Compounds for the treatment of neurodegenerative and metabolic disorders

1 . 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 R 1 and R 2 are independently hydrogen (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkoxy; and

each R 3 is independently selected hydrogen, (C 1 -C 4 )alkyl optionally substituted with OH, (C 1 -C 4 )alkoxy, or heteroaryl, and provided that both R 3 are not hydrogen; or, both R 3 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 (C 1 -C 4 )alkyl optionally substituted with —OH or (C 1 -C 4 )alkoxyl,

or,

an effective dose of a pyrazolopyrimidine compound of Formula (II)

or a pharmaceutically acceptable salt thereof,

wherein in Formula (II):

each R a1 and R a2 is independently hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxyl, (C 1 -C 4 )haloalkoxyl, 2 to 4 membered heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R b1 , R b2 , and R b3 is independently hydrogen, halo, (C 1 -C 4 )alkyl,—S(O) 2 R d ,—S(O) 2 OR d , or (C 1 -C 4 )haloalkyl; or R b2 and R b3 are joined together to form an aryl or heteroaryl;

each R c and R d is independently hydrogen or (C 1 -C 4 )alkyl;

Ar is mono- or bi-cyclic aryl or heteroaryl, optionally substituted with one or more halo, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxyl, (C 1 -C 4 )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):

L 1 is a bond, C 1 -C 4 alkylene, or 2 to 4-membered heteroalkylene;

R 1 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, (C 1 -C 4 )alkyl, hydroxy (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxyl,—C(═O) (C 1 -C 4 )alkyl,—C(═O)N(R) 2 , or —C(═NR) (C 1 -C 4 )alkyl, wherein the (C 1 -C 4 )alkyl is unsubstituted or substituted with heterocycloalkyl;

each R is independently H,—OH, (C 1 -C 4 )alkyl, or (C 1 -C 4 )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;

R 2 occurs 0, 1, or 2 times, and is (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, or SO 2 N(R 4 ) 2 ; and

each R 3 and R 4 is independently H, or (C 1 -C 4 )alkyl,

or,

an effective dose of a compound of Formula (IV)

or a pharmaceutically acceptable salt thereof;

wherein in Formula (IV):

R 1 is hydrogen, (C 1 -C 4 )alkyl,—C(O) OH,—C(O)O—(C 1 -C 4 )alkyl,—C(O) NHNHR 6 ,—C(O) NR 6 —((C 1 -C 4 )alkylene)-NHR 6 ,—C(O) NR 6 (C 1 -C 4 )alkyl, or —C(O) NR 6 -cycloalkylene-NHR 6 ;

R 3 is hydrogen or (C 1 -C 4 )alkyl;

each R 2 , R 4 , R 5 is independently hydrogen, halo, (C 1 -C 4 )alkyl,—C(O)O—(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxyl, (C 1 -C 4 )haloalkyl, or CN; and

each R 6 is hydrogen or (C 1 -C 4 )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, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, CN,—S(O) 2 NH 2 , oxo,—NH 2 , (C 1 -C 4 )alkoxyl, or —NHC(O) (C 1 -C 4 )alkyl;

each R 1 and R 2 is independently hydrogen, (C 1 -C 4 )alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with halo or (C 1 -C 4 )alkyl, or R 1 and R 2 attached to nitrogen join together to form a 5 to 6 membered heterocycloalkyl; and

R 3 is hydrogen, or hydroxy-(C 1 -C 4 )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.

2 . The method of claim 1 , wherein compounds of Formula (I) to (XVI) inhibit protein ADP-ribosylation reactions, inhibit NAD cleavage by protein deacetylases or glycohydrolases, or increase NAD synthesis.

3 . The method of claim 1 wherein the patient is afflicted with a metabolic disorder, aging, a degenerative disease, a neurodegenerative disease, neuronal degeneration associated with multiple sclerosis, hearing loss, retinal damage or multiple sclerosis, brain or cardiac ischemia, kidney failure, kidney disease, traumatic brain injury, or an axonopathy.

4 . The method of claim 1 , wherein the patient is afflicted with a prion disease, Parkinson's disease or other synucleinopathy, Alzheimer's disease, amyotrophic lateral sclerosis, a tauopathy or diabetes mellitus.

5 . The method of claim 1 , wherein the compound of Formula (I) is any one of these structures, including their pharmaceutically acceptable salt forms:

or, the compound of Formula (II) is any one these structures, including their pharmaceutically acceptable salt forms:

or, the compound of Formula (III) is any one of these structures, including their pharmaceutically acceptable salt forms:

or, the compound of Formula (IV) is any one of these structures, including their pharmaceutically acceptable salt forms:

or, the compound of Formula (V) is any one of:

or, the compound of formula (VI) is any one of:

or, the compound of formulas (VII)—(XVI) is any one of these structures, including their pharmaceutically acceptable salt forms: