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

Patent metadata

Field	Value
Publication number	US-11648243-B2
Application number	US-202017108528-A
Country	US
Kind code	B2
Filing date	Dec 1, 2020
Priority date	Oct 10, 2016
Publication date	May 16, 2023
Grant date	May 16, 2023

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, CCH 3 , CF or N, wherein zero, one or two of X 1 , X 2 , X 3 and X 4 is N;
A is H, Cl, CN, methyl, ethyl or cyclopropyl;
B is:
(a) hydrogen,
(b) C 1 -C 6 alkyl optionally substituted with 1-3 fluoros,
(c) hydroxyC 2 -C 6 alkyl- wherein the alkyl portion is optionally substituted with a C 3 -C 6 cycloalkylidene ring,
(d) dihydroxyC 3 -C 6 alkyl- wherein the alkyl portion is optionally substituted with a C 3 -C 6 cycloalkylidene ring,
(e) (C 1 -C 6 alkoxy)C 1 -C 6 alkyl- optionally substituted with 1-3 fluoros,
(f) (R 1 R 2 N)C 1 -C 6 alkyl- where R 1 and R 2 are independently selected from H, C 1 -C 6 alkyl (optionally substituted with 1-3 fluoros), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl- and (C 1 -C 6 alkoxy)C(═O)—;
(g) hetAr 1 C 1 -C 3 alkyl-, where hetAr 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 C 1 -C 6 alkyl substituents;
(h) (C 3 -C 6 cycloalkyl)C 1 -C 3 alkyl-,
(i) (hetCyc a )C 1 -C 3 alkyl-,
(j) hetCyc a ,
(k) (R 1 R 2 N)C(═O)C 1 -C 6 alkyl- where R 1 and R 2 are independently selected from H and C 1 -C 6 alkyl,
(l) (R 1 R 2 N)C(═O)—, where R 1 and R 2 are independently selected from H and C 1 -C 6 alkyl, or
(m) hetCyc a C(═O)C 1 -C 6 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, C 1 -C 6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC 1 -C 6 alkyl, halogen, (C 1 -C 6 alkyl)C(═O)—, C 1 -C 6 alkoxy, oxo, and (C 1 -C 6 alkoxy)C(═O)—;
Ring D is a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen;
each Ra is independently C 1 -C 6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC 1 -C 6 alkyl or (C 1 -C 6 alkoxy)C 1 -C 6 alkyl-;
Rb is (a) hydroxy, (b) cyclopropyl, (c) hetCyc b CH 2 —, R i R j NC(═O)CH 2 OCH 2 — where R i and R j are independently H or C 1 -C 6 alkyl, (e) R c R d N—, (f) R c R d NCH 2 —, (g) C 1 -C 6 alkoxy-, (h) (C 1 -C 4 alkyl)-C(═O)NH— wherein said alkyl portion is optionally substituted with hetCyc b , hetAr a , C 1 -C 6 alkoxy- or R′R″N—, or said alkyl portion is optionally substituted with two substituents independently selected from R′R″N— and OH, where each R′ and R″ is independently hydrogen or C 1 -C 6 alkyl, (i) (R′R″N)C 1 -C 6 alkoxy(CH 2 ) n — where n is 0 or 1 and R′ and R″ are independently hydrogen or C 1 -C 6 alkyl, (j) hetCyc b (C 1 -C 3 alkyl)OCH 2 —, (k) hetCyc b C(═O)NH— or (l) hetAr a C(═O)NH—;
hetCyc b is a 4-6 membered heterocyclic ring, a 7-8 membered bridged heterocyclic ring, or a 7-10 membered heterospirocyclic ring, each ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc b is optionally substituted with one or more substituents independently selected from OH, fluoro, C 1 -C 6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC 1 -C 6 alkyl- (optionally substituted with 1-3 fluoros), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl-, (C 1 -C 6 alkoxy)C(═O)—, C 1 -C 6 alkoxy, and R′R″N— where R′ and R″ are independently hydrogen or C 1 -C 6 alkyl;
hetAr a is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S herein hetAr a is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 fluoros), and C 1 -C 6 alkoxy (optionally substituted with 1-3 fluoros);
R c is hydrogen or C 1 -C 6 alkyl;
R d is hydrogen, C 1 -C 6 alkyl (optionally substituted with 1-3 fluoros), (C 1 -C 6 alkoxy)C(═O)—, hydroxy C 1 -C 6 alkyl (optionally substituted with 1-3 fluoros), (hydroxy C 1 -C 6 alkyl)C(═O)—, (C 1 -C 6 alkyl)C(═O)—, (R k R l N)C 1 -C 6 alkyl- where R k and R l are independently H or C 1 -C 6 alkyl, R m R n NC(═O)C 1 -C 6 alkyl- where R m and R n are independently H or C 1 -C 6 alkyl, PhCH 2 — wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C 1 -C 6 alkyl (optionally substituted with 1-3 fluoros), C 1 -C 6 alkoxy (optionally substituted with 1-3 fluoros), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl- (optionally substituted with 1-3 fluoros), C 3 -C 6 cycloalkyl, hydroxyC 1 -C 6 alkyl, (C 1 -C 6 alkyl)SO 2 —, R e R f N— and (R e R f N)C 1 -C 6 alkyl- where each Re and Rf is independently H or C 1 -C 6 alkyl, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl-, or
hetCyc c where hetCyc c is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C 1 -C 6 alkyl;
n is 0, 1, 2, 3, 4, 5 or 6;
m is 0 or 1;
E is:
(a) hydrogen,
(b) hydroxy,
(c) C 1 -C 6 alkyl optionally substituted with 1-3 fluoros,
(d) Ar 1 C 1 -C 6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros,
(e) hetAr 2 C 1 -C 6 alkyl-,
(f) (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy-,
(g) Ar 1 O—,
(h) hetAr 2 —O—,
(i) Ar 1 NR g — where R g is H or C 1 -C 6 alkyl,
(j) hetAr 2 NR g — where R g is H or C 1 -C 6 alkyl,
(k) R 3 C(═O)NR g — where R g is H or C 1 -C 6 alkyl,
(l) Ar 1 C(═O)NR g — where R g is H or C 1 -C 6 alkyl,
(m) hetAr 2 C(═O)NR g (CH 2 ) p — where p is 0 or 1 and R g is H or C 1 -C 6 alkyl,
(n) R 4 R 5 NC(═O)—,
(o) Ar 1 NR g C(═O)—, where R g is H or C 1 -C 6 alkyl,
(p) hetAr 2 NR g C(═O)—, where R g is H or C 1 -C 6 alkyl,
(q) Ar 1 (C 1 -C 6 alkyl)C(═O)— wherein said alkyl portion is optionally substituted with OH, hydroxy(C 1 -C 6 alkyl), C 1 -C 6 alkoxy or NH 2 ,
(r) hetCyc 5 C(═O)—,
(s) R 4 R 5 NC(═O)NR g — wherein R g is H or C 1 -C 6 alkyl,
(t) (C 1 -C 6 alkyl)SO 2 —,
(u) Ar 1 (C 1 -C 6 alkyl)C(═O)NR g — where R g is H or C 1 -C 6 alkyl,
(v) hetAr 4 C(═O)NR g — where R g is H or C 1 -C 6 alkyl,
(w) hetAr 2 S(═O)—,
(x) (C 3 -C 6 cycloalkyl)CH 2 SO 2 —,
(y) Ar 1 (C 1 -C 6 alkyl)SO 2 —,
(z) hetAr 2 SO 2 —,
(aa) Ar 1 ,
(bb) hetAr 2 ,
(cc) hetCyc 5 ,
(dd) C 1 -C 6 alkoxy,
(ee) Ar 1 (C 1 -C 6 alkyl)-O—,
(ff) hetAr 2 (C 1 -C 6 alkyl)-O—,
(gg) hetAr 2 —O—C 1 -C 6 alkyl-,
(hh) Ar 1 (C 1 -C 6 alkyl)NR g — where R g is H or C 1 -C 6 alkyl,
(ii) hetAr 2 —S—,
(jj) Ar 2 SO 2 NR g (CH 2 ) p — where p is O or 1 and R g is H or C 1 -C 6 alkyl,
(kk) (C 1 -C 6 alkoxy)C(═O)—,
(ll) (C 1 -C 6 alkyl)NR g C(═O)O— where R g is H or C 1 -C 6 alkyl,
(mm) (C 1 -C 6 alkyl)NR g SO 2 — where R g is H or C 1 -C 6 alkyl,
(nn) hetCyc 5 C(═O)NR g — where R g is H or C 1 -C 6 alkyl,
(oo) Q-NR h (C 1 -C 3 alkyl)C(═O)NR g — where R g and R h are independently H or C 1 -C 6 alkyl and Q is H, C 1 -C 6 alkyl or (C 1 -C 6 alkyl)OC(═O)—,

where R g and R h are independently H or C 1 -C 6 alkyl, Q is H, C 1 -C 6 alkyl or (C 1 -C 6 alkyl)OC(═O)— and r is 1, 2, 3 or 4,

where R g and R h are independently H or C 1 -C 6 alkyl and Q is H, C 1 -C 6 alkyl or (C 1 -C 6 alkyl)OC(═O)— and r is 1, 2, 3 or 4,

where R g is H or C 1 -C 6 alkyl and Q is H, C 1 -C 6 alkyl or (C 1 -C 6 alkyl)OC(═O)—,

Assignees

• 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

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• A61P1/12

  Antidiarrhoeals · 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

• A61K31/5377

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