Compounds for the treatment of neurodegenerative and metabolic disorders

A method for one or more selected from

• (i) inhibiting NAD consumption and/or increasing NAD synthesis in a patient,
• (ii) preventing or inhibiting NAD depletion in a patient,
• (iii) improving a condition linked to alterations of NAD metabolism in a patient, wherein the condition is a synucleinopathy or amyotrophic lateral sclerosis,
• (iv) providing protection from toxicity of misfolded proteins in a patient, or
• (v) treating a protein misfolding neurodegenerative disease in a patient, wherein the protein misfolding neurodegenerative disease is a synucleinopathy or amyotrophic lateral sclerosis,
• the method comprising administering to the patient an effective dose of a triazolophthalazine compound of Formula (I)
• or a pharmaceutically acceptable salt thereof,
• wherein in Formula (I):
• each R1 and R2 are independently hydrogen (C1-C4)alkyl, or (C1-C4)alkoxy;
• and
• each R3 is independently selected hydrogen, (C1-C4)alkyl optionally substituted with OH, (C1-C4)alkoxy, or heteroaryl, and provided that both R3 are not hydrogen;
• or, both R3 together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocyclyl ring comprising at least an additional heteroatom selected from O, S, S—O, S(═O)—O, or NR, wherein R is (C1-C4)alkyl optionally substituted with —OH or (C1-C4)alkoxyl,
• or,
• an effective dose of a pyrazolopyrimidine compound of Formula (II)
• or a pharmaceutically acceptable salt thereof,
• wherein in Formula (II):
• each Ra1 and Ra2 is independently hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxyl, (C1-C4)haloalkoxyl, 2 to 4 membered heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• each Rb1, Rb2, and Rb3 is independently hydrogen, halo, (C1-C4)alkyl,—S(O)2Rd,—S(O)2ORd, or (C1-C4)haloalkyl;
• or Rb2 and Rb3 are joined together to form an aryl or heteroaryl;
• each Rc and Rd is independently hydrogen or (C1-C4)alkyl;
• Ar is mono- or bi-cyclic aryl or heteroaryl, optionally substituted with one or more halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxyl, (C1-C4)haloalkoxyl, or heteroaryl;
• and
• n=2, 3, 4, or 5,
• or,
• an effective dose of a compound of Formula (III)
• or a pharmaceutically acceptable salt thereof,
• wherein in Formula (III):
• L1 is a bond, C1-C4 alkylene, or 2 to 4-membered heteroalkylene;
• R1 is mono- or bi-cyclic cycloalkyl, heterocycloalkyl, aryl, alkylaryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, alkylaryl or heteroaryl is optionally substituted with one or more selected from halo, (C1-C4)alkyl, hydroxy (C1-C4)alkyl, (C1-C4)alkoxyl,—C(═O) (C1-C4)alkyl,—C(═O)N(R)2, or —C(═NR) (C1-C4)alkyl, wherein the (C1-C4)alkyl is unsubstituted or substituted with heterocycloalkyl;
• each R is independently H,—OH, (C1-C4)alkyl, or (C1-C4)alkoxyl, or two R together with the nitrogen atom to which it is bonded form a heterocycloalkyl, optionally further comprising an O atom in the heterocyclyl ring;
• R2 occurs 0, 1, or 2 times, and is (C1-C4)alkyl, (C1-C4)haloalkyl, or SO2N(R4)2;
• and
• each R3 and R4 is independently H, or (C1-C4)alkyl,
• or,
• an effective dose of a compound of Formula (IV)
• or a pharmaceutically acceptable salt thereof;
• wherein in Formula (IV):
• R1 is hydrogen, (C1-C4)alkyl,—C(O) OH,—C(O)O—(C1-C4)alkyl,—C(O) NHNHR6,—C(O) NR6—((C1-C4)alkylene)-NHR6,—C(O) NR6 (C1-C4)alkyl, or —C(O) NR6-cycloalkylene-NHR6;
• R3 is hydrogen or (C1-C4)alkyl;
• each R2, R4, R5 is independently hydrogen, halo, (C1-C4)alkyl,—C(O)O—(C1-C4)alkyl, (C1-C4)alkoxyl, (C1-C4)haloalkyl, or CN;
• and
• each R6 is hydrogen or (C1-C4)alkyl;
• or,
• an effective dose of a compound of Formula (V)
• or a pharmaceutically acceptable salt thereof,
• wherein in Formula (V):
• Ar is mono- or bi-cyclic aryl or heteroaryl, optionally substituted one or more with halo, (C1-C4)alkyl, (C1-C4)haloalkyl, CN,—S(O)2NH2, oxo,—NH2, (C1-C4)alkoxyl, or —NHC(O) (C1-C4)alkyl;
• each R1 and R2 is independently hydrogen, (C1-C4)alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with halo or (C1-C4)alkyl, or R1 and R2 attached to nitrogen join together to form a 5 to 6 membered heterocycloalkyl;
• and
• R3 is hydrogen, or hydroxy-(C1-C4)alkyl,
• or,
• an effective dose of a compound of formula (VI)
• wherein in formula (VI), the indicated dashed double bond is optionally present, each R is independently selected from H, OH, or (C1-C4)alkoxyl, or O-glycosyl, provided that at least two R groups are non-hydrogen,
• or,
• an effective dose of a compound of formulas (VII)—(XV), or demethylated derivatives (phenolic analogs) thereof, or methyl ethers thereof, in the case of phenols or other alcohols:
• wherein in formula (VII), X is a pharmaceutically acceptable salt;
• wherein in formula (VIII), X is a pharmaceutically acceptable salt;
• and including all pharmaceutically acceptable salt forms,
• and including all pharmaceutically acceptable salt forms,
• wherein in formula (XI), X is a pharmaceutically acceptable salt;
• and including all pharmaceutically acceptable salt forms,
• and including all pharmaceutically acceptable salt forms,
• and including all pharmaceutically acceptable salt forms,
• or,
• an effective dose of a compound of formula (XVI)
• and including all pharmaceutically acceptable salt forms.