Immunoproteasome Inhibitors

A method of treating a disease chosen from an autoimmune disorder, an inflammatory disorder, and a hematological disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I′):

• or a pharmaceutically acceptable salt thereof, wherein:
• W is —O—P-Q-C(R8a)═C(R8b)(R8c), —N(R8a)—P-Q-C(R8a)═C(R8b)(R8c), or a group of formula
• wherein:
• A1 is hydrogen;
• hydroxy;
• alkyl which is optionally substituted with 1-2 substituents chosen from halo, hydroxy, and —N(H)—C(═O)-alkyl;
• —S(═O)2-alkyl;
• heterocycyl;
• aryl;
• or heteroaryl;
• wherein each of said heterocyclyl, aryl and heteroaryl is independently optionally substituted with 1-3 substituents independently chosen from halo, hydroxy, alkyl, alkoxy, cyano, haloalkyl, —NH2, —NH(alkyl), —N(alkyl)2, heterocyclyl, aryl, and heteroaryl;
• R′ is H or alkyl;
• R1 is H or alkyl;
• P is -alkyl-N(R)—, -alkyl-aryl-N(R)—, or
• Z is a covalent bond, -alkyl-, or -alkyl-O-alkyl-;
• ring A with the ring nitrogen atom shown is an optionally substituted saturated mono- or multicyclic 4 to 10 membered heterocyclyl;
• each R independently is hydrogen or alkyl;
• Q is —C(═O)— or —S(═O)2—;
• R8a is hydrogen or cyano;
• R8b is hydrogen or alkyl;
• or
• R8a and R8b are taken together to form a bond;
• and
• R8c is hydrogen or alkyl which is optionally substituted with 1-2 substituents chosen from cycloalkyl and heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-2 substituents chosen from halo, alkyl, and heterocyclyl;
• Rb1 is alkyl which is optionally substituted with 1-2 substituents chosen from cycloalkenyl, aryl and heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with 1-2 substituents chosen from alkyl, halo, hydroxy, alkoxy, cyano, haloalkyl, —NH2, —NH(alkyl), and —N(alkyl)2;
• Rb2 and Rb3 are independently hydrogen or C1-6 alkyl;
• or
• Rb2 and Rb3 together with the boron atom to which they are shown attached form an optionally substituted cyclic boronic ester having 2 to 20 carbons, and optionally containing one or two additional cyclic heteroatoms chosen from N, O and S;
• and
• m and n are independently 0 or 1;
• provided that when W is —O—P-Q-C(R8a)═C(R8b)(R8c), or a group of formula
• wherein m and n are each 0, then P is not -alkyl-N(R)— or
• wherein ring A with the ring nitrogen atom as shown is an optionally substituted saturated monocyclic five- to seven-membered heterocyclyl with only the one nitrogen shown as the ring heteroatom, and wherein Z is connected to ring A at a carbon atom adjacent to the ring nitrogen atom.

A method of inhibiting Large Multifunctional Protease 2 (LMP2) and/or Large Multifunctional Protease 7 (LMP7) in a subject comprising administering to said subject in need of said inhibition a therapeutically effective amount of a compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• W is —O—P-Q-C(R8a)═C(R8b)(R8c), —N(R′)—P-Q-C(R8a)═C(R8b)(R8c), or a group of formula
• A1 is hydrogen, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or —S(═O)2-alkyl, wherein said alkyl of said —S(═O)2-alkyl is optionally substituted;
• R′ is H or optionally substituted alkyl;
• each R1 is H or optionally substituted alkyl;
• P is -alkyl-, -alkyl-O-alkyl-, -alkyl-N(R)—, -alkyl-aryl-N(R)—, -alkyl-N(R)-aryl-N(R)—, -alkyl-O-aryl-N(R)—, -alkyl-aryl-alkyl-N(R)—, -alkyl-heteroaryl-N(R)—, -alkyl-cycloalkyl-N(R)—, -alkyl-O-cycloalkyl-N(R)—, -alkyl-N(R)-cycloalkyl-N(R)—, -alkyl-O-alkyl-N(R)—, -alkyl-N(R)— alkyl-N(R)—,
• wherein each instance of alkyl, aryl, heteroaryl, and cycloalkyl is optionally substituted;
• Z and Z1 are independently a covalent bond, -alkyl-, -alkyl-O—, -alkyl-N(R)—, or -alkyl-O— alkyl-, wherein each instance of alkyl is optionally substituted;
• ring A with the ring nitrogen atom shown is an optionally substituted saturated mono- or multicyclic 4 to 10 membered heterocyclyl;
• ring J with the ring nitrogen atom and ring Y1 atom shown is an optionally substituted saturated 4 to 10 membered heterocyclyl;
• Y1 is C or N;
• Z2 is a covalent bond or N(R);
• each R is independently hydrogen or optionally substituted alkyl;
• Q is —C(═O)— or —S(═O)2—;
• each R8a independently is hydrogen, halogen, or cyano;
• each R8b independently is hydrogen or optionally substituted alkyl;
• or
• each R8a and R8b independently are taken together to form a bond;
• and
• each R8c independently is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
• Rb1 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or optionally substituted heterocyclyl;
• Rb2 and Rb3 are independently hydrogen or optionally substituted C1-6 alkyl;
• or
• Rb2 and Rb3 together with the boron atom to which they are shown attached form an optionally substituted cyclic boronic ester having 2 to 20 carbons, and optionally containing one or two additional cyclic heteroatoms chosen from N, O and S;
• and
• m and n are independently 0 or 1;
• provided that when W is —O—P-Q-C(R8a)═C(R8b)(R8c), or a group of formula
• wherein m and n are each 0, then P is not -alkyl-N(R)—, -alkyl-(C3-C6) cycloalkyl-N(R)—, alkyl-O-alkyl-N(R)—, or
• wherein each instance of alkyl, and cycloalkyl is optionally substituted, ring A with the ring nitrogen atom as shown is an optionally substituted saturated monocyclic five- to seven-membered heterocyclyl with only the one nitrogen shown as the ring heteroatom, and wherein Z is connected to ring A at a carbon atom adjacent to the ring nitrogen atom;
• and
• provided that when W is —O—P-Q-C(R8a)═C(R8b)(R8c), or a group of formula
• wherein m and n are each 0, and P is
• wherein Y1 in ring J is nitrogen, then Z2 is a covalent bond.