Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
Provided herein are compounds of the Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, X 1 , X 2 , X 3 , X 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.
1. A compound of the Formula I:
and pharmaceutically acceptable salts thereof, wherein:
X 1 , X 2 , X 3 and X 4 are independently CH, CF or N, wherein zero, one or two of X 1 , X 2 , X 3 and X 4 is N;
A is H, CN, Cl, CH 3 —, CH 3 CH 2 —, cyclopropyl, —CH 2 CN or —CH(CN)CH 3 ;
B is
(a) hydrogen,
(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,
(d) dihydroxyC3-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,
(f) (R 1 R 2 N)C1-C6 alkyl- wherein R 1 and R 2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros);
(g) hetAr 1 C1-C3 alkyl-, wherein 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 C1-C6 alkyl substituents;
(h) (C3-C6 cycloalkyl)C1-C3 alkyl-,
(i) (hetCyc a )C1-C3 alkyl-, or
(j) hetCyc a ;
hetCyc a is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and 0 and is optionally substituted with OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxyC1-C6 alkyl-;
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 to E;
E is
(a) hydrogen,
(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,
(d) (C1-C6 alkyl)C(═O)— wherein said alkyl portion is optionally substituted with 1-3 fluoros or with a R g R h N— substituent wherein R g and R h are independently H or C1-C6 alkyl,
(f) (C1-C6 alkoxy)C(═O),
(l) hetAr 2 C(═O)—,
(o) R 3 R 4 NC(═O)—,
(s) Ar 1 SO 2 —,
(t) hetAr 2 SO 2 —,
(v) Ar 1 C(═O)—,
(cc) hetAr 2 , or
(dd) C3-C6 cycloalkyl;
R 3 is H or C1-C6 alkyl; and
R 4 is C1-C6 alkyl.
2. A compound according to claim 1 , wherein X 1 is N; X 2 , X 3 , and X 4 are each CH.
3. A compound according to claim 1 , wherein A is CN.
4. A compound according to claim 1 , wherein B is (C1-C6 alkoxy)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.
5. A compound according to 1 , wherein Ring D is unsubstituted.
6. A pharmaceutical composition, comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
7. A method for treating cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
8. A method of treating a RET-associated cancer in a patient, the method comprising administering to a patient identified or diagnosed as having a RET-associated cancer a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
9. A method of treating a RET-associated cancer in a patient, the method comprising:
determining that the cancer in the patient is a RET-associated cancer; and
administering to a patient determined to have a RET-associated cancer a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
10. A method for inhibiting RET kinase activity in a mammalian cell, the method comprising contacting the mammalian cell with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
11. The method of claim 10 , wherein the mammalian cancer cell is a mammalian RET-associated cancer cell.
12. A method for inhibiting metastasis of a cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.