Boronic acid derivatives and therapeutic uses thereof

A method of synthesizing a compound having the structure

• or a salt thereof, comprising:
• (a) reacting
• with bis(pinacolato)diboron in the presence of a first palladium complex to form a first intermediate
• (b) deprotecting the first intermediate to form a second intermediate
• (c) reacting the second intermediate with
• to form a third intermediate
• (d) reacting the third intermediate with diiodomethane form a fourth intermediate
• (e) reacting the fourth intermediate with (+)-pinanediol to form a fifth intermediate
• (f) deprotecting the fifth intermediate to arrive at
• or a salt thereof.

A compound of formula I-3, having the structure

• wherein
• Z is —B(OR″′)2;
• each of R′, R″ and R″′ is independently a hydroxy protecting group, R′, R″′ with the oxygen atoms to which they are attached form an acetal protecting group;
• each of J, L, and M is independently CR12 or N (nitrogen);
• R12 is selected from the group consisting of hydrogen, 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)C1-6 alkyl, optionally substituted (C6-10 aryl)C1-6 alkyl, (C6-10 aryl)C1-6 alkoxy, optionally substituted (5-10 membered heteroaryl)C1-6 alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, sulfhydryl, —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, —NRfS(O)2NRfORd, and —(CH2)p—Y6—(CH2)qK;
• Y6 is selected from the group consisting of —S—, —S(O)—, —S(O)2—, —O—, —CRfRg—, and —NRf—;
• K is selected from the group consisting of C-amido;
• N-amido;
• S-sulfonamido;
• N-sulfonamido;
• —NRfC(O)NRfRg;
• —NRfS(O)2NRfRg;
• —C(═NRe)Rc;
• —C(═NRe)NRfRg;
• —NRfCRc(═NRe);
• —NRfC(═NRc)NRfRg;
• C1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkoxy, amino, halogen, C-amido, and N-amido;
• C6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, amino, halogen, C-amido, and N-amido;
• C3-7 carbocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, amino, halogen, C-amido, and N-amido;
• 5-10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, amino, halogen, C-amido, and N-amido;
• and 3-10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, amino, halogen, C-amido, and N-amido;
• 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 p and q is independently 0 or 1.

A compound of formula I-4, having the structure

• wherein
• Z is —B(OR″′)2;
• each of R′, R″ and R″′ is independently a hydroxy protecting group, or R′, R″ with the oxygen atoms to which they are attached form an acetal protecting group;
• Y2 is absent;
• n 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)C1-6 alkyl, optionally substituted (3-10 membered heterocyclyl)C1-6 alkyl, optionally substituted (C6-10 aryl)C1-6 alkyl, (C6-10 aryl)C1-6 alkoxy, optionally substituted (5-10 membered heteroaryl)C1-6 alkyl, 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, —NR'S(O)2NRfRg, —C(═NRe)Rc, —C(═NRc)NRfRg, —NRfCRc(═NRe), —NRfC(═NRe)NRfRg, —S(O)(CH2)1-3Rc, and —NRfS(O)2NRfORd;
• each of J, L, and M is independently CR12 or N (nitrogen);
• R12 is selected from the group consisting of hydrogen, 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)C1-6 alkyl, optionally substituted (C6-10 aryl)C1-6 alkyl, (C6-10 aryl)C1-6 alkoxy, optionally substituted (5-10 membered heteroaryl)C1-6 alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, sulfhydryl, —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, —NRfS(O)2NRfORd, and —(CH2)p—Y6—(CH2)qK;
• Y6 is selected from the group consisting of —S—, —S(O)—, —S(O)2—, —O—, —CRfRg—, and —NRf—;
• K is selected from the group consisting of C-amido;
• N-amido;
• S-sulfonamido;
• N-sulfonamido;
• —NRfC(O)NRfRg;
• —NRfS(O)2NRfRg;
• —C(═NRe)Rc;
• —C(═NRe)NRfRg;
• —NRfCRc(═NRe);
• —NRfC(═NRc)NRfRg;
• C1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkoxy, amino, halogen, C-amido, and N-amido;
• C6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, amino, halogen, C-amido, and N-amido;
• C3-7 carbocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, amino, halogen, C-amido, and N-amido;
• 5-10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, amino, halogen, C-amido, and N-amido;
• and 3-10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, amino, halogen, C-amido, and N-amido;
• 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 p and q is independently 0 or 1.