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

Patent metadata

Field	Value
Publication number	US-10144734-B2
Application number	US-201715858929-A
Country	US
Kind code	B2
Filing date	Dec 29, 2017
Priority date	Oct 10, 2016
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

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 compound of the Formula I:

and pharmaceutically acceptable salts and solvates 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 0 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 i 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. A compound according to 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. A compound according to 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. A compound according to 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. A compound according to 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. A compound according to 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. A compound according to 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. A compound according to claim 3 , wherein X 1 is N, and X 2 , X 3 and X 4 are CH.

9. A compound according to 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-((3 S,4 S)-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-((3 S,4 S)-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 thereof.

10. A compound according to 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 thereof.

11. A compound according to 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 thereof.

12. A compound according to 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 thereof.

13. A compound according to 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-carbonitrile, or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 1 , wherein the compound of Formula I is
(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, or a pharmaceutically acceptable s

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

• A61P1/12

  Antidiarrhoeals · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title