CN103649087B

CN103649087B - Substituted imidazopyridine and intermediate thereof

Info

Publication number: CN103649087B
Application number: CN201280027576.6A
Authority: CN
Inventors: M·科皮茨; U·克拉尔; A·温内尔; R·诺伊豪斯; G·西迈斯特
Original assignee: Bayer Pharma AG
Current assignee: Bayer Pharma AG
Priority date: 2011-04-06
Filing date: 2012-03-28
Publication date: 2016-11-30
Anticipated expiration: 2032-03-28

Abstract

The present invention relates to the substituted Imidazopyridine of formula I, wherein R³、R⁵With A as defined in the claims, the method relating to preparing described compound, relate to pharmaceutical composition and the combination comprising described compound, and relate to described compound as sole agent or with other active ingredient combinations preparation for treating or preventing disease, the particularly purposes in the pharmaceutical composition of hyperproliferative disorders and/or angiogenesis disease.

Description

Substituted imidazopyridine and intermediate thereof

Technical field

The present invention relates to the substituted Imidazopyridine of formula I that is as described herein and that define, prepare describedization The method of compound, the pharmaceutical composition comprising described compound and combination, described compound are in preparation treatment or prophylactic Purposes in pharmaceutical composition and can be used for preparing the midbody compound of described compound.

Background technology

The present invention relates to suppress the change of Mps-1 (monopolar spindle 1) kinases (also referred to as TTK, TTK) Compound.Mps-1 is bispecific Ser/Thr kinases, and it is at mitosis check point (also referred to as spindle check point, spindle Assemble check point) activation in play pivotal role, thus during mitosis, guarantee suitable chromosome separation [Abrieu A et al.,Cell,2001,106,83-93].Each somatoblast need to guarantee that the chromosome decile replicated is to two daughter cells. When entering mitosis, chromosome is attached to micro-pipe of spindle (spindle apparatus) at their centromere On.Mitosis check point is the monitoring mechanism being just activated simply by the presence of unattached centromere, and prevents from having the most attached The mitotic cell of the chromosome enters the later stage, thus completes cell division [Suijkerbuijk SJ and Kops GJ,Biochemica et Biophysica Acta,2008,1786,24-31;Musacchio A and Salmon ED, Nat Rev Mol Cell Biol.,2007,8,379-93].The most all of centromere is with the i.e. the two poles of the earth of correct amphiorentation Form is adhered to mitosis spindle, then meet check point, and this cell enters the later stage, proceeds mitosis.Have Silk division check point is made up of the complex network of multiple indispensable protein, including MAD (mitotic blockade defect, MAD1-3) and Bub (not by benzimidazole suppression and sprout, Bub1-3) member of family, dynein CENP-E, Mps-1 kinases and other Component, the overexpression in proliferative cell (such as cancerous cell) and tissue of the many in these [Yuan B et al., Clinical Cancer Research,2006,12,405-10].Reticent, chemical genetics and Mps-1 kinases by shRNA- Chemical inhibitor have proven to Mps-1 kinase activity mitosis check point signal conduct in pivotal role [Jelluma N et al.,PLos ONE,2008,3,e2415;Jones MH et al.,Current Biology,2005,15,160-65; Dorer RK et al.,Current Biology,2005,15,1070-76;Schmidt M et al.,EMBO Reports,2005,6,866-72]。

The still incomplete mitosis check point function reduced is sent out by the evidence having abundance with aneuploidy and tumor Life connects [Weaver BA and Cleveland DW, Cancer Research, 2007,67,10103-5;King RW,Biochimica et Biophysica Acta,2008,1786,4-14].By contrast, it has been recognized that mitosis is examined Test a little completely inhibit cause serious chromosomal errors to separate and apoptosis-induced in tumor cell [Kops GJ et al., Nature Reviews Cancer,2005,5,773-85;Schmidt M and Medema RH,Cell Cycle,2006, 5,159-63;Schmidt M and Bastians H,Drug Resistance Updates,2007,10,162-81].Cause This, suppressed by the Mps-1 kinases of mitosis check point or the pharmacology of other components and abolished mitosis check point generation The new way of table treatment proliferative disorders, described proliferative disorders includes entity tumor such as cancer and sarcoma and leukemia and pouring Bar malignant tumor or other diseases relevant to uncontrolled cell proliferation.

Fixed anti-mitosis medicine such as vinca alkaloids, taxanes or Epothilones activate SAC, by making Microtubule dynamics is stable or instability is carried out induced mitogenesis and stagnated.This stagnation prevents sister Chromosome Separation Correlative from forming two Daughter cell.The mitotic arrest extended promotes cell entrance mitosis to terminate (mitotic exit) and do not occur kytoplasm to divide Split, or mitosis failure, cause cell death.

By contrast, Mps-1 inhibitor induction SAC inactivation, this acceleration cell, by mitotic process, causes serious Chromosomal errors separate (chromosomal missegregation) ultimately result in cell death.

These discoveries show that Mps-1 inhibitor should have therapeutic value, for treat homoiothermic animal such as people with increase The relevant proliferative disorders of uncontrolled proliferative cell process, such as cancer, inflammation, arthritis, viral disease, god Through degenerative disease such as Alzheimer, cardiovascular disease or fungal disease.

Therefore, Mps-1 inhibitor represents and is regarded as single medicament or with other drug combination with supplement therapy selection Valuable compounds therefrom.

Prior art has been disclosed the different compounds showing depression effect kinase whose to Mps-1.WO2010/ 124826A1 discloses substituted imidazoquinolie compounds as Mps-1 kinases or the inhibitor of TTK.WO2011/ 026579A1 discloses substituted quinolin-2-ylamine as Mps-1 inhibitor.WO2011/013729A1 discloses the imidazoles of thick sum Derivant is as Mps-1 inhibitor.WO2011/063908A1, WO2011/064328A1 and WO2011063907A1 disclose Triazolopyridine derivatives is as the kinase whose inhibitor of Mps-1.

But, the background of Mps-1 inhibitors of kinases not yet discloses imidazopyridine derivatives.Disclosed imidazo pyrrole Piperidine derivatives is used for treating or preventing various disease:

WO2004/026867A2 and WO2007/032936A2 discloses as cell cycle protein dependent kinase (CDK) Inhibitor is for treating the disease relevant to CDK and the substituted imidazopyridine of disease.

WO2008/029152A2 discloses the bicyclic heteroaryl compounds for treating Duchenne's dystrophy.At other Compound also refer to substituted imidazopyridine.

WO2008/082490A2 discloses for treating the substituted of disease that C-Jun-N-terminal Kinase (JNK1) mediates Imidazopyridine.

WO2008/134553A1 discloses the substituted imidazopyridine of the disease for treating sodium channel mediation and middle nitrogen Indenes.

Therefore, above-mentioned prior art do not describe as described herein with definition, and the hereinafter referred to as " present invention Compound " the most substituted Imidazopyridine of formula I of the present invention or its stereoisomer, tautomerism Body, N-oxide, hydrate, solvate or salt, or their mixture, or their pharmacological activity.

And, above-mentioned prior art does not describe the compound purposes as Mps-1 inhibitor of the present invention.

Have now found that the compound of the present invention has astonishing and favourable character, and which constitute the base of the present invention Plinth.

Specifically, have surprisingly been found that the compound of the present invention effectively suppresses Mps-1 kinases, and therefore can use In treatment or prevent uncontrolled cell growth, breed and/or survive, unsuitable cellullar immunologic response or unsuitable carefully The disease of born of the same parents' inflammatory response, or be attended by the growth of uncontrolled cell, breed and/or survive, unsuitable cellular immunization Response or the disease of unsuitable cellular inflammation response, especially, wherein said uncontrolled cell growth, propagation and/or Survival, unsuitable cellullar immunologic response or unsuitable cellular inflammation response are kinase mediated by Mps-1, and such as blood swells Tumor, solid tumor and/or their transfer, such as leukemia and myelodysplastic syndrome, malignant lymphoma, include cerebroma and Brain metastes is at interior tumor of head and neck, the breast tumor including non-fire power and small cell lung tumor, gastrointestinal tract Tumor, endocrine tumors, breast tumor and other gynecological tumors, including tumor of kidney, tumor of bladder and tumor of prostate Urologic neoplasms, cutaneous tumor and sarcoma and/or their transfer.

Summary of the invention

The present invention relates to compounds of formula I, or its stereoisomer, tautomer, N-oxide, hydrate, Solvate or salt, or their mixture:

Wherein:

A represents

Group；

Wherein * indicates the point that described group is connected with the remainder of molecule；

Z represents-C (=O) N (H) R¹Or-C (=S) N (H) R¹Group；

R¹Represent hydrogen atom or C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-or aryl-group；

Wherein said C₃-C₆-cycloalkyl-or aryl-group optionally by 1,2,3 or 4 identical selected from following group or Differently replace: halogen ,-OH ,-CN, C₁-C₆-alkyl-, C₁-C₆-alkoxyl-, C₃-C₆-cycloalkyl-, HO-C₁-C₆-alkyl-；

Wherein said C₁-C₆-alkyl-radical optionally by 1,2,3 or 4 selected from following group identical or different take Generation: halogen ,-OH ,-CN, C₁-C₆-alkoxyl-, C₃-C₆-cycloalkyl-, HO-C₁-C₆-alkyl-；

R²Represent hydrogen atom or C₁-C₆-alkyl-or C₃-C₆-cycloalkyl-group；

Wherein said C₃-C₆-cycloalkyl-group is optionally identical or different selected from following group by 1,2,3 or 4 Replace: halogen, OH ,-CN ,-C₁-C₆-alkyl ,-C₁-C₆-alkoxyl；

Wherein said C₁-C₆-alkyl-radical optionally by 1,2,3 or 4 selected from following group identical or different take Generation: halogen, OH ,-CN ,-C1-C₆-alkoxyl；

R³Represent hydrogen atom or halogen atom or-CN, C₁-C₆-alkyl-,-(CH₂)_m-C₂-C₆-thiazolinyl ,-(CH₂)_m-C₄- C₈-cycloalkenyl group ,-(CH₂)_m-C₂-C₆-alkynyl ,-(CH₂)_m-C₃-C₆-cycloalkyl ,-(CH₂)_m-(3-to 7-unit Heterocyclylalkyl) ,- (CH₂)_m-(4-to 8-unit heterocycloalkenyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, R^6a(R^6b)N-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 7-unit heterocycle alkane Base-, C₂-C₆-thiazolinyl-, C₄-C₈-cycloalkenyl group-, C₂-C₆-alkynyl-, aryl-,-C₁-C₆-alkyl-aryl-group ,-C₁-C₆-alkyl-miscellaneous Aryl, heteroaryl-, C₁-C₆-alkyl-X-,-X-(CH₂)_m-C₂-C₆-thiazolinyl ,-X-(CH₂)_m-C₄-C₈-cycloalkenyl group ,-X-(CH₂)_m- C₂-C₆-alkynyl ,-X-(CH₂)_m-C₃-C₆-cycloalkyl ,-X-(CH₂)_m-(3-to 7-unit Heterocyclylalkyl) ,-X-(CH₂)_m-(4-to 8- Unit heterocycloalkenyl), aryl-X-, heteroaryl-X-,-C (=O) R⁶、-C(=O)N(H)R^6a、-C(=O)N(R^6a)R^6b、-C(=O)O- R⁶、-N(R^6a)R^6b、-NO₂、-N(H)C(=O)R⁶、-OR⁶、-SR⁶、-S(=O)R⁶、-S(=O)₂R⁶、-S(=O)(=NR^6a)R^6b、-S(= O)₂N(R^6b)R^6c、-S-(CH₂)_n-N(R^6a)R^6bOr-S-(CH₂)_n-(3-to 7-unit Heterocyclylalkyl) group；

Wherein said C₁-C₆-alkyl-,-(CH₂)_m-C₂-C₆-thiazolinyl ,-(CH₂)_m-C₂-C₆-alkynyl ,-(CH₂)_m-C₃-C₆-ring Alkyl, aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 7-unit Heterocyclylalkyl-, C₂-C₆- Thiazolinyl-, C₄-C₈-cycloalkenyl group-, C₂-C₆-alkynyl-, aryl-, C₁-C₆-alkyl-X-,-X-(CH₂)_m-C₂-C₆-thiazolinyl ,-X- (CH₂)_m-C₄-C₈-cycloalkenyl group ,-X-(CH₂)_m-C₂-C₆-alkynyl ,-X-(CH₂)_m-C₃-C₆-cycloalkyl ,-X-(CH₂)_m-(3-to 7- Unit Heterocyclylalkyl) ,-X-(CH₂)_m-(4-to 8-unit heterocycloalkenyl), aryl-X-, heteroaryl-X-,-C₁-C₆-alkyl-aryl-group ,- C₁-C₆-alkyl-heteroaryl or heteroaryl-group are optionally by 1,2,3,4 or 5 R⁷Group replaces identical or differently；

R^4a、R^4b、R^4c、R^4dRepresent hydrogen atom or halogen atom or-CN ,-OH, C independently of each other₁-C₆-alkyl-, C₁- C₆-alkoxyl-, halo-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxyl-, R^6a(R^6b)N-C₁-C₆-alkyl-, HO-C₁-C₆-alkane Base-, NC-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-or halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-radical；

R⁵Represent hydrogen atom or C₁-C₆-alkyl-,-(CH₂)_n-C₂-C₆-thiazolinyl ,-(CH₂)_n-C₂-C₆-alkynyl ,- (CH₂)_m-C₃-C₆-cycloalkyl ,-(CH₂)_m-(3-to 7-unit Heterocyclylalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkane Base-, halo-C₁-C₆-alkyl-, R^6a(R^6b)N-C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-,-C₁-C₆-alkyl-CN, C₁-C₆-alkane Epoxide-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 7-unit Heterocyclylalkyl-, C₄-C₈-cycloalkenyl group-, aryl-or heteroaryl-group；

Wherein said C₁-C₆-alkyl-,-(CH₂)_n-C₂-C₆-thiazolinyl ,-(CH₂)_n-C₂-C₆-alkynyl ,-(CH₂)_m-C₃-C₆-ring Alkyl ,-(CH₂)_m-(3-to 7-unit Heterocyclylalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆- Alkyl-, R^6a(R^6b)N-C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-,-C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkane Base-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 7-unit Heterocyclylalkyl-, C₄-C₈-cycloalkenyl group-, Aryl-or heteroaryl-group are optionally by 1,2,3,4 or 5 R⁸Group replaces identical or differently；

R⁶、R^6a、R^6b、R^6cRepresent hydrogen atom or C independently of each other₁-C₆-alkyl-, HO-C₁-C₆-alkyl-, C₃-C₆-ring Alkyl-, C₂-C₆-thiazolinyl-, 3-to 7-unit Heterocyclylalkyl-, aryl-, heteroaryl-, aryl-C₁-C₆-alkyl-or heteroaryl-C₁- C₆-alkyl-radical；

Wherein said C₃-C₆-cycloalkyl-group optionally by 1 or 2 selected from following group identical or different replace: Halogen ,-OH ,-CN, C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-, C₁-C₆-alkoxyl-, halo-C₁-C₆-alkyl-, halo-C₁- C₆-alkoxyl-；

R⁷Represent hydrogen atom or halogen atom or HO-,-CN, C₁-C₆-alkoxyl-, C₁-C₆-alkyl-, halo-C₁-C₆- Alkyl-, halo-C₁-C₆-alkoxyl-, R^6a(R^6b)N-C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆- Alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₂-C₆-thiazolinyl-, C₂-C₆-alkynyl-, 3-to 7-unit Heterocyclylalkyl-, virtue Base-, heteroaryl-,-C (=O) R⁶、-C(=O)N(H)R^6a、-C(=O)N(R^6a)R^6b、-C(=O)O-R⁶、-N(R^6a)R^6b、-NO₂、-N (H)C(=O)R⁶、-N(R^6c)C(=O)R⁶、-N(H)C(=O)N(R^6a)R^6b、-N(R^6c)C(=O)N(R^6a)R^6b、-N(H)C(=O) OR⁶、-N(R^6c)C(=O)OR⁶、-N(H)S(=O)R⁶、-N(R^6c)S(=O)R⁶、-N(H)S(=O)₂R⁶、-N(R^6c)S(=O)₂R⁶、-N=S (=O)(R^6a)R^6b、-OR⁶、-O(C=O)R⁶、-O(C=O)N(R^6a)R^6b、-O(C=O)OR⁶、-SR⁶、-S(=O)R⁶、-S(=O)N(H) R⁶、-S(=O)N(R^6a)R^6b、-S(=O)₂R⁶、-S(=O)₂N(H)R⁶、-S(=O)₂N(R^6a)R^6bOr-S (=O) (=NR^6c)R⁶Group；

Wherein said aryl-or heteroaryl-group are optionally by 1,2 or 3 C₁-C₆-alkyl-radical is identical or differently Replace；

Or

As 2 R⁷Group on aromatic ring with ortho position each other in the presence of, described 2 R⁷Group forms bridge together: * O (CH₂)₂O*、*O(CH₂) O*, * NH (C (=O)) NH*, wherein * represents the point being connected to described aromatic ring；

R⁸Represent hydrogen atom or halogen atom or-CN, C₁-C₆-alkoxyl-, C₁-C₆-alkyl-, halo-C₁-C₆-alkane Base-, R^6a(R^6b)N-C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alcoxyl Base-C₁-C₆-alkyl-, C₂-C₆-thiazolinyl-, C₂-C₆-alkynyl-, 3-to 7-unit Heterocyclylalkyl-, aryl-, heteroaryl-,-C (=O) R⁶、-C(=O)N(H)R^6a、-C(=O)N(R^6a)R^6b、-C(=O)O-R⁶、-N(R^6a)R^6b、-NO₂、-N(H)C(=O)R⁶、-N(R^6c)C (=O)R⁶、-N(H)C(=O)N(R^6a)R^6b、-N(R^6c)C(=O)N(R^6a)R^6b、-N(H)C(=O)OR⁶、-N(R^6c)C(=O)OR⁶、-N (H)S(=O)R⁶、-N(R^6c)S(=O)R⁶、-N(H)S(=O)₂R⁶、-N(R^6c)S(=O)₂R⁶、-N=S(=O)(R^6a)R^6b、-OR⁶、-O(C =O)R⁶、-O(C=O)N(R^6a)R^6b、-O(C=O)OR⁶、-SR⁶、-S(=O)R⁶、-S(=O)N(H)R⁶、-S(=O)N(R^6a)R^6b、-S(= O₂)R⁶、-S(=O)₂N(H)R⁶、-S(=O)₂N(R^6a)R^6b、-S(=O)(=NR^6c)R⁶Or-S (=O)₂-(3-to 7-unit Heterocyclylalkyl) Group；

Wherein said 3-to 7-unit Heterocyclylalkyl-or heteroaryl-group are optionally by 1,2,3 or 4 C₁-C₆-alkyl-base Group replaces identical or differently；

M is integer 0,1,2,3,4,5 or 6；

N is integer 0,1,2,3,4 or 5；And

X is S, S (=O), S (=O)₂、O、NR⁶、CR^6aR^6b、C(=CR^6aR^6b), C (=O) or C (OH) (R^6a)。

The invention still further relates to prepare the method for described compound, the pharmaceutical composition comprising described compound and combination, institute State compound in the purposes prepared in treatment or prophylactic pharmaceutical composition and to can be used for preparing described compound Midbody compound.

Detailed description of the invention

Term referred to herein preferably has a following meanings:

Term " halogen atom " or " halo-" are understood to mean that fluorine, chlorine, bromine or iodine atom.

Term " C₁-C₆-alkyl " it is interpreted as preferably representing the straight or branched with 1,2,3,4,5 or 6 carbon atoms , saturated monovalent hydrocarbon, such as methyl, ethyl, propyl group, butyl, amyl group, hexyl, isopropyl, isobutyl group, sec-butyl, tertiary fourth Base, isopentyl, 2-methyl butyl, 1-methyl butyl, 1-ethyl propyl, 1,2-dimethyl propyl, neopentyl, 1,1-dimethyl propylene Base, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 2-ethyl-butyl, 1-ethyl-butyl, 3,3-diformazan Base butyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-diformazan Base butyl, or their isomer.Especially, described group has 1,2,3 or 4 carbon atom (" C₁-C₄-alkyl "), such as Methyl, ethyl, propyl group, butyl, isopropyl, isobutyl group, sec-butyl, the tert-butyl group, more particularly, described group has 1,2 or 3 Carbon atom (" C₁-C₃-alkyl "), such as methyl, ethyl, n-pro-pyl or isopropyl.

Term " halo-C₁-C₆-alkyl " it is interpreted as preferably representing saturated monovalence C of straight or branched₁-C₆-alkyl, its Middle term " C₁-C₆-alkyl " as hereinbefore defined, and wherein one or more hydrogen atoms in the way of identical or different by halogen Element atom replaces, i.e. the most independent between halogen atom.Especially, described halogen atom is F.Described halo-C₁-C₆-alkyl is Such as-CF₃、-CHF₂、-CH₂F、-CF₂CF₃Or-CH₂CF₃。

Term " C₁-C₆-alkoxyl " it is interpreted as preferred expression-O-(C₁-C₆-alkyl) straight or branched saturated Univalent perssad, wherein term " alkyl " is as hereinbefore defined, such as methoxyl group, ethyoxyl, positive propoxy, isopropoxy, positive fourth Epoxide, isobutoxy, tert-butoxy, sec-butoxy, amoxy, isoamoxy or positive hexyloxy, or their isomer.

Term " halo-C₁-C₆-alkoxyl " it is interpreted as preferably representing the saturated of straight or branched as defined above Monovalence C₁-C₆-alkoxyl, wherein one or more hydrogen atoms are replaced by halogen atom in the way of identical or different.Especially, Described halogen atom is F.Described halo-C₁-C₆-alkoxyl is such as-OCF₃、-OCHF₂、-OCH₂F、-OCF₂CF₃Or- OCH₂CF₃。

Term " C₁-C₆-alkoxy-C₁-C₆-alkyl " it is interpreted as preferably representing straight or branched as defined above Saturated monovalence C₁-C₆-alkyl, wherein one or more hydrogen atoms in the way of identical or different by C as defined above₁- C₆-alkoxyl replaces, such as methoxyalkyl, ethyoxyl alkyl, allyloxyalkyl, isopropoxy alkyl, butoxy alkyl, different Butoxy alkyl, tert-butoxy alkyls, sec-butoxy alkyl, amoxy alkyl, isoamoxy alkyl, hexyloxy alkyl or they Isomer.

Term " halo-C₁-C₆-alkoxy-C₁-C₆-alkyl " be interpreted as preferably representing straight chain as defined above or Saturated monovalence C of side chain₁-C₆-alkoxy-C₁-C₆-alkyl, wherein one or more hydrogen atoms quilt in the way of identical or different Halogen atom replaces.Especially, described halogen atom is F.Described halo-C₁-C₆-alkoxy-C₁-C₆-alkyl be such as- CH₂CH₂OCF₃、-CH₂CH₂OCHF₂、-CH₂CH₂OCH₂F、-CH₂CH₂OCF₂CF₃Or-CH₂CH₂OCH₂CF₃。

Term " C₂-C₆-thiazolinyl " it is interpreted as preferably representing the monovalent hydrocarbon of straight or branched, it comprises one or more Double bond, and it has 2,3,4,5 or 6 carbon atoms, particularly 2 or 3 carbon atom (" C₂-C₃-thiazolinyl "), it should be appreciated that in institute Stating in the case of thiazolinyl comprises more than one double bond, described double bond can disconnected from each other or conjugation.Described thiazolinyl e.g. ethylene Base, pi-allyl, (E)-2-methyl ethylene, (Z)-2-methyl ethylene, high allyl, (E)-but-2-ene base, (Z)-butyl-2- Thiazolinyl, (E)-but-1-ene base, (Z)-but-1-ene base, amyl-4-thiazolinyl, (E)-amyl-3-thiazolinyl, (Z)-amyl-3-thiazolinyl, (E)- Amyl-2-thiazolinyl, (Z)-amyl-2-thiazolinyl, (E)-amyl-1-thiazolinyl, (Z)-amyl-1-thiazolinyl, hex-5-thiazolinyl, (E)-hex-4-thiazolinyl, (Z)-hex-4-thiazolinyl, (E)-hex-3-thiazolinyl, (Z)-hex-3-thiazolinyl, (E)-hex-2-thiazolinyl, (Z)-hex-2-thiazolinyl, (E)-hex- 1-thiazolinyl, (Z)-hex-1-thiazolinyl, isopropenyl, 2-methyl-prop-2-thiazolinyl, 1-methyl-prop-2-thiazolinyl, 2-methyl-prop-1-alkene Base, (E)-1-methyl-prop-1-thiazolinyl, (Z)-1-methyl-prop-1-thiazolinyl, 3-methyl butyl-3-thiazolinyl, 2-methyl butyl-3-thiazolinyl, 1- Methyl butyl-3-thiazolinyl, 3-methyl but-2-ene base, (E)-2-methyl but-2-ene base, (Z)-2-methyl but-2-ene base, (E)-1- Methyl but-2-ene base, (Z)-1-methyl but-2-ene base, (E)-3-methyl but-1-ene base, (Z)-3-methyl but-1-ene base, (E)-2-methyl but-1-ene base, (Z)-2-methyl but-1-ene base, (E)-1-methyl but-1-ene base, (Z)-1-methyl but-1-ene Base, 1,1-dimethyl propylene-2-thiazolinyl, 1-ethyl acrylate-1-thiazolinyl, 1-propyl ethylene base, 1-isopropyl-ethylene base, 4-methylpent- 4-thiazolinyl, 3-methylpent-4-thiazolinyl, 2-methylpent-4-thiazolinyl, 1-methylpent-4-thiazolinyl, 4-methylpent-3-thiazolinyl, (E)-3- Methylpent-3-thiazolinyl, (Z)-3-methylpent-3-thiazolinyl, (E)-2-methylpent-3-thiazolinyl, (Z)-2-methylpent-3-thiazolinyl, (E)-1-methylpent-3-thiazolinyl, (Z)-1-methylpent-3-thiazolinyl, (E)-4-methylpent-2-thiazolinyl, (Z)-4-methylpent-2-alkene Base, (E)-3-methylpent-2-thiazolinyl, (Z)-3-methylpent-2-thiazolinyl, (E)-2-methylpent-2-thiazolinyl, (Z)-2-methylpent- 2-thiazolinyl, (E)-1-methylpent-2-thiazolinyl, (Z)-1-methylpent-2-thiazolinyl, (E)-4-methylpent-1-thiazolinyl, (Z)-4-methyl Amyl-1-thiazolinyl, (E)-3-methylpent-1-thiazolinyl, (Z)-3-methylpent-1-thiazolinyl, (E)-2-methylpent-1-thiazolinyl, (Z)-2- Methylpent-1-thiazolinyl, (E)-1-methylpent-1-thiazolinyl, (Z)-1-methylpent-1-thiazolinyl, 3-ethyl butyl-3-thiazolinyl, 2-ethyl Butyl-3-thiazolinyl, 1-ethyl butyl-3-thiazolinyl, (E)-3-ethyl but-2-ene base, (Z)-3-ethyl but-2-ene base, (E)-2-ethyl But-2-ene base, (Z)-2-ethyl but-2-ene base, (E)-1-ethyl but-2-ene base, (Z)-1-ethyl but-2-ene base, (E)-3- Ethyl but-1-ene base, (Z)-3-ethyl but-1-ene base, 2-ethyl but-1-ene base, (E)-1-ethyl but-1-ene base, (Z)-1- Ethyl but-1-ene base, 2-propyl group acrylate-2-thiazolinyl, 1-propyl group acrylate-2-thiazolinyl, 2-isopropyl acrylate-2-thiazolinyl, 1-isopropyl acrylate-2- Thiazolinyl, (E)-2-propyl group acrylate-1-thiazolinyl, (Z)-2-propyl group acrylate-1-thiazolinyl, (E)-1-propyl group acrylate-1-thiazolinyl, (Z)-1-propyl group Acrylate-1-thiazolinyl, (E)-2-isopropyl acrylate-1-thiazolinyl, (Z)-2-isopropyl acrylate-1-thiazolinyl, (E)-1-isopropyl acrylate-1-thiazolinyl, (Z)-1-isopropyl acrylate-1-thiazolinyl, (E)-3,3-dimethyl propylene-1-thiazolinyl, (Z)-3,3-dimethyl propylene-1-thiazolinyl, 1-(1,1- Dimethyl ethyl) vinyl, butyl-1,3-dialkylene, amyl-1,4-dialkylene, hex-1,5-dialkylene or methyl hexadienyl.Special Not, described group is vinyl or pi-allyl.

Term " C₂-C₆-alkynyl " it is interpreted as preferably representing the monovalent hydrocarbon of straight or branched, it comprises one or more Three keys, and it comprises 2,3,4,5 or 6 carbon atoms, particularly 2 or 3 carbon atom (" C₂-C₃-alkynyl ").Described C₂-C₆- Alkynyl be such as acetenyl, acrylate-1-alkynyl, Propargyl, butyl-1-alkynyl, butyl-2-alkynyl, butyl-3-alkynyl, amyl-1-alkynyl, Amyl-2-alkynyl, amyl-3-alkynyl, amyl-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynes Base, 1-methyl Propargyl, 2-methyl butyl-3-alkynyl, 1-methyl butyl-3-alkynyl, 1-methyl butyl-2-alkynyl, 3-methyl butyl- 1-alkynyl, 1-ethyl Propargyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, 1-methylpent-4-alkynyl, 2-methyl Amyl-3-alkynyl, 1-methylpent-3-alkynyl, 4-methylpent-2-alkynyl, 1-methylpent-2-alkynyl, 4-methylpent-1-alkynyl, 3- Methylpent-1-alkynyl, 2-ethyl butyl-3-alkynyl, 1-ethyl butyl-3-alkynyl, 1-ethyl butyl-2-alkynyl, 1-propyl group acrylate-2-alkynes Base, 1-isopropyl Propargyl, 2.2-dimethyl butyrate-3-alkynyl, 1,1-dimethyl butyrate-3-alkynyl, 1,1-dimethyl butyrate-2- Alkynyl or 3.3-dimethyl butyrate-1-alkynyl.Especially, described alkynyl is acetenyl, acrylate-1-alkynyl or Propargyl.

Term " C₃-C₆-cycloalkyl " it is understood to mean that saturated monovalent monocyclic hydrocarbon ring, it is former that it comprises 3,4,5 or 6 carbon Son (" C₃-C₆-cycloalkyl ").Described C₃-C₆-cycloalkyl is such as cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl ring.

Term " C₄-C₈-cycloalkenyl group " it is interpreted as preferably representing monovalent monocyclic or dicyclo hydrocarbon ring, it comprises 4,5,6,7 or 8 Individual carbon atom and 1,2,3 or 4 double bonds being conjugated or be not conjugated, as long as the size of described cyclenes basic ring allows.Described C₄-C₈- Cycloalkenyl group is such as monocycle hydrocarbon ring such as cyclobutane base, cyclopentenyl or cyclohexenyl group, or dicyclo hydrocarbon ring such as cyclo-octadiene base Ring.

Term " 3-to 7-unit Heterocyclylalkyl " is understood to mean that saturated monovalent monocyclic or dicyclo hydrocarbon ring, it comprises 2,3, 4,5 or 6 carbon atoms, and one or more comprise heteroatomic group, described group selected from C (=O), O, S, S (=O), S (= O)₂、NR^a, wherein R^aRepresent hydrogen atom, or C₁-C₆-alkyl-or halo-C₁-C₆-alkyl-radical；Described Heterocyclylalkyl may The remainder of molecule it is connected to by any one carbon atom or nitrogen-atoms (if present).

Especially, described 3-to 7-unit Heterocyclylalkyl can comprise 2,3,4 or 5 carbon atoms and one or more above That mentions comprises heteroatomic group (" 3-to 6-unit Heterocyclylalkyl "), and more particularly, described Heterocyclylalkyl can comprise 4 or 5 Individual carbon atom and one or more mentioned above comprise heteroatomic group (" 5-to 6-unit Heterocyclylalkyl "), wherein 3-is extremely Two adjacent atoms of 7-unit Heterocyclylalkyl-group are optionally replaced in the way of forming aryl-or heteroaryl-group.

Especially, being not limited except as, described Heterocyclylalkyl can be such as 4-ring, such as azetidinyl, oxa-ring Butane group；Or 5-ring, such as tetrahydrofuran base, dialkyl group (dioxolinyl), pyrrolidinyl, imidazolidinyl, pyrazolidine Base, pyrrolinyl；Or 6-ring, such as THP trtrahydropyranyl, piperidyl, morpholinyl, dithiane base, thio-morpholinyl, piperazinyl Or trithiane base；Or 7-ring, such as diazaBase (diazepanyl) ring.Optionally, described Heterocyclylalkyl can be benzene And thick sum.

Described heterocyclic radical can be dicyclo, is not limited except as, such as 5,5-ring, such as hexahydro ring five [c] pyrroles-2 (1H)-yl) ring；Or 5,6-unit's dicyclos, such as hexahydropyrrolo also [1,2-a] pyrazine-2 (1H)-basic ring.

As mentioned above, described in comprise nitrogen-atoms ring can be that part is undersaturated, i.e. it can comprise one Or multiple double bond, be not limited except as, such as 2,5-dihydro-1H-pyrrole radicals, 4H-[1,3,4] thiadiazine base, 4,5-dihydro azoles Base or 4H-[Isosorbide-5-Nitrae] thiazine basic ring, or it can be the thick sum of benzo, is not limited except as, such as dihydro-isoquinoline basic ring.

Term " 4-to 8-unit heterocycloalkenyl " is understood to mean that undersaturated monovalent monocyclic or dicyclo hydrocarbon ring, it comprises 4, 5,6,7 or 8 carbon atoms, and one or more comprise heteroatomic group, described group is selected from C (=O), O, S, S (=O), S (=O)₂、NR^a, wherein R^aRepresent hydrogen atom, or C₁-C₆-alkyl-or halo-C₁-C₆-alkyl-radical；Described heterocycloalkenyl can The remainder of molecule can be connected to by any one carbon atom or nitrogen-atoms (if present).The example of described heterocycloalkenyl can To comprise one or more double bond, the double aziridinyl (3H-diazirinyl) of such as 4H-pyranose, 2H-pyranose, 3H-, 2, 5-dihydro-1H-pyrrole radicals, [1,3]-dioxolyl ([1,3] dioxolyl), 4H-[1,3,4] thiadiazine base, 2, 5-dihydrofuran base, 2,3 dihydro furan base, 2,5-dihydro-thiophene base, 2,3-dihydro-thiophene base, 4,5-dihydro oxazolyl or 4H-[Isosorbide-5-Nitrae] thiazinyl, or it can be the thick sum of benzo.

Term " aryl " is interpreted as preferably representing the monovalence virtue with 6,7,8,9,10,11,12,13 or 14 carbon atoms Race or the monocycle of partially aromatic, dicyclo or tricyctic hydrocarbon ring (" C₆-C₁₄-aryl "), particularly there is the ring (" C of 6 carbon atoms₆- Aryl "), such as phenyl or xenyl；Or there is the ring (" C of 9 carbon atoms₉-aryl "), such as indanyl or indenes Base；Or there is the ring (" C of 10 carbon atoms₁₀-aryl "), such as tetrahydro naphthyl, dihydro naphthyl or naphthyl；Or tool There is the ring (" C of 13 carbon atoms₁₃-aryl "), such as fluorenyl；Or there is the ring (" C of 14 carbon atoms₁₄-aryl "), example Such as anthryl, wherein two adjacent atoms of aryl-group optionally quilt in the way of forming 3-to 7-unit Heterocyclylalkyl-group Replace.

Term " heteroaryl " is interpreted as preferably representing the monocycle of monovalence, dicyclo or tricyclic aromatic loop systems, it has 5, 6,7,8,9,10,11,12,13 or 14 annular atomses (" 5-to 14-unit heteroaryl "), particularly 5 or 6 or 9 or 10 atoms, and And it comprises at least one hetero atom that can be identical or different, described hetero atom is such as oxygen, nitrogen or sulfur, additionally, at every kind In the case of can be benzo-fused, wherein two adjacent atoms of heteroaryl-group optionally with formed 3-to 7-unit miscellaneous The mode of cycloalkyl-group is replaced.Especially, heteroaryl selected from thienyl, furyl, pyrrole radicals, oxazolyl, thiazolyl, Imidazole radicals, pyrazolyl, isoxazolyl, isothiazolyl, di azoly, triazolyl, thiadiazolyl group, thiophene-4H-pyrazolyl (thia- 4H-pyrazolyl) etc., and their benzo derivative, such as benzofuranyl, benzothienyl, benzoxazolyl group, benzene And isoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indyl, isoindolyl etc.；Or pyridine radicals, pyridazinyl, Pyrimidine radicals, pyrazinyl, triazine radical etc., and their benzo derivative, such as quinolyl, quinazolyl, isoquinolyl etc.；Or Person's azocine base (azocinyl), indolizine base, purine radicals etc., and their benzo derivative；Or cinnolines base, phthalazinyl, Quinazolyl, quinoxalinyl, naphthyridinyl (naphthpyridinyl), pteridyl, carbazyl, acridinyl, phenazinyl, phenothiazine Base, phenazinyl, ton base or oxepin base (oxepinyl) etc..

Generally and except as otherwise noted, heteroaryl or heteroarylene groups groups include its all possible isomeric form, such as Its position isomer.Therefore, for some illustrative limiting examples, term pyridine radicals or pyridylidene include pyridine-2- Base, sub-pyridine-2-base, pyridin-3-yl, sub-pyridin-3-yl, pyridin-4-yl and sub-pyridin-4-yl；Or term thienyl or Sub-thienyl includes thiophene-2-base, sub-thiophene-2-base, thiene-3-yl and sub-thiene-3-yl.

As used the most in the whole text, term " C₁-C₆" at " C₁-C₆-alkyl ", " C₁-C₆-haloalkyl ", " C₁-C₆-alkoxyl " Or " C₁-C₆-halogenated alkoxy " definition linguistic context in be understood to mean that the carbon atom with 1-6 limited quantity, i.e. 1,2, 3, the alkyl of 4,5 or 6 carbon atoms.Should also be understood that described term " C₁-C₆" it is to be understood as included in any sub-range therein, Such as C₁-C₆、C₂-C₅、C₃-C₄、C₁-C₂、C₁-C₃、C₁-C₄、C₁-C₅、C₁-C₆；Particularly C₁-C₂、C₁-C₃、C₁-C₄、C₁-C₅、C₁- C₆；More particularly C₁-C₄；At " C₁-C₆-haloalkyl " or " C₁-C₆-halogenated alkoxy " in the case of be even more particularly C₁-C₂。

Similarly, terms used herein " C₂-C₆", as used the most in the whole text, such as at " C₂-C₆-thiazolinyl " and “C₂-C₆-alkynyl " definition linguistic context in be understood to mean that the carbon atom with 2-6 limited quantity, i.e. 2,3,4,5 or 6 The alkenyl or alkynyl of carbon atom.Should also be understood that described term " C₂-C₆" it is to be understood as included in any sub-range therein, such as C₂-C₆、C₃-C₅、C₃-C₄、C₂-C₃、C₂-C₄、C₂-C₅；Particularly C₂-C₃。

Additionally, terms used herein " C₃-C₆", as used the most in the whole text, such as at " C₃-C₆-cycloalkyl " determine The linguistic context of justice is understood to mean that the carbon atom with 3-6 limited quantity, the cycloalkyl of i.e. 3,4,5 or 6 carbon atoms.Also Should be understood that described term " C₃-C₆" it is to be understood as included in any sub-range therein, such as C₃-C₆、C₄-C₅、C₃-C₅、C₃- C₄、C₄-C₆、C₅-C₆；Particularly C₃-C₆。

As used herein, term " leaving group " refers to the former of the stable material of instead bonding electrons in chemical reaction Son or the group of atom.Preferably, leaving group is selected from: halo, particularly chlorine, bromine or iodine, mesyl epoxide, to toluene sulphur Acyloxy, trifyl epoxide, nine fluorine fourth sulfonyl epoxides, (the bromo-benzene of 4-) sulfonyl epoxide, (4-nitro-benzene) sulphur Acyloxy, (2-nitro-benzene)-sulfonyl epoxide, (4-isopropyl-benzene) sulfonyl epoxide, (2,4,6-tri--isopropyls-benzene)- Sulfonyl epoxide, (2,4,6-trimethyls-benzene) sulfonyl epoxide, (the 4-tert-butyl group-benzene) sulfonyl epoxide, benzenesulfonyl epoxide with And (4-methoxyl group-benzene) sulfonyl epoxide.

Term " substituted " refers to that one or more hydrogen of specified atom are replaced by the selection from pointed group, bar Part is to form stable compound not less than specified atom normal atom valency in the current situation and described replacement.Take Combination for base and/or variable is only only permission when this combination forms stable compound.

Term " optionally substituted " refers to optionally be replaced by specific group, atomic group or part.

The substituent group of loop systems refers to the substituent group being connected with armaticity or non-aromatic ring systems system, the most described substituent group generation For hydrogen available in described loop systems.

Terms used herein " one or many ", such as should in the definition of the substituent group of the general formula compound of the present invention Be understood to mean that " once, twice, three times, four times or five times, the most once, twice, three times or four times, more particularly one Secondary, twice or thrice, be even more particularly once or twice ".

Present invention additionally comprises all suitable isotopic variations of the compound of the present invention.The coordination of the compound of the present invention But element variant is defined as at least one of which atom and is had same atoms ordinal number usual or that mainly find former with nature The atom of the atomic mass that protonatomic mass is different replaces.The isotopic example of the compound that can mix the present invention include hydrogen, carbon, The isotope of nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, the most such as²H (deuterium),³H (tritium),¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³³P、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁹I and¹³¹I.Some isotopic variations of the compound of the present invention, such as Wherein mix one or more radiosiotope such as³H or¹⁴Those isotopic variations of C can be used for medicine and/or substrate tissue Distribution research.Tritiated and carbon-14 is¹⁴C isotope is particularly preferred, because they easily prepared and detectabilities.Additionally, use coordination Element can provide some caused by bigger metabolic stability to treat advantage as deuterium replaces, the Half-life in vivo such as increased or subtract Few dosage needs, and the most in some cases can be preferred.The isotopic variations of the compound of the present invention is the most permissible Prepared by conventional method well known by persons skilled in the art, such as by illustrative method, or by hereafter embodiment Described preparation, uses the suitable isotopic variations of suitable reagent.

When the plural form of the words such as compound used herein, salt, polymorph, hydrate, solvate, it should be understood that For being also represented by the compound of odd number, salt, polymorph, isomer, hydrate, solvate etc..

It is the most sane that " stable compound " or " stable structure " refers to, it is possible to stands to be separated to from reactant mixture Purity and be configured to the compound of effective therapeutic agent.

According to first aspect, the present invention relates to compounds of formula I:

Wherein:

A represents

Group；

Z represents-C (=O) N (H) R¹Or-C (=S) N (H) R¹Group；

R²Represent hydrogen atom or C₁-C₆-alkyl-or C₃-C₆-cycloalkyl-group；

Or

M is integer 0,1,2,3,4,5 or 6；

N is integer 0,1,2,3,4 or 5；And

About the compound of Formulas I above, in a preferred embodiment,

A represents

Group；

Wherein * indicates the point that described group is connected with the remainder of molecule.

About the compound of Formulas I above, in another preferred embodiment of the present,

A represents

R¹Represent C₁-C₆-alkyl-radical；

Wherein said C₁-C₆-alkyl-radical optionally by 1,2,3 or 4 selected from following group identical or different take Generation: halogen ,-OH ,-CN, C₁-C4-alkoxyl-, C₃-C₆-cycloalkyl-.

R¹Represent C₁-C₄-alkyl-radical；

Wherein said C₁-C₄-alkyl-radical optionally by 1,2 or 3 selected from following group identical or different replace: Halogen ,-OH ,-CN, C₁-C₃-alkoxyl-, C₃-C₆-cycloalkyl-.

R¹Represent methyl-or ethyl-group；

Wherein said methyl-or ethyl-group optionally by 1,2 or 3 selected from following group identical or different take Generation: halogen ,-OH ,-CN, C₁-C₃-alkoxyl-, C₃-C₆-cycloalkyl-.

R¹Represent methyl-or ethyl-group.

R¹Represent C₃-C₆-cycloalkyl-group；

Wherein said C₃-C₆-cycloalkyl-group is optionally identical or different selected from following group by 1,2,3 or 4 Replace: halogen ,-OH ,-CN, C₁-C₆-alkyl-, C₁-C₆-alkoxyl-, C₃-C₆-cycloalkyl-, HO-C₁-C₆-alkyl-.

Preferably, described C₃-C₆-cycloalkyl-group is substituted or unsubstituted cyclopropyl-or cyclobutyl-group.More excellent Selection of land, described C₃-C₆-cycloalkyl-group is substituted or unsubstituted cyclopropyl-group.

R¹Represent C₃-C₆-cycloalkyl-group；

Wherein said C₃-C₆-cycloalkyl-group optionally by 1,2 or 3 selected from following group identical or different take Generation: halogen ,-CN, C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, HO-C₁-C₆-alkyl-.

R¹Represent C₃-C₆-cycloalkyl-group；

Wherein said C₃-C₆-cycloalkyl-group is optionally replaced selected from following group by one :-F ,-CN, C₁-C₂- Alkyl-, C₃-C₆-cycloalkyl-, HO-C₁-C₂-alkyl-.

R¹Represent aryl-group；

Wherein said aryl-group optionally by 1,2,3 or 4 selected from following group identical or different replace: halogen Element ,-OH ,-CN, C₁-C₆-alkyl-, C₁-C₆-alkoxyl-, C₃-C₆-cycloalkyl-, HO-C₁-C₆-alkyl-.Preferably, described virtue Base-group is substituted or unsubstituted Phenyl-group.

R¹Represent aryl-group；

Wherein said aryl-group optionally by 1,2 or 3 selected from following group identical or different replace: halogen Element ,-CN, C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-.Preferably, described aryl-group is substituted or unsubstituted phenyl-base Group.

R¹Represent aryl-group；

Wherein said aryl-group is optionally by 1,2 or 3 C₁-C₆-alkyl-radical replaces identical or differently.Preferably Ground, described aryl-group is substituted or unsubstituted Phenyl-group.

About the compound of Formulas I above, in another preferred embodiment of the present, R¹It is selected from:

Methyl, ethyl,

R¹Represent methyl-group or cyclopropyl-group；

Wherein said cyclopropyl-group is optionally substituted with at least one fluorine atom.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-or heteroaryl-group；Its Described in aryl-or heteroaryl-group optionally by 1,2,3 or 4 R⁷Group replaces identical or differently.Described aryl-base Group's preferably substituted or unsubstituted Phenyl-group.Described heteroaryl-group is preferably substituted or unsubstituted pyridine radicals-base Group.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-group；Wherein said virtue Base-group is by 1 or 2 R⁷Group replaces identical or differently.Described aryl-group be preferably substituted or unsubstituted phenyl- Group.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-X-or heteroaryl-X-base Group；Wherein said aryl-X-or heteroaryl-X-group are optionally by 1,2,3 or 4 R⁷Group replaces identical or differently.Institute State aryl-group and be preferably substituted or unsubstituted Phenyl-group.Described heteroaryl-group is the most substituted or unsubstituted Pyridine radicals-group.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-X-group；Wherein said virtue Base-X-group is by 1 or 2 R⁷Group replaces identical or differently.Described aryl-group is preferably substituted or unsubstituted benzene Base-group.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-O-or heteroaryl-O-base Group；Wherein said aryl-O-or heteroaryl-O-group are optionally by 1,2,3 or 4 R⁷Group replaces identical or differently.Institute State aryl-group and be preferably substituted or unsubstituted Phenyl-group.Described heteroaryl-group is the most substituted or unsubstituted Pyridine radicals-group.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-O-group；Wherein said virtue Base-O-group is by 1 or 2 R⁷Group replaces identical or differently.Described aryl-group is preferably substituted or unsubstituted benzene Base-group.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-S (=O)_p-or heteroaryl-S (=O)_p-group；Wherein said aryl-S (=O)_p-or heteroaryl-S (=O)_p-group is optionally by 1,2,3 or 4 R⁷Group phase Together or differently replace.Integer p is equal to 0,1 or 2.Preferably, p=0 or p=2.It is highly preferred that p=0.Described aryl-group is preferred It it is substituted or unsubstituted Phenyl-group.Described heteroaryl-group is preferably substituted or unsubstituted pyridine radicals-group.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-S (=O)_p-group；Wherein institute State aryl-S (=O)_p-group is by 1 or 2 R⁷Group replaces identical or differently.Integer p is equal to 0,1 or 2.Preferably, p=0 or p =2.It is highly preferred that p=0.Described aryl-group is preferably substituted or unsubstituted Phenyl-group.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-NR⁶-or heteroaryl-NR⁶- Group；Wherein said aryl-NR⁶-or heteroaryl-NR⁶-group is optionally by 1,2,3 or 4 R⁷Group takes identical or differently Generation.Described aryl-group is preferably substituted or unsubstituted Phenyl-group.Described heteroaryl-group preferably replaces or does not takes Pyridine radicals-the group in generation.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-NH-or heteroaryl-NH-base Group；Wherein said aryl-NH-or heteroaryl-NH-group are optionally by 1,2,3 or 4 R⁷Group replaces identical or differently. Described aryl-group is preferably substituted or unsubstituted Phenyl-group.Described heteroaryl-group preferably replaces or unsubstituted Pyridine radicals-group.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-CR^6aR^6b-or heteroaryl- CR^6aR^6b-group；Wherein said aryl-CR^6aR^6b-or heteroaryl-CR^6aR^6b-group is optionally by 1,2,3 or 4 R⁷Group phase Together or differently replace.Described aryl-group is preferably substituted or unsubstituted Phenyl-group.Described heteroaryl-group is preferred It it is substituted or unsubstituted pyridine radicals-group.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-CH₂-or heteroaryl-CH₂- Group；Wherein said aryl-CH₂-or heteroaryl-CH₂-group is optionally by 1,2,3 or 4 R⁷Group takes identical or differently Generation.Described aryl-group is preferably substituted or unsubstituted Phenyl-group.Described heteroaryl-group preferably replaces or does not takes Pyridine radicals-the group in generation.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-C (=O)-or heteroaryl-C (=O)-group；Wherein said aryl-C (=O)-or heteroaryl-C (=O)-group are optionally by 1,2,3 or 4 R⁷Group is identical Or differently replace.Described aryl-group is preferably substituted or unsubstituted Phenyl-group.Described heteroaryl-group is preferably Substituted or unsubstituted pyridine radicals-group.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent hydrogen atom or-CN, C₁-C₆-alkane Base-,-(CH₂)_m-C₂-C₆-thiazolinyl ,-(CH₂)_m-C₂-C₆-alkynyl, aryl-, heteroaryl-, aryl-X-group；

Wherein said C₁-C₆-alkyl-,-(CH₂)_m-C₂-C₆-thiazolinyl ,-(CH₂)_m-C₂-C₆-alkynyl, aryl-, aryl-X- Or heteroaryl-group is optionally by 1 or 2 R⁷Group replaces identical or differently.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent heteroaryl-group, its optionally by 1 or 2 R⁷Group replaces identical or differently.Described heteroaryl-group is preferably substituted or unsubstituted pyridine radicals-group.

About the compound of Formulas I above, in another preferred embodiment of the present, R³It is selected from:

H、H₃C-CH₂-、H₃C-S-、H₃C-S(O)₂-、HO-CH₂-CH₂-、HO-CH₂-CH₂-CH₂-、H₃C-CH(OH)-、H₂C= CH-、

R³Represent pyridine radicals-, phenyl-, phenyl-O-or phenyl-S-group；

Wherein said Phenyl-group is by methyl-group and-C (=O) N (H) R^6aGroup replaces, or by HO-CH₂-group Replace；

Wherein said phenyl-O-group optionally by 1 or 2 selected from following group identical or different replace :-F, H₃C-O-、HO-、H₃C-；

Wherein said phenyl-S-group optionally by 1 or 2 selected from following group identical or different replace :-F, H₃C-O-、HO-、H₃C-。

About the compound of Formulas I above, in another preferred embodiment of the present, R^4a、R^4b、R^4cAnd R^4dIt is selected from independently of each other Hydrogen, halogen ,-CN, C₁-C₆-alkyl-, C₁-C₆-alkoxyl-, halo-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxyl-.

R^4aAnd R^4dRepresent hydrogen atom or halogen atom, or-CN, C independently of each other₁-C₆-alkyl-, C₁-C₆-alcoxyl Base-, halo-C₁-C₆-alkyl-or halo-C₁-C₆-alkoxyl-group.

In another preferred embodiment of the present invention, R^4aWith^4dRepresent hydrogen atom or halogen atom independently of each other, or Person C₁-C₆-alkyl-, C₁-C₆-alkoxyl-or halo-C₁-C₆-alkyl-radical.

In another preferred embodiment of the present invention, R^4aAnd R^4dRepresent hydrogen.

In another preferred embodiment of the present invention, R^4bAnd R^4cRepresent hydrogen atom or halogen atom independently of each other, or Person-CN ,-OH, C₁-C₆-alkyl-, C₁-C₆-alkoxyl-group.

In another preferred embodiment of the present invention, R^4bAnd R^4cRepresent hydrogen atom or halogen atom independently of each other, or Person-CN ,-OH, C₁-C₆-alkyl-, C₁-C₆-alkoxyl-group；Condition is group R^4bAnd R^4cIn at least one is not hydrogen atom.

In another preferred embodiment of the present invention, R^4bAnd R^4cRepresent hydrogen or C independently of each other₁-C₆-alkyl-radical.

In another preferred embodiment of the present invention, R^4bAnd R^4cRepresent hydrogen or C independently of each other₁-C₄-alkyl-radical； Condition is group R^4bAnd R^4cIn at least one is not hydrogen atom.

In another preferred embodiment of the present invention, group R^4bAnd R^4cIn an expression hydrogen atom, and another table Show selected from following group: halo-,-CN ,-OH, C₁-C₆-alkyl-, C₁-C₆-alkoxyl-, halo-C₁-C₆-alkyl-, halo- C₁-C₆-alkoxyl-, R^6a(R^6b)N-C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-, NC-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁- C₆-alkyl-and halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-.

In another preferred embodiment of the present invention, group R^4bAnd R^4cIn an expression hydrogen atom, and another table Show selected from following group: halo-,-CN ,-OH, C₁-C₆-alkyl-and C₁-C₆-alkoxyl-.

In another preferred embodiment of the present invention

R^4b=C₁-C₄-alkyl-and R^4c=hydrogen；Or

R^4b=hydrogen and R^4c=C₁-C₄-alkyl-.

In another preferred embodiment of the present invention

R^4a=H, R^4b=H, R^4c=CH₃And R^4d=H；Or

R^4a=H、R^4b=CH₃、R^4c=H and R^4d=H。

R⁵Expression-(CH₂)_n-C₂-C₆-thiazolinyl ,-(CH₂)_n-C₂-C₆-alkynyl ,-(CH₂)_m-C₃-C₆-cycloalkyl ,-(CH₂)_m- (3-to 7-unit Heterocyclylalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, R^6a(R^6b) N-C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-,-C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆- Alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 7-unit Heterocyclylalkyl-, C₄-C₈-cycloalkenyl group-, aryl-or heteroaryl- Group；

Described-(CH₂)_n-C₂-C₆-thiazolinyl ,-(CH₂)_n-C₂-C₆-alkynyl ,-(CH₂)_m-C₃-C₆-cycloalkyl ,-(CH₂)_m-(3- To 7-unit Heterocyclylalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, R^6a(R^6b)N- C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-,-C₁-C₆-alkyl-CN, C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkane Epoxide-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 7-unit Heterocyclylalkyl-, C₄-C₈-cycloalkenyl group-, aryl-or heteroaryl-base Group is optionally by 1,2,3,4 or 5 R⁸Group replaces identical or differently.

R⁵Represent C₁-C₆-alkyl-,-(CH₂)_m-(3-to 7-unit Heterocyclylalkyl)-, C₁-C₆-alkoxy-C₁-C₆-alkyl-or Halo-C₁-C₆-alkyl-radical；

Wherein said C₁-C₆-alkyl-,-(CH₂)_m-(3-to 7-unit Heterocyclylalkyl)-, C₁-C₆-alkoxy-C₁-C₆-alkyl- Or halo-C₁-C₆-alkyl-radical is optionally by 1,2 or 3 R⁸Group replaces identical or differently.

R⁵It is selected from: H, (CH₃)₂CH-、CHF₂-、CF₃-、CF₃-CH₂-、CF₃-CH₂-CH₂-、CF₃-CH(OH)-、HO-CH₂-、 HO-C(CH₃)₂-、HO-C(CH₃)₂CH₂-、HO-CH₂-CH(OH)-、H₃C-O-CH₂-、H₂N-CH₂-CH₂-、H₂N-C(CH₃)₂-、 (CH₃)₂N-CH₂-、(CH₃)₂N-CH₂-CH₂-、(CH₃)₂N-CH₂-CH₂-CH₂-、(CH₃)₂N-C(CH₃)₂-、H₃C-S(=O)₂- CH₂-、H₃C-S(=O)₂-CH₂-CH₂-、HO-S(=O)₂-CH₂-、HO-S(=O)₂-CH₂-CH₂-、NC-CH₂-、H₃C-C(=O)-N (H)-CH₂、H₃C-C(=O)-N(H)-CH₂-CH₂-、H₂N-C(=O)-CH₂-、(CH₃)₂N-C(=O)-CH₂-、H₃C-N(H)-C(= O)-N(CH₃)-CH₂-CH₂-、

R⁵Represent selected from following group:

R⁶、R^6a、R^6bAnd R^6cRepresent hydrogen atom, or C independently of each other₁-C₆-alkyl-, C₃-C₆-cycloalkyl-or aryl- C₁-C₆-alkyl-radical；

Wherein said C₃-C₆-cycloalkyl-group optionally by 1 or 2 selected from following group identical or different replace: Halogen ,-OH ,-CN, C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-, C₁-C₆-alkoxyl-, halo-C₁-C₆-alkyl-, halo-C₁- C₆-alkoxyl-.

Wherein said C₃-C₆-cycloalkyl-group optionally by 1 or 2 selected from following group identical or different replace: Halogen ,-OH ,-CN, C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-.

R^6aRepresent hydrogen atom or methyl-group or C₃-C₆-cyclopropyl-group；Wherein said C₃-C₆-cyclopropyl-group is appointed Selection of land is replaced by-CN a group.

R⁷Represent hydrogen atom or halogen atom, or HO-,-CN, C₁-C₆-alkoxyl-, C₁-C₆-alkyl-, halo-C₁- C₆-alkyl-, halo-C₁-C₆-alkoxyl-, R^6a(R^6b)N-C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁- C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₂-C₆-thiazolinyl-, C₂-C₆-alkynyl-, 3-to 7-unit heterocycle alkane Base-, aryl-, heteroaryl-,-C (=O) R⁶、-C(=O)N(H)R^6a、-C(=O)N(R^6a)R^6b、-C(=O)O-R⁶、-N(R^6a)R^6b、- NO₂、-N(H)C(=O)R⁶、-N(R^6c)C(=O)R⁶、-N(H)C(=O)N(R^6a)R^6b、-N(R^6c)C(=O)N(R^6a)R^6b、-N(H)C(= O)OR⁶、-N(R^6c)C(=O)OR⁶、-N(H)S(=O)R⁶、-N(R^6c)S(=O)R⁶、-N(H)S(=O)₂R⁶、-N(R^6c)S(=O)₂R⁶、-N =S(=O)(R^6a)R^6b、-OR⁶、-O(C=O)R⁶、-O(C=O)N(R^6a)R^6b、-O(C=O)OR⁶、-SR⁶、-S(=O)R⁶、-S(=O)N (H)R⁶、-S(=O)N(R^6a)R^6b、-S(=O)₂R⁶、-S(=O)₂N(H)R⁶、-S(=O)₂N(R^6a)R^6bOr-S (=O) (=NR^6c)R⁶Base Group；

Wherein said aryl-or heteroaryl-group are optionally by 1,2 or 3 C₁-C₆-alkyl-radical is identical or differently Replace.

About the compound of Formulas I above, in another preferred embodiment of the present, R³Represent aryl-or aryl-X-group, its By two R of mutual adjacent bit⁷Group replaces, said two R⁷Group forms bridge together: * O (CH₂)₂O*、*O(CH₂)O*、*NH(C (=O)) NH*, wherein * represents the point being connected to described aromatic ring.

R⁷Represent hydrogen atom or halogen atom, or HO-,-CN, C₁-C₆-alkoxyl-, C₁-C₆-alkyl-, halo-C₁- C₆-alkyl-, H₂N-C₁-C₆-alkyl-, C₂-C₆-thiazolinyl, 3-to 7-unit Heterocyclylalkyl-,-C (=O) N (H) R^6a、-N(R^6a)R^6b、-C (=O)O-R⁶、-N(H)C(=O)R⁶、-OR⁶Or-SR⁶Group；

R⁷Represent halogen atom, or HO-, C₁-C₆-alkoxyl-, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, halo- C₁-C₆-alkoxyl-, HO-C₁-C₆-alkyl-,-C (=O) N (H) R^6a、-N(R^6a)R^6b、-C(=O)O-R⁶Or-OR⁶Group.

R⁸Represent halogen atom, or-CN ,-OH, C₁-C₆-alkoxyl-, C₁-C₆-alkyl-, HO-C₁-C₆-alkyl ,-C (= O)N(R^6a)R^6b、-N(R^6a)R^6b、-N(H)C(=O)R⁶、-N(R^6c)C(=O)N(R^6a)R^6b、-S(=O)₂R⁶Or-S (=O)₂OH group.

In another preferred embodiment of the present, the present invention relates to the compound of Formulas I, wherein X is S.

X is S (=O).

X is S (=O)₂。

X is O.

X is NR⁶.Preferably, X is NH or N (CH₃).Most preferably, X is NH.

X is CR^6aR^6b.Preferably, X is CH₂。

X is C (=O).

Z represents-C (=O) N (H) R¹Group.

N is 1.

M is 0 or 1.

It should be understood that the invention still further relates to any combination of above-mentioned preferred embodiment.

Some examples of combination are given below.But, the present invention is not limited to these combinations.

In a preferred embodiment, the present invention relates to the compound of Formulas I, or its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or their mixture:

Wherein:

A represents

Z represents-C (=O) N (H) R¹Group or-C (=S) N (H) R¹Group；

R¹Represent C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-or aryl-group；

R³Represent hydrogen atom or halogen atom, or-CN, C₁-C₆-alkyl-,-(CH₂)_m-C₂-C₆-thiazolinyl ,-(CH₂)_m- C₄-C₈-cycloalkenyl group ,-(CH₂)_m-C₂-C₆-alkynyl ,-(CH₂)_m-C₃-C₆-cycloalkyl ,-(CH₂)_m-(3-to 7-unit Heterocyclylalkyl) ,- (CH₂)_m-(4-to 8-unit heterocycloalkenyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, R^6a(R^6b)N-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 7-unit heterocycle alkane Base-, C₂-C₆-thiazolinyl-, C₄-C₈-cycloalkenyl group-, C₂-C₆-alkynyl-, aryl-,-C₁-C₆-alkyl-aryl-group ,-C₁-C₆-alkyl-miscellaneous Aryl, heteroaryl-, C₁-C₆-alkyl-X-,-X-(CH₂)_m-C₂-C₆-thiazolinyl ,-X-(CH₂)_m-C₄-C₈-cycloalkenyl group ,-X-(CH₂)_m- C₂-C₆-alkynyl ,-X-(CH₂)_m-C₃-C₆-cycloalkyl ,-X-(CH₂)_m-(3-to 7-unit Heterocyclylalkyl) ,-X-(CH₂)_m-(4-to 8- Unit heterocycloalkenyl), aryl-X-, heteroaryl-X-,-C (=O) R⁶、-C(=O)N(H)R^6a、-C(=O)N(R^6a)R^6b、-C(=O)O- R⁶、-N(R^6a)R^6b、-NO₂、-N(H)C(=O)R⁶、-OR⁶、-SR⁶、-S(=O)R⁶、-S(=O)₂R⁶、-S(=O)(=NR^6a)R^6b、-S(= O)₂N(R^6b)R^6c、-S-(CH₂)_n-N(R^6a)R^6bOr-S-(CH₂)_n-(3-to 7-unit Heterocyclylalkyl) group；

R^4a、R^4b、R^4c、R^4dRepresent hydrogen atom or halogen atom, or-CN ,-OH, C independently of each other₁-C₆-alkyl-, C₁- C₆-alkoxyl-, halo-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxyl-, R^6a(R^6b)N-C₁-C₆-alkyl-, HO-C₁-C₆-alkane Base-, NC-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-radical；

R⁵Represent hydrogen atom, or C₁-C₆-alkyl-,-(CH₂)_n-C₂-C₆-thiazolinyl ,-(CH₂)_n-C₂-C₆-alkynyl ,- (CH₂)_m-C₃-C₆-cycloalkyl ,-(CH₂)_m-(3-to 7-unit Heterocyclylalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkane Base-, halo-C₁-C₆-alkyl-, R^6a(R^6b)N-C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-,-C₁-C₆-alkyl-CN, C₁-C₆-alkane Epoxide-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 7-unit Heterocyclylalkyl-, C₄-C₈-cycloalkenyl group-, aryl-or heteroaryl-group；

R⁶、R^6a、R^6b、R^6cRepresent hydrogen atom, or C independently of each other₁-C₆-alkyl-, HO-C₁-C₆-alkyl-, C₃-C₆- Cycloalkyl-, C₂-C₆-thiazolinyl-, 3-to 7-unit Heterocyclylalkyl-, aryl-, heteroaryl-, aryl-C₁-C₆-alkyl-or heteroaryl- C₁-C₆-alkyl-radical；

R⁷Represent hydrogen atom or halogen atom, or HO-,-CN, C₁-C₆-alkoxyl-, C₁-C₆-alkyl-, halo-C₁- C₆-alkyl-, halo-C₁-C₆-alkoxyl-, R^6a(R^6b)N-C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁- C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₂-C₆-thiazolinyl-, C₂-C₆-alkynyl-, 3-to 7-unit heterocycle alkane Base-, aryl-, heteroaryl-,-C (=O) R⁶、-C(=O)N(H)R^6a、-C(=O)N(R^6a)R^6b、-C(=O)O-R⁶、-N(R^6a)R^6b、- NO₂、-N(H)C(=O)R⁶、-N(R^6c)C(=O)R⁶、-N(H)C(=O)N(R^6a)R^6b、-N(R^6c)C(=O)N(R^6a)R^6b、-N(H)C(= O)OR⁶、-N(R^6c)C(=O)OR⁶、-N(H)S(=O)R⁶、-N(R^6c)S(=O)R⁶、-N(H)S(=O)₂R⁶、-N(R^6c)S(=O)₂R⁶、-N =S(=O)(R^6a)R^6b、-OR⁶、-O(C=O)R⁶、-O(C=O)N(R^6a)R^6b、-O(C=O)OR⁶、-SR⁶、-S(=O)R⁶、-S(=O)N (H)R⁶、-S(=O)N(R^6a)R^6b、-S(=O)₂R⁶、-S(=O)₂N(H)R⁶、-S(=O)₂N(R^6a)R^6b、-S(=O)(=NR^6c)R⁶Group；

Or

R⁸Represent hydrogen atom or halogen atom, or-CN, C₁-C₆-alkoxyl-, C₁-C₆-alkyl-, halo-C₁-C₆-alkane Base-, R^6a(R^6b)N-C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alcoxyl Base-C₁-C₆-alkyl-, C₂-C₆-thiazolinyl-, C₂-C₆-alkynyl-, 3-to 7-unit Heterocyclylalkyl-, aryl-, heteroaryl-,-C (=O) R⁶、-C(=O)N(H)R^6a、-C(=O)N(R^6a)R^6b、-C(=O)O-R⁶、-N(R^6a)R^6b、-NO₂、-N(H)C(=O)R⁶、-N(R^6c)C (=O)R⁶、-N(H)C(=O)N(R^6a)R^6b、-N(R^6c)C(=O)N(R^6a)R^6b、-N(H)C(=O)OR⁶、-N(R^6c)C(=O)OR⁶、-N (H)S(=O)R⁶、-N(R^6c)S(=O)R⁶、-N(H)S(=O)₂R⁶、-N(R^6c)S(=O)₂R⁶、-N=S(=O)(R^6a)R^6b、-OR⁶、-O(C =O)R⁶、-O(C=O)N(R^6a)R^6b、-O(C=O)OR⁶、-SR⁶、-S(=O)R⁶、-S(=O)N(H)R⁶、-S(=O)N(R^6a)R^6b、-S(= O₂)R⁶、-S(=O)₂N(H)R⁶、-S(=O)₂N(R^6a)R^6b、-S(=O)(=NR^6c)R⁶Or-S (=O)₂-(3-to 7-unit Heterocyclylalkyl) Group；

M is integer 0,1,2,3,4,5 or 6；

N is integer 0,1,2,3,4 or 5；And

X is S, S (=O), S (=O)₂、O、NR⁶, C (=O) or CR^6aR^6b。

In another preferred embodiment of the present, the present invention relates to the compound of Formulas I, or its stereoisomer, tautomerism Body, N-oxide, hydrate, solvate or salt, or their mixture:

Wherein:

A represents

Z represents-C (=O) N (H) R¹Or-C (=S) N (H) R¹Group；

R¹Represent C₁-C₆-alkyl-or C₃-C₆-cycloalkyl-group；

Wherein said C₃-C₆-cycloalkyl-group is optionally identical or different selected from following group by 1,2,3 or 4 Replace: halogen ,-OH ,-CN, C₁-C₆-alkyl-, C₁-C₆-alkoxyl-, C₃-C₆-cycloalkyl-, HO-C₁-C₆-alkyl-；

M is integer 0,1,2,3,4,5 or 6；

N is integer 0,1,2,3,4 or 5；And

X is S, S (=O), S (=O)₂、O、NR⁶, C (=O) or CR^6aR^6b。

Wherein:

A represents

Z represents-C (=O) N (H) R¹Or-C (=S) N (H) R¹Group；

R¹Represent C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-or aryl-group；

Wherein said C₁-C₆-alkyl-or C₃-C₆-cycloalkyl-or aryl-group optionally by 1,2,3 or 4 selected from Under group replace identical or differently: halogen ,-OH ,-CN, C₁-C₆-alkyl-, C₁-C₆-alkoxyl-, C₃-C₆-cycloalkyl-, HO-C₁-C₆-alkyl-；

R³Represent hydrogen atom or-CN, C₁-C₆-alkyl-,-(CH₂)_m-C₂-C₆-thiazolinyl ,-(CH₂)_m-C₂-C₆-alkynyl, virtue Base-, heteroaryl-, aryl-X-group；

Wherein said C₁-C₆-alkyl-,-(CH₂)_m-C₂-C₆-thiazolinyl ,-(CH₂)_m-C₂-C₆-alkynyl, aryl-, aryl-X- Or heteroaryl-group is optionally by 1,2 or 3 R⁷Group replaces identical or differently；

R⁵Represent hydrogen atom, or C₁-C₆-alkyl-,-(CH₂)_n-C₂-C₆-thiazolinyl ,-(CH₂)_n-C₂-C₆-alkynyl ,-(CH₂) m_-C₃-C₆-cycloalkyl ,-(CH₂)_m-(3-to 7-unit Heterocyclylalkyl), aryl-C₁-C₆-alkyl-, heteroaryl-C₁-C₆-alkyl-, halogen Generation-C₁-C₆-alkyl-, R^6a(R^6b)N-C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-,-C₁-C₆-alkyl-CN, C₁-C₆-alkoxyl- C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-, 3-to 7-unit Heterocyclylalkyl-, C₄-C₈- Cycloalkenyl group-, aryl-or heteroaryl-group；

M is integer 0,1,2,3,4,5 or 6；

N is integer 0,1,2,3,4 or 5；And

X is S, S (=O), S (=O)₂、O、NR⁶, C (=O) or CR^6aR^6b。

Wherein:

A represents

Z represents-C (=O) N (H) R¹Or-C (=S) N (H) R¹Group；

R¹Represent C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-or aryl-group；

R^4a、R^4b、R^4c、R^4dRepresent hydrogen or C independently of each other₁-C₆-alkyl-radical；

Or

M is integer 0,1,2,3,4,5 or 6；

N is integer 0,1,2,3,4 or 5；And

X is S, S (=O), S (=O)₂、O、NR⁶, C (=O) or CR^6aR^6b。

Wherein:

A represents

Z represents-C (=O) N (H) R¹Or-C (=S) N (H) R¹Group；

R¹Represent C₁-C₆-alkyl-, C₃-C₆-cycloalkyl-or aryl-group；

R⁶、R^6a、R^6b、R^6cRepresent hydrogen atom, C independently of each other₁-C₆-alkyl-, C₃-C₆-cycloalkyl-or aryl-C₁-C₆- Alkyl-radical；

Wherein said C₃-C₆-cycloalkyl-group optionally by 1 or 2 selected from following group identical or different replace: Halogen ,-OH ,-CN, C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-；

M is integer 0,1,2,3,4,5 or 6；

N is integer 0,1,2,3,4 or 5；And

X is S, S (=O), S (=O)₂、O、NR⁶, C (=O) or CR^6aR^6b。

Wherein:

A represents

Z represents-C (=O) N (H) R¹Or-C (=S) N (H) R¹Group；

R¹Represent C₁-C₃-alkyl-or C₃-C₆-cycloalkyl-group；

Wherein said C₃-C₆-cycloalkyl-group is optionally identical or different selected from following group by 1,2,3 or 4 Replace: halogen ,-OH ,-CN, C₁-C₃-alkyl-, C₁-C₃-alkoxyl-, C₃-C₆-cycloalkyl-, HO-C₁-C₃-alkyl-；

Wherein said C₁-C₃-alkyl-radical optionally by 1,2,3 or 4 selected from following group identical or different take Generation: halogen ,-OH ,-CN, C₁-C₃-alkoxyl-, C₃-C₆-cycloalkyl-, HO-C₁-C₃-alkyl-；

R⁷Represent halogen atom, or HO-, C₁-C₆-alkoxyl-, C₁-C₆-alkyl-, halo-C₁-C₆-alkyl-, halo- C₁-C₆-alkoxyl-, HO-C₁-C₆-alkyl-,-C (=O) N (H) R^6a、-N(R^6a)R^6b、-C(=O)O-R⁶Or-OR⁶Group；

M is integer 0,1,2,3,4,5 or 6；

N is integer 0,1,2,3,4 or 5；And

X is S, S (=O), S (=O)₂、O、NR⁶, C (=O) or CR^6aR^6b。

Wherein:

A represents

Z represents-C (=O) N (H) R¹Or-C (=S) N (H) R¹Group；

R¹Represent C₁-C₃-alkyl-or cyclopropyl-group；

Wherein said cyclopropyl-group optionally by 1,2 or 3 selected from following group identical or different replace: halogen Element ,-OH ,-CN, C₁-C₃-alkyl-；

Wherein said C₁-C₃-alkyl-radical optionally by 1,2 or 3 selected from following group identical or different replace: Halogen ,-OH ,-CN, C₁-C₃-alkoxyl-；

R^4a、R^4b、R^4dRepresent hydrogen atom；

R^4cRepresent halogen atom, or-CN ,-OH, C₁-C₃-alkyl-, C₁-C₃-alkoxyl-, halo-C₁-C₃-alkyl-, Halo-C₁-C₃-alkoxyl-, R^6a(R^6b)N-C₁-C₃-alkyl-, HO-C₁-C₃-alkyl-, NC-C₁-C₃-alkyl-, C₁-C₃-alcoxyl Base-C₁-C₃-alkyl-or halo-C₁-C₃-alkoxy-C₁-C₃-alkyl-radical；

M is integer 0,1,2,3,4,5 or 6；

N is integer 0,1,2,3,4 or 5；And

X is S, S (=O), S (=O)₂、O、NR⁶, C (=O) or CR^6aR^6b。

Wherein:

A represents

R¹Represent methyl-group or cyclopropyl-group；

Wherein said cyclopropyl-group is optionally substituted with at least one fluorine atom；

R³Represent pyridine radicals-, phenyl-, phenyl-O-or phenyl-S-group；

Wherein said phenyl-S-group optionally by 1 or 2 selected from following group identical or different replace :-F, H₃C-O-、HO-、H₃C-；

R⁵Represent selected from following group:

Wherein * indicates the surplus of described group and molecule Remaining part divides the point of connection；

R^6aRepresent hydrogen atom or methyl-group or C₃-C₆-cyclopropyl-group；

Wherein said C₃-C₆-cyclopropyl-group is optionally replaced by-CN a group.

It should be understood that any subgroup that the present invention relates in any embodiment of the present invention of the compound of general formula I Close.

More specifically, the present invention includes the compounds of formula I disclosed in following this paper experimental section.

The compound of the present invention can comprise one or more asymmetric center, and this depends on desired various substituent group Position and character.Asymmetric carbon atom can exist by (R) or (S) configuration, obtains in the case of having an asymmetric center Racemic mixture, and obtain non-enantiomer mixture in the case of there is multiple asymmetric center.In some cases, Due to the blocked rotation around particular key, it is also possible to there is unsymmetry, such as this center key connects two of specific compound The aromatic ring being replaced.

Substituent group on ring can exist with cis or trans form.Expection all such configuration (includes enantiomer and non- Enantiomer) all it is included in the scope of the present invention.

Preferably compound is those compounds producing more desirable biologic activity.The separation of the compounds of this invention , purification or partially purified isomer and stereoisomer or racemic mixture or non-enantiomer mixture also wrap Include in the scope of the present invention.The purification of this kind of material and separation can be realized by standard technique known in the art.

Optical isomer can be obtained according to conventional methods, such as by using optically-active acid by resolving racemic mixtures Or alkali forms diastereomeric salt, or by forming covalent diastereomeric.The example of suitable acid is tartaric acid, diacetyl Base tartaric acid, ditoluoyltartaric and camphorsulfonic acid.The mixture of diastereomer can physics based on them and/ Or chemical differences, by methods known in the art as being separated into their single diastereomeric by chromatography or fractional crystallization Isomer.Then from the diastereoisomeric salt separated, discharge optically-active alkali or acid.The side of another kind of different separating optical isomers Method is included in and carries out or do not carry out using under conditions of conventional derivation chiral chromatography (such as, chirality HPLC column), and it can be through Cross optimum selection the separation of enantiomer to be maximized.Suitably chirality HPLC column is produced by Diacel, such as Chiracel OD With Chiracel OJ etc., the most all can select routinely.Also enzyme process can be used under conditions of carrying out or not performing the derivatization to divide From.Likewise it is possible to by using the synthesis of the chirality of optically-active raw material to obtain the optically-active compound of the present invention.

In order to different types of isomer is made a distinction from each other, with reference to IUPAC rule E part (Pure Appl Chem45,11-30,1976)。

The present invention includes all possible stereoisomer of the compounds of this invention, and it is single stereoisomers or described Any mixture of any ratio of stereoisomer.Can be by any suitable art methods such as chromatography, especially It is that such as chiral chromatography realizes the single stereoisomers such as single enantiomer of the compound of the present invention or single diastereomer Separation.

Additionally, the compound of the present invention can be presented in tautomer.Such as, the pyrazoles as heteroaryl is comprised Part any present invention compound such as can presented in 1H tautomer or 2H tautomer, or even with Presented in the mixture of the two tautomer of any amount, or comprise appointing of the triazole part as heteroaryl The compound of what present invention such as can presented in 1H tautomer, 2H tautomer or 4H tautomer, or Even presented in the mixture of described 1H, 2H and 4H tautomer of any amount:

The present invention includes all possible tautomer of the compounds of this invention, and it is single tautomer or described Any mixture of any ratio of tautomer.

Additionally, the compound of the present invention can be presented in N-oxide, it is defined as in the compound of the present invention At least one nitrogen is oxidized.The present invention includes the N-oxide that all such is possible.

Additionally, the present invention includes all possible crystal form or the polymorph of the compounds of this invention, it can be single The mixture of any ratio of polymorph or more than one polymorph.

The compound of the present invention can be presented in hydrate or solvate, and wherein the compound of the present invention comprises work For the polar solvent of the structural element of described compound lattice, the most such as water, methanol or ethanol.Polar solvent particularly water Amount can exist with stoichiometric proportion or non-stoichiometric.In the case of stoichiometric solvates is such as hydrate, may It is half (hemi-) solvate or hydrate, (half (semi-)) solvate or hydrate, a solvate or hydration respectively Thing, sesquialter solvate or hydrate, two solvates or hydrate, three solvates or hydrate, four solvates or water Compound, five solvates or hydrate etc..The present invention includes all such hydrate or solvate.

In an embodiment of above-mentioned aspect, the present invention relates to compound vertical of the Formulas I of any of above embodiment Body isomer, tautomer, N-oxide, hydrate, solvate or salt or the form of their mixture.

Have surprisingly been found that the compound of the described present invention effectively suppresses Mps-1 kinases, and therefore may be used for Treat or prevent the growth of uncontrolled cell, breed and/or survive, unsuitable cellullar immunologic response or unsuitable cell The disease of inflammatory response, or be attended by the growth of uncontrolled cell, breed and/or survive, unsuitable cellular immunization should Answering or the disease of unsuitable cellular inflammation response, especially, wherein said uncontrolled cell grows, breeds and/or deposit Living, unsuitable cellullar immunologic response or unsuitable cellular inflammation response are kinase mediated by Mps-1, and such as blood swells Tumor, solid tumor and/or their transfer, such as leukemia and myelodysplastic syndrome, malignant lymphoma, include cerebroma and Brain metastes is at interior tumor of head and neck, the breast tumor including non-fire power and small cell lung tumor, gastrointestinal tract Tumor, endocrine tumors, breast tumor and other gynecological tumors, including tumor of kidney, tumor of bladder and tumor of prostate Urologic neoplasms, cutaneous tumor and sarcoma and/or their transfer.

It is therefore contemplated that the compound of Formulas I has the value as therapeutic agent above.

Therefore, in another embodiment, the present invention relates to the compound of general formula I, or its stereoisomer, mutually Tautomeric, N-oxide, hydrate, solvate or salt, particularly its pharmaceutically acceptable salt, or their mixing Thing, is used for treating or preventing disease.

In another embodiment, the present invention provide a kind of treat patient in need with increase uncontrolled increasing The method growing the relevant disease of sexual cell process, described method includes the compound of the Formulas I to described patient's effective dosage.

Term " treatment (treating) " or the use of " treatment (treatment) " that presents is mentioned in the whole text are conventional , such as manage or nursing for the purpose of the situation of the disease or disease of resisting, alleviate, reduce, prevent, improve such as sarcoma Individual.

Term " individual " or " patient " include can suffering from cell proliferative disorders or can otherwise benefit from It is administered the biology of the compound of the present invention, such as people and non-human animal.As described herein, it is preferred to people include suffering from or be prone to suffering from There is the human patients of cell proliferative disorders or correlation behavior.Term " non-human animal " includes vertebrates, such as mammal, Such as non-human primates, sheep, cattle, Canis familiaris L., cat and rodent such as mice, and nonmammalian, as chicken, Amphibian, creep dynamic Thing etc..

Term " cell proliferative disorders " or " disease relevant to the uncontrolled proliferative cell process increased " bag Include the disease relating to less desirable or uncontrolled cell proliferation.The compound of the present invention can be used to prevent, suppresses, hinders Break, reduce, reduce, control cell proliferation and/or cell division, and/or cause apoptosis.This method includes in need Body (including mammal, including people) is administered a certain amount of effective treatment or prevents the compound of the present invention of described disease, or Its pharmaceutically acceptable salt of person, isomer, polymorph, metabolite, hydrate or solvate.

In another embodiment, the present invention relates to compounds of formula I, or its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, particularly its pharmaceutically acceptable salt, or their mixture, it is used for controlling Treating or prevention disease, wherein said disease is the growth of uncontrolled cell, breeds and/or survive, unsuitable cellular immunization Response or the disease of unsuitable cellular inflammation response, especially, wherein said uncontrolled cell growth, propagation and/or Survival, unsuitable cellullar immunologic response or unsuitable cellular inflammation response are by mitogen-activated protein kinase (MEK- ERK) approach mediates, and more particularly, wherein said uncontrolled cell grows, breeds and/or survive, unsuitable cell The disease of immunne response or unsuitable cellular inflammation response is neoplastic hematologic disorder, solid tumor and/or their transfer, such as white blood Sick and myelodysplastic syndrome, malignant lymphoma, tumor of head and neck including cerebroma and brain metastes, include non-little carefully Born of the same parents' lung tumor and small cell lung tumor are in interior breast tumor, gastroenteric tumor, endocrine tumors, breast tumor and other gynecological Tumor, urologic neoplasms, cutaneous tumor and sarcoma including tumor of kidney, tumor of bladder and tumor of prostate and/or it Transfer.

The invention still further relates to the useful form of compound as disclosed herein, such as metabolite, hydrate, solvate, The most pharmaceutically acceptable salt of prodrug, salt, internal hydrolyzable ester and co-precipitation thing.

Term " pharmaceutically acceptable salt " refers to the relative nontoxic of the compound of the present invention, mineral acid or organic acid addition Salt.For example, with reference to S.M.Berge, et al. " Pharmaceutical Salts, " J.Pharm.Sci.1977,66,1-19.

The suitable pharmaceutically acceptable salt of the compounds of this invention can be the tool such as comprising nitrogen-atoms in chain or ring There are the acid-addition salts of enough the compounds of this invention of alkalescence, the acid-addition salts such as formed: such as hydrochloric acid, hydrogen with following mineral acid Bromic acid, hydroiodic acid, sulphuric acid, pyrosulfuric acid (bisulfuric acid), phosphoric acid or nitric acid；Or the acid formed with following organic acid Addition salts: such as formic acid, acetic acid, acetoacetic acid, acetone acid, trifluoroacetic acid, propanoic acid, butanoic acid, caproic acid, enanthic acid, hendecanoic acid, the moon The acid of cinnamic acid, benzoic acid, salicylic acid, 2-(4-hydroxy benzoyl) benzoic acid, dextrocamphoric acid., cinnamic acid, Pentamethylene. propanoic acid, didextrose (digluconic acid), 3-hydroxy-2-naphthoic acid, nicotinic acid, flutter acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, bitterness Acid, pivalic acid, 2-ethylenehydrinsulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, lauryl sulphate acid, ethyl sulfonic acid, benzenesulfonic acid, P-methyl benzenesulfonic acid, methanesulfonic acid, 2-LOMAR PWA EINECS 246-676-2, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, Malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptose, Phosphoglycerol, aspartic acid, sulfosalicylic acid, hemisulfic acid (hemisulfuric acid) or Hydrogen thiocyanate.

Additionally, the suitable pharmaceutically acceptable salt of another kind with enough acid the compounds of this invention is alkali metal salt Such as sodium salt or potassium salt, alkali salt such as calcium salt or magnesium salt, ammonium salt, or with the organic of the acceptable cation of physiology is provided Alkali formed salt, the salt such as formed with following material: N-methyl-glucamine, dimethyl-glycosamine, ethyl-glycosamine, rely Propylhomoserin, dicyclohexylamine, 1,6-hexamethylene diamine, ethanolamine, glycosamine, sarcosine, serinol, three-hydroxy-methyl-aminomethane, Amino-propanediol, sovak-alkali, 1-amino-2,3,4-butantriol.Additionally, Basic nitrogen-containing groups can be with following reagent quaternary ammonium Change: low alkyl group halogen, such as methyl, ethyl, propyl group and butyl chloride compound, bromide and iodide；Dialkyl sulfate, such as Dimethyl sulfate, dithyl sulfate, dibutyl sulfate and diamyl sulfates；Long chain halide such as decyl, lauryl, Semen Myristicae Base and stearyl chlorides, bromide and iodide；Aralkyl halide such as benzyl and phenylethyl bromide etc..

Those skilled in the art will further recognize that, the acid-addition salts of compound required for protection can be by multiple Any one in known method makes described compound prepare with suitable mineral acid or organic acid reaction.Or, the present invention The alkali metal salt of acid compound and alkali salt make the compound of the present invention with suitable by various known methods Prepared by alkali reaction.

The present invention includes all possible salt of the compounds of this invention, its be single salt or described salt any ratio appoint What mixture.

Terms used herein " internal hydrolyzable ester " is understood to mean that the chemical combination of the present invention comprising carboxyl or hydroxyl The internal hydrolyzable ester of thing, such as, be hydrolyzed in human body or animal body thus produce the pharmaceutically acceptable of parent acid or alcohol Ester.For carboxyl, suitable pharmaceutically acceptable ester includes such as Arrcostab, cycloalkyl ester and the phenylalkyl being optionally substituted Ester particularly benzyl ester, C₁-C₆Alkoxy methyl ester, such as methoxymethyl ester, C₁-C₆Alkanoyloxymethyl ester such as special penta Acyloxymethyl ester, phthalidyl ester, C₃-C₈Cycloalkyloxy-carbonyloxy group-C₁-C₆Arrcostab such as 1-cyclohexylcarbonyloxyethyl ester； 1,3-dioxole-2-carbonvlmethyl ester (1,3-dioxolen-2-onylmethyl), such as 5-methyl isophthalic acid, 3-dioxy Heterocyclic pentene-2-carbonvlmethyl ester；And C₁-C₆-Cialkoxycarbonyloxyethyl esters, such as 1-methoxycarbonyloxyethyl ester, and And described ester can be formed on any carboxyl of the compound of the present invention.

The internal hydrolyzable ester of the compounds of this invention comprising hydroxyl includes inorganic acid ester (such as phosphate ester), [α]-acyl Epoxide alkyl ether and related compound, described related compound breaks to form parent hydroxy due to the internal hydrolysis of described ester. The example of [α]-acyloxyalkyi ethers includes acetoxy-methyl ether (acetoxymethoxy) and 2,2-dimethylpropanoyloxy Methyl ether (2,2-dimethylpropionyloxy methoxy).The selection of the group of internal hydrolyzable ester is formed with hydroxyl Including alkanoyl, benzoyl, phenyl acetyl and substituted benzoyl and phenyl acetyl, alkoxy carbonyl group (to be formed Alkyl carbonate), dialkyl carbamoyl and N-(di-alkyaminoethyl group)-N-alkyl-carbamoyl be (to form amino Formic acid esters), dialkylaminoacetyl and carboxyacetyl.The present invention includes all such ester.

The compound of Formulas I can be administered as unique medicament or the therapeutic combination extra with one or more is given Medicine, wherein said combination will not cause unacceptable ill effect.This therapeutic alliance includes being administered single medicine dosage The compound of contained I and the preparation of therapeutic agent that one or more are extra, and the compound of Medicine-feeding type I and oneself is independent Pharmaceutical dosage formulation in every kind of extra therapeutic agent.For example, it is possible to by the compound of Formulas I and therapeutic agent in single oral agents Amount compositions such as tablet or capsule are administered to patient together, or every kind of medicament can be given in independent dosage particles Medicine.

When using independent dosage particles, the compound of Formulas I and therapeutic agent that one or more are extra can be existed The substantially the same time (such as, or is administered in the time (such as, sequentially) staggered respectively simultaneously).

On the other hand, the present invention provides a kind of pharmaceutical composition, and it comprises compounds of formula I, or its solid is different Structure body, tautomer, N-oxide, hydrate, solvate or salt, particularly its pharmaceutically acceptable salt, or they Mixture, and pharmaceutically acceptable diluent or carrier.

Preferably, drug regimen comprises:

-one or more compounds of formula I, or its stereoisomer, tautomer, N-oxide, hydrate, Solvate or salt, particularly its pharmaceutically acceptable salt, or their mixture；And

-one or more are selected from following material: taxane, such as docetaxel, paclitaxel or taxol；Epothilones, The such as grand or husky dagger-axe of appropriate of ipsapirone, handkerchief is grand；Mitoxantrone；Prednisolone (Predinisolone)；Dexamethasone；Female Mo Siting；Vinblastine；Vincristine；Doxorubicin；Amycin；Idarubicin；Daunorubicin；Bleomycin；Etoposide；Ring Phosphamide；Ifosfamide；Procarbazine；Melphalan；5-fluorouracil；Capecitabine；Fludarabine；Cytosine arabinoside；Ara- C；The chloro-2 '-deoxyadenosine of 2-；Thioguanine；Androgen antagonist, such as flutamide, cyproterone acetate or bicalutamide；Boron is for assistant Rice；Platinum derivatives, such as cisplatin or carboplatin；Chlorambucil；Methotrexate；And Rituximab.

On the other hand, the present invention provides a kind of method preparing pharmaceutical composition.Said method comprising the steps of: make The compound of at least one Formulas I as defined above combines with at least one pharmaceutically acceptable carrier, and makes the group of gained Synthesize suitable form of medication.

On the other hand, the present invention provides the compound of Formulas I as defined above in preparation for treating or preventing cell Purposes in the pharmaceutical composition of proliferative disorders.In certain embodiments, described cell proliferative disorders is cancer.

The active component of Formulas I can be with whole body and/or local action.For this purpose, it can be executed in an appropriate manner With, such as, oral, parenteral, pulmonary, nasal cavity, Sublingual, to tongue, buccal, rectum, transdermal, conjunctiva, locally (otically) or Person is administered as implant or support.

When the compound of the present invention is administered to humans and animals as medicine, they can itself be administered, or as medicine Compositions is administered, and described pharmaceutical composition comprises the active ingredient combination pharmacy of such as 0.1-99.5% (more preferably 0.5-90%) Acceptable carrier.

The most selected route of administration, can be with suitably hydration by conventional method well known by persons skilled in the art The compound of the present invention and/or the pharmaceutical composition of the present invention that form uses are formulated as pharmaceutically acceptable dosage form.

The actual dose level of the active component in the pharmaceutical composition of the present invention and the time course of administration can change To obtain the amount of active component, compositions and the mode of administration of the expectation treatment response effectively realizing particular patient, and to trouble Person is nontoxic.

According on the other hand, the method that the present invention relates to prepare the compound of the present invention, described method includes testing herein Step described in part.

According to another aspect, the method that the invention still further relates to prepare the compound of general formula I.

According to the first embodiment, the present invention relates to a kind of method preparing compounds of formula I, described method include with Lower step:

Make the midbody compound of formula IV:

Wherein R⁵Define with A such as mutual-through type I above, and R^3’For halogen atom,

React with the compound of formula IVa:

R³-Y

IVa

Wherein R³As mutual-through type I defines above, and Y is that substituent group replaced in coupling reaction, such as hydrogen are former Son, or boric acid base group, or the ester of boric acid base group,

Thus compounds of formula I is obtained when optionally deprotecting:

Wherein R³、R⁵Define with A such as mutual-through type I above.

According to the second embodiment, a kind of method that the invention still further relates to compound preparing general formula I, described method Comprise the following steps:

Make the midbody compound of formula II:

Wherein R³And R⁵As mutual-through type I defines above, and Q is halogen atom

React with the compound of formula IIa:

A-Y

IIa

Wherein A such as mutual-through type I above defines, and Y is substituent group replaced in coupling reaction, such as boronate Group or the ester of boric acid base group,

Thus compounds of formula I is obtained when optionally deprotecting:

Wherein R³、R⁵Define with A such as mutual-through type I above.

According to the 3rd embodiment, a kind of method that the invention still further relates to compound preparing general formula I, described method Comprise the following steps:

Make the midbody compound of formula VII:

Wherein R³Define with A such as mutual-through type I above, and V be leaving group, such as halogen atom,

React with the compound of formula VIIa:

R⁵-CH₂-NH₂

VIIa

Wherein R⁵As mutual-through type I defines above,

Thus compounds of formula I is obtained when optionally deprotecting:

Wherein R³、R⁵Define with A such as mutual-through type I above.

According to the 4th embodiment, a kind of method that the invention still further relates to compound preparing general formula I, described method Comprise the following steps:

Make the midbody compound of formula VII:

Wherein R³Define with A such as mutual-through type I above, and V is NH₂-group

React with the compound of formula VIIb:

O=CHR⁵

VIIb

Wherein R⁵As mutual-through type I defines above,

Thus compounds of formula I is obtained when optionally deprotecting:

Wherein R³、R⁵Define with A such as mutual-through type I above.

According on the other hand, the present invention relates to the compounds of formula I that can be used for preparing the present invention, especially for herein The midbody compound of described method.

In particular it relates to compounds of formula IV:

Wherein R⁵Define with A such as mutual-through type I above, and R^3’For halogen atom.

The invention still further relates to compounds of formula II:

Wherein R³And R⁵As mutual-through type I defines above, and Q is halogen atom.

The invention still further relates to compounds of formula VII:

Wherein R³And R⁵As mutual-through type I defines above, and V is NH2-group or halogen atom.

Experimental section

As described above, another aspect of the present invention is the method for the compound for preparing the present invention.

Following table lists the abbreviation used in this joint and embodiment part.NMR peak form is described when occurring in spectrum, Do not consider the effect of possible higher order.

Use Autonom2000 plug-in unit [the MDL Information Systems Inc. (Elsevier of ISIS/Draw ] or the ICS name instrument 12.01 of ACD laboratory generates the title of compound MDL).In some cases, commercially available examination is used The title generally accepted of agent.

Other abbreviations have itself to implication well known to those skilled in the art.By Examples below, the application is described The various aspects of invention, it is not construed as in any way limiting the present invention.

Scheme hereinafter described and method illustrate the general synthetic schemes of the compounds of formula I of the present invention, and not It is intended to it is limited.Those skilled in the art understand that the conversion order of example in scheme can be modified in every way.Cause This, it is not intended to the conversion order of example in restricted version.Additionally, any substituent A, R³Or NH-CH₂-R⁵Exchange can be Realize before or after exemplified conversion reaction.These modifications can be the introducing of such as blocking group, blocking group Cutting, the reduction of functional group or oxidation, halogenation, metallize, replace, be cyclized, be condensed or well known by persons skilled in the art other Reaction.These convert those conversions including introducing the degree of functionality making the further change of substituent group.Suitably blocking group and Their introducing and fracture are to well known to a person skilled in the art (to see, e.g. T.W.Greene and P.G.M.Wuts in Protective Groups in Organic Synthesis,3^rdedition,Wiley1999).Instantiation is subsequently Described in paragraph.Additionally, as known to those skilled in the art, two or more consecutive steps can so be carried out, institute State and between step, do not carry out post processing, such as " one pot " reaction.

The synthesis of the compounds of formula I of the present invention

Compounds of formula I can synthesize as shown in scheme, wherein R³、R⁵Have above given by mutual-through type I with A Implication, and R^3’, Q represent that leaving group, V represent the most protected NH2-group or leaving group.Typical leaving group The example of group includes but not limited to halogen atom such as chlorine, bromine or iodine atom, or S (O)_pR⁶-group such as methyl sulphonyl-, trifluoro Methanesulfonates-or nine fluorine butane sulphonic acid esters-group, p is 0,1 or 2.

Scheme illustrates permission R³、R^3’、R⁵, the route that changes during synthesizing of Q, V and A.R³、R^3’、R⁵, official in Q, V and A Energy part can be at each suitable stage conversion of synthesis.

But, other routes can be used for synthesizing target compound.

The compound of Formula X I can be purchased or can according to method synthesis well known by persons skilled in the art (see, Such as Tschitschibabin;Jegorow,Zhurnal Russkago Fiziko-Khimicheskago Obshchestva,1928,60,689;Fray,M.Jonathan et al.,Journal of Medicinal Chemistry, 1995,38,3524 3535 or Cai, Sui Xiong et al., Journal of Medicinal Chemistry,1997,40,3679-3686)。

The compound of Formula X can be purchased or (can see, example according to method synthesis well known by persons skilled in the art Such as Loiseau, Philippe R.et al.European Journal of Medicinal Chemistry, 1987,22, 457 462 or WO200426867A2,2004,32-33).

The compound of Formula IX can be purchased or can according to method synthesis well known by persons skilled in the art (see, Such as Gudmundsson, Kristjan S.;Johns, Brian A., Organic Letters, 2003,5,1369 1372 or WO201070008A1,2010,68)。

Leaving group Q can by method known to those skilled in the art introduce general formula X, VI or III compound with Obtain the compound of formula IX, V or II.As an example, halogen can utilize such as N-iodine butanimide, N-bromine butanimide Or the halide reagent of N-chloro-succinimide, at atent solvent such as DMF or 1-methylpyrrolidin-2-ketone, Such as room temperature introduces at a temperature of the boiling point of solvent.

The compound of formula I, IV or VIII can be by the coupling reaction between the reagent of formula Y-A from formula II, V or IX Compound obtain, wherein A is as hereinbefore defined, and Y represents suitable functional group, by Y, can be turned by Y, group A On the Q-group with carbon atom of the compound moving to Formula II, V or IX.In A-Y, the example of the appropriate functional group of Y includes boric acid A-B(OH)₂Or or the ester A-B (OC of boric acid₁-C₆-alkyl)₂.Described coupling reaction suitable catalyst (such as based on The catalyst of palladium, such as acid chloride (II), tetrakis triphenylphosphine palladium (0), double (triphenylphosphine)-Palladous chloride. (II) or (1,1'-pair (diphenylphosphino) ferrocene) dichloro palladium (II)) and the appropriate addn such as phosphine such as P (oTol) that is optionally present₃Or triphenyl Carry out in the presence of phosphine, and optionally there is suitable solvent such as the suitable alkali such as potassium carbonate in oxolane, 2-methyl Acrylate-2 acid esters, tetrabutyl amine fluoride or tripotassium phosphate.

The example of such coupling reaction can be at entitled " Metal-Catalyzed Cross-Coupling Reactions”,Armin de Meijere(Editor), Diederich(Editor)September2004, The textbook of Wiley Interscience ISBN:978-3-527-30518-6 finds.

The compound of formula I, II, III or VII can utilize formula Y-R³Reagent by coupling reaction from formula IV, V, The compound of VI or VIII obtains, wherein R³As hereinbefore defined, and Y represents suitable functional group, by Y, group R³Permissible It is transferred to the R with carbon atom of the compound of formula IV, V, VI or VIII^3’On.Appropriate functional group for the Y of coupling reaction Example is prepared given by the compound of formula I, IV or VIII as described above for the compound from formula II, V or IX.

Coupling reaction includes that the coupling reaction such as Sonogashira coupling reaction carried out with alkynes of metal catalytic is to introduce Alkynes, the Heck coupling reaction carried out with alkene to introduce alkene, the Hartwig Buchwald coupling reaction carried out with amine with Introduce amine.

Y-R³In Y also may indicate that acidic hydrogen, it can be by the conjunction in suitable solvent such as DMSO or oxolane Suitable alkali such as sodium hydroxide removes at a temperature of rt to boiling point.The nucleopilic reagent of gained such as primary amine or secondary amine, alkoxide, mercaptides Or the group with carboanion is substituted for the R in the compound of formula IV, V, VI or VIII^3’To increase secondary amine or uncle The group that amine, ether, thioether or carbon atom connect is to obtain the compound of formula I, II, III or VII.

The compound of formula I, II, III or VII containing secondary amine or tertiary amine, ether or thioether can also pass through Ullmann type Coupling reaction, in the presence of suitable catalyst such as catalyst based on copper such as oxalic acid copper (II), at suitable alkali such as carbon In the presence of acid caesium, start to build from the compound of formula IV, V, VI or VIII, wherein R^3’Represent leaving group such as iodine, bromine or Chlorine atom.It is optionally possible to add suitable part such as DMG or phenyl hydrogen pyrrolidin-2-yl phosphonate ester (phenyl hydrogen pyrrolidin-2-ylphosphonate)。

In the case of V represents leaving group, R⁵-CH₂The introducing of-group can pass through Formula VII, the change of VIII, IX or X In compound, the nucleophilic displacement of fluorine of V realizes, i.e. in suitable solvent such as DMF or 1-methylpyrrolidin-2-ketone Suitable alkali such as DIPEA in the presence of with suitable amine R⁵-CH₂-NH₂React at a temperature of the boiling point of room temperature to solvent with Obtain the amine of formula I, IV, V or VI.

In the case of V represents leaving group, R⁵-CH₂The introducing of-group can also realize in coupling reaction, wherein makes Formula VII, VIII, IX or X compound in V and suitable amine R⁵-CH₂-NH₂Reaction, optionally at suitable catalyst such as Pd₂dba₃In the presence of BINAP, optionally by suitable alkali such as sodium tert-butoxide, at suitable solvent such as N, N-dimethyl methyl Amide or 1-methylpyrrolidin-2-ketone carry out obtaining the amine of formula I, IV, V or VI.

The most protected NH is represented at V₂In the case of-group, it is NH at deprotection₂After-group, R₅-CH₂-group Introducing can be reacted by reductive amination and realize, use suitable solvent such as formula O=CHR in acetic acid⁵Aldehyde, properly Reducing agent such as sodium triacetoxy borohydride (sodium tris (acetato-kappaO) (hydrido) borate) or cyanogen Base sodium borohydride, is carried out at a temperature of the boiling point of room temperature to solvent.

Formulas I, II, III, IV, V, VI, VII, VIII, IX, X or XI compound in residue can optionally repair Decorations.Such as thioether can be with the such as 3-chloroperoxybenzoic acid of the oxidant in atent solvent such as dichloromethane or acetone, permonosulphuric acid Hydrogen potassium or dimethyldioxirane aoxidize respectively.According to the stoichiometric proportion of oxidant Yu above-claimed cpd, can obtain sulfoxide, Sulfone or its mixture.

Furthermore, it is possible to by any method known to those skilled in the art the compound of the Formulas I of the present invention is converted into Any salt as herein described.Similarly, can be by any method known to those skilled in the art by the change of the Formulas I of the present invention Any salt of compound is converted into free compound.

Prepared according to the methods of the invention compound and intermediate may need purification.The purification of organic compound is this Known to skilled person, and the method that the identical compound of several purification can be there is.In some cases, may be not required to Want purification.In some cases, described compound can carry out purification by crystallization.In some cases, can be closed by use Suitable solvent is stirred the removal of impurity of making a return journey.In some cases, described compound can pass through chromatograph, particularly flash chromatography Being purified, it uses the most pre-filled silica gel pillar, such as from Separtis asFlash silica gel OrFlash NH2 silica gel and suitable chromatographic system such as Flashmaster II (Separtis) or Isolera system The combination of the gradient liquid of system (Biotage) and eluent such as hexane/EtOA or DCM/ methanol.In some cases, describedization Compound can be purified by preparation HPLC, and it uses such as is furnished with diode array detector and/or online electron spray The Waters automatic purification instrument of ion mass-spectrometer and suitable pre-filled reversed-phase column and auxiliary agent such as trifluoroacetic acid, first can be comprised The combination of the gradient liquid of the eluent such as water and acetonitrile of acid or ammonia.

UPLC-MS analysis is carried out as follows:

Method A: system: UPLC Acquity (Waters), is furnished with PDA detector and Waters ZQ mass spectrograph；Post: Acquity BEH C181.7μm2.1x50mm；Temperature: 60 DEG C；Solvent orange 2 A: water+0.1% formic acid；Solvent B: acetonitrile；Gradient: 99%A →1%A(1.6min)→1%A(0.4min)；Flow velocity: 0.8mL/min；Sampling volume: (0.1mg-1mg/mL sample is dense for 1.0 μ l Degree)；Detection: PDA sweep limits 210-400nm is fixing and ESI (+), sweep limits 170-800m/z

INTERMEDIATES Example 1-1: preparation 6,8-bis-bromo-imidazo [1,2-a] pyrazine

Under rt, to stirring commercially available (Apollo) 3-bromo-6,8-dichloro-imidazole also [1,2-a] pyridine (1.00g, 3.76mmol) solution in NMP (40mL) the most disposably adds 2.31g [4-[(cyclopropylamino) carbonyl] phenyl]- Boric acid (11.28mmol, 3eq), 614mg Pd (dppf) Cl₂(0.75mmol, 0.2eq) and wet chemical (1M, 3mL). After heating 40min at 130 DEG C in microwave oven, add water and precipitation is leached, washing and be dried.Pure by preparation HPLC Change, it is thus achieved that 481mg (36.95%) N-cyclopropyl-4-(6,8-dichloro-imidazoles also [1,2-a] pyridin-3-yl) Benzoylamide:¹H- NMR(300MHz,CDCl₃):δ=8.51(1H),8.00–7.91(3H),7.81–7.68(4H),2.85(1H),0.68(1H), 0.57(1H)ppm.

INTERMEDIATES Example 2-1: preparation N-cyclopropyl-4-(6,8-dichloro-imidazole also [1,2-a] pyridin-3-yl) benzoyl Amine

Under rt, to N-cyclopropyl-4-(6,8-dichloro-imidazoles also [1, the 2-a] pyridin-3-yl) Benzoylamide of stirring (320mg, 0.92mmol) solution in NMP (30mL) the most disposably adds 67.6mg2-methyl-prop 1-amine (0.92mmol, 1eq), 169mg (1E, 4E)-1,5-diphenyl amyl-1,4-diene-3-ketone-palladium (3:2) (0.185mmol, 0.2eq), 345.3mg1,1'-dinaphthalene-2,2'-diyl double (diphenylphosphine) (0.55mmol, 0.6eq) and the 222.1mg tert-butyl alcohol Sodium (2.31mmol, 2.5eq).After heating 40min at 150 DEG C in microwave oven, being filtered by solution, residue is also used by evaporation Water grinds.The chloro-8-of 70mg (19.7%) 4-{6-[(2-methyl-propyl) amino] imidazoles is obtained by preparation HPLC purification residues And [1,2-a] pyridin-3-yl-N-cyclopropyl-phenyl Methanamide:¹H-NMR(300MHz,CDCl₃):δ7.88(2H),7.68(1H), 7.60(2H),7.55(1H),6.28(1H),6.10(1H),5.41(1H),3.09(2H),2.95(1H),1.05(6H),0.91 (2H),0.66(2H)

INTERMEDIATES Example 3-1: preparation 6-bromine imidazo [1,2-a] pyridine-8-amine

Under rt, to 5-bromopyridine-2 of stirring, the 3-diamidogen (278g, 1478mmol) solution in isopropanol (2.2L) In disposably add 2-Chloro-1-ethanal (255g, 1626mmol).In a nitrogen atmosphere return stirring overnight after, by mixture under rt again Stirring 60min.Suspension is filtered, and by the washing of remaining solid isopropanol and is vacuum dried at 50 DEG C.It is re-dissolved in first In alcohol and evaporate acquisition brown solid 6-bromine imidazo [1,2-a] pyridine-8-amine (124g, 40%):¹H-NMR(300MHz,d₆- DMSO):δ=8.39(2H),8.12(2H),6.92(1H)ppm.

INTERMEDIATES Example 4-1: preparation 6-bromo-3-iodine imidazo [1,2-a] pyridine-8-amine

At 0 DEG C, to 6-bromine imidazo [1,2-a] pyridine-8-amine (20.6g, 97.15mmol) of stirring at THF (100mL) suspension in drips the NIS (25.4g, 112.87mmol, 1.16eq) solution in 215mL THF.Stirring 2h After, add isolute adsorbent (Biotage) (20g) and by mixture vaporising under vacuum.Residue is loaded in quick post Go up and pass through flash chromatography (ethyl acetate/hexane) purification of crude product to obtain 25.6g6-bromo-3-iodine imidazo [1,2-a] pyrrole Pyridine-8-amine (78.2%).¹H-NMR(300MHz,d₆-DMSO):δ=7.60(1H),7.54(1H,d),6.38(1H),6.12(2H) ppm.UPLC-MS:RT=0.98min;m/z(ES+)339.0[MH⁺];The MW=338.0. required

INTERMEDIATES Example 5-1: preparation 4-(8-amino-6-bromine imidazo [1,2-a] pyridin-3-yl)-N-cyclopropyl-2- Methyl benzamide

Under rt, to the 6-bromo-3-iodine imidazo [1,2-a] pyridine-8-amine (8.52g, 22.69mmol) of stirring at THF (450mL) in the solution in the most disposably add 7.176g N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-base) Benzoylamide (23.82mmol, 1.05eq), 3.706g Pd (dppf) Cl₂(4.54mmol, 0.2eq) with wet chemical (1M, 68mL).After being stirred overnight under rt, mixture is heated at 60 DEG C 24h, and Add 1.434g N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-base) Benzoylamide After, at 80 DEG C, heat 48h.After filtering by ALLOX and evaporate, by thick material by purification by flash chromatography to obtain 4.93g (56%) 4-(8-amino-6-bromine imidazo [1,2-a] pyridin-3-yl)-N-cyclopropyl-2-methyl benzamide:¹H-NMR (300MHz,d₆-DMSO):δ=8.31(1H),7.78+7.74(1H),7.59(1H),7.45+7.44(2H),7.40+7.38 (1H),6.41+6.37(1H),6.15+6.10(2H),2.81(1H),2.36(3H),0.66(1H),0.50(1H)ppm.UPLC- MS:RT=0.82min;m/z(ES+)386.3[MH⁺];The MW=385.3. required

INTERMEDIATES Example 6-1: the preparation bromo-8-of 4-{6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-N-cyclopropyl-2-methyl benzamide

Under rt, to 4-(8-amino-6-bromine imidazo [1,2-a] the pyridin-3-yl)-N-cyclopropyl-2-methyl of stirring In the Benzoylamide (3g, 5.87mmol) solution in dichloroethanes (60mL) add 3,3,3-trifluoro propionic aldehyde (4.58g, 40.88mmol,7eq).After stirring 2h, add sodium triacetoxy borohydride (9.12g, 40.88mmol, 7eq) and trifluoroacetic acid (3.33g, 29.2mmol, 5eq), and stir the mixture for 1h.After adding DCM (100mL), by organic phase washed with water and steam Send out.By residue by purification by flash chromatography to obtain the bromo-8-of 2.51g4-{6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N-cyclopropyl-2-methyl benzamide (66.9%).¹H-NMR(300MHz,d₆-DMSO):δ=8.32 (1H),7.81(1H),7.60(1H),7.46+7.44(2H),7.41+7.39(1H),6.63(1H),6.32(1H),3.49 (2H),2.81(1H),2.64(2H),2.36+2.35(3H),0.66(1H),0.50(1H)ppm.UPLC-MS:RT=1.22min; m/z(ES+)482.3[MH⁺];The MW=481.3. required

INTERMEDIATES Example 12: preparation [4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] boric acid

Step A: preparation 4-bromo-N-cyclopropyl-2-methyl benzamide

Under rt, in the 4-bromo-2-ar-Toluic acid (300g, the 1.4mol) solution in DCM (8.4L) of stirring one Secondary property adds cyclopropylamine (79.64g, 1.4mol) and EDC (320.9g, 1.67mol).After being stirred overnight, by solution washed with water, And aqueous phase is used DCM back extraction.The organic phase with sodium sulfate of merging is dried, filters and evaporate.Remaining solid is different with two Propyl ether grinds, and filters, washs and be vacuum dried to obtain 260g (73.4%) 4-bromo-N-cyclopropyl-2-methyl benzamide:¹H-NMR(300MHz,CDCl₃):δ=7.34(s,1H),7.27(d,1H),7.14(d,1H),5.96(bs,1H),2.85(m, 1H),2.38(s,3H),0.85(m,2H),0.59(m,2H)ppm.

Step B: preparation N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-base) Benzoylamide

Under rt, to molten in dioxane (2L) of 4-bromo-N-cyclopropyl-2-methyl benzamide (260g, 1.02mol) Liquid adds double-(pinacol)-two boron (390g, 1.53mol), 2-dicyclohexyl phosphino--2', 4', 6'-tri isopropyl biphenyl (19.5g, 40.9mmol), potassium acetate (150.6g, 1.53mol) and three-(dibenzalacetone)-two palladium (0) (9.37g, 10.2mmol), and by mixture reflux 6h.After being cooled to rt, add water (3L) and ethyl acetate (5L), and mixture is stirred Mix 15min.By organic phase washed with water, use Na₂(SO₄) be dried, filter and evaporate.Flash chromatography (ethyl acetate/hexane) obtains 308g (56.3%) N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-base) benzoyl Amine:¹H-NMR(300MHz,CDCl₃):δ=7.63(s,1H),7.60(d,1H),7.28(d,1H),5.94(bs,1H),2.87(m, 1H),2.41(s,3H),1.33(s,6H),0.85(m,2H),0.59(m,2H)ppm.

Step C: preparation [4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] boric acid

Under rt, to N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-bases) benzene In the Methanamide (20.2g, 67.13mol) solution in acetone (300mL) add sodium metaperiodate (43.1g, 201.40mol) and Ammonium acetate (134.26mol, 134mL1M aqueous solution), and stir the mixture for 3h.Add more water (120mL), and will mixing Thing is stirred for 2h at 40 DEG C.After adding 4N HCl (32mL), remove organic facies under vacuo, and by residue ethyl acetate Extraction.Organic facies saturated nacl aqueous solution is washed, filters with Whatman filter and evaporate.Residue is re-dissolved in toluene In and evaporate (twice) to obtain 14.59g (94.3%) [4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] boric acid:¹H-NMR (300MHz,d₆-DMSO):δ=8.21(1H),8.04(2H),7.56(2H),7.17(1H),2.77(1H),2.25(3H),0.62 (2H),0.47(2H)ppm.

Embodiment 1-1: preparation N-cyclopropyl-4-{8-[(2-methyl-propyl) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

Under rt, to the chloro-8-of 4-{6-[(2-methyl-propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N-cyclopropyl Benzoylamide (50mg, 0.13mmol) adds 145mg TEA (1.43mmol) and 5mg in the solution in ethanol (15mL) successively Pd/C (10%), then stirs 2.5h under rt by mixture in hydrogen atmosphere and under normal pressure.After filtration, by solution evaporation, and By residue by preparation HPLC purification to obtain 4.7mg (10.3%) N-cyclopropyl-4-{8-[(2-methyl-propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl } Benzoylamide:¹H-NMR(300MHz,d₆-DMSO):δ=8.46(1H),7.93(2H),7.80 (1H),7.71–7.65(3H),6.76(1H),6.15(1H),5.99(1H),3.03(2H),2.84(1H),0.92(6H),0.67 (2H),0.56(2H)

Embodiment 2-1: preparation N-cyclopropyl-4-{6-[2-(hydroxymethyl) phenyl]-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

By bromo-for 0.06mmol4-{6-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N- Cyclopropyl-2-methyl benzamide, 0.13mmol [2-(hydroxymethyl) phenyl] boric acid (18.9mg, 2eq), 0.012mmol Pd (dppf)Cl₂(10.18mg, 0.2eq), 2mL NMP and 0.187mmol potassium carbonate (0.19mL, 1M, 3eq in water) are little in sealing In Ping, mixed being incorporated under microwave exposure at 130 DEG C heats 40min.Heat block reheats overnight at 120 DEG C and cools down To rt, solution filters and is prepared HPLC to obtain 17.3mg (55%) N-cyclopropyl-4-{6-[2-(hydroxymethyl) benzene Base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide:¹H-NMR (300MHz,CDCl₃):δ=7.82(1H),7.60–7.50(3H),7.48–7.30(6H),6.27(1H),6.02(1H),5.84 (1H),4.64(2H),3.58(2H),3.40(2H,tr),2.90(1H),2.56(2H),2.45(3H),0.88(2H),0.61 (2H)ppm;UPLC-MS:RT=1.02min;m/z(ES+)509.6[MH⁺];The MW=508.6. required

Suitable INTERMEDIATES Example 6 is similarly used with said method and suitable boric acid builds (building Block) preparing following COMPOUNDS EXAMPLE [unless expressly stated, uses LC-MS method A to gather LC-MS data such as retention time (RT, in terms of min) or the mass spectra peak observed]:

Embodiment 3-1: preparation N-cyclopropyl-4-{6-[(3-fluoro-5-aminomethyl phenyl) sulfanyl]-8-[(3,3,3-trifluoro Propyl group) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

24mg is added in 85.5mg (0.6mmol) 3-fluoro-5-methylbenzene phenyl-sulfhydrate solution in 2.0mL DMSO (0.6mmol) sodium hydride mixture is stirred under rt 1h.

Add the bromo-8-of 48mg (0.1mmol) 4-{6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base }-N-cyclopropyl-2-methyl benzamide mixture is heated at 160 DEG C 1h.Mixture is filtered and to pass through HPLC pure Change to obtain 20mg (35%) title compound.UPLC-MS:RT=1.47min;m/z(ES+)543.6[MH⁺];The MW=required 542.6.¹H-NMR(300MHz,d6-DMSO):δ=8.31(1H),7.87(1H),7.66(1H),7.49–7.45(2H),7.39 (1H),6.93(1H),6.85(2H),6.54(1H),6.13(1H),3.44(2H),2.81(1H),2.55(2H),2.35(3H), 2.21(3H),0.66(2H),0.55(2H)ppm.

Suitable thiol derivative is similarly used with said method and suitable Br-intermediate 6 prepares following compound Embodiment [unless expressly stated, uses LC-MS method A gather LC-MS data such as retention time (RT, in terms of min) or observe Mass spectra peak]:

Embodiment 4-1 prepares N-cyclopropyl-2-methyl-4-{6-(methylsulfanyl)-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

To the bromo-8-of 170.0mg (0.35mmol) 4-{6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-N-cyclopropyl-2-methyl benzamide solution in 2.0mL DMSO adds 124mg (1.77mmol) methanthiol Sodium, and mixture is stirred at 70 DEG C 1h.After stirring 3h at 100 DEG C, add water and mixture is extracted with ethyl acetate. Organic phase washed with water and saturated nacl aqueous solution are washed, is dried and evaporates to obtain 158mg title compound (100%) .UPLC- MS:RT=1.08min;m/z(ES+)449.5[MH⁺];The MW=448.5 required

Embodiment 5-1: preparation N-cyclopropyl-4-{6-[(3-fluoro-5-aminomethyl phenyl) sulfanyl]-8-[(3,3,3-trifluoro Propyl group) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

To 158mg (0.35mmol) N-cyclopropyl-2-methyl-4-{6-(methylsulfanyl)-8-[(3,3,3-trifluoropropyl Base) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide solution in 20mL DMF adds 651mg (1.06mmol) potassium peroxydisulfate (potassium hydrogen peroxymonosulfate), and mixture is stirred overnight under rt in nitrogen atmosphere.Add water And mixture DCM is extracted.Organic phase washed with water and saturated nacl aqueous solution are washed, is dried and evaporates to obtain 150mg mark Topic compound (88%) .UPLC-MS:RT=1.08min;m/z(ES+)481.5[MH⁺];The MW=480.5. required¹H-NMR (300MHz,d6-DMSO):δ=8.37(1H),8.12(1H),7.76(1H),7.52–7.48(2H),7.45(1H),6.82 (1H),6.50(1H),3.56(2H),3.27(3H),2.81(1H),2.69(2H),2.37(3H),0.66(2H),0.51(2H) ppm.

Embodiment 6-1: preparation N-cyclopropyl-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazoles And [1,2-a] pyridin-3-yl-2-methyl benzamide

4-{6-bromo-8-[(the 3,3,3-trifluoropropyl that 78mg (162 μm ol) is prepared will be comprised according to INTERMEDIATES Example 6-1 Base) amino] imidazo [1,2-a] pyridin-3-yl-N-cyclopropyl-2-methyl benzamide, 109mg3-fluorophenol, 634mg carbon Acid caesium, 3.3mg N, the mixture of N-dimethylglycine, 6.4mg copper chloride (I) and 1.5mL1,4-dioxane is at 120 DEG C Microwave exposure is utilized to heat 4 hours.Pour the mixture in water, and be extracted with ethyl acetate.Organic layer sodium sulfate is dried. After filtering and removing solvent, by residue by chromatogram purification to obtain 1.2mg (1%) title compound: m/z (ES+) 513 [MH⁺];The MW=512.2. required¹H-NMR(CDCl₃):δ=0.62(2H),0.90(2H),2.49(3H),2.51(2H),2.92 (1H),3.56(2H),5.50(1H),5.88(1H),5.99(1H),6.75-6.83(2H),7.22-7.31(2H),7.35 (1H),7.37(1H),7.43(1H),7.55(1H),7.60(1H)ppm.

Embodiment 6-2: preparation N-cyclopropyl-4-{6-(2-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-bromo-8-[(the 3,3,3-trifluoro that 50.5mg (105 μm ol) is prepared will be comprised according to INTERMEDIATES Example 6-1 Propyl group) amino] imidazo [1,2-a] pyridin-3-yl-N-cyclopropyl-2-methyl benzamide, 74.6mg2-fluoro-4-methoxyl group Phenol, 171mg cesium carbonate, 4.77mg (RS)-phenyl hydrogen pyrrolidin-2-yl phosphonate ester, 4.2mg copper chloride (I) and 1mL1,4-bis- The mixture of alkane utilizes microwave exposure to heat at 120 DEG C 2 hours.Pour the mixture in water and with ethyl acetate and methanol Mixture extraction.Organic layer sodium sulfate is dried.After filtering and removing solvent, by residue by chromatogram purification to obtain 7.0mg (14%) title compound: m/z (ES+) 543 [MH⁺];The MW=542.2. required

¹H-NMR(DMSO-d6):δ=0.49(2H),0.65(2H),2.29(3H),2.62(2H),2.80(1H),3.47 (2H),3.72(3H),6.12(1H),6.54(1H),6.73(1H),7.00(1H),7.20(1H),7.29-7.36(3H),7.43 (1H),7.59(1H),8.28(1H)ppm.

Embodiment 7 (the optional approach described in embodiment 6-1) N-cyclopropyl-4-{6-(3-fluorophenoxy)-8-[(3,3,3- Trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

{ 3-[4-(the cyclopropylcarbamoyl)-3-methyl prepared according to INTERMEDIATES Example 7a to 31mg (51 μm ol) Phenyl]-6-(3-fluorophenoxy) imidazo [1,2-a] pyridine-8-base } (3,3,3-trifluoro propyl) t-butyl carbamate exists Solution in 0.5mL dichloromethane adds 58.5 μ L trifluoroacetic acids, and mixture is heated under microwave exposure at 50 DEG C 1 Hour.Remove solvent, and residue is passed through chromatogram purification to obtain 19mg (73%) title compound.

¹H-NMR(DMSO-d6):δ=0.48(2H),0.64(2H),2.33(3H),2.61(2H),2.79(1H),3.45 (2H),6.10(1H),6.58(1H),6.85-6.95(3H),7.29-7.48(4H),7.60-7.70(2H),8.28(1H)ppm.

Embodiment 7a{3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(3-fluorophenoxy) imidazo [1, 2-a] pyridine-8-base } (3,3,3-trifluoro propyl) t-butyl carbamate

{ the bromo-3-of 6-in the way of embodiment 6-1 is similar, 200mg (344 μm ol) prepared according to INTERMEDIATES Example 7b [4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (3,3,3-trifluoro propyl) amino T-butyl formate converts with in post processing with obtain 32mg (15%) title compound after purification.

The bromo-3-of embodiment 7b{6-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8- Base } (3,3,3-trifluoro propyl) t-butyl carbamate

(the 6-bromo-3-iodine imidazo [1,2-a] that 2.62g (4.91mmol) is prepared will be comprised according to INTERMEDIATES Example 7c Pyridine-8-base) [4-(ring prepared according to INTERMEDIATES Example 12 of (3,3,3-trifluoro propyl) t-butyl carbamate, 1.61g Propvlcarbamovl)-3-aminomethyl phenyl] boric acid, 100mg (1,1 ,-bis-(diphenylphosphino) ferrocene) dichloro palladium (II), The mixture of 6.1mL2M cesium carbonate aqueous solution and 30mL oxolane stirs 2 hours at 55 DEG C.Addition 50mg (1,1 ,-bis- (diphenylphosphino) ferrocene) dichloro palladium (II) continue to stir extra 2 hour.Add water and by mixture ethyl acetate Extraction.By the washing of organic layer saline and it is dried with sodium sulfate.Filter and remove after solvent, by residue by chromatogram purification with Obtain 2.15g (75%) title compound.

Embodiment 7c (6-bromo-3-iodine imidazo [1,2-a] pyridine-8-base) (3,3,3-trifluoro propyl) tertiary fourth of carbamic acid Ester

(6-bromine imidazo [1,2-a] pyridine-8-prepared according to INTERMEDIATES Example 7d to 5.00g (12.25mmol) Base) (3,3,3-trifluoro propyl) t-butyl carbamate solution in 75mL N,N-dimethylformamide adds 71.25g N-iodine butanimide, and mixture is stirred 1.5 hours at 23 DEG C.Add ethyl acetate, and mixture is used saturated sulfur Sodium thiosulfate solution, water wash, and are dried with sodium sulfate.After filtering and removing solvent, by residue by chromatogram purification to obtain Obtain 5.92g (90%) title compound.

Embodiment 7d (6-bromine imidazo [1,2-a] pyridine-8-base) (3,3,3-trifluoro propyl) t-butyl carbamate

The bromo-N-of 6-(3,3,3-trifluoro propyl) miaow prepared according to INTERMEDIATES Example 7e to 16.24g (52,71mmol) Azoles also [1,2-a] pyridine-8-amine solution in 62mL oxolane adds 25.31g Bis(tert-butoxycarbonyl)oxide, 644mg N, N-lutidines-4-amine, and mixture is stirred 4 hours at 55 DEG C.Add ethyl acetate and by mixture saturated carbon Acid hydrogen sodium solution washing, and be dried with sodium sulfate.After filtering and removing solvent, by residue by chromatogram purification to obtain 20.9g (97%) title compound.

The bromo-N-of embodiment 7e 6-(3,3,3-trifluoro propyl) imidazo [1,2-a] pyridine-8-amine

To comprise 6-bromine imidazo [1,2-a] pyridine that 21.7g (102.3mmol) prepared according to INTERMEDIATES Example 3-1- The mixture of the 18.16mL acetic acid in 8-amine, 13.05mL3,3,3-trifluoro propionic aldehyde, 1.3L dichloromethane is dividedly in some parts altogether 65.07g sodium triacetoxy borohydride (sodium tris (acetato-kappaO) (hydrido) borate (1-)).Will be mixed Compound stirred 3 as a child at 23 DEG C so that it is be cooled to 3 DEG C, and added 300mL4M liquefied ammonia carefully.By mixture dichloro Methane extracts, and by the washing of organic layer saline and is dried with sodium sulfate.After filtering and removing solvent, residue is passed through chromatographically pure Change to obtain 16.26g (52%) title compound.

Embodiment 8 4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-N, 2-dimethyl benzamide

To comprise 4-{6-(3-fluorophenoxy)-8-that 18mg (38 μm ol) prepared according to INTERMEDIATES Example 8a [(3,3, 3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl-2-ar-Toluic acid, 28.5 μ L first in oxolane (2M) Amine aqueous solution, 21.7mg N-[(dimethylamino) (3H-[1,2,3] triazol [4,5-b] pyridin-3-yl epoxide) methylene]-N- The mixture of methyl hexafluorophosphoric acid first ammonium, 7.0mg N, N-lutidines-4-amine and 0.9mL N,N-dimethylformamide exists It is stirred overnight at 23 DEG C.Remove solvent and residue is passed through chromatogram purification to obtain 16.1mg (83%) title compound.

¹H-NMR(CDCl₃):δ=2.41-2.68(2H),2.49(3H),3.02(3H),3.55(2H),5.49(1H),5.82 (1H),5.99(1H),6.71(1H),6.75-6.83(2H),7.27(1H),7.35(1H),7.37(1H),7.46(1H),7.56 (1H),7.61(1H)ppm.

Embodiment 8a 4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-2-ar-Toluic acid

The 4-{8-[(uncle in the way of embodiment 7 is similar, 100mg (205 μm ol) prepared according to INTERMEDIATES Example 8b Butoxy carbonyl) (3,3,3-trifluoro propyl) amino]-6-(3-fluorophenoxy) imidazo [1,2-a] pyridin-3-yl }-2-methyl Benzoic acid converts to obtain 97mg (100%) title compound after post processing.

Embodiment 8b 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(3-fluorophenoxy) imidazoles And [1,2-a] pyridin-3-yl-2-ar-Toluic acid

4-{8-[(tert-butoxycarbonyl) (the 3,3,3-trifluoro prepared according to INTERMEDIATES Example 8c to 50mg (85 μm ol) Propyl group) amino]-6-(3-fluorophenoxy) imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate is at 1.8mL tetrahydrochysene Solution in furan and 0.5mL methanol adds 1.28mL1M lithium hydroxide aqueous solution, and it is little that mixture stirs at 23 DEG C 1 Time.Add water to be also acidified by adding 1M hydrochloric acid by mixture, and with dichloromethane and methanol extraction.Organic layer salt is washed Wash and be dried with sodium sulfate.After filtering and removing solvent, residue is titled to obtain 107mg (100%) by chromatogram purification Compound.

Embodiment 8c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(3-fluorophenoxy) imidazoles And [1,2-a] pyridin-3-yl-2-methyl toluate

The 4-in the way of INTERMEDIATES Example 7a is similar, 550mg (988 μm ol) prepared according to INTERMEDIATES Example 8d { the bromo-8-of 6-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene Methyl formate converts with in post processing with obtain 287mg (54%) title compound after purification.

The bromo-8-of embodiment 8d 4-{6-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-2-methyl toluate

In the way of INTERMEDIATES Example 7b is similar, 2.50g (4.68mmol) is prepared according to INTERMEDIATES Example 7c (6-bromo-3-iodine imidazo [1,2-a] pyridine-8-base) (3,3,3-trifluoro propyl) t-butyl carbamate utilizes [4-(methoxyl group Carbonyl)-3-aminomethyl phenyl] boric acid converts with in post processing with obtain 1.83g (67%) title compound after purification.

Embodiment 9 4,4'-{8-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] imidazo [1,2-a] pyridine-3,6-two Base } double (N-cyclopropyl-2-methyl benzamides)

{ double [the 4-of 3,6-in the way of embodiment 7 is similar, 91mg (134 μm ol) prepared according to INTERMEDIATES Example 9a (cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (tetrahydrochysene-2H-pyrans-4-ylmethyl) T-butyl carbamate converts with in post processing with obtain 42.3mg (52%) title compound after purification.

¹H-NMR(DMSO-d6):δ=0.45-0.54(4H),0.60-0.70(4H),1.17-1.32(2H),1.59-1.69 (2H),1.95(1H),2.35(3H),2.36(3H),2.75-2.87(2H),3.18-3.27(4H),3.78-3.87(2H), 6.22(1H),6.39(1H),7.31(1H),7.39-7.55(5H),7.61(1H),7.84(1H),8.24(1H),8.32(1H) ppm.

Embodiment 9a { double [4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-of 3,6- Base } (tetrahydrochysene-2H-pyrans-4-ylmethyl) t-butyl carbamate

In the way of INTERMEDIATES Example 7b is similar, 1.00g (1.865mmol) is prepared according to INTERMEDIATES Example 9b (6-bromo-3-iodine imidazo [1,2-a] pyridine-8-base) (tetrahydrochysene-2H-pyrans-4-ylmethyl) t-butyl carbamate is at 120 DEG C Lower conversion is with in post processing with obtain 670mg (53%) title compound after purification.

Embodiment 9b (6-bromo-3-iodine imidazo [1,2-a] pyridine-8-base) (tetrahydrochysene-2H-pyrans-4-ylmethyl) amino T-butyl formate

In the way of INTERMEDIATES Example 7c is similar, 2.22g (5.41mmol) is prepared according to INTERMEDIATES Example 9c (6-bromine imidazo [1,2-a] pyridine-8-base) (tetrahydrochysene-2H-pyrans-4-ylmethyl) t-butyl carbamate converts with at Hou Chu Manage and obtain 2.87g (99%) title compound after purification.

Embodiment 9c (6-bromine imidazo [1,2-a] pyridine-8-base) (tetrahydrochysene-2H-pyrans-4-ylmethyl) carbamic acid uncle Butyl ester

In the way of INTERMEDIATES Example 7d is similar, 1.85g (5.964mmol) is prepared according to INTERMEDIATES Example 9d The bromo-N-of 6-(tetrahydrochysene-2H-pyrans-4-ylmethyl) imidazo [1,2-a] pyridine-8-amine converts in post processing and to obtain after purification Obtain 1.41g (58%) title compound.

The bromo-N-of embodiment 9d6-(tetrahydrochysene-2H-pyrans-4-ylmethyl) imidazo [1,2-a] pyridine-8-amine

In the way of INTERMEDIATES Example 7e is similar, 3.00g (14.15mmol) is prepared according to INTERMEDIATES Example 3-1 6-bromine imidazo [1,2-a] pyridine-8-amine utilizes tetrahydrochysene-2H-pyrans-4-formaldehyde to convert in post processing and to obtain after purification 2.57g (53%) title compound.

Embodiment 10 N-ethyl-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2- A] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-fluorobenzene in the way of embodiment 8 is similar, 18mg (38 μm ol) prepared according to INTERMEDIATES Example 8a Epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes ethamine to turn Change with in post processing with obtain 15.3mg (76%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.26(3H),2.46-2.58(2H),2.50(3H),3.50(2H),3.56(2H),5.48 (1H),5.75(1H),5.99(1H),6.72(1H),6.76-6.82(2H),7.27(1H),7.36(1H),7.38(1H),7.46 (1H),7.56(1H),7.61(1H)ppm.

Embodiment 11 4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-2-methyl-N-(1-methylcyclopropyl groups) Benzoylamide

4-{6-(the 3-fluorobenzene in the way of embodiment 8 is similar, 18mg (38 μm ol) prepared according to INTERMEDIATES Example 8a Epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 1-methyl Cyclopropyl ammonium chloride (cyclopropanaminium chloride) converts with in post processing with obtain 13.7mg after purification (65%) title compound.

¹H-NMR(CDCl₃):δ=0.76(2H),0.87(2H),1.52(3H),2.48(3H),2.51(2H),3.56(2H), 5.47(1H),5.99(1H),6.08(1H),6.69-6.82(3H),7.27(1H),7.34(1H),7.36(1H),7.40(1H), 7.55(1H),7.59(1H)ppm.

Embodiment 12 N-[rel-(1S, 2S)-2-fluorine cyclopropyl]-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro Propyl group) amino] imidazo [1,2-a] pyridin-3-yl-2-methyl benzamide (rac-A), N-{ [(1R, 2R) or (1S, 2S)]-2-fluorine cyclopropyl }-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-2-methyl benzamide (ent-A or A) and N-{ [(1S, 2S) or (1R, 2R)]-2-fluorine cyclopropyl }-4-{6-(3- Fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl-2-methyl benzamide (A or ent-A)

4-{6-(the 3-fluorobenzene in the way of embodiment 8 is similar, 18mg (38 μm ol) prepared according to INTERMEDIATES Example 8a Epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes rel- (1S, 2S)-2-fluorine cyclopropyl ammonium chloride converts with in post processing with obtain 14.1mg (66%) racemic title compound after purification Thing A.

¹H-NMR(CDCl₃):δ=1.02(1H),1.27(1H),2.46-2.58(2H),2.51(3H),3.06(1H),3.56 (2H),4.76(1H),5.48(1H),5.99(1H),6.03(1H),6.72(1H),6.75-6.83(2H),7.27(1H),7.37 (1H),7.39(1H),7.49(1H),7.56(1H),7.61(1H)ppm.

Utilize chiral column pass through HPLC separate 8.7mg rac-A (16 μm ol) with obtain 2.2mg (25%) ent-A or A with And 2.1mg (24%) A or ent-A.

Embodiment 13 N-(1-anocy clopropyl)-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-fluorobenzene in the way of embodiment 8 is similar, 18mg (38 μm ol) prepared according to INTERMEDIATES Example 8a Epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 1-cyano group Cyclopropyl ammonium chloride converts with in post processing with obtain 7.5mg (35%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.38(2H),1.66(2H),2.43-2.63(2H),2.51(3H),3.55(2H),5.49 (1H),6.00(1H),6.44(1H),6.71(1H),6.75-6.84(2H),7.27(1H),7.33-7.47(3H),7.55 (1H),7.60(1H).

Embodiment 14 4-{6-acetenyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }- N, 2-dimethyl benzamide

The 4-{6-acetylene in the way of embodiment 8 is similar, 14mg (36 μm ol) prepared according to INTERMEDIATES Example 14a Base-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid convert with in post processing Obtain 12.4mg (86%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.45-2.61(2H),2.54(3H),3.04(4H),3.61(2H),5.36(1H),5.82 (1H),6.17(1H),7.37(1H),7.39(1H),7.50(1H),7.55(1H),7.91(1H)ppm.

Embodiment 14a 4-{6-acetenyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base }-2-ar-Toluic acid

The 4-in the way of INTERMEDIATES Example 8b is similar, 93mg (232 μm ol) prepared according to INTERMEDIATES Example 14b { 6-acetenyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate turns Change with in post processing with obtain 70.8mg (79%) title compound after purification.

Embodiment 14b 4-{6-acetenyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base }-2-methyl toluate

The 4-{8-in the way of embodiment 7 is similar, 122.9mg (245 μm ol) prepared according to INTERMEDIATES Example 14c [(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-acetenyl imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene Methyl formate converts with in post processing with obtain 93mg (85%) title compound after purification.

Embodiment 14c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-acetenyl imidazo [1, 2-a] pyridin-3-yl }-2-methyl toluate

To comprise 4-{8-that 169mg (295 μm ol) prepared according to INTERMEDIATES Example 14d [(tert-butoxycarbonyl) (3, 3,3-trifluoro propyl) amino]-6-[(trimethyl silyl) acetenyl] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene 295 μ L tetra-n-butyl ammonium fluorides and the mixture of 1.4mL oxolane in methyl formate, oxolane (1M) stir at 23 DEG C Mix 20 minutes.Add saturated ammonium chloride solution and mixture is extracted with ethyl acetate.Organic layer sodium sulfate is dried.Filter After removing solvent, residue is passed through chromatogram purification to obtain 122.9mg (75%) title compound.

Embodiment 14d 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-[(trimethyl silyl Base) acetenyl] imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate

The bromo-8-of the 4-{6-[(tert-butoxycarbonyl) that 50mg (90 μm ol) is prepared will be comprised according to INTERMEDIATES Example 8d (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl-2-methyl toluate, 35.3mg acetenyl (three Methyl) silane, double (triphenylphosphine) Palladous chloride. (II) of 6.3mg, 1.7mg Copper diiodide (I), 0.82mL N-isopropyl acrylate-2-amine and The mixture of 0.82mL dioxane heats 10 minutes at 80 DEG C under microwave exposure.Remove solvent and residue is passed through chromatograph Purification is to obtain 59.9mg (99%) title compound.

Embodiment 15 N-ethyl-4-{6-acetenyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl benzamide

The 4-{6-acetylene in the way of embodiment 8 is similar, 14mg (36 μm ol) prepared according to INTERMEDIATES Example 14a Base-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilize ethamine convert with In post processing with obtain 12.1mg (81%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.28(3H),2.48-2.61(2H),2.54(3H),3.04(1H),3.52(2H),3.61 (2H),5.36(1H),5.78(1H),6.17(1H),7.38(1H),7.39(1H),7.50(1H),7.54(1H),7.91(1H) ppm.

Embodiment 16 4-{6-acetenyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }- N-[rel-(1R, 2R)-2-fluorine cyclopropyl]-2-methyl benzamide

The 4-{6-acetylene in the way of embodiment 8 is similar, 14mg (36 μm ol) prepared according to INTERMEDIATES Example 14a Base-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilize rel-(1S, 2S)-2-fluorine cyclopropyl ammonium chloride converts with in post processing with obtain 12.3mg (77%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.04(1H),1.29(1H),2.49-2.60(2H),2.55(3H),3.05(1H),3.08 (1H),3.61(2H),4.78(1H),5.37(1H),6.04(1H),6.17(1H),7.38(1H),7.40(1H),7.51-7.58 (2H),7.91(1H)ppm.

Embodiment 17 4-{6-acetenyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }- 2-methyl-N-(1-methylcyclopropyl groups) Benzoylamide

The 4-{6-acetylene in the way of embodiment 8 is similar, 14mg (36 μm ol) prepared according to INTERMEDIATES Example 14a Base-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 1-methyl ring third Ammonium chloride converts with in post processing with obtain 10.1mg (63%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.77(2H),0.89(2H),1.54(3H),2.45-2.60(2H),2.51(3H),3.04 (1H),3.61(2H),5.36(1H),6.10(1H),6.16(1H),7.35(1H),7.37(1H),7.44(1H),7.53(1H), 7.89(1H)ppm.

Embodiment 18 N-(1-anocy clopropyl)-4-{6-acetenyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

The 4-{6-acetylene in the way of embodiment 8 is similar, 14mg (36 μm ol) prepared according to INTERMEDIATES Example 14a Base-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 1-cyano group ring third Ammonium chloride converts with in post processing with obtain 11.8mg (72%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.40(2H),1.68(2H),2.48-2.61(2H),2.55(3H),3.05(1H),3.61 (2H),5.37(1H),6.17(1H),6.46(1H),7.36-7.50(3H),7.54(1H),7.89(1H)ppm.

Embodiment 19 N-cyclopropyl-4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl }-2-methyl benzamide

In the way of embodiment 8 is similar, by 20mg (41 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 19a, (5-is fluoro- 2-methylphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid profit Convert with cyclopropylamine with in post processing with obtain 20.1mg (93%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.62(2H),0.89(2H),2.27(3H),2.42-2.60(2H),2.48(3H),2.92 (1H),3.57(2H),5.50(1H),5.92(1H),6.00(1H),6.57(1H),6.73(1H),7.17(1H),7.30-7.37 (2H),7.41(1H),7.45(1H),7.53(1H)ppm.

Embodiment 19a 4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-2-ar-Toluic acid

In the way of INTERMEDIATES Example 8b is similar, 805mg (1.61mmol) is prepared according to INTERMEDIATES Example 19b 4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-first Yl benzoic acid methyl ester converts with in post processing with obtain 736mg (89%) title compound after purification.

Embodiment 19b 4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-2-methyl toluate

The 4-{8-in the way of embodiment 7 is similar, 1.06g (1.77mmol) prepared according to INTERMEDIATES Example 19c [(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(5-fluoro-2-methylbenzene epoxide) imidazo [1,2-a] pyridine- 3-yl }-2-methyl toluate converts with in post processing with obtain 861mg (97%) title compound after purification.

Embodiment 19c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(5-fluoro-2-methylbenzene Epoxide) imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate

In the way of INTERMEDIATES Example 7b is similar, 1.36g (2.34mmol) is prepared according to INTERMEDIATES Example 19d [6-(5-fluoro-2-methylbenzene epoxide)-3-iodine imidazo [1,2-a] pyridine-8-base] (3,3,3-trifluoro propyl) carbamic acid uncle Butyl ester utilize [4-(methoxycarbonyl)-3-aminomethyl phenyl] boric acid convert with post processing and obtain after purification 1.12g (79%) mark Topic compound.

Embodiment 19d [6-(5-fluoro-2-methylbenzene epoxide)-3-iodine imidazo [1,2-a] pyridine-8-base] (3,3,3-tri- Fluoropropyl) t-butyl carbamate

In the way of INTERMEDIATES Example 7c is similar, 1.10g (2.43mmol) is prepared according to INTERMEDIATES Example 19e [6-(5-fluoro-2-methylbenzene epoxide) imidazo [1,2-a] pyridine-8-base] (3,3,3-trifluoro propyl) t-butyl carbamate turns Change with in post processing with obtain 1.37g (97%) title compound after purification.

Embodiment 19e [6-(5-fluoro-2-methylbenzene epoxide)-3-iodine imidazo [1,2-a] pyridine-8-base] (3,3,3-tri- Fluoropropyl) t-butyl carbamate

In the way of INTERMEDIATES Example 7d is similar, 1.06g (3.00mmol) is prepared according to INTERMEDIATES Example 19f 6-(5-fluoro-2-methylbenzene epoxide)-N-(3,3,3-trifluoro propyl) imidazo [1,2-a] pyridine-8-amine converts with in post processing Obtain 1.17g (82%) title compound after purification.

Embodiment 19f 6-(5-fluoro-2-methylbenzene epoxide)-N-(3,3,3-trifluoro propyl) imidazo [1,2-a] pyridine- 8-amine

In the way of INTERMEDIATES Example 7e is similar, 1.06g (4.11mmol) is prepared according to INTERMEDIATES Example 19g 6-(5-fluoro-2-methylbenzene epoxide) imidazo [1,2-a] pyridine-8-amine converts with in post processing with obtain 1.06g after purification (73%) title compound.

Embodiment 19g 6-(5-fluoro-2-methylbenzene epoxide) imidazo [1,2-a] pyridine-8-amine

The 6-bromine in the way of embodiment 6-1 is similar, 3.00g (14.15mmol) prepared according to INTERMEDIATES Example 3-1 Imidazo [1,2-a] pyridine-8-amine utilizes 5-fluoro-2-methylbenzene phenol to convert with in post processing with obtain 1.10g (30%) after purification Title compound.

Embodiment 20 4-{6-(3-hydroxyl acrylate-1-alkynes-1-base)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-N, 2-dimethyl benzamide

4-{6-(the 3-hydroxyl in the way of embodiment 8 is similar, 14mg (34 μm ol) prepared according to INTERMEDIATES Example 20a Base acrylate-1-alkynes-1-base)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid Convert with in post processing with obtain 7.3mg (51%) title compound after purification.

¹H-NMR(CD₃OD):δ=2.46(3H),2.59(2H),2.92(3H),3.58(2H),4.36(2H),6.26(1H), 7.41-7.47(2H),7.49(1H),7.56(1H),7.89(1H)ppm.

Embodiment 20a 4-{6-(3-hydroxyl acrylate-1-alkynes-1-base)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-2-ar-Toluic acid

The 4-in the way of INTERMEDIATES Example 8b is similar, 83mg (192 μm ol) prepared according to INTERMEDIATES Example 20b { 6-(3-hydroxyl acrylate-1-alkynes-1-base)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-first Yl benzoic acid methyl ester converts with in post processing with obtain 58.1mg (72%) title compound after purification.

Embodiment 20b 4-{6-(3-hydroxyl acrylate-1-alkynes-1-base)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-2-methyl toluate

The 4-{8-[(uncle in the way of embodiment 7 is similar, 146mg (275 μm ol) prepared according to INTERMEDIATES Example 20c Butoxy carbonyl) (3,3,3-trifluoro propyl) amino]-6-(3-hydroxyl acrylate-1-alkynes-1-base) imidazo [1,2-a] pyridine-3- Base }-2-methyl toluate converts with in post processing with obtain 82.9mg (63%) title compound after purification.

Embodiment 20c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(3-hydroxyl acrylate-1-alkynes- 1-yl) imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate

The 4-in the way of INTERMEDIATES Example 14d is similar, 200mg (359 μm ol) prepared according to INTERMEDIATES Example 8d { the bromo-8-of 6-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene Methyl formate utilizes acrylate-2-alkynes-1-alcohol to convert with in post processing with obtain 146.1mg (76%) title compound after purification.

Embodiment 21 N-ethyl-4-{6-(3-hydroxyl acrylate-1-alkynes-1-base)-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-hydroxyl in the way of embodiment 8 is similar, 14mg (34 μm ol) prepared according to INTERMEDIATES Example 20a Base acrylate-1-alkynes-1-base)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid Ethamine is utilized to convert with in post processing with obtain 11.2mg (75%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.28(3H),2.36-2.60(2H),2.52(3H),3.52(2H),3.59(2H),4.49 (2H),5.39(1H),5.86(1H),6.12(1H),7.34(1H),7.36(1H),7.47(1H),7.53(1H),7.83(1H) ppm.

Embodiment 22 4-{6-(3-hydroxyl acrylate-1-alkynes-1-base)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-2-methyl-N-(1-methylcyclopropyl groups) Benzoylamide

4-{6-(the 3-hydroxyl in the way of embodiment 8 is similar, 14mg (34 μm ol) prepared according to INTERMEDIATES Example 20a Base acrylate-1-alkynes-1-base)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid 1-methylcyclopropyl groups ammonium chloride is utilized to convert with in post processing with obtain 11.6mg (74%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.77(2H),0.89(2H),1.53(3H),2.34-2.60(2H),2.50(3H),3.59 (2H),4.49(2H),5.30(1H),5.39(1H),6.12(1H),6.16(1H),7.31(1H),7.34(1H),7.41(1H), 7.52(1H),7.81(1H)ppm.

Embodiment 23 N-(1-anocy clopropyl)-4-{6-(3-hydroxyl acrylate-1-alkynes-1-base)-8-[(3,3,3-trifluoropropyl Base) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-hydroxyl in the way of embodiment 8 is similar, 14mg (34 μm ol) prepared according to INTERMEDIATES Example 20a Base acrylate-1-alkynes-1-base)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid 1-anocy clopropyl ammonium chloride is utilized to convert with in post processing with obtain 4.0mg (25%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.41(2H),1.68(2H),2.46-2.61(2H),2.49(3H),3.58(2H),4.48 (2H),5.38(1H),6.10(1H),6.79(1H),7.25-7.45(4H),7.51(1H),7.76(1H)ppm.

Embodiment 24 N-cyclobutyl-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-fluorobenzene in the way of embodiment 8 is similar, 17mg (36 μm ol) prepared according to INTERMEDIATES Example 8a Epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes ring butylamine Hydrochlorate converts with in post processing with obtain 16.5mg (83%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.78(2H),1.94(2H),2.38-2.59(4H),2.49(3H),3.52(2H),4.59 (1H),5.50(1H),5.92(1H),5.99(1H),6.71(1H),6.76-6.84(2H),7.27(1H),7.35(1H),7.37 (1H),7.46(1H),7.56(1H),7.60(1H)ppm.

Embodiment 25 4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2- A] pyridin-3-yl }-N, 2-dimethyl benzamide

In the way of embodiment 8 is similar, by 20mg (41 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 19a, (5-is fluoro- 2-methylphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid turns Change with in post processing with obtain 16.0mg (78%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.28(3H),2.40-2.61(2H),2.49(3H),3.02(3H),3.57(2H),5.50 (1H),5.80(1H),5.99(1H),6.58(1H),6.73(1H),7.17(1H),7.33(1H),7.35(1H),7.45(1H), 7.47(1H),7.54(1H)ppm.

Embodiment 26 N-ethyl-4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazoles And [1,2-a] pyridin-3-yl-2-methyl benzamide

In the way of embodiment 8 is similar, by 20mg (41 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 19a, (5-is fluoro- 2-methylphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid profit Convert with ethamine with in post processing with obtain 18.8mg (85%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.26(3H),2.28(3H),2.49(3H),2.50-2.59(2H),3.50(2H),3.57 (2H),5.49(1H),5.74(1H),5.99(1H),6.58(1H),6.73(1H),7.17(1H),7.34(1H),7.35(1H), 7.45(1H),7.47(1H),7.55(1H)ppm.

Embodiment 27 4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2- A] pyridin-3-yl }-2-methyl-N-(1-methylcyclopropyl groups) Benzoylamide

In the way of embodiment 8 is similar, by 20mg (41 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 19a, (5-is fluoro- 2-methylphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid profit Convert with 1-methylcyclopropyl groups ammonium chloride with in post processing with obtain 18.6mg (80%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.76(2H),0.87(2H),1.52(3H),2.28(3H),2.43-2.62(2H),2.46 (3H),3.57(2H),5.48(1H),5.99(1H),6.06(1H),6.58(1H),6.74(1H),7.18(1H),7.32(1H), 7.33(1H),7.39(1H),7.45(1H),7.54(1H)ppm.

Embodiment 28 N-(1-anocy clopropyl)-4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoropropyl Base) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

In the way of embodiment 8 is similar, by 20mg (41 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 19a, (5-is fluoro- 2-methylphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid profit Convert with 1-anocy clopropyl ammonium chloride with in post processing with obtain 13.3mg (59%) title compound after purification.

¹H-NMR(CD₃OD):δ=1.33(2H),1.57(2H),2.23(3H),2.42(3H),2.58(2H),3.57(2H), 6.16(1H),6.69(1H),6.79(1H),7.24(1H),7.38-7.45(4H),7.56(1H)ppm.

Embodiment 29 N-[rel-(1S, 2S)-2-fluorine cyclopropyl]-4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3, 3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

In the way of embodiment 8 is similar, by 20mg (41 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 19a, (5-is fluoro- 2-methylphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid profit Convert with rel-(1S, 2S)-2-fluorine cyclopropyl ammonium chloride with in post processing with obtain 19.0mg (85%) title compound after purification Thing.

¹H-NMR(CDCl₃):δ=1.02(1H),1.27(1H),2.28(3H),2.42-2.61(2H),2.50(3H),3.05 (1H),3.57(2H),4.73(1H),5.52(1H),5.96-6.08(2H),6.57(1H),6.73(1H),7.17(1H),7.35 (1H),7.36(1H),7.47(1H),7.48(1H),7.54(1H)ppm.

Embodiment 30 N-cyclopropyl-4-{6-(2,3-difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazoles And [1,2-a] pyridin-3-yl-2-methyl benzamide

4-{6-(the 2,3-in the way of embodiment 8 is similar, 56mg (114 μm ol) prepared according to INTERMEDIATES Example 30a Difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } utilization of-2-ar-Toluic acid Cyclopropylamine converts with in post processing with obtain 44.2mg (69%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.63(2H),0.90(2H),2.43-2.59(2H),2.48(3H),2.92(1H),3.57 (2H),5.49(1H),5.89(1H),6.03(1H),6.77(1H),6.90-7.03(2H),7.33(1H),7.35(1H),7.42 (1H),7.54(2H)ppm.

Embodiment 30a 4-{6-(2,3-difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-2-ar-Toluic acid

The 4-in the way of INTERMEDIATES Example 8b is similar, 153mg (303 μm ol) prepared according to INTERMEDIATES Example 30b { 6-(2,3-difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene Methyl formate converts with in post processing with obtain 112.7mg (76%) title compound after purification.

Embodiment 30b 4-{6-(2,3-difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-2-methyl toluate

The 4-{8-[(uncle in the way of embodiment 7 is similar, 191mg (316 μm ol) prepared according to INTERMEDIATES Example 30c Butoxy carbonyl) (3,3,3-trifluoro propyl) amino]-6-(2,3-difluorobenzene epoxide) imidazo [1,2-a] pyridin-3-yl }-2- Methyl toluate converts with in post processing with obtain 170mg (96%) title compound after purification.

Embodiment 30c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(2,3-difluorobenzene oxygen Base) imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate

In the way of INTERMEDIATES Example 7b is similar, 305mg (523 μm ol) is prepared according to INTERMEDIATES Example 30d [6-(2,3-difluorobenzene epoxide)-3-iodine imidazo [1,2-a] pyridine-8-base] (3,3,3-trifluoro propyl) t-butyl carbamate [4-(methoxycarbonyl)-3-aminomethyl phenyl] boric acid is utilized to convert with in post processing with to obtain 202mg (61%) after purification titled Compound.

Embodiment 30d [6-(2,3-difluorobenzene epoxide)-3-iodine imidazo [1,2-a] pyridine-8-base] (3,3,3-trifluoro Propyl group) t-butyl carbamate

In the way of INTERMEDIATES Example 7c is similar, 288mg (630 μm ol) is prepared according to INTERMEDIATES Example 30e [6-(2,3-difluorobenzene epoxide) imidazo [1,2-a] pyridine-8-base] (3,3,3-trifluoro propyl) t-butyl carbamate converts With in post processing with obtain 308mg (84%) title compound after purification.

Embodiment 30e [6-(2,3-difluorobenzene epoxide) imidazo [1,2-a] pyridine-8-base] (3,3,3-trifluoro propyl) T-butyl carbamate

The 6-in the way of INTERMEDIATES Example 7d is similar, 290mg (812 μm ol) prepared according to INTERMEDIATES Example 30f (2,3-difluorobenzene epoxide)-N-(3,3,3-trifluoro propyl) imidazo [1,2-a] pyridine-8-amine converts with at post processing and purification Rear acquisition 291mg (74%) title compound.

Embodiment 30f 6-(2,3-difluorobenzene epoxide)-N-(3,3,3-trifluoro propyl) imidazo [1,2-a] pyridine-8-amine

In the way of INTERMEDIATES Example 7e is similar, 373mg (1.43mmol) is prepared according to INTERMEDIATES Example 30g 6-(2,3-difluorobenzene epoxide) imidazo [1,2-a] pyridine-8-amine converts to obtain the thick material of 500mg after post processing, its bag Product containing some incomplete reductions.Compound mixture is dissolved in 20mL ethanol, adds 76mg palladium/carbon (10%), and will mixing Thing is stirred overnight in a hydrogen atmosphere.After filtering and removing solvent, by residue by chromatogram purification to obtain 294.8mg (52%) title compound.

Embodiment 30g 6-(2,3-difluorobenzene epoxide) imidazo [1,2-a] pyridine-8-amine

The 6-bromine miaow in the way of embodiment 6-1 is similar, 5.00g (23.6mmol) prepared according to INTERMEDIATES Example 3-1 Azoles also [1,2-a] pyridine-8-amine utilizes 2,3-difluorophenol to convert with in post processing with to obtain 373mg (6%) after purification titled Compound.

Embodiment 31 4-{6-(3-chlorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-N-cyclopropyl-2-methyl benzamide

4-{6-(the 3-chlorine in the way of embodiment 8 is similar, 20mg (41 μm ol) prepared according to INTERMEDIATES Example 31a Phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes ring third Amine converts with in post processing with obtain 12.7mg (56%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.62(2H),0.99(2H),2.42-2.60(2H),2.49(3H),2.92(1H),3.56 (2H),5.49(1H),5.90(1H),5.98(1H),6.90(1H),6.99(1H),7.06(1H),7.24(1H),7.34(1H), 7.37(1H),7.43(1H),7.55(1H),7.58(1H)ppm.

Embodiment 31a 4-{6-(3-chlorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-ar-Toluic acid

The 4-in the way of INTERMEDIATES Example 8b is similar, 272mg (540 μm ol) prepared according to INTERMEDIATES Example 31b { 6-(3-chlorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid Methyl ester converts with in post processing with obtain 260mg (98%) title compound after purification.

Embodiment 31b 4-{6-(3-chlorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl toluate

The 4-{8-[(uncle in the way of embodiment 7 is similar, 330mg (546 μm ol) prepared according to INTERMEDIATES Example 31c Butoxy carbonyl) (3,3,3-trifluoro propyl) amino]-6-(3-chlorophenoxy) imidazo [1,2-a] pyridin-3-yl }-2-methyl Essence of Niobe converts with in post processing with obtain 277mg (100%) title compound after purification.

Embodiment 31c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(3-chlorophenoxy) miaow Azoles also [1,2-a] pyridin-3-yl }-2-methyl toluate

The 4-{6-in the way of embodiment 6-1 is similar, 1.00g (1.80mmol) prepared according to INTERMEDIATES Example 8d Bromo-8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid Methyl ester utilizes 3-chlorophenol to convert with in post processing with obtain 344mg (30%) title compound after purification.

Embodiment 32 4,4'-{8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-diyl } double (N-cyclopropyl-2-methyl benzamide)

The 4,4'-{8-in the way of embodiment 8 is similar, 20mg (40 μm ol) prepared according to INTERMEDIATES Example 32a [(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-diyl } double (2-ar-Toluic acids) utilize cyclopropylamine to turn Change with in post processing with obtain 6.0mg (25%) title compound after purification.

¹H-NMR(DMSO-d6):δ=0.50(4H),0.66(4H),2.35(3H),2.37(3H),2.69(2H),2.81 (2H),3.59(2H),6.36(1H),6.44(1H),7.32(1H),7.41(1H),7.46-7.55(4H),7.63(1H),7.90 (1H),8.23(1H),8.31(1H)ppm.

Embodiment 32a 4,4'-{8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-diyl } double (2-ar-Toluic acid)

In the way of INTERMEDIATES Example 8b is similar, 930mg (1.77mmol) is prepared according to INTERMEDIATES Example 32b Dimethyl 4,4'-{8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-diyl } double (2-methylbenzene first Acid esters) convert with in post processing with obtain 743mg (80%) title compound after purification.

Embodiment 32b dimethyl 4,4'-{8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6- Diyl } double (2-methyl benzoic acid esters)

The dimethyl 4 in the way of embodiment 7 is similar, 1.15g (1.84mmol) prepared according to INTERMEDIATES Example 32c, 4'-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-diyl } double (2-first Yl benzoic acid ester) convert with in post processing with obtain 956mg (94%) title compound after purification.

Embodiment 32c dimethyl 4,4'-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridine-3,6-diyl } double (2-methyl benzoic acid esters)

In the way of INTERMEDIATES Example 7b is similar, 1.31g (2.45mmol) is prepared according to INTERMEDIATES Example 7c (6-bromo-3-iodine imidazo [1,2-a] pyridine-8-base) (3,3,3-trifluoro propyl) t-butyl carbamate utilizes at 120 DEG C [4-(methoxycarbonyl)-3-aminomethyl phenyl] boric acid converts with in post processing with obtain 1.16g (72%) title compound after purification Thing.

Embodiment 33 N-cyclopropyl-2-methyl-4-{6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10.0mg (22 μm ol) prepared according to INTERMEDIATES Example 33a { 6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid utilizes cyclopropylamine to convert With in post processing with obtain 5.6mg (49%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.62(2H),0.89(2H),2.40-2.60(2H),2.47(3H),2.92(1H),3.54 (2H),5.45(1H),5.92(1H),6.02(1H),7.01(2H),7.09(1H),7.28-7.44(5H),7.55(2H),ppm.

Embodiment 33a 2-methyl-4-{6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base } benzoic acid

In the way of INTERMEDIATES Example 8b is similar, 492mg (1.05mmol) is prepared according to INTERMEDIATES Example 33b 2-methyl-4-{6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } essence of Niobe Convert with in post processing with obtain 352mg (70%) title compound after purification.

Embodiment 33b 2-methyl-4-{6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base } essence of Niobe

The 4-{8-in the way of embodiment 7 is similar, 602mg (1.06mmol) prepared according to INTERMEDIATES Example 33c [(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-phenoxy group imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene Methyl formate converts with in post processing with obtain 492mg (99%) title compound after purification.

Embodiment 33c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-phenoxy group imidazo [1, 2-a] pyridin-3-yl }-2-methyl toluate

In the way of INTERMEDIATES Example 7b is similar, 692mg (1.26mmol) is prepared according to INTERMEDIATES Example 33d (3-iodo-6-phenoxy group imidazo [1,2-a] pyridine-8-base) (3,3,3-trifluoro propyl) t-butyl carbamate utilizes [4-(first Epoxide carbonyl)-3-aminomethyl phenyl] boric acid converts with in post processing with obtain 606mg (84%) title compound after purification.

Embodiment 33d (3-iodo-6-phenoxy group imidazo [1,2-a] pyridine-8-base) (3,3,3-trifluoro propyl) amino first Tert-butyl acrylate

In the way of INTERMEDIATES Example 7c is similar, 590mg (1.40mmol) is prepared according to INTERMEDIATES Example 33e (6-phenoxy group imidazo [1,2-a] pyridine-8-base) (3,3,3-trifluoro propyl) t-butyl carbamate converts with in post processing Obtain 696mg (91%) title compound after purification.

Embodiment 33e (6-phenoxy group imidazo [1,2-a] pyridine-8-base) (3,3,3-trifluoro propyl) carbamic acid uncle Butyl ester

In the way of INTERMEDIATES Example 7d is similar, 535mg (1.67mmol) is prepared according to INTERMEDIATES Example 33f 6-phenoxy group-N-(3,3,3-trifluoro propyl) imidazo [1,2-a] pyridine-8-amine converts in post processing and to obtain after purification 590mg (80%) title compound.

Embodiment 33f 6-phenoxy group-N-(3,3,3-trifluoro propyl) imidazo [1,2-a] pyridine-8-amine

In the way of INTERMEDIATES Example 30f is similar, 850mg (3.27mmol) is prepared according to INTERMEDIATES Example 33g 6-(3-chlorophenoxy) imidazo [1,2-a] pyridine-8-amine converts with in post processing with obtain 638mg (61%) title after purification Compound.

Embodiment 33g 6-(3-chlorophenoxy) imidazo [1,2-a] pyridine-8-amine

The 6-bromine in the way of embodiment 6-1 is similar, 3.00g (14.15mmol) prepared according to INTERMEDIATES Example 3-1 Imidazo [1,2-a] pyridine-8-amine utilizes 3-chlorophenol to convert with in post processing with to obtain 854mg (216%) after purification titled Compound.

Embodiment 34 4-{6-(3-chlorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-N, 2-dimethyl benzamide

4-{6-(the 3-chlorine in the way of embodiment 8 is similar, 20mg (41 μm ol) prepared according to INTERMEDIATES Example 31a Phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl-2-ar-Toluic acid convert with Post processing and obtain 14.3mg (66%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.42-2.59(2H),2.50(3H),3.02(3H),3.56(2H),5.50(1H),5.82 (1H),5.98(1H),6.90(1H),7.00(1H),7.06(1H),7.24(1H),7.36(1H),7.38(1H),7.46(1H), 7.56(1H),7.59(1H)ppm.

Embodiment 35 4-{6-(3-chlorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-N-Ethyl-2-Methyl Benzoylamide

4-{6-(the 3-chlorine in the way of embodiment 8 is similar, 20mg (41 μm ol) prepared according to INTERMEDIATES Example 31a Phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes ethamine Convert with in post processing with obtain 13.4mg (60%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.26(3H),2.46-2.59(2H),2.50(3H),3.47-3.61(4H),5.51 (1H),5.76(1H),5.98(1H),6.90(1H),7.00(1H),7.07(1H),7.23(1H),7.36(1H),7.38(1H), 7.46(1H),7.56(1H),7.59(1H)ppm.

Embodiment 36 4-{6-(3-chlorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-2-methyl-N-(1-methylcyclopropyl groups) Benzoylamide

4-{6-(the 3-chlorine in the way of embodiment 8 is similar, 20mg (41 μm ol) prepared according to INTERMEDIATES Example 31a Phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 1-first Cyclopropyl ammonium chloride converts with in post processing with obtain 13.3mg (57%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.76(2H),0.87(2H),1.52(3H),2.45-2.58(2H),2.48(3H),3.56 (2H),5.48(1H),5.98(1H),6.07(1H),6.90(1H),6.99(1H),7.07(1H),7.23(1H),7.34(1H), 7.36(1H),7.40(1H),7.55(1H),7.58(1H)ppm.

Embodiment 37 4-{6-(3-chlorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-N-(1-anocy clopropyl)-2-methyl benzamide

4-{6-(the 3-chlorine in the way of embodiment 8 is similar, 35mg (71 μm ol) prepared according to INTERMEDIATES Example 31a Phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 1-cyanogen Cyclopropyl ammonium chloride converts with in post processing with obtain 20.4mg (57%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.37(2H),1.66(2H),2.43-2.64(2H),2.51(3H),3.55(2H),5.49 (1H),5.98(1H),6.48(1H),6.90(1H),6.99(1H),7.07(1H),7.25(1H),7.33-7.46(3H),7.55 (1H),7.58(1H)ppm.

Embodiment 38 4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-2-methyl-N-(1-methyl-cyclobutyl) Benzoylamide

4-{6-(the 3-chlorine in the way of embodiment 8 is similar, 20mg (41 μm ol) prepared according to INTERMEDIATES Example 31a Phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 1-first Tetramethylcyclobutyl amine converts with in post processing with obtain 12.5mg (52%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.60(3H),1.85-2.01(2H),2.09-2.18(2H),2.42(2H),2.47- 2.58(2H),2.50(3H),3.56(2H),5.50(1H),5.83(1H),5.99(1H),6.72(1H),6.75-6.83(2H), 7.27(1H),7.35(1H),7.36(1H),7.46(1H),7.56(1H),7.61(1H)ppm.

Embodiment 39 4-{6-(3-chlorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-N-[rel-(1R, 2R)-2-fluorine cyclopropyl]-2-methyl benzamide (rac-A), 4-{6-(3-chlorophenoxy)-8- [(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N-{ [(1S, 2S) or (1R, 2R)]-2-fluorine ring third Base }-2-methyl benzamide (A or ent-A) and 4-{6-(3-chlorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl }-N-{ [(1R, 2R) or (1S, 2S)]-2-fluorine cyclopropyl }-2-methyl benzamide (ent-A Or A)

4-{6-(the 3-chlorine in the way of embodiment 8 is similar, 35mg (71 μm ol) prepared according to INTERMEDIATES Example 31a Phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes rel- (1S, 2S)-2-fluorine cyclopropyl ammonium chloride converts with in post processing with obtain 22.9mg (56%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.02(1H),1.27(1H),2.46-2.57(2H),2.52(3H),3.06(1H),3.56 (2H),4.77(1H),5.51(1H),5.97-6.04(2H),6.90(1H),7.00(1H),7.07(1H),7.23(1h),7.37 (1H),7.39(1H),7.49(1H),7.57(1H),7.60(1H)ppm.

Chiral column is utilized to separate to obtain 7.2mg (43%) ent.-A or A by HPLC 16.9mg rac-A (31 μm ol) And 7.7mg (46%) A or ent.-A.

Embodiment 40 N-(2,6-diethyl phenyl)-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-fluorobenzene in the way of embodiment 8 is similar, 17mg (36 μm ol) prepared according to INTERMEDIATES Example 8a Epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 2,6-bis- MEA converts with in post processing with obtain 15.0mg (66%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.27(6H),2.48(2H),2.62(3H),2.73(4H),3.53(2H),5.44(1H), 6.01(1H),6.71-6.84(3H),7.20(2H),7.24-7.32(3H),7.44(1H),7.46(1H),7.50(1H),7.65 (1H),7.68(1H)ppm.

Embodiment 41 4,4'-{8-[methyl (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-two Base } double (N, 2-dimethyl benzamides)

The 4,4'-{8-in the way of embodiment 8 is similar, 20mg (40 μm ol) prepared according to INTERMEDIATES Example 32a [(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-diyl } double (2-ar-Toluic acids) convert with at Hou Chu Manage and obtain 4.9mg (22%) title compound after purification.

¹H-NMR(DMSO-d6):δ=2.37(3H),2.39(3H),2.70(2H),2.74(6H),3.59(2H),6.36 (1H),6.46(1H),7.36(1H),7.45(1H),7.48-7.56(4H),7.64(1H),7.92(1H),8.12(1H),8.20 (1H)ppm.

Embodiment 42 N-cyclopropyl-4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-bromo-8-[(the 3,3,3-trifluoropropyl that 200mg (416 μm ol) is prepared will be comprised according to INTERMEDIATES Example 42a Base) amino] imidazo [1,2-a] pyridin-3-yl-N-cyclopropyl-2-methyl benzamide, 472mg3-fluoro-4-methoxybenzene Phenol 3-fluorophenol, 975mg cesium carbonate, 18.9mg (RS) phenyl hydrogen pyrrolidin-2-yl phosphonate ester, 16.4mg copper chloride (I) and The mixture of 4mL1,4-dioxane utilizes microwave exposure to heat at 130 DEG C 4 hours.Pour the mixture in water, and use acetic acid Ethyl ester and methanol extraction.Organic layer sodium sulfate is dried.After filtering and removing solvent, by residue by chromatogram purification to obtain Obtain 23.2mg (10%) title compound.

¹H-NMR(CDCl₃):δ=0.62(2H),0.90(2H),2.45-2.57(2H),2.48(3H),2.92(1H),3.56 (2H),3.87(3H),5.44(1H),5.90(1H),5.98(1H),6.74(1H),6.83(1H),6.91(1H),7.33(1H), 7.35(1H),7.42(1H),7.49(1H),7.53(1H)ppm.

The bromo-8-of embodiment 42a 4-{6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N- Cyclopropyl-2-methyl benzamide

The 4-{6-prepared according to INTERMEDIATES Example 42b by 750mg (1.70mmol) in the way of embodiment 8 is similar is bromo- 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilize cyclopropylamine convert with In post processing with obtain 589mg (69%) title compound after purification.

The bromo-8-of embodiment 42b 4-{6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2- Ar-Toluic acid

In the way of INTERMEDIATES Example 8b is similar, 787mg (1.73mmol) is prepared according to INTERMEDIATES Example 42c The bromo-8-of 4-{6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } conversion of-2-methyl toluate To obtain 769mg (96%) title compound after post processing.

The bromo-8-of embodiment 42c 4-{6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2- Methyl toluate

The 4-{6-prepared according to INTERMEDIATES Example 8d by 1000mg (1.80mmol) in the way of embodiment 7 is similar is bromo- 8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid first Ester converts with in post processing with obtain 801mg (93%) title compound after purification.

Embodiment 43 4,4'-{8-[methyl (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-two Base } double [N-(1-anocy clopropyl)-2-methyl benzamides]

The 4,4'-{8-in the way of embodiment 8 is similar, 20mg (40 μm ol) prepared according to INTERMEDIATES Example 32a [(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-diyl } double (2-ar-Toluic acids) utilize 1-cyano group ring Propyl ammonium chloride converts with in post processing with obtain 2.9mg (4%) title compound after purification.

¹H-NMR(DMSO-d6):δ=1.25(4H),1.53(4H),2.38(3H),2.40(3H),2.62-2.79(2H), 3.59(2H),6.38(1H),6.46(1H),7.39(1H),7.49(1H),7.54(1H),7.56-7.61(3H),7.67(1H), 7.94(1H),9.13(1H),9.21(1H)ppm.

Embodiment 44 4,4'-{8-[methyl (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-two Base } double [2-methyl-N-(1-methylcyclopropyl groups) Benzoylamides]

The 4,4'-{8-in the way of embodiment 8 is similar, 20mg (40 μm ol) prepared according to INTERMEDIATES Example 32a [(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-diyl } double (2-ar-Toluic acids) utilize 1-methyl ring Propyl ammonium chloride converts with in post processing with obtain 8.4mg (33%) title compound after purification.

¹H-NMR(DMSO-d6):δ=0.56(4H),0.69(4H),1.36(3H),1.37(3H),2.33(3H),2.35 (3H),2.49-2.77(2H),3.59(2H),6.36(1H),6.43(1H),7.27(1H),7.37(1H),7.43-7.54 (4H),7.62(1H),7.88(1H),8.37(1H),8.46(1H)ppm.

Embodiment 45 4,4'-{8-[methyl (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-two Base } double (N-Ethyl-2-Methyl Benzoylamides)

The 4,4'-{8-in the way of embodiment 8 is similar, 20mg (40 μm ol) prepared according to INTERMEDIATES Example 32a [(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-diyl } double (2-ar-Toluic acids) utilize ethamine to convert With in post processing with obtain 5.3mg (23%) title compound after purification.

¹H-NMR(DMSO-d6):δ=1.09(3H),1.10(3H),2.37(3H),2.38(3H),2.70(2H),3.23 (4H),3.59(2H),6.36(1H),6.45(1H),7.34(1H),7.44(1H),7.48-7.56(4H),7.64(1H),7.91 (1H),8.18(1H),8.27(1H)ppm.

Embodiment 46 N-(2,6-diethyl phenyl)-4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoropropyl Base) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

In the way of embodiment 8 is similar, by 15mg (31 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 19a, (5-is fluoro- 2-methylphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid profit Convert with 2,6-diethylaniline with in post processing with obtain 6.7mg (35%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.27(6H),2.29(3H),2.45(2H),2.60(3H),2.74(4H),3.51(2H), 5.35(1H),6.00(1H),6.58(1H),6.74(1H),7.14-7.24(3H),7.29(1H),7.37-7.40(4H),7.50 (1H),7.66(1H)ppm.

Embodiment 47 N-cyclobutyl-4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl }-2-methyl benzamide

In the way of embodiment 8 is similar, by 15mg (31 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 19a, (5-is fluoro- 2-methylphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid profit Convert with ring butylamine with in post processing with obtain 14.7mg (88%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.70-1.84(2H),1.85-2.03(2H),2.28(3H),2.42-2.60(4H), 2.48(3H),3.57(2H),4.60(1H),5.46(1H),5.89(1H),5.99(1H),6.57(1H),6.73(1H),7.17 (1H),7.34(1H),7.35(1H),7.42-7.49(2H),7.55(1H)ppm.

Embodiment 48 Rel-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-2-methyl-N-[(1R, 2R)-2-methylcyclopropyl groups] Benzoylamide

4-{6-(the 3-fluorobenzene in the way of embodiment 8 is similar, 20mg (42 μm ol) prepared according to INTERMEDIATES Example 8a Epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes rel- (1R, 2R)-2-methyl cyclopropylamine converts with in post processing with obtain 15.5mg (66%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.66(1H),0.75(1H),0.98(1H),1.16(3H),2.44-2.58(2H),2.49 (3H),2.60(1H),3.56(2H),5.50(1H),5.85(1H),5.99(1H),6.72(1H),6.79-6.82(2H),7.27 (1H),7.34(1H),7.36(1H),7.42(1H),7.55(1H),7.60(1H)ppm.

Embodiment 49 N-[double (the cyclopropyl)-1-base of 1,1'-]-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoropropyl Base) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-fluorobenzene in the way of embodiment 8 is similar, 20mg (42 μm ol) prepared according to INTERMEDIATES Example 8a Epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 1,1'-double (cyclopropyl)-1-ammonium chloride converts with in post processing with obtain 14.3mg (58%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.22(2H),0.49(2H),0.72(2H),0.82(2H),1.57(1H),2.44-2.59 (2H),2.49(3H),3.56(2H),5.48(1H),5.99(1H),6.10(1H),6.71(1H),6.75-6.83(2H),7.27 (1H),7.34(1H),7.36(1H),7.43(1H),7.55(1H),7.60(1H)ppm.

Embodiment 50 4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-N-[1-(hydroxymethyl) cyclopropyl]-2-methyl benzamide

4-{6-(the 3-fluorobenzene in the way of embodiment 8 is similar, 30mg (63 μm ol) prepared according to INTERMEDIATES Example 8a Epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 1-(hydroxyl Methyl) cyclopropyl ammonium chloride converts with in post processing with obtain 23.3mg (64%) title compound after purification.

¹H-NMR(DMSO-d6):δ=0.65(2H),0.72(2H),2.33(3H),2.54-2.67(2H),3.46(2H), 3.52(2H),4.70(1H),6.10(1H),6.56(1H),6.86-6.94(3H),7.31-7.44(4H),7.63(1H),7.64 (1H),8.43(1H)ppm.

Embodiment 51 N-(1-cyano group cyclobutyl)-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-fluorobenzene in the way of embodiment 8 is similar, 20mg (42 μm ol) prepared according to INTERMEDIATES Example 8a Epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 1-amino Tetramethylene. formonitrile HCN is with in post processing with obtain 13.7mg (56%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.11-2.36(2H),2.43-2.58(4H),2.53(3H),2.83-2.95(2H), 3.56(2H),5.49(1H),6.00(1H),6.23(1H),6.72(1H),6.77-6.83(2H),7.28(1H),7.39(1H), 7.41(1H),7.51(1H),7.57(1H),7.60(1H)ppm.

Embodiment 52 N-cyclopropyl-4-{6-(3-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazoles And [1,2-a] pyridin-3-yl-2-methyl benzamide

4-{6-(the 3-first in the way of embodiment 8 is similar, 20mg (41 μm ol) prepared according to INTERMEDIATES Example 52a Epoxide phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } utilization of-2-ar-Toluic acid Cyclopropylamine converts with in post processing with obtain 13.1mg (58%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.62(2H),0.89(2H),2.42-2.60(2H),2.48(3H),2.91(1H),3.54 (2H),3.78(3H),5.48(1H),5.92(1H),6.02(1H),6.54-6.68(3H),7.21(1H),7.33(1H),7.36 (1H),7.41(1H),7.54(1H),7.58(1H)ppm.

Embodiment 52a 4-{6-(3-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-2-ar-Toluic acid

The 4-in the way of INTERMEDIATES Example 8b is similar, 231mg (95 μm ol) prepared according to INTERMEDIATES Example 52b { 6-(3-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene Methyl formate converts with in post processing with obtain 211mg (99%) title compound after purification.

Embodiment 52b 4-{6-(3-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-2-methyl toluate

The 4-{8-[(uncle in the way of embodiment 7 is similar, 536mg (894 μm ol) prepared according to INTERMEDIATES Example 52c Butoxy carbonyl) (3,3,3-trifluoro propyl) amino]-6-(3-methoxyphenoxy) imidazo [1,2-a] pyridin-3-yl }-2- Methyl toluate converts with in post processing with obtain 236mg (53%) title compound after purification.

Embodiment 52c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(3-methoxybenzene oxygen Base) imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate

The 4-{6-in the way of embodiment 6-1 is similar, 1.00g (1,80mmol) prepared according to INTERMEDIATES Example 8d Bromo-8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid Methyl ester utilizes 3-methoxyphenol to convert with in post processing with obtain 536mg (50%) title compound after purification.

Embodiment 53 N-(1-anocy clopropyl)-4-{6-(3-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-first in the way of embodiment 8 is similar, 35mg (72 μm ol) prepared according to INTERMEDIATES Example 52a Epoxide phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } utilization of-2-ar-Toluic acid 1-anocy clopropyl ammonium chloride converts with in post processing with obtain 15.1mg (36%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.37(2H),1.66(2H),2.43-2.59(2H),2.50(3H),3.55(2H),3.78 (3H),5.44(1H),6.03(1H),6.42(1H),6.54-6.68(3H),7.22(1H),7.35(1H),7.39(1H),7.42 (1H),7.54(1H),7.57(1H)ppm.

Embodiment 54 4-{6-(3-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-2-methyl-N-(1-methylcyclopropyl groups) Benzoylamide

4-{6-(the 3-first in the way of embodiment 8 is similar, 20mg (41 μm ol) prepared according to INTERMEDIATES Example 52a Epoxide phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } utilization of-2-ar-Toluic acid 1-methylcyclopropyl groups ammonium chloride converts with in post processing with obtain 13.0mg (56%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.76(2H),0.86(2H),1.52(3H),2.42-2.59(2H),2.47(3H),3.55 (2H),3.78(3H),5.46(1H),6.02(1H),6.08(1H),6.55-6.68(3H),7.22(1H),7.33(1H),7.35 (1H),7.39(1H),7.53(1H),7.57(1H)ppm.

Embodiment 55 4-{6-(3-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-N, 2-dimethyl benzamide

4-{6-(the 3-first in the way of embodiment 8 is similar, 20mg (41 μm ol) prepared according to INTERMEDIATES Example 52a Epoxide phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } conversion of-2-ar-Toluic acid With in post processing with obtain 12.5mg (58%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.42-2.59(2H),2.49(3H),3.02(3H),3.55(2H),3.78(3H),5.48 (1H),5.82(1H),6.02(1H),6.55-6.67(3H),7.22(1H),7.35(1H),7.37(1H),7.45(1H),7.55 (1H),7.59(1H)ppm.

Embodiment 56 N-ethyl-4-{6-(3-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-first in the way of embodiment 8 is similar, 20mg (41 μm ol) prepared according to INTERMEDIATES Example 52a Epoxide phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } utilization of-2-ar-Toluic acid Ethamine converts with in post processing with obtain 12.6mg (57%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.26(3H),2.42-2.59(2H),2.49(3H),3.45-3.61(4H),3.78 (3H),5.47(1H),5.77(1H),6.02(1H),6.54-6.68(3H),7.22(1H),7.35(1H),7.37(1H),7.45 (1H),7.55(1H),7.59(1H)ppm.

Embodiment 57 N-(1-anocy clopropyl)-2-methyl-4-{6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (22 μm ol) prepared according to INTERMEDIATES Example 33a { 6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid utilizes 1-cyano group ring third Ammonium chloride converts with in post processing with obtain 7.6mg (63%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.37(2H),1.65(2H),2.42-2.60(2H),2.49(3H),3.54(2H),5.45 (1H),6.03(1H),6.51(1H),7.01(2H),7.10(1H),7.28-7.44(5H),7.54(2H)ppm.

Embodiment 58 2-methyl-N-(1-methylcyclopropyl groups)-4-{6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (22 μm ol) prepared according to INTERMEDIATES Example 33a { 6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid utilizes 1-methyl ring third Ammonium chloride converts with in post processing with obtain 8.3mg (71%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.75(2H),0.86(2H),1.51(3H),2.42-2.59(2H),2.46(3H),3.54 (2H),5.46(1H),6.02(1H),6.08(1H),7.01(2H),7.09(1H),7.29-7.42(5H),7.53(1H),7.55 (1H)ppm.

Embodiment 59 N, 2-dimethyl-4-{6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (22 μm ol) prepared according to INTERMEDIATES Example 33a { 6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid converts with in post processing Obtain 6.7mg (62%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.42-2.59(2H),2.48(3H),3.01(3H),3.54(2H),5.46(1H),5.83 (1H),6.02(1H),7.01(2H),7.09(1H),7.29-7.39(4H),7.44(1H),7.54(1H),7.57(1H)ppm.

Embodiment 60 N-Ethyl-2-Methyl-4-{6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (22 μm ol) prepared according to INTERMEDIATES Example 33a { 6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid utilize ethamine convert with In post processing with obtain 6.4mg (57%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.26(3H),2.41-2.59(2H),2.48(3H),3.44-3.60(4H),5.46 (1H),5.76(1H),6.03(1H),7.01(2H),7.09(1H),7.29-7.39(4H),7.44(1H),7.55(1H),7.57 (1H)ppm.

Embodiment 61 Rel-4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl-N-[(1R, 2R)-2-methylcyclopropyl groups] Benzoylamide

In the way of embodiment 8 is similar, by 10mg (21 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 19a, (5-is fluoro- 2-methylphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid profit Convert with rel-(1R, 2R)-2-methyl cyclopropylamine with in post processing with obtain 9.6mg (82%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.66(1H),0.75(1H),0.98(1H),1.16(3H),2.28(3H),2.46-2.57 (2H),2.48(3H),2.60(1H),3.57(2H),5.47(1H),5.86(1H),5.99(1H),6.57(1H),6.73(1H), 7.17(1H),7.32(1H),7.34(1H),7.40(1H),7.46(1H),7.54(1H)ppm.

Embodiment 62 N-[double (the cyclopropyl)-1-base of 1,1'-]-4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3- Trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

In the way of embodiment 8 is similar, by 10mg (21 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 19a, (5-is fluoro- 2-methylphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid profit Convert with double (the cyclopropyl)-1-ammonium chloride of 1,1'-with in post processing with obtain 9.5mg (78%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.23(2H),0.49(2H),0.72(2H),0.82(2H),1.57(1H),2.28(3H), 2.46-2.59(2H),2.48(3H),3.57(2H),5.47(1H),5.99(1H),6.10(1H),6.58(1H),6.73(1H), 7.17(1H),7.33(1H),7.34(1H),7.41(1H),7.46(1H),7.54(1H)ppm.

Embodiment 63 N-(1-cyano group cyclobutyl)-4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoropropyl Base) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

In the way of embodiment 8 is similar, by 10mg (21 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 19a, (5-is fluoro- 2-methylphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid profit Convert with 1-amino Tetramethylene. formonitrile HCN with in post processing with obtain 8.1mg (66%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.11-2.35(2H),2.28(3H),2.43-2.59(4H),2.52(3H),2.89 (2H),3.57(2H),5.48(1H),6.00(1H),6.25(1H),6.58(1H),6.74(1H),7.18(1H),7.36(1H), 7.38(1H),7.46(1H),7.49(1H),7.55(1H)ppm.

Embodiment 64 N-cyclopropyl-2-methyl-4-{6-[4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoropropyl Base) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 20mg (37 μm ol) prepared according to INTERMEDIATES Example 64a { 6-[4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzene first Acid-utilising cyclopropylamine converts with in post processing with obtain 13.3mg (59%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.62(2H),0.90(2H),2.43-2.59(2H),2.49(3H),2.92(1H),3.56 (2H),5.49(1H),5.89(1H),5.98(1H),7.00(2H),7.18(2H),7.33(1H),7.35(1H),7.42(1H), 7.55(1H),7.56(1H)ppm.

Embodiment 64a 2-methyl-4-{6-[4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl } benzoic acid

The 2-in the way of INTERMEDIATES Example 8b is similar, 233mg (421 μm ol) prepared according to INTERMEDIATES Example 64b Methyl-4-{6-[4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base } essence of Niobe converts to obtain 234mg (maximum 100%) title compound after post processing.

Embodiment 64b 2-methyl-4-{6-[4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl } essence of Niobe

The 4-{8-[(uncle in the way of embodiment 7 is similar, 292mg (447 μm ol) prepared according to INTERMEDIATES Example 64c Butoxy carbonyl) (3,3,3-trifluoro propyl) amino]-6-[4-(trifluoromethoxy) phenoxy group] imidazo [1,2-a] pyridine-3- Base }-2-methyl toluate converts with in post processing with obtain 239mg (97%) title compound after purification.

Embodiment 64c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-[4-(trifluoromethoxy) Phenoxy group] imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate

The 4-{6-in the way of embodiment 6-1 is similar, 750mg (1.35mmol) prepared according to INTERMEDIATES Example 8d Bromo-8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid Methyl ester utilizes 4-(trifluoromethoxy) phenol to convert with in post processing with obtain 296mg (34%) title compound after purification.

Embodiment 65 N-(1-anocy clopropyl)-2-methyl-4-{6-[4-(trifluoromethoxy) phenoxy group]-8-[(3,3, 3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 30mg (56 μm ol) prepared according to INTERMEDIATES Example 64a { 6-[4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzene first Acid-utilising 1-anocy clopropyl ammonium chloride converts with in post processing with obtain 19.1mg (54%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.37(2H),1.66(2H),2.42-2.63(2H),2.50(3H),3.55(2H),5.50 (1H),5.99(1H),6.45(1H),7.00(2H),7.18(2H),7.32-7.47(3H),7.55(1H),7.57(1H)ppm.

Embodiment 66 2-methyl-N-(1-methylcyclopropyl groups)-4-{6-[4-(trifluoromethoxy) phenoxy group]-8-[(3,3, 3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 20mg (37 μm ol) prepared according to INTERMEDIATES Example 64a { 6-[4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzene first Acid-utilising 1-methylcyclopropyl groups ammonium chloride converts with in post processing with obtain 13.8mg (60%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.76(2H),0.86(2H),1.52(3H),2.43-2.59(2H),2.47(3H),3.56 (2H),5.50(1H),5.98(1H),6.06(1H),7.01(2H),7.18(2H),7.32(1H),7.34(1H),7.39(1H), 7.55(1H),7.56(1H)ppm.

Embodiment 67 N, 2-dimethyl-4-{6-[4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 20mg (37 μm ol) prepared according to INTERMEDIATES Example 64a { 6-[4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzene first Acid converts with in post processing with obtain 11.8mg (55%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.43-2.59(2H),2.49(3H),3.02(3H),3.56(2H),5.50(1H),5.78 (1H),5.99(1H),7.01(2H),7.18(2H),7.35(1H),7.36(1H),7.46(1H),7.56(1H),7.58(1H) ppm.

Embodiment 68 N-Ethyl-2-Methyl-4-{6-[4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoropropyl Base) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 20mg (37 μm ol) prepared according to INTERMEDIATES Example 64a { 6-[4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzene first Acid-utilising ethamine converts with in post processing with obtain 12.6mg (57%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.26(3H),2.42-2.60(2H),2.49(3H),3.45-3.61(4H),5.50 (1H),5.75(1H),5.99(1H),7.01(2H),7.18(2H),7.35(1H),7.36(1H),7.46(1H),7.56(1H), 7.58(1H)ppm.

Embodiment 69 N-cyclopropyl-4-{6-(2-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

The bromo-8-of 4-{6-in the way of embodiment 42 is similar, 20mg (37 μm ol) prepared according to INTERMEDIATES Example 42a [(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N-cyclopropyl-2-methyl benzamide utilizes 2- Fluoro-4-methoxyphenol converts with in post processing with obtain 17.8mg (8%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.62(2H),0.90(2H),2.41-2.60(2H),2.46(3H),2.92(1H),3.57 (2H),3.80(3H),5.43(1H),5.91(1H),6.06(1H),6.64(1H),6.75(1H),7.02(1H),7.29(1H), 7.31(1H),7.36(1H),7.39(1H),7.50(1H)ppm.

Embodiment 70 N-(1-anocy clopropyl)-4-{6-(2,3-difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 2,3-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 30a Difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } utilization of-2-ar-Toluic acid 1-anocy clopropyl ammonium chloride converts with in post processing with obtain 8.4mg (71%) title compound after purification.

¹H-NMR(DMSO-d6):δ=1.23(2H),1.52(2H),2.35(3H),2.55-2.67(2H),3.46(2H), 6.18(1H),6.60(1H),6.94(1H),7.07-7.18(2H),7.42(1H),7.47(1H),7.48(1H),7.67(1H), 7.70(1H),9.17(1H)ppm.

Embodiment 71 4-{6-(2,3-difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-2-methyl-N-(1-methylcyclopropyl groups) Benzoylamide

4-{6-(the 2,3-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 30a Difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } utilization of-2-ar-Toluic acid 1-methylcyclopropyl groups ammonium chloride converts with in post processing with obtain 8.9mg (76%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.76(2H),0.87(2H),1.52(3H),2.45-2.59(2H),2.47(3H),3.57 (2H),5.49(1H),6.03(1H),6.07(1H),6.77(1H),6.90-7.03(2H),7.32(1H),7.34(1H),7.39 (1H),7.52-7.56(2H)ppm.

Embodiment 72 4-{6-(2,3-difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-N, 2-dimethyl benzamide

4-{6-(the 2,3-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 30a Difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } conversion of-2-ar-Toluic acid With in post processing with obtain 9.2mg (85%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.46-2.58(2H),2.49(3H),3.02(3H),3.57(2H),5.51(1H),5.80 (1H),6.03(1H),6.77(1H),6.90-7.03(2H),7.34(1H),7.36(1H),7.45(1H),7.55(1H),7.56 (1H)ppm.

Embodiment 73 4-{6-(2,3-difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-N-Ethyl-2-Methyl Benzoylamide

4-{6-(the 2,3-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 30a Difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } utilization of-2-ar-Toluic acid Ethamine converts with in post processing with obtain 8.8mg (79%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.26(3H),2.46-2.58(2H),2.49(3H),3.51(2H),3.57(2H),5.49 (1H),5.75(1H),6.03(1H),6.78(1H),6.90-7.03(2H),7.34(1H),7.36(1H),7.45(1H),7.55 (1H),7.56(1H)ppm.

Embodiment 74 N-cyclopropyl-2-methyl-4-{6-[3-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoropropyl Base) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 20mg (37 μm ol) prepared according to INTERMEDIATES Example 74a { 6-[3-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzene first Acid-utilising cyclopropylamine converts with in post processing with obtain 12.2mg (54%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.62(2H),0.89(2H),2.43-2.59(2H),2.49(3H),2.92(1H),3.56 (2H),5.52(1H),5.89(1H),5.98(1H),6.88(1H,6.90-6.98(2H),7.31(1H),7.34(1H),7.36 (1H),7.43(1H),7.56(1H),7.59(1H)ppm.

Embodiment 74a 2-methyl-4-{6-[3-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl } benzoic acid

The 2-in the way of INTERMEDIATES Example 8b is similar, 231mg (417 μm ol) prepared according to INTERMEDIATES Example 74b Methyl-4-{6-[3-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base } essence of Niobe converts to obtain 233mg (maximum 100%) title compound after post processing.

Embodiment 74b 2-methyl-4-{6-[3-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl } essence of Niobe

The 4-{8-[(uncle in the way of embodiment 7 is similar, 300mg (459 μm ol) prepared according to INTERMEDIATES Example 74c Butoxy carbonyl) (3,3,3-trifluoro propyl) amino]-6-[3-(trifluoromethoxy) phenoxy group] imidazo [1,2-a] pyridine-3- Base }-2-methyl toluate converts with in post processing with obtain 237mg (93%) title compound after purification.

Embodiment 74c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-[3-(trifluoromethoxy) Phenoxy group] imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate

The 4-{6-in the way of embodiment 6-1 is similar, 750mg (1.35mmol) prepared according to INTERMEDIATES Example 8d Bromo-8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid Methyl ester utilizes 3-(trifluoromethoxy) phenol to convert with in post processing with obtain 301mg (32%) title compound after purification.

Embodiment 75 N-(1-anocy clopropyl)-2-methyl-4-{6-[3-(trifluoromethoxy) phenoxy group]-8-[(3,3, 3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 30mg (56 μm ol) prepared according to INTERMEDIATES Example 74a { 6-[3-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzene first Acid-utilising 1-anocy clopropyl ammonium chloride converts with in post processing with obtain 18.5mg (52%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.37(2H),1.66(2H),2.43-2.58(2H),2.51(3H),3.55(2H),5.51 (1H),5.99(1H),6.45(1H),6.85-7.01(3H),7.30-7.46(4H),7.56(1H),7.60(1H)ppm.

Embodiment 76 2-methyl-N-(1-methylcyclopropyl groups)-4-{6-[3-(trifluoromethoxy) phenoxy group]-8-[(3,3, 3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 20mg (37 μm ol) prepared according to INTERMEDIATES Example 74a { 6-[3-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzene first Acid-utilising 1-methylcyclopropyl groups ammonium chloride converts with in post processing with obtain 13.0mg (56%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.76(2H),0.87(2H),1.52(3H),2.43-2.59(2H),2.48(3H),3.56 (2H),5.50(1H),5.98(1H),6.06(1H),6.86-6.98(3H),7.29-7.43(4H),7.55(1H),7.59(1H) ppm.

Embodiment 77 N-Ethyl-2-Methyl-4-{6-[3-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoropropyl Base) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 20mg (37 μm ol) prepared according to INTERMEDIATES Example 74a { 6-[3-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzene first Acid-utilising ethamine converts with in post processing with obtain 13.0mg (59%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.26(3H),2.42-2.59(2H),2.50(3H),3.45-3.62(4H),5.52 (1H),5.76(1H),5.98(1H),6.86-7.00(3H),7.29-7.40(3H),7.46(1H),7.56(1H),7.61(1H) ppm.

Embodiment 78 N, 2-dimethyl-4-{6-[3-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 20mg (37 μm ol) prepared according to INTERMEDIATES Example 74a { 6-[3-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzene first Acid converts with in post processing with obtain 12.5mg (58%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.43-2.59(2H),2.50(3H),3.02(3H),3.56(2H),5.51(1H),5.79 (1H),5.98(1H),6.86-6.98(3H),7.29-7.40(3H),7.46(1H),7.56(1H),7.61(1H)ppm.

Embodiment 79 N-cyclopropyl-4-{6-(2-methoxyphenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 2-first in the way of embodiment 8 is similar, 50mg (107 μm ol) prepared according to INTERMEDIATES Example 79a Phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes ring Propylamine converts with in post processing with obtain 41.1mg (72%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.62(2H),0.89(2H),2.49-2.62(2H),2.51(3H),2.92(1H),3.64 (2H),3.85(3H),5.31(1H),5.97(1H),6.38(1H),7.01(1H),7.04(1H),7.30-7.45(5H),7.53 (1H),7.88(1H)ppm.

Embodiment 79a 4-{6-(2-methoxyphenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-ar-Toluic acid

By 628mg (maximum 1.30mmol) according to INTERMEDIATES Example 79b system in the way of INTERMEDIATES Example 8b is similar Standby 4-{6-(2-methoxyphenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-first Yl benzoic acid methyl ester converts with in post processing with obtain 337mg (55%) title compound after purification.

Embodiment 79b 4-{6-(2-methoxyphenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl toluate

The 4-{8-in the way of embodiment 7 is similar, 759mg (1.30mmol) prepared according to INTERMEDIATES Example 79c [(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(2-methoxyphenyl) imidazo [1,2-a] pyridin-3-yl }- 2-methyl toluate converts to obtain the thick title compound of 872mg after post processing.

Embodiment 79c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(2-methoxyphenyl) Imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate

The bromo-8-of the 4-{6-[(tert-butoxycarbonyl) that 750g (1.35mmol) is prepared will be comprised according to INTERMEDIATES Example 8d (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl-2-methyl toluate, 410mg (2-methoxyl group Phenyl) boric acid, 18mL normal propyl alcohol, 1.35mL2M wet chemical, 1.0mL1-N-methyl-2-2-pyrrolidone N, 35.4mg triphenyl The mixture of phosphine and double (triphenylphosphine) palladium of 94.9mg heats 2 hours at 120 DEG C under microwave exposure.Solution is cooled down, adds Enter water and with ethyl acetate and methanol extraction.It is dried by organic phases washed with brine and with sodium sulfate.After filtering and removing solvent Residue (915mg) is directly used without being further purified.

Embodiment 80 4-{6-(2-methoxyphenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl-N-(1-methylcyclopropyl groups) Benzoylamide

4-{6-(the 2-first in the way of embodiment 8 is similar, 50mg (107 μm ol) prepared according to INTERMEDIATES Example 79a Phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 1- Methylcyclopropyl groups ammonium chloride converts with in post processing with obtain 43.2mg (74%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.76(2H),0.87(2H),1.52(3H),2.48-2.63(2H),2.49(3H),3.64 (2H),3.85(3H),5.30(1H),6.12(1H),6.38(1H),7.01(1H),7.04(1H),7.30-7.44(5H),7.53 (1H),7.87(1H)ppm.

Embodiment 81 4-{6-(2-methoxyphenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-N, 2-dimethyl benzamide

4-{6-(the 2-first in the way of embodiment 8 is similar, 50mg (107 μm ol) prepared according to INTERMEDIATES Example 79a Phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl-2-ar-Toluic acid convert with In post processing with obtain 38.7mg (72%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.50-2.63(2H),2.51(3H),3.02(3H),3.64(2H),3.85(3H),5.30 (1H),5.86(1H),6.38(1H),7.01(1H),7.05(1H),7.31-7.48(5H),7.54(1H),7.89(1H)ppm.

Embodiment 82 N-ethyl-4-{6-(2-methoxyphenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 2-first in the way of embodiment 8 is similar, 50mg (107 μm ol) prepared according to INTERMEDIATES Example 79a Phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes second Amine converts with in post processing with obtain 40.1mg (72%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.26(3H),2.50-2.62(2H),2.52(3H),3.51(2H),3.64(2H),3.85 (3H),5.31(1H),5.81(1H),6.38(1H),7.01(1H),7.05(1H),7.31-7.48(5H),7.55(1H),7.89 (1H)ppm.

Embodiment 83 N-cyclopropyl-4-{6-[3-fluoro-4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoropropyl Base) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

In the way of embodiment 8 is similar, by 20mg (36 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 83a, [3-is fluoro- 4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl Benzoic acid utilizes cyclopropylamine to convert with in post processing with obtain 13.0mg (58%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.62(2H),0.90(2H),2.44-2.60(2H),2.50(3H),2.92(1H),3.57 (2H),5.53(1H),5.89(1H),5.96(1H),6.77(1H)=,6.83(1H),7.24(1H),7.34(1H),7.37 (1H),7.43(1H),7.56(1H),7.61(1H)ppm.

Embodiment 83a 4-{6-[3-fluoro-4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl }-2-ar-Toluic acid

The 4-in the way of INTERMEDIATES Example 8b is similar, 221mg (387 μm ol) prepared according to INTERMEDIATES Example 83b { 6-[3-fluoro-4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base }-2-methyl toluate converts with in post processing with obtain 220mg (maximum 100%) title compound after purification.

Embodiment 83b 4-{6-[3-fluoro-4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl }-2-methyl toluate

The 4-{8-[(uncle in the way of embodiment 7 is similar, 286mg (426 μm ol) prepared according to INTERMEDIATES Example 83c Butoxy carbonyl) (3,3,3-trifluoro propyl) amino]-6-[3-fluoro-4-(trifluoromethoxy) phenoxy group] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl toluate converts with in post processing with obtain 227mg (93%) title compound after purification.

Embodiment 83c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-[3-fluoro-4-(fluoroform Epoxide) phenoxy group] imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate

The 4-{6-in the way of embodiment 6-1 is similar, 750mg (1.35mmol) prepared according to INTERMEDIATES Example 8d Bromo-8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid Methyl ester utilizes 3-fluoro-4-(trifluoromethoxy) phenol to convert with in post processing with obtain 293mg (32%) title compound after purification Thing.

Embodiment 84 N-(1-anocy clopropyl)-4-{6-[3-fluoro-4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3- Trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

In the way of embodiment 8 is similar, by 30mg (54 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 83a, [3-is fluoro- 4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl Benzoic acid utilizes 1-anocy clopropyl ammonium chloride to convert with in post processing with obtain 19.3mg (55%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.37(2H),1.67(2H),2.44-2.61(2H),2.52(3H),3.56(2H),5.53 (1H),5.96(1H),6.43(1H),6.77(1H),6.83(1H),7.24(1H),7.36(1H),7.40(1H),7.44(1H), 7.57(1H),7.61(1H)ppm.

Embodiment 85 4-{6-[3-fluoro-4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl }-2-methyl-N-(1-methylcyclopropyl groups) Benzoylamide

In the way of embodiment 8 is similar, by 20mg (36 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 83a, [3-is fluoro- 4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl Benzoic acid utilizes 1-methylcyclopropyl groups ammonium chloride to convert with in post processing with obtain 13.2mg (55%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.76(2H),0.87(2H),1.52(3H),2.44-2.60(2H),2.48(3H),3.57 (2H),5.53(1H),5.96(1H),6.06(1H),6.77(1H),6.84(1H),7.24(1H),7.33(1H),7.35(1H), 7.41(1H),7.56(1H),7.60(1H)ppm.

Embodiment 86 4-{6-[3-fluoro-4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl }-N, 2-dimethyl benzamide

In the way of embodiment 8 is similar, by 20mg (36 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 83a, [3-is fluoro- 4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl Benzoic acid preparation is with in post processing with obtain 12.3mg (57%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.45-2.60(2H),2.51(3H),3.02(3H),3.57(2H),5.53(1H),5.78 (1H),5.96(1H),6.78(1H),6.84(1H),7.24(1H),7.36(1H),7.38(1H),7.47(1H),7.57(1H), 7.62(1H)ppm.

Embodiment 87 N-ethyl-4-{6-[3-fluoro-4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

In the way of embodiment 8 is similar, by 20mg (36 μm ol), according to 4-{6-prepared by INTERMEDIATES Example 83a, [3-is fluoro- 4-(trifluoromethoxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl Benzoic acid utilizes ethamine to convert with in post processing with obtain mg (%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.26(3H),2.43-2.61(2H),2.50(3H),3.45-3.62(4H),5.53 (1H),5.76(1H),5.96(1H),6.77(1H),6.84(1H),7.24(1H),7.36(1H),7.37(1H),7.47(1H), 7.57(1H),7.62(1H)ppm.

Embodiment 88 N, 2-dimethyl-4-{6-(pyridin-4-yl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 20mg (45 μm ol) prepared according to INTERMEDIATES Example 88a { 6-(pyridin-4-yl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid convert with Post processing and obtain 10.5mg (48%) title compound after purification.

¹H-NMR(DMSO-d6):δ=2.39(3H),2.62-2.79(2H),2.74(3H),3.60(2H),6.47(1H), 6.54(1H),7.45(1H),7.52-7.61(2H),7.67(1H),7.72(2H),8.08(1H),8.22(1H),8.59(2H) ppm.

Embodiment 88a 2-methyl-4-{6-(pyridin-4-yl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2- A] pyridin-3-yl } benzoic acid

The 2-in the way of INTERMEDIATES Example 8b is similar, 399mg (878 μm ol) prepared according to INTERMEDIATES Example 88b Methyl-4-{6-(pyridin-4-yl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid first Ester converts with in post processing with obtain 300mg (78%) title compound after purification.

Embodiment 88b 2-methyl-4-{6-(pyridin-4-yl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2- A] pyridin-3-yl } essence of Niobe

The 4-{8-[(uncle in the way of embodiment 7 is similar, 487mg (878 μm ol) prepared according to INTERMEDIATES Example 88c Butoxy carbonyl) (3,3,3-trifluoro propyl) amino]-6-(pyridin-4-yl) imidazo [1,2-a] pyridin-3-yl }-2-methyl Essence of Niobe converts to obtain 532mg (maximum 100%) thick title compound after post processing.

Embodiment 88c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(pyridin-4-yl) imidazoles And [1,2-a] pyridin-3-yl-2-methyl toluate

The 4-in the way of INTERMEDIATES Example 79c is similar, 500mg (899 μm ol) prepared according to INTERMEDIATES Example 8d { the bromo-8-of 6-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene Methyl formate utilizes pyridin-4-yl boric acid to convert to obtain 601mg (maximum 100%) thick title compound after post processing.

Embodiment 89 N-Ethyl-2-Methyl-4-{6-(pyridin-4-yl)-8-[(3,3,3-trifluoro propyl) amino] imidazoles And [1,2-a] pyridin-3-yl Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 20mg (45 μm ol) prepared according to INTERMEDIATES Example 88a { 6-(pyridin-4-yl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid utilizes ethamine Convert with in post processing with obtain 9.7mg (43%) title compound after purification.

¹H-NMR(DMSO-d6):δ=1.09(3H),2.39(3H),2.62-2.79(2H),3.24(2H),3.60(2H), 6.47(1H),6.54(1H),7.44(1H),7.52-7.61(2H),7.66(1H),7.71(2H),8.08(1H),8.29(1H), 8.59(2H)ppm.

Embodiment 90 2-methyl-N-(1-methylcyclopropyl groups)-4-{6-(pyridin-4-yl)-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 20mg (45 μm ol) prepared according to INTERMEDIATES Example 88a { 6-(pyridin-4-yl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid utilizes 1-first Cyclopropyl ammonium chloride converts with in post processing with obtain 7.1mg (32%) title compound after purification.

¹H-NMR(DMSO-d6):δ=0.56(2H),0.70(2H),1.37(3H),2.36(3H),2.62-2.78(2H), 3.60(2H),6.47(1H),6.54(1H),7.38(1H),7.50-7.58(2H),7.65(1H),7.71(2H),8.06(1H), 8.48(1H),8.59(2H)ppm.

Embodiment 91 N-(1-anocy clopropyl)-2-methyl-4-{6-(pyridin-4-yl)-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 30mg (68 μm ol) prepared according to INTERMEDIATES Example 88a { 6-(pyridin-4-yl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid utilizes 1-cyanogen Cyclopropyl ammonium chloride converts with in post processing with obtain 4.2mg (11%) title compound after purification.

¹H-NMR(DMSO-d6):δ=1.25(2H),1.54(2H),2.40(3H),2.49-2.78(2H),3.60(2H), 6.48(1H),6.55(1H),7.49(1H),7.59(1H),7.62(1H),7.69(1H),7.72(2H),8.08(1H),8.59 (2H),9.23(1H)ppm.

-6-vinyl imidazole is also for embodiment 92 N-cyclopropyl-2-methyl-4-{8-[(3,3,3-trifluoro propyl) amino] [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 92a { 8-[(3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] pyridin-3-yl } benzoic acid utilizes cyclopropylamine to convert With in post processing with obtain 9.1mg (83%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.64(2H),0.91(2H),2.49-2.63(2H),2.52(3H),2.94(1H),3.64 (2H),5.28(1H),5.33(1H),5.68(1H),5.98(1H),6.32(1H),6.57(1H),7.36(1H),7.39(1H), 7.45(1H),7.47(1H),7.63(1H)ppm.

Embodiment 92a 2-methyl-4-{8-[(3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] pyrrole Pyridine-3-base } benzoic acid

The 2-in the way of INTERMEDIATES Example 8b is similar, 240mg (595 μm ol) prepared according to INTERMEDIATES Example 92b Methyl-4-{8-[(3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] pyridin-3-yl } essence of Niobe turns Change with in post processing with obtain 183.7mg (75%) title compound after purification.

Embodiment 92b 2-methyl-4-{8-[(3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] pyrrole Pyridine-3-base } essence of Niobe

The 4-{8-[(uncle in the way of embodiment 7 is similar, 363mg (721 μm ol) prepared according to INTERMEDIATES Example 92c Butoxy carbonyl) (3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] pyridin-3-yl }-2-ar-Toluic acid Methyl ester converts with in post processing with obtain 242.9mg (79%) title compound after purification.

Embodiment 92c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1, 2-a] pyridin-3-yl }-2-methyl toluate

The 4-in the way of INTERMEDIATES Example 79c is similar, 500mg (899 μm ol) prepared according to INTERMEDIATES Example 8d { the bromo-8-of 6-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene Methyl formate utilizes 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolan to convert with in post processing and after purification Obtain 367mg (81%) title compound.

Embodiment 93 N, 2-dimethyl-4-{8-[(3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] Pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 92a { 8-[(3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] pyridin-3-yl } benzoic acid converts with in post processing Obtain 8.1mg (78%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.49-2.63(2H),2.53(3H),3.04(3H),3.65(2H),5.29(1H),5.34 (1H),5.69(1H),5.88(1H),6.33(1H),6.58(1H),7.38(1H),7.40(1H),7.47-7.53(2H),7.65 (1H)ppm.

Embodiment 94 N-Ethyl-2-Methyl-4-{8-[(3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1, 2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 92a { 8-[(3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] pyridin-3-yl } benzoic acid utilize ethamine convert with In post processing with obtain 9.4mg (88%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.28(3H),2.50-2.62(2H),2.53(3H),3.52(2H),3.65(2H),5.28 (1H),5.34(1H),5.69(1H),5.84(1H),6.32(1H),6.57(1H),7.38(1H),7.39(1H),7.48(1H) .7.49(1H),7.64(1H)ppm.

Embodiment 95 2-methyl-N-(1-methylcyclopropyl groups)-4-{8-[(3,3,3-trifluoro propyl) amino]-6-vinyl Imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 92a { 8-[(3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] pyridin-3-yl } benzoic acid utilizes 1-methyl ring third Ammonium chloride converts with in post processing with obtain 6.8mg (60%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.77(2H),0.89(2H),1.53(3H),2.49-2.63(2H),2.51(3H),3.65 (2H),5.29(1H),3.32(1H),5.68(1H),6.13(1H),6.32(1H),6.57(1H),7.36(1H),7.38(1H), 7.44(1H),7.48(1H),7.63(1H)ppm.

Embodiment 96 N-(1-anocy clopropyl)-2-methyl-4-{8-[(3,3,3-trifluoro propyl) amino]-6-vinyl Imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 92a { 8-[(3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] pyridin-3-yl } benzoic acid utilizes 1-cyano group ring third Ammonium chloride converts with in post processing with obtain 8.6mg (74%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.39(2H),1.67(2H),2.48-2.63(2H),2.52(3H),3.64(2H),5.28 (1H),5.31(1H),5.69(1H),6.33(1H),6.56(1H),6.66(1H),7.36(1H),7.40(1H),7.42-7.48 (2H),7.63(1H)ppm.

Embodiment 97 N-[rel-(1S, 2S)-2-fluorine cyclopropyl]-2-methyl-4-{8-[(3,3,3-trifluoro propyl) ammonia Base]-6-vinyl imidazole also [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 92a { 8-[(3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] pyridin-3-yl } benzoic acid utilize rel-(1S, 2S)-2-fluorine cyclopropyl ammonium chloride converts with in post processing with obtain 10.2mg (89%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.04(1H),1.28(1H),2.48-2.64(2H),2.54(3H),3.07(1H),3.64 (2H),4.78(1H),5.29(1H),5.33(1H),5.69(1H),6.10(1H),6.32(1H),6.57(1H),7.38(1H), 7.40(1H),7.48(1H),7.52(1H),7.64(1H)ppm.

Embodiment 98 2-methyl-N-[rel-(1S, 2S)-2-methylcyclopropyl groups]-4-{8-[(3,3,3-trifluoro propyl) ammonia Base]-6-vinyl imidazole also [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 92a { 8-[(3,3,3-trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] pyridin-3-yl } benzoic acid utilize rel-(1R, 2R)-2-methyl cyclopropylamine converts with in post processing with obtain 10.0mg (88%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.67(1H),0.77(1H),0.99(1H),1.17(3H),2.45-2.66(3H),2.51 (3H),3.64(2H),5.28(1H),5.34(1H),5.68(1H),5.96(1H),6.32(1H),6.57(1H),7.35(1H), 7.37(1H),7.44(1H),7.47(1H),7.63(1H)ppm.

Embodiment 99 N-cyclopropyl-4-{6-ethyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl benzamide

The 4-{6-ethyl in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 99a- 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilize cyclopropylamine convert with In post processing with obtain 6.8mg (62%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.64(2H),0.91(2H),1.24(3H),2.46-2.65(4H),2.52(3H),2.93 (1H),3.60(2H),5.24(1H),5.97(1H),6.04(1H),7.37(1H),7.39(1H),7.45(1H),7.47(1H), 7.53(1H)ppm.

Embodiment 99a 4-{6-ethyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }- 2-ar-Toluic acid

The 4-{8-[(uncle in the way of embodiment 7 is similar, 183mg (372 μm ol) prepared according to INTERMEDIATES Example 99b Butoxy carbonyl) (3,3,3-trifluoro propyl) amino]-6-ethyl imidazol(e) also [1,2-a] pyridin-3-yl }-2-ar-Toluic acid turns Change with in post processing with obtain 150.8mg (93%) title compound after purification.

Embodiment 99b 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-ethyl imidazol(e) also [1,2- A] pyridin-3-yl }-2-ar-Toluic acid

The 4-in the way of INTERMEDIATES Example 8b is similar, 201mg (398 μm ol) prepared according to INTERMEDIATES Example 99c { 8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-ethyl imidazol(e) also [1,2-a] pyridin-3-yl }-2-methyl Essence of Niobe converts with in post processing with obtain 183mg (93%) title compound after purification.

Embodiment 99c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-ethyl imidazol(e) also [1,2- A] pyridin-3-yl }-2-methyl toluate

4-{8-[(the tert-butoxycarbonyl) (3,3,3-prepared according to INTERMEDIATES Example 92c to 132mg (262 μm ol) Trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] pyridin-3-yl }-2-methyl toluate is in 5mL ethanol Solution adds 13.9mg palladium/carbon (10%), and mixture is stirred vigorously 1.5 hours in a hydrogen atmosphere at 23 DEG C.Filter After removing solvent, by residue by chromatogram purification to obtain 112.1mg (80%) title compound.

Embodiment 100 4-{6-ethyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }- N, 2-dimethyl benzamide

The 4-{6-ethyl in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 99a- 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid convert with in post processing and Obtain 5.4mg (52%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.24(3H),2.48-2.65(4H),2.53(3H),3.04(3H),3.60(2H),5.25 (1H),5.85(1H),6.05(1H),7.39(1H),7.40(1H),7.49(2H),7.54(1H)ppm.

Embodiment 101 N-ethyl-4-{6-ethyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-2-methyl benzamide

The 4-{6-ethyl in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 99a- 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilize ethamine convert with Post processing and obtain 7.6mg (71%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.24(3H),1.27(3H),2.48-2.63(4H),2.53(3H),3.52(2H),3.60 (2H),5.25(1H),5.82(1H),6.04(1H),7.39(1H),7.40(1H),7.45-7.52(2H),7.54(1H)ppm.

Embodiment 102 4-{6-ethyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }- 2-methyl-N-(1-methylcyclopropyl groups) Benzoylamide

The 4-{6-ethyl in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 99a- 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 1-methylcyclopropyl groups Ammonium chloride converts with in post processing with obtain 8.7mg (77%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.77(2H),0.88(2H),1.24(3H),1.53(3H),2.47-2.64(4H),2.50 (3H),3.60(2H),5.26(1H),6.04(1H),6.15(1H),7.36(1H),7.38(1H),7.43(1H),7.47(1H), 7.52(1H)ppm.

Embodiment 103 N-(1-anocy clopropyl)-4-{6-ethyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

The 4-{6-ethyl in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 99a- 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes 1-anocy clopropyl Ammonium chloride converts with in post processing with obtain 9.5mg (82%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.24(3H),1.39(2H),1.67(2H),2.48-2.63(4H),2.53(3H),3.61 (2H),5.28(1H),6.05(1H),6.64(1H),7.36-7.48(4H),7.53(1H)ppm.

Embodiment 104 4-{6-ethyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }- N-[rel-(1S, 2S)-2-fluorine cyclopropyl]-2-methyl benzamide

The 4-{6-ethyl in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 99a- 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilize rel-(1S, 2S)- 2-fluorine cyclopropyl ammonium chloride converts with in post processing with obtain 9.3mg (81%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.04(1H),1.19-1.34(1H),1.25(3H),2.47-2.63(4H),2.54 (3H),3.07(1H),3.61(2H),4.78(1H),5.28(1H),6.03-6.13(2H),7.38-7.56(5H)ppm.

Embodiment 105 4-{6-ethyl-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }- 2-methyl-N-[rel-(1S, 2S)-2-methylcyclopropyl groups] Benzoylamide

The 4-{6-ethyl in the way of embodiment 8 is similar, 10mg (26 μm ol) prepared according to INTERMEDIATES Example 99a- 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilize rel-(1R, 2R)- 2-methyl cyclopropylamine converts with in post processing with obtain 10.4mg (92%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.68(1H),0.77(1H),0.99(1H),1.17(3H),1.24(3H),2.46-2.65 (5H),2.52(3H),3.60(2H),5.27(1H),5.94(1H),6.04(1H),7.36(1H),7.39(1H),7.44(1H), 7.47(1H),7.53(1H)ppm.

Embodiment 106 4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N, 2-dimethyl benzamide

4-{6-(the 3-in the way of embodiment 8 is similar, 30mg (60 μm ol) prepared according to INTERMEDIATES Example 106a Fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene first Acid converts with in post processing with obtain 12.5mg (39%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.42-2.60(2H),2.49(3H),3.02(3H),3.55(2H),3.87(3H),5.47 (1H),5.83(1H),5.98(1H),6.74(1H),6.82(1H),6.92(1H),7.33(1H),7.35(1H),7.45(1H), 7.50(1H),7.53(1H)ppm.

Embodiment 106a 4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid

In the way of INTERMEDIATES Example 8b is similar, 966mg (1.87mmol) is prepared according to INTERMEDIATES Example 106b 4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2- Methyl toluate converts with in post processing with obtain 201mg (21%) title compound after purification.

Embodiment 106b 4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate

In the way of INTERMEDIATES Example 6-1 is similar, 850mg (1.86mmol) is prepared according to INTERMEDIATES Example 106c The bromo-8-of 4-{6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl-2-methyl toluate profit With 3-fluoro-4-methoxyphenol convert with after post processing obtain 2.3g crude product, its comprise about 40% title compound and Directly use without being further purified.

The bromo-8-of embodiment 106c 4-{6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2- Methyl toluate

The 4-{6-prepared according to INTERMEDIATES Example 8d by 2.90g (5.21mmol) in the way of embodiment 7 is similar is bromo- 8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid first Ester converts with in post processing with obtain 2.33mg (98%) title compound after purification.

Embodiment 107 N-ethyl-4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-in the way of embodiment 8 is similar, 30mg (60 μm ol) prepared according to INTERMEDIATES Example 106a Fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene first Acid-utilising ethamine converts with in post processing with obtain 11.6mg (35%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.26(3H),2.42-2.59(2H),2.49(3H),3.45-3.61(4H),3.87 (3H),5.48(1H),5.78(1H),5.99(1H),6.74(1H),6.83(1H),6.91(1H),7.34(1H),7.35(1H), 7.45(1H),7.50(1H),7.54(1H)ppm.

Mg (85%) title compound.

¹H-NMR(CDCl₃):δ=0.62(2H),0.89(2H),2.44-2.58(2H),2.47(3H),2.92(1H),3.55 (2H),5.04(2H),5.48(1H),5.92(1H),6.02(1H),6.92-7.00(4H),7.29-7.48(9H),7.51(1H) ppm.

Embodiment 109a 4-{6-[4-(benzyloxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-2-ar-Toluic acid

4-{6-[4-(the benzyloxy will prepared according to INTERMEDIATES Example 109b in the way of INTERMEDIATES Example 8b is similar Base) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate turns Change with in post processing with obtain 16.3mg (3%) title compound after purification.

Embodiment 109b 4-{6-[4-(benzyloxy) phenoxy group]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-2-methyl toluate

4-{6-[4-(benzyloxy) the benzene oxygen will prepared according to INTERMEDIATES Example 109c in the way of embodiment 7 is similar Base]-8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene first Acid methyl ester converts to obtain the title compound of crude form after post processing, and it directly uses without being further purified.

Embodiment 109c 4-{6-[4-(benzyloxy) phenoxy group]-8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate

The 4-{6-prepared according to INTERMEDIATES Example 8d by 500mg (899 μm ol) in the way of embodiment 6-1 is similar is bromo- 8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid first Ester utilizes 4-(benzyloxy) phenol to convert to obtain title compound after post processing, and it directly uses without being further purified.

Embodiment 110 N-cyclopropyl-4-{6-(4-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-[4-(benzyloxy) phenoxy group]-the 8-[(3,3,3-prepared according to embodiment 109 to 8.0mg (13 μm ol) Trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N-cyclopropyl-2-methyl benzamide is in 254 μ L ethanol Solution adds 0.54 μ L pyridine and 1mg palladium/carbon.Mixture is stirred vigorously 16 hours in a hydrogen atmosphere at 23 DEG C.Cross After filter and removing solvent, residue is passed through chromatogram purification to obtain 4.6mg (68%) title compound.

¹H-NMR(CDCl₃):δ=0.63(2H),0.89(2H),2.43-2.56(2H),2.46(3H),2.91(1H),3.54 (2H),3.86(1H),5.46(1H),5.97(1H),6.04(1H),6.83(2H),6.93(2H),7.30(1H),7.32(1H), 7.39(1H),7.41(1H),7.52(1H)ppm.

Embodiment 111 N-cyclopropyl-2-methyl-4-{6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3-trifluoropropyl Base) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (25 μm ol) prepared according to INTERMEDIATES Example 111a { 6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid Utilize cyclopropylamine purification with in post processing with obtain 7.7mg (70%) title compound after purification.

¹H-NMR (CDCl₃):δ=0.64(2H),0.91(2H),1.89(3H),2.48-2.62(2H),2.52(3H), 2.94(1H),3.63(2H),5.29(1H),5.97(1H),6.11-6.33(3H),7.36(1H),7.39(1H),7.43-7.49 (2H),7.57(1H)ppm.

Embodiment 111a 2-methyl-4-{6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl } benzoic acid

In the way of INTERMEDIATES Example 8b is similar, 400mg (958 μm ol) is prepared according to INTERMEDIATES Example 111b 2-methyl-4-{6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base } essence of Niobe converts with in post processing with obtain 259.3mg (64%) title compound after purification.

Embodiment 111b 2-methyl-4-{6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl } essence of Niobe

The 4-{8-in the way of embodiment 7 is similar, 522mg (1.01mmol) prepared according to INTERMEDIATES Example 111c [(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-[(1E)-propyl-1-alkene-1-base] imidazo [1,2-a] pyridine- 3-yl }-2-methyl toluate converts with in post processing with obtain 403mg (91%) title compound after purification.

Embodiment 111c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-[(1E)-propyl-1-alkene- 1-yl] imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate

The 4-in the way of INTERMEDIATES Example 79c is similar, 500mg (899 μm ol) prepared according to INTERMEDIATES Example 8d { the bromo-8-of 6-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene Methyl formate utilizes (1E)-propyl-1-alkene-1-ylboronic acid to convert with in post processing with to obtain 465mg (100%) after purification titled Compound.

Embodiment 112 N, 2-dimethyl-4-{6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (25 μm ol) prepared according to INTERMEDIATES Example 111a { 6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid Convert with in post processing with obtain 8.7mg (84%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.89(3H),2.49-2.62(2H),2.53(3H),3.04(3H),3.63(2H),5.29 (1H),5.89(1H),6.12-6.32(3H),7.37(1H),7.39(1H),7.47(1H),7.49(1H),7.58(1H)ppm.

Embodiment 113 N-Ethyl-2-Methyl-4-{6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (25 μm ol) prepared according to INTERMEDIATES Example 111a { 6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid Ethamine is utilized to convert with in post processing with obtain 9.4mg (88%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.28(3H),1.90(3H),2.48-2.63(2H),2.53(3H),3.52(2H),3.63 (2H),5.29(1H),5.82(1H),6.12-6.32(3H),7.38(1H),7.39(1H),7.47(1H),7.49(1H),7.58 (1H)ppm.

Embodiment 114 2-methyl-N-(1-methylcyclopropyl groups)-4-{6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3- Trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (25 μm ol) prepared according to INTERMEDIATES Example 111a { 6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid 1-methylcyclopropyl groups ammonium chloride is utilized to convert with in post processing with obtain 10.5mg (93%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.77(2H),0.89(2H),1.54(3H),1.90(3H),2.46-2.63(2H),2.51 (3H),3.63(2H),5.26(1H),6.08-6.31(4H),7.36(1H),7.38(1H),7.43(1H),7.47(1H),7.56 (1H)ppm.

Embodiment 115 N-(1-anocy clopropyl)-2-methyl-4-{6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3- Trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (25 μm ol) prepared according to INTERMEDIATES Example 111a { 6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid 1-anocy clopropyl ammonium chloride is utilized to convert with in post processing with obtain 9.4mg (81%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.39(2H),1.68(2H),1.90(3H),2.48-2.63(2H),2.54(3H),3.63 (2H),5.26(1H),6.11-6.31(3H),6.48(1H),7.38(1H),7.42(1H),7.45(1H),7.46(1H),7.57 (1H)ppm.

Embodiment 116 N-[rel-(1S, 2S)-2-fluorine cyclopropyl]-2-methyl-4-{6-[(1E)-propyl-1-alkene-1-base]- 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (25 μm ol) prepared according to INTERMEDIATES Example 111a { 6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid Rel-(1S, 2S)-2-fluorine cyclopropyl ammonium chloride is utilized to convert with in post processing with obtain 7.5mg (66%) title compound after purification Thing.

¹H-NMR(CDCl₃):δ=1.04(1H),1.28(1H),1.89(3H),2.47-2.63(2H),2.54(3H),3.08 (1H),3.63(2H),4.78(1H),5.27(1H),6.06(1H),6.10-6.32(3H),7.39(1H),7.40(1H),7.47 (1H),7.52(1H),7.58(1H)ppm.

Embodiment 117 2-methyl-N-[rel-(1S, 2S)-2-methylcyclopropyl groups]-4-{6-[(1E)-propyl-1-alkene-1- Base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (25 μm ol) prepared according to INTERMEDIATES Example 111a { 6-[(1E)-propyl-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzoic acid Rel-(1R, 2R)-2-methyl cyclopropylamine is utilized to convert with in post processing with obtain 9.4mg (83%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.67(1H),0.77(1H),1.00(1H),1.17(3H),1.90(3H),2.46-2.65 (2H),2.52(3H),3.63(2H),5.26(1H),5.89(1H),6.11-6.30(3H),7.36(1H),7.38(1H),7.45 (1H),7.47(1H),7.57(1H)ppm.

Embodiment 118 N-[rel-(1R, 2R)-2-fluorine cyclopropyl]-4-{6-[(1Z)-3-hydroxyl acrylate-1-alkene-1-base]- 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

The 4-{6-in the way of embodiment 8 is similar, 10mg (24 μm ol) prepared according to INTERMEDIATES Example 108a [(1Z)-3-hydroxyl acrylate-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2- Ar-Toluic acid utilizes rel-(1S, 2S)-2-fluorine cyclopropyl ammonium chloride to convert with in post processing with obtain 8.1mg after purification (71%) title compound.

¹H-NMR(CDCl₃):δ=1.05(1H),1.28(1H),2.48-2.60(2H),2.52(3H),3.06(1H),3.60 (2H),4.38(2H),4.77(1H),5.37(1H),5.94(1H),6.07(1H),6.15(1H),6.46(1H),7.36(1H), 7.40(1H),7.49(1H),7.51(1H),7.66(1H),ppm.

Embodiment 119 4-{6-[(1Z)-3-hydroxyl acrylate-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] imidazoles And [1,2-a] pyridin-3-yl-N, 2-dimethyl benzamide

The 4-{6-in the way of embodiment 8 is similar, 10mg (24 μm ol) prepared according to INTERMEDIATES Example 108a [(1Z)-3-hydroxyl acrylate-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2- Ar-Toluic acid converts with in post processing with obtain 8.5mg (82%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.48-2.61(2H),2.50(3H),3.02(3H),3.59(2H),4.37(2H),5.41 (1H),5.90-6.01(2H),6.07(1H),6.45(2H),7.34(1H),7.39(1H),7.45(1H),7.50(1H),7.66 (1H)ppm.

Embodiment 120 N-ethyl-4-{6-[(1Z)-3-hydroxyl acrylate-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

The 4-{6-in the way of embodiment 8 is similar, 10mg (24 μm ol) prepared according to INTERMEDIATES Example 108a [(1Z)-3-hydroxyl acrylate-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2- Ar-Toluic acid utilizes ethamine to convert with in post processing with obtain 7.0mg (66%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.27(3H),2.48-2.61(2H),2.51(3H),3.51(2H),3.60(2H),4.38 (2H),5.40(1H),5.88(1H),5.94(1H),6.08(1H),6.46(1H),7.35(1H),7.39(1H),7.46(1H), 7.51(1H),7.66(1H)ppm.

Embodiment 121 4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] Imidazo [1,2-a] pyridin-3-yl }-N, 2-dimethyl benzamide

4-{6-(the 3-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 121a Fluoro-4-methoxyphenoxy)-8-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] imidazo [1,2-a] pyridin-3-yl }-2- Ar-Toluic acid converts with in post processing with obtain 8.2mg (76%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.40(2H),1.75(2H),1.94(1H),2.49(3H),3.01(3H),3.14(2H), 3.39(2H),3.87(3H),3.99(2H),5.42(1H),5.85(1H),5.97(1H),6.74(1H),6.83(1H),6.90 (1H),7.34(1H),7.36(1H),7.44(1H),7.47(1H),7.52(1H)ppm.

Embodiment 121a 4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] Imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid

In the way of INTERMEDIATES Example 8b is similar, 40.9mg (79 μm ol) is prepared according to INTERMEDIATES Example 121b 4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2- Methyl toluate converts with in post processing with obtain 31.1mg (78%) title compound after purification.

Embodiment 121b 4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate

The 4-in the way of embodiment 6-1 is similar, 373.5mg (815 μm ol) prepared according to INTERMEDIATES Example 121c { the bromo-8-of 6-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate 3-fluoro-4-methoxyphenol is utilized to convert with in post processing with obtain 40.9mg (9%) title compound after purification.

The bromo-8-of embodiment 121c 4-{6-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] imidazo [1,2-a] pyridine- 3-yl }-2-methyl toluate

The 4-{6-in the way of embodiment 7 is similar, 581.5mg (1.04mmol) prepared according to INTERMEDIATES Example 121d Bromo-8-[(tert-butoxycarbonyl) (tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-first Yl benzoic acid methyl ester converts with in post processing with obtain 458mg (89%) title compound after purification.

The bromo-8-of embodiment 121d 4-{6-[(tert-butoxycarbonyl) (tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] imidazoles And [1,2-a] pyridin-3-yl-2-methyl toluate

In the way of INTERMEDIATES Example 7b is similar, 863mg (1.61mmol) is prepared according to INTERMEDIATES Example 9b (6-bromo-3-iodine imidazo [1,2-a] pyridine-8-base) (tetrahydrochysene-2H-pyrans-4-ylmethyl) t-butyl carbamate utilizes [4- (methoxycarbonyl)-3-aminomethyl phenyl] boric acid converts with in post processing with obtain 689.4mg (77%) title compound after purification.

Embodiment 122 N-ethyl-4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(tetrahydrochysene-2H-pyrans-4-Ji Jia Base) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 121a Fluoro-4-methoxyphenoxy)-8-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] imidazo [1,2-a] pyridin-3-yl }-2- Ar-Toluic acid utilizes ethamine to convert with in post processing with obtain 9.1mg (82%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.26(3H),1.40(2H),1.76(2H),1.94(1H),2.49(3H),3.14(2H), 3.39(2H),3.50(2H),3.87(3H),4.00(2H),5.42(1H),5.79(1H),5.97(1H),6.75(1H),6.82 (1H),6.90(1H),7.34(1H),7.36(1H),7.44(1H),7.47(1H),7.52(1H)ppm.

Embodiment 123 N-cyclopropyl-4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(tetrahydrochysene-2H-pyrans-4-Ji Jia Base) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 121a Fluoro-4-methoxyphenoxy)-8-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] imidazo [1,2-a] pyridin-3-yl }-2- Ar-Toluic acid utilizes cyclopropylamine to convert with in post processing with obtain 9.6mg (85%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.63(2H),0.89(2H),1.40(2H),1.75(2H),1.94(1H),2.48(3H), 2.92(1H),3.14(2H),3.39(2H),3.87(3H),3.99(2H),5.41(1H),5.94(1H),5.97(1H),6.74 (1H),6.82(1H),6.90(1H),7.32(1H),7.35(1H),7.41(1H),7.46(1H),7.52(1H)ppm.

Embodiment 124 N-[rel-(1S, 2S)-2-fluorine cyclopropyl]-4-{6-(3-fluoro-4-methoxyphenoxy)-8- [(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-in the way of embodiment 8 is similar, 20mg (40 μm ol) prepared according to INTERMEDIATES Example 106a Fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene first Acid-utilising rel-(1S, 2S)-2-fluorine cyclopropyl ammonium chloride converts with in post processing with to obtain 11.9mg (51%) after purification titled Compound.

¹H-NMR(D CDCl₃):δ=1.03(1H),1.27(1H),2.46-2.57(2H),2.51(3H),3.06(1H), 3.56(2H),3.87(3H),4.77(1H),5.47(1H),5.99(1H),6.01(1H),6.74(1H),6.83(1H),6.91 (1H),7.35(1H),7.37(1H),7.48(1H),7.51(1H),7.54(1H)ppm.

Embodiment 125 4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl-N-[rel-(1S, 2S)-2-methylcyclopropyl groups] Benzoylamide

4-{6-(the 3-in the way of embodiment 8 is similar, 20mg (40 μm ol) prepared according to INTERMEDIATES Example 106a Fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene first Acid-utilising rel-(1R, 2R)-2-methyl cyclopropylamine converts with in post processing with obtain 10.9mg (47%) title compound after purification Thing.

¹H-NMR(CDCl₃):δ=0.66(1H),0.76(1H),0.98(1H),1.16(3H),2.43-2.57(2H),2.48 (3H),2.60(1H),3.55(2H),3.87(3H),5.47(1H),5.87(1H),5.99(1H),6.74(1H),6.83(1H), 6.91(1H),7.32(1H),7.34(1H),7.41(1H),7.50(1H),7.53(1H)ppm.

Embodiment 126 4-{6-(3-hydroxypropyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-N, 2-dimethyl benzamide

4-{6-(the 3-hydroxyl in the way of embodiment 8 is similar, 10mg (24 μm ol) prepared according to INTERMEDIATES Example 126a Base propyl group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl-2-ar-Toluic acid convert with Post processing and obtain 6.9mg (67%) title compound after purification.

¹H-NMR(CD₃OD):δ=1.84(2H),2.46(3H),2.54-2.68(4H),2.79(2H),2.91(3H),3.58 (4H),6.24(1H),7.43-7.51(4H),7.66(1H)ppm.

Embodiment 126a4-{6-(3-hydroxypropyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-ar-Toluic acid

In the way of INTERMEDIATES Example 99c is similar, 69.6mg (166 μm ol) is prepared according to INTERMEDIATES Example 108a 4-{6-[(1Z)-3-hydroxyl acrylate-1-alkene-1-base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base }-2-ar-Toluic acid converts with in post processing with obtain 58.6mg (84%) title compound after purification.

Embodiment 127 N-ethyl-4-{6-(3-hydroxypropyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-hydroxyl in the way of embodiment 8 is similar, 10mg (24 μm ol) prepared according to INTERMEDIATES Example 126a Base propyl group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes ethamine Convert with in post processing with obtain 10.1mg (95%) title compound after purification.

¹H-NMR(CD₃OD):δ=1.23(3H),1.84(2H),2.46(3H),2.54-2.67(4H),2.79(2H),3.40 (2H),3.58(4H),6.26(1H),7.43-7.49(3H),7.50(1H),7.65(1H)ppm.

Embodiment 128 N-cyclopropyl-4-{6-(3-hydroxypropyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 3-hydroxyl in the way of embodiment 8 is similar, 10mg (24 μm ol) prepared according to INTERMEDIATES Example 126a Base propyl group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes ring third Amine converts with in post processing with obtain 9.7mg (89%) title compound after purification.

¹H-NMR(CD₃OD):δ=0.62(2H),0.81(2H),1.84(2H),2.45(3H),2.54-2.66(4H),2.87 (1H),3.52-3.63(4H),6.25(1H),7.42-7.48(3H),7.50(1H),7.65(1H)ppm.

Embodiment 129 N-cyclopropyl-4-{6-(3-fluoro-4-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

N-cyclopropyl-4-{6-(the 3-fluoro-4-methoxybenzene oxygen prepared according to embodiment 42 to 15.2mg (28 μm ol) Base)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide is at 2.4mL dichloro Solution in methane adds the 2M Boron tribromide solution in 89.7 μ L dichloromethane, and by mixture at 23 DEG C stirred Night.Add the 2M Boron tribromide solution in 56 μ L dichloromethane of Part II, and continue to stir extra 6 hour.Add first Alcohol also removes solvent.By residue by chromatogram purification to obtain 7.4mg (47%) title compound.

¹H-NMR(DMSO-d6):δ=0.49(2H),0.65(2H),2.31(3H),2.61(2H),2.80(1H),3.45 (2H),6.06(1H),6.49(1H),6.74(1H),6.89(1H),6.98(1H),7.31-7.47(4H),7.59(1H),8.27 (1H),9.62(1H)ppm.

Embodiment 130 4-{6-(3-fluoro-4-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-N, 2-dimethyl benzamide

4-{6-(the fluoro-4-of 3-in the way of embodiment 129 is similar, 8.8mg (17 μm ol) prepared according to embodiment 106 Methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N, 2-dimethyl benzene first Amide converts with in post processing with obtain 5.3mg (59%) title compound after purification.

¹H-NMR(DMSO-d6):δ=2.33(3H),2.55-2.67(2H),2.72(3H),3.45(2H),6.06(1H), 6.50(1H),6.75(1H),6.89(1H),6.98(1H),7.36-7.42(3H),7.44(1H),7.61(1H),8.17(1H), 9.62(1H)ppm.

Embodiment 131 N-ethyl-4-{6-(3-fluoro-4-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl }-2-methyl benzamide

N-ethyl-the 4-{6-in the way of embodiment 129 is similar, 11.8mg (22 μm ol) prepared according to embodiment 107 (3-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl Benzoylamide converts with in post processing with obtain 5.8mg (48%) title compound after purification.

¹H-NMR(DMSO-d6):δ=1.08(3H),2.33(3H),2.53-2.70(2H),3.22(2H),3.45(2H), 6.07(1H),6.50(1H),6.75(1H),6.89(1H),6.98(1H),7.35-7.44(4H),7.60(1H),8.23(1H), 9.62(1H)ppm.

Embodiment 132 N-cyclopropyl-4-{6-(2-hydroxy phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 2-in the way of embodiment 10 is similar, 10mg (22 μm ol) prepared according to INTERMEDIATES Example 132a Hydroxy phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes ring Propylamine converts with in post processing with obtain 7.7mg (67%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.63(2H),0.87(2H),2.35-2.53(2H),2.39(3H),2.90(1H),3.55 (2H),5.30(1H),5.33(1H),6.21(1H),6.30(1H),6.98(1H),7.05(1H),7.22-7.35(4H),7.40 (1H),7.81(1H)ppm.

Embodiment 132a 4-{6-(2-hydroxy phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-ar-Toluic acid

The 4-{8-in the way of embodiment 129 is similar, 241mg (423 μm ol) prepared according to INTERMEDIATES Example 132b [(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(2-methoxyphenyl) imidazo [1,2-a] pyridin-3-yl }- 2-ar-Toluic acid converts with in post processing with obtain 157mg (77%) title compound after purification.

Embodiment 132b 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(2-methoxyphenyl) Imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid

In the way of INTERMEDIATES Example 8b is similar, 524mg (maximum 899 μm ol) is prepared according to INTERMEDIATES Example 79c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(2-methoxyphenyl) imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl toluate converts with in post processing with obtain 360mg (67%) title compound after purification.

Embodiment 133 4-{6-(2-hydroxy phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-N, 2-dimethyl benzamide

4-{6-(the 2-hydroxyl in the way of embodiment 8 is similar, 10mg (22 μm ol) prepared according to INTERMEDIATES Example 132a Base phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl-2-ar-Toluic acid convert with Post processing and obtain 6.4mg (59%) title compound after purification.

¹H-NMR(CDCl₃):δ=2.38-2.54(2H),2.41(3H),3.00(3H),3.57(2H),5.30(1H),5.34 (1H),6.08(1H),6.30(1H),6.98(1H),7.04(1H),7.23-7.32(3H),7.36(1H),7.42(1H),7.82 (1H)ppm.

Embodiment 134 N-ethyl-4-{6-(2-hydroxy phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 2-hydroxyl in the way of embodiment 8 is similar, 10mg (22 μm ol) prepared according to INTERMEDIATES Example 132a Base phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes ethamine Convert with in post processing with obtain 5.2mg (47%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.25(3H),2.38-2.55(2H),2.42(3H),3.49(2H),3.57(2H),5.35 (1H),5.97(1H),6.28(1H),6.99(1H),7.04(1H),7.22-7.33(4H),7.38(1H),7.45(1H),7.81 (1H)ppm.

Embodiment 135 N-[rel-(1S, 2S)-2-fluorine cyclopropyl]-4-{6-(2-hydroxy phenyl)-8-[(3,3,3-trifluoro Propyl group) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 2-hydroxyl in the way of embodiment 8 is similar, 10mg (22 μm ol) prepared according to INTERMEDIATES Example 132a Base phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes rel- (1S, 2S)-2-fluorine cyclopropyl ammonium chloride converts with in post processing with obtain 6.1mg (52%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.05(1H),1.25(1H),2.28-2.56(2H),2.45(3H),3.04(1H),3.57 (2H),4.75(1H),5.36(1H),6.18(1H),6.28(1H),6.95-7.11(2H),7.23-7.36(4H),7.38- 7.50(2H),7.83(1H)ppm.

Embodiment 136 N-cyclopropyl-4-{6-(3-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

N-cyclopropyl-the 4-{6-in the way of embodiment 129 is similar, 18.8mg (36 μm ol) prepared according to embodiment 52 (3-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-toluyl Amine converts with in post processing with obtain 9.1mg (47%) title compound after purification.

¹H-NMR(DMSO-d6):δ=0.49(2H),0.65(2H),2.32(3H),2.52-2.70(2H),2.79(1H), 3.46(2H),6.09(1H),6.39(1H),6.42-6.48(2H),6.51(1H),7.09(1H),7.34(1H),7.40(1H), 7.41(1H),7.53(1H),7.62(1H),8.26(1H),9.49(1H)ppm.

Embodiment 137 4-{6-(3-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl-N-(1-methylcyclopropyl groups) Benzoylamide

4-{6-(the 3-methoxyl group in the way of embodiment 129 is similar, 12.8mg (24 μm ol) prepared according to embodiment 54 Phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl-N-(1-methyl ring third Base) Benzoylamide converts with in post processing with obtain 5.1mg (39%) title compound after purification.

¹H-NMR(DMSO-d6):δ=0.55(2H),0.68(2H),1.35(3H),2.31(3H),2.61(2H),3.45 (2H),6.08(1H),6.39(1H),6.43-6.48(2H),6.51(1H),7.09(1H),7.31(1H),7.38(1H),7.40 (1H),7.52(1H),7.61(1H),8.41(1H),9.49(1H)ppm.

Embodiment 138 N-ethyl-4-{6-(3-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

N-ethyl-the 4-{6-in the way of embodiment 129 is similar, 20.5mg (40 μm ol) prepared according to embodiment 56 (3-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-toluyl Amine converts with in post processing with obtain 12.1mg (58%) title compound after purification.

¹H-NMR(DMSO-d6):δ=1.08(3H),2.34(3H),2.53-2.70(2H),3.22(2H),3.46(2H), 6.09(1H),6.40(1H),6.42-6.48(2H),6.51(1H),7.09(1H),7.34-7.46(3H),7.54(1H),7.62 (1H),8.22(1H),9.49(1H)ppm.

Embodiment 139 4-{6-(3-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-N, 2-dimethyl benzamide

4-{6-(the 3-methoxyl group in the way of embodiment 129 is similar, 22.4mg (45 μm ol) prepared according to embodiment 55 Phenoxy group)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N, 2-dimethyl benzamide turns Change with in post processing with obtain 6.7mg (31%) title compound after purification.

¹H-NMR(DMSO-d6):δ=2.34(3H),2.53-2.68(2H),2.72(3H),3.45(2H),6.08(1H), 6.39(1H),6.44(1H),6.46(1H),6.54(1H),7.09(1H),7.38-7.45(3H),7.55(1H),7.63(1H), 8.18(1H),9.51(1H)ppm.

Embodiment 140 2-methyl-4-{3-[3-methyl-4-(methylcarbamoyl) phenyl]-8-[(3,3,3-trifluoro Propyl group) amino] imidazo [1,2-a] pyridine-6-base } essence of Niobe

In the way of INTERMEDIATES Example 79c is similar, 408mg (905 μm ol) is prepared according to INTERMEDIATES Example 140a The bromo-8-of 4-{6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N, 2-dimethyl benzamide profit Convert with [4-(methoxycarbonyl)-3-aminomethyl phenyl] boric acid with in post processing with obtain 356mg (68%) title compound after purification Thing.

¹H-NMR(DMSO-d6):δ=2.38(3H),2.56(3H),2.62-2.78(2H),2.74(3H),3.59(2H), 3.80(3H),6.40(1H),6.50(1H),7.45(1H),7.50-7.66(5H),7.87(1H),7.97(1H),8.22(1H) ppm.

The bromo-8-of embodiment 140a 4-{6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N, 2-dimethyl benzamide

The 4-{6-prepared according to INTERMEDIATES Example 42b by 400mg (904 μm ol) in the way of embodiment 8 is similar is bromo- 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid convert with in post processing and Obtain 409mg (99%) title compound after purification.

Embodiment 141 N-cyclopropyl-4-{6-(2-hydroxyethyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

4-{6-(the 2-hydroxyl in the way of embodiment 8 is similar, 10mg (25 μm ol) prepared according to INTERMEDIATES Example 141a Base ethyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-ar-Toluic acid utilizes ring third Amine converts with in post processing with obtain 10mg (91%) title compound after purification.

¹H-NMR(CD₃OD):δ=0.62(2H),0.81(2H),2.45(3H),2.60(2H),2.74(2H),2.86(1H), 3.60(2H),3.78(2H),6.27(1H),7.42-7.54(4H),7.70(1H),ppm.

Embodiment 141a 4-{6-(2-hydroxyethyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-ar-Toluic acid

In the way of INTERMEDIATES Example 8b is similar, 23.6mg (56 μm ol) is prepared according to INTERMEDIATES Example 141b 4-{6-(2-hydroxyethyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene first Acid methyl ester converts to obtain 21mg (83%) title compound after post processing.

Embodiment 141b 4-{6-(2-hydroxyethyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl toluate (A) and 4-{6-[(1RS)-1-hydroxyethyl]-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate (B)

The 4-{8-in the way of embodiment 7 is similar, 218mg (418 μm ol) prepared according to INTERMEDIATES Example 141c [(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(2-hydroxyethyl) imidazo [1,2-a] pyridin-3-yl }-2- Methyl toluate and 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-[(1RS)-1-hydroxyl second Base] imidazo [1,2-a] pyridin-3-yl-2-methyl toluate mixture convert in post processing and to obtain after purification 23.6mg (13%) title compound A and 34.9mg (20%) title compound B.

Embodiment 141c 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoro propyl) amino]-6-(2-hydroxyethyl) miaow Azoles also [1,2-a] pyridin-3-yl }-2-methyl toluate (A) and 4-{8-[(tert-butoxycarbonyl) (3,3,3-trifluoropropyl Base) amino]-6-[(1RS)-1-hydroxyethyl] imidazo [1,2-a] pyridin-3-yl }-2-methyl toluate (B)

4-{8-[(the tert-butoxycarbonyl) (3,3,3-prepared according to INTERMEDIATES Example 92c to 217mg (431 μm ol) Trifluoro propyl) amino]-6-vinyl imidazole also [1,2-a] pyridin-3-yl }-2-methyl toluate is at 7.4mL tetrahydrochysene furan The solution muttered adds 2.16mL1M borine-tetrahydrofuran solution.Mixture is stirred 2 days at 23 DEG C.It is cooled to 3 DEG C After, add 325 μ L water and 325 μ L hydrogenperoxide steam generators (in 30% water), and at 23 DEG C, continue stirring 2 hours.Mixture is fallen Enter in water and be extracted with ethyl acetate.The organic layer sodium sulfate of merging is dried.After filtering and removing solvent, directly contain mixed The crude product of compound title compound is without being further purified.

Embodiment 142 4-{6-(2-hydroxyethyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-N, 2-dimethyl benzamide

4-{6-(the 2-hydroxyl in the way of embodiment 8 is similar, 10mg (25 μm ol) prepared according to INTERMEDIATES Example 141a Base ethyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl-2-ar-Toluic acid convert with Post processing and obtain 8.2mg (79%) title compound after purification.

¹H-NMR(CD₃OD):δ=2.46(3H),2.60(2H),2.74(2H),2.91(3H),3.60(2H),3.78(2H), 6.27(1H),7.45-7.51(4H),7.71(1H)ppm.

Embodiment 143 N-cyclopropyl-4-{6-[(1RS)-1-hydroxyethyl]-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl }-2-methyl benzamide

The 4-{6-in the way of embodiment 8 is similar, 11mg (27 μm ol) prepared according to INTERMEDIATES Example 143a [(1RS)-1-hydroxyethyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene first Acid-utilising cyclopropylamine converts with in post processing with obtain 11.7mg (97%) title compound after purification.

¹H-NMR(CD₃OD):δ=0.62(2H),0.81(2H),1.46(3H),2.45(3H),2.52-2.69(2H),2.86 (1H),3.61(2H),4.79(1H),6.32(1H),7.43-7.49(3H),7.52(1H),7.82(1H)ppm.

Embodiment 143a4-{6-[(1RS)-1-hydroxyethyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2- A] pyridin-3-yl }-2-ar-Toluic acid

In the way of INTERMEDIATES Example 8b is similar, 34.9mg (83 μm ol) is prepared according to INTERMEDIATES Example 141b 4-{6-[(1RS)-1-hydroxyethyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-first Yl benzoic acid methyl ester converts to obtain 34.1mg title compound after post processing, and it directly uses without being further purified.

Embodiment 144 4-{6-[(1RS)-1-hydroxyethyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2- A] pyridin-3-yl }-N, 2-dimethyl benzamide

The 4-{6-in the way of embodiment 8 is similar, 11mg (27 μm ol) prepared according to INTERMEDIATES Example 143a [(1RS)-1-hydroxyethyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene first Acid converts with in post processing with obtain 7.5mg (63%) title compound after purification.

¹H-NMR(CD₃OD):δ=1.46(3H),2.46(3H),2.53-2.69(2H),2.91(3H),3.61(2H),4.80 (1H),6.32(1H),7.44-7.55(4H),7.83(1H)ppm.

Embodiment 145 N-ethyl-4-{6-[(1RS)-1-hydroxyethyl]-8-[(3,3,3-trifluoro propyl) amino] imidazoles And [1,2-a] pyridin-3-yl-2-methyl benzamide

The 4-{6-in the way of embodiment 8 is similar, 11mg (27 μm ol) prepared according to INTERMEDIATES Example 143a [(1RS)-1-hydroxyethyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methylbenzene first Acid-utilising ethamine converts with in post processing with obtain 11.4mg (97%) title compound after purification.

¹H-NMR(CD₃OD):δ=1.23(3H),1.46(3H),2.46(3H),2.52-2.69(2H),3.40(2H),3.61 (2H),4.80(1H),6.33(1H),7.45-7.55(4H),7.83(1H)ppm.

Embodiment 146 N-cyclopropyl-4-{6-(3-fluoro-2-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

The 4-in the way of INTERMEDIATES Example 6-1 is similar, 50mg (104 μm ol) prepared according to INTERMEDIATES Example 42a { the bromo-8-of 6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N-cyclopropyl-2-methyl benzamide Utilize 3-fluoro-2-methoxyphenol purification with in post processing with obtain 10.0mg (16%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.62(2H),0.89(2H),2.43-2.58(2H),2.47(3H),2.91(1H),3.56 (2H),3.97(3H),5.49(1H),5.92(1H),6.03(1H),6.73(1H),6.86-6.98(2H),7.31(1H),7.33 (1H),7.40(1H),7.48(1H),7.53(1H)ppm.

Embodiment 147 4-{3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridine-6-base }-N, 2-dimethyl benzamide

4-{3-[the 4-in the way of embodiment 8 is similar, 10mg (19 μm ol) prepared according to INTERMEDIATES Example 147a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-6- Base }-2-ar-Toluic acid converts with in post processing with obtain 9.3mg (86%) title compound after purification.

¹H-NMR(CD₃OD):δ=0.63(2H),0.82(2H),2.44(3H),2.46(3H),2.57-2.72(2H),2.88 (1H),2.90(3H),3.68(2H),6.51(1H),7.37-7.52(6H),7.56(1H),7.90(1H)ppm.

Embodiment 147a 4-{3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridine-6-base }-2-ar-Toluic acid

In the way of INTERMEDIATES Example 8b is similar, 363mg (659 μm ol) is prepared according to INTERMEDIATES Example 147b 4-{3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridine-6-base }-2-methyl toluate converts with in post processing with obtain 265mg (67%) title compound after purification.

Embodiment 147b 4-{3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridine-6-base }-2-methyl toluate

In the way of INTERMEDIATES Example 79c is similar, 437mg (907 μm ol) is prepared according to INTERMEDIATES Example 42a The bromo-8-of 4-{6-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N-cyclopropyl-2-toluyl Amine utilizes [4-(methoxycarbonyl)-3-aminomethyl phenyl] boric acid to convert with in post processing with obtain 397mg (72%) title after purification Compound.

Embodiment 148 4-{3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridine-6-base }-N-Ethyl-2-Methyl Benzoylamide

4-{3-[the 4-in the way of embodiment 8 is similar, 10mg (19 μm ol) prepared according to INTERMEDIATES Example 147a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-6- Base }-2-ar-Toluic acid utilizes ethamine to convert with in post processing with obtain 10.4mg (94%) title compound after purification.

¹H-NMR(CD₃OD):δ=0.63(2H),0.82(2H),1.22(3H),2.44(3H),2.46(3H),2.55-2.73 (2H),2.88(1H),3.39(2H),3.68(2H),6.52(1H),7.37-7.52(6H),7.56(1H),7.90(1H)ppm.

Embodiment 149 4-{3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridine-6-base }-2-methyl-N-(1-methylcyclopropyl groups) Benzoylamide

4-{3-[the 4-in the way of embodiment 8 is similar, 10mg (19 μm ol) prepared according to INTERMEDIATES Example 147a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-6- Base }-2-ar-Toluic acid utilize 1-methylcyclopropyl groups ammonium chloride convert with post processing and obtain after purification 9.1mg (83%) mark Topic compound.

¹H-NMR(CDCl₃):δ=0.64(2H),0.76(2H),0.82-0.94(4H),1.52(3H),2.49(3H),2.51 (3H),2.58(2H),2.94(1H),3.67(2H),5.51(1H),6.00(1H),6.08(1H),6.32(1H),7.28-7.43 (5H),7.47(1H),7.54(1H),7.81(1H)ppm.

Embodiment 150 4-(6-{4-[(1-anocy clopropyl) carbamoyl]-3-aminomethyl phenyl }-8-[(3,3,3-tri- Fluoropropyl) amino] imidazo [1,2-a] pyridin-3-yl)-N-cyclopropyl-2-methyl benzamide

4-{3-[the 4-in the way of embodiment 8 is similar, 10mg (19 μm ol) prepared according to INTERMEDIATES Example 147a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-6- Base }-2-ar-Toluic acid utilize 1-anocy clopropyl ammonium chloride convert with post processing and obtain after purification 5.3mg (45%) mark Topic compound.

¹H-NMR(CD₃OD):δ=0.62(2H),0.81(2H),1.34(2H),1.57(2H),2.45(6H),2.64(2H), 2.87(1H),3.67(2H),6.51(1H),7.39-7.57(7H),7.90(1H)ppm.

Embodiment 151 4-{3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridine-6-base }-N-[1-(hydroxymethyl) cyclopropyl]-2-methyl benzamide

4-{3-[the 4-in the way of embodiment 8 is similar, 10mg (19 μm ol) prepared according to INTERMEDIATES Example 147a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-6- Base }-2-ar-Toluic acid utilizes 1-(hydroxymethyl) cyclopropyl ammonium chloride to convert with in post processing with obtain 7.0mg after purification (59%) title compound.

¹H-NMR(CD₃OD):δ=0.63(2H),0.82(2H),0.86-0.92(4H),2.44(3H),2.46(3H), 2.56-2.73(2H),2.88(1H),3.63-3.74(4H),6.51(1H),7.39-7.52(6H),7.56(1H),7.89(1H) ppm.

Embodiment 152 4-{3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridine-6-base }-N-[rel-(1S, 2S)-2-fluorine cyclopropyl]-2-methyl benzamide

4-{3-[the 4-in the way of embodiment 8 is similar, 10mg (19 μm ol) prepared according to INTERMEDIATES Example 147a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-6- Base }-2-ar-Toluic acid utilize rel-(1S, 2S)-2-fluorine cyclopropyl ammonium chloride convert in post processing and to obtain after purification 6.7mg (58%) title compound.

¹H-NMR(CD₃OD):δ=0.62(2H),0.81(2H),1.05(1H),1.18(1H),2.44(3H),2.45(3H), 2.64(2H),2.86(2H),3.67(2H),4.69(1H),6.51(1H),7.40(1H),7.42(1H),7.43-7.51(4H), 7.55(1H),7.90(1H)ppm.

Embodiment 153 4-{6-(4-carbamoyl-3-aminomethyl phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazoles And [1,2-a] pyridin-3-yl-N-cyclopropyl-2-methyl benzamide

4-{3-[the 4-in the way of embodiment 8 is similar, 10mg (19 μm ol) prepared according to INTERMEDIATES Example 147a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-6- Base }-2-ar-Toluic acid utilizes ammonia (0.5M, in dioxane) to convert with in post processing with obtain 8.7mg (83%) title after purification Compound.

¹H-NMR(CD₃OD):δ=0.63(2H),0.82(2H),2.48(3H),2.49(3H),2.55-2.73(2H),2.88 (1H),3.68(2H),6.52(1H),7.41-7.53(6H),7.56(1H),7.91(1H)ppm.

Embodiment 154 4-{6-(4-{ [rel-(1S, 2S)-2-fluorine cyclopropyl] carbamoyl }-3-aminomethyl phenyl)-8- [(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N, 2-dimethyl benzamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 154a 3-[3-methyl-4-(methylcarbamoyl) phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 6-yl } benzoic acid utilizes rel-(1S, 2S)-2-fluorine cyclopropyl ammonium chloride to convert with in post processing with obtain 7.1mg after purification (61%) title compound.

¹H-NMR(CDCl₃):δ=1.04(1H),1.27(1H),2.52-2.64(2H),2.52(6H),3.02-3.09 (1H),3.03(3H),3.67(2H),4.76(1H),5.42(1H),5.90(1H),6.07(1H),6.32(1H),7.33(1H), 7.35(1H),7.38-7.47(3H),7.50(1H),7.55(1H),7.83(1H)ppm.

Embodiment 154a 2-methyl-4-{3-[3-methyl-4-(methylcarbamoyl) phenyl]-8-[(3,3,3-trifluoro Propyl group) amino] imidazo [1,2-a] pyridine-6-base } benzoic acid

The 2-methyl in the way of INTERMEDIATES Example 8b is similar, 322mg (614 μm ol) prepared according to embodiment 140- 4-{3-[3-methyl-4-(methylcarbamoyl) phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-6-base } essence of Niobe converts with in post processing with obtain 249mg (72%) title compound after purification.

Embodiment 155 4-{6-(4-{ [1-(hydroxymethyl) cyclopropyl] carbamoyl }-3-aminomethyl phenyl)-8-[(3, 3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N, 2-dimethyl benzamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 154a 3-[3-methyl-4-(methylcarbamoyl) phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 6-yl } benzoic acid utilize 1-(hydroxymethyl) cyclopropyl ammonium chloride convert with post processing and obtain after purification 7.5mg (63%) mark Topic compound.

¹H-NMR(CD₃OD):δ=0.87(4H),2.43(3H),2.46(3H),2.58-2.71(2H),2.91(3H), 3.64-3.71(4H),6.50(1H),7.38-7.45(3H),7.50(3H),7.55(1H),7.90(1H)ppm.

Embodiment 156 4-(6-{4-[(1-anocy clopropyl) carbamoyl]-3-aminomethyl phenyl }-8-[(3,3,3-tri- Fluoropropyl) amino] imidazo [1,2-a] pyridin-3-yl)-N, 2-dimethyl benzamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 154a 3-[3-methyl-4-(methylcarbamoyl) phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 6-yl } benzoic acid utilizes 1-anocy clopropyl ammonium chloride to convert with in post processing with obtain 6.0mg (53%) title compound after purification Thing.

¹H-NMR(CD₃OD):δ=1.34(2H),1.57(2H),2.45(3H),2.46(3H),2.56-2.72(2H),2.91 (3H),3.67(2H),6.50(1H),7.38-7.52(6H),7.56(1H),7.91(1H)ppm.

Embodiment 157 2-methyl-N-(1-methylcyclopropyl groups)-4-{3-[3-methyl-4-(methylcarbamoyl) benzene Base]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-6-base } Benzoylamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 154a 3-[3-methyl-4-(methylcarbamoyl) phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 6-yl } benzoic acid utilizes 1-methylcyclopropyl groups ammonium chloride to convert with in post processing with obtain 5.2mg (47%) title compound after purification Thing.

¹H-NMR(CDCl₃):δ=0.76(2H),0.87(2H),1.52(3H),2.43-2.68(2H),2.49(3H),2.52 (3H),3.04(3H),3.66(2H),5.82(1H),5.91(1H),6.10(1H),6.34(1H),7.28-7.43(5H),7.50 (1H),7.54(1H),7.81(1H)ppm.

Embodiment 158 4-{6-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridin-3-yl }-N, 2-dimethyl benzamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 154a 3-[3-methyl-4-(methylcarbamoyl) phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 6-yl } benzoic acid utilizes cyclopropylamine to convert with in post processing with obtain 7.4mg (65%) title compound after purification.

¹H-NMR(CDCl₃):δ=0.63(2H),0.89(2H),2.44-2.65(2H),2.50(3H),2.51(3H),2.91 (1H),3.04(3H),3.66(2H),5.43(1H),5.89-6.02(2H),6.32(1H),7.27-7.43(5H),7.49 (1H),7.54(1H),7.82(1H)ppm.

Embodiment 159 4-{6-[4-(ethylaminocarbonyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl }-N, 2-dimethyl benzamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 154a 3-[3-methyl-4-(methylcarbamoyl) phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 6-yl } benzoic acid utilizes ethamine to convert with in post processing with obtain 7.6mg (69%) title compound after purification.

¹H-NMR(CDCl₃):δ=1.26(3H),2.49-2.65(2H),2.51(6H),3.04(3H),3.50(2H),3.67 (2H),5.44(1H),5.81(1H),5.94(1H),6.34(1H),7.30-7.45(5H),7.49(1H),7.55(1H),7.83 (1H)ppm.

Embodiment 160 4-{6-(4-carbamoyl-3-aminomethyl phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazoles And [1,2-a] pyridin-3-yl-N, 2-dimethyl benzamide

2-methyl-the 4-in the way of embodiment 8 is similar, 10mg (20 μm ol) prepared according to INTERMEDIATES Example 154a 3-[3-methyl-4-(methylcarbamoyl) phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 6-yl } benzoic acid utilizes ammonia (0.5M, in dioxane) with in post processing with obtain 6.3mg (60%) title compound after purification.

¹H-NMR(CD₃OD):δ=2.46(3H),2.48(3H),2.55-2.72(2H),2.91(3H),3.67(2H),6.51 (1H),7.41-7.52(6H),7.56(1H),7.91(1H)ppm.

Embodiment 161 N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(3-fluorophenoxy) imidazo [1, 2-a] pyridin-3-yl }-2-methyl benzamide

To 174.18mg (0.3mmol) { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(3-fluorobenzene oxygen Base) imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate solution in 1.0mLDCM adds Add 3mL TFA and 200 μ L water, and by mixture stirred overnight 1h.

After evaporation, by residue by HPLC purification to obtain 36mg (24%) title compound.UPLC MS:RT= 1.18min;m/z(ES+)481.5[MH+];The MW=480.5. required¹H-NMR(300MHz,DMSO-d6),δ[ppm]=0.43- 0.54(2H),0.60-0.70(2H),2.33(3H),2.79(1H),3.60-3.81(3H),6.32(1H),6.66(1H), 6.81-6.94(3H),7.29-7.40(2H),7.40-7.50(2H),7.63-7.75(2H),8.28(1H).

Embodiment 161a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(3-fluorophenoxy) imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate

To 164.83mg (0.3mmol) the bromo-3-of 6-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1, 2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate solution in 4.0mL dioxane adds 782mg (2.4mmol) cesium carbonate, 11.88mg (0.12mmol) copper chloride (I) and 12.37mg (0.12mmol) dimethylglycine, and Mixture is stirred at 160 DEG C 1h.Solvent removes and is directly used in by residue later step under vacuo without entering one Step purification.

UPLC MS:RT=1.37min;m/z(ES+)581.6[MH+];The MW=580.6. required

Embodiment 161b { the bromo-3-of 6-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyrrole Pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate

To 3.5g (6.97mmol) (6-bromo-3-iodine imidazo [1,2-a] pyridine-8-base) (2,2-bis-fluoro ethyl) amino first Tert-butyl acrylate solution in 100mL THF adds 2.29g (10.46mmol) [4-(cyclopropylcarbamoyl)-3-methyl Phenyl] boric acid, 0.569g (0.697mmol) Pd (dppf) Cl₂With 20.91mL (20.91mmol, 1M aqueous solution) potassium carbonate, and Mixture is stirred at 55 DEG C 2h with in post processing with obtain 2.41g (62.9%) title compound after purification.

UPLC MS:RT=1.28min;m/z(ES+)550.46[MH+];The MW=549.4. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.46-0.55(2H),0.62-0.71(2H),1.33(10H),2.37(3H),2.76-2.87(1H), 4.17(2H),7.38-7.45(2H),7.48-7.57(2H),7.79(1H),8.34(1H),8.56(1H).

Embodiment 161c (6-bromo-3-iodine imidazo [1,2-a] pyridine-8-base) (2,2-bis-fluoro ethyl) carbamic acid uncle Butyl ester

To 5.9g (15.68mmol) (6-bromine imidazo [1,2-a] pyridine-8-base) (2,2-bis-fluoro ethyl) carbamic acid uncle Butyl ester solution in 80mL DMF adds 17.64g (78.41mmol) 1-iodol alkane-2,5-diketone, and mixture is existed 2h is stirred with in post processing with obtain 5.91g (80%) title compound after purification at 40 DEG C.

UPLC MS:RT=1.39min;m/z(ES+)503.1[MH+];The MW=502.1. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=1.29(10H),4.12(2H),7.45(1H),7.72(1H),8.43(1H).

Embodiment 161d (6-bromine imidazo [1,2-a] pyridine-8-base) (2,2-bis-fluoro ethyl) t-butyl carbamate

To the bromo-N-of 5.39g (19.52mmol) 6-(2,2-bis-fluoro ethyl) imidazo [1,2-a] pyridine-8-amine at 250mL Solution in THF adds 19.76g (27mL, 195.23mmol) TEA, 0.48g (3.9mmol) DIPEA and 29.82g (136.66mmol) Bis(tert-butoxycarbonyl)oxide solution in 50mL THF, and mixture is stirred at 40 DEG C 48h with rear Process and obtain 7.42g (94.2%) title compound after purification.

UPLC MS:RT=1.20min;m/z(ES+)377.2[MH+];The MW=376.2. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=1.22-1.40(10H),4.14(2H),7.31(1H),7.57(1H),7.94(1H),8.86(1H).

The bromo-N-of embodiment 161e 6-(2,2-bis-fluoro ethyl) imidazo [1,2-a] pyridine-8-amine

5.30g is added in the difluoro acetaldehyde of 8.00g (100mmol) fresh preparation solution in 560mL DCM (25mmol) 6-bromine imidazo [1,2-a] pyridine-8-amine, 26.49g (125mmol) sodium triacetoxy borohydride and 28.5g (18.56mL, 250mmol) TFA, and mixture is stirred under rt 72h with post processing and obtain after purification 4.0g (58%) mark Topic compound.

UPLC MS:RT=0.71min;m/z(ES+)277.1[MH+];The MW=276.1. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=3.69(2H),6.36(1H),6.54(1H),7.41(1H),7.77(1H),8.10(1H).

Embodiment 161f difluoro acetaldehyde

At-78 DEG C, in 13.96g (110mmol) oxalyl chloride solution in 280mL DCM, drip 52.28mL (220mmol)DMSO.After stirring 2min, the 8.21g (100mmol) 2 being slowly added in 283mL DCM, 2-difluoroethanol, and will Mixture stirs 1h at-78 DEG C.Add 30.35g (300mmol) TEA, and make mixture rise to rt in 90min to obtain Title compound in solution, it is used for later step without further work-up.

Embodiment 162 N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(4-methoxyphenoxy) imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

{ 3-[the 4-in the way of embodiment 161 is similar, 178mg (300 μm ol) prepared according to INTERMEDIATES Example 162a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(4-methoxyphenoxy) imidazo [1,2-a] pyridine-8-base } (2,2- Two fluoro ethyls) t-butyl carbamate utilizes TFA to convert with in post processing with obtain 6.3mg (3%) title compound after purification.

UPLC MS:RT=1.11min;m/z(ES+)493.5[MH+];The MW=492.5. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.44-0.54(2H),0.61-0.69(2H),2.30(3H),2.79(1H),3.65(3H),3.67- 3.71(3H),6.49(1H),6.52-6.59(1H),6.75-6.80(2H),6.87-6.94(2H),7.00-7.06(2H), 7.32-7.42(2H),7.74(1H),8.29(1H)

Embodiment 162a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(4-methoxyphenoxy) miaow Azoles also [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate

{ the 6-in the way of embodiment 161a is similar, 165mg (300 μm ol) prepared according to INTERMEDIATES Example 161b Bromo-3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) ammonia Base t-butyl formate utilizes 4-methoxyphenol to convert to obtain thick title compound after evaporation, and it is directly used in later step Without being further purified.

UPLC MS:RT=1.34min;m/z(ES+)593.6[MH+];The MW=592.6. required

Embodiment 163 N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(2,3-difluorobenzene epoxide) imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

{ 3-[the 4-in the way of embodiment 161 is similar, 179mg (300 μm ol) prepared according to INTERMEDIATES Example 163a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(2,3-difluorobenzene epoxide) imidazo [1,2-a] pyridine-8-base } (2,2- Two fluoro ethyls) t-butyl carbamate utilizes TFA to convert with in post processing with obtain 17.9mg (11%) title compound after purification Thing.

UPLC MS:RT=1.25min;m/z(ES+)499.5[MH+];The MW=498.5. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.44-0.54(2H),0.60-0.70(2H),2.33(3H),2.79(1H),3.63-3.81(3H), 6.39-6.44(1H),6.67-6.74(1H),6.93(1H),7.05-7.21(2H),7.32-7.39(1H),7.40-7.47 (2H),7.71(2H),8.29(1H)

Embodiment 163a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(2,3-difluorobenzene epoxide) miaow Azoles also [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate

{ the 6-in the way of embodiment 161a is similar, 165mg (300 μm ol) prepared according to INTERMEDIATES Example 161b Bromo-3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) ammonia Base t-butyl formate utilizes 2, and 3-difluorophenol converts to obtain thick title compound after evaporation, and it is directly used in later step Without being further purified.

UPLC MS:RT=1.37min;m/z(ES+)599.6[MH+];The MW=598.6. required

Embodiment 164 N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(5-fluoro-2-methylbenzene epoxide) miaow Azoles also [1,2-a] pyridin-3-yl }-2-methyl benzamide

{ 3-[the 4-in the way of embodiment 161 is similar, 179mg (300 μm ol) prepared according to INTERMEDIATES Example 164a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(5-fluoro-2-methylbenzene epoxide) imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate utilizes TFA to convert with in post processing with obtain 19.6mg (13%) title after purification Compound.

UPLC MS:RT=1.30min;m/z(ES+)495.5[MH+];The MW=494.5. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.44-0.52(2H),0.60-0.69(2H),2.20(3H),2.31(3H),2.79(1H),3.71 (3H),6.30-6.35(1H),6.65(1H),6.74(1H),6.84(1H),7.23-7.31(1H),7.32-7.37(1H), 7.37-7.44(2H),7.50(1H),7.67(1H),8.28(1H).

Embodiment 164a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(5-fluoro-2-methylbenzene epoxide) Imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate

{ the 6-in the way of embodiment 161a is similar, 165mg (300 μm ol) prepared according to INTERMEDIATES Example 161b Bromo-3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) ammonia Base t-butyl formate utilizes 5-fluoro-2-methylbenzene phenol to convert to obtain thick title compound after evaporation, and it is directly used in rear one Step is without being further purified.

UPLC MS:RT=1.42min;m/z(ES+)595.6[MH+];The MW=594.6. required

Embodiment 165 N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(2,5-difluorobenzene epoxide) imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

{ 3-[the 4-in the way of embodiment 161 is similar, 179mg (300 μm ol) prepared according to INTERMEDIATES Example 165a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(5-fluoro-2-methylbenzene epoxide) imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate utilizes TFA to convert with in post processing with to obtain 11.6mg (7%) after purification titled Compound.

UPLC MS:RT=1.24min;m/z(ES+)499.5[MH+];The MW=498.5. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.44-0.53(2H),0.60-0.69(2H),2.33(3H),2.79(1H),3.63-3.81(3H), 6.40(1H),6.66-6.75(1H),6.91-7.07(2H),7.33-7.48(4H),7.67-7.76(2H),8.29(1H).

Embodiment 165a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(5-fluoro-2-methylbenzene epoxide) Imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate

{ the 6-in the way of embodiment 161a is similar, 165mg (300 μm ol) prepared according to INTERMEDIATES Example 161b Bromo-3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) ammonia Base t-butyl formate utilizes 2, and 5-difluorophenol converts to obtain thick title compound after evaporation, and it is directly used in later step Without being further purified.

UPLC MS:RT=1.36min;m/z(ES+)599.6[MH+];The MW=598.6. required

Embodiment 166 N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(2,5-difluorobenzene epoxide) imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

{ 3-[the 4-in the way of embodiment 161 is similar, 179mg (300 μm ol) prepared according to INTERMEDIATES Example 166a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(3-fluoro-2-methylbenzene epoxide) imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate utilizes TFA to convert with in post processing with obtain 44.7mg (24%) title after purification Compound.

UPLC MS:RT=1.31min;m/z(ES+)495.5[MH+];The MW=494.5. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.43-0.53(2H),0.65(2H),2.15(3H),2.31(3H),2.79(1H),3.72(3H), 6.30-6.37(1H),6.64(1H),6.74(1H),6.87-6.97(1H),7.14(1H),7.30-7.43(3H),7.48 (1H),7.66(1H),8.28(1H).

Embodiment 166a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(3-fluoro-2-methylbenzene epoxide) Imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate

{ the 6-in the way of embodiment 161a is similar, 165mg (300 μm ol) prepared according to INTERMEDIATES Example 161b Bromo-3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) ammonia Base t-butyl formate utilizes 3-fluoro-2-methylbenzene phenol to convert to obtain thick title compound after evaporation, and it is directly used in rear one Step is without being further purified.

UPLC MS:RT=1.43min;m/z(ES+)595.6[MH+];The MW=594.6. required

Embodiment 167 N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(3-fluoro-4-methoxyphenoxy) Imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

The N-ring third in the way of embodiment 161 is similar, 179mg (300 μm ol) prepared according to INTERMEDIATES Example 167a Base-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(3-fluoro-4-methoxyphenoxy) imidazo [1,2-a] pyridin-3-yl }- 2-methyl benzamide utilizes TFA to convert with in post processing with obtain 10.8mg (4%) title compound after purification.

UPLC MS:RT=1.22min;m/z(ES+)511.5[MH+];The MW=510.5. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.45-0.53(2H),0.62-0.69(2H),2.32(3H),2.76-2.83(1H),3.66(3H), 3.68-3.74(3H),6.36(1H),6.60-6.63(1H),6.85-6.91(1H),7.03-7.14(2H),7.33-7.39 (1H),7.40-7.45(2H),7.54(1H),7.72(1H),8.28(1H).

Embodiment 167a N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(3-fluoro-4-methoxyphenoxy) Imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

{ the 6-in the way of embodiment 161a is similar, 165mg (300 μm ol) prepared according to INTERMEDIATES Example 161b Bromo-3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) ammonia Base t-butyl formate utilizes 3-fluoro-4-methoxyphenol to convert to obtain thick title compound after evaporation, after it is directly used in One step is without being further purified.

UPLC MS:RT=1.34min;m/z(ES+)611.6[MH+];The MW=610.6. required

Embodiment 168 { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(2-hydroxy benzoyl) imidazoles And [1,2-a] pyridine-8-base (2,2-bis-fluoro ethyl) t-butyl carbamate

{ 3-[the 4-in the way of embodiment 161 is similar, 179mg (300 μm ol) prepared according to INTERMEDIATES Example 168a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(2-hydroxy benzoyl) imidazo [1,2-a] pyridine-8-base } (2,2- Two fluoro ethyls) t-butyl carbamate utilizes TFA to convert with in post processing with obtain 7.2mg (4%) title compound after purification.

UPLC MS:RT=1.23min;m/z(ES+)491.5[MH+];The MW=490.5. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.43-0.54(2H),0.59-0.69(2H),2.36(3H),2.74-2.86(1H),3.80(3H), 6.72(1H),6.83(1H),7.24(2H),7.29(1H),7.40-7.48(3H),7.50-7.56(2H),7.78(1H),8.34 (1H),8.51(1H)

Embodiment 168a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(2-hydroxy benzoyl) miaow Azoles also [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate

{ the bromo-3-of 6-[4-(the cyclopropylamino formyl prepared according to INTERMEDIATES Example 161b to 240mg (437 μm ol) Base)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2,2-bis-fluoro ethyl) t-butyl carbamate is at 10mL toluene In suspension in add 3mg (7 μm ol) butyl two-1-adamantyl phosphine, 1mg (4.37 μm ol) acid chloride (II), 90mg (655 μm ol) 2-hydroxyphenyl boronic acid and 70 μ L (437 μm ol) N, N, N', N'-tetra-methylenedimine, and by mixture 100 At DEG C in high-pressure sterilizing pot, under 12 bar carbon monoxide pressures, heat 22h.Remove organic solvent under vacuo, be dissolved in acetic acid Ethyl ester, washs with 1N NaOH and water, is dried and evaporates to obtain the thick title compound of 190mg (73%), and it is directly used in rear one Step is without being further purified.

UPLC MS:RT=1.34min;m/z(ES+)611.6[MH+];The MW=610.6. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.45-0.54(2H),0.61-0.69(2H),1.29-1.43(9H),2.37(3H),2.80(1H), 4.14-4.30(2H),7.23-7.31(3H),7.45(3H),7.59(1H),7.74(1H),7.93(1H),8.36(1H),9.07 (1H)

Embodiment 169 N-cyclopropyl-4-{6-(3-fluorophenoxy)-8-[(2-methoxy ethyl) amino] imidazo [1, 2-a] pyridin-3-yl }-2-methyl benzamide

In the way of embodiment 161 is similar, 163.04mg (0.284mmol) is prepared according to INTERMEDIATES Example 169a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(3-fluorophenoxy) imidazo [1,2-a] pyridine-8-base } (2- Methoxy ethyl) t-butyl carbamate utilizes TFA to convert with in post processing with obtain 14.7mg (10%) title compound after purification Thing.

UPLC MS:RT=1.12min;m/z(ES+)475.5[MH+];The MW=474.5. required

Embodiment 169a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(3-fluorophenoxy) imidazo [1,2-a] pyridine-8-base } (2-methoxy ethyl) t-butyl carbamate

In the way of embodiment 161a is similar, 163.04mg (0.3mmol) is prepared according to INTERMEDIATES Example 169b { the bromo-3-of 6-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2,2-difluoro second Base) t-butyl carbamate utilize 3-fluorophenol convert to obtain thick title compound after evaporation, its be directly used in after a step Rapid without being further purified.

UPLC MS:RT=1.22min;m/z(ES+)575.7[MH+];MW=574.7. embodiment 169b{6-required is bromo- 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2-methoxy ethyl) amino T-butyl formate

(the 6-in the way of embodiment 161b is similar, 4.76g (9.59mmol) prepared according to INTERMEDIATES Example 169c Bromo-3-iodine imidazo [1,2-a] pyridine-8-base) (2-methoxy ethyl) t-butyl carbamate utilization [4-(cyclopropylamino Formoxyl)-3-aminomethyl phenyl] boric acid converts with in post processing with obtain 3.96g (73.7%) title compound after purification.

UPLC MS:RT=1.17min;m/z(ES+)544.5[MH+];The MW=543.5. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.46-0.54(2H),0.62-0.71(2H),1.31(9H),2.37(3H),2.82(1H),3.15 (3H),3.42(2H),3.85(2H),7.34(1H),7.39-7.44(1H),7.49-7.55(2H),7.76(1H),8.33 (1H),8.52(1H).

Embodiment 169c (6-bromo-3-iodine imidazo [1,2-a] pyridine-8-base) (2-methoxy ethyl) carbamic acid uncle Butyl ester

(the 6-in the way of embodiment 161c is similar, 9.61g (25.96mmol) prepared according to INTERMEDIATES Example 169d Bromine imidazo [1,2-a] pyridine-8-base) (2-methoxy ethyl) t-butyl carbamate utilizes 1-iodol alkane-2,5-diketone Convert with in post processing with obtain 9.62g (74.7%) title compound after purification.

UPLC MS:RT=1.34min;m/z(ES+)497.1[MH+];The MW=496.1. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=1.27(9H),3.11(3H),3.39(2H),3.80(2H),7.38(1H),7.70(1H),8.40 (1H).

Embodiment 169d (6-bromine imidazo [1,2-a] pyridine-8-base) (2-methoxy ethyl) t-butyl carbamate

The 6-in the way of embodiment 161d is similar, 7.3g (27.02mmol) prepared according to INTERMEDIATES Example 169e Bromo-N-(2-methoxy ethyl) imidazo [1,2-a] pyridine-8-amine utilizes Bis(tert-butoxycarbonyl)oxide to convert with in post processing and pure 9.62g (90.9%) title compound is obtained after change.

UPLC MS:RT=1.13min;m/z(ES+)371.2[MH+];The MW=370.2. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=1.27(9H),3.12(3H),3.39(2H),3.82(2H),7.24(1H),7.55(1H),7.91 (1H),8.81(1H).

The bromo-N-of embodiment 169e 6-(2-methoxy ethyl) imidazo [1,2-a] pyridine-8-amine

In the way of embodiment 161e is similar, 8.2g (38.72mmol) 6-bromine imidazo [1,2-a] pyridine-8-amine is utilized The methoxyl group acetaldehyde prepared according to INTERMEDIATES Example 169f converts with in post processing with obtain 7.55g (72.2%) after purification and mark Topic compound.

UPLC MS:RT=0.69min;m/z(ES+)271.1[MH+];The MW=270.1. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=3.25(3H),3.32-3.38(2H),3.46-3.56(2H),6.08(1H),6.18(1H),7.38 (1H),7.75(1H),8.03(1H).

Embodiment 169f methoxyl group acetaldehyde

2-methyl cellosolve is utilized to turn 15.2g (200mmol) 2-methyl cellosolve in the way of embodiment 161f is similar Changing to obtain the title compound in solution, it is directly used in later step without further work-up.

Embodiment 170 N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(4-methoxyphenoxy) imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

{ 3-[the 4-in the way of embodiment 161 is similar, 163mg (286 μm ol) prepared according to INTERMEDIATES Example 170a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(2-methylphenoxy) imidazo [1,2-a] pyridine-8-base } (2-methoxy Base ethyl) t-butyl carbamate utilizes TFA with in post processing with obtain 20.2mg (15%) title compound after purification.

UPLC MS:RT=1.11min;m/z(ES+)471.6[MH+];The MW=470.6. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.44-0.52(2H),0.59-0.69(2H),2.21(3H),2.28(3H),2.79(1H),3.25 (3H),3.32-3.39(2H),3.50-3.58(2H),6.07-6.16(2H),6.92(1H),6.98-7.06(1H),7.13 (1H),7.23-7.30(2H),7.30-7.38(3H),7.58(1H),8.25(1H)

Embodiment 170a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(2-methylphenoxy) imidazoles And [1,2-a] pyridine-8-base (2-methoxy ethyl) t-butyl carbamate

{ the 6-in the way of embodiment 161a is similar, 163mg (300 μm ol) prepared according to INTERMEDIATES Example 169b Bromo-3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2-methoxy ethyl) ammonia Base t-butyl formate utilize 2-methylphenol convert to obtain thick title compound after evaporation, its be directly used in later step without Need to be further purified.

UPLC MS:RT=1.22min;m/z(ES+)571.7[MH+];The MW=570.7. required

Embodiment 171 N-cyclopropyl-4-{6-(3,4-difluorobenzene epoxide)-8-[(2-methoxy ethyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

{ 3-[the 4-in the way of embodiment 161 is similar, 163mg (275 μm ol) prepared according to INTERMEDIATES Example 171a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(3,4-difluorobenzene epoxide) imidazo [1,2-a] pyridine-8-base } (2-first Epoxide ethyl) t-butyl carbamate utilizes TFA to convert with in post processing with obtain 8.5mg (6%) title compound after purification.

UPLC MS:RT=1.14min;m/z(ES+)493.5[MH+];The MW=492.5. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.44-0.53(2H),0.60-0.70(2H),2.33(3H),2.80(1H),3.24(3H),3.32- 3.39(2H),3.48-3.55(2H),6.07(1H),6.15-6.24(1H),6.84-6.92(1H),7.21(1H),7.31- 7.40(2H),7.40-7.47(2H),7.57-7.66(2H),8.26(1H)

Embodiment 171a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(3,4-difluorobenzene epoxide) miaow Azoles also [1,2-a] pyridine-8-base } (2-methoxy ethyl) t-butyl carbamate

{ the 6-in the way of embodiment 161a is similar, 163mg (300 μm ol) prepared according to INTERMEDIATES Example 169b Bromo-3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2-methoxy ethyl) ammonia Base t-butyl formate utilizes 3, and 4-difluorophenol converts to obtain thick title compound after evaporation, and it is directly used in later step Without being further purified.

UPLC MS:RT=1.24min;m/z(ES+)593.7[MH+];The MW=592.7. required

Embodiment 172 N-cyclopropyl-4-{6-(3,4-difluorobenzene epoxide)-8-[(2-methoxy ethyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

{ 3-[the 4-in the way of embodiment 161 is similar, 163mg (277 μm ol) prepared according to INTERMEDIATES Example 172a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(5-fluoro-2-methylbenzene epoxide) imidazo [1,2-a] pyridine-8-base } (2-methoxy ethyl) t-butyl carbamate utilizes TFA to convert with in post processing with obtain 16.9mg (12%) title after purification Compound.

UPLC MS:RT=1.15min;m/z(ES+)489.6[MH+];The MW=488.6. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.46-0.52(2H),0.61-0.68(2H),2.20(3H),2.31(3H),2.79(1H),3.24 (3H),3.36(2H),3.48-3.56(2H),6.08(1H),6.17(1H),6.75(1H),6.79-6.88(1H),7.27 (1H),7.33-7.42(3H),7.45(1H),7.60(1H),8.26(1H).

Embodiment 172a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(5-fluoro-2-methylbenzene epoxide) Imidazo [1,2-a] pyridine-8-base } (2-methoxy ethyl) t-butyl carbamate

{ the 6-in the way of embodiment 161a is similar, 163mg (300 μm ol) prepared according to INTERMEDIATES Example 169b Bromo-3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2-methoxy ethyl) ammonia Base t-butyl formate utilizes 5-fluoro-2-methylbenzene phenol to convert to obtain thick title compound after evaporation, and it is directly used in rear one Step is without being further purified.

UPLC MS:RT=1.26min;m/z(ES+)589.7[MH+];The MW=588.7. required

Embodiment 173 N-cyclopropyl-4-{6-(2,3-difluorobenzene epoxide)-8-[(2-methoxy ethyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

{ 3-[the 4-in the way of embodiment 161 is similar, 163mg (275 μm ol) prepared according to INTERMEDIATES Example 173a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(2,3-difluorobenzene epoxide) imidazo [1,2-a] pyridine-8-base } (2-first Epoxide ethyl) t-butyl carbamate utilizes TFA to convert with in post processing with obtain 10.6mg (7.5%) title compound after purification Thing.

UPLC MS:RT=1.14min;m/z(ES+)493.5[MH+];The MW=492.5. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.45-0.52(2H),0.61-0.69(2H),2.33(3H),2.79(1H),3.24(3H),3.36 (2H),3.48-3.55(2H),6.18(1H),6.24(1H),6.95(1H),7.06-7.20(2H),7.32-7.38(1H), 7.39-7.45(2H),7.63-7.68(2H),8.27(1H)

Embodiment 173a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(2,3-difluorobenzene epoxide) miaow Azoles also [1,2-a] pyridine-8-base } (2-methoxy ethyl) t-butyl carbamate

{ the 6-in the way of embodiment 168a is similar, 163mg (300 μm ol) prepared according to INTERMEDIATES Example 169b Bromo-3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2-methoxy ethyl) ammonia Base t-butyl formate utilizes 2, and 3-difluorophenol converts to obtain thick title compound after evaporation, and it is directly used in later step Without being further purified.

UPLC MS:RT=1.24min;m/z(ES+)593.7[MH+];The MW=592.7. required

Embodiment 174 N-cyclopropyl-4-{6-(5-fluoro-2-hydroxy benzoyl)-8-[(2-methoxy ethyl) amino] Imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

{ 3-[the 4-in the way of embodiment 161 is similar, 260mg (431 μm ol) prepared according to INTERMEDIATES Example 174a (cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(5-fluoro-2-hydroxy benzoyl) imidazo [1,2-a] pyridine-8-base } (2-methoxy ethyl) t-butyl carbamate utilizes TFA to convert with in post processing with to obtain 184mg (85%) after purification titled Compound.

UPLC MS:RT=1.18min;m/z(ES+)503.6[MH+];The MW=502.6. required¹H-NMR(300MHz, DMSO-d6),δ[ppm]=0.46-0.53(2H),0.61-0.69(2H),2.36(3H),2.80(1H),3.26-3.29(3H), 3.42-3.50(2H),3.56-3.63(2H),6.23(1H),6.62-6.67(1H),7.23-7.33(3H),7.41-7.47 (1H),7.48-7.53(2H),7.73(1H),8.32(1H),8.47(1H)

Embodiment 174a { 3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-6-(5-fluoro-2-(2-hydroxybenzoyl) Base) imidazo [1,2-a] pyridine-8-base } (2-methoxy ethyl) t-butyl carbamate

{ the 6-in the way of embodiment 161a is similar, 300mg (552 μm ol) prepared according to INTERMEDIATES Example 169b Bromo-3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl] imidazo [1,2-a] pyridine-8-base } (2-methoxy ethyl) ammonia Base t-butyl formate utilizes (5-fluoro-2-hydroxyphenyl) boric acid to convert to obtain 260mg (78%) title compound after post processing Thing.

UPLC MS:RT=1.28min;m/z(ES+)603.7[MH+];The MW=602.7. required

Embodiment 175 N-cyclopropyl-4-{6-(5-fluoro-2-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

The N-ring third in the way of embodiment 129 is similar, 17mg (31 μm ol) prepared according to INTERMEDIATES Example 175a Base-4-{6-(5-fluoro-2-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base }-2-methyl benzamide utilizes Boron tribromide to convert with in post processing with obtain 1.7mg (10%) title compound after purification.

UPLC MS:RT=1.08min;m/z(ES+)529.5[MH+];The MW=528.5.5. required¹H-NMR(400MHz, DMSO-d6),Shift[ppm]=0.46-0.52(2H),0.62-0.68(2H),2.29(3H),2.57-2.69(2H),2.79 (1H),3.47(2H),6.11(1H),6.47-6.53(1H),6.77-6.85(1H),6.87-6.95(2H),7.29-7.38 (3H),7.55-7.63(1H),8.27(1H),9.50(1H)

Embodiment 175a N-cyclopropyl-4-{6-(5-fluoro-2-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

The 4-{6-in the way of embodiment 6-1 is similar, 100mg (208 μm ol) prepared according to INTERMEDIATES Example 6-1 Bromo-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N-cyclopropyl-2-methyl benzamide profit Converting with 5-fluoro-2-methoxyphenol to obtain thick title compound after post processing, it is directly used in later step without entering One step purification.

Embodiment 176 N-cyclopropyl-4-{6-(3-fluoro-2-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] Imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

3-fluoro-2-methoxyphenol is utilized to prepare N-cyclopropyl-4-{6-(3-in the way of embodiment 175 is similar with 175a Fluoro-2-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-toluyl Amine is with in post processing with obtain 2.3mg (6%) title compound after purification.

UPLC MS:RT=1.08min;m/z(ES+)529.5[MH+];The MW=528.5.5. required¹H-NMR(400MHz, DMSO-d6),Shift[ppm]=0.45-0.52(2H),0.61-0.69(2H),2.28(3H),2.57-2.69(2H),2.79 (1H),3.47(2H),6.11(1H),6.42-6.54(1H),6.70-6.86(1H),6.86-6.93(2H),7.29-7.38 (3H),7.57-7.61(1H),8.27(1H),9.50(1H)

Embodiment 177 N-cyclopropyl-4-{6-[(5-fluorine pyridin-3-yl) epoxide]-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

The 4-{6-prepared according to INTERMEDIATES Example 6-1 by 96mg (200 μm ol) in the way of embodiment 6-1 is similar is bromo- 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N-cyclopropyl-2-methyl benzamide utilizes 5- Fluorine pyridine-3-alcohol converts with in post processing with obtain 9mg (9%) title compound after purification.

UPLC MS:RT=1.13min;m/z(ES+)514.5[MH+];The MW=513.5.5. required¹H-NMR(300MHz, DMSO-d6),Shift[ppm]=0.49(2H),0.65(2H),2.33(3H),2.56-2.68(2H),2.79(1H),3.42- 3.51(2H),6.16(1H),6.59(1H),7.32-7.39(1H),7.40-7.55(3H),7.65(1H),7.74(1H), 8.23-8.32(3H)

Embodiment 178 N-cyclopropyl-4-{6-[(5-fluoro-6-methoxypyridine-3-base) epoxide]-8-[(3,3,3-trifluoro Propyl group) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide

The 4-{6-prepared according to INTERMEDIATES Example 6-1 by 96mg (200 μm ol) in the way of embodiment 6-1 is similar is bromo- 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N-cyclopropyl-2-methyl benzamide utilizes 5- Fluoro-6-methoxypyridine-3-alcohol converts with in post processing with obtain 15mg (15%) title compound after purification.

UPLC MS:RT=1.21min;m/z(ES+)544.5[MH+];The MW=543.5.5. required¹H-NMR(300MHz, DMSO-d6),Shift[ppm]=0.44-0.53(2H),0.60-0.69(2H),2.32(3H),2.56-2.71(2H),2.79 (1H),3.45(2H),3.88(3H),6.12(1H),6.57(1H),7.32-7.38(1H),7.39-7.46(2H),7.56 (1H),7.62(1H),7.70(1H),7.87(1H),8.29(1H)

The pharmaceutical composition of the compound of the present invention

The invention still further relates to the pharmaceutical composition of the compound comprising one or more present invention.These compositionss can be used Desired pharmacotoxicological effect is realized by being administered to patient in need.For the purposes of the present invention, patient is to need to control Treat specified disease situation or the mammal including people of disease.Therefore, the present invention includes such pharmaceutical composition, its Comprise the compound or its salt of the present invention of pharmaceutically acceptable carrier and pharmacy effective dose.Pharmaceutically acceptable carrier is preferably Such carrier, its under the concentration consistent with the effective active of active component to patient's relative nontoxic and harmless, thus by institute State any side effect that carrier causes and will not destroy the beneficial effect of described active component.The compound of pharmacy effective dose is preferably The specified disease situation treated is produced result or produces the amount of impact.Can use include i.e. releasing, slow release and timing Delivery formulations, can by the compound of the present invention and pharmacy well known in the art at interior any effective conventional dosage unit forms The carrier accepted is administered the most as follows: oral, parenteral, locally, nasal cavity, eye (ophthalmically), eye (optically), Sublingual, rectum, vagina administration etc..

For oral administration, described compound can be formulated as solid or liquid preparation, such as capsule, pill, sheet Agent, containing lozenge (troche), lozenge (lozenge), melten gel agent (melt), powder, solution, suspensoid or Emulsion, and can To prepare according to the method for preparing pharmaceutical composition known in the art.Solid unit dosage form can be capsule, its Can be common hard capsule or soft capsule gelatine type, comprise such as surfactant, lubricant and inert filler such as breast Sugar, sucrose, calcium phosphate and corn starch.

In another embodiment, can be by the compound of the present invention and conventional tablet bases (such as lactose, sucrose and jade Rice starch) together and it is pressed into tablet with following combinations of substances: binding agent, such as arabic gum, corn starch or gelatin；For After adjunctive administration, described tablet decomposes and the disintegrating agent of dissolution, such as potato starch, alginic acid, corn starch and guar gum, west Tragacanth, arabic gum；For improving the mobility of tablet granulation and preventing tablet material from adhering to tablet mould and drift The lubricant on surface, such as Talcum, stearic acid or magnesium stearate, calcium stearate or zinc stearate；And it is used for improving described The organoleptic properties of tablet also makes dyestuff, coloring agent and the flavoring agent that they are easier to be accepted by patients, such as Oleum menthae, wintergreen oil Or cherry essence.Suitable excipient for oral liquid dosage forms includes dicalcium phosphate and diluent such as water and alcohol (such as Ethanol, benzyl alcohol and polyvinyl alcohol), add or without pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.Permissible There are other materials various as coating or for changing the physical form of dosage unit.Such as can use Lac, sugar or two Person is by tablet, pill or capsule coating.

Dispersible powder and granule are suitable for preparing aqueous suspension.They provide with dispersant or wetting agent, Suspending agent and the active component of one or more preservative mixing.Suitably dispersant or wetting agent and the example of suspending agent Be mentioned above those.Other excipient, such as those described above sweeting agent, flavoring agent and coloring can also be there is Agent.

The pharmaceutical composition of the present invention can also be the form of oil in water emulsion.Oil phase can be vegetable oil such as liquid stone Wax, or the mixture of vegetable oil.Suitably emulsifying agent can be (1) naturally occurring natural gum, such as Radix Acaciae senegalis and west Tragacanth, (2) naturally occurring phospholipid, such as soybean phospholipid and lecithin, (3) derived from fatty acid and the ester of hexitan or The condensation product of partial ester, such as dehydrated sorbitol mono-fatty acid ester, (4) described partial ester and oxirane, such as polyoxyethylene mountain Pears sugar alcohol acid anhydride monoleate.Described Emulsion can also comprise sweeting agent and flavoring agent.

Can by described active component is suspended in vegetable oil such as Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois or Person is suspended in mineral oil such as liquid paraffin and prepares Oil suspensions.Described Oil suspensions can comprise thickening agent, example Such as Cera Flava, hard paraffin or spermol.Described suspensoid can also comprise one or more preservative, such as P-hydroxybenzoic acid Ethyl ester or P-hydroxybenzoic acid n-propyl；One or more coloring agent；One or more flavoring agents；And one or more sweet tastes Agent, such as sucrose or saccharin.

Can be with sweeting agent such as glycerol, propylene glycol, Sorbitol or sucrose syrup blend agent and elixir.This kind of preparation also may be used To comprise demulcent and preservative (such as methyl hydroxybenzoate and propylparaben) and flavoring agent and coloring agent.

The compound of the present invention can also be carried out parenteral with the injectable dosage of described compound, the most subcutaneous, Intravenous, ophthalmic, intrasynovial, intramuscular or Intraperitoneal medication, described injectable dosage preferably has the physiology of pharmaceutical carrier In acceptable diluent, described pharmaceutical carrier can be the mixture of sterile liquid or liquid, such as water, saline, dextrose Aqueous solution and relevant sugar juice, alcohol such as ethanol, isopropanol or hexadecanol, glycol such as propylene glycol or Polyethylene Glycol, glycerol ketals Such as 2,2-dimethyl-1,1-dioxolanes-4-methanol, ether such as PEG 400, oil, fatty acid, fatty acid ester or fatty acid Glyceride or acetylizad fatty glyceride, add or without pharmaceutically acceptable surfactant such as soap or decontamination Agent, suspending agent such as pectin, carbomer, methylcellulose, hydroxypropyl methylcellulose or carboxymethyl cellulose, or emulsifying agent and Other pharmaceutical auxiliaries.

The example of the oil that may be used for the parenteral administration of the present invention is those of oil, animal, plant or synthesis source Oil, such as Oleum Arachidis hypogaeae semen, soybean oil, Oleum sesami, Oleum Gossypii semen, Semen Maydis oil, olive oil, vaseline oil and mineral oil.Suitably fat Acid includes oleic acid, stearic acid, isostearic acid and myristic acid.Suitably fatty acid ester is that such as ethyl oleate and myristic acid are different Propyl ester.Suitably soap includes that fatty acid alkali metal salt, ammonium salt and triethanolamine salt, suitable detergent include cationic soil release Agent, such as dimethyl dialkyl ammonium halide, alkylpyridinium halides and alkyl amine acetate；Anionic detergent, such as alkyl sulphur Hydrochlorate, arylsulphonate and alkene sulfonate, alkyl sulfate and alkyl sulfo succinate, olefin sulphates and alkene sulfo group Succinate, ether sulfate and sulfosuccinates and monoglyceride sulfates and monoglyceride 2-Sulfosuccinic acid Salt；Non-ionic detergent, such as fatty amine oxide, fatty acid alkanol amides and poly-(oxyethylene-oxypropylene), epoxy second Alkyl copolymer or epoxy propane copolymer；And both sexes detergent, such as alkyl-Beta-alanine salt and 2-alkyl imidazoline season Ammonium salt, and mixture.

The parenteral composition of the present invention would generally comprise the described active component of about 0.5-about 25 weight % in the solution. Can also advantageously use preservative and buffer agent.In order to minimize or eliminate the stimulation to injection site, this based composition can To comprise nonionic surfactant, it has the hydrophil lipophil balance (HLB) of preferably from about 12-about 17.Surface in this kind of preparation The amount of activating agent is preferably from about 5-about 15 weight %.Described surfactant can be the one-component with above HLB, or It it is the mixture of two or more components with desired HLB.

Example for the surfactant of parenteral administration is polyethylene sorbitan fatty esters of gallic acid, such as, be dehydrated Sorbitol monooleate, and the high molecular weight adducts of oxirane and hydrophobic base, described hydrophobic base is by ring Ethylene Oxide and propylene glycol condensation are formed.

Described pharmaceutical composition can be the form of Injectable sterile aqueous suspension.Can use according to known method Following material this kind of suspensoid of preparation: suitable dispersant or wetting agent and suspending agent, such as sodium carboxymethyl cellulose, methyl Cellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragakanta and Radix Acaciae senegalis；Dispersant or moistening The condensation product such as polyoxyethylene 8 stearate of agent, its phospholipid that can be naturally-occurring such as lecithin, epoxyalkane and fatty acid Ester, condensation product such as the heptadecaethylene oxycetanol of oxirane and long-chain fatty alcohol, oxirane and derived from fatty acid With the condensation product such as polyoxyethylene 80 sorbitan monooleate of the partial ester of hexitol, or oxirane with derived from fatty acid and The condensation product of the partial ester of hexitan such as polyethylene sorbitan monoleate.

Sterile injectable preparation can also is that the Injectable sterile in the acceptable diluent of nontoxic parenteral or solvent Solution or suspension.The diluent that can use and solvent are such as water, Ringer's solution, isotonic sodium chloride solution and isotonic Portugal Grape sugar juice.Additionally, aseptic fixed oil is conventionally used as solvent or suspension media.For this purpose, can use appoint The fixed oil what is gentle, including monoglyceride or the Diglyceride of synthesis.Additionally, the fatty acid of such as oleic acid is permissible For preparing injectable thing.

The compositions of the present invention can also be administered for the form of the suppository of the rectally of medicine.Can pass through will Medicine mixes with suitable non-irritating excipient and prepares these compositionss, described excipient be at normal temperatures solid still For liquid and melt the most in the rectum to discharge described medicine under rectal temperature.This kind of material such as cocoa butter and poly-second two Alcohol.

Another kind of preparation for the method for the present invention uses transdermal delivery device (" patch ").This kind of transdermal patch is permissible It is used for providing the continuously or discontinuously input of the compound of the present invention of controlled amounts.For delivering the structure of the transdermal patch of medicament With use be well known in the art (see, e.g. on June 11st, 1991 authorize U.S. Patent No. 5,023,252, it is quoted Add herein).This kind of patch can be configured to for continuously, pulsed or on-demand delivery medicament.

Controlled release preparation for parenteral includes liposome microsphere known in the art, polymer microballoon and polymer Gel preparation.

May need or must pass through mechanical delivery device described pharmaceutical composition is delivered to patient.For delivering medicament The structure of mechanical delivery device and use be well known in the art.The direct technology that medicine is such as administered directly to brain is usual Relate to the ventricular system that drug delivery tube is inserted patient to walk around blood brain barrier.For medicament being transported to the specific of health A kind of such implanted delivery system of anatomical area is described in the U.S. Patent No. 5,011 authorized on April 30th, 1991, No. 472.

The compositions of the present invention or can also optionally comprise other routines of commonly referred to carrier or diluent Pharmaceutically acceptable formulation ingredients.The conventional method that this based composition is prepared as suitable dosage form can be used.This constituents Including being described in below with reference to those in document with method, described list of references all quotes addition herein: Powell, M.F.et al.,"Compendium of Excipients for Parenteral Formulations"PDA Journal of Pharmaceutical Science& Technology1998,52(5),238-311;Strickley,R.G"Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1"PDA Journal of Pharmaceutical Science&Technology1999,53(6),324- 349;and Nema,S.et al.,"Excipients and Their Use in Injectable Products"PDA Journal of Pharmaceutical Science & Technology1997,51(4),166-171.

May be used for described compositions being formulated as expecting that the common drug composition of route of administration includes time suitably:

Acidulant (example includes but not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid)；

Basifier (example include but not limited to ammonia, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, Sodium carbonate, sodium hydroxide, triethanolamine (triethanolamine), triethanolamine (trolamine))；

Adsorbent (example includes but not limited to Powderd cellulose and activated carbon)；

(example includes but not limited to carbon dioxide, CCl to aerosol propellant₂F₂、F₂ClC-CClF₂And CClF₃)；

Drive air agent (air displacement agents) (example includes but not limited to nitrogen and argon)；

Antifungal preservative (example include but not limited to benzoic acid, butoben, ethyl hydroxybenzoate, methyl hydroxybenzoate, Propylparaben, sodium benzoate)；

(example includes but not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, trichlorine to anti-microbial preservative The tert-butyl alcohol, phenol, phenethanol, phenylmercuric nitrate and thimerosal)；

Antioxidant (example include but not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, Hypophosphorous acid, thioglycerol, propylgallate, sodium ascorbate, sodium sulfite, rongalite, pyrosulfurous acid Sodium)；

Binding material (example include but not limited to block polymer, natural and synthetic rubber, polyacrylate, polyurethane, Silicone, polysiloxanes and SB)；

(example includes but not limited to potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous citric acid sodium and Fructus Citri Limoniae to buffer agent Acid sodium dihydrate)；

(example includes but not limited to syrup acacia, aromatic syrup, aromatic elixir, cherry syrup, cocoa to carrier Syrup, orange syrup, syrup, Semen Maydis oil, mineral oil, Oleum Arachidis hypogaeae semen, Oleum sesami, antibacterial sodium chloride injection and antibacterial injection With water)；

Chelating agen (example includes but not limited to edetate sodium and edetic acid)；

Coloring agent (example include but not limited to FD&C Red No.3, FD&C Red No.20, FD&C Yellow No.6, FD&C Blue No.2, D&C Green No.5, D&C Orange No.5, D&C Red No.8, caramel and iron oxide red)；

Clarifier (example includes but not limited to bentonite)；

(example includes but not limited to arabic gum, cetomacrogol, spermol, glyceryl monostearate, ovum phosphorus to emulsifying agent Fat, dehydrated sorbitol mono-fatty acid ester, polyoxyethylene 50 monostearate)；

Become capsule (example includes but not limited to gelatin and cellulose acetate-phthalate)；

Spice (example includes but not limited to Oleum Anisi Stellati, Oleum Cinnamomi, cocoa, menthol, orange oil, Oleum menthae and vanillin)；

Wetting agent (example includes but not limited to glycerol, propylene glycol and Sorbitol)；

Grinding agent (example includes but not limited to mineral oil and glycerol)；

(example includes but not limited to Oleum Arachidis hypogaeae semen (arachis oil), mineral oil, olive oil, Oleum Arachidis hypogaeae semen (peanut to oil Oil), Oleum sesami and vegetable oil)；

(example includes but not limited to lanoline, hydrophilic ointment, polyethylene glycol ointment, vaseline oil, hydrophilic all to ointment base Intellectual circle's oil, simple ointment, yellow ointment and cold cream)；

(example includes but not limited to monohydroxy or polyhydroxy alcohols, monovalence or multivalence alcohol to penetration enhancers (transdermal delivery) Class, saturated or unsaturated fatty acids alcohols, saturated or unsaturated fatty acids esters, saturated or unsaturated dicarboxylic class, quintessence oil class, phospholipid Acyl derivative, cephalin, terpenoid, amide-type, ethers, ketone and ureas)；

Plasticizer (example includes but not limited to diethyl phthalate and glycerol)；

(example includes but not limited to ethanol, Semen Maydis oil, Oleum Gossypii semen, glycerol, isopropanol, mineral oil, oleic acid, Semen arachidis hypogaeae to solvent Oil, purified water, water for injection, sterile water for injection and Sterile Water for Irrigation)；

Sclerosing agent (example include but not limited to spermol, cetyl esters wax, microwax, paraffin, stearyl alcohol, white beeswax and Cera Flava)；

Suppository base (example includes but not limited to cocoa butter and Polyethylene Glycol (mixture))；

Surfactant (example include but not limited to benzalkonium chloride, nonoxinol 10, octoxinol 9, polyoxyethylene sorbitan monoleate, Sodium lauryl sulphate and sorbitan monopalmitate)；

(example includes but not limited to agar, bentonite, carbomer, sodium carboxymethyl cellulose, hydroxy ethyl fiber to suspending agent Element, hydroxypropyl cellulose, hydroxypropyl methylcellulose, Kaolin, methylcellulose, Tragacanth and aluminium-magnesium silicate)；

(example includes but not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, Pyrusussuriensis to sweeting agent Sugar alcohol and sucrose)；

Tablet antitack agent (example includes but not limited to magnesium stearate and Talcum)；

(example includes but not limited to that arabic gum, alginic acid, sodium carboxymethyl cellulose, compressible sugar, ethyl are fine to tablet binding agent Dimension element, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone and pregelatinized Starch)；

(example includes but not limited to that calcium hydrogen phosphate, Kaolin, lactose, mannitol, crystallite are fine for tablet and capsule diluent Dimension element, Powderd cellulose, winnofil, sodium carbonate, sodium phosphate, Sorbitol and starch)；

(example includes but not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl in tablet coating agent Methylcellulose, methylcellulose, ethyl cellulose, cellulose acetate-phthalate and Lac)；

Tablet direct pressing excipient (example includes but not limited to calcium hydrogen phosphate)；

(example includes but not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline Cellulose, Po Lakelin potassium to tablet disintegrant (polacrillin potassium), crospolyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch)；

Tablet fluidizer (example includes but not limited to silica sol, corn starch and Talcum)；

(example includes but not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and stearic acid to tablet lubricants Zinc)；

Tablets/capsules agent opacifier (example includes but not limited to titanium dioxide)；

Tablet polishing agent (example includes but not limited to Brazil wax and white beeswax)；

Thickening agent (example includes but not limited to Cera Flava, spermol and paraffin)；

Tonicity agents (example includes but not limited to dextrose and sodium chloride)；

(example includes but not limited to alginic acid, bentonite, carbomer, sodium carboxymethyl cellulose, Methyl cellulose to viscosity-increasing agent Element, polyvinylpyrrolidone, sodium alginate and Tragacanth)；And

(example includes but not limited to heptadecaethylene oxycetanol, lecithin, sorbitol monooleate, gathers wetting agent Oxygen ethylene sorbitol monooleate and Myrj 45).

The pharmaceutical composition of the present invention can be exemplified below:

Aseptic IV solution: sterile water for injection can be used to prepare the 5mg/mL solution expecting compound of the present invention, And regulate pH if desired.With aseptic 5% dextrose, described solution is diluted to 1-2mg/mL be used for being administered, and at about 60min Interior with IV administered by infusion.

The lyophilized powder being administered for IV: the expectation compound of the present invention of (i) 100-1000mg lyophilized powder form can be used, (ii) 32-327mg/mL sodium citrate, and (iii) 300-3000mg Dextran 40 prepares sterile preparation.Use aseptic injection The concentration redissolved by said preparation to 10-20mg/mL with saline or 5% dextrose, then dilutes further with saline or 5% dextrose To 0.2-0.4mg/mL, and IV injects or IV administered by infusion in 15-60 minute.

Intramuscular injection suspensoid: following solution or suspensoid can be prepared for intramuscular injection:

The compound of the desired water-insoluble present invention of 50mg/mL

5mg/mL sodium carboxymethyl cellulose

4mg/mL TWEEN80

9mg/mL sodium chloride

9mg/mL benzyl alcohol

Hard-shell capsule agent: by by 100mg divided active component, 150mg lactose, 50mg cellulose and 6mg magnesium stearate Substantial amounts of unit capsules prepared by the two-piece type hard galantine capsule of filling standard.

Gelseal: prepare active component mixing in digestible oil such as soybean oil, Oleum Gossypii semen or olive oil Compound, and it is injected into, by positive displacement pump, the soft gelatin glue that the gelatin of fusing comprises active component described in 100mg with formation Capsule.Capsule is washed and is dried.Described active component can be dissolved in the mixture of Polyethylene Glycol, glycerol and Sorbitol with system Standby water miscibility medicinal mixture.

Tablet: it is prepared by a conventional method a large amount of tablet, thus dosage unit comprises 100mg active component, 0.2mg colloid Silicon dioxide, 5mg magnesium stearate, 275mg microcrystalline Cellulose, 11mg starch and 98.8mg lactose.Suitable aqueous and non-aqueous Coating can be used to increase palatability, improve outward appearance and stability or postpone to absorb.

Immediate-release tablet formulations/capsule: these are the solid oral dosage forms prepared by conventional method and new method.It is not required to use water And by these unit oral, for dissolution at once and the delivery of medicine.Described active component is blended in comprise the most sugared, bright In the liquid of the composition of glue, pectin and sweeting agent.These liquid curings are made to be solid by lyophilization and solid state extraction techniques Tablet or caplet.Can be by tabletting together with sugared with viscoelasticity and thermoelastic for medical compounds and polymer or effervescence component with system The standby porous matrix of rapid release under conditions of need not water.

Combined therapy

The compound of the present invention can be administered as unique medicament or give with one or more other pharmaceutical agent combinations Medicine, wherein said combination will not cause unacceptable ill effect.The invention still further relates to this kind of combination.For example, it is possible to incite somebody to action this Compound and the known anti-excess proliferative disease of invention or the medicament of other indications etc. and with their mixture and Combination is combined.Other indication medicaments include but not limited to anti-angiogenic agent, mitotic inhibitor, alkylating agent, resist Metabolism agent, DNA-embed antibiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme inhibitor, topoisomerase enzyme level Agent, biological response modifier or hormone antagonist.

Other medicament can be 131I-chTNT, 1: PN: WO02056903 PAGE: 25 claimed protein, abiraterone, aclarubicin, aldesleukin, A Lun Pearl monoclonal antibody, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, Anastrozole, arglabin, three oxidations two Arsenic, asparaginase, azacitidine, basiliximab, BAY80-6946, BAY1000394, BAY86-9766 (RDEA119), Belotecan, bendamustine, Avastin, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, cloth House Rayleigh, busulfan, Cabazitaxel (cabazitaxel), calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, Carmustine, block appropriate rope monoclonal antibody, celecoxib, celmoleukin, Cetuximab, chlorambucil, chlormadinone, chlormethine, Cisplatin, cladribine, clodronic acid, clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytosine arabinoside, Dacca bar Piperazine, actinomycin D, darbepoetin α, Dasatinib, daunorubicin, decitabine, Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2, denileukin-toxin is even Connect thing, Shu Dankang, deslorelin, dibrospidium chloride, docetaxel, doxifluridine, doxorubicin, doxorubicin+estrone, According to storehouse pearl monoclonal antibody, edrecolomab, elliptinium acetate, eltrombopag olamine, Endostatin, enocitabine, epirubicin, epitiostanol, Epoetin Alfa, epoetin beta, eptaplatin, eribulin, Erlotinib, estradiol, estramustine, etoposide, according to dimension Mo Si, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, fotemustine, fluorine dimension department Group, Ganite (Fujisawa)., ganirelix, gefitinib, gemcitabine, lucky trastuzumab, glutoxim, goserelin, Maxamine, Histrelin, hydroxyurea, I-125 kind (seed), ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, she replaces by horse Buddhist nun, miaow quinoline not moral, an improsulfan, interferon-alpha, interferon-β, IFN-γ, her wooden monoclonal antibody, irinotecan, ipsapirone, orchid Auspicious peptide, Lapatinib, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, lisuride, Lip river Platinum, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine, first ammonia butterfly Purine, methoxsalen, methylamino ketone valeric acid (Methyl aminolevulinate), methyltestosterone, rice lumbering peptide, miltefosine, Miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, how Draw shore, AMN107, nilutamide, Buddhist nun's trastuzumab, nimustine, C-283, method wood monoclonal antibody, omeprazole, Austria difficult to understand Puri interleukin, oxaliplatin, p53 gene therapy, paclitaxel, Pa Lifuming, palladium-103 kinds, pamidronic acid, Victibix, handkerchief Azoles handkerchief Buddhist nun, pegaspargase, PEG-epoetin beta (methoxyl group PEG-epoetin beta), Pei Feisi booth, PEG Interferon Alpha-2b, Pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, Picibanil, pirarubicin, Pu Lesha Good fortune, plicamycin, poliglusam, polyestradiol phosphate, polysaccharide-K, porfimer sodium, Pralatrexate, prednimustine, the third kappa Hydrazine, quinagolide, raloxifene, Raltitrexed, Ranimustine, razoxane, regorafenib, risedronic acid, rituximab list Anti-, sieve meter new, romiplostim, Sargramostim, western general Ruse T, sizofiran, sobuzoxane, CMNa (sodium Glycididazole), Sorafenib, streptozocin, Sutent, talaporfin, Tamibarotene, tamoxifen, Ta Suona Bright, teceleukin, ftorafur, ftorafur+gimeracil+oteracil, temoporfin, temozolomide, CCI-779, for Buddhist nun Pool glycosides, testosterone, tetrofosmin, Thalidomide, phosphinothioylidynetrisaziridine, thymalfasin, thioguanine, torr pearl monoclonal antibody, hycamtin, Tuo Rui meter Sweet smell, tositumomab, ET-743, Herceptin, treosulfan, retinoic acid, trilostane, triptorelin, trofosfamide, color Propylhomoserin, ubenimex, valrubicin, ZD6474, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, Vinflunine, vinorelbine, SAHA, vorozole, 90Y glass microsphere, zinostatin, Zinostatin stimalamer, azoles carry out phosphine Acid, zorubicin.

Preferably, other medicament is selected from: afinitor, aldesleukin, alendronic Acid, alpha-interferon (alfaferone), alitretinoin, allopurinol, aliopurinol in ailopurinol sodium for injection (aloprim), PalonosetronHydrochloride injection (aloxi), altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, Anastrozole, dolasetron sheet (anzmet), Aranesp injection (aranesp), arglabin, arsenic trioxide, A Nuoxin, 5-azacytidine, azathioprine, BCG or Tice BCG, Beta spit of fland, betamethasone acetate, betamethasone sodium phosphate, bexarotene, Bleomycin Sulphate, bromine urine Glycosides, bortezomib, busulfan, calcitonin, alemtuzumab (campath), capecitabine, carboplatin, Casodex, cefesone, west Not interleukin, daunorubicin, chlorambucil, cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide, cytosine arabinoside, Dacarbazine, actinomycin D, daunorubicin liposome, dexamethasone, dexamethasone sodium phosphate, estradiol valerate, Buddhist nun be situated between in vain Element-toxin junctional complex, medrat, deslorelin, dexrazoxane, diethylstilbestrol, Fluconazole, docetaxel, deoxidation Floxuridine, doxorubicin, dronabinol, DW-166HC, leuprorelin acetate (eligard), rasburicase injection (elitek), epirubicin hydrochloride injection (ellence), aprepitant capsule (emend), epirubicin, Epoetin Alfa, Erythropoietin preparation, eptaplatin, levamisole, Estrace, estradiol, estramustine phosphate sodium, alkynes are female Alcohol, amifostine, etidronic acid, etoposide injection, etoposide, fadrozole, farston, filgrastim, finasteride, Filgrastim, floxuridine, fluconazol, fludarabine, monophosphate floxuridine, 5-fluorouracil (5-FU), fluoxymesterone, Flutamide, formestane, fosteabine, fotemustine, fulvestrant, gamma globulin (gammagard), gemcitabine, Ji are appropriate Pearl monoclonal antibody, imatinib mesylate, Gliadel, goserelin, Granisetron Hydrochloride, histrelin and U.S. are new, hydrogenation can Pine (hydrocortone), red hydroxynonyl adenine (eyrthro-hydroxynonyladenine), hydroxyurea, for her Not monoclonal antibody, idarubicin, ifosfamide, interferon-alpha, α 2 interferon, α-2A interferon, α-2B interferon, α-n1 interferon, α-n3 interferon, interferon-β, γ-1a interferon, interleukin-2, Intron A, Iressa, irinotecan, Kytril, sulphuric acid are fragrant Mushroom polysaccharide, letrozole, folinic acid, leuproside, leuprolide acetate, levamisole, l-leucovorin calcium salt (levofolinic Acid calcium salt), levothyroxine sodium, levothyroxine sodium preparation, lomustine, lonidamine, dronabinol, Chlormethine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estriol tablet, Ismipur, U.S. department Sodium, methotrexate, Metvix, miltefosine, minocycline, ametycin, mitotane, mitoxantrone, Modrenal, Myocet, nedaplatin, filgrastim (neulasta), rHuIL-11 (neumega), excellent Bao Jin, nilutamide, Nova Obtain scholar, NSC-631570, OCT-43, octreotide, Ondansetron Hydrochloride, orapred, oxaliplatin, paclitaxel, prednisone phosphoric acid Preparation of sodium, pegaspargase, PEG-IFN alpha-2a, pentostatin, Picibanil, pilocarpine hydrochloride, pirarubicin, general card Mycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, recombinant human erythropoiesis Element α, Raltitrexed, RDEA119, Libiee, etidronic acid rhenium-186 (rhenium-186etidronate), Rituximab, sieve Disturb element (roferon-A), romurtide, Shu Lejin, kind peaceful, Sargramostim, semustine, sizofiran, sobuzoxane, prednisolone note Penetrate agent, sparfosic acid, stem cell therapy, streptozocin, strontium chloride 89, levothyroxine sodium, tamoxifen, tamsulosin, Ta Suona Bright, testolactone, taxotere, teceleukin, temozolomide, teniposide, Testosterone Propionate, Testred, thioguanine, Phosphinothioylidynetrisaziridine, thyrotropin, tiludronic acid, hycamtin, toremifene, tositumomab, Herceptin, treosulfan, Retinoic acid, methotrexate (trexall), trimethyl tripolycyanamide, trimetrexate, triptorelin acetate, flutter acid triptorelin, UFT, uridnine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, You Leizuo Fecula injection, Zinostatin stimalamer, ondansetron, ABI-007, acolbifene, gamma interferon 1-b, affinitak, aminopterin, Arzoxifene, A Suolini, atamestane, atrasentan, Sorafenib (BAY43-9006), Avastin, CCI-779, CDC-501, celecoxib, Cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, DSLIM, dutasteride, Ai Te click woods, eflornithine, exatecan, fenretinide, Maxamine, histrelin hydrogel Implant, holmium-166DOTMP, ibandronic acid, IFN-γ, PEG-IFN α-2b (intron-PEG), ipsapirone, spoon Hole hemocyanin, L-651582, Lanreotide, lasofoxifene, libra, lonafarnib, Miproxifene, minodronic acid (minodronate), MS-209, MTP-PE liposome, MX-6, nafarelin, Nemorubicin, Neovastat, Nola Qu Sai, Ao Limeisheng, onco-TCS, osidem, PPX, Pamidronate Disodium, PN-401, QS-21, quazepam, R- 1549, raloxifene, ranpirnase, 13CRA, Satraplatin, seocalcitol, T-138067, Tarceva, 22 carbon Acid and paclitaxel conjugates, α-1 thymosin, tiazofurine, Zarnestra, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar, vapreotide, vatalanib, Verteporfin, vinflunine, Z-100 and zoledronic acid or Combinations thereof.

The optional anti-hyper-proliferative medicament that can add described compositions includes but not limited to the 11st edition Merck index (1996) compound listed in the cancer chemotherapeutic drug scheme (quoted and add herein), such as asparaginase, bleomycin, Carboplatin, carmustine, chlorambucil, cisplatin, L-ASP, cyclophosphamide, cytosine arabinoside, dacarbazine, actinomycetes Element D, daunorubicin, doxorubicin (amycin), epirubicin, Epothilones, epothilone derivate, etoposide, 5-fluorine Uracil, altretamine, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, chlormethine, Ismipur, U.S. Department sodium, methotrexate, ametycin, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, he Not former times sweet smell, thioguanine, hycamtin, vinblastine, vincristine and vindesine.

Other anti-hyper-proliferative medicaments that the applicable compositions with the present invention is used together include but not limited to Goodman And Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), Molinoff et al. edits, and McGraw-Hill publishes, the 1225-1287 page, generally acknowledges and be used in (1996) (quoting addition herein) Those compounds of neoplastic disease treatment, such as aminoglutethimide, L-ASP, azathioprine, 5-azacytidine, carat Qu Bin, busulfan, diethylstilbestrol, 2', 2'-difluoro deoxycytidine, docetaxel, red hydroxynonyl adenine, ethinylestradiol, 5-fluorine BrdU, monophosphate floxuridine, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, Interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphono acetyl Base-L-Aspartic acid salt (PALA), plicamycin, semustine, teniposide, Testosterone Propionate, thiotepa, trimethyl melamine Amine, uridnine and vinorelbine.

Other the anti-hyper-proliferative medicaments being suitable for being used together with the compositions of the present invention include but not limited to that other are anticancer Medicament such as Epothilones and derivant thereof, irinotecan, raloxifene and hycamtin.

Can also be by the compound of the present invention and protein for treatment agent combination medicine-feeding.It is suitable for treating cancer or other blood vessels Generate disease and be suitable for and this kind of protein for treatment agent that is used together of the compositions of the present invention include but not limited to interferon (example Such as α, β or IFN-γ), super agonistic monoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin, anti-FAP Antibody, YH-16, lucky trastuzumab, infliximab, Cetuximab, Herceptin, denileukin diftitox, Rituximab, thymosin α1, Avastin, mecasermin, woods mecasermin, oprelvekin, natalizumab, RhMBL, MFE-CP1+ZD-2767-P, ABT-828, ErbB2-specific immunity toxin, SGN-35, MT-103, Lin Feipei, AS- 1402, B43-genistein, the radioimmunotherapy agent of L-19 system, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT- 322, rhCC10, r (m) CRP, MORAb-009, A Weikuming (aviscumine), MDX-1307, Her-2 vaccine, APC- 8024, NGR-hTNF, rhH1.3, IGN-311, Endostatin, volt Lip river former times monoclonal antibody, PRO-1762, come husky wood monoclonal antibody, SGN-40, Pertuzumab, EMD-273063, L19-IL-2 fusion protein, PRX-321, CNTO-328, MDX-214, for adding pool peptide (tigapotide), CAT-3888, draw shellfish pearl monoclonal antibody, launch a particle radiosiotope crosslinking lintuzumab, EM- 1421, HyperAcute vaccine, celmoleukin monoclonal antibody, galiximab, HPV-16-E7, Javelin-carcinoma of prostate, Javelin-melanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004-MelQbG10, WT1 peptide, Ao Gefu monoclonal antibody, method wood difficult to understand Monoclonal antibody, prick calamite monoclonal antibody, the pungent interleukin of shellfish, WX-G250, Albuferon, aflibercept, Shu Dankang, vaccine, CTP- 37, according to husband's monoclonal antibody or 131I-chTNT-1/B.The monoclonal antibody that can be used as protein for treatment agent includes but not limited to that Luo Dan is not anti- CD3, abciximab, edrecolomab, daclizumab, gemtuzumab Ozogamicin Mylotarg CDP 771 (gentuzumab), A Lun pearl monoclonal antibody, for emol list Anti-, Cetuximab, Avastin (bevicizumab), efalizumab, adalimumab, omalizumab, Mo Luodan Anti-CD3, Rituximab, daclizumab, Herceptin, palivizumab, basiliximab and infliximab.

The compound of the present invention can also be (such as Avastin, Mabthera, Erbitux, conspicuous with biopharmaceuticals such as antibody Sai Ting) or recombiant protein combination.

The compound of the present invention can also combine with antiangiogenic agent, such as with Avastin, Ah former times for Buddhist nun, DAST, Recentin, Sorafenib or Sutent combination.Can also be with proteasome inhibitor, mTOR inhibitors, hormone antagonist or steroid Body metabolic enzyme inhibitor combines.

Generally, compound or the combination of compositions use of cytotoxic agent and/or cytostatics with the present invention can be risen To following effect:

(1) compared with any one medicament individually dosed, produce more in terms of reducing tumor growth or even eliminating tumor Good effect,

(2) allow to be administered chemotherapeutic agents with less amount,

(3) providing chemotherapeutic agent, it is well tolerated by the patient, and with single medicament chemotherapy and some combine Viewed in therapy compare, its less harmful pharmacology's complication having,

(4) allow in mammal particularly people, treat broader spectrum of various cancers type,

(5) higher response rate in subject is provided,

(6) compared with standard chemotherapeutic treatment, the longer time-to-live is provided for subject patient,

(7) longer tumor development time is provided, and/or

(8) compared with the known case that the combination of other cancer agents produces antagonistic effect, obtain at least be used alone Effect that medicament is the best and tolerability results.

Make cell to radiosensible method

In a different embodiment of the present invention, the compound of the present invention can be used to make cell quick to radiation Sense.That is, before the radiation treatment of cell, described cell and the unused present invention's are made with the compound treated cells of the present invention When compound carries out any process, the situation of described cell is compared and is easier to DNA damage and cell death.On the one hand, use The compound treated cells of at least one present invention.

Therefore, the present invention also provides for killing the method for cell, wherein by the compound of one or more present invention with conventional X-ray therapy combined administration is in cell.

The present invention also provides for a kind of method making cell be easier to generation cell death, wherein before processing described cell With cell described in the compound treatment of one or more present invention to cause or inducing cell death.On the one hand, with a kind of or After cell described in the compound treatment of the multiple present invention, by least one compound or at least one method or combinations thereof Process described cell to cause DNA damage thus for suppressing Normocellular function or killing described cell.

In one embodiment, by described cell being killed with at least one DNA damage agent process cell.That is, use After the compound treated cells of one or more present invention makes described cell by cell death sensitivity, use at least one DNA damage Agent processes described cell to kill this cell.The DNA damage agent that can be used for the present invention includes but not limited to that chemotherapeutics is (the most suitable Platinum), ionizing radiation (X-ray, ultraviolet radiation), carcinogen and mutagenic agent.

In another embodiment, by processing cell to cause or induced DNA damage is by institute by least one method State cell to kill.This kind of method includes but not limited to: active cell signal transduction path (causes when described approach is activated DNA damage), suppression cell signaling pathway (causing DNA damage when described approach is suppressed) and inducing cell in Biochemical change (wherein said change causes DNA damage).As limiting examples, the DNA in cell can be suppressed to repair Multiple approach, thus stop the reparation of DNA damage and cause the abnormal accumulation of DNA damage in cell.

In one aspect of the invention, before other induction carrying out radiating or carry out causing DNA Damage, it is administered this The compound of invention.In another aspect of this invention, in other induction of the DNA damage that carries out radiating or carry out to cause cell It is administered simultaneously the compound of the present invention.In another aspect of this invention, in other induction of radiation or the DNA damage causing cell The compound of the present invention it is administered immediately after beginning.

On the other hand, described cell is external.In another embodiment, described cell is internal.

As mentioned above, have surprisingly been found that the compound of the present invention effectively suppresses Mps-1, and therefore may be used For treating or prevent the growth of uncontrolled cell, breeding and/or survive, unsuitable cellullar immunologic response or inappropriate The disease of cellular inflammation response, or be attended by the growth of uncontrolled cell, breed and/or survive, unsuitable cell Immunne response or the disease of unsuitable cellular inflammation response, especially, the growth of wherein said uncontrolled cell, propagation And/or survive, unsuitable cellullar immunologic response or unsuitable cellular inflammation response are mediated by Mps-1, such as blood Tumor, solid tumor and/or their transfer, such as leukemia and myelodysplastic syndrome, malignant lymphoma, include cerebroma With brain metastes at interior tumor of head and neck, the breast tumor including non-fire power and small cell lung tumor, gastrointestinal Road tumor, endocrine tumors, breast tumor and other gynecological tumors, including tumor of kidney, tumor of bladder and tumor of prostate Urologic neoplasms, cutaneous tumor and sarcoma and/or their transfer.

Therefore, according on the other hand, the present invention relates to the as described herein and compounds of formula I of definition, or it stands Body isomer, tautomer, N-oxide, hydrate, solvate or salt, the most pharmaceutically acceptable salt, or it Mixture, be used for treating or prevent disease as mentioned above.

Therefore, another special aspect of the present invention be compounds of formula I mentioned above or its stereoisomer, Tautomer, N-oxide, hydrate, solvate or salt, particularly its pharmaceutically acceptable salt, or theirs is mixed Compound purposes in treatment or prevention disease.

Therefore, another special aspect of the present invention be compounds of formula I as described above preparation for treatment or Purposes in prophylactic pharmaceutical composition.

The disease mentioned in first two sections is the growth of uncontrolled cell, breeds and/or survive, unsuitable cellular immunization Response or the disease of unsuitable cellular inflammation response, or be attended by the growth of uncontrolled cell, breed and/or survive, Unsuitable cellullar immunologic response or the disease of unsuitable cellular inflammation response, especially, wherein said uncontrolled carefully Intracellular growth, breeding and/or survive, unsuitable cellullar immunologic response or unsuitable cellular inflammation response are to be mediated by Mps-1 , such as neoplastic hematologic disorder, solid tumor and/or their transfer, such as leukemia and myelodysplastic syndrome, malignant lymphatic Tumor, the tumor of head and neck including cerebroma and brain metastes, the breast including non-fire power and small cell lung tumor Portion's tumor, gastroenteric tumor, endocrine tumors, breast tumor and other gynecological tumors, include tumor of kidney, tumor of bladder and prostatitis Adenoncus tumor is in interior urologic neoplasms, cutaneous tumor and sarcoma and/or their transfer.

As used herein, in the context of the present invention, particularly at " unsuitable cellullar immunologic response or unsuitable Cellular inflammation response " context in, term " unsuitable " be interpreted as preferably representing than normal response more weak or higher also And relevant to the pathology of described disease, cause or cause the response of pathology of described disease.

Preferably, described purposes is the treatment for disease or prevention, and wherein said disease is neoplastic hematologic disorder, solid tumor And/or their transfer.

The method for the treatment of hyperproliferative disorders

The present invention relates to a kind of hyperproliferative disorders using the compounds of this invention and combinations thereof thing treatment mammal Method.Compound can be used to suppress, blocks, reduces, reduces cell proliferation and/or cell division, and/or causes apoptosis. This method includes being administered this of a certain amount of described disease of effective treatment to mammal including people in need Bright compound, or its pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester etc.. Hyperproliferative disorders includes but not limited to psoriasis, keloid and the hypertrophy of other influences skin, benign prostatic hyperplasia (BPH), solid tumor such as breast carcinoma, respiratory cancer, the brain cancer, genital cancer, digestive tract cancer, urinary tract cancer, cancer eye, hepatocarcinoma, skin Skin cancer, head and neck cancer, thyroid carcinoma, parathyroid carcinoma and the transfer of their far-end.These diseases also include lymphoma, sarcoma and Leukemia.

The example of breast carcinoma includes but not limited to that IDC, ILC, ductal carcinoma in situ and original position are the least Leaf cancer.

The example of respiratory tract cancer include but not limited to small cell lung cancer and nonsmall-cell lung cancer and bronchial adenoma and Pleuropulinonary blastoma.

The example of the brain cancer includes but not limited to brain stem and hypothalamic gliomas, cerebellum and cerebral astrocytoma, becomes neural Solencyte tumor, ependymoma and neuroectodermal tumor and pinealoma.

Genital orgnas,male's tumor includes but not limited to carcinoma of prostate and carcinoma of testis.Tumors of female reproductive organ include but not It is limited to carcinoma of endometrium, cervical cancer, ovarian cancer, cancer of vagina and carcinoma vulvae and sarcoma of uterus.

Digestive tract tumor includes but not limited to anus cancer, colon cancer, colorectal carcinoma, the esophageal carcinoma, carcinoma of gallbladder, gastric cancer, pancreas Adenocarcinoma, rectal cancer, carcinoma of small intestine and salivary-gland carcinoma.

Urinary tumor includes but not limited to bladder cancer, carcinoma of penis, renal carcinoma, carcinoma of renal pelvis, carcinoma of ureter, carcinoma of urethra and people Papillary renal carcinoma.

Cancer eye includes but not limited to intraocular melanoma and retinoblastoma.

The example of hepatocarcinoma includes but not limited to hepatocarcinoma (with or without the hepatocarcinoma of fibrolamellar variation), cancer of biliary duct (intrahepatic cholangiocarcinoma) and Combination hepatocyte cholangiocarcinoma cells.

Skin carcinoma include but not limited to squamous cell carcinoma, Kaposi sarcoma, malignant melanoma, Merkel cell skin cancer with And non-melanoma skin carcinoma.

Head and neck cancer includes but not limited to that laryngeal carcinoma, hypopharyngeal cancer, nasopharyngeal carcinoma, oropharynx cancer, lip cancer, oral cancer and squamous epithelial cancer are thin Born of the same parents.Lymphoma includes but not limited to AIDS associated lymphoma, non-Hodgkin lymphoma, cutaneous T cell lymphoma, Hugh Burkitt lymph Tumor, Hodgkin and central nervous system lymphoma.

Sarcoma includes but not limited to soft tissue sarcoma, osteosarcoma, malignant fibrohistiocytoma, lymphosarcoma and band Myosarcoma.

Leukemia includes but not limited to the white blood of acute myeloid leukaemia, acute lymphoblastic leukemia, chronic lymphocytic Disease, chronic myelogenous leukemia and hairy cell leukemia.

These diseases have obtained good sign in the mankind, but are also present in other sucklings with similar etiology and move In thing, and can treat by being administered the pharmaceutical composition of the present invention.

Term " treatment (treating) " or the use of " treatment (treatment) " that presents is mentioned in the whole text are conventional , the such as situation etc. of the disease or disease in order to resist, alleviate, reduce, prevent, improve such as sarcoma.

The method for the treatment of kinases disease

The present invention also provides for the method for treating the relevant disease of kinase activity outer to abnormal mitogen born of the same parents, described Disease includes but not limited to apoplexy, heart failure, hepatomegaly, megalocardia, diabetes, Alzheimer, cystic fibrosis, different Plant the symptom of transplant rejection, septic shock or asthma.

The compound of the present invention of effective dose can be used to treat this kind of disease, mentions including previous Background section Those diseases (such as cancer).However, it is possible to this kind of cancer of the compounds for treating of the present invention and other diseases, and with effect machine Relation between system and/or described kinases with described disease is unrelated.

Phrase " abnormal kinase activity " or " abnormal tyrosine kinase activity " include encoding described kinase whose gene or Any unconventionality expression of the polypeptide of its coding or activity.The example of this kind of abnormal activity includes but not limited to described gene or polypeptide Overexpression；Gene amplification；Produce constitutive activity or highly active kinase activity sudden change；Gene mutation, lack, take Generation, interpolation etc..

The present invention also provides for the method suppressing the outer kinase activity of kinase activity particularly mitogen born of the same parents, and described method includes The compound of the present invention of effective dosage, including its salt, polymorph, metabolite, hydrate, solvate, prodrug (such as Ester) and diastereomeric form.Can be in cell (the most external), or at mammalian subject, in particular for The cell of the human patients for the treatment of suppresses kinase activity.

The method for the treatment of angiogenesis disease

The present invention also provides for treating the disease relevant to excessive and/or abnormal angiogenesis and the method for disease.

Organism is probably harmful by inappropriate expression and the unconventionality expression of angiogenesis.Many pathological state nothing to do withs (extraneous) growth of blood vessel is correlated with.These include that such as diabetic retinopathy, ischemic retinal vein block And retinopathy of prematurity [Aiello et al.New Engl.J.Med.1994,331,1480;Peer et Al.Lab.Invest.1995,72,638], age-related macular degeneration [AMD；See Lopez et Al.Invest.Opththalmol.Vis.Sci.1996,37,855], neovascular glaucoma, psoriasis, retrolental After hypertrophy disease, fibrohemangioma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, blood vessel transplantation the narrowest Narrow etc..Additionally, the blood supply relevant to cancerous tissue and tumor tissues increases promotes growth, cause quick tumor to increase and turn Move.Additionally, neovascularity and the vasculolymphatic cancerous tumor cell (renegade cell) that is grown to provide the approach of leaving in tumor, promote Enter transfer and cause cancer to spread.Therefore, the compound of the present invention can be used to treatment and/or prevents any blood mentioned above Pipe generates disease, and its mode is for such as suppressing and/or reducing vascularization；Suppress, block, reduce, reduce endothelial cell proliferation Or the other types relevant to angiogenesis, and cause cell death or the apoptosis of this kind of cell.

Dosage and administration

The standard that can be used for treating the compound of hyperproliferative disorders and angiogenesis disease is evaluated based on known being used for Laboratory technique, by standard toxotest and by for determining the treatment to disease condition mentioned above in mammal Standard pharmacological measure, and by these results are carried out with the result for the known drug for the treatment of these disease conditions Relatively, can readily determine that the effective dose of the compound of the present invention for treating every kind of desired indication.At these In the treatment of one of disease condition be administered active component amount can great changes will take place according to following considering: spy used Determine compound and dosage unit, administering mode, the course for the treatment of, the age of subject patient and sex and the disease shape treated The nature and extent of condition.

The total amount of active component to be administered is typically about 0.001mg/kg-about 200mg/kg body weight/day, and preferably from about 0.01mg/kg-about 20mg/kg body weight/day.Clinically can dosage regimen be every day the dosed administration of to three time extremely Every surrounding dosed administration once.Additionally, " withdrawal time " (wherein not giving Patient drug within certain a period of time) is for pharmacology The whole machine balancing learned between effect and toleration is probably favourable.Unit dose can comprise about 0.5mg-about 1500mg activity Composition, and can be administered one or more times daily, or less than being administered once a day.By include intravenous, intramuscular, Subcutaneous and parenteral injection in interior injection and uses the ADD of infusion techniques administration to be preferably 0.01-200mg/ Kg TBW.Averagely every day, rectal dosage regimen was preferably 0.01-200mg/kg TBW.Averagely every day, vaginal dosage scheme was excellent Elect 0.01-200mg/kg TBW as.Averagely topical dosage regimen every day is preferably and is administered 0.1-200mg one to four time every day. Transdermal concentration is preferably the concentration needed for maintaining the daily dosage of 0.01-200mg/kg.Averagely every day, inhalation dose scheme was preferred For 0.01-100mg/kg TBW.

Certainly, concrete initial dose and the maintenance dose scheme of every patient can change according to following factor: clinic is examined The character of disease condition determined by disconnected doctor and the order of severity, age of patient active, described of particular compound used With holistic health, administration time, route of administration, the discharge rate of medicine, drug regimen etc..The compound of the present invention, its The desired therapeutic modality of pharmaceutically acceptable salt, ester or compositions and dose quantity can be utilized often by those skilled in the art The treatment test of rule determines.

Preferably, the disease of described method is neoplastic hematologic disorder, entity tumor and/or their transfer.

The compound of the present invention is particularly useful for treatment and prevents (i.e. prevention) growth and metastasis of tumours, particularly accepts Or do not accept all indications and the growth and metastasis of tumours of the entity tumor in stage of the pre-treatment of described tumor growth.

The method of testing of specific pharmacological property or pharmaceutical properties is to well known to a person skilled in the art.

Embodiment test experiments as herein described is used for illustrating the present invention, and the invention is not restricted to provided reality Execute example.

Biological characteristis: proliferation assay

Tumor cell (MCF7, hormonal dependent human breast cancer cell, the ATCC HTB22 that will cultivate；NCI-H460, people is non- Small cell lung cancer cell, ATCC HTB-177；DU145, hormonal dependent Human Prostate Cancer Cells, ATCC HTB-81；HeLa- MaTu, human cervical carcinoma cell, EPO-GmbH, Berlin；HeLa-MaTu-ADR, multidrug resistance human cervical carcinoma cell, EPO- GmbH, Berlin；HeLa people's cervix cells, ATCC CCL-2；B16F10 mouse black-in tumor cell, ATCC CRL-6475) with 5000 cells/well (MCF7, DU145, HeLa-MaTu-ADR), 3000 cells/well (NCI-H460, HeLa-MaTu, What the density of HeLa) or 1000 cells/well (B16F10) was inoculated in the microtitration plate of 96-hole is added with 10% hyclone 200 μ l each of which growth medium in.After 24 hours, by the cell violet staining of one block of plate (plate when zero) (see Hereafter), simultaneously with adding various concentration (0 μM and the scope of 0.01-30 μM；Final concentration of the 0.5% of solvent dimethyl sulfoxide) The fresh culture (200 μ l) of tested substance replace the culture medium in other plates.Cell is trained in the presence of tested substance Support 4 days.By by crystal violet cell dyeing being measured cell proliferation: at room temperature measure 11% the penta of point by adding 20 μ l/ Cell is fixed 15 minutes by dialdehyde solution.After fixing cell being washed three times with water, plate is dried at room temperature for.By adding Enter 100 μ l/ and measure 0.1% crystal violet solution (pH3.0) of point by cell dyeing.After the cell of dyeing being washed three times with water, Plate is dried at room temperature for.10% acetic acid solution measuring point by adding 100 μ l/ carrys out dissolving dye.Lead under 595nm wavelength Cross spectrphotometric method for measuring delustring.By the cell of measured value is normalized to zero point plate extinction value (=0%) and untreated (0 μM) Delustring (=100%) calculates the change of cell quantity, in percentage.Use the software side by 4 parameter fittings of our company Formula determines IC₅₀Value.

Mps-1 kinase assays

Human kinase Mps-1 makes biotinylated peptide substrate phosphorylation.By from anti-phosphorylation serine/Soviet Union's ammonia of europium labelling Acid antibody (as donor) is to the time of the streptavidin (SA-Xlent) (as receptor) of the allophycocyanin labelling of crosslinking Resolved fluorescent resonance energy transfer (TR-FRET) realizes the detection to Phosphorylated products.Test compound is to kinase activity Suppression.

Use N-end GST-labelling people's total length restructuring Mps-1 kinases (purchased from Invitrogen, Karslruhe, Germany,cat.no PV4071).By aminoacid sequence PWDPDDADITEILG, (C-end is amide form thereof, is purchased from Biosynthan GmbH, Berlin) biotinylation peptide be used as kinase reaction substrate.

For measuring, the 50nl test-compound 100 times of concentration solution in DMSO are moved liquid to black low capacity 384 hole In microtitration plate (Greiner Bio-One, Frickenhausen, Germany), add and measure buffer [the former vanadium of 0.1mM Acid is received, 10mM MgCl₂, 2mM DTT, 25mM HepespH7.7,0.05%BSA, 0.001%Pluronic F-127] in Mps-1 solution 2 μ l, and by mixture at 22 DEG C incubation 15min to make test-compound tie in advance before kinase reaction starts It is bonded to Mps-1.Then by adding 16.7 adenosine triphosphates of 3 μ l, (it is final concentration of that ATP, 16.7 μMs=> 5 μ l measures in volume 10 μMs) and the peptide substrates (1.67 μMs=> 5 μ l measure final concentration of 1 μM in volumes) solution in measuring buffer initiate sharp Enzyme reaction, and by the mixture of gained response time of incubation 60min at 22 DEG C.Activity according to enzyme batch adjusts survey The concentration of Mps-1 in fixed, and suitably select the mensuration having in the range of linearity, at about 1nM, (5 μ l survey typical enzyme concentration Determine the final concentration in volume) scope in.By add 3 μ l HTRF detectable (100mM Hepes pH7.4,0.1% BSA, 40mM EDTA, 140nM streptavidin-XLent [#61GSTXLB, Fa.Cis Biointernational, Marcoule, France], the anti-phosphorylation of 1.5nM (Ser/Thr)-europium-antibody [#AD0180, PerkinElmer LAS, Rodgau-J ü gesheim, Germany] solution terminate reaction.

By the mixture of gained at 22 DEG C incubation 1h so that the peptide of phosphorylation be bound to anti-phosphorylation (Ser/Thr)-europium- Antibody.Turned to the resonance energy of streptavidin-XLent by anti-phosphorylation (Ser/Thr) antibody of measurement europium labelling subsequently In-migration evaluates the amount of phosphorylated substrate.Therefore, at Viewlux TR-FRET reader (PerkinElmer LAS, Rodgau-J ü Gesheim, Germany) in measure excite at 350nm after fluorescent emission at 620nm and 665nm.Will " blank-correction Normalization ratio " (the specific reading of Viewlux is similar to the ratio of transmitting at traditional 665nm and 622nm, Qi Zhong Before calculating this ratio, from 665nm signal, deduct the blank and crosstalk of Eu donor) as the measuring of amount of phosphorylated substrate. By data normalization (enzyme reaction=0% not having inhibitor suppresses, every other mensuration component but do not have enzyme=100% to suppress).? With 10 variable concentrations (20 μMs, 6.7 μMs, 2.2 μMs, 0.74 μM, 0.25 μ in 20 μMs of-1nM scopes on identical microtitration plate M, 82nM, 27nM, 9.2nM, 3.1nM and 1nM, dilution series dilutes 100 times of dense storage solutions by series 1:3 before measurement Level prepare) test test-compound, parallel two parts of each concentration is carried out, and utilizes in house software to pass through 4 parameters The Fitting Calculation IC₅₀Value.

It was surprisingly found that the inhibitory activity of compounds of formula I can be by R³For aryl-X-or heteroaryl-X-base Group affects energetically.It is therefore preferable that wherein R³Represent that (X is selected from O, S, S (=O), S (=O) for aryl-X-or heteroaryl-X-group₂、 NR, CR ' R ' ') the compound of general formula I.

Table

Spindle assembly checkpoint measures

During spindle assembly checkpoint guarantees mitosis, chromosome is properly separated.When entering mitosis, Chromosome starts condensation and with the phosphorylated histone H3 on serine 10.The dephosphorylation of the histone H 3 on serine 10 In the later stage, and terminate latter stage early stage.Therefore, the phosphorylation of the histone H 3 on serine 10 can serve as silk The label of the cell in division.Nocodazole is microtubule destabilizing material.Therefore, nocodazole interference microtubule dynamics is also Spindle assembly checkpoint is made to move.In mitosis, cells arrest is in the G2/M transition period, and shows on serine 10 Phosphated lanolin.Having in the presence of nocodazole is eliminated by Mps-1 inhibitor suppression spindle assembly checkpoint Silk division blocks, and cell completes mitosis prematurely.By having the thin of phosphorylated histone H3 on serine 10 The minimizing of born of the same parents detects this change.The compound induced mitogenesis being used as to measure the present invention by this reduction is broken through The labelling of the ability of (mitotic breakthrough).

The cell of people Cervix neoplasms system HeLa (ATCC CCL-2) cultivated is connect with the density of 2500 cells/well Kind in the microtitration plate of 384-hole be added with 1% (v/v) glutamine, 1% (v/v) penicillin, 1% (v/v) streptomycin and In the 20 μ l Dulbeco's culture medium of 10% (v/v) hyclone, (w/o is phenol red, w/o Sodium Pyruvate, w1000mg/ml Fructus Vitis viniferae Sugar, w pyridoxol).At 37 DEG C after overnight incubation, the nocodazole in the 10 μ l/ holes of final concentration of 0.1 μ g/ml is added cell In.After cultivating 24h, cells arrest is in the G2/M phase of cell cycle progression.Add with various concentration and be dissolved in dimethyl sulfoxide (DMSO) In test-compound (in 0 μM, and the scope of 0.005 μM-10 μMs；Final concentration of 0.5% (v/v) of solvent DMSO).It is being subject to In the presence of examination compound, cell is cultivated at 37 DEG C 4h.Afterwards, by cell at 4 DEG C in phosphate buffered saline (PBS) (PBS) In 4% (v/v) paraformaldehyde in fixing overnight, the most at room temperature 0.1% (v/v) Triton X in PBS^TMIn 100 thoroughly Change 20min, and the at room temperature middle closing of 0.5% (v/v) bovine serum albumin (BSA) in PBS 15min.Wash with PBS After, by the antibody-solutions in 20 μ l/ holes, (anti-phospho-histone H clones 3H10, FITC；Upstate,Cat#16-222;1:200 Dilution) add in cell, at room temperature cultivate 2h.Afterwards, by cells rinsed with PBS, by 20 μ l/ hole HOECHST33342 dyestuffs Solution (5 μ g/ml) adds in cell, and cell is cultivated 12min the most at room temperature.By cells rinsed with PBS twice, Then cover with PBS and store until being used for analyzing at 4 DEG C.With Perkin Elmer OPERA^TM High-Content Analysis reads plate instrument and obtains image.By image analysis software MetaXpress from Molecular devices^TMUse thin Born of the same parents' cycle application module analyzes image.In this measures, measure the phosphorylation group egg on HOECHST33342 and serine 10 White H3 the two labelling.HOECHST33342 marker DNA also is used for counting cell quantity.Phospho-histone on serine 10 The dyeing of H3 determines the quantity of mitotic cell.It is thin that the suppression of Mps-1 decreases mitosis in the presence of nocodazole The quantity of born of the same parents, this represents unsuitable mitotic progression.Original mensuration is analyzed further by four parameter logistic regression analyses Data are to determine the IC of every kind of test-compound₅₀Value.

It is obvious to a person skilled in the art that it is kinase whose to use suitable reagent can carry out other Mps similarly Measure.

Therefore, the compound of the present invention effectively suppresses one or more Mps-1 kinases, and be therefore suitable for treatment or Preventing the growth of uncontrolled cell, breed and/or survive, unsuitable cellullar immunologic response or unsuitable cellular inflammation should The disease answered, especially, wherein said uncontrolled cell grows, breeds and/or survive, unsuitable cellullar immunologic response Or unsuitable cellular inflammation response is mediated by Mps-1, more particularly, wherein said uncontrolled cell growth, increase Growing and/or survive, the disease of unsuitable cellullar immunologic response or unsuitable cellular inflammation response is neoplastic hematologic disorder, solid tumor And/or their transfer, such as leukemia and myelodysplastic syndrome, malignant lymphoma, include that cerebroma and brain metastes exist In tumor of head and neck, breast tumor including non-fire power and small cell lung tumor, gastroenteric tumor, interior point Secrete tumor, breast tumor and other gynecological tumors, urinary system including tumor of kidney, tumor of bladder and tumor of prostate swells Tumor, cutaneous tumor and sarcoma and/or their transfer.

The research (including the calculating of the internal blood clearance (CL) of liver) of metabolic stability in vitro in rat hepatocytes

By 2-step perfusion from Han Wistar rat isolating hepatocytes.After perfusion, carefully from rat taking-up liver: Open Glisson's capsule, and hepatocyte is leniently shaken in the culture dish with ice-cold WME.The cell suspending liquid of gained is led to Cross sterile gauze to filter in 50ml falcon pipe, and be at room temperature centrifuged 3min with 50 × g.Cell precipitation is resuspended in In 30ml WME, and pass throughGradient is centrifuged 2 times with 100 × g.By hepatocyte Williams ' culture medium E (WME) again wash and be resuspended in the culture medium comprising 5%FCS.Cells viability is determined by trypanblue exclusion method.

Metabolic stability is measured, hepatocyte is distributed in the WME comprising 5%FCS, with 1.0 × 10⁶Individual living cells/ The Density Distribution of ml is in vial.Add the final concentration of test-compound to 1 μM.During incubation, hepatocyte is suspended Liquid persistent oscillation, and gather aliquot 2,8,16,30,45 and 90min, add isopyknic cold methanol to it immediately. By sample freeze overnight at-20 DEG C, it is centrifuged 15 minutes with 3000rpm subsequently, and by supernatant with being furnished with LCMS/MS detection Agilent1200HPLC-systematic analysis.

The half-life of test-compound is determined from concentration-time profile.Intrinsic clearance is calculated from the half-life.With extra ginseng Together with number hepatic blood flow, internal with external hepatocyte amount.Calculate the internal blood clearance (CL) of liver and maximum oral bio Availability (F_max).Use following parameter value: hepatic blood flow-4.2L/h/kg rat；Concrete liver weight-32g/kg rat body weight；Body Interior hepatocyte-1.1x10⁸Cell/g liver, hepatocyte-0.5x10⁶/ml。

It was surprisingly found that the metabolic stability of compounds of formula I can be by the group R different from hydrogen atom^4bWith R^4cIn at least one affect energetically.Therefore, R^4bAnd/or R^4cSelected from halo-,-CN ,-OH, C₁-C₆-alkyl-, C₁-C₆-alkane Epoxide-, halo-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxyl-, R^6a(R^6b)N-C₁-C₆-alkyl-, HO-C₁-C₆-alkyl-, NC-C₁-C₆-alkyl-, C₁-C₆-alkoxy-C₁-C₆-alkyl-, halo-C₁-C₆-alkoxy-C₁-C₆-alkyl-.Preferably, R^4b And/or R^4cSelected from halo-,-CN ,-OH, C₁-C₆-alkyl-, C₁-C₆-alkoxyl-；It is highly preferred that R^4bAnd/or R^4cSelected from halogen Generation-, C₁-C₆-alkyl-；Most preferably, R^4bAnd/or R^4cSelected from halo-, C₁-C₃-alkyl-.

It was surprisingly found that the metabolic stability of compounds of formula I can be 1,1,1-trifluoroethyl group R⁵Affect energetically.Therefore preferably R⁵It it is the compound of the Formulas I of 1,1,1-trifluoroethyl group.

Claims

1. compounds of formula I, or its stereoisomer, tautomer or salt, or their mixture:

Wherein:

A represents

R¹Represent methyl-group or cyclopropyl-group；

Wherein said cyclopropyl-group is optionally replaced by 1 fluorine atom；

R³Represent pyridine radicals-, phenyl-, phenyl-O-or phenyl-S-group；

Wherein said Phenyl-group is by methyl group and-C (=O) N (H) R^6aGroup replaces, or by HO-CH₂-group replaces,

Wherein said phenyl-O-group optionally by 1 or 2 selected from following group identical or different replace :-F, H₃C-O-、 HO-、H₃C-,

Wherein said phenyl-S-group optionally by 1 or 2 selected from following group identical or different replace :-F, H₃C-O-、 HO-、H₃C-；

R⁵Represent selected from following group:

R^6aRepresent hydrogen atom, or methyl-group or cyclopropyl-group；

Wherein said cyclopropyl-group is optionally replaced by 1-CN group.

2. the compound of claim 1, or its stereoisomer, tautomer or salt, or their mixture, its choosing From:

N-cyclopropyl-4-{6-[2-(hydroxymethyl) phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl benzamide,

N-cyclopropyl-2-methyl-4-{6-(pyridin-4-yl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base } Benzoylamide,

N-cyclopropyl-4-{6-[(3-fluoro-5-aminomethyl phenyl) sulfanyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-2-methyl benzamide,

N-cyclopropyl-4-{6-[(2,3-difluorophenyl) sulfanyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2- A] pyridin-3-yl }-2-methyl benzamide,

N-cyclopropyl-2-methyl-4-{6-(Phenylsulfanyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base } Benzoylamide,

N-cyclopropyl-4-{6-[(3-fluorophenyl) sulfanyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl benzamide,

N-cyclopropyl-4-{6-[(2-hydroxy phenyl) sulfanyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-2-methyl benzamide,

N-cyclopropyl-4-{6-(2-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-2-methyl benzamide,

N-cyclopropyl-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base }-2-methyl benzamide,

4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N, 2-bis- Methyl benzamide,

4,4 '-{ 8-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] imidazo [1,2-a] pyridine-3,6-diyl } double (N-rings third Base-2-methyl benzamide),

N-[rel-(1S, 2S)-2-fluorine cyclopropyl]-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazoles And [1,2-a] pyridin-3-yl-2-methyl benzamide,

N-{ [(1R, 2R) or (1S, 2S)]-2-fluorine cyclopropyl }-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide,

N-{ [(1S, 2S) or (1R, 2R)]-2-fluorine cyclopropyl }-4-{6-(3-fluorophenoxy)-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide,

N-cyclopropyl-4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl benzamide,

4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }- N, 2-dimethyl benzamide,

N-[rel-(1S, 2S)-2-fluorine cyclopropyl]-4-{6-(5-fluoro-2-methylbenzene epoxide)-8-[(3,3,3-trifluoro propyl) ammonia Base] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide,

N-cyclopropyl-4-{6-(2,3-difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-2-methyl benzamide,

4,4 '-{ 8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-diyl } double (N-cyclopropyl-2-first Yl-benzamide),

N-cyclopropyl-2-methyl-4-{6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base } Benzoylamide,

4,4 '-{ 8-[methyl (3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3,6-diyl } double (N, 2-diformazans Yl-benzamide),

N-cyclopropyl-4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-2-methyl benzamide,

N-cyclopropyl-4-{6-(3-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-2-methyl benzamide,

4-{6-(3-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N, 2-dimethyl benzamide,

N, 2-dimethyl-4-{6-phenoxy group-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl } benzene Methanamide,

4-{6-(2,3-difluorobenzene epoxide)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N, 2-dimethyl benzamide,

N, 2-dimethyl-4-{6-(pyridin-4-yl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base } Benzoylamide,

4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base }-N, 2-dimethyl benzamide,

N-cyclopropyl-4-{6-(4-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base }-2-methyl benzamide,

4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-N, 2-dimethyl benzamide,

N-cyclopropyl-4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide,

N-[rel-(1S, 2S)-2-fluorine cyclopropyl]-4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) Amino] imidazo [1,2-a] pyridin-3-yl }-2-methyl benzamide,

N-cyclopropyl-4-{6-(3-fluoro-4-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl benzamide,

4-{6-(3-fluoro-4-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }- N, 2-dimethyl benzamide,

N-cyclopropyl-4-{6-(3-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine-3- Base }-2-methyl benzamide,

4-{6-(3-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridin-3-yl }-N, 2- Dimethyl benzamide,

N-cyclopropyl-4-{6-(3-fluoro-2-methoxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] Pyridin-3-yl }-2-methyl benzamide,

4-{3-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridine-6-base }-N, 2-dimethyl benzamide,

4-(6-{4-[(1-anocy clopropyl) carbamoyl]-3-aminomethyl phenyl }-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl)-N-cyclopropyl-2-methyl benzamide,

4-{6-(4-carbamoyl-3-aminomethyl phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-N-cyclopropyl-2-methyl benzamide,

4-(6-{4-[(1-anocy clopropyl) carbamoyl]-3-aminomethyl phenyl }-8-[(3,3,3-trifluoro propyl) amino] miaow Azoles also [1,2-a] pyridin-3-yl)-N, 2-dimethyl benzamide,

4-{6-[4-(cyclopropylcarbamoyl)-3-aminomethyl phenyl]-8-[(3,3,3-trifluoro propyl) amino] imidazo [1, 2-a] pyridin-3-yl }-N, 2-dimethyl benzamide,

4-{6-(4-carbamoyl-3-aminomethyl phenyl)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyridine- 3-yl }-N, 2-dimethyl benzamide,

N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(3-fluorophenoxy) imidazo [1,2-a] pyridin-3-yl }- 2-methyl benzamide,

N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(4-methoxyphenoxy) imidazo [1,2-a] pyridine-3- Base }-2-methyl benzamide,

N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(2,3-difluorobenzene epoxide) imidazo [1,2-a] pyridine-3- Base }-2-methyl benzamide,

N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(5-fluoro-2-methylbenzene epoxide) imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl benzamide,

N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(2,5-difluorobenzene epoxide) imidazo [1,2-a] pyridine-3- Base }-2-methyl benzamide,

N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(3-fluoro-2-methylbenzene epoxide) imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl benzamide,

N-cyclopropyl-4-{8-[(2,2-bis-fluoro ethyl) amino]-6-(3-fluoro-4-methoxyphenoxy) imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl benzamide,

N-cyclopropyl-4-{6-(5-fluoro-2-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl benzamide,

N-cyclopropyl-4-{6-(3-fluoro-2-hydroxyphenoxy)-8-[(3,3,3-trifluoro propyl) amino] imidazo [1,2-a] pyrrole Pyridine-3-base }-2-methyl benzamide.

3. the method preparing compound any one of claim 1-2, said method comprising the steps of:

-make the midbody compound of formula IV:

Wherein

R⁵Define with A mutual-through type I as any one of claim 1-2, and R^3’For halogen atom；

React with the compound of formula IVa:

R³-Y

IVa

Wherein

R³As any one of claim 1-2, mutual-through type I defines,

Y is hydrogen atom replaced in coupling reaction or boric acid base group or the ester of boric acid；

Thus obtain compounds of formula I:

Wherein

Wherein R³、R⁵Define with A mutual-through type I as any one of claim 1-2.

4. the method preparing compound any one of claim 1-2, said method comprising the steps of:

-make the midbody compound of formula II:

Wherein

R³And R⁵As any one of claim 1-2, mutual-through type I defines, and Q is halogen atom；

React with the compound of formula IIa:

A-Y

IIa

Wherein

A mutual-through type I as any one of claim 1-2 defines,

Y is the ester of boric acid base group replaced in coupling reaction or boric acid；

Thus obtain compounds of formula I:

Wherein R³、R⁵Define with A mutual-through type I as any one of claim 1-2.

5. the method preparing compound any one of claim 1-2, said method comprising the steps of:

-make the midbody compound of formula VII:

Wherein

R³Define with A mutual-through type I as any one of claim 1-2；And V is halogen atom；

React with the compound of formula VIIa:

R⁵-CH₂-NH₂

VIIa

Wherein

R⁵As any one of claim 1-2, mutual-through type I defines；

Thus obtain compounds of formula I:

Wherein R³、R⁵Define with A mutual-through type I as any one of claim 1-2.

6. the method preparing compound any one of claim 1-2, said method comprising the steps of:

-make the midbody compound of formula VII:

Wherein

R³Define with A mutual-through type I as any one of claim 1-2, and V is NH₂-group；

Reductive amination reaction is carried out with the compound of formula VIIb:

O=CHR⁵

VIIb

Wherein

R⁵As any one of claim 1-2, mutual-through type I defines；

Thus obtain compounds of formula I:

Wherein R³、R⁵Define with A mutual-through type I as any one of claim 1-2.

7. a pharmaceutical composition, it comprises the compound any one of claim 1-2, or its stereoisomer, change Isomer, pharmaceutically acceptable salt, or their mixture, and pharmaceutically acceptable diluent or carrier.

8. a pharmaceutical composition, it comprises:

Compound any one of-one or more claim 1-2, or its stereoisomer, tautomer, pharmacy can The salt accepted, or their mixture；And

-one or more are selected from following material: taxane；Epothilones；Prednisolone；Dexamethasone；Estramustine；Changchun Alkali；Vincristine；Doxorubicin；Amycin；Idarubicin；Daunorubicin；Bleomycin；Etoposide；Cyclophosphamide；Different ring Phosphamide；Procarbazine；Melphalan；5-fluorouracil；Capecitabine；Fludarabine；Cytosine arabinoside；Ara-C；2-is chloro-2 '-de- Oxygen adenosine；Thioguanine；Androgen antagonist；Bortezomib；Platinum derivatives；Chlorambucil；Methotrexate；And rituximab list Anti-.

9. the compound any one of claim 1-2, or its stereoisomer, tautomer or it is pharmaceutically acceptable Salt, or their mixture preparation for treatment or prophylactic medicine in purposes, wherein said disease is not The growth of in check cell, hyper-proliferative and/or survival, unsuitable cellullar immunologic response or unsuitable cellular inflammation should The disease answered, the growth of wherein said uncontrolled cell, hyper-proliferative and/or survival, unsuitable cellullar immunologic response or Person's unsuitable cellular inflammation response is mediated by mitogen-activated protein kinase (MEK-ERK) approach.

10. the purposes of claim 9, wherein said disease is neoplastic hematologic disorder, solid tumor and/or their transfer.