Pyrrolone or pyrrolidinone melanin concentrating hormone receptor-1 antagonists

Patent metadata

Field	Value
Publication number	US-9499482-B2
Application number	US-201314425165-A
Country	US
Kind code	B2
Filing date	Sep 3, 2013
Priority date	Sep 5, 2012
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

The present invention provides compounds of Formula (I): as defined in the specification and compositions comprising any of such novel compounds. These compounds are melanin concentrating hormone receptor-1 (MCHR1) antagonists which may be used as medicaments.

First claim

What is claimed is:

1. A compound of Formula II:

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
is independently a single or double bond; provided that when is a single bond, R 1 is H or C 1-4 alkyl; and when is a double bond R 1 is absent;

X is independently O or S;
X 1 is independently N or CR 5 ;
X 2 is independently N or CR 6 ;
ring B is independently C 3-6 carbocycle or a 5- to 10-membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, NR e , O, and S(O) p ;
E is independently selected from: a bond, O and CH 2 ;
R 2 , at each occurrence, is independently at selected from: H, halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 haloalkylthio, R 9 , and —O—R 9 ;
R 3 , R 4 , R 5 and R 6 , at each occurrence, are independently selected from: H, halogen, OH, CN, NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C 1-6 haloalkylthio;
R 8 , at each occurrence, is independently selected from: H, C 1-6 alkyl, C 1-6 alkoxy, halogen, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 haloalkylthio, CN, C 3-6 cycloalkyl, and —O—C 3-6 cycloalkyl;
R 9 , at each occurrence, is independently a C 3-6 carbocycle or a 3- to 6-membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, NR e , O, and S(O) p ; wherein said carbocycle and heterocycle are each substituted with 0-3 R b ;
R 12 is independently selected from: H, C 1-8 alkyl substituted with 0-3 R a , C 1-4 haloalkyl, CO(C 1-4 alkyl), COCH 2 O(C 1-4 alkyl), CO 2 (C 1-4 alkyl), SO 2 R f , —(CH 2 ) s —(C 3-6 carbocycle substituted with 0-2 R b ),

R 13 is independently H or C 1-4 alkyl;
alternatively, R 12 and R 13 are combined, together with the nitrogen atom they are attached to, form a 4- to 10-membered heterocycle containing carbon atoms and additional 1-2 heteroatoms selected from the group consisting of N, NR e , O, and S(O) p ; wherein said heterocycle is substituted with 0-3 R c and may form a spiro ring;
R a , at each occurrence, is independently selected from: halogen, OR d , CH 2 OR d , CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, C(O)C 1-4 alkyl, CO 2 H, CO 2 C 1-4 alkyl, SO(C 1-4 alkyl), and SO 2 (C 1-4 alkyl);
R b , at each occurrence, is independently selected from: halogen, OH, CN, CH 2 OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, and —O—C 3-6 cycloalkyl;
R c , at each occurrence, is independently selected from: ═O, halogen, OR d , CH 2 OR d , CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, NH 2 , N(C 1-4 alkyl) 2 , CH 2 C 1-4 alkoxy, C 1-4 haloalkoxy, CONH 2 , CO 2 (C 1-4 alkyl), CO 2 Bn, SO 2 C 1-4 alkyl, NHCOC 1-4 alkyl, NHCOC 1-4 haloalkyl, NHCO 2 C 1-4 alkyl, NHCO 2 Ph, NHCO 2 Bn, C 3-6 cycloalkyl, pyrrolidinyl, and morpholinyl; and
R d , at each occurrence, is independently selected from: H, C(O)C 1-4 alkyl, C(O)(Ph), C(O)CH 2 NH 2 , —C(O)CH(C 1-4 alkyl)NH 2 , —C(O)CH 2 CO 2 H, —C(O)(CH 2 ) 2 CO 2 H, and P(O)(OH) 2 ;
R e , at each occurrence, is independently H, C 1-4 alkyl, C(O)C 1-4 alkyl, CO 2 (C 1-4 alkyl), CO 2 Bn, pyrimidinyl and pyrazinyl;
R f is independently selected from: C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, Ph,

n, at each occurrence, is independently 1, 2, and 3;
p, at each occurrence, is independently 0, 1 or 2; and
s, at each occurrence, is independently 0, 1, or 2.

2. A compound according to claim 1 , wherein the compound is of Formula (III):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 , wherein the compound is of Formula (IIIa):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
is a single or double bond;
R 2 is independently C 3-6 cycloalkyl or phenyl substituted with 0-2 R b ;
R 8 is independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and C 3-6 cycloalkyl;
R 12 is independently at selected from: H, C 1-6 alkyl, CH 2 CH 2 OH, CH 2 CH 2 (C 1-4 alkoxy), CH 2 CN, C 1-4 haloalkyl, CO(C 1-4 alkyl, COCH 2 O(C 1-4 alkyl), CO 2 (C 1-4 alkyl), SO 2 (C 1-4 alkyl), SO 2 CH 2 CF 3 , SO 2 (C 3-6 cycloalkyl), SO 2 Ph, C 3-6 cycloalkyl,

R 13 is independently H or C 1-4 alkyl;
alternatively, R 12 and R 13 are combined, together with the nitrogen atom they are attached to, form a heterocycle substituted with 0-3 R c ; wherein said heterocycle is independently at selected from:

R b , at each occurrence, is independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
R c , at each occurrence, is independently selected from: ═O, halogen, OH, CH 2 OH, CN, NH 2 , N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, CH 2 C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CONH 2 , SO 2 C 1-4 alkyl, NHCOC 1-4 alkyl, NHCOC 1-4 haloalkyl, NHCO 2 C 1-4 alkyl, NHCO 2 Bn, C 3-6 cycloalkyl, pyrrolidinyl, and morpholinyl; and
n, at each occurrence, is independently 1, or 2.

4. A compound according to claim 1 , wherein the compound is of Formula (IIIb):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
is a single or double bond;
NR 12 R 13 is independently at selected from: NH 2 , NH(C 1-6 alkyl), N(C 1-4 alkyl) 2 , NH(CH 2 CH 2 OH), NH(CH 2 CH 2 (C 1-4 alkoxy)), NH(CH 2 CN), NH(C 1-4 haloalkyl), N(C 1-2 alkyl)(CH 2 CH 2 OH), NH(CO(C 1-4 alkyl)), N(C 1-2 alkyl)(CO(C 1-4 alkyl)), N(C 1-2 alkyl)(COCH 2 O(C 1-4 alkyl)), N(C 1-2 alkyl)(CO 2 (C 1-4 alkyl)), NH(SO 2 (C 1-4 alkyl)), N(C 1-2 alkyl)(SO 2 (C 1-4 alkyl)), N(C 1-2 alkyl)(SO 2 CH 2 CF 3 ), N(C 1-2 alkyl)(SO 2 Ph),

and
R 8 is independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and cyclopropyl.

5. A compound according to claim 1 , wherein:
NR 12 R 13 is independently at selected from: NH 2 , NHMe, NH(t-Bu), NMe 2 , NH(CH 2 CH 2 OH), NH(CH 2 CH 2 OMe), NH(CH 2 CN), NH(CH 2 CF 3 ), N(Me)(CH 2 CH 2 OH), NH(COMe), N(Me)(COMe), N(Me)(COCH 2 OMe), N(Me)(CO 2 Me), N(Me)(CO 2 Et), NH(SO 2 Me), N(Me)(SO 2 Me), N(Me)(SO 2 Et), N(Me)(SO 2 Pr), N(Me)(SO 2 (i-Pr)), N(Me)(SO 2 (i-Bu)), N(Me)(SO 2 CH 2 CF 3

Assignees

• Bristol Myers Squibb Co

Inventors

• Washburn William N
• Murugaiah Subbaiah Murugaiah Andappan
• Ahmad Saleem

Classifications

• A61K31/422

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title

• C07D403/12

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

• C07D413/12

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

• A61K31/435

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title