Patent ID: 9645139
Date: 2017-05-09
CPC Classifications: A61K,C12Q,G01N

Claim:
1. A method for identifying a compound having cell-protective activity, comprising: incubating a test compound with a nicotinamide phosphoribosyltransferase (NAMPT); measuring an activity of the NAMPT; and identifying the test compound as having cell-protective activity when there is an increase in the activity of the NAMPT compared to a control that is not incubated with the test compound, wherein the test compound is a compound having formula (I): wherein: each of R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), nitro, —C(O)O(C 1 -C 6 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 alkyl), and —S(O) 2 N(C 1 -C 6 alkyl) 2 ; R and R′ are defined according to (1), (2), (3) or (4) below: (1) R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II): wherein each of R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), nitro, —C(O)O(C 1 -C 6 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6 alkyl), and —S(O) 2 N(C 1 -C 6 alkyl) 2 ; or (2) R and R′ together with C2 and C3, respectively, form a fused heteroaryl ring containing 6 ring atoms, wherein from 1-2 independently selected ring atoms is N; and wherein said heteroaryl ring is optionally substituted with from 1-2 independently selected R b ; or (3) R and R′ together with C 2 and C 3 , respectively, form a fused heterocyclic ring containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and wherein said heterocyclic ring is optionally substituted with from 1-3 independently selected R a ; or (4) each of R and R′ is, independently, hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each of L 1 and L 2 is, independently, C 1 -C 3 alkylene, which is optionally substituted with from 1-2 independently selected R c ; A is: (i) CR (ii) C⊚O; or (iii) C (iv) heterocycloalkylene containing from 3-5 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(C Z is: (i) —NR (ii) —C(O)NR (iii) —OR (iv) —S(O) (v) heterocycloalkenyl containing from 5-6 ring atoms, wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C (vi) C (vii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C (viii) C (ix) arylheterocyclyl containing from 8-14 ring atoms, wherein: (x) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein: (xi) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein: each of R 10 and R 11 is independently selected from the substituents delineated collectively in (a) through (1) below: (a) hydrogen; (b) C (c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C (d) C (e) —C(O) (C (f) C (g) C (h) arylheterocyclyl containing from 8-14 ring atoms, wherein: (i) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein: (j) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein: (k) C (l) C provided that one of R R 12 is: (i) C6-C10 aryl that is optionally substituted with from 1-4 R (ii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C (iii) C (iv) C (v) arylheterocyclyl containing from 8-14 ring atoms, wherein: (vi) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein: or (vii) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein: R 13 is: (i) C (ii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C (iii) C or (iv) arylheterocyclyl containing from 8-14 ring atoms, wherein: or (v) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein: or (vi) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein: R a at each occurrence is, independently selected from halo, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, oxo, thioxo, ═NH, ═N(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and cyano; R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below: (aa) C (bb) halo; hydroxyl; cyano; nitro; —NH (cc) C (dd) phenyl or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C R c at each occurrence is, independently selected from halo, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and cyano; R d at each occurrence is, independently selected from hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and cyano; and R e at each occurrence is, independently selected from hydroxyl, C 1 -C 6 alkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thiohaloalkoxy; —NH 2 ; —NH(C 1 -C 6 alkyl); —N(C 1 -C 6 alkyl) 2 ; —NHC(O)(C 1 -C 6 alkyl); cyano; —C(O)H; —C(O)(C 1 -C 6 alkyl); —C(O)(C 1 -C 6 haloalkyl); —C(O)OH; —C(O)O(C 1 -C 6 alkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); —C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); —SO 2 N(C 1 -C 6 alkyl) 2 ; and L 3 -(C 1 -C 6 alkylene)-biotin, where in L 3 is a —O—, —NH—, —NCH 3 —, —C(O)—, —C(O)NH—, —C(O)NCH 3 —, —NHC(O)—, or —NCH 3 C(O)—.