CN104684906A

CN104684906A - NAMPT inhibitors

Info

Publication number: CN104684906A
Application number: CN201380036899.6A
Authority: CN
Inventors: M.L.柯丁; K.隆格内克; T.M.汉森; R.F.克拉克; B.索伦森; H.R.海曼; 嵇志琴
Original assignee: AbbVie Inc
Current assignee: AbbVie Inc
Priority date: 2012-05-11
Filing date: 2013-05-10
Publication date: 2015-06-03
Anticipated expiration: 2033-05-10
Also published as: CA2873075A1; MX2014013752A; JP2015516436A; WO2013170113A1; CN104684906B; EP2852585A1

Abstract

Disclosed are compounds which inhibit the activity of NAMPT, compositions containing the compounds and methods of treating diseases during which NAMPT is expressed.

Description

NAMPT inhibitor

This application claims the right of priority of the U.S.Provisional Serial No. 61/779702 of U.S.Provisional Serial No. 61/719008 that the U.S.Provisional Serial No. that submits on May 11st, 2012 on October 26th, 61/645685,2012 submits and submission on March 13rd, 2013, they are incorporated herein by reference by entirety.

Invention field

The method of the disease of NAMPT is expressed in the compound that the present invention relates to the activity of suppression NAMPT, the composition comprising these compounds and treatment during disease.

Background of invention

NAD+ (Reduced nicotinamide-adenine dinucleotide) is the coenzyme (Ziegkel, the M. that play a crucial role in necessary process on a lot of physiology eur. J. Biochem. 267,1550-1564,2000).NAD is required for some intracellular signaling paths; poly-ADP-ribosylation in repairing comprising DNA, the list-ADP-ribosylation in the intracellular signaling of immunity system and G-protein coupling; and its deacetylase activity of deacetylase also needs the NAD (people such as Garten, A. trends in Endocrinology and Metabolism, 20,130-138,2008).

The enzyme of the Phosphoribosyl (phosphoribosylation) that NAMPT (also referred to as PBEF (PBEF) and Visfatin) is catalysis niacinamide and be the rate-limiting enzyme in one of two salvage pathwaies of NAD.

Increasing evidence shows that NAMPT inhibitor has the potential as carcinostatic agent.The basis that cancer cells has higher NAD upgrades (turnover), and also shows higher energy requirement compared with normal cell.In addition, the NAMPT reporting increase in colorectal carcinoma expresses (Van Beijnum, the people such as J.R. int. J. Cancer, and NAMPT participates in the vasculogenesis (people such as Kim, S.R. 101,118-127,2002) biochem. Biophys. Res. Commun. 357,150-156,2007).The micromolecular inhibitor of NAMPT has demonstrated and to have caused in cell NAD+ level to reduce and the final inducing death of neoplastic cells (people such as Hansen, CM anticancer Res. 20,42111-4220,2000) and suppress (the people such as Olese, U.H. of tumor growth in heteroplastic transplantation model mol Cancer Ther.9,1609-1617,2010).

NAMPT inhibitor also has the potential (people such as Galli, M. of the therapeutical agent as inflammation and metabolic disturbance cancer Res.70,8-11,2010).Such as, NAMPT is the leading enzyme in T and bone-marrow-derived lymphocyte.The Selective depression of NAMPT causes the NAD+ loss in lymphocyte, thus blocks the expansion with autoimmune disease progress, and the cell type of expressing other NAD+ generation passes may no longer need.Small molecules NAMPT inhibitor (FK866) has demonstrated selective exclusion propagation and the apoptosis of induced activation T cell, and in the animal model of sacroiliitis (Collagen-Induced Arthritis) effective (people such as Busso, N. plos One3, e2267,2008).FK866 improves the performance (people such as Bruzzone, S of experimental autoimmune encephalomyelitis (EAE) (model of autoimmune disorders of T cell mediation) plos One4, e7897,2009).NaMPT activity improves the NF-kB transcriptional activity in human vascular endothelial, causes MMP-2 and MMP-9 to activate, and demonstrates effect in the complication of obesity that NAMPT inhibitor mediates in preventing inflammation and the diabetes B (people such as Adya, R. diabetes Care, 31,758-760,2008).

Summary of the invention

Therefore one embodiment of the invention relate to compound or its pharmacy acceptable salt, and it can be used as the inhibitor of NAMPT, and this compound has formula (IA)

Formula (IA);

Wherein

X ¹for N and X ²for CR ¹; Or

X ¹for CR ¹and X ²for N; Or

X ¹for CR ¹and X ²for CR ¹;

Y ¹for

Wherein represent the tie point with carbonyl, represent the tie point with nitrogen-containing hetero aryl;

R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, OH, NH ₂, CN, NO ₂, F, Cl, Br and I;

R ²independently selected from C ₄-C ₆-alkyl, C ₄-C ₆-thiazolinyl, C ₄-C ₆-alkynyl, aryl, 3-12 unit heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ²in C ₄-C ₆-alkyl, C ₄-C ₆-thiazolinyl and C ₄-C ₆-alkynyl is replaced independently selected from following substituting group by one or more separately: R ³, OR ³, SR ³, S (O) R ³, SO ₂r ³, C (O) R ³, CO (O) R ³, OC (O) R ³, OC (O) OR ³, NH ₂, NHR ³, N (R ³) ₂, NHC (O) R ³, NR ³c (O) R ³, NHS (O) ₂r ³, NR ³s (O) ₂r ³, NHC (O) OR ³, NR ³c (O) OR ³, NHC (O) NH ₂, NHC (O) NHR ³, NHC (O) N (R ³) ₂, NR ³c (O) NHR ³, NR ³c (O) N (R ³) ₂, C (O) NH ₂, C (O) NHR ³, C (O) N (R ³) ₂, C (O) NHOH, C (O) NHOR ³, C (O) NHSO ₂r ³, C (O) NR ³sO ₂r ³, SO ₂nH ₂, SO ₂nHR ³, SO ₂n (R ³) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ³, C (N) N (R ³) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ²in aryl, 3-12 unit heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, SR ⁴, S (O) R ⁴, SO ₂r ⁴, C (O) R ⁴, CO (O) R ⁴, OC (O) R ⁴, OC (O) OR ⁴, NH ₂, NHR ⁴, N (R ⁴) ₂, NHC (O) R ⁴, NR ⁴c (O) R ⁴, NHS (O) ₂r ⁴, NR ⁴s (O) ₂r ⁴, NHC (O) OR ⁴, NR ⁴c (O) OR ⁴, NHC (O) NH ₂, NHC (O) NHR ⁴, NHC (O) N (R ⁴) ₂, NR ⁴c (O) NHR ⁴, NR ⁴c (O) N (R ⁴) ₂, C (O) NH ₂, C (O) NHR ⁴, C (O) N (R ⁴) ₂, C (O) NHOH, C (O) NHOR ⁴, C (O) NHSO ₂r ⁴, C (O) NR ⁴sO ₂r ⁴, SO ₂nH ₂, SO ₂nHR ⁴, SO ₂n (R ⁴) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁴, C (N) N (R ⁴) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I;

R ³, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group and heterocyclic radical; Wherein R ³in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁵, OR ⁵, SR ⁵, S (O) R ⁵, SO ₂r ⁵, C (O) R ⁵, CO (O) R ⁵, OC (O) R ⁵, OC (O) OR ⁵, NH ₂, NHR ⁵, N (R ⁵) ₂, NHC (O) R ⁵, NR ⁵c (O) R ⁵, NHS (O) ₂r ⁵, NR ⁵s (O) ₂r ⁵, NHC (O) OR ⁵, NR ⁵c (O) OR ⁵, NHC (O) NH ₂, NHC (O) NHR ⁵, NHC (O) N (R ⁵) ₂, NR ⁵c (O) NHR ⁵, NR ⁵c (O) N (R ⁵) ₂, C (O) NH ₂, C (O) NHR ⁵, C (O) N (R ⁵) ₂, C (O) NHOH, C (O) NHOR ⁵, C (O) NHSO ₂r ⁵, C (O) NR ⁵sO ₂r ⁵, SO ₂nH ₂, SO ₂nHR ⁵, SO ₂n (R ⁵) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁵, C (N) N (R ⁵) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ³in aryl, cycloalkyl, cycloalkenyl group and heterocyclic radical optionally replaced independently selected from following substituting group by one or more separately: R ⁶, OR ⁶, SR ⁶, S (O) R ⁶, SO ₂r ⁶, C (O) R ⁶, CO (O) R ⁶, OC (O) R ⁶, OC (O) OR ⁶, NH ₂, NHR ⁶, N (R ⁶) ₂, NHC (O) R ⁶, NR ⁶c (O) R ⁶, NHS (O) ₂r ⁶, NR ⁶s (O) ₂r ⁶, NHC (O) OR ⁶, NR ⁶c (O) OR ⁶, NHC (O) NH ₂, NHC (O) NHR ⁶, NHC (O) N (R ⁶) ₂, NR ⁶c (O) NHR ⁶, NR ⁶c (O) N (R ⁶) ₂, C (O) NH ₂, C (O) NHR ⁶, C (O) N (R ⁶) ₂, C (O) NHOH, C (O) NHOR ⁶, C (O) NHSO ₂r ⁶, C (O) NR ⁶sO ₂r ⁶, SO ₂nH ₂, SO ₂nHR ⁶, SO ₂n (R ⁶) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁶, C (N) N (R ⁶) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I;

R ⁴, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ⁴in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁷, OR ⁷, SR ⁷, S (O) R ⁷, SO ₂r ⁷, C (O) R ⁷, CO (O) R ⁷, OC (O) R ⁷, OC (O) OR ⁷, NH ₂, NHR ⁷, N (R ⁷) ₂, NHC (O) R ⁷, NR ⁷c (O) R ⁷, NHS (O) ₂r ⁷, NR ⁷s (O) ₂r ⁷, NHC (O) OR ⁷, NR ⁷c (O) OR ⁷, NHC (O) NH ₂, NHC (O) NHR ⁷, NHC (O) N (R ⁷) ₂, NR ⁷c (O) NHR ⁷, NR ⁷c (O) N (R ⁷) ₂, C (O) NH ₂, C (O) NHR ⁷, C (O) N (R ⁷) ₂, C (O) NHOH, C (O) NHOR ⁷, C (O) NHSO ₂r ⁷, C (O) NR ⁷sO ₂r ⁷, SO ₂nH ₂, SO ₂nHR ⁷, SO ₂n (R ⁷) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁷, C (N) N (R ⁷) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I;

R ⁵, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ⁵in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁸, OR ⁸, SR ⁸, S (O) R ⁸, SO ₂r ⁸, NHR ⁸, N (R ⁸) ₂, C (O) R ⁸, C (O) NH ₂, C (O) NHR ⁸, C (O) N (R ⁸) ₂, NHC (O) R ⁸, NR ⁸c (O) R ⁸, NHSO ₂r ⁸, NHC (O) OR ⁸, SO ₂nH ₂, SO ₂nHR ⁸, SO ₂n (R ⁸) ₂, NHC (O) NH ₂, NHC (O) NHR ⁸, OH, (O), C (O) OH, N ₃, CN, NH ₂, F, Cl, Br and I;

R ⁶, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ⁶in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁹, OR ⁹, SR ⁹, S (O) R ⁹, SO ₂r ⁹, NHR ⁹, N (R ⁹) ₂, C (O) R ⁹, C (O) NH ₂, C (O) NHR ⁹, C (O) N (R ⁹) ₂, NHC (O) R ⁹, NR ⁹c (O) R ⁹, NHSO ₂r ⁹, NHC (O) OR ⁹, SO ₂nH ₂, SO ₂nHR ⁹, SO ₂n (R ⁹) ₂, NHC (O) NH ₂, NHC (O) NHR ⁹, OH, (O), C (O) OH, N ₃, CN, NH ₂, CF ₃, CF ₂cF ₃, F, Cl, Br and I;

R ⁷, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group;

R ⁸, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group;

R ⁹, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group;

Wherein by R ⁴, R ⁵, R ⁶, R ⁷, R ⁸and R ⁹the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, OR ¹⁰, SR ¹⁰, S (O) R ¹⁰, C (O) C (O) R ¹⁰, SO ₂r ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, OC (O) R ¹⁰, OC (O) OR ¹⁰, NH ₂, NHR ¹⁰, N (R ¹⁰) ₂, NHC (O) R ¹⁰, NR ¹⁰c (O) R ¹⁰, NHS (O) ₂r ¹⁰, NR ¹⁰s (O) ₂r ¹⁰, NHC (O) OR ¹⁰, NR ¹⁰c (O) OR ¹⁰, NHC (O) NH ₂, NHC (O) NHR ¹⁰, NHC (O) N (R ¹⁰) ₂, NR ¹⁰c (O) NHR ¹⁰, NR ¹⁰c (O) N (R ¹⁰) ₂, C (O) NH ₂, C (O) NHR ¹⁰, C (O) N (R ¹⁰) ₂, C (O) NHOH, C (O) NHOR ¹⁰, C (O) NHSO ₂r ¹⁰, C (O) NR ¹⁰sO ₂r ¹⁰, SO ₂nH ₂, SO ₂nHR ¹⁰, SO ₂n (R ¹⁰) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹⁰, C (N) N (R ¹⁰) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I;

R ¹⁰, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹⁰in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, S (O) R ¹¹, SO ₂r ¹¹, C (O) R ¹¹, CO (O) R ¹¹, OC (O) R ¹¹, OC (O) OR ¹¹, NH ₂, NHR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, NR ¹¹c (O) R ¹¹, NHS (O) ₂r ¹¹, NR ¹¹s (O) ₂r ¹¹, NHC (O) OR ¹¹, NR ¹¹c (O) OR ¹¹, NHC (O) NH ₂, NHC (O) NHR ¹¹, NHC (O) N (R ¹¹) ₂, NR ¹¹c (O) NHR ¹¹, NR ¹¹c (O) N (R ¹¹) ₂, C (O) NH ₂, C (O) NHR ¹¹, C (O) N (R ¹¹) ₂, C (O) NHOH, C (O) NHOR ¹¹, C (O) NHSO ₂r ¹¹, C (O) NR ¹¹sO ₂r ¹¹, SO ₂nH ₂, SO ₂nHR ¹¹, SO ₂n (R ¹¹) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹¹, C (N) N (R ¹¹) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ¹⁰in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced independently selected from following substituting group by one or more separately: R ¹², OR ¹², SR ¹², S (O) R ¹², SO ₂r ¹², C (O) R ¹², CO (O) R ¹², OC (O) R ¹², OC (O) OR ¹², NH ₂, NHR ¹², N (R ¹²) ₂, NHC (O) R ¹², NR ¹²c (O) R ¹², NHS (O) ₂r ¹², NR ¹²s (O) ₂r ¹², NHC (O) OR ¹², NR ¹²c (O) OR ¹², NHC (O) NH ₂, NHC (O) NHR ¹², NHC (O) N (R ¹²) ₂, NR ¹²c (O) NHR ¹², NR ¹²c (O) N (R ¹²) ₂, C (O) NH ₂, C (O) NHR ¹², C (O) N (R ¹²) ₂, C (O) NHOH, C (O) NHOR ¹², C (O) NHSO ₂r ¹², C (O) NR ¹²sO ₂r ¹², SO ₂nH ₂, SO ₂nHR ¹², SO ₂n (R ¹²) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹², C (N) N (R ¹²) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I;

R ¹¹, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹¹in alkyl, thiazolinyl and alkynyl optionally replaced by alkyl or alkoxyl group separately; Wherein R ¹¹in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced by alkyl or alkoxyl group separately; With

R ¹², when occurring at every turn, be the independent alkyl selected.

In an embodiment of formula (IA), X ¹for CR ¹and X ²for CR ¹.In another embodiment of formula (IA), R ¹, be hydrogen when occurring at every turn.In another embodiment of formula (IA), X ¹for CR ¹, X ²for CR ¹, and R ¹be hydrogen when occurring at every turn.In another embodiment of formula (IA), Y ¹for wherein represent the tie point with carbonyl, represent the tie point with nitrogen-containing hetero aryl.In another embodiment of formula (IA), Y ¹for wherein represent the tie point with carbonyl, represent the tie point with nitrogen-containing hetero aryl; And R ²for phenyl; Wherein R ²in phenyl separately by an OR ⁴replace.In another embodiment of formula (IA), Y ¹for wherein represent the tie point with carbonyl, represent the tie point with nitrogen-containing hetero aryl; And R ²for phenyl; Wherein R ²in phenyl separately by a R ⁴replace.In another embodiment of formula (IA), Y ¹for wherein represent the tie point with carbonyl, represent the tie point with nitrogen-containing hetero aryl; R ²for phenyl; Wherein R ²in phenyl separately by an OR ⁴replace, and R ⁴it is heterocyclic radical when occurring at every turn.In another embodiment of formula (IA), Y ¹for wherein represent the tie point with carbonyl, represent the tie point with nitrogen-containing hetero aryl; R ²for phenyl; Wherein R ²in phenyl separately by a R ⁴replace, and R ⁴it is heterocyclic radical when occurring at every turn.

Another embodiment relates to compound, and it is

N-[4-({ 1-[(2S)-2-methylbutyryl base] azetidine-3-base } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [1-(tetrahydrochysene-2H-pyrans-4-base ethanoyl) piperidin-4-yl] oxygen base } phenyl) azetidine-1-methane amide;

3-(5-fluorine pyridin-3-yl)-N-(4-{ [1-(tetrahydrochysene-2H-pyrans-4-base ethanoyl) piperidin-4-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-[4-({ 1-[(2S)-2-methylbutyryl base] piperidin-4-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-[4-({ 1-[(2R)-tetrahydrofuran (THF)-2-base carbonyl] piperidin-4-yl } oxygen base) phenyl] azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [1-(3,3,3-trifluoropropyl acyl group) piperidin-4-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-(4-{ [1-(2-hydroxy-2-methyl propionyl) piperidin-4-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(6-picoline-3-base)-N-(4-{ [1-(tetrahydrochysene-2H-pyrans-4-base ethanoyl) piperidin-4-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-(4-{1-[(2S)-2-methylbutyryl base]-1,2,3,6-tetrahydropyridine-4-bases } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran (THF)-2-base carbonyl]-1,2,3,6-tetrahydropyridine-4-bases } phenyl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran (THF)-2-base carbonyl]-1,2,3,6-tetrahydropyridine-4-bases } phenyl) azetidine-1-methane amide;

N-{4-[1-(2-hydroxy-2-methyl propionyl)-1,2,3,6-tetrahydropyridine-4-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) methyl benzoate;

N-(4-cyano-phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

4-[4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) butyl] piperidines-1-t-butyl formate;

N-{4-[1-(2,2-dimethylbutanoyl)-1,2,3,6-tetrahydropyridine-4-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3,3-dimethylbutanoyl)-1,2,3,6-tetrahydropyridine-4-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropyl acyl group)-1,2,3,6-tetrahydropyridine-4-base] phenyl } azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluoro butyryl radicals)-1,2,3,6-tetrahydropyridine-4-base] phenyl } azetidine-1-methane amide;

N-{4-[1-(Methoxyacetyl)-1,2,3,6-tetrahydropyridine-4-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(methylsulfanyl) ethanoyl]-1,2,3,6-tetrahydropyridine-4-base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(Ethoxyacetyl base)-1,2,3,6-tetrahydropyridine-4-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(2-methoxy ethoxy) ethanoyl]-1,2,3,6-tetrahydropyridine-4-bases } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[3-(methylsulfanyl) propionyl]-1,2,3,6-tetrahydropyridine-4-base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(cyclopropyl carbonyl)-1,2,3,6-tetrahydropyridine-4-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(Cyclopropyl-acetyl)-1,2,3,6-tetrahydropyridine-4-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2-methylpropionyl)-1,2,3,6-tetrahydropyridine-4-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-[4-({ 1-[(2R)-tetrahydrofuran (THF)-2-base carbonyl] azetidine-3-base } oxygen base) phenyl] azetidine-1-methane amide;

3-(pyridin-3-yl)-N-[4-({ 1-[(2S)-tetrahydrofuran (THF)-2-base carbonyl] azetidine-3-base } oxygen base) phenyl] azetidine-1-methane amide;

N-(4-{ [1-(2-hydroxy-2-methyl propionyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-[4-({ 1-[(2S)-tetrahydrofuran (THF)-2-base carbonyl] piperidin-4-yl } oxygen base) phenyl] azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [1-(thiophene-2-base carbonyl) piperidin-4-yl] oxygen base } phenyl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [1-(thiene-3-yl-carbonyl) piperidin-4-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-[4-({ 1-[(1-Acetylpiperidin-4-base) carbonyl] piperidin-4-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ 1-[(2-methylcyclopropyl groups) carbonyl] piperidin-4-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ 1-[(1-methyl isophthalic acid H-pyrroles-2-base) carbonyl] piperidin-4-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ 1-[3-(morpholine-4-base) propionyl] piperidin-4-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ 1-[3-(4-methylpiperazine-1-yl) propionyl] piperidin-4-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-[4-({ 1-[3-(pyrrolidin-1-yl) propionyl] piperidin-4-yl } oxygen base) phenyl] azetidine-1-methane amide;

N-(4-{ [1-(Cyclopropyl-acetyl) piperidin-4-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(3-methylvaleryl) piperidin-4-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(4-methylvaleryl) piperidin-4-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[(1-butyryl radicals piperidin-4-yl) oxygen base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(2,2-Dimethylpropanoyl) piperidin-4-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(3,3-dimethylbutanoyl) piperidin-4-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(Ethoxyacetyl base) piperidin-4-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(cyclopropyl carbonyl) piperidin-4-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(Methoxyacetyl) piperidin-4-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[(tetrahydrofuran (THF)-3-ylmethyl) formamyl] phenyl } azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(tetrahydrochysene-2H-pyrans-4-base ethanoyl) piperidin-4-yl] phenyl } azetidine-1-methane amide;

N-{4-[1-(2-hydroxy-2-methyl propionyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran (THF)-2-base carbonyl] piperidin-4-yl } phenyl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran (THF)-3-base carbonyl) piperidin-4-yl] phenyl } azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran (THF)-2-base carbonyl] piperidin-4-yl } phenyl) azetidine-1-methane amide;

N-{4-[1-(Cyclopropyl-acetyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2-methylpropionyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-benzoyl piperidine-4-base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropyl acyl group) piperidin-4-yl] phenyl } azetidine-1-methane amide;

3-[4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) phenyl] tetramethyleneimine-1-t-butyl formate;

(3R)-3-[4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) phenoxy group] tetramethyleneimine-1-t-butyl formate;

(3S)-3-[4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) phenoxy group] tetramethyleneimine-1-t-butyl formate;

3-[4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) phenyl] azetidine-1-t-butyl formate;

3-[4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) phenoxy group] azetidine-1-t-butyl formate;

3-(pyridin-3-yl)-N-{4-[1-(tetrahydrochysene-2H-pyrans-4-base ethanoyl) pyrrolidin-3-yl] phenyl } azetidine-1-methane amide;

N-{4-[1-(2-methylpropionyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran (THF)-2-base carbonyl] pyrrolidin-3-yl } phenyl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran (THF)-2-base carbonyl] pyrrolidin-3-yl } phenyl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran (THF)-3-base carbonyl) pyrrolidin-3-yl] phenyl } azetidine-1-methane amide;

N-{4-[1-(Cyclopropyl-acetyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2-hydroxy-2-methyl propionyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-benzoyl pyrrole compound alkane-3-base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropyl acyl group) pyrrolidin-3-yl] phenyl } azetidine-1-methane amide;

N-{4-[1-(cyclopropyl carbonyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(2S)-2-methylbutyryl base] pyrrolidin-3-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-butyryl radicals pyrrolidin-3-yl) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [(3R)-1-(tetrahydrochysene-2H-pyrans-4-base ethanoyl) pyrrolidin-3-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(2-methylpropionyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-[4-({ (3R)-1-[(2S)-tetrahydrofuran (THF)-2-base carbonyl] pyrrolidin-3-yl } oxygen base) phenyl] azetidine-1-methane amide;

3-(pyridin-3-yl)-N-[4-({ (3R)-1-[(2R)-tetrahydrofuran (THF)-2-base carbonyl] pyrrolidin-3-yl } oxygen base) phenyl] azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [(3R)-1-(tetrahydrofuran (THF)-3-base carbonyl) pyrrolidin-3-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(Cyclopropyl-acetyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(2-hydroxy-2-methyl propionyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-benzoyl pyrrole compound alkane-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [(3R)-1-(3,3,3-trifluoropropyl acyl group) pyrrolidin-3-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(cyclopropyl carbonyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ (3R)-1-[(2S)-2-methylbutyryl base] pyrrolidin-3-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-butyryl radicals pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [(3S)-1-(tetrahydrochysene-2H-pyrans-4-base ethanoyl) pyrrolidin-3-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-(4-{ [(3S)-1-(2-methylpropionyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-[4-({ (3S)-1-[(2S)-tetrahydrofuran (THF)-2-base carbonyl] pyrrolidin-3-yl } oxygen base) phenyl] azetidine-1-methane amide;

3-(pyridin-3-yl)-N-[4-({ (3S)-1-[(2R)-tetrahydrofuran (THF)-2-base carbonyl] pyrrolidin-3-yl } oxygen base) phenyl] azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [(3S)-1-(tetrahydrofuran (THF)-3-base carbonyl) pyrrolidin-3-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-(4-{ [(3S)-1-(Cyclopropyl-acetyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3S)-1-(2-hydroxy-2-methyl propionyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3S)-1-benzoyl pyrrole compound alkane-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [(3S)-1-(3,3,3-trifluoropropyl acyl group) pyrrolidin-3-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-(4-{ [(3S)-1-(cyclopropyl carbonyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ (3S)-1-[(2S)-2-methylbutyryl base] pyrrolidin-3-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3S)-1-butyryl radicals pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(tetrahydrochysene-2H-pyrans-4-base ethanoyl) azetidine-3-base] phenyl } azetidine-1-methane amide;

N-{4-[1-(2-methylpropionyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{1-[(2S)-tetrahydrofuran (THF)-2-base carbonyl] azetidine-3-base } phenyl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{1-[(2R)-tetrahydrofuran (THF)-2-base carbonyl] azetidine-3-base } phenyl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran (THF)-3-base carbonyl) azetidine-3-base] phenyl } azetidine-1-methane amide;

N-{4-[1-(Cyclopropyl-acetyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2-hydroxy-2-methyl propionyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-benzoyl azetidine-3-base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(3,3,3-trifluoropropyl acyl group) azetidine-3-base] phenyl } azetidine-1-methane amide;

N-{4-[1-(cyclopropyl carbonyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(2S)-2-methylbutyryl base] azetidine-3-base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-butyryl radicals azetidine-3-base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

4-[4-({ [3-(2-chloropyridine-3-base) azetidine-1-base] carbonyl } is amino) phenyl] piperidines-1-t-butyl formate;

4-[4-({ [3-(4-chloropyridine-3-base) azetidine-1-base] carbonyl } is amino) phenyl] piperidines-1-t-butyl formate;

N-(4-{ [1-(Cyclopropyl-acetyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(furans-2-base carbonyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

4-[4-({ [3-(2-fluorine pyridin-3-yl) azetidine-1-base] carbonyl } is amino) phenyl] piperidines-1-t-butyl formate;

N-{4-[(1-pentanoyl azetidine-3-base) oxygen base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ 1-[(2-methoxy ethoxy) ethanoyl] azetidine-3-base } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(Ethoxyacetyl base) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(Methoxyacetyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(3-methylvaleryl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ 1-[(1S, 4R)-two ring [2.2.1]-2-in heptan base ethanoyl] azetidine-3-base } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(2,3-dimethylbutanoyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(4-methylvaleryl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ 1-[(2-methylcyclopropyl groups) carbonyl] azetidine-3-base } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [1-(4,4,4-trifluoro butyryl radicals) azetidine-3-base] oxygen base } phenyl) azetidine-1-methane amide;

N-(4-{ [1-(2-methylpropionyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(2,2-Dimethylpropanoyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[(1-butyryl radicals azetidine-3-base) oxygen base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[(1-propionyl azetidine-3-base) oxygen base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(2,2-dimethylbutanoyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(3-methylbutyryl base) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(3,3-dimethylbutanoyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [1-(3,3,3-trifluoropropyl acyl group) azetidine-3-base] oxygen base } phenyl) azetidine-1-methane amide;

N-[4-({ 1-[(1-methylcyclopropyl groups) carbonyl] azetidine-3-base } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(2-methylvaleryl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[(1-ethanoyl azetidine-3-base) oxygen base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(Cyclohexylacetyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(cyclohexyl-carbonyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(cyclopropyl carbonyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [1-(thiophene-2-base carbonyl) azetidine-3-base] oxygen base } phenyl) azetidine-1-methane amide;

N-(4-{ [1-(cyclopentylcarbonyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(morpholine-4-base ethanoyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [1-(1,3-thiazoles-5-base carbonyl) azetidine-3-base] oxygen base } phenyl) azetidine-1-methane amide;

N-[4-({ 1-[(3,5-dimethyl-1,2-oxazole-4-base) carbonyl] azetidine-3-base } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [1-(thiene-3-yl-carbonyl) azetidine-3-base] oxygen base } phenyl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [1-(1,3-thiazoles-4-base carbonyl) azetidine-3-base] oxygen base } phenyl) azetidine-1-methane amide;

N-(4-{ [1-(1,2-oxazole-5-base carbonyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ 1-[(4-methylpiperazine-1-yl) ethanoyl] azetidine-3-base } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(N, N-dimethyl-β-alanyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(furans-3-base carbonyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ 1-[(1-methylcyclohexyl) carbonyl] azetidine-3-base } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(Cyclopentylacetyl) azetidine-3-base] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [1-(1,3-thiazoles-2-base carbonyl) azetidine-3-base] oxygen base } phenyl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [1-(pyrrolidin-1-yl ethanoyl) azetidine-3-base] oxygen base } phenyl) azetidine-1-methane amide;

3-(2-fluorine pyridin-3-yl)-N-{4-[1-(2-hydroxy-2-methyl propionyl) piperidin-4-yl] phenyl } azetidine-1-methane amide;

N-{4-[1-(2-methyl-propyl)-1H-pyrazoles-4-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-propyl group-1H-pyrazoles-4-base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{1-[(3S)-tetrahydrofuran (THF)-3-base carbonyl] piperidin-4-yl } phenyl) azetidine-1-methane amide;

3-(4-chloropyridine-3-base)-N-(4-{1-[(3S)-tetrahydrofuran (THF)-3-base carbonyl] piperidin-4-yl } phenyl) azetidine-1-methane amide;

3-(2-chloropyridine-3-base)-N-{4-[1-(2-hydroxy-2-methyl propionyl) piperidin-4-yl] phenyl } azetidine-1-methane amide;

4-(pyridin-3-yl)-N-(4-{ [1-(tetrahydrochysene-2H-pyrans-4-base ethanoyl) piperidin-4-yl] oxygen base } phenyl) piperazine-1-methane amide;

N-[4-(1-pentanoyl piperidin-4-yl) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(2-methylcyclopropyl groups) carbonyl] piperidin-4-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(1S, 4R)-two ring [2.2.1]-2-in heptan base ethanoyl] piperidin-4-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(4-methylvaleryl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3-methylvaleryl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3-ethoxy-c acyl group) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2,2-dimethylbutanoyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3,3-dimethylbutanoyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2,2-Dimethylpropanoyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-butyryl radicals piperidin-4-yl) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(Ethoxyacetyl base) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3-methylbutyryl base) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(N-ethanoyl-L-leucyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(2-methoxy ethoxy) ethanoyl] piperidin-4-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(cyclohexyl-carbonyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(Cyclohexylacetyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluoro butyryl radicals) piperidin-4-yl] phenyl } azetidine-1-methane amide;

N-{4-[1-(cyclopentylcarbonyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(1-methylcyclohexyl) carbonyl] piperidin-4-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(furans-3-base carbonyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-Acetylpiperidin-4-base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(Methoxyacetyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(thiene-3-yl-carbonyl) piperidin-4-yl] phenyl } azetidine-1-methane amide;

N-(4-{1-[(3 methyl thiophene-2-base) carbonyl] piperidin-4-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(morpholine-4-base ethanoyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(thiophene-2-base carbonyl) piperidin-4-yl] phenyl } azetidine-1-methane amide;

N-(4-{1-[(5-thiotolene-2-base) carbonyl] piperidin-4-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(furans-2-base carbonyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(1-methyl isophthalic acid H-pyrroles-2-base) carbonyl] piperidin-4-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-propionyl piperidin-4-yl) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(1-methylcyclopropyl groups) carbonyl] piperidin-4-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(pyrrolidin-1-yl ethanoyl) piperidin-4-yl] phenyl } azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazoles-2-base carbonyl) piperidin-4-yl] phenyl } azetidine-1-methane amide;

N-{4-[1-(Cyclopentylacetyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2,3-dimethylbutanoyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-pentanoyl azetidine-3-base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(2-methylcyclopropyl groups) carbonyl] azetidine-3-base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(1S, 4R)-two ring [2.2.1]-2-in heptan base ethanoyl] azetidine-3-base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(4-methylvaleryl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3-methylvaleryl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3-ethoxy-c acyl group) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2,2-dimethylbutanoyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3,3-dimethylbutanoyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2,2-Dimethylpropanoyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(Ethoxyacetyl base) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3-methylbutyryl base) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(N-ethanoyl-L-leucyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(2-methoxy ethoxy) ethanoyl] azetidine-3-base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(cyclohexyl-carbonyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(Cyclohexylacetyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluoro butyryl radicals) azetidine-3-base] phenyl } azetidine-1-methane amide;

N-{4-[1-(cyclopentylcarbonyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(1-methylcyclohexyl) carbonyl] azetidine-3-base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(furans-3-base carbonyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-ethanoyl azetidine-3-base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(Methoxyacetyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(thiene-3-yl-carbonyl) azetidine-3-base] phenyl } azetidine-1-methane amide;

N-(4-{1-[(3 methyl thiophene-2-base) carbonyl] azetidine-3-base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(morpholine-4-base ethanoyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(thiophene-2-base carbonyl) azetidine-3-base] phenyl } azetidine-1-methane amide;

N-(4-{1-[(5-thiotolene-2-base) carbonyl] azetidine-3-base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(furans-2-base carbonyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(1-methyl isophthalic acid H-pyrroles-2-base) carbonyl] azetidine-3-base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-propionyl azetidine-3-base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(1-methylcyclopropyl groups) carbonyl] azetidine-3-base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazoles-2-base carbonyl) azetidine-3-base] phenyl } azetidine-1-methane amide;

N-{4-[1-(Cyclopentylacetyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2,3-dimethylbutanoyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(cyclopentyl-methyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(cyclohexyl methyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3,3-dimethylbutyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2-methyl amyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2-methyl-propyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3-methyl butyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2-ethyl-butyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2,2-dimethyl propyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2-methyl butyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-butyl piperidine-4-base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-propylpiperdine-4-base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2-cyclopropylethyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran (THF)-3-ylmethyl) piperidin-4-yl] phenyl } azetidine-1-methane amide;

N-{4-[1-(2,2-dimethylbutyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(cyclopentyl-methyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(cyclohexyl methyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3,3-dimethylbutyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(Cvclopropvlmethvl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2-methyl amyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran (THF)-2-ylmethyl) azetidine-3-base] phenyl } azetidine-1-methane amide;

N-{4-[1-(2-methyl-propyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3-methyl butyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2-ethyl-butyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2,2-dimethyl propyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2-methyl butyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(tetrahydrofuran (THF)-3-ylmethyl) azetidine-3-base] phenyl } azetidine-1-methane amide;

N-{4-[1-(2,2-dimethylbutyl) azetidine-3-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-pentanoyl pyrrolidin-3-yl) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3-methylvaleryl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(1S, 4R)-two ring [2.2.1]-2-in heptan base ethanoyl] pyrrolidin-3-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(Cyclopentylacetyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(2-methylcyclopropyl groups) carbonyl] pyrrolidin-3-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(morpholine-4-base ethanoyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(furans-3-base carbonyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(pyrrolidin-1-yl ethanoyl) pyrrolidin-3-yl] phenyl } azetidine-1-methane amide;

N-{4-[1-(N, N-dimethyl-β-alanyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(1,3-thiazoles-2-base carbonyl) pyrrolidin-3-yl] phenyl } azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(thiene-3-yl-carbonyl) pyrrolidin-3-yl] phenyl } azetidine-1-methane amide;

N-(4-{1-[(1-methylcyclopropyl groups) carbonyl] pyrrolidin-3-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(3 methyl thiophene-2-base) carbonyl] pyrrolidin-3-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(4,4,4-trifluoro butyryl radicals) pyrrolidin-3-yl] phenyl } azetidine-1-methane amide;

N-(4-{1-[(4-methylpiperazine-1-yl) ethanoyl] pyrrolidin-3-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(5-oxo-L-prolyl base) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3-ethoxy-c acyl group) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(4-methylvaleryl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(1-methylcyclohexyl) carbonyl] pyrrolidin-3-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-acetyl-pyrrolidine-3-base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(Cyclohexylacetyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-propionyl pyrrolidin-3-yl) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(2-methoxy ethoxy) ethanoyl] pyrrolidin-3-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[3-(morpholine-4-base) propionyl] pyrrolidin-3-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2,2-Dimethylpropanoyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[(5-thiotolene-2-base) carbonyl] pyrrolidin-3-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-{4-[1-(thiophene-2-base carbonyl) pyrrolidin-3-yl] phenyl } azetidine-1-methane amide;

N-(4-{1-[(1-methyl isophthalic acid H-pyrroles-2-base) carbonyl] pyrrolidin-3-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(furans-2-base carbonyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{1-[3-(piperidin-1-yl) propionyl] pyrrolidin-3-yl } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(Ethoxyacetyl base) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3,3-dimethylbutanoyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2,2-dimethylbutanoyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2-oxo propionyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(Methoxyacetyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(cyclohexyl-carbonyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(3-methylbutyryl base) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(cyclopentylcarbonyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-{4-[1-(2,3-dimethylbutanoyl) pyrrolidin-3-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-pentanoyl pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(3-methylvaleryl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [1-(two rings [2.2.1]-2-in heptan base ethanoyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(Cyclopentylacetyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ (3R)-1-[(2-methylcyclopropyl groups) carbonyl] pyrrolidin-3-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(morpholine-4-base ethanoyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(furans-3-base carbonyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [(3R)-1-(pyrrolidin-1-yl ethanoyl) pyrrolidin-3-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(5-oxo-D-prolyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(N, N-dimethyl-β-alanyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [(3R)-1-(1,3-thiazoles-2-base carbonyl) pyrrolidin-3-yl] oxygen base } phenyl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [(3R)-1-(thiene-3-yl-carbonyl) pyrrolidin-3-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-[4-({ (3R)-1-[(1-methylcyclopropyl groups) carbonyl] pyrrolidin-3-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ (3R)-1-[(3 methyl thiophene-2-base) carbonyl] pyrrolidin-3-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [(3R)-1-(4,4,4-trifluoro butyryl radicals) pyrrolidin-3-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-[4-({ (3R)-1-[(4-methylpiperazine-1-yl) ethanoyl] pyrrolidin-3-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(5-oxo-L-prolyl base) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(3-ethoxy-c acyl group) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(4-methylvaleryl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ (3R)-1-[(1-methylcyclohexyl) carbonyl] pyrrolidin-3-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(Cyclohexylacetyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(N-ethanoyl-L-leucyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-propionyl pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ (3R)-1-[(2-methoxy ethoxy) ethanoyl] pyrrolidin-3-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ (3R)-1-[3-(morpholine-4-base) propionyl] pyrrolidin-3-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(2,2-Dimethylpropanoyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ (3R)-1-[(5-thiotolene-2-base) carbonyl] pyrrolidin-3-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

3-(pyridin-3-yl)-N-(4-{ [(3R)-1-(thiophene-2-base carbonyl) pyrrolidin-3-yl] oxygen base } phenyl) azetidine-1-methane amide;

N-[4-({ (3R)-1-[(1-methyl isophthalic acid H-pyrroles-2-base) carbonyl] pyrrolidin-3-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(furans-2-base carbonyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-({ (3R)-1-[3-(piperidin-1-yl) propionyl] pyrrolidin-3-yl } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(Ethoxyacetyl base) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(3,3-dimethylbutanoyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(2,2-dimethylbutanoyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(Methoxyacetyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(cyclohexyl-carbonyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(3-methylbutyryl base) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(cyclopentylcarbonyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(2,3-dimethylbutanoyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-[4-(1-benzoyl piperidine-4-base) phenyl]-3-(pyridazine-3-base) azetidine-1-methane amide;

N-{4-[1-(2-fluoro benzoyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide;

N-{4-[1-(2-methyl benzoyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide;

N-{4-[1-(2,2-Dimethylpropanoyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide;

N-{4-[1-(cyclopropyl carbonyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide;

N-[4-(1-Acetylpiperidin-4-base) phenyl]-3-(pyridazine-3-base) azetidine-1-methane amide;

N-{4-[1-(3,3-dimethylbutanoyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide;

N-{4-[1-(cyclobutyl carbonyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide;

3-(pyridazine-3-base)-N-{4-[1-(4,4,4-trifluoro butyryl radicals) piperidin-4-yl] phenyl } azetidine-1-methane amide;

3-(pyridazine-3-base)-N-{4-[1-(3,3,3-trifluoropropyl acyl group) piperidin-4-yl] phenyl } azetidine-1-methane amide;

N-(4-{1-[(1-methylcyclopropyl groups) carbonyl] piperidin-4-yl } phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide;

N-{4-[1-(Cyclopropyl-acetyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide;

N-{4-[(1-benzoyl piperidine-4-base) methyl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide;

N-(4-{ [1-(2-fluoro benzoyl) piperidin-4-yl] methyl } phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide;

N-(4-{ [1-(2,2-Dimethylpropanoyl) piperidin-4-yl] methyl } phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide;

N-(4-{ [1-(3,3-dimethylbutanoyl) piperidin-4-yl] methyl } phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide;

N-(4-{ [1-(2-ethylbutanoyl base) piperidin-4-yl] methyl } phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide;

3-(pyridazine-3-base)-N-(4-{ [1-(4,4,4-trifluoro butyryl radicals) piperidin-4-yl] methyl } phenyl) azetidine-1-methane amide;

N-(4-{ [1-(2-methylpropionyl) piperidin-4-yl] methyl } phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide;

N-{4-[(1-Acetylpiperidin-4-base) methyl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide;

N-[4-({ 1-[(2S)-2-methylbutyryl base] piperidin-4-yl } methyl) phenyl]-3-(pyridazine-3-base) azetidine-1-methane amide;

N-[4-({ 1-[(1-methylcyclopropyl groups) carbonyl] piperidin-4-yl } methyl) phenyl]-3-(pyridazine-3-base) azetidine-1-methane amide; With its pharmacy acceptable salt.

Another embodiment relates to the composition being used for the treatment of following disease: inflammation and tissue repair obstacle, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic conditions, tetter, comprises psoriasis, the skin injury of allergic dermatitis and induced by ultraviolet irradiation, autoimmune disorder, comprise systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, mandatory spondylitis, tissue and organ rejection, alzheimer's disease, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein said cancer selected from breast cancer, prostate cancer, lung cancer, colorectal carcinoma, cervical cancer, ovarian cancer, skin carcinoma, CNS cancer, bladder cancer, carcinoma of the pancreas, leukemia, lymphoma or Hokdkin disease, emaciation, the inflammation relevant with some viral infection to infection, comprise acquired immune deficiency syndrome (AIDS) (AIDS), adult respiratory distress syndrome, and ataxia-telangiectasia, described composition comprises formula (IA) compound or its pharmacy acceptable salt of vehicle and treatment significant quantity.

Another embodiment relates to the method for the following disease for the treatment of patient: inflammation and tissue repair obstacle, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic conditions, tetter, comprises psoriasis, the skin injury of allergic dermatitis and induced by ultraviolet irradiation, autoimmune disorder, comprise systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, mandatory spondylitis, tissue and organ rejection, alzheimer's disease, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein said cancer selected from breast cancer, prostate cancer, lung cancer, colorectal carcinoma, cervical cancer, ovarian cancer, skin carcinoma, CNS cancer, bladder cancer, carcinoma of the pancreas, leukemia, lymphoma or Hokdkin disease, emaciation, the inflammation relevant with some viral infection to infection, comprise acquired immune deficiency syndrome (AIDS) (AIDS), adult respiratory distress syndrome, and ataxia-telangiectasia, described method comprises formula (IA) compound from significant quantity to described patient or its pharmacy acceptable salt that give to treat.

Another embodiment relates to the method for the following disease for the treatment of patient: inflammation and tissue repair obstacle, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic conditions, tetter, comprises psoriasis, the skin injury of allergic dermatitis and induced by ultraviolet irradiation, autoimmune disorder, comprise systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, mandatory spondylitis, tissue and organ rejection, alzheimer's disease, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein said cancer selected from breast cancer, prostate cancer, lung cancer, colorectal carcinoma, cervical cancer, ovarian cancer, skin carcinoma, CNS cancer, bladder cancer, carcinoma of the pancreas, leukemia, lymphoma or Hokdkin disease, emaciation, the inflammation relevant with some viral infection to infection, comprise acquired immune deficiency syndrome (AIDS) (AIDS), adult respiratory distress syndrome, with ataxia-telangiectasia or spleen cancer, described method comprises formula (IA) compound from significant quantity to described patient or its pharmacy acceptable salt that give to treat, with a kind of additional treatment agent for the treatment of significant quantity or more than a kind of additional treatment agent.

Detailed Description Of The Invention

This describes in detail and is only intended to make others skilled in the art to understand the invention of applicant, its principle and practical application thereof, to make others skilled in the art revise in many forms and to apply the present invention, with the requirement making them can adapt to specific end use best.This specification sheets and specific embodiment thereof are only intended to illustrate.Therefore, the present invention is not limited thereto the embodiment described in patent application and can revise in many aspects.

Abbreviation and definition

Unless made separate stipulations herein, the Science and Technology term of use related to the present invention should have the implication that those of ordinary skill in the art understand usually.The implication of these terms and scope should be clear, if but have any potential ambiguity, the definition provided herein has precedence over any dictionary or external definition.In this application, unless otherwise specified, the use of "or" refers to "and/or".In addition, term " comprises (including) " and the use of other form, and such as " comprising (includes) " and " comprising (included) ", is not restrictive." comprise (comprise) " about the word in present patent application (comprising claim) or the use of " comprising (comprises) " or " comprising (comprising) ", applicant points out, unless requirement separately in literary composition, these words should the clear understanding explained of facultative and nonexcludability and using based on them, applicant wishes, in this patent application of explanation, so to explain each in these words when comprising following patent requirement.About the variable occurred in any substituting group or in compound of the present invention or other formula any in this article once, its definition in everywhere is independent of its definition in other everywhere.Substituent combination is the ability tolerable when such combination produces stable compound only.Stable compound is the compound that it can be separated from reaction mixture with useful purity.

It being understood that all combinations herein keep suitable valency, the monovalence part with more than one atom is connected by their left end, and divalent moiety is drawn from left to right.

As used in the specification and the appended claims, unless made contrary regulation, following term has shown implication:

Term " alkyl " (being combined alone or with another one or multiple term) refers to and usually contains 1 to about 10 carbon atoms; Or in another embodiment 1 to about 8 carbon atoms; 1 to about 6 carbon atoms in another embodiment; 1 to the straight or branched saturated hydrocarbyl substituting group of about 4 carbon atoms in another embodiment.Substituent example like this comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl and hexyl etc.

Term " thiazolinyl " (being combined alone or with another one or multiple term) refers to containing one or more double bond and usual 2 to about 10 carbon atoms; Or in another embodiment 2 to about 8 carbon atoms; 2 to about 6 carbon atoms in another embodiment; 2 to the straight or branched hydrocarbyl substituent of about 4 carbon atoms in another embodiment.Substituent example like this comprises vinyl, 2-propenyl, 3-propenyl, Isosorbide-5-Nitrae-pentadienyl, Isosorbide-5-Nitrae-butadienyl, 1-butylene base, crotyl and 3-butenyl etc.

Term " alkynyl " (being combined alone or with another one or multiple term) refers to containing one or more triple bond and usual 2 to about 10 carbon atoms; Or in another embodiment 2 to about 8 carbon atoms; 2 to about 6 carbon atoms in another embodiment; 2 to the straight or branched hydrocarbyl substituent of about 4 carbon atoms in another embodiment.Substituent example like this comprises ethynyl, 2-propynyl, 3-proyl, 2-butyne base and 3-butynyl etc.

Term " carbocylic radical " (being combined alone or with another one or multiple term) refers to saturated cyclic (i.e. " cycloalkyl "), fractional saturation ring-type (i.e. " cycloalkenyl group ") or completely undersaturated (i.e. " aryl ") hydrocarbyl substituent containing 3 to 14 carboatomic ring atoms (" annular atoms " is the atom of the one or more rings forming cyclic substituents of being bonded together).Carbocylic radical can be the ring structure of monocycle (monocycle) or many rings.

Carbocylic radical can be usually containing 3 to 8 annular atomses, more generally 3 to 6 annular atomses, then the single ring architecture of more generally 5 to 6 annular atomses.The example of such monocyclic carbocyclyl residues comprises cyclopropyl (cyclopropane base), cyclobutyl (tetramethylene base), cyclopentyl (pentamethylene base), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexyl), cyclohexenyl, cyclohexadienyl and phenyl.Carbocylic radical also can be many rings (can contain more than one ring).The example of many rings carbocylic radical comprises bridging, condenses and volution carbocylic radical.In volution carbocylic radical, an atom is that two different rings have.The example of volution carbocylic radical is spiro cyclopentane base.In bridging carbocylic radical, ring shares at least two total non-adjacent atoms.The example of bridging carbocylic radical comprises two rings [2.2.1] heptane base, two rings [2.2.1] hept-2-ene" base and adamantyl.In condensed ring carbocylic radical system, two or more rings can condense together, so that two rings share a public key.Two-or the example of three-condensed ring carbocylic radical comprise naphthyl, tetrahydro naphthyl (tetralinyl), indenyl, indanyl (indanyl), anthryl, phenanthryl and decahydronaphthalene naphthyl.

Term " cycloalkyl " (being combined alone or with another one or multiple term) refers to the saturated cyclic substituting group containing 3 to 14 carboatomic ring atoms.Cycloalkyl can be usually containing 3 to 8 carboatomic ring atoms, the more generally monocyclic carbocyclic ring of 3 to 6 annular atomses.The example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Cycloalkyl also can be many rings or contain more than one ring.The example of polycyclic naphthene base comprises bridging, condenses and volution carbocylic radical.

Term " aryl " (being combined alone or with another one or multiple term) refers to the aromatic carbocyclyl groups containing 6 to 14 carboatomic ring atoms.Aryl can be monocycle or many rings (namely can contain more than one ring).When many cyclophanes ring, only need in polycyclic system ring unsaturated, and remaining ring can be saturated, fractional saturation or undersaturated.The example of aryl comprises phenyl, naphthyl, indenyl, indanyl, and tetrahydro naphthyl.

In some cases, the carbonatoms in hydrocarbyl substituent (such as alkyl, thiazolinyl, alkynyl or cycloalkyl) is by prefix " C _x-C _y-" instruction, wherein x is the minimal number of the carbon atom in substituting group, and y is maximum number.Therefore, such as, " C ₁-C ₆-alkyl " refer to alkyl substituent containing 1 to 6 carbon atom.Illustrate further, C ₃-C ₈-cycloalkyl refers to the stable hydrocarbon basic ring containing 3 to 8 carboatomic ring atoms.

Term " hydrogen " (being combined alone or with another one or multiple term) refers to hydrogen base and can be described to-H.

Term " hydroxyl " (being combined alone or with another one or multiple term) refers to-OH.

Term " carboxyl " (being combined alone or with another one or multiple term) refers to-C (O)-OH.

Term " amino " (being combined alone or with another one or multiple term) refers to-NH ₂.

Term " halogen " or " halo " (being combined alone or with another one or multiple term) refer to fluorine-based (it can be described to-F), chloro (it can be described to-Cl), bromo (it can be described to-Br) or iodo (it can be described to-I).

If substituting group is described to " replacement ", then non-hydrogen group replaces the hydrogen base on this substituent carbon or nitrogen.Therefore, such as, the alkyl substituent of replacement is that wherein at least one non-hydrogen group replaces the alkyl substituent of the hydrogen base on this alkyl substituent.Such as, single fluoroalkyl is by the alkyl of fluorine-based replacement, and fluoroalkyl is by the alkyl of two fluorine-based replacements.Should be realized that, if there is more than one replacement on substituting group, each non-hydrogen group can identical or different (unless otherwise specified).

If substituting group is described to " optional replacement ", this substituting group can (1) not replace, or (2) are substituted.If substituting group is described to optionally be replaced by the non-hydrogen group of maximum specific quantity, this substituting group can (1) not replace; Or (2) are by the non-hydrogen group of maximum this specific quantity or by can the maximum quantity of the position of substitution replace on this substituting group at most, see which is less.Therefore, such as, if substituting group is described to optionally by the heteroaryl that maximum 3 non-hydrogen groups replace, then have be less than 3 can the position of substitution any heteroaryl optionally by most only with this heteroaryl have can replace by the as many non-hydrogen group of the position of substitution.Such as, tetrazyl (its only have can the position of substitution) is optionally replaced by a maximum non-hydrogen group.For illustrating further, if amino nitrogen is described to optionally be replaced by maximum 2 non-hydrogen groups, then primary amino nitrogen is optionally replaced by maximum 2 non-hydrogen groups, and secondary amino nitrogen is optionally replaced by maximum only 1 non-hydrogen group.Optionally replaced by one or more non-hydrogen group if substituting group is described as, then this substituting group can (1) not be substituted; Or (2) can the number of the position of substitution be replaced by maximum on the most nearly this substituting group.Therefore, if such as substituting group is described as optionally by the heteroaryl that one or more non-hydrogen group replaces, then have 3 any heteroaryls that can be substituted position can optionally by one, two or three non-hydrogen groups replace.In order to example, tetrazyl (its only have can the position of substitution) can optionally be replaced by a maximum non-hydrogen group.

This patent application is used interchangeably term " substituting group " and " group (radical) ".

Prefix " halo " refers to that the substituting group that prefix connects is replaced by one or more independent halogen group selected.Such as, haloalkyl refers to the alkyl substituent that wherein at least one hydrogen base is substituted by halogen group.The example of haloalkyl comprises chloromethyl, 1-bromotrifluoromethane, methyl fluoride, difluoromethyl, trifluoromethyl and 1,1,1-trifluoroethyl.Should be realized that, if substituting group is replaced by more than one halogen group, these halogen groups can identical or different (unless otherwise specified).

Prefix " perhalogeno " refers to that each hydrogen base on the substituting group that prefix connects is substituted by the halogen group independently selected, and each hydrogen base namely on this substituting group is substituted by halogen group.If all halogen groups are identical, prefix generally designates halogen group.Therefore, such as, term " perfluor " refers to that each hydrogen base on the substituting group that prefix connects is substituted by fluorine-based.Such as, term " perfluoroalkyl " refers to the alkyl substituent of each hydrogen base of wherein fluorine-based replacement.

Term " carbonyl " (being combined alone or with another one or multiple term) refer to-C (O)-.

Term " aminocarboxyl " (being combined alone or with another one or multiple term) refers to-C (O)-NH ₂.

Term " oxo " (being combined alone or with another one or multiple term) refers to (=O).

Term " oxygen base " (being combined alone or with another one or multiple term) refers to ether substituting group and can be described to-O-.

Term " alkyl hydroxy " (being combined alone or with another one or multiple term) refers to-alkyl-OH.

Term " alkylamino " (being combined alone or with another one or multiple term) refers to-alkyl-NH ₂.

Term " alkoxyl group " (being combined alone or with another one or multiple term) refers to alkyl oxide substituting group, i.e.-O-alkyl.This substituent example comprises methoxyl group (-O-CH ₃), oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.

Term " alkyl-carbonyl " (being combined alone or with another one or multiple term) refers to-C (O)-alkyl.

Term " aminoalkylcarbonyl " (being combined alone or with another one or multiple term) refers to-C (O)-alkyl-NH ₂.

Term " alkoxy carbonyl " (being combined alone or with another one or multiple term) refers to-C (O)-O-alkyl.

Term " carbocyclylcarbonyl " (being combined alone or with another one or multiple term) refers to-C (O)-carbocylic radical.

Similarly, term " Heterocyclylcarbonyl " (being combined alone or with another one or multiple term) refers to-C (O)-heterocyclic radical.

Term " carbocylic radical alkyl-carbonyl " (being combined alone or with another one or multiple term) refers to-C (O)-alkyl-carbocyclyl.

Similarly, term " heterocyclyl alkyl carbonyl " (being combined alone or with another one or multiple term) refers to-C (O)-alkyl-heterocyclyl groups.

Term " carbocylic radical oxygen base carbonyl " (being combined alone or with another one or multiple term) refers to-C (O)-O-carbocylic radical.

Term " carbocyclylalkoxy carbonyl " (being combined alone or with another one or multiple term) refers to-C (O)-O-alkyl-carbocyclyl.

Term " sulfo-(thio) " or " thia (thia) " (being combined alone or with another one or multiple term) refer to thioether substituent, and namely wherein bivalent sulfur atom replaces the ether substituting group of ether oxygen atom.This substituting group can be described to-S-.This such as " alkyl-thio-alkyl " refers to alkyl-S-alkyl (alkyl-sulfanyl (sulfanyl)-alkyl).

Term " mercaptan (thiol) " or " sulfydryl " (being combined alone or with another one or multiple term) refer to mercapto substituent and can be described to-SH.

Term " (thiocarbonyl) " (being combined alone or with another one or multiple term) refers to the carbonyl that wherein Sauerstoffatom is substituted by sulphur.This substituting group can be described to-C (S)-.

Term " alkylsulfonyl " (being combined alone or with another one or multiple term) refers to-S (O) ₂-.

Term " amino-sulfonyl " (being combined alone or with another one or multiple term) refers to-S (O) ₂-NH ₂.

Term " sulfinyl " or " sulfoxide group " (being combined alone or with another one or multiple term) refer to-S (O)-.

Term " heterocyclic radical " (being combined alone or with another one or multiple term) refers to (i.e. " heterocycloalkenyl ") or completely undersaturated (i.e. " heteroaryl ") ring structure of saturated (i.e. " Heterocyclylalkyl ") containing 3 to 14 annular atomses altogether, fractional saturation.At least one in annular atoms is heteroatoms (i.e. oxygen, nitrogen or sulphur), and all the other annular atomses are independently selected from carbon, oxygen, nitrogen and sulphur.Heterocyclic radical can be the ring structure of monocycle (monocycle) or many rings.

Heterocyclic radical can be monocycle, and it is usually containing 3 to 7 annular atomses, more generally 3 to 6 annular atomses, more more generally 5 to 6 annular atomses.The example of monocyclic heterocycles base comprises 1,2,3,6-tetrahydropyridine, thio-morpholinyl, THP trtrahydropyranyl, furyl, dihydrofuran base, tetrahydrofuran base, thienyl (thio-furan base), dihydro-thiophene base, tetrahydro-thienyl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, imidazolinyl, imidazolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl, triazolyl, tetrazyl, oxazolyl, oxazolidinyl, isoxazole alkyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazoline base, thiazolidyl, isothiazole alkyl, thiadiazolyl group, oxadiazolyl (comprises 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazan base) or 1,3,4-oxadiazolyl), oxatriazole base (comprising 1,2,3,4-oxatriazole base or 1,2,3,5-oxatriazole base), Er oxazolyl (comprises 1,2,3-bis-oxazolyl, 1,2,4-bis-oxazolyl, 1,3,2-bis-oxazolyl or 1,3,4-bis-oxazolyl), Evil thiazolyl, oxygen thia cyclopentenyl (oxathiolyl), oxathiolane base (oxathiolanyl), pyranyl, dihydro pyranyl, thiapyran base, tetrahydro thiapyran base, pyridyl (azine group), piperidyl, diazine (comprises pyridazinyl (1,2-diazine base), pyrimidyl (1,3-diazines base) or pyrazinyl (1,4-diazines base)), piperazinyl, pyrrolidin-2-one base (pyrrolidin-2-only), triazinyl (comprises 1,3,5-triazines base, 1,2,4-triazinyl and 1,2,3-triazinyl), oxazinyl (comprises 1,2-oxazinyl, 1,3-oxazinyl or Isosorbide-5-Nitrae-oxazinyl), Evil thiazinyl (comprises 1,2,3-Evil thiazinyl, 1,2,4-Evil thiazinyl, 1,2,5-Evil thiazinyl or 1,2,6-Evil thiazinyl), oxadiazine base (comprises 1,2,3-oxadiazine base, 1,2,4-oxadiazine base, Isosorbide-5-Nitrae, 2-oxadiazine base or 1,3,5-oxadiazine base)), morpholinyl, azepine base (azepinyl), oxa-base (oxepinyl), thia base (thiepinyl) and diaza base (diazepinyl).

Heterocyclic radical also can be many rings (can contain more than one ring).The example of multiring heterocyclic comprises bridging, condenses and Spirocyclic heterocyclic base.In Spirocyclic heterocyclic base, an atom is that two different rings have.In bridged heterocyclic base, ring shares at least two total non-adjacent atoms.In fused ring heterocycle base, two or more rings can condense together, so that two rings share a public key.The example of fused ring heterocycle base comprises six hydrogen-furo [3,4-c] pyrroles, six hydrogen-furo [3,4-b] pyrroles, octahydro-pyrrolo-[3,4-b] pyridine, octahydro-pyrrolo-[3,4-c] pyridine, (3aR, 6aR)-5-methyl-octahydro-pyrrolo-[3,4-b] pyrroles, (3aR, 6aR)-octahydro-pyrrolo-[3,4-b] pyrroles, 6-methyl-2,6-diaza-two ring [3.2.0] heptane, (3aS, 6aR)-2-methyl-octahydro-pyrrolo-[3,4-c] pyrroles, decahydro-[1,5] naphthyridines, 2,3-dihydro benzo furyl, 2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indyl, thieno-[3,2-c] pyridyl, furo [3,2-c] pyridyl, phthalazines-1 (2H)-one base, isoquinolyl, isoquinoline 99.9-1 (2H)-one base, 5,6,7,8-tetrahydrochysene phthalazines-1 (2H)-one base, fluorine phthalazines-1 (2H)-one base, (Z)-3H-benzo [d] [1,2] diaza-4 (5H)-one base, (trifluoromethyl) phthalazines-1 (2H)-one base, pyrrolo-[1,2-d] [1,2,4] triazine-1 (2H)-one base, 1,2,3,4-tetrahydro isoquinolyl, 2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxa glutinous rehmannia base, 5,6,7,8-tetrahydrochysene phthalazines-1 (2H)-one base, 5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazinyl, 5,6,7,8-imidazolidine is [1,5-a] pyrazinyl also, thieno-[3,2-c] pyridyl, furo [3,2-c] pyridyl, indolizine base, pyranopyrrolyl, 4H-quinolizinyl, purine radicals, naphthyridinyl, pyridopyridine base (comprises pyrido [3,4-b]-pyridyl, pyrido [3,2-b]-pyridyl or pyrido [4,3-b]-pyridyl) and pteridyl.Other example of fused ring heterocycle base comprises benzo-fused heterocycle base, as benzimidazolyl-, benzo [d] [1, 3] dioxa cyclopentenyl, indyl, pseudoindoyl (isobenzazolyl, false pseudoindoyl), indoleninyl(pseudoindolyl), iso indazolyl (benzopyrazoles base), quinolyl (benzazinyl) (comprising quinolyl (1-benzazinyl) or isoquinolyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolyl, benzodiazine base (comprises cinnolines base (1, 2-benzodiazine base) or quinazolyl (1, 3-benzodiazine base)), benzopyranyl (comprising chromanyl or isochroman base), benzoxazinyl (comprises 1, 3, 2-benzoxazinyl, 1, 4, 2-benzoxazinyl, 2, 3, 1-benzoxazinyl or 3, 1, 4-benzoxazinyl) and Ben Bing Yi oxazinyl (comprise 1, 2-Ben Bing Yi oxazinyl or 1, 4-Ben Bing Yi oxazinyl).The example of Spirocyclic heterocyclic base comprises Isosorbide-5-Nitrae-dioxa-8-azaspiro [4.5] decyl.

Term " 3-12 unit heterocyclic radical " (being combined alone or with another one or multiple term) refers to and altogether contains saturated (i.e. " Heterocyclylalkyl ") of 3 to 12 annular atomses, (i.e. " heterocycloalkenyl ") or completely undersaturated (i.e. " heteroaryl ") ring structure of fractional saturation.At least one annular atoms is heteroatoms (i.e. oxygen, nitrogen or sulphur), and all the other annular atomses are independently selected from carbon, oxygen, nitrogen and sulphur.3-12 unit heterocyclic radical can be monocycle (monocycle) or many rings ring structure.

Term " Heterocyclylalkyl " (being combined alone or with another one or multiple term) refers to saturated heterocyclyl.

Term " heteroaryl " (being combined alone or with another one or multiple term) refers to the aromatic heterocyclic radical containing 5 to 14 annular atomses.Heteroaryl can be monocycle or 2 or 3 fused rings.The example of heteroaryl substituent comprises 6 yuan of ring substituents, as pyridyl, pyrazinyl (pyrazyl), pyrimidyl, pyridazinyl and 1,3,5-, 1,2,4-or 1,2,3-triazinyl; 5-unit ring substituents, as imidazolyl (imidazyl), furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-unit fused ring substituents, if benzimidazole thiophanate is for furyl, benzoisoxazole base, benzoxazolyl and purine radicals; With 6/6-unit condensed ring, as benzopyranyl, quinolyl, isoquinolyl, cinnolines base, quinazolyl and benzoxazinyl.

Connect the substituent prefix of polycomponent and be only applicable to the first component.Such as, term " alkyl-cycloalkyl " is containing two components: alkyl and cycloalkyl.Therefore, C ₁-C ₆c on-alkyl-cycloalkyl ₁-C ₆-prefix refers to that the alkyl component of alkyl-cycloalkyl contains 1 to 6 carbon atom; C ₁-C ₆-prefix does not describe cycloalkyl component.For illustrating further, the prefix " halo " on halogenated alkoxy alkyl refers to that the only alkoxy component of alkoxyalkyl substituent is replaced by one or more halogen group.If instead or additionally there is halogen substiuted in alkyl component, this substituting group will change into and be described as " alkoxyalkyl of halogen substiuted " but not " halogenated alkoxy alkyl ".Finally, if only there is halogen substiuted in alkyl component, this substituting group will change into and being described as " alkoxyhaloalkyl groups ".

Term " treatment (treat, treating and treatment) " refers to and alleviates or eliminate a disease and/or the method for its subsidiary symptom.

Term " prevention (prevent, preventing and prevention) " refers to the method preventing disease and/or its subsidiary paresthesia epilepsy or prevent object from falling ill." prevention " used herein also comprises the risk of falling ill postponing disease and/or its subsidiary paresthesia epilepsy and reduction object.

Term " treatment significant quantity " refers to the compound administration amount being enough to one or more symptoms preventing the development of one or more symptoms of treated illness or obstacle or alleviate treated illness or obstacle to a certain extent.

Term " modulation " refers to that compound improves or reduces the ability of kinase whose function or activity." modulation " that use with its various forms is herein intended to comprise the antagonism of the activity relevant to kinases, excitement, partial agonist and/or partial agonist.Kinase inhibitor such as combines partially or completely to hinder stimulation, reduces, prevents, postpones activation, passivation, subtracts quick or lower the compound of signal transduction.Kinase activation agent is the compound such as combining to stimulate, improve, open, activate, promote, increase work, sensitization or raise signal transduction.

The product that term used herein " composition " is intended to comprise the predetermined component comprising specified amount and any product directly or indirectly produced by the combination of the predetermined component of specified amount." pharmaceutically acceptable " refers to that carrier, thinner or vehicle must be compatible with other composition of preparation and harmless to its recipient.

" object " is defined as in this article and comprises animal, as Mammals, includes but not limited to, primate (such as people), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse etc.In preferred embodiments, this is to liking people.

the compound of isotopic enrichment or mark

Compound of the present invention can exist with the form of isotope-labeled or isotopic enrichment, this form contain one or more have be different from the abundantest naturally occurring nucleidic mass or the nucleidic mass of total mass number or the atom of total mass number.Isotropic substance can be radioactive or inactive isotropic substance.The isotropic substance of atom as hydrogen, carbon, phosphorus, sulphur, fluorine, chlorine and iodine includes but not limited to ²h, ³h, ¹³c, ¹⁴c, ¹⁵n, ¹⁸o, ³²p, ³⁵s, ¹⁸f, ³⁶cl, and ¹²⁵i.Other isotopic compounds containing these and/or other atom within the scope of the invention.

In another embodiment, isotope-labeled compound contain deuterium ( ²h), tritium ( ³h) or ¹⁴c isotropic substance.The general method preparation that isotope-labeled compound of the present invention can be known by those of ordinary skill in the art.This type of isotope-labeled compound can be prepared by replacing cold reagent with the isotope-labeled reagent easily obtained easily by carrying out step disclosed in embodiment disclosed herein and scheme.In some cases, compound can adopt isotope-labeled agent treated with the common atom of its isotopic exchange, such as, can pass through deuterium acid as D ₂sO ₄/ D ₂the effect of O is by hydrogen exchange one-tenth deuterium.In addition to that mentioned above, correlation step and intermediate are disclosed in the people such as such as Lizondo, J, drugs Fut, 21 (11), 1116 (1996); The people such as Brickner, S J , J Med Chem, 39 (3), 673 (1996); The people such as Mallesham, B, org Lett, 5 (7), 963 (2003); PCT open WO1997010223, WO2005099353, WO1995007271, WO2006008754; The US patent No. 7538189; 7534814; 7531685; 7528131; 7521421; 7514068; 7511013; With US patent application publication number 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; In 20090082471, these methods are incorporated to herein as a reference.

Isotope-labeled compound of the present invention can measure the validity in binding tests as standard.Containing isotopic compound for studying the internal metabolism home to return to (people such as Blake of compound in drug research with the mechanism of action and pathways metabolism by evaluating nonisotopically labelled parent compound j. Pharm. Sci.64,3,367-391 (1975)).This type of metabolism research is important in the design of safe and effective medicine, because give the active compound in vivo of patient or prove the poisonous or carcinogenic (people such as Foster because of the metabolite produced by parent compound, Advances in Drug Research the 14th volume, 2-36 page, Academic press, London, 1985; The people such as Kato, J. labelled Comp. Radiopharmaceut., 36 (10): 927-932 (1995); The people such as Kushner, can. J. Physiol. Pharmacol., 77,79-88 (1999).

In addition, the medicine containing non radioactive isotope, as being called the deuterated medicine of " heavy medicine ", may be used for treating relevant disease active in NAMPT and illness.The isotopic amount existed in compound is increased to and is called enrichment higher than its natural abundance.The example of the amount of enrichment comprises about 0.5,1,2,3,4,5,6,7,8,9,10,12,16,21,25,29,33,37,42,46,50,54,58,63,67,71,75,79,84,88,92,96 to about 100 mol %.The normal atom of at the most about 15% is replaced Mammals with heavy isotope, comprise in rodent and dog and realized and maintained several days periods to several weeks, and observe MIN untoward reaction (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84:770; Thomson J F, Ann. New York Acad. Sci 1960 84:736; The people such as Czakja D M, Am. J. Physiol. 1961 201:357).Find to adopt the acute replacement of the deuterium high human body fluid to 15%-23% do not cause toxicity (people such as Blagojevic N. " Dosimetry & Treatment Planning for Neutron Capture Therapy ", Zamenhof R, Solares G and Harling O compiles. 1994. Advanced Medical Publishing, Madison Wis. 125-134 page; Diabetes Metab. 23:251 (1997)).

The cold labeling of medicine can change its physico-chemical property, such as pKa and lipid solubility.If isotropic substance replaces the region that have impact on and participate in ligand-receptor interaction, then these impacts and change can affect the pharmacodynamics reaction of drug molecule.Although some physical propertiess of stable isotopic labeling molecule be different from unlabelled those, but chemistry and biology character is identical, except an important exception: because the quality of heavy isotope increases, anyly relate to heavy isotope and another monatomic key can be stronger than the identical key between light isotope and this atom.Therefore, isotropic substance mixes metabolism or Enzymatic transformation position described reaction of slowing down, and may change the pharmacokinetic profile relative to heterotope compound or effect.

compound

X in selecting type (I) compound independently ¹, X ², Y ¹, R ¹and R ²proper group.Embodiment of the present invention can be combined.This type of combination is considered also within the scope of the invention.Such as, any one X is expected ¹, X ², Y ¹, R ¹and R ²embodiment can with any other X ¹, X ², Y ¹, R ¹and R ²the embodiment combination of middle restriction.

the embodiment of formula (I)

Therefore one embodiment of the invention relate to compound or its pharmacy acceptable salt, and it can be used as the inhibitor of NAMPT, and this compound has formula (I)

Formula (I);

Wherein

X ¹for N and X ²for CR ¹; Or

X ¹for CR ¹and X ²for N; Or

X ¹for CR ¹and X ²for CR ¹;

Y ¹for

R ¹², when occurring at every turn, be the independent alkyl selected.

In an embodiment of formula (I), X ¹for N and X ²for CR ¹.In another embodiment of formula (I), X ¹for CR ¹and X ²for N.In another embodiment of formula (I), X ¹for CR ¹and X ²for CR ¹.In another embodiment of formula (I), X ¹for CR ¹, X ²for CR ¹and R ¹when occurring at every turn independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, OH, NH ₂, CN, NO ₂, F, Cl, Br and I.In another embodiment of formula (I), X ¹for CR ¹, X ²for CR ¹and R ¹when occurring at every turn independently selected from hydrogen, alkyl, F, Cl, Br and I.In another embodiment of formula (I), X ¹for CR ¹, X ²for CR ¹and R ¹be hydrogen when occurring at every turn.

In an embodiment of formula (I), R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, OH, NH ₂, CN, NO ₂, F, Cl, Br and I.In another embodiment of formula (I), R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, F, Cl, Br and I.In another embodiment of formula (I), R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, F and Cl.In another embodiment of formula (I), R ¹be hydrogen when occurring at every turn.

In an embodiment of formula (I), Y ¹for

Wherein represent the tie point with carbonyl, represent the tie point with nitrogen-containing hetero aryl.In another embodiment of formula (I), Y ¹for

Wherein represent the tie point with carbonyl, represent the tie point with nitrogen-containing hetero aryl.In another embodiment of formula (I), Y ¹for wherein represent the tie point with carbonyl, represent the tie point with nitrogen-containing hetero aryl.

In an embodiment of formula (I), R ²independently selected from C ₄-C ₆-alkyl, C ₄-C ₆-thiazolinyl, C ₄-C ₆-alkynyl, aryl, 3-12 unit heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ²in C ₄-C ₆-alkyl, C ₄-C ₆-thiazolinyl and C ₄-C ₆-alkynyl is replaced independently selected from following substituting group by one or more separately: R ³, OR ³, SR ³, S (O) R ³, SO ₂r ³, C (O) R ³, CO (O) R ³, OC (O) R ³, OC (O) OR ³, NH ₂, NHR ³, N (R ³) ₂, NHC (O) R ³, NR ³c (O) R ³, NHS (O) ₂r ³, NR ³s (O) ₂r ³, NHC (O) OR ³, NR ³c (O) OR ³, NHC (O) NH ₂, NHC (O) NHR ³, NHC (O) N (R ³) ₂, NR ³c (O) NHR ³, NR ³c (O) N (R ³) ₂, C (O) NH ₂, C (O) NHR ³, C (O) N (R ³) ₂, C (O) NHOH, C (O) NHOR ³, C (O) NHSO ₂r ³, C (O) NR ³sO ₂r ³, SO ₂nH ₂, SO ₂nHR ³, SO ₂n (R ³) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ³, C (N) N (R ³) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ²in aryl, 3-12 unit heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, SR ⁴, S (O) R ⁴, SO ₂r ⁴, C (O) R ⁴, CO (O) R ⁴, OC (O) R ⁴, OC (O) OR ⁴, NH ₂, NHR ⁴, N (R ⁴) ₂, NHC (O) R ⁴, NR ⁴c (O) R ⁴, NHS (O) ₂r ⁴, NR ⁴s (O) ₂r ⁴, NHC (O) OR ⁴, NR ⁴c (O) OR ⁴, NHC (O) NH ₂, NHC (O) NHR ⁴, NHC (O) N (R ⁴) ₂, NR ⁴c (O) NHR ⁴, NR ⁴c (O) N (R ⁴) ₂, C (O) NH ₂, C (O) NHR ⁴, C (O) N (R ⁴) ₂, C (O) NHOH, C (O) NHOR ⁴, C (O) NHSO ₂r ⁴, C (O) NR ⁴sO ₂r ⁴, SO ₂nH ₂, SO ₂nHR ⁴, SO ₂n (R ⁴) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁴, C (N) N (R ⁴) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (I), R ²independently selected from C ₄-C ₆-alkyl and aryl; Wherein R ²in C ₄-C ₆-alkyl is replaced independently selected from following substituting group by one or more separately: R ³, F, Cl, Br and I; Wherein R ²in aryl optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴, CN, F, Cl, Br and I.In another embodiment of formula (I), R ²independently selected from C ₄-C ₆-alkyl and aryl; Wherein R ²in C ₄-C ₆-alkyl is separately by one or more R ³replace; Wherein R ²in aryl optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴and CN.In another embodiment of formula (I), R ²for C ₄-C ₆-alkyl; Wherein R ²in C ₄-C ₆-alkyl is separately by one or more R ³replace.In another embodiment of formula (I), R ²for aryl; Wherein R ²in aryl replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴and CN.In another embodiment of formula (I), R ²for aryl; Wherein R ²in aryl separately by C (O) NHR ⁴replace.In another embodiment of formula (I), R ²for phenyl; Wherein R ²in phenyl separately by C (O) NHR ⁴replace.In another embodiment of formula (I), R ²for phenyl; Wherein R ²in phenyl separately by an OR ⁴replace.In another embodiment of formula (I), R ²for phenyl; Wherein R ²in phenyl separately by a R ⁴replace.

In an embodiment of formula (I), R ³, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group and heterocyclic radical; Wherein R ³in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁵, OR ⁵, SR ⁵, S (O) R ⁵, SO ₂r ⁵, C (O) R ⁵, CO (O) R ⁵, OC (O) R ⁵, OC (O) OR ⁵, NH ₂, NHR ⁵, N (R ⁵) ₂, NHC (O) R ⁵, NR ⁵c (O) R ⁵, NHS (O) ₂r ⁵, NR ⁵s (O) ₂r ⁵, NHC (O) OR ⁵, NR ⁵c (O) OR ⁵, NHC (O) NH ₂, NHC (O) NHR ⁵, NHC (O) N (R ⁵) ₂, NR ⁵c (O) NHR ⁵, NR ⁵c (O) N (R ⁵) ₂, C (O) NH ₂, C (O) NHR ⁵, C (O) N (R ⁵) ₂, C (O) NHOH, C (O) NHOR ⁵, C (O) NHSO ₂r ⁵, C (O) NR ⁵sO ₂r ⁵, SO ₂nH ₂, SO ₂nHR ⁵, SO ₂n (R ⁵) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁵, C (N) N (R ⁵) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ³in aryl, cycloalkyl, cycloalkenyl group and heterocyclic radical optionally replaced independently selected from following substituting group by one or more separately: R ⁶, OR ⁶, SR ⁶, S (O) R ⁶, SO ₂r ⁶, C (O) R ⁶, CO (O) R ⁶, OC (O) R ⁶, OC (O) OR ⁶, NH ₂, NHR ⁶, N (R ⁶) ₂, NHC (O) R ⁶, NR ⁶c (O) R ⁶, NHS (O) ₂r ⁶, NR ⁶s (O) ₂r ⁶, NHC (O) OR ⁶, NR ⁶c (O) OR ⁶, NHC (O) NH ₂, NHC (O) NHR ⁶, NHC (O) N (R ⁶) ₂, NR ⁶c (O) NHR ⁶, NR ⁶c (O) N (R ⁶) ₂, C (O) NH ₂, C (O) NHR ⁶, C (O) N (R ⁶) ₂, C (O) NHOH, C (O) NHOR ⁶, C (O) NHSO ₂r ⁶, C (O) NR ⁶sO ₂r ⁶, SO ₂nH ₂, SO ₂nHR ⁶, SO ₂n (R ⁶) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁶, C (N) N (R ⁶) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (I), R ³, when occurring at every turn, be heterocyclic radical independently; Wherein R ³in heterocyclic radical optionally replaced independently selected from following substituting group by one or more separately: CO (O) R ⁶, F, Cl, Br and I.In another embodiment of formula (I), R ³, when occurring at every turn, be heterocyclic radical independently; Wherein R ³in heterocyclic radical separately optionally by one or more CO (O) R ⁶replace.

In an embodiment of formula (I), R ⁶, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ⁶in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁹, OR ⁹, SR ⁹, S (O) R ⁹, SO ₂r ⁹, NHR ⁹, N (R ⁹) ₂, C (O) R ⁹, C (O) NH ₂, C (O) NHR ⁹, C (O) N (R ⁹) ₂, NHC (O) R ⁹, NR ⁹c (O) R ⁹, NHSO ₂r ⁹, NHC (O) OR ⁹, SO ₂nH ₂, SO ₂nHR ⁹, SO ₂n (R ⁹) ₂, NHC (O) NH ₂, NHC (O) NHR ⁹, OH, (O), C (O) OH, N ₃, CN, NH ₂, CF ₃, CF ₂cF ₃, F, Cl, Br and I.In another embodiment of formula (I), R ⁶it is alkyl when occurring at every turn.

In an embodiment of formula (I), R ⁴, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ⁴in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁷, OR ⁷, SR ⁷, S (O) R ⁷, SO ₂r ⁷, C (O) R ⁷, CO (O) R ⁷, OC (O) R ⁷, OC (O) OR ⁷, NH ₂, NHR ⁷, N (R ⁷) ₂, NHC (O) R ⁷, NR ⁷c (O) R ⁷, NHS (O) ₂r ⁷, NR ⁷s (O) ₂r ⁷, NHC (O) OR ⁷, NR ⁷c (O) OR ⁷, NHC (O) NH ₂, NHC (O) NHR ⁷, NHC (O) N (R ⁷) ₂, NR ⁷c (O) NHR ⁷, NR ⁷c (O) N (R ⁷) ₂, C (O) NH ₂, C (O) NHR ⁷, C (O) N (R ⁷) ₂, C (O) NHOH, C (O) NHOR ⁷, C (O) NHSO ₂r ⁷, C (O) NR ⁷sO ₂r ⁷, SO ₂nH ₂, SO ₂nHR ⁷, SO ₂n (R ⁷) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁷, C (N) N (R ⁷) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, OR ¹⁰, SR ¹⁰, S (O) R ¹⁰, C (O) C (O) R ¹⁰, SO ₂r ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, OC (O) R ¹⁰, OC (O) OR ¹⁰, NH ₂, NHR ¹⁰, N (R ¹⁰) ₂, NHC (O) R ¹⁰, NR ¹⁰c (O) R ¹⁰, NHS (O) ₂r ¹⁰, NR ¹⁰s (O) ₂r ¹⁰, NHC (O) OR ¹⁰, NR ¹⁰c (O) OR ¹⁰, NHC (O) NH ₂, NHC (O) NHR ¹⁰, NHC (O) N (R ¹⁰) ₂, NR ¹⁰c (O) NHR ¹⁰, NR ¹⁰c (O) N (R ¹⁰) ₂, C (O) NH ₂, C (O) NHR ¹⁰, C (O) N (R ¹⁰) ₂, C (O) NHOH, C (O) NHOR ¹⁰, C (O) NHSO ₂r ¹⁰, C (O) NR ¹⁰sO ₂r ¹⁰, SO ₂nH ₂, SO ₂nHR ¹⁰, SO ₂n (R ¹⁰) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹⁰, C (N) N (R ¹⁰) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (I), R ⁴, when occurring at every turn, independently selected from alkyl and heterocyclic radical; Wherein R ⁴in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ⁷, F, Cl, Br and I; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.In another embodiment of formula (I), R ⁴it is heterocyclic radical when occurring at every turn.In another embodiment of formula (I), R ⁴it is heterocyclic radical when occurring at every turn; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.

In an embodiment of formula (I), R ⁷, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group.In another embodiment of formula (I), R ⁷, when occurring at every turn, be heterocyclic radical independently.

In an embodiment of formula (I), R ¹⁰, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹⁰in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, S (O) R ¹¹, SO ₂r ¹¹, C (O) R ¹¹, CO (O) R ¹¹, OC (O) R ¹¹, OC (O) OR ¹¹, NH ₂, NHR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, NR ¹¹c (O) R ¹¹, NHS (O) ₂r ¹¹, NR ¹¹s (O) ₂r ¹¹, NHC (O) OR ¹¹, NR ¹¹c (O) OR ¹¹, NHC (O) NH ₂, NHC (O) NHR ¹¹, NHC (O) N (R ¹¹) ₂, NR ¹¹c (O) NHR ¹¹, NR ¹¹c (O) N (R ¹¹) ₂, C (O) NH ₂, C (O) NHR ¹¹, C (O) N (R ¹¹) ₂, C (O) NHOH, C (O) NHOR ¹¹, C (O) NHSO ₂r ¹¹, C (O) NR ¹¹sO ₂r ¹¹, SO ₂nH ₂, SO ₂nHR ¹¹, SO ₂n (R ¹¹) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹¹, C (N) N (R ¹¹) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ¹⁰in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced independently selected from following substituting group by one or more separately: R ¹², OR ¹², SR ¹², S (O) R ¹², SO ₂r ¹², C (O) R ¹², CO (O) R ¹², OC (O) R ¹², OC (O) OR ¹², NH ₂, NHR ¹², N (R ¹²) ₂, NHC (O) R ¹², NR ¹²c (O) R ¹², NHS (O) ₂r ¹², NR ¹²s (O) ₂r ¹², NHC (O) OR ¹², NR ¹²c (O) OR ¹², NHC (O) NH ₂, NHC (O) NHR ¹², NHC (O) N (R ¹²) ₂, NR ¹²c (O) NHR ¹², NR ¹²c (O) N (R ¹²) ₂, C (O) NH ₂, C (O) NHR ¹², C (O) N (R ¹²) ₂, C (O) NHOH, C (O) NHOR ¹², C (O) NHSO ₂r ¹², C (O) NR ¹²sO ₂r ¹², SO ₂nH ₂, SO ₂nHR ¹², SO ₂n (R ¹²) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹², C (N) N (R ¹²) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I; R ¹¹, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹¹in alkyl, thiazolinyl and alkynyl optionally replaced by alkyl or alkoxyl group separately; Wherein R ¹¹in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced by alkyl or alkoxyl group separately; R ¹², when occurring at every turn, be the independent alkyl selected.In another embodiment of formula (I), R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH, F, Cl, Br and I; Wherein R ¹⁰in heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹², C (O) R ¹², F, Cl, Br and I; R ¹¹, when occurring at every turn, independently selected from alkyl, heterocyclic radical and cycloalkyl; Wherein R ¹¹in alkyl separately optional alkoxy replace; Wherein R ¹¹in heterocyclic radical and cycloalkyl optionally replaced by alkyl separately; R ¹², when occurring at every turn, be the independent alkyl selected.In another embodiment of formula (I), R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH and F; Wherein R ¹⁰in heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹²with C (O) R ¹²; R ¹¹, when occurring at every turn, independently selected from alkyl, heterocyclic radical and cycloalkyl; Wherein R ¹¹in alkyl separately optional alkoxy replace; Wherein R ¹¹in heterocyclic radical and cycloalkyl optionally replaced by alkyl separately; R ¹², when occurring at every turn, be the independent alkyl selected.

One embodiment of the invention relate to compound or its pharmacy acceptable salt, and it can be used as the inhibitor of NAMPT, and this compound has formula (I)

Formula (I);

Wherein

X ¹for CR ¹and X ²for CR ¹;

Y ¹for

R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, F and Cl;

R ²independently selected from C ₄-C ₆-alkyl and aryl; Wherein R ²in C ₄-C ₆-alkyl is separately by one or more R ³replace; Wherein R ²in aryl optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴and CN;

R ³, when occurring at every turn, be heterocyclic radical; Wherein R ³in heterocyclic radical separately optionally by one or more CO (O) R ⁶replace;

R ⁴, when occurring at every turn, independently selected from alkyl and heterocyclic radical; Wherein R ⁴in alkyl separately optionally by one or more R ⁷replace;

R ⁶, when occurring at every turn, be alkyl independently;

R ⁷, when occurring at every turn, be heterocyclic radical independently;

Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰with CO (O) R ¹⁰;

R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH and F; Wherein R ¹⁰in heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹²with C (O) R ¹²;

R ¹¹, when occurring at every turn, independently selected from alkyl, heterocyclic radical and cycloalkyl; Wherein R ¹¹in alkyl separately optional alkoxy replace; Wherein R ¹¹in heterocyclic radical optionally replaced by alkyl separately; With

R ¹², when occurring at every turn, be the independent alkyl selected.

Another embodiment relates to the compound with formula (I) again, and it comprises embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, and its pharmacy acceptable salt.

the embodiment of formula (II)

On the other hand, the invention provides formula (II) compound

(II)；

With its pharmacy acceptable salt; Wherein X ¹, X ², R ¹and R ²as herein to as described in formula (I).

One embodiment of the invention relate to formula (II) compound or its pharmacy acceptable salt;

Wherein

X ¹for N and X ²for CR ¹; Or

X ¹for CR ¹and X ²for N; Or

X ¹for CR ¹and X ²for CR ¹;

R ¹², when occurring at every turn, be the independent alkyl selected.

In an embodiment of formula (II), X ¹for N and X ²for CR ¹.In another embodiment of formula (II), X ¹for CR ¹and X ²for N.In another embodiment of formula (II), X ¹for CR ¹and X ²for CR ¹.In another embodiment of formula (II), X ¹for CR ¹, X ²for CR ¹, and R ¹when occurring at every turn independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, OH, NH ₂, CN, NO ₂, F, Cl, Br and I.In another embodiment of formula (II), X ¹for CR ¹, X ²for CR ¹, and R ¹when occurring at every turn independently selected from hydrogen, alkyl, F, Cl, Br and I.In another embodiment of formula (II), X ¹for CR ¹, X ²for CR ¹and R ¹be hydrogen when occurring at every turn.

In an embodiment of formula (II), R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, OH, NH ₂, CN, NO ₂, F, Cl, Br and I.In another embodiment of formula (II), R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, F, Cl, Br and I.In another embodiment of formula (II), R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, F and Cl.In another embodiment of formula (II), R ¹be hydrogen when occurring at every turn.

In an embodiment of formula (II), R ²independently selected from C ₄-C ₆-alkyl, C ₄-C ₆-thiazolinyl, C ₄-C ₆-alkynyl, aryl, 3-12 unit heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ²in C ₄-C ₆-alkyl, C ₄-C ₆-thiazolinyl and C ₄-C ₆-alkynyl is replaced independently selected from following substituting group by one or more separately: R ³, OR ³, SR ³, S (O) R ³, SO ₂r ³, C (O) R ³, CO (O) R ³, OC (O) R ³, OC (O) OR ³, NH ₂, NHR ³, N (R ³) ₂, NHC (O) R ³, NR ³c (O) R ³, NHS (O) ₂r ³, NR ³s (O) ₂r ³, NHC (O) OR ³, NR ³c (O) OR ³, NHC (O) NH ₂, NHC (O) NHR ³, NHC (O) N (R ³) ₂, NR ³c (O) NHR ³, NR ³c (O) N (R ³) ₂, C (O) NH ₂, C (O) NHR ³, C (O) N (R ³) ₂, C (O) NHOH, C (O) NHOR ³, C (O) NHSO ₂r ³, C (O) NR ³sO ₂r ³, SO ₂nH ₂, SO ₂nHR ³, SO ₂n (R ³) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ³, C (N) N (R ³) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ²in aryl, 3-12 unit heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, SR ⁴, S (O) R ⁴, SO ₂r ⁴, C (O) R ⁴, CO (O) R ⁴, OC (O) R ⁴, OC (O) OR ⁴, NH ₂, NHR ⁴, N (R ⁴) ₂, NHC (O) R ⁴, NR ⁴c (O) R ⁴, NHS (O) ₂r ⁴, NR ⁴s (O) ₂r ⁴, NHC (O) OR ⁴, NR ⁴c (O) OR ⁴, NHC (O) NH ₂, NHC (O) NHR ⁴, NHC (O) N (R ⁴) ₂, NR ⁴c (O) NHR ⁴, NR ⁴c (O) N (R ⁴) ₂, C (O) NH ₂, C (O) NHR ⁴, C (O) N (R ⁴) ₂, C (O) NHOH, C (O) NHOR ⁴, C (O) NHSO ₂r ⁴, C (O) NR ⁴sO ₂r ⁴, SO ₂nH ₂, SO ₂nHR ⁴, SO ₂n (R ⁴) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁴, C (N) N (R ⁴) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (II), R ²independently selected from C ₄-C ₆-alkyl and aryl; Wherein R ²in C ₄-C ₆-alkyl is replaced independently selected from following substituting group by one or more separately: R ³, F, Cl, Br and I; Wherein R ²in aryl optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴, CN, F, Cl, Br and I.In another embodiment of formula (II), R ²independently selected from C ₄-C ₆-alkyl and aryl; Wherein R ²in C ₄-C ₆-alkyl is separately by one or more R ³replace; Wherein R ²in aryl optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴and CN.In another embodiment of formula (II), R ²for C ₄-C ₆-alkyl; Wherein R ²in C ₄-C ₆-alkyl is separately by one or more R ³replace.In another embodiment of formula (II), R ²for aryl; Wherein R ²in aryl replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴and CN.In another embodiment of formula (II), R ²for aryl; Wherein R ²in aryl separately by C (O) NHR ⁴replace.In another embodiment of formula (II), R ²for phenyl; Wherein R ²in phenyl separately by C (O) NHR ⁴replace.In another embodiment of formula (II), R ²for phenyl; Wherein R ²in phenyl separately by an OR ⁴replace.In another embodiment of formula (II), R ²for phenyl; Wherein R ²in phenyl separately by a R ⁴replace.

In an embodiment of formula (II), R ³, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group and heterocyclic radical; Wherein R ³in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁵, OR ⁵, SR ⁵, S (O) R ⁵, SO ₂r ⁵, C (O) R ⁵, CO (O) R ⁵, OC (O) R ⁵, OC (O) OR ⁵, NH ₂, NHR ⁵, N (R ⁵) ₂, NHC (O) R ⁵, NR ⁵c (O) R ⁵, NHS (O) ₂r ⁵, NR ⁵s (O) ₂r ⁵, NHC (O) OR ⁵, NR ⁵c (O) OR ⁵, NHC (O) NH ₂, NHC (O) NHR ⁵, NHC (O) N (R ⁵) ₂, NR ⁵c (O) NHR ⁵, NR ⁵c (O) N (R ⁵) ₂, C (O) NH ₂, C (O) NHR ⁵, C (O) N (R ⁵) ₂, C (O) NHOH, C (O) NHOR ⁵, C (O) NHSO ₂r ⁵, C (O) NR ⁵sO ₂r ⁵, SO ₂nH ₂, SO ₂nHR ⁵, SO ₂n (R ⁵) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁵, C (N) N (R ⁵) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ³in aryl, cycloalkyl, cycloalkenyl group and heterocyclic radical optionally replaced independently selected from following substituting group by one or more separately: R ⁶, OR ⁶, SR ⁶, S (O) R ⁶, SO ₂r ⁶, C (O) R ⁶, CO (O) R ⁶, OC (O) R ⁶, OC (O) OR ⁶, NH ₂, NHR ⁶, N (R ⁶) ₂, NHC (O) R ⁶, NR ⁶c (O) R ⁶, NHS (O) ₂r ⁶, NR ⁶s (O) ₂r ⁶, NHC (O) OR ⁶, NR ⁶c (O) OR ⁶, NHC (O) NH ₂, NHC (O) NHR ⁶, NHC (O) N (R ⁶) ₂, NR ⁶c (O) NHR ⁶, NR ⁶c (O) N (R ⁶) ₂, C (O) NH ₂, C (O) NHR ⁶, C (O) N (R ⁶) ₂, C (O) NHOH, C (O) NHOR ⁶, C (O) NHSO ₂r ⁶, C (O) NR ⁶sO ₂r ⁶, SO ₂nH ₂, SO ₂nHR ⁶, SO ₂n (R ⁶) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁶, C (N) N (R ⁶) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (II), R ³, when occurring at every turn, be heterocyclic radical independently; Wherein R ³in heterocyclic radical optionally replaced independently selected from following substituting group by one or more separately: CO (O) R ⁶, F, Cl, Br and I.In another embodiment of formula (II), R ³, when occurring at every turn, be heterocyclic radical independently; Wherein R ³in heterocyclic radical separately optionally by one or more CO (O) R ⁶replace.

In an embodiment of formula (II), R ⁶, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ⁶in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁹, OR ⁹, SR ⁹, S (O) R ⁹, SO ₂r ⁹, NHR ⁹, N (R ⁹) ₂, C (O) R ⁹, C (O) NH ₂, C (O) NHR ⁹, C (O) N (R ⁹) ₂, NHC (O) R ⁹, NR ⁹c (O) R ⁹, NHSO ₂r ⁹, NHC (O) OR ⁹, SO ₂nH ₂, SO ₂nHR ⁹, SO ₂n (R ⁹) ₂, NHC (O) NH ₂, NHC (O) NHR ⁹, OH, (O), C (O) OH, N ₃, CN, NH ₂, CF ₃, CF ₂cF ₃, F, Cl, Br and I.In another embodiment of formula (II), R ⁶it is alkyl when occurring at every turn.

In an embodiment of formula (II), R ⁴, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ⁴in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁷, OR ⁷, SR ⁷, S (O) R ⁷, SO ₂r ⁷, C (O) R ⁷, CO (O) R ⁷, OC (O) R ⁷, OC (O) OR ⁷, NH ₂, NHR ⁷, N (R ⁷) ₂, NHC (O) R ⁷, NR ⁷c (O) R ⁷, NHS (O) ₂r ⁷, NR ⁷s (O) ₂r ⁷, NHC (O) OR ⁷, NR ⁷c (O) OR ⁷, NHC (O) NH ₂, NHC (O) NHR ⁷, NHC (O) N (R ⁷) ₂, NR ⁷c (O) NHR ⁷, NR ⁷c (O) N (R ⁷) ₂, C (O) NH ₂, C (O) NHR ⁷, C (O) N (R ⁷) ₂, C (O) NHOH, C (O) NHOR ⁷, C (O) NHSO ₂r ⁷, C (O) NR ⁷sO ₂r ⁷, SO ₂nH ₂, SO ₂nHR ⁷, SO ₂n (R ⁷) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁷, C (N) N (R ⁷) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, OR ¹⁰, SR ¹⁰, S (O) R ¹⁰, C (O) C (O) R ¹⁰, SO ₂r ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, OC (O) R ¹⁰, OC (O) OR ¹⁰, NH ₂, NHR ¹⁰, N (R ¹⁰) ₂, NHC (O) R ¹⁰, NR ¹⁰c (O) R ¹⁰, NHS (O) ₂r ¹⁰, NR ¹⁰s (O) ₂r ¹⁰, NHC (O) OR ¹⁰, NR ¹⁰c (O) OR ¹⁰, NHC (O) NH ₂, NHC (O) NHR ¹⁰, NHC (O) N (R ¹⁰) ₂, NR ¹⁰c (O) NHR ¹⁰, NR ¹⁰c (O) N (R ¹⁰) ₂, C (O) NH ₂, C (O) NHR ¹⁰, C (O) N (R ¹⁰) ₂, C (O) NHOH, C (O) NHOR ¹⁰, C (O) NHSO ₂r ¹⁰, C (O) NR ¹⁰sO ₂r ¹⁰, SO ₂nH ₂, SO ₂nHR ¹⁰, SO ₂n (R ¹⁰) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹⁰, C (N) N (R ¹⁰) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (II), R ⁴, when occurring at every turn, independently selected from alkyl and heterocyclic radical; Wherein R ⁴in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ⁷, F, Cl, Br and I; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.In another embodiment of formula (II), R ⁴it is heterocyclic radical when occurring at every turn.In another embodiment of formula (II), R ⁴it is heterocyclic radical when occurring at every turn; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.

In an embodiment of formula (II), R ⁷, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group.In another embodiment of formula (II), R ⁷, when occurring at every turn, be heterocyclic radical independently.

In an embodiment of formula (II), R ¹⁰, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹⁰in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, S (O) R ¹¹, SO ₂r ¹¹, C (O) R ¹¹, CO (O) R ¹¹, OC (O) R ¹¹, OC (O) OR ¹¹, NH ₂, NHR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, NR ¹¹c (O) R ¹¹, NHS (O) ₂r ¹¹, NR ¹¹s (O) ₂r ¹¹, NHC (O) OR ¹¹, NR ¹¹c (O) OR ¹¹, NHC (O) NH ₂, NHC (O) NHR ¹¹, NHC (O) N (R ¹¹) ₂, NR ¹¹c (O) NHR ¹¹, NR ¹¹c (O) N (R ¹¹) ₂, C (O) NH ₂, C (O) NHR ¹¹, C (O) N (R ¹¹) ₂, C (O) NHOH, C (O) NHOR ¹¹, C (O) NHSO ₂r ¹¹, C (O) NR ¹¹sO ₂r ¹¹, SO ₂nH ₂, SO ₂nHR ¹¹, SO ₂n (R ¹¹) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹¹, C (N) N (R ¹¹) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ¹⁰in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced independently selected from following substituting group by one or more separately: R ¹², OR ¹², SR ¹², S (O) R ¹², SO ₂r ¹², C (O) R ¹², CO (O) R ¹², OC (O) R ¹², OC (O) OR ¹², NH ₂, NHR ¹², N (R ¹²) ₂, NHC (O) R ¹², NR ¹²c (O) R ¹², NHS (O) ₂r ¹², NR ¹²s (O) ₂r ¹², NHC (O) OR ¹², NR ¹²c (O) OR ¹², NHC (O) NH ₂, NHC (O) NHR ¹², NHC (O) N (R ¹²) ₂, NR ¹²c (O) NHR ¹², NR ¹²c (O) N (R ¹²) ₂, C (O) NH ₂, C (O) NHR ¹², C (O) N (R ¹²) ₂, C (O) NHOH, C (O) NHOR ¹², C (O) NHSO ₂r ¹², C (O) NR ¹²sO ₂r ¹², SO ₂nH ₂, SO ₂nHR ¹², SO ₂n (R ¹²) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹², C (N) N (R ¹²) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I; R ¹¹, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹¹in alkyl, thiazolinyl and alkynyl optionally replaced by alkyl or alkoxyl group separately; Wherein R ¹¹in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced by alkyl or alkoxyl group separately; R ¹², when occurring at every turn, be the independent alkyl selected.In another embodiment of formula (II), R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH, F, Cl, Br and I; Wherein R ¹⁰in heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹², C (O) R ¹², F, Cl, Br and I; R ¹¹, when occurring at every turn, independently selected from alkyl, heterocyclic radical and cycloalkyl; Wherein R ¹¹in alkyl separately optional alkoxy replace; Wherein R ¹¹in heterocyclic radical and cycloalkyl optionally replaced by alkyl separately; R ¹², when occurring at every turn, be the independent alkyl selected.In another embodiment of formula (II), R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH and F; Wherein R ¹⁰in heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹²with C (O) R ¹²; R ¹¹, when occurring at every turn, independently selected from alkyl, heterocyclic radical and cycloalkyl; Wherein R ¹¹in alkyl separately optional alkoxy replace; Wherein R ¹¹in heterocyclic radical and cycloalkyl optionally replaced by alkyl separately; R ¹², when occurring at every turn, be the independent alkyl selected.

One embodiment of the invention relate to compound or its pharmacy acceptable salt, and it can be used as the inhibitor of NAMPT, and this compound has formula (II)

Formula (II);

Wherein

X ¹for CR ¹and X ²for CR ¹;

R ⁶, when occurring at every turn, be alkyl independently;

R ⁷, when occurring at every turn, be heterocyclic radical independently;

R ¹², when occurring at every turn, be the independent alkyl selected.

Another embodiment relates to the compound with formula (II), and it comprises embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, and its pharmacy acceptable salt.

the embodiment of formula (III)

On the other hand, the invention provides formula (III) compound

(III)；

With its pharmacy acceptable salt; Wherein work as R ²during for aryl in formula (I), R ^4xas herein for R ²on substituting group described in.

One embodiment of the invention relate to formula (III) compound or its pharmacy acceptable salt;

Wherein

R ^4xindependently selected from R ⁴, OR ⁴, SR ⁴, S (O) R ⁴, SO ₂r ⁴, C (O) R ⁴, CO (O) R ⁴, OC (O) R ⁴, OC (O) OR ⁴, NH ₂, NHR ⁴, N (R ⁴) ₂, NHC (O) R ⁴, NR ⁴c (O) R ⁴, NHS (O) ₂r ⁴, NR ⁴s (O) ₂r ⁴, NHC (O) OR ⁴, NR ⁴c (O) OR ⁴, NHC (O) NH ₂, NHC (O) NHR ⁴, NHC (O) N (R ⁴) ₂, NR ⁴c (O) NHR ⁴, NR ⁴c (O) N (R ⁴) ₂, C (O) NH ₂, C (O) NHR ⁴, C (O) N (R ⁴) ₂, C (O) NHOH, C (O) NHOR ⁴, C (O) NHSO ₂r ⁴, C (O) NR ⁴sO ₂r ⁴, SO ₂nH ₂, SO ₂nHR ⁴, SO ₂n (R ⁴) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁴, C (N) N (R ⁴) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I;

Wherein by R ⁴and R ⁷the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, OR ¹⁰, SR ¹⁰, S (O) R ¹⁰, C (O) C (O) R ¹⁰, SO ₂r ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, OC (O) R ¹⁰, OC (O) OR ¹⁰, NH ₂, NHR ¹⁰, N (R ¹⁰) ₂, NHC (O) R ¹⁰, NR ¹⁰c (O) R ¹⁰, NHS (O) ₂r ¹⁰, NR ¹⁰s (O) ₂r ¹⁰, NHC (O) OR ¹⁰, NR ¹⁰c (O) OR ¹⁰, NHC (O) NH ₂, NHC (O) NHR ¹⁰, NHC (O) N (R ¹⁰) ₂, NR ¹⁰c (O) NHR ¹⁰, NR ¹⁰c (O) N (R ¹⁰) ₂, C (O) NH ₂, C (O) NHR ¹⁰, C (O) N (R ¹⁰) ₂, C (O) NHOH, C (O) NHOR ¹⁰, C (O) NHSO ₂r ¹⁰, C (O) NR ¹⁰sO ₂r ¹⁰, SO ₂nH ₂, SO ₂nHR ¹⁰, SO ₂n (R ¹⁰) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹⁰, C (N) N (R ¹⁰) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I;

R ¹², when occurring at every turn, be the independent alkyl selected.

In an embodiment of formula (III), R ^4xindependently selected from R ⁴, OR ⁴, SR ⁴, S (O) R ⁴, SO ₂r ⁴, C (O) R ⁴, CO (O) R ⁴, OC (O) R ⁴, OC (O) OR ⁴, NH ₂, NHR ⁴, N (R ⁴) ₂, NHC (O) R ⁴, NR ⁴c (O) R ⁴, NHS (O) ₂r ⁴, NR ⁴s (O) ₂r ⁴, NHC (O) OR ⁴, NR ⁴c (O) OR ⁴, NHC (O) NH ₂, NHC (O) NHR ⁴, NHC (O) N (R ⁴) ₂, NR ⁴c (O) NHR ⁴, NR ⁴c (O) N (R ⁴) ₂, C (O) NH ₂, C (O) NHR ⁴, C (O) N (R ⁴) ₂, C (O) NHOH, C (O) NHOR ⁴, C (O) NHSO ₂r ⁴, C (O) NR ⁴sO ₂r ⁴, SO ₂nH ₂, SO ₂nHR ⁴, SO ₂n (R ⁴) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁴, C (N) N (R ⁴) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (III), R ^4xindependently selected from R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴, CN, F, Cl, Br and I.In another embodiment of formula (III), R ^4xindependently selected from R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴and CN.In another embodiment of formula (III), R ^4xfor C (O) NHR ⁴.In another embodiment of formula (III), R ^4xfor OR ⁴.In another embodiment of formula (III), R ^4xfor R ⁴.

In an embodiment of formula (III), R ⁴, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ⁴in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁷, OR ⁷, SR ⁷, S (O) R ⁷, SO ₂r ⁷, C (O) R ⁷, CO (O) R ⁷, OC (O) R ⁷, OC (O) OR ⁷, NH ₂, NHR ⁷, N (R ⁷) ₂, NHC (O) R ⁷, NR ⁷c (O) R ⁷, NHS (O) ₂r ⁷, NR ⁷s (O) ₂r ⁷, NHC (O) OR ⁷, NR ⁷c (O) OR ⁷, NHC (O) NH ₂, NHC (O) NHR ⁷, NHC (O) N (R ⁷) ₂, NR ⁷c (O) NHR ⁷, NR ⁷c (O) N (R ⁷) ₂, C (O) NH ₂, C (O) NHR ⁷, C (O) N (R ⁷) ₂, C (O) NHOH, C (O) NHOR ⁷, C (O) NHSO ₂r ⁷, C (O) NR ⁷sO ₂r ⁷, SO ₂nH ₂, SO ₂nHR ⁷, SO ₂n (R ⁷) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁷, C (N) N (R ⁷) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, OR ¹⁰, SR ¹⁰, S (O) R ¹⁰, C (O) C (O) R ¹⁰, SO ₂r ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, OC (O) R ¹⁰, OC (O) OR ¹⁰, NH ₂, NHR ¹⁰, N (R ¹⁰) ₂, NHC (O) R ¹⁰, NR ¹⁰c (O) R ¹⁰, NHS (O) ₂r ¹⁰, NR ¹⁰s (O) ₂r ¹⁰, NHC (O) OR ¹⁰, NR ¹⁰c (O) OR ¹⁰, NHC (O) NH ₂, NHC (O) NHR ¹⁰, NHC (O) N (R ¹⁰) ₂, NR ¹⁰c (O) NHR ¹⁰, NR ¹⁰c (O) N (R ¹⁰) ₂, C (O) NH ₂, C (O) NHR ¹⁰, C (O) N (R ¹⁰) ₂, C (O) NHOH, C (O) NHOR ¹⁰, C (O) NHSO ₂r ¹⁰, C (O) NR ¹⁰sO ₂r ¹⁰, SO ₂nH ₂, SO ₂nHR ¹⁰, SO ₂n (R ¹⁰) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹⁰, C (N) N (R ¹⁰) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (III), R ⁴, when occurring at every turn, independently selected from alkyl and heterocyclic radical; Wherein R ⁴in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ⁷, F, Cl, Br and I; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.In another embodiment of formula (III), R ⁴, when occurring at every turn, be heterocyclic radical.In another embodiment of formula (III), R ⁴, when occurring at every turn, be heterocyclic radical; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.

In an embodiment of formula (III), R ⁷, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group.In another embodiment of formula (III), R ⁷, when occurring at every turn, be heterocyclic radical independently.

In an embodiment of formula (III), R ¹⁰, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹⁰in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, S (O) R ¹¹, SO ₂r ¹¹, C (O) R ¹¹, CO (O) R ¹¹, OC (O) R ¹¹, OC (O) OR ¹¹, NH ₂, NHR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, NR ¹¹c (O) R ¹¹, NHS (O) ₂r ¹¹, NR ¹¹s (O) ₂r ¹¹, NHC (O) OR ¹¹, NR ¹¹c (O) OR ¹¹, NHC (O) NH ₂, NHC (O) NHR ¹¹, NHC (O) N (R ¹¹) ₂, NR ¹¹c (O) NHR ¹¹, NR ¹¹c (O) N (R ¹¹) ₂, C (O) NH ₂, C (O) NHR ¹¹, C (O) N (R ¹¹) ₂, C (O) NHOH, C (O) NHOR ¹¹, C (O) NHSO ₂r ¹¹, C (O) NR ¹¹sO ₂r ¹¹, SO ₂nH ₂, SO ₂nHR ¹¹, SO ₂n (R ¹¹) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹¹, C (N) N (R ¹¹) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ¹⁰in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced independently selected from following substituting group by one or more separately: R ¹², OR ¹², SR ¹², S (O) R ¹², SO ₂r ¹², C (O) R ¹², CO (O) R ¹², OC (O) R ¹², OC (O) OR ¹², NH ₂, NHR ¹², N (R ¹²) ₂, NHC (O) R ¹², NR ¹²c (O) R ¹², NHS (O) ₂r ¹², NR ¹²s (O) ₂r ¹², NHC (O) OR ¹², NR ¹²c (O) OR ¹², NHC (O) NH ₂, NHC (O) NHR ¹², NHC (O) N (R ¹²) ₂, NR ¹²c (O) NHR ¹², NR ¹²c (O) N (R ¹²) ₂, C (O) NH ₂, C (O) NHR ¹², C (O) N (R ¹²) ₂, C (O) NHOH, C (O) NHOR ¹², C (O) NHSO ₂r ¹², C (O) NR ¹²sO ₂r ¹², SO ₂nH ₂, SO ₂nHR ¹², SO ₂n (R ¹²) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹², C (N) N (R ¹²) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I; R ¹¹, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹¹in alkyl, thiazolinyl and alkynyl optionally replaced by alkyl or alkoxyl group separately; Wherein R ¹¹in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced by alkyl or alkoxyl group separately; R ¹², when occurring at every turn, be the independent alkyl selected.In another embodiment of formula (III), R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH, F, Cl, Br and I; Wherein R ¹⁰in heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹², C (O) R ¹², F, Cl, Br and I; R ¹¹, when occurring at every turn, independently selected from alkyl, heterocyclic radical and cycloalkyl; Wherein R ¹¹in alkyl separately optional alkoxy replace; Wherein R ¹¹in heterocyclic radical and cycloalkyl optionally replaced by alkyl separately; R ¹², when occurring at every turn, be the independent alkyl selected.In another embodiment of formula (III), R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH and F; Wherein R ¹⁰in heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹²with C (O) R ¹²; R ¹¹, when occurring at every turn, independently selected from alkyl, heterocyclic radical and cycloalkyl; Wherein R ¹¹in alkyl separately optional alkoxy replace; Wherein R ¹¹in heterocyclic radical and cycloalkyl optionally replaced by alkyl separately; R ¹², when occurring at every turn, be the independent alkyl selected.

One embodiment of the invention relate to compound or its pharmacy acceptable salt, and it can be used as the inhibitor of NAMPT, and this compound has formula (III)

Formula (III);

Wherein

R ^4xindependently selected from R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴and CN;

R ⁷, when occurring at every turn, be heterocyclic radical independently;

Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰cO (O) R ¹⁰;

R ¹², when occurring at every turn, be the independent alkyl selected.

Another embodiment relates to the compound with formula (III), and it comprises embodiment 1, 2, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 114, 115, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 157, 158, 159, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, and its pharmacy acceptable salt.

the embodiment of formula (IA)

Formula (IA);

Wherein

X ¹for N and X ²for CR ¹; Or

X ¹for CR ¹and X ²for N; Or

X ¹for CR ¹and X ²for CR ¹;

Y ¹for

R ¹², when occurring at every turn, be the independent alkyl selected.

In an embodiment of formula (IA), X ¹for N and X ²for CR ¹.In another embodiment of formula (IA), X ¹for CR ¹and X ²for N.In another embodiment of formula (IA), X ¹for CR ¹and X ²for CR ¹.In another embodiment of formula (IA), X ¹for CR ¹, X ²for CR ¹and R ¹when occurring at every turn independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, OH, NH ₂, CN, NO ₂, F, Cl, Br and I.In another embodiment of formula (IA), X ¹for CR ¹, X ²for CR ¹and R ¹when occurring at every turn independently selected from hydrogen, alkyl, F, Cl, Br and I.In another embodiment of formula (IA), X ¹for CR ¹, X ²for CR ¹and R ¹be hydrogen when occurring at every turn.

In an embodiment of formula (IA), R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, OH, NH ₂, CN, NO ₂, F, Cl, Br and I.In another embodiment of formula (IA), R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, F, Cl, Br and I.In another embodiment of formula (IA), R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, F and Cl.In another embodiment of formula (IA), R ¹be hydrogen when occurring at every turn.

In an embodiment of formula (IA), Y ¹for

Wherein represent the tie point with carbonyl, represent the tie point with nitrogen-containing hetero aryl.In another embodiment of formula (IA), Y ¹for

Wherein represent the tie point with carbonyl, represent the tie point with nitrogen-containing hetero aryl.In another embodiment of formula (IA), Y ¹for wherein represent the tie point with carbonyl, represent the tie point with nitrogen-containing hetero aryl.

In an embodiment of formula (IA), R ²independently selected from C ₄-C ₆-alkyl, C ₄-C ₆-thiazolinyl, C ₄-C ₆-alkynyl, aryl, 3-12 unit heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ²in C ₄-C ₆-alkyl, C ₄-C ₆-thiazolinyl and C ₄-C ₆-alkynyl is replaced independently selected from following substituting group by one or more separately: R ³, OR ³, SR ³, S (O) R ³, SO ₂r ³, C (O) R ³, CO (O) R ³, OC (O) R ³, OC (O) OR ³, NH ₂, NHR ³, N (R ³) ₂, NHC (O) R ³, NR ³c (O) R ³, NHS (O) ₂r ³, NR ³s (O) ₂r ³, NHC (O) OR ³, NR ³c (O) OR ³, NHC (O) NH ₂, NHC (O) NHR ³, NHC (O) N (R ³) ₂, NR ³c (O) NHR ³, NR ³c (O) N (R ³) ₂, C (O) NH ₂, C (O) NHR ³, C (O) N (R ³) ₂, C (O) NHOH, C (O) NHOR ³, C (O) NHSO ₂r ³, C (O) NR ³sO ₂r ³, SO ₂nH ₂, SO ₂nHR ³, SO ₂n (R ³) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ³, C (N) N (R ³) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ²in aryl, 3-12 unit heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, SR ⁴, S (O) R ⁴, SO ₂r ⁴, C (O) R ⁴, CO (O) R ⁴, OC (O) R ⁴, OC (O) OR ⁴, NH ₂, NHR ⁴, N (R ⁴) ₂, NHC (O) R ⁴, NR ⁴c (O) R ⁴, NHS (O) ₂r ⁴, NR ⁴s (O) ₂r ⁴, NHC (O) OR ⁴, NR ⁴c (O) OR ⁴, NHC (O) NH ₂, NHC (O) NHR ⁴, NHC (O) N (R ⁴) ₂, NR ⁴c (O) NHR ⁴, NR ⁴c (O) N (R ⁴) ₂, C (O) NH ₂, C (O) NHR ⁴, C (O) N (R ⁴) ₂, C (O) NHOH, C (O) NHOR ⁴, C (O) NHSO ₂r ⁴, C (O) NR ⁴sO ₂r ⁴, SO ₂nH ₂, SO ₂nHR ⁴, SO ₂n (R ⁴) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁴, C (N) N (R ⁴) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (IA), R ²independently selected from C ₄-C ₆-alkyl and aryl; Wherein R ²in C ₄-C ₆-alkyl is replaced independently selected from following substituting group by one or more separately: R ³, F, Cl, Br and I; Wherein R ²in aryl optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴, CN, F, Cl, Br and I.In another embodiment of formula (IA), R ²independently selected from C ₄-C ₆-alkyl and aryl; Wherein R ²in C ₄-C ₆-alkyl is separately by one or more R ³replace; Wherein R ²in aryl optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴and CN.In another embodiment of formula (IA), R ²for C ₄-C ₆-alkyl; Wherein R ²in C ₄-C ₆-alkyl is separately by one or more R ³replace.In another embodiment of formula (IA), R ²for aryl; Wherein R ²in aryl replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴and CN.In another embodiment of formula (IA), R ²for aryl; Wherein R ²in aryl separately by C (O) NHR ⁴replace.In another embodiment of formula (IA), R ²for phenyl; Wherein R ²in phenyl separately by C (O) NHR ⁴replace.In another embodiment of formula (IA), R ²for phenyl; Wherein R ²in phenyl separately by an OR ⁴replace.In another embodiment of formula (IA), R ²for phenyl; Wherein R ²in phenyl separately by a R ⁴replace.

In an embodiment of formula (IA), R ³, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group and heterocyclic radical; Wherein R ³in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁵, OR ⁵, SR ⁵, S (O) R ⁵, SO ₂r ⁵, C (O) R ⁵, CO (O) R ⁵, OC (O) R ⁵, OC (O) OR ⁵, NH ₂, NHR ⁵, N (R ⁵) ₂, NHC (O) R ⁵, NR ⁵c (O) R ⁵, NHS (O) ₂r ⁵, NR ⁵s (O) ₂r ⁵, NHC (O) OR ⁵, NR ⁵c (O) OR ⁵, NHC (O) NH ₂, NHC (O) NHR ⁵, NHC (O) N (R ⁵) ₂, NR ⁵c (O) NHR ⁵, NR ⁵c (O) N (R ⁵) ₂, C (O) NH ₂, C (O) NHR ⁵, C (O) N (R ⁵) ₂, C (O) NHOH, C (O) NHOR ⁵, C (O) NHSO ₂r ⁵, C (O) NR ⁵sO ₂r ⁵, SO ₂nH ₂, SO ₂nHR ⁵, SO ₂n (R ⁵) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁵, C (N) N (R ⁵) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ³in aryl, cycloalkyl, cycloalkenyl group and heterocyclic radical optionally replaced independently selected from following substituting group by one or more separately: R ⁶, OR ⁶, SR ⁶, S (O) R ⁶, SO ₂r ⁶, C (O) R ⁶, CO (O) R ⁶, OC (O) R ⁶, OC (O) OR ⁶, NH ₂, NHR ⁶, N (R ⁶) ₂, NHC (O) R ⁶, NR ⁶c (O) R ⁶, NHS (O) ₂r ⁶, NR ⁶s (O) ₂r ⁶, NHC (O) OR ⁶, NR ⁶c (O) OR ⁶, NHC (O) NH ₂, NHC (O) NHR ⁶, NHC (O) N (R ⁶) ₂, NR ⁶c (O) NHR ⁶, NR ⁶c (O) N (R ⁶) ₂, C (O) NH ₂, C (O) NHR ⁶, C (O) N (R ⁶) ₂, C (O) NHOH, C (O) NHOR ⁶, C (O) NHSO ₂r ⁶, C (O) NR ⁶sO ₂r ⁶, SO ₂nH ₂, SO ₂nHR ⁶, SO ₂n (R ⁶) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁶, C (N) N (R ⁶) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (IA), R ³, when occurring at every turn, be heterocyclic radical independently; Wherein R ³in heterocyclic radical optionally replaced independently selected from following substituting group by one or more separately: CO (O) R ⁶, F, Cl, Br and I.In another embodiment of formula (IA), R ³, when occurring at every turn, be heterocyclic radical independently; Wherein R ³in heterocyclic radical separately optionally by one or more CO (O) R ⁶replace.

In an embodiment of formula (IA), R ⁶, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ⁶in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁹, OR ⁹, SR ⁹, S (O) R ⁹, SO ₂r ⁹, NHR ⁹, N (R ⁹) ₂, C (O) R ⁹, C (O) NH ₂, C (O) NHR ⁹, C (O) N (R ⁹) ₂, NHC (O) R ⁹, NR ⁹c (O) R ⁹, NHSO ₂r ⁹, NHC (O) OR ⁹, SO ₂nH ₂, SO ₂nHR ⁹, SO ₂n (R ⁹) ₂, NHC (O) NH ₂, NHC (O) NHR ⁹, OH, (O), C (O) OH, N ₃, CN, NH ₂, CF ₃, CF ₂cF ₃, F, Cl, Br and I.In another embodiment of formula (IA), R ⁶it is alkyl when occurring at every turn.

In an embodiment of formula (IA), R ⁴, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ⁴in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁷, OR ⁷, SR ⁷, S (O) R ⁷, SO ₂r ⁷, C (O) R ⁷, CO (O) R ⁷, OC (O) R ⁷, OC (O) OR ⁷, NH ₂, NHR ⁷, N (R ⁷) ₂, NHC (O) R ⁷, NR ⁷c (O) R ⁷, NHS (O) ₂r ⁷, NR ⁷s (O) ₂r ⁷, NHC (O) OR ⁷, NR ⁷c (O) OR ⁷, NHC (O) NH ₂, NHC (O) NHR ⁷, NHC (O) N (R ⁷) ₂, NR ⁷c (O) NHR ⁷, NR ⁷c (O) N (R ⁷) ₂, C (O) NH ₂, C (O) NHR ⁷, C (O) N (R ⁷) ₂, C (O) NHOH, C (O) NHOR ⁷, C (O) NHSO ₂r ⁷, C (O) NR ⁷sO ₂r ⁷, SO ₂nH ₂, SO ₂nHR ⁷, SO ₂n (R ⁷) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁷, C (N) N (R ⁷) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, OR ¹⁰, SR ¹⁰, S (O) R ¹⁰, C (O) C (O) R ¹⁰, SO ₂r ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, OC (O) R ¹⁰, OC (O) OR ¹⁰, NH ₂, NHR ¹⁰, N (R ¹⁰) ₂, NHC (O) R ¹⁰, NR ¹⁰c (O) R ¹⁰, NHS (O) ₂r ¹⁰, NR ¹⁰s (O) ₂r ¹⁰, NHC (O) OR ¹⁰, NR ¹⁰c (O) OR ¹⁰, NHC (O) NH ₂, NHC (O) NHR ¹⁰, NHC (O) N (R ¹⁰) ₂, NR ¹⁰c (O) NHR ¹⁰, NR ¹⁰c (O) N (R ¹⁰) ₂, C (O) NH ₂, C (O) NHR ¹⁰, C (O) N (R ¹⁰) ₂, C (O) NHOH, C (O) NHOR ¹⁰, C (O) NHSO ₂r ¹⁰, C (O) NR ¹⁰sO ₂r ¹⁰, SO ₂nH ₂, SO ₂nHR ¹⁰, SO ₂n (R ¹⁰) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹⁰, C (N) N (R ¹⁰) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (IA), R ⁴, when occurring at every turn, independently selected from alkyl and heterocyclic radical; Wherein R ⁴in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ⁷, F, Cl, Br and I; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.In another embodiment of formula (IA), R ⁴it is heterocyclic radical when occurring at every turn.In another embodiment of formula (IA), R ⁴it is heterocyclic radical when occurring at every turn; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.

In an embodiment of formula (IA), R ⁷, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group.In another embodiment of formula (IA), R ⁷, when occurring at every turn, be heterocyclic radical independently.In another embodiment of formula (IA), R ⁷it is heterocyclic radical when occurring at every turn; Wherein by R ⁷the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.

In an embodiment of formula (IA), R ¹⁰, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹⁰in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, S (O) R ¹¹, SO ₂r ¹¹, C (O) R ¹¹, CO (O) R ¹¹, OC (O) R ¹¹, OC (O) OR ¹¹, NH ₂, NHR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, NR ¹¹c (O) R ¹¹, NHS (O) ₂r ¹¹, NR ¹¹s (O) ₂r ¹¹, NHC (O) OR ¹¹, NR ¹¹c (O) OR ¹¹, NHC (O) NH ₂, NHC (O) NHR ¹¹, NHC (O) N (R ¹¹) ₂, NR ¹¹c (O) NHR ¹¹, NR ¹¹c (O) N (R ¹¹) ₂, C (O) NH ₂, C (O) NHR ¹¹, C (O) N (R ¹¹) ₂, C (O) NHOH, C (O) NHOR ¹¹, C (O) NHSO ₂r ¹¹, C (O) NR ¹¹sO ₂r ¹¹, SO ₂nH ₂, SO ₂nHR ¹¹, SO ₂n (R ¹¹) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹¹, C (N) N (R ¹¹) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ¹⁰in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced independently selected from following substituting group by one or more separately: R ¹², OR ¹², SR ¹², S (O) R ¹², SO ₂r ¹², C (O) R ¹², CO (O) R ¹², OC (O) R ¹², OC (O) OR ¹², NH ₂, NHR ¹², N (R ¹²) ₂, NHC (O) R ¹², NR ¹²c (O) R ¹², NHS (O) ₂r ¹², NR ¹²s (O) ₂r ¹², NHC (O) OR ¹², NR ¹²c (O) OR ¹², NHC (O) NH ₂, NHC (O) NHR ¹², NHC (O) N (R ¹²) ₂, NR ¹²c (O) NHR ¹², NR ¹²c (O) N (R ¹²) ₂, C (O) NH ₂, C (O) NHR ¹², C (O) N (R ¹²) ₂, C (O) NHOH, C (O) NHOR ¹², C (O) NHSO ₂r ¹², C (O) NR ¹²sO ₂r ¹², SO ₂nH ₂, SO ₂nHR ¹², SO ₂n (R ¹²) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹², C (N) N (R ¹²) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I; R ¹¹, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹¹in alkyl, thiazolinyl and alkynyl optionally replaced by alkyl or alkoxyl group separately; Wherein R ¹¹in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced by alkyl or alkoxyl group separately; R ¹², when occurring at every turn, be the independent alkyl selected.In another embodiment of formula (IA), R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH, F, Cl, Br and I; Wherein R ¹⁰in aryl, heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹², C (O) R ¹², F, Cl, Br and I; R ¹¹, when occurring at every turn, independently selected from alkyl, heterocyclic radical and cycloalkyl; Wherein R ¹¹in alkyl separately optional alkoxy replace; Wherein R ¹¹in heterocyclic radical and cycloalkyl optionally replaced by alkyl separately; R ¹², when occurring at every turn, be the independent alkyl selected.In another embodiment of formula (IA), R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH and F; Wherein R ¹⁰in aryl, heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹², C (O) R ¹²and F; R ¹¹, when occurring at every turn, independently selected from alkyl, heterocyclic radical and cycloalkyl; Wherein R ¹¹in alkyl separately optional alkoxy replace; Wherein R ¹¹in heterocyclic radical and cycloalkyl optionally replaced by alkyl separately; R ¹², when occurring at every turn, be the independent alkyl selected.

One embodiment of the invention relate to compound or its pharmacy acceptable salt, and it can be used as the inhibitor of NAMPT, and this compound has formula (IA)

Formula (IA);

Wherein

X ¹for CR ¹and X ²for CR ¹;

Y ¹for

R ³it is heterocyclic radical when occurring at every turn; Wherein R ³in heterocyclic radical separately optionally by one or more CO (O) R ⁶replace;

R ⁶, when occurring at every turn, be alkyl independently;

R ⁷, when occurring at every turn, be heterocyclic radical independently;

Wherein by R ⁴and R ⁷the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰with CO (O) R ¹⁰;

R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH and F; Wherein R ¹⁰in aryl, heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹², C (O) R ¹²and F;

R ¹², when occurring at every turn, be the independent alkyl selected.

Another embodiment relates to the compound with formula (IA), and it comprises

4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) methyl benzoate;

N-(4-cyano-phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

the embodiment of formula (IIA)

On the other hand, the invention provides formula (IIA) compound

(IIA)；

With its pharmacy acceptable salt; Wherein X ¹, X ², R ¹and R ²as herein to as described in formula (IA).

One embodiment of the invention relate to formula (IIA) compound or its pharmacy acceptable salt;

Wherein

X ¹for N and X ²for CR ¹; Or

X ¹for CR ¹and X ²for N; Or

X ¹for CR ¹and X ²for CR ¹;

R ¹², when occurring at every turn, be the independent alkyl selected.

In an embodiment of formula (IIA), X ¹for N and X ²for CR ¹.In another embodiment of formula (IIA), X ¹for CR ¹and X ²for N.In another embodiment of formula (IIA), X ¹for CR ¹and X ²for CR ¹.In another embodiment of formula (IIA), X ¹for CR ¹, X ²for CR ¹and R ¹when occurring at every turn independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, OH, NH ₂, CN, NO ₂, F, Cl, Br and I.In another embodiment of formula (IIA), X ¹for CR ¹, X ²for CR ¹, and R ¹when occurring at every turn independently selected from hydrogen, alkyl, F, Cl, Br and I.In another embodiment of formula (IIA), X ¹for CR ¹, X ²for CR ¹, and R ¹be hydrogen when occurring at every turn.

In an embodiment of formula (IIA), R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, OH, NH ₂, CN, NO ₂, F, Cl, Br and I.In another embodiment of formula (IIA), R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, F, Cl, Br and I.In another embodiment of formula (IIA), R ¹, when occurring at every turn, independently selected from hydrogen, alkyl, F and Cl.In another embodiment of formula (IIA), R ¹be hydrogen when occurring at every turn.

In an embodiment of formula (IIA), R ²independently selected from C ₄-C ₆-alkyl, C ₄-C ₆-thiazolinyl, C ₄-C ₆-alkynyl, aryl, 3-12 unit heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ²in C ₄-C ₆-alkyl, C ₄-C ₆-thiazolinyl and C ₄-C ₆-alkynyl is replaced independently selected from following substituting group by one or more separately: R ³, OR ³, SR ³, S (O) R ³, SO ₂r ³, C (O) R ³, CO (O) R ³, OC (O) R ³, OC (O) OR ³, NH ₂, NHR ³, N (R ³) ₂, NHC (O) R ³, NR ³c (O) R ³, NHS (O) ₂r ³, NR ³s (O) ₂r ³, NHC (O) OR ³, NR ³c (O) OR ³, NHC (O) NH ₂, NHC (O) NHR ³, NHC (O) N (R ³) ₂, NR ³c (O) NHR ³, NR ³c (O) N (R ³) ₂, C (O) NH ₂, C (O) NHR ³, C (O) N (R ³) ₂, C (O) NHOH, C (O) NHOR ³, C (O) NHSO ₂r ³, C (O) NR ³sO ₂r ³, SO ₂nH ₂, SO ₂nHR ³, SO ₂n (R ³) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ³, C (N) N (R ³) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ²in aryl, 3-12 unit heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, SR ⁴, S (O) R ⁴, SO ₂r ⁴, C (O) R ⁴, CO (O) R ⁴, OC (O) R ⁴, OC (O) OR ⁴, NH ₂, NHR ⁴, N (R ⁴) ₂, NHC (O) R ⁴, NR ⁴c (O) R ⁴, NHS (O) ₂r ⁴, NR ⁴s (O) ₂r ⁴, NHC (O) OR ⁴, NR ⁴c (O) OR ⁴, NHC (O) NH ₂, NHC (O) NHR ⁴, NHC (O) N (R ⁴) ₂, NR ⁴c (O) NHR ⁴, NR ⁴c (O) N (R ⁴) ₂, C (O) NH ₂, C (O) NHR ⁴, C (O) N (R ⁴) ₂, C (O) NHOH, C (O) NHOR ⁴, C (O) NHSO ₂r ⁴, C (O) NR ⁴sO ₂r ⁴, SO ₂nH ₂, SO ₂nHR ⁴, SO ₂n (R ⁴) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁴, C (N) N (R ⁴) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (IIA), R ²independently selected from C ₄-C ₆-alkyl and aryl; Wherein R ²in C ₄-C ₆-alkyl is replaced independently selected from following substituting group by one or more separately: R ³, F, Cl, Br and I; Wherein R ²in aryl optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴, CN, F, Cl, Br and I.In another embodiment of formula (IIA), R ²independently selected from C ₄-C ₆-alkyl and aryl; Wherein R ²in C ₄-C ₆-alkyl is separately by one or more R ³replace; Wherein R ²in aryl optionally replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴and CN.In another embodiment of formula (IIA), R ²for C ₄-C ₆-alkyl; Wherein R ²in C ₄-C ₆-alkyl is separately by one or more R ³replace.In another embodiment of formula (IIA), R ²for aryl; Wherein R ²in aryl replaced independently selected from following substituting group by one or more separately: R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴and CN.In another embodiment of formula (IIA), R ²for aryl; Wherein R ²in aryl separately by C (O) NHR ⁴replace.In another embodiment of formula (IIA), R ²for phenyl; Wherein R ²in phenyl separately by C (O) NHR ⁴replace.In another embodiment of formula (IIA), R ²for phenyl; Wherein R ²in phenyl separately by an OR ⁴replace.In another embodiment of formula (IIA), R ²for phenyl; Wherein R ²in phenyl separately by a R ⁴replace.

In an embodiment of formula (IIA), R ³, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group and heterocyclic radical; Wherein R ³in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁵, OR ⁵, SR ⁵, S (O) R ⁵, SO ₂r ⁵, C (O) R ⁵, CO (O) R ⁵, OC (O) R ⁵, OC (O) OR ⁵, NH ₂, NHR ⁵, N (R ⁵) ₂, NHC (O) R ⁵, NR ⁵c (O) R ⁵, NHS (O) ₂r ⁵, NR ⁵s (O) ₂r ⁵, NHC (O) OR ⁵, NR ⁵c (O) OR ⁵, NHC (O) NH ₂, NHC (O) NHR ⁵, NHC (O) N (R ⁵) ₂, NR ⁵c (O) NHR ⁵, NR ⁵c (O) N (R ⁵) ₂, C (O) NH ₂, C (O) NHR ⁵, C (O) N (R ⁵) ₂, C (O) NHOH, C (O) NHOR ⁵, C (O) NHSO ₂r ⁵, C (O) NR ⁵sO ₂r ⁵, SO ₂nH ₂, SO ₂nHR ⁵, SO ₂n (R ⁵) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁵, C (N) N (R ⁵) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ³in aryl, cycloalkyl, cycloalkenyl group and heterocyclic radical optionally replaced independently selected from following substituting group by one or more separately: R ⁶, OR ⁶, SR ⁶, S (O) R ⁶, SO ₂r ⁶, C (O) R ⁶, CO (O) R ⁶, OC (O) R ⁶, OC (O) OR ⁶, NH ₂, NHR ⁶, N (R ⁶) ₂, NHC (O) R ⁶, NR ⁶c (O) R ⁶, NHS (O) ₂r ⁶, NR ⁶s (O) ₂r ⁶, NHC (O) OR ⁶, NR ⁶c (O) OR ⁶, NHC (O) NH ₂, NHC (O) NHR ⁶, NHC (O) N (R ⁶) ₂, NR ⁶c (O) NHR ⁶, NR ⁶c (O) N (R ⁶) ₂, C (O) NH ₂, C (O) NHR ⁶, C (O) N (R ⁶) ₂, C (O) NHOH, C (O) NHOR ⁶, C (O) NHSO ₂r ⁶, C (O) NR ⁶sO ₂r ⁶, SO ₂nH ₂, SO ₂nHR ⁶, SO ₂n (R ⁶) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁶, C (N) N (R ⁶) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (IIA), R ³, when occurring at every turn, be heterocyclic radical independently; Wherein R ³in heterocyclic radical optionally replaced independently selected from following substituting group by one or more separately: CO (O) R ⁶, F, Cl, Br and I.In another embodiment of formula (IIA), R ³, when occurring at every turn, be heterocyclic radical independently; Wherein R ³in heterocyclic radical separately optionally by one or more CO (O) R ⁶replace.

In an embodiment of formula (IIA), R ⁶, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ⁶in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁹, OR ⁹, SR ⁹, S (O) R ⁹, SO ₂r ⁹, NHR ⁹, N (R ⁹) ₂, C (O) R ⁹, C (O) NH ₂, C (O) NHR ⁹, C (O) N (R ⁹) ₂, NHC (O) R ⁹, NR ⁹c (O) R ⁹, NHSO ₂r ⁹, NHC (O) OR ⁹, SO ₂nH ₂, SO ₂nHR ⁹, SO ₂n (R ⁹) ₂, NHC (O) NH ₂, NHC (O) NHR ⁹, OH, (O), C (O) OH, N ₃, CN, NH ₂, CF ₃, CF ₂cF ₃, F, Cl, Br and I.In another embodiment of formula (IIA), R ⁶it is alkyl when occurring at every turn.

In an embodiment of formula (IIA), R ⁴, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ⁴in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁷, OR ⁷, SR ⁷, S (O) R ⁷, SO ₂r ⁷, C (O) R ⁷, CO (O) R ⁷, OC (O) R ⁷, OC (O) OR ⁷, NH ₂, NHR ⁷, N (R ⁷) ₂, NHC (O) R ⁷, NR ⁷c (O) R ⁷, NHS (O) ₂r ⁷, NR ⁷s (O) ₂r ⁷, NHC (O) OR ⁷, NR ⁷c (O) OR ⁷, NHC (O) NH ₂, NHC (O) NHR ⁷, NHC (O) N (R ⁷) ₂, NR ⁷c (O) NHR ⁷, NR ⁷c (O) N (R ⁷) ₂, C (O) NH ₂, C (O) NHR ⁷, C (O) N (R ⁷) ₂, C (O) NHOH, C (O) NHOR ⁷, C (O) NHSO ₂r ⁷, C (O) NR ⁷sO ₂r ⁷, SO ₂nH ₂, SO ₂nHR ⁷, SO ₂n (R ⁷) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁷, C (N) N (R ⁷) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, OR ¹⁰, SR ¹⁰, S (O) R ¹⁰, C (O) C (O) R ¹⁰, SO ₂r ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, OC (O) R ¹⁰, OC (O) OR ¹⁰, NH ₂, NHR ¹⁰, N (R ¹⁰) ₂, NHC (O) R ¹⁰, NR ¹⁰c (O) R ¹⁰, NHS (O) ₂r ¹⁰, NR ¹⁰s (O) ₂r ¹⁰, NHC (O) OR ¹⁰, NR ¹⁰c (O) OR ¹⁰, NHC (O) NH ₂, NHC (O) NHR ¹⁰, NHC (O) N (R ¹⁰) ₂, NR ¹⁰c (O) NHR ¹⁰, NR ¹⁰c (O) N (R ¹⁰) ₂, C (O) NH ₂, C (O) NHR ¹⁰, C (O) N (R ¹⁰) ₂, C (O) NHOH, C (O) NHOR ¹⁰, C (O) NHSO ₂r ¹⁰, C (O) NR ¹⁰sO ₂r ¹⁰, SO ₂nH ₂, SO ₂nHR ¹⁰, SO ₂n (R ¹⁰) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹⁰, C (N) N (R ¹⁰) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (IIA), R ⁴, when occurring at every turn, independently selected from alkyl and heterocyclic radical; Wherein R ⁴in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ⁷, F, Cl, Br and I; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.In another embodiment of formula (IIA), R ⁴it is heterocyclic radical when occurring at every turn.In another embodiment of formula (IIA), R ⁴it is heterocyclic radical when occurring at every turn; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.

In an embodiment of formula (IIA), R ⁷, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group.In another embodiment of formula (IIA), R ⁷, when occurring at every turn, be heterocyclic radical independently.In another embodiment of formula (IIA), R ⁷it is heterocyclic radical when occurring at every turn; Wherein by R ⁷the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.

In an embodiment of formula (IIA), R ¹⁰, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹⁰in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, S (O) R ¹¹, SO ₂r ¹¹, C (O) R ¹¹, CO (O) R ¹¹, OC (O) R ¹¹, OC (O) OR ¹¹, NH ₂, NHR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, NR ¹¹c (O) R ¹¹, NHS (O) ₂r ¹¹, NR ¹¹s (O) ₂r ¹¹, NHC (O) OR ¹¹, NR ¹¹c (O) OR ¹¹, NHC (O) NH ₂, NHC (O) NHR ¹¹, NHC (O) N (R ¹¹) ₂, NR ¹¹c (O) NHR ¹¹, NR ¹¹c (O) N (R ¹¹) ₂, C (O) NH ₂, C (O) NHR ¹¹, C (O) N (R ¹¹) ₂, C (O) NHOH, C (O) NHOR ¹¹, C (O) NHSO ₂r ¹¹, C (O) NR ¹¹sO ₂r ¹¹, SO ₂nH ₂, SO ₂nHR ¹¹, SO ₂n (R ¹¹) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹¹, C (N) N (R ¹¹) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ¹⁰in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced independently selected from following substituting group by one or more separately: R ¹², OR ¹², SR ¹², S (O) R ¹², SO ₂r ¹², C (O) R ¹², CO (O) R ¹², OC (O) R ¹², OC (O) OR ¹², NH ₂, NHR ¹², N (R ¹²) ₂, NHC (O) R ¹², NR ¹²c (O) R ¹², NHS (O) ₂r ¹², NR ¹²s (O) ₂r ¹², NHC (O) OR ¹², NR ¹²c (O) OR ¹², NHC (O) NH ₂, NHC (O) NHR ¹², NHC (O) N (R ¹²) ₂, NR ¹²c (O) NHR ¹², NR ¹²c (O) N (R ¹²) ₂, C (O) NH ₂, C (O) NHR ¹², C (O) N (R ¹²) ₂, C (O) NHOH, C (O) NHOR ¹², C (O) NHSO ₂r ¹², C (O) NR ¹²sO ₂r ¹², SO ₂nH ₂, SO ₂nHR ¹², SO ₂n (R ¹²) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹², C (N) N (R ¹²) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I; R ¹¹, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹¹in alkyl, thiazolinyl and alkynyl optionally replaced by alkyl or alkoxyl group separately; Wherein R ¹¹in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced by alkyl or alkoxyl group separately; R ¹², when occurring at every turn, be the independent alkyl selected.In another embodiment of formula (IIA), R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH, F, Cl, Br and I; Wherein R ¹⁰in aryl, heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹², C (O) R ¹², F, Cl, Br and I; R ¹¹, when occurring at every turn, independently selected from alkyl, heterocyclic radical and cycloalkyl; Wherein R ¹¹in alkyl separately optional alkoxy replace; Wherein R ¹¹in heterocyclic radical and cycloalkyl optionally replaced by alkyl separately; R ¹², when occurring at every turn, be the independent alkyl selected.In another embodiment of formula (IIA), R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH and F; Wherein R ¹⁰in aryl, heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹², C (O) R ¹²and F; R ¹¹, when occurring at every turn, independently selected from alkyl, heterocyclic radical and cycloalkyl; Wherein R ¹¹in alkyl separately optional alkoxy replace; Wherein R ¹¹in heterocyclic radical and cycloalkyl optionally replaced by alkyl separately; R ¹², when occurring at every turn, be the independent alkyl selected.

One embodiment of the invention relate to compound or its pharmacy acceptable salt, and it can be used as the inhibitor of NAMPT, and this compound has formula (IIA)

Formula (IIA);

Wherein

X ¹for CR ¹and X ²for CR ¹;

R ⁶, when occurring at every turn, be alkyl independently;

R ⁷, when occurring at every turn, be heterocyclic radical independently;

R ¹², when occurring at every turn, be the independent alkyl selected.

Another embodiment relates to the compound with formula (IIA), and it comprises

4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) methyl benzoate;

N-(4-cyano-phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

the embodiment of formula (IIIA)

On the other hand, the invention provides formula (IIIA) compound

(IIIA)；

With its pharmacy acceptable salt; Wherein work as R ²during for aryl in formula (IA), R ^4xas herein for R ²on substituting group described in.

One embodiment of the invention relate to formula (IIIA) compound or its pharmacy acceptable salt;

Wherein

R ¹², when occurring at every turn, be the independent alkyl selected.

In an embodiment of formula (IIIA), R ^4xindependently selected from R ⁴, OR ⁴, SR ⁴, S (O) R ⁴, SO ₂r ⁴, C (O) R ⁴, CO (O) R ⁴, OC (O) R ⁴, OC (O) OR ⁴, NH ₂, NHR ⁴, N (R ⁴) ₂, NHC (O) R ⁴, NR ⁴c (O) R ⁴, NHS (O) ₂r ⁴, NR ⁴s (O) ₂r ⁴, NHC (O) OR ⁴, NR ⁴c (O) OR ⁴, NHC (O) NH ₂, NHC (O) NHR ⁴, NHC (O) N (R ⁴) ₂, NR ⁴c (O) NHR ⁴, NR ⁴c (O) N (R ⁴) ₂, C (O) NH ₂, C (O) NHR ⁴, C (O) N (R ⁴) ₂, C (O) NHOH, C (O) NHOR ⁴, C (O) NHSO ₂r ⁴, C (O) NR ⁴sO ₂r ⁴, SO ₂nH ₂, SO ₂nHR ⁴, SO ₂n (R ⁴) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁴, C (N) N (R ⁴) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (IIIA), R ^4xindependently selected from R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴, CN, F, Cl, Br and I.In another embodiment of formula (IIIA), R ^4xindependently selected from R ⁴, OR ⁴, CO (O) R ⁴, C (O) NHR ⁴and CN.In another embodiment of formula (IIIA), R ^4xfor C (O) NHR ⁴.In another embodiment of formula (IIIA), R ^4xfor OR ⁴.In another embodiment of formula (IIIA), R ^4xfor R ⁴.

In an embodiment of formula (IIIA), R ⁴, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ⁴in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ⁷, OR ⁷, SR ⁷, S (O) R ⁷, SO ₂r ⁷, C (O) R ⁷, CO (O) R ⁷, OC (O) R ⁷, OC (O) OR ⁷, NH ₂, NHR ⁷, N (R ⁷) ₂, NHC (O) R ⁷, NR ⁷c (O) R ⁷, NHS (O) ₂r ⁷, NR ⁷s (O) ₂r ⁷, NHC (O) OR ⁷, NR ⁷c (O) OR ⁷, NHC (O) NH ₂, NHC (O) NHR ⁷, NHC (O) N (R ⁷) ₂, NR ⁷c (O) NHR ⁷, NR ⁷c (O) N (R ⁷) ₂, C (O) NH ₂, C (O) NHR ⁷, C (O) N (R ⁷) ₂, C (O) NHOH, C (O) NHOR ⁷, C (O) NHSO ₂r ⁷, C (O) NR ⁷sO ₂r ⁷, SO ₂nH ₂, SO ₂nHR ⁷, SO ₂n (R ⁷) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ⁷, C (N) N (R ⁷) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, OR ¹⁰, SR ¹⁰, S (O) R ¹⁰, C (O) C (O) R ¹⁰, SO ₂r ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, OC (O) R ¹⁰, OC (O) OR ¹⁰, NH ₂, NHR ¹⁰, N (R ¹⁰) ₂, NHC (O) R ¹⁰, NR ¹⁰c (O) R ¹⁰, NHS (O) ₂r ¹⁰, NR ¹⁰s (O) ₂r ¹⁰, NHC (O) OR ¹⁰, NR ¹⁰c (O) OR ¹⁰, NHC (O) NH ₂, NHC (O) NHR ¹⁰, NHC (O) N (R ¹⁰) ₂, NR ¹⁰c (O) NHR ¹⁰, NR ¹⁰c (O) N (R ¹⁰) ₂, C (O) NH ₂, C (O) NHR ¹⁰, C (O) N (R ¹⁰) ₂, C (O) NHOH, C (O) NHOR ¹⁰, C (O) NHSO ₂r ¹⁰, C (O) NR ¹⁰sO ₂r ¹⁰, SO ₂nH ₂, SO ₂nHR ¹⁰, SO ₂n (R ¹⁰) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹⁰, C (N) N (R ¹⁰) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I.In another embodiment of formula (IIIA), R ⁴, when occurring at every turn, independently selected from alkyl and heterocyclic radical; Wherein R ⁴in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ⁷, F, Cl, Br and I; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.In another embodiment of formula (IIIA), R ⁴, when occurring at every turn, be heterocyclic radical.In another embodiment of formula (IIIA), R ⁴, when occurring at every turn, be heterocyclic radical; Wherein by R ⁴the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.

In an embodiment of formula (IIIA), R ⁷, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group.In another embodiment of formula (IIIA), R ⁷, when occurring at every turn, be heterocyclic radical independently.In another embodiment of formula (IIIA), R ⁷it is heterocyclic radical when occurring at every turn; Wherein by R ⁷the cyclic group represented optionally is replaced independently selected from following substituting group by one or more independently: R ¹⁰, C (O) C (O) R ¹⁰, C (O) R ¹⁰, CO (O) R ¹⁰, F, Cl, Br and I.

In an embodiment of formula (IIIA), R ¹⁰, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹⁰in alkyl, thiazolinyl and alkynyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, S (O) R ¹¹, SO ₂r ¹¹, C (O) R ¹¹, CO (O) R ¹¹, OC (O) R ¹¹, OC (O) OR ¹¹, NH ₂, NHR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, NR ¹¹c (O) R ¹¹, NHS (O) ₂r ¹¹, NR ¹¹s (O) ₂r ¹¹, NHC (O) OR ¹¹, NR ¹¹c (O) OR ¹¹, NHC (O) NH ₂, NHC (O) NHR ¹¹, NHC (O) N (R ¹¹) ₂, NR ¹¹c (O) NHR ¹¹, NR ¹¹c (O) N (R ¹¹) ₂, C (O) NH ₂, C (O) NHR ¹¹, C (O) N (R ¹¹) ₂, C (O) NHOH, C (O) NHOR ¹¹, C (O) NHSO ₂r ¹¹, C (O) NR ¹¹sO ₂r ¹¹, SO ₂nH ₂, SO ₂nHR ¹¹, SO ₂n (R ¹¹) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹¹, C (N) N (R ¹¹) ₂, CNOH, CNOCH ₃, OH, (O), CN, N ₃, NO ₂, F, Cl, Br and I; Wherein R ¹⁰in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced independently selected from following substituting group by one or more separately: R ¹², OR ¹², SR ¹², S (O) R ¹², SO ₂r ¹², C (O) R ¹², CO (O) R ¹², OC (O) R ¹², OC (O) OR ¹², NH ₂, NHR ¹², N (R ¹²) ₂, NHC (O) R ¹², NR ¹²c (O) R ¹², NHS (O) ₂r ¹², NR ¹²s (O) ₂r ¹², NHC (O) OR ¹², NR ¹²c (O) OR ¹², NHC (O) NH ₂, NHC (O) NHR ¹², NHC (O) N (R ¹²) ₂, NR ¹²c (O) NHR ¹², NR ¹²c (O) N (R ¹²) ₂, C (O) NH ₂, C (O) NHR ¹², C (O) N (R ¹²) ₂, C (O) NHOH, C (O) NHOR ¹², C (O) NHSO ₂r ¹², C (O) NR ¹²sO ₂r ¹², SO ₂nH ₂, SO ₂nHR ¹², SO ₂n (R ¹²) ₂, C (O) H, C (O) OH, C (N) NH ₂, C (N) NHR ¹², C (N) N (R ¹²) ₂, CNOH, CNOCH ₃, OH, CN, N ₃, NO ₂, F, Cl, Br and I; R ¹¹, when occurring at every turn, independently selected from alkyl, thiazolinyl, alkynyl, aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group; Wherein R ¹¹in alkyl, thiazolinyl and alkynyl optionally replaced by alkyl or alkoxyl group separately; Wherein R ¹¹in aryl, heterocyclic radical, cycloalkyl and cycloalkenyl group optionally replaced by alkyl or alkoxyl group separately; R ¹², when occurring at every turn, be the independent alkyl selected.In another embodiment of formula (IIIA), R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH, F, Cl, Br and I; Wherein R ¹⁰in aryl, heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹², C (O) R ¹², F, Cl, Br and I; R ¹¹, when occurring at every turn, independently selected from alkyl, heterocyclic radical and cycloalkyl; Wherein R ¹¹in alkyl separately optional alkoxy replace; Wherein R ¹¹in heterocyclic radical and cycloalkyl optionally replaced by alkyl separately; R ¹², when occurring at every turn, be the independent alkyl selected.In another embodiment of formula (IIIA), R ¹⁰, when occurring at every turn, independently selected from alkyl, aryl, heterocyclic radical and cycloalkyl; Wherein R ¹⁰in alkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹¹, OR ¹¹, SR ¹¹, N (R ¹¹) ₂, NHC (O) R ¹¹, OH and F; Wherein R ¹⁰in aryl, heterocyclic radical and cycloalkyl optionally replaced independently selected from following substituting group by one or more separately: R ¹², C (O) R ¹²and F; R ¹¹, when occurring at every turn, independently selected from alkyl, heterocyclic radical and cycloalkyl; Wherein R ¹¹in alkyl separately optional alkoxy replace; Wherein R ¹¹in heterocyclic radical and cycloalkyl optionally replaced by alkyl separately; R ¹², when occurring at every turn, be the independent alkyl selected.

One embodiment of the invention relate to compound or its pharmacy acceptable salt, and it can be used as the inhibitor of NAMPT, and this compound has formula (IIIA)

Formula (IIIA);

Wherein

R ⁷, when occurring at every turn, be heterocyclic radical independently;

R ¹², when occurring at every turn, be the independent alkyl selected.

Another embodiment relates to the compound with formula (IIIA), and it comprises

4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) methyl benzoate;

N-(4-cyano-phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

N-(4-{ [(3R)-1-(2,3-dimethylbutanoyl) pyrrolidin-3-yl] oxygen base } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide; With its pharmacy acceptable salt.

pharmaceutical composition, combination treatment, methods for the treatment of and administration

Another embodiment comprises the pharmaceutical composition containing the compound and vehicle with formula (I).

Another embodiment comprises the method for the treatment of mammiferous cancer, and it comprises, and give to treat to Mammals can the compound with formula (I) of receiving amount.

Another embodiment relates to the composition for the treatment of the disease expressing NAMPT during disease, and described composition comprises the compound with formula (I) of vehicle and treatment significant quantity.

Another embodiment relates to the method expressing the disease of NAMPT during disease for the treatment of patient, and described method comprises the compound with formula (I) giving to treat significant quantity to this patient.

Another embodiment relates to the composition being used for the treatment of following disease: inflammation and tissue repair obstacle, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic conditions, tetter, comprises psoriasis, the skin injury of allergic dermatitis and induced by ultraviolet irradiation, autoimmune disorder, comprise systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, mandatory spondylitis, tissue and organ rejection, alzheimer's disease, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein said cancer selected from breast cancer, prostate cancer, lung cancer, colorectal carcinoma, cervical cancer, ovarian cancer, skin carcinoma, CNS cancer, bladder cancer, carcinoma of the pancreas, leukemia, lymphoma or Hokdkin disease, emaciation, the inflammation relevant with some viral infection to infection, comprise acquired immune deficiency syndrome (AIDS) (AIDS), adult respiratory distress syndrome, and ataxia-telangiectasia, described composition comprises the compound with formula (I) of vehicle and treatment significant quantity.

Another embodiment relates to the method for the following disease for the treatment of patient: inflammation and tissue repair obstacle, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic conditions, tetter, comprises psoriasis, the skin injury of allergic dermatitis and induced by ultraviolet irradiation, autoimmune disorder, comprise systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, mandatory spondylitis, tissue and organ rejection, alzheimer's disease, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein said cancer selected from breast cancer, prostate cancer, lung cancer, colorectal carcinoma, cervical cancer, ovarian cancer, skin carcinoma, CNS cancer, bladder cancer, carcinoma of the pancreas, leukemia, lymphoma or Hokdkin disease, emaciation, the inflammation relevant with some viral infection to infection, comprise acquired immune deficiency syndrome (AIDS) (AIDS), adult respiratory distress syndrome, and ataxia-telangiectasia, described method comprises the compound with formula (I) giving to treat significant quantity to this patient.

Another embodiment relates to the composition being used for the treatment of the disease expressing NAMPT during disease, and described composition comprises the compound with formula (I) of vehicle and treatment significant quantity with a kind of additional treatment agent for the treatment of significant quantity or more than a kind of additional treatment agent.

Another embodiment relates to the method expressing the disease of NAMPT during disease being used for the treatment of patient, described method comprise to this patient give treat significant quantity the compound with formula (I) and treatment significant quantity a kind of additional treatment agent or more than a kind of additional treatment agent.

Another embodiment relates to the composition being used for the treatment of following disease: inflammation and tissue repair obstacle, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic conditions, tetter, comprises psoriasis, the skin injury of allergic dermatitis and induced by ultraviolet irradiation, autoimmune disorder, comprise systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, mandatory spondylitis, tissue and organ rejection, alzheimer's disease, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein said cancer selected from breast cancer, prostate cancer, lung cancer, colorectal carcinoma, cervical cancer, ovarian cancer, skin carcinoma, CNS cancer, bladder cancer, carcinoma of the pancreas, leukemia, lymphoma or Hokdkin disease, emaciation, the inflammation relevant with some viral infection to infection, comprise acquired immune deficiency syndrome (AIDS) (AIDS), adult respiratory distress syndrome, and ataxia-telangiectasia, described composition comprises the compound with formula (I) of vehicle and treatment significant quantity with a kind of additional treatment agent for the treatment of significant quantity or more than a kind of additional treatment agent.

Another embodiment relates to the method for the following disease for the treatment of patient: inflammation and tissue repair obstacle, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic conditions, tetter, comprises psoriasis, the skin injury of allergic dermatitis and induced by ultraviolet irradiation, autoimmune disorder, comprise systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, mandatory spondylitis, tissue and organ rejection, alzheimer's disease, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein said cancer selected from breast cancer, prostate cancer, lung cancer, colorectal carcinoma, cervical cancer, ovarian cancer, skin carcinoma, CNS cancer, bladder cancer, carcinoma of the pancreas, leukemia, lymphoma or Hokdkin disease, emaciation, the inflammation relevant with some viral infection to infection, comprise acquired immune deficiency syndrome (AIDS) (AIDS), adult respiratory distress syndrome, and ataxia-telangiectasia, described method comprise to this patient give treat significant quantity the compound with formula (I) and treatment significant quantity a kind of additional treatment agent or more than a kind of additional treatment agent.

The metabolite with the compound of formula (I) produced by external or internal metabolism process also may be used for treating the disease relevant to NAMPT.

Can in vitro or internal metabolism also may be used for treating the disease relevant to NAMPT to form some precursor compound with the compound of formula (I).

The compound with formula (I) can exist with acid salt, base addition salt or zwitterionic form.Between separation period or prepare the salt of compound after compound purifying.The acid salt of compound is derived from those of this compound and acid-respons.Such as, the acetate of described compound, adipate, alginates, supercarbonate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, two gluconate, formate, fumarate, glycerophosphate, glutaminate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, lactobionate, lactic acid salt, maleate, tri-methyl p-toluenesulfonate salt, mesylate, naphthalenesulfonate, nicotinate, oxalate, embonate, pectate, persulphate, phosphoric acid salt, picrate, propionic salt, succinate, tartrate, thiocyanate-, trichloroacetate, trifluoroacetate, tosilate, be believed to comprise in the present invention with undecane hydrochlorate.The base addition salt of described compound is as those of the reaction of the oxyhydroxide of lithium, sodium, potassium, calcium and magnesium, carbonate or supercarbonate derived from this compound and positively charged ion.

Can such as through cheek, through eye, oral, infiltration, parenteral (in intramuscular, intraperitoneal, breastbone, intravenously, subcutaneous), rectum, locally, there is through skin or vagina the compound of formula (I).

The compound with formula (I) for the treatment of significant quantity depends on the recipient for the treatment of, illness to be treated and its severity, composition, administration time, route of administration, treatment time length, compound efficacy, its clearance rate containing described compound and whether jointly gives other drug.For the preparation of being about 0.03 to about 200 mg/kg body weight with single dose or with the amount with the compound of the present invention of formula (I) that fractionated dose gives the composition of patient every day.Single dose compositions contains the combination of this tittle or its approximate number.

Have formula (I) compound can with or not administration together with vehicle.Vehicle comprises such as coating material or additive, as absorption enhancer, antioxidant, tackiness agent, buffer reagent, Drug coating, tinting material, thinner, disintegrating agent, emulsifying agent, extender, filler, seasonings, wetting Agent for Printing Inks, lubricant, essence, sanitas, propelling agent, releasing agent, sterilizing agent, sweeting agent, solubilizing agent, wetting agent and its mixture.

For the preparation of comprising such as agar with the vehicle comprising the composition of the compound with formula (I) of solid dosage oral administration, alginic acid, aluminium hydroxide, benzylalcohol, peruscabin, 1,3 butylene glycol, carbomer, Viscotrol C, Mierocrystalline cellulose, rhodia, theobroma oil, W-Gum, Semen Maydis oil, Oleum Gossypii semen, Crospovidone, triglyceride, ethanol, ethyl cellulose, Laurate ethyl, ethyl oleate, fatty acid ester, gelatin, germ oil, glucose, glycerine, peanut (groundnut) oil, Vltra tears, Virahol, isotonic saline solution, lactose, magnesium hydroxide, Magnesium Stearate, Fructus Hordei Germinatus, N.F,USP MANNITOL, monoglyceride, sweet oil, peanut (peanut) oil, potassium phosphate salt, yam starch, polyvidone, propylene glycol, Ringer's solution, Thistle oil, sesame oil, Xylo-Mucine, sodium phosphate salt, sodium lauryl sulphate, sorbose sodium alkoxide, soybean oil, stearic acid, sodium stearyl base ester, sucrose, tensio-active agent, talcum, tragacanth gum, tetrahydrofurfuryl alcohol, triglyceride level, water, with its mixture.For the preparation of will with liquid dosage form through eye or peroral administrationly comprise the vehicle with the composition of the compound of formula (I) of the present invention and comprise the fatty acid ester of such as 1,3 butylene glycol, Viscotrol C, Semen Maydis oil, Oleum Gossypii semen, ethanol, sorbitan, germ oil, peanut oil, glycerine, Virahol, sweet oil, polyoxyethylene glycol, propylene glycol, sesame oil, water and its mixture.Such as Chlorofluorocarbons (CFCs), ethanol, water and its mixture is comprised for the preparation of wanting the vehicle with the composition of the compound of formula (I) of the present invention that comprises of infiltration administration.Such as 1,3 butylene glycol, Viscotrol C, Semen Maydis oil, Oleum Gossypii semen, dextrose, germ oil, peanut (groundnut) oil, liposome, oleic acid, sweet oil, peanut (peanut) oil, Ringer's solution, Thistle oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chlorrde solution, water and its mixture is comprised for the preparation of wanting the vehicle with the composition of the compound of formula (I) of the present invention that comprises of administered parenterally.Such as theobroma oil, polyoxyethylene glycol, wax and its mixture is comprised for the preparation of wanting the vehicle with the composition of the compound of formula (I) of the present invention that comprises of rectum or vagina administration.

Have formula (I) compound estimate with alkylating agent, angiogenesis inhibitor, antibody, metabolic antagonist, antimitotic agent, antiproliferative, antiviral agent, aurora kinase inhibitors, apoptosis promotor (such as Bcl-xL, Bcl-w and Bfl-1) inhibitor, death receptor pathway * activator, Bcr-Abl kinase inhibitor, BiTE(Bi-Specific T cell Engager) antibody, antibody drug conjugate, biological response modifier, cell cycle protein dependent kinase inhibitor, cell cycle inhibitor, cyclooxygenase-2 inhibitor, DVDs, leukemia viral oncogene homologue (ErbB2) acceptor inhibitor, growth factor receptor inhibitors, heat shock protein(HSP) (HSP)-90 inhibitor, histon deacetylase (HDAC) (HDAC) inhibitor, hormonotherapy medicine, immune substance, the inhibitor of apoptotic proteins (IAPs) inhibitor, intercalation microbiotic, kinase inhibitor, kinesin inhibitor, Jak2 inhibitor, the mammalian target of rapamycin inhibitor, microRNA ' s, the extracellular signal-regulated kinase inhibitor that mitogen activates, multivalent binding proteins, NSAID (non-steroidal anti-inflammatory drug) (NSAIDs), poly-ADP (adenosine diphosphate (ADP))-ribose polymerase (PARP) inhibitor, platinum chemotherapeutics, polo-sample kinases (Plk) inhibitor, PI-3 kinase (PI3K) inhibitor, proteasome inhibitor, purine analogue, pyrimidine analogue, receptor tyrosine kinase inhibitors, retinoid/deltoids, plant alkaloid, little suppression Yeast Nucleic Acid (siRNAs), topoisomerase enzyme inhibitor, ubiquitin ligase inhibitor etc. use together and are useful when using with one or more these agents.

BiTE antibody is the bi-specific antibody by guiding T-cell challenges cancer cells in conjunction with two cells simultaneously.T-cell attacks target cancer cells subsequently.The example of BiTE antibody comprises adecatumumab(Micromet MT201), blinatumomab (Micromet MT103) etc.Be not subject to theory, but one of mechanism of T-cell initiation target cancer cell-apoptosis is the exocytosis by molten born of the same parents' property grain fraction (comprising pore-forming protein and granzyme B).

SiRNAs is the molecule with endogenous RNA base or chemical modification Nucleotide.This modification does not eliminate cytoactive, but gives the cellular potency of stability and/or the raising improved.The example of chemical modification comprise thiophosphoric acid class, 2'-deoxynucleotide, containing 2'-OCH ₃ribonucleotide, 2'-F-ribonucleotide, 2'-methoxyethyl ribonucleoside acid, its combination etc.SiRNA can have different lengths (such as 10-200 bps) and structure (such as hairpin structure, list/double-strand, bulge, breach/gap, mismatch) and process to provide active gene reticent in cell.Double-strand siRNA(dsRNA) Nucleotide of equal amts can be had on each chain (blunt end) or asymmetric end (overhang).The overhang of 1-2 Nucleotide can be present in be had on justice and/or antisense strand, and is present on 5'-and/or the 3'-end of given chain.

Multivalent binding proteins is the associated proteins comprising two or more antigen binding sites.Multivalent binding proteins is engineered to be had three or more antigen binding sites and not to be usually naturally occurring antibody.Term " multi-specific binding protein " refers to can the associated proteins of or uncorrelated target relevant in conjunction with two or more.Two variable domain (DVD) associated proteins is the tetravalence or the multivalent binding proteins that comprise two or more antigen binding sites.Such DVDs can be (can in conjunction with two or more antigen) of monospecific (can in conjunction with an antigen) or polyspecific.The DVD associated proteins comprising two heavy chain DVD polypeptide and two light chain DVD polypeptide is referred to as DVD Ig's.Each semi-inclusive heavy chain DVD polypeptide, light chain DVD polypeptide and two antigen binding sites of DVD Ig.Each binding site contains a heavy chain variable domain and a light-chain variable domain, and each antigen binding site has total 6 CDR to participate in antigen combination.

Alkylating agent comprises altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), Chlorambucil, CLORETAZINE ^?(laromustine, VNP 40101M), endoxan, dacarbazine (decarbazine), Emcyt, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), Mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, mustargen N-oxide compound, ranomustine, Temozolomide, thiophene are for group, TREANDA ^?(bendamustine), treosulfan, rofosfamide etc.

Angiogenesis inhibitor comprises endothelium-specific receptor Tyrosylprotein kinase (Tie-2) inhibitor, EGF-R ELISA (EGFR) inhibitor, insulin-like growth factor-2 acceptor (IGFR-2) inhibitor, MMP-2 (MMP-2) inhibitor, Matrix Metalloproteinase-9 (MMP-9) inhibitor, platelet-derived growth factor receptor (PDGFR) inhibitor, thrombospondin analogue, vascular endothelial growth factor receptor Tyrosylprotein kinase (VEGFR) inhibitor etc.

Metabolic antagonist comprises ALIMTA ^?(pemetrexed disodium, LY231514, MTA), 5-azacitidine, XELODA ^?(capecitabine), carmofur, LEUSTAT ^?(CldAdo), Clofarex, cytosine arabinoside, cytosine arabinoside octadecyl phosphoric acid salt, cytarabin, Decitabine, Deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-RIBOSE base imidazoles-4-methane amide), enocitabine, ethnylcytidine, fludarabine, separately or the 5 FU 5 fluorouracil, the GEMZAR that combine with formyl tetrahydrofolic acid ^?(gemcitabine), hydroxyurea, ALKERAN ^?(melphalan), purinethol, Ismipur riboside, methotrexate, mycophenolic acid, Nelzarabine, Nolatrexed (nolatrexed), octadecyl phosphoric acid salt (ocfosfate), pelitrexol, pentostatin, Raltitrexed, ribavirin, triapine, Trimetrexate, S-1, tiazofurine, Tegafur, TS-1, vidarabine, UFT etc.

Antiviral agent comprises ritonavir, Plaquenil etc.

Aurora kinase inhibitors comprises ABT-348, AZD-1152, MLN-8054, VX-680, aurora A-specificity kinase inhibitor, aurora B-specificity kinase inhibitor and pan-aurora kinase inhibitors etc.

Bcl-2 protein inhibitor comprises AT-101((-) gossypol), GENASENSE ^?(G3139 or Ao Limosen (oblimersen) (Bcl-2-target antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'-chlorine (1, 1'-biphenyl)-2-base) methyl) piperazine-1-base) benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfartyl) methyl) propyl group) is amino)-3-nitrobenzene sulfonamide) (ABT-737), N-(4-(4-((2-(4-chloro-phenyl-)-5, 5-dimethyl-1-hexamethylene-1-alkene-1-base) methyl) piperazine-1-base) benzoyl)-4-(((1R)-3-(morpholine-4-base)-1-((phenylsulfartyl) methyl) propyl group) is amino)-3-((trifluoromethyl) alkylsulfonyl) benzsulfamide (ABT-263), GX-070(obatoclax) etc.

Bcr-Abl kinase inhibitor comprises DASATINIB ^?(BMS-354825), GLEEVEC ^?(imatinib) etc.

CDK inhibitor comprises AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 etc.

Cox 2 inhibitor comprises ABT-963, ARCOXIA ^?(Etoricoxib), BEXTRA ^?(valdecoxib), BMS347070, CELEBREX ^?(celecoxib), COX-189(lumiracoxib), CT-3, DERAMAXX ^?(SC 59046), JTE-522,4-methyl-2-(3,4-3,5-dimethylphenyl)-1-(4-aminosulfonylphenyl-1H-pyrroles), MK-663(Etoricoxib), NS-398, Parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX ^?(rofecoxib) etc.

EGFR inhibitor comprises ABX-EGF, anti-EGFR immunoliposome, EGF-vaccine, EMD-7200, ERBITUX ^?(Cetuximab), HR3, IgA antibody, IRESSA ^?(Gefitinib), TARCEVA ^?(erlotinib or OSI-774), TP-38, EGFR fusion rotein, TYKERB ^?(lapatinibditosylate) etc.

ErbB2 acceptor inhibitor comprises CP-724-714, CI-1033(card how for Buddhist nun), HERCEPTIN ^?(trastuzumab), TYKERB ^?(lapatinibditosylate), OMNITARG ^?(2C4, petuzumab), TAK-165, GW-572016(ionafarnib), GW-282974, EKB-569, PI-166, dHER2(HER2 vaccine), APC-8024(HER-2 vaccine), anti-HER/2neu bi-specific antibody, B7.her2IgG3, AS HER2 trifunctional bi-specific antibody, mAB AR-209, mAB 2B-1 etc.

NSC 630176 comprises depsipeptide, LAQ-824, MS-275, trapoxin, Vorinostat (SAHA), TSA, valproic acid etc.

HSP-90 inhibitor comprises 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024,17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB ^?(people's recombinant antibodies of HSP-90), NCS-683664, PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009 etc.

The inhibitor of inhibitor of apoptosis protein comprises HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242 etc.

Antibody drug conjugate comprises anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35, SGN-75 etc.

Death receptor pathway * activator comprises antibody or other reagent of TRAIL, target TRAIL or death receptor (such as DR4 and DR5), as Apomab, his native pearl (conatumumab) of west, ETR2-ST01, GDC0145, (carrying out husky wooden monoclonal antibody), HGS-1029, LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitor comprises Eg5 inhibitor, as AZD4877, ARRY-520; CENPE inhibitor, as GSK923295A etc.

JAK-2 inhibitor comprises CEP-701(lesaurtinib), XL019 and INCB018424 etc.

Mek inhibitor comprises ARRY-142886, ARRY-438162 PD-325901, PD-98059 etc.

MTOR inhibitors comprises AP-23573, CCI-779, everolimus, RAD-001, rapamycin, CCI-779, the competitive TORC1/TORC2 inhibitor of ATP-, comprises PI-103, PP242, PP30, Torin 1 etc.

NSAID (non-steroidal anti-inflammatory drug) comprises AMIGESIC ^?(salsalate), DOLOBID ^?(diflunisal), MOTRIN ^?(Ibuprofen BP/EP), ORUDIS ^?(Ketoprofen BP 93), RELAFEN ^?(nabumetone), FELDENE ^?(piroxicam), Ibuprofen cream, ALEVE ^?(Naproxen Base) and NAPROSYN ^?(Naproxen Base), VOLTAREN ^?(diclofenac), INDOCIN ^?(indomethacin), CLINORIL ^?(sulindac), TOLECTIN ^?(tolmetin), LODINE ^?(R-ETODOLAC), TORADOL ^?(ketorolac), DAYPRO ^?(Taisho)) etc.

PDGFR inhibitor comprises C-451, CP-673, CP-868596 etc.

Platinum chemotherapeutics comprises cis-platinum, ELOXATIN ^?(oxaliplatin), eptalatin, lobaplatin, S 254, PARAPLATIN ^?(carboplatin), Satraplatin, JM473 etc.

Polo-sample kinase inhibitor comprises BI-2536 etc.

PI-3 kinase (PI3K) inhibitor comprises wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765 etc.

Thrombospondin analogue comprises ABT-510, ABT-567, ABT-898, TSP-1 etc.

VEGFR inhibitor comprises AVASTIN ^?(rhuMAb-VEGF), ABT-869, AEE-788, ANGIOZYME (ribozyme (Ribozyme Pharmaceuticals(Boulder of inhibiting angiogenesis, and Chiron CO.), (Emeryville, CA)), Axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN(pegaptamib), NEXAVAR ^?(Xarelto, BAY43-9006), pazopanib (GW-786034), PTK787 (PTK-787, ZK-222584), SUTENT ^?(Sutent, SU-11248), VEGF trap, ZACTIMA (ZD6474, ZD-6474) etc.

Microbiotic comprises intercalation microbiotic aclarubicin, dactinomycin, amrubicin, anthracycline, Zorubicin, BLENOXANE ^?(bleomycin), daunorubicin, CAELYX ^?or MYOCET ^?(liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS ^?(idarubicin), ametycin, Nemorubicin, neocarzinostatin, peplomycin, pirarubicin, butterfly mycin, stimalamer, streptozotocin, VALSTAR ^?(valrubicin), zinostatin etc.

Topoisomerase enzyme inhibitor comprises aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, Belotecan, BN-80915, CAMPTOSAR ^?(CPT-11), camptothecine, CARDIOXANE ^?(ADR-529), fluorine are for health (diflomotecan), edotecarin, ELLENCE ^?or PHARMORUBICIN ^?(epirubicin), Etoposide, Exatecan, 10-hydroxycamptothecine, gefitinib, lurtotecan, mitoxantrone, Rubitecan (orathecin), pirarbucin, China fir fine jade, Rubitecan, sobuzoxane, SN-38, tafluposide, topotecan etc.

Antibody comprises AVASTIN ^?(rhuMAb-VEGF), CD40-specific antibody, chTNT-1/B, promise monoclonal antibody, ERBITUX ^?(Cetuximab), HUMAX-CD4 ^?(pricking wooden monoclonal antibody (zanolimumab)), IGF1R-specific antibody, lintuzumab, PANOREX ^?(Edrecolomab), RENCAREX ^?(WX G250), RITUXAN ^?(Rituximab), ticilimumab, trastuzimab, CD20 Antibody types I and II etc.

ARIMIDEX drawn together by hormonotherapy cartridge bag ^?(Anastrozole), AROMASIN ^?(Exemestane), arzoxifene, CASODEX ^?(bicalutamide), CETROTIDE ^?(cetrorelix), Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2, deslorelin, DESOPAN ^?(Win-24540), dexamethasone, DROGENIL ^?(Drogenil), EVISTA ^?(raloxifene), AFEMA (fadrozole), FARESTON ^?(toremifene), FASLODEX ^?(fulvestrant), FEMARA ^?(letrozole), Formestane, glucocorticosteroid, HECTOROL ^?(doxercalciferol), RENAGEL ^?(2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate), Lasofoxifene, leuprorelin acetate, MEGACE ^?(megestrol), MIFEPREX ^?(mifepristone), NILANDRON (Nilutamide), NOLVADEX ^?(TAMOXIFEN CITRATE), PLENAXIS (abarelix), prednisone, PROPECIA ^?(finasteride), rilostane, SUPREFACT ^?(buserelin), TRELSTAR ^?(luteinizing hormone releasing hormone (LHRH)), VANTAS ^?(histrelin implant), VETORYL ^?(Win-24540 or modrastane), ZOLADEX ^?(fosrelin, goserelin) etc.

Deltoids and retinoid comprise seocalcitol (EB1089, CB1093), lexacalcitrol(KH1060), HPR (fenretinide), PANRETIN ^?(aliretinoin), ATRAGEN ^?(liposome vitamin A acid), TARGRETIN ^?(bexarotene), LGD-1550 etc.

PARP inhibitor comprises ABT-888(veliparib), Aura handkerchief Buddhist nun, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 etc.

Plant alkaloid includes but not limited to vincristine(VCR), vinealeucoblastine(VLB), vindesine, vinorelbine etc.

Proteasome inhibitor comprises VELCADE ^?(Velcade), MG132, NPI-0052, PR-171 etc.

The example of immune substance comprises Interferon, rabbit and other immunostimulant.Interferon, rabbit comprises interferon alpha, Intederon Alpha-2a, Interferon Alpha-2b, interferon beta, interferon-gamma-1a, ACTIMMUNE ^?(gamma interferon 1-b) or interferon-gamma-n1, its combination etc.Other reagent comprises ALFAFERONE ^?(IFN-α), BAM-002(Sleep-promoting factor B), BEROMUN ^?(tasonermin), BEXXAR ^?(tositumomab), CAMPATH ^?(alemtuzumab), CTLA4(cytotoxic lymphocite antigen 4), dacarbazine, denileukin, epratuzumab, GRANOCYTE (lenograstim), lentinan, white corpuscle interferon-alpha, Imiquimod, the anti-CTLA-4 of MDX-010(), melanoma vaccines, mitumomab, Sch-39300, MYLOTARG (WAY-CMA 676 difficult to understand azoles rice star), NEUPOGEN ^?(filgrastim), OncoVAC-CL, OVAREX ^?(oregovomab), pemtumomab(Y-muHMFG1), PROVENGE ^?(sipuleucel-T), sargaramostim, schizophyllum abamectin (sizofilan), teceleukin, THERACYS ^?(bacille Calmette-Guerin vaccine), ubenimex, VIRULIZIN ^?(immunotherapy, Lorus Pharmaceuticals), Z-100(Specific Substance of Maruyama(SSM)), WF-10(Tetrachlorodecaoxide(TCDO)), PROLEUKIN ^?(rIL-2), ZADAXIN ^?(Thymosin-Alpha1), ZENAPAX ^?(Zenapax), ZEVALIN ^?(90Y-ibritumomab tiuxetan) etc.

Biological response modifier is the defense mechanism or the biological respinse that change live organism, if histiocytic survival, growth or differentiation are with the reagent making them have anti-tumor activity, and comprise krestin, lentinan, Schizophyllan, molten chain bacterium PF-3512676(CpG-8954), ubenimex etc.

Pyrimidine analogue comprises cytosine arabinoside (ara C or Arabinoside C), cytarabin, doxifluridine, FLUDARA ^?(fludarabine), 5-FU(5-Fluracil), floxuridine, GEMZAR ^?(gemcitabine), TOMUDEX ^?(ratitrexed), TROXATYL (triacetyl uridine troxacitabine) etc.

Purine analogue comprises LANVIS ^?(Tioguanine) and PURI-NETHOL ^?(purinethol).

Antimitotic agent comprises batabulin, Epothilone D (KOS-862), N-(2-((4-hydroxy phenyl) is amino) pyridin-3-yl)-4-methoxybenzenesulphoismide, ipsapirone (BMS 247550), taxol, TAXOTERE ^?(Docetaxel), PNU100940(109881), a handkerchief soil dragon (patupilone), XRP-9881(larotaxel), Vinflunine, ZK-EPO(synthesize ebormycine) etc.

Ubiquitin ligase inhibitor comprises MDM2 inhibitor if nutlins, NEDD8 inhibitor is as MLN4924 etc.

Compound of the present invention also can be used as the radiosensitizer strengthening radiotherapeutic effect.Radiotherapeutic example comprises external beam radiation therapy, teletherapy, brachytherapy and sealing, unencapsulated source radiotherapy etc.

In addition, the compound with formula (I) can with other following chemotherapeutic agent, as ABRAXANE (ABI-007), ABT-100(farnesyl transferase inhibitor), ADVEXIN ^?(Ad5CMV-p53 vaccine), ALTOCOR ^?or MEVACOR ^?(lovastatin), AMPLIGEN ^?(poly I:poly C12U, synthesis RNA), APTOSYN ^?(exisulind), AREDIA ^?(pamidronic acid), arglabin, L-ASP, Atamestane (1-methyl-3,17-diketone-androstane-Isosorbide-5-Nitrae-diene), AVAGE ^?(Tazarotene), AVE-8062(combreastatin derivative), BEC2(mitumomab), cachectin or cachexin(tumour necrosis factor), canvaxin(vaccine), CEAVAC ^?(cancer vaccine), CELEUK ^?(celmoleukin), CEPLENE ^?(histamine dihydrochloric acid), CERVARIX ^?(Human-papilloma Vaccine), CHOP (C:CYTOXAN ^?(endoxan); H: Zorubicin (hydroxydoxorubicin); O: vincristine(VCR) (ONCOVIN); P: prednisone), CYPAT (cyproterone acetate), combrestatin A4P, DAB (389) EGF(be fused to catalysis and the translocation domain of the diphtheria toxin on human epidermal growth factor via His-Ala connexon) or TransMID-107R (diphtheria toxin), dacarbazine, dactinomycin, DMXAA (DMXAA), eniluracil, EVIZON (lactic acid squalamine), DIMERICINE ^?(T4N5 liposome emulsion), circle suberite lactone (discodermolide), DX-8951f(Exatecan mesylate), enzastaurin, EPO906(epithilone B), GARDASIL ^?(tetravalence human papillomavirus (6,11,16,18 type) recombiant vaccine), GASTRIMMUNE ^?, GENASENSE ^?, GMK(Sphingolipids,sialo combined vaccine), GVAX ^?(prostate cancer vaccine), halofuginone hydrobromide, histerelin, hydroxycarbamide, Ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR(cintredekin besudotox), IL-13-Pseudomonas exotoxin, interferon-' alpha ', interferon-γ, JUNOVAN or MEPACT (rice lumbering peptide), Luo Nafani (lonafarnib), 5,10-CH2-THFA, miltefosine (Hexadecylphosphocholine), NEOVASTAT ^?(AE-941), NEUTREXIN ^?(glucuronic acid trimetrexate), NIPENT ^?(pentostatin), ONCONASE ^?(rnase), ONCOPHAGE ^?(melanoma vaccines treatment), ONCOVAX ^?(IL-2 vaccine), ORATHECIN (Rubitecan), OSIDEM ^?(antibody basilar cell medicine), OVAREX ^?mAb(mouse monoclonal antibody), taxol, PANDIMEX (comprising the aglycone saponin from ginseng of 20 (S) protopanoxadiol (aPPD) and 20 (S) Protopanaxatriol (aPPT)), Victibix, PANVAC ^?cancer vaccine in-VF(research), your (phenoxodiol), Procarbazine of the appropriate Supreme Being of pegaspargase, PEG interferon A, benzene, rebimastat, REMOVAB ^?(catumaxomab), REVLIMID ^?(Revlimid), RSR13(Efaproxiral), SOMATULINE ^?lA(Lanreotide), SORIATANE ^?(Etretin), staurosporine (streptomycete staurospore), talabostat(PT100), TARGRETIN ^?(bexarotene), TAXOPREXIN ^?(DHA-taxol), TELCYTA ^?(canfosfamide, TLK286), temilifene, TEMODAR ^?(Temozolomide), Tesmilifene, Thalidomide, THERATOPE ^?(STn-KLH), amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio) the quinazoline dihydrochlorides of thymitaq(2-), TNFERADE (adenovirus carrier: the DNA vector of the gene containing tumor necrosis factor-alpha), TRACLEER ^?or ZAVESCA ^?(bosentan), vitamin A acid (retinoic acid), Tetrrine, TRISENOX ^?(white arsenic), VIRULIZIN, ukrain(are from the alcaloid-derivatives of pilewort plant), vitaxin(anti-α v β 3 antibody), XCYTRIN ^?(motexafin gadolinium), XINLAY (atrasentan), XYOTAX (paclitaxel poliglumex), YONDELIS ^?(ET-743), ZD-6126, ZINECARD ^?(dexrazoxane), ZOMETA ^?(Zoledronic acid (zolendronic acid)), zorubicin etc.

data

The compound utilizing time resolved fluorescence Resonance energy transfer (TR-FRET) binding analysis method to carry out having formula (I) is as the mensuration of the effectiveness of the binding substances of NAMPT and the inhibitor of NAMPT.

time resolved fluorescence Resonance energy transfer (TR-FRET) the binding analysis method of NAMPT

In pure DMSO by test compounds serial dilution (usual 11 half-logs) to 50X final concentration, then use analysis buffer (50 mM HEPES (NaOH), pH 7.5,100 mM NaCl, 10 mM MgCl ₂, 1 mM DTT, 1% glycerine) and be diluted to 3X and 6% DMSO.6 L are transferred to the 384 low volume plates in hole (Owens Corning #3673).Add the 1.5X solution containing enzyme, probe and antibody of 12 L wherein.Ultimate density in 18 L reactions is 1X analysis buffer, 2% DMSO, 6.8 nM NAMPT (people, recombinant chou, C-terminal His-tag), 200 nM probes (being effectively conjugated to the niacinamide-competitive inhibitor of Oregon Green 488) and the anti-His antibody of 1 nM Tb-(Invitrogen # PV5895).At room temperature make molecular balance 3 hours, then reading (Perkin Elmer on Envision multiple labeling plate reader; Ex=337 nm, Em=520 and 495 nm).By temporal resolution FRET ratio (Em ₅₂₀/ Em ₄₉₅) relative to contrast normalization method, adopt this base of a fruit equation model of four parameter logistics to measure IC50s according to compound concentration curve plotting.

adopt time resolved fluorescence Resonance energy transfer (TR-FRET) the binding analysis method of the NAMPT of PRPP

Compound treatment identical with the analysis that there is not substrate with data processing (as mentioned above).Final concentration is 1X analysis buffer, 2% DMSO, 2 nM NAMPT, 2 nM probes, the anti-His antibody of 1 nM Tb-(Invitrogen # PV5895), 200 M PRPP and 2.5 mM ATP.Within 16 hours, be there is potential enzyme modification to make test compounds in molecular balance before measuring.

Table 1 illustrates the effectiveness of the functional suppression of the compound with formula I NAMPT.

Table 1

Nd=countless certificate.

nAMPT cell proliferating determining

PC3 cell to be seeded in 500 cells/well in the RPMI medium of 90 L containing 10% hot deactivation FBS in 96 hole blackboards (Corning #3904) and at 37 DEG C and 5% CO ₂lower overnight incubation adheres to make cell and hole.Ensuing one day, in pure DMSO by test compounds serial dilution to 1000X final concentration, then use RPMI medium to 10X and 1% DMSO.Then the 10X compound of 10 L is transferred in the hole containing cell to produce 10 times of dilution (10 M to 1 x 10 ^-5m) dose response.At 37 DEG C and 5% CO ₂lower to cell cultures 5 days, then use Cell Titer Glo reagent (Promega #G7571) to measure cell viability.Calculate per-cent inhibiting value and use Assay Explorer software to fit to S shape dose response curve to measure IC50.Suppressing whether to be because NAMPT suppresses to evaluate cell viability, also under 0.3 mM nmn exists, carrying out proliferation assay.

Table 2 illustrates the result of cell proliferating determining.

Table 2

Nd=countless certificate.

The compound of NAMPT is suppressed to can be used for treating the disease wherein relating to NF-KB and activate.These class methods can be used for treating various disease, comprise inflammation and tissue repair obstacle, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic conditions, tetter, comprises psoriasis, the skin injury of allergic dermatitis and induced by ultraviolet irradiation, autoimmune disorder, comprise systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, mandatory spondylitis, tissue and organ rejection, alzheimer's disease, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein said cancer selected from breast cancer, prostate cancer, lung cancer, colorectal carcinoma, cervical cancer, ovarian cancer, skin carcinoma, CNS cancer, bladder cancer, carcinoma of the pancreas, leukemia, lymphoma or Hokdkin disease, emaciation, the inflammation relevant with some viral infection to infection, comprise acquired immune deficiency syndrome (AIDS) (AIDS), adult respiratory distress syndrome, and ataxia-telangiectasia.

Describe in cancer therapy in WO 97/48696 and relate to NAMPT.Describe in immunosuppression in WO 97/48397 and relate to NAMPT.Describe in WO 2003/80054 and relate to NAMPT in the treatment of the disease relating to vasculogenesis.Describe in WO 2008/025857 in the treatment of rheumatoid arthritis and septic shock and relate to NAMPT.Describe in WO 2009/109610 and relate to NAMPT in ischemic prevention and therapy.

Cancer includes but not limited to that neoplastic hematologic disorder and solid tumor types are as acoustic tumor, acute leukemia, Acute Lymphoblastic Leukemia, acute myelogenous leukemia (monocarpotic cellularity, myeloblastic, gland cancer, angiosarcoma, astrocytoma, myelo-monocytic and promyelocytic leukemic cell), acute t-chronic myeloid leukemia, rodent cancer, cholangiocarcinoma, bladder cancer, the cancer of the brain, mammary cancer (comprising estrogen receptor positive mammary cancer), bronchogenic carcinoma, Burkitt lymphoma, cervical cancer, chondrosarcoma, spinal cord knurl, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocyte) leukemia, chronic lymphocytic leukemia, colorectal carcinoma, colorectal carcinoma, craniopharyngioma, cystadenocarcinoma, bad propagation change (dysplasia and change life), embryonal carcinoma, carcinoma of endometrium, endotheliosarcoma, ependymoma, epithelial cancer, erythroleukemia, the esophageal carcinoma, estrogen receptor positive mammary cancer, idiopathic thrombocythemia, Ewing's tumor, fibrosarcoma, cancer of the stomach, sexual cell carcinoma of testis, gestational trophoblastic disease, glioblastoma, head and neck cancer, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, the insensitive prostate cancer of hormone, leiomyosarcoma, liposarcoma, lung cancer (comprising small cell lung cancer and nonsmall-cell lung cancer), lymphangioendothelial sarcoma, lymphangiosarcoma, lymphocytoblast leukemia, (lymphoma, comprises Diffuse Large B-Cell Lymphoma to lymphoma, follicular lymphoma, hodgkin's lymphoma and non Hodgkin lymphoma), bladder, mammary gland, colon, lung, ovary, pancreas, prostate gland, the malignant tumour in skin and uterus and hyperproliferative disorder, the lymphoid malignancies in T cell or B cell source, leukemia, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelomatosis, myelomatosis, myxosarcoma, neuroblastoma, oligodendroglioma, oral carcinoma, osteogenic sarcoma, ovarian cancer, carcinoma of the pancreas, papillary gland cancer, papillary carcinoma, periphery T cell lymphatic cancer, pinealoma, polycythemia, prostate cancer (comprising hormone insensitive (intractable) prostate cancer), the rectum cancer, renal cell carcinoma, retinoblastoma, rhabdosarcoma, sarcoma, sebaceous carcinoma, spermocytoma, skin carcinoma, small cell lung cancer, solid tumor (cancer and sarcoma), cancer of the stomach, squamous cell carcinoma, synovioma, syringocarcinoma, carcinoma of testis (comprising sexual cell carcinoma of testis), thyroid carcinoma, macroglobulinemia Waldenstron, testicular tumor, uterus carcinoma, wilms' tumor etc.

scheme and experiment

Below abbreviation has specified implication.ADDP represents 1,1'-(azo dicarbapentaborane) two piperidines; AD-mixes-β and represents (DHQD) ₂pHAL, K ₃fe (CN) ₆, K ₂cO ₃and K ₂sO ₄mixture; 9-BBN represents 9-borabi cyclo (3.3.1) nonane; Boc represents tert-butoxycarbonyl; (DHQD) ₂pHAL represents hydroquinidine Isosorbide-5-Nitrae-phthalazines two base diethyl ether; DBU represents 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene; DIBAL represents diisobutyl aluminium hydride; DIEA represents diisopropyl ethyl amine; DMAP represents N, N-dimethyl aminopyridine; DMF represents DMF; Dmpe represents two (dimethyl phosphino-) ethane of 1,2-; DMSO represents dimethyl sulfoxide (DMSO); Dppb represents Isosorbide-5-Nitrae-bis-(diphenylphosphino)-butane; Dppe represents two (diphenylphosphino) ethane of 1,2-; Dppf represents two (diphenylphosphino) ferrocene of 1,1'-; Dppm represents two (diphenylphosphino) methane of 1,1-; EDACHCl represents 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; Fmoc represents fluorenylmethoxycarbonyl groups; HATU represents O-(7-azepine benzo triazol-1-yl)-N, N'N'N'-tetramethyl-urea hexafluorophosphate; HMPA represents hexamethylphosphoramide; IPA represents Virahol; MP-BH ₃represent macropore triethyl methyl polystyrene cyano group ammonium borohydride; TEA represents triethylamine; TFA represents trifluoroacetic acid; THF represents tetrahydrofuran (THF); NCS represents N-chloro-succinimide; NMM represents N-methylmorpholine; NMP represents N-crassitude; PPh ₃represent triphenylphosphine.

Following scheme is demonstrated to provide those to be considered to the most useful with step of the present invention that is easy understand with the description of concept aspect.Compound of the present invention can be prepared by synthetic chemistry method, and embodiment illustrates in this article.Be intended to be interpreted as that the order of method steps can change on demand, can replace with reagent, solvent and reaction conditions those that specifically mention on demand, and can on demand by unstable radical protection and deprotection.

scheme

Scheme 1

As shown in scheme 1, formula (1) compound (wherein X ¹, X ²and R ¹described in (I), n is 1 or 2, m is 1 or 2, when n is 1 or 2 and m is 1, X is CH, and X is N or CH when n is 2 and m is 2) lower and formula (2) compound (wherein R can be there is at two (2, the 5-dioxo pyrrolidin-1-base) ester of carbonic acid and alkali (such as but not limited to diisopropyl ethyl amine) ²as described herein) react with the compound providing formula (3).This reaction is at room temperature carried out usually in solvent is such as but not limited to acetonitrile.

Scheme 2

4-(4-aminophenyl) piperidines-1-t-butyl formate can with formula (1) compound (wherein X ¹, X ²and R ¹described in (I), n is 1 or 2, m is 1 or 2, when n is 1 or 2 and m is 1, X is CH, and X is N or CH when n is 2 and m is 2) there is lower reaction with the compound providing formula (4) at two (2, the 5-dioxo pyrrolidin-1-base) ester of carbonic acid and alkali (such as but not limited to diisopropyl ethyl amine).This reaction is at room temperature carried out usually in solvent is such as but not limited to acetonitrile.Preparation formula (5) compound is carried out such as but not limited to trifluoroacetic acid process formula (4) compound by adopting acid in solvent is such as but not limited to methylene dichloride.Formula (7) compound (it is the representative of formula (I) compound) can make formula (5) compound and formula (6) compound (wherein R under existing such as but not limited to diisopropyl ethyl amine at alkali ¹⁰as described herein) react and prepare.This reaction can relate to use carboxyl activator such as but not limited to N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride, ester activator such as but not limited to I-hydroxybenzotriazole hydrate.This reaction is at room temperature carried out usually in solvent is such as but not limited to DMF, N,N-dimethylacetamide or its mixture.Or, formula (5) compound can with formula (8) compound (wherein R ¹⁰as described herein) react to provide formula (9) compound (it is the representative of formula (I) compound).Described reaction is usually carried out and can be carried out at elevated temperatures under the existence of reductive agent such as but not limited to sodium triacetoxy borohydride and acetic acid in solvent is such as but not limited to methyl alcohol.

Scheme 3

As shown in Scheme 3, lower and formula (1) compound (wherein X can be there is such as but not limited to diisopropyl ethyl amine in 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate at two (2, the 5-dioxo pyrrolidin-1-base) ester of carbonic acid and alkali ¹, X ²and R ¹described in (I), n be 1 or 2, m be 1 or 2, when n is 1 or 2 and m is 1, X is CH, and when n is 2 and m is 2, X is N or CH) reaction to provide formula (10) compound.This reaction is at room temperature carried out usually in solvent is such as but not limited to acetonitrile.Can by carrying out preparation formula (11) compound with acid such as but not limited to trifluoroacetic acid process formula (10) compound in solvent is such as but not limited to methylene dichloride.Can by making formula (11) compound and formula (6) compound (wherein R under alkali exists such as but not limited to diisopropyl ethyl amine ¹⁰as described herein) react preparation formula (12) compound (it is the representative of formula (I) compound).This reaction can relate to and uses carboxyl activator such as but not limited to N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride and ester activator such as but not limited to I-hydroxybenzotriazole hydrate.This reaction is at room temperature carried out usually in solvent is such as but not limited to DMF, N,N-dimethylacetamide or its mixture.

Embodiment

Present following examples and be considered to the most useful and the step of the present invention of easy understand and the description of concept aspect to provide those.Use ACD/ChemSketch Ver. 12.5 (20 April 2011), Advanced Chemistry Development Inc., Toronto, or ChemDraw Ver. 9.0.7 (CambridgeSoft Ontario), Cambridge, MA) to each embodiment compound and intermediate name.

experiment

Embodiment 1

N-[4-({ 1-[(2S)-2-methylbutyryl base] azetidine-3-base } oxygen base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide

Embodiment 1A

3-(4-nitrophenoxy) azetidine-1-t-butyl formate

By 3-hydroxy azetidine-1-t-butyl formate (4.0 g, 23.3 mmol), fluoro-4-oil of mirbane (6.1 g of 1-, 43.0 mmol), potassium hydroxide aqueous solution (the 5.9 M solution of 35.5 ml, 209 mmol) and Tetrabutyl amonium bromide (0.975 g, 3.0 mmol) is mixed be incorporated in 40 DEG C at stir and spend the night.This reaction cooled, dilute with water is also extracted with ethyl acetate three times.By the organism drying (sodium sulfate) merged, filter and concentrate.By the flash chromatography eluting resistates of positive to provide title compound.

Embodiment 1B

3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate

In 250 mL SS pressure bottles, by 3-(4-nitrophenoxy) azetidine-1-t-butyl formate (1g, 3.40 mmol) and tetrahydrofuran (THF) (20 ml) is added into 5% carbon, and to carry palladium (wet, 0.200 g, 1.879 mmol) and under 30 psi and room temperature, this mixture is stirred 1 hour.Filter this mixture by nylon membrane and concentrated filtrate to provide title compound.

Embodiment 1C

3-(4-(3-(pyridin-3-yl) azetidine-1-formamido-) phenoxy group) azetidine-1-t-butyl formate

By 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate (1.17 g, 4.43 mmol) and carbonic acid two (2,5-dioxo pyrrolidin-1-base) ester (1.134 g, 4.43 mmol) mixing at room temperature stirring 1 hour in the acetonitrile (22.13 ml).Add 3-(azetidine-3-base) pyridine dihydrochloride (0.948 g, 4.65 mmol) and diisopropyl ethyl amine (3.09 ml, 17.71 mmol) and reaction mixture is stirred and spend the night.Remove acetonitrile by rotary evaporation and resistates is dissolved in methylene dichloride, and with normal-phase chromatography method chromatography to provide title compound.

Embodiment 1D

N-(4-(azetidine-3-base oxygen base) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide

3-(4-(3-(pyridin-3-yl) azetidine-1-formamido-) phenoxy group) azetidine-1-t-butyl formate (800 mg, 1.885 mmol) in methylene dichloride (9.42 mL) is added in 20 mL bottles.Add trifluoroacetic acid (1.4 mL, 18.17 mmol) and at room temperature stir this reaction mixture 1.5 hours.Under reduced pressure remove volatile matter to provide title compound.

Embodiment 1E

(S)-N-(4-(1-(2-methylbutyryl base) azetidine-3-base oxygen base) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide

At room temperature by N-(4-(azetidine-3-base oxygen base) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide (1 g, 1.805 mmol), (S)-2-Methyl Butyric Acid (0.221 g, 2.166 mmol) and N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (0.519 g, 2.71 mmol) mixing in dimethyl formamide (9.03 mL).Add I-hydroxybenzotriazole hydrate (0.415 g, 2.71 mmol) and diisopropyl ethyl amine (0.946 ml, 5.42 mmol) and at room temperature stir this reaction mixture and spend the night.Add water and methylene dichloride and remove organism by transfer pipet.Concentrated also reversed phase chromatography provides (S)-N-(4-(1-(2-methylbutyryl base) azetidine-3-base oxygen base) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide.

table 1.

Substantially prepare following examples as described in Example 1, replace with suitable carboxylic acid with in suitable amine and embodiment 1E with in suitable alcohol, embodiment 1C in embodiment 1A.Some products by flash chromatography, and pass through other products of rp-hplc method purifying.Therefore, some embodiments are separated into trifluoroacetate.

Embodiment 9

N-(4-{1-[(2S)-2-methylbutyryl base]-1,2,3,6-tetrahydropyridine-4-bases } phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide

Embodiment 9A

4-(4-nitrophenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate

In 350 mL sealing load flasks, by bromo-for 1-4-oil of mirbane (4.00 g, 19.80 mmol), 4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base)-5,6-dihydropyridine-1 (2H)-t-butyl formate (6.74 g, 21.78 mmol) and sodium carbonate (4.41 g, 41.6 mmol) mixing in tetrahydrofuran (THF) (60 ml), water (30 ml) and methyl alcohol (10 ml).This mixture is purged circulation by three vacuum/nitrogen.Add [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (II) methylene dichloride (0.485 g, 0.594 mmol), under a nitrogen by this reaction mixture heated overnight at 70 DEG C.Cool this reaction mixture, to dilute with water by ethyl acetate and be separated each layer.Be extracted with ethyl acetate water layer and the concentrated organic layer merged.Normal-phase chromatography method provides title compound.

Embodiment 9B

4-(4-aminophenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate

As described in embodiment 1B, prepare title compound, substitute 3-(4-nitrophenoxy) azetidine-1-t-butyl formate with 4-(4-nitrophenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate.

Embodiment 9C

4-(4-(3-(pyridin-3-yl) azetidine-1-formamido-) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formates

As described in embodiment 1C, prepare title compound, substitute 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate with 4-(4-aminophenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate.

Embodiment 9D

3-(pyridin-3-yl)-N-(4-(1,2,3,6-tetrahydropyridine-4-base) phenyl) azetidine-1-methane amide

As described in embodiment 1D, prepare title compound, substitute 3-(4-(3-(pyridin-3-yl) azetidine-1-formamido-) phenoxy group) azetidine-1-t-butyl formate with 4-(4-(3-(pyridin-3-yl) azetidine-1-formamido-) phenyl) piperidines-1-t-butyl formate.

Embodiment 9E

Title compound is prepared as described in embodiment 1E, with 3-(pyridin-3-yl)-N-(4-(1,2,3,6-tetrahydropyridine-4-base) phenyl) azetidine-1-methane amide substitutes N-(4-(azetidine-3-base oxygen base) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide.

table 2.

Substantially prepare following examples as described in Example 9, replace with suitable carboxylic acid in embodiment 9E.By some products of flash chromatography, and by other products of rp-hplc method purifying.Therefore, some embodiments are separated into trifluoroacetate.

Embodiment 13

4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) methyl benzoate

By 3-(azetidine-3-base) pyridine, two trifluoroacetic acid (75 mg, 0.207 mmol) and diisopropyl ethyl amine (0.109 ml, 0.622 mmol) add in the methylene dichloride (2072 μ l) in 20 mL bottles.Add 4-isocyanato-methyl benzoate (47.7 mg, 0.269 mmol), at room temperature stir this mixture 2 hours and concentrated by rotary evaporation.By normal-phase chromatography method Purification to provide title compound.

Embodiment 14

N-(4-cyano-phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide

As described in embodiment 13, prepare title compound, substitute 4-isocyanato-methyl benzoate with 4-isocyanato-cyanobenzene.

Embodiment 15

4-[4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) butyl] piperidines-1-t-butyl formate

As described in embodiment 1C, prepare title compound, substitute 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate with 4-(4-aminobutyl) piperidines-1-t-butyl formate.

Embodiment 49

3-(pyridin-3-yl)-N-{4-[(tetrahydrofuran (THF)-3-ylmethyl) formamyl] phenyl } azetidine-1-methane amide

Embodiment 49A

4-amino-N-((tetrahydrofuran (THF)-3-base) methyl) benzamide

As described in embodiment 1E, prepare title compound, substitute N-(4-(azetidine-3-base oxygen base) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide with (tetrahydrofuran (THF)-3-base) methylamine and substitute (S)-2-Methyl Butyric Acid with PABA.

Embodiment 49B

As described in embodiment 1C, prepare title compound, substitute 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate by 4-amino-N-((tetrahydrofuran (THF)-3-base) methyl) benzamide.

Embodiment 50

3-(pyridin-3-yl)-N-{4-[1-(tetrahydrochysene-2H-pyrans-4-base ethanoyl) piperidin-4-yl] phenyl } azetidine-1-methane amide

Embodiment 50A

4-(4-(3-(pyridin-3-yl) azetidine-1-formamido-) phenyl) piperidines-1-t-butyl formate

As described in embodiment 1C, prepare title compound, substitute 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate with 4-(4-aminophenyl) piperidines-1-t-butyl formate.

Embodiment 50B

N-(4-(piperidin-4-yl) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide

Embodiment 50C

As described in embodiment 1E, prepare title compound, substitute N-(4-(azetidine-3-base oxygen base) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide with N-(4-(piperidin-4-yl) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide and substitute (S)-2-Methyl Butyric Acid with tetrahydrochysene-2H-pyrans-4-guanidine-acetic acid.

table 3.

Substantially as described in embodiment 50, prepare following examples, substitute with suitable carboxylic acid with in suitable amine and embodiment 50C in embodiment 50A.By some products of flash chromatography, and by other products of rp-hplc method purifying.Therefore, some embodiments are separated into trifluoroacetate.

Embodiment 59

3-[4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) phenyl] tetramethyleneimine-1-t-butyl formate

As described in embodiment 1C, prepare title compound, substitute 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate with 3-(4-aminophenyl) tetramethyleneimine-1-t-butyl formate.

Embodiment 60

(3R)-3-[4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) phenoxy group] tetramethyleneimine-1-t-butyl formate

As embodiment 1A-C prepares title compound, with the 3-hydroxy azetidine-1-t-butyl formate in (R)-3-hydroxyl pyrrolidine-1-t-butyl formate alternate embodiment 1A.

Embodiment 61

(3S)-3-[4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) phenoxy group] tetramethyleneimine-1-t-butyl formate

Title compound is prepared, with the 3-hydroxy azetidine-1-t-butyl formate in (S)-3-hydroxyl pyrrolidine-1-t-butyl formate alternate embodiment 1A as described in embodiment 1A-C.

Embodiment 62

3-[4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) phenyl] azetidine-1-t-butyl formate

As described in embodiment 1C, prepare title compound, substitute 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate with 3-(4-aminophenyl) azetidine-1-t-butyl formate.

Embodiment 63

3-[4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) phenoxy group] azetidine-1-t-butyl formate

Title compound is prepared as described in embodiment 1C.

Embodiment 112

4-[4-({ [3-(2-chloropyridine-3-base) azetidine-1-base] carbonyl } is amino) phenyl] piperidines-1-t-butyl formate

As described in embodiment 1C, prepare title compound, substitute 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate with 4-(4-aminophenyl) piperidines-1-t-butyl formate and substitute 3-(azetidine-3-base) pyridine dihydrochloride with 3-(azetidine-3-base)-2-chloropyridine.

Embodiment 113

4-[4-({ [3-(4-chloropyridine-3-base) azetidine-1-base] carbonyl } is amino) phenyl] piperidines-1-t-butyl formate

As described in embodiment 1C, prepare title compound, substitute 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate with 4-(4-aminophenyl) piperidines-1-t-butyl formate and substitute 3-(azetidine-3-base) pyridine dihydrochloride with 3-(azetidine-3-base)-4-chloropyridine.

Embodiment 116

4-[4-({ [3-(2-fluorine pyridin-3-yl) azetidine-1-base] carbonyl } is amino) phenyl] piperidines-1-t-butyl formate

As described in embodiment 1C, prepare title compound, substitute 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate with 4-(4-aminophenyl) piperidines-1-t-butyl formate and substitute 3-(azetidine-3-base) pyridine dihydrochloride with 3-(azetidine-3-base)-2-fluorine pyridine.

Embodiment 157

N-{4-[1-(2-methyl-propyl)-1H-pyrazoles-4-base] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide

Embodiment 157A

N-(4-bromophenyl)-3-(pyridin-3-yl) azetidine-1-methane amide

As described in embodiment 13, prepare title compound, substitute 4-isocyanato-methyl benzoate with 1-bromo-4-isocyanato-benzene.

Embodiment 157B

Title compound is prepared, with 1-isobutyl--4-(4,4 as described in embodiment 9A, 5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base)-1H-pyrazoles substitutes 4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base)-5,6-dihydropyridine-1 (2H)-t-butyl formates and substitute the bromo-4-oil of mirbane of 1-with N-(4-bromophenyl)-3-(pyridin-3-yl) azetidine-1-methane amide.

Embodiment 158

N-[4-(1-propyl group-1H-pyrazoles-4-base) phenyl]-3-(pyridin-3-yl) azetidine-1-methane amide

Title compound is prepared as described in embodiment 157, with 1-propyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) 1-isobutyl--4-(4,4 in-1H-pyrazoles alternate embodiment 157B, 5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base)-1H-pyrazoles.

Embodiment 162

4-(pyridin-3-yl)-N-(4-{ [1-(tetrahydrochysene-2H-pyrans-4-base ethanoyl) piperidin-4-yl] oxygen base } phenyl) piperazine-1-methane amide

Embodiment 162A

4-(piperidin-4-yl oxygen base) aniline

As described in embodiment 1D, prepare title compound, substitute 3-(4-(3-(pyridin-3-yl) azetidine-1-formamido-) phenoxy group) azetidine-1-t-butyl formate with 4-(4-amino-benzene oxygen) piperidines-1-t-butyl formate.

Embodiment 162B

1-(4-(4-amino-benzene oxygen) piperidin-1-yl)-2-(tetrahydrochysene-2H-pyrans-4-base) ethyl ketone

As described in embodiment 1E, prepare title compound, substitute N-(4-(azetidine-3-base oxygen base) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide and alternative (the S)-2-Methyl Butyric Acid of 2-(tetrahydrochysene-2H-pyrans-4-base) acetic acid with 4-(piperidin-4-yl oxygen base) aniline.

Embodiment 162C

As described in embodiment 1C, prepare title compound, substitute 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate with 1-(4-(4-amino-benzene oxygen) piperidin-1-yl)-2-(tetrahydrochysene-2H-pyrans-4-base) ethyl ketone and substitute 3-(azetidine-3-base) pyridine dihydrochloride with 1-(pyridin-3-yl) piperazine.

Embodiment 231

N-{4-[1-(cyclopentyl-methyl) piperidin-4-yl] phenyl }-3-(pyridin-3-yl) azetidine-1-methane amide

Embodiment 231A

Embodiment 231B

N-(4-(piperidin-4-yl) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide

Embodiment 231C

N-(4-(piperidin-4-yl) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide, two trifluoroacetic acids (67 mg be dissolved in methyl alcohol (2.0 mL) are added in 20 mL bottles, 0.12 mmol), then pentamethylene formaldehyde (13 mg be dissolved in methyl alcohol (0.45 mL) are added, 0.13 mmol), then pure acetic acid (68 μ L, 1.2 mmol) is added.Reaction mixture is shaken 2 hours at 70 DEG C.Afterwards, add MP-Cyanoborohydride (272 mg, 2-3 mmol/g) resin and shake gained mixture overnight at 70 DEG C.Filter reaction mixture and be concentrated into drying.Resistates to be dissolved in 1:1 DMSO/ methyl alcohol and by reverse phase chromatography purifying.

table 4.

Substantially as described in embodiment 231, prepare following examples, substitute with suitable aldehyde with in suitable amine and embodiment 231C in embodiment 231A.By some products of flash chromatography, and by other products of rp-hplc method purifying.Therefore, some embodiments are separated into trifluoroacetate.

Embodiment 336

N-[4-(1-benzoyl piperidine-4-base) phenyl]-3-(pyridazine-3-base) azetidine-1-methane amide

Embodiment 336A

4-(4-(3-(pyridazine-3-base) azetidine-1-formamido-) phenyl) piperidines-1-t-butyl formate

As described in embodiment 1C, prepare title compound, substitute 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate with 4-(4-aminophenyl) piperidines-1-t-butyl formate and substitute 3-(azetidine-3-base) pyridine dihydrochloride with 3-(azetidine-3-base) pyridazine hydrochloride.

Embodiment 336B

N-(4-(piperidin-4-yl) phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide

As described in embodiment 1D, prepare title compound, substitute 3-(4-(3-(pyridin-3-yl) azetidine-1-formamido-) phenoxy group) azetidine-1-t-butyl formate with 4-(4-(3-(pyridazine-3-base) azetidine-1-formamido-) phenyl) piperidines-1-t-butyl formate.

Embodiment 336C

As described in embodiment 1E, prepare title compound, substitute N-(4-(azetidine-3-base oxygen base) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide with N-(4-(piperidin-4-yl) phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide and substitute (S)-2-Methyl Butyric Acid with phenylformic acid.

table 5.

Substantially as described in embodiment 336, prepare following examples, substitute with suitable carboxylic acid in embodiment 336C.

Embodiment	Title	MS
			337	N-{4-[1-(2-fluoro benzoyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 460 (M+H) ⁺
338	N-{4-[1-(2-methyl benzoyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 456 (M+H) ⁺
			339	N-{4-[1-(2,2-Dimethylpropanoyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 422 (M+H) ⁺
340	N-{4-[1-(cyclopropyl carbonyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 406 (M+H) ⁺
			341	N-[4-(1-Acetylpiperidin-4-base) phenyl]-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 380 (M+H) ⁺
342	N-{4-[1-(3,3-dimethylbutanoyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 436 (M+H) ⁺
			343	N-{4-[1-(cyclobutyl carbonyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 420 (M+H) ⁺
344	3-(pyridazine-3-base)-N-{4-[1-(4,4,4-trifluoro butyryl radicals) piperidin-4-yl] phenyl } azetidine-1-methane amide	(ESI(+)) m/e 462 (M+H) ⁺
			345	3-(pyridazine-3-base)-N-{4-[1-(3,3,3-trifluoropropyl acyl group) piperidin-4-yl] phenyl } azetidine-1-methane amide	(ESI(+)) m/e 448 (M+H) ⁺
346	N-(4-{1-[(1-methylcyclopropyl groups) carbonyl] piperidin-4-yl } phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 420 (M+H) ⁺
			347	N-{4-[1-(Cyclopropyl-acetyl) piperidin-4-yl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 420 (M+H) ⁺

Embodiment 348

N-{4-[(1-benzoyl piperidine-4-base) methyl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide

Embodiment 348A

4-(pyridin-4-yl methyl) aniline

As described in embodiment 1B, prepare title compound, substitute 3-(4-nitrophenoxy) azetidine-1-t-butyl formate with 4-(4-nitrobenzyl) pyridine.

Embodiment 348B

The fluoro-N-of 2,2,2-tri-(4-(pyridin-4-yl methyl) phenyl) ethanamide

4-(pyridin-4-yl methyl) aniline (21.6 g, 117 mmol) and triethylamine (19.61 ml, the 141 mmol) solution in methylene dichloride (586 ml) are cooled to 0 DEG C.Trifluoroacetic anhydride (19.87 ml, 141 mmol) is dropwise added by feed hopper through 20 minutes.At 0 DEG C, stir this mixture 1 hour, then at room temperature stir 2 hours.Then this reaction mixture of vacuum concentration, by normal phase column chromatography method purifying gained resistates to provide title compound.

Embodiment 348C

The fluoro-N-of 2,2,2-tri-(4-(piperidin-4-ylmethyl) phenyl) ethanamide

By 2,2, the fluoro-N-of 2-tri-(4-(pyridin-4-yl methyl) phenyl) ethanamide (28.5 g, 102 mmol) and acetic acid (205 ml) be added in 500 mL stainless steel pressure bottles platinum oxide (IV) (3.42 g, 15.06 mmol) in and under 40 psi, this mixture is stirred 16 hours.This mixture is filtered and vacuum concentration by nylon membrane; And gained resistates to be dissolved in methyl alcohol (100 mL) and to be poured onto in ether (600 mL).Filtering precipitate, also dry to provide title compound with washed with diethylether.

Embodiment 348D

4-(4-aminobenzyl) piperidines-1-t-butyl formate

By 2,2, the fluoro-N-of 2-tri-(4-(piperidin-4-ylmethyl) phenyl) ethanamide (26.4 g, 92 mmol) solution in methylene dichloride (369 ml) is cooled to 0 DEG C and slowly adds triethylamine (19.28 ml, 138 mmol).In gained solution, tert-Butyl dicarbonate (22.14 g, 101 mmol)/methylene dichloride (75 ml) is added by feed hopper through 10 minutes.This 0 DEG C of mixture stirred 2 hours and slowly warmly to spend the night.This reaction mixture is cooled to 0 DEG C again, with 1 N sodium hydroxide (100 ml) process, is warmed to room temperature and stirs 1 hour.Be separated double-deck and with water and salt water washing organism, by dried over mgso, filter and vacuum concentration.By normal-phase chromatography method Purification to provide title compound.

Embodiment 348E

4-(4-(3-(pyridazine-3-base) azetidine-1-formamido-) benzyl) piperidines-1-t-butyl formate

As described in embodiment 1C, prepare title compound, substitute 3-(4-amino-benzene oxygen) azetidine-1-t-butyl formate with 4-(4-aminobenzyl) piperidines-1-t-butyl formate and substitute 3-(azetidine-3-base) pyridine dihydrochloride with 3-(azetidine-3-base) pyridazine hydrochloride.

Embodiment 348F

N-(4-(piperidin-4-ylmethyl) phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide

As described in embodiment 1D, prepare title compound, substitute 3-(4-(3-(pyridin-3-yl) azetidine-1-formamido-) phenoxy group) azetidine-1-t-butyl formate with 4-(4-(3-(pyridazine-3-base) azetidine-1-formamido-) benzyl) piperidines-1-t-butyl formate.

Embodiment 348G

As described in embodiment 1E, prepare title compound, substitute N-(4-(azetidine-3-base oxygen base) phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide with N-(4-(piperidin-4-ylmethyl) phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide and substitute (S)-2-Methyl Butyric Acid with phenylformic acid.

table 6.

Substantially prepare following examples as described in Example 1, also use the suitable amine as described in embodiment 1C with the isoindoline in 1,3-dihydro-2 h-pyrrole also [3,4-c] pyridine alternate embodiment 1A.

Embodiment	Title	MS
			349	N-(4-{ [1-(2-fluoro benzoyl) piperidin-4-yl] methyl } phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 474 (M+H) ⁺
350	N-(4-{ [1-(2,2-Dimethylpropanoyl) piperidin-4-yl] methyl } phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 474 (M+H) ⁺
			351	N-(4-{ [1-(3,3-dimethylbutanoyl) piperidin-4-yl] methyl } phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 450 (M+H) ⁺
352	N-(4-{ [1-(2-ethylbutanoyl base) piperidin-4-yl] methyl } phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 450 (M+H) ⁺
			353	3-(pyridazine-3-base)-N-(4-{ [1-(4,4,4-trifluoro butyryl radicals) piperidin-4-yl] methyl } phenyl) azetidine-1-methane amide	(ESI(+)) m/e 476 (M+H) ⁺
354	N-(4-{ [1-(2-methylpropionyl) piperidin-4-yl] methyl } phenyl)-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 422 (M+H) ⁺
			355	N-{4-[(1-Acetylpiperidin-4-base) methyl] phenyl }-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 394 (M+H) ⁺
356	N-[4-({ 1-[(2S)-2-methylbutyryl base] piperidin-4-yl } methyl) phenyl]-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 436 (M+H) ⁺
			357	N-[4-({ 1-[(1-methylcyclopropyl groups) carbonyl] piperidin-4-yl } methyl) phenyl]-3-(pyridazine-3-base) azetidine-1-methane amide	(ESI(+)) m/e 434 (M+H) ⁺

Claims

1. formula (IA) compound, or the upper acceptable salt of its treatment,

Formula (IA);

Wherein

X ¹for N and X ²for CR ¹; Or

X ¹for CR ¹and X ²for N; Or

X ¹for CR ¹and X ²for CR ¹;

Y ¹for

R ¹², when occurring at every turn, be the independent alkyl selected.

2. compound according to claim 1, or its treatment upper acceptable salt, wherein X ¹for CR ¹and X ²for CR ¹.

3. compound according to claim 1 or claim 2, or its treatment upper acceptable salt, wherein R ¹be hydrogen when occurring at every turn.

4. compound according to claim 1, or its treatment upper acceptable salt, wherein Y ¹for wherein represent the tie point with carbonyl, represent the tie point with nitrogen-containing hetero aryl.

5. compound according to claim 4, or its treatment upper acceptable salt, wherein R ²for phenyl; Wherein R ²in phenyl separately by OR ⁴replace.

6. compound according to claim 4, or its treatment upper acceptable salt, wherein R ²for phenyl; Wherein R ²in phenyl separately by R ⁴replace.

7. the compound described in claim 5 or 6, or its treatment upper acceptable salt, wherein R ⁴be heterocyclic radical independently.

8. compound according to claim 1, it is selected from

4-({ [3-(pyridin-3-yl) azetidine-1-base] carbonyl } is amino) methyl benzoate;

N-(4-cyano-phenyl)-3-(pyridin-3-yl) azetidine-1-methane amide;

9. be used for the treatment of the composition of following disease: inflammation and tissue repair obstacle, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic conditions, tetter, comprises psoriasis, the skin injury of allergic dermatitis and induced by ultraviolet irradiation, autoimmune disorder, comprise systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, mandatory spondylitis, tissue and organ rejection, alzheimer's disease, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein said cancer selected from breast cancer, prostate cancer, lung cancer, colorectal carcinoma, cervical cancer, ovarian cancer, skin carcinoma, CNS cancer, bladder cancer, carcinoma of the pancreas, leukemia, lymphoma or Hokdkin disease, emaciation, the inflammation relevant with some viral infection to infection, comprise acquired immune deficiency syndrome (AIDS) (AIDS), adult respiratory distress syndrome, and ataxia-telangiectasia, described composition comprises compound or its pharmacy acceptable salt of the claim 1 of vehicle and treatment significant quantity.

10. treat the method for the following disease of patient: inflammation and tissue repair obstacle, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic conditions, tetter, comprises psoriasis, the skin injury of allergic dermatitis and induced by ultraviolet irradiation, autoimmune disorder, comprise systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, mandatory spondylitis, tissue and organ rejection, alzheimer's disease, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein said cancer selected from breast cancer, prostate cancer, lung cancer, colorectal carcinoma, cervical cancer, ovarian cancer, skin carcinoma, CNS cancer, bladder cancer, carcinoma of the pancreas, leukemia, lymphoma or Hokdkin disease, emaciation, the inflammation relevant with some viral infection to infection, comprise acquired immune deficiency syndrome (AIDS) (AIDS), adult respiratory distress syndrome, and ataxia-telangiectasia, described method comprises the compound from the claim 1 for the treatment of significant quantity to described patient or its pharmacy acceptable salt that give.

The method of the following disease of 11. treatment patients: inflammation and tissue repair obstacle, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic conditions, tetter, comprises psoriasis, the skin injury of allergic dermatitis and induced by ultraviolet irradiation, autoimmune disorder, comprise systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, mandatory spondylitis, tissue and organ rejection, alzheimer's disease, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein said cancer selected from breast cancer, prostate cancer, lung cancer, colorectal carcinoma, cervical cancer, ovarian cancer, skin carcinoma, CNS cancer, bladder cancer, carcinoma of the pancreas, leukemia, lymphoma or Hokdkin disease, emaciation, the inflammation relevant with some viral infection to infection, comprise acquired immune deficiency syndrome (AIDS) (AIDS), adult respiratory distress syndrome, with ataxia-telangiectasia or spleen cancer, described method comprises the compound from the claim 1 for the treatment of significant quantity to described patient or its pharmacy acceptable salt that give, with a kind of additional treatment agent for the treatment of significant quantity or more than a kind of additional treatment agent.