US 2016/0355488 A1 · TRIAZOLES FOR THE TREATMENT OF DEMYELINATING DISEASES

Abstract

The invention relates to triazole compounds of formula I and I′ or pharmaceutically acceptable salts thereof, useful as modulators of demyelinating diseases: The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, methods of using the compositions and kits thereof in the treatment of various demyelinating and neurodegenerative diseases, including multiple sclerosis.

A compound of formula (I′), or a pharmaceutically acceptable salt thereof,

wherein:
X1 is CH or N;
X2 is CRX2 or N;
X3 is CR3 or N;
where R3 and RX2 are each independently selected from the group consisting of hydrogen, halogen, C1-4alkyl, C1-4haloalkyl, —OC1-4alkyl, and cyano;
provided that X1, X2, and X3 are not simultaneously N, X2 and X3 are not simultaneously N and X1 and X3 are not simultaneously N;
L1 is a bond, —O—, —NR5—, —NR5—C1-4alkylene-, —O—C1-4alkylene-, —C1-4alkylene-, or —C(O)—, wherein R5 is hydrogen or C1-4alkyl;
R1 is -G1-L2-R6, -G1-L2-R7, G2, G3, G4, G5, G6, or -≡-G5;
G1 is
i) a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C1-3alkylene bridge between two non-adjacent ring atoms, G1 being optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halogen, hydroxyl, and oxo;
or
ii) a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halogen, hydroxyl, and oxo;
L2 is a bond, a —C1-3alkylene-, or —C(O)—;
R6 is
a) a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C1-3alkylene bridge between two non-adjacent ring atoms and being optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, —CH2S(O)2phenyl, halogen, hydroxyl, and oxo;
b) a 5- or 6-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the monocyclic heteroaryl being optionally substituted with 1-3 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halogen, and hydroxyl;
c) a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L2, the second ring being a C3-8cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halogen, hydroxyl, and oxo;
or
d) a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur and being optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halogen, hydroxyl, and oxo;
R7 is
a) a 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halogen, hydroxyl, —C(O)OC1-4alkyl, —C(O)OH, and oxo;
or
b) phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halogen, hydroxyl, —C(O)OC1-4alkyl, and —C(O)OH;
G2 is a 4- to 8-membered monocyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, the monocyclic heterocycle optionally containing one double bond and/or a C1-3alkylene bridge between two non-adjacent ring atoms, G2 being optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C1-4alkyl, —C(O)C3-6cycloalkyl, —C(O)OC1-4alkyl, —C(O)OC1-4haloalkyl, —C(O)NH2, —C(O)NH(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH(—C1-6alkylene-OC1-4alkyl), —C(O)N(C1-4alkyl)(-C1-6alkylene-OC1-4alkyl), —C(O)NH(—C1-6alkylene-OH), —C(O)N(C1-4alkyl)(-C1-6alkylene-OH), —NH(—C1-6alkylene-OC1-4alkyl), —N(C1-4alkyl)(-C1-6alkylene-OC1-4alkyl), —NH(—C1-6alkylene-OH), —N(C1-4alkyl)(-C1-6alkylene-OH), —C(O)C1-4haloalkyl, —OC1-4alkyl, —C1-6alkylene-OC1-4alkyl, —C1-6alkylene-OH, —C1-6alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C1-4alkyl, —C1-6alkylene-NH2, —C1-6alkylene-NH(C1-4alkyl), —C1-6alkylene-N(C1-4alkyl)(C1-4alkyl), —C1-4alkylene-C(O)OC1-4alkyl, —C1-4alkylene-C(O)OH, —NHC(O)(C1-4alkyl), —N(C1-4alkyl)C(O)(C1-4alkyl), —NH2, —NH(C1-4alkyl), and —N(C1-4alkyl)(C1-4alkyl);
G3 is a 7- to 12-membered spiro heterocycle comprising a first ring and a second ring, the first ring being a 4- to 8-membered monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen and oxygen and being attached to L1, the second ring being a C3-8cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1-2 oxygen atoms wherein two atoms of the second ring are attached to one carbon of the first ring to form a spirocycle, and wherein G3 is optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halogen, hydroxyl, and oxo;
G4 is a 7- to 12-membered fused bicyclic heterocycle containing 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G4 being optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halogen, hydroxyl, and oxo;
G5 is 3- to 8-membered cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halogen, hydroxyl, oxo, cyano, —C(O)C1-4alkyl, —C(O)C3-6cycloalkyl, —C(O)OC1-4alkyl, —C(O)OC1-4haloalkyl, —C(O)NH2, —C(O)NH(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH(—C1-6alkylene-OC1-4alkyl), —C(O)N(C1-4alkyl)(-C1-6alkylene-OC1-4alkyl), —C(O)NH(—C1-6alkylene-OH), —C(O)N(C1-4alkyl)(-C1-6alkylene-OH), —NH(—C1-6alkylene-OC1-4alkyl), —N(C1-4alkyl)(-C1-6alkylene-OC1-4alkyl), —NH(—C1-6alkylene-OH), —N(C1-4alkyl)(-C1-6alkylene-OH), —C(O)C1-4haloalkyl, —OC1-4alkyl, —C1-4alkylene-OC1-4alkyl, —C1-6alkylene-OH, —C1-6alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C1-4alkyl, —C1-4alkylene-C(O)OC1-4alkyl, —C1-4alkylene-C(O)OH, —NHC(O)(C1-4alkyl), —N(C1-4alkyl)C(O)(C1-4alkyl), —NH2, —NH(C1-4alkyl), and —N(C1-4alkyl)(C1-4alkyl);
G6 is a monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, G6 being optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halogen, hydroxyl, cyano, phenyl, —C(O)C1-4alkyl, —C(O)C3-6cycloalkyl, —C(O)OC1-4alkyl, —C(O)OC1-4haloalkyl, —C(O)NH2, —C(O)NH(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C(O)NH(—C1-6alkylene-OC1-4alkyl), —C(O)N(C1-4alkyl)(-C1-6alkylene-OC1-4alkyl), —C(O)NH(—C1-6alkylene-OH), —C(O)N(C1-4alkyl)(-C1-6alkylene-OH), —NH(—C1-6alkylene-OC1-4alkyl), —N(C1-4alkyl)(-C1-6alkylene-OC1-4alkyl), —NH(—C1-6alkylene-OH), —N(C1-4alkyl)(-C1-6alkylene-OH), —C(O)C1-4haloalkyl, —OC1-4alkyl, —C1-4alkylene-OC1-4alkyl, —C1-6alkylene-OH, —C1-6alkylene substituted by 2 groups independently selected from hydroxyl and —OC(O)C1-4alkyl, —C1-4alkylene-C(O)OC1-4alkyl, —C1-4alkylene-C(O)OH, —NHC(O)(C1-4alkyl), —N(C1-4alkyl)C(O)(C1-4alkyl), —NH2, —NH(C1-4alkyl), and —N(C1-4alkyl)(C1-4alkyl);
R2 is C1-4alkyl, C1-4haloalkyl, halogen, hydroxyl, cyano, —S(O)2C1-4alkyl, —S(O)C1-4alkyl, —SC1-4alkyl, —OC1-4alkyl, —OC1-4haloalkyl, —C(O)C1-4alkyl, —C(O)OC1-4alkyl, —C(O)NH2, —C(O)NH(C1-4alkyl), —C(O)N(C1-4alkyl)(C1-4alkyl), —C1-4alkylene-OC1-4alkyl, —C1-4alkylene-OH, or G10, G10 being a C3-6cycloalkyl, C5-6cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen and optionally containing 1 double bond, G10 being optionally substituted with 1-2 substituents independently selected from oxo, halogen, C1-4alkyl, C1-4haloalkyl, and G20, G20 being a C3-6cycloalkyl or a 4- to 8-membered monocyclic heterocycle containing 1 to 2 heteroatoms independently selected from nitrogen and oxygen, G20 being optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halogen, hydroxyl, and oxo;
and
R4 is phenyl or a 6-membered heteroaryl containing 1-3 nitrogen atoms, R4 being optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, —S(O)2C1-4alkyl, —S(O)C1-4alkyl, —SC1-4alkyl, C1-4alkyl, C1-4haloalkyl, —OC1-4alkyl, —OC1-4haloalkyl, —C1-4alkylene-OC1-4alkyl, —C1-4alkylene-N(C1-4alkyl)(C1-4alkyl), —NH(C1-4alkylene-OC1-4alkyl), —NH(C1-4alkylene-OH), —N(C1-4alkyl)(C1-4alkylene-OC1-4alkyl), —N(C1-4alkyl)(C1-4alkylene-OH), —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)(C1-4alkyl), C3-6cycloalkyl, C5-6cycloalkenyl, or a 4- to 8-membered monocyclic heterocycle containing 1-2 nitrogen atoms, the C3-6cycloalkyl, the C5-6cycloalkenyl, and the 4- to 8-membered monocyclic heterocycle being independently optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, hydroxyl, —OC1-4alkyl, C1-4alkyl, C1-4haloalkyl, —C1-4alkylene-OC1-4alkyl, and —C1-4alkylene-OH.

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Triazoles for the treatment of demyelinating diseases

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Triazoles for the treatment of demyelinating diseases

Life of this patent

Abstract

Claims87