Ether linked triazoles as nrf2 activators

A compound of Formula (I):

• wherein:
• B is —O(CH2)-triazolyl, —O(CH2)m, —O(CH2)m-oxazolyl, —O(CH2)m-oxadiazolyl and —O(CH2)m-isoxazolyl, wherein each of the —O(CH2)-triazolyl, —O(CH2)m, —O(CH2)m, —O(CH2)m-oxazolyl, —O(CH2)m-oxadiazolyl or —O(CH2)m-isoxazolyl is unsubstituted or substituted by 1 or 2 substituents independently selected from —C1-6alkyl, —(CH2)m—O—C1-3alkyl, —(CH2)n—C3-7cycloalkyl, —(CH2)m—C4-7heterocycloalkyl, —(CH2)n-phenyl, —(CH2)n-phenyl-(CH2)n-aryl, —(CH2)n-phenyl-(CH2)n-heteroaryl, —(CH2)n—C3-7cycloalkyl, —(CH2)n—C3-7heterocycloalkyl, —(CH2)n—C3-7heterocycloalkyl-(CH2)n—C3-7heterocycloalkyl, —(CH2)n—C3-7heterocycloalkyl-C(O)R′, —(CH2)n—C3-7heterocycloalkyl-C(O) C3-7heterocycloalkyl, —(CH2)n—C3-7heterocycloalkyl-C(O)—C3-7cycloalkyl, —(CH2)n—C3-7heterocycloalkyl-C(O)aryl, —(CH2)n-phenyl-(CH2)n—C4-7 heterocycloalkyl, —(CH2)2—O—(CH2)2—OR4, CN, C1-6alkylNR4R5, C1-6alkylNC(O)R7, C1-6alkylNC(O)OR4 and halo and wherein each of the moieties —(CH2)n-phenyl, —(CH2)n-phenyl-(CH2)n-aryl, —(CH2)n-phenyl-(CH2)n-heteroaryl, —(CH2)n—C3-7cycloalkyl, —(CH2)n—C3-7 heterocycloalkyl, —(CH2)n—C3-7heterocycloalkyl-(CH2)n—C3-7heterocycloalkyl, —(CH2)n—C3-7 heterocycloalkyl-C(O)R′, —(CH2)n—C3-7heterocycloalkyl-C(O) C3-7heterocycloalkyl, —(CH2)n—C3-7 heterocycloalkyl-C(O)—C3-7cycloalkyl, —(CH2)n—C3-7heterocycloalkyl-C(O)aryl, —(CH2)n-phenyl-(CH2)n—C4-7heterocycloalkyl, —(CH2)2—O—(CH2)2—OR4 are unsubstituted or further substituted by 1, 2 or 3 substituents independently selected from —C1-4alkyl, —SO2R4, halo, —(CH2)n, —(CH2)nC(O)OR4, —(CH2)mOH, —C(O)R7;
• D is —C(O)OH, —C(O)CR′, —C(O)NHSO2CH3, —SO2NHC(O)CH3, 5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, or tetrazolyl;
• R1 is independently hydrogen, —OH, —C1-3alkyl, —C1-3alkylOR′, F, —C3-6spirocycloalkyl, oxetane, or the two R1 groups together with the carbon to which they are attached form a cyclopropyl group;
• R′ is hydrogen, —C1-4alkyl or —NH2;
• R2 is hydrogen, —C1-4alkyl, —CF3, or halo;
• R3 is —(CH2)m;
• R4 is hydrogen or —C1-3alkyl;
• or, when R2 is —C1-4alkyl, R3 is —(CH2)m—, and m is 2 or 3, R2 and R3 together form a cycloalkyl ring fused to the phenyl ring to which they are attached;
• A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, pyridyl, benzimidazolyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl, dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, pyrrolidinyl, oxazepane or morpholinyl;
• wherein each of tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, pyridyl, benzimidazolyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl, dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, pyrrolidinyl, oxazepane or morpholinyl is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl, —C3-6spirocycloalkyl, halo, CN, —O—C1-3alkyl, —CH2—O—CH3, and OH;
• and wherein the piperidinyl is further unsubstituted or substituted by a substituent independently selected from pyrazolyl, —CH2pyrazolyl, and oxadiazolyl each of which is unsubstituted or substituted by —C1-3alkyl, or, when A is piperidinyl, it is unsubstituted or substituted by —SO2R, wherein R is C1-3alkyl, phenyl or C3-7cycloalkyl;
• and wherein the oxazepane is further unsubstituted or substituted by 1 or 2 substituents independently selected from —C1-3alkyl and —C3-7cycloalkyl;
• and wherein the morpholinyl is further unsubstituted or substituted by phenyl which phenyl is unsubstituted or independently substituted by a substituent selected from C1-3 alkyl and —O—C1-3 alkyl;
• and wherein the pyrrolidinyl is further optionally substituted by a triazolyl group which is optionally substituted by —C1-3alkyl;
• and wherein the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups each are further unsubstituted or substituted by 1, 2 or 3 substituents independently selected from —CH2—C4-7 cycloalkyl, —CH2—C5-7heterocycloalkyl, —CH2-azabicycloheptanyl, —CH2-oxepane, and —CH2— azabicyclohexanyl, and wherein each of —CH2—C4-7cycloalkyl, —CH2—C5-7heterocycloalkyl, —CH2— azabicycloheptanyl, —CH2-oxepane, or —CH2-azabicyclohexanyl, including the —CH2—, are further unsubstituted or substituted by 1 or 2 substituents independently selected from —C1-3 alkyl and F;
• or, A is,
• R5 is hydrogen or C1-5alkyl;
• R6 is hydrogen or —C1-4alkyl;
• R7 is hydrogen, aryl, heteroaryl, C5-10heterocycloalkyl, —C1-4alkyl or —C3-7cycloalkyl;
• X is independently CH or N;
• Y is independently CH or N;
• Z is O, CH2, NR5, S, S(O), SO2;
• wherein, when A is,
• A is unsubstituted of substituted by one, two or three substituents independently selected from halo, —CF3, —C1-4alkyl, —CN, —OMe, —C(O)NH2, —OCF3, and —C1-4alkylNR6R8;
• R8 is hydrogen, —C1-5alkyl, —C3-7cycloalkyl, —C4-8heterocycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-SO2C1-3alkyl, —C1-3alkyl-C4-8heterocycloalkyl, —C1-3alkyl-C(O)NR5R6, or heteroaryl, wherein each of —C1-5alkyl, —C3-7cycloalkyl, —C4-7 heterocycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-C(O)NR5R6, or heteroaryl is unsubstituted or substituted by one or two substituents independently selected from —OH,
• —CO2H, —C(O)NR5R6, —C(O)OR5, —N—C(O)—C1-3alkyl, F, —CN, —CH—F2, —CF3, —(CH2)n—O—(CH2)m—CH3, and —C3-7cycloalkyl, a 5-6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from O, N and S;
• R9 is -phenyl, —C3-7cycloalkyl, —C3-7heterocycloalkyl containing 1 or 2 heteroatoms selected from O, N and S, -5-10-membered aryl ring or a -5-10-membered heteroaryl ring, containing 1, 2 or 3 heteroatoms selected from O, N and S, wherein each of -phenyl, —C3-7cycloalkyl, —C3-7heterocycloalkyl containing 1 or 2 heteroatoms selected from O, N and S, -5-10-membered aryl ring or a -5-10-membered heteroaryl ring, containing 1, 2 or 3 heteroatoms selected from O, N and S is unsubstituted or independently substituted by one or two substituents selected from halo, —C(O)OH, —CF3, —C1-4alkyl, —CN, —OMe, —C(O)NH2, —OCF3, and —C1-4alkylNR6R8;
• R10 is independently selected from hydrogen, halo, —C(O)OH, —CF3, —C1-4alkyl, —CN, —OMe, —C(O)NH2, —OCF3, and —C1-4alkylNR6R8;
• m is 1, 2, 3 or 4;
• and
• n is 0, 1, 2 or 3;
• or a pharmaceutically acceptable salt thereof.