US 10,881,652 B2 · Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors

Abstract

Provided herein are compounds of the Formula I: or pharmaceutically acceptable salt or solvate thereof, wherein A, B, X1, X2, X3, X4, Ring D, E, Ra, Rb, 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.

A compound of the Formula I:

and pharmaceutically acceptable salts and solvates thereof, wherein:
X1, X2, X3 and X4 are independently CH, CCH3, CF or N, wherein zero, one or two of X1, X2, X3 and X4 is N;
A is H, Cl, methyl, ethyl or cyclopropyl;
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) (R1R2N)C1-C6 alkyl- where R1 and R2 are independently selected from H, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- and (C1-C6 alkoxy)C(═O)—
(g) hetAr1C1-C3 alkyl-, where hetAri 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) (hetCyca)C1-C3 alkyl-,
(j) hetCyca,
(k) (R1R2N)C(═O)C1-C6 alkyl- where R1 and R2 are independently selected from H and C1-C6 alkyl,
(l) (R1R2N)C(═O)—, where R1 and R2 are independently selected from H and C1-C6 alkyl, or
(m) hetCycaC(═O)C1-C6 alkyl-;
hetCyca 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
(i) a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen,
(ii) a saturated 7-8 membered bridged heterocyclic ring having one ring heteroatom which is nitrogen, or
(iii) a saturated 7-11 membered heterospirocyclic ring system having one ring heteroatom which is nitrogen;
each Ra is independently C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl or (C1-C6 alkoxy)C1-C6 alkyl-;
Rb is (a) hydroxy, (b) cyclopropyl, (c) hetCycbCH2—, (d) RiRjNC(═O)CH2OCH2— where R1 and Rj are independently H or C1-C6 alkyl, (e) RcRdN—, (f) RcRdNCH2—, (g) C1-C6 alkoxy-, (h) (C1-C4 alkyl)-C(═O)NH— wherein said alkyl portion is optionally substituted with hetCycb, hetAra, C1-C6 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 C1-C6 alkyl, (i) (R′R″N)C1-C6 alkoxy(CH2)n— where n is 0 or 1 and R′ and R″ are independently hydrogen or C1-C6 alkyl, (j) hetCycb(C1-C3 alkyl)OCH2—, (k) hetCycbC(═O)NH— or (l) hetAraC(═O)NH—;
hetCycb 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 hetCycb is optionally substituted with one or more substituents independently selected from OH, fluoro, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl-, (C1-C6 alkoxy)C(═O)—, C1-C6 alkoxy, and R′R″N— where R′ and R″ are independently hydrogen or C1-C6 alkyl;
hetAra is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S herein hetAra 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), and C1-C6 alkoxy (optionally substituted with 1-3 fluoros);
Rc is hydrogen or C1-C6 alkyl;
Rd is
hydrogen,
C1-C6 alkyl (optionally substituted with 1-3 fluoros),
(C1-C6 alkoxy)C(═O)—,
hydroxyC1-C6 alkyl (optionally substituted with 1-3 fluoros),
(hydroxyC1-C6 alkyl)C(═O)—,
(C1-C6 alkyl)C(═O)—,
(RkRlN)C1-C6 alkyl- where Rk and Rl are independently H or C1-C6 alkyl,
RmRnNC(═O)C1-C6 alkyl- where Rm and Rn are independently H or C1-C6 alkyl, PhCH2— wherein the phenyl 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), C3-C6 cycloalkyl, hydroxyC1-C6 alkyl, (C1-C6 alkyl)SO2—, ReRfN— and (ReRfN)C1-C6 alkyl- where each Re and Rf is independently H or C1-C6 alkyl,
(C1-C6 alkoxy)C1-C6 alkyl-, or
hetCycc where hetCycc is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N and O and optionally substituted with C1-C6 alkyl;
n is 0, 1, 2, 3, 4, 5 or 6;
m is 0 or 1;
E is:
(a) hydrogen,
(b) hydroxy,
(c) C1-C6 alkyl optionally substituted with 1-3 fluoros,
(d) Ar1C1-C6 alkyl- wherein said alkyl portion is optionally substituted with 1-3 fluoros,
(e) hetAr2C1-C6 alkyl-,
(f) (C1-C6 alkoxy)C1-C6 alkoxy-,
(g) Ar1O—,
(h) hetAr2—O—,
(i) Ar1NRg— where Rg is H or C1-C6 alkyl,
(j) hetAr2NRg— where Rg is H or C1-C6 alkyl,
(k) R3C(═O)NRg— where Rg is H or C1-C6 alkyl;
(l) Ar1C(═O)NRg— where Rg is H or C1-C6 alkyl,
(m) hetAr2C(═O)NRg(CH2)p— where p is 0 or 1 and Rg is H or C1-C6 alkyl,
(n) R4R5NC(═O)—,
(o) Ar1NRgC(═O)—, where Rg is H or C1-C6 alkyl,
(p) hetAr2NRgC(═O)—, where Rg is H or C1-C6 alkyl,
(q) Ar1(C1-C6 alkyl)C(═O)— wherein said alkyl portion is optionally substituted with OH, hydroxy(C1-C6 alkyl), C1-C6 alkoxy or NH2,
(r) hetCyc5C(═O)—,
(s) R4R5NC(═O)NRg— where Rg is H or C1-C6 alkyl,
(t) (C1-C6 alkyl)SO2—,
(u) Ar1(C1-C6 alkyl)C(═O)NRg— where Rg is H or C1-C6 alkyl,
(v) hetAr4C(═O)NRg— where Rg is H or C1-C6 alkyl,
(w) hetAr2—S(═O)—,
(x) (C3-C6 cycloalkyl)CH2SO2—,
(y) Ar1(C1-C6 alkyl)SO2—,
(z) hetAr2SO2—,
(aa) Ar1,
(bb) hetAr2,
(cc) hetCyc5,
(dd) C1-C6 alkoxy,
(ee) Ar1(C1-C6 alkyl)-O—,
(ff) hetAr2(C1-C6 alkyl)-O—,
(gg) hetAr2—O—C1-C6 alkyl-,
(hh) Ar1(C1-C6 alkyl)NRg— where Rg is H or C1-C6 alkyl,
(ii) hetAr2—S—,
(jj) Ar2SO2NRg(CH2)p— where p is 0 or 1 and Rg is H or C1-C6 alkyl,
(kk) (C1-C6 alkoxy)C(═O)—,
(ll) (C1-C6 alkyl)NRgC(═O)O— where Rg is H or C1-C6 alkyl,
(mm) (C1-C6 alkyl)NRgSO2— where Rg is H or C1-C6 alkyl,
(nn) hetCyc5C(═O)NRg— where Rg is H or C1-C6 alkyl,
(oo) Q-NRh(C1-C3 alkyl)C(═O)NRg— where Rg and Rh are independently H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(═O)—,
(pp)
where Rg and Rh are independently H or C1-C6 alkyl, Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(═O)— and r is 1, 2, 3 or 4,
(qq)
where Rg and Rh are independently H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(═O)—,
(rr)
where Rg is H or C1-C6 alkyl and Q is H, C1-C6 alkyl or (C1-C6 alkyl)OC(═O)—,
(ss) RgRhN— where Rg and Rh are independently H or C1-C6 alkyl,
(tt) (C3-C6 cycloalkyl)C(═O)NRg— where the cycloalkyl is optionally and independently substituted with one or more halogens,
(uu) (C1-C6 alkyl)C(═O)NRgCH2— where Rg is H or C1-C6 alkyl, or
(vv) C1-C6 alkyl)SO2NR— where Rg is H or C1-C6 alkyl;
Ar1 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)SO2—, ReRfN— and (ReRfN)C1-C6 alkyl- where each Re and Rf is independently H or C1-C6 alkyl;
hetAr2 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 hetAr2 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-;
hetCyc5 is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and oxo;
R3 is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2—, (C3-C6 cycloalkyl)O—, (C3-C6 cycloalkyl)CH2O—, hetCyc7O—, 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;
R4 is H or C1-C6 alkyl;
R5 is Ar2, hetAr3, Ar2CH2—, hetCyc6-CH2—, hydroxyC1-C6 alkyl-, (C3-C6 cycloalkyl)CH2—, or C1-C6 alkyl optionally substituted with 1-3 fluoros;
Ar2 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, and RgRhN— where Rg and Rh are independently H or C1-C6 alkyl, or Ar2 is phenyl fused to a 6 membered heterocyclic ring having a ring nitrogen atom and optionally substituted with C1-C6 alkyl;
hetAr3 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and 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), and (C1-C6 alkoxy)C1-C6 alkyl-(optionally substituted with 1-3 fluoros);
hetAr4 is pyridin-4(1H)-onyl or pyridin-2(1H)-onyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen;
hetCyc6 is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S;
and
hetCyc7 is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S.

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

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

Life of this patent

Abstract

Claims14