Triazoles for the treatment of demyelinating dieases

A method of treating or reducing the severity of one or more symptoms of multiple sclerosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I′), or a pharmaceutically acceptable salt thereof,

• wherein:
• X1 is CH;
• X2 is CRX2;
• X3 is CR3;
• where R3 and RX2 are each independently selected from the group consisting of hydrogen, halogen, C1-4alkyl, C1-4haloalkyl, —OC1-4alkyl, and cyano;
• L1 is a bond, —O—, —NR5—, —NR5—C1-4alkylene-, —O—C1-4alkylene-, —C1-4alkylene-, —C(O)—, —NR5C(O)—, —OC(O)—, —NR5C(O)NR5—, —NR5C(O)O—, —NR5—C1-4alkylene-C(O)—, —O—C1-4alkylene-C(O)—, —C1-4alkylene-C(O)—, —NR5C(O)—C1-4alkylene-, —OC(O)—C1-4alkylene-, —NR5C(O)NR5—C1-4alkylene-, —NR5C(O)O—C1-4alkylene-, or —NR5—C1-4alkylene-O—, wherein each R5 is independently hydrogen or C1-4alkyl, and the C1-4alkylene of —NR5—C1-4alkylene-, —O—C1-4alkylene-, —C1-4alkylene-, NR5—C1-4alkylene-C(O)—, —O—C1-4alkylene-C(O)—, —C1-4alkylene-C(O)—, —NR5C(O)—C1-4alkylene-, —OC(O)—C1-4alkylene-, —NR5C(O)NR5—C1-4alkylene-, —NR5C(O)O—C1-4alkylene-, or —NR5—C1-4alkylene-O— is optionally substituted with 1-6 halogens;
• R1 is -G1-L2-R6, -G1-L2-R7, G2, G3, G4, 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 —C1-6alkylene-, —C(O)—, —O—, or —NR5′—, wherein the —C1-6alkylene- is optionally substituted with 1-6 halogens and 1-2 C1alkylene units of the —C1-6alkylene- are optionally replaced with —C(O)—, —O—, or —NR5′—, wherein each R5′ is independently hydrogen or C1-4alkyl;
• 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, oxo, —OC1-4alkyl, —C1-6alkylene-OC1-4alkyl, and —C1-6alkylene-OH;
• 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, hydroxyl, —OC1-4alkyl, —C1-6alkylene-OC1-4alkyl, and —C1-6alkylene-OH;
• 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, oxo, —OC1-4alkyl, —C1-6alkylene-OC1-4alkyl, and —C1-6alkylene-OH;
• 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, oxo, —OC1-4alkyl, —C1-6alkylene-OC1-4alkyl, and —C1-6alkylene-OH;
• 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, oxo, —OC1-4alkyl, —C1-6alkylene-OC1-4alkyl, and —C1-6alkylene-OH;
• 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, —C(O)OH, —OC1-4alkyl, —C1-6alkylene-OC1-4alkyl, and —C1-6alkylene-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, —C1-6alkylene-cyano, —C(O)C1-4alkyl, —C(O)—C1-6alkylene-OC1-4alkyl, —C(O)—C1-6alkylene-OH, —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, —OC1-4haloalkyl, —C1-6alkylene-OC1-4alkyl, —C1-6alkylene-OH, —C1-6alkylene-NH2, —C1-6alkylene-NH(C1-4alkyl), —C1-6alkylene-N(C1-4alkyl)(C1-4alkyl), —O—C1-6alkylene-NH2, —O—C1-6alkylene-NH(C1-4alkyl), —O—C1-6alkylene-N(C1-4alkyl)(C1-4alkyl), —O—C1-6alkylene-OC1-4alkyl, —O—C1-6alkylene-OH, —C1-4alkylene-O—C1-4alkylene-OC1-4alkyl, —C1-4alkylene-O—C1-4alkylene-OH, —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), —N(C1-4alkyl)(C1-4alkyl), —S(O)1-2C1-4alkyl, —C1-6alkylene-S(O)1-2C1-4alkyl, and a —C1-6alkylene substituted by 2 groups independently selected from hydroxyl, —OC(O)C1-4alkyl, —OC1-4alkyl, —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.