Macrocyclic compounds as usp1 inhibitors

A compound of Formula I or a pharmaceutically acceptable salt thereof:

• Wherein
• Ring A is selected from the following structures:
• Y and Y1 are independently a chemical bond or selected from NR1, O, S, S(O)2 or C(R1)2;
• Each of X0, X1, X2, X3, X4, Xa, Xb and Xc is independently selected from N or CR1;
• X5 and X8 are independently selected from C(R1), C(R1)2, O, S or NR1;
• r and q are independently 0, 1, 2, 3 or 4;
• X6 is NRb, C═O, CRaRb;
• X7 is N or CR1;
• Xd is independently a chemical bond or selected from CH2, C(O), O, S, S(O)2, O or NRd;
• R1 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 halogenated alkyl, C1-C6 alkoxy, C1-6 alkylthio, hydroxyl, nitro, formyl, —CN, —SF5, —NRaRb, carboxyl, —C(O)Ra, —C(O)2C1-C6 alkyl, —C(O)NRaRb, —S(O)2Rc, —S(O)2NRaRb, —P(O)Me2 and —P(O)(OMe)2;
• Two R1 on the same carbon atom or adjacent carbon atoms together with carbon atom(s) can form an oxo group or a three- to six-membered carbocyclic ring, four- to eight-membered bicyclic ring or five- to eight-membered spirocyclic ring which is optionally substituted with Re or a three- to six-membered carbocyclic ring, four- to eight-membered bicyclic ring or five- to eight-membered spirocyclic ring which contains one, two or three heteroatom(s) such as S, O or NRd;
• Ra and Rb are independently hydrogen, CH2CH2OH, CH2CMe2OH, C1-C6 alkanol, C1-C6 halogenated alkanol, substituted/non-substituted C1-C10 alkyl, substituted/non-substituted C3-C10 cycloalkyl, substituted/non-substituted C2-C10 alkenyl, substituted/non-substituted C6-C20 aryl, or substituted/non-substituted C3-C14 heteroaryl respectively;
• Ra and Rb can form 3-8 membered carbocyclic rings or 4-8 membered heterocyclic rings, which contain sulfur, oxygen, NH or NRd;
• Rc represents C1-C10 alkyl, C3-C10 cycloalkyl, C6-C20 aryl, or C3-C14 heteroaryl;
• Rc can be substituted by one or more radical groups selected from halogen, hydroxyl, amino, nitro, cyano, formyl, carboxyl, alkoxy, —CF3 and —SF5;
• Rd is selected from the group consisting of hydrogen, C1-6alkyl, C3-6cyclolkyl, C3-6fluorocycloalkyl, C1-6fluoroalkyl, C0-6alkylene-aryl, C0-6alkylene-heteroaryl, C(O)C1-6alkyl, C(O)NRaRb, C(O)aryl, S(O)2C1-6alkyl, S(O)2C3-6cycloalkyl, S(O)2ary, S(O)2NRaRb;
• Re is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 halogenated alkyl, C1-C6 alkoxy, nitro, formyl, —CN, —SF5, NH2, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C20 aryl, or C3-C14 heteroaryl;
• Each of R2 and R3 is independently selected from the group consisting of H, NRaRb, C1-C6 alkoxy, C1-6 alkylthio, halogen, CN, C1-6alkyl, C3-C6cyclolkyl, C3-C6fluorocycloalkyl, C1-C6fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are unsubstituted or substituted with one or more substituents selected from halogen, C1-C6alkyl, C1-C6halogenated alkyl, C3-C10cycloalkyl, C3-C10 cycloalkoxy, C1-C6alkoxy, hydroxyl, nitro, formyl, —CN, —SF5, —NRaRb, carboxyl, —C(O)Ra, —C(O)2C1-C6alkyl, —C(O)NRaRb, —S(O)2Rc, —S(O)2NRaRb, —P(O)Me2 and —P(O)(OMe)2;
• R2 and R3, together with the carbon atom to which they are both attached to, complete a three- to six-membered carbocyclic ring, four- to ten-membered bicyclic ring or five- to ten-membered spirocyclic ring which is optionally substituted with Rd or a three- to six-membered carbocyclic ring, four- to eight-membered bicyclic ring or five- to eight-membered spirocyclic ring which contains one, two or three heteroatom(s) such as S, O or NRd;
• Ring E represents C6-C20 aromatic ring or C1-C20 heteroaromatic ring substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 alkanol, C1-C6 halogenated alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C1-C6 alkoxy, hydroxyl, nitro, formyl, —CN, —SF5, NRaRb, carboxyl, —C(O)Ra, —C(O)2C1-C6 alkyl, —C(O)NRaRb, —SO2Rc, —S(O)2NRaRb, —P(O)Me2 and —P(O)(OMe)2;
• is selected from the following structures:
• Ring F represents C6-C14aromatic ring, C1-C20 heteroaromatic ring, C3-C14 carbocyclic ring, C4-C14bicarbocyclic ring, C5-C14spirocarbocyclic ring, C4-C14heterocyclic ring, C4-C14heterobicyclic ring, C5-C14heterotricyclic ring, C5-C14heterospirocyclic ring with 0 to 5 of O, N or S atoms independently;
• Ring F is substituted with one or more R4;
• Preferably
• is selected from the following structures:
• R4 represents unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6hydroxyalkyl, CN, halogen, S(O)2NH2, —C(O)Ra, —C(O)2Ra, —NRbRb, —NRaC(O)Rb, —NRaC(O)NRaRa, —C(O)NRaRb, —S(O)2NRaRb, —NRaS(O)2Rb, optionally C6-C10 aryl and C1-C10heteroaryl;
• R4 is unsubstituted or substituted by one or more groups selected from:
• halogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6 halogenated cycloalkyl, C1-C6halogenated alkyl, C1-C6alkoxy, hydroxyl, nitro, formyl, —CN, —SF5, NRaRb, carboxyl, —C(O)Ra, —C(O)2C1-C6 alkyl, —C(O)NRaRb, —S(O)2Rc, —S(O)2NRaRb, —P(O)Me2 and —P(O)(OMe)2;
• preferably, R4 is selected from the following structures:
• L is selected from —(CH2)p—, —O(CH2)p, —(CH2)p, S(O)v(CH2)p—, —S(O)2(NR5)(CH2)p—, —(CH2)pS(O)v—, —(CH2)pSO2(NR5)—, —NR5(CH2)p—, —(CH2)pNR5—, —(CH2)pO(CH2)r—, —(CH2)pNR5(CH2)r—, —(CH2)pS(O)v(CH2)r—, —(CH2)p SO2(NR5)(CH2)r—, —(CH2)pS(CH2)r—, —O(CH2)pO—, —NR5(CH2)pNR6—, S(O)v(CH2)pC(O)N—, —(CH2)pS(O)v, —S(O)v(CH2)pR—, —O(CH2)pNR5—, —NR5(CH2)pO—, —S(O)v(CH2)pNR5—, —NR5(CH2)pS(O)v—, O(CH2)pSO(NR5)—, —SO(NR5)(CH2)pO—, —SO(NR5)(CH2)pNR6—, —NR5(CH2)pSO(NR6)—, —(CH2)pCF2(CH2)r—, —(CH2)pCHF(CH2)r—, —(CF2)4—, —(CF2)5—, —(CH2)pC(O)—, —O(CH2)pC(O)—, —(CH2)pC(O)NR5—, —(CH2)pC(S)NR5—, —(CH2)pCH(CF3)NR5—, —(CH2)pNR5C(O)—, —(CH2)pNR5CH(CF3)—, —C(O)NR5(CH2)p—, —CH(CF3)NR5(CH2)p—, —C(S)NR5(CH2)p—, —O(CH2)pC(O)NR5—, —O(CH2)pC(S)NR5—, —S(O)v(CH2)pC(O)—, —O(CH2)pC(O)NR5—, —NR5C(O)(CH2)pC(O)NR6—, —C(O)NR5(CH2)pC(O)NR6—, —C(O)NR5(CH2)pNR6C(O)—, —NR5C(O)(CH2)pNR6C(O)—, —S(O)v(CH2)pO—, —O(CH2)pS(O)v—, —S(O)v(CH2)p—, —(CH2)pS(O)v—, —S(O)v(CH2)pS(O)v—, —NR5(CH2)pC(O)NR6—, —NR5C(O)(CH2)p—, —NR5CH(CF3)(CH2)p—, —NR5(CH2)pO—, —(CH2)rOC(O)(CH2)p—, —OC(O)(CH2)p—, —OC(O)(CH2)pS(O)v—, —(CH2)pCRaa═CRbb(CH2)r—, —NR5(CH2)pCRaa═CRbb(CH2)r—, —NR5C(O)(CH2)pCRaa═CRbb (CH2)r—, —(CH2)pCRaa═CRbb(CH2)rC(O)NR5—, —(CH2)pNR5C(O)NR6(CH2)r—, —(CH2)pNR5C(S)NR6(CH2)r—, —(CH2)pNR5S(O)2NR6(CH2)r—, —(CH2)pS(O)v(CH2)r—, —(CH2)pS(O)2NR5(CH2)r—, —(CH2)pNR5(O)v(CH2)r—, —(CH2)pS(CH2)r—, —(CH2)pC≡C(CH2)r—, —O(CH2)pCRaa═CRbb(CH2)r—, —O(CH2)pC≡C(CH2)r—, —(CH2)pCRaa═CRbb (CH2)rO—, —(CH2)pC≡C(CH2)rO—, —O(CH2)pCRaa═CRbb (CH2)rO—, —O(CH2)pC≡C(CH2)rO—, —S(O)v(CH2)pCRaa═CRbb(CH2)r—, S(O)v(CH2)pC≡C(CH2)r—, —(CH2)pCRaa═CRbb (CH2)rS(O)v—, —(CH2)pC≡C(CH2)rS(O)v—, —O(CH2)pCRaa═CRbb(CH2)rS(O)v—, —O(CH2)pC≡C(CH2)rS(O)v—, —S(O)v(CH2)pCRaa═CRbb(CH2)rO—, —S(O)v(CH2)pC≡C(CH2)rO—, —C(O)NR5S(O)2(CH2)p—, or —(CH2)pS(O)2NR6C(O)—;
• or L is L1-L2-L3;
• L1 and L3 are independently selected from —(CH2)p—, —O(CH2)p—, —S(CH2)p—, —NR5(CH2)p—, —(CH2)pNR5—, —(CH2)pO—, —(CH2)pS—, —(CH2)pC(O)—, —C(O)(CH2)p—, —(CH2)pC(O)NR5—, —NR5C(O)(CH2)p—, —(CH2)pCRaa═CRbb(CH2)r—, —O(CH2)pCRaa═CRbb(CH2)r—, —(CH2)pCRaa═CRbb(CH2)rO—, —S(CH2)pCRaa═CRbb(CH2)r—, —(CH2)pCRaa═CRbb (CH2)rS—, —O(CH2)pCRaa═CRbb (CH2)rS—, or —S(CH2)pCRaa═CRbb (CH2)rO—;
• L2 is a C2-6heterocyclic ring, an C6-10aryl ring or a C1-9heteroaryl ring;
• CRaa═CRbb (olefinic double bond) in L, L1 and L3 includes both E and Z geometric isomers;
• Raa and Rbb are independently selected from H, halogen, C1-6alkyl, C1-6halogenated alkyl, C3-6 cycloalkyl, C3-6halogenated cycloalkyl;
• p is 1, 2, 3, 4, 5 or 6;
• v is 0, 1 or 2;
• R5 and R6 are independently selected from hydrogen, C1-6alkyl, C3-6cycloalkyl.