Small molecule inhibitors of ubiquitin specific protease 1 (usp1) and uses thereof

A compound having the structure of Formula (IVa), or a pharmaceutically acceptable salt thereof,

• wherein,
• Y1 is N or CRY1;
• Y2 is N or CRY2;
• Y3 is N or CRY3;
• Y4 is N or CRY4;
• R1 is hydrogen, —CN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C2-7 heterocycloalkyl;
• each of R4 and R4′ is independently selected from hydrogen, halo, —CN, —OR11, —SR11, —N(R12)(R11), optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl;
• or R4 and R4′ taken together form an oxo;
• or R4 and R4′ taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
• each of R5 and R5′ is independently selected from hydrogen, halo, —CN, —OR11, —SR11, —N(R12)(R11), optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl;
• or R5 and R5′ taken together form an oxo;
• or R5 and R5′ taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
• each of R6 and R6′ is independently selected from hydrogen, halo, —CN, —OR11, —SR11, —N(R12)(R11), optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 cycloalkyl, and optionally substituted C2-7 heterocycloalkyl;
• or R6 and R6′ taken together form an oxo;
• or R6 and R6′ taken together with the carbon to which they are attached form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
• each of R8 and R9 is independently selected from hydrogen, halo, —CN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, and optionally substituted C2-6 alkynyl;
• or R8 and R9 taken together with the carbon to which they are attached form an optionally substituted 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
• ring A is monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heterocycloalkyl, or bicyclic heterocycloalkyl;
• each of RA is independently selected from halogen, —NO2, oxo, —CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, —OR11, —SR11, —N(R12)(R11), —C(O)R12, —C(O)OR12, —OC(O)R12, —OC(O)N(R12)(R11), —C(O)N(R12)(R11), —N(R12)C(O)R12, —N(R12)C(O)OR12, —N(R12)C(O)N(R12)(R11), —N(R12)2S(O)2(R12), —S(O)R12, —S(O)2R12, and —S(O)2N(R12)(R11);
• R11 is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C2-7 heterocycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted —C1-4 alkylene-C3-8 cycloalkyl, optionally substituted —C1-4 alkylene-C2-7 heterocycloalkyl, optionally substituted —C1-4 alkylene-phenyl, or optionally substituted —C1-4 alkylene-heteroaryl;
• each of R12 is independently selected from hydrogen, —NO2, —CN, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6 carbocycle and 3- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, —OH, oxo, amino, —NO2, —CN, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;
• RB1 is optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, or optionally substituted bicyclic heteroaryl;
• each of RY1, RY2, RY3 and RY4 is independently selected from hydrogen, halo, —CN, —NO2, —OR11, —SR11, —N(R12)(R11), optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, —OR11, —SR11, —N(R12)(R11), —C(O)R12, —C(O)OR12, —OC(O)R12, —OC(O)N(R12)(R11), —C(O)N(R12)(R11), —N(R12)C(O)R12, —N(R12)C(O)OR12, —N(R12)C(O)N(R12)(R11), —N(R12)S(O)2(R12), —S(O)R12, —S(O)2R12, —S(O)2N(R12)(R11), optionally substituted C3-8 cycloalkyl, optionally substituted C2-9 heterocycloalkyl, optionally substituted naphthyl, optionally substituted phenyl, optionally substituted monocyclic heteroaryl, and optionally substituted bicyclic heteroaryl;
• or
• RY1 and RY2 are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl;
• or
• RY3 and RY4 are taken together with the carbons to which they are attached to form an optionally substituted C3-8 cycloalkyl or optionally substituted C2-9 heterocycloalkyl;
• m is 0, 1, 2, 3, or 4;
• and
• p is 0 or 1.