Boronate ester compounds and pharmaceutical compositions thereof

A process for generating a compound of Formula (II)

• or a pharmaceutically acceptable salt thereof, wherein
• A is 0, 1, or 2;
• P is Rc—C(O)—;
• Rc is RD;
• RD is substituted or unsubstituted mono- or bicyclic ring system selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrobenzoxazinyl;
• Ra is hydrogen, C1-6 aliphatic,
• C1-6 fluoroaliphatic, —(CH2)m—CH2—RB, —(CH2)m—CH2—NHC(═NR4)NH—Y, —(CH2)m—CH2—CON(R4)2, —(CH2)m—CH2—N(R4)CON(R4)2, —(CH2)m—CH(R6)N(R4)2, —(CH2)m—CH(R5a)—OR5b,
• or —(CH2)m—CH(R5)—SR5;
• Ra1 is hydrogen, C1-6 aliphatic,
• C1-6 fluoroaliphatic, —(CH2)m—CH2—RB, —(CH2)m—CH2—NHC(═NR4)NH—Y, —(CH2)m—CH2—CON(R4)2, —(CH2)m—CH2—N(R4)CON(R4)2, —(CH2)m—CH(R6)N(R4)2, —(CH2)m—CH(R5a)—OR5b,
• or —(CH2)m—CH(R5)—SR5;
• each Ra2 independently is hydrogen, C1-6 aliphatic,
• C1-6 fluoroaliphatic, —(CH2)m—CH2—RB, —(CH2)m—CH2—NHC(═NR4)NH—Y, —(CH2)m—CH2—CON(R4)2, —(CH2)m—CH2—N(R4)CON(R4)2, —(CH2)m—CH(R6)N(R4)2, —(CH2)m—CH(R5a)—OR5b,
• or —(CH2)m—CH(R5)—SR5;
• each RB independently is a substituted or unsubstituted mono- or bicyclic ring system;
• each R4 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
• or two R4 on the same nitrogen atom, taken together with the nitrogen atom, form a substituted or unsubstituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;
• each R5 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
• each R5a independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
• each R5b independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
• each R6 independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group;
• Y is hydrogen, —CN, or —NO2;
• m is 0, 1, or 2;
• each of Rb1 and Rb2 independently is hydrogen, —CO2H, —OH, or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
• each of Rb3 and Rb4 independently is hydrogen, —CO2H, or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
• or Rb2 and Rb4 are each independently hydrogen, and Rb1 and Rb3, taken together with the carbon atoms to which they are attached, form an unsubstituted or substituted fused 4- to 8-membered non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S, wherein said ring may be optionally fused to an unsubstituted or substituted 4- to 8-membered non-aromatic ring, or 5- to 6-membered aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S;
• or Rb2 and Rb4 are absent, and Rb1 and Rb3, taken together with the carbon atoms to which they are attached, form an unsubstituted or substituted fused 5- to 6-membered aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S, wherein said ring may be optionally fused to an unsubstituted or substituted 4- to 8-membered non-aromatic ring, or 5- to 6-membered aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S;
• and
• n is 0 or 1;
• the process comprising:
• (1a) coupling a compound of Formula (vi) with a compound, P-LG, to form a compound of Formula (vii)
• wherein PG is hydrogen or a protecting group;
• and LG is a leaving group;
• (2a) deprotecting the compound of Formula (vii) to form a compound of Formula (viia)
• (3a) coupling the compound of Formula (viia) with a compound of Formula (i) to form a compound of Formula (iv)
• wherein X− is a counter anion;
• (4) deprotecting the compound of Formula (iv) to form a compound of Formula (v)
• and
• (5) reacting the compound of Formula (v) with an alpha hydroxy carboxylic acid or a beta hydroxy carboxylic acid to form a compound of Formula (II).