Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10172845-B2
Application number	US-201815861244-A
Country	US
Kind code	B2
Filing date	Jan 3, 2018
Priority date	Oct 10, 2016
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

Provided herein are compounds of the Formula I:

or pharmaceutically acceptable salt or solvate thereof, wherein A, B, X 1 , X 2 , X 3 , X 4 , Ring D, E, R a , R b , n and m 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.

First claim

What is claimed is:

1. A method for treating a cancer that exhibits a dysregulation of a RET gene, a RET protein, or expression or activity or level of any of the same, the method comprising:
administering a therapeutically effective amount of a compound having Formula I or a pharmaceutically acceptable salt or solvate thereof:

wherein:
X 1 , X 2 , X 3 and X 4 are independently CH or N, wherein zero, one or two of X 1 , X 2 , X 3 and X 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 a C3-C6 cycloalkylidene ring, or
(i) (hetCyc a )C1-C3 alkyl-;
hetCyc 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, halogen, (C1-C6 alkyl)C(═O)—, C1-C6 alkoxy, oxo, and (C1-C6 alkoxy)C(═O)—;
Ring D is
a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen;
each R a is independently C1-C6 alkyl (optionally substituted with 1-3 fluoros);
R b is (a) hydroxy;
n is 0 or 1;
m is 0 or 1;
E is:
(e) hetAr 2 C1-C6 alkyl-,
(h) hetAr 2 —O—,
(k) R 3 C(═O)NR g — where R g is H or C1-C6 alkyl,
(l) Ar 1 C(═O)NR g — where R g is H or C1-C6 alkyl, or
(m) hetAr 2 C(═O)NR g (CH 2 ) p — where p is 0 or 1 and R g is H or C1-C6 alkyl;
Ar 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), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyC1-C6 alkyl, (C1-C6 alkyl)SO 2 —, R e R f N— and (R e R f N)C1-C6 alkyl- where each R e and R f is independently H or C1-C6 alkyl;
hetAr 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 having 1-2 ring nitrogen atoms, wherein hetAr 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) and hydroxyC1-C6 alkoxy-;
R 3 is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH 2 —, (C3-C6 cycloalkyl)O—, (C3-C6 cycloalkyl)CH 2 O—, hetCyc 7 O—, Ph-O—, or (C1-C6 alkoxy)C1-C6 alkyl-; wherein each of said C3-C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH, or R′R″N— where R′ and R″ are independently hydrogen or C1-C6 alkyl; and
hetCyc 7 is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S.

2. The method of claim 1 , wherein Ring D is

wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1 , X 2 , X 3 and X 4 , and the asterisk indicates the point of attachment of Ring D to the E group.

3. The method of claim 2 , wherein D is

wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1 , X 2 , X 3 and X 4 , and the asterisk indicates the point of attachment of Ring D to the E group.

4. The method of claim 3 , wherein D is

wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1 , X 2 , X 3 and X 4 , and the asterisk indicates the point of attachment of Ring D to the E group.

5. The method of claim 3 , wherein D is

wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1 , X 2 , X 3 and X 4 , and the asterisk indicates the point of attachment to the E group.

6. The method of claim 3 , wherein E is:
(e) hetAr 2 C1-C6 alkyl-,
(h) hetAr 2 —O—,
(l) Ar 1 C(═O)NR g — where R g is H or C1-C6 alkyl, or
(m) hetAr 2 C(═O)NR g (CH 2 ) p — where p is 0 or 1 and R g is H or C1-C6 alkyl.

7. The method of claim 3 , wherein B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.

8. The method of claim 1 , wherein X 1 is N, and X 2 , X 3 and X 4 are CH.

9. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of:
N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide;
6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;
6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;
6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;
(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;
N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide;
3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide;
N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide;
6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; and
3-chloro-N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)picolinamide;
or a pharmaceutically acceptable salt or solvate thereof.

10. The method of claim 1 , wherein the compound of Formula I is
N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide, or a pharmaceutically acceptable salt or solvate thereof.

11. The method of claim 1 , wherein the compound of Formula I is
6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof.

12. The method of claim 1 , wherein the compound of Formula I is
6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof.

13. The method of claim 1 , wherein the compound of Formula I is
6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carb

Assignees

• Array Biopharma Inc
• Array Biopharma Inc

Inventors

• Andrews Steven W
• Aronow Sean
• Blake James F
• Brandhuber Barbara J
• Collier James
• Cook Adam
• Haas Julia
• Jiang Yutong
• Kolakowski Gabrielle R
• Mcfaddin Elizabeth A
• Mckenney Megan L
• Mcnulty Oren T
• Metcalf Andrew T
• Moreno David A
• Ramann Ginelle A
• Tang Tony P
• Ren Li
• Walls Shane M

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/4545 Primary

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title