groups);
each R8Independently of each other is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C6-C14Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, - (C)1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (C6-C14Aryl), - (C)1-C3Alkylene) (5-6 membered heteroaryl), or- (C)1-C3Alkylene) (3-6 membered heterocyclyl), wherein R is8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C6-C14Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, - (C)1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (C6-C14Aryl), - (C)1-C3Alkylene) (5-6 membered heteroaryl), and — (C)1-C3Alkylene) (3-6 membered heterocyclyl) is independently optionally substituted with: halogen, oxo, -CN, -OR13、-NR13R14、-P(O)(OR13)(OR14) Phenyl optionally substituted by halogen, or C optionally substituted by halogen, -OH or oxo1-C6An alkyl group;
R9and R10Each independently is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C6-C14Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, - (C)1-C3Alkylene) NR11R12、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-6 membered heterocyclic group), - (C)1-C3Alkylene) (5-6 membered heteroaryl) or- (C)1-C3Alkylene) (C6Aryl) in which said R is9And R10C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C6-C14Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, - (C)1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-6 membered heterocyclic group), - (C)1-C3Alkylene) (5-6 membered heteroaryl) and — (C)1-C3Alkylene) (C6Aryl) is independently optionally substituted with: halogen, oxo, -CN, -OR13、-NR13R14Or C optionally substituted by halogen, -OH or oxo1-C6An alkyl group;
or R9And R10Together with the atoms to which they are attached form a 3-6 membered heterocyclyl optionally substituted with: halogen, oxo, -OR13、-NR3R14Or C optionally substituted by halogen, oxo or-OH1-C6An alkyl group;
R11and R12Each independently hydrogen, C optionally substituted by halogen or oxo1-C6Alkyl, C optionally substituted by halogen or oxo2-C6Alkenyl, or C optionally substituted by halogen or oxo2-C6An alkynyl group;
or R11And R12Together with the atoms to which they are attached form a 3-6 membered heterocyclyl optionally substituted with: halogen, oxo or C optionally substituted by halogen or oxo1-C6An alkyl group; and is
R13And R14Each independently hydrogen, C optionally substituted by halogen or oxo1-C6Alkyl, C optionally substituted by halogen or oxo2-C6Alkenyl, or C optionally substituted by halogen or oxo2-C6An alkynyl group;
or R13And R14Together with the atoms to which they are attached form a 3-6 membered heterocyclyl optionally substituted with: halogen, oxo or C optionally substituted by oxo or halogen1-C6An alkyl group.
2. The compound of claim 1, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2Is H, oxo, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, halogen, -CN, -OR8、-C(O)NR9R10、-C(O)R8、-C(O)OR8、-OC(O)R8、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)2R8、-NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-(C1-C3Alkylene) CN, - (C)1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene) (C3-C6Cycloalkyl), -S (O) R8、-(C1-C3Alkylene) OR8、-(C1-C3Alkylene) (5-10 membered heteroaryl), each of which is optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group.
3. A compound according to claim 1 or 2, or a tautomer or tautomer thereofAn isomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2Selected from: H. oxo, methyl, phenyl, cyclopropyl, fluoro, chloro, bromo, -CN, methoxy,
4. The compound of any one of claims 1-3, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2Is H.
5. The compound of claim 1, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (II):
6. the compound of any one of claims 1-5, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4Is H, oxo, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, -CN, -NR9R10Halogen, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, -C (O) NR9R10、-OR8、-SR8、-C(O)OR8or-NR8C(O)R9Each of which is independently optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group.
7. The compound of any one of claims 1-6, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4Selected from: H. oxo, methyl, ethyl,-CN, phenyl, cyclopropyl, bromo, chloro, methoxy,
8. A compound according to any one of claims 1 to 7, or a mixture thereofA mutant or isomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4Is H.
9. The compound of any one of claims 1-4, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (III):
10. the compound of any one of claims 1-9, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1Is H or methyl.
11. The compound of any one of claims 1-10, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1Is H.
12. The compound of any one of claims 1-11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a is optionally further substituted with R6Substituted C6-C12And (4) an aryl group.
13. The compound of any one of claims 1-12, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a is optionally substituted with R6Substituted phenyl or naphthyl.
14. The compound of any one of claims 1-11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a is optionally further substituted with R6Substituted 5 to 10 membered heteroaryl.
15. The compound of any one of claims 1-11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a isWherein R is6a、R6b、R6c、R6d、R6eAnd R6fEach independently is H, C1-C6Alkyl, halogen, -CN, or-OC1-C6An alkyl group.
16. The compound of any one of claims 1-11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a isWherein R is6b、R6c、R6d、R6e、R6fAnd R6gEach independently is H, C1-C6Alkyl, halogen, -CN, or-OC1-C6An alkyl group.
17. The compound of any one of claims 1-11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a isWherein X1Selected from N, C, and CH; x2Selected from NH, O, and S; and R is6a、R6bAnd R6cEach independently is H, C1-C6Alkyl, halogen, -CN, or-OC1-C6An alkyl group.
18. The compound of any one of claims 1-11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a isWherein X1Selected from N, C, and CH; x2Selected from NH, O, and S; and R is6g、R6bAnd R6cEach independently is H, C1-C6Alkyl, halogen, -CN, or-OC1-C6An alkyl group.
19. The compound of any one of claims 1-11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a is selected from the group consisting of pyridyl, quinolyl, isoquinolyl, quinoxalyl, cinnolinyl, quinazolinyl, naphthyridinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzisoxazolyl, benzooxadiazolyl, benzothiophenyl, benzisothiazolyl, benzothiadiazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazopyridyl, or a pharmaceutically acceptable salt of any of the foregoing, wherein a is selected from the group consisting of pyridyl, quinolyl, isoquinolyl, quinoxalinyl, cinnolinyl, quinazolinyl, naphthyridinyl, and benzoxazolyl, or benzoxazolyl, isoxazolyl, or benzoxazolyl, or pyrimidinyl, or one of any one of the foregoing is selected from a, Triazolopyridinyl, furopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, oxadiazolidopyridinyl, thienopyridinyl, thiazolopyridinyl, isothiazolopyridinyl, thiadiazolopyridinyl, thienopyridinyl, phthalazinyl, pyrazolothiazolyl, and imidazothiazolyl, each optionally substituted with R6And (4) substitution.
20. The compound of any one of claims 1-10, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a is selected from:
each of which is optionally substituted with R6And (4) substitution.
21. The compound of any one of claims 1-11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a is optionally further substituted with R6A substituted 9 to 10 membered carbocyclic ring.
22. The compound of any one of claims 1-11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a is selected from the group consisting of decahydronaphthyl, octahydroindenyl, 1,2,3, 4-tetrahydronaphthyl, and 2, 3-dihydroindenyl, each optionally substituted with R6And (4) substitution.
23. The compound of any one of claims 1-11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a is optionally further substituted with R6Substituted 9 to 10 membered heterocyclic ring.
24. The compound of any one of claims 1-11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a is selected from the group consisting of tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, indolinyl, isoindolinyl, tetrahydronaphthyridinyl, and hexahydrobenzimidazolyl, each optionally further substituted with R6And (4) substitution.
25. The compound of any one of claims 1-11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a is selected from the group consisting of Each of which is optionally substituted with R6And (4) substitution.
26. The compound of any one of claims 1-25, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R6Independently is C optionally substituted1-C6Alkyl groups: halogen, oxo, C3-C6Cycloalkyl, - (C)1-C3Alkylene) (C6-C14Aryl), -CN, -OR8、-NR9R10or-NR8S(O)2R9。
27. The compound of any one of claims 1-11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein a is selected from:
28. the compound of any one of claims 1-27, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is optionally further substituted with R7A substituted phenyl group.
29. The compound of any one of claims 1-27, or a tautomer or isomer thereof, or of any of the foregoingA pharmaceutically acceptable salt wherein B is optionally further substituted with R7Substituted 5 to 6 membered heteroaryl.
30. The compound of any one of claims 1-27, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl, each optionally substituted with R7And (4) substitution.
31. The compound of any one of claims 1-27, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is furanyl, pyridinyl, oxazolyl, or oxadiazolyl, each independently with R7And (4) substitution.
32. The compound of any one of claims 1-27, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is optionally further substituted with R7A substituted 5 to 6 membered fully saturated carbocyclic ring.
33. The compound of any one of claims 1-27, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is optionally further substituted with R7Substituted cyclopentyl or cyclohexyl.
34. The compound of any one of claims 1-27, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is optionally further substituted with R7Substituted 9 to 10 membered heteroaryl.
35. The compound of any one of claims 1-27, or a tautomer or isomer thereofOr a pharmaceutically acceptable salt of any of the foregoing, wherein B is selected from pyridyl, quinolyl, isoquinolyl, quinoxalinyl, cinnolinyl, quinazolinyl, naphthyridinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzisoxazolyl, benzooxadiazolyl, benzothiophenyl, benzisothiazolyl, benzothiadiazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazopyridinyl, triazolopyridyl, furopyridinyl, isoxazolopyridyl, oxadiazolopyridyl, oxadiazolidyl, quinoxalinyl, quinazolinyl, pyrazolopyridyl, quinoxalinyl, and quinoxalopyridyl, Thienopyridinyl, thiazolopyridinyl, isothiazolopyridinyl, thiadiazolopyridinyl, thienopyridinyl, phthalazinyl, pyrazolothiazolyl and imidazothiazolyl, each optionally substituted with R7And (4) substitution.
36. The compound of any one of claims 1-27, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is selected from:
each of which is optionally substituted with R7And (4) substitution.
37. A compound according to any one of claims 1-36, or a tautomer or isomer thereof, or any of the foregoingA pharmaceutically acceptable salt of wherein each R7Independently is C1-C6Alkyl, halogen, or-CN.
38. The compound of any one of claims 1-27, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein B is selected from:
39. the compound of any one of claims 1-38, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3Is H.
40. A compound selected from the compounds set forth in table 1, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
41. A pharmaceutical composition comprising a compound of any one of claims 1-40, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier.
42. A method of treating a disease mediated by the adenosine signaling pathway in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-40, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
43. A method of treating cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1-40, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
44. Inhibition of subtype A in cells2a、A2bOr A3The adenosine receptor of (a), which comprises administering to the cell a compound according to any one of claims 1 to 40, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
45. The method of claim 44, wherein the adenosine receptor is subtype A2aIn (1).
46. Use of a compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a disease mediated by the adenosine signalling pathway.
47. A kit comprising a compound of any one of claims 1-40, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
Technical Field
The present disclosure relates generally to therapeutic agents for use in therapy mediated by the G protein-coupled receptor (GPCR) signaling pathway, and more particularly to compounds that inhibit adenosine receptors (such as a)2AAn antagonist). The disclosure also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compounds or compositions in the treatment of diseases associated with the GPCR signaling pathway.
Background
Adenosine Receptors (ARs) are distributed throughout the body and are responsible for a variety of biological functions. Seven transmembrane G-protein coupled receptors (GPCRs) are divided into four distinct subtypes: a. the1、A2A、A2BAnd A3。A2AAnd A2BAR stimulates the activity of adenylyl cyclase, including an increase in cAMP levels. A. the2AAR has unique tissue localization, distinct biochemical pathways, and specific pharmacological characteristics.
Adenosine is one of the most important neuromodulators in humans in both the central and peripheral nervous systems. Adenosine is released from tumor cells and reaches immunosuppressive levels in the extracellular fluid of tumors (Blay et al (1997), Cancer Res.,57(13), p. 2602-5). The extracellular fluid of solid cancers contains adenosine at immunosuppressive concentrations. As above. This increase in adenosine concentration is a result of an increase in CD73 (exo-5' -nucleotidase) and CD39 (nucleoside triphosphate dephosphorylating enzyme) enzymes, which are responsible for the direct catabolism of ATP to adenosine. These upregulations are triggered by hypoxia and the production of HIF-1 α. High levels of adenosine surrounding tumor cells via activation of multiple adenosine receptor subtypes (and in particular A)2AReceptor) to modulate a variety of immune cells (e.g., CD 4)+T cell and cytotoxic CD8+T cells) leading to inhibition of pro-inflammatory activity and up-regulation of anti-inflammatory molecules with immunoregulatory cells (Kumar et al (2013), adenosines as an endogenous immune regulator in cancer)pathogenis, where to a gour Purriergic Signal, 9(2), pages 145-65 and Sitkowsky et al, Hotile, hypoxia-A2-adenosine fetal biology as the next barrier to over com for tumor immunology, cancer immunol. Res.2(7), page 598-; ohta (2016), A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironmental, frontiers in immunology, article No. 7, pages 1-11). Chimeric Antigen Receptor (CAR) T cells have been shown to up-regulate A2AR following Antigen-specific stimulation in vitro and in vivo (Beavls (2017), Targeting the Adenosine 2A Receptor genes chiral Antigen Receptor T Cell efficacy. J of Clin invest.127(3): page 929-941).
The survival of cancer cells depends on their ability to avoid attack by the immune system. In addition, tumor cells may override the immune system to promote tumor survival and metastasis. Adenosine, whose concentration increases in the hypoxic region of solid tumors, has been thought to interfere with tumor cell recognition by cytolytic effector cells of the immune system. (Tuite and Riss (2013) Recent details in the pharmacological physical treatment of Parkinson's disease. expert Opin. investig. drugs,12(8) pages 1335-52, Popoli et al (2002) Blockade of structural adenosine A2Areceiver products, through a predictive mechanism, a hierarchical approach to a hierarchical approach in a hierarchical approach of the hierarchy, J.Neurosci,22(5) pp.1967-75, Gessi et al (2011). Adenose receivers and cancer. Biochim Biophys Acta,1808(5), pp.1400-12).
Although all adenosine receptors now have an increasing number of recognized biological effects in tumors, a2AAnd A3Subtypes appear to be promising targets for therapeutic development. In particular, A2AActivation of the receptor results in immunosuppression which reduces anti-tumor immunity and thereby stimulates tumor growth.
A2BThe receptor is another potential target for therapeutic development. A believed to be expressed on tumor cells2BThe autocrine/paracrine stimulation of (A) enhances their metastatic potential, and (B) is2BBlockade can reduce tumor metastasis in an immunologically independent manner (Beavis et al (2013). Blockade of A)2A receptors potently suppresses the metabolism of CD73+Tumors.Proc.Natl.Acad.Sci.,110(36) pp. 14711-6). A. the2BExpression was also associated with Relapse Free Survival (RFS) of triple negative breast cancer, suggesting that this pathway may be clinically relevant. A. the2BBlockade also has the potential to modulate the immunosuppressive properties of tumor-associated immune cells, including dendritic cells and Myeloid suppressor cells (MDSCs) (Cekic et al (2011.) inhibitor A2B receptor blocks growth of broad and break tumors.j. immune.188 (1), p. 198-2Badenosin receptor-induced VEGF production and angiogenesis in a mouse melanoma model.oncotarget6(29), pp 27478-89; iannone et al (2013) Block of A2BThe adenosine receiver reduces the growth and the immunity of the mediated by muscle-derived regulatory cells in a motor model of the metabolism. Neopalasia, 15(12), pages 1400-9.
There remains a continuing need for new therapies to treat diseases and disorders associated with the adenosine signaling pathway.
Disclosure of Invention
In one aspect, there is provided a compound of formula (I):
or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A, B, R1、R2、R3And R4As detailed herein.
In some embodiments, the compound of formula (I), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, has formula (II) or formula (III), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, as detailed herein. In some embodiments, there is provided a compound of formula (II), or a tautomer thereof, or a salt of any of the foregoing. In some embodiments, there is provided a compound of formula (III), or a tautomer thereof, or a salt of any of the foregoing.
In another aspect, a method is provided for any one or more of: (a) treating a disease, such as a proliferative disease, in an individual in need thereof; (b) enhancing an immune response in an individual in need thereof; (c) inhibiting tumor metastasis in a subject in need thereof; (d) modulating the activity of a G protein-coupled receptor signaling pathway in a subject in need thereof; (e) modulating adenosine receptors (such as A) in a subject in need thereof2AReceptor) activity; and (f) increasing natural killer cell activity in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound of formula (I) or any related formula (such as formula (II) or formula (III)), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, a method is provided for any one or more of: (a) treating a disease, such as a proliferative disease, in an individual in need thereof; (b) enhancing an immune response in an individual in need thereof; (c) inhibiting tumor metastasis in a subject in need thereof; (d) modulating the activity of a G protein-coupled receptor signaling pathway in a subject in need thereof; (e) modulating adenosine receptors (such as A) in a subject in need thereof2AReceptor) activity; and (f) increasing natural killer cell activity in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound of formula (I) or any related formula (such as formula (II) or formula (III)), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, a compound of formula (I) or any related formula (such as formula (II) or formula (III)), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is administered to a subject in combination with another therapeutic agent. In some embodiments, a compound of formula (I) or any related formula (such as formula (II) or formula (III)), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is administered to a subject in combination with another therapeutic agent.
Also provided is a pharmaceutical composition comprising: (A) a compound as detailed herein, such as a compound of formula (I) or any related formula (such as formula (II) or formula (III)), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (B) a pharmaceutically acceptable carrier or excipient. In some embodiments, there is provided a pharmaceutical composition comprising: (A) a compound as detailed herein, such as a compound of formula (I) or any related formula (such as formula (II) or formula (III)), or a tautomer or isomer thereof, or a salt of any of the foregoing, and (B) a pharmaceutically acceptable carrier or excipient. Also provided are kits comprising a compound detailed herein or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, together with instructions for use. Also provided are kits comprising a compound or salt thereof as detailed herein and instructions for use. Also provided is a compound detailed herein or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in the manufacture of a medicament for the treatment of cancer. Also provided is a compound as detailed herein, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of cancer.
Detailed Description
Definition of
For purposes herein, the use of the terms "a" or "an" and the like refer to one or more than one unless expressly stated otherwise.
As used herein, "alkenyl" refers to a moiety having at least one site of ethylenic unsaturation (i.e., having at least one moiety of the formula C ═ C) and having the specified number of carbon atoms (i.e., C)2-C10Meaning two to ten carbon atoms) or a combination thereof. The alkenyl group may be in the "cis" or "trans" configuration, or alternatively in the "E" or "Z" configuration. Specific alkenyl radicals are those having from 2 to 20 carbon atoms ("C)2-C20Alkenyl ") having 2 to 8 carbon atoms (" C)2-C8Alkenyl ") having 2 to 6 carbon atoms (" C)2-C6Alkenyl "), or having 2 to 4 carbon atoms (" C)2-C4Alkenyl ") groups. Examples of alkenyl groups include, but are not limited to, groups such asThe group of (a): vinyl (ethenyl) (or vinyl (vinyl)), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-2-enyl, but-3-enyl, but-1, 3-dienyl, 2-methylbut-1, 3-dienyl, homologs and isomers thereof, and the like.
The term "alkyl" means and includes having the indicated number of carbon atoms (i.e., C)1-C10Meaning one to ten carbons) of saturated straight and branched monovalent hydrocarbon structures and combinations thereof. Specific alkyl radicals are those having from 1 to 20 carbon atoms ("C)1-C20Alkyl "). More specific alkyl radicals are those having from 1 to 8 carbon atoms ("C)1-C8Alkyl "), 3 to 8 carbon atoms (" C3-C8Alkyl "), 1 to 6 carbon atoms (" C1-C6Alkyl "), 1 to 5 carbon atoms (" C1-C5Alkyl group "), or 1 to 4 carbon atoms (" C)1-C4Alkyl groups "). Examples of alkyl groups include, but are not limited to, groups such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.
As used herein, "alkylene" refers to the same residue as alkyl, but having a divalent character. Specific alkylene groups are those having from 1 to 6 carbon atoms ("C)1-C6Alkylene "), 1 to 5 carbon atoms (" C1-C5Alkylene "), 1 to 4 carbon atoms (" C1-C4Alkylene ") or 1 to 3 carbon atoms (" C)1-C3Alkylene ") groups. Examples of alkylene groups include, but are not limited to, groups such as: methylene (-CH)2-) ethylene (-CH2CH2-) propylene (-CH)2CH2CH2-) butylene (-CH)2CH2CH2CH2-) isopropylidene (-CH2-C(H)(CH3)-CH2-) and the like.
As used herein, "alkynyl" refers to a moiety having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C ≡ C) and having the designationNumber of carbon atoms (i.e., C)2-C10Meaning two to ten carbon atoms) or a combination thereof. Particular alkynyl radicals are those having from 2 to 20 carbon atoms ("C)2-C20Alkynyl "), having 2 to 8 carbon atoms (" C2-C8Alkynyl "), having 2 to 6 carbon atoms (" C2-C6Alkynyl "), or having 2 to 4 carbon atoms (" C ")2-C4Alkynyl ") of a cyclic alkyl group. Examples of alkynyl groups include, but are not limited to, groups such as: ethynyl (or ethynyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs or isomers thereof and the like.
The term "aryl" refers to and includes polyunsaturated aromatic hydrocarbon groups. The aryl group can contain additional fused rings (e.g., 1 to 3 rings), including additional fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings. In one variation, the aryl group contains 6 to 14 ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, and the like.
The terms "cycloalkyl" or "carbocycle" are used interchangeably and refer to and include cyclic monovalent hydrocarbon structures that may be fully saturated, monounsaturated, or polyunsaturated, but are non-aromatic, having the indicated number of carbon atoms (e.g., C)1-C10Meaning one to ten carbons). Cycloalkyl or carbocyclic groups may consist of one ring (such as cyclohexyl) or multiple rings (such as adamantyl), but do not include aryl groups. Cycloalkyl or carbocycle containing more than one ring may be fused, spiro or bridged, or combinations thereof. Preferred cycloalkyl or carbocycle is a cyclic hydrocarbon having from 3 to 13 ring carbon atoms. More preferred cycloalkyl or carbocycle is a cyclic hydrocarbon having from 3 to 8 ring carbon atoms ("C)3-C8Cycloalkyl "). Examples of cycloalkyl or carbocyclic groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.
"halo" or "halogen" refers to an element of the group 17 series having an atomic number of 9 to 85. Preferred halogen radicalsIncluding fluorine, chlorine, bromine, and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl, etc., refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups (which may be, but need not be, the same halo group); thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl groups. Alkyl groups in which each hydrogen is replaced with a halo group are referred to as "perhaloalkyl groups". Preferred perhaloalkyl groups are trifluoroalkyl (-CF)3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which a halogen replaces each H in the hydrocarbon that makes up the alkyl portion of the alkoxy group. An example of perhaloalkoxy is trifluoromethoxy (-OCF)3)。
The term "heteroaryl" refers to and includes unsaturated aromatic ring groups having 1 to 10 ring carbon atoms and at least one ring heteroatom (including but not limited to heteroatoms such as nitrogen, oxygen, and sulfur), wherein the nitrogen and sulfur atoms are optionally oxidized, and one or more nitrogen atoms are optionally quaternized. Heteroaryl groups may be attached to the rest of the molecule at a ring carbon or at a ring heteroatom. Heteroaryl groups can contain additional fused rings (e.g., 1 to 3 rings), including additional fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl, and the like. Examples of heteroaryl groups also include, but are not limited to, pyridyl, pyrimidinyl, thienyl, furyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, pyrrolyl, pyrazolyl, 1,3, 4-oxadiazolyl, imidazolyl, isothiazolyl, triazolyl, 1,3, 4-thiadiazolyl, tetrazolyl, benzofuranyl, benzothienyl, pyrazolopyridyl, indazolyl, benzothiazolyl, benzoxazolyl, or benzimidazolyl and the like.
In one variation, a heteroaryl group containing at least one additional non-aromatic fused ring (e.g., cycloalkyl or heterocyclyl) is attached to the parent structure at a ring atom of the additional ring. In another variation, a heteroaryl group containing at least one additional non-aromatic ring (e.g., cycloalkyl or heterocyclyl) is attached to the parent structure at a ring atom of the aromatic ring.
The term "heterocycle" or "heterocyclyl" refers to a saturated or unsaturated non-aromatic group having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms (such as nitrogen, sulfur, or oxygen) wherein the nitrogen and sulfur atoms are optionally oxidized and one or more of the nitrogen atoms are optionally quaternized. The heterocyclic group may have a single ring or multiple condensed rings, but does not include a heteroaryl group. Heterocycles comprising more than one ring can be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings can be aryl, cycloalkyl or heterocyclyl. Examples of heterocyclyl groups include, but are not limited to, tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 2, 3-dihydrobenzo [ b ] thiophen-2-yl, 4-amino-2-oxopyrimidin-1 (2H) -yl, and the like.
In one variation, a heterocyclyl containing at least one additional ring that does not contain a heteroatom (such as a fused additional ring) is attached to the parent structure at a ring atom of the additional ring. In another variation, a heterocyclyl containing at least one additional ring that does not contain a heteroatom (such as a fused additional ring) is attached to the parent structure at a ring atom of the heteroatom-containing ring.
"oxo" refers to the moiety ═ O.
Unless otherwise specified, "optionally substituted" means that a group can be unsubstituted or substituted with one or more (e.g., 1,2,3,4, or 5) of the substituents listed for the group, where the substituents can be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3,2 to 4, 3 to 4, 1 to 3, 1 to 4, or 1 to 5 substituents.
By "pharmaceutically acceptable carrier" is meant an ingredient of a pharmaceutical formulation other than the active ingredient that is not toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.
As used herein, "treatment" is a means for obtaining beneficial or desired results, including clinical results. For example, beneficial or desired results include, but are not limited to, one or more of the following: reducing symptoms caused by the disease, improving the quality of life of patients with the disease, reducing the dose of other drugs required to treat the disease, delaying the progression of the disease, and/or prolonging survival of the individual. With respect to cancer or other unwanted cell proliferation, beneficial or desired results include shrinking tumors (reducing tumor size); reducing the growth rate of the tumor (such as inhibiting tumor growth); reducing the number of cancer cells; inhibit, slow or slow down and preferably stop cancer cell infiltration to peripheral organs to some extent; inhibit (slow to some extent and preferably stop) tumor metastasis; inhibiting tumor growth; preventing or delaying the occurrence and/or recurrence of a tumor; and/or relieve to some extent one or more symptoms associated with cancer. In some embodiments, beneficial or desired results include prevention or delay of occurrence and/or recurrence, such as occurrence and/or recurrence of unwanted cellular proliferation.
As used herein, "delaying the progression of a disease" means delaying, impeding, slowing, delaying, stabilizing and/or delaying the progression of a disease (such as cancer). This delay may be of varying lengths of time depending on the medical history and/or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay may actually encompass prevention, such that the individual does not develop the disease. For example, the development of advanced cancers, such as metastases, may be delayed.
As used herein, an "effective dose" or "effective amount" of a compound or salt thereof or a pharmaceutical composition is an amount sufficient to achieve a beneficial or desired result. For prophylactic use, beneficial or desired results include results such as: eliminating or reducing the risk, reducing the severity of, or delaying the onset of a disease, including biochemical, histological, and/or behavioral symptoms of the disease, complications thereof, and intermediate pathological phenotypes exhibited during the development of the disease. For therapeutic use, beneficial or desired results include the following: ameliorating, alleviating, delaying or reducing one or more symptoms caused by the disease; increasing the quality of life of those suffering from the disease; reducing the dose of other drugs required to treat the disease; such as enhancing the effect of another drug via targeting, delaying the progression of the disease, and/or prolonging survival. With respect to cancer or other unwanted cell proliferation, an effective amount comprises an amount sufficient to cause shrinkage of a tumor and/or reduce the growth rate of a tumor (such as inhibiting tumor growth), or prevent or delay other unwanted cell proliferation. In some embodiments, an effective amount is an amount sufficient to delay development. In some embodiments, an effective amount is an amount sufficient to prevent or delay the onset and/or recurrence. An effective amount may be administered in one or more administrations, in the case of cancer, the effective amount of the drug or composition may be: (i) reducing the number of cancer cells; (ii) reducing tumor size; (iii) inhibit, retard, slow down and preferably prevent to some extent the infiltration of cancer cells into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibiting tumor growth; (vi) preventing or delaying the occurrence and/or recurrence of a tumor; and/or (vii) relieve to some extent one or more symptoms associated with cancer. An effective dose may be administered in one or more administrations. For the purposes of this disclosure, an effective dose of a compound or salt or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment, either directly or indirectly. It is contemplated and understood that an effective dose of a compound or salt thereof or a pharmaceutical composition may or may not be combined with another drug, compound or pharmaceutical composition. Thus, an "effective dose" may be considered in the context of administering one or more therapeutic agents, and administration of a single agent in an effective amount may be considered if the desired result can be achieved or achieved in combination with one or more other agents.
As used herein, the term "subject" is a mammal, including a human. Individuals include, but are not limited to, humans, cows, horses, cats, dogs, rodents, or primates. In some embodiments, the individual is a human. The individual (such as a human) may have advanced disease or a lesser degree of disease, such as a low tumor burden. In some embodiments, the individual is at an early stage of a proliferative disease (such as cancer). In some embodiments, the individual is in an advanced stage of a proliferative disease (such as advanced cancer).
Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself. For example, a description referring to "about X" includes a description of "X".
It is to be understood that the aspects and variations described herein also include "consisting of and/or" consisting essentially of the aspects and variations.
Compound (I)
In one aspect, there is provided a compound of formula (I):
or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
R1is H or C1-C6Alkyl, wherein R is1C of (A)1-C6Alkyl is optionally substituted by oxo or RaSubstitution;
R2and R4Each independently is H, RbOr an oxo group;
R3is H or Rc；
Each Ra、RbAnd RcIndependently is C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C＝NH(OR8)、-C(O)R8、-OC(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-C(O)NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-P(O)(OR9)(OR10)、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, - (C)1-C3Alkylene) CN, - (C)1-C3Alkylene) OR8、-(C1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene) CF3、-(C1-C3Alkylene) NO2、-C＝NH(OR8)、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene) OC (O) R8、-(C1-C3Alkylene group) C (O) OR8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) OC (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)OR9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-C(O)(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene group P (O) (OR)9)(OR10)、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-12 membered heterocyclic group), - (C)1-C3Alkylene) (5-to 10-membered heteroaryl) or- (C)1-C3Alkylene) (C6-C14Aryl) in which each R isa、RbAnd RcIndependently optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group;
is a single or double bond, wherein when it is a double bond, R2Is an oxo group;
is a single or double bond, whereinWhen it is a double bond, R4Is an oxo group;
andone of which is a double bond and the other isEach is a single bond;
a is C6-C12Aryl, 5-to 10-membered heteroaryl, 9-to 10-membered carbocyclic ring, or 9-to 10-membered heterocyclic ring, wherein C of A is6-C12Aryl, 5-to 10-membered heteroaryl, 9-to 10-membered carbocyclic ring, or 9-to 10-membered heterocyclic ring is optionally further defined by R6Substitution;
b is phenyl, 5-to 6-membered heteroaryl, 5-to 6-membered carbocycle, 5-to 6-membered heterocycle, or 9-to 10-membered heteroaryl, wherein said phenyl, 5-to 6-membered heteroaryl, 5-to 6-membered carbocycle, 5-to 6-membered heterocycle, or 9-to 10-membered heteroaryl of B is optionally further substituted with R7Substitution;
each R6And R7Independently is oxo, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C＝NH(OR8)、-C(O)R8、-OC(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-C(O)NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-P(O)(OR9)(OR10)、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, - (C)1-C3Alkylene) CN, - (C)1-C3Alkylene) OR8、-(C1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene) CF3、-(C1-C3Alkylene) NO2、-C＝NH(OR8)、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene) OC (O) R8、-(C1-C3Alkylene group) C (O) OR8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) OC (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)OR9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-C(O)(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene group P (O) (OR)9)(OR10)、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-12 membered heterocyclic group), - (C)1-C3Alkylene) (5-to 10-membered heteroaryl) or- (C)1-C3Alkylene) (C6-C14Aryl) in which each R is6And R7Independently optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group, a carboxyl group,
each R8Independently of each other is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C6-C14Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, - (C)1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (C6-C14Aryl), - (C)1-C3Alkylene) (5-6 membered heteroaryl), or- (C)1-C3Alkylene) (3-6 membered heterocyclyl), wherein R is8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C6-C14Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, - (C)1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (C6-C14Aryl), - (C)1-C3Alkylene) (5-6 membered heteroaryl), and — (C)1-C3Alkylene) (3-6 membered heterocyclyl) is independently optionally substituted with: halogen, oxo, -CN, -OR13、-NR13R14、-P(O)(OR13)(OR14) Phenyl optionally substituted by halogen, or C optionally substituted by halogen, -OH or oxo1-C6An alkyl group;
R9and R10Each independently is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C6-C14Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, - (C)1-C3Alkylene) NR11R12、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-6 membered heterocyclic group), - (C)3-C6Cycloalkylene) (5-6 membered heteroaryl), - (C)1-C3Alkylene) (5-6 membered heteroaryl) or- (C)1-C3Alkylene) (C6Aryl) in which said R is9And R10C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C6-C14Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, - (C)1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-6 membered heterocyclic group), - (C)3-C6Cycloalkylene) (5-6 membered heteroaryl), - (C)1-C3Alkylene) (5-6 membered heteroaryl) and — (C)1-C3Alkylene) (C6Aryl) is independently optionally substituted with: halogen, oxo, -CN, -OR13、-NR13R14Or C optionally substituted by halogen, -OH or oxo1-C6An alkyl group;
or R9And R10Together with the atoms to which they are attached form a 3-6 membered heterocyclyl optionally substituted with: halogen, oxo, -OR13、-NR3R14Or C optionally substituted by halogen, oxo or-OH1-C6An alkyl group;
R11and R12Each independently hydrogen, C optionally substituted by halogen or oxo1-C6Alkyl, C optionally substituted by halogen or oxo2-C6Alkenyl, or C optionally substituted by halogen or oxo2-C6An alkynyl group;
or R11And R12Together with the atoms to which they are attached form a 3-6 membered heterocyclyl optionally substituted with: halogen, oxo or C optionally substituted by halogen or oxo1-C6An alkyl group; and is
R13And R14Each independently hydrogen, C optionally substituted by halogen or oxo1-C6Alkyl, optionallyC substituted by halogen or oxo2-C6Alkenyl, or C optionally substituted by halogen or oxo2-C6An alkynyl group;
or R13And R14Together with the atoms to which they are attached form a 3-6 membered heterocyclyl optionally substituted with: halogen, oxo or C optionally substituted by oxo or halogen1-C6An alkyl group.
In some embodiments, there is provided a compound of formula (I):
or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
R1is H or C1-C6Alkyl, wherein R is1C of (A)1-C6Alkyl is optionally substituted by oxo or RaSubstitution;
R2and R4Each independently is H, RbOr oxo, with the proviso that when R is2is-NR9R10When then R is9And R10Is not H;
R3is H or Rc；
Each Ra、RbAnd RcIndependently is C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C＝NH(OR8)、-C(O)R8、-OC(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-C(O)NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-P(O)(OR9)(OR10)、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, - (C)1-C3Alkylene) CN, - (C)1-C3Alkylene) OR8、-(C1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene) CF3、-(C1-C3Alkylene) NO2、-C＝NH(OR8)、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene) OC (O) R8、-(C1-C3Alkylene group) C (O) OR8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) OC (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)OR9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-C(O)(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene group P (O) (OR)9)(OR10)、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-12-membered heterocyclic group), - (C)1-C3Alkylene) (5-to 10-membered heteroaryl) or- (C)1-C3Alkylene) (C6-C14Aryl) in which each R isa、RbAnd RcIndependently optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group;
is a single or double bond, wherein when it is a double bond, R2Is an oxo group;
is a single or double bond, whereinWhen it is a double bond, R4Is an oxo group;
andone is a double bond and the other is a single bond;
a is C6-C12Aryl, 5-to 10-membered heteroaryl, 9-to 10-membered carbocyclic ring, or 9-to 10-membered heterocyclic ring, wherein C of A is6-C12Aryl, 5-to 10-membered heteroaryl, 9-to 10-membered carbocyclic ring, or 9-to 10-membered heterocyclic ring is optionally further defined by R6Substitution;
b is phenyl, 5-to 6-membered heteroaryl, 5-to 6-membered carbocyclic ring5-to 6-membered heterocycle, or 9-to 10-membered heteroaryl, wherein said phenyl, 5-to 6-membered heteroaryl, 5-to 6-membered carbocycle, 5-to 6-membered heterocycle, or 9-to 10-membered heteroaryl of B is optionally further substituted with R7Substitution;
each R6And R7Independently is oxo, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C＝NH(OR8)、-C(O)R8、-OC(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-C(O)NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-P(O)(OR9)(OR10)、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, - (C)1-C3Alkylene) CN, - (C)1-C3Alkylene) OR8、-(C1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene) CF3、-(C1-C3Alkylene) NO2、-C＝NH(OR8)、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene) OC (O) R8、-(C1-C3Alkylene group) C (O) OR8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) OC (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)OR9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-C(O)(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene group P (O) (OR)9)(OR10)、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-12 membered heterocyclic group), - (C)1-C3Alkylene) (5-to 10-membered heteroaryl) or- (C)1-C3Alkylene) (C6-C14Aryl) in which each R is6And R7Independently optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group, a carboxyl group,
with the proviso that when R1Is C1-C6When alkyl is present, then R6Is oxo, C1-C6Alkyl radical、C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C＝NH(OR8)、-C(O)R8、-OC(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-C(O)NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-P(O)(OR9)(OR10)、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, - (C)1-C3Alkylene) CN, - (C)1-C3Alkylene) OR8、-(C1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene) CF3、-(C1-C3Alkylene) NO2、-C＝NH(OR8)、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene) OC (O) R8、-(C1-C3Alkylene group) C (O) OR8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) OC (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)OR9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-C(O)(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene group P (O) (OR)9)(OR10)、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-12 membered heterocyclic group), - (C)1-C3Alkylene) (5-to 10-membered heteroaryl) or- (C)1-C3Alkylene) (C6-C14Aryl groups);
each R8Independently of each other is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C6-C14Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, - (C)1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (C6-C14Aryl), - (C)1-C3Alkylene) (5-6 membered heteroaryl), or- (C)1-C3Alkylene) (3-6 membered heterocyclyl), wherein R is8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C6-C14Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, - (C)1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (C6-C14Aryl), - (C)1-C3Alkylene) (5-6 membered heteroaryl), and — (C)1-C3Alkylene) (3-6 membered heterocyclyl) is independently optionally substituted with: halogen, oxo, -CN, -OR13、-NR13R14、-P(O)(OR13)(OR14) Optionally substituted by halogenOr C optionally substituted by halogen, -OH or oxo1-C6An alkyl group;
R9and R10Each independently is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C6-C14Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, - (C)1-C3Alkylene) NR11R12、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-6 membered heterocyclic group), - (C)1-C3Alkylene) (5-6 membered heteroaryl) or- (C)1-C3Alkylene) (C6Aryl) in which said R is9And R10C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C6-C14Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, - (C)1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-6 membered heterocyclic group), - (C)1-C3Alkylene) (5-6 membered heteroaryl) and — (C)1-C3Alkylene) (C6Aryl) is independently optionally substituted with: halogen, oxo, -CN, -OR13、-NR13R14Or C optionally substituted by halogen, -OH or oxo1-C6An alkyl group;
or R9And R10Together with the atoms to which they are attached form a 3-6 membered heterocyclyl optionally substituted with: halogen, oxo, -OR13、-NR3R14Or C optionally substituted by halogen, oxo or-OH1-C6An alkyl group;
R11and R12Each independently hydrogen, C optionally substituted by halogen or oxo1-C6Alkyl, C optionally substituted by halogen or oxo2-C6Alkenyl, or C optionally substituted by halogen or oxo2-C6An alkynyl group;
or R11And R12Together with the atoms to which they are attached form a 3-6 membered heterocyclyl optionally substituted with: halogen, oxo or C optionally substituted by halogen or oxo1-C6An alkyl group; and is
R13And R14Each independently hydrogen, C optionally substituted by halogen or oxo1-C6Alkyl, C optionally substituted by halogen or oxo2-C6Alkenyl, or C optionally substituted by halogen or oxo2-C6An alkynyl group;
or R13And R14Together with the atoms to which they are attached form a 3-6 membered heterocyclyl optionally substituted with: halogen, oxo or C optionally substituted by oxo or halogen1-C6An alkyl group.
In some variations of formula (I), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound 3-phenyl-2- (quinolin-6-yl) pyrido [2,3-b ] pyrazin-8 (5H) -one, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is excluded. Thus, in some variations there is provided a compound of formula (I), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, that is not 3-phenyl-2- (quinolin-6-yl) pyrido [2,3-b ] pyrazin-8 (5H) -one, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some variations of formula (I), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound 3-phenyl-2- (quinolin-6-yl) pyrido [2,3-b ] pyrazin-8 (5H) -one, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is included. In some variations of formula (I) or a pharmaceutically acceptable salt thereof, the compound 3-phenyl-2- (quinolin-6-yl) pyrido [2,3-b ] pyrazin-8 (5H) -one, or a pharmaceutically acceptable salt thereof, is excluded. Thus, in some variations there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, provided that the compound is not 3-phenyl-2- (quinolin-6-yl) pyrido [2,3-b ] pyrazin-8 (5H) -one, or a pharmaceutically acceptable salt thereof. In some variations of formula (I) or a pharmaceutically acceptable salt thereof, 3-phenyl-2- (quinolin-6-yl) pyrido [2,3-b ] pyrazin-8 (5H) -one, or a pharmaceutically acceptable salt thereof, is included.
In some embodiments of the compounds of formula (I), when R is2Is oxo, R3And R4Is H, and B is (C)1-C3Alkylene) NR9R10Substituted phenyl or phenyl, then A is 5-to 10-membered heteroaryl, 9-to 10-membered carbocycle, or 9-to 10-membered heterocycle, wherein said 5-to 10-membered heteroaryl, 9-to 10-membered carbocycle, or 9-to 10-membered heterocycle of A is optionally further substituted with R6Substitution; and when R is2Is oxo, R3And R4Is H, and A is (C)1-C3Alkylene) NR9R10Substituted phenyl or phenyl, then B is 5-to 6-membered heteroaryl, 5-to 6-membered carbocycle, 5-to 6-membered heterocycle, or 9-to 10-membered heteroaryl, wherein said 5-to 6-membered heteroaryl, 5-to 6-membered carbocycle, 5-to 6-membered heterocycle, or 9-to 10-membered heteroaryl of B is optionally further substituted with R7And (4) substitution. In some embodiments of the compounds of formula (I), when R is2Is oxo and B is (C)1-C3Alkylene) NR9R10Substituted phenyl or phenyl, then A is 5-to 10-membered heteroaryl, 9-to 10-membered carbocycle, or 9-to 10-membered heterocycle, wherein said 5-to 10-membered heteroaryl, 9-to 10-membered carbocycle, or 9-to 10-membered heterocycle of A is optionally further substituted with R6Substitution; and when R is2Is oxo and A is (C)1-C3Alkylene) NR9R10Substituted phenyl or phenyl, then B is 5-to 6-membered heteroaryl, 5-to 6-membered carbocycle, 5-to 6-membered heterocycle, or 9-to 10-membered heteroaryl, wherein said 5-to 6-membered heteroaryl, 5-to 6-membered carbocycle, 5-to 6-membered heterocycle, or 9-to 10-membered heteroaryl of B is optionally further substituted with R7And (4) substitution.
In some embodiments of compounds of formula (I), the compound is not a compound in table 1X, or a tautomer or isomer thereof, or a salt of any of the foregoing.
TABLE 1X
Compound numbering
Name (R)
1.1x
2, 3-diphenyl-3, 4-dihydropyrido [2,3-b ]]Pyrazin-6 (2H) -ones
1.2x
2- (4- (aminomethyl) phenyl) -3-phenyl-3, 4-dihydropyrido [2,3-b ]]Pyrazin-6 (2H) -ones
1.3x
3- (4- (aminomethyl) phenyl) -2-phenyl-3, 4-dihydropyrido [2,3-b ]]Pyrazin-6 (2H) -ones
In some embodiments of the compounds of formula (I), A is selected from C6-C12Aryl and 5 to 10 membered heteroaryl, wherein C of A is6-C12Aryl and 5-to 10-membered heteroaryl optionally further substituted by R6And (4) substitution. In some embodiments of compounds of formula (I), B is selected from phenyl and 5-to 6-membered heteroaryl, wherein said phenyl and 5-to 6-membered heteroaryl of B are optionally further substituted with R7And (4) substitution. In some embodiments of the compounds of formula (I), A is selected from C6-C12Aryl and 5 to 10 membered heteroaryl, wherein C of A is6-C12Aryl and 5-to 10-membered heteroaryl optionally further substituted by R6Substitution; and B is selected from phenyl and 5-to 6-membered heteroaryl, wherein said phenyl and 5-to 6-membered heteroaryl of B are optionally further substituted by R7And (4) substitution.
In some embodiments of formula (I), Ra、RbAnd RcIndependently is C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-C(O)NR9R10、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl or C6-C14And (4) an aryl group.
In some embodiments of formula (I), Ra、RbAnd RcIndependently is C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-C(O)NR9R10、-NR8C(O)R9、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl or C6-C14And (4) an aryl group.
In some embodiments of formula (I), Ra、RbAnd RcIndependently is C1-C6Alkyl, halogen, -CN, -OR8、-SR8or-NR9R10。
In some embodiments of formula (I), Ra、RbAnd RcIndependently is-CH3Halogen, -CN or-OCH3。
In some embodiments of compounds of formula (I), R2Is H, oxo, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, halogen, -CN, -OR8、-C(O)NR9R10、-C(O)R8、-C(O)OR8、-OC(O)R8、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)2R8、-NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-(C1-C3Alkylene) CN, - (C)1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-C1-C3Alkylene) (C3-C6Cycloalkyl), -S (O) R8、-(C1-C3Alkylene) OR8Or is- (C)1-C3Alkylene) (5-10 membered heteroaryl), each of which is optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group. In some embodiments, R2Is H. In some embodiments, R2Is an oxo group.
In some embodiments of compounds of formula (I), R2Selected from: H. oxo, methyl, phenyl, cyclopropyl, fluoro, chloro, bromo, -CN, methoxy,
In some embodiments of compounds of formula (I), R3Is H, -CN, halogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, -OR8、-C(O)NR9R10、-(C1-C3Alkylene) NR9R10、-NR9R10、-C(O)NR9R10、-NR8C(O)R9、-SR8、-C(O)R8、-OC(O)R8、-C(O)OR8、-OC(O)NR9R10、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)R9、-S(O)NR9R10、-S(O)2NR9R10、-(C1-C3Alkylene) CN, - (C)1-C3Alkylene) OR8、-(C1-C3Alkylene) SR8、-(C1-C3Alkylene) (3-12 membered heterocyclic group), - (C)1-C3Alkylene) (C6-C14Aryl), - (C)1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-C(O)NR8S(O)2R9Or is- (C)1-C3Alkylene) NR8C(O)R9Each of which is optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, orC optionally substituted by oxo, -OH or halogen1-C6An alkyl group. In some embodiments, R3Is H. In some embodiments, R3Is a halogen. In some embodiments, R3Is C1-C6An alkyl group. In some embodiments, R3is-NR9R10。
In some embodiments of compounds of formula (I), R3Selected from: H. -CN, bromine, fluorine, chlorine, methyl, cyclopropyl,A hydroxyl group, a methoxy group,
In some embodiments of compounds of formula (I), R4Is H, oxo, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, -CN, -NR9R10Halogen, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, -C (O) NR9R10、-OR8、-SR8、-C(O)OR8or-NR8C(O)R9Each of which is independently optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene) C (O)R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group. In some embodiments, R4Is H. In some embodiments, R4Is an oxo group. In some embodiments, R4Is C1-C6An alkyl group. In some embodiments, R4is-NR9R10. In some embodiments, R4is-OR8。
In some embodiments of compounds of formula (I), R4Selected from: H. oxo, methyl, ethyl,-CN, phenyl, cyclopropyl, bromo, chloro, methoxy,
In some embodiments of compounds of formula (I), R1、R2And R3Each is H and R4Is an oxo group. In some embodiments of compounds of formula (I), R1、R3And R4Each is H and R2Is an oxo group.
In some embodiments, there is provided a compound of formula (II):
or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A, B, R1、R3And R4As defined for formula (I).
In some embodiments of compounds of formula (II), R3And R4Is not H. In some embodiments, R3And R4Is at least one of C1-C6Alkyl, halogen, C6-C14Aryl, -CN, OR-OR8. In some embodiments, R1、R3And R4Each is H.
In some embodiments, there is provided a compound of formula (III):
or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein A, B, R1、R2And R3As defined for formula (I).
In some embodiments of compounds of formula (III), R2And R3Is not H. In some embodiments, R2And R3Is at least one of C1-C6Alkyl, halogen, C6-C14Aryl, -CN, OR-OR8. In some embodiments, R1、R2And R3Each is H.
In some embodiments of compounds of formula (I), (II), or (III), R1Is C1-C6An alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or isobutyl. In some embodiments of compounds of formula (I), (II), or (III), R1Is H or C1-C6An alkyl group. In some embodiments of compounds of formula (I), (II), or (III), R1Is H or methyl. In some embodiments, R1Is H.
In some embodiments of the compounds of formula (I) or (III), R2Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, halogen, -CN, -OR8、-C(O)NR9R10、-C(O)R8、-C(O)OR8、-OC(O)R8、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)2R8、-NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-(C1-C3Alkylene) CN, - (C)1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene) (C3-C6Cycloalkyl), -S (O) R8、-(C1-C3Alkylene) OR8Or is- (C)1-C3Alkylene) (5-10 membered heteroaryl), each of which is optionally substituted with: halogen, oxo, and,-OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group. In some embodiments, R2Is H.
In some embodiments of the compounds of formula (I) or (III), R2Selected from: H. methyl, phenyl, cyclopropyl, fluoro, chloro, bromo, -CN, methoxy,
In some embodiments of the compounds of formula (I) or (II), R4Is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, -CN, -NR9R10Halogen, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, -C (O) NR9R10、-OR8、-SR8、-C(O)OR8or-NR8C(O)R9Each of which is independently optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group. In some embodiments, R4Is C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-C(O)NR9R10、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl or C6-C14And (4) an aryl group. In some embodiments of compounds of formula (I), (II), or (III), R4Is C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-C(O)NR9R10、-NR8C(O)R9、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl or C6-C14And (4) an aryl group. In some embodiments of compounds of formula (I), (II), or (III), R4Is C1-C6Alkyl, halogen, -CN, -OR8、-SR8or-NR9R10. In some embodiments of compounds of formula (I), (II), or (III), R4is-CH3Halogen, -CN or-OCH3. In some embodiments of compounds of formula (I), (II), or (III), R4Is H or methyl. In the formulae (I), (II)) In some embodiments of the compounds of (I), (II), or (III)4Is H, C1-C6Alkyl, halogen, -CN, OR-OR8。
In some embodiments of the compounds of formula (I) or (II), R4Selected from: H. methyl, ethyl,-CN, phenyl, cyclopropyl, bromo, chloro, methoxy,
In some embodiments of the compounds of formula (I), (II), or (III), a is optionally further substituted with R6Substituted C6-C12And (4) an aryl group. In some embodiments, a is optionally substituted with R6Substituted C6-C12Aryl, wherein each R6Independently is C optionally substituted1-C6Alkyl groups: halogen, -CN, -OR8、-NR9R10or-NR8S(O)2R9. In some embodiments, a is optionally substituted with R6Substituted phenyl or naphthyl. In some embodiments, a is phenyl. In some embodiments, a is naphthyl. In some embodiments, a is phenyl or naphthyl substituted with one or more groups selected from: halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-NR8S(O)2R9、-C(O)NR8S(O)2R9、-OC(O)R8、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、C3-C6Cycloalkyl and C optionally substituted by halogen1-C6An alkyl group. In some embodiments, a is phenyl optionally substituted with one or more groups selected from: halogen, -CN, -OR8、-NR9R10and-NR8S(O)2R9. In some embodiments, a is phenyl optionally substituted with one or more groups selected from: halogen, -CN, -OH, -OC1-C6Alkyl, -NH2、-NO2、C3-C6Cycloalkyl and C optionally substituted by halogen1-C6An alkyl group. In some embodiments, a is phenyl optionally substituted with one or more groups selected from: halogen, -OH, and C1-C6An alkyl group.
In some embodiments of the compounds of formula (I), (II), or (III), a is optionally further substituted with R6Substituted 5 to 10 membered heteroaryl. In some embodiments, a is optionally substituted with R6Substituted 5 to 10 membered heteroaryl, wherein each R6Independently is C optionally substituted1-C6Alkyl groups: halogen, oxo, -CN, C3-C6Cycloalkyl, -OR8Or is- (C)1-C3Alkylene) (C6-C14Aryl). In some embodiments, a is selected from pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, naphthyridinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzisoxazolyl, benzooxadiazolyl, benzothiophenyl, benzisothiazolyl, benzothiadiazolyl, pyrrolyl, isoquinolinyl, quinazolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and thiadiazolyl, pyridazinyl, pyrazinyl, thienyl, and thienylA pyridinyl group, a pyrazolopyridyl group, an imidazopyridyl group, a triazolopyridyl group, a furopyridyl group, an oxazolopyridyl group, an isoxazolopyridyl group, an oxadiazolyl pyridyl group, a thienopyridyl group, a thiazolopyridyl group, an isothiazolopyridyl group, a thiadiazolopyridyl group, a thienopyridyl group, a phthalazinyl group, a pyrazolothiazolyl group and an imidazothiazolyl group, each optionally substituted with R6And (4) substitution. In one variation, via R6The optional substitution of (a) provides an unsubstituted moiety. In one variation, via R6Is optionally substituted with 1-3R6(which may be the same or different) substituted moieties. In some embodiments, a is a 5 to 10 membered heteroaryl optionally further substituted with one or more groups selected from: halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-C(O)NR8S(O)2R9、-OC(O)R8、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、C3-C6Cycloalkyl and C optionally substituted by halogen1-C6An alkyl group. In some embodiments, a is a 5 to 10 membered heteroaryl optionally further substituted with one or more groups selected from: c1-C6Alkyl, halogen, -CN, -OH, and-OC1-C6An alkyl group.
In some embodiments, a is optionally further substituted with R6A substituted 10-membered heteroaryl, wherein the 10-membered heteroaryl is an 6/6 ring fused system (i.e., a ring system formed by a 6-membered ring fused to a 6-membered ring). In some embodiments, a is a 9-membered heteroaryl, wherein the 9-membered heteroaryl is an 6/5 ring fused system (i.e., a ring system formed by the fusion of a 6-membered ring with a 5-membered ring). In some embodiments, the 6/5 ring fused system of a is attached to the remainder of the compound via a 6-membered ring. In other embodiments, the 6/5 ring fused system of A is linked to the alkylation via a 5 membered ringThe remainder of the compound is attached.
In some embodiments, a is selected from:
each is optionally substituted by R6And wherein the wavy line indicates attachment to the parent structure. In one variation, such groups are not substituted with R6And (4) further substituting. In some of these embodiments, R6Independently is C optionally substituted1-C6Alkyl groups: halogen, oxo, C3-C6Cycloalkyl, - (C)1-C3Alkylene) (C6-C14Aryl), -CN, -OR8、-NR9R10or-NR8S(O)2R9. In some of these embodiments, such groups are substituted with 1-3R6(which may be the same or different) substitutions.
In some embodiments of the compounds of formula (I), (II), or (III), a is optionally further substituted with R6A substituted 9 to 10 membered carbocyclic ring. In some embodiments, a is a 10-membered carbocyclic ring, wherein the 10-membered carbocyclic ring is an 6/6 ring fused system (i.e., a ring system formed by a 6-membered ring fused to a 6-membered ring). In some embodiments, a is a 9-membered carbocyclic ring, wherein the 9-membered carbocyclic ring is an 6/5 ring fused system (i.e., a ring system formed by a 6-membered ring fused to a 5-membered ring). In some embodiments, the 6/5 ring fused system of a is attached to the remainder of the compound via a 6-membered ring. In other embodiments, the 6/5 ring fused system of a is attached to the remainder of the compound via a 5-membered ring. In some embodiments, a is a fully saturated 9 to 10 membered carbocyclic ring. In some embodiments, a is a partially saturated 9 to 10 membered carbocyclic ring. In some embodiments of the compounds of formula (I), (II), or (III), A is selected from decahydronaphthyl, octahydroindenyl, 1,2,3, 4-tetrahydronaphthyl, and 2, 3-dihydroindenyl, each optionallyBy R6And (4) substitution. In some embodiments, a is a 9 to 10 membered carbocyclic ring optionally further substituted with one or more groups selected from: halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-C(O)NR8S(O)2R9、-OC(O)R8、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、C3-C6Cycloalkyl and C optionally substituted by halogen1-C6An alkyl group. In some embodiments, a is a 9 to 10 membered carbocyclic ring optionally further substituted with one or more groups selected from: c1-C6Alkyl, halogen, -CN, -OH, and-OC1-C6An alkyl group.
In some embodiments, a is optionally further substituted with R6Substituted 9 to 10 membered heterocyclic ring. In some embodiments, a is optionally further substituted with R6A substituted 10-membered heterocyclic ring, wherein the 10-membered heterocyclic ring is an 6/6 ring fused system (i.e., a ring system formed by a 6-membered ring fused to a 6-membered ring). In some embodiments, a is a 9-membered heterocyclic ring, wherein the 9-membered heterocyclic ring is an 6/5 ring fused system (i.e., a ring system formed by the fusion of a 6-membered ring with a 5-membered ring). In some embodiments, the 6/5 ring fused system of a is attached to the remainder of the compound via a 6-membered ring. In other embodiments, the 6/5 ring fused system of a is attached to the remainder of the compound via a 5-membered ring. In some embodiments, a is a fully saturated 9 to 10 membered heterocyclic ring. In some embodiments, a is a partially saturated 9 to 10 membered heterocyclic ring. In some embodiments, a is selected from tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, indolinyl, isoindolinyl, tetrahydronaphthyridinyl, and hexahydrobenzimidazolyl, each optionally further substituted with R6And (4) substitution. In some embodiments, a is a 9 to 10 membered heterocyclic ring optionally further substituted with one or more groups selected from: halogenElement, -CN, -OR8、-SR8、-NR9R10、-NO2、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-C(O)NR8S(O)2R9、-OC(O)R8、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、C3-C6Cycloalkyl and C optionally substituted by halogen1-C6An alkyl group. In some embodiments, a is a 9 to 10 membered heterocyclic ring optionally further substituted with one or more groups selected from: c1-C6Alkyl, halogen, -CN, -OH, and-OC1-C6An alkyl group. In some embodiments, a is selected from Each is optionally substituted by R6And (4) substitution. In some embodiments, such groups are not substituted with R6And (4) further substituting. In some embodiments, such groups are substituted with 1-3R6(which may be the same or different) further substitution. In some of these embodiments, R6Independently selected from halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-C(O)NR8S(O)2R9、-OC(O)R8、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、C3-C6Cycloalkyl and C optionally substituted by halogen1-C6An alkyl group. In some embodiments, R6Independently selected from C1-C6Alkyl, halogen, -CN, -OH, and-OC1-C6An alkyl group.
In some embodiments of the compounds of formula (I), (II), or (III), each R6Independently selected from halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-C(O)NR8S(O)2R9、-OC(O)R8、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、C3-C6Cycloalkyl and C optionally substituted by halogen1-C6An alkyl group. In some embodiments, R6Independently selected from C1-C6Alkyl, halogen, -CN, and-OR8。
In some embodiments of the compounds of formula (I), (II), or (III), a is selected from:
in some embodiments of the compounds of formula (I), (II), or (III), a is selected from:
in some embodiments, a is
In some embodiments of the compounds of formula (I), (II), or (III), A is
In some embodiments of the compounds of formula (I), (II), or (III), A is
It is understood that each description of A may be related to R1-R4As if each combination were specifically and individually listed. It is to be similarly understood that each description of A can be with each description of B (and further with R)1-R4Each description of (b) combinations as if each combination were specifically and individually listed. For example, in one aspect, it is understood that each description of A can be in one aspect with R1、R3Each is hydrogen and R2And R4Is hydrogen and R2And R4Is a variant of oxo. In one such variation, each description of A is in one aspect related to where R1、R2、R3Each is hydrogen and R4Are modified combinations of oxo groups. In another such variation, each description of a is in one aspect with R1、R3、R4Each is hydrogen and R2Are modified combinations of oxo groups. Such embodiments may be further combined with each of the descriptions of B.
In some embodiments of the compounds of formula (I), (II), or (III), B is optionally further defined by R7A substituted phenyl group. In some embodiments, B is optionally furtherBy R7Substituted 5 to 6 membered heteroaryl. In some embodiments, B is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl, each optionally substituted with R7And (4) substitution. In some embodiments, B is furyl, pyridyl, oxazolyl, or oxadiazolyl, each independently substituted with R7And (4) substitution. In some of these embodiments, R7Independently of one another is halogen, C1-C6Alkyl, OR-OR8。
In some embodiments of the compounds of formula (I), (II), or (III), B is optionally further defined by R7A substituted 5 to 6 membered carbocyclic ring. In some embodiments, B is optionally further substituted with R7A substituted fully saturated 5 to 6 membered carbocyclic ring. In some embodiments, B is optionally further substituted with R7Substituted cyclopentyl or cyclohexyl. In some embodiments, B is a 5 to 6 membered carbocyclic ring optionally substituted with one or more groups selected from: halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-C(O)NR8S(O)2R9、-OC(O)R8、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、C3-C6Cycloalkyl and C optionally substituted by halogen1-C6An alkyl group. In some embodiments, B is a 5 to 6 membered carbocyclic ring optionally substituted with halo.
In some embodiments of the compounds of formula (I), (II), or (III), B is optionally further defined by R7Substituted 5 to 6 membered heterocyclic ring. In some embodiments, B is optionally further substituted with R7A substituted fully saturated 5 to 6 membered heterocyclic ring. In some embodiments, B is optionally further substituted with R7Substituted pyrrolidinesA group, a pyrazolidinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a1, 3-dioxolanyl group, a tetrahydrothienyl group, an oxathiolanyl group (oxathiolanyl group), a sulfolane group, a piperidyl group, a piperazinyl group, a tetrahydropyranyl group, a dioxanyl group, a thianyl group, a dithianyl group, a trithianyl group, a morpholinyl group, or a thiomorpholinyl group. In some embodiments, B is a 5 to 6 membered heterocyclic ring optionally substituted with one or more groups selected from: halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-C(O)NR8S(O)2R9、-OC(O)R8、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、C3-C6Cycloalkyl and C optionally substituted by halogen1-C6An alkyl group. In some embodiments, B is a 5 to 6 membered heterocyclic ring optionally substituted with halo.
In some embodiments of the compounds of formula (I), (II), or (III), B is optionally further defined by R7Substituted 9 to 10 membered heteroaryl. In some embodiments, B is selected from the group consisting of pyridyl, quinolyl, isoquinolyl, quinoxalyl, cinnolinyl, quinazolinyl, naphthyridinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzisoxazolyl, benzooxadiazolyl, benzothiophenyl, benzisothiazolyl, benzothiadiazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazopyridinyl, triazolopyridinyl, furopyridinyl, oxazolopyridyl, isoxazolopyridyl, oxadiazolopyridyl, thienopyridinyl, furopyridinyl, and the like, Thiazolopyridinyl, isothiazolopyridinyl, thiadiazolopyridinyl, thienopyridinyl, phthalazinyl, pyrazoloThiazolyl, pyrazolothiazolyl and imidazothiazolyl, each optionally substituted with R7And (4) substitution. In one aspect, such groups are unsubstituted. In another aspect, such groups are substituted with 1-3R7(which may be the same or different) substitutions. In some embodiments, B is a 9 to 10 membered heteroaryl optionally substituted with one or more groups selected from: halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-C(O)NR8S(O)2R9、-OC(O)R8、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、C3-C6Cycloalkyl and C optionally substituted by halogen1-C6An alkyl group. In some embodiments, B is a 9 to 10 membered heteroaryl optionally substituted with halo.
In some embodiments of compounds of formula (I), (II), or (III), R7Independently selected from halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C(O)R8、-C(O)OR8、-C(O)NR9R10、-C(O)NR8S(O)2R9、-OC(O)R8、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、C3-C6Cycloalkyl and C optionally substituted by halogen1-C6An alkyl group. In some embodiments, R7Is a halogen.
In some embodiments of the compounds of formula (I), (II), or (III), B is selected from:
in some embodiments of the compounds of formula (I), (II), or (III), B is selected from:
each of which is optionally substituted with R7And (4) substitution. In one variation, such groups are unsubstituted. In another variation, such groups are substituted with 1,2,3, or 4R7And (4) substitution. In some of these embodiments, each R is7Independently is C1-C6Alkyl, halogen, or-CN.
In some embodiments of the compounds of formula (I), (II), or (III), B is selected from:
in some embodiments, B isIn some embodiments, B is
In some embodiments of the compounds of formula (I), (II), or (III), a is each optionally further substituted with R6Substituted C6-C12Aryl or 5-to 10-membered heteroaryl, and B is each optionally further substituted by R7Substituted phenyl or 5 to 6 membered heteroaryl. In some embodiments, a is optionally further substituted with R6Substituted C6-C12Aryl, and B is optionally further substituted with R7A substituted phenyl group. In some embodiments, a is optionally further substituted with R6Substituted C6-C12Aryl, and B is optionally further substituted with R7Substituted 5 to 6 membered heteroaryl. In some embodiments, a is 5 optionally further substituted with R6Substituted to 10 membered heteroaryl, and B is optionally further substituted by R7A substituted phenyl group. In some embodiments, a is optionally further substituted with R6A substituted 5 to 10 membered heteroaryl, and B is optionally further substituted by R7Substituted 5 to 6 membered heteroaryl.
In some embodiments of the compounds of formula (I), (II), or (III), a is each optionally further substituted with R6A substituted 9 to 10 membered carbocyclic ring or 9 to 10 membered heterocyclic ring, and B is each optionally further substituted by R7Substituted phenyl, 5-to 6-membered heteroaryl, 5-to 6-membered carbocycle, or 5-to 6-membered heterocycle. In some embodiments, a is optionally further substituted with R6A substituted 9 to 10 membered carbocyclic ring, and B is optionally further substituted by R7A substituted phenyl group. In some embodiments, a is optionally further substituted with R6A substituted 9 to 10 membered carbocyclic ring, and B is optionally further substituted by R7Substituted 5 to 6 membered heteroaryl. In some embodiments, a is optionally further substituted with R6A substituted 9 to 10 membered carbocyclic ring, and B is optionally further substituted by R7A substituted 5 to 6 membered carbocyclic ring. In some embodiments, a is optionally further substituted with R6A substituted 9 to 10 membered carbocyclic ring, and B is optionally further substituted by R7Substituted 5 to 6 membered heterocyclic ring.
In some embodiments of the compounds of formula (I), (II), or (III), a is each optionally further substituted with R6Substituted C6-C12Aryl or 5-to 10-membered heteroaryl, and B is each optionally further substituted by R7Substituted 5 to 6 membered carbocyclic ring or 5 to 6A 6-membered heterocyclic ring. In some embodiments, a is optionally further substituted with R6Substituted C6-C12Aryl, and B is optionally further substituted with R7A substituted 5 to 6 membered carbocyclic ring. In some embodiments, a is optionally further substituted with R6Substituted C6-C12Aryl, and B is optionally further substituted with R7Substituted 5 to 6 membered heterocyclic ring. In some embodiments, a is optionally further substituted with R6A substituted 5 to 10 membered heteroaryl, and B is optionally further substituted by R7A substituted 5 to 6 membered carbocyclic ring. In some embodiments, a is optionally further substituted with R6A substituted 5 to 10 membered heteroaryl, and B is optionally further substituted by R7Substituted 5 to 6 membered heterocyclic ring. In some embodiments, when a is phenyl or pyridinyl (either of which is optionally further substituted by R)6Substituted), B is not a saturated heterocycle.
In some embodiments of the compounds of formula (I), (II), or (III), a is each optionally further substituted with R6Substituted C6-C12Aryl or 5-to 10-membered heteroaryl, and B is each optionally further substituted by R7A substituted 9 to 10 membered carbocyclic ring. In some embodiments, a is optionally further substituted with R6Substituted C6-C12Aryl, and B is optionally further substituted with R7A substituted 9 to 10 membered carbocyclic ring. In some embodiments, a is optionally further substituted with R6A substituted 5 to 10 membered heteroaryl, and B is optionally further substituted by R7A substituted 9 to 10 membered carbocyclic ring.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6b、R6c、R6d、R6eAnd R6fEach independently is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C＝NH(OR8)、-C(O)R8、-OC(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-C(O)NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-P(O)(OR9)(OR10)、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, - (C)1-C3Alkylene) CN, - (C)1-C3Alkylene) OR8、-(C1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene) CF3、-(C1-C3Alkylene) NO2、-C＝NH(OR8)、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene) OC (O) R8、-(C1-C3Alkylene group) C (O) OR8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) OC (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)OR9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-C(O)(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene group P (O) (OR)9)(OR10)、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-12 membered heterocyclic group), - (C)1-C3Alkylene) (5-to 10-membered heteroaryl) or- (C)1-C3Alkylene) (C6-C14Aryl) in which each R is6a、R6b、R6c、R6d、R6eAnd R6fIndependently optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6b、R6c、R6d、R6eAnd R6fEach independently is H, C1-C6Alkyl, halogen, -CN, or-OC1-C6An alkyl group. In some embodiments, R6a、R6b、R6c、R6d、R6eAnd R6fEach is H. In some embodiments, R6a、R6b、R6c、R6d、R6eAnd R6fIs Cl, F, Br, or I. In some embodiments, R6a、R6b、R6c、R6d、R6eAnd R6fIs Cl. In some embodiments, R6a、R6b、R6c、R6d、R6eAnd R6fOne of which is halogen and the others are each H. In some embodiments, R6a、R6b、R6c、R6d、R6eAnd R6fIs halogen and R6a、R6b、R6c、R6d、R6eAnd R6fIs one of C1-C6An alkyl group. In some embodiments, R6a、R6b、R6c、R6d、R6eAnd R6fIs Cl and R6a、R6b、R6c、R6d、R6eAnd R6fOne of them is methyl. In some embodiments, R6aIs C1-C6An alkyl group. In some embodiments, R6bIs C1-C6An alkyl group. In some embodiments, R6cIs C1-C6An alkyl group. In some embodiments, R6dIs C1-C6An alkyl group. In some embodiments, R6eIs C1-C6An alkyl group. In some embodiments, R6fIs C1-C6An alkyl group. In some embodiments, R6aIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6bIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6cIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6dIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6eIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6fIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6aIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6aIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6aIs C1-C6Alkyl and R6dIs a halogen. In some embodiments, R6aIs C1-C6Alkyl and R6eIs a halogen. In some embodiments, R6aIs C1-C6Alkyl and R6fIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6aIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6dIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6eIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6fIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6aIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6dIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6eIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6fIs a halogen. In some embodiments, R6dIs C1-C6Alkyl and R6aIs a halogen. In some embodiments, R6dIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6dIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6dIs C1-C6Alkyl and R6eIs a halogen. In some embodiments, R6dIs C1-C6Alkyl and R6fIs a halogen. In some embodiments, R6eIs C1-C6Alkyl and R6aIs a halogen. In some embodiments, R6eIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6eIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6eIs C1-C6Alkyl and R6dIs a halogen. In some embodiments, R6eIs C1-C6Alkyl and R6fIs a halogen. In some embodiments, R6fIs C1-C6Alkyl and R6aIs a halogen. In some embodiments, R6fIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6fIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6fIs C1-C6Alkyl and R6dIs a halogen. In some embodiments, R6fIs C1-C6Alkyl and R6eIs a halogen. In some embodiments, R6a、R6b、R6c、R6d、R6eAnd R6fTwo of which are halogens. In some embodiments, R6a、R6b、R6c、R6d、R6eAnd R6fTwo of (A) are C1-C6An alkyl group.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6b、R6c、R6d、R6eAnd R6fOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6b、R6c、R6d、R6eAnd R6fEach of the remainder of (a) is H; and B is optionally substituted with R7A substituted phenyl group.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6b、R6c、R6d、R6eAnd R6fOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6b、R6c、R6d、R6eAnd R6fEach of the remainder of (a) is H; and B is optionally substituted with R7Substituted 5 to 6 membered heteroaryl.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6b、R6c、R6d、R6eAnd R6fOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6b、R6c、R6d、R6eAnd R6fEach of the remainder of (a) is H; and B is optionally substituted with R7A substituted 5 to 6 membered carbocyclic ring.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6b、R6c、R6d、R6eAnd R6fOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6b、R6c、R6d、R6eAnd R6fEach of the remainder of (a) is H; and B is optionally substituted with R7Substituted 5 to 6 membered heterocyclic ring.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6b、R6c、R6d、R6eAnd R6fOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6b、R6c、R6d、R6eAnd R6fEach of the remainder of (a) is H; and B is optionally substituted with R7Substituted 9 to 10 membered heteroaryl.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6b、R6c、R6d、R6eAnd R6fOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6b、R6c、R6d、R6eAnd R6fEach of the remainder of (a) is H; and B is selected from:
in some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6b、R6c、R6d、R6eAnd R6fOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6b、R6c、R6d、R6eAnd R6fEach of the remainder of (a) is H; and B is selected from:
in some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6b、R6c、R6d、R6eAnd R6fOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6b、R6c、R6d、R6eAnd R6fEach of the remainder of (a) is H; and B is selected from
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6b、R6c、R6d、R6eAnd R6fOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6b、R6c、R6d、R6eAnd R6fEach of the remainder of (a) is H; and B is selected from
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6b、R6c、R6d、R6e、R6fAnd R6gEach independently is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C＝NH(OR8)、-C(O)R8、-OC(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-C(O)NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-P(O)(OR9)(OR10)、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, - (C)1-C3Alkylene) CN, - (C)1-C3Alkylene) OR8、-(C1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene) CF3、-(C1-C3Alkylene) NO2、-C＝NH(OR8)、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene) OC (O) R8、-(C1-C3Alkylene group) C (O) OR8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) OC (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)OR9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-C(O)(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene group P (O) (OR)9)(OR10)、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-12 membered heterocyclic group), - (C)1-C3Alkylene) (5-to 10-membered heteroaryl) or- (C)1-C3Alkylene) (C6-C14Aryl) in which each R is6b、R6c、R6d、R6e、R6fAnd R6gIndependently optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6b、R6c、R6d、R6e、R6fAnd R6gEach independently is H, C1-C6Alkyl, halogen, -CN, or-OC1-C6An alkyl group. In some embodiments, R6b、R6c、R6d、R6e、R6fAnd R6gEach is H. In some embodiments, R6b、R6c、R6d、R6e、R6fAnd R6gIs Cl, F, Br, or I. In some embodiments of the present invention, the substrate is,R6b、R6c、R6d、R6e、R6fand R6gIs Cl. In some embodiments, R6b、R6c、R6d、R6e、R6fAnd R6gOne of which is halogen and the others are each H. In some embodiments, R6b、R6c、R6d、R6e、R6fAnd R6gIs halogen and R6b、R6c、R6d、R6e、R6fAnd R6gIs one of C1-C6An alkyl group. In some embodiments, R6b、R6c、R6d、R6e、R6fAnd R6gIs Cl and R6b、R6c、R6d、R6e、R6fAnd R6gOne of them is methyl. In some embodiments, R6gIs C1-C6An alkyl group. In some embodiments, R6bIs C1-C6An alkyl group. In some embodiments, R6cIs C1-C6An alkyl group. In some embodiments, R6dIs C1-C6An alkyl group. In some embodiments, R6eIs C1-C6An alkyl group. In some embodiments, R6fIs C1-C6An alkyl group. In some embodiments, R6gIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6bIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6cIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6dIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6eIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.In some embodiments, R6fIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6gIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6gIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6gIs C1-C6Alkyl and R6dIs a halogen. In some embodiments, R6gIs C1-C6Alkyl and R6eIs a halogen. In some embodiments, R6gIs C1-C6Alkyl and R6fIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6gIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6dIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6eIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6fIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6gIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6dIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6eIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6fIs a halogen. In some embodiments, R6dIs C1-C6Alkyl and R6gIs a halogen. In some embodiments, R6dIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6dIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6dIs C1-C6Alkyl and R6eIs a halogen. In some embodiments, R6dIs C1-C6Alkyl and R6fIs a halogen. In some embodiments, R6eIs C1-C6Alkyl and R6gIs a halogen. In some embodiments, R6eIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6eIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6eIs C1-C6Alkyl and R6dIs a halogen. In some embodiments, R6eIs C1-C6Alkyl and R6fIs a halogen. In some embodiments, R6fIs C1-C6Alkyl and R6gIs a halogen. In some embodiments, R6fIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6fIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6fIs C1-C6Alkyl and R6dIs a halogen. In some embodiments, R6fIs C1-C6Alkyl and R6eIs a halogen. In some embodiments, R6b、R6c、R6d、R6e、R6fAnd R6gTwo of which are halogens. In some embodiments, R6b、R6c、R6d、R6e、R6fAnd R6gTwo of (A) are C1-C6An alkyl group.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6b、R6c、R6d、R6e、R6fAnd R6gOne ofOne or two are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6b、R6c、R6d、R6e、R6fAnd R6gEach of the remainder of (a) is H; and B is optionally substituted with R7A substituted phenyl group.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6b、R6c、R6d、R6e、R6fAnd R6gOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6b、R6c、R6d、R6e、R6fAnd R6gEach of the remainder of (a) is H; and B is optionally substituted with R7Substituted 5 to 6 membered heteroaryl.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6b、R6c、R6d、R6e、R6fAnd R6gOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6b、R6c、R6d、R6e、R6fAnd R6gEach of the remainder of (a) is H; and B is optionally substituted with R7A substituted 5 to 6 membered carbocyclic ring.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6b、R6c、R6d、R6e、R6fAnd R6gOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6b、R6c、R6d、R6e、R6fAnd R6gEach of the remainder of (a) is H; and B is optionally substituted with R7Substituted 5 to 6 membered heterocyclic ring.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6b、R6c、R6d、R6e、R6fAnd R6gOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6b、R6c、R6d、R6e、R6fAnd R6gEach of the remainder of (a) is H; and B is optionally substituted with R7Substituted 9 to 10 membered heteroaryl.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6b、R6c、R6d、R6e、R6fAnd R6gOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6b、R6c、R6d、R6e、R6fAnd R6gEach of the remainder of (a) is H; and B is selected from:
in some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6b、R6c、R6d、R6e、R6fAnd R6gOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6b、R6c、R6d、R6e、R6fAnd R6gEach of the remainder of (a) is H; and B is selected from:
in some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6b、R6c、R6d、R6e、R6fAnd R6gOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6b、R6c、R6d、R6e、R6fAnd R6gEach of the remainder of (a) is H; and B is selected from
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6b、R6c、R6d、R6e、R6fAnd R6gOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6b、R6c、R6d、R6e、R6fAnd R6gEach of the remainder of (a) is H; and B is selected from
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein X1Selected from N, C, and CH; x2Selected from NH, O, and S; and R is6a、R6bAnd R6cEach independently is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C＝NH(OR8)、-C(O)R8、-OC(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-C(O)NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-P(O)(OR9)(OR10)、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, - (C)1-C3Alkylene) CN, - (C)1-C3Alkylene) OR8、-(C1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene) CF3、-(C1-C3Alkylene) NO2、-C＝NH(OR8)、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene) OC (O) R8、-(C1-C3Alkylene group) C (O) OR8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) OC (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)OR9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-C(O)(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene group P (O) (OR)9)(OR10)、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-12 membered heterocyclic group), - (C)1-C3Alkylene) (5-to 10-membered heteroaryl) or- (C)1-C3Alkylene) (C6-C14Aryl) in which each R is6a、R6bAnd R6cIndependently optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein X1Selected from N, C, and CH; x2Selected from NH, O, and S; and R is6a、R6bAnd R6cEach independently is H, C1-C6Alkyl, halogen, -CN, or-OC1-C6An alkyl group. In some embodiments of the compounds of formula (I), (II), or (III), A is
In some embodiments, R6a、R6bAnd R6cEach is H. In some embodiments, R6a、R6bAnd R6cIs Cl, F, Br, or I. In some embodiments, R6a、R6bAnd R6cIs Cl. In some embodiments, R6a、R6bAnd R6cOne of which is halogen and the others are each H. In some embodiments, R6a、R6bAnd R6cIs halogen and R6a、R6bAnd R6cIs one of C1-C6An alkyl group. In some embodiments, R6a、R6bAnd R6cIs Cl and R6a、R6bAnd R6cOne of them is methyl. In some embodiments, R6aIs C1-C6An alkyl group. In some embodiments, R6bIs C1-C6An alkyl group. In some embodiments, R6cIs C1-C6An alkyl group. In some embodiments, R6aIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6bIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6cIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6aIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6aIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6aIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6aIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6a、R6bAnd R6cTwo of which are halogens. In some embodiments, R6a、R6bAnd R6cTwo of (A) are C1-C6An alkyl group.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6bAnd R6cEach of the remainder of (a) is H; and B is optionally substituted with R7A substituted phenyl group.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6bAnd R6cEach of the remainder of (a) is H; and B is optionally substituted with R7Substituted 5 to 6 membered heteroaryl.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6bAnd R6cEach of the remainder of (a) is H; and B is optionally substituted with R7A substituted 5 to 6 membered carbocyclic ring.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6bAnd R6cEach of the remainder of (a) is H; and B is optionally substituted with R7Substituted 5 to 6 membered heterocyclic ring.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6bAnd R6cEach of the remainder of (a) is H; and B is optionally substituted with R7Substituted 9 to 10 membered heteroaryl.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6bAnd R6cEach of the remainder of (a) is H; and B is selected from:
in some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6bAnd R6cEach of the remainder of (a) is H; and B is selected from:
in some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6bAnd R6cEach of the remainder of (a) is H; and B is selected from
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6a、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6a、R6bAnd R6cEach of the remainder of (a) is H; and B is selected from
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein X1Selected from N, C, and CH; x2Selected from NH, O, and S; and R is6g、R6bAnd R6cEach independently is H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, halogen, -CN, -OR8、-SR8、-NR9R10、-NO2、-C＝NH(OR8)、-C(O)R8、-OC(O)R8、-C(O)OR8、-C(O)NR9R10、-OC(O)NR9R10、-NR8C(O)R9、-NR8C(O)OR9、-NR8C(O)NR9R10、-S(O)R8、-S(O)2R8、-NR8S(O)R9、-C(O)NR8S(O)R9、-NR8S(O)2R9、-C(O)NR8S(O)2R9、-S(O)NR9R10、-S(O)2NR9R10、-P(O)(OR9)(OR10)、C3-C6Cycloalkyl, 3-12 membered heterocyclyl, 5-to 10-membered heteroaryl, C6-C14Aryl, - (C)1-C3Alkylene) CN, - (C)1-C3Alkylene) OR8、-(C1-C3Alkylene) SR8、-(C1-C3Alkylene) NR9R10、-(C1-C3Alkylene) CF3、-(C1-C3Alkylene) NO2、-C＝NH(OR8)、-(C1-C3Alkylene group) C (O) R8、-(C1-C3Alkylene) OC (O) R8、-(C1-C3Alkylene group) C (O) OR8、-(C1-C3Alkylene group) C (O) NR9R10、-(C1-C3Alkylene) OC (O) NR9R10、-(C1-C3Alkylene) NR8C(O)R9、-(C1-C3Alkylene) NR8C(O)OR9、-(C1-C3Alkylene) NR8C(O)NR9R10、-(C1-C3Alkylene) S (O) R8、-(C1-C3Alkylene) S (O)2R8、-(C1-C3Alkylene) NR8S(O)R9、-C(O)(C1-C3Alkylene) NR8S(O)R9、-(C1-C3Alkylene) NR8S(O)2R9、-(C1-C3Alkylene group) C (O) NR8S(O)2R9、-(C1-C3Alkylene) S (O) NR9R10、-(C1-C3Alkylene) S (O)2NR9R10、-(C1-C3Alkylene group P (O) (OR)9)(OR10)、-(C1-C3Alkylene) (C3-C6Cycloalkyl), - (C)1-C3Alkylene) (3-12 membered heterocyclic group), - (C)1-C3Alkylene) (5-to 10-membered heteroaryl) or- (C)1-C3Alkylene) (C6-C14Aryl) in which each R is6g、R6bAnd R6cIndependently optionally substituted with: halogen, oxo, -OR11、-NR11R12、-C(O)R11、-CN、-S(O)R11、-S(O)2R11、-P(O)(OR11)(OR12)、-(C1-C3Alkylene) OR11、-(C1-C3Alkylene) NR11R12、-(C1-C3Alkylene group) C (O) R11、-(C1-C3Alkylene) S (O) R11、-(C1-C3Alkylene) S (O)2R11、-(C1-C3Alkylene group P (O) (OR)11)(OR12)、C3-C8Cycloalkyl, or C optionally substituted by oxo, -OH or halogen1-C6An alkyl group.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein X1Selected from N, C, and CH; x2Selected from NH, O, and S; and R is6g、R6bAnd R6cEach independently is H, C1-C6Alkyl, halogen, -CN, or-OC1-C6An alkyl group. In some embodiments of the compounds of formula (I), (II), or (III), A is
In some embodiments, R6g、R6bAnd R6cEach is H. In some embodiments, R6g、R6bAnd R6cIs Cl, F, Br, or I. In some embodiments, R6g、R6bAnd R6cIs Cl. In some embodiments, R6g、R6bAnd R6cOne of which is halogen and the others are each H. In some embodiments, R6g、R6bAnd R6cIs halogen and R6g、R6bAnd R6cIs one of C1-C6An alkyl group. In some embodiments, R6g、R6bAnd R6cIs Cl and R6g、R6bAnd R6cOne of them is methyl. In some embodiments, R6gIs C1-C6An alkyl group. In some embodiments, R6bIs C1-C6An alkyl group. In some embodiments, R6cIs C1-C6An alkyl group. In some embodiments, R6gIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6bIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6cIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R6gIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6gIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6gIs a halogen. In some embodiments, R6bIs C1-C6Alkyl and R6cIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6gIs a halogen. In some embodiments, R6cIs C1-C6Alkyl and R6bIs a halogen. In some embodiments, R6g、R6bAnd R6cTwo of (1)Is a halogen. In some embodiments, R6g、R6bAnd R6cTwo of (A) are C1-C6An alkyl group.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6g、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6g、R6bAnd R6cEach of the remainder of (a) is H; and B is optionally substituted with R7A substituted phenyl group.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6g、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6g、R6bAnd R6cEach of the remainder of (a) is H; and B is optionally substituted with R7Substituted 5 to 6 membered heteroaryl.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6g、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6g、R6bAnd R6cEach of the remainder of (a) is H; and B is optionally substituted with R7A substituted 5 to 6 membered carbocyclic ring.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6g、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6g、R6bAnd R6cEach of the remainder of (a) is H; and B is optionally substituted with R7Substituted 5 to 6 membered heterocyclic ring.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6g、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6g、R6bAnd R6cEach of the remainder of (a) is H; and B is optionally substituted with R7Substituted 9 to 10 membered heteroaryl.
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6g、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6g、R6bAnd R6cEach of the remainder of (a) is H; and B is selected from:
in some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6g、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6g、R6bAnd R6cEach of the remainder of (a) is H; and B is selected from:
in some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6g、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6g、R6bAnd R6cEach of the remainder of (a) is H; and B is selected from
In some embodiments of the compounds of formula (I), (II), or (III), A isWherein R is6g、R6bAnd R6cOne or two of (A) are independently selected from C1-C6Alkyl, halogen, -CN, and-OC1-C6Alkyl, and R6g、R6bAnd R6cEach of the remainder of (a) is H; and B is selected from
In the description herein, it is to be understood that each description, variation, embodiment, or aspect of a section can be combined with each description, variation, embodiment, or aspect of other sections as if each combination described were specifically and individually listed. For example, each description, variation, embodiment or aspect provided herein with respect to a of formula (I) can be with R1、R2、R3、R4And B, as if each combination were specifically and individually listed. It will also be understood that, where applicable, all descriptions, variations, embodiments or aspects of formula (I) apply equally to the other formulae detailed herein, and are described equally as if each description, variation, embodiment or aspect were set forth separately and individually for all formulae. For example, where applicable, all descriptions, variations, embodiments or aspects of formula (I) are equally applicable to formulas (II) and (III) as detailed herein, and are equally described as if each description, variation, embodiment or aspect were separately and individually listed for all formulas.
Also provided are salts, such as pharmaceutically acceptable salts, of the compounds mentioned herein. The invention also includes any or all stereochemical forms of the compounds described, including any enantiomeric or diastereomeric form, as well as any tautomeric or other form.
In one aspect, a compound as detailed herein can be in a purified form, and compositions comprising the compound in a purified form are detailed herein. Compositions, such as compositions of substantially pure compounds, comprising a compound or salt thereof as detailed herein are provided. In some embodiments, the composition containing a compound or salt thereof as detailed herein is in a substantially pure form. Unless otherwise indicated, "substantially pure" refers to a composition containing no more than 35% impurities, wherein the impurities refer to compounds other than the compound or salt thereof that makes up the majority of the composition. In some embodiments, a substantially pure composition of a compound or salt thereof is provided, wherein the composition contains no more than 25%, 20%, 15%, 10%, or 5% impurities. In some embodiments, a substantially pure composition of a compound or salt thereof is provided, wherein the composition comprises, or is no more than 3%, 2%, 1%, or 0.5% impurities.
Representative compounds are listed in table 1. It is to be understood that the individual enantiomers and diastereomers (if not depicted) are encompassed herein, and their respective structures can be readily determined therefrom.
TABLE 1
In some embodiments, provided herein are compounds described in table 1, or tautomers or isomers thereof, or pharmaceutically acceptable salts of any of the foregoing, and uses thereof.
Where applicable, the embodiments and variations described herein apply to compounds of any of the formulae detailed herein.
Representative examples of compounds detailed herein are depicted herein, including intermediates and final compounds according to the present disclosure. It will be appreciated that in one aspect, any of the compounds described may be used in the methods detailed herein, including (where applicable) intermediate compounds that may be isolated and administered to an individual.
Even if no salt is depicted, the compounds depicted herein may be present as salts, and it is understood that the disclosure includes all salts and solvates of the compounds depicted herein, as well as non-salt and non-solvate forms of the compounds, as well understood by those skilled in the art. In some embodiments, a salt of a compound provided herein is a pharmaceutically acceptable salt. N-oxides are also provided and described where one or more tertiary amine moieties are present in the compound.
Where any one of the compounds described herein may exist in tautomeric forms, each tautomeric form is contemplated, even though only one or some tautomeric forms may be explicitly depicted. The tautomeric forms specifically depicted may or may not be the predominant form in solution or when used according to the methods described herein.
The disclosure also includes any or all stereochemical forms of the described compounds, including any enantiomeric or diastereomeric forms. The structures or names are intended to encompass all possible isomers of the depicted compounds.
Additionally, the structures or names are intended to encompass tautomeric forms of the compounds described herein. For example, when R is1When hydrogen, the tautomer of formula (II) is of formula (IIa):
similarly, when R is1When hydrogen, the tautomer of formula (III) is formula (IIIa):
the invention also encompasses all forms of the compounds, such as crystalline or non-crystalline forms of the compounds. Also contemplated are compositions comprising a compound of the invention, such as compositions that are substantially pure compounds (including specific stereochemical forms thereof), or compositions that comprise a mixture of compounds of the invention in any ratio (including two or more stereochemical forms, such as in a racemic or non-racemic mixture).
The invention also relates to isotopically labeled and/or isotopically enriched forms of the compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically labeled, such as an isotopically labeled compound of formula (I) described herein or a variant thereof, wherein a portion of one or more atoms is replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15O, 17O, 32P, 35S、18F、36And (4) Cl. Certain isotopically-labeled compounds (e.g.3H and14C) can be used for compound or substrate tissue distribution research. Heavier isotopes (such as deuterium (b) (ii))2H) Incorporation) may confer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in some circumstances.
Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures analogous to those described in the accompanying examples using an appropriate isotopically-labeled reagent in place of the corresponding unlabeled reagent.
The invention also includes any or all metabolites of any of the compounds described. Metabolites may include any chemical species produced by the biotransformation of any of the compounds described, such as intermediates and metabolites of the compounds, such as would be produced in vivo upon administration to a human.
Provided are articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container. The container may be a vial, canister, ampoule, pre-filled syringe, iv bag, or the like.
Preferably, the compounds detailed herein are orally bioavailable. However, the compounds may also be formulated for parenteral (e.g., intravenous) administration.
One or more of the compounds described herein may be used in the preparation of a medicament by combining one or more compounds as the active ingredient with pharmacologically acceptable carriers known in the art. The carrier may be in various forms based on the form of treatment of the drug. In one variation, the manufacture of the medicament is used in any of the methods disclosed herein, e.g., for treating cancer.
General synthetic method
The compounds of the invention can be prepared by a variety of methods as generally described below and more particularly described in the examples below (such as the schemes provided in the examples below). In the following description of the process, when used in the depicted formula, the symbols should be understood to represent those groups described above with respect to the formulae herein.
Where it is desired to obtain a particular enantiomer of a compound, this may be achieved using any suitable conventional procedure for separating or resolving enantiomers from mixtures of the corresponding enantiomers. Thus, for example, diastereomeric derivatives can be produced by reaction of a mixture of enantiomers (e.g., a racemate) with an appropriate chiral compound. The diastereomers may then be separated and the desired enantiomer recovered by any convenient means (e.g., by crystallization). In another resolution method, chiral high performance liquid chromatography can be used to separate the racemates. Alternatively, if desired, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes.
Chromatography, recrystallization, and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or otherwise purify the reaction product.
Solvates and/or polymorphs of the compounds provided herein, or pharmaceutically acceptable salts thereof, are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are typically formed during crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability and/or solubility. Various factors, such as recrystallization solvent, crystallization rate, and storage temperature, may cause the single crystal form to dominate.
In some embodiments, the compounds of formula (I) may be synthesized according to scheme 1,2,3, or 4.
Scheme 1
Wherein A, B and R3Is as defined for formula (I) or any variant thereof as detailed herein. It is understood that modifications can be made to scheme 1, such as further substitutions of the depicted structures. Specific examples are provided in the examples section below.
Scheme 2
Wherein A, B and R2Is as defined for formula (I) or any variant thereof as detailed herein. It is understood that modifications may be made to scheme 2, such as further substitutions of the depicted structures. Specific examples are provided in the examples section below.
Scheme 3
Wherein A, B and R3Is as defined for formula (I) or any variant thereof as detailed herein. It is understood that modifications can be made to scheme 3, such as further substitutions of the depicted structures. Specific examples are provided in the examples section below.
Scheme 4
A, B, R therein2And R3Is as defined for formula (I) or any variant thereof as detailed herein. It is understood that modifications may be made to scheme 4, such as further substitutions of the depicted structures. Specific examples are provided in the examples section below.
It will be appreciated that the steps involved in the synthetic routes of the present invention are clearly familiar to those skilled in the art, as are the general synthetic schemes 1,2,3 and 4, wherein the substituents described in the compounds of formula (I) herein can be varied by selecting the appropriate starting materials and reagents utilized in the steps presented.
Pharmaceutical compositions and formulations
The present disclosure includes pharmaceutical compositions of any of the compounds detailed herein. Accordingly, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt with an inorganic or organic acid. The pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
In one aspect, a compound as detailed herein can be in a purified form, and compositions comprising the compound in a purified form are detailed herein. Compositions, such as compositions of substantially pure compounds, comprising a compound or salt thereof as detailed herein are provided. In some embodiments, the composition containing a compound or salt thereof as detailed herein is in a substantially pure form.
In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, a composition is provided that contains the compound in a substantially pure form. In another variation, the disclosure includes a pharmaceutical composition comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, a method of administering a compound is provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are applicable to any of the compounds or forms thereof detailed herein.
The compounds or salts thereof detailed herein can be formulated for any useful delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compounds or salts thereof can be formulated with suitable carriers to provide delivery forms including, but not limited to, tablets, caplets, capsules (such as hard or soft elastic gelatin capsules), cachets, lozenges, gels, dispersions, suppositories, ointments, poultices (creams), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalants), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.
One or more compounds or salts thereof described herein can be used to prepare a formulation, such as a pharmaceutical formulation, by combining one or more compounds or salts thereof as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. The carrier can be in various forms depending on the treatment modality of the system (e.g., transdermal patch and oral tablet). In addition, the pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators and salts for regulating the osmotic pressure, buffers, coating agents or antioxidants. Formulations containing the compounds may also contain other substances having valuable therapeutic properties. The pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 20 th edition (2000), which is incorporated herein by reference.
The compounds as described herein may be administered to an individual in the form of generally accepted oral compositions such as tablets, coated tablets, and gel capsules, emulsions or suspensions in hard or soft shells. Examples of carriers that can be used in the preparation of such compositions are lactose, corn starch or derivatives thereof, talc, stearates or salts thereof and the like. Acceptable carriers for gelatin capsules having a soft shell are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. In addition, the pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators and salts for regulating the osmotic pressure, buffers, coating agents or antioxidants.
Any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a pharmaceutically acceptable salt thereof can be formulated in a 10mg tablet.
Also described are compositions comprising the compounds provided herein. In one variation, the composition comprises a compound or salt thereof and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided.
Application method
The compounds and compositions detailed herein (such as pharmaceutical compositions containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient) can be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in vitro methods, such as in vitro methods of administering a compound or composition to a cell for screening purposes and/or for quality control assays.
Provided herein is a method of treating a disease in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or any embodiment, variant, or aspect thereof (collectively, compounds of formula (I) or compounds of the invention or compounds detailed or described herein) or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of treating a disease mediated by a G protein-coupled receptor signaling pathway in a subject, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is mediated by a class a G protein-coupled receptor. In some embodiments, the disease is mediated by a class B G protein-coupled receptor. In some embodiments, the disease is mediated by a class C G protein-coupled receptor. In some embodiments, the G protein-coupled receptor is a purine G protein receptor. In some embodiments, the G protein-coupled receptor is an adenosine receptor, such as a1、A2A、A2BAnd A3Any one of the receptors.
The compounds of the present invention or salts thereof are believed to be effective in the treatment of a variety of diseases and disorders. For example, in some embodiments, the compositions of the invention may be used to treat proliferative diseases, such as cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is any one of the following: adult and pediatric oncology, mucinous and round cell carcinomas, locally advanced tumors, metastatic cancers, human soft tissue sarcomas (including Ewing's sarcoma), cancer metastases (including lymphatic metastases), squamous cell cancers (particularly head and neck squamous cell carcinomas), esophageal squamous cell cancers, oral cancers, hematologic malignancies (including multiple myeloma), leukemias (including acute lymphocytic leukemia, acute non-lymphocytic leukemia, chronic myelocytic leukemia, and hairy cell leukemia), effusion lymphomas (coelomic-based lymphomas), thymic lymphoma lung cancer (including small cell carcinoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, adrenal cortex cancer, ACTH-producing tumors, non-small cell carcinomas), breast cancer (including small cell carcinoma and ductal carcinoma), Gastrointestinal cancer (including gastric cancer, colon cancer, colorectal cancer, polyps associated with colorectal neoplasms), pancreatic cancer, liver cancer, urinary cancer (including bladder cancer, including primary superficial bladder tumor, bladder invasive transitional cell cancer, and muscle invasive bladder cancer), prostate cancer, female genital tract malignancy (including ovarian cancer, primary peritoneal epithelial tumor, cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, uterine cancer, and ovarian follicular solid tumor), male genital tract malignancy (including testicular cancer and penile cancer), kidney cancer (including renal cell carcinoma), brain cancer (including endogenous brain tumor, neuroblastoma, astrocytic brain tumor, glioma, metastatic tumor cell invasion in the central nervous system), bone cancer (including osteoma and osteosarcoma), skin cancer (including melanoma, tumor progression of human skin keratinocytes, renal cell carcinoma), prostate cancer, and/or a Squamous cell carcinoma), thyroid carcinoma, retinoblastoma, neuroblastoma, peritoneal fluid, malignant pleural fluid, mesothelioma, wilm's tumor, gallbladder carcinoma, trophoblastic tumor, hemangiothecoma, and kaposi's sarcoma.
In some embodiments, the compounds of the invention or salts thereof are used to treat tumors that produce high levels of ATP and/or adenosine. For example, in some embodiments, the extracellular concentration of adenosine in a tumor is 10-20 times greater than in adjacent tissue. In some embodiments, the compounds of the invention or salts thereof are used to treat tumors that express high levels of exonucleotidase. In some embodiments, the exonucleotidase is CD 39. In some embodiments, the exonucleotidase is CD 73.
Also provided herein is a method of enhancing an immune response in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Adenosine receptors are known to play an immunosuppressive role in cancer biology. The high levels of adenosine present in the tumor microenvironment bind to adenosine receptors on immune cells to provide an immunosuppressive microenvironment. In particular, adenosine is reacted with A2AThe binding of the receptor providesImmunosuppressive signals that inhibit T cell proliferation, cytokine production, and cytotoxicity. A. the2AReceptor signaling is implicated in adenosine-mediated inhibition of NK cell cytotoxicity, NKT cytokine production, and CD40L upregulation. Thus, use of A2AReceptor antagonists (such as those provided herein) can reverse the immunosuppressive effects of adenosine on immune cells. In some embodiments, the immune response is enhanced by enhancing the activity of Natural Killer (NK) cells with a compound of formula (I) or a salt thereof. In some embodiments, a compound of the invention or salt thereof increases NK cell-mediated cytotoxicity. In some embodiments, by enhancing CD8+T cell activity to enhance the immune response. In some embodiments, a compound of the invention or a salt thereof causes an inflammatory response in the tumor microenvironment.
The present disclosure further provides a method of increasing natural killer cell activity in a subject, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some of these embodiments, the compound of the invention or salt thereof increases NK cell-mediated cytotoxicity. In some embodiments, the compound of formula (I) or salt thereof increases the number of NK cells.
The compounds of formula (I) or salts thereof may be used to modulate the activity of G protein receptor-coupled signaling pathway proteins. In some embodiments, the compound of formula (I) or a salt thereof activates a G protein receptor-coupled signaling pathway protein (i.e., is an agonist of a G protein receptor). In some embodiments, the compound of formula (I) or salt thereof inhibits a G protein receptor-coupled signaling pathway protein (i.e., is a G protein receptor antagonist). In some embodiments, the compound of formula (I) or salt thereof is an adenosine receptor antagonist. In some embodiments, the compound of formula (I) or salt thereof is A1、A2A、A2BAnd A3An antagonist of any one of the receptors.
Thus, also provided herein is a method of modulating a in an individual2AA method of activity of a receptor, the method comprising administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically thereofAn acceptable salt. In some embodiments, the compound of formula (I) or salt thereof is A2AA receptor antagonist. In some embodiments, a compound of formula (I) or a salt thereof is substituted with a2AReceptor signaling is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, a compound of formula (I) or a salt thereof is substituted with a2AReduced receptor signaling by 40% -99%, 50% -99%, 60% -99%, 70% -99%, 80% -99%, 90% -99%, or 95% -99%. In some of these embodiments, the compound of formula (I) or a salt thereof has an IC of less than 1 μ M, less than 900nM, less than 800nM, less than 700nM, less than 600nM, less than 500nM, less than 400nM, less than 300nM, less than 200nM, less than 100nM, less than 10nM, less than 1nM, or less than 100pM50And A2AReceptor binding. In some embodiments, [ compound x ]]IC at 500nM to 100pM, 400nM to 100pM, 300nM to 100pM, 200nM to 100pM, or 100nM to 100pM50And A2AReceptor binding.
Also provided herein is a method of modulating a in an individual2BA method of activity of a receptor, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or salt thereof is A2BA receptor antagonist. In some embodiments, a compound of formula (I) or a salt thereof is substituted with a2BReceptor signaling is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, a compound of formula (I) or a salt thereof is substituted with a2BReduced receptor signaling by 40% -99%, 50% -99%, 60% -99%, 70% -99%, 80% -99%, 90% -99%, or 95% -99%. In some of these embodiments, the compound of formula (I) or a salt thereof has an IC of less than 1 μ M, less than 900nM, less than 800nM, less than 700nM, less than 600nM, less than 500nM, less than 400nM, less than 300nM, less than 200nM, less than 100nM, less than 10nM, less than 1nM, or less than 100pM50And A2BReceptor binding. In some embodiments, a compound of formula (I) or a salt thereof has an IC of 500nM to 100pM, 400nM to 100pM, 300nM to 100pM, 200nM to 100pM, or 100nM to 100pM50And A2BReceptor binding.
Also provided herein is a method of modulating a in an individual3A method of activity of a receptor, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or salt thereof is A3A receptor antagonist. In some embodiments, a compound of formula (I) or a salt thereof is substituted with a3Receptor signaling is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, a compound of formula (I) or a salt thereof is substituted with a3Reduced receptor signaling by 40% -99%, 50% -99%, 60% -99%, 70% -99%, 80% -99%, 90% -99%, or 95% -99%. In some of these embodiments, the compound of formula (I) or a salt thereof has an IC of less than 1 μ M, less than 900nM, less than 800nM, less than 700nM, less than 600nM, less than 500nM, less than 400nM, less than 300nM, less than 200nM, less than 100nM, less than 10nM, less than 1nM, or less than 100pM50And A3Receptor binding. In some embodiments, a compound of formula (I) or a salt thereof has an IC of 500nM to 100pM, 400nM to 100pM, 300nM to 100pM, 200nM to 100pM, or 100nM to 100pM50And A3Receptor binding.
In some embodiments, the invention includes a method of inhibiting tumor metastasis in a subject in need thereof, the method comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the metastasis is to the lung, liver, lymph node, bone, adrenal gland, brain, peritoneum, muscle, or vagina. In some embodiments, the compound of formula (I) or a salt thereof inhibits metastasis of melanoma cells. In some embodiments, the present disclosure includes a method of delaying tumor metastasis, the method comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some of these embodiments, the transfer time is delayed by 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months or more following treatment with a compound of the invention.
In some embodiments, a compound of formula (I) or a salt thereof is used to treat an individual having a proliferative disease, such as a cancer described herein. In some embodiments, the individual is at risk of developing a proliferative disease (such as cancer). In some of these embodiments, the individual is determined to be at risk of developing cancer based on one or more risk factors. In some of these embodiments, the risk factor is a family history and/or gene associated with cancer. In some embodiments, the individual has a cancer that expresses high levels of a nucleotide metabolizing enzyme. In some embodiments, the nucleotide metabolizing enzyme is a nucleotidase, such as CD73 (exo-5 '-nucleotidase, exo 5' NT enzyme). In some of these embodiments, the individual has a cancer that expresses high levels of a nucleotidase, such as CD 73. In any of these embodiments, the nucleotide metabolizing enzyme is an exonucleotidase. In some embodiments, the exonucleotide enzyme degrades adenosine monophosphate. In some embodiments, the nucleotide metabolizing enzyme is CD39 (ectonucleoside triphosphate diphosphohydrolase 1, E-NTPD enzyme 1). In some of these embodiments, the individual has a cancer that expresses high levels of CD 39. In some embodiments, the individual has a condition that expresses high levels of adenosine receptors (such as a)2AReceptor) of the cancer.
Combination therapy
As provided herein, the presently disclosed compounds or salts thereof can modulate the activity of G protein-coupled receptor signaling pathways (e.g., act as a)2AReceptor antagonists) to activate the immune system, which results in a significant anti-tumor effect. Therefore, the compound of the present invention or a salt thereof may be used in combination with other anticancer agents to enhance tumor immunotherapy. In some embodiments, provided herein is a method of treating a disease mediated by a G protein-coupled receptor signaling pathway in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or a drug thereofA pharmaceutically acceptable salt and an additional therapeutic agent. In some embodiments, the disease mediated by a G protein-coupled receptor signaling pathway is a proliferative disease, such as cancer.
In some embodiments, the additional therapeutic agent is cancer immunotherapy. In some embodiments, the additional therapeutic agent is an immunostimulatory agent. In some embodiments, the additional therapeutic agent targets a checkpoint protein. In some embodiments, the additional therapeutic agent is effective to stimulate, enhance or improve an immune response against the tumor.
In another aspect, provided herein is a combination therapy wherein a compound of formula (I) is co-administered (either separately or simultaneously) with one or more additional agents effective to stimulate an immune response, thereby further enhancing, stimulating or up-regulating the immune response in a subject. For example, there is provided a method for stimulating an immune response in a subject, the method comprising administering to the subject a compound of formula (I) or a salt thereof and one or more immunostimulatory antibodies (such as an anti-PD-1 antibody, an anti-PD-L1 antibody, and/or an anti-CTLA-4 antibody), such that an immune response is stimulated in the subject, e.g., to inhibit tumor growth. As another example, a method for stimulating an immune response in a subject is provided, the method comprising administering to the subject a compound of formula (I) or a salt thereof and one or more immunostimulatory antibodies or immunotherapy, like Chimeric Antigen Receptor (CAR) T cell therapy, such as an anti-PD-1 antibody, an anti-PD-L1 antibody, and/or an anti-CTLA-4 antibody, such that the immune response is stimulated in the subject, e.g., to inhibit tumor growth. In one embodiment, a compound of formula (I) or a salt thereof and an anti-PD-1 antibody are administered to the subject. In another embodiment, a compound of formula (I) or a salt thereof and an anti-PD-L1 antibody are administered to the subject. In yet another embodiment, the compound of formula (I) or a salt thereof and an anti-CTLA-4 antibody are administered to the subject. In another embodiment, the immunostimulatory antibody (e.g., an anti-PD-1 antibody, an anti-PD-L1 antibody, and/or an anti-CTLA-4 antibody) is a human antibody. Alternatively, the immunostimulatory antibody may be, for example, a chimeric antibody or a humanized antibody (e.g., prepared from a mouse anti-PD-1 antibody, an anti-PD-L1 antibody, and/or an anti-CTLA-4 antibody). In another embodiment, a compound of formula (I) or a salt thereof and CAR T cells (genetically modified T cells) are administered to the subject.
In one embodiment, the present disclosure provides a method for treating a proliferative disease (e.g., cancer) comprising administering to a subject a compound of formula (I) or a salt thereof and an anti-PD-1 antibody. In further embodiments, the compound of formula (I) or salt thereof is administered at a sub-therapeutic dose, the anti-PD-1 antibody is administered at a sub-therapeutic dose, or both are administered at a sub-therapeutic dose. In another embodiment, the disclosure provides a method for altering an adverse event associated with treatment of a hyperproliferative disease with an immunostimulant, the method comprising administering to a subject a compound of formula (I) or a salt thereof and a sub-therapeutic dose of an anti-PD-1 antibody. In certain embodiments, the subject is a human. In certain embodiments, the anti-PD-1 antibody is a human sequence monoclonal antibody.
In one embodiment, the present invention provides a method for treating a hyperproliferative disease (e.g., cancer) comprising administering to a subject a compound of formula (I) or a salt thereof and an anti-PD-L1 antibody. In further embodiments, the compound of formula (I) or salt thereof is administered at a sub-therapeutic dose, the anti-PD-L1 antibody is administered at a sub-therapeutic dose, or both are administered at a sub-therapeutic dose. In another embodiment, the invention provides a method for altering adverse events associated with treatment of a hyperproliferative disease with an immunostimulant, said method comprising administering to a subject a compound of formula (I) or a salt thereof and a subtherapeutic dose of an anti-PD-L1 antibody. In certain embodiments, the subject is a human. In certain embodiments, the anti-PD-L1 antibody is a human sequence monoclonal antibody.
In certain embodiments, a combination of therapeutic agents discussed herein can be administered simultaneously as a single composition in a pharmaceutically acceptable carrier, or simultaneously as separate compositions each in a pharmaceutically acceptable carrier. In another embodiment, the combination of therapeutic agents may be administered sequentially. For example, the anti-CTLA-4 antibody and the compound of formula (I) or salt thereof can be administered sequentially, such as first administering the anti-CTLA-4 antibody, and second administering the compound of formula (I) or salt thereof; or administering first a compound of formula (I) or a salt thereof and second an anti-CTLA-4 antibody. Additionally or alternatively, the anti-PD-1 antibody and the compound of formula (I) or salt thereof can be administered sequentially, such as first administering the anti-PD-1 antibody and second administering the compound of formula (I) or salt thereof; or first administering a compound of formula (I) or a salt thereof and second administering an anti-PD-1 antibody. Additionally or alternatively, the anti-PD-L1 antibody and the compound of formula (I) or salt thereof can be administered sequentially, such as first administering the anti-PD-L1 antibody, and second administering the compound of formula (I) or salt thereof; or first administering a compound of formula (I) or a salt thereof and second administering an anti-PD-L1 antibody.
Further, if more than one dose of the combination therapy is administered sequentially, the order of sequential administration may be reversed or maintained in the same order, sequential administration may be combined with simultaneous administration, or any combination thereof, at each time point of administration.
Optionally, the combination of compounds of formula (I) or salts thereof may be further combined with immunogenic agents such as cancer cells, purified tumor antigens (including recombinant proteins, peptides and carbohydrate molecules), cells and cells transfected with genes encoding immunostimulatory cytokines.
The compounds of formula (I) or salts thereof may also be further combined with standard cancer treatments. For example, a compound of formula (I) or a salt thereof may be effectively combined with a chemotherapeutic regimen. In these cases, the dose of other chemotherapeutic agents administered with the combination of the present disclosure may be reduced (Mokyr et al (1998) Cancer Research 58: 5301-5304). Other combination therapies for compounds having formula (I) or salts thereof include radiation, surgery, or hormone blockade (depletion). The angiogenesis inhibitor may also be combined with a compound of formula (I) or a salt thereof. Inhibition of angiogenesis leads to tumor cell death, which can supply a source of tumor antigens to the host antigen presentation pathway.
In another example, a compound of formula (I) or a salt thereof may be used to bind to an anti-tumor antibody. For example, and without wishing to be bound by theory, treatment with an anti-cancer antibody or an anti-cancer antibody conjugated to a toxin can result in cancer cell death (e.g., tumor cells), which will enhance the immune response mediated by CTLA-4, PD-1, PD-L1, or the compound of formula (I) or a salt thereof. In an exemplary embodiment, treatment of a hyperproliferative disease (e.g., a cancer tumor) may include the combination of an anti-cancer antibody with a compound of formula (I) or a salt thereof and an anti-CTLA-4 and/or anti-PD-1 and/or anti-PD-L1 antibody, either simultaneously or sequentially or any combination thereof, which may enhance the anti-tumor immune response of the host. Other antibodies that may be used to activate host immune reactivity may be further used in combination with the compound of formula (I) or a salt thereof.
In some embodiments, a compound of formula (I) or a salt thereof may be combined with an anti-CD 73 therapy, such as an anti-CD 73 antibody.
In some embodiments, a compound of formula (I) or a salt thereof may be combined with an anti-CD 39 therapy, such as an anti-CD 39 antibody.
In yet a further embodiment, the compound of formula (I) or a salt thereof is combined with another G protein receptor antagonist (such as adenosine a)1And/or A3Antagonist) is administered in combination.
Methods of administration and administration
The dosage of a compound administered to an individual (such as a human) can vary with the particular compound or salt thereof, the method of administration, and the particular disease being treated (such as the type and stage of cancer). In some embodiments, the amount of the compound or salt thereof is a therapeutically effective amount.
In one aspect, the effective amount of the compound may be a dose of between about 0.01 and about 100 mg/kg. Considering conventional factors such as the mode or route of administration or drug delivery; the pharmacokinetics of the agent; the severity and course of the disease to be treated; the health, condition and body weight of a subject, an effective amount or dose of a compound of the invention can be determined by conventional methods, such as modeling, dose escalation, or clinical trials. Exemplary doses are in the range of about 0.7 mg/day to 7 g/day, or about 7 mg/day to 350 mg/day, or about 350 mg/day to 1.75 g/day, or about 1.75 to 7 g/day.
In one aspect, any of the methods provided herein can comprise administering to the individual a pharmaceutical composition comprising an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.
A compound or composition of the invention can be administered to an individual according to an effective dosing regimen for a desired period of time or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may last for the duration of the life of the individual. In one variation, the compound is administered on a daily or intermittent schedule. The compound may be administered to the individual continuously (e.g., at least once per day) over a period of time. The frequency of administration may also be less than once daily, for example, about once weekly. The frequency of administration may be more than once per day, for example two or three times per day. The frequency of administration may also be intermittent, including a "drug-off period" (e.g., once daily for 7 days, then no administration for 7 days, repeated for any 14 day period, such as about 2 months, about 4 months, about 6 months, or longer). Any frequency of administration may be with any of the compounds described herein and any dosage described herein.
The compounds provided herein or salts thereof can be administered to an individual via a variety of routes including, for example, intravenous, intramuscular, subcutaneous, oral, and transdermal. The compounds provided herein may be administered frequently at low doses, referred to as "rhythmic therapy," or as part of maintenance therapy using the compound alone or in combination with one or more additional drugs. Rhythmic or maintenance therapy may include cyclical administration of a compound provided herein. Rhythmic or maintenance therapy may include intratumoral administration of a compound provided herein.
In one aspect, the invention provides a method of treating cancer in an individual by parenterally administering to the individual (e.g., a human) an effective amount of a compound or a salt thereof. In some embodiments, the route of administration is intravenous, intraarterial, intramuscular, or subcutaneous. In some embodiments, the route of administration is oral. In still other embodiments, the route of administration is transdermal.
The invention also provides compositions (including pharmaceutical compositions) and other methods described herein for treating, preventing, and/or delaying the onset and/or progression of cancer, as described herein. In certain embodiments, the composition comprises a pharmaceutical formulation in unit dosage form.
Also provided are articles of manufacture comprising a compound of the disclosure or salt thereof, compositions, and unit doses described herein in a suitable package for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampoules, bottles, jars, flexible packaging and the like. The article may further be sterilized and/or sealed.
Reagent kit
The present disclosure further provides kits for carrying out the methods of the invention, the kits comprising one or more compounds described herein or a composition comprising a compound described herein. The kit may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein, or a pharmaceutically acceptable salt thereof. The kit may be for any one or more of the uses described herein, and accordingly may contain instructions for treating cancer.
The kit will generally comprise suitable packaging. Kits may comprise one or more containers containing any of the compounds described herein. Each component (if more than one component is present) may be packaged in a separate container, or some components may be combined in one container with cross-reactivity and shelf-life permitting.
The kit may be in unit dosage form, in bulk packaging (e.g., multi-dose packaging), or in sub-unit doses. For example, a kit can be provided containing a sufficient dose of a compound as disclosed herein and/or a second pharmaceutically active compound useful for the diseases detailed herein (e.g., hypertension) to provide effective treatment of an individual for an extended period of time, such as any one of one week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or longer. Kits may also include a plurality of unit doses of the compound and instructions for use, and packaged in amounts sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compound pharmacies).
The kit may optionally include a set of instructions, typically written instructions, relating to the use of one or more components of the methods of the invention, although electronic storage media (e.g., magnetic or optical disks) containing the instructions are also acceptable. The instructions included in the kit typically include information about the components and their administration to the individual.
The invention may be further understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting.
Examples
Synthetic examples
Example S1: synthesis of 3-phenyl-2- (quinolin-6-yl) pyrido [2,3-b ] pyrazin-8 (5H) -one (Compound No. 1.5)
Step 1: synthesis of 6-phenylpyrazin-2-amine: to a solution of 6-chloropyrazin-2-amine (1.00g, 7.75mmol, 1 equivalent) in 1, 4-dioxane (30mL) was added phenylboronic acid (1.42g, 11.62mmol, 1.5 equivalents), K3PO4(3.286g, 15.50mmol, 2 equiv.), Pd (OAc)2(0.086g, 0.38mmol, 0.05 eq), 1' -bis (diphenylphosphino) ferrocene (0.214g, 0.38mmol, 0.05 eq). The reaction mixture was treated with N2The atmosphere was deoxygenated and the reaction mixture was heated at 100 ℃ overnight. The reaction was monitored by TLC and LCMS and after 18h the reaction was complete. The reaction mixture was cooled to room temperature, filtered through a bed of ciliates and washed with ethyl acetate (2 × 20 mL). The reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (2X 50 mL). The separated organic layer was dried over sodium sulfate and under reduced pressureAnd (4) concentrating. The crude product was used as CH3OH-CH2Cl2The system was purified by Combiflash as eluent to give 1.10g (63%) of 6-phenylpyrazin-2-amine. LCMS: 172[ M +1 ]]+。
Step 2: synthesis of 5-bromo-6-phenylpyrazin-2-amine: to a solution of 6-phenylpyrazin-2-amine (0.150g, 0.877mmol, 1 eq) in DMF (3mL) was added N-bromosuccinimide (0.156g, 0.877mmol, 1 eq) and the reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC and NMR. Upon completion, the reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with water (5 × 20mL), then brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product, which was purified by combifallsh on silica gel using EtOAc-hexanes system as eluent to give 100mg (46%) of 5-bromo-6-phenylpyrazin-2-amine. LCMS: 251[ M +1 ]]+。
And step 3: synthesis of 6-phenyl-5- (quinolin-6-yl) pyrazin-2-amine: to a stirred solution of quinolin-6-ylboronic acid (0.100g, 0.57mmol, 1.2 equivalents) and 5-bromo-6-phenylpyrazin-2-amine (0.120g, 0.48mmol, 1.0 equivalents) in dioxane (3mL) was added 2M Na2CO3Aqueous solution (0.101g, 0.96mmol, 2.0 equiv., 0.5 mL). Will react with N2Purging for 5 min. To this reaction mixture was added Pd (dppf) Cl2DCM (0.020g, 5 mol%) and with N2Purge again for another 5 min. The reaction mixture was heated at 90 ℃ for 4 h. The reaction mixture was allowed to cool to room temperature and extracted with ethyl acetate (2 × 35 mL). The combined organic layers were washed (brine) and dried (anhydrous Na)2SO4) And concentrated in vacuo to give a solid residue which was purified by normal phase silica gel flash column chromatography to give the desired product as an off-white solid (0.030g, 21%). LCMS: 299[ M +1 ]]+。
And 4, step 4: synthesis of 3-bromo-6-phenyl-5- (quinolin-6-yl) pyrazin-2-amine: to a solution of 6-phenyl-5- (quinolin-6-yl) pyrazin-2-amine (20mg, 0.068mmol, 1 eq) in acetonitrile (12mL) was added N-bromosuccinimide (12mg, 0.068mmol, 1 eq) portionwise at room temperature) And the reaction mixture was allowed to stir at room temperature. The progress of the reaction was monitored by TLC and the reaction was found to be complete after 13 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water (3 × 20mL) and dried over anhydrous sodium sulfate. Removal of the solvent gave a crude product which was purified by reverse phase HPLC to give 10mg (40%) of 3-bromo-6-phenyl-5- (quinolin-6-yl) pyrazin-2-amine. LCMS: 377[ M +1 ]]+。
And 5: synthesis of 3-amino-5-phenyl-6- (quinolin-6-yl) pyrazine-2-carbonitrile: to a stirred solution of 6-phenyl-5- (quinolin-6-yl) pyrazin-2-amine (0.220g, 0.58mmol, 1.0 equiv.) in NMP (1.5mL) was added cuprous cyanide (0.155g, 1.74mmol, 3.0 equiv.). The reaction mixture was allowed to stir at 170 ℃ for 1 h. The reaction progress was monitored by LCMS. The reaction mixture was allowed to cool to room temperature and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed (brine) and dried (anhydrous Na)2SO4) And concentrated in vacuo to give a solid which was purified by normal phase column chromatography to give the desired product as an off-white solid (0.020g, 10%). LCMS: 324[ M +1 ]]+。
Step 6: synthesis of 1- (3-amino-5-phenyl-6- (quinolin-6-yl) pyrazin-2-yl) ethan-1-one: to a stirred solution of 3-amino-5-phenyl-6- (quinolin-6-yl) pyrazine-2-carbonitrile (0.100g, 0.32mmol, 1.0 eq) in THF (5mL) was added 3M MeMgBr (1mL, 0.360g, 10.0 eq, 3.0mmol) in ether at 0 ℃. The resulting reaction mixture was stirred at 50 ℃ for 16 h. The reaction mixture was then cooled to room temperature and slowly acidified with dilute HCl. The acidified reaction mixture was stirred at 50 ℃ for 1 h. The reaction mixture was allowed to cool to room temperature again and extracted by using ethyl acetate (2 × 25 mL). The combined organic layers were washed (brine) and dried (anhydrous Na)2SO4) And concentrated under vacuum to give the desired product as a pale yellow solid (0.090g, 97%) LCMS: 291[ M +1 ]]+。
And 7: 3-phenyl-2- (quinolin-6-yl) pyrido [2,3-b]Synthesis of pyrazin-8 (5H) -one: to 1- (6-amino-3- (quinolin-6-yl) -2,3' -bipyridin-5-yl) ethanone (0.090g, 0.31mmol, 1.00 equiv.) to a solution in 1,4 dioxane (5mL) was added DMF: DMA (0.044g, 0.37mmol, 1.2 equiv.). The reaction mixture was heated at 90 ℃ for 30 minutes. The reaction was monitored by TLC and LCMS. The reaction solvent was evaporated under reduced pressure. The obtained semi-solid crude material was re-dissolved in DMF (2mL) and Cs was added2CO3(0.150g, 0.46mmol, 1.5 equiv.). The reaction mixture was heated again at 90 ℃ for 18 h. The reaction progress was monitored by LCMS. The reaction mixture was diluted with ice-cold water (25mL) and extracted by using ethyl acetate (3 × 25 mL). The residue was purified by reverse phase column chromatography to give the desired product (0.010g, 10%). LCMS 351[ M +1 ]]+；1H NMR(400MHz,DMSO-d6)δ8.92(d,J＝3.07Hz,1H),8.35(d,J＝7.45Hz,1H),8.14(br s,1H),8.06(d,J＝5.26Hz,1H),7.91(d,J＝8.77Hz,1H),7.65(d,J＝7.02Hz,1H),7.45-7.59(m,3H),7.29-7.44(m,3H),6.33(d,J＝7.02Hz,1H)。
Example S2: synthesis of 5-methyl-3-phenyl-2- (quinolin-6-yl) pyrido [2,3-b ] pyrazin-8 (5H) -one (Compound No. 1.8)
To 3-phenyl-2- (quinolin-6-yl) pyrido [2,3-b]To a solution of pyrazin-8 (5H) -one (10mg, 0.02mmol, 1.00 equiv) in DMF (5mL) was added cesium carbonate (18.5mg, 0.05mmol, 2.0 equiv). After 10min methyl iodide (3mg, 0.02mmol, 1.2 equiv.) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ice-cold water (20mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with water (5X 20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.004g, 40%). LCMS 351[ M +1 ]]+.1H NMR(DMSO-d6,400MHz)δ8.94(s,1H),8.39(d,1H),8.24(d,1H),8.19(s,1H),7.94(d,1H),7.66(d,1H),7.55-7.61(m,2H),7.43(d,1H),7.34-7.40(m,3H),6.37(d,1H),3.94(s,3H)。
Example S3: synthesis of 2- (8-chloroquinolin-6-yl) -3-phenylpyrido [2,3-b ] pyrazin-6 (5H) -one (Compound No. 1.12)
Step 1: synthesis of 5- (8-chloroquinolin-6-yl) -6-phenylpyrazin-2-amine: to a solution of 5-bromo-6-phenylpyrazin-2-amine (1g, 4mmol, 1 eq) in 1,4 dioxane (50mL): water (10mL) was added 8-chloroquinolin-6-ylboronic acid (990mg, 4.8mmol, 1.2 eq), Na2CO3(840mg, 8.0mmol, 2 equiv.), PdCl2(dppf) DCM complex (160mg, 0.2mmol, 0.05 eq.). The reaction mixture was treated with N2The atmosphere was deoxygenated and the reaction mixture was heated at 80 ℃ for 18 h. The reaction was monitored by NMR and LCMS. The reaction mixture was diluted with water (150mL) and extracted with ethyl acetate (2X 250 mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by normal phase silica gel column chromatography to give the title compound (150mg, 12%), LCMS: 333[ M +1 ]]+。
Step 2: synthesis of 3-bromo-5- (8-chloroquinolin-6-yl) -6-phenylpyrazin-2-amine: to a solution of 5- (8-chloroquinolin-6-yl) -6-phenylpyrazin-2-amine (1.6g, 4.81mmol, 1 eq) in DMF (20mL) at 0 deg.C was added N-bromosuccinimide (0.85g, 4.81mmol, 1.0 eq). The reaction mixture was stirred at the same temperature for 2 h. The reaction was monitored by TLC. Water was added to the reaction and a solid precipitated out. The solid was filtered and dried to be used in the next step without further purification (1.1g, 55%). LCMS: 412[ M +1 ]]+。
And step 3: (2E) -3- [ 3-amino-6- (8-chloroquinolin-6-yl) -5-phenylpyrazin-2-yl]Synthesis of methyl prop-2-enoate: to a stirred solution of 3-bromo-5- (8-chloroquinolin-6-yl) -6-phenylpyrazin-2-amine (0.50g, 1.21mmol, 1.0 equiv.) and methyl prop-2-enoate (0.207g, 2.43mmol, 2.0 equiv.) in dioxane (10mL) was added DIPEA (0.3mL, 1.81mmol, 1.5 equiv.) and the reaction was performed using N2Purging for 5 min. Thereafter adding Pd2dba3(0.018g, 0.02mmol, 2 mol%) and tri-tert-butylphosphonium tetrafluoroborate (0.017g, 0.06mmol, 5 mol%) and N2Purge again for 5 min. Then will beThe reaction was heated at 120 ℃ for 12 h. The reaction was allowed to cool to room temperature and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed (brine) and dried (anhydrous Na)2SO4) And concentrated under vacuum to give a solid, which was purified by normal phase silica gel column chromatography to give the title compound (0.20g, 40%). LCMS: 417[ M +1 ]]+。
And 4, step 4: 2- (8-chloroquinolin-6-yl) -3-phenylpyrido [2,3-b]Synthesis of pyrazin-6 (5H) -one: metallic sodium (0.044g, 4.0 equiv., 1.92mmol) was added to ethanol (2mL) at 0 ℃. The resulting mixture was stirred at this temperature for 15 min. (2E) -3- [ 3-amino-6- (8-chloroquinolin-6-yl) -5-phenylpyrazin-2-yl ] amine at 0 DEG C]A solution of methyl prop-2-enoate (0.200g, 0.48mmol, 1.0 equiv) in ethanol (3mL) was added to the above reaction mixture and the resulting reaction mixture was heated at 80 ℃ for 12 h. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure and the crude product was directly purified by normal phase silica gel column chromatography to give the title compound (0.007g, 3.0%). LCMS 384[ M +1 ]]+.1H NMR(DMSO-d6,400MHz)δ12.71(s,1H),9.03(dd,,1H),8.39(dd,1H),8.13(1H),8.04(d,1H),7.85(d,1H),7.65(dd,1H),7.44-7.52(m,2H),7.34-7.43(m,3H),6.92(dd,1H)。
Example S4: synthesis of 3-phenyl-2- (quinolin-6-yl) pyrido [2,3-b ] pyrazin-6 (5H) -one (Compound No. 1.4)
Step 1: synthesis of 3-amino-5-phenyl-6- (quinolin-6-yl) pyrazine-2-carbaldehyde: to a stirred solution of 3-amino-5-phenyl-6- (quinolin-6-yl) pyrazine-2-carbonitrile (0.20g, 0.619mmol, 1.0 eq) in THF (10mL) was added a 1M solution of DIBAL-H in toluene (2.1mL, 2.1mmol, 3.5 eq) and the reaction mixture was allowed to stir at 0 ℃ for 30 min. The progress of the reaction was monitored by TLC and 2M HCl in water (16mL) was added dropwise to the reaction mixture at 0 ℃ and the reaction mixture was allowed to stir at the same temperature for 10 min. The reaction mixture was basified with saturated sodium carbonate solution (20mL)And extracted with ethyl acetate (3 × 75 mL). The combined organic layers were washed (brine) and dried (anhydrous Na)2SO4) And concentrated in vacuo to give a yellow solid which was used as such in the next step without further purification (0.27 g). LCMS: 327[ M +1 ]]+。
Step 2: (2E) -3- [ 3-amino-5-phenyl-6- (quinolin-6-yl) pyrazin-2-yl]Synthesis of ethyl prop-2-enoate: to a solution of ethyl 2-diethoxyphosphorylacetate (0.18g, 0.83mmol, 1.0 equiv.) in THF (10mL) at 0 deg.C was added NaH (0.037g, 0.91mmol, 1.1 equiv.). To this mixture was added 3-amino-5-phenyl-6- (quinolin-6-yl) pyrazine-2-carbaldehyde (0.27g, 0.83mmol, 1.0 equiv.). The progress of the reaction was monitored by TLC. The reaction mixture was quenched by addition of cold water and extracted by using ethyl acetate. The combined organic layers were washed (brine) and dried (anhydrous Na)2SO4) And concentrated in vacuo to give the desired product as a yellow solid, which was purified by normal phase silica gel column chromatography to give the title compound (0.221g, 67%). LCMS: 397[ M +1 ]]+。
And step 3: 3-phenyl-2- (quinolin-6-yl) pyrido [2,3-b]Synthesis of pyrazin-6 (5H) -one: metallic sodium (0.053, 4.0 equiv., 2.23mmol) was added to ethanol (2mL) at 0 ℃. The resulting mixture was stirred at this temperature for 15 min. (2E) -3- [ 3-amino-5-phenyl-6- (quinolin-6-yl) pyrazin-2-yl at 0 ℃]A solution of ethyl prop-2-enoate (0.221g, 0.48mmol, 1.0 equiv.) in ethanol (3mL) was added to the above reaction mixture and the resulting reaction mixture was heated at 80 ℃ for 12 h. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure and it was directly purified by normal phase silica gel column chromatography to give the title compound (0.015g, 7.0%). LCMS 351[ M +1 ]]+；1H NMR(DMSO-d6 400MHz)δ12.66(s,1H),8.90-8.93(m,1H),8.32(d,1H),8.08-8.13(m,2H),7.90(d,1H),7.63(dd,1H),7.54(dd,1H),7.45(d,2H),7.30-7.42(m,3H),6.90(d,1H)。
Example S5: synthesis of 2- (8-chloroquinolin-6-yl) -3- (3-methyl-1H-pyrazol-1-yl) pyrido [2,3-b ] pyrazin-6 (5H) -one (Compound No. 1.185)
Step 1: 3- [ 3-amino-6- (8-chloroquinolin-6-yl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazin-2-yl]Synthesis of methyl prop-2-enoate: to a stirred solution of 3-bromo-5- (8-chloroquinolin-6-yl) -6- (3-methyl-1H-pyrazol-1-yl) pyrazin-2-amine (1.00g, 2.41mmol, 1.0 equiv.) and methyl prop-2-enoate (0.412g, 4.83mmol, 2.0 equiv.) in dioxane (10mL) was added DIPEA (0.7mL, 3.61mmol, 1.5 equiv.) and the reaction was run with N2Purging for 5 min. Thereafter adding Pd2dba3(0.044g, 0.04mmol, 2 mol%) and tri-tert-butylphosphonium tetrafluoroborate (0.035g, 0.12mmol, 5 mol%) and N2Purge again for 5 minutes. The reaction was then heated at 120 ℃ for 12 h. The reaction was allowed to cool to room temperature and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed (brine) and dried (anhydrous Na)2SO4) And concentrated in vacuo to give a solid, which was purified by normal phase silica gel column chromatography to give the title compound (0.700g, 70%). LCMS: 421[ M +1 ]]+。
Step 2: 2- (8-chloroquinolin-6-yl) -3- (3-methyl-1H-pyrazol-1-yl) pyrido [2,3-b]Synthesis of pyrazin-6 (5H) -one: to 3- [ 3-amino-6- (8-chloroquinolin-6-yl) -5- (3-methyl-1H-pyrazol-1-yl) pyrazin-2-yl]To a stirred solution of methyl prop-2-enoate in DMF (10mL) was added cesium carbonate (0.384g, 1.19mmol), the resulting mixture was stirred at this temperature for 15min and then heated at 100 ℃ for 12 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed (brine) and dried (anhydrous Na)2SO4) And concentrated in vacuo to give the crude product, which was purified by RP-HPLC to give the title compound (20mg, 11%). LCMS 389[ M +1 ]]+；1H NMR(DMSO-d6,400MHz)δ12.80(br s,1H),9.04(dd,J＝1.75,3.95Hz,1H),8.48(dd,J＝1.53,8.55Hz,1H),8.09-8.15(m,2H),8.04(d,J＝1.75Hz,1H),7.64-7.71(m,2H),6.91(d,J＝9.65Hz,1H),6.40(d,J＝2.63Hz,1H),1.23(s,3H)。
Example S6: synthesis of 2- (8-chloroquinolin-6-yl) -3- (1-methyl-1H-pyrazol-3-yl) pyrido [2,3-b ] pyrazin-6 (5H) -one (Compound No. 1.184)
Step 1: synthesis of 5- (8-chloroquinolin-6-yl) -6- (1-methyl-1H-pyrazol-3-yl) pyrazin-2-amine: to a stirred solution of 6-chloro-5- (quinolin-6-yl) pyrazin-2-amine (1.0g, 3.44mmol, 1.0 equiv.) in dioxane water (16mL:4mL) was added 1-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.860g, 4.12mmol, 1.2 equiv.). The reaction mixture was purged with nitrogen for 5min and then charged with Na2CO3(0.73g, 6.88mmol, 2.0 equiv.) and Pd (dppf) Cl2DCM complex (0.080g, 10 mol%). The reaction mixture was again purged with nitrogen. The reaction mixture was allowed to heat at 100 ℃ for 16 h. The reaction was monitored by TLC and LCMS. The reaction mixture was filtered through celite and distilled. The reaction was diluted with water and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed (brine) and dried (anhydrous Na)2SO4) And concentrated in vacuo to give the crude product, which was purified by normal phase silica gel column chromatography to give the title compound (0.400g, 34%). LCMS: 337[ M +1 ]]+。
Step 2: synthesis of 3-bromo-5- (8-chloroquinolin-6-yl) -6- (1-methyl-1H-pyrazol-3-yl) pyrazin-2-amine: to a stirred solution of 5- (8-chloroquinolin-6-yl) -6- (1-methyl-1H-pyrazol-3-yl) pyrazin-2-amine (0.400g, 1.18mmol, 1 eq) in DMF (5ml) was added NBS (210mg, 1.18mmol, 1.0 eq) at 0 ℃ and the reaction mixture was stirred at 0 ℃ for 10 min. The reaction was monitored by TLC and LCMS and found complete after 10 min. The reaction mixture was quenched with cold water 10mL and extracted with EtOAc (3 × 20 mL). The resulting solution was concentrated under reduced pressure. The crude product was purified by normal phase column chromatography to give the title compound (0.300g, 61%). LCMS: 415[ M +1 ]]+。
And step 3: 3- (3-amino-6- (8-chloroquinolin-6-yl) -5- (1-methyl-1H-pyrazol-3-yl)) Synthesis of pyrazin-2-yl) acrylic acid methyl ester: to a stirred solution of 3-bromo-5- (8-chloroquinolin-6-yl) -6- (1-methyl-1H-pyrazol-3-yl) pyrazin-2-amine (0.132g, 0.31mmol, 1.0 equiv.) and methyl prop-2-enoate (0.058g, 0.63mmol, 2.0 equiv.) in dioxane (5mL) was added DIPEA (0.1mL, 0.46mmol, 1.5 equiv.) and the reaction was run with N2Purging for 5 min. Thereafter adding Pd2dba3(0.006g, 0.006mmol, 2 mol%) and tri-tert-butylphosphonium tetrafluoroborate (0.005g, 0.01mmol, 5 mol%) and N2Purge again for 5 minutes. The reaction was then heated at 120 ℃ for 12 h. The reaction was allowed to cool to room temperature and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed (brine) and dried (anhydrous Na)2SO4) And concentrated under vacuum to give a solid, which was purified by normal phase silica gel column chromatography to give the title compound (0.80g, 60%). LCMS: 421[ M +1 ]]+。
And 4, step 4: 2- (8-chloroquinolin-6-yl) -3- (1-methyl-1H-pyrazol-3-yl) pyrido [2,3-b]Synthesis of pyrazin-6 (5H) -one: to a stirred solution of methyl 3- (3-amino-6- (8-chloroquinolin-6-yl) -5- (1-methyl-1H-pyrazol-3-yl) pyrazin-2-yl) acrylate (0.080g, 0.19mmol, 1.0 equiv) in DMF (5mL) was added cesium carbonate (0.123g, 0.38mmol, 2.0 equiv). The resulting mixture was stirred at this temperature for 15min and then heated at 120 ℃ for 12 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed (brine) and dried (anhydrous Na)2SO4) And concentrated in vacuo to give the crude product, which was purified by normal phase silica gel column chromatography to give the title compound (10mg, 13%). LCMS 389[ M +1 ]]+；1H NMR(DMSO-d6,400MHz)δ12.64(br.s.,1H),9.05(br.s.,1H),8.49(d,1H),8.13(br.s.,1H),8.06(d,1H),7.93(br.s.,1H),7.71(br.s.,2H),6.87(d,1H),6.37(br.s.,1H),3.72(s,3H)。
It will be appreciated that the compounds from table 1(1.1-1.3, 1.6-1.7, 1.9-1.11, 1.13-1.183, 1.186-2.219) are synthesized by general synthetic scheme 1, scheme 2, scheme 3, scheme 4 or a route involving steps clearly familiar to those skilled in the art, wherein the substituents described in the compounds of formula (I) herein can be varied by selecting the appropriate starting materials and reagents utilized in the steps presented.
Biological examples
Example B1. radioligand binding competition assay
Example B1(a)
Selected compounds were tested for binding to adenosine A2A, a1, A2B, and A3 receptors using a binding competition assay.
A general protocol for the radioligand binding competition assay is as follows. Competitive binding was performed in duplicate in wells of 96-well plates (Master Block, Greiner, 786201) containing binding buffer (optimized for each receptor), membrane extract (amount of protein/well optimized for each receptor), radiotracer (final concentration optimized for each receptor), and test compound. Nonspecific binding was determined by incubation with a 200-fold excess of cold competitor. The sample was incubated at 25 ℃ for 60 minutes at a final volume of 0.1mL and then filtered through a filter plate. Filters were washed six times with 0.5mL of ice-cold wash buffer (optimized for each receptor) and 50 μ L of Microscint 20(Packard) was added to each filter. The filter plate was sealed, incubated on an orbital shaker for 15min, and scintillation was counted with TopCount for 30 seconds per filter.
For A2AAdenosine receptor radioligand binding assay the following modifications were made to the general protocol. GF/C filters (Perkin Elmer, 6005174) presoaked for 2h at room temperature in 0.01% Brij were used. Filters were washed six times with 0.5mL ice-cold wash buffer (50mM Tris pH 7.4) and 50. mu.L of Microscint 20(Packard) was added to each well. The plate was then incubated on an orbital shaker for 15min and then on a TopCount TM meter for 1 min/well.
For evaluation of adenosine A2AAnother radioligand binding assay for binding affinity of the receptor assay was performed in duplicate in wells of 384 plates. The assay buffer contained DPBS 500mM, MgCl20.1mM and 1% DMSO. By mixing 25.98. mu.L of 33.4. mu.g/mL human adenosine A2AMembrane preparation (Perkin Elmer, RBHA2AM400UA), 28. mu.L of 20μ g/mL ADA and 932 μ L of 3.33mg/mL SPA beads) were mixed to prepare a membrane bead suspension and the mixture was incubated at room temperature for 20 min. 20 μ L of 15nM radiotracer (C3H-SCH 58261) were mixed at various concentrations into each well containing the test article and the plates were centrifuged at 1000rpm for 1 minute. To each well, 30 μ L of membrane bead suspension was added. The plates were sealed and incubated at room temperature for 1h and vigorous mixing was performed on a plate mixer. Place the plate on Microbeta2(Perkin Elmer, 2450 and 0010).
For adenosine A1Radioligand binding competition assays similar procedure was used except that the following reagents were used: CHO-K1-A1 cell membrane; comprising HEPES 25mM pH7.4, MgCl2 5mM、CaCl21mM, NaCl 100mM, saponin 10 μ g/mL binding buffer; comprising HEPES 25mM pH7.4, MgCl2 5mM、CaCl21mM, NaCl 100mM washing buffer; unifilter GF/B-was treated with 0.5% PEI for 2 h; and 1.6nM of3H-DPCPX is used as a tracer.
Similarly, the following reagents were used for adenosine a2BRadioligand binding competition assay: HEK-293-A2BCell membrane, 20 μ g/well, pre-incubated with 25 μ g/mL adenosine deaminase for 30min at room temperature; a binding buffer comprising HEPES 10mM pH7.4, EDTA 1mM, 0.5% BSA; wash buffer comprising HEPES 10mM pH7.4, EDTA 1 mM; unifilter GF/C-was treated with 0.5% PEI for 2 h; and 10nM3H-DPCPX is used as a tracer.
For adenosine A3Radioligand binding competition assay using the following reagents: CHO-K1-A3 cell membrane, 1.5 μ g/well; containing HEPES 25mM pH7.4, MgCl2 5mM、CaCl21mM, 0.5% BSA in binding buffer; containing HEPES 25mM pH7.4, MgCl2 5mM、CaCl21mM of washing buffer; unifilter GF/C-was treated with 0.5% BS for 2 h; and 0.4nM of125I-AB-MECA as a tracer.
The results of the binding assay are given as the percentage of residual binding at a given concentration. The percentage of residual binding means the binding of the compound in the presence of the competitor, normalized to the amount of binding in the absence of the competitor.
Example B1(B)
Using a second A2AAdenosine receptor radioligand binding assay protocol. The protocol used adenosine A2a (human) membrane (Perkinelmer RBHA2AM400UA) at a concentration of 5. mu.g/well/100. mu.l and a final concentration of 6nM of radioligand [3H]CGS-21680 (Cat. No. Perkinelmer-NET1021250 UC). Test compounds were diluted with DMSO to make 8-point 4-fold serial dilutions starting at 0.2 mM. CGS-15943 is a reference compound. Mu.l of compound/high control/low control was transferred to assay plates according to plate map, then 100. mu.l of membrane stock solution and 100. mu.l of assay buffer (50mM Tris-HCl, 10mM MgCl. sub.L)21mM EDTA, pH 7.4). The plates were sealed and incubated at room temperature for 2 hours. Unifilter-96GF/C filter plates (Perkin Elmer catalog No. 6005174) were submerged in 50. mu.l of 0.3% PEI/well for at least 0.5 hour at room temperature. When the binding assay was completed, the reaction mixture was filtered through GF/C plates using a Perkin Elmer Filtermate Harvester and each plate was washed 4 times with cold wash buffer (50mM Tris-HCl, 154mM NaCl, pH 7.4). The filter plate was dried at 50 degrees for 1 hour. After drying, the bottom of the filter plate wells were sealed, 50 μ l of Perkin Elmer Microscint 20 mixture was added, and the top of the filter plate was sealed. Counting the number of traces on the filter using a Perkin Elmer MicroBeta2 plate reader3H. Data were analyzed with GraphPad Prism 5 to obtain bound ICs50The value is obtained. The "inhibition [% control ] was calculated using the following formula]": % Inh-100 (1-background subtracted measurement/background subtracted HC value), where HC is high control. A2a binding to IC50The values are shown in table B1.
Using a second A1Adenosine receptor radioligand binding assay protocol. The protocol used adenosine A1 (human) membrane (Perkinelmer ES-010-M400UA) at a concentration of 2.5. mu.g/well/100. mu.l and a final concentration of radioligand [3H ] at 1nM]DPCPX (catalog number Perkinelmer-NET974250 UC). Test compounds were tested at a final concentration of 200 nM. CGS-15943 (reference compound) was tested at 8-point 4-fold serial dilutions starting at the highest concentration of 1. mu.M. Transfer 1. mu.l of compound/high control/low control to assay plate according to plate mapThen 100. mu.l of membrane stock solution and 100. mu.l of buffer in assay (25mM HEPES, 5mM MgCl. RTM.) were transferred2，1mM CaCl2100mM NaCl, pH 7.4). The plates were sealed and incubated at room temperature for 1 hour. Unifilter-96GF/C filter plates (Perkin Elmer catalog No. 6005174) were submerged in 50. mu.l of 0.3% PEI/well for at least 0.5 hour at room temperature. When the binding assay was complete, the reaction mixture was filtered through GF/C plates using a Perkin Elmer Filtermate Harvester and each plate was washed with cold wash buffer (25mM HEPES, 5mM MgCl. RTM2，1mM CaCl2100mM NaCl, pH 7.4) were washed 4 times. The filter plate was dried at 50 degrees for 1 hour. After drying, the bottom of the filter plate wells were sealed, 50 μ l of Perkin Elmer Microscint 20 mixture was added, and the top of the filter plate was sealed. Counting the number of traces on the filter using a Perkin Elmer MicroBeta2 plate reader3H. Data were analyzed with GraphPad Prism 5 to obtain binding IC of reference compound50The value is obtained. The "inhibition [% control ] was calculated using the following formula]": % Inh-100 (1-background subtracted measurement/background subtracted HC value), where HC is high control.
TABLE B1
Example B2 cAMP assay
Compound 1.5 was tested for functional activity using assay 2 below to detect the presence of cAMP. Assay 1 is an alternative assay for this purpose. G protein coupled receptors (such as A)2A) Leads to the activation of adenylyl cyclase, which converts ATP to cAMP, which serves as a downstream signaling molecule. Acting as a GPCR (or specifically A)2AReceptor) antagonist results in a decrease in intracellular cAMP concentration.
Measurement 1: the assay uses expression of human recombinant adenosine A2AReceptorsThe HEK-293 cell of (1), which was grown in antibiotic-free medium prior to testing. The cells were isolated by gentle washing with PBS-EDTA (5mM EDTA), recovered by centrifugation and suspended in assay buffer (KRH: 5mM KCl, 1.25mM MgSO 24124mM NaCl, 25mM HEPES, 13.3mM glucose, 1.25mM KH2PO4，1.45mM CaCl20.5g/L BSA, supplemented with Rolipram).
12 μ L of cells were mixed with 6 μ L of increasing concentrations of test compound and then incubated for 10 min. Thereafter, to correspond to the historical EC80To a final concentration of 6. mu.L of the reference agonist. The plates were then incubated at room temperature for 30 min. After addition of lysis buffer and 1 hour incubation, the cells were incubated withThe kit estimates cAMP concentration according to manufacturer's instructions.
Assay 2 (table B2): the assay uses expression of human recombinant adenosine A2AHEK-293 cells of the receptor, which cells were grown in antibiotic-free medium prior to testing. 100nL of test article at a final concentration of 100X were transferred to the assay plate by Echo. Cells were washed twice with 5mL PBS and 10 μ Ι _ of cells were mixed with 5mL PBS. After aspirating PBS and adding 1.5mL versine, cells were incubated at 37 ℃ for 2-5 min. After centrifugation, 4mL of medium was added and the cell density was adjusted to 5,000 cells/well with stimulation buffer. 10 μ L of cells were aliquoted into assay plates, centrifuged at 1000rpm for 1 minute, and incubated at room temperature for 60 minutes. mu.L of 4 × Eu-cAMP tracer solution and 5. mu.L of 4 × UlightTManti-cAMP solution was added to assay plates, then centrifuged and incubated at room temperature for 60 min. Plates were read on EnVision. Reduction of Compound 1.5A2AIC of cAMP levels50Shown in table B2. For example, human recombinant adenosine A may also be expressed1Similar assays were performed on HEK-293 cells of the receptor to detect adenosine A1Inhibition of activation of the receptor.
Table B2.
Example B3: a. the2AGTP gamma of receptor35S scintillation proximity assay
Determination of test Compounds and A Using Scintillation Proximity Assay (SPA)2AKinetic characterization of binding of the receptor.
For antagonist testing, recombinant human A was expressed2AHEK-293 cells of the recipient Membrane extracts were prepared, mixed with GDP (vol: vol) and incubated at pH7.4 in the presence of 20mM HEPES; 100mM NaCl, 10. mu.g/mL saponin, 5mM MgCl2Is incubated on ice for at least 15 min. In parallel, before starting the reaction, GTP γ 235S]Mix with beads (volume: volume). The following reagents were added sequentially to wells of optiplate (perkin elmer): 25 μ L of test compound or reference ligand, 25 μ L of membrane GDP mixture, 25 μ L of historical EC80And 25. mu.L of a solution of the reference agonist (2) diluted in the assay buffer to give 0.1nM of GTP γ 235S](Perkinelmer NEG 030X). The plates were incubated at room temperature for 1 hour. Then, 20 μ L of IGEPAL was added at room temperature for 30 minutes. After this incubation, 20 μ L of beads (PVT-anti-rabbit (Perkinelmer, RPNQ0016)) diluted in assay buffer at 50mg/mL (0.5mg/10 μ L) and 20 μ L of anti-Galpha.S/olf antibody were added for final incubation at room temperature for 3 hours. The plates were then centrifuged at 2000rpm for 10min, incubated at room temperature for 1 hour and counted for 1 min/well using a Perkinelmer TopCount reader.
Example B4: functional T cell assay
Human T cell activation assay: fresh human blood was diluted with the same volume of PBS and buffy coat containing Peripheral Blood Mononuclear Cells (PBMCs) was prepared and applied at 2x 106The density of/mL was resuspended in the medium. 2x 10 to5One PBMC (in 100 μ L) was placed in each well of a 96-well flat-bottom plate. 25 u L10 times serial dilution of 8x final concentration or single concentration of compounds added to the indicated hole and at 37 ℃/5% CO2And (5) performing medium incubation for 30 min. 25 μ L of NECA (1 μ M) at 8 × final concentration was added to the indicated wells and at 37 ℃/5% CO2In hatchingAnd culturing for 30 min. Beads contained in a T cell activation/amplification kit (Miltenyi biotec catalog No. 130-091-441) at a bead to cell ratio of 1:6 in 50. mu.L were added to all wells with a final DMSO concentration of 0.1% and a final volume of 200. mu.L. 60 μ L of supernatants after 24h and 48h incubation were collected for TNF- α and IFN- γ concentration evaluation using the TNF- α ELISA ready-set-go kit (eBioscience, catalog # 88-7346-77) and the IFN- γ ELISA ready-set-go kit (eBioscience, catalog # 88-7316-77), respectively.
Example B5: cAMP assay
CD8+ T cells were isolated from Peripheral Blood Mononuclear Cells (PBMCs) from normal donors using a CD8+ T lymphocyte enrichment kit.
CD8 alone, together with 3. mu.M NECA, or in the presence of 1. mu.M of a compound of interest with or without 3. mu.M NECA, were cultured in 96-well plates coated with anti-CD 3 antibody+T cell (1X 10)5). Cells were incubated at 37 ℃ and 5% CO2Incubate for 30min, and stop the reaction by adding 200 μ Ι _ of 0.1M hydrochloric acid. cAMP levels were determined by ELISA kit.
Example B6: antitumor activity in immunooncology mouse models
The anti-tumor activity of the test article is assessed as monotherapy or combination therapy in a selective mouse model (e.g., a syngeneic model, a xenograft model, or PDX). Using the MC-38 homology model as an example: female C57BL/6 mice were inoculated subcutaneously in the right flank with MC-38 cells for tumor development. Selecting tumor size range of 40-85mm five days after tumor inoculation3And using stratified random grouping into subgroups, wherein 10 mice/group are based on their tumor volume. Mice received predefined treatments including vehicle, test article at different doses alone, test article at different doses plus other anti-cancer therapies, and other anti-cancer therapy controls. Body weight and tumor size were measured three times per week during the treatment period. Tumor volume in mm using the formula3Represents: v ═ 0.5a x b2Wherein a and b are the major and minor diameters of the tumor, respectively. Tumor size was used to calculate both Tumor Growth Inhibition (TGI) and T/C values. When a single animal is presentUpon reaching the termination endpoint (e.g., at TV)>1000mm3In case (a), the mice were euthanized. The time from inoculation to termination was taken as its survival time. Survival curves were plotted by the Kaplan-Meier method. At the end of the study, plasma and tumor samples were collected to explore biomarkers.
Example B7 mouse splenocyte assay
Determination of IC of Compounds for reversing NECA inhibition of mIFN γ Release in mouse splenocytes isolated from Balb/c mice50The value is obtained. mIFN γ release is CD3e/CD28 induced release. Mouse splenocytes (2X 10)5Individual cells/well) were coated with anti-mouse CD3e (2.5 μ g/ml, overnight at 4 ℃; catalog No. 14-0032-82, eBioscience) and then activated in an incubator at 37 ℃, 5% CO2Next (cell culture conditions) were incubated with serially diluted compounds (3-fold, 8-point dose reactions starting at 1. mu.M) for 30min in the presence of NECA (at concentrations such as 0.1, 3.0, or 6.0. mu.M; Cat. No. E2387, Sigma) and then they were treated with anti-murine CD28 (0.1. mu.g/ml soluble; Cat. No. 16-0289-81, eBiosciences). The splenocytes were further incubated under cell culture conditions for 72 h; the supernatants were then harvested and diluted to 1:100 and ELISA was performed according to the manufacturer's protocol (mIFN-. gamma.kit; catalog numbers 555138 and 550534, BD Biosciences). The plate was read on a plate reader by measuring the absorbance at 450 nm. The value of the reversal of ifn- γ release of NECA inhibition by compounds was calculated by the following formula:
wherein [ mIFN-gamma]TestingIs the test reading, [ mIFN-. gamma. ]]Blank spaceIs the average reading obtained from blank wells, and [ mIFN-. gamma. ]]NECAIs the average reading obtained from activated cells treated with NECA. IC was calculated by fitting the curves to a "four parameter variable slope logistic model" using Graph Pad Prism50The value is obtained.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain minor changes and modifications may be practiced in light of the above teachings. Therefore, the description and examples should not be construed as limiting the scope of the invention.
All references, such as publications, patents, and published patent applications, are incorporated by reference herein in their entirety.
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