US2020291026A1PendingUtilityA1
Macrocyclic compounds as trk kinase inhibitors
Est. expiryMay 20, 2030(~3.8 yrs left)· nominal 20-yr term from priority
Inventors:Steven W. AndrewsKevin Ronald CondroskiJulia HaasYutong JiangGabrielle R. KolakowskiJeongbeob SeoHong YangQian Zhao
C07D 519/00C07D 498/22C07D 487/22C07D 487/04C07D 471/22A61P 43/00A61P 35/02A61P 35/00A61P 33/02A61P 31/04A61P 31/00A61P 29/00A61P 25/28A61P 25/04A61P 25/00A61K 31/519Y02A50/30
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Claims
Abstract
Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R 2 , R 2a , R 3 , R 3a , and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of the general Formula I
or pharmaceutically acceptable salts thereof, wherein:
ring A is selected from rings A-1, A-2 and A-3 having the structures:
wherein the wavy line labeled 1 indicates the point of attachment of ring A to ring B and the wavy line labeled 2 indicates the point of attachment of ring A to W;
X is N or CH;
Y is H or F;
R 1 is H, (1-3C)alkoxy or halogen;
ring B is selected from rings B-1 and B-2 having the structures:
wherein the wavy line labeled 3 indicates the point of attachment to ring A and the wavy line labeled 4 indicates the point of attachment to the pyrazolo[1,5-a]pyrimidine ring of Formula I;
W is O, NH or CH 2 , wherein when ring A is A-2, then W is CH 2 ;
m is 0, 1 or 2;
D is carbon, R 2 and R 2a are independently H, F, (1-3 C)alkyl or OH (provided that R 2 and R 2a are not both OH), and R 3 and R 3a are independently H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl, or
D is carbon or nitrogen, R 2 and R 3 are absent, and R 2a and R 3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;
Z is *—NR 4a C(═O)—, *—ONHC(═O)—, *—NR 4b CH 2 — or *—OC(═O)—, wherein the asterisk indicates the point of attachment of Z to the carbon bearing R 3 ;
R 4a is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C alkyl) or dihydroxy(2-6C alkyl);
R 4b is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)—, (3-6C cycloalkyl)C(O)—, Ar 1 C(O)—, HOCH 2 C(O)—, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar 2 (SO 2 )—, HO 2 CCH 2 — or (1-6C alkyl)NH(CO)—;
Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy;
Ar 2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy; and
R 5 and R 6 are independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl.
2 . A compound of claim 1 having the general Formula
or a pharmaceutically acceptable salt thereof, wherein:
ring A is selected from rings A-1, A-2 and A-3 having the structures:
wherein the wavy line labeled 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula I and the wavy line labeled 2 indicates the point of attachment of ring A to W;
X is N or CH;
Y is H or F;
R 1 is H, (1-3C)alkoxy or halogen;
W is O, NH or CH 2 , wherein when ring A is A-2, then W is CH 2 ;
m is 0, 1 or 2;
R 2 and R 2a are independently H, F, or OH, provided that R 2 and R 2a are not both OH;
R 3 is H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl;
Z is *—NR 4a C(═O)—, *—ONHC(═O)—, *—NR 4b CH 2 — or *—OC(═O)—, wherein the asterisk indicates the point of attachment of Z to the carbon bearing R 3 ;
R 4a is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C alkyl) or dihydroxy(2-6C alkyl);
R 4b is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)—, (3-6C cycloalkyl)C(O)—, Ar 1 C(O)—, HOCH 2 C(O)—, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar 2 (SO 2 )—, HO 2 CCH 2 — or (1-6C alkyl)NH(CO)—;
Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy;
Ar 2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy; and
R 5 and R 6 are independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl.
3 . A compound according to claim 1 or 2 , wherein ring A is ring A-1 having the structure
4 . A compound according to claim 3 , wherein X is CH.
5 . A compound according to claim 3 , wherein X is N.
6 . A compound according to claim 1 or 2 , wherein ring A is ring A-3 having the structure
7 . A compound according to any of claims 1 - 6 , wherein W is O.
8 . A compound according to any of claims 1 - 6 , wherein W is NH.
9 . A compound according to any of claims 1 - 6 , wherein W is CH.
10 . A compound according to claim 1 or 2 , wherein ring A is ring A-2 having the structure
11 . A compound according to any of claims 1 - 10 , wherein Y is F.
12 . A compound according to any of claims 1 - 10 , wherein Y is H.
13 . A compound according to any of claims 1 - 12 , wherein R 1 is H.
14 . A compound according to any of claims 1 - 12 , wherein R 1 is (1-3 C)alkyl or (1-3 C)alkoxy.
15 . A compound according to claim 14 , wherein R 1 is methyl or methoxy.
16 . A compound according to any of claims 1 - 12 , wherein R 1 is halogen.
17 . A compound according to claim 16 , wherein R 1 is fluoro.
18 . A compound according to any of claims 1 - 17 , wherein Z is *—NR 4a C(═O)—.
19 . A compound according to claim 18 , wherein R 4a is hydrogen.
20 . A compound according to claim 18 , wherein R 4a is (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C alkyl) or dihydroxy(2-6C alkyl).
21 . A compound according to claim 20 , wherein R 4a is (1-6C)alkyl.
22 . A compound according to any of claims 1 - 17 , wherein Z is *—ONHC(═O)—.
23 . A compound according to any of claims 1 - 17 , wherein Z is *—NR 4b CH 2 —.
24 . A compound according to claim 23 , wherein R 4b is H.
25 . A compound according to claim 23 , wherein R 4b is selected from (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl and trifluoro(1-6C)alkyl.
26 . A compound according to claim 25 , wherein R 4b is (1-6C)alkyl.
27 . A compound according to claim 23 , wherein R 4b is selected from (1-6C alkyl)C(O)—, (3-6C cycloalkyl)C(O)—, Ar 1 C(O)— and HOCH 2 C(O)—.
28 . A compound according to claim 27 , wherein R 4b is (1-6C alkyl)C(O)—.
29 . A compound according to claim 23 , wherein R 4b is selected from (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, and Ar 2 (SO 2 )—.
30 . A compound according to claim 29 , wherein R 4b is (1-6C alkyl)sulfonyl.
31 . A compound according to claim 23 , wherein R 4b is HO 2 CCH 2 —.
32 . A compound according to claim 23 , wherein R 4b is (1-6C alkyl)NH(CO)—.
33 . A compound according to any of claim 1 or 3 - 32 , wherein D is carbon, R 2 and R 2a are independently H, F, (1-3 C)alkyl or OH (provided that R 2 and R 2a are not both OH), and R 3 and R 3a are independently H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl.
34 . A compound according to any of claims 1 - 33 , wherein R 2 and R 2a are each hydrogen.
35 . A compound according to any of claims 1 - 33 , wherein R 2 and R 2a are each fluoro.
36 . A compound according to any of claims 1 - 33 , wherein R 2 is hydrogen and R 2a is fluoro.
37 . A compound according to any of claims 1 - 33 , wherein R 2 is hydrogen and R 2a is OH.
38 . A compound according to claim 1 or 3 - 33 , wherein R 2 is H and R 2a is methyl, or R 2 and R 2a are both methyl.
39 . A compound according to claim 1 or 3 - 33 , wherein:
R 3 and R 3a are H; or
R 3a is methyl and R 3 is H; or
R 3a and R 3a are both methyl.
40 . A compound according to claim 1 or 3 - 32 , wherein D is carbon or nitrogen, R 2 and R 3 are absent, and R 2a and R 3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms.
41 . A compound according to any of claims 1 - 40 , wherein ring B is ring B-1:
and
R 5 and R 6 are independently H, F, OH, methyl, ethyl, HOCH 2 — or HOCH 2 CH 2 —.
42 . A compound according to claim 41 , wherein R 5 is hydrogen and R 6 is H, F, OH, methyl, ethyl, HOCH 2 — or HOCH 2 CH 2 —.
43 . A compound according to claim 42 , wherein R 6 is H.
44 . A compound according to claim 1 or 3 - 40 , wherein ring B is ring B-2:
45 . A compound according to any of claims 1 - 44 , wherein m is 0.
46 . A compound according to any of claims 1 - 44 , wherein m is 1.
47 . A compound according to any of claims 1 - 44 , wherein m is 2.
48 . A compound according to any of claims 1 - 47 having the absolute configuration of Figure 1-a:
49 . A compound according to any of claims 1 - 47 having the absolute configuration of Figure 1-b
50 . A pharmaceutical composition, which comprises a compound of Formula I as defined in any one of claims 1 to 49 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
51 . A method for treating a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease or Trypanosoma cruzi infection in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I as defined in any one of claims 1 to 49 , or a pharmaceutically acceptable salt thereof.
52 . The method of claim 51 , wherein the disease or disorder is pain.
53 . A compound of Formula I as defined in any one of claims 1 to 49 , or a pharmaceutically acceptable salt thereof, for use in the treatment of pain, cancer, inflammation, neurodegenerative disease or Trypanosoma cruzi infection.
54 . A process for the preparation of a compound of claim 1 , which comprises:
(a) for a compound of Formula I wherein Z is *—NHC(═O)—, and ring A, ring B, W, D, R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula II
where P 1 is H or a carboxyl protecting group, in the presence of a coupling reagent and a base; or
(b) for a compound of Formula I wherein W is O, ring A is formula A-1:
X is N, and ring B, D, Z, Y, R 1 , R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula III
where n is 1, 2, 3 or 4 and L 1 is a leaving group or atom, in the presence of a base; or
(c) for a compound of Formula I wherein W is CH 2 , ring A is formula A-2:
and ring B, Z, D, Y, R 1 , R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula IV
where L 2 is a leaving group or atom, in the presence of a base; or
(d) for a compound of Formula I wherein Z is *—NHC(═O)—, and ring A, ring B, W, D, R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula V
in the presence of a base and a coupling reagent; or
(e) for a compound of Formula I wherein Z is *—NHCH 2 —, and ring A, ring B, W, D, R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula VI
in the presence of a reducing agent; or
(f) for a compound of Formula I wherein Z is *—NHCH 2 —, and ring A, ring B, W, D, R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula VII
in the presence of triphenylphosphine; or
(g) for a compound of Formula I wherein ring A, ring B, W, D, m, R 2 , R 2a , R 3 , and R 3a are as defined for Formula I, Z is *—NR 4b CH 2 —, and R 4b is (1-6C alkyl)C(O)—, (3-6C cycloalkyl)C(O)—, Ar 1 C(O)—, HOCH 2 C(O)—, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, or Ar 2 (SO 2 )—, coupling a corresponding compound having the formula VIII
with a reagent having the formula (1-6C alkyl)C(O)-L 3 , (3-6C cycloalkyl)C(O)-L 3 , Ar 1 C(O)-L 3 , HOCH 2 C(O)-L 3 , (1-6C alkyl)(SO 2 )-L 3 , (3-6C cycloalkyl)(SO 2 )-L 3 , or Ar 2 (SO 2 )-L 3 , respectively, where L 3 is a leaving atom, in the presence of a base; or
(h) for a compound of Formula I wherein ring A, ring B, W, D, R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, Z is *—NR 4b CH 2 —, and R 4b is (1-6C alkyl)NH(CO)—, reacting a compound having the formula VIII
with a reagent having the formula (1-6C alkyl)N═C═O in the presence of a base; or
(i) for a compound of Formula I wherein R 2 is F, R 2a is H, and ring A, ring B, Z, W, D, R 3 , R 3a , and m are as defined for Formula I, reacting a corresponding compound having the formula IX
with a fluorination reagent;
(j) for a compound of Formula I wherein W is O, ring A is formula A-1,
X is CH, and Y, R 1 , D, ring B, Z, R 2 , R 2a , R 3 and m are as defined for Formula I, cyclizing a corresponding compound having the formula X
where n is 1, 2, 3 or 4 and L 1 is a leaving group or atom, in the presence of a base; and
optionally removing any protecting groups and optionally preparing a salt thereof.
55 . The method of claim 54 , wherein:
ring B is ring B-1 having the structure:
D is carbon;
R 2 and R 2a are independently H, F, (1-3 C)alkyl or OH, provided that R 2 and R 2a are not both OH; and
R 3 and R 3a are independently H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl.Join the waitlist — get patent alerts
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