Boronic acid derivatives and therapeutic uses thereof

A pharmaceutical composition, comprising:

• a monosaccharide or monosaccharide derivative or monosaccharide derivative and
• a compound of Formula (III):
• or pharmaceutically acceptable salts thereof, wherein:
• A is selected from the group consisting of C5-10 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl;
• Xa is —C(RgRh)—, —O—, —S—, —S(O)—, —S(O)2—, or —NR1—;
• Ra is selected from the group consisting of —H, halogen, optionally substituted —C1-6 alkyl, —OH, —C(O)OR, optionally substituted —O—C1-6 alkyl, —NR1R2, and —N(OR3)R1, optionally substituted —S—C1-6 alkyl, —C(O)NR1R2, —S(O)2NR1R2, —CN, optionally substituted —S(O)—C1-6 alkyl, optionally substituted —S(O)2—C1-6 alkyl, and a carboxylic acid isoster;
• Rb is selected from the group consisting of —H, halogen, optionally substituted —C1-6 alkyl, —OH, —C(O)OR, optionally substituted —O—C1-6 alkyl, —NR1R2, and —N(OR3)R1, optionally substituted —S—C1-6 alkyl, —C(O)NR1R2, —S(O)2NR1R2, —CN, optionally substituted —S(O)—C1-6 alkyl, optionally substituted —S(O)2—C1-6 alkyl, and a carboxylic acid isoster, and
• Rc is selected from the group consisting of —OH, optionally substituted —O—C1-6 alkyl, —NR1R2, and —N(OR3)R1, or Rb and Rc together with intervening atoms form a 5-8 membered boron ester ring, optionally comprising additional 1-3 heteroatoms selected from Oxygen (O), Sulfur(S) or Nitrogen (N);
• Rd is selected from the group consisting of hydrogen, —OH, optionally substituted —O—C1-6 alkyl, —NR1R2, and —N(OR3)R1, or
• when Rb and Rc do not together form a 5-8 membered boron ester ring, then optionally Rc and Rd together with intervening atoms form a 5-15 membered boron ester or amide ring, optionally comprising additional 1-3 heteroatoms selected from O, S, and N;
• Re is independently selected from the group consisting of hydrogen, optionally substituted C1-6alkyl, optionally substituted C3-7cycloalkyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl, or Rd and Re together with the nitrogen to which they are attached form a 5-8 membered heterocyclic ring, optionally comprising additional 1-3 heteroatoms selected from O, S or N;
• Rf is independently selected from the group consisting of —H, —OH, —C(O)G, —C(O)OG, —S(O)2G, —C(═NR1R2)G, —C(═NOR3)G, optionally substituted C1-6 alkyl, optionally substituted —O—C1-6alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl;
• Rg and Rh are each independently selected from the group consisting of —H, C1-6 alkyl, —OH, —OC1-6alkyl, —SC1-6alkyl, C3-10cycloalkyl, C2-10alkenyl, C2-10alkynyl, —NR1C(O)R5, —NR1S(O)2R3, —C(O)R5, —C(O)OR3-alkylaryl, optionally substituted C6-10 aryl, optionally substituted —O—C6-10aryl, —CN, optionally substituted 5-10 membered heteroaryl, optionally substituted —O-heteroaryl, optionally substituted 3-10 membered heterocyclyl, —S(O)(R3)R4, —S(O)2R3, —R1—O—COOR3, or Rg and Rh together with the carbon to which they are attached form a C3-8 cycloalkyl or a 4-8 membered heterocyclyl;
• R is selected from the group consisting of —H, halogen, —C1-9alkyl, —CR5R6OC(O)C1-9alkyl, —CR5R6OC(O)OC1-9alkyl, and
• G is selected from the group consisting of hydrogen, —NR1R2, —CH2N3, —C(O)NR1R2, —CH2C(O)NR1R2, —CH2S(O)2NR1R2, —(CH2)n—Y—Z, —(CH2)n—Y—X, —O—(CH2)n—C(O)NR1R2, —SR3, —CH2NR1C(O)R5, —C(═NOR3)—X, —C(═NOR3)—Z, —C(O)OR3, —C(O)—X, —C(O)—Z, —S(O)2R3, —C(O)NR1OR3, —NR1(OR3), —NR1C(O)R3, —NR1C(O)NR2R1a, —NR1C(O)OR3, —NR1S(O)2R3, —NR1S(O)2NR2R1a, —NR1NR2R1a, —C(O)NR1NR2R1a, —S(O)2NR1NR2R1a, —C(═NR1)R5, —C(═NR1)NR2R1a, —NR1CR3(═NR2), and —NR1C(═NR2)NR1aR2a, optionally substituted C1-10 alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
• X is hydrogen or optionally substituted C1-9alkyl;
• Y is selected from a group consisting of —S—, —S(O)—, —S(O)2—, —CH2—, —O—, —O—CH2—, —C(O)—, and —NR1—;
• Z is selected from optionally substituted C3-8 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl;
• each R1, R2, R1a and R2a are independently selected from the group consisting of —H, optionally substituted —C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
• R3 is hydrogen, optionally substituted C1-10alkyl, —optionally substituted C1-10alkyl-COOH, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
• each R5 and R6 are independently selected from the group consisting of —H, —OH, —optionally substituted alkoxyl, optionally substituted —C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
• R4 is present 1 to 5 times and each R4 is independently selected from the group consisting of —H, —OH, halogen, —CF3, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl, cyano, C1-C6 alkoxy(C1-C6)alkyl, aryloxy, sulfhydryl (mercapto), and —CH2)m—Y′—(CH2)pM′;
• m and p are independently 0 to 3;
• Y′ is selected from the group consisting of —S—, —S(O)—, —S(O)2—, —O—, —CR5R6—, and —NR1—;
• M′ is selected from the group consisting of —C(O)NR1R2;
• —C(O)NR1OR3;
• —NR1C(O)R5;
• —NR1C(O)NR2R1a;
• NR1C(O)OR3;
• —NR1S(O)2R3;
• —NR1S(O)2NR2R1a;
• C(═NR1)R5;
• C(NR1)NR2R1a;
• —NR1CR5(═NR2);
• NR1C(═NR)NR1aR2a;
• C1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting, —OR3, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R5;
• C3-10 cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R5;
• C6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R5;
• 5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R5;
• and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR1, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R5;
• and
• each n is independently 0-3.

A chemical complex, comprising a complex between a monosaccharide or monosaccharide derivative and a compound having the structure of formula (III):

• or pharmaceutically acceptable salts thereof, wherein:
• A is selected from the group consisting of C5-10 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl;
• Xa is —C(RgRh)—, —O—, —S—, —S(O)—, —S(O)2—, or —NR1—;
• Ra is selected from the group consisting of —H, halogen, optionally substituted —C1-6 alkyl, —OH, —C(O)OR, optionally substituted —O—C1-6 alkyl, —NR1R2, and —N(OR3)R1, optionally substituted —S—C1-6 alkyl, —C(O)NR1R2, —S(O)2NR1R2, —CN, optionally substituted —S(O)—C1-6 alkyl, optionally substituted —S(O)2—C1-6 alkyl, and a carboxylic acid isoster;
• Rb is selected from the group consisting of —H, halogen, optionally substituted —C1-6 alkyl, —OH, —C(O)OR, optionally substituted —O—C1-6 alkyl, —NR1R2, and —N(OR3)R1, optionally substituted —S—C1-6 alkyl, —C(O)NR1R2, —S(O)2NR1R2, —CN, optionally substituted —S(O)—C1-6 alkyl, optionally substituted —S(O)2—C1-6 alkyl, and a carboxylic acid isoster, and
• Rc is selected from the group consisting of —OH, optionally substituted O—C1-6 alkyl, —NR1R2, and —N(OR3)R1, or Rb and Rc together with intervening atoms form a 5-8 membered boron ester ring, optionally comprising additional 1-3 heteroatoms selected from Oxygen (O), Sulfur(S) or Nitrogen (N);
• Rd is selected from the group consisting of hydrogen, —OH, optionally substituted —O—C1-6 alkyl, —NR1R2, and —N(OR3)R1, or
• when Rb and Rc do not together form a 5-8 membered boron ester ring, then optionally Rc and Rd together with intervening atoms form a 5-15 membered boron ester or amide ring, optionally comprising additional 1-3 heteroatoms selected from O, S, and N;
• Re is independently selected from the group consisting of hydrogen, optionally substituted C1-6alkyl, optionally substituted C3-7cycloalkyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl, or Rd and Re together with the nitrogen to which they are attached form a 5-8 membered heterocyclic ring, optionally comprising additional 1-3 heteroatoms selected from O, S or N;
• Rf is independently selected from the group consisting of —H, —OH, —C(O)G, —C(O)OG, —S(O)2G, —C(═NR1R2)G, —C(═NOR3)G, optionally substituted C1-6 alkyl, optionally substituted —O—C1-6alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl;
• Rg and Rh are each independently selected from the group consisting of —H, C1-6 alkyl, —OH, —OC1-6alkyl, —SC1-6alkyl, C3-10cycloalkyl, C2-10alkenyl, C2-10alkynyl, —NR1C(O)R5, —NR1S(O)2R3, —C(O)R5, —C(O)OR3-alkylaryl, optionally substituted C6-10 aryl, optionally substituted —O—C6-10aryl, —CN, optionally substituted 5-10 membered heteroaryl, optionally substituted —O-heteroaryl, optionally substituted 3-10 membered heterocyclyl, —S(O)(R3)R4, —S(O)2R3, —R1—O—COOR3, or Rg and Rh together with the carbon to which they are attached form a C3-8 cycloalkyl or a 4-8 membered heterocyclyl;
• R is selected from the group consisting of —H, halogen, —C1-9alkyl, —CR5R6OC(O)C1-9alkyl, —CR5R6OC(O)OC1-9alkyl, and
• G is selected from the group consisting of hydrogen, —NR1R2, —CH2N3, —C(O)NR1R2, —CH2C(O)NR1R2, —CH2S(O)2NR1R2, —(CH2)n—Y—Z, —(CH2)n—Y—X, —O—(CH2)n—C(O)NR1R2, —SR3, —CH2NR1C(O)R5, —C(═NOR3)—X, —C(═NOR3)—Z, —C(O)OR3, —C(O)—X, —C(O)—Z, —S(O)2R3, —C(O)NR1OR3, —NR1(OR3), —NR1C(O)R3, —NR1C(O)NR2R1a, —NR1C(O)OR3, —NR1S(O)2R3, —NR1S(O)2NR2R1a, —NR1NR2R1a, —C(O)NR1NR2R1a, —S(O)2NR1NR2R1a, —C(═NR1)R5, —C(═NR1)NR2R1a, —NR1CR3(═NR2), and —NR1C(═NR2)NR1aR2a, optionally substituted C1-10 alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
• X is hydrogen or optionally substituted C1-9alkyl;
• Y is selected from a group consisting of —S—, —S(O)—, —S(O)2—, —CH2—, —O—, —O—CH2—, —C(O)—, and —NR1—;
• Z is selected from optionally substituted C3-8 cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl;
• each R1, R2, R1a and R2a are independently selected from the group consisting of —H, optionally substituted —C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
• R3 is hydrogen, optionally substituted C1-10alkyl, —optionally substituted C1-10alkyl-COOH, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
• each R5 and R6 are independently selected from the group consisting of —H, —OH, —optionally substituted alkoxyl, optionally substituted —C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
• R4 is present 1 to 5 times and each R4 is independently selected from the group consisting of —H, —OH, halogen, —CF3, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl, cyano, C1-C6 alkoxy(C1-C6)alkyl, aryloxy, sulfhydryl (mercapto), and —(CH2)m—Y′—(CH2)pM′;
• m and p are independently 0 to 3;
• Y′ is selected from the group consisting of —S—, —S(O)—, —S(O)2—, —O—, —CR5R6—, and —NR1—;
• M′ is selected from the group consisting of —C(O)NR1R2;
• —C(O)NR1OR3;
• —NR1C(O)R5;
• —NR1C(O)NR2R1a;
• —NR1C(O)OR3;
• —NR1S(O)2R3;
• —NR1S(O)2NR2R1a;
• —C(═NR1)R5;
• —C(═NR1)NR2R1a;
• —NR1CR5(═NR2);
• —NR1C(═NR2)NR1aR2a;
• C1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting, —OR3, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R5;
• C3-10 cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R5;
• C6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R5;
• 5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R5;
• and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR1, —NR1R2, halogen, —C(O)NR1R2, and —NR1C(O)R5;
• and
• each n is independently 0-3.