Boronic acid derivatives and therapeutic uses thereof

A compound having the structure of Formula VI, or a pharmaceutically acceptable salt thereof:

• wherein
• r is an integer of 0 or 1;
• each of R2 and R3 is independently selected from the group consisting of H, amino, halogen, cyano, hydroxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 haloalkoxy, optionally substituted (C1-6 alkoxy) C1-6 alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted (C3-7carbocyclyl) C1-6alkyl, optionally substituted (3-10 membered heterocyclyl) C1-6alkyl, optionally substituted (C6-10aryl) C1-6alkyl, (C6-10aryl) C1-6alkoxy, optionally substituted (5-10 membered heteroaryl) C1-6alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SRc, —C(O)(CH2)0-3SRc, —C(O)(CH2)1-3Rd, —NRfC(O)NRfRg, —NRfS(O)2NRfRg, —C(═NRe)Rc, —C(═NRe)NRfRg, —NRfCRc(═NRe), —NRfC(═NRe)NRfRg, —S(O)(CH2)1-3Rc, and —NRfS(O)2NRfORd;
• m is an integer of 0 or 1;
• each Ra and Rb is independently selected from the group consisting of H, amino, halogen, cyano, hydroxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 haloalkoxy, optionally substituted (C1-6 alkoxy) C1-6 alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted (C3-7carbocyclyl) C1-6alkyl, optionally substituted (3-10 membered heterocyclyl) C1-6alkyl, optionally substituted (C6-10aryl) C1-6alkyl, (C6-10aryl) C1-6alkoxy, optionally substituted (5-10 membered heteroaryl) C1-6alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SRc, —C(O)(CH2)0-3SRc, —C(O)(CH2)1-3Rd, —NRfC(O)NRfRg, —NRfS(O)2NRfRg, —C(═NRe) Rc, —C(═NRe)NRfRg, —NRfCRc(═NRe), —NRfC(═NRe)NRfRg, —S(O)(CH2)1-3Rc, and —NRfS(O)2NRfORd, or Ra and Rb together with the atoms to which they are attached form a ring or ring system selected from the group consisting of C3-7carbocyclyl, and 3-10 membered heterocyclyl, each optionally substituted with one or more R5;
• R5 is —Y5—(CH2)t-G;
• t is an integer of 0 or 1;
• G is selected from the group consisting of H, amino, halogen, cyano, hydroxy, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 haloalkoxy, optionally substituted (C1-6 alkoxy) C1-6 alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted (C3-7carbocyclyl) C1-6alkyl, optionally substituted (3-10 membered heterocyclyl) C1-6alkyl, optionally substituted (C6-10aryl) C1-6alkyl, (C6-10aryl) C1-6alkoxy, optionally substituted (5-10 membered heteroaryl) C1-6alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SRc, —C(O)(CH2)0-3SRc, —C(O)(CH2)1-3Rd, —NRfC(O)NRfRg, —NRfS(O)2NRfRg, —C(═NRe) Rc, —C(═NRe)NRfRg, —NRfCRc(═NRe), —NRfC(═NRe)NRfRg, —S(O)(CH2)1-3Rc, and —NRfS(O)2NRfORd;
• R6 is selected from the group consisting of optionally substituted-(CH2)nC(O) OR and a carboxylic acid isostere;
• n is an integer selected from 0 to 6;
• R is selected from the group consisting of H, C1-9 alkyl, —CR10R11OC(O)C1-9alkyl, —CR10R11OC(O)C3-7carbocyclyl, —CR10R11OC(O)(3 to 7 membered heterocyclyl), —CR10R11OC(O)C2-8alkoxyalkyl, —CR10R11OC(O)OC1-9alkyl, —CR10R11OC(O)OC3-7carbocyclyl, —CR10R11OC(O)O(3 to 7 membered heterocyclyl), —CR10R11OC(O)OC2-8alkoxyalkyl, —CR10R11OC(O)C6-10aryl, —CR10R11OC(O)OC6-10aryl, —CR10R11C(O)NR13R14, —CR10R11OC(O)O(CH2)1-3C(O)NR13R14, —CR10R10OC(O)O(CH2)2-3OC(O)C1-4 alkyl, —CR10R11OC(O)O(CH2)1-3C(O)OC1-4 alkyl, —CR10R11OC(O)(CH2)1-3OC(O)C1-4 alkyl, and
• R7 is selected from the group consisting of OH, optionally substituted C1-6 alkoxy, amino, and —N(OR8) R9;
• each R8 and R9 is independently selected from the group consisting of H, halogen, optionally substituted C1-4alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
• each R10 and R11 is independently selected from the group consisting of H, optionally substituted C1-4alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
• each R13 and R14 is independently selected from the group consisting of H, optionally substituted C1-6alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
• R15 is optionally substituted C1-6 alkyl;
• Y2 is selected from the group consisting of —O—, —S—, and —NR9—;
• Y5 is selected from the group consisting of —S—, —S(O)—, —S(O)2—, —O—, —CRfRg—, and —NRg—, or Y5 is absent;
• each Rc, Rd, Re, Rf, and Rg are independently selected from the group consisting of H, halogen, optionally substituted C1-4alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
• and
• each Rh and Ri is independently selected from the group consisting of H, halogen, cyano, amino, C-amido, N-amido, optionally substituted C1-4alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
• or Rh and Ri together with the atoms to which they are attached form a spirocyclic ring or ring system selected from the group consisting of C3-7 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, each optionally substituted with one or more R5.