Claims for Patent: 10,112,942

Summary for Patent: 10,112,942

Title:	Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
Abstract:	Provided herein are compounds of the Formula I: ##STR00001## and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, X.sup.1, X.sup.2, X.sup.3, X.sup.4, Ring D, and E have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.
Inventor(s):	Andrews; Steven W. (Boulder, CO), Aronow; Sean (Boulder, CO), Blake; James F. (Boulder, CO), Brandhuber; Barbara J. (Boulder, CO), Cook; Adam (Boulder, CO), Haas; Julia (Boulder, CO), Jiang; Yutong (Boulder, CO), Kolakowski; Gabrielle R. (Boulder, CO), McFaddin; Elizabeth A. (Boulder, CO), McKenney; Megan L. (Boulder, CO), McNulty; Oren T. (Boulder, CO), Metcalf; Andrew T. (Boulder, CO), Moreno; David A. (Boulder, CO), Tang; Tony P. (Boulder, CO), Ren; Li (Boulder, CO)
Assignee:	Array BioPharma Inc. (Boulder, CO)
Application Number:	15/858,240
Patent Claims:	1. A compound of the Formula I: ##STR00939## and pharmaceutically acceptable salts and solvates thereof, wherein: X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are independently CH or N, wherein zero, one or two of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is N; A is CN; B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros, (c) hydroxyC2-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoros or a C3-C6 cycloalkylidene ring, (e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros, (f) (R.sup.1R.sup.2N)C1-C6 alkyl-, wherein said alkyl portion is optionally substituted with OH and wherein R.sup.1 and R.sup.2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros); (g) hetAr.sup.1C1-C3 alkyl-, wherein hetAr.sup.1 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents; or (i) (hetCyc.sup.a)C1-C3 alkyl-, hetCyc.sup.a- is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(.dbd.O)--, (C1-C6 alkoxy)C1-C6 alkyl- and fluoro, or wherein hetCyc.sup.a is substituted with oxo; Ring D is (i) a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, or (ii) a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, wherein each of said rings is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl which is optionally substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; E is (h) Ar.sup.1C1-C6 alkyl-, (j) hetAr.sup.2C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoros, or (l) hetAr.sup.2C(.dbd.O)--, Ar.sup.1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), R.sup.eR.sup.fN-- wherein R.sup.e and R.sup.f are independently H or C1-C6 alkyl, (R.sup.pR.sup.qN)C1-C6 alkoxy- wherein R.sup.P and R.sup.q are independently H or C1-C6 alkyl, and (hetAr.sup.a)C1-C6 alkyl- wherein hetAr.sup.a is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms, or Ar.sup.1 is a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and 0; and hetAr.sup.2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S or a 9-10 membered bicyclic heteroaryl ring having 1-3 ring nitrogen atoms, wherein hetAr.sup.2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-(optionally substituted with 1-3 fluoros), R.sup.eR.sup.fN-- wherein R.sup.e and R.sup.f are independently H or C1-C6 alkyl, OH, (C1-C6 alkoxy)C1-C6 alkoxy- and C3-C6 cycloalkyl. 2. A compound according to claim 1, wherein Ring D is ##STR00940## wherein the wavy line indicates the point of attachment to the ring comprising X.sup.1, X.sup.2, X.sup.3 and X.sup.4, and the asterisk indicates the point of attachment to the E group, and wherein said ring is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl which is optionally substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. 3. A compound according to claim 2, wherein E is: (h) Ar.sup.1C1-C6 alkyl-, or (j) hetAr.sup.2C1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros. 4. A compound according to claim 1, wherein Ring D is ##STR00941## wherein the wavy line indicates the point of attachment to the ring comprising X.sup.1, X.sup.2, X.sup.3 and X.sup.4, and the asterisk indicates the point of attachment to the E group, and wherein said ring is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl which is optionally substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. 5. A compound according to claim 4, wherein E is (j) hetAr.sup.2C1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros, or (l) hetAr.sup.2C(.dbd.O)--. 6. A compound according to claim 3, wherein B is (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros, or (i) (hetCyc.sup.a)C1-C3 alkyl-. 7. A compound according to claim 5, wherein B is (b) C1-C6 alkyl optionally substituted with 1-3 fluoros, or (c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, (f) (R.sup.1R.sup.2N)C1-C6 alkyl-, wherein said alkyl portion is optionally substituted with OH and wherein R.sup.1 and R.sup.2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros); (g) hetAr.sup.1C1-C3 alkyl-, wherein hetAr.sup.1 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents; or (i) (hetCyc.sup.a)C1-C3 alkyl-. 8. A compound according to claim 1, wherein X.sup.1 is N, and X.sup.2, X.sup.3 and X.sup.4 are CH. 9. A compound according to claim 1, wherein the compound of Formula I is selected from the group consisting of: 4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo- [1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicy- clo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; (R)-6-(2-hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin- -1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- -diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-car- bonitrile; 6-(2-methoxyethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)pipe- razin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicy- clo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-d- iazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbo- nitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]he- ptan-3-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-ca- rbonitrile; 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-y- l)pyridin-3-yl)-6-((l-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyrid- ine-3-carbonitrile; and 6-ethoxy-4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicycl- o[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 1, wherein the compound of Formula I is 4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo- [1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 1, wherein the compound of Formula I is 6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicy- clo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 12. A compound according to claim 1, wherein the compound of Formula I is (R)-6-(2-hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin- -1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 13. A compound according to claim 1, wherein the compound of Formula I is 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- -diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-car- bonitrile, or a pharmaceutically acceptable salt thereof. 14. A compound according to claim 1, wherein the compound of Formula I is 6-(2-methoxyethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl- )pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 15. A compound according to claim 1, wherein the compound of Formula I is 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicy- clo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 16. A compound according to claim 1, wherein the compound of Formula I is 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-d- iazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbo- nitrile, or a pharmaceutically acceptable salt thereof. 17. A compound according to claim 1, wherein the compound of Formula I is 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-y- l)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitri- le, or a pharmaceutically acceptable salt thereof. 18. A compound according to claim 1, wherein the compound of Formula I is 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-y- l)pyridin-3-yl)-6-((1-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyrid- ine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 19. A compound according to claim 1, wherein the compound of Formula I is 6-ethoxy-4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicycl- o[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 20. A pharmaceutical composition, comprising a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier. 21. A pharmaceutical composition according to claim 20, wherein the compound of Formula I is 4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo- [1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 22. A pharmaceutical composition according to claim 20, wherein the compound of Formula I is 6-(2-hydroxyethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicy- clo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 23. A pharmaceutical composition according to claim 20, wherein the compound of Formula I is (R)-6-(2-hydroxypropoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin- -1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition according to claim 20, wherein the compound of Formula I is 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- -diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-car- bonitrile, or a pharmaceutically acceptable salt thereof. 25. A pharmaceutical composition according to claim 20, wherein the compound of Formula I is 6-(2-methoxyethoxy)-4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl- )pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 26. A pharmaceutical composition according to claim 20, wherein the compound of Formula I is 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicy- clo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 27. A pharmaceutical composition according to claim 20, wherein the compound of Formula I is 6-(2-(dimethylamino)ethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-d- iazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbo- nitrile, or a pharmaceutically acceptable salt thereof. 28. A pharmaceutical composition according to claim 20, wherein the compound of Formula I is 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-y- l)pyridin-3-yl)-6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carbonitri- le, or a pharmaceutically acceptable salt thereof. 29. A pharmaceutical composition according to claim 20, wherein the compound of Formula I is 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-y- l)pyridin-3-yl)-6-((1-methyl-1H-imidazol-4-yl)methoxy)pyrazolo[1,5-a]pyrid- ine-3-carbonitrile, or a pharmaceutically acceptable salt thereof. 30. A pharmaceutical composition according to claim 20, wherein the compound of Formula I is 6-ethoxy-4-(5-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicycl- o[3.1.1]heptan-3-yl)pyrazin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof.