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

Patent metadata

Field	Value
Publication number	US-9809561-B2
Application number	US-201415103414-A
Country	US
Kind code	B2
Filing date	Dec 19, 2014
Priority date	Dec 20, 2013
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

The invention provides certain bicylic heterocyclic compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 , 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.

First claim

What is claimed is:

1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof,
wherein:
X 1 is C(R 2 );
X 2 is 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 ; and
(t.) —C(O)CF 3 ;
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 1 -C 3 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 1 -C 6 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 1 -C 3 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 R 4 is a group of the formula

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is H or methyl.

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

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.

7. The compound of claim 6 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-

Assignees

• Merck Sharp & Dohme
• Lycera Corp

Inventors

• Aicher Thomas D
• Vanhuis Chad A
• Thomas William D
• Maclean John K
• Andresen Brian M
• Barr Kenneth J
• Bienstock Corey E
• Anthony Neville J
• Daniels Matthew
• Liu Kun
• Liu Yuan
• White Catherine M
• Lapointe Blair T
• Sciammetta Nunzio
• Simov Vladimir

Classifications

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title