US 9,809,561 B2 · Tetrahydronaphthyridine, benzoxazine, aza-benzoxazine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease

Abstract

The invention provides certain bicylic heterocyclic compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein X1, X2, R1, R2, R3, R4, and Cy are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds of the Formula (I) or pharmaceutically acceptable salts thereof, and methods of using the compounds of the Formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same for treating diseases or conditions mediated by RORgammaT.

A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof,
wherein:
X1 is C(R2);
X2 is O;
R1 is H, C1-C3 alkyl, or C1-C3 alkyl substituted by hydroxy;
R2 is H, halo, or C1-C3 alkyl;
R3 is selected from the group consisting of:
(a.) H;
(b.) C1-C6 alkyl;
(c.) —(C(Ra)2)n1OH;
(d.) —(C(Ra)2)n1N(Rb)2;
(e.) —(C(Ra)2)n1N(H)C(O)N(Rb)2;
(f.) —(C(Ra)2)n1N(H)C(O)Rd;
(g.) —(C(Ra)2)n1N(H)S(O)2N(Rb)2;
(h.) —(C(Ra)2)n1N(H)S(O)2Rd;
(i.) —(C(Ra)2)n2CO2Rc;
(j.) —(C(Ra)2)n2C(O)N(Rb)2;
(k.) —(C(Ra)2)n1S(O)2N(Rb)2;
(l.) —(C(Ra)2)n2N(H)C(O)ORd;
(m.) —(C(Ra)2)n2C(O)N(H)S(O)2Rd;
(n.) —(C(Ra)2)n1N(H)S(O)2ORd;
(o.) —(C(Ra)2)n1S(O)n3Rd;
(p.) —(C(Ra)2)n2C(O)N(H)ORd;
(q.) —(C(Ra)2)n1CN;
(r.) —CH or —(C(Ra)2)n1—CH;
(s.) —C(Ra)2O—CC;
and
(t.) —C(O)CF3;
each Ra is independently H, C1-C3 alkyl, C1-C3 fluoroalkyl, or C3-C6 cycloalkyl, or alternatively two Ra when bonded to a common carbon atom may together with the common carbon atom form a cyclopropyl ring;
each Rb is independently:
(i.) H;
(ii.) C1-C6 alkyl, wherein said C1-C6 alkyl is unsubstituted or independently substituted by 1 to 3 fluoro, or hydroxyl;
(iii.) —(CH2)n3CO2Re;
or
(iv.) —CC or —CH2—CC;
or
alternatively, two Rb together with the N atom to which they are attached form a 5- to 9-membered heterocyclyl, wherein said heterocyclyl is a saturated, partially saturated, or aromatic ring system containing 0, 1, or 2 additional heteroatoms independently selected from the group consisting of N, O, S, and S(O)2;
wherein said heterocyclyl is unsubstituted or substituted by 1 to 4 moieties independently selected from the group consisting of C1-C6 alkyl, C1-C3 alkoxy, fluoro, hydroxyl, oxo, cyano, amino, C1-C3 alkylamino, and C1-C3 dialkylamino;
Rc is
(i.) H;
(ii.) C1-C6 alkyl, wherein said C1-C6 alkyl is unsubstituted or independently substituted by 1 to 3 fluoro or hydroxy;
or
(iii.) —CC or CH2—CC;
Rd is
(i.) C1-C6 alkyl, wherein said C1-C6 alkyl is unsubstituted or independently substituted by 1 to 3 fluoro or hydroxy;
(ii). —C(O)N(Rf)2;
or
(iii.) —CC or CH2—CC;
Re is H or C1-C3 alkyl;
Rf is H or C1-C3 alkyl;
ring CH is
(i.) C3-C6 cycloalkyl;
(ii.) phenyl;
or
(iii.) a 4- to 9-membered mono- or bicyclic heterocyclyl, wherein said heterocyclyl is a saturated, partially saturated, or aromatic ring system containing 1 to 4 heteroatoms independently selected from the group consisting of N, O, S, and S(O)2;
wherein ring CH is unsubstituted or independently substituted by 1 to 4 C1-C6 alkyl, C1-C3 alkoxy, halo, hydroxyl, oxo, cyano, amino, C1-C3 alkylamino, or C1-C3 dialkylamino;
ring CC is
(i.) C3-C6 cycloalkyl;
(ii.) phenyl;
or
(iii.) a heterocyclyl of the formula
wherein said heterocyclyl is a 5- to 9-membered heterocyclyl, wherein said heterocyclyl is a saturated, partially saturated, or aromatic ring system that contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, S, and S(O)2;
wherein ring CC is unsubstituted or independently substituted by 1 to 4 C1-C6 alkyl, C1-C3 alkoxy, halo, hydroxyl, oxo, cyano, amino, C1-C3 alkylamino, or C1-C3 dialkylamino;
the subscript n1 is 1, 2, or 3;
the subscript n2 is 0, 1, 2, or 3;
the subscript n3 is 1 or 2;
R4 is
(a.) C1-C8 alkyl, wherein said C1-C8 alkyl of R4 is unsubstituted or independently substituted by 1 to 6 halo, C1-C3 alkoxy, hydroxy, cyano, trimethylsilyl, or methylsulfonyl;
(b.) C2-C8 alkenyl, wherein said C2-C8 alkenyl of R4 is unsubstituted or independently substituted by 1 to 6 fluoro or cyano;
or
(c.) a group of the formula -M-RCH;
M is
(i.) a bond;
or
(ii.) C1-C6 alkylene, wherein said C1-C6 alkylene of M is unsubstituted or substituted by 1 to 6 fluoro;
RCH is a ring selected from the group consisting of
(i.) C3-C9 mono- or bicycloalkyl;
(ii.) phenyl;
and
(iii.) a 3- to 6-membered heterocyclyl, wherein said heterocyclyl of RCH is a saturated, partially saturated or aromatic ring system containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S;
wherein RCH is unsubstituted or independently substituted by 1 to 4 halo, C1-C3 alkyl, C1-C3 trifluoroalkyl, cyano, C1-C4 alkylcarbonylamino, or oxo;
Cy is
(a.) phenyl;
(b.) C3-C6 cycloalkyl;
or
(c.) a 5- to 9-membered mono- or bicyclic heterocyclyl, wherein said heterocyclyl of Cy is a saturated, partially saturated, or aromatic ring system containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, S and S(O)2;
wherein Cy is unsubstituted or independently substituted by 1 to 4 Rk moieties selected from the group consisting of:
(i.) C1-C6 alkyl, wherein said C1-C6 alkyl is unsubstituted or independently substituted by 1 to 3 hydroxy or fluoro;
(ii.) C1-C6 alkoxy, wherein said C1-C6 alkoxy is unsubstituted or independently substituted by 1 to 3 fluoro, hydroxy, amino, (C1-C3 alkyl)amino, di(C1-C3 alkyl)amino, methoxy, or phenyl;
(iii.) —N(Re1)2;
(iv.) —O(CH2)n4C(O)N(Re1)2;
(v.) —O(CH2)n5CO2Re1;
(vi.) hydroxyl;
(vii.) oxo;
(viii.) halo;
(ix.) C1-C3 alkylsulfonyl;
(x.) cyano;
(xi.) oxetanyl;
and
(xii.) cyclopropyl;
or alternatively, two Rk moieties, when substituted on adjacent ring atoms of Cy, form a second ring, wherein said second ring is a 5- to 7-membered saturated, partially saturated, or aromatic ring system that contains 0, 1, or 2 heteroatoms independently selected from the group consisting of N, O, and S;
wherein said second ring is unsubstituted or substituted by 1 to 3 Rk moieties independently selected from (i)-(xi);
each Re1 is independently H or C1-C3 alkyl;
the subscript n4 is 1, 2, or 3;
and
the subscript n5 is 1, 2, or 3.

103 more elements

Tetrahydronaphthyridine, benzoxazine, aza-benzoxazine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease

Life of this patent

Tetrahydronaphthyridine, benzoxazine, aza-benzoxazine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease

Life of this patent

Abstract

Claims16