US 9,809,561 B2
Tetrahydronaphthyridine, benzoxazine, aza-benzoxazine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease
Thomas D. Aicher, Ann Arbor, MI (US); Chad A. VanHuis, Hartland, MI (US); William D. Thomas, San Jose, CA (US); John K. MacLean, Brookline, MA (US); Brian M. Andresen, Boston, MA (US); Kenneth J. Barr, Boston, MA (US); Corey E. Bienstock, Natick, MA (US); Neville J. Anthony, Northborough, MA (US); Matthew Daniels, Somerville, MA (US); Kun Liu, Boston, MA (US); Yuan Liu, Billerica, MA (US); Catherine M. White, Boston, MA (US); Blair T. Lapointe, Boston, MA (US); Nunzio Sciammetta, Boston, MA (US); and Vladimir Simov, Boston, MA (US)
Assigned to MERCK SHARP & DOHME CORP., Rahway, NJ (US); and LYCERA CORPORATION, Ann Arbor, MI (US)
Appl. No. 15/103,414
Filed by Merck Sharp & Dohme Corp., Rahway, NJ (US); and Lycera Corporation, Ann Arbor, MI (US)
PCT Filed Dec. 19, 2014, PCT No. PCT/US2014/071671
§ 371(c)(1), (2) Date Jun. 10, 2016,
PCT Pub. No. WO2015/095795, PCT Pub. Date Jun. 25, 2015.
Claims priority of provisional application 61/919,120, filed on Dec. 20, 2013.
Prior Publication US 2016/0304476 A1, Oct. 20, 2016
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 265/36 (2006.01); C07D 413/14 (2006.01); C07D 215/58 (2006.01); C07D 401/06 (2006.01); C07D 401/12 (2006.01); C07D 413/04 (2006.01); C07D 471/04 (2006.01); A61K 31/4375 (2006.01); A61K 31/47 (2006.01); A61K 31/4709 (2006.01); A61K 31/538 (2006.01); A61K 45/06 (2006.01); C07D 413/06 (2006.01); C07D 413/12 (2006.01); C07D 417/06 (2006.01); C07D 487/04 (2006.01)
CPC C07D 265/36 (2013.01) [A61K 31/4375 (2013.01); A61K 31/47 (2013.01); A61K 31/4709 (2013.01); A61K 31/538 (2013.01); A61K 45/06 (2013.01); C07D 215/58 (2013.01); C07D 401/06 (2013.01); C07D 401/12 (2013.01); C07D 413/04 (2013.01); C07D 413/06 (2013.01); C07D 413/12 (2013.01); C07D 413/14 (2013.01); C07D 417/06 (2013.01); C07D 471/04 (2013.01); C07D 487/04 (2013.01)] 16 Claims
 
1. A compound of the Formula (I)

OG Complex Work Unit Drawing
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

OG Complex Work Unit Drawing
 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.