Dipeptides as inhibitors of human immunoproteasomes

A method of treating cancer, immunologic disorders, autoimmune disorders, neurodegenerative disorders, or inflammatory disorders in a subject or for providing immunosuppression for transplanted organs or tissues in a subject, said method comprising:

• administering to the subject in need thereof a compound of the Formula (Ia):
• wherein
• R1a is selected from the group consisting of bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic non-aromatic heterocycle, wherein bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-6 alkyl, and C1-6 alkoxy;
• R2a is selected from the group consisting of C1-6 alkyl, —CH2OC1-6 alkyl, —CH2Ar, and heteroaryl, wherein aryl (Ar) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-6 alkyl, and C1-6 alkoxy;
• R3a is selected from the group consisting of —CH2OC1-6 alkyl, —CHmC(O)NHR5a, and —CH2C(O)R5a;
• R4a is selected from the group consisting of —C(O)(CH2)nPh, —C(O)CH2NR6aR7a, —SO2Ar, —SO2C1-6 alkyl, —C(O)(CH2)nHet, —C(O)C1-6 alkyl, —C(O)CF3, heteroaryl, and —(CH2)nNR6aR7a, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-6 alkyl, and C1-6 alkoxy;
• R5a is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, non-aromatic heterocycle, —NR6aR7a, and —CR8aR9a;
• R6a, R7a, R8a, and R9a are each independently selected from the group consisting of H, C1-6 alkyl, and —(CH2)kOH;
• or R6a and R7a are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, azepane, azetidine, or morpholine ring;
• or R8a and R9a are taken together with the carbon to which they are attached to form an oxetane ring;
• m is 1 or 2;
• n is 0, 1, 2, or 3;
• and
• k is 1, 2, or 3.

A compound of Formula (I):

• wherein
• R1 is bicyclic aryl optionally substituted 1 time with a substituent selected independently at each occurrence thereof from the group consisting of halogen and C1-6 alkyl;
• R2 is selected from the group consisting of C1-6 alkyl, —CH2OC1-6 alkyl, and —CH2Ar, wherein aryl (Ar) can be optionally substituted 1 time with halogen;
• R3 is independently selected at each occurrence thereof from the group consisting of —CH2OC1-6 alkyl and —(CH2)mC(O)NHR5;
• R4 is selected from the group consisting of —C(O)(CH2)nPh, —SO2Ar, —SO2C1-6 alkyl, —C(O)(CH2)nHet, and —C(O)C(O)Het, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted 1 time with C1-6 alkyl;
• R5 is selected from the group consisting of C1-4 alkyl and —CR8R9;
• R8 and R9 are taken together with the carbon to which the are attached to form an oxetane ring;
• X is —(CH2)q—,
• Y is O;
• m is 1 or 2,
• n is 0 or 2;
• q is 1;
• and
• s is 1.

A method of treating cancer, immunologic disorders, autoimmune disorders, neurodegenerative disorders, or inflammatory disorders in a subject or for providing immunosuppression for transplanted organs or tissues in a subject, said method comprising

• administering to the subject in need thereof a compound of the Formula (I):
• wherein
• R1 is bicyclic aryl optionally substituted 1 time with a substituent selected independently at each occurrence thereof from the group consisting of halogen and C1-6 alkyl;
• R2 is selected from the group consisting of C1-6 alkyl, —CH2OC1-6 alkyl, and —CH2Ar, wherein aryl (Ar) can be optionally substituted 1 time with halogen;
• R3 is independently selected at each occurrence thereof from the group consisting of —CH2OC1-6 alkyl and —(CH2)mC(O)NHR5;
• R4 is selected from the group consisting of —C(O)(CH2)nPh, —SO2Ar, —SO2C1-6 alkyl, —C(O)(CH2)nHet, and —C(O)C(O)Het, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted 1 time with C1-6 alkyl;
• R5 is selected from the group consisting of C1-4 alkyl and —CR8R9;
• R8 and R9 are taken together with the carbon to which they are attached to form an oxetane ring;
• X is —(CH2)q—;
• Y is O;
• m is 1 or 2;
• n is 0 or 2;
• q is 1;
• and
• s is 1.