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

1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof,

wherein:

X 1 is C(R 2 ) or N;

X 2 is CH 2 or C(O);

R 1 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted by hydroxy;

R 2 is H, halo, or C 1 -C 3 alkyl;

R 3 is selected from the group consisting of:

(a.) H;

(b.) C 1 -C 6 alkyl;

(c.) —(C(R a ) 2 ) n1 OH;

(d.) —(C(R a ) 2 ) n1 N(R b ) 2 ;

(e.) —(C(R a ) 2 ) n1 N(H)C(O)N(R b ) 2 ;

(f.) —(C(R a ) 2 ) n1 N(H)C(O)R d ;

(g.) —(C(R a ) 2 ) n1 N(H)S(O) 2 N(R b ) 2 ;

(h.) —(C(R a ) 2 ) n1 N(H)S(O) 2 R d ;

(i.) —(C(R a ) 2 ) n2 CO 2 R c ;

(j.) —(C(R a ) 2 ) n2 C(O)N(R b ) 2 ;

(k.) —(C(R a ) 2 ) n1 S(O) 2 N(R b ) 2 ;

(l.) —(C(R a ) 2 ) n2 N(H)C(O)OR d ;

(m.) —(C(R a ) 2 ) n2 C(O)N(H)S(O) 2 R d ;

(n.) —(C(R a ) 2 ) n1 N(H)S(O) 2 OR d ;

(o.) —(C(R a ) 2 ) n1 S(O) n3 R d ;

(p.) —(C(R a ) 2 ) n2 C(O)N(H)OR d ;

(q.) —(C(R a ) 2 ) n1 CN;

(r.) —C H or (C(R a ) 2 ) n1 —C H ;

(s.) —C(R a ) 2 O—C C ;

(t.) —C(O)CF 3 ;

(u.) —OH, with the proviso that R 3 is —OH only when X 2 is CH 2 ; and

(v.) —N(R b ) 2 , with the proviso that R 3 is —N(R b ) 2 only when X 2 is CH 2 ;

each R a is independently H, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, or C 3 -C 6 cycloalkyl, or alternatively two R a when bonded to a common carbon atom may together with the common carbon atom form a cyclopropyl ring;

each R b is independently:

(i.) H;

(ii.) C 1 -C 6 alkyl, wherein said C 1 -C 6 alkyl is unsubstituted or independently substituted by 1 to 3 fluoro, or hydroxyl;

(iii.) —(CH 2 ) n3 CO 2 R e ; or

(iv.) —C C or —CH 2 —C C ; or

alternatively, two R b 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 C 1 -C 6 alkyl, C 1 -C 3 alkoxy, fluoro, hydroxyl, oxo, cyano, amino, C 1 -C 3 alkylamino, and C 1 -C 3 dialkylamino;

R c is

(i.) H;

(ii.) C 1 -C 6 alkyl, wherein said C 1 -C 6 alkyl is unsubstituted or independently substituted by 1 to 3 fluoro or hydroxy; or

(iii.) —C C or CH 2 —C C ;

R d is

(i.) C 1 -C 6 alkyl, wherein said C 1 -C 6 alkyl is unsubstituted or independently substituted by 1 to 3 fluoro or hydroxy;

(ii). —C(O)N(R f ) 2 ; or

(iii.) —C C or CH 2 —C C ;

R e is H or C 1 -C 3 alkyl;

R f is H or C 1 -C 3 alkyl;

ring C H is

(i.) C 3 -C 6 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 C H is unsubstituted or independently substituted by 1 to 4 C 1 -C 6 alkyl, C 1 -C 3 alkoxy, halo, hydroxyl, oxo, cyano, amino, C 1 -C 3 alkylamino, or C 1 -C 3 dialkylamino;

ring C C is

(i.) C 3 -C 6 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 C C is unsubstituted or independently substituted by 1 to 4 C 1 -C 6 alkyl, C 1 -C 3 alkoxy, halo, hydroxyl, oxo, cyano, amino, C 1 -C 3 alkylamino, or C 1 -C 3 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;

R 4 is

(a.) C 1 -C 8 alkyl, wherein said C 1 -C 8 alkyl of R 4 is unsubstituted or independently substituted by 1 to 6 halo, C alkoxy, hydroxy, cyano, trimethylsilyl, or methylsulfonyl;

(b.) C 2 -C 8 alkenyl, wherein said C 2 -C 8 alkenyl of R 4 is unsubstituted or independently substituted by 1 to 6 fluoro or cyano; or

(c.) a group of the formula M-R CH ;

M is

(i.) a bond; or

(ii.) C 1 -C 6 alkylene, wherein said C alkylene of M is unsubstituted or substituted by 1 to 6 fluoro;

R CH is a ring selected from the group consisting of

(i.) C 3 -C 9 mono- or bicycloalkyl;

(ii.) phenyl; and

(iii.) a 3- to 6-membered heterocyclyl, wherein said heterocyclyl of R CH 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 R CH is unsubstituted or independently substituted by 1 to 4 halo, C 1 -C 3 alkyl, C trifluoroalkyl, cyano, C 1 -C 4 alkylcarbonylamino, or oxo;

Cy is

(a.) phenyl;

(b.) C 3 -C 6 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 R k moieties selected from the group consisting of:

(i.) C 1 -C 6 alkyl, wherein said C 1 -C 6 alkyl is unsubstituted or independently substituted by 1 to 3 hydroxy or fluoro;

(ii.) C 1 -C 6 alkoxy, wherein said C 1 -C 6 alkoxy is unsubstituted or independently substituted by 1 to 3 fluoro, hydroxy, amino, (C 1 -C 3 alkyl)amino, di(C 1 -C 3 alkyl)amino, methoxy, or phenyl;

(iii.) —N(R e1 ) 2 ;

(iv.) —O(CH 2 ) n4 C(O)N(R e1 ) 2 ;

(v.) —O(CH 2 ) n5 CO 2 R e1 ;

(vi.) hydroxyl;

(vii.) oxo;

(viii.) halo;

(ix.) C 1 -C 3 alkylsulfonyl;

(x.) cyano;

(xi.) oxetanyl; and

(xii.) cyclopropyl;

or alternatively, two R k 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 R k moieties independently selected from (i)-(xi);

each R e1 is independently H or C 1 -C 3 alkyl;

the subscript n4 is 1, 2, or 3; and

the subscript n5 is 1, 2, or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 is N and X 2 is CH 2 .

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is a group of the formula

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Cy is a group of the formula

wherein the subscript s is 0, 1, 2, or 3.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is a group of the formula —(C(R a ) 2 ) n1 N(H)S(O) 2 N(R b ) 2 .

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein the subscript n1 is 1, and each R b is independently:

(i.) H;

(ii.) C 1 -C 4 alkyl, wherein said C 1 -C 4 alkyl is unsubstituted or substituted by 1 to 3 fluoro; or

(iii.) —C C ; or

alternatively, two R b together with the N atom to which they are attached form a 5- to 6-membered heterocyclyl, wherein said heterocyclyl is selected from the group consisting of pyrrolidinyl, piperidinyl, and morpholinyl; wherein said heterocyclyl is unsubstituted or substituted by 1 to 2 moieties independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 3 alkoxy, fluoro, hydroxyl, oxo, cyano, amino, C 1 -C 3 alkylamino, and C 1 -C 3 dialkylamino; and

ring C C is C 3 -C 6 cycloalkyl;

wherein ring C C is unsubstituted or independently substituted by 1 to 2 C 1 -C 6 alkyl, C 1 -C 3 alkoxy, halo, hydroxyl, oxo, cyano, amino, C 1 -C 3 alkylamino, or C 1 -C 3 dialkylamino.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 is N and X 2 is CH 2 ;

R 1 is H or methyl;

R 2 is H;

R 3 is —(C(R a ) 2 ) n1 N(H)S(O) 2 N(R b ) 2 ;

R 4 is a group of the formula

and

Cy is a group of the formula

wherein the subscript s is 0, 1, 2, or 3.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein each R b is independently:

(i.) H;

(ii.) C 1 -C 4 alkyl, wherein said C 1 -C 4 alkyl is unsubstituted or substituted by 1 to 3 fluoro; or

(iii.) —C C ; or

alternatively, two R b together with the N atom to which they are attached form a 5- to 6-membered heterocyclyl, wherein said heterocyclyl is selected from the group consisting of pyrrolidinyl, piperidinyl, and morpholinyl; wherein said heterocyclyl is unsubstituted or substituted by 1 to 2 moieties independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 3 alkoxy, fluoro, hydroxyl, oxo, cyano, amino, C 1 -C 3 alkylamino, and C 1 -C 3 dialkylamino; and

ring C C is C 3 -C 6 cycloalkyl;

wherein ring C C is unsubstituted or independently substituted by 1 to 2 C 1 -C 6 alkyl, C 1 -C 3 alkoxy, halo, hydroxyl, oxo, cyano, amino, C 1 -C 3 alkylamino, or C 1 -C 3 dialkylamino.

9. A method of treating a disease or condition mediated by RORgammaT comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need of such treatment, wherein the disease or condition is multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriasis, rheumatoid arthritis, asthma, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis, or mucosal leishmaniasis.

10. The method of claim 9 , wherein the disease or condition is ankylosing spondylitis or psoriasis.

11. The method of claim 9 , wherein the compound is a compound of claim 7 .

12. The compound of claim 1 , wherein X 1 is CH; X 2 is CH 2 ; and

R 3 is —(C(R a ) 2 ) n1 N(H)C(O)R d ; —(C(R a ) 2 ) n1 N(H)S(O) 2 N(R b ) 2 , —(C(R a ) 2 ) n1 N(H)S(O) 2 R d , —(C(R a ) 2 ) n2 C(O)N(R b ) 2 , —(C(R a ) 2 ) n1 S(O) 2 N(R b ) 2 , —(C(R a ) 2 ) n2 N(H)C(O)OR d , —(C(R a ) 2 ) n2 C(O)N(H)S(O) 2 R d , or —(C(R a ) 2 ) n1 N(H)S(O) 2 OR d .

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein Cy is a group of the formula

wherein the subscript s is 0, 1, 2, or 3.

14. The compound of claim 2 , wherein R 3 is —(C(R a ) 2 ) n1 N(H)S(O) 2 N(R b ) 2 , —(C(R a ) 2 ) n1 N(H)S(O) 2 R d , —(C(R a ) 2 ) n2 C(O)N(R b ) 2 , —(C(R a ) 2 ) n1 S(O) 2 N(R b ) 2 , —(C(R a ) 2 ) n2 N(H)C(O)OR d , —(C(R a ) 2 ) n2 C(O)N(H)S(O) 2 R d , or —(C(R a ) 2 ) n1 H(H)S(O) 2 OR d .

15. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

16. A pharmaceutical composition comprising a compound of claim 12 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

17. A pharmaceutical composition comprising a compound of claim 14 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

18. A compound selected from the following, or a pharmaceutically acceptable salt thereof:

(S)-tert-butyl (5-((4-fluorophenyl)sulfonyl)-6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

(S)-benzyl tert-butyl (1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate;

benzyl tert-butyl (1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate;

benzyl tert-butyl (1-((3-cyanophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate;

benzyl tert-butyl (1-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate;

(S)-benzyl (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

(S)-neopentyl (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

(R)-neopentyl (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

tert-butyl (5-((4-fluorophenyl)sulfonyl)-7-hydroxy-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

(R)-neopentyl (5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

(S)-neopentyl (5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

tert-butyl (7-(hydroxymethyl)-5-(m-tolylsulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

tert-butyl (5-((3,4-difluorophenyl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

(R or S)-neopentyl (5-((4-fluorophenyl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

(S or R)-neopentyl (5-((4-fluorophenyl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

neopentyl ((S)-5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

(R)-1,1,1-trifluoro-2-methylpropan-2-yl (5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

(S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoic acid;

(R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoic acid;

1,1,1-trifluoro-2-methylpropan-2-yl (1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate;

2,2,2-trifluoro-1,1-dimethylethyl {1-[(3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl]-1,2,3,4-tetrahydroquinolin-7-yl}carbamate;

2,2,2-trifluoro-1,1-dimethylethyl (1-{[1-ethyl-3-(2-hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}-1,2,3,4-tetrahydroquinolin-7-yl)carbamate;

2,2,2-trifluoro-1,1-dimethylethyl {1-[(3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl]-1,2,3,4-tetrahydroquinolin-7-yl}carbamate;

2,2,2-trifluoro-1,1-dimethylethyl (1-{[2-(trifluoromethyl)pyridin-4-yl]sulfonyl}-1,2,3,4-tetrahydroquinolin-7-yl)carbamate;

(R)-1,1,1-trifluoro-2-methylpropan-2-yl (3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate;

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate;

(R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid;

(S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid;

(R)-3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1-((5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid;

(R)-3-(1-((4-fluoro-3-methoxyphenyl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid;

(S)-3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1-((5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid;

(S)-3-(1-((4-fluoro-3-methoxyphenyl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid;

1,1,1-trifluoro-2-methylpropan-2-yl (5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-8-oxo-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;

1,1,1-trifluoro-2-methylpropan-2-yl (1-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-4-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamate;

(R)-tert-butyl (6-methyl-8-oxo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate; and

(S)-tert-butyl (6-methyl-8-oxo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate.