NZ615300B2 - Triazolopyridine compounds as pim kinase inhibitors - Google Patents

Triazolopyridine compounds as pim kinase inhibitors Download PDF

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NZ615300B2
NZ615300B2 NZ615300A NZ61530012A NZ615300B2 NZ 615300 B2 NZ615300 B2 NZ 615300B2 NZ 615300 A NZ615300 A NZ 615300A NZ 61530012 A NZ61530012 A NZ 61530012A NZ 615300 B2 NZ615300 B2 NZ 615300B2
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alkyl
alkoxy
formula
compound
tert
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NZ615300A
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James F Blake
Meese Lisa A De
Robert Kirk Delisle
James M Graham
Huerou Yvan Le
Michael Lyon
John E Robinson
Eli M Wallace
Bin Wang
Rui Xu
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Array Biopharma Inc
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Priority claimed from PCT/US2012/026572 external-priority patent/WO2012154274A1/en
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Abstract

This disclosure relates to a family of triazolopyridine compounds of general formula I, wherein R1, R2, R3, R4 and R10 are as disclosed in the specification. Their use as PIM kinase inhibitors are also disclosed, including their use for treating inflammatory or autoimmune disorders. Example compounds include: (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-((R)-2-methoxypropoxy)quinolin-2-yl)[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine di-hydrochloride 2-(2-(6-((S)-1-((S)-3-amino-3-methylpyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-7-yl)ethanol (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(7-((S)-2-methoxypropoxy)quinolin-2-yl)[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine (S)-1-((R)-2,2,2-trifluoro-1-(3-(7-((R)-2-methoxypropoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine dihydrochloride (S)-1-((S)-1-(3-(7-ethoxy-6-fluoroquinolin-2-yl)-[1,24]triazolo[4,3-alpyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-amine dihydrochloride s include: (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-((R)-2-methoxypropoxy)quinolin-2-yl)[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine di-hydrochloride 2-(2-(6-((S)-1-((S)-3-amino-3-methylpyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-7-yl)ethanol (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(7-((S)-2-methoxypropoxy)quinolin-2-yl)[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine (S)-1-((R)-2,2,2-trifluoro-1-(3-(7-((R)-2-methoxypropoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine dihydrochloride (S)-1-((S)-1-(3-(7-ethoxy-6-fluoroquinolin-2-yl)-[1,24]triazolo[4,3-alpyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-amine dihydrochloride

Description

TRIAZOLOPYRIDINE COMPOUNDS AS PIM KINASE INHIBITORS BACKGROUND OF THE INVENTION The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to a process for making the compounds and to the use of the compounds in therapy. More particularly, it relates to certain lopyridine compounds useful in the treatment and prevention of diseases which can be treated with a PIM kinase inhibitor, including diseases mediated by PIM kinases. Particular compounds of this invention have been found to be inhibitors of PIM-1 and/or PIM-2 and/or PIM-3.
Protein kinases constitute a family of structurally related enzymes that are responsible for the control of a vast array of cellular processes.
The PIM kinase sub-family consists of three ct serine/threonine protein kinase isoforms (PIM-1, -2 and -3) belonging to the calmodulin-dependent protein kinase- related (CAMK) group. PIM-2 and PIM-3 are respectively 58% and 69% identical to PIM-1 at the amino acid level.
The over-expression of PIM-1 has been reported in various human lymphomas and acute leukemias (Amson, R. et al., Proc. Natl. Acad. Sci. U.S.A., 1989, 86: 8857-8861).
PIM-1 has been shown to synergize with c-Myc to drive lymphomagenesis r M., et al., Nature, 1989, 340; 61-63), and plays an ant role in cytokine signaling in T-cell development (Schmidt, T., et al., EMBO J, 1998, 17:5349-5359). In addition, there is evidence that PIM-1 is over-expressed in prostatic neoplasia and human prostate cancer (Valdman, A. et al., The Prostate, 2004, 60: 367-371; Cibull, T.L. et al., J. Clin. Path01., 2006, 59: 285-288) and may serve as a useful biomarker in identification of prostate cancer (Dhanasekaran, SM. et al., Nature, 2001, ): 822-826). PIM-1 has been shown to be critical for IL-6 mediated proliferation of hematopoietic cells (Hirano, T., et al., Oncogene 2000, 19:2548-2556), as well as STAT3 ed cell cycle progression (Shirogane, T., et al., Immunity 1999, 11:709. ly, it has been discovered that PIM-1 is up-regulated by Flt-3 and may play an important role in Flt-3 mediated cell survival (Kim, K.T. et al sz'a, 2005, 105(4): 767). Since Flt-3 itself is ated in leukemias like AML, additional knockdown of PIM-1 may be a useful approach to treating leukemias driven by Flt-3 or various mutations. Accordingly, PIM-1 inhibitors may be useful as eutic agents for a variety of cancers such as hematological cancers.
PIM-2 is a highly conserved serine/threonine kinase involved in cell proliferation and the prevention of apoptosis (Baytel et al., Biochim. Biophys. Acta Gene Struct. Expr. 1442: 274 (1998)). PIM-2 is upregulated in AML, CLL, and possibly in prostate .
PIM-3 is a oncogene identified in pancreatic liver and colon cancers, and is an apoptotic regulator (Popivanova, B., et al., Cancer Sci., 98(3): 321 (2007)).
Based upon the direct involvement of the PIM kinases in a wide variety of cancers downstream of STAT3/5 activation, it is expected that inhibition of the PIM kinases will result in tion of proliferation and al of multiple cancer cell types. This would then be expected to provide a therapeutic benefit to cancer patients with a variety of cancers (both solid tumor and hematologic settings), as well as other conditions that are mediated by PIM kinase signaling.
In addition to the malignant cells ed above, PIM kinases are also expressed in hematopoietically-derived cell lines and hematopoietically-derived primary cells ing cells of the immune system such as B cells, T cells, monocytes, macrophages, eosinophils, basophils, and dendritic cells. Expression of PIM kinases can be induced, for example, by cytokines which utilize Jak/Stat signaling, such as IL-2, IL-3,IL-4, IL-5, IL-6, IL-7, IL-9, IL-12, IL-15, GM-CSF, IFNOL, IFNy, erythropoietin, thrombopoietin, and tin, and the generation, differentiation, maintenance and activation of hematopoietically-derived cells is dependent on these cytokines. Moreover, PIM proteins have been shown to be required for the efficient proliferation of peripheral T cells ed by T-cell receptor and IL-2 signaling (Mikkers, et al., Mol. Cell Biol., 2004, 6104). gh the exact mechanism of action of PIM kinases in an immunological setting has yet to be fully defined, they have been reported to phosphorylate a number of substrates involved in ar proliferation, entiation, and survival (Bullock et al., J. Biol. Chem., 2005 280:41675; Chen et al., PNAS 2002 99:2175; Dautry et al. J. Biol. Chem. 1998 263:17615).
Chronic and acute inflammatory and autoimmune diseases are associated with the overproduction of flammatory cytokines and activation of immune cells against the body’s own tissues. However, many of these diseases are not adequately treated by t therapies and/or these therapies have significant side effects/risks.
A particular example of an autoimmune disease is multiple sclerosis (MS).
MS is a progressive central nervous system (CNS) inflammatory autoimmune disease wherein the immune system mounts responses against CNS components. The resulting damage to axons and nerves leads to progressive neurological impairment and significant disability. MS affects over 2.5 million people worldwide (www.nationalmssocietyorg); WO 54274 however many current therapies are only moderately effective and have questionable risk factors A need therefore remains for compounds and methods for treating autoimmune and inflammatory diseases.
International patent application, ation number WO 2004/05 8769 discloses, inter alia, certain 3-aryl and 3-N-arylamino-substituted [l,2,4]triazolo[4,3- b]pyridazines purported to t several protein kinases, ing PIM-l.
SUMMARY OF THE INVENTION It has now been found that [l,2,4]triazolo[4,3-a]pyridine compounds bearing a quinolinyl group at the 3 position of the triazolopyridine ring are inhibitors of PIM s, in particular PIM-l and/or PIM-2 and/or PIM-3 kinases, which are useful for treating diseases such as cancers and atory diseases.
More specifically, one aspect of the present invention provides compounds of Formula I: / N R1 R10 R3 and stereoisomers, pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, R3, R4 and R10 are as defined herein. r aspect of the t invention provides compounds of Formula I having the Formula IA: / N R1 and stereoisomers, pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, R3, and R4 are as defined herein.
Another aspect of the present invention provides methods of preventing or ng a disease or disorder modulated by PIM-l and/or PIM-2 and/or PIM-3, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof.
Examples of such diseases and disorders include, but are not limited to, immune cellassociated diseases and disorders, such as inflammatory and mune diseases.
Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the t invention or a pharmaceutically acceptable salt f. r aspect of the present invention provides the compounds of the present invention for use in therapy. r aspect of the present invention provides the compounds of the present invention for use in the treatment of immune cell-associated diseases. In one embodiment, the immune cell-associated disease is an inflammatory disease. In one embodiment, the immune cell-associated e is an mune disease.
Another aspect of the present invention provides the compounds of the present invention for use in the treatment of cancer.
Another aspect of the present invention provides the use of a compound of this invention in the cture of a medicament for the treatment of immune cell-associated diseases and disorders, such as inflammatory and autoimmune diseases.
Another aspect of the present invention provides the use of a compound of this invention in the manufacture of a ment for the treatment of cancer.
Another aspect of the present invention provides intermediates for preparing compounds of Formula I.
Another aspect of the t invention includes methods of preparing, methods of separation, and methods of purification of the compounds of this invention.
ED PTION OF THE INVENTION Provided herein are compounds, and pharmaceutical formulations thereof, that are potentially useful in the ent of diseases, conditions and/or disorders modulated by PIM-l and/or PIM-2 and/or PIM-3.
One embodiment provides compounds of Formula I having the formula: N/ N R1 ~N/ N\ R2 2012/026572 and stereoisomers, pharmaceutically acceptable salts and solvates thereof, wherein: R1 is H, halogen, CN, OH, alkyl, fluoro(l-6C)alkyl, difluoro(l- 6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, cyano(l-6C)alkyl, (l-3C alkoxy)(l- yl (optionally substituted with hydroxy), di(l-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, fluoro(l-6C)alkoxy, difluoro(l-6C)alkoxy, ro(l-6C)alkoxy, hydroxy(2-6C)alkoxy, cyano(l-6C)alkoxy, (l-3C alkoxy)(2-6C)alkoxy, di(l-3C alkoxy)(2-6C)alkoxy, (3-6C cycloalkyl)methoxy, oxetanylmethoxy (optionally substituted with methyl), (l-6C alkyl)sulfanyl, -C(=O)NRaRb, -CH2C(=O)NR°Rd, or (3-6C)cycloalkyl ally substituted with -CHZOH or -CHZO(l-4C alkyl); Ra, Rb, Rc and Rd are independently selected from H and (l-4C)alkyl; R2 is H, halogen, CN, OH, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l- 6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (l-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy (optionally substituted with (l-6C alkyl)C(=O)O-, amino(l-6C alkyl)C(=O)O-, or phenyl(C=O)O-), fluoro( l -6C)alkoxy, difluoro( l -6C)alkoxy, trifluoro( l -6C)alkoxy, hydroxy(2-6C)alkoxy, (l-3C alkoxy)(2-6C)alkoxy, (3-6C cycloalkyl)methoxy, (3- 6C)cycloalkoxy (optionally substituted with OH), oxetanylmethoxy (optionally tuted with methyl), ydropyranyloxy, (l-6C alkyl)sulfanyl, hydroxy(2-6C sulfanyl, (1- 3c alkylsulfanyl)(2-6C)alkoxy, -COOH, hetArl, NReRf, -NReC(=O)Rf, oxetanyl, or cyclopropyl optionally substituted with -CHZOH or -CHZO(l-6C ; or R1 and R2 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having 1 - 2 ring heteroatoms independently selected from O and N, wherein said ring is optionally tuted with (l-4C)alkyl; hetAr1 is a 5-6 membered heteroaryl ring haVing one or two ring nitrogen atoms and optionally substituted with one or more groups selected from (l-6C)alkyl; Re and Rf are independently H, (l-6C)alkyl or cyclopropyl optionally substituted with (l-4C)alkyl; R3 is H, halogen or alkyl; R4 is R5 R58 R6 EXNQ‘R7 R9 R8 .
R5 is CF3, CHZF, CHFZ, methyl or ethyl; R5&1 is H or methyl; or R5 and R5&1 together with the atom to which they are attached form a ropyl ring; R6 is H, NH2, OH, (l-6C alkyl)NH-, fluoro(l-6C alkyl)NH-, hydroxy(l-6C NH-, (3-6C cycloalkyl)CH2NH-, (l-6C alkyl)C(=O)NH-, (l-6C alkyl)OC(=O)NH- (optionally substituted with 5-methyloxo-l,3-dioxolyl), or amino(l-6C)alkyl-; R7 is H, (l-6C)alkyl, fluoro(l-6C)alkyl or hydroxy(l-6C)alkyl; or R6 and R7 er with the atom to which they are attached form a 5-6 ed yclic heterocycle having a ring nitrogen atom; R8 is H, halogen, OH, or (l-6C)alkoxy, or R6 and R8 together with the carbon atoms to which they are attached form a cyclopropyl ring optionally tuted with NH2; R9 is H, or R6 and R9 together form a linking group haVing the a -CH2NH- which links the carbon atoms to which they are attached; and R10 is H or halogen.
In one embodiment, compounds of Formula I include compounds having the Formula IA: / N R1 N\N, N\ R2 and stereoisomers, pharmaceutically acceptable salts and es thereof, wherein: R1 is H, halogen, CN, OH, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l- 6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, cyano(l-6C)alkyl, (l-3C alkoxy)(l- 6C)alkyl (optionally substituted with hydroxy), C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, fluoro(l-6C)alkoxy, difluoro(l-6C)alkoxy, trifluoro(l-6C)alkoxy, hydroxy(2-6C)alkoxy, cyano(l-6C)alkoxy, (l-3C alkoxy)(2-6C)alkoxy, di(l-3C alkoxy)(2-6C)alkoxy, (3-6C cycloalkyl)methoxy, oxetanylmethoxy (optionally substituted with methyl), (l-6C alkyl)sulfanyl, -C(=O)NRaRb, -CH2C(=O)NR°Rd, or (3-6C)cycloalkyl optionally substituted with -CHZOH or -CHZO(l-4C alkyl); Ra, Rb, RC and RC1 are independently selected from H and (l-4C)alkyl; 2012/026572 R2 is H, halogen, CN, OH, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l- 6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (l-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy (optionally substituted with (l-6C alkyl)C(=O)O- or amino(l-6C alkyl)C(=O)O-), fluoro(l- 6C)alkoxy, difluoro(l-6C)alkoxy, trifluoro(l-6C)alkoxy, hydroxy(2-6C)alkoxy, (l-3C alkoxy)(2-6C)alkoxy, (3-6C cycloalkyl)methoxy, oxetanylmethoxy nally substituted with methyl), tetrahydropyranyloxy, (l-6C alkyl)sulfanyl, hydroxy(2-6C alkyl)sulfanyl, (1- 3c alkylsulfanyl)(2-6C)alkoxy,-COOH, hetArl, -C(=O)NReRf, -NReC(=O)Rf, or ropyl optionally substituted with -CHZOH or -CHZO(l-6C alkyl); or R1 and R2 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having 1 - 2 ring atoms independently selected from O and N, wherein said ring is ally substituted with (l-4C)alkyl; hetAr1 is a 5-6 membered heteroaryl ring haVing one or two ring nitrogen atoms and optionally substituted with one or more groups selected from (l-6C)alkyl; Re and Rf are independently H, (l-6C)alkyl or cyclopropyl optionally substituted with (l-4C)alkyl; R3 is H, halogen or (1-6C)alkyl; R4 is R5 R58 R6 R9 R8 R5 is CF3, CHZF, CHFZ, methyl or ethyl; R5&1 is H or methyl; or R5 and R5&1 together with the atom to which they are attached form a cyclopropyl ring; R6 is H, NHz, OH, (l-6C NH-, fluoro(l-6C alkyl)NH-, hydroxy(l-6C alkyl)NH-, (3-6C cycloalkyl)CH2NH-, (l-6C alkyl)C(=O)NH-, (l-6C alkyl)OC(=O)NH- or amino(l -6C)alkyl-; R7 is H, (l-6C)alkyl, fluoro(l-6C)alkyl or y(l-6C)alkyl; or R6 and R7 er with the atom to which they are attached form a 5-6 membered spirocyclic heterocycle having a ring nitrogen atom; R8 is H, halogen, OH, or (l-6C)alkoxy, or R6 and R8 together with the carbon atoms to which they are ed form a cyclopropyl ring optionally substituted with NH2; and R9 is H, or WO 54274 R6 and R9 together form a linking group having the formula -CH2NH- which links the carbon atoms to which they are attached.
The terms "(l-6C)alkyl", "(l-4C)alkyl" and )alkyl" as used herein refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one to six carbon atoms, one to four carbon atoms, and one to three carbon atoms, respectively. es include, but are not limited to, methyl, ethyl, l-propyl, 2-propyl, l-butyl, 2-methyl- l-propyl, 2—butyl, 2-methylpropyl, 2,2-dimethylpropyl, l-pentyl, yl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 3-methyl-l-butyl, 2-methyl-l-butyl, l, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.
The terms "fluoro(l-6C)alkyl," "hydroxy(l-6C)alkyl," "cyano(l-6C)alkyl," "amino(l-6C)alkyl" and "(l-3C alkoxy)(l-6C)alkyl" as used herein refer to a (l-6C)alkyl group as defined herein, wherein one of the hydrogen atoms is replaced with fluorine or a hydroxy, cyano (NEG), amino or alkoxy group, respectively.
The term "difluoro(l-6C)alkyl" as used herein refers to a (l-6C)alkyl group as defined herein, wherein two of the hydrogen atoms are each replaced with fluorine.
The term "trifluoro(l-6C)alkyl" as used herein refers to a (l-6C)alkyl group as defined herein, wherein three of the en atoms are each replaced with fluorine.
The term "di(l-3Calkoxy)(l-6C)alkyl" as used herein refers to a (l-6C)alkyl group as defined herein, wherein two of the hydrogen atoms on the alkyl portion are each replaced with a (1-3C)alkoxy group.
The terms )alkoxy" and "(l-4C)alkoxy" and "(2-6C)alkoxy" as used herein refers to saturated linear or branched-chain monovalent alkyl ether ls of one to six carbon atoms, one to four carbon atoms, or two to six carbon atoms, respectively, wherein the term "alkyl" is as defined above and the radical is on the oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, and butoxy.
The terms "fluoro(l-6C)alkoxy", ro(l-6C)alkoxy", and trifluoro(1- 6C)alkoxy" as used herein refer to (l-6C)alkoxy groups as defined herein, wherein one, two or three of the hydrogen atoms of the alkoxy group are each replaced by fluorine, respectively.
The terms "hydroxy(2-6C)alkoxy," "cyano(l-6C)alkoxy," and "(l-3C alkoxy)(2-6C)alkoxy" as used herein refer to (2-6C)alkoxy groups and (l-6C)alkoxy groups as defined herein, wherein one of the hydrogen atoms of the alkoxy group is replaced by a hydroxy, cyano (NEG), or a (l-3C)alkoxy group, respectively.
The term "(3-6C)cycloalkyl" as used herein refers to a cyclopropyl, cyclobutyl cyclopentyl or cyclohexyl ring.
The term "(3-6C cycloalkyl)methoxy" as used herein refers to a methoxy radical wherein one of the hydrogen atoms is replace by a (3-6C cycloalkyl) group as defined herein.
The terms "(l-6C alkyl)sulfanyl," "(l-4C alkyl)sulfanyl" and (l-3C alkyl)sulfanyl as used herein refer to a (l-6C alkyl)S-, (l-4C alkyl)S- or (l-3C alkyl)S- group, respectively, wherein the radical is on the sulfur atom and the (l-6C alkyl) portion is as defined above. Examples include sulfanyl (CH3S-), ethylsulfanyl (CH2CH2S-) and isopropylsulfanyl 2CHS-).
The terms "(l-3C alkylsulfanyl)(2-6C)alkoxy" and "(l-3C alkylsulfanyl)(2- 4C)alkoxy" as used herein refer to a (2-6C)alkoxy group or a (2-4C)alkoxy group, respectively, as defined herein, wherein a carbon atom of the alkoxy group is substituted with a (l-3C alkyl)sulfanyl group as d herein.
The term "hydroxy(2-6C alkyl)sulfanyl" as used herein refers to a (2-6C alkyl)sulfanyl group as defined herein, wherein one of the hydrogen atoms is replace by a hydroxy.
The term "oxetanylmethoxy" as used herein refers to a methoxy radical wherein one of the hydrogen atoms is replace by an oxetanyl group.
The term "halogen" as used herein means F, Cl, Br or I.
When words are used to describe a substituent, the rightmost-described component of the substituent is the ent that has the free valence. To illustrate, cyclopropylmethoxy refers to a methoxy l, wherein the radical is on the oxygen atom and the carbon atom of the methoxy l is substituted with a cyclopropyl group as shown: In one embodiment, R1 is H.
In one embodiment, R1 is halogen. In one embodiment, R1 is selected from F and Cl. In one embodiment, R1 is F. In one ment, R1 is Cl.
In one embodiment, R1 is CN.
In one embodiment, R1 is OH.
In one embodiment, R1 is (l-6C)alkyl. In one embodiment, R1 is (l-4C)alkyl.
In one embodiment, R1 is ed from methyl, ethyl, isopropyl, and tert—butyl.
In one embodiment, R1 is fluoro(l-6C)alkyl. In one embodiment, R1 is l-4C)alkyl. In one ment, R1 is fluoromethyl.
In one embodiment, R1 is difluoro(l-6C)alkyl. In one ment, R1 is difluoro(l-4C)alkyl. In one embodiment, R1 is omethyl.
In one embodiment, R1 is trifluoro(l-6C)alkyl. In one embodiment, R1 is trifluoro(l-4C)alkyl. In one embodiment, R1 is romethyl.
In one embodiment, R1 is hydroxy(l-6C)alkyl. In one embodiment, R1 is 4-hydroxymethylbutyl, 2-hydroxypropyl and 3-hydroxymethylpropyl, which can be represented by the structures: \NkVOH \J:OH fon respectively.
In one embodiment, R1 is cyano(l-6C)alkyl. In one embodiment, R1 is cyano(l-4C)alkyl. In one ment, R1 is 2-cyanopropyl which can be represented by the ure: it“.
In one embodiment, R1 is (l-3C alkoxy)(l-6C)alkyl optionally substituted with hydroxy. In one embodiment, R1 is (l-3C alkoxy)(l-4C)alkyl. In one embodiment, R1 is 2-methoxyethyl, l-methylmethoxypropyl or methoxymethyl which can be ented by the structures: “(\O/ VO/ ro\ MAI MA] In one embodiment, R1 is di(l-3C alkoxy)(l-6C)alkyl. In one embodiment, R1 is di(l-3C )(l-4C)alkyl. In one embodiment, R1 is (l-4C)alkyl substituted by two methoxy groups. In one embodiment, R1 is l,3-dimethoxymethylpropanyl which can be represented by the structure: In one embodiment, R1 is (l-6C)alkoxy. In one embodiment, R1 is (l-4C)alkoxy. In one embodiment, R1 is y, ethoxy or isopropoxy.
In one embodiment, R1 is fluoro(l-6C)alkoxy. In one embodiment, R1 is fluoro(l-4C)alkoxy. In one embodiment, R1 is fluoromethoxy.
In one embodiment, R1 is difluoro(l-6C)alkoxy. In one embodiment, R1 is difluoro(l-4C)alkoxy. In one embodiment, R1 is difluoromethoxy.
] In one embodiment, R1 is trifluoro(1-6C)alkoxy. In one embodiment, R1 is trifluoro(1-4C)a1koxy. In one embodiment, R1 is trifluoromethoxy or 2,2,2-trifluoroethoxy.
In one embodiment, R1 is trifluoromethoxy.
In one embodiment, R1 is hydroxy(2-6C)alkoxy. In one embodiment, R1 is hydroxy(2-4C)alkoxy. In one ment, R1 is 2-hydroxyethoxy, 2-hydroxyisopropoxy, 2—hydroxypropoxy, 2-hydroxymethy1propoxy or 3-hydroxypropoxy, which can be represented by the structures: O/\/OH OJ\/OH | $fi/OH ?/V<OH ?/\/\OH respectively.
In one embodiment, R1 is cyano(1-6C)alkoxy. In one embodiment, R1 is cyano(1-4C)alkoxy. In one embodiment, R1 is ethoxy, which can be represented by the structure: 9 CN In one ment, R1 is (1—3c alkoxy)(2-6C)alkoxy. In one embodiment, R1 is (1-3C alkoxy)(2-4C)alkoxy. In one embodiment, R1 is (2-4C)alkoxy substituted by methoxy. In one embodiment, R1 is 2-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 3-methoxypropoxy, 2-methy1methoxypropoxy or 2-methy1 methoxypropoxy, which can be represented by the structures: O/\/O\ OMO/ O 0\ Ok/O\ | | I I vav MN MN vav 0 X tively.
In one embodiment, R1 is di(1-3C )(2-6C)alkoxy. In one embodiment, R1 is di(1-3C alkoxy)(2-4C)alkoxy. In one embodiment, R1 is 1,3-dimethoxypropanyloxy which can be represented by the structure: In one embodiment, R1 is (3-6C lky1)methoxy. In one embodiment, R1 is cyclopropylmethoxy, which can be represented by the structure: W23%.
In one ment, R1 is ylmethoxy ally substituted by methyl.
In one embodiment, R1 is (3-methyloxetanyl)methoxy which can be represented by the structure: 53.be In one embodiment, R1 is (l-6C alkyl)sulfanyl. In one ment, R1 is (l-4C alkyl)sulfanyl. In one embodiment, R1 is ethylsulfanyl, which can be represented by the structure: In one ment, R1 is C(=O)NRaRb. In one embodiment, Ra is hydrogen.
In one embodiment, R21 is (l-6C alkyl). In one embodiment, R81 is (l-4C alkyl). In one embodiment, Rb is hydrogen. In one embodiment, Rb is (l-6C alkyl). In one embodiment, Rb is (l-4C alkyl). In one embodiment, Rb is methyl or isopropyl. In one embodiment, R1 is -C(=O)NHCH(CH3)2.
In one embodiment, R1 is O)NR°Rd. In one embodiment, Rc is hydrogen. In one embodiment, Rc is (l-6C alkyl). In one embodiment, Rc is (l-4C alkyl). In one ment, Rc is methyl. In one embodiment, Rd is hydrogen. In one embodiment, Rd is (l-6C . In one embodiment, Rd is (l-4C alkyl). In one embodiment, Rd is methyl, ethyl or isopropyl. In one embodiment, R1 is -CH2(C=O)NHCH2CH3 or -CH2(C=O)N(CH3)2.
In one embodiment, R1 is (3-6C)cycloalkyl optionally substituted with -CH20H or l-4C alkyl). In one embodiment, R1 is (3-6C)cycloalkyl optionally substituted with -CH20H or -CH20CH3. In one embodiment, R1 is cyclopropyl optionally substituted with -CH20H or -CH20CH3. In one embodiment, R1 is cyclopropyl, hydroxymethylcyclopropyl or (methoxymethyl)cyclopropyl, which can be represented by the structures : 3 Am w In one embodiment, R1 is selected from H, F, Cl, CN, OH, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, 4-hydroxymethylbutyl, oxypropyl, 3-hydroxymethylpropyl, 2-cyanopropyl, 2-methoxyethyl, l-methylmethoxyprop- 2-yl, methoxymethyl, l,3-dimethoxymethylpropanyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, romethoxy, 2-hydroxyethoxy, 2-hydroxyisopropoxy, 2-hydroxypropoxy, 2-hydroxymethylpropoxy, 3-hydroxypropoxy, cyanomethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 3-methoxypropoxy, 2-methyl- 2-methoxypropoxy, 2-methylmethoxypropoxy, l ,3 -dimethoxypropanyloxy, cyclopropylmethoxy, hyloxetanyl)methoxy, ethylsulfanyl, -C(=O)NHCH(CH3)2, -CH2(C=O)NHCH2CH3, -CH2(C=O)N(CH3)2, cyclopropyl, hydroxymethylcyclopropyl and (methoxymethyl)cyclopropyl.
In one embodiment, R1 is selected from H, (l-6C)alkyl, (3-6C)cycloalkyl optionally substituted with -CH20H or -CH20(l-4C alkyl), (l-6C)alkoxy, trifluoro(l- 6C)alkoxy, hydroxy(2-6C)alkoxy, (l-3C alkoxy)(2-6C)alkoxy, and (3- 6C)cycloalkylmethoxy.
In one embodiment, R1 is selected from H, methyl, ethyl, pyl, tert-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, oxypropoxy, 3-methoxypropoxy, 2-ethoxyethoxy, l,3-dimethoxypropanyloxy and ropylmethoxy.
In one embodiment, R1 is ed from halogen, CN, OH, l-6C)alkyl, difluoro(l-6C)alkyl, ro(l-6C)alkyl, hydroxy(l-6C)alkyl, cyano(l-6C)alkyl, di(l-3C alkoxy)(l-6C)alkyl, fluoro(l-6C)alkoxy, difluoro(l-6C)alkoxy, trifluoro(l-6C)alkoxy, cyano(l-6C)alkoxy, di(l-3C )(2-6C)alkoxy, oxetanylmethoxy (optionally substituted with methyl), (l-6C alkyl)sulfanyl, -C(=O)NRaRb, and -CH2C(=O)NR°Rd.
In one embodiment, R2 is H.
In one embodiment, R2 is halogen. In one embodiment, R2 is ed from F, Br and Cl. In one embodiment, R2 is F. In one embodiment, R2 is Br. In one embodiment, R2 is Cl.
In one embodiment, R2 is CN.
In one embodiment, R2 is OH.
In one embodiment, R2 is (l-6C)alkyl. In one embodiment, R2 is methyl.
In one embodiment, R2 is fluoro(l-6C)alkyl. In one embodiment, R2 is fluoro(l-4C)alkyl. In one embodiment, R2 is fluoromethyl.
In one embodiment, R2 is difluoro(l-6C)alkyl. In one ment, R2 is difluoro(l-4C)alkyl. In one embodiment, R2 is difluoromethyl.
In one embodiment, R2 is trifluoro(l-6C)alkyl. In one embodiment, R2 is trifluoro(l-4C)alkyl. In one embodiment, R2 is trifluoromethyl.
In one embodiment, R2 is hydroxy(l-6C)alkyl. In one embodiment, R2 is hydroxy(l-4C)alkyl. In one embodiment, R2 is 2-hydroxyethyl or 2-hydroxy methylpropyl.
] In one embodiment, R2 is (l-3C alkoxy)(l-6C)alkyl. In one embodiment, R2 is (l-3C alkoxy)(l-4C)alkyl. In one embodiment, R2 is (l-4C)alkyl substituted by methoxy.
In one ment, R2 is 2-methoxyethyl.
In one embodiment, R2 is (l-6C)alkoxy optionally substituted with (l-6C alkyl)C(=O)O-, amino(l-6C alkyl)C(=O)O- or phenyl(C=O)O-. In one embodiment, R2 is (l- 6C)alkoxy optionally substituted with (l-6C alkyl)C(=O)O- or amino(l-6C alkyl)C(=O)O-.
In one ment, R2 is (l-4C)alkoxy optionally substituted with (l-6C alkyl)C(=O)O-, amino(l-6C alkyl)C(=O)O- or phenyl(C=O)O-. In one embodiment, R2 is (l-4C)alkoxy ally substituted with (l-6C alkyl)C(=O)O- or amino(l-6C alkyl)C(=O)O-. In one embodiment, R2 is alkoxy optionally tuted with CH3C(=O)O-, (CH3)2CHC(=O)O-, (CH3CH2)2CHC(=O)O-, (CH3CH2)C(CH3)2C(=O)O-, NHZCH[CH(CH3)2]C(=O)O- or phenyl(C=O)O-. In one embodiment, R2 is (l-4C)alkoxy optionally substituted with CH3C(=O)O-, (CH3)2CHC(=O)O-, (CH3CH2)2CHC(=O)O-, (CH3CH2)C(CH3)2C(=O)O- or NHZCH[CH(CH3)2]C(=O)O-. In one embodiment, R2 is methoxy, ethoxy, isopropoxy, CH3C(=O)OCH2CHzO-, (CH3)2CHC(=O)OCH2CHzO-, (CH3CH2)2CHC(=O)OCH2CHgO-, (CH3CH2)C(CH3)2C(=O)OCH2CH20- or NHZCH[CH(CH3)2]C(=O)OCH2CHgO-.
In one embodiment, R2 is fluoro(l-6C)alkoxy. In one embodiment, R2 is l-4C)alkoxy. In one embodiment, R2 is fluoromethoxy.
In one embodiment, R2 is difluoro(l-6C)alkoxy. In one embodiment, R2 is difluoro(l-4C)alkoxy. In one embodiment, R2 is difluoromethoxy.
] In one embodiment, R2 is trifluoro(l-6C)alkoxy. In one embodiment, R2 is trifluoro(l -4C)alkoxy. In one embodiment, R2 is trifluoromethoxy or 2,2,2-trifluoroethoxy.
] In one embodiment, R2 is hydroxy(2-6C)alkoxy. In one embodiment, R2 is hydroxy(2-4C)alkoxy. In one embodiment, R2 is 2-hydroxyethoxy.
] In one embodiment, R2 is (l-3C alkoxy)(2-6C)alkoxy. In one embodiment, R2 is (l-3C alkoxy)(2-4C)alkoxy. In one embodiment, R2 is (2-4C)alkoxy substituted by methoxy. In one embodiment, R2 is 2-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, or 2-ethyoxyethoxy, which can be ented by the structures: O/ 0 .171/ ro/ E/OJ\O/ [71/0\/\O/\ 2012/026572 tively.
In one embodiment, R2 is (3-6C cycloalkyl)methoxy. In one embodiment, R2 is cyclopropylmethoxy which can be represented by the structure: 510% In one embodiment, R2 is oxetanylmethoxy optionally substituted by methyl.
In one embodiment, R2 is (3-methyloxetanyl)methoxy which can be represented by the structure: ,1]qu In one embodiment, R2 is (3-6C)cycloalkoxy (optionally substituted with OH).
In one embodiment, R2 is cyclopentoxy optionally substituted with OH. In one embodiment, R2 is oxycylopentoxy.
In one embodiment, R2 is tetrahydropyranyloxy, which can be represented by the structure: *1/00 In one embodiment, R2 is (l-6C alkyl)sulfanyl. In one embodiment, R2 is (l- 4C all<yl)sulfanyl. In one embodiment, R2 is ethylsulfanyl or isopropylsulfanyl, which can be ented by the structures: as“ task In one embodiment, R2 is y(2-6C alkyl)sulfanyl. In one embodiment, R2 is hydroxy(2-4C alkyl)sulfanyl. In one embodiment, R2 is 2-hydroxyethylsulfanyl, which can be represented by the structure: S/\/OH In one embodiment, R2 is (l-3C alkylsulfanyl)(2-6C)alkoxy. In one embodiment, R2 is (l-3C alkylsulfanyl)(2-4C)alkoxy. In one embodiment, R2 is 2-(methylsulfanyl)ethoxy, which can be represented by the ure: In one embodiment, R2 is -COOH.
In one embodiment, R2 is hetArl. In one embodiment, hetAr1 is pyrazolyl or pyridinyl optionally substituted with one or more groups selected from (l-6C)alkyl. In one embodiment, hetAr1 is pyrazolyl or pyridinyl optionally substituted with one or more methyl groups. Examples of R2 when represented by hetAr1 include l,3-dimethyl-pyrazolyl, 1,5- dimethyl-pyrazolyl, l-methylpyrazolyl, l,3-dimethylpyrazolyl, 4-methylpyrazol-l-yl and pyridyl, which can be represented by the structures: N{ / / ii / 31 /N I ‘N w?— ’NI ”l, / *4“ \ In one embodiment, R2 is -C(=O)NReRf. In one embodiment, Re is hydrogen.
In one embodiment, Re is (l-6C alkyl). In one embodiment, Re is (l-4C alkyl). In one embodiment, Re is methyl. In one ment, Rf is hydrogen. In one ment, Rf is (l-6C alkyl). In one embodiment, Rf is (l-4C alkyl). In one embodiment, Rf is methyl, ethyl, or 2—methylbutyl. In one embodiment, Rf is cyclopropyl optionally substituted with (l- 4C)alkyl. In one embodiment, Rf is cyclopropyl ally substituted with methyl. In one embodiment, es of R2 when represented by -C(=O)NR‘3Rf include methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, tert-butylcarbamoyl, isopentylcarbamoyl, l-methylcyclpropylcarbamoyl and dimethylcarbamoyl, which can be represented by the structures: 0 O N/ N/\ EANJ\ 12%J< H H H H 0 O O figkN KIN/5 N/ HAs H | In one embodiment, R2 is -NReC(=O)Rf. In one embodiment, Re is hydrogen.
In one embodiment, Re is (l-6C alkyl). In one embodiment, Re is (l-4C alkyl). In one embodiment, Re is methyl. In one embodiment, Rf is en. In one embodiment, Rf is (l-6C alkyl). In one ment, Rf is (l-4C alkyl). In one ment, Rf is methyl, ethyl, propyl, isopropyl or tert-butyl. In one embodiment, examples of R2 when represented by (=O)Rf include O)NHCH(CH3)2 and -NHC(=O)NHC(CH3)3, which can be represented by the structures: ,(HFA 0 ,(Hfi 2012/026572 respectively.
] In one embodiment, R2 is oxetanyl.
In one embodiment, R2 is cyclopropyl optionally substituted with CHZOH or -CH20(l-6C alkyl). In one embodiment, R2 is ropyl optionally substituted with CHzOH or CH20CH3. In one embodiment, R2 is selected from ropyl, hydroxymethylcyclopropyl and methoxymethylcyclopropyl, which can be represented by the structures : X fife A? In one embodiment, R2 is selected from H, F, Br, Cl, CN, OH, trifluoromethyl, 2-hydroxyethyl, 2-hydroxymethylpropyl, 2-methoxyethyl, methoxy, ethoxy, isopropoxy, CH3C(=O)OCH2CHgO-, (CH3)2CHC(=O)OCH2CHgO-, (CH3CH2)2CHC(=O)OCH2CHgO-, (CH3CH2)C(CH3)2C(=O)OCH2CH20-, CH(CH3)2]C(=O)OCH2CHgO-, phenyl(C=O)O-, difluoro-methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2- hydroxyethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 2- ethyoxyethoxy, cyclopropylmethoxy, (3-methyloxetanyl)methoxy, 2-hydroxycylopentoxy, tetrahydropyranyloxy, ethylsulfanyl, isopropylsulfanyl, 2-hydroxyethylsulfanyl, 2- (methylsulfanyl)ethoxy, -COOH, l,3-dimethyl-pyrazolyl, l,5-dimethyl-pyrazolyl, l- methylpyrazolyl, l ,3 -dimethylpyrazol-5 -yl, 4-methylpyrazol- l -yl pyrid-3 -yl, methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, tert-butylcarbamoyl, isopentylcarbamoyl, l-methylcyclpropylcarbamoyl, dimethylcarbamoyl, -NH(C(=O)CH (CH3)2, -NHC(=O)NHC(CH3)3, oxetanyl, cyclopropyl, hydroxymethylcyclopropyl and methoxymethyl-cyclopropyl.
In one ment, R2 is selected from H, F, Br, Cl, CN, OH, romethyl, 2-hydroxyethyl, 2-hydroxymethylpropyl, 2-methoxyethyl, methoxy, ethoxy, poxy, CH3C(=O)OCH2CHzO-, (CH3)2CHC(=O)OCH2CHzO-, (CH3CH2)2CHC(=O)OCH2CHzO-, (CH3CH2)C(CH3)2C(=O)OCH2CH20-, NH2CH[CH(CH3)2]C(=O)OCH2CHzO-, difluoro- methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 3-methoxypropoxy, oxypropoxy, 2-ethyoxyethoxy, cyclopropylmethoxy, (3-methyloxetanyl)methoxy, tetrahydropyranyloxy, ethylsulfanyl, isopropylsulfanyl, 2-hydroxyethylsulfanyl, 2-(methylsulfanyl)ethoxy, -COOH, l,3-dimethyl-pyrazolyl, 1,5- dimethyl-pyrazolyl, l-methylpyrazolyl, l,3-dimethylpyrazolyl, 4-methylpyrazol-l- yl 3-yl, methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, tert-butylcarbamoyl, isopentylcarbamoyl, l-methylcyclpropylcarbamoyl, dimethylcarbamoyl, -NH(C(=O)CH (CH3)2, -NHC(=O)NHC(CH3)3, cyclopropyl, hydroxymethylcyclopropyl and methoxymethyl-cyclopropyl.
In one embodiment, R2 is selected from H, (l-3C alkoxy)(l-6C)alkyl, hydroxy(2-6C)alkoxy, and (l-6C)alkoxy which is optionally substituted with (l-6C alkyl)C(=O)O- or amino(l-6C alkyl)C(=O)O-.
In one embodiment, R2 is selected from H, 2-methoxyethoxy, oxyprop- 2-oxy, 2-methoxypropoxy, 2-ethyoxyethoxy, and 2-hydroxyethoxy.
In one embodiment, R2 is selected from halogen, CN, OH, (l-6C)alkyl, fluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, y(l-6C)alkyl, l- 6C)alkoxy, difluoro(l-6C)alkoxy, trifluoro(l-6C)alkoxy, (l-3C alkoxy)(2-6C)alkoxy, (3-6C cycloalkyl)methoxy, oxetanylmethoxy (optionally substituted with methyl), tetrahydro- pyranyloxy, (l-6C alkyl)sulfanyl, hydroxy(2-6C alkyl)sulfanyl, (l-3C ulfanyl)(2- 6C)alkoxy, -COOH, hetArl, -C(=O)NReRf, -NReC(=O)Rf, and cyclopropyl optionally substituted with -CH20H or l-6C .
In one embodiment, R1 and R2 together with the atoms to which they are ed form a 5-6 membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from O and N, wherein said ring is optionally substituted with (l- yl. In one embodiment,_R1 and R2 together with the atoms to which they are attached form a 5 membered heterocyclic ring haVing a ring oxygen atom and optionally substituted with (l-4C)alkyl, such as methyl. A particular example of a ring formed by R1 and R2 together with the atoms to which they are attached includes the ure: 3 0 ] In one embodiment, R3 is H.
In one embodiment, R3 is halogen. In one embodiment, R3 is F.
In one embodiment, R3 is (l-6C)alkyl. In one embodiment, R3 is (l-4C)alkyl.
In one embodiment, R3 is methyl.
In one embodiment, R3 is selected from H, F and methyl.
In one embodiment, R3 is selected from H and F.
] In one embodiment, R1 is H; R2 is H, F, Br, Cl, CN, OH, trifluoromethyl, 2-hydroxyethyl, 2-hydroxymethylpropyl, 2-methoxyethyl, methoxy, ethoxy, isopropoxy, CH3C(=O)OCH2CH20-, (CH3)2CHC(=O)OCH2CH20-, (CH3CH2)2CHC(=0)OCH2CH20-, (CH3CH2)C(CH3)2C(=O)OCH2CHgO-, NHZCH[CH(CH3)2]C(=O)OCH2CHzO-, o- methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, oxypropoxy, 2-methoxypropoxy, 2-ethyoxyethoxy, cyclopropylmethoxy, (3-methyloxetanyl)methoxy, tetrahydropyranyloxy, ethylsulfanyl, isopropylsulfanyl, 2-hydroxyethylsulfanyl, hylsulfanyl)ethoxy, -COOH, l,3-dimethyl-pyrazolyl, 1,5- dimethyl-pyrazolyl, l-methylpyrazolyl, methylpyrazolyl, ylpyrazol-l- yl pyridyl, methylcarbamoyl, ethylcarbamoyl, pylcarbamoyl, tert-butylcarbamoyl, isopentylcarbamoyl, l-methylcyclpropylcarbamoyl, dimethylcarbamoyl, cyclopropyl, hydroxymethylcyclopropyl or methoxymethylcyclopropyl; and R3 is H, F or methyl.
In one embodiment, R2 is H; R1 is H, F, Cl, CN, OH, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, 4-hydroxymethylbutyl, 2-hydroxypropyl, 3-hydroxy methylpropyl, 2-cyanopropyl, 2-methoxyethyl, l -methylmethoxypropyl, methoxymethyl, l,3-dimethoxymethylpropanyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxyisopropoxy, 2—hydroxypropoxy, 2-hydroxymethylpropoxy, 3-hydroxypropoxy, cyanomethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 3-methoxypropoxy, 2-methyl- 2-methoxypropoxy, 2-methylmethoxypropoxy, l ,3 -dimethoxypropanyloxy, cyclopropylmethoxy, (3-methyloxetanyl)methoxy, ethylsulfanyl, -C(=O)NHCH(CH3)2, -CH2(C=O)NHCH2CH3, -CH2(C=O)N(CH3)2, cyclopropyl, hydroxymethylcyclopropyl and xymethyl)cyclopropyl; and R3 is H, F or methyl.
In one embodiment, R3 is H; R1 is H, F, Cl, CN, OH, methyl, ethyl, isopropyl, utyl, trifluoromethyl, 4-hydroxymethylbutyl, 2-hydroxypropyl, 3-hydroxy methylpropyl, 2-cyanopropyl, 2-methoxyethyl, l lmethoxypropyl, methoxymethyl, l,3-dimethoxymethylpropanyl, methoxy, ethoxy, poxy, difluoromethoxy, trifluoromethoxy, 2-hydroxyethoxy, oxyisopropoxy, oxypropoxy, 2-hydroxymethylpropoxy, 3-hydroxypropoxy, cyanomethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 3-methoxypropoxy, 2-methyl- 2-methoxypropoxy, 2-methylmethoxypropoxy, l ,3 -dimethoxypropanyloxy, cyclopropylmethoxy, (3-methyloxetanyl)methoxy, ethylsulfanyl, -C(=O)NHCH(CH3)2, -CH2(C=O)NHCH2CH3, -CH2(C=O)N(CH3)2, cyclopropyl, hydroxymethylcyclopropyl and (methoxymethyl)cyclopropyl, and R2 is H, F, Br, Cl, CN, OH, trifluoromethyl, 2-hydroxyethyl, 2-hydroxymethylpropyl, 2-methoxyethyl, methoxy, ethoxy, isopropoxy, CH3C(=O)OCH2CHzO-, (CH3)2CHC(=O)OCH2CHzO-, (CH3CH2)2CHC(=O)OCH2CHzO-, (CH3CH2)C(CH3)2C(=O)OCH2CHgO-, NHZCH[CH(CH3)2]C(=O)OCH2CHzO-, difluoro- methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 2-ethyoxyethoxy, cyclopropylmethoxy, (3-methyloxetany1)methoxy, tetrahydropyranyloxy, ethylsulfanyl, isopropylsulfanyl, 2-hydroxyethylsulfanyl, 2-(methy1sulfany1)ethoxy, -COOH, 1,3-dimethy1-pyrazolyl, 1,5- dimethyl-pyrazolyl, 1-methylpyrazoly1, 1,3-dimethy1pyrazoly1, 4-methy1pyrazol yl pyridyl, carbamoyl, ethylcarbamoyl, isopropylcarbamoyl, tert-butylcarbamoyl, isopentylcarbamoyl, 1-methy1cyclpropy1carbamoyl, dimethylcarbamoyl, cyclopropyl, hydroxymethylcyclopropyl or methoxymethylcyclopropyl; and R2 is H, F, Br, C1, CN, OH, trifluoromethyl, 2-hydroxyethyl, 2-hydroxymethy1propy1, oxyethy1, methoxy, , poxy, CH3C(=O)OCH2CHzO-, (CH3)2CHC(=O)OCH2CHzO-, (CH3CH2)2CHC (=O)OCH2CHgO-, 2)C(CH3)2C(=O)OCH2CHzO-, NHgCH[CH(CH3)2]C(=O)OCH2 CHzO-, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, oxyethoxy, 2-methoxyethoxy, oxypropoxy, 2-methoxypropoxy, 2-ethyoxyethoxy, cyclopropylmethoxy , (3-methyloxetany1)methoxy, tetrahydropyranyloxy, ethylsulfanyl, pylsulfanyl, 2-hydroxyethylsulfanyl, 2-(methy1su1fany1)ethoxy, -COOH, 1,3-dimethy1— pyrazoly1, 1,5-dimethy1-pyrazolyl, 1-methylpyrazoly1, 1,3-dimethy1pyrazolyl, 4-methy1pyrazoly1 pyridy1, methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, tert-butylcarbamoyl, isopentylcarbamoyl, 1 -methylcyclpropylcarbamoyl, dimethylcarbamoyl, cyclopropyl, ymethylcyclopropyl or methoxymethylcyclopropyl.
In one embodiment, R2 and R3 are H, and R1 is H, F, C1, CN, OH, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, 4-hydroxymethylbuty1, 2-hydroxyprop yl, 3-hydroxymethy1propy1, 2-cyanopropyl, 2-methoxyethy1, 1-methy1—3- methoxyprop-Z-yl, methoxymethyl, 1,3-dimethoxymethy1propany1, methoxy, ethoxy, isopropoxy, omethoxy, trifluoromethoxy, oxyethoxy, 2-hydroxyisopropoxy, 2—hydroxypropoxy, 2-hydroxymethy1propoxy, 3-hydroxypropoxy, cyanomethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 3-methoxypropoxy, 2-methy1— 2-methoxypropoxy, 2-methy1—3-methoxypropoxy, 1 ,3 -dimethoxypropanyloxy, cyclopropylmethoxy, (3-methyloxetany1)methoxy, ethylsulfanyl, -C(=O)NHCH(CH3)2, =O)NHCH2CH3, -CH2(C=O)N(CH3)2, cyclopropyl, hydroxymethylcyclopropyl and (methoxymethyl)cyclopropyl.
In one embodiment, R1 and R3 are H; and R2 is H, F, Br, C1, CN, OH, trifluoromethyl, 2-hydroxyethyl, 2-hydroxymethy1propy1, 2-methoxyethy1, methoxy, ethoxy, isopropoxy, CH3C(=O)OCH2CHzO-, (CH3)2CHC(=O)OCH2CHzO-, (CH3CH2)2CHC (=O)OCH2CHgO-, (CH3CH2)C(CH3)2C(=O)OCH2CHzO-, NHgCH[CH(CH3)2]C(=O)OCH2 CH20-, omethoxy, trifiuoromethoxy, 2,2,2-trifiuoroethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 2-ethyoxyethoxy, cyclopropylmethoxy, (3-methyloxetanyl)methoxy, tetrahydropyranyloxy, ethylsulfanyl, isopropylsulfanyl, 2-hydroxyethylsulfanyl, 2-(methylsulfanyl)ethoxy, -COOH, l,3-dimethylpyrazolyl , l,5-dimethyl-pyrazolyl, l-methylpyrazolyl, l,3-dimethylpyrazolyl, 4-methylpyrazol-l-yl pyridyl, methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, tert-butylcarbamoyl, isopentylcarbamoyl, l-methylcyclpropylcarbamoyl, dimethylcarbamoyl, cyclopropyl, hydroxymethylcyclopropyl or methoxymethylcyclopropyl.
In one embodiment, R1 is selected from H, (l-6C)alkyl, (3-6C)cycloalkyl optionally substituted with -CH20H or -CH20(l-4C alkyl), (l-6C)alkoxy, trifiuoro(l- 6C)alkoxy, hydroxy(2-6C)alkoxy, (l-3C alkoxy)(2-6C)alkoxy, and (3- 6C)cycloalkylmethoxy; R2 is selected from H, (l-3C alkoxy)(l-6C)alkyl, hydroxy(2- oxy, and (l-6C)alkoxy which is optionally substituted with (l-6C C(=O)O- or l-6C alkyl)C(=O)O-; and R3 is H or F.
In one ment, R1 is selected from H and (l-3C alkoxy)(2-6C)alkoxy; R2 is H; and R3 is H or F.
Referring now to R4, which has the structure: R5 Rsa R9 R8 in one embodiment, R4 has the absolute configuration shown in Figure la, ] where R5, Rsa, R6, R7, R8 and R9 are as defined herein.
In one embodiment, R4 has the te configuration shown in Figure Ib L52")LN; R6 ZquIIR7 R9 R8 where R5, Rsa, R6, R7, R8 and R9 are as defined herein.
In one embodiment, R4 has the absolute configuration shown in Figure Ic N R7 R9 R8 where R5, Rsa, R6, R7, R8 and R9 are as defined herein.
In one embodiment, R4 has the absolute ration shown in Figure 1d Rf: R5a R9 R8 where R5, Rsa, R6, R7, R8 and R9 are as defined herein.
In one embodiment, R5 is CF3.
In one embodiment, R5 is CHZF.
In one ment, R5 is CHFZ.
In one embodiment, R5 is methyl.
In one embodiment, R5 is ethyl.
In one embodiment, R5&1 is H.
In one embodiment, R5&1 is methyl.
In one embodiment, R5 is CF3, CHZF, CHFZ, methyl or ethyl and R5&1 is H.
In one embodiment, R5 is CF3 or methyl, and R581 is H.
In one embodiment, R5 is CF3 and R5&1 is H.
In one ment, R5 is methyl, and R5&1 is H.
In one embodiment, R5 is CF3, CHZF, CHFZ, methyl or ethyl and R5&1 is methyl.
In one embodiment, R5 is CF3 or methyl, and R5&1 is .
In one embodiment, R5 is CF3 and R5&1 is methyl.
In one embodiment, R5 and R5&1 are both .
In one embodiment, R5 and R5&1 together with the atom to which they are attached form a cyclopropyl ring.
In one embodiment, R6 is H.
In one embodiment, R6 is NHZ.
] In one embodiment, R6 is OH.
In one embodiment, R6 is (1-6C alkyl)NH-. In one embodiment, R6 is (1-4C alkyl)NH-. In one ment, R6 is CH3NH-, (CH3)2CHNH- or (CH3)2N—.
In one embodiment, R6 is fluoro(l-6C alkyl)NH-. In one ment, R6 is fluoro(l-4C alkyl)NH-. In one embodiment, R6 is FCHZCHZNH: In one embodiment, R6 is hydroxy(l-6C alkyl)NH-. In one ment, R6 is hydroxy(l-4C alkyl)NH-. In one embodiment, R6 is HOCHZCHZNH-.
In one embodiment, R6 is (3-6C cycloalkyl)CH2NH-. In one embodiment, R6 is (cyclopropyl)CH2NH-.
In one embodiment, R6 is (l-6C alkyl)C(=O)NH-. In one embodiment, R6 is (1-4c alkyl)C(=O)NH-. In one embodiment, R6 is CH3C(=O)NH-.
In one embodiment, R6 is (l-6C alkyl)OC(=O)NH- optionally tuted with -methyloxo-l,3-dioxolyl. In one embodiment, R6 is (l-4C OC(=O)NH- optionally substituted with 5-methyloxo-l,3-dioxolyl. In one embodiment, R6 is (CH3)3COC(=O)NH- or a group represented by the structure: In one embodiment, R6 is amino(l-6C)alkyl-. In one embodiment, R6 is amino(l-4C)alkyl-. In one embodiment, R6 is NHZCH2-.
In one embodiment, R6 is selected from H, NHZ, OH, CH3NH-, (CH3)2 CHNH-, FCHZCHZNH-, HOCHZCHZNH-, (cyclopropyl)CH2NH-, CH3C(=O)NH-, (CH3)3COC(=O)NH- and NH2CH2-.
In one embodiment, R7 is H.
In one embodiment, R7 is alkyl. In one embodiment, R7 is (l-4C)alkyl.
In one embodiment, R7 is methyl or ethyl.
In one embodiment, R7 is fluoro(l-6C)alkyl. In one ment, R7 is l-4C)alkyl. In one embodiment, R7 is FCH2-.
In one embodiment, R7 is hydroxy(l-6C)alkyl. In one embodiment, R7 is hydroxy(l-4C)alkyl. In one embodiment, R7 is HOCH2-.
In one embodiment, R7 is selected from H, methyl, ethyl, FCHZ- and HOCH2-.
In one embodiment, R7 is H and R6 is H, -NH2, OH, (1—oc alkyl)NH-, fluoro(l-6C NH-, hydroxy(l-6C alkyl)NH-, (3-6C lkyl)CH2NH-, (l-6C alkyl)C(=O)NH-, (l-6C alkyl)OC(=O)NH- or amino(l-6C)alkyl-.
In one embodiment, R7 is H and R6 is H, NHZ, OH, , CHNH-, FCHZCHZNH-, HOCHZCHZNH-, (cyclopropyl)CH2NH-, CH3C(=O)NH-, (CH3)3COC(=O) NH- or NHzCH2-.
In one embodiment, R7 is H and R6 is NH2, CH3NH-, (CH3)2CHNH-, FCHZCHZNH-, HOCHZCHZNH-, (cyclopropyl)CH2NH-, O)NH-, (CH3)3COC(=O) NH- or NHzCH2-.
In one embodiment, R7 is H and R6 is NH2.
In one embodiment, R7 is methyl and R6 is H, -NH2, OH, (1-6C alkyl)NH-, fluoro(l-6C alkyl)NH-, y(l-6C alkyl)NH-, (3-6C cycloalkyl)CH2NH-, (l-6C alkyl)C(=O)NH-, (l-6C alkyl)OC(=O)NH- or amino(l-6C)alkyl-.
In one embodiment, R7 is methyl and R6 is H, NH2, OH, , (CH3)2CHNH-, ZNH-, HOCHZCHZNH-, (cyclopropyl)CH2NH-, CH3C(=O)NH-, (CH3)3COC(=O)NH- or NHZCH2-.
In one embodiment, R7 is methyl and R6 is NHZ, CH3NH-, (CH3)2CHNH-, FCHZCHZNH-, HOCHZCHZNH-, (cyclopropyl)CH2NH-, O)NH-, (CH3)3COC(=O) NH- or NHZCH2-.
In one embodiment, R7 is methyl and R6 is NH2.
In one embodiment, R6 and R7 together with the atom to which they are attached form a 5-6 membered spirocyclic heterocycle haVing a ring nitrogen atom. An example of an R4 group wherein R6 and R7 together with the atom to which they are attached form a 5-6 membered spirocyclic heterocycle haVing a ring nitrogen atom is the structure: RWLN5 NH “an. R8 wherein R5, Rsa, R8 and R9 are as defined herein. In one embodiment, R8 is H.
In one embodiment, R9 is H. In one embodiment, R8 and R9 are both H.
In one embodiment, R8 is H.
In one embodiment, R8 is halogen. In one embodiment, R8 is F.
In one embodiment, R8 is OH.
In one embodiment, R8 is (l-6C)alkoxy. In one ment, R8 is -OMe.
In one embodiment, R8 is selected from H, F, OH or -OMe.
In one embodiment, R8 is selected from H, F, or OH.
In one embodiment, R6 and R8 er with the carbon atoms to which they are attached form a cyclopropyl ring optionally substituted with NH2. An example of an R4 group wherein R6 and R8 together with the carbon atoms to which they are attached form a cyclopropyl ring is the structure: wherein R5, Rsa, R7 and R9 are as defined herein. In one embodiment, R7 is H.
In one embodiment, R9 is H. In one ment, R7 and R9 are both H.
] In one embodiment, R9 is H.
In one embodiment, R6 and R9 together form a linking group haVing the formula -CH2NH- which links the carbon atoms to which they are attached, thereby forming a ic ring which can be represented by the ure: E’NféNH An example of an R4 group wherein R6 and R9 together form a linking group haVing the formula -CH2NH- which links the carbon atoms to which they are attached is the ure: R5 N/\ “Ma, wherein R5, Rsa, R7 and R8 are as defined herein. In one embodiment, R7 is H.
In one embodiment, R8 is H. In one embodiment, R7 and R8 are both H.
In one embodiment, R5 is CF3; R5&1 is H; R8 and R9 are H; R6 is ed from H, NH2, OH, (l-6C alkyl)NH-, fluoro(l-6C alkyl)NH-, y(l-6C alkyl)NH-, (3-6C cycloalkyl)CH2NH-, (l-6C alkyl)C(=O)NH-, (l-6C alkyl)OC(=O)NH- or amino(l-6C)alkyl-; and R7 is selected from H, methyl, ethyl, FCHZ- and HOCH2-.
In one embodiment, R5 is CF3; R5&1 is H; R8 and R9 are H; R6 is selected from H, NHZ, OH, CH3NH-, (CH3)2CHNH-, FCHZCHZNH; HOCHZCHZNH-, (cyclopropyl)CH2NH-, CH3C(=O)NH-, (CH3)3COC(=O)NH-, and NHZCH2-; and R7 is selected from H, methyl, ethyl, FCHZ- and HOCH2-.
In one embodiment, R5 is CF3; R5&1 is H; R8 and R9 are H; R6 is selected from H, NHZ, OH, CH3NH-, (CH3)2CHNH-, FCHZCHZNH; HOCHZCHZNH-, (cyclopropyl) CHZNH-, CH3C(=O)NH-, (CH3)3COC(=O)NH-, and NHZCH2-; and R7 is H or methyl.
In one embodiment, R5 is CF3; R5&1 is H; R8 and R9 are H; R6 is NHZ; and R7 is H or methyl.
In one embodiment, R5 is methyl; R5&1 is H; R8 and R9 are H; R6 is selected from H, NHZ, OH, CH3NH-, (CH3)2CHNH-, FCHZCHZNH-, HOCHZCHZNH; (cyclopropyl)CH2NH-, CH3C(=O)NH-, (CH3)3COC(=O)NH-, and NHZCH2-; and R7 selected from H, methyl, ethyl, FCHZ- and HOCH2-.
In one embodiment, R5 is methyl; R5&1 is H; R8 and R9 are H; R6 is selected from H, NHZ, OH, CH3NH-, CHNH-, FCHZCHZNH-, HOCHZCHZNH; (cyclopropyl)CH2NH-, CH3C(=O)NH-, (CH3)3COC(=O)NH-, and NHZCH2-; and R7 is H or methyl.
In one embodiment, R5 is methyl; R5&1 is H; R8 and R9 are H; R6 is NHZ; and R7 is H or methyl.
In one embodiment, R4 is ed from F F Fi Pi NH2 a. “Q a :“F‘g :NQ/NY fiobwfilkwibffl F3om FFOFY 0 film :FNCYFIX Fig? F F FixF F F F .2 Fix OH N N F“ F“ Pi: 2. NQ< is a “QC F OH NH2 NH2 F F Ft:1cmOH i Pi 2cm.F Picng EQHN F F F F F F FF | N\ NH atx NN NH2 "m. H 0/ "mF0 including the enantiomers and diastereomers f.
In one embodiment of Formula I, R1 is ed from H, (l-6C)alkyl, (3- 6C)cycloalkyl optionally substituted with -CH20H or -CH20(l-4C , (l-6C)alkoxy, trifluoro(l-6C)alkoxy, hydroxy(2-6C)alkoxy, (l-3C alkoxy)(2-6C)alkoxy, and (3- 6C)cycloalkylmethoxy; R2 is selected from H, (l-3C alkoxy)(l-6C)alkyl, hydroxy(2- 6C)alkoxy, and (l-6C)alkoxy which is optionally substituted with (l-6C alkyl)C(=O)O- or amino(l-6C alkyl)C(=O)O-; R3 is H or F; R5 is CF3; R5&1 is H; R6 is selected from H, NH2, OH, (l-6C alkyl)NH-, fluoro(l-6C alkyl)NH-, hydroxy(l-6C alkyl)NH-, (3-6C cycloalkyl)CH2NH-, (l-6C alkyl)C(=O)NH-, (l-6C alkyl)OC(=O)NH- or amino(l-6C)alkyl-; R7 is H or (l-6C)alkyl; R8 is H; and R9 is H.
In one embodiment of Formula I, R1 is selected from H, (l-6C)alkyl, (3- 6C)cycloalkyl optionally tuted with -CH20H or -CH20(l-4C alkyl), (l-6C)alkoxy, trifluoro(l-6C)alkoxy, hydroxy(2-6C)alkoxy, (l-3C alkoxy)(2-6C)alkoxy, and (3- loalkylmethoxy; R2 is selected from H, (l-3C alkoxy)(l-6C)alkyl, y(2- 6C)alkoxy, and (l-6C)alkoxy which is optionally substituted with (l-6C alkyl)C(=O)O- or amino(l-6C alkyl)C(=O)O-; R3 is H or F; R5 is CF3; R5&1 is H; R6 is NH2; R7 is H or (1- 6C)alkyl; R8 is H; and R9 is H.
In one embodiment, R10 is H.
In one embodiment, R10 is halogen. In one embodiment, R10 is F.
In one ment, the nd of Formula I is selected from any one of es 1-328 or a pharmaceutically acceptable salt thereof. In one embodiment, the salt of a compound of Example 1-328 is a hydrochloride and dihydrochloride salt.
It will be appreciated that n compounds according to the invention may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.
It will further be appreciated that the compounds of Formula I or their salts may be isolated in the form of es, and accordingly that any such solvate is included within the scope of the present ion. For example, compounds of Formula I can exist in unsolvated as well as solvated forms with ceutically acceptable solvents such as water, ethanol, and the like.
The compounds of Formula I include pharmaceutically acceptable salts thereof. In addition, the compounds of Formula I also include other salts of such compounds which are not necessarily ceutically acceptable salts, and which may be useful as intermediates for ing and/or purifying compounds of a I and/or for separating enantiomers of compounds of Formula I. Particular examples of salts include hydrochloride and dihydrochloride salts of compounds of Formula I.
The term "pharmaceutically acceptable" indicates that the substance or ition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
Compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in ular when mentioned in relation to a compound according to Formula 1, comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, when hydrogen is ned, it is understood to refer to 1H, 2H, 3H or mixtures thereof; when carbon is mentioned, it is understood to refer to 11C, 12C, 13 C, 14C or es thereof; when nitrogen is mentioned, it is understood to refer to 13N, 14N, 15N or es thereof; when oxygen is mentioned, it is understood to refer to 14O, 15O, 16O, 17O, 18O or mixtures thereof; and when fluoro is mentioned, it is understood to refer to 18F, 19F or es thereof The nds according to the invention therefore also comprise compounds with one or more isotopes of one or more atom, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been ed by one of its radioactive enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the present invention, r radioactive or not, are intended to be encompassed within the scope of the present invention.
According to another aspect, the t invention provides a process for the preparation of a compound of Formula I or a salt thereof as defined herein which comprises: (a) ng a corresponding compound of formula II or a protected derivative thereof Hl\|l N where R4 is as defined for Formula I, with a corresponding nd having the formula III or a protected derivative thereof ] where R1, R2 and R3 are as defined for Formula I, in the presence of an organo hypervalent iodine t; or (b) for a compound of Formula I where R2 is hetAr1 or a cyclopropyl ring optionally substituted with -CH20H or -CH20(l-6C alkyl), reacting a corresponding compound having the formula IV or a protected derivative thereof: / N R1 NxN/ N\ Br where R1, R3 and R4 are as defined for Formula I, with a reagent having the formula OR\B/x ORy O \B/RX \ \ hetArl or Cyc respectively, where hetAr1 is as defined for Formula I, Cyc is cyclopropyl optionally substituted with -CH20H or -CH20(l-6C alkyl), and RK and Ry are H or (1- 6C)alkyl, or RK and Ry together with the atoms to which they are connected form a 5-6 ed ring optionally substituted with 1-4 substituents selected from (l-3C , wherein said reaction takes place in the presence of a palladium catalyst and optionally in the presence of a base and a ligand; or ] (c) for a compound of Formula I where R2 is -NReC(=O)Rf, reacting a corresponding compound having the formula IV or a protected tive thereof: CS/ N R1 \N/ N\ Br where R1, R3 and R4 are as defined for Formula I, with a reagent having the formula HNR‘3C(=O)Rf in the presence of a base and a metal catalyst; or (d) for a compound of Formula I where R2 is (l-6C alkyl)sulfanyl or hydroxy(2-6C alkyl)sulfanyl, reacting a corresponding compound having the formula IV or a protected derivative thereof: / N R1 \N/ N\ Br ] where R1, R2, R3 and R4 are as defined for Formula I, with a reagent having the formula HS(l-6C alkyl) or HS(l-6C alkyl)OH, respectively, in the presence of a base; or (e) for a compound of a I where R2 is -C(=O)NReRf, ng a corresponding compound having the formula V or a protected tive thereof: i: R1 o [NYE/lilo“R3 where R1, R3 and R4 are as defined for Formula I, with a reagent having the formula HNReRf, where Re and Rf are as defined for Formula I, in the presence of a base and a coupling reagent; or (f) for a compound of Formula I where R1 is -CH2C(=O)NR°Rd, coupling a corresponding compound having the formula VI or a protected derivative thereof , N OH N‘N/ N\ R2 where R2, R3 and R4 are as defined for Formula I, with a reagent having the a HNRCRd, where R0 and Rd are as defined for Formula I, in the presence of a base and a coupling reagent; or (g) for a nd of Formula I where R2 is (l-6C)alkoxy substituted with (l-6C alkyl)C(=O)O-, ng a corresponding compound having the formula VII or a protected derivative thereof , N R1 \N/ /N O(1—6C OH ] where R1, R3 and R4 are as defined for Formula I, with a (l-6C)alkyl acid anhydride or a (l-6C)alkyl acid chloride in the presence of a base; or ] (h) for a nd of Formula I where R2 is (l-6C)alkoxy substituted with amino(l-6C alkyl)C(=O)O-, coupling a corresponding compound having the formula VII or a protected derivative thereof , N R1 \N/ /N O(1—6C alkyI)OH where R1, R3 and R4 are as defined for Formula I, with a compound having the formula PlNH(l-6C alkyl)C(=O)OH where P1 is H or an amine protecting group, in the presence of a base and a coupling reagent; or (i) for a compound of Formula I where R4 is a moiety having the structure where R5, Rsa, and R7 are as defined for Formula I, R8 is H, halogen, OH, or (l-6C)alkoxy, and R9 is H, reacting a corresponding compound having the formula VIII where R1, R2, R3, R5, Rsa, and R7 are as defined for a I, R8 is H, halogen, OH, or (l-6C)alkoxy, and R9 is H, with a (l-6C)alkylcarboxylic acid anhydride or a (l-6C)alkylcarboxylic acid chloride in the presence of a base; or (j) for a compound of Formula I where R4 is a moiety having the structure R5 R5, ,(1—6C alkyl) where R5, Rsa, and R7 are as defined for Formula I, R8 is H, halogen, OH, or (l-6C)alkoxy, and R9 is H, reacting a corresponding compound haVing the formula VIII VIII where R1, R2, R3, R5, R5&1 and R7 are as defined for Formula I, R8 is H, n, OH, or (l-6C)alkoxy, and R9 is H, with a aldehyde or a ted (1- 6C)aldehyde in the presence of a catalyst and a base followed by treatment with a reducing agent; or (k) for a compound of Formula I where R4 is a moiety having the structure R5 R53 157%NfiR7N(1—6C alkyl) R9 R8 where R5, Rsa, and R7 are as defined for Formula I, R8 is H, halogen, OH, or (l-6C)alkoxy, and R9 is H, reacting a corresponding compound haVing the formula VIII WO 54274 where R1, R2, R3, R5, Rsa, and R7 are as defined for Formula I, R8 is H, halogen, OH, or (l-6C)alkoxy, and R9 is H, in the presence of a reagent having the formula HC(=O)(l-5C alkyl) and a reducing agent; or (1) for a compound of a I where R4 is a moiety having the structure Me NHP2 157%N R7 R9 R8 where R7 is as defined for Formula I, R8 is H, halogen, OH, or alkoxy, R9 is H, and P2 is H or an amine protecting group, reacting a corresponding compound having the formula IX NfN/N R1 /N R2 where R1, R2, and R3 are as defined for Formula I, in the presence of a Lewis acid, followed by treatment with a reducing agent; and removing any protecting group or groups and, if desired, forming a salt.
Referring to method (a), the organo alent iodine reagent refers to any hypervalent iodine reagent suitable for forming heterocyclic rings. Examples e iodobenzene diacetate and [hydroxy(tosyloxy)iodo]benzene (HTIB), which can be prepared by treating iodobenzene diacetate with p—toluenesulfonic acid monohydrate in itrile.
Suitable solvent systems when using iodobenzene diacetate include methanolic potassium hydroxide. Suitable solvent systems when using HTIB include neutral solvents, for e acetonitrile or dioxane. The reaction can be performed at a temperature ranging from 80 to 110 CC.
Referring to method (b), suitable palladium catalysts include PdClz(dppf)*dcm, Pd(PPh3)4, Pd2(dba)3, Pd(OAc)2 and Pd(PPh3)2Clz. Suitable ligands include P(Cy)3, XPHOS, DIPHOS and rac-BINAP. The base may be, for example, an amine base such as triethylamine. Convenient solvents include IPA and toluene. The reaction can be conveniently performed at a ature ranging from t temperature to 120 CC, for example from 80 to 110 CC.
Referring to method (c), suitable metal catalysts include copper and palladium catalysts. An example is copper (I) iodide. Suitable bases include alkali metal bases, such as alkali metal phosphates, such as potassium phosphate. Suitable solvents include aprotic solvents such as toluene. The reaction is iently performed at elevated temperatures, for example at 90 CC.
Referring to method (d), le bases include amine bases, such as a tertiary amine base, such as DIEA (diisopropylethylamine) and triethylamine. Convenient solvents include aprotic solvents such as ethers (for e tetrahydrofuran or p-dioxane) or toluene.
The reaction is conveniently med at ed temperatures, for example at 150 CC. ing to methods (e) and (f) le coupling reagents include HATU, HBTU, TBTU, DCC (N,N'-dicyclohexylcarbodiimide), DIEC (l-(3-dimethylaminopropyl) ethylcarboiimide), or any other amide coupling reagents well known to persons skilled in the art. Suitable bases include amine bases such as DIEA or triethylamine. Convenient solvents include aprotic solvents such as DCM, ethers (for e tetrahydrofuran or p-dioxane), e, DMF, or DME. The reaction is conveniently performed at t temperature.
Referring to method (g), the base may be, for example, a tertiary amine, such as ylamine, dimethylaminopyridine (DMAP), or isopropylethylamine, or an alkali metal hydride or ate. Suitable solvents include DCM, DCE, THF, and DMF.
The reaction can be performed at ambient temperature.
Referring to method (h), suitable coupling reagents include DCC (N,N'- dicyclohexylcarbodiimide), and DIEC (l-(3-dimethylaminopropyl)ethylcarboiimide). The base may be, for example, a tertiary amine, such as ylamine, dimethylaminopyridine (DMAP) or N,N-diisopropylethylamine, or an alkali metal hydride or carbonate. Suitable solvents include DCM, DCE, THF, and DMF. ing to method (i), the base may be, for example, a tertiary amine, such as triethylamine, dimethylaminopyridine (DMAP), or N,N—diisopropylethylamine. Suitable solvents include DCM, DCE, THF, and DMF. The reaction can be performed at ambient temperature.
Referring to method (j), an example of a protected de is trimethyl orthoformate. The base may be, for example, a tertiary amine, such as triethylamine, dimethylaminopyridine (DMAP), or N,N—diisopropylethylamine. Suitable reducing agents include Na(OAc)3BH and NaCNBHg. Suitable solvents include alcohols such as methanol.
The reaction is conveniently performed at temperatures between 0 CC and ambient temperature.
Referring to method (k), the base may be, for example, a tertiary amine, such as triethylamine, dimethylaminopyridine (DMAP), or N,N-diisopropylethylamine. Suitable reducing agents include Na(OAc)3BH and NaCNBHg. le solvents include alcohols such as methanol. The reaction is conveniently performed at temperatures between 0 oC and ambient temperature.
Referring to method (1), an example of a suitable Lewis acid is tetraisopropoxytitanium. The base may be, for e, a tertiary amine, such as triethylamine, dimethylaminopyridine (DMAP), or N,N-diisopropylethylamine. Suitable reducing agents include )3BH and NaCNBHg. Suitable solvents include alcohols such as methanol. The reaction is conveniently performed at ambient temperature.
As used , the phrase "a protected derivative thereof‘ refers to a compound as described herein having one or more substituents which are protected with a suitable protecting group. Amine groups in compounds described in any of the above methods may be protected with any convenient amine protecting group, for example as described in Greene & Wuts, eds., “Protecting Groups in Organic Synthesis”, 2Ild ed. New York; John Wiley & Sons, Inc., 1991. Examples of amine protecting groups include acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl (BOC), and [2- (trimethylsilyl)ethoxy]methyl (SEM). se, carboxyl groups may be protected with any convenient carboxyl protecting group, for example as bed in Greene & Wuts, eds., “Protecting Groups in Organic Synthesis”, 2Ild ed. New York; John Wiley & Sons, Inc., 1991.
Examples of carboxyl protecting groups include (l-6C)alkyl groups, such as methyl, ethyl and t-butyl. Alcohol groups may be protected with any convenient l protecting group, for example as described in Greene & Wuts, eds., “Protecting Groups in c Synthesis”, 2Ild ed. New York; John Wiley & Sons, Inc., 1991. Examples of alcohol protecting groups include benzyl, trityl, silyl ethers, and the like. For example, in n embodiments of the methods described above where R6 is NH, the amino moiety is protected with an alkoxycarbonyl group, such as a BOC protecting group, as follows: HN’ZLOK0 R5 R53 QANRQ“ R9 R8 The compounds of the formulas 11, IV, V, VI, VII, VIII and IX are also believed to be novel and are ed as further s of the ion.
In one embodiment, the compound of formula II has the structure II-A fjinHP7F F HN N/ R II-A including enantiomers and diastereomers thereof, where P3 is H or an amine protecting group and R7 is H, (l-6C)alkyl, fluoro(l-6C)alkyl or hydroxy(l-6C)alkyl. In one embodiment, R7 is H or (l-6C)alkyl. In one embodiment, R7 is H or (l-C)alkyl. In one embodiment, R7 is H or methyl. In one embodiment, R7 is hydrogen. In one embodiment, R7 is methyl.
Compounds of Formula II-A can be prepared according to Scheme 1.
CPS CPS CF3 hydrazine R7 R7 R7 \ N —> \ N + _, L. N/ L1 N HN N 1 2 3 4 Scheme 1 In Scheme 1, R7 is as defined H or methyl, L1 is a leaving group or atom, such as a halogen, for example chloro, and P3 is an amino protecting group.
] Compounds of Formula II-A and II-B are also believed to be novel and are ed as r aspects of the invention.
The y of compounds to act as PIM-l, PIM-2 or PIM-3 inhibitors may be demonstrated by the enzyme assays described in Examples A, B and C, respectively.
Compounds of Formula I have been found to be inhibitors of PIM-l and/or PIM-2 and/or PIM-3, and are useful for ng diseases and disorders which can be treated with a PIM-l and/or PIM-2 and/or PIM-3 kinase inhibitor, including diseases mediated by PIM-l and/or PIM-2 and/or PIM-3 kinases. Accordingly, another aspect of this invention provides a method of treating diseases or disorder mediated by a PIM-l and/or PIM-2 and/or PIM-3 kinase in a mammal, sing administering to said mammal one or more compounds of a I or a pharmaceutically acceptable salt thereof in an amount effective to treat said disease or disorder.
A subset of compounds sed herein were found to have an IC50 value for PIM-l that is at least 10 fold less than the IC50 value for PIM-2 and further to have an IC50 value for PIM-3 approximately equivalent to that observed for PIM-l, when tested in the enzyme assays described in Examples A, B and C. As a further example, ular compounds disclosed herein were found to have an IC50 value for PIM-l that is at least 100 2012/026572 fold less than the IC50 value for PIM-2, and further to have an IC50 value for PIM-3 approximately lent to that observed for PIM-l, when tested in the enzyme assays described in Examples A, B and C.
Accordingly, also provided herein are compounds of Formula I which are highly potent PIM-l/PIM-3 dual inhibitors and are highly selective for PIM-l and PIM-3 relative to PIM-2, wherein a compound that is highly selective for PIMl is defined as a nd having an IC50 value for PIM-l that is at least 10 fold less than the IC50 value for PIM-2 when tested in the enzyme assays described in Examples A and B, and a compound that is highly selective for PIM3 is defined as a compound having an IC50 value for PIM-3 that is at least 10 fold less than the IC50 value for PIM-2 when tested in the enzyme assays bed in Examples B and C. es of disease and disorders which can be treated using a compound of Formula I include transplant ion and autoimmune and inflammatory diseases and disorders. Examples of autoimmune diseases and disorders include le sclerosis (MS), systemic lupus erythematosis, inflammatory bowel disease (IBD), Crohn's disease, irritable bowel syndrome, pancreatitis, ulcerative colitis, diverticulosis, Grave's disease, arthritis (including rheumatoid arthritis, juvenile rheumatoid tis, osteoarthritis, psoriatic tis and ankylosing spondylitis), myasthenia gravis, vasculitis, autoimmune thyroiditis, dermatitis (including atopic dermatitis and eczematous dermatitis), psoriasis, derma, asthma, allergy, systemic sis, vitiligo, graft vs. host disease (GVHD), Sjogren's syndrome, glomerulonephritis, IgA nephoropathy, diabetes mellitus (type I) and .
Particular examples of diseases and disorders which can be d using a compound of Formula I include inflammatory diseases, including diseases and disorders mediated by T and B cell fianction. Particular examples of such diseases include multiple sclerosis, inflammatory bowel disease, lupus, psoriasis and rheumatoid arthritis.
Accordingly, a further embodiment of this invention es a method of treating an inflammatory or autoimmune disease in a mammal in need thereof, comprising administering to a mammal in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the disease is toid arthritis. In one embodiment, the disease is lupus. In one embodiment, the disease is multiple sis. In one embodiment, the disease is inflammatory bowel disease. In one embodiment, the disease is psoriasis.
Expression of PIM kinases in immune cells can be induced by cytokines present during immune responses. Immune cells are critically ent on cytokines for differentiation and development of effector fianctions during normal and enic immune responses. Thus, compounds of the invention may be usefial for treating diseases and disorders characterized by aberrant cytokine production and responses and/or aberrant immune cell activation.
Accordingly, r embodiment of the invention provides a method of treating diseases and disorders characterized by aberrant cytokine production and responses and/or aberrant immune cell tion in a mammal in need thereof, comprising administering to a mammal in need thereof a compound of a I or a pharmaceutically acceptable salt thereof ] Another embodiment es a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of diseases and disorders terized by aberrant cytokine production and responses and/or aberrant immune cell activation in a mammal. Examples of such diseases and disorders include mune and inflammatory diseases. e E describes a method for determining the ability of a compound of Formula I to inhibit the eration of T cells, as well inhibit cytokine production by T cells stimulated through T cell receptors and by cytokines in vitro. The effect of a compound on IL-4 production and IL-22 production ts the utility of compounds of Formula I in treating diseases where these cytokines have been shown to play a role. Particular examples of such diseases include asthma, MS and inflammatory bowel disease (IBD), lupus, psoriasis and rheumatoid arthritis.
As an extension of the in vitro data, Example F describes a method of determining the y of a compound of Formula I to inhibit the generation of T cells responses to antigen in vivo as assessed by proliferation and cytokine production ex vivo.
Since T cell activation or proliferation and cytokine production are often key components of autoimmune diseases, the data provided by the assay described in Example F supports the y of compounds of Formula I in treating diseases associated with T cell proliferation and cytokine production, including autoimmune diseases such as those described herein.
B cells are also critically dependent on cytokines for production of particular types of immunoglobulins, called dy (Ab) isotypes, in a process referred to as isotype switching. Over time, isotype switching can be observed in mice which have been immunized with proteins to produce dies, which can then be quantified (Shi et al, 1999 Immunity 10:197-206). Example G describes a method of determining the ability of a compound of Formula Ito t the production of cytokine-stimulated Ab isotypes in response to protein immunization. The ability of compounds of Formula I to affect B cells ts their use in ng autoimmune and inflammatory diseases, including diseases thought to be associated in part by enic B cell and Ab responses. Examples of such diseases include lupus, multiple sis and rheumatoid arthritis.
Example H describes a method of determining the effectiveness a compound of Formula I in a T cell-mediated murine model of experimental autoimmune encephalomyelitis (EAE). Furthermore, Example I describes a method of determining the effectiveness of a compound of Formula I in a second EAE model in which the disease is caused by generating an immune response to a central nervous system (CNS) protein. EAE mimics many of the pathological features of multiple sclerosis (MS), and these models are widely used to model human disease and its treatment.
T cells also play in role in the inflammatory bowel disease (IBD), which is an autoimmune disease. Example J bes a method of determining the effectiveness of a nd of Formula I in a T cell-mediated model of this disease.
Lupus is an autoimmune disease characterized by aberrant T and B cell ses. In particular, lupus ts can exhibit elevated cytokine levels and increased amounts of uclear antibodies (Abs). In lupus, Abs can deposit in the kidneys and mediate tissue damage resulting in nephritis. Example K describes a murine model of lupus, and provides a method of determining the effectiveness of a compound of Formula I to decrease the tion of anti-DNA Abs as well as decrease proteinuria, a e of kidney .
Particular compounds of this invention are inhibitors of PIM-l and therefore are useful in treating diseases and disorders mediated by PIM-l, such as cancers, for example hematological cancers and solid tumors (e.g., breast cancer, colon cancer, gliomas).
Examples of logical cancers include, but are not limited to leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's e (also called Hodgkin's lymphoma), and myeloma, for instance, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), c lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), acute undifferentiated ia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AML with eage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), and multiple myeloma (MM).
Additional examples of hematological cancers e myeloproliferative disorders (MPD) such as polycythemia vera (PV), essential thrombocytopenia (ET) and idiopathic primary myelof1brosis (IMF/IPF/PMF). Certain cancers which can be treated with compounds of Formula I are cancers which of hematological origin, such as, but not limited to, cancers derived from T cells or B cells.
Accordingly, a further embodiment of this invention provides a method of treating cancer in a mammal in need thereof, comprising administering to a mammal in need f a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is of hematological origin. In one embodiment, the cancer derives from T cells. In one embodiment, the cancer derives from B cells.
In the field of medical oncology it is normal practice to use a combination of different forms of ent to treat each patient with . In medical oncology the other ent(s) of such conjoint treatment in on to compositions of the present invention may be, for example, surgery, herapy, chemotherapy, signal uction inhibitors and/or monoclonoal antibodies. Compounds of Formula I therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional drugs, for example a chemotherapeutic that works by the same or by a different mechanism of action.
Accordingly, a further aspect of this invention includes a method of treating cancer, comprising administering one or more compounds of Formula I in combination with one or more agents selected from mitotic inhibitors, alkylating agents, anti-metabolites, nse DNA or RNA, alating antibiotics, growth factor tors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis tors, cytostatic agents anti-androgens, targeted dies, A reductase inhibitors, and prenyl-protein transferase inhibitors.
Compounds of the t invention may also be used in combination with one or more additional drugs, for example an anti-inflammatory compound, an immunosuppressive compound or an immunodepleting agent that works by the same or a different ism of action.
Compounds of the invention may be administered together in a unitary pharmaceutical composition or separately and, when stered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.
As used herein, terms "treat" or "treatment" refer to therapeutic or palliative or measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms ated with a disorder or condition, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or tion of the e state, and remission (whether partial or , whether detectable or undetectable. "Treatment" can also mean ging survival as ed to expected survival if not receiving ent.
In certain embodiments, compounds of Formula I are useful for preventing diseases and disorders as defined herein (for example autoimmune diseases, inflammatory diseases, and cancer). The term "preventing” as used herein means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as bed herein, or a symptom thereof.
The phrase "effective amoun " means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat or prevent a particular disease, condition, or disorder mediated by a PIM-l and/or PIM-2 and/or PIM-3 , (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular e, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of Formula I that will correspond to such an amount will vary depending upon factors such as the particular compound, e condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
As used herein, the term "mammal" refers to a warm-blooded animal that has or is at risk of developing a disease described herein and es, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
Compounds of the invention may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. ly or orally), the nose, lungs, musculature or vasculature, or transdermally or dermally. Compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, sions, syrups, , suppositories, gels, ons, patches etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and r active agents. If parenteral stration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infilsion. Such compositions form a further aspect of the invention. An example of a suitable oral dosage form is a tablet ning about 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg of the compound of the invention compounded with about 90-30 mg ous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone ("PVP") K30, and about 1-10 mg magnesium stearate. The ed ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the ium stearate and compressed to tablet form using conventional equipment. An aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, 6. g. a phosphate buffer, adding a tonicifier, for example a salt such sodium chloride, if desired. The solution is typically d, for example using a 0.2 micron filter, to remove impurities and contaminants.
Another formulation may be prepared by mixing a compound described herein and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug g Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy.
Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, g agents, lubricating agents, emulsifiers, suspending , preservatives, antioxidants, opaquing agents, ts, processing aids, colorants, sweeteners, perfuming agents, flavoring , diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound described herein or pharmaceutical composition f) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
Accordingly, another aspect of the present invention provides a pharmaceutical composition, which comprises a compound of Formula I or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.
According to r aspect, the present invention provides a compound of Formula I or a ceutically acceptable salt or solvate thereof, for use in therapy, such as the treatment of a PIM-l and/or PIM-2 and/or PIM-3 kinase-mediated ion.
According to a further , the present invention provides a compound of Formula I, or a ceutically acceptable salt or solvate f, for use in the treatment of a PIM-l and/or PIM-2 and/or PIM-3 kinase-mediated condition, as defined hereinabove.
Another aspect of the present invention provides a compound of this invention for use in the treatment of inflammatory and autoimmune diseases. In one ment, the disease is selected from multiple sclerosis, inflammatory bowel disease, lupus, psoriasis and rheumatoid arthritis.
] Another aspect of the present invention provides a compound of this invention for use in the treatment of cancer. In one embodiment, the cancer is of hematological origin.
In one ment, the cancer derives from T cells. In one embodiment, the cancer derives from B cells.
Another aspect of the present ion provides the use of a compound of this ion in the manufacture of a medicament for the treatment of inflammatory and autoimmune diseases. In one embodiment, the disease is selected from multiple sclerosis, inflammatory bowel disease, lupus, psoriasis and rheumatoid arthritis.
Another aspect of the present invention provides the use of a compound of this invention in the cture of a ment for the treatment of cancer.
Abbreviations used in herein have the following definitions: Abbreviation Definition ACN acetonitrile BoczO tert—butox carbon 1 dc -2HBF4 bis ' ' ooroane tetrafluoroboric acid DMA meth lacetam1de.
DMAP dimeth lam1no o ridine DME d1methox ethane DPPA di hen lohos oho l az1de Fe acac 3 tris acet lacetonato iron III (2-(7-aza- l H-benzotriazole- l -yl)- l , l ,3 ,3 -tetramethyluronium hexafluoro o hos 0 hate ch tric clohex lohos ohine PdClg(dppf) *dcm l l diphenylphosphino)ferrocene-palladium(II)dichloride romethane com o lex Examples ] The following es illustrate the invention. In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Acros, Lancaster, TCI or Maybridge unless otherwise indicated, and were used without further purification unless otherwise indicated. Tetrahydrofuran (THF), dichloromethane (DCM, methylene chloride), toluene, and dioxane were purchased from h in Sure seal bottles and used as received unless otherwise ted.
] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the on flasks were typically fitted with rubber septa for the uction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Column chromatography was done on a Biotage system (Manufacturer: Dyax Corporation) having a silica gel column or on a silica SepPak cartridge s). Chiral chromatography was done on Chiraltech® columns unless otherwise ted.
Example A Enzyme PIM-l Assay The assay for the determination of PIM-l activity is based on the incorporation of [33P]PO4 from [y-33P]ATP into PIM2tide substrate and capture of the radiolabeled peptide onto a Whatman P81 (phosphocellulose) filter plate. The amount of radiolabeled product is then measured by liquid scintillation counting. The final buffer conditions were as follows: 20 mM K+MOPS, pH 7.4, 10 mM MgC12, 0.005% Tween-20, 1 mM DTT. Assay mixtures contained 35 uM [y—33P]ATP (20 uCi/mL), 7.5 uM PIM2tide and 0.25 nM PIM-l in a total volume of 50 [LL Incubations were carried out for 60 min at 22 CC and quenched with 75 [LL of 200 mM H3PO4, filtered through a Whatman P81 plate and washed (1 x 200 uL and 5 x 100 uL) with 200 mM H3PO4. Fifty uL of liquid scintillation cocktail were then added per well, and the plate was counted for 30 s/well using a TopCount NXT.
Ex Determinations: ] nds were prepared at 50x the final concentration in DMSO by conducting 3-fold serial dilutions from a 500-uM ediate dilution to give a 10-point dosing curve having a high dose of 10 uM. One-uL ts of these were then transferred to the assay mixtures above to give a final concentration of DMSO of 2%. A standard or reference compound was typically included on each assay plate to validate that plate. For each plate, percent of control (POC) values were calculated for each well. IC50 values were estimated from the FCC values using a standard 4-parameter ic model. The IC50 is defined as the concentration of inhibitor at which the FCC equals 50 for the fitted curve.
Averaged IC50 values of compounds tested in this assay are provided in Table 1.
Example B PIM-2 Assay ] Assay was performed as described in Example A, using 4 uM [y-33P]ATP (20 uCi/mL), 1.0 uM PIM2tide and 1.5 nM GST-tagged recombinant filll-length human Pim-2 in place of PIM-l. Averaged IC50 values of compounds tested in this assay are provided in Table 1.
Example C PIM-3 Assay Assay was performed as described in Example A, using 30 uM [y-33P]ATP (20 uCi/mL), 3.75 uM PIM2tide and 0.5 nM recombinant rat PIM-3 in place of PIM-l.
Averaged IC50 values of compounds tested in this assay are provided in Table 1.
TABLE 1 N0. IC50 (HM) IC50 (HM) IC50 (HM) N0. IC50 11M 1M IC50 11M 1——0—24 —__— ——__ ——_fi_ —n_ :9 ——__ ——__ >100 _I_ WO 54274 Example 2012/026572 Example 2012/026572 Example PIM-l N0. IC50 11M —=157 3.44 WO 54274 Example PIM-l N0. IC50 11M —=204 0.48 2012/026572 Example PIM-l N0. IC50 11M —=251 0.75 Example PIM-1 PIM-2 PIM-3 N0. IC50 11M IC50 11M IC50 11M 298 0.27 ND: Not determined Example D Cellular Proliferation Assay The assay for determination of the antiproliferative ty of multiple PIM inhibitors in the JAKZ-driven cell lines is conducted as follows. Cells are plated out to 96- well plates at an initial density of 10,000 cells/well in 95 uL. Compounds are prepared at 20X the final concentration in DMSO by conducting 3-fold serial dilutions to give a 10-point dosing curve having a high dose of 1000 uM. Aliquots (5 uL) of these dilutions are then transferred to the appropriate wells of the 96-well plates containing cells to yield a final DMSO concentration of 0.5%. The cells are then incubated with nd for 72 hours at 37 °C, 5% C02. CelltiterBlue reagent (Promega, Catalog #: G8080) is then added (20 W0 2012/154274 l) and incubated at 37 °C, 5% C02 for 1-8 hours depending on the cell line being analyzed. The plate is then quantified employing a fluorescence plate reader (Model: Gemini [Molecular s]; Settings: 560 nm (Ex)/590 nm (Em) 570 nm (cut-off) [CellTiter Blue Assay].
The values for each well are then converted to a percent of untreated control (POC). These POC values are then d as a function of nd concentration. A 4- parameter curve-fit analysis is performed for each compound dilution and an IC50 value is calculated from this curve. Examples of cell lines which may be used in the assay are listed below (all are commercially available from ATCC®). Compounds described herein were shown or will be shown to be effective in this model.
-F BaF3 Mouse oro-B-cell line -G BaF3 TEL-JAK2 Mouse oro-B-cell transformed with TEL-JAK2 filSlOI‘l -H BaF2 BCR—Abl Mouse oro-B-cell transformed with BCR—Abl filSlOIl T cell in vitro functional assays The in vitro assays which can be used to assess the effects of the compounds of the ion are described in assays A, B, C and D below. CD4+ T cells are isolated from red blood cell-depleted cytes of C57Bl/6J mice (Jackson Laboratories, catalog # 000664) using CD4+ T cell ion kit (Miltenyi, catalog # 130860).
] In assay (A), purified CD4+ T cells are plated in 96 well plates at 90000 cells/well in 90 [LL A dilution series of the compounds are prepared at lOOx the final concentration in DMSO and then diluted 10-fold into complete media (le stocks). lO uL of 10x compound stocks are added to appropriate wells of 96 well plates containing cells and incubated for 1 hour at 37 °C, 5% C02. The cell/compound es are then transferred to a 96 well plate coated with anti-CD3 mAb (l ug/mL; BD Pharmingen, catalog # 553057) and soluble anti-CD28 mAb (l ug/mL; BD Pharmingen, catalog #553294) was added. Plates are cultured at 37 °C, 5% C02 for 40 hours. 20 uL of the culture are removed for determination of proliferation using the CellTitre-GloTM luminescent assay (Promega, Catalog #G757l) according to the manufacturer’s protocol. The plate is fied on a Packard TopCount instrument using luminescence protocol and data analyzed using Prism software.
W0 2012/154274 In assay (B), d CD4+ cells are treated with compound and stimulated as described for assay (A). After 40 hours, supernatants are assayed for IL-2 using R&D duo set ELISA kits (catalog #DY402). ELISA plates are quantified relative to a standard curve using Molecular DeVices Versamax Reader at 450 nM and Softmax Pro software.
In assay (C), 1,000,000 cells/mL of d CD4+ T cells are mixed with 1 ug/mL anti-CD28, 10 ng/mL IL-4 (R&D Systems cat # 404-ML-010/CF) and 2 ug/mL anti- IFNy (R&D s catalog # ABNA) and placed into plates coated with 1 ug/mL anti- CD3. After 5 days, cells are harvested, washed and incubated overnight at 37 °C, 5% C02.
The ing day, 50,000 cells are plated into each well of a 96 well plate. A dilution series of compounds are prepared at 200K the final concentration in DMSO, then 10X stocks are prepared by dilution in cell culture media. 10 uL of 10X stocks are added to the cells in the 96-well plate and incubated for 2 hours at 37 0C, 5% C02. Cell/compound mixtures are then transferred to wells coated with 0.1 ug anti-CD3 and incubated at 37 0C, 5% C02. Culture supernatants are removed 18 hours later and tested for IL-4 levels by ELISA (R&D Systems catalog # DY404). ELISA plates are quantified relative to a standard curve using Molecular DeVices Versamax Reader at 450 nM and Softmax Pro software.
In assay (D), 1,000,000 cells/mL of purified CD4+ T cells are mixed with 1 ug/mL anti-CD28, 50 ng/mL IL-6 (R&D s cat # 406-ML-025/CF), 1 ng/mL TGFB (R&D Systems cat # 303-B2-002), 2 ug/mL anti-IL-4 (R&D Systems catalog # -NA), 2 ug/mL anti-IFNy (R&D Systems catalog # ABNA) and placed into plates coated with 1 ug/mL anti-CD3. After 4 days, cells are harvested, washed and 100,000 cells are plated into 96 well plate. A dilution series of nds are prepared at 200K the final concentration in DMSO, then 10X stocks are prepared by dilution in cell culture media. 10 uL of 10X stocks are added to the cells in the 96-well plate. After 2 hours, 50 ng IL-23 (R&D Systems catalog # 1887-ML-010/CF) is added to each well and 18 hours later supernatants are removed and tested for IL-22 levels by ELISA (R&D Systems g # M2200). ELISA plates are fied relative to a standard curve using Molecular DeVices Versamax Reader at 450nM and Softmax Pro software. Compounds described herein were shown or will be shown to be effective in this model.
Example F T cell in V1VO onal assay The effect of compounds of Formula I on T cell ses can be determined by the following experiment. On Day 0, C57BL/6 (Jackson Laboratories #000664, 6-8 weeks of age) are zed at the base of the tail with 100 ug of hen egg lysozyme (HEL; Sigma #L7773) with complete Freund’s adjuvant (CFA; Sigma #F5881). Starting on Day 0 and continuing until Day 7, mice are dosed twice a day by oral administration with vehicle (water) or the compound of Formula I (200 mg/kg). On Day 7, popiteal lymph nodes are removed, single cell sions are prepared and 500,000 cells in 200 uL are activated in 96 well plates with the indicated dose of HEL peptide. Following incubation for 72 hours at 37 °C, 5% C02, supematants are harvested for IFNy ELISA (R&D Systems catalog #MIF00) and proliferation is assessed using the CellTitre-GloTM scent assay (Promega, Catalog #G7571) with both assays performed according to the cturer’s ol. ELISA plates are quantified relative to a rd curve using Molecular Devices Versamax Reader at 450 nM and Softmax Pro software; proliferation can be quantitated on a Packard TopCount instrument using luminescence protocol and data analyzed using excel software. Compounds described herein were shown or will be shown to be effective in this model.
Example G B cell in vivo functional assay The effect of a compound of a I on B cell responses can be determined with the following experiment. On Day 0, 6J mice (Jackson Laboratories #000664, 6-8 weeks of age) are immunized at the base of the tail with 20 ug of hen egg lysozyme (HEL; Sigma #L7773) with complete Freund’s adjuvant (CFA; Sigma #F5881). Mice are re- immunized on day 7 with 20 ug HEL in alum (Pierce catalog #77161). Starting on Day 0 and continuing through Day 28, mice are dosed once a day by oral administration with vehicle (water) or the compound of Formula I (200 mg/kg). Serum is collected on days 0, 7, 14, 21, and 28 and analyzed for HEL-specific total IgG, IgGl, IgG2a, IgG2b, and IgG3 antibody production by capture ELISA (antibodies sed from Invitrogen, catalog Nos. M30007, M32107, M32307, M32507 and M32607). ELISA plates are quantitated using Molecular Devices ax reader at 450 nM. The group mean titer of each antibody analyte is ted to percent of vehicle control (= 100%). nds described herein were shown or will be shown to be effective in this model.
Example H Adop_tive Transfer Exp_erimental mune halomyelitis The effect of a compound of Formula I on an autoimmune disease induced by T cells can be determined using an adoptive transfer EAE model, an animal model of human multiple sclerosis (Brain (2006), 129, 1953-1971). This model relies on the injection of T cells from animals with EAE into disease-free host animals. This injection of cells is known to those skilled in the art as ve transfer. By injecting the animals with activated, encephalogenic T cells, this model is focused on the pathogenic stage of EAE autoimmune disease. On Day -l4, C57BL/6 mice (Taconic Farms; 10 weeks old) are immunized with a disease-causing protein, MOG(35-55) peptide in te Freund’s nt (Hooke Laboratories, catalog 13). On Day -3, s are harvested, single cell suspensions are prepared and then 5,000,000 cells/mL are stimulated with 20 ug/mL MOG(33-55) peptide (Open Biosystems), 30 ng/mL IL-12 (R&D Systems catalog #419-ML-010), 10 ug/mL anti- IFNy antibody (BD Biosciences catalog 8) at 37 0C, 5% C02. On Day 0, 1,500,000 of these cells are injected intravenously into the tail veins of C57BL/6 recipient mice. The recipient mice are divided into treatment groups for vehicle (distilled water; 10 mL/kg) or the compound of Formula I (200 mg/kg), both administered by oral gavage twice daily for 26 days. The recipient mice are scored daily days 0 through 26 using the clinical g system shown in Table 2. Compounds described herein were shown or will be shown to be effective in this model.
Table2 Score Observations no s motoms 1.0 lim tail 2.0 lim. tail and weakness of hind le_s 3.0 limp tail and complete hind limb paralysis, or partial front and hind limb paralysis, or severe head tilting combined with pushing against cage wall and s._innin when oicked uo b tail 4.0 lim. tail, comolete hind limb oaral sis and oartial front limb oaral sis .0 Full bod oaral sis, or s oontaneous rolling or found dead due to aral sis Example I MOGg 35-55 z-induced Experimental Autoimmune Encephalomyelitis ] An onal method of determining the effect of compounds of Formula I on an autoimmune disease associated with T cells and cytokines uses the MOG-induced experimental autoimmune encephalomyelitis (EAE) model. duced EAE is an animal model of human multiple sis (Brain (2006), 129, 1953-1971).
On Day 0, C57BL/6J mice (Jackson Laboratories #000664, 6-8 weeks of age) are injected subcutaneously with 100 uL of complete Freund’s adjuvant (CFA) prepared as a 1:1 emulsion of (a) incomplete Freund’s adjuvant , catalog #263910) containing 8 mg/mL m. tuberculosis H37RA (Difco, g # 231141) and (b) phosphate buffered saline (PBS) containing 1 mg/mL MOG(35-55) e (California Peptide Research Inc). On the day 0 and 2, mice are injected intravenously with 200 ng of pertussis toxin (List Biological Laboratories, catalog #181). On day 7, the mice are randomized into treatment groups which receive vehicle (distilled water) or the compound of a I (200 mg/kg) administered by oral gavage twice daily from days 7 through 27. The mice are scored daily on days 7 through 37 using the clinical scoring system shown in Table 3. nds described herein were shown or will be shown to be ive in this model.
Table 3 Score 2.0 oartial hind limb 2.5 oartial hind limb 3.0 full hind limb oaral sis 3.5 full hind limb oaral sis and oartial front limb oaral sis 4.0 full bod o aral sis Example J CD4+CD45RBhi Adoptive Transfer Inflammatom Bowel e The following adoptive transfer model of inflammatory bowel disease (IBD) can be med to determine the effect of compounds of Formula I on IBD, which is an autoimmune disease associated with T cells and cytokines.
On Day 0, CD4+ T cells are isolated from the spleens of female AnNCrl mice (Charles River Laboratories; 12 weeks old) as described in Example E. The resulting cells are labeled with fluorescent dies against CD4 and CD45 markers and are sorted by flow cytometry for CD4+CD45RBhi cells based on fluorescence. 400,000 CD4+CD45RBhi cells are then injected intraperitoneally into C.Bl7/Icr-PrkchCid/IcrIcoCrl mice (Charles River Laboratories strain code 236; 12 weeks old). This injection of cells is known to those skilled in the art as "adoptive transfer". On Day 21, mice are ized into groups for oral gavage treatment with vehicle (1% carboxymethylcellulose sodium (CMC)/0.5% Tween 80 once daily; CMC, Sigma catalog #C9481, Tween 80 Sigma catalog #Pl754) or the compound of Formula I (200 mg/kg; twice daily). ents continued through Day 42.
At the sion of the study, mice are sacrificed and the distal half of their colons are placed in 10% neutral buffered formalin (Richard Allen Scientific catalog #53120- 1) and paraffin embedded, sectioned into 4 um slices and stained with hematoxylin and eosin (H&E) for analysis by a board certified veterinary pathologist.
For each H&E stained section, submucosal edema is quantitated by ing the distance from the muscularis mucosa to the internal border of the outer muscle layer in a non-tangential area thought to most representative the severity of this change. Mucosal thickness is also measured in a non-tangential area of the n that best represented the overall mucosal thickness. This parameter is tive of gland elongation and mucosal hyperplasia. The extent of inflammation (macrophage, lymphocyte and polymorphonuclear leukocyte (PMN) infiltrate) is assigned severity scores according to the criteria provided in Table 4.
Table 4 Severity Criteria score 1 Minimal (generally focal affecting 1-10% of mucosa or if diffuse then minimal 2 Mild _enerall- focal affecting ll-25% of mucosa or if e then mild te (26-50% of mucosa affected with areas of gland loss ed by The parameters reflecting epithelial cell amage are scored individually using a percent area involved scoring method are provided in Table 5.
Table 5 1-10% of the mucosa affected 26-50% of the mucosa affected 51-75% of the mucosa affected —76-100% of the mucosa affected Parameters that are scored using percent involvement included: colon glandular epithelial loss (this includes crypt epithelial as well as remaining gland epithelial loss), and colon erosion (this reflects loss of surface epithelium and generally is associated with mucosal hemorrhage (reflective of the bleeding seen clinically and at necropsy). The three scored parameters (inflammation, glandular lial loss, and erosion) are ultimately summed to arrive at a sum of histopathology , which indicates the overall damage and would have a maximum score of 15. Compounds described herein were shown or will be shown to be effective in this model.
Example K MRL/lpr Lupus Model MRL/lpr is considered to be an animal model of systemic lupus erythematosus (SLE), an autoimmune disease (Cohen and Maldonado 2003, Current Protocols in Immunology Chapter 15, Unit 15.20). MRL/lpr mice have a defect in the apoptosis of ted lymphocytes and over time develop a spontaneous and severe lymphoproliferative disorder characterized by enlarged lymphoid organs, auto-antibody tion and kidney disease resulting in proteinuria. SLE patients also exhibit auto- dies, and some patients p kidney disease. To determine the effect of compounds of Formula I in this model of SLE, the following experiment can be conducted.
MRL/MpJ-Fas<lpr> and age-matched MRL/MpJ l mice (Jackson Laboratories, catalog #000485 and #000486, respectively) are d once daily with vehicle (1% CMC/0.5% Tween 80) or twice daily with the compound of Formula I (200 mg/kg) for weeks. Body weights, lymphadenopathy and urine protein levels are monitored weekly.
Urine protein levels are determined with Bayer Albustix dipsticks (Bayer catalog #2191) and scored according to the scale provided in Table 6.
Table 6 Urine rotein levels none detected trace amounts Serum levels of anti-ds-DNA antibody are ed by ELISA (Alpha Diagnostic, catalog #5120) on Day 28 and upon study termination. ELISA plates are quantitated using a lar s Versamax plate reader at 450 nM and titers calculated relative using to a standard curve using a 4-parameter curve fit with Softmax Pro software.
Compounds described herein were shown or will be shown to be effective in this model.
Preparation A IN/Boc ylcarbamate Step A: Pre aration of benz l 3- tert-butox carbon lamino methylpyrrolidinecarboxylate: Prepared as bed in ational Publication WO 40320 A1, Example D, Steps A-D.
Step B: Separation of enantiomers [R [-benzyl 3-]tert-butoxycarbonylamino 2 meth l rrolidinecarbox late and -benz l 3- tert-butox carbon lamino meth l- pyrrolidinecarboxylate: A racemic mixture of benzyl 3-(tert-butoxycarbonylamino) methylpyrrolidinecarboxylate (14.5 g, 43.3 mmol) was separated via preparative supercritical fluid chromatography under the following conditions: Column: IC 20 mm x 250 mm; flow rate: 65 mL/min; mobile phase A: 90% supercritical C02; mobile phase B: 10% isopropyl alcohol; UV detection wavelength: 214 nm. Peak one: retention time: 4.6 s; recovery: (R)-benzyl t-butoxycarbonylamino)methylpyrrolidinecarboxylate (5.97 g, 17.87 mmol). Peak two: retention time: 6.8 minutes; recovery: (S)-benzyl 3-(tert- butoxycarbonylamino)methylpyrrolidinecarboxylate (5.98 g, 17.89 mmol).
Step C: Pre aration of R -tert-but l 3-meth l rrolidin lcarbamate: Prepared as described in WC 2009/140320A1, Example D, Step E, using (R)-benzyl 3-(tertbutoxycarbonylamino )methylpyrrolidinecarboxylate in place of racemic benzyl 3-(tertbutoxycarbonylamino )methylpyrrolidinecarboxylate.
Step D: Pre aration of -tert-but l 3-meth l rrolidin lcarbamate: Prepared as described in International Publication W02009/140320A1, Example D, Step E, using (S)-benzyl 3-(tert-butoxycarbonylamino)methylpyrrolidinecarboxylate in place of racemic benzyl 3-(tert—butoxycarbonylamino)methylpyrrolidinecarboxylate.
Preparation B H N H N [N , Boc , Boc ylcarbamate ] Step A: Pre n of 1-benzl 3-methl 3-methl rrolidine dicarboxylate: Prepared as described by Mendiola, et al., Organic Process Research & pment (2009) 13, 292-296, using methyl methacrylate in place of methyl acrylate.
Step B: Pre n of benz l 3- tert-butox carbon lamino methylpyrrolidinecarboxylate: Prepared as described in International Publication WO 2009/140320A1, Example D, Steps C-D. 2012/026572 Step C: Separation of enantiomers [R [-benzyl 3-]tert-butoxycarbonylamino1 meth l rrolidine-l-carbox late and -benz l 3- tert-butox carbon lamino methylpyrrolidinecarboxylate: Separated as described in Preparation A, Step B.
Step D: Pre aration of R -tert-but l 3-meth l rrolidin lcarbamate: Prepared as described in International Publication WC 2009/ 140320A1, Example D, Step E using (R)-benzyl 3-(tert-butoxycarbonylamino)methylpyrrolidinecarboxylate in place of racemic benzyl 3-(tert—butoxycarbonylamino)methylpyrrolidinecarboxylate Step E: Pre aration of -tert-but l 3-meth l in mate: Prepared as described in International Publication WC 2009/140320A1, Example D, Step E, using (S)-benzyl 3-(tert-butoxycarbonylamino)methylpyrrolidinecarboxylate in place of racemic benzyl 3-(tert-butoxycarbonylamino)methylpyrrolidinecarboxylate.
Preparation C HN\DLN—Boc -tert-but l3-meth l rrolidin lcarbamate Step A: Pre aration of R methac lo l hen loxazolidinone: To a solution of (R)phenyloxazolidinone (65.00 g, 398.3 mmol) in dry THF (612.8 mL) at - 78 0C was quickly added n-BuLi (167.3 mL, 418.3 mmol) dropwise, and the mixture was stirred at -78 0C for 0.5 hours. To this cold stirring solution was quickly added dropwise a solution of methacryloyl chloride (40.86 mL, 418.3 mmol) in THF (60 mL), and the mixture was d to warm to ambient temperature and stirred for 0.5 hours. Water (300 mL) was added and the suspension was stirred for 1 hour and then d to give d product as a hard solid cake (66 g). The filtrate was concentrated under reduced pressure to a yellow solid residue, which was taken up in EtzO (400 mL) and filtered to give additional pure desired product (9 g). The products were combined to give (R)methacryloylphenyloxazolidin one (75 g, 81% yield).
Step B: Pre aration of R benz lmeth l rrolidinecarbon l phenyloxazolidin-Z-one: To a solution of methacryloylphenyloxazolidinone (135.00 g, 583.79 mmol) and TFA (4.497 mL, 58.379 mmol) in dry toluene (50 mL) at <10 0C was quickly added dropwise N—benzylmethoxy-N-((trimethylsilyl)methyl)methanamine (194.16 mL, 758.93 mmol), and the mixture was stirred at ambient temperature ght.
The reaction was d and the filtrate was extracted with 4N HCl (3 x 250 mL). The s layer was washed with ethyl acetate (250 mL) then made basic with solid K2C03 to pH 10. The basic aqueous layer was ted with ethyl acetate (4 x 400 mL), dried (MgSO4), filtered and concentrated under reduced pressure to e ((S)—l-benzyl pyrrolidinecarbonyl)phenyloxazolidinone (145 g, 399 mmol, 68% yield) as a dark oil.
Step C: Pre aration of R -benz l 3-meth l R oxo phenyloxazolidinecarbonyl)pyrrolidine-l-carboxylate: To a suspension of (R)((S) benzylmethylpyrrolidinecarbonyl)phenyloxazolidinone (145.50 g, 399.25 mmol) and NaHC03 (33.54 g, 399.25 mmol) in dry DCE (1000 mL) at ambient temperature was added dropwise a solution of benzylchloroformate (134.87 mL, 958.19 mmol) in DCE (100 mL) and the reaction was stirred at ambient temperature for 24 hours. The reaction was diluted with 1N HCl (500 mL) and the layers were separated. The organic layer was washed with 1M HCl (250 mL), dried (MgSO4), filtered and concentrated under reduced pressure to a thick yellow residue. The residue was purified by flash chromatography (5% ethyl acetate/DCM) to give (R)-benzyl 3-methyl((R)oxophenyloxazolidine carbonyl)pyrrolidinecarboxylate (85.1 g, 208.35 mmol, 52.2 % yield).
Step D: Preparation of 1R2gbenzyloxycarbonyl)—3-methylp_yrrolidine carboxylic acid: To a solution of 2N LiOH-HZO (26.43 g, 629.8 mmol) was added 30% H202 (51.94 mL, 503.9 mmol) at 0 CC. To this stirring cold mixture was added a solution of (R)- benzyl 3 -methyl-3 -((R)oxophenyloxazolidinecarbonyl)pyrrolidinecarboxylate (102.9 g, 251.9 mmol) in THF (350 mL). The reaction was stirred at 0 CC for 1 hour. To the reaction was added a solution of sodium sulfite (79.38 g, 629.8 mmol) in water (150 mL).
The on was warmed to ambient temperature and stirred for 30 s. Ethyl acetate (500 mL) was added. The aqueous layer was ted, acidified with solid potassium hydrogen sulfate to pH<3, extracted with ethyl acetate (3 x 500 mL), washed with brine, dried (MgSO4), filtered and concentrated under reduced re to give a solid residue (60 g). The solid was dissolved in a mixture of ethyl acetate/Hexanes (250 mL/800 mL) with heating to reflux. After complete dissolution, the mixture was d to cool overnight to give white granular crystals. The solids were filtered and the filtrate concentrated under reduced re and again subjected to crystallization conditions to give 5 g of additional solids. The combined solids were again subjected to crystallization conditions using ethyl e/hexanes (200 mL/600 mL) to give (R)(benzyloxycarbonyl)methylpyrrolidine carboxylic acid (40 g, 163.7 mmol, 65% yield; >99% e.e.). Chiral HPLC method: 100 A, ISO Col 2 ADH 5 min (R); 12.110 min (S)).
Step E: Preparation of (fig-benzyl 3-carbamoylmethylp_yrrolidine-l- carboxylate: To a mixture of (S)(benzyloxycarbonyl)methylpyrrolidinecarboxylic WO 54274 acid (32.87 g, 124.8 mmol), BoczO (29.97 g, 137.3 mmol) in ethyl acetate (200 mL) was added pyridine (12.62 mL, 156.1 mmol) and the reaction mixture was stirred at ambient ature for 3 hours. A solution of 28-30% w/w NH4OH/water (21.79 mL, 162.3 mmol) was added. The on was d at ambient temperature for 5 hours. Water (50 mL) was added. The organic layer was separated, washed with 1N HC1 (50 mL) and brine, dried and concentrated under reduced pressure to give (S)-benzyl amoylmethylpyrrolidine carboxylate (31.30 g, 119.3 mmol, 95.6 % yield) as an oil.
Step F: Pre aration of -benz l 3- tert-butox carbon lamino methylpyrrolidinecarboxylate: To (S)-Benzyl 3-carbamoylmethylpyrrolidine carboxylate (35.61 g, 135.8 mmol) in 1:1 MeCN/HZO (100 mL) was added rifiuoroacetoxy)iodo]benzene (58.38 g, 135.8 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and then at 86 CC (bath) for 2 hours. After cooling to t temperature, trated HC1 (14.85 g, 407.3 mmol) and ether (200 mL) were added. The aqueous layer was ted and basified by K2C03 (46.91 g, 339.4 mmol). To the ing solution was added THF (150 mL) and BoczO (37.04 g, 169.7 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (100 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3:1 hexane/ethyl acetate) on silica gel to give (S)-benzyl 3-(tert-butoxycarbonylamino) methylpyrrolidinecarboxylate (42.30 g, 126.5 mmol, 93.2 % yield) as an oil.
Step G: Preparation of ]§[-tert-butyl 3-methylp_yrrolidinylcarbamate: A mixture of (S)-benzyl 3-(tert-butoxycarbonylamino)methylpyrrolidinecarboxylate (29.35 g, 87.77 mmol) and 10% Pd/C (4.670 g, 4.388 mmol) in ethanol (50 mL) was charged with hydrogen (1 atmosphere) and stirred at ambient temperature overnight. The catalyst was removed by filtration and washed with ethanol (2 x 50 mL). The filtrated was concentrated under reduced pressure to give (S)-tert-butyl 3-methylpyrrolidinylcarbamate (17.13 g, 85.53 mmol, 97.45 % yield) as an oil. MS APCI (+) m/z 201 (M+1) detected.
Preparation D HN\ [W'N—Boc R -tert-but l3-meth l rrolidin lcarbamate Prepared as described in Preparation C using (S)phenyloxazolidinone in place of (R)phenyloxazolidinone in Step A.
Preparation E \ \“Q<\ OH h drazin l ridin leth l rrolidinol Step A: Pre aration of rrolidinone h drochloride: To a solution of tert- butyl 3-oxopyrrolidinecarboxylate (12.50 g, 67.49 mmol) in DCM (90 mL) was added 4M HCl in dioxane (84.36 mL, 337.4 mmol) at ambient temperature. The reaction was stirred for 3 hours. The itate was d to give pyrrolidinone hydrochloride (7.4 g, 60.9 mmol, 90.2% yield) which was used in the next step without purification.
Step B: Preparation of 1-benzylpyrrolidinone: To a solution of pyrrolidin one hydrochloride (7.40 g, 60.9 mmol) in DCE (122 mL) was added ethyl acetate (23.9 mL, 137 mmol) followed by benzyl chloride (8.63 g, 68.2 mmol) at ambient temperature. The reaction was heated to 70 0C for 2 hours. The reaction was cooled, diluted with DCM (100 mL), water (100 mL), the layers were separated, and the organic layer was dried (MgSO4), filtered and concentrated under d pressure to give 1-benzylpyrrolidinone (10.01 g, 57.2 mmol, 93.9% yield).
] Step C: Pre aration of +/- 1-benz lmeth l rrolidinol: A solution of 1- pyrrolidinone (9.98 g, 57.0 mmol) in THF (57.0 mL) at -20 0C was added to 1.4M MeMgBr (85.4 mL, 120 mmol). When addition was complete, the ice bath was removed and the reaction was allowed to warm to t temperature and then quenched with water (200 mL). The mixture was diluted with saturated NH4Cl (200 mL) and ethyl acetate (300 mL) and stirred vigorously for 5 s. An inseparable emulsion formed with fine particulates.
The reaction mixture was filtered under vacuum and the layers were separated. The aqueous layer was extracted with ethyl acetate (200 mL) and the organic layer was washed with brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to an oil which was purified by flash chromatography (0-5% Methanol/DCM) to give (+/-)1-benzyl methylpyrrolidinol (6.10 g, 31.9 mmol, 56.0 % .
Step D: Pre aration of +/- 3-meth l inol: A solution of 1-benzyl methylpyrrolidinol (5.80 g, 30.3 mmol) and 10% Pd/C (9.68 g, 9.10 mmol) in methanol (35 mL) was d with ammonium formate (19.1 g, 303 mmol). The resulting black suspension was heated at a gentle reflux overnight. The reaction was allowed to cool to ambient ature and filtered through a Celite® bed. The filtrate was evaporated in vacuo to give (+/-) 3-methylpyrrolidinol as a dark oil.
Step E: Pre aration of 1- methylpyrrolidinol: A mixture of 3-methylpyrrolidinol (1.41 g, 13.9 mmol), (R)(6- pyridinyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (4.30 g, 12.5 mmol) and K2C03 (1.93 g, 13.9 mmol) in THF (69.7 mL, 13.9 mmol) was heated in a sealed tube to 50 OC overnight. The reaction was filtered, concentrated under reduced pressure and the residue was purified by preparative HPLC (C18, 300 g, 10% MeCN/water to 95% MeCN/water over column volumes) to give 1-((S)(6-chloropyridinyl)-2,2,2-trifiuoroethyl) methylpyrrolidinol (2.01 g, 48.9 % yield).
Step F: Se aration of reomers 1 and 2 of 1- ro ridin yl[-2,2,2-trifluoroethyl[methylp_yrrolidinol: A diastereomeric mixture of 1-((S)(6- pyridinyl)-2,2,2-trifiuoroethyl)methylpyrrolidinol (2.01 g) was ted to preparative chiral supercritical fluid chromatographic separation under the following conditions: Column ADH 20 mm x 250 mm; flow rate: 50 mL/min mobile phase A: ritical C02; mobile phase B: methanol with 0.5% diethyl amine; Gradient: 10% mobile phase B isocratic; UV detection ngth: 214 nm. Peak 1 (diastereomer 1): retention time: 8.3 min; (0.643 g). Peak 2 (diastereomer 2): retention time 9.2 min (0.696 g).
Step H: Preparation of Diastereomer 1 of 3-methyl]]§[-2,2,2-trifluoro]6- hydrazinylpyridinyl[ethyl[pyrrolidinol: To a solution of Diastereomer 1 of 1-((S)(6- chloropyridinyl)-2,2,2-trifluoroethyl)methylpyrrolidinol (0.550 g, 1.866 mmol) in sec-butanol (10 mL) was added ine (0.8786 mL, 27.99 mmol) and stirred at 125 OC overnight. The reaction was concentrated from methanol (3 x 30 mL) to give Diastereomer 1 of 3-methyl((S)-2,2,2-trifluoro(6-hydrazinylpyridinyl)ethyl)pyrrolidinol (0.580 g, 1.998 mmol, 107.1 % yield).
Step 1: Pre aration of Diastereomer 2 of 3-meth l -2 2 2-trifluoro 6- hydrazinylpyridinyl[ethyl[pyrrolidinol: Prepared as described in Step H using Diastereomer 2 from Step G in place of Diastereomer 1 to give Diastereomer 2 of 3-methyl- 1-((S)-2,2,2-trifluoro(6-hydrazinylpyridinyl)ethyl)pyrrolidinol (0.628 g, 2.163 mmol, 110.9 % yield).
Preparation F H N\ WWOH2 M N/ Pre aration of Diastereomer 1 of 3-meth l R -2 2 2-trifluoro 6-h drazin l ridin l eth l inol and Diastereomer 2 of 3-meth l R -2 2 2-trifluoro 6- h drazin l ridin leth l rrolidinol Prepared as described in Preparation E using (S)(6-chloropyridinyl)- trifluoroethyl trifluoromethanesulfonate in place of (R)(6-chloropyridinyl)-2,2,2- trifiuoroethyl trifluoromethanesulfonate in Step E.
Example 1 F3C h/lj N N N\N / 3S 2 2 2-trifluoro 3- 8-methox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine dih drochloride Step A: Pre aration of 1- 6-chloro ridin l -2 2 2-trifluoroethanol: To a solution of 6-chloronicotinaldehyde (5.93 g, 41.9 mmol) and CsF (1.27 g, 8.38 mmol) in DME (350 mL) was added trimethyl(trifluoromethyl)silane (9.82 mL, 62.8 mmol) in THF (30 mL) at 0 °C. The reaction mixture was allowed to warm to ambient temperature and the reaction was d at ambient temperature for 18 hours. 1 N HCl (50 mL) in water was added and the reaction was stirred at ambient temperature for 1 hour. Ethyl acetate (100 mL) was added. The organic layer was separated, washed with ted sodium bicarbonate and brine, dried m sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate) to give 1-(6- chloropyridinyl)-2,2,2-trifluoroethanol (8.8 g, 99.3%) as an oil.
Step B: Pre aration of 1- ro ridin l-22 2-trifiuoroeth l trifluoromethanesulfonate: To a solution of 1-(6-chloropyridinyl)-2,2,2-trifiuoroethanol (4.00 g, 17.96 mmol) and triethylamine (2.75 mL, 19.76 mmol) in DCM (30 mL) was added trifluoromethanesulfonic anhydride (3.17 mL, 18.86 mmol) at -40 °C and the reaction was stirred at -40 °C for 1 hour. Hexane (150 mL) and water (40 mL) were added. The organic layer was ted, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced re to give 1 loropyridin-3 -yl)-2,2,2-trifiuoroethyl trifluoromethanesulfonate (6.0 g, 97.2%) as a yellow solid.
Step C: Pre aration of tert—but 1 3S 1- 6-chloro ridin 1 trifluoroethyl[pyrrolidinylcarbamate: A solution of 1-(6-chloropyridinyl)-2,2,2- trifluoroethyl trifluoromethanesulfonate (0.55 g, 1.60 mmol), K2C03 (0.33 g, 2.40 mmol), and (S)-tert—butyl pyrrolidinylcarbamate (0.42 g, 2.24 mmol) in THF (8 mL) was stirred at 50 °C for 20 hours. Water (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 hexane/ethyl acetate) to give tert—butyl (3 S)(1-(6-chloropyridinyl)-2,2,2- trifluoroethyl)pyrrolidinylcarbamate (0.45 g, 74.0%) as a white solid.
Step D: Pre aration of tert—but 1 3S 2 2 2-trifluoro-l- 6- hydrazinylpyridinyl[ethyl[pyrrolidinylcarbamate: A solution of tert—butyl (3 1-(6- chloropyridinyl)-2,2,2-trifluoroethyl)pyrrolidinylcarbamate (5.74 g, 15.11 mmol) and anhydrous hydrazine (4.74 mL, 151.1 mmol) in i-BuOH (20 mL) in a sealed tube was stirred at 130 °C for 18 hours. After cooling to ambient temperature, water (10 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give tert—butyl (3 S)- l 2-trifluoro- l -(6-hydrazinylpyridin-3 - yl)ethyl)pyrrolidinylcarbamate (5.34 g, 94.1%) as a white foam solid.
Step E: Pre aration of tert—but 1 3S 2 2 2-trifluoro-l- 3- 8- methox uinolin l- 12 4 triazolo 4 3-a ridin leth l in mate: A solution of tert—butyl (3S)(2,2,2-trifluoro(6-hydrazinylpyridinyl)ethyl)pyrrolidin ylcarbamate (0.20 g, 0.53 mmol) and 8-methoxyquinolinecarbaldehyde (0.105 g, 0.53 mmol) in EtOH (10 mL) was d at ambient temperature for 1 hour. The solvent was removed under reduced pressure. The residue was ved in DCM (10 mL) and iodobenzene diacetate (0.189 g, 0.59 mmol) was added. The on mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with ethyl acetate) to give tert—butyl (3S)(2,2,2- trifluoro(3 -(8-methoxyquinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - amate (0.27 g, 93.4%) as off white solid.
Step F: Pre aration of 3S 2 2 2-trifluoro-l- 3- ox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine dih drochloride: To a solution of tert—butyl (3 S)(2,2,2-trifluoro(3 thoxyquinolinyl)-[1,2,4]triazolo[4,3 -a]pyridin- 6-yl)ethyl)pyrrolidinylcarbamate (0.050 g, 0.092 mmol) in DCM (0.5 mL) was added 5 N HCl (2.30 mL, 9.22 mmol) in IPA. The reaction mixture was stirred at t temperature for 30 minutes. The solvent was removed under reduced pressure. The solid obtained was suspended in ACN (3 mL) and stirred at ambient temperature for 5 minutes. The solid which formed was collected by filtration to give (3 S)-l-(2,2,2-trifluoro-l-(3-(8-methoxyquinolin ,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinamine as the di-HCl salt (0.043 g, 90.5%) as light yellow solid. LCMS APCI (+) m/z 443(M+H).
Example 2 \ 2 HCI N N\ Br \ / | N\N / 3S -l- l- 3- 7-bromo uinolin l - l 2 4 triazolo 4 3-a ridin l -2 2 2- trifluoroeth l rrolidinamine dih drochloride Step A: Pre aration of tert—but 1 3S l- 3- 7-bromo uinolin l- l 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidin lcarbamate: Prepared as described in Example 1, Steps A-E, using 7-bromoquinolinecarbaldehyde in place of 8- methoxyquinolinecarbaldehyde in Step E.
Step B: Pre aration of 3S l- 3- 7-bromo uinolin l - l 2 4 triazolo 4 3-a idin l -2 2 uoroeth l rrolidinamine dih drochloride: Prepared as described in e 1, Step F, using tert—butyl (3S)-l-(l-(3-(7-bromoquinolin- 2-yl)—[ l ,2,4]triazolo [4,3 idinyl)-2,2,2-trifluoroethyl)pyrrolidin-3 bamate in place of tert-butyl (3 S)-l-(2,2,2-trifluoro-l-(3-(8-methoxyquinolinyl)-[l,2,4]triazolo[4,3- a]pyridinyl)ethyl)pyrrolidinylcarbamate. LCMS APCI (+) m/z 49l(M+H).
Example 3 N\N / 3S -l- l- 3- 7-c clo ro l uinolin l - l 2 4 triazolo 4 3-a ridin l -2 2 2- roeth l rrolidinamine dih drochloride Step A: Pre aration tert—but 1 3S l- 3- 7-c clo ro l uinolin l- l 2 4 triazolo 4 3-a - l -2 2 uoroeth l rrolidin lcarbamate: A solution of tert—butyl (3 S)- l -( l -(3-(7-bromoquinolinyl)-[l ,2,4]triazolo[4,3-a]pyridinyl)-2,2,2- trifluoroethyl)pyrrolidinylcarbamate (Example 2, Step A; 0.25 g, 0.42 mmol), Pd(OAc)2 (0.0048 g, 0.021 mmol), P(Cy)3 (0.013 g, 0.047 mmol), and cyclopropylboronic acid (0.073 g, 0.85 mmol) in toluene (4 mL) and water (0.4 mL) was stirred at 100 °C for 6 hours. After cooling to ambient temperature, ethyl acetate (20 mL) and water (5 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced re. The residue was purified by flash chromatography on silica gel (ethyl e) to give tert—butyl (3S)-l-(l-(3-(7-cyclopropquuinolinyl)- [l,2,4]triazolo[4,3-a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidinylcarbamate (0.224 g, 95.9%) as a solid.
Step B: Pre aration of 3S l- 3- 7-c clo ro l uinolin l- l 2 4 triazolo 4 3-a idin l -2 2 2-trifluoroeth l inamine dih drochloride: Prepared as described in Example 1, Step F, using tert-butyl (3S)—l-(l-(3-(7- cyclopropquuinolinyl)-[ l ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidin- 3-ylcarbamate in place of utyl (3S)-l-(2,2,2-trifluoro-l-(3-(8-methoxyquinolinyl)- [l,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate. LCMS APCI (+) m/z 453 (M+H).
Example 4 I ,_. I p—A N J; HE.a:NO ,_.O J; L.” a 6- leth l rrolidinamine trih drochloride Step A: Pre aration ut 1 3S 2 2 2-trifluoro-l- 3- 7- l-meth l-lH- razol l uinolin l- 12 4 triazolo 4 3-a ridin l eth l rrolidin lcarbamate: A solution of tert—butyl (3S)-l-(l-(3-(7-bromoquinolinyl)-[l,2,4]triazolo[4,3-a]pyridin yl)-2,2,2-trifluoroethyl)pyrrolidinylcarbamate (Example 2, Step A; 0.18 g, 0.30 mmol), lmethyl (4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-lH-pyrazole (0.127 g, 0.61 mmol), PdClz(dppf)*dcm 9 g, 0.030 mmol), and triethylamine (0.064 mL, 0.46 mmol) in IPA (3 mL) was heated at 100 °C for 3 hours. After g to ambient temperature, the residue was directly purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CHgCN/water gradient; 30 CV) to give tert—butyl (3S)—l-(2,2,2- trifluoro(3 -(7-(1-methyl-1H-pyrazolyl)quinolinyl)-[1 ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate (0.15 g, 83.2%) as a solid.
Step B: Pre aration of 3S 2 2 2-trifluoro 3- 7- 1 4- l uinolin l - 1 2 4 triazolo 4 3-a ridin leth l rrolidinamine trihydrochloride: Prepared as described in Example 1 using utyl (3 2,2,2-trifluoro- 1-(3 -(7-( 1 -methyl- 1 H-pyrazolyl)quinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate in place of tert—butyl (3 S)(2,2,2-trifluoro(3-(8- methoxyquinolinyl)-[1 ,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate in Step F. LCMS APCI (+) m/z 493 (M+H).
Example 5 F3C h/Ij 2HC| roeth l rrolidinamine dih drochloride Step A: Pre aration 8- c clo ro lmethox meth l uinoline: A solution of 2-methquuinolinol (10.0 g, 62.82 mmol), (bromomethyl)cyclopropane (17.0 g, 125.6 mmol), and K2C03 (17.80 g, 128.8 mmol) in acetone (50 mL) in a sealed flask was stirred at 88 °C for 2 days. After cooling to ambient temperature, the acetone was removed under reduced pressure. DCM (100 mL) and water (50 mL) were added. The organic layer was ted, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was d by flash chromatography on silica gel (DCM) to give 8- (cyclopropylmethoxy)methquuinoline (13.2 g, 98.5%) as a solid.
Step B: Preparation of 8-1cyclopropylmethoxy[guinolinecarbaldehyde: To a solution of 8-(cyclopropylmethoxy)methquuinoline (3.00 g, 14.1 mmol) in dioxane (100 mL) and water (1.0 mL) was added SeOz (1.87 g, 16.9 mmol). The on mixture was stirred at reflux for 2 hours. After cooling to t temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (1 :4 hexane/DCM) to give 8- (cyclopropylmethoxy)quinolinecarbaldehyde (3.1 g, 97.0%) as a solid Step C: Pre aration of 3S l- 3- 8- c clo r0 lmethox uinolin l- l 2 4 triazolo 4 3-a idin l -2 2 2-trifluor0eth l rrolidinamine dih oride: Prepared as described in Example 1, Step E-F, using 8-(cyclopropylmethoxy)quinoline carbaldehyde in place of 8-meth0xyquin0linecarbaldehyde. LCMS APCI (+) m/z 483 (M+H).
Example 6 yl [guinoline Prepared as bed in Example 1, Steps A-E, using pyrrolidine in place of (S)-tert—butyl pyrrolidinylcarbamate in Step C. LCMS APCI (+) m/z 428 (M+H).
Example 7 N N\ \ / | N\N / 3S -l- 2 2 2-trifluor0-l- 3- 8-methox n l - l 2 4 triazolo 4 3-a ridin leth l rrolidinol Prepared as described in Example 1, Steps A-E, using (S)-pyrrolidinol in place of (S)—tert—butyl pyrrolidinylcarbamate in Step C. LCMS APCI (+) m/z 444 (M+H).
NH 2 l eth l rrolidinamine dih drochloride Step A: Pre n of tert—but l S S -2 22-trifluoro 3- 8- methox n l- 12 4 triazolo 4 3-a ridin leth l rrolidin lcarbamate: The enantiomerically pure tert—butyl (S)((S)-2,2,2-trifluoro(3-(8-methoxyquinolin yl)-[1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate was separated from tertbutyl (3 2,2,2-trifluoro(3 -(8-methoxyquinolinyl)-[1,2,4]triazolo[4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate (mixture was prepared as in Example 1, Steps A-E) by chiral supercritical fluid chromatography (SFC). Conditions for analytical chromatography: Rt of the (S,S) diastereomer = 6.53 min; Rt of the (R, S) diastereomer = 7.02 min; OD-H, Chiral Technologies 4.6mm x 250 mm, 20% MeOH with 0.1% DEA at 3.0 mL/min. Outlet pressure: 100 bar. Conditions for preparative chromatography: OD-H, Chiral Technologies mm x 250 mm, 20% MeOH with 0.1% DEA at 50 mL/min. Outlet pressure: 100 bar.
Step B: Pre aration of S S -2 2 2-trifluoro 3- 8-methox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine dih drochloride: To a on of tert-butyl (S)((S)-2,2,2-trifluoro(3-(8-methoxyquinolinyl)-[1,2,4]triazolo[4,3- a]pyridinyl)ethyl)pyrrolidinylcarbamate (0.074 g, 0.14 mmol) in DCM (0.5 mL) was added 5 N HCl (2.73 mL, 13.6 mmol) in IPA. The reaction mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure. The solid obtained was suspended in ACN (3 mL) and stirred at ambient ature for 5 minutes. The resulting solid was collected by filtration to give (S)((S)-2,2,2-trifluoro(3-(8- methoxyquinolinyl)-[1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinamine as the di- HCl salt (0.066 g, 93.9%) as a solid. LCMS APCI (+) m/z 443 (M+H).
Example 9A ] Step A: Pre aration of ut l S R -22 2-trifluoro 3- 8- methox n l- 12 4 lo 4 3-a ridin leth l rrolidin lcarbamate: The enantiomerically pure tert—butyl (S)((R)-2,2,2-trifluoro(3-(8-methoxyquinolin yl)-[1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate was separated from tert- butyl (3 S)(2,2,2-trifluoro(3 -(8-methoxyquinolinyl)-[1,2,4]triazolo[4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate (prepared as in Example 1, Steps A-E) by chiral SFC (Conditions for analytical chromatography: Rt of the (S,S) diastereomer = 6.53 min; Rt of the (R, S) diastereomer = 7.02 min; OD-H, Chiral Technologies 4.6mm x 250 mm, 20% MeOH with 0.1% DEA at 3.0 mL/min. Outlet pressure: 100 bar. Conditions for preparative chromatography: OD-H, Chiral logies 20 mm x 250 mm, 20% MeOH with 0.1% DEA at 50 . Outlet pressure: 100 bar).
Step B: Pre aration of S R -2 2 2-trifluoro 3- 8-methox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l inamine dih drochloride: To a solution of tert—butyl (S)((R)-2,2,2-trifluoro(3 -(8-methoxyquinolinyl)-[ 1 ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinylcarbamate (0.061 g, 0.11 mmol) in DCM (0.5 mL) was added 5 N HCl (2.25 ml, 11.2 mmol) in IPA. The on mixture was stirred at ambient ature for 1 hour. The solvent was removed under reduced pressure. The solid obtained was suspended in ACN (3 mL) and stirred at ambient temperature for 5 minutes. The resulting solid was collected by filtration to give ((R)-2,2,2-trifluoro(3-(8- methoxyquinolinyl)-[1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinamine as the di- HCl salt (0.052 g, 89.7%) as a solid. LCMS APCI (+) m/z 443 (M+H).
Example 9B Step A: Pre aration of 1- 6-chloro ridin l -2 2 2-trifluoroethanone: To a solution of methyl 6-chloronicotinate (150.0 g, 874.2 mmol) and CsF (1.73 g, 11.36 mmol) in DME (480 mL) was added trimethyl(trifluoromethyl)silane (138.9 mL, 939.8 mmol) dropwise. The reaction mixture was stirred at ambient ature for 3 hours. 4 N HCl (655.7 mL, 2623 mmol) in water was added, and the mixture was stirred at ambient temperature for 18 hours. Ethyl acetate (500 mL) was added. The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give brown oil. The oil was dissolved in benzene (200 mL) and then dehydrated by water/benzene in a Dean-Stark apparatus. After 18 hours, mixture was led under reduced pressure to give 1-(6-chloropyridinyl)-2,2,2- trifluoroethanone (171 g, 93.3%) as white solid.
Step B: Preparation of 16-chlorop_yridinyl)—2,2,2-trifluoroethanol: To a solution of 1-(6-chloropyridinyl)-2,2,2-trifluoroethanone (46.8 g, 223.3 mmol) and 1.0 M KOtBu (4.47 mL, 4.47 mmol) in t—BuOH in IPA (136 mL) and toluene (34 mL) in a autoclave was added ro{(S)-(-)-2,2'-bis[di(3,5-xylyl)-phosphino-1,1'-binaphthyl}[(2S)- (+)-1,1-bis(4-methoxyphenyl)methyl-1,2-butanediamine (0.273 g, 0.22 mmol) (Strem Chemicals). The reaction mixture was degassed by three vacuum-filling with nitrogen cycles.
Hydrogen was introduced into the autoclave at a pressure of 300 psi and then reduced to 20 psi by slowly releasing the stop valve. After this procedure was repeated three times, the autoclave was pressurized to 300 psi with en. The reaction e was vigorously stirred at ambient temperature for 4 days (pressure was recharged to 300 psi when the internal pressure d below 200 psi). The pressure was released and the solvent was d under reduced pressure. Ethyl acetate (300 mL) and 10% citric acid solution (50 mL) were added. The c layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced re. The residue was purified by flash chromatography on silica gel (3:1 DCM/ethyl acetate) to give (S)(6-chloropyridinyl)-2,2,2- trifluoroethanol (46.76 g, 99.0%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 86.4% e.e. (S)-enantiomer). (S)(6-chloropyridinyl)-2,2,2-trifluoroethanol (97.8 g, 462 mmol, 76% e.e.) was dissolved in 4.5% ethyl acetate/hexane (v/v) (2170 mL) with heating to reflux.
After complete dissolution, it was slowly cooled to ambient temperature ght. The resulting solid was collected by filtration, washed with hexane and dried to give (S)-l-(6- chloropyridinyl)-2,2,2-trifluoroethanol (62.5 g, 63.9%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 98.8% e.e. (S)-enantiomer).
Step C: Pre aration of S 6-chloro ridin l-22 2-trifluoroeth l romethanesulfonate: To a solution of (S)(6-chloropyridinyl)-2,2,2- trifluoroethanol (50.0 g, 236.3 mmol) and lutidine (33.03 mL, 283.6 mmol) in DCM (500 mL) was added trifluoromethanesulfonic anhydride (43.74 ml, 260.0 mmol) slowly at -40 °C.
The reaction mixture was stirred at -40 °C for 3 hours. Water (200 mL) was added. The c layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate) to give (S)(6-chloropyridinyl)-2,2,2-trifiuoroethyl trifiuoromethanesulfonate (79.8 g, 98.3%) as white solid.
Step D: Pre aration of tert—but l S R 6-chloro 3- l-2 22- trifiuoroethyl)pyrrolidinylcarbamate: A solution of (S)(6-chloropyridinyl)-2,2,2- trifiuoroethyl trifiuoromethanesulfonate (79.8 g, 232 mmol), (S)-tert—butyl pyrrolidin ylcarbamate (51.9 g, 279 mmol), and K2C03 (44.9 g, 325 mmol) in THF (500 mL) was stirred at 56 °C for 18 hours. After cooling to ambient temperature, water (200 mL) and ethyl acetate (200 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate) to give a thick oil. The oil was dissolved in ether (200 mL) and hexane (500 mL) was added. The solution was trated to about 200 mL and d at ambient temperature for 1 hour. Hexane (300 mL) was added, and the resulting solid was ted by filtration to give tert—butyl (S)((R)(6- chloropyridinyl)-2,2,2-trifiuoroethyl)pyrrolidinylcarbamate (68.2 g, 77.3%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes/10% (1:1 MeOH/EtOH) at 1.0 mL/min, >99% d.e. (R,S)—diastereomer).
] Step E: Pre aration of tert—but l S R -2 2 2-trifiuoro 6- hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate: A solution of tert—butyl ((R) (6-chloropyridinyl)-2,2,2-trifiuoroethyl)pyrrolidinylcarbamate (68.5 g, 180.4 mmol) and anhydrous ine (56.61 mL, 1804 mmol) in i-BuOH (80 mL) was stirred at 106 °C in a sealed flask for 16 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was partitioned in ethyl acetate (800 mL) and water (100 mL). The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give utyl (S)((R)-2,2,2-trifiuoro(6- inylpyridinyl)ethyl)pyrrolidinylcarbamate (68.1 g, 95.6%) as white foam solid.
Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexane/10% (1:1 MeOH/EtOH) at 1.0 , >99% d.e. (R,S)—diastereomer).
Step F: Pre aration of tert—but l S R -2 2 2-trifiuoro 3- 8- methox uinolin l- 12 4 triazolo 4 3-a 6- leth l rrolidin lcarbamate: A solution of tert—butyl (S)((R)-2,2,2-trifiuoro(6-hydrazinylpyridinyl)ethyl)pyrrolidin- 3-ylcarbamate (0.279 g, 0.67 mmol) and 8-methoxyquinolinecarbaldehyde (0.125 g, 0.67 mmol) in EtOH (10 mL) was stirred at ambient temperature for 18 hours. The solvent was d under reduced pressure. The residue was dissolved in DCM (10 mL) and iodobenzene diacetate (0.259 g, 0.80 mmol) was added. The mixture was stirred at ambient temperature for 2 hours. Ethyl acetate (20 mL) and ted sodium onate (10 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced re. The residue ed was purified by flash chromatography on silica gel (20:1 ethyl acetate/MeOH) to give tert—butyl ((R)-2,2,2- trifluoro(3 -(8-methoxyquinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - ylcarbamate (0.140 g, 38.6%) as a solid.
Step G: Pre aration of S R -2 2 2-trifluoro 3- 8-methox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine dih drochloride: To a solution of tert—butyl (S)((R)-2,2,2-trifluoro(3 -(8-methoxyquinolinyl)-[1,2,4]triazolo[4,3 - a]pyridinyl)ethyl)pyrrolidinylcarbamate (0.140 g, 0.26 mmol) in DCM ( 1.0 mL) was added 5 N HCl (5.16 ml, 25.80 mmol) in IPA. The mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure to give a solid. The solid was suspended in ACN (5 mL) and stirred for 10 minutes. The solid was collected by filtration and dried to give (S)((R)-2,2,2-trifluoro(3-(8-methoxyquinolinyl)- [1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinamine as the di-HCl salt (0.104 g, 78.2%) as a solid. Specific rotation: [(1]24D = -1.010 (c = 1.01, MeOH).
Example 10 2 2 2-trifiuoroeth l rrolidinamine dih drochloride ed as described in Example 8 using tert—butyl (3S)(1-(3-(8- (cyclopropylmethoxy)quinolinyl)-[1 ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2- trifluoroethyl)pyrrolidinylcarbamate (Prepared as in Example 5, Steps A-C) in place of tert—butyl (3 2,2,2-trifluoro(3 -(8-methoxyquinolinyl)-[1,2,4]triazolo[4,3 -a]pyridin- thyl)pyrrolidinylcarbamate and isolating peak 1 during the chiral separation in Step A. LCMS APCI (+) m/z 483 (M+H). e 1 1 2 2 2-trifluoroeth l rrolidinamine dih drochloride ed as described in Example 9A using tert—butyl (3S)—l-(l-(3-(8- (cyclopropylmethoxy)quinolinyl)-[ l ,2,4]triazolo [4,3 idinyl)—2,2,2- trifluoroethyl)pyrrolidinylcarbamate (Prepared as in Example 5, Steps A-C) in place of tert—butyl (3 S)- l -(2,2,2-trifluoro- l -(3 thoxyquinolinyl)-[ l ,2,4]triazolo [4,3 -a]pyridin- 6-yl)ethyl)pyrrolidinylcarbamate and isolating peak 2 during the chiral separation in Step A. LCMS APCI (+) m/z 483 (M+H).
Example 12 / NQ,NH2 / N S -l- S -l- 3- 7-c clo ro l uinolin l - l 2 4 triazolo 4 3-a r1d1n l -2 2 2- trifluoroethl rrolidinamine Prepared as described in Example 8, Steps A-B, substituting tert—butyl (3S)-l- (l-(3 -(7-cyclopropquuinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2- trifluoroethyl)pyrrolidinylcarbamate (Example 3, Step A) for tert—butyl (3 S)-l-(2,2,2- trifluoro- l -(3 -(8-methoxyquinolinyl)- [l ,2,4]triazolo [4,3 idinyl)ethyl)pyrrolidin-3 - ylcarbamate and isolating Peak 1 during the chiral separation in Step A. LCMS APCI (+) m/z 453 (M+H).
Example 13 S -l- R -l- 3- 7-c clo ro l uinolin l - l 2 4 lo 4 3-a ridin l -2 2 2- trifluoroethl rrolidinamine Prepared as described in Example 8, Steps A-B, substituting utyl (3S)-l- (l-(3 -(7-cyclopropquuinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2- trifluoroethyl)pyrrolidinylcarbamate (Example 3, Step A) for tert—butyl (3 S)-l-(2,2,2- trifluoro- l -(3 -(8-methoxyquinolinyl)- [l ,2,4]triazolo [4,3 idinyl)ethyl)pyrrolidin-3 - ylcarbamate, isolating Peak 2 during the chiral separation in Step A. LCMS APCI (+) m/z 453 (M+H). e 14 Prepared as described in Example 8, Steps A-B, using tert—butyl (3 S)-l-(2,2,2- trifluoro-l -(3 -(7-( 1 -methyl- 1 H-pyrazolyl)quinolinyl)-[ l ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidin—3-ylcarbamate le 4, Step A) in place of tert—butyl (3S)-l-(2,2,2- trifluoro- l -(3 -(8-methoxyquinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - amate and isolating peak 1 during the chiral separation in Step A. LCMS APCI (+) m/z 493 (M+H).
Example 15 3 HCI N\ \ / | N\N / S -l- R -2 2 2-trifluoro-l- 3- 7- l-meth l-lH- 4- l u1nolin l - Prepared as described in Example 9A, Steps A-B, using tert—butyl (3S)—l- (2,2,2-trifluoro- l -(3 -(7-( 1 -methyl- 1 H-pyrazolyl)quinolinyl)-[ l ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinylcarbamate (Example 4, Step A) in place of tert—butyl (3 S)- l-(2,2,2-trifluoro- l -(3 -(8-methoxyquinolinyl)-[ l ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate and isolating peak 2 during the chiral separation in Step A.
LCMS APCI (+) m/z 493 (M+H).
Example 16 F30 N 2HC| | 0 N N\ \ / | N\N / 3R 1- 3- 8- c clo ro lmethox uinolin l - 1 2 4 lo 4 3-a ridin-6 1- 2 2 2-trifluoroeth l rrolidinamine dih drochloride Prepared as described in Example 1, Steps A-F, using (R)—tert—butyl pyrrolidinylcarbamate in place of (S)-tert—butyl idinylcarbamate in Step C, and substituting 8-(cyclopropylmethoxy)quinolinecarbaldehyde for 8-methoxyquinoline carbaldehyde in Step E. LCMS APCI (+) m/z 483 (M+H).
Example 17 3 HCI N\N / 3S 1- 3- 8-tert-but l uinolin l - 1 2 4 lo 4 3-a ridin-6 l eth l rrolidin amine rochloride Step A: Preparation of methyl 6-hydrazinylnicotinate: A solution of methyl 6-fluoronicotinate (13.9 g, 89.60 mmol) and hydrazine (5.625 ml, 179.2 mmol) in THF (200 mL) were heated at 56 CC for 2 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure and water (200 mL) was added. The suspension was stirred at ambient temperature for 1 hour. The solid was collected by filtration, washed with water and dried to give methyl 6-hydrazinylnicotinate (13.4 g, 89.5%) as a solid.
Step B: Pre aration of E -meth l 6- 2- 8-tert-but l uinolin yl [methylene [hydrazinyl [nicotinate: A solution of methyl 6-hydrazinylnicotinate (1.00 g, .98 mmol) and 8-tert—butquuinolinecarbaldehyde (1.28 g, 5.98 mmol) in absolute ethanol (20 mL) was stirred at ambient temperature for 4 hours. The solid that formed was collected by filtration, washed with l (10 mL), ether (100 mL) and dried to give (E)—methyl 6-(2- ((8-tert—butquuinolinyl)methylene)hydrazinyl)nicotinate (1.78 g, 82.1%) as a solid.
Step C: Preparation of 3-]8-tert—butylguinolinyl[-| 1,2,4|triazolo|4,3- alpyridinecarboxylic acid: To a suspension of thyl (8-tert—butquuinolin yl)methylene)hydrazinyl)nicotinate (1.78 g, 4.91 mmol) in DCM (40 mL) was added iodobenzene diacetate (1.90 g, 5.89 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. The solvent was removed, and the resulting residue was suspended in 1:1 hexane/ether (50 mL) and stirred at ambient temperature for 10 minutes. The solid that formed was collected by filtration. The solid was then suspended in 1:1 THF/H20 (50 mL) and LiOH-HZO (0.82 g, 19.6 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours. THF was removed under reduced pressure. The resulting aqueous solution was acidified with saturated potassium hydrogen sulfate to pH~3-4. The solid that formed was collected by filtration, washed with water, 1:1 hexane/ether (50 mL) and dried to give 3-(8-tert—butquuinolinyl)-[1,2,4]triazolo[4,3-a]pyridinecarboxylic acid (1.55 g, 91.1%) as solid.
Step D: Pre n of 3- 8-tert—but l n l -N-methox - | triazolo|4,3-a|pyridinecarboxamide: A solution of 3-(8-tert—butquuinolinyl)- [1,2,4]triazolo[4,3-a]pyridinecarboxylic acid (0.60 g, 1.73 mmol) and N,O- dimethylhydroxylamine hydrochloride (0.25 g, 2.60 mmol) and DIEA (0.91 mL, 5.20 mmol) in DMF (1 mL) was added HATU (1.15 g, 3.03 mmol) and the reaction e was stirred at ambient temperature for 1 hour. Water (10 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1 :3 hexane/ethyl e) to give 3-(8-tert-butquuinolinyl)-N-methoxy-N- methyl-[1,2,4]triazolo[4,3-a]pyridinecarboxamide (0.54 g, 80.6%) as solid.
Step E: Preparation of 1-[3tert—butylguinolinylH 1,2,4|triazolo|4,3- a|pyridinyl[ethanone: To a solution of ert—butquuinolinyl)-N-methoxy-N-methyl- [1,2,4]triazolo[4,3-a]pyridinecarboxamide (0.54 g, 1.40 mmol) in THF (10 mL) was added 1 N MeMgBr (2.00 mL, 2.79 mmol) in THF at -78 °C. After addition, the on mixture was allowed to warm to ambient temperature and stirred at ambient for 20 hours. Water (10 mL) and ethyl e (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), d and concentrated under reduced pressure. The residue was d by flash chromatography on silica gel (1:1 DCM/ethyl acetate) to give 1-(3-(8- tert—butquuinolinyl)-[1,2,4]triazolo[4,3-a]pyridinyl)ethanone (0.385 g, 80.0%) as solid.
Step F: Pre aration of tert—but 1 3S 1- 3- 8-tert—but l uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidin lcarbamate: To a solution of (S)-tert— butyl pyrrolidinylcarbamate (0.502 g, 2.69 mmol), 1-(3-(8-tert—butquuinolinyl)- [1,2,4]triazolo[4,3-a]pyridinyl)ethanone (0.464 g, 1.35 mmol) in THF (20 mL) was added tetraisopropoxytitanium (0.79 mL, 2.69 mmol) and the reaction mixture was stirred at ambient ature for 18 hours. Ethanol (2 mL) and NaBH4 (0.204 g, 5.39 mmol) were added and the mixture was d at ambient temperature for 2 hours. Water (10 mL), trated ammonium hydroxide (2 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), d and concentrated under reduced pressure. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-90% CHgCN/water gradient; 25 CV) to give utyl (3 S)(1-(3-(8-tert—butquuinolinyl)-[1,2,4]triazolo[4,3-a]pyridin yl)ethyl)pyrrolidinylcarbamate (0.485 g, 69.9%) as solid.
] Step G: Pre aration of 3S 1- 3- 8-tert—but l uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine trih oride: To a solution of tert—butyl (3 S)—1-(1-(3 -(8-tert—butquuinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate (0.028 g, 0.0544 mmol) in DCM (2 mL) was added 5 N HCl (0.33 ml, 1.63 mmol) in IPA. The mixture was stirred at ambient temperature for 1 hour.
The solvent was removed under reduced pressure to give (3 S)(1-(3-(8-tert—butquuinolin- 2-yl)-[1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinamine l salt (0.027 g, 94.7%) as solid. LCMS APCI (+) m/z 4l5(M+H).
Example 18 F3C h/Jj 3HC| \ / I | N N\ \ N \ / | N\N / 3S 2 2 2-trifluoro 3- 7- ridin l uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine tri-h drochloride Prepared as described in Example 4, Steps A-B, using 3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)pyridine in place of 1-methyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1H-pyrazole in Step A. LCMS APCI (+) m/z 490 (M+H).
Example 19 F3C D‘OH N N N\N / 3S 4S 2 2 2-trifluoro 3- 8-methox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidine-3 4-diol Prepared as described in Example 1, Steps A-E, using (3 S,4S)-pyrrolidine-3,4- diol in place of (S)-tert—butyl pyrrolidinylcarbamate in Step C. LCMS APCI (+) m/z 460 (M+H).
Example 20 F30 H wNQ’\ 2HC| / N 0% 3 1- 3- 8- C clo ro lmethox uinolin l - 1 2 4 triazolo 4 3-a ridin-6 1- 2 2 2-trifluoroeth l -N—meth l rrolidinamine dih drochloride ] Step A: Pre aration of -benz l3— tert-butox carbon lamino rrolidine-l- carboxylate: To a solution of (S)-tert—butyl pyrrolidinylcarbamate (6.0 g, 32.2 mmol) and DIEA (12.5 g, 16.8 mL, 96.6 mmol) in dichloromethane (60 mL) cooled to 0 0C on an ice- bath was added benzyl chloroformate (8.7 g, 7.2 mL, 48.3 mmol), and the resulting mixture stirred at 0 0C for 2 hours. The mixture was diluted with dichloromethane (30 mL) and washed successively with cold aqueous 10% HCl, water, saturated sodium onate solution and brine. The c phase was dried (MgSO4), filtered and concentrated under reduced pressure. The e was d by flash chromatography silica gel (Biotage, 65M; 20% ethyl e/hexanes) to afford (S)—benzyl 3-(tertbutoxycarbonylamino )pyrrolidinecarboxylate (10 g, 97 %).
Step B: Pre aration of -benz l 3- tert—butox carbon lmeth 1 amino )pyrrolidine-l-carboxylate: To a sion of 60% dispersion of sodium hydride in mineral oil (1.5 g, 37.5 mmol) in anhydrous DMF (20 mL) cooled on an ice-bath to 0 0C was added dropwise a solution of (S)-benzy1 3-(tert—butoxycarbonylamino)pyrrolidine carboxylate (10 g, 31.2 mmol) in anhydrous DMF (100 mL). The resulting mixture was stirred at 0 0C for 1 hour then at ambient temperature for 2 hours. The mixture was subsequently cooled to 0 0C and treated dropwise with iodomethane (2.1 mL, 34.3 mmol), and the mixture stirred at 0 0C for 1 hour then warmed to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with water (300 mL) and the mixture extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residual oil was purified by column chromatography (Biotage, 65M; 10-20% ethyl acetate: hexanes) to afford (S)-benzyl 3-(tert—butoxycarbonyl(methyl)amino)pyrrolidinecarboxylate (7.2 g, 69%).
Step C: Preparation of ]§[-tert-butyl methylgpyrrolidinyl[carbamate: To a suspension of 5% Pd/C (4.60 g, 2.16 mmol) in ethanol (40 mL) was added slowly a solution of (S)-benzyl 3-(tert—butoxycarbonyl(methyl)amino)pyrrolidinecarboxylate (7.2 g, 21.6 mmol) in ol (20 mL). The mixture was evacuated and backfilled with nitrogen and then evacuated and backfilled with hydrogen then stirred under a hydrogen atmosphere for 2 hours. The suspension was d through a pad of Celite and washed with methanol (60 mL). The filtrate was concentrated under reduced pressure to afford (S)-tert—butyl methyl(pyrrolidinyl)carbamate (4.3 g, 99%).
] Step D: Pre aration of tert—but l 3 1- 6-chloro ridin l -2 2 2- trifiuoroethyl [pyrrolidinyl] methyl [carbamate: Prepared as described in Example 1, Step C, using 1-(6-chloropyridinyl)-2,2,2-trifluoroethyl trifiuoromethanesulfonate (1.50 g, 4.37 mmol) and (S)-tert—butyl (pyrrolidinyl)carbamate (1.2 g, 6.11 mmol) to afford tyl (3S)( 1 -(6-chloropyridin-3 -yl)-2,2,2-trifluoroethyl)pyrrolidin-3 -yl(methyl)carbamate (1.15 g, 67%).
Step E: Pre aration of tert-but l meth l 3 222-trifluoro 6- h drazin l 3- leth l rrolidin lcarbamate: Prepared as described in Example 1, Step D, using tert—butyl (3S)(1-(6-chloropyridinyl)-2,2,2-trifluoroethyl)pyrrolidin yl(methyl)carbamate (1.15 g, 2.92 mmol) to afford tert—butyl methyl((3S)(2,2,2-trifluoro- 1-(6-hydrazinylpyridinyl)ethyl)pyrrolidinyl)carbamate (1.0 g, 88%).
] Step F: Preparation of ]3S [] 1-[3]cyclopropylmethoxy[guinolinyl[- 1 2 4 lo 4 3-a ridin l -2 2 2-trifluoroeth l -N-meth l rrolidinamine dihydrochloride: A solution of 8-(cyclopropylmethoxy)quinolinecarbaldehyde (0.14 g, 0.62 mmol) and tert—butyl methyl((3S)(2,2,2-trifiuoro(6-hydrazinylpyridin yl)ethyl)pyrrolidinyl)carbamate (0.20 g, 0.51 mmol) in ethanol (10 mL) was stirred at ambient ature for 16 hours. The t was removed under reduced re. The residue was dissolved in dichloromethane (10 mL) and treated with iodobenzene diacetate (0.20 g, 0.62 mmol) and stirred at ambient temperature for 4 hours. The mixture was partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate solution (10 mL). The organic layer was separated, washed with brine, dried (MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M; 10-90% CHgCN/water gradient). The residue was dissolved in dichloromethane (1 mL), treated with TFA (4 mL) and stirred at t temperature for 1 hour. The solution was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M; 10-70% water nt). The TFA salt was dissolved in methanol (0.50 mL) and treated with 2N HCl in diethyl ether (4 mL) and stirred for 10 minutes. The solvent was removed under reduced pressure and the solid obtained suspended in MeCN (5 mL) and stirred for 10 minutes. The solid was collected by filtration to afford -(l-(3-(8- (cyclopropylmethoxy)quinolinyl)-[ l ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2-trifluoroethyl)- N—methylpyrrolidinamine (0.129 g, 44%). LCMS APCI (+) m/z 497(M + H).
Example 21 2HC| / NQANHZ 2 2 2-trifluoroeth l rrolidin l amine dih oride Prepared as described in Example 1, Steps A-F, using (S)-tert—butyl pyrrolidin- 3-ylmethylcarbamate in place of (S)-tert—butyl pyrrolidinylcarbamate in Step C, and substituting 8-(cyclopropylmethoxy)quinolinecarbaldehyde for 8-methoxyquinoline dehyde in Step E. MS APCI (+) m/z 497 (M+1) detected. e 22 2 2 2-trifluoroeth l rrolidinamine Prepared as described in Example 9A, Steps A-B, using tert—butyl (3R)-l-(l- (3 -(8-(cyclopropylmethoxy)quinolinyl)-[ l ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2- trifluoroethyl)pyrrolidinylcarbamate in place of tert—butyl (3S)-l-(2,2,2-trifluoro-l-(3-(8- methoxyquinolinyl)-[ l ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 -ylcarbamate and isolating peak 2 during the chiral separation in Step A. LCMS APCI (+) m/z 483 (M+H). e 23 2 2 2-trifluoroeth l rrolidinamine Prepared as bed in Example 8, Steps A-B, using tert—butyl (3R)—l-(l-(3- (8-(cyclopropylmethoxy)quinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridinyl)—2,2,2- trifluoroethyl)pyrrolidinylcarbamate in place of tert—butyl (3S)-l-(2,2,2-trifluoro-l-(3-(8- methoxyquinolinyl)-[ l ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 -ylcarbamate and ing peak 1 during the chiral separation in Step A. LCMS APCI (+) m/z 483 (M+H). e 24 2HC| / NQ”‘\\NH2 3 -l- l- 3- 8- c clo ro lmethox uinolin l - l 2 4 triazolo 4 3-a ridin-6 1- 2 2 2-trifluoroeth l rrolidin l methanamine dih drochloride Prepared as described in Example 1, Steps A-F, using (R)-tert—butyl pyrrolidinylmethylcarbamate in place of rt—butyl idinylmethylcarbamate in Step C, and using 8-(cyclopropylmethoxy)quinolinecarbaldehyde in place of 8- methoxyquinolinecarbaldehyde in Step E. MS APCI (+) m/Z 497 (M+l) detected. 2012/026572 Example 25 2HC| / NENH a ridin l c clo r0 lmethox uinoline dih drochloride ed as described in Example 1, Steps A-F, using (lR,4R)-tert—butyl 2,5- diazabicyclo[2.2.l]heptanecarboxylate in place of (S)-tert—butyl pyrrolidin ylmethylcarbamate in Step C, and using 8-(cyclopropylmethoxy)quinolinecarbaldehyde in place of 8-meth0xyquinolinecarbaldehyde in Step E. MS APCI (+) m/Z 495 (M+l) detected.
Example 26 2HC| F3C N9...NH2: l -2 2 2-trifluor0eth l azabic clo 3.1.0 hexanesanamine dih drochloride Prepared as described in Example 1, Steps A-F, using tert—butyl (lR,5S,6S) azabicyclo[3.l.0]hexanesanylcarbamate in place of (S)-tert—butyl pyrrolidin ylmethylcarbamate in Step C, and using 8-(cyclopropylmethoxy)quinolinecarbaldehyde in place of 8-meth0xyquinolinecarbaldehyde in Step E. MS APCI (+) m/z 495 (M+l) detected.
Example 27 2 HCI 2012/026572 l- l- 3- 8- c clo ro lmethox uinolin l - l 2 4 triazolo 4 3-a ridin l -2 2 2- trifluoroethyl1methylpyrrolidinamine dihydrochloride Prepared as described in Example 1, Steps A-F, using (+/-) utyl 3- methylpyrrolidinylcarbamate in place of (S)-tert—butyl pyrrolidinylmethylcarbamate in Step C, and using 8-(cyclopropylmethoxy)quinolinecarbaldehyde in place of 8- methoxyquinolinecarbaldehyde in Step E to provide a mixture of products. The products were separated by semi-preparative HPLC to give the title product. MS APCI (+) m/z 497 (M+l) detected.
Example 28 2 HCI / NQLNHZ /N OH 2- 6- l- 3-aminometh l rrolidin-l- l -2 2 2-trifluoroeth l - l 2 4 triazolo 4 3-a ridin- 3- l uinolinol dih drochloride Prepared as described in Example 1, Steps A-F, using (+/-) tert—butyl 3- methylpyrrolidinylcarbamate in place of rt—butyl pyrrolidinylmethylcarbamate in Step C, and using 8-(cyclopropylmethoxy)quinolinecarbaldehyde in place of 8- methoxyquinolinecarbaldehyde in Step E to provide a mixture of products. The ts were separated by semi-preparative HPLC to give the named product. MS APCI (+) m/z 443 (M+l) detected.
Example 29 F3C '6 2HC| N N CF3 N\N / 3S -l- 2 2 2-trifluoro-l- 3- 7- trifluorometh l uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidinamine dih oride Step A: Pre aration 2-meth l trifluorometh l ne: To a solution of 3-(trifluoromethyl)aniline (12.43 mL, 99.92 mmol) in 6 N HCl (50 mL) in water was added (E)-butenal (18.77 mL, 229.8 mmol) dropwise at reflux. The reaction was stirred at reflux for 3 hours. After cooling to ambient temperature, ethyl acetate (200 mL) was added. The aqueous layer was separated, basified with ammonium hydroxide to about pH 9, and extracted with DCM (2 x 200 mL). The ed organic layers were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 2-methyl (trifluoromethyl)quinoline (6.1 g, 28.9%) as a solid.
Step B: Pre aration of 3S 2 2 2-trifluoro 3- 7- trifiuorometh l uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine dih drochloride: Prepared as described in Example 5, Steps A-C, using 2-methyl(trifiuoromethyl)quinoline in place of 8-(cyclopropylmethoxy)methquuinoline in Step B. LCMS APCI (+) m/z 481 (M+H).
Example 30 F3C '6 2HC| 2- 6- 1- S amino rrolidin-l- l -2 2 2-trifiuoroeth l - 1 2 4 triazolo 4 3-a 3 1- N—iso ro l uinolinecarboxamide dih oride Step A: Pre aration 2-meth l necarbox lic acid: A mixture of 2- methyl(trifluoromethyl)quinoline (5.2 g, 24.6 mmol) and 80% H2S04 (18.1 g, 148 mmol) was heated at 230 °C for 20 minutes. After cooling to ambient temperature, the mixture was basified by 6 N NaOH to about pH 12. The resulting solid was removed by filtration. The filtrate was acidified by 2 N HCl to about pH 3, extracted with 3:1 DCM/IPA (2 x 50 mL), dried (sodium sulfate), d and concentrated under d pressure to give 2- methquuinolinecarboxylic acid (3.3 g, 71.6%) as a solid.
Step B: Preparation methyl 2-methylguinolinecarboxylate: To a on of 2-methquuinolinecarboxylic acid (1.00 g, 5.34 mmol) and K2C03 (2.36 g, 17.1 mmol) in DMA (10 mL) was added Mel (0.35 mL, 5.61 mmol) dropwise at ambient temperature. The reaction was stirred at ambient ature for 18 hours. Water (30 mL) and ethyl acetate (50 mL) were added. The organic layer was ted, washed with water and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1 :5 hexane/ethyl acetate) to give methyl 2- methquuinolinecarboxylate (0.99 g, 92.1%) as a solid.
] Step C: Preparation methyl 2-formylguinolinecarboxylate: To a solution of methyl 2-methquuinolinecarboxylate (0.99 g, 4.92 mmol) in dioxane (60 mL) and water (0.6 mL) was added SeOz (0.66 g, 5.90 mmol) and the mixture was stirred at reflux for 2 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:4 hexane/ethyl acetate) to give methyl 2- uinolinecarboxylate (0.75 g, 70.8%) as a solid.
Step D: Preparation of 2-1 6-1 l-gg S 11 tert—butoxycarbonylamino [pyrrolidin-l- l -2 2 2-trifluoroeth l - 1 2 4 triazolo 4 3-a ridin l uinolinecarbox lic acid: A solution of tert—butyl (3 S)(2,2,2-trifluoro(6-hydrazinylpyridinyl)ethyl)pyrrolidin ylcarbamate (Example 1, Step D; 0.46 g, 1.03 mmol) and methyl 2-formquuinoline carboxylate (0.22 g, 1.03 mmol) in EtOH (10 mL) was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in DCM (10 mL) and iodo benzene diacetate (0.40 g, 1.24 mmol) was added. The mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and ted sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was dissolved in THF (5 mL) and 2 N LiOH (5.15 mL, 10.30 mmol) was added. The e was stirred at ambient temperature for 6 hours. Ether (20 mL) was added. The s layer was separated and acidified with saturated potassium hydrogen sulfate to about pH 3. The resulting solid was collected by filtration to give 2-(6-(1-((S)(tert— butoxycarbonylamino)pyrrolidinyl)-2,2,2-trifluoroethyl)- [1 ,2,4]triazolo [4,3 -a]pyridin-3 - nolinecarboxylic acid (0.45 g, 78.5%) as a solid.
Step E: Pre aration of tert—but 1 3S 2 2 2-trifluoro 3- 7- ._. U1O HO ._.8HU‘SO ._. CHBOIPNI ._. I p—A N L FF5a:NO ._.O L L.”a: ridin leth l in ylcarbamate: To a solution of 2-(6-(1-((S)(tert-butoxycarbonylamino)pyrrolidinyl)- trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridinyl)quinolinecarboxylic acid (0.075 g, 0.135 mmol), HATU (0.062 g, 0.16 mmol) and propanamine (0.057 ml, 0.67 mmol) in DMF (1 mL) was added DIEA (0.047 mL, 0.27 mmol) and the on e was stirred at ambient temperature for 4 hours. The reaction mixture was purified directly by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-90% CHgCN/water gradient; 3 0 CV)) to give tert-butyl (3 S)(2,2,2-trifluoro(3 -(7- (isopropylcarbamoyl)quinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - ylcarbamate (0.023 g, 28.6%) as a solid.
Step F: Pre aration of 2- 6- 1- S amino rrolidin-l- l trifluoroeth l - 1 2 4 triazolo 4 3-a ridin-3 l -N-iso ro l uinolinecarboxamide dihydrochloride: To a solution of tert—butyl (3S)(2,2,2-trifluoro(3-(7- (isopropylcarbamoyl)quinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - ylcarbamate (0.023 g, 0.039 mmol) in DCM (0.5 mL) was added 5 N HCl (0.39 mL, 1.92 mmol) in IPA. The mixture was d at ambient temperature for 1 hour. The t was removed under reduced pressure to give 2-(6-(1-((S)aminopyrrolidinyl)-2,2,2- trifluoroethyl)-[ 1 riazolo [4,3 -a]pyridin-3 -yl)-N-isopropquuinolinecarboxamide dihydrochloride (0.023 g, 95.7%) as a solid. LCMS APCI (+) m/z 498 (M+H).
Example 31 F3Ca WN3’/\ 2HC| l eth l rrolidinamine dih oride Step A: Pre aration of 8-iso ro ox uinolinecarbaldeh de: Prepared as described in Example 5, Steps A-B, using 2-iodopropane in place of (bromomethyl)cyclopropane in Step A.
Step B: Pre aration of S R -2 2 uoro 3- 8-iso ro ox uinolin- 2- l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine dih drochloride: Prepared as described in Example 9B, Steps A-G, using ropoxyquinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 471 (M+H).
Specific rotation: [(1]20D = +2.830 (c = 1.07, MeOH).
Example 32 2012/026572 ] To a solution of (3S)(1-(3-(8-(cyclopropylmethoxy)quinolinyl)- [1,2,4]triazolo[4,3-a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidinamine le 5; 0.15 g, 0.27 mmol), DIEA (0.14 mL, 0.81 mmol) and trimethyl orthoformate (0.59 mL, 5.40 mmol) in methanol (6 mL) was added acetone (0.30 mL, 0.41 mmol) and the mixture stirred at ambient temperature for 18 hours. The solution was cooled to 0 0C on an ice-bath and sodium borohydride (0.02 g, 0.54 mmol) was added and the mixture stirred at ambient temperature for 1 hour, then poured in a saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried (MgSO4) filtered and trated under reduced re. The e was purified by reverse phase chromatography (Biotage SP4, C-18 25M; 10-70% CHgCN/water gradient).
The residue was stirred in methanol (0.20 mL) and treated with 2N HCl in diethyl ether (2 mL) and stirred for 30 minutes and the ts removed under reduced pressure. The residue was ved in methanol (0.50 mL) and treated with dichloromethane (0.50 mL) and hexanes (0.50 mL) and concentrated under reduced pressure to afford (3S)(1-(3-(8- (cyclopropylmethoxy)quinolinyl)-[1 ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2-trifluoroethyl)- N—isopropylpyrrolidinamine (0.49 g, 30%). LCMS APCI (+) m/z 525 (M + H).
Example 33 6- l eth l rrolidinamine trih drochloride Prepared as described in Example 1, Steps D-F, using tert-butyl (3S)(1-(6- fluoropyridinyl)ethyl)pyrrolidinylcarbamate in place of tert-butyl (3 S)(1-(6- chloropyridinyl)-2,2,2-trifluoroethyl)pyrrolidinylcarbamate in Step D and substituting (R)(1-methoxypropanyloxy)quinolinecarbaldehyde for 8-methoxyquinoline carbaldehyde in Step E. LCMS APCI (+) m/z 447 (M+H).
WO 54274 Example 34 l-N-iso r0 1 uinolinecarb0xamide dih drochloride Prepared as described in Example 30, Steps A-F, using tert—butyl (S)-l-((R)- trifluor0-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate (Example 9B, Steps A-E) in place of tert—butyl (3 S)-l-(2,2,2-triflu0r0-l-(6-hydrazinylpyridin yl)ethyl)pyrrolidinylcarbamate in Step D. LCMS APCI (+) m/z 498 (M+H).
Example 35 2 HCI yl )-N,N—dimethylguinolinecarb0xamide dihydrochloride Prepared as described in e 30, Steps A-F, using tert—butyl (S)-l-((R)- 2,2,2-trifluor0-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate (Example 9B, Steps A-E) in place of tert—butyl (3 S)-l-(2,2,2-triflu0r0-l-(6-hydrazinylpyridin yl)ethyl)pyrrolidinylcarbamate in Step D, and using dimethyl amine in place of propan amine in Step E . LCMS APCI (+) m/z 484 (M+H).
Example 36 a ridin leth l rrolidinamine dih drochloride Step A: Pre aration of tert—but l meth l R -2 2 2-trifluoro 6- hydrazinylpyridinyl[ethyl[pyrrolidinyl[carbamate: Prepared as be in Example 20 using (S)(6-chloropyridinyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate in place of hloropyridinyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate.
Step B: Pre aration of -N—meth l R -2 22-trifluoro 3- 8- iso ro ox uinolin l - 1 2 4 triazolo 4 3-a ridin-6 l eth l inamine dihydrochloride: Prepared as described in Example 9B, Steps A-G, using tert—butyl methyl((S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -yl)carbamate in place of tert—butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridinyl)ethyl)pyrrolidin- 3-yl)carbamate and using 8-isopropoxyquinolinecarbaldehyde in place of 8- methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 485 (M + H).
Example 37 trifluoroethyl [pyrrolidinamine dihydrochloride Step A: Preparation of 8-ethylmethylguinoline: A on of 2-ethylaniline (4.00 g, 33.0 mmol) in 6 N HCl (40 mL) was added (E)—butenal (6.20 ml, 75.9 mmol) dropwise at reflux. The reaction was heated at reflux for 3 hours. After cooling to ambient temperature, ethyl acetate (40 mL) was added. The aqueous layer was separated, basif1ed with ammonium ide to about pH 9, and extracted with DCM (2 x 50 mL). The combined organic layer was dried (sodium sulfate) and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel (3:1 /DCM) to give 8- ethylmethquuinoline (3.34 g, 59.1%) as a solid.
Step B: Preparation of 8-ethylguinolinecarbaldehyde: A solution of 8-ethyl- 2-methquuinoline (3.34 g, 19.5 mmol) in dioxane (150 mL) and water (1.5 mL) was added SeOg (2.60 g, 23.4 mmol) and the mixture was stirred at reflux for 2 hours. After cooling to t temperature, the solid was removed by filtration and washed with DCM. The filtrate was trated under reduced pressure and the residue was purified by flash chromatography on silica gel (1:1 hexane/DCM) to give 8-ethquuinolinecarbaldehyde (3.1 g, 85.8%) as a solid.
Step C: Pre aration of S -l- R -l- 3- 8-eth l uinolin l - l 2 4 triazolo 4 3-a idin l -2 2 2-trifluor0eth l inamine dih drochloride: Prepared as described in Example 9B, Steps A-G, using 8-ethquuinolinecarbaldehyde in place of 8-meth0xyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 441 (M+H). e 38 2 HCI N N\ N/\ \ / I H N\N / 2- 6- R -l- S amin0 rrolidin-l- l -2 2 2-triflu0r0eth l - l 2 4 triazolo 4 3-a ridin yl z-N-ethylguinolinecarboxamide dihydrochloride Prepared as described in Example 30, Steps A-F, using tert—butyl (S)-l-((R)- 2,2,2-triflu0r0-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert- butyl (3 S)- l -(2,2,2-triflu0r0-l drazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate in Step D, and using ethyl amine in place of propanamine in Step E . LCMS APCI (+) m/z 484 (M+H).
Example 39 2 HCI U) I p—A I 7U L. I DJ I ?°0 O_.O HO _. C,_..BOEPNI _. I p—A N L 5:“,_.. a:NO _.O L L.” a: EQ.,_.P O\ I _. IN N 'F’ trifluoroethyl )pyrrolidinamine dihydrochloride Prepared as described in Example 37, Steps A-C, using opropylaniline in place of 2-ethylaniline in Step A. LCMS APCI (+) m/z 453 (M+H).
Example 40 S -l- R -2 2 uor0-l- 3- 8- trifluoromethox n l - l 2 4 triazolo 4 3- a |pyridinyl )ethyl )pyrrolidinamine dihydrochloride ] Prepared as described in Example 37 using 2-(trifluoromethoxy)aniline in place of 2-ethylaniline in Step A. LCMS APCI (+) m/z 497 (M+H).
Example 41 2 HCI ,_. CHBOrPNI ,_. I p—A N L H»E.93NO ,_.O L L.”93 HHO.HPC?“ yl )ethyl )pyrrolidinamine dihydrochloride Prepared as described in e 37, Steps A-C, using 2-isopropylaniline in place of 2-ethylaniline in Step A. LCMS APCI (+) m/z 455 (M+H).
Example 42 yl z-N-methylguinolinecarboxamide dihydrochloride Prepared as described in Example 30, Steps A-F, using tert—butyl (S)-l-((R)— 2,2,2-trifluor0-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert- butyl (3 S)-l-(2,2,2-trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in Step D, and using methylamine in place of propanamine in Step E . LCMS APCI (+) m/z 470 (M+H).
Example 43 -l- R -l- 3- 8- c clo ro lmethox uinolin l - l 2 4 triazolo 4 3-a ridin l - 2 2 2-trifluoroeth l -N—meth l rrolidinamine dih drochloride Prepared as described in Example 9B, Steps A-G, using tert—butyl methyl((S)- l-((R)-2,2,2-trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinyl)carbamate in place of utyl (S)- l -((R)-2,2,2-trifluoro- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 - yl)carbamate and using 8-(cyclopropylmethoxy)quinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 497 (M + H).
Example 44 l uinolin lisobut ramide Step A: Pre n of tert-But 1 3S -l- l- 3- 7-bromo uinolin l- l 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidin lcarbamate: Prepared as described in Example 1, Steps A-E, using 7-bromoquinolinecarbaldehyde in place of 8- methoxyquinolinecarbaldehyde in Step E.
Step B: Pre aration of tert—but 1 3S -l- 2 2 2-trifluoro-l- 3- 7- isobut ramido uinolin l- 12 4 triazolo 4 3-a ridin l eth l rrolidin ylcarbamate: tert-Butyl (3S)-l-(l-(3-(7-bromoquinolinyl)-[l,2,4]triazolo[4,3-a]pyridin yl)-2,2,2-trifluoroethyl)pyrrolidinylcarbamate (50 mg, 0.085 mmol), yramide (18.4 mg, 0.211 mmol), K3P04 (53.8 mg, 0.254 mmol), and Cu(I)I (1.61 mg, 0.0085 mmol) were d into a 40 mL Teflon® capped Vial. The Vial was purged with N2, followed by addition of toluene (20 mL) and Nl,N2-dimethylethane-l,2-diamine (4.55 uL, 0.042 mmol).
The reaction was sealed and heated to 90 0C ght, after which the reaction complete by TLC. The crude reaction was concentrated, then purified by flash column chromatography ng with 10% CM), affording the desired product (55 mg, 97% yield).
Step C: Pre aration of N— 2- 6- l- S amino rrolidin-l- l trifluoroeth l - l 2 4 triazolo 4 3-a ridin l uinolin l isobut : tert-Butyl (3 S)- l -(2,2,2-trifluoro- l -(3 -(7-isobutyramidoquinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate (56 mg, 0.094 mmol) was weighed into a 100 mL 1 neck round bottom flask, and dissolve in 5 mL of chloroform, followed by addition of HCl (937 uL, 3.7 mmol). The reaction was then d to stir at ambient temperature for 1 hour, at which time the deprotection was complete and light yellow precipitate formed. The reaction was concentrated under vacuum, affording N—(2-(6-(l-((S)aminopyrrolidin-l-yl)-2,2,2- trifluoroethyl)-[l,2,4]triazolo[4,3-a]pyridinyl)quinolinyl)isobutyramide (32 mg, 69 % yield) as a light yellow semi-solid. LCMS APCI (+) m/z 498.2 (M+H).
Example 45 roethyl )pyrrolidinamine ochloride Prepared as described in Example 37, Steps A-C, using 2-tert—butylaniline in place of 2-ethylaniline in Step A. LCMS APCI (+) m/z 469 (M+H).
Example 46 yl z-N-tert-butylguinolinecarboxamide dihydrochloride Prepared as described in Example 30, Steps A-F, using tert—butyl (S)-l-((R)- 2,2,2-trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert- butyl (3 S)- l -(2,2,2-trifluoro-l drazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate in Step D, and using tert—butylamine in place of propanamine in Step E. LCMS APCI (+) m/z 512 (M+H).
Example 47 D 2 HCI trifluoroethyl )pyrrolidinamine dihydrochloride ] Prepared as described in Example 9B, Steps A-G, using (R)-tert—butyl pyrrolidinylcarbamate in place of (S)-tert—butyl pyrrolidinylcarbamate in Step D, and using 8-cyclopropquuinolinecarbaldehyde in place of 8-methoxyquinoline carbaldehyde in Step F. LCMS APCI (+) m/z 453 (M+H).
Example 48 o ro l necarboxamide dih drochloride Step A: Pre aration of R 6-chloro ridin l -2 2 2-trifluoroethanol: To a solution of 1-(6-chloropyridinyl)-2,2,2-trifluoroethanone (Example 9B, Step A; 85.0 g, 406 mmol) and 1.0 M KOtBu (8.11 mL, 8.11 mmol) in t—BuOH in IPA (200 mL) and toluene (50 mL) in a autoclave was added dichloro {(R)-(+)-2,2'-bis[di(3,5-xylyl)-phosphino-1,1'- binaphthyl}[(2R)-(-)-1,1-bis(4-methoxyphenyl)methyl-1,2-butanediamine (0.991 g, 0.81 mmol) (Strem als). The on mixture was degassed by three vacuum-filling with nitrogen cycles. Hydrogen was introduced into the autoclave at a pressure of 300 psi and then reduced to 20 psi by slowly releasing the stop valve. After this procedure was repeated three times, the autoclave was pressurized to 520 psi with hydrogen. The reaction mixture was Vigorously stirred at ambient ature for 2 days (pressure was recharged to 520 psi when the al pressure dropped below 200 psi). The pressure was released and the solvent was removed under reduced pressure. Ethyl acetate (300 mL) and 10% citric acid solution (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The e was purified by flash chromatography on silica gel (3:1 DCM/ethyl acetate) to give (S)(6-chloropyridinyl)- 2,2,2-trifluoroethanol (83.5 g, 97.3%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 77.2% e.e. antiomer). (R)(6-chloropyridinyl)-2,2,2-trifluoroethanol (171 g, 808 mmol, 77.2% e.e.) was dissolved in 4.5% ethyl e/hexane (V/V) (3410 mL) with heating to reflux. After complete dissolution, it was slowly cooled to ambient temperature overnight.
The resulting solid was collected by filtration, washed with hexane and dried to give (R) (6-chloropyridinyl)-2,2,2-trifluoroethanol (97.1 g, 56.8%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes: 10% (1:1 MeOH/EtOH) at 1.0 mL/min, 98.9% e.e. (R)-enantiomer).
] Step B: Pre aration of tert-but l S S -2 22-trifluoro 6- hydrazinylpyridinyl[ethyl[pyrrolidinylcarbamate: Prepared as described in Example 9B, Steps C-E, using (R)—1-(6-chloropyridinyl)-2,2,2-trifluoroethanol in place of (6- chloropyridinyl)-2,2,2-trifluoroethanol in Step C.
Step C: Pre aration of 2- 6- S S amino rrolidin l trifluoroeth l - 1 2 4 triazolo 4 3-a ridin l -N-iso ro l uinolinecarboxamide dihydrochloride: Prepared as described in Example 30, Steps A-F, using tert—butyl (S) ((S)-2,2,2-trifluoro(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert—butyl (3 S)(2,2,2-trifluoro- 1 drazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate in Step D. LCMS APCI (+) m/z 498 (M+H).
Example 49 l-N-iso ro l uinolinecarboxamide dih drochloride ed as bed in Example 30, Steps A-F, using tert—butyl (R)((R)- 2,2,2-trifluoro(6-hydrazinylpyridin-3 hyl)pyrrolidin-3 -ylcarbamate (prepared following the procedure of Example 1, Steps A-D) in place of tert—butyl (3S)—1-(2,2,2- trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in Step D. LCMS APCI (+) m/z 498 (M+H).
Example 50 N— 3 1- 3- 8- c clo ro lmethox uinolin l - 12 4 triazolo 4 3-a ridin l- 2 2 2-trifluoroeth l rrolidin l acetamide A solution of -(1-(3 -(8-(cyclopropylmethoxy)quinolinyl)- [1,2,4]triazolo[4,3-a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidinamine (Example 5; 0.15 g, 0.27 mmol), DIEA (0.14 mL, 0.81 mmol) and acetic anhydride (0.038 mL, 0.41 mmol) in dichloromethane (4 mL) was stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was ted and washed with aqueous 1N HCl (5 mL), water and brine, then dried (MgSO4), filtered and concentrated under reduced pressure to afford N—((3S)(1-(3-(8- (cyclopropylmethoxy)quinolinyl)-[1 riazolo [4,3 -a]pyridinyl)-2,2,2- roethyl)pyrrolidinyl)acetamide (0.076 g, 54%). LCMS APCI (+) m/z 525 (M + H).
Example 51 trifluoroeth l rrolidinamine dih drochloride Prepared as described in Example 9B, Steps C-G, using (R)(6- chloropyridinyl-2,2,2-trifluoroethanol in place of (S)(6-chloropyridin-3 -yl-2,2,2- trifluoroethanol in Step C, and using 8-cyclopropquuinolinecarbaldehyde in place of 8- yquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 453 (M+H).
Example 52 l-N-iso ro l uinolinecarboxamide Prepared as described in Example 30, Steps A-E, using tert—butyl ((S)- 2,2,2-trifluoro(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert- butyl (3 S)- l -(2,2,2-triflu0r0-l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate in Step D. LCMS APCI (+) m/z 498 (M+H).
Example 53 l -N- l-meth lc clo r0 1 uinolinecarb0xamide dih drochloride Prepared as described in Example 30, Steps A-F, using tert—butyl (S)-l-((R)- 2,2,2-trifluor0-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert- butyl (3 S)- l -(2,2,2-triflu0r0-l drazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate in Step D, and using l-methylcyclopropanamine in place of propanamine in Step E . LCMS APCI (+) m/z 510 (M+H). e 54 yl rt-butv_lguinolinecarboxamide dihydrochloride Prepared as described in Example 30, Steps A-F, using tert—butyl (R)-l-((R)- 2,2,2-triflu0r0-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert- butyl (3 S)- l -(2,2,2-triflu0r0-l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate in Step D, and using tert—butylamine in place of propanamine in Step E. LCMS APCI (+) m/z 512 (M+H).
Example 55 2- 6- R -l- R amin0 rrolidin-l- l -2 2 2-trifluor0eth l - l 2 4 triazolo 4 3-a ridin l -N- l-meth lc clo r0 1 necarb0xamide dih drochloride Prepared as described in Example 30, Steps A-F, using tert-butyl ((R)- 2,2,2-triflu0r0-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tertbutyl (3 S)- l -(2 riflu0r0- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate in Step D, and using l-methylcyclopropanamine in place of amine in Step E . LCMS APCI (+) m/z 510 (M+H).
Example 56 / NQMHZ trifluoroeth l rrolidinamine Step A: Pre aration of 8-c clo r0 1 uinilinecarbaldeh de: Prepared according to Example 37, Steps A-B, using 2-cyclopr0pylaniline in place of 2-ethylaniline in Step A.
Step B: Pre aration of R -l- S -l- 3- 8-c clo r0 1 uinolin l- l 2 4 triazolo 4 3-a idin l -2 2 2-trifluor0eth l rrolidinamine: Prepared as described in Example 9B, Steps A-F, using 8-cyclopropquuinilinecarbaldehyde in place of 8-meth0xyquinolinecarbaldehyde in Step F and using tert—butyl (R)-l-((S)-2,2,2- trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert—butyl (S)- l 2,2,2-trifluor0- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate in Step F. LCMS APCI (+) m/z 453.2 (M+H).
Example 57 F3C H N—iso r0 l 6- R -2 2 2-triflu0r0-l- S meth lamino rrolidin-l- l eth l - l 2 4 lo 4 3-a ridin l uinolinecarb0xamide Prepared as described in Example 30, Steps A-E, using tert-butyl methyl((S)- l-((R)-2,2,2-triflu0ro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinyl)carbamate in place of tert—butyl (3 S)- l -(2,2,2-triflu0ro- l -(3 sopropylcarbamoyl)quinolinyl)- [l ,2,4]triazolo [4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate. LCMS APCI (+) m/z 512 (M+H).
Example 58 F3 H ”I OAK t-but l 6- R -2 2 2-triflu0r0-l- S meth lamino rrolidin-l- l eth l - l 2 4 triazolo 4 3-a ridin l uinolinecarb0xamide Prepared as bed in Example 30, Steps A-E substituting tert—butyl methyl((S)- l -((R)-2,2,2-trifluor0- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 - bamate for tert-butyl (3 S)-l-(2,2,2-trifluor0-l-(3-(7-(isopr0pylcarbam0yl)quinolin yl)-[l,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate in Step D, and using tert—butylamine in place of propanamine in Step E. LCMS APCI (+) m/z 526.3 (M+H).
Example 59 dNQ'1 .\\NH2 2HC| / N l-N-tert— ent l uinolinecarb0xamide dih drochloride Prepared as described in Example 30 using utyl (R)-l-((R)-2,2,2- trifluoro-l-(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidinylcarbamate in place of tert—butyl (3 S)- l -(2,2,2-triflu0ro- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate in Step D, and using 2-methylbutanamine in place of propanamine in Step E . LCMS APCI (+) m/z 526 (M+H).
Example 60 F3Ca :i‘§/\ {:7’N 2HCI / N 2 2 2-trifluoroeth l inamine dih drochloride Step A: Pre aration of 8-bromofluorometh l uinoline: Prepared as described in e 37, Step A, using ofluoroaniline in place of 2-ethylaniline.
Step B: Preparation of 8-cyclop_rop_ylfluoromethylguinoline: A solution of 8-bromofluoromethquuinoline (1.00 g, 4.17 mmol), Pd(OAc)2 (0.047 g, 0.21 mmol), P(Cy)3 (0.13 g, 0.46 mmol), K3PO4 (3.09 g, 14.6 mmol) and cyclopropylboronic acid (0.72 g, 8.33 mmol) in toluene (20 mL) and water (2 mL) was stirred at 100 °C for 8 hours. After cooling to ambient temperature, ethyl acetate (20 mL) and water (5 mL) were added. The organic layer was separated, washed with brine, dried m sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3:1 hexane/DCM) to give 8-cyclopropylfluoromethquuinoline (0.78 g, 92.7%) as an oil.
Step C: Pre aration of S 1 2 4 triazolo 4 3-a idin l -2 2 2-trifluoroeth l rrolidinamine dih drochloride: Prepared as described in Example 37 using 8-cyclopropylfluoromethquuinoline in place of 8-ethylmethquuinoline in Step B. LCMS APCI (+) m/z 471 (M+H).
Example 61 dNQ3? MNHZ 2HCI N\/ N roeth l inamine dih drochloride Step A: Pre aration of tert—but l R R 3- 7-bromo uinolin 1- 1 2 4 triazolo 4 3-a ridin l -2 2 uoroeth l rrolidin lcarbamate: Prepared as described in Example 9B, Steps A-F, using 7-bromoquinolinecarbaldehyde in place of 8- methoxyquinolinecarbaldehyde in Step F.
Step B: Pre aration of R -l- R -l- 3- 7-c clo r0 1 uinolin l- l 2 4 triazolo 4 3-a idin l -2 2 uor0eth l rrolidinamine dih drochloride: ed as described in Example 3, Steps A-B, using tert—butyl (R)-l-((R)-l-(3-(7- bromoquinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2-trifluor0ethyl)pyrrolidin-3 - ylcarbamate in place of tert—butyl (3S)—l-(l-(3-(7-br0m0quinolinyl)-[l,2,4]triazolo[4,3- a]pyridinyl)—2,2,2-triflu0roethyl)pyrr0lidinylcarbamate in Step A. LCMS APCI (+) m/z 453 (M+H).
Example 62 2HC| F C3 ,1 ,—‘\\‘.
{VD/N NE NH l 2 4 triazolo 4 3-a ridin l tert—but l uinoline Prepared as described in Example 1, Steps A-F, using )-tert—butyl 2,5- diazabicyclo[2.2.l]heptanecarboxylate in place of (S)-tert—butyl pyrrolidin ylmethylcarbamate in Step C, and using 8-tert-butquuin0linecarbaldehyde in place of 8- methoxyquinolinecarbaldehyde in Step E. MS APCI (+) m/Z 481 (M+l) detected.
Example 63 2HC| 1. / \\"\ dbNE NH /N 2- 6- R -l- lS 4S -2 5-diazabic clo 221 he tan l -2 2 2-trifluor0eth l - l 2 4 triazolo 4 3-a ridin l fluoro uinoline dih drochloride Step B: Prepared as described in Example 1, Steps A-F, using (lS,4S)-tert- butyl 2,5-diazabicyclo[2.2.l]heptanecarboxylate in place of (S)-tert—butyl idin ylmethylcarbamate in Step C, and using 7-fluoroquinolinecarbaldehyde (prepared as described in e 1, Steps A-E, using 3-flu0r0aniline) in place of 8-meth0xyquinoline carbaldehyde in Step E. MS APCI (+) m/Z 443 (M+l) detected. e 64 2HCI F C3 :— ,—\—\‘\.
N; NH / \ \—/' N/ N Prepared as described in Example 1, Steps A-F, using (lS,4S)-tert—butyl 2,5- diazabicyclo[2.2.l]heptanecarboxylate in place of (S)-tert—butyl pyrrolidin ylmethylcarbamate in Step C, and using 7-chloroquinoline-Z-carbaldehyde (prepared as described in Example 1, Steps A-E, using r0aniline)) in place of 0xyquinoline- 2-carbaldehyde in Step E. MS APCI (+) m/Z 459 (M+l) detected.
Example 65 2 HCI F39. /—\ {\f-/N N? NH Prepared as described in Example 1, Steps A-F, using (lS,4S)-tert—butyl 2,5- diazabicyclo[2.2.l]heptanecarboxylate in place of (S)-tert—butyl pyrrolidin ylmethylcarbamate in Step C, and using 8-cyclopropquuinolinecarbaldehyde in place of 8-meth0xyquinolinecarbaldehyde in Step E. MS APCI (+) m/Z 465 (M+l) detected.
Example 66 2HCI F39. /—\ {\f-/N N? NH ed as described in Example 1, Steps A-F, using (lS,4S)-tert-butyl 2,5- diazabicyclo[2.2.l]heptanecarboxylate in place of rt-butyl pyrrolidin ylmethylcarbamate in Step C, and using 8-ethquuinolinecarbaldehyde in place of 8- methoxyquinolinecarbaldehyde in Step E. MS APCI (+) m/z 453 (M+l) detected.
Example 67 2HC| F39. /—\ d\~_// N; NH N 0% 2- 6- R -l- lS 4S -2 5-diazabic clo 2.2.1 he tan l -2 2 2-trifluor0eth l - l 2 4 triazolo 4 3-a ridin l c clo r0 lmethox uinoline dih drochloride Prepared as described in Example 1, Steps A-F, using (lS,4S)-tert—butyl 2,5- diazabicyclo[2.2.l]heptanecarboxylate in place of (S)-tert—butyl pyrrolidin ylmethylcarbamate in Step C, and using 8-(cyclopropylmethoxy)quinolinecarbaldehyde in place of 8-meth0xyquinolinecarbaldehyde in Step E. MS APCI (+) m/Z 495 (M+l) detected.
Example 68 2HC| F39. /—\ {\f-/N N? NH N Br 2- 6- R -l- lS 4S -2 5-diazabic clo 221 he tan l -2 2 2-trifluor0eth l - l 2 4 triazolo 4 3-a ridin l bromo uinoline dih drochloride ed as described in e 1, Steps A-F, using (lS,4S)-tert—butyl 2,5- icyclo[2.2.l]heptanecarboxylate in place of (S)-tert—butyl pyrrolidin ylmethylcarbamate in Step C, and using 7-bromoquinolinecarbaldehyde (prepared as described in Example 1, Steps A-E, using 3-br0m0aniline) in place of 8-meth0xyquinoline- 2-carbaldehyde in Step E. MS APCI (+) m/Z 504 (M+l) detected.
Example 69 2 2 2-trifluoroeth l rrolidinamine dih drochloride ] Step A: Preparation of 7-bromomethoxymethylguinoline: To a solution of 7-bromomethquuinolinol (4.10 g, 14.64 mmol) and C82C03 (11.92 g, 36.59 mmol) in NMP (20 mL) was added iodomethane (1.01 mL, 16.10 mmol) at 0 °C. The reaction was warmed to ambient temperature and stirred at ambient ature for 40 minutes. Water (30 mL) was and added and ted with DCM (30 mL), dried (sodium e), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM) to give 7-bromomethoxymethquuinoline (3.62 g, 91.23%) as an oil.
Step B: Preparation of 7-cyclopropylmethoxymethylguinoline: A on of 7-bromomethoxymethquuinoline (1.00 g, 3.97 mmol), Pd(OAc)2 (0.045 g, 0.198 mmol), P(Cy)3 (0.122 g, 0.44 mmol) and cyclopropylboronic acid (0.68 g, 7.93 mmol) in toluene (4 mL) and water (0.4 mL) was stirred at 100 °C for 6 hours. After cooling to ambient temperature, ethyl acetate (20 mL) and water (5 mL) were added. The c layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give 7-cyclopropylmethoxymethquuinoline (0.84 g, 99%) as an oil.
Step C: Pre aration of S R 3- 7-c clo ro lmethox uinolin l - 1 2 4 triazolo 4 3-a 6- l -2 2 2-trifluoroeth l rrolidinamine dihydrochloride: Prepared as described in Example 37, Steps A-C, using 7-cyclopropyl methoxymethquuinoline in place of 8-ethylmethquuinoline in Step B. LCMS APCI (+) m/z 483 (M+H).
Example 70 ”INQ’NHZ / N N.N/ N I “7% / O N— 2- 6- R -l- S amino rrolidin-l- l -2 2 uor0eth l - l 2 4 triazolo 4 3- a |pyridinyl [guinolinyl [isobutyramide Prepared as described in Example 44, Steps B-C, substituting tert-butyl (S)-l- ((R)-2,2,2-triflu0r0- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 bamate (Example 9B, Steps A-E) for tert-butyl (3 S)-l-(2,2,2-trifluor0-l-(6-hydrazinylpyridin yl)pyrrolidinylcarbamate in Step B. LCMS APCI (+) m/z 498.2 (M+H).
Example 71 a ridinl uinolin l ivalamide Prepared as described in Example 44, Steps B-C, substituting tert—butylamide for isopropylamide and tert-butyl (S)—l-((R)-2,2,2-trifluor0-l-(6-hydrazinylpyridin yl)ethyl)pyrrolidinylcarbamate for (3 S)- l -(2,2,2-triflu0ro- l -(6-hydrazinylpyridin-3 - yl)ethyl)pyrrolidinylcarbamate in Step B. LCMS APCI (+) m/z 512.2 (M+H).
Example 72 N\N / 3R 4R R -2 2 2-triflu0r0-l- 3- 8-is0 r0 0x uinolin l - l 2 4 triazolo 4 3- a ridin leth l rrolidine-3 4-diol ] Prepared as described in Example 9B, Steps A-F, using )-pyrrolidine- 3,4-diol in place of (S)-tert—butyl pyrrolidinylcarbamate in Step D, and using 8- isopropoxyquinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 488 (M+H).
Example 73 3R 4R -l- R -l- 3- 8-eth l uinolin l - l 2 4 lo 4 3-a ridin-6I ,_. IN N ’F’ trifluoroeth l rrolidine-3 4-diol Prepared as described in Example 9B, Steps A-F, using (3R,4R)-pyrrolidine- 3,4-diol in place of rt—butyl pyrrolidinylcarbamate in Step D, and using 8- ethquuinoline-Z-carbaldehyde in place of 8-meth0xyquinolinecarbaldehyde in Step F.
LCMS APCI (+) m/z 458 (M+H).
Example 74 3R 4R -l- R -l- 3- 8-tert-bu l uinolin l - l 2 4 triazolo 4 3-a ridin-6I ,_. IN N ’F’ trifluoroeth l rrolidine-3 4-diol Prepared as described in Example 9B, Steps A-F, using (3R,4R)-pyrrolidine- 3,4-diol in place of (S)-tert—butyl pyrrolidinylcarbamate in Step D, and using 8-tert— butquuinoline-Z-carbaldehydeldehyde in place of 8-meth0xyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 486 (M+H).
Example 75 0 r0 0x necarbonitrile dih drochloride ] Step A: Preparation of 7-bromoisopropoxymethylguinoline: A solution of omethquuinolinol (1.00 g, 4.20 mmol), K2C03 (1.74 g, 12.6 mmol), and 2- iodopropane (0.84 ml, 8.40 mmol) in e (20 mL) was stirred at 88 °C in a seal tube for 24 hours. After cooling to ambient temperature, ethyl acetate (50 mL) and water (30 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 7-bromoisopropoxymethquuinoline (1.13 g, 96.0%) as an oil.
Step B: Preparation of 8-isopropoxymethylguinolinecarbonitrile: A solution of 7-bromoisopropoxymethquuinoline (1.13 g, 4.03 mmol), PdC12(dppf) dichloromethane adduct (0.165 g, 0.202 mmol), zinc (0.063 g, 0.97 mmol) and dicyanozinc (0.31 g, 2.62 mmol) in DMA (5 mL) was stirred at 100 °C for 18 hours. After cooling to t temperature, water (10 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM) to give ropoxymethquuinolinecarbonitrile (0.83 g, 91.1%) as a solid.
Step C: Pre aration of 2- 6- R S amino rrolidin-l- l trifiuoroeth l - 1 2 4 triazolo 4 3-a ridin l iso ro ox uinolinecarbonitrile dihydrochloride: ed as described in Example 37 using 8-isopropoxy methquuinolinecarbonitrile in place of 8-ethylmethquuinoline in Step B. LCMS APCI (+) m/z 496 (M+H).
Example 76 / N\ N/T\NH 2 HCI Prepared as described in e 67, using (1S,4S)—tert-butyl 5-((S)-2,2,2- trifiuoro(6-hydrazinylpyridin-3 hyl)-2,5 -diazabicyclo [2.2. 1]heptanecarboxylate in place of (lS,4S)-tert—butyl 5-((R)-2,2,2-trifiuoro(6-hydrazinylpyridinyl)ethyl)-2,5- diazabicyclo[2.2.1]heptanecarboxylate. LCMS APCI (+) m/z 495 (M+H). e 77 / \ \"\/NH 2HC| / N Step A: Pre n of 1S4 l 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l -2 5-diazabic clo 2.2.1 he tane carboxylate: Prepared according to the method of Example 68 substituting (lS,4S)-tert—butyl((S)-2,2,2-trifluoro- l -(6-hydrazinylpyridin-3 -yl)ethyl)-2,5 -diazabicyclo [2 .2. l]heptane carboxylate for (lS,4S)-tert—butyl-5 2,2,2-trifluoro- l -(6-hydrazinylpyridin-3 hyl)- 2,5-diazabicyclo[2.2. l]heptanecarboxylate.
Step B: Pre aration of 2- 6- l -2 2 2-trifluoroeth l - l 2 4 triazolo 4 3-a ridin l c clo ro l uinoline dihydrochloride: Prepared according to the method of Example 3 tuting (lS,4S)—tert— butyl 5 -((S)- l -(3 -(7-bromoquinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2- trifluoroethyl)—2,5-diazabicyclo[2.2.l]heptanecarboxylate for tert—butyl (3S)—l-(l-(3-(7- bromoquinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidin-3 - ylcarbamate. LCMS APCI (+) m/Z 465 (M+H).
Example 78 Fgc,’ . N trifluoroeth l rrolidine-3 4-diol Prepared as described in Example 9B, Steps A-F, using (3R,4R)-pyrrolidine- 3,4-diol in place of rt—butyl pyrrolidinylcarbamate in Step D, and substituting 8- cyclopropquuinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 470 (M+H).
Example 79 roeth l rrolidinamine Prepared as described in Example 31 using iodoethane in place of 2- iodopropane in Step A. LCMS APCI (+) m/z 457 (M+H). e 80 F C3 H 2HC| .1 “3’ N Cf F / N \o \N N\ Step A: Pre aration of -benz l 3- tert—butox carbon 12- th lamino rrolidine-l-carbox late: To a solution of (S)-benzyl 3-(tertbutoxycarbonylamino )pyrrolidine-l-carboxylate (2.3 g, 7.1 mmol) and 1-fluoro bromoethane in anhydrous DMF (15 mL) was added a 60% dispersion of sodium hydride in mineral oil (0.43 g, 10.7 mmol). The mixture was d at 50 0C for 18 hours under nitrogen atmosphere. The on mixture was partitioned between water (50 mL) and ethyl acetate (100 mL). The organic layer was separated and washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 40M; 10-20% ethyl acetate/hexane gradient) to afford (S)-benzyl 3-(tert—butoxycarbonyl(2-fluoroethylamino)pyrrolidinecarboxylate (1.77 g, 35%).
Step B: Pre aration of tert—but l trifluoroethyl[pyrrolidinyl]2-fluoroethyl[carbamate: To a suspension of 5% Pd/C (1.4 g, 2.2 mmol) in ethanol (12 mL) was added slowly a on of (S)-benzyl 3-(tert- butoxycarbonyl(2-fluoroethyl)amino)pyrrolidinecarboxylate (2.44 g, 21.6 mmol) in methanol (5 mL). The mixture was evacuated and backfilled with nitrogen and then ted and backfilled with hydrogen, then stirred under a hydrogen atmosphere for 2 hours. The suspension was filtered through a pad of Celite and washed with a methanol (50 ml). The filtrate was concentrated under reduced re to afford (S)-tert—butyl 2- fluoroethyl(pyrrolidinyl)carbamate. To a on of (S)-l-(6-chloropyridinyl)-2,2,2- trifluoroethyl trifluoromethanesulfonate (0.97 g, 2.82 mmol) in anhydrous THF (5 mL) was added (S)-tert—butyl 2-fluoroethyl(pyrrolidinyl)carbamate (0.92 g, 3.95 mmol) and K2C03 (0.59 g, 4.23 mmol). The resulting mixture was heated with stirring at 50 0C for 18 hours.
After cooling to ambient temperature the mixture was partitioned between water (12 mL) and ethyl acetate (30 mL). The c layer was separated, washed with brine, dried (MgSO4), ed and concentrated under reduced pressure and the residue obtained purified by column chromatography (Biotage 25M; 10% ethyl acetate: hexanes) to afford tert—butyl (S)-l-((R)-l- (6-chloropyridinyl)-2,2,2-trifluoroethyl)pyrrolidinyl(2-fluoroethyl)carbamate (0.58 g, 48%).
Step C: Pre n of tert—but l2-fluoroeth l S -l- R -2 2 2-trifluoro-l- 6- hydrazinylpyridinyl[ethyl[pyrrolidinyl[carbamate: Prepared as bed in Example 9B, Step E, substituting tert-butyl (S)- l -((R)- l -(6-chloropyridin-3 -yl)-2,2,2- trifluoroethyl)pyrrolidinyl(2-fluoroethyl)carbamate (0.58 g, 1.36 mmol) to afford tert- butyl 2-fluoroethyl((S)- l -((R)-2,2,2-trifluoro- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 - yl)carbamate (0.523 g, 92%).
Step D: Pre n of tert—but l2-fluoroeth l -l- R -2 2 uoro-l- 3- 8-methox uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidin l carbamate: Prepared as described in Example 9B, Step F, using tert-butyl 2-fluoroethyl((S)-l-((R)-2,2,2- trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinyl)carbamate (0.10 g, 0.237 mmol) in place of tert—butyl (S)-l-((R)-2,2,2-trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidin bamate and 8-methoxyquinolinecarbaldehyde (0.044 g, 0.237 mmol). LCMS APCI (+) m/z 589 (M + H).
Step E: Pre aration of -N— 2-fluoroeth l -l- R -2 2 2-trifluoro-l- 3- 8- methox uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidinamine dihydrochloride: Prepared as described in Example 9B, Step G, substituting utyl 2- fluoroethyl((S)— l -((R)-2,2,2-trifluoro- l -(3 -(8-methoxyquinolinyl)- [l ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinyl)carbamate. LCMS APCI (+) m/z 489 (M + H).
Example 81 F3Q H = NQ’ 12HCIN /\ J\F N/ N O N |N\ Step A: Pre n of tert—but l2-flu0r0eth l -l- R -2 2 2-trifluor0-l- 3- 8-is0 r0 0x uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidin ylzcarbamate: Prepared as described in Example 9B, Step F, using tert—butyl 2- fluoroethyl((S)— l -((R)-2,2,2-triflu0r0- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 - yl)carbamate (0.10 g, 0.237 mmol) in place of tert—butyl (S)-l-((R)-2,2,2-triflu0r0-l-(6- hydrazinylpyridinyl)ethyl)pyrrolidinyl)carbamate and using 8-is0pr0p0xyquinoline carbaldehyde (0.051 g, 0.237 mmol) in place of 8-methoxyquinolinecarbaldehyde.
LCMS APCI (+) m/z 617 (M + H).
Step B: Pre aration of S -N— 2-fluor0eth l -l- R -2 2 2-trifluor0-l- 3- 8- iso r0 0x n l - l2 4 triazolo 4 3-a ridin l eth l rrolidinamine dihydrochloride: ed as described in Example 9B, Step G, substituting tert—butyl 2- fluoroethyl((S)— l -((R)-2,2,2-triflu0r0- l -(3 -(8-is0propoxyquinolinyl)—[ l ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinyl)carbamate in Step G. LCMS APCI (+) m/z 517 (M + H). e 82 6- leth l rrolidine-3 4-diol Prepared as described in Example 9B, Steps A-F, using (3R,4R)-pyrrolidine- ol in place of (S)-tert—butylpyrrolidinylcarbamate in Step D and using 8- isopropoxyquinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 488 (M + H).
Example 83 Step A: Pre aration of 2-c clo ro lnitrobenzoic acid: A on of 2- bromonitrobenzoic acid (1.17 g, 4.28 mmol), Pd(OAc)2 (0.048 g, 0.21 mmol), P(Cy)3 (0.132 g, 0.471 mmol), K3PO4 (3.18 g, 15.0 mmol) and cyclopropylboronic acid (0.735 g, 8.56 mmol) in toluene (4 mL) and water (1 mL) was stirred at 100 °C for 6 hours. After cooling to ambient temperature, ethyl acetate (20 mL) and water (5 mL) were added. The aqueous layer was ted and ed with saturated potassium hydrogen sulfate to about pH 3-4. The resulting solid was collected by filtration to give 2-cyclopropylnitrobenzoic acid (0.63 g, 71.0%) as a solid.
Step B: Preparation of 3-aminocyclopropylbenzoic acid: A solution of 2- cyclopropylnitrobenzoic acid (0.63 g, 3.04 mmol) and 5% Pt/C (0.59 g, 0.152 mmol) in methanol (10 mL) was charged with 40 psi of hydrogen and shaken for 3 hours. The catalyst was removed by filtration and washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to give 3-aminocyclopropylbenzoic acid (0.51 g, 94.1%) as a solid.
Step C: Preparation of op_rop_ylmethylguinolinecarboxylic acid: A solution of 3-aminocyclopropylbenzoic acid (0.507 g, 2.86 mmol) in 6 N HCl (8 mL) was added (E)-butenal (0.47 mL, 5.72 mmol) dropwise at reflux. The reaction mixture was stirred at reflux for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with sodium hydroxide to about pH 12 and DCM (20 mL) was added. The aqueous layer was separated and acidified with saturated potassium hydrogen e to about pH 3-4.
The aqueous layer was then extracted with 3:1 CHClg/IPA (2 x 30 mL), dried (sodium sulfate), filtered and concentrated under d pressure to give 8-cyclopropyl uinolinecarboxylic acid (0.18 g, 27.7%) as a solid.
Step D: Preparation of N—tert—butylcyclop_rop_ylmethylguinoline carboxamide: To a solution of 8-cyclopropylmethquuinolinecarboxylic acid (0.050 g, 0.220 mmol) and 2-methylpropanamine (0.116 mL, 1.10 mmol) in DMF (1 mL) was added HATU (0.125 g, 0.33 mmol) at ambient temperature and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was purified directly by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-90% CH3CN/Wat61' gradient; 25 column volumes) to give N—tert-butylcyclopropyl methquuinolinecarboxamide (0.033 g, 53.1%) as a solid.
Step E: Pre aration of 2- 6- R -l- S no rrolidin-l- l trifluoroeth l - l 2 4 triazolo 4 3-a ridin-3 rt-but lc clo ro l uinoline amide dihydrochloride: Prepared as described in Example 37 using N—tert—butyl-S- cyclopropylmethquuinolinecarboxamide in place of 8-ethylmethquuinoline in Step B. LCMS APCI (+) m/z H).
Example 84 / _,INQ,NH2 N CN yl [guinolinecarbonitrile ] Prepared as described in Example 31, Steps A-B, substituting 7- cyanoquinolinecarbaldehyde for 8-methoxycarbaldehyde in Step B. LCMS APCI (-) m/z 436 (Ml-H).
Example 85 910i 2- 6- S -l- R tert-butox carbon lamino rrolidin-l- l -2 2 2-trifluoroeth l - l 2 4 triazolo 4 3-a ridin l uinolinecarbox lic acid Prepared as described in Example 30, substituting tert—butyl (R)((S)-2,2,2- trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate for tert—butyl (3 S)-l- -trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate. LCMS APCI (-) m/z 555(Ml-H).
Example 86 \‘N0% ‘ O a ridin leth l rrolidinamine h drochloride Step A: Preparation of 6-fluoromethylguinolin01: To 2-amino fluorophenol (5.0 g, 39 mmol) in refluxing 6N HCl (50 mL) was added dropwise over 10 minutes t—2-enal (5.5 g, 79 mmol). The reaction was heated to reflux for 3 hours then cooled down and neutralized (pH = 7-8) by addition of NH4OH. The s phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated to yield 6-fluoromethquuinolinol (5.7 g, 82 % yield) as a dark oil which solidified upon standing.
Step B: Preparation of 6-fluoroisopropoxymethylguinoline: To 6-fluoro- 2-methquuinolinol (1.0 g, 5.6 mmol) in acetone (20 mL) were added 2-iodopropane (1.9 g, 11 mmol) and K2C03 (2.3 g, 17 mmol). The reaction was heated to 70 0C for 20 hours in a sealed tube and then cooled. Water was added and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried with MgSO4, filtered and concentrated under d pressure to yield 6-fluoroisopropoxymethquuinoline (1.1 g, 89 % yield) as a dark oil.
Step C: Preparation of 6-fluoroisopropoxyguinolinecarbaldehyde: To 6- fluoroisopropoxymethquuinoline (1.1 g, 5.02 mmol) in dioxane/water (3.5 ml/0.3 mL) at ambient temperature was added selenium dioxide (0.668 g, 6.02 mmol) and the reaction was heated to reflux for 2-3 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The crude al was purified by reverse phase tography (SP4, 25M, g with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 6- fluoroisopropoxyquinolinecarbaldehyde (410 mg, 35.0 % yield) as a tan solid.
Step D: Pre aration of tert—but l S R -2 2 2-trifluoro 6- E 6- fluoroiso ro ox uinolin lmeth lene h drazin l ridin leth l rrolidin ylcarbamate: tert—Butyl (S)((R)—2,2,2-trifluoro(6-hydrazinylpyridin-3 - yl)ethyl)pyrrolidinylcarbamate (1 00 mg, 0.266 mmol) and 6-fluoro isopropoxyquinolinecarbaldehyde (62.1 mg, 0.266 mmol) were stirred in ethanol (5 mL) for 72 hours at t temperature. The reaction was concentrated under d pressure to yield tert-butyl (S)((R)—2,2,2-trifluoro(6-((E)((6-fluoroisopropoxyquinolin hylene)hydrazinyl)pyridinyl)ethyl)pyrrolidinylcarbamate (157 mg, 99.8 % yield) as a yellow paste.
Step E: Pre aration of tert-but l S R -2 22-trifluoro 3- 6-fluoro iso ro ox uinolin l - 1 2 4 triazolo 4 3-a ridin-6I ,— ("DH{27‘ l—‘ 5‘;OEO.H.?DJ I ,—8E}552,("D To tert-butyl (S)((R)—2,2,2-trifluoro(6-((E)((6-fluoroisopropoxyquinolin yl)methylene)hydrazinyl)pyridinyl)ethyl)pyrrolidinylcarbamate (157 mg, 0.266 mmol) in DCM (10 mL) was added iodosobenzene diacetate (94.2 mg, 0.292 mmol) and the reaction was stirred at ambient temperature for 2 hours. The reaction was concentrated to dryness and the residue d by reverse phase chromatography (SP4, 12M, g with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield tert-butyl (S)((R)-2,2,2-trifluoro- l-(3 -(6-fiuoroisopropoxyquinolinyl)-[ 1 riazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin- 3-ylcarbamate (124 mg, 79.3 % yield) as a beige solid.
Step F: S -l- R -2 2 2-trifluoro 3- 6-fluoroiso ro ox uinolin l - | 1,2,4 |triazolo| 4,3-a|p§gidinyl[ethyl[pyrrolidinamine hydrochloride: To utyl (S)- 1-((R)-2,2,2-trifluoro(3 -(6-fluoroisopropoxyquinolinyl)-[1,2,4]triazolo[4,3 - a]pyridinyl)ethyl)pyrrolidinylcarbamate (120 mg, 0.204 mmol) was added TFA (2 mL) and the reaction was stirred for 30 minutes. After concentrating to dryness, the residue was dissolved in methanol and added to 2N HCl in ether. The resulting solid was filtered and dried under high vacuum to yield (S)((R)-2,2,2-trifluoro(3-(6-fiuoro isopropoxyquinolinyl)-[1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidinamine (105 mg, 105 % yield) hydrochloride as a beige solid. LCMS APCI (+) m/z 489(M+H). Specific rotation: 1) = +1.43° (c = 0.93, MeOH).
Example 87 dNQ’T: HCI/ 0 N./ NY l-N-iso ro l uinolinecarboxamide dih drochloride Prepared as described in Example 83, Steps C-E, using 2-aminobenzoic acid in place of 3-aminocyclopropylbenzoic acid in Step C, and substituting propanamine for 2-methylpropanamine in Step D. LCMS APCI (+) m/z 498(M+H). e 88 Cf3m/ N N N l uinolinecarbonitrile dih drochloride Step A: Pre aration of 2-meth l uinolin l trifiuoromethanesulfonate: A solution of 2-methquuinolinol (10.0 g, 62.8 mmol) and 2,6-lutidine (10.2 mL, 88 mmol) in anhydrous dichloromethane (200 mL) was cooled to -20 0C and treated with romethanesulfonic anhydride (12.7 mL, 75.4 mmol). The ing e was stirred at -20 0C for 1 hour then quenched by on of water (50 mL). The organic layers were ted and washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 40 M; 5% ethyl acetate/hexane) to afford 2-methquuinolinyl trifiuoromethanesulfonate (18 g, 98%).
Step B: Preparation of 2-methylguinolinecarbonitrile: To a solution of 2- uinolinyl trifiuoromethanesulfonate (3.0 g, 10.3 mmol) in acetonitrile (26 mL) was added sodium cyanide (1.0 g, 20.6 mmol). The solution was degassed under nitrogen for 10 minutes, followed by addition of copper (I) iodide (0.20 g, 1.03 mmol) and Pd(PPh3)4 (0.60 g, 0.52 mmol) under nitrogen. The mixture was heated at reflux for 2 hours. After cooling the mixture was diluted with ethyl acetate (50 mL) and filtered through Celite and washed with ethyl acetate (50 mL). The filtrate was washed with water and brine, dried (MgSO4), filtered and concentrated under d pressure. The residue was purified by column chromatography (Biotage, 40 M; 20% ethyl acetate: hexanes) to afford 2-methquuinoline carbonitrile (1.70 g, 98%).
] Step C: Preparation of 2-formylguinolinecarbonitrile: To a solution of 2- methquuinolinecarbonitrile (1.70 g, 10.1 mmol) in 1,4-dioxane (50 mL) and water (1 mL), was added selenium dioxide (2.80 g, 25.3 mmol) and the resulting mixture heated at reflux for 7 hours. After cooling to ambient ature, the solids formed were removed by filtration through a pad of Celite® and washed with 1:1 mixture of ethyl acetate/dichloromethane (50 mL). The filtrate was concentrated under reduced pressure and the residue obtained purified by column chromatography (Biotage, 40M; 1% MeOH: dichloromethane) to give 2-formquuinolinecarbonitrile (1.51 g, 82%).
Step D: Pre aration of 2- 6- R S amino rrolidin-l- l trifluoroeth l - 1 2 4 triazolo 4 3-a ridin l uinolinecarbonitrile dih drochloride: Prepared as described in Example 9B, Steps F and G, using tert-butyl (S)((R)-2,2,2- ro-l-(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidinylcarbamate and quuinoline- onitrile in Step F. LCMS APCI (+) m/z 438 (M + H).
Example 89 N/\5\ 2HCI / N CN 1 2 4 triazolo 4 3-a ridin l uinolinecarbonitrile dih drochloride Prepared as described in Example 9B, Steps A-G, using (1S,4S)—tert-butyl 5- ((R)—2,2,2-trifluoro(6-hydrazinylpyridin-3 -yl)ethyl)-2,5 -diazabicyclo [2 .2. 1]heptane ylate in place of tert—butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin yl)ethyl)pyrrolidineylcarbamate and using 2-formquuinolinecarbonitrile in place of 8- methoxyquinilinecarbaldehyde in Step F. LCMS APCI (+) m/z 450 (M + H). e 90 2HCI / Nc/NN2 a ridin leth l rrolidinamine dih drochloride Prepared as described in Example 8 using (R)-tert—butyl 3-methylpyrrolidin ylcarbamate (Preparation A) in place of (S)-tert—butyl pyrrolidinylmethylcarbamate, and substituting 8-isopropoxyquinolinecarbaldehyde for 8-methoxyquinolinecarbaldehyde.
MS APCI (+) m/z 485 (M+1) detected. e 91 2HC| {{NQ/“NHZF3C ”50$ ed as described in Example 1 using (R)-tert—butyl 3-methylpyrrolidin ylcarbamate (Preparation A) in place of rt—butyl pyrrolidinylmethylcarbamate, and tuting 8-isopropoxyquinolinecarbaldehyde for 8-methoxyquinolinecarbaldehyde.
MS APCI (+) m/z 485 (M+l) detected.
Example 92 2HC| / N\DLNH2 Step A: Pre aration of tert trifluoroeth l meth l rrolidin lcarbamate: Prepared as described in Example 1, Step C using (S)-tert—butyl 3-methylpyrrolidinylcarbamate (Preparation A) in place of (S)-tert— butyl pyrrolidinylcarbamate.
Step B: Pre aration of tert—but l meth l-l- -2 22-trifluoro-l- 6- h drazin l ridin leth l rrolidin lcarbamate: Prepared as described in Example 1, Step D using tert—butyl ((S)-l-(6-chloropyridinyl)—2,2,2-trifluoroethyl) methylpyrrolidinylcarbamate in place of tert—butyl (3S)-l-(l-(6-chloropyridinyl)-2,2,2- trifluoroethyl)pyrrolidinylcarbamate.
Step C: Pre n of tert—but l meth l-l- -2 2 2-trifluoro-l- 6- - 2- 8-iso ' ' ro ox uinolin lmeth lene h drazin l rrolidin ylcarbamate: To a solution of tert-butyl (S)methyl-l-((S)-2,2,2-trifluoro-l-(6- hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate (1.30 g, 3.34 mmol) in Ethanol (25 mL) was added 8-isopropoxyquinolinecarbaldehyde (0.719 g, 3.34 mmol) and stirred at 2012/026572 ambient temperature overnight. The reaction was concentrated and the residue purified by chromatography (C18, 300 g, 10% MeCN/water to 95% MeCN/water over 25 column volumes) to give tert—butyl (S)-3 -methyl((S)-2,2,2-trifluoro(6-((E)((8- isopropoxyquinolinyl)methylene)hydrazinyl)pyridinyl)ethyl)pyrrolidinylcarbamate (1.33 g, 2.27 mmol, 67.9 % yield).
] Step D: Pre aration of tert-but l meth l -2 2 2-trifluoro 3- 8- iso ro ox uinolin l - 1 2 4 triazolo 4 3-a ridin-6I _. ('DH{:7 _. :1Or9.H.?b.) I _.8E}53('9 To a stirred solution of tert—butyl (S)methyl((S)-2,2,2-trifluoro(6-((E)((8- isopropoxyquinolinyl)methylene)hydrazinyl)pyridinyl)ethyl)pyrrolidinylcarbamate (1.33 g, 2.27 mmol) in DCM (20 mL) was added iodo benzene diacetate (0.949 g, 2.95 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and then partitioned between ethyl acetate and saturated aqueous NaHCOg. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by chromatography (1 :3 /ethyl acetate) to give tert—butyl (S)-3 -methyl((S)-2,2,2-trifluoro(3 -(8-isopropoxyquinolinyl)- [1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate (1.30 g, 98%).
Step E: Pre aration of meth l -2 2 2-trifluoro 3- 8- iso ro ox uinolin l - 12 4 lo 4 3-a 6- leth l rrolidinamine dihydrochloride: To a stirred solution of tert—butyl (S)methyl((S)-2,2,2-trifiuoro(3- (8-isopropoxyquinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 -ylcarbamate (1.30 g, 2.22 mmol) in DCM (20 mL) was added 4N HCl in e (5.56 mL, 22.2 mmol).
The reaction mixture was stirred at t temperature for 3 hours. Diethyl ether (100 mL) was added to the reaction mixture. The suspension was stirred for 10 min. The solid was ted by filtration to give methyl((S)-2,2,2-trifiuoro(3-(8-isopropoxyquinolin- 2-yl)-[1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinamine dihydrochloride (1.20 g, 97%). MS APCI (+) m/z 485 (M+1) detected. Specific rotation: [0t]20D = -2.140 (c = 0.97, MeOH).
Example 93 2HC| S meth l-l- R -2 2 2-trifluoro-l- 3- 8-iso ro ox uinolin l - l 2 4 triazolo 4 3- a |pyridinyl [ethyl lidinamine dihydrochloride Prepared as described in Example 1 using (S)-tert—butyl 3-methylpyrrolidin ylcarbamate (Preparation A) in place of (S)-tert—butyl pyrrolidinylmethylcarbamate, and tuting 8-isopropoxyquinolinecarbaldehyde for 8-methoxyquinolinecarbaldehyde.
MS APCI (+) m/z 485 (M+l) detected.
Example 94 2HC| trifluoroeth lmeth l rrolidinamine dih drochloride Prepared as described in Example 1, Steps A-E using (R)-tert—butyl 3- methylpyrrolidinylcarbamate (Preparation A) in place of (S)-tert—butyl pyrrolidin ylmethylcarbamate, and substituting opropquuinolinecarbaldehyde for 8- methoxyquinolinecarbaldehyde, and ting the omers according to the chiral chromatography conditions described in Example 8, Step A, followed by preparation of the HCl salt according to Example 8, Step B. MS APCI (+) m/Z 467 (M+l) detected.
Example 95 2HC| CV 2 / N R -l- R -l- 3- 8-c clo ro l uinolin l - l 2 4 triazolo 4 3-a r1d1n l -2 2 2- trifluoroeth lmeth l rrolidinamine dih drochloride ed as described in Example 1 using (R)-tert—butyl 3-methylpyrrolidin amate (Preparation A) in place of (S)-tert—butyl pyrrolidinylmethylcarbamate, and substituting 8-cyclopropquuinolinecarbaldehyde for 8-methoxyquinolinecarbaldehyde.
MS APCI (+) m/z 467 (M+l) detected.
Example 96 2 HCI N NH2 trifluoroeth th l rrolidinamine dih drochloride Prepared as described in Example 1, Steps A-E using (S)-tert—butyl 3- methylpyrrolidinylcarbamate (Preparation A) in place of rt—butyl pyrrolidin ylcarbamate, and substituting 8-cyclopropquuinolinecarbaldehyde for 8- methoxyquinolinecarbaldehyde, and separating the enantiomers ing to the chiral chromatography conditions described in Example 8, Step A, followed by preparation of the HCl salt according to e 8, Step B. MS APCI (+) m/Z 467 (M+l) detected.
Example 97 2HCI / N S -l- R -l- 3- 8-c clo ro l uinolin l - l 2 4 triazolo 4 3-a r1d1n l -2 2 2- trifluoroeth lmeth l rrolidinamine dih drochloride Prepared as described in Example 1 using (S)-tert—butyl 3-methylpyrrolidin ylcarbamate (Preparation A) in place of (S)-tert—butyl pyrrolidinylmethylcarbamate, and substituting 8-cyclopropquuinolinecarbaldehyde for 8-methoxyquinolinecarbaldehyde.
MS APCI (+) m/z 467 (M+l) detected.
Example 98 Pg; NH2 d9’N N/ /N S -l- R -2 2 2-trifiuoro-l- 3- 6-fiuoro 2-methox ethox uinolin l - l 2 4 triazolo 4 3-a idin-6 l eth l rrolidinamine h drochloride Prepared as described in Example 86, substituting 2-iodopropane in Step B with l-bromomethoxyethane (32 mg, 64% yield). LCMS APCI (+) m/z 505 (M+H).
Example 99 Step A: Preparation of 8-]bromomethyl[methylguinoline: To a solution of 2,8-dimethquuinoline (3.00 g, 19.1 mmol) in carbon tetrachloride (50 mL) were added benzoyl peroxide 9 g, 0.057 mmol) and N—bromosuccinimide (3.57 g, 20.0 mmol). The reaction mixture was heated at reflux for 18 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was ved in DCM (100 mL), washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give 8-(bromomethyl)methquuinoline (1.50 g, 33.3%) as a solid.
Step B: Preparation of ethylguinolinyl[acetonitrile: To a solution of 8-(bromomethyl)methquuinoline (1.50 g, 6.35 mmol) in DMSO (20 mL) was added NaCN (0.62 g, 12.7 mmol). The mixture was stirred at ambient temperature for 10 s.
Water (100 mL) and ether (100 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), and trated under d pressure. The residue was purified by flash chromatography on silica gel (l:l hexane/ethyl acetate) to give 2-(2- methquuinolinyl)acetonitrile (0.75 g, 58.3%) as a solid.
Step C: Preparation of 2-methylg2-methylguinolinyl[propanenitrile: To a mixture of 60% NaH (0.33 g, 8.15 mmol) in DMSO (15 mL) at 20-35 °C was slowly added a solution of 2-(2-methquuinolinyl)acetonitrile (0.75 g, 3.70 mmol) and thane (0.58 mL, 9.26 mmol) in THF (5 mL). The on mixture was stirred at ambient temperature for hours. Brine (40 mL) and ether (50 mL) were added. The c layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure.
The residue was purified by flash tography on silica gel (30:1 hexane/ethyl acetate) to give 2-methyl(2-methquuinolinyl)propanenitrile (0.17 g, 22.1%) as a solid.
Step D: Pre aration of 2- 2- 6- R S amino rrolidin l -2 2 2- trifiuoroeth l- 12 4 triazolo 4 3-a ridin l uinolin l meth l ro anenitrile dihydrochloride: ed as described in Example 37, Steps B-C, using 2-methyl(2- methquuinolinyl)propanenitrile in place of 8-ethylmethquuinoline in Step B. LCMS APCI (+) m/z 480(M+H).
Example 100 trifiuoroeth l rrolidin lamino ethanol dih oride Step A: Pre aration of -benz l 3- tert—butox carbon l2-tert— butox eth 1 amino rrolidinecarbox late: To a solution of (S)-benzyl 3-(tert— butoxycarbonylamino)pyrrolidinecarboxylate (2.50 g, 7.80 mmol) in anhydrous DMF (20 mL) cooled to 0 0C in an ice bath was added a 60% dispersion of sodium hydride in mineral oil (0.47 g, 11.7 mmol). The mixture was allowed to warm to ambient temperature and stirred for 1 hour. 2-tert-Butoxyethyl methanesulfonate (2.3 g, 11.7 mmol) was added and the e was stirred at 0 0C in an ice bath, then allowed to slowly warm to ambient ature and stirred for 18 hours. The mixture was partitioned between water (50 mL) and ethyl e (100 mL). The layers were separated and washed with aqueous 1N HCl, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 40M; 20% ethyl e/hexane) to afford (S)-benzyl 3-(tert—butoxycarbonyl(2-tert—butoxyethyl)amino)pyrrolidinecarboxylate (2.87 g, 88%).
Step B: Pre aration of -tert—but l 2-tert—butox eth l in bamate: Prepared as described in Example 20 using (S)-benzyl 3-(tert— butoxycarbonyl(2-tert—butoxyethyl)amino)pyrrolidinecarboxylate (2.87 g, 6.82 mmol) in place of (S)-benzyl 3-(tert—butoxycarbonyl(methyl)amino)pyrrolidinecarboxylate in Step C to provide the desired product in quantitative yield. 2012/026572 Step C: Pre aration of tert-bu l 2-tert-butox ethl S R 6- chloropyridinyl[-2,2,2-trifluoroethyl[pyrrolidinyl[carbamate: Prepared as described in Example 9B, Step D, using (S)(6-chloropyridin-3 -yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (1.50 g, 4.37 mmol) and (S)-tert—butyl 2—tert— butoxyethyl(pyrrolidinyl)carbamate (2.0 g, 6.98 mmol) in place of (S)-tert—butyl pyrrolidinylcarbamate (1.69 g, 81%) Step D: Preparation of tert—butyl 2-tert—butoxyethyl]]§[]]R[-2,2,2-trifluoro- 1hydrazinylpyridinyl[ethyl[pyrrolidinyl[carbamate: Prepared as described in Example 9B, Step E, using tert—butyl 2-tert—butoxyethyl((S)—1-((R)(6-chloropyridinyl)- 2,2,2-trifluoroethyl)pyrrolidinyl)carbamate (1.69 g, 3.52 mmol) in place of tert—butyl (S)- 1-((R)(6-chloropyridinyl)-2,2,2-trifluoroethyl)pyrrolidinylcarbamate (1.55 g, 93%) Step E Pre aration of 2- R 3- 8-tert—but l uinolin l- 1 2 4 triazolo 4 3-a 6- l -2 2 2-trifluoroeth l rrolidin lamino ethanol dihydrochloride: Prepared as bed in Example 9B, Step F, using tert—butyl 2-tert— butoxyethyl((S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin-3 hyl)pyrrolidin-3 - yl)carbamate in place of utyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin yl)ethyl)pyrrolidineylcarbamate and substituting 8-tert—butquuinolinecarbaldehyde.
LCMS APCI (+) m/z 513 (M + H).
Example 101 6- l eth l rrolidin lamino ethanol dih drochloride Prepared as described in Example 9B, Step F, using tert—butyl 2-tert- butoxyethyl((S)((R)-2,2,2-trifluoro- 1 drazinylpyridin-3 -yl)ethyl)pyrrolidin-3 - bamate in place of tert-butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin yl)ethyl)pyrrolidineylcarbamate and using 8-isopropoxyquinolinecarbaldehyde in place of 8-methoxyquinilinecarbaldehyde. LCMS APCI (+) m/z 515 (M + H).
Example 102 a 6- leth l rrolidin lamino ethanol dih drochloride Prepared as described in Example 9B, Step F, using tert—butyl 2-tert- butoxyethyl((S)- l -((R)-2,2,2-triflu0r0- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 - yl)carbamate in place of utyl (S)-l-((R)-2,2,2-trifluor0-l-(6-hydrazinylpyridin yl)ethyl)pyrrolidineylcarbamate substituting 6-fluor0is0pr0p0xyquinoline carbaldehyde in place of 8-meth0xyquinilinecarbaldehyde. LCMS APCI (+) m/z 533 (M+H).
Example 103 / NQMOH leth l rrolidinol Step A: Pre aration of 8-iso r0 ox uinolinecarbaldeh de: Prepared as described in Example 5, Steps A-B, using 2-iodopropane in place of (bromomethyl)cyclopropane in Step A.
Step B: Pre aration of R -l- S -2 2 2-triflu0r0-l- 3- 8-is0 r0 0x uinolin- 2- l- l 2 4 lo 4 3-a ridin l eth l inol: Prepared as described in Example 9B, Steps A-F, using (R)-l-((S)-2,2,2-trifluoro-l-(6-hydrazinylpyridin yl)ethyl)pyrrolidin-3 -ol in place of tert-butyl (S)- l -((R)-2,2,2-trifluor0- l -(6- hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate and using 8-is0pr0p0xyquinoline carbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 472.1 (M+H).
Example 104 F C3 NO.\\OH / \ N/ N \N/ N\ leth l rrolidinol Prepared as described in e 103, substituting 8-tert—butquuinoline carbaldehyde for 8-isopropoxyquinolinecarbaldehyde. LCMS APCI (+) m/z 470.1 (M+H).
Example 105 ’1 NQ’NH2 / \ 2HC| / N O\ N‘N/ Step A: Pre aration of dieth l 2- 2-meth l uinolin l malonate: A solution of 8-bromomethquuinoline (2.00 g, 9.01 mmol), Pd(PtBu3)2 (0.23 g, 0.45 mmol), C82C03 (11.74 g, 36.02 mmol) and diethyl malonate (2.73 mL, 18.01 mmol) in dioxane (25 mL) was heated at 118 °C in a sealed tube for 1 hour. After cooling to t temperature, ethyl acetate (30 mL) and water (15 mL) were added. The organic layer was separated, washed with brine, dried m sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (7:1 /ethyl e) to give diethyl 2-(2-methquuinolinyl)malonate (2.24 g, 82.54%) as an oil.
Step B: Preparation of 2-]2-methylguinolinyl[acetic acid: A solution of diethyl 2-(2-methquuinolinyl)malonate (2.34 g, 7.77 mmol), 6 N HCl (7.77 mL, 46.6 mmol) in water, and acetic acid (7.77 mL) was heated at 106 °C for 18 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure to give 2-(2- methquuinolinyl)acetic acid (1.56 g, 99.8 %) as a solid.
Step C: Preparation of methyl 2-[2-methylguinolinyl[acetate: To a solution of 2-(2-methquuinolinyl)acetic acid (1.45 g, 7.21 mmol) in dry MeOH (100 mL) was added chlorotrimethylsilane (1.82 mL, 14.4 mmol) dropwise at 0 °C. After addition, the reaction mixture was stirred at reflux for 2 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was partitioned n ethyl acetate (50 mL) and saturated sodium bicarbonate (20 mL). The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced re.
The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give methyl 2-(2-methquuinolinyl)acetate (1.35 g, 87.0%) as an oil.
Step D: Preparation of methyl 2-methylg2-methylguinolinyl)propanoate: To a mixture of NaH (0.58 g, 14.43 mmol) in DMSO (15 mL) at 20-35 °C was slowly added a solution of methyl 2-(2-methquuinolinyl)acetate (1.35 g, 6.272 mmol) and iodomethane (1.08 ml, 17.25 mmol) in THF (5 mL). The reaction mixture was stirred at ambient temperature for 20 hours. Brine (20 mL) and ether (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give methyl 2-(2-methquuinolinyl)propanoate (1.44 g, 100%) as an oil. The methyl 2-(2-methquuinolinyl)propanoate (1.44 g, 6.28 mmol) was taken up in THF (10 mL) and 1 N lithium imethylsilyl)amide (12.56 mL, 12.56 mmol) in THF was added at 0 °C. After addition, the reaction mixture was stirred at ambient temperature for 40 s. Iodomethane (0.78 mL, 12.56 mmol) was added dropwise and the on mixture was d at ambient temperature for 18 hours. Water (10 mL) and ether (50 mL) were added. The organic layer was separated, washed with brine, dried m e), filtered and trated under reduced pressure. The residue was purified by flash chromatography on silica gel (8:1 hexane/ethyl e) to give methyl yl(2-methquuinolin yl)propanoate (0.67 g, 43.9%) as an oil.
Step E: Preparation of 2-methylg2-methylguinolinyl)p_rop_anol: To a solution of methyl 2-methyl(2-methquuinolinyl)propanoate (0.57 g, 2.3 mmol) in THF (10 mL) was added1 N LAH (5.9 mL, 5.9 mmol) in THF at 0 °C and stirred at 0 °C for 6 hours. Sodium sulfate decahydrate (2.0 g) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. The solid was removed by filtration and washed with ethyl acetate (30 mL). The filtrate was trated under reduced pressure and the residue was purified by flash chromatography on silica gel (1:1 hexane/ethyl acetate) to give 2- methyl(2-methquuinolinyl)propanol (0.43 g, 85%) as an oil.
Step F: Pre aration of 8- 1-methox meth l ro an lmeth l uinoline: To a solution of 2-methyl(2-methquuinolinyl)propanol (0.43 g, 2.00 mmol) and iodomethane (0.37 mL, 5.99 mmol) in DMSO (10 mL) was added NaH (0.16 g, 3.99 mmol) at ambient temperature and stirred at ambient temperature for 30 minutes. Water (10 mL) and ether (40 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 8-(l-methoxy propanyl)methquuinoline (0.43 g, 93.0%) as an oil.
Step G: Pre aration of S -l- meth l ro an l uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidinamine dihydrochloride: ed as described in Example 37, Steps B-C, using 8-(l-methoxy methylpropanyl)methquuinoline in place of 8-ethylmethquuinoline in Step B.
LCMS APCI (+) m/z 499(M+H).
Example 106 a ridin l uinolin t ramide Step A: Pre aration of S -l- R -l- 3- 7-bromo uinolin l - l 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidinol: Prepared as described in Example 30, Steps A-F, using rrolidinol in place of tert—butyl (3S)-l-(2,2,2- trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in Step D.
Step B: Pre aration of N— 2- 6- R -2 2 uoro-l- S h drox rrolidin-l- l eth l- 12 4 triazolo 4 3-a ridin l uinolin lisobut ramide: Prepared as described in Example 44, Steps B-C, tuting ((R)-l-(3-(7- bromoquinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidin-3 -ol for tert-Butyl (3 S)- l -(l -(3-(7-bromoquinolinyl)-[ l ,2,4]triazolo[4,3-a]pyridinyl)-2,2,2- trifluoroethyl)pyrrolidinylcarbamate. LCMS APCI (+) m/z 499.1 (M+H).
Example 107 N— 2- 6- R -2 2 2-trifluor0-l- S h drox rrolidin-l- l eth l - l 2 4 triazolo 4 3- a |pyridinyl [guinolinyl [pivalamide ] Prepared as bed in e 44, Steps B-C, substituting (S)-l-((R)-l-(3- (7-brom0quinolinyl)-[ l riazolo [4,3 -a]pyridinyl)—2,2,2-trifluor0ethyl)pyrrolidin-3 -ol for tert-Butyl (3 S)- l -( l -(3-(7-br0m0quinolinyl)-[ l ,2,4]triazolo[4,3-a]pyridinyl)-2,2,2- trifluoroethyl)pyrr0lidinylcarbamate and tert—butylamide for isopropylamide.. LCMS APCI (+) m/z 513.3 (M+H).
Example 108 Prepared as described in Example 86, using 2-aminofluorophenol in place of 2-aminofluor0phenol in Step A and using l-br0m0meth0xyethane in place of 2- iodopropane in Step B. LCMS APCI (+) m/z 505 (M+H).
Example 109 a ridin leth l rrolidinamine h drochloride Prepared as described in Example 86, using 2-aminofluorophenol in place of 2-amin0fluor0phenol in Step A. LCMS APCI (+) m/z 489 (M+H).
Example 110 F3C, NH2 ’- NJ 2 HCI / \ O\ N O\ N\ / N N \ Prepared as described in Example 105 using l 2-(2-methquuinolin yl)malonate in place of methyl ethquuinolinyl)acetate in Step D. LCMS APCI (+) m/z 529(M+H).
Example 1 1 1 F3C’ - NS;NH2 / \ 2H0 / N O N/ N\ a ridin leth l rrolidinamine dih drochloride Prepared as described in Example 105 using methyl 2-(2-methquuinolin yl)acetate in place of methyl 2-(2-methquuinolinyl)acetate in Step D. LCMS APCI (+) m/z 471(M+H).
Example 112 F30: “3’NH2 / \ N/ N 2HCI \ / N N \ Step A: Pre aration of meth l 1- 2-meth l uinolin yl[cyclopropanecarboxylate: To a solution of methyl 2-(2-methquuinolinyl)acetate (0.78 g, 3.62 mmol) in DMSO (10 mL) and THF (5 mL) was added 60% NaH (0.72 g, 18.12 mmol) and the reaction mixture was stirred at t temperature for 30 minutes. 1-Bromo- 2-chloroethane (0.90 mL, 10.87 mmol) was added slowly, and the reaction e was stirred at ambient temperature for 40 hours. Water (10 mL) and ether (50 mL) were added.
The organic layer was ted, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (7:1 hexane/ethyl acetate) to give methyl 1-(2-methquuinolin yl)cyclopropanecarboxylate (0.416 g, 47.6%) as an oil.
Step B: Pre aration of S R -2 2 2-trifluoro 3- 8- 1- methox meth l c clo ro l uinolin l- 12 4 triazolo 4 3-a ridin l eth l rrolidinamine dih drochloride: Prepared as described in Example 105 using methyl 1-(2-methquuinolinyl)cyclopropanecarboxylate in place of methyl 2-methyl(2- methquuinolinyl)propanoate in Step E. LCMS APCI (+) m/z 497(M+H). e 113 F 3C4, N H2 / \ S R -2 2 2-trifluoro 3- 6-fluoromethox uinolin l - 1 2 4 triazolo 4 3- a ridin leth l rrolidinamine h drochloride Step A: Pre aration of omethox meth l uinoline: To 4-fluoro methoxyaniline (1.0 g, 7.1 mmol) in refluxing 6N HCl (20 mL) was added dropwise (E)-but- 2-enal (0.99 g, 14 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was neutralized with ammonium hydroxide and extracted with DCM. The combined c phases were dried over MgSO4, filtered and concentrated under reduced pressure to yield 6-fluoromethoxymethquuinoline as a brown solid.
Step B: Preparation of 6-fluoromethoxyguinolinecarbaldehyde: To 6- 7-methoxymethquuinoline (1.4 g, 7.3 mmol) in dioxane/water (10 ml/1 mL) at ambient temperature was added selenium e (0.97 g, 8.8 mmol) and the reaction was heated to reflux for 2-3 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by e phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 6- fluoromethoxyquinolinecarbaldehyde (1.1 g, 73 % yield) as a tan solid.
Step C: Pre aration of ut l S R -2 2 2-trifluoro 6- E 6- fluoromethox uinolin lmeth lene h drazin l ridin l eth l rrolidin ylcarbamate: To 6-fluoromethoxyquinolinecarbaldehyde (54.7 mg, 0.266 mmol) in ethanol (5 mL) was added tert-butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin yl)pyrrolidinylcarbamate (100 mg, 0.266 mmol) and the reaction was stirred for 24 hours at ambient temperature. The on was concentrated to dryness and used as is in the next step. 2012/026572 Step D: Pre aration of tertmethox uinolin l- 12 4 triazolo 4 3-a ridin leth l in lcarbamate: To tert—butyl (S)((R)-2,2,2-trifiuoro(6-((E)((6-fluoromethoxyquinolin yl)methylene)hydrazinyl)pyridinyl)ethyl)pyrrolidinylcarbamate (150 mg, 0.267 mmol) in DCM (5 mL) was added iodosobenzene acetate (112 mg, 0.347 mmol), and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by e phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield tert-butyl (S)-l-((R)-2,2,2-trifluoro(3-(6-fluoro methoxyquinolinyl)—[ 1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 -ylcarbamate (109 mg, 72.9 % yield) as beige solid.
Step E: Pre aration of S R -2 2 uoro 3- o methox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine hydrochloride: tert—Butyl (S)((R)-2,2,2-trifluoro(3 oromethoxyquinolinyl)- [1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate (109 mg, 0.194 mmol) was stirred in TFA (3 mL) for 1 hour and then concentrated. The residue was dissolved in minimum methanol and added dropwise to a 4N HCl in ether solution. The resulting solid was filtered and dried to yield (S)((R)-2,2,2-trifluoro(3-(6-fluoromethoxyquinolin yl)-[1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinamine (67 mg, 74.8 % yield) hydrochloride as an off-white solid. LCMS APCI (+) m/z 461 (M+H). c rotation: [(11201) = +1.07° (c = 0.96, MeOH).
Example 114 “3’NH2 / \ 2HC| N CH N/ N\ 1- 2- 6- R S amino rrolidin-l- l -2 2 2-trifluoroeth l - 1 2 4 triazolo 4 3- a ridin l uinolin lc clo ro lmethanol dih drochloride Step A: Pre aration of 8- 1- tert—but h lsil lox meth lc clo ro l- 2-methylguinoline: To a solution of (l-(2-methquuinolinyl)cyclopropyl)methanol (0.050 g, 0.234 mmol) and triethylamine (0.065 mL, 0.47 mmol) in DCM (5 mL) was added TBSOTf (0.065 mL, 0.28 mmol) at t temperature and the reaction was stirred at ambient temperature for 1 hour. Saturated sodium bicarbonate (10 mL) and DCM (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10:1 hexane/ethyl acetate) to give 8-(1-((tert— butyldimethylsilyloxy)methyl)cyclopropyl)methquuinoline (0.071 g, 92.5%) as an oil.
Step B: Pre aration of 1- 2- 6- R S no rrolidin-l- l trifluoroeth l- 12 4 triazolo 4 3-a ridin l uinolin lc clo ro lmethanol dihydrochloride: Prepared as described in Example 37, Steps B-C, using 8-(1-((tert— butyldimethylsilyloxy)methyl)cyclopropyl)methquuinoline in place of 8-ethyl methquuinoline in Step B. LCMS APCI (+) m/z H).
Example 115 F3C/,' NH 2 / \ N \o N/\/ N /N| S R -2 2 2-trifluoro 3- 6-fluoromethox uinolin l - 1 2 4 triazolo 4 3- a ridin leth l rrolidinamine h drochloride ] Step A: Pre aration of 6-fluoromethox h l uinoline: To 4-fluoro methoxyaniline (370 mg, 2.62 mmol) in refluxing 6N HCl (5 mL) was added dropwise (E)- butenal (367 mg, 5.24 mmol). The reaction was heated to reflux for 2 hours then cooled and neutralized with NH4OH. The aqueous phase was extracted with DCM, and the combined organic phases dried over MgSO4 and trated to yield 6-fluoromethoxy methquuinoline (500 mg, 99.8 % yield) as a brown solid.
Step B: ation of 6-fluoromethoxyguinolinecarbaldehyde: To 6- fluoromethoxymethquuinoline (500 mg, 2.62 mmol) in dioxane/water (5 mL/0.5 mL) at ambient temperature was added selenium dioxide (348 mg, 3.14 mmol) and the reaction was heated to reflux for 2-3 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The e was purified by e phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 6-fluoro- 8-methoxyquinolinecarbaldehyde (423 mg, 78.8 % yield) as a tan solid.
Step C: Pre aration of tert-but l S R -2 2 2-trifluoro 6- E 6- fluoromethox uinolin lmeth lene h drazin l ridin l eth l rrolidin ylcarbamate: tert—Butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin-3 - yl)ethyl)pyrrolidinylcarbamate (200 mg, 0.533 mmol) and 6-fluoromethoxyquinoline carbaldehyde (109 mg, 0.533 mmol) were stirred in ethanol at ambient temperature for 24 hours. The reaction was concentrated and used as is in the next step.
Step D: Pre aration of tert—but l S R -2 22-trifluoro 3- 6-fluoro methox uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidin lcarbamate: To tert—butyl (S)((R)-2,2,2-trifluoro(6-((E)((6-fluoromethoxyquinolin yl)methylene)hydrazinyl)pyridinyl)ethyl)pyrrolidinylcarbamate (300 mg, 0.533 mmol) in DCM (5 mL) was added iodosobenzene diacetate (206 mg, 0.640 mmol) and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by e phase tography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield utyl ((R)-2,2,2-trifluoro(3-(6-fluoro methoxyquinolinyl)-[1 ,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate (1 89 mg, 63.2 % yield) as a beige solid Step E: Pre aration of S R -2 2 2-trifluoro 3- 6-fluoro methox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine hydrochloride: tert—butyl (S)((R)-2,2,2-trifluoro(3-(6-fluoromethoxyquinolinyl)- [1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate (189 mg, 0.337 mmol) was d in TFA (3 mL) for 1 hour then concentrated. The residue was ved in minimum methanol and added dropwise to a 4N HCl in ether solution. The resulting solid was filtered and dried to yield (S)((R)-2,2,2-trifluoro(3-(6-fluoromethoxyquinolinyl)- [1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinamine hydrochloride (77 mg, 49.6 % yield) as an off-white solid. LCMS APCI (+) m/z 461 (M+H). Specific on: [(11201) = — 0.150 (c = 0.97, MeOH).
Example 116 F304, NH2 a ridin leth l rrolidinamine h drochloride Step A: Pre aration of 2 8-dimeth l uinolinol: To 3-aminomethylphenol (5.0 g, 41 mmol) in refluxing 6N HCl (100 mL) was added dropwise (E)-butenal (5.7 g, 81 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was neutralized with ammonium ide and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced re to yield 2,8- dimethquuinolinol (9.0 g, 51 % yield) as a brown solid.
Step B: Preparation of 7-isop_rop_oxy-2,8-dimethylguinoline: 2,8- Dimethquuinolinol (1.0 g, 2.31 mmol), propane (0.785 g, 4.62 mmol) and potassium carbonate (0.957 g, 6.93 mmol) in acetone (15 mL) were heated to 70 0C in a sealed tube for 18 hours. After cooling, water (20 mL) was added and the aqueous phase was extracted with DCM. The combined c phases were dried over MgSO4, d and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of ACN 100:0 to 0:100, 20 column volumes) to yield 7-isopropoxy-2,8-dimethquuinoline (120 mg, 24.1 % yield) as an oil Step C: Preparation of 7-isop_rop_oxymethylguinolinecarbaldehyde: To 7- isopropoxy-2,8-dimethquuinoline (120 mg, 0.557 mmol) in dioxane/water (5 mL /0.5 mL) at ambient ature was added selenium dioxide (74.2 mg, 0.669 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, d and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7- isopropoxymethquuinolinecarbaldehyde (45 mg, 35.2 % yield) as a tan solid.
Step D: Pre aration of S R trifiuoro 3- 7-iso ro ox meth l uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidinamine hydrochloride: Prepared as in Example 86 Steps D, E, and F, replacing 6-fluoro isopropoxyquinolinecarbaldehyde in Step D with 7-isopropoxymethquuinoline carbaldehyde. LCMS APCI (+) m/z 485 (M+H).
Example 117 ] Step A: Pre aration of 7- 2-methox ethox -2 8-dimeth l uinoline: 1-Bromo- 2-methoxyethane (0.64 g, 4.6 mmol), 2,8-dimethquuinolinol (1.0 g, 2.3 mmol) and potassium carbonate (0.96 g, 6.9 mmol) in acetone (15 mL) were heated to 70 0C in a sealed tube for 18 hours. After cooling, water (20 mL) was added and the aqueous phase was extracted with DCM. The ed organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was d by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-(2-methoxyethoxy)-2,8-dimethquuinoline (90 mg, 17 % yield) as an oil Step B: Pre aration of 7- 2-methox ethox meth l uinoline carbaldehyde: To 7-(2-methoxyethoxy)-2,8-dimethquuinoline (90 mg, 0.39 mmol) in e/water (5 mL /0.5 mL) at ambient temperature was added selenium dioxide (52 mg, 0.47 mmol) and the reaction was heated to reflux for 1 hour. After cooling, the reaction was filtered and the solids washed with DCM. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-(2-methoxyethoxy)methquuinolinecarbaldehyde (67 mg, 70 % yield) as a tan solid.
Step C: Pre n of ut l S R -2 2 2-trifluoro 6- E 7- 2- methox ethox meth l uinolin lmeth lene h drazin l 3 -ylcarbamate: utyl ((R)-2,2,2-trifiuoro(6-hydrazinylpyridin-3 - yl)ethyl)pyrrolidinylcarbamate (98.0 mg, 0.261 mmol) and 7-(2-methoxyethoxy) methquuinolinecarbaldehyde (64 mg, 0.261 mmol) were stirred in ethanol at ambient temperature for 24 hours. The reaction was concentrated and used as is in the next step.
Step D: Preparation of tert—butyl gS[]]R[-2,2,2-trifiuoro-l-]3-[7-[2- methox ethox meth l uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidin ylcarbamate: To tert—butyl (S)((R)-2,2,2-trifluoro(6-((E)((7-(2-methoxyethoxy) methquuinolinyl)methylene)hydrazinyl)pyridinyl)ethyl)pyrrolidinylcarbamate (1 5 7 mg, 0.261 mmol) in DCM (5 mL) was added iodosobenzene diacetate (101 mg, 0.313 mmol) and the reaction was stirred at ambient ature for 2 hours. After concentration, the residue was purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0: 100, 20 column volumes) to yield tert-butyl (S)((R)-2,2,2-trifluoro- 1-(3 -(7-(2-methoxyethoxy)methquuinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate (93 mg, 59.4 % yield) as a beige solid Step E: Preparation of gS[]]R[-2,2,2-trifluoro]3-] ethoxyethoxy[- 8-meth l uinolin l - 1 2 4 lo 4 3-a ridin l eth l rrolidinamine hydrochloride: tert—butyl (S)((R)-2,2,2-trifiuoro(3-(7-(2-methoxyethoxy) methquuinolinyl)-[ 1 ,2,4]triazolo [4,3 idinyl)ethyl)pyrrolidin-3 -ylcarbamate (93 mg, 0.15 mmol) was stirred in TFA (3 mL) for 1 hour and then concentrated. The residue was dissolved in minimum methanol and added se to a 4N HCl in ether solution. The resulting solid was filtered and dried to yield (S)((R)-2,2,2-trifluoro(3-(7-(2- methoxyethoxy)methquuinolinyl)-[ 1 ,2,4]triazolo [4,3 idinyl)ethyl)pyrrolidin-3 - amine hydrochloride (87 mg, 112 % yield) as an off-white solid. LCMS APCI (+) m/z 501 (M+H).
Example 118 F304.
N(:IANHZ N O\ / o N\N/ /N Step A: Pre aration of 8- 1-methox ro an lox meth l uinoline: To 2-methquuinolinol (1.0 g, 6.28 mmol) in THF (5 mL) was added PPh3 (6.92 g, 26.4 mmol), DEAD (1.58 ml, 10.1 mmol) and 1-methoxypropanol (0.736 g, 8.17 mmol). The reaction was stirred for 24 hours at ambient temperature and then water was added. The aqueous phase was extracted with DCM and the ed organic phases dried over MgSO4, filtered and purified by reverse chromatography (SP4, 40M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 8-(1-methoxypropanyloxy) methquuinoline (1.0 g, 68.8 % yield) as a clear liquid ] Step B: Pre aration of 8- ox ro an lox uinoline carbaldehyde: To 8-(1-methoxypropanyloxy)methquuinoline (1.0 g, 4.32 mmol) in dioxane/water (10/1 mL) was added selenium dioxide (0.576 g, 5.19 mmol) and the reaction was heated to reflux for 2 hours. The reaction was concentrated to dryness and the residue purified by reverse phase chromatography (SP4, 25M, g with a gradient of ACN 100:0 to 0:100, 20 column volumes) to yield 8-(1-methoxypropanyloxy)quinoline dehyde (874 mg, 82.4 % yield) as a solid Step C: Prep_aration of 138111 1R[-2,2,2-trifluorog3-g8-1 1-methoxyprop_an- 2- lox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine hydrochloride: Prepared as in Example 86 Steps D, E, and F, replacing 6-fluoro isopropoxyquinolinecarbaldehyde in Step D with 8-(1-methoxypropanyloxy)quinoline- 2-carbaldehyde. LCMS APCI (+) m/z 501 (M+H).
Example 119 F304, N H2 a ridin leth l rrolidinamine h drochloride Step A: Pre aration of 6-fluoromethox meth l ne: To 4-fluoro yaniline (4.0 g, 28 mmol) refluxing in 6N HCl (50 mL) was added dropwise (E)—but- 2-enal (4.0 g, 57 mmol). The on was heated to reflux for 2 hours then cooled and neutralized with NH4OH. The c phase was extracted with DCM. The combined organic phases dried over MgSO4, filtered and concentrated under reduced pressure to provide 6-fluoromethoxymethquuinoline (5.2 g, 96 % yield) as a dark brown paste.
Step B: Preparation of 6-fluoromethylguinolinol: 6-Fluoromethoxy methquuinoline (5.2 g, 19 mmol) was heated to reflux in 48% aqueous HBr for 48 hours.
After cooling, the reaction was basified (pH 8) by addition of NH4OH. The resulting solid was filtered, washed with water and dried to yield 6-fluoromethquuinolinol (4.5 g, 93 % yield) as a black solid.
Step C: Preparation of 6-fluoroisop_rop_oxymethylguinoline: To 6-fluoro- 2-methquuinolinol (800 mg, 3.16 mmol) in acetone (5 mL) were added 2-iodopropane (1075 mg, 6.32 mmol) and potassium carbonate (1310 mg, 9.48 mmol). The reaction was stirred at 70°C in a sealed tube for 18 hours then cooled and diluted with water. The aqueous phase was extracted with DCM, dried over MgSO4, d and concentrated under reduced pressure to yield 6-fluoroisopropoxymethquuinoline (270 mg, 39.0 % yield) as an oil.
] Step D: Preparation of 6-fluoroisopropoxyguinolinecarbaldehyde: To 6- fluoroisopropoxymethquuinoline (270 mg, 1.23 mmol) in dioxane/water (5 mL /0.05 mL) was added selenium dioxide (164 mg, 1.48 mmol) and the on was heated to reflux for 2 hours. After cooling and concentrating, the residue was purified by chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield oisopropoxyquinolinecarbaldehyde as a solid.
Step E: Pre aration of tert-but l S -l- Rtrifluoro-l- 6- E 6- fluoroiso ro ox uinolin lmeth lene h drazin l ridin leth l rrolidin ylcarbamate: tert-Butyl (S)- l -((R)-2,2,2-trifluoro- l drazinylpyridin-3 -yl)ethyl) pyrrolidinylcarbamate (451 mg, 1.20 mmol) and 6-fiuoroisopropoxyquinoline carbaldehyde (280 mg, 1.20 mmol) in ethanol (5 mL) were stirred at ambient temperature for 24 hours. After concentration, the residue was used in the next step without purification.
Step F: Pre n of tert-bu l S R trifiuoro 3- 6-fluoro iso ro ox n l- 12 4 triazolo 4 3-a ridin leth l rrolidin lcarbamate: To tert-butyl (S)((R)-2,2,2-trifiuoro(6-((E)((6-fiuoroisopropoxyquinolin yl)methylene)hydrazinyl)pyridinyl)ethyl)pyrrolidinylcarbamate (700 mg, 1.19 mmol) in DCM was added iodosobenzene acetate (496 mg, 1.54 mmol) and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of ACN 100:0 to 0:100, 25 column volumes) to yield tert-butyl (S)((R)-2,2,2-trifiuoro(3-(6-fiuoro isopropoxyquinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 -ylcarbamate (280 mg, 40.1 % yield) as a beige solid.
Step G: Pre aration of S R -2 2 2-trifiuoro 3- 6-fiuoro iso ro ox uinolin l - 12 4 triazolo 4 3-a ridin l eth l inamine: tert- Butyl (S)((R)-2,2,2-trifiuoro(3-(6-fiuoroisopropoxyquinolinyl)- ]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate (280 mg, 0.476 mmol) was stirred in TFA (3 mL) for 1 hour then concentrated. The residue was dissolved in minimum methanol and added dropwise to a 4N HCl in ether solution. The ing solid was filtered and dried to yield (S)((R)-2,2,2-trifiuoro(3-(6-fiuoroisopropoxyquinolinyl)- [1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinamine (150 mg, 64.6 % yield) hydrochloride as an off-white solid. LCMS APCI (+) m/z 489 (M+H).
Example 120 F3C/,' NH 2 S R -2 2 uoro 3- 6-fiuoro 2-methox ethox uinolin l - 1 2 4 triazolo 4 3-a idin l eth l rrolidinamine h drochloride Prepared as in Example 119 substituting propane in Step C with 1- bromomethoxyethane. LCMS APCI (+) m/z 505 (M+H).
Example 121 UNH2 / \ 2HCI \N/ |N\ Step A: Pre aration of 2- 6-fluorometh l n l -2 o_l: Prepared as described in Example 105 using 8-bromofluoromethquuinoline in place of 8-bromomethquuinoline in Step A.
Step B: Pre aration of 2- 2- 6- R S amino rrolidin-l- l -2 2 2- trifluoroeth l- 12 4 triazolo 4 3-a ridin l fluoro uinolin lmeth l ro anol dihydrochloride: Prepared as described in e 114 using 2-(6-fluoromethquuinolin- 8-yl)—2-methylpropanol in place of (1-(2-methquuinolinyl)cyclopropyl)methanol in Step A. LCMS APCI (+) m/z 503(M+H).
Example 122 a ridin lfluoro uinolin lox eth lacetate h drochloride ] Step A: Pre aration of 2- 2- 6- R S tert- butox carbon lamino rrolidin-l- l -2 2 2-trifluoroeth l - 1 2 4 triazolo 4 3-a ridin yl[fluoroguinolinyloxy[ethyl acetate: Prepared as in Example 119 (Steps A-F) tuting 2-iodopropane in Step C with 2-bromoethyl acetate.
Step B: Pre aration of 2- 2- 6- R S amino rrolidin-l- l trifluoroeth l- 12 4 lo 4 3-a ridin lfluoro uinolin lox eth l acetate: 2- (2-(6-((R)((S)-3 -(tert-butoxycarbonylamino)pyrrolidinyl)-2,2,2-trifluoroethyl)— [1,2,4]triazolo[4,3-a]pyridinyl)fluoroquinolinyloxy)ethyl e (40 mg, 0.063 mmol) was stirred in TFA (3 mL) for 1 hour and then concentrated. The residue was WO 54274 dissolved in minimum methanol and added dropwise to a 4N HCl in ether solution. The ing solid was filtered and dried to yield 6-((R)-l-((S)aminopyrrolidin-l-yl)- 2,2,2-trifluoroethyl)- [l ,2,4]triazolo [4,3 -a]pyridin-3 -yl)fiuoroquinolinyloxy)ethyl acetate (27 mg, 80 % yield) hydrochloride as an off-white solid. LCMS APCI (+) m/z 505 (M+H).
Example 123 a ridin lfluoro uinolin lox ethanol h drochloride Step A: Pre aration of tert—but l S -l- R -2 2 2-trifluoro-l- 3- 6-fluoro 2- h drox ethox n l - l 2 4 triazolo 4 3-a ridin l eth l rrolidin ylcarbamate: To 2-(2-(6-((R)-l-((S)(tert—butoxycarbonylamino)pyrrolidin-l-yl)-2,2,2- trifluoroethyl)-[l,2,4]triazolo[4,3-a]pyridinyl)fluoroquinolinyloxy)ethyl acetate (250 mg, 0.395 mmol) (Example 122, Step A) in MeOH (5 mL) was added 2N LiOH (1 mL) and the reaction was stirred at ambient temperature for 1 hour. The reaction was concentrated and the residue purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of ACN 100:0 to 0:100, 25 column volumes) to yield tert-butyl (S)-l-((R)-2,2,2-trifluoro- l-(3 -(6-fluoro(2-hydroxyethoxy)quinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate (210 mg, 90.0 % yield) as a white solid.
Step B: Pre aration of 2- 2- 6- R -l- S amino rrolidin-l- l -2 2 2- trifluoroeth l- 12 4 triazolo 4 3-a ridin l fluoro uinolin lox ethanol h dro- chloride: tert—butyl (S)- l 2,2,2-trifluoro- l -(3 -(6-fluoro(2-hydroxyethoxy)quinolin yl)-[l,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate (200 mg, 0.339 mmol) was stirred in TFA (3 mL) for 1 hour and then concentrated. The residue was dissolved in minimum ol and added se to a 4N HCl in ether solution. The resulting solid was filtered and dried to yield 2-(2-(6-((R)-l-((S)aminopyrrolidin-l-yl)-2,2,2- trifluoroethyl)-[l,2,4]triazolo[4,3-a]pyridinyl)fluoroquinolinyloxy)ethanol (128 mg, 77.1 % yield) hydrochloride as an off-white solid. LCMS APCI (+) m/z 491 (M+H).
WO 54274 e 124 F3C/Il N H2 \N/ /N| o\ a ridin leth l rrolidinamine h drochloride ] Prepared as in Example 117, substituting l-br0m0meth0xyethane in Step A with iodomethane. LCMS APCI (+) m/z 457 (M+H).
Example 125 / “3’NH22 HCI / N OH N\ / N N\ l- 2- 6- R -l- S amin0 rrolidin-l- l -2 2 2-trifluor0eth l - l 2 4 triazolo 4 3- a 3- lfluor0 uinolin lc clo r0 lmethanol dih drochloride Prepared as described in Example 114 using 2-(6-fluoromethquuinolin yl)methylpr0pan-l-ol in place of (l-(2-methquuinolinyl)cyclopr0pyl)methanol in Step A. LCMS APCI (+) m/z 501(M+H).
Example 126 F3C; dNQ’OH HCI/ N OH S -l- R -2 2 2-trifluor0-l- 3- 6-fluor0 l- h drox meth lc clo r0 1 uinolin l - l 2 4 triazolo 4 3-a ridin l eth l inol h drochloride Step A: Pre aration of S -l- R -l- 3- 7-br0m0 uinolin l - l 2 4 triazolo 4 3-a idin l -2 2 2-trifluor0eth l rrolidinol: Prepared as in Example 1, Steps A-E, using (S)-pyrrolidinol in place of (S)—tert—butyl pyrrolidin ylcarbamate in Step C.
Step B: Pre aration of 8- l- tert—but ldimeth lsil lox meth l cyclopropyl[flu0r0methylguinoline: Prepared according to Example 114, Step A, using u0r0methquuinolinyl)methylpr0pan-l-ol in place of (l-(2-methquuinolin yl)cyclopr0pyl)methanol.
Step C: Pre n of S -l- R -2 2 2-trifluor0-l- 3- 6-fluor0 l- h drox lmeth l c clo r0 1 uinolin l - l 2 4 triazolo 4 3-a ol hydrochloride: Prepared as bed in Example 114, Step B, using (S)-l-((R)-l- (3 -(7-br0m0quinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridinyl)—2,2,2-triflu0r0ethyl)pyrrolidin- 3-01 and 8-(l-(((tert-butyldimethylsilyl)0xy)methyl)cyclopropyl)flu0romethquuinoline.
LCMS APCI (+) m/z 502(M+H).
Example 127 a ridin leth l rrolidinamine h drochloride Prepared as in Example 86, substituting 4-fluoromethoxyaniline in Step A with 2-aminomethylphenol and 2-i0dopr0pane in Step B with iodomethane. LCMS APCI (+) m/z 457 (M+H).
Example 128 F304, 0‘N H2 / \ N J\ a ridin leth l rrolidinamine h oride Prepared as in Example 86, substituting 4-fluoromethoxyaniline in Step A with 2-amin0methylphenol. LCMS APCI (+) m/z 485 (M+H). 2012/026572 Example 129 Fsc’: NH2 d30HN 2 HCI / N O"< N.N/ N\ 3S 4R amino R -2 2 2-trifiuoro 3- 8-iso ro ox uinolin l - 1 2 4 triazolo 4 3- a ridin leth l rrolidinol dih oride Step A: Pre aration of 3S4 -tert—but l 3 4-dih drox rrolidine-l- ylate: To a stirred solution of (3S,4S)—pyrrolidine-3,4-diol (2.49 g, 24.1 mmol) (Example 19) in methanol (70 mL) at t ature was added triethylamine (6.7 mL, 48.3 mmol), followed by DMAP (0.12 g, 0.97 mmol) and BoczO (7.90 g, 36.2 mmol). The mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; % MeOH/dichloromethane) to afford (3S,4S)—tert—butyl 3,4-dihydroxypyrrolidine carboxylate (2.79 g, 57%).
Step B: Pre aration of 3S 4 -tert—but l 3- bis 4-methox hen l hen lmethox h drox rrolidine-l-carbox late: To a solution of )—tert—butyl 3,4-dihydroxypyrrolidinecarboxylate (2.79 g, 13.7 mmol) in anhydrous pyridine (144 mL) was added 4,4'-(chloro(phenyl)methylene)bis(methoxybenzene) (5.43 g 15.2 mmol) and the resulting mixture d at ambient temperature for 4 days. The reaction was quenched with methanol (10 mL) and concentrated under reduced pressure. The residue was stirred in diethyl ether (150 mL) and the solid which precipitated was collected by filtration. The filtrate was concentrated under reduced pressure and purified by column chromatography (Biotage, 40M; 1% methanol: dichloromethane) to afford (3S,4S)—tert—butyl 3-(bl's(4- methoxyphenyl)(phenyl)methoxy)hydroxypyrrolidinecarboxylate (4.48 g, 65%).
Step C: Pre aration of 3S4 -tert—but l 3- bis 4-methox hen l hen l methox meth lsulfon lox rrolidine-l-carbox late: To a solution of (3S,4S)—tert— butyl 3-(bis(4-methoxyphenyl)(phenyl)methoxy)hydroxypyrrolidinecarboxylate (3.50 g, 6.92 mmol) and DMAP (4.23 g, 34.61 mmol) in dichloromethane (60 mL) at 0 0C in an ice bath was added methanesulfonyl chloride (2.69 mL, 34.61 mmol) se. The ing mixture was stirred at ambient temperature for 1 hour, cooled to 0 0C in an ice bath and quenched with water (15 mL). The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution (60 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give )—tert—butyl 3-(bz's(4- yphenyl)(phenyl)methoxy)(methylsulfonyloxy)pyrrolidinecarboxylate (4 . 0 1 g, 99%).
Step D: Preparation of g3R,4§)—tert-butyl 3-azidogbisg4-methoxypheny11 gphenyl )methoxyzpyrrolidinecarboxylate: To a solution of (3S,4S)-tert—butyl 3-(bz's(4- yphenyl)(phenyl)methoxy)(methylsulfonyloxy)pyrrolidinecarboxylate (4.0 g, 6.85 mmol) in anhydrous DMSO (70 mL) was added sodium azide (1.78 g, 27.4 mmol). The resulting mixture was heated at 100 0C for 18 hours. The solution was cooled to ambient temperature, poured into water (150 mL) and the solid which ted was collected by filtration and washed with water and dried to afford (3R,4S)-tert—butyl 3-azido(bz's(4- methoxyphenyl)(phenyl)methoxy)pyrrolidinecarboxylate (3 .37 g, 93%).
Step E: Preparation of 13R,4§ -butyl 3-1benzyloxycarbonylamino2 gbisg4-methoxyphenyl )1 phenyl )methoxy )pyrrolidine-l-carboxylate: To a solution of (3R,4S)— utyl 3-azido(bz's(4-methoxyphenyl)(phenyl)methoxy)pyrrolidinecarboxylate (3.0 g, 5.65 mmol) in anhydrous THF (70 mL) was added nylphosphine (2.97 g, 11.3 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated under reduced pressure and to the residue were added methanol (35 mL) and a 0.5 N sodium hydroxide solution (35 mL). The mixture was stirred at ambient ature 18 hours, and then partitioned between water (35 mL) and ethyl acetate (150 mL). The layers were separated and the aqueous layer was back extracted with ethyl acetate.
The combined organic extracts washed with water and brine, dried (MgSO4), filtered and concentrated under reduce pressure. The residue was purified by column chromatography (Biotage 40M; 2.5% MeOH: dichloromethane). To a solution of (3R,4S)-tert—butyl 3-amino- 4-(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidinecarboxylate (2.85 g, 5.65 mmol) in a 50% mixture of 1,4-dioxane/water (20 mL) was added sodium ate (0.72 g, 6.78 mmol) and the mixture cooled to 0 0C in an ice bath. Benzyl chloroformate (1 mL, 6.78 mmol) was added dropwise and the mixture was stirred at 0 0C for 30 minutes and then at t temperature for 18 hours. The mixture was partitioned between water (20 mL) and diethyl ether (100 mL), and the layers were separated. The organic layer was washed sequentially with water, saturated sodium bicarbonate and brine, then dried (MgSO4), filtered and trated under reduced pressure. The residue was purified by column chromatography (Biotage 40M 25% ethyl acetate/hexanes) to afford (3R,4S)—tert—butyl 3- (benzyloxycarbonylamino)(bis(4-methoxyphenyl)(phenyl)methoxy)pyrrolidine carboxylate (2.18 g, 60%).
Step F: Preparation of Benzyl [3R,4§ [hydroxypyrrolidinylcarbamate: A solution of (3R,4S)-tert—butyl 3-(benzyloxycarbonylamino)(bis(4- methoxyphenyl)(phenyl)methoxy)pyrrolidinecarboxylate (2.18 g, 3.14 mmol) was stirred in a 10% TFA/dichloromethane solution (30 mL) for 30 s. The solution was concentrated under reduced pressure and the residue dissolved in ethyl acetate (15 mL) and d with 2N HCl-diethyl ether (30 mL) for 1 hour. The resulting precipitate was collected by filtration and washed with ethyl acetate and dried to an off-white solid. The solid was dissolved in a 50% MeOH: dichloromethane solution (30 mL) and stirred with solid sodium carbonate (5 g) for 2.5 hours. The solids were collected by filtration and washed with 50% MeOH/dichloromethane solution and the filtrate concentrated under reduced pressure to give benzyl (3R,4S)hydroxypyrrolidinylcarbamate (0.80 g, 99%).
] Step G: Preparation of benzyl 13R,4§ []]R[] 6-chloropyridinyl[-2,2,2- trifiuoroethyl[hydroxypyrrolidinylcarbamate: Prepared as described in e 9B using (S)(6-chloropyridinyl)-2,2,2-trifiuoroethyl trifiuoromethanesulfonate (1.06 g, 3.08 mmol) and benzyl (3R,4S)hydroxypyrrolidinylcarbamate (0.802 g, 3.39 mmol) in place of (S)-tert-butyl pyrrolidinylcarbamate in Step D (1.16 g, 88%).
Step H: Pre aration of tert—but 1 3R 4 h drox R -2 2 2-trifiuoro g6-hydrazinylpyridinyl[ethyl[pyrrolidinylcarbamate: To a solution of benzyl (3R,4S) ((R)(6-chloropyridin-3 -yl)-2,2,2-trifiuoroethyl)hydroxypyrrolidinylcarbamate (1 . 1 6 g, 2.7 mmol) in acetonitrile (2 mL) cooled to 0 0C in an ice bath was added iodotrimethylsilane (1.22 mL, 8.10 mmol) and the mixture allowed to warm to ambient temperature for 1 hour. The reaction mixture was poured into aqueous 1N HCl (15 mL) and d for 10 minutes and extracted with diethyl ether. The s layer was pH adjusted to with a 5N sodium hydroxide solution and ted with ethyl acetate. The organic extract was dried (MgSO4), filtered and trated under reduced pressure. The residue (0.512 g, 1.29 mmol) was combined with anhydrous hydrazine (0.81 mL, 25.87 mmol) in i-BuOH (3 mL) in a sealed tube and heated with stirring at 100 0C for 18 hours. After cooling, the mixture was partitioned between water (15 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was washed with saturated sodium bicarbonate and brine, dried (MgSO4) d and concentrated under reduced pressure to afford tert—butyl (3R,4S)- 4-hydroxy((R)-2,2,2-trifiuoro(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 bamate (0.44 g, 86%).
Step 1: Pre aration of 3S 4R amino R -2 2 uoro 3- 8- iso ro ox uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidinol dih dro- 2012/026572 chloride: Prepared as described in Example 9B using tert-butyl (3R,4S)hydroxy-l-((R)- 2,2,2-triflu0r0-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert- butyl (S)- l 2,2,2-trifluor0- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidine-3 -ylcarbamate and substituting 8-is0pr0xyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 487 (M + H).
Example 130 3’: NH2 dN Z OH2HCI / N N./ N 3S 4R amin0-l- R -l- 3- 8-tert—but l uinolin l - l 2 4 tr1azolo 4 3-a r1d1n l - 2 2 uoroeth l rrolidinol dih drochloride ed as described in Example 9B using tert—butyl (3R,4S)hydroxy-l- ((R)-2,2,2-triflu0r0-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert—butyl (S)- l -((R)-2,2,2-trifluor0- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidine-3 - ylcarbamate and substituting 8-tert—butquuinolinecarbaldehyde for 8-meth0xyquinoline dehyde in Step F. LCMS APCI (+) m/z 485 (M + H).
Example 131 “O:NH2 / \ OH 2HCI / N N\ / N O\ 3S 4R amin0-l- R -2 2 2-trifluor0-l- 3- 6-flu0r0meth0x uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidinol dih drochloride Prepared as described in e 9B using tert—butyl (3R,4S)hydroxy-l- ((R)-2,2,2-triflu0r0-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert—butyl (S)- l -((R)-2,2,2-trifluor0- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidine-3 - ylcarbamate and substituting 6-fluor0meth0xyquinolinecarbaldehyde for 8- methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 477 (M + H).
Example 132 F30, ‘— NH2 N\ 2HCI / Z \ OH / N O/< N/ N\ Prepared as described in Example 9B using tert—butyl (3R,4S)hydroxy-l- ((R)-2,2,2-trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert—butyl (S)- l -((R)-2,2,2-trifluoro- l drazinylpyridin-3 -yl)ethyl)pyrrolidine-3 - ylcarbamate and substituting oisopropoxyquinolinecarbaldehyde for 8- methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 505 (M + H). e 133 F304, NH 2 trifluoroeth l rrolidinamine h drochloride Step A: Pre aration of 7-ethox rometh l uinoline: 6-fluoro methquuinolinol (500 mg, 1.41 mmol) (Example 119, Step B), potassium carbonate (585 mg, 4.23 mmol) and bromoethane (308 mg, 2.82 mmol) in e (10 mL) were stirred at 70 0C in a sealed tube for 20 hours. After dilution with water (50 mL) the reaction was extracted with DCM. The organic phases were concentrated and the residue purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column s) to yield 7-ethoxyfluoromethquuinoline (190 mg, 65.6 % yield) as a solid.
Step B: Preparation of 7-ethoxyfluoroguinolinecarbaldehyde: To 7- ethoxyfluoromethquuinoline (180 mg, 0.877 mmol) in dioxane/water (5 mL /0.05 mL) was added selenium dioxide (136 mg, 1.23 mmol) and the reaction was heated to reflux for 2 hours. After cooling, DCM was added followed by MgSO4. After concentration, the residue was used in the next step without purification.
] Step C: Pre aration of tert-butl S R6- E 7-ethox fluoro uinolin lmeth lene h drazin l ridin l-2 2 2-trifluoroeth l rrolidin ylcarbamate: tert—butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin-3 - yl)ethyl)pyrrolidinylcarbamate (240 mg, 0.639 mmol) and 7-ethoxyfluoroquinoline carbaldehyde (140 mg, 0.639 mmol) in ethanol (5 mL) were stirred at ambient temperature for 24 hours. After concentration, the residue was used in the next step t purification.
Step D: tert-but l S R 3- 7-ethox fluoro uinolin l - 1 2 4 triazolo 4 3-a ridin l -2 2 uoroeth l rrolidin lcarbamate: To tert-butyl (S)((R)(6-((E)((7-ethoxyfiuoroquinolinyl)methylene)hydrazinyl)pyridin-3 -yl)- 2,2,2-trifluoroethyl)pyrrolidinylcarbamate (368 mg, 0.638 mmol) in DCM was added iodosobenzene acetate (267 mg, 0.830 mmol) and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by e phase chromatography (SP4, 25M, g with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield tert-butyl ((R)(3 -(7-ethoxyfluoroquinolinyl)- ]triazolo[4,3-a]pyridinyl)-2,2,2-trifiuoroethyl)pyrrolidinylcarbamate (265 mg, 72.3 % yield) as a beige solid Step E: a |pyridinyl )—2,2,2-trifluoroethyl )pyrrolidin-3 -amine: tert-butyl (S)((R)(3 -(7-ethoxy- 6-fiuoroquinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidin-3 - ylcarbamate (265 mg, 0.461 mmol) was stirred in TFA (3 mL) for 1 hour and then concentrated. The residue was dissolved in minimum methanol and added dropwise to a 4N HCl in ether solution. The resulting solid was filtered and dried to yield (S)((R)—1-(3-(7- ethoxyfluoroquinolinyl)—[1,2,4]triazolo[4,3 -a]pyridinyl)-2,2,2- trifluoroethyl)pyrrolidinamine (186 mg, 85.0 % yield) hydrochloride as an off-white solid.
LCMS APCI (+) m/z 475 (M+H). c rotation: [(11241) = 1.840 (c = 1.03, MeOH).
Example 134 F3C/,' N H2 Prepared as in Example 133, substituting bromoethane in Step A with (bromomethyl)cyclopropane. LCMS APCI (+) m/z 501 (M+H).
Example 135 F30 0‘NH 2 a ridin leth l rrolidinamine h drochloride ] Prepared as in Example 86, tuting tert—butyl (S)((R)-2,2,2-trifluoro (6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in Step D with utyl (S)—1-((S)- 2,2,2—trifluoro(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate. LCMS APCI (+) m/z 489 (M+H).
Example 136 F30 0‘NH2 / \ S S -2 2 2-triflu0r0 3- 6-flu0r0meth0x uinolin l - 1 2 4 triazolo 4 3- a ridin leth l rrolidinamine h drochloride Prepared as in Example 113, substituting tert—butyl (S)((R)-2,2,2-trifluoro- 1-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in Step C with tert-butyl (S) ((S)-2 ,2,2-triflu0r0(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 bamate. LCMS APCI (+) m/z 461 (M+H).
Example 137 N:NH2 / \ OH / N N\ / 2HCI 3S 4R amino-l- R -2 2 2-trifluoro-l- 3- 8-methox uinolin l - l 2 4 triazolo 4 3- a 6- leth l rrolidinoldih drochloride Prepared as described in Example 9B, using tert-butyl (3R,4S)hydroxy-l- ((R)-2,2,2-trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert—butyl (S)- l -((R)-2,2,2-trifluoro- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidine-3 - ylcarbamate in Step F. LCMS APCI (+) m/z 459 (M + H).
Example 138 F3C/,' N H 2 / \ \N/ /NI 0\ a 6- leth l inamine h drochloride Step A: Pre aration of 7-methox -2 6-dimeth l uinoline: To 3-methoxy methylaniline (1.0 g, 7.29 mmol) in refluxing in 6N HCl (50 mL) was added dropwise (E)- butenal (1.02 g, 14.6 mmol) . The reaction was heated to reflux for 2 hours then cooled down and neutralized with NH4OH. The organic phase was extracted with DCM and the combined c phases dried over MgSO4, filtered and concentrated under reduced pressure to leave a dark residue. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-methoxy-2,6-dimethquuinoline (580 mg, 29.7 % yield) as a beige solid.
Step B: Preparation of 7-methoxymethylguinolinecarbaldehyde: To 7- methoxy-2,6-dimethquuinoline (580 mg, 3.10 mmol) in dioxane/water (IS/0.015 mL) was added selenium dioxide (447 mg, 4.03 mmol) and the on was heated to reflux for 5 hours. After cooling, DCM was added followed by MgSO4. After concentration, the residue was used in the next step without purification.
Step C: Pre aration of tert—but l methox meth l uinolin l meth lene h drazin l ylcarbamate: tert—butyl (S)- l -((R)-2,2,2-trifluoro- l -(6-hydrazinylpyridin-3 - yl)ethyl)pyrrolidinylcarbamate (187 mg, 0.497 mmol) and oxymethquuinoline- aldehyde (100 mg, 0.497 mmol) in l (5 mL) were stirred at ambient temperature for 24 hours. After tration, the residue was used in the next step without purification.
Step D: Pre aration of tert—but l S -l- R -2 2 2-trifluoro-l- 3- 7-methox - 6-meth l uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidin lcarbamate: To tert—butyl (S)- l -((R)—2,2,2-trifluoro- l E)((7-methoxymethquuinolin yl)methylene)hydrazinyl)pyridinyl)ethyl)pyrrolidinylcarbamate (278 mg, 0.498 mmol) in DCM was added benzene diacetate (208 mg, 0.647 mmol) and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by e phase chromatography (SP4, 25M, eluting with a nt of water/ACN 100:0 to 0:100, 25 column volumes) to yield tert-butyl (S)((R)-2,2,2-trifluoro(3-(7-methoxy methquuinolinyl)-[ l ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 bamate (l30 mg, 46.9 % yield) as a beige solid Step E: Pre aration of S -l- R -2 2 2-trifluoro-l- 3- 7-methox meth l uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidinamine hydrochloride: tert—Butyl (S)- l -((R)-2,2,2-trifluoro- l -(3 -(7-methoxymethquuinolinyl)- [l,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate (154 mg, 0.277 mmol) was stirred in TFA (3 mL) for 1 hour then concentrated. The residue was dissolved in minimum methanol and added dropwise to a 4N HCl in ether solution. The resulting solid was filtered and dried to yield (S)-l-((R)-2,2,2-trifluoro-l-(3-(7-methoxymethquuinolinyl)- [l,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinamine (109 mg, 86.3 % yield) hydrochloride as a solid. LCMS APCI (+) m/z 457 (M+H). e 139 “3’NH2 2HC| / N N/ IN\ 0\ l eth l rrolidinamine dih drochloride Prepared according to the method of Example 113 substituting 3- methoxyaniline for 4-fluoromethoxyaniline. LCMS APCI (+) m/Z 443 (M+H).
Example 140 NS,NH2 / \ : 2HCI / N O/\/ \ N\ / N Step A: Pre aration of R 1-methox ro an lox meth l uinoline: To a solution of 2-methquuinolinol (1.0 g, 6.3 mmol) in tetrahydrofuran (5.2 mL, 6.3 mmol) was added triphenylphosphine (6.9 g, 26 mmol), diethyl azodicarboxylate (1.6 mL, 10 mmol), and (S)methoxypropanol (0.80 mL, 8.2 mmol) and the ant e allowed to stir at ambient temperature for 24 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2 x 20 mL). The combined organic ts dried over sodium sulfate, filtered and concentrated under reduced pressure. ation of the residue by reverse phase chromatography on C18 (0-80% itrile/water) afforded the title compound (0.46 g, 28%).
Step B: Pre aration of R 1-methox ro an lox uinoline carbaldehyde: To a solution of (R)(1-methoxypropanyloxy)methquuinoline (0.45 g, 1.9 mmol) in dioxane (35 mL) and water (0.35 mL) was added selenium dioxide (0.26 g, 2.3 mmol) and the resultant e heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title compound (0.42 g, 88%).
Step C: methox ro an lox uinolin l- 12 4 triazolo 4 3-a ridin-6I ,_. (é ,_. 8EQ.5H” ylcarbamate: A solution of tert—butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin yl)ethyl)pyrrolidinylcarbamate (0.33 g, 0.87 mmol) and (R)(1-methoxypropan quinolinecarbaldehyde (0.21 g, 0.87 mmol) in ethanol (4.3 mL, 0.87 mmol) was d to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (4.3 mL) and iodosobenzene ate (0.31 g, 0.95 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (ZS-100% acetonitrile/water) to give the title compound (0.38 g, 73%).
Step D: Pre aration of R -2 2 2-trifluoro 3- 8- R methox ro an lox uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidin amine ochloride: To a solution of tert—butyl (S)((R)-2,2,2-trifluoro-l-(3-(8-((R) ypropanyloxy)quinolinyl)—[ 1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - ylcarbamate (0.37 g, 0.61 mmol) in dichloromethane (1 mL) was added hydrochloric acid (5- 6M in 2-propanol; 8.7 mL, 0.61 mmol). The reaction mixture was d at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the resulting solid was suspended in acetonitrile (3 mL) and stirred at ambient temperature for 5 minutes. The solid was collected by vacuum filtration to give the title compound (0.31 g, 87%). LCMS APCI (+) m/Z 501 (M+H). Specific rotation: [(1]st = 0.480 (c = 1.03, MeOH).
CExample 141 /N:Q1N\j’NH2 2HC| ed according to the method of Example 140 substituting (R) methoxypropanol for (S)methoxypropanol. LCMS APCI (+) m/Z 501 (M+H).
Example 142 pf// NQ’NHZ l eth l rrolidinamine dih drochloride ] Prepared according to the method of Example 119 substituting 3- yaniline for 4-fluoromethoxyaniline in Step A. LCMS APCI (+) m/z 471 (M+H).
WO 54274 2012/026572 e 143 F39. “3’NH2 d 2HC| / N N / N o\ 2 2 2-trifluoroeth l rrolidinamine dih drochloride Step A: Pre aration of 8-c clo ro lmethox meth l uinoline: Prepared according to Example 37, Step A, substituting 2-bromomethoxyaniline for 2-ethylaniline.
Step B: Pre aration of 8-c clo ro lmethox uinolinecarbaldeh de: Prepared according to Example 60, Step B, replacing 8-bromofluoromethquuinoline with 8-cyclopropylmethoxy—2-methylguinoline.
Step C: l 2 4 triazolo 4 3-a ridin-6I ,_. [b N 'F’HE.II!COHO ("DH5‘ fi—‘ Cl0EQ.5.PL.” 93E.5("D Q.5.5‘ 9:OO5‘fi—‘0H5.Q..0.
Prepared as described in Example 9B, using 8-cyclopropylmethoxyquinoline carbaldehyde in place of 8-ethylmethquuinoline in Step F. LCMS APCI (+) m/Z 483 (M+H).
Example 144 Na}NH2 / \ 2 HCI / N N\ / O Step A: Pre aration of 8-c clo ro lmethox meth l uinoline: Prepared according to the method of Example 60 substituting omethoxyaniline for ofluoroaniline.
Step B: Preparation of methyl-8,9-dihydrofi1ro|2,3-h|guinoline: A solution of 8-cyclopropylmethoxymethquuinoline (0.53 g, 2.5 mmol) in hydrobromic acid (48%; 9.9 mL, 2.5 mmol) was heated at reflux for 3 days. After cooling, the reaction mixture was neutralized to pH 8 by on of ammonium hydroxide and extracted with dichloromethane (3 x 20 mL). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced re. Purification by reverse phase chromatography on C18 (0-100 % acetonitrile/water) afforded the title compound (0.39 g, 79%).
Step C: Pre aration of 3 1R -2 22-trifluoro 3- 8-meth 1-8 9- dih drofuro 2 3-h uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine dihydrochloride: Prepared according to the method of Example 37, Steps B and C, substituting 2,8-dimethyl-8,9-dihydrofuro[2,3-h]quinoline for 8-ethylmethquuinoline in Step B. LCMS APCI (+) m/z 469 (M+H).
Example 145 3’: 2HCI /\ ”OH / N N‘ / N N\ 3R 4R amino R 3- —but l uinolin l - 1 2 4 triazolo 4 3-a ridin l - 2 2 2-trifluoroeth l rrolidinol dih drochloride ] Step A: Pre n of 3R 4R -tert—but l 3- benz lox carbon lamino hydroxypyrrolidinecarboxylate: To a solution of (3R,4R)-tert—butyl 3-amino hydroxypyrrolidine-l-carboxylate (4.40 g, 21.76 mmol) and N32C03 (2.77 g, 26.11 mmol) in dioxane (50 mL) and water (50 mL) was added Cbz-Cl (3.87 mL, 26.11 mmol) at 0 °C. The reaction mixture was warmed to ambient temperature and stirred at ambient temperature for 3 hours. Ethyl acetate (50 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give (3R,4R)- tert—butyl 3-(benzyloxycarbonylamino)hydroxypyrrolidinecarboxylate (4.91 g, 67.1%) as an oil.
Step B: Preparation of benzyl g3R,4R[hydroxypyrrolidinylcarbamate: To a on of (3R,4R)-tert-butyl zyloxycarbonylamino)hydroxypyrrolidine carboxylate (4.91 g, 14.60 mmol) in DCM (20 mL) was added TFA (11.25 mL, 146.0 mmol) and the mixture was stirred at t temperature for 1 hour. The solvent was removed under d pressure. 6 N HCl in water (10 mL) was added. The mixture was stirred at ambient temperature for 30 minutes and neutralized with saturated sodium bicarbonate to about pH 8. It was extracted with DCM: IPA=4:1 (50 mL). The organic layer was separated, 2012/026572 dried (sodium sulfate), filtered and trated under reduced pressure to give benzyl (3R,4R)hydroxypyrrolidinylcarbamate (2.45 g, 71.0%) as a solid.
Step C: Preparation of benzyl g3R,4R)ggR)—1-g 6-chlorop_yridinyl)-2,2,2- trifluoroethyl2hydroxypyrrolidinylcarbamate: A solution of (6-chloropyridin yl)-2,2,2-trifluoroethyl romethanesulfonate (2.50 g, 7.28 mmol), benzyl (3R,4R) hydroxypyrrolidinylcarbamate (2.41 g, 10.2 mmol) and K2C03 (1.51 g, 10.9 mmol) in THF (40 mL) was stirred at 56 °C for 12 hours. Water (20 mL) and ethyl acetate (40 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20:1 ethyl acetate/MeOH) to give benzyl (3R,4R)((R)(6- chloropyridinyl)-2,2,2-trifiuoroethyl)hydroxypyrrolidinylcarbamate (1.85 g, 59.2%) as a solid.
Step D: Preparation of benzyl tert-butyl g3R,4R)gng-l-g6-chloropyridin yl)-2,2,2-trifluoroethyl2hydroxypyrrolidinylcarbamate: To a solution of benzyl (3R,4R)((R)(6-chloropyridinyl)-2,2,2-trifiuoroethyl)hydroxypyrrolidin-3 - ylcarbamate (1.85 g, 4.30 mmol) in ACN (20 mL) was added iodotrimethylsilane (1.85 mL, 12.9 mmol) at 0 °C. After on, the reaction e was warmed to ambient temperature and stirred at ambient temperature for 1 hour. ACN was d under reduced pressure. 1 N HCl (10 mL) and ether (20 mL) were added. The aqueous layer was separated and basified with solid NaOH to about pH 12. THF (15 mL) and BoczO (1.88 g, 8.61 mmol) were added.
The mixture was stirred at t temperature for 20 hours. Ethyl acetate (20 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:2 hexane/ethyl acetate) to give tert—butyl (3R,4R)((R)(6-chloropyridin- 3-yl)-2,2,2-trifiuoroethyl)hydroxypyrrolidinylcarbamate (0.67 g, 39.3%) as a solid .
Step E: Pre aration of 3R 4R amino R 3- -but l uinolin l - 1 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidinol dih drochloride: Prepared as described in Example 9B using tert-butyl (3R,4R)((R)(6-chloropyridin yl)-2,2,2-trifluoroethyl)hydroxypyrrolidinylcarbamate in place of tert—butyl (S)((R)- 1-(6-chloropyridinyl)-2,2,2-trifiuoroethyl)pyrrolidinylcarbamate in Step E, and substituting -butquuinolinecarbaldehyde for 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 485(M+H).
Example 146 3R 4R amin0-l- R -2 2 2-triflu0r0-l- 3- 8-is0 r0 0x uinolin l - l 2 4 triazolo 4 3- a ridin l eth l rrolidinol dih oride Prepared as described in Example 9B using tert—butyl (3R,4R)—l-((R)-l-(6- chloropyridinyl)—2,2,2-trifluor0ethyl)hydr0xypyrrolidinylcarbamate in place of tertbutyl (S)— l -((R)- l lor0pyridin-3 -yl)-2,2,2-trifluor0ethyl)pyrrolidin-3 -ylcarbamate in Step E, and substituting 8-is0pr0p0xyquinolinecarbaldehyde for 8-meth0xyquinoline carbaldehyde in Step F. LCMS APCI (+) m/z H).
Example 147 3R 4R amin0-l- R -2 2 2-trifluor0-l- 3- 6-flu0r0is0 r0 0x n l - l 2 4 triazolo 4 3-a ridin l eth l rrolidinol dih drochloride Prepared as described in Example 9B using tert—butyl (3R,4R)-l-((R)-l-(6- chloropyridinyl)-2,2,2-triflu0roethyl)hydr0xypyrrolidinylcarbamate in place of tert- butyl (S)— l -((R)- l -(6-chloropyridin-3 ,2,2-trifluoroethyl)pyrrolidin-3 -ylcarbamate in Step E, and substituting 6-fluoroisopropoxyquinolinecarbaldehyde for 8- methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 505(M+H).
Example 148 F3c;_ “9’NH2 /\ 2HCI / N N/ N\ O\/\O/ R -2 2 2-trifluoro 3- 7- 2-methox ethox uinolin l - 1 2 4 triazolo 4 3- a |pyridinyl [ethyl [pyrrolidinamine ochloride Step A: ation of 7methoxyethoxy[methylguinoline: A mixture of 2-methquuinolinol (0.20 g, 1.3 mmol), 1-bromomethoxyethane (0.24 mL, 2.5 mmol) and potassium carbonate (0.52 g, 3.8 mmol) in acetone (5.0 mL, 1.3 mmol) was heated at 70 °C for 12 hours. The cooled reaction mixture was diluted with water (10 mL) extracted with romethane (3 x 20 mL). The combined c extracts were dried over ium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (10-50% ethyl acetate/hexanes) to provide title compound (0.16 g, 60%).
Step B: Preparation of 7methoxyethoxy[guinolinecarbaldehyde: To a solution of 7-(2-methoxyethoxy)methquuinoline (0.16 g, 0.76 mmol) in dioxane (15 mL) and water (0.15 mL) was added selenium dioxide (0.10 g, 0.91 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title nd (0.12 g, 70%).
Step C: Pre aration of tert—but l R -2 2 2-trifluoro 3- 7- 2- methox ethox uinolin l - 1 2 4 lo 4 3-a ridin l eth l rrolidin ylcarbamate: A solution of tert—butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin yl)ethyl)pyrrolidinylcarbamate (0.20 g, 0.53 mmol) and 7-(2-methoxyethoxy)quinoline carbaldehyde (0.12 g, 0.53 mmol) in ethanol (2.7 mL, 0.53 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (2.7 mL) and benzene diacetate (0.19 g, 0.59 mmol) was added. The reaction mixture was stirred at ambient ature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The c layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (0- 100% acetonitrile/water) to give the title compound (0.20 g, 63%).
Step D: Pre aration of R -2 2 2-trifluoro 3- 7- 2- methox ethox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine dihydrochloride: To a solution of utyl (S)((R)-2,2,2-trifluoro(3-(7-(2- methoxyethoxy)quinolinyl)- [1 ,2,4]triazolo [4,3 idinyl)ethyl)pyrrolidin-3 - ylcarbamate (0.20 g, 0.33 mmol) in dichloromethane (1 mL) was added hydrochloric acid (5- 6M in anol; 8.3 mL, 0.61 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the solid obtained was suspended in itrile (3 mL) and stirred at ambient temperature for 5 minutes. The solid formed was collected by vacuum filtration to give the title nd (0.17 g, 91%). LCMS APCI (+) m/z 487 (M+H).
Example 149 F3C4 . NQ’NH2 / N \N/ N\ I Oro/ Step A: Pre n of R 1-methox ro an lox meth l uinoline: To a solution of 2-methquuinolinol (0.20 g, 1.3 mmol) in ydrofuran (1.1 mL, 1.3 mmol) was added triphenylphosphine (0.82 g, 3.1 mmol), diethyl azodicarboxylate (0.32 mL, 2.0 mmol), and (S)methoxypropanol (0.16 mL, 1.6 mmol) and the resultant mixture allowed to stir at ambient temperature for 24 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2 x 20 mL). The combined c extracts dried over sodium sulfate, filtered and concentrated under reduced pressure. ation by reverse phase chromatography on C18 (0-80% acetonitrile/water) afforded the title compound (0.22 g, 66%).
] Step B: Pre aration of R 1-methox ro an lox uinoline carbaldehyde: To a solution of (R)(1-methoxypropanyloxy)methquuinoline (0.22 g, 0.96 mmol) in dioxane (7 mL) and water (0.07 mL) was added selenium dioxide (0.13 g, 1.2 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under d pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title nd (0.11 g, 46%).
Step C: methox ro an lox uinolin l- 12 4 triazolo 4 3-a ridin-6I ,— ("DH{27‘ 1—‘ 5EO.H?L.” ylcarbamate: A solution of tert—butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin yl)ethyl)pyrrolidinylcarbamate (0.17 g, 0.44 mmol) and (R)(1-methoxypropan 2012/026572 yloxy)quinolinecarbaldehyde (0.11 g, 0.44 mmol) in ethanol (2.2 mL, 0.44 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was d under reduced pressure. The e was dissolved in dichloromethane (2.2 mL) and iodosobenzene diacetate (0.16 g, 0.49 mmol) was added. The reaction mixture was stirred at ambient ature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by e phase chromatography on C18 (0-100% acetonitrile/water) to give the title compound (0.11 g, 42%).
Step D: Pre aration of R -2 2 2-trifluoro 3- 7- R methox ro an lox uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidin amine dihydrochloride: To a on of tert—butyl (S)((R)-2,2,2-trifluoro(3-(7-((R) methoxypropanyloxy)quinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - ylcarbamate (0.11 g, 0.18 mmol) in dichloromethane (1 mL) was added hydrochloric acid (5- 6M in 2-propanol; 9.2 mL, 0.18 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the resulting solid was suspended in acetonitrile (3 mL) and stirred at ambient temperature for 5 minutes. The solid formed was collected by vacuum filtration to give the title compound (0.084 g, 77%). LCMS APCI (+) m/z 501 (M+H).
Example 150 F3Ca - NQ’NH2 d 2 HCI / N Prepared according to the method of e 149 substituting (R) methoxypropanol for (S)methoxypropanol. LCMS APCI (+) m/Z 501 (M+H).
Example 151 F30: UNH2 / N l -2 2 2-trifluoroeth l rrolidinamine dih drochloride Step A: Pre n of 8-bromometh l uinolinol: Prepared according to the method of Example 144, Step B, substituting 8-bromomethoxymethquuinoline for 8-cyclopropylmethoxymethquuinoline.
Step B: Preparation of 8-bromoisop_rop_oxymethylguinoline: A mixture of 8-bromomethquuinolinol (0.093 g, 0.39 mmol), 2-iodopropane (0.078 mL, 0.78 mmol) and potassium ate (0.16 g, 1.2 mmol) in acetone (1.6 mL, 0.39 mmol) was heated at 70 CC for 12 hours. After cooling, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and trated under reduced pressure. Purification by normal phase chromatography on silica (10% ethyl acetate/hexanes) provided the title compound.
Step C: Pre n of 2- l - l 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l inamine dihydrochloride: Prepared according to the method of Example 143, Steps B and C, substituting 8-bromoisopropoxymethquuinoline for 8-cyclopropylmethoxy uinoline. LCMS APCI (+) m/z 511 (M+H).
Example 152 F30r aNQ’ 2 HCI / N Prepared according to the method of Example 151 substituting 1-bromo methoxyethane for 2-iodopropane in Step B. LCMS APCI (+) m/Z 527 (M+H).
Example 153 “3’NH2 / \ 2HCI N/ N \ / N O N \ Step A: Pre aration of 7-bromofiuorometh l uinoline: To a solution of 3-bromofiuoroaniline (10.00 g, 52.63 mmol) in 6N HCl (150 mL) was added (E)—but enal (7.524 mL, 92.10 mmol) dropwise over 10 minutes at 106 °C. The reaction was stirred at 106 °C for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with ammonium ide to about pH 12, extracted with DCM (2x100 mL), dried (sodium sulfate), filtered and concentrated under reduced re. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 5:1) to give 7-bromofluoro methquuinoline (3.26 g, 25.8%) as a solid.
Step B: Pre aration of S R -2 2 2-trifiuoro 3- o 2- methox eth l uinolin l- 1 2 4 triazolo 4 3-a 6- l eth l rrolidinamine dihydrochloride: Prepared as described in Example 105 using 7-bromofluoro methquuinoline in place of 8-bromomethquuinoline in Step A. LCMS APCI (+) m/z 489(M+H). Specific rotation: [(1]26D = 0.730 (c = 1.10, MeOH).
Example 154 / N N, / N N\ fluorometh l R -2 2 uoro 3- 8-iso ro ox n l - 1 2 4 triazolo 4 3-a ridine l eth l rrolidineamine dih drochloride Step A: Pre aration of eth l 2- fluorometh 1 ac late: To a solution of ethyl roxymethyl)acrylate (3.0 g, 23.1 mmol) in dichloromethane (40 mL) cooled to -78 0C, was added DAST (3.32 mL, 25.4 mmol). The reaction mixture was stirred at -78 0C for 30 minutes and then at ambient temperature for 1 hour. The reaction was quenched with water (40 mL) and the layers were separated. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford ethyl 2- (fiuoromethyl)acrylate (2.54 g, 83%).
] Step B: Preparation of ethyl 1-benzylgfluoromethyl[pyrrolidine carboxylate: To a solution of ethyl 2-(fiuoromethyl)acrylate (2.54 g, 19.2 mmol) and N- benzyl-N—(methoxymethyl)trimethylsilylmethylamine (5.1 mL, 19.2 mmol) in dichloromethane (15 mL) cooled to 0 0C in an ice bath, was added 1M solution of TFA in dichloromathane (1.8 mL), and the resulting mixture stirred at 0-2 0C for 75 minutes. The reaction was diluted with romethane (20 mL) and washed with saturated sodium bicarbonate on, brine and dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes) to afford ethyl 1-benzyl(fiuoromethyl)pyrrolidinecarboxylate (2.98 g, 58%).
Step C: Preparation of ethyl 3-]fiuoromethyl[pyrrolidinecarboxylate: A solution of ethyl 1-benzyl(fluoromethyl)pyrrolidinecarboxylate (2.98 g, 11.2 mmol) and ammonium formate (3.54 g, 56.2 mmol) in ethanol (100 mL) was flushed with nitrogen for minutes. 10% Pd/C (1.2 g, 1.12 mmol) was added and the mixture heated at reflux for 30 minutes. The on mixture was cooled to ambient temperature, d through a pad of Celite, washing with ethanol (50 mL). The filtrate was trated under reduced pressure to afford ethyl 3-(fiuoromethyl)pyrrolidinecarboxylate (1.86 g, 95%).
Step D: Preparation of 1-benzyl 3-ethyl 3-]fluoromethyl[pyrrolidine-1,3- dicarboxylate: To a solution of ethyl 3-(fiuoromethyl)pyrrolidinecarboxylate (1.86 g, .62 mmol) in a 1:1 e of 1,4-dioxane/water (18 mL) was added sodium carbonate (1.35 g, 12.74 mmol) and the mixture cooled to 0 0C in an ice bath. Benzyl chloroformate (1.79 mL, 12.74 mmol) was added dropwise and the resulting mixture was stirred at 0 0C for minutes, then at t temperature for 18 hours. The mixture was partitioned between water and ether, and the layers ted. The organic layer was washed tially with water, saturated sodium onate solution and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography (Biotage 25M; 15% ethyl acetate/hexanes) to afford 1-benzyl 3-ethyl 3-(fluoromethyl)pyrrolidine-1,3- dicarboxylate (3.3 g, 100%).
Step E: Preparation of 1-gbenzyloxycarbonyl[]fluoromethyl[pyrrolidine carboxylic acid: To a solution of 1-benzylethyl 3-(fluoromethyl)pyrrolidine-1,3- dicarboxylate (3.3 g, 10.7 mmol) in anhydrous THF (30 mL) cooled to 0 0C in an ice bath, was added LiOH-HZO (1.79 g, 42.7 mmol) ed by water (6 mL). The mixture was stirred at ambient temperature for 3 hours, diluted with water and washed with ethyl acetate, then acidified with aqueous 1M HCl. The solution was extracted with ethyl acetate and the combined organic extracts were washed brine, then dried (MgSO4), filtered and concentrated under reduced pressure to give zyloxycarbonyl)(fluoromethyl)pyrrolidine carboxylic acid (2.77 g, 92%).
Step F: Pre aration of benz l 3- tert—butox carbon lamino gfiuoromethyl[pyrrolidine-l-carboxylate: To a on of 1-(benzyloxycarbonyl) (fluoromethyl)pyrrolidinecarboxylic acid (2.77 g, 9.85 mmol) in anhydrous t—BuOH (30 mL) was added triethylamine (6.86 mL, 49.24 mmol) and diphenyl oryl azide (3.29 mL, 14.77 mmol). The mixture was heated at reflux for 16 hours under a nitrogen atmosphere. The e was cooled to ambient temperature, and partitioned between diethyl ether and water. The organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried (MgSO4), d and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M, 20% ethyl acetate/hexanes) to afford benzyl 3-(tert-butoxycarbonylamino)(fluoromethyl)pyrrolidine- 1-carboxylate (2.27 g, 65%).
Step G: Preparation of tert—butyl 3-]fluoromethyl[pyrrolidinylcarbamate: A solution of ethyl benzyl(tert—butoxycarbonylamino)(fiuoromethyl)pyrrolidine ylate (2.27 g, 6.44 mmol) and ammonium formate (3.03 g, 32.2 mmol) in ethanol (60 mL) was flushed with nitrogen for 15 minutes. 10% Pd/C (0.69 g, 0.644 mmol) was added and the mixture heated at reflux for 30 s. The reaction mixture was cooled to ambient temperature, filtered through a pad of Celite and washed with ethanol (30 mL) and concentrated under reduced pressure to afford tert—butyl 3-(fluoromethyl)pyrrolidin ylcarbamate (1.4 g, 100%).
Step H: Preparation of utyl 1-]]R[]6-chloropyridinyl[-2,2,2- trifiuoroethyl[]fluoromethyl[pyrrolidin—3-ylcarbamate: Prepared as bed in Example 9B using (S)(6-chloropyridinyl)-2,2,2-trifiuoroethyl trifluoromethanesulfonate (1.10 g, 3.20 mmol) and tert—butyl 3-(fluoromethyl)pyrrolidinylcarbamate (0.70 g, 3.21 mmol) in place of (S)-tert-butyl pyrrolidinylcarbamate in Step D (1.03 g, 78%).
Step 1: Pre aration of ut l 3- eth l R -2 2 2-trifluoro 6- h drazin l ridin leth l rrolidin lcarbamate: Prepared as described in Example 9B substituting tert—butyl 1 -((R)(6-chloropyridin-3 -yl)-2,2,2-trifluoroethyl)-3 -(fluoromethyl) pyrrolidinylcarbamate (1.0 g, 2.43 mmol) in Step E (0.980 g, 99%).
] Step J: Preparation of tert—butyl 3-]fluoromethyl)—1-]]R[-2,2,2-trifluoro]3- 8-iso ro ox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidin ylcarbamate: ed as described in Example 9B using tert—butyl 3-(fiuoromethyl)—1-((R)— 2,2,2-trifluoro(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in place of tert- butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidine-3 bamate and substituting 8-isopropoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 603 (M + H).
Step K: Stereoisomer of tert—but l 3- fluorometh l R -2 2 2-trifluoro- 1- 3- 8-iso ro ox n l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidin ylcarbamate: The racemic material from Step J was purified by Chiral HPLC (OD-H, Chiral Technologies) 10% EtOH: 90% hexanes, to provide the first g peak as a single stereoisomer (99% ee), designated (S) stereoisomer by proton NMR analysis of the Mosher amide.
Step L: Pre aration of fluorometh l R -2 2 2-trifluoro 3- 8- iso ro ox uinolin l - 12 4 triazolo 4 3-a ridine leth l rrolidineamine dihydrochloride: Prepared as described in Example 9B, Step G, substituting tert—butyl 3- (fiuoromethyl)((R)-2,2,2-trifluoro(3 -(8-isopropoxyquinolinyl)-[ 1 ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinylcarbamate. LCMS APCI (+) m/z 503 (M + H).
Example 155 1 .nNHZ / \ J\2HCI / N O Step A: Pre aration of Stereoisomer R of ut l3— fluorometh l R - 2 2 2-trifluoro 3- 8-iso ro ox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l pyrrolidinylcarbamate: The racemic material from Example 154, Step J, was d by Chiral HPLC (OD-H, Chiral Technologies) eluting with 10% EtOH/90% hexanes, to provide the second eluting peak as a single stereoisomer (99% ee), designated (R) by 1H NMR analysis of the Mosher amide.
Step B: Preparation of ]fiuoromethyl[]]R[-2,2,2-trifluoro]3-]8- iso ro ox uinolin l - 12 4 triazolo 4 3-a ridine leth l rrolidineamine WO 54274 dihydrochloride: Prepared as described in Example 9B, Step G, substituting (R)—tert—butyl 3- (fluoromethyl)- l -((R)-2,2,2-trifluoro- l -(3 -(8-isopropoxyquinolinyl)-[ l ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinylcarbamate. LCMS APCI (+) m/z 503 (M + H).
Example 156 F3C," NQ‘NHZ S -l- R -2 2 2-trifluoro-l- 3- 6-fluoro tetrah dro-2H- ran lox uinolin l - l 2 4 triazolo 4 3-a idin l eth l rrolidinamine h oride Prepared as in Example 133, substituting iodoethane in Step A with 4- bromotetrahydro-2H-pyran. LCMS APCI (+) m/z 531 (M+H).
Example 157 F3C/,' NH2 oro uinolinol h oride (S)- l -((R)- l -(3 -(7-(cyclopropylmethoxy)fluoroquinolinyl)- [l,2,4]triazolo [4,3-a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidinamine hydrochloride (Example 134; 50 mg, 0.1 mmol) was heated to 60 CC in 6N HCl in IPA for 3 days. After concentration, the residue was dissolve in 1 mL of MeOH then added to 2N HCl in ether. The resulting solid was dried under high vacuum to yield 2-(6-((R)-l-((S)aminopyrrolidin-lyl )-2,2,2-trifluoroethyl)—[ l ,2,4]triazolo [4,3 -a]pyridin-3 -yl)fluoroquinolinol hydrochloride (39 mg, 87 % yield) as a solid. LCMS APCI (+) m/z 447 (M+H).
Example 158 F304, 6/ ”CIA NH2 N 0% N\/ N N / Prepared as in Example 86, substituting 2-iodo-propane in Step B with (bromomethyl)cyclopropane. LCMS APCI (+) m/z 501 (M+H).
Example 159 ' NQ’NH2 d 2HCI / N O/\/ \ N\ / Step A: Pre aration of R fluoro l-methox ro an lox methylguinoline: To a on of 6-fluoromethquuinolinol (0.50 g, 2.8 mmol) in tetrahydrofuran (2.4 mL, 2.8 mmol) was added triphenylphosphine (2.6 g, 9.9 mmol), ropyl azodicarboxylate (0.91 mg, 4.5 mmol), and (S)-l-methoxypropanol (0.33 mg, 3.7 mmol) and the resultant mixture allowed to stir at t temperature for 24 hours. The reaction mixture was diluted with water (10 mL) and extracted with romethane (2 x 20 mL). The combined organic extracts dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by normal phase chromatography on silica gel (0-2% methanol/dichloromethane) afforded the title compound which was taken on to the subsequent step without fiarther purification, assuming theoretical yield (0.70 g, 100%) was ed, despite being contaminated with residual triphenylphosphine oxide.
Step B: Pre aration of R fluoro l-methox ro an lox uinoline- 2-carbaldehyde: To a solution of (R)fluoro(l-methoxypropanyloxy) methquuinoline (0.70 g, 2.8 mmol) in e (55 mL) and water (0.55 mL) was added selenium dioxide (0.38 g, 3.4 mmol) and the resultant mixture heated at reflux for 2 hours.
The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The e was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-30% ethyl acetate/hexanes) to afford the title compound (0.66 g, 89%).
Step C: Pre aration of ut l -l- R -2 2 uoro-l- 3- 6-fluoro R -l-methox ro an lox uinolin l - l 2 4 triazolo 4 3-a ridin yl[ethyl[pmolidinylcarbamate: A solution of tert—butyl (S)-l-((R)-2,2,2-trifluoro-l-(6- hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate (0.16 g, 0.43 mmol) and (R)fluoro- 8-(1-methoxypropanyloxy)quinolinecarbaldehyde (0.11 g, 0.43 mmol) in ethanol (2.2 mL, 0.43 mmol) was allowed to stir at t temperature for 12 hours. The t was removed under reduced pressure. The residue was dissolved in dichloromethane (2.2 mL) and iodosobenzene diacetate (0.15 g, 0.47 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and ted sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and trated under reduced pressure. The e was purified by reverse phase chromatography on C18 (0-100% acetonitrile/water) to give the title compound (0.12 g, 44%).
Step D: Pre n of R -2 2 2-trifluoro 3- 6-fiuoro R methox ro an lox uinolin l- 12 4 triazolo 4 3-a ridin-6 leth l rrolidin amine dihydrochloride: To a solution of tert—butyl ((R)-2,2,2-trifiuoro(3-(6-fiuoro ((R)methoxypropanyloxy)quinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate (0.12 g, 0.19 mmol) in dichloromethane (0.5 mL) was added hydrochloric acid (5-6M in 2-propanol; 9.5 mL, 0.61 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the solid obtained was suspended in acetonitrile (3 mL) and stirred at ambient temperature for 5 s. The solid formed was collected by vacuum filtration to give the title compound (0.89 g, 79%). LCMS APCI (+) m/Z 519 (M+H). Specific rotation: [(1124]D = 2.440 (c = 0.97, MeOH).
Example 160 {(3NH2 ”1mm Prepared according to the method of Example 149, substituting 6-fiuoro methquuinolinol for 2-methquuinolinol in Step A. LCMS APCI (+) m/Z 519 (M+H). e 161 2HCI / N CF3 N\ / N a ridin leth l rrolidinamine dih drochloride Prepared according to the method of Example 140, Steps B-D, substituting 8- (trifiuoromethyl)quinolinecarbaldehyde for (R)(1-methoxypropanyloxy)quinoline carbaldehyde in Step B. LCMS APCI (+) m/z 481 (M+H).
Example 162 Step A: Pre aration of 3R 4R but l 3-azidoh drox ine-l- carboxylate: A 500 mL round-bottomed flask was charged with utyl 6-oxa azabicyclo[3.1.0]hexanecarboxylate (15.42 g, 83.25 mmol), (1S,2S)-(—)-[1,2- cyclohexanediamino-N,N'—bis(3,5-di-t-butylsalicylidene)]chromium (III) chloride (1.18 g, 1.67 mmol) and azidotrimethylsilane (12.8 mL, 91.58 mmol) and the resulting e was stirred at ambient temperature under a nitrogen atmosphere for 48 hours. The dark red-brown mixture was diluted with chloroform (250 mL) and washed tially with water and brine, dried (MgSO4), filtered and concentrated under d pressure. The residue was dissolved in methanol (830 mL) and treated with potassium carbonate (11.51 g, 83.25 mmol) and the mixture was stirred at ambient temperature for 5 hours. The methanolic solution was filtered through a pad of Celite washed with methanol and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous back extracted with EtOAc. The combined organic extracts were washed with saturated sodium bicarbonate on, water and brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (Biotage 40M; 20% ethyl e/hexanes) to give )-tert—butyl ohydroxypyrrolidinecarboxylate (18 g, 95%). Enantiomeric excess was determined by Chiral HPLC (AD-H, Chiralcel, 10% EtOH: 90% hexanes at 0.80 mL/min, 94.5% e.e.
Step B: Preparation of g3R,4R[azidopyrrolidinol: )-tert—butyl 3- azidohydroxypyrrolidinecarboxylate (3.6 g, 16.0 mmol) was stirred in 10% TFA in dichloromethane (100 mL) for 2 hours. The mixture was concentrated under reduced pressure and the e obtained ved in a 10% MeOH/dichloromethane solution (50 mL) and treated with potassium carbonate (20 g) and the suspension stirred at ambient temperature for 2 hours, then filtered through a pad of Celite and washed with 10% MeOH: dichloromethane. The filtrate was concentrated to afford )azidopyrrolidinol in quantitative yield.
Step C: Pre n of 3R 4R azido R 6-chloro ridin l -2 2 2- trifiuoroethyl[pyrrolidinol: Prepared as described in Example 9B using (S)(6- chloropyridinyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (5.06 g, 14.7 mmol) and (3R,4R)azidopyrrolidinol (2.08 g, 16.2 mmol) in place of (S)-tert—butyl pyrrolidin ylcarbamate in Step D (2.44 g, 52%).
Step D: Pre aration of 5- 1R 3R azidofiuoro rrolidin-l- l -2 2 2- trifiuoroethyl[chloropyridine: To a solution of (3S,4R)azido((R)(6-chloropyridin- 3-yl)-2,2,2-trifluoroethyl)pyrrolidinol (2.4 g, 7.5 mmol) in romethane (30 mL) at -78 0C, was added diethylaminosulfur trifluoride (1.17 mL, 8.95 mmol). The resulting solution was allowed to warm to ambient temperature and stirred overnight. The mixture was concentrated under reduced re and the e was dissolved in ethyl acetate and washed with water and brine, then dried (MgSO4), filtered and concentrated. The crude residue was purified by column chromatography (Biotage, 40M; 10-25% ethyl acetate/hexanes gradient) to afford 5-((1R)-l-((3R)azidofluoropyrrolidinyl)-2,2,2- trifiuoroethyl)chloropyridine (1.02 g, 42%).
Step E: Pre aration of tert—but 1 3R R -l- 6-chloro 3- l -2 2 2- trifluoroethyl[fluorop_yrrolidinylcarbamate: To a solution of 5-((lR)((3R)azido fluoropyrrolidinyl)-2,2,2-trifluoroethyl)chloropyridine (1.0 g, 3.15 mmol) in anhydrous THF (40 mL) was added triphenylphosphine (1.65 g, 6.30 mmol). The resulting mixture was stirred at ambient temperature overnight then concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and 0.5 M sodium hydroxide solution (20 mL).
The mixture was stirred at ambient temperature overnight and then concentrated. The residue was adjusted to pH 3 with aqueous 6N HCl and washed with dichloromethane. The aqueous layer was d with 5N NaOH and the solution extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated.
The crude amine was dissolved in ethyl e (10 mL) and DIEA (1.10 mL, 6.30 mmol) was added. The mixture cooled to 0 0C in an ice bath and BoczO (0.83 g, 3.78 mmol) was added The mixture was allowed to warm to ambient temperature and stirred overnight, then partitioned between water and ethyl acetate. The layers were separated and the organic layer was washed sequentially with aqueous 1N HCl, saturated sodium bicarbonate solution and brine, then dried (MgSO4) filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 25M; 10-20% ethyl acetate/hexanes gradient) to afford tert—butyl (3R)((R)(6-chloropyridinyl)-2,2,2-trifluoroethyl) yrrolidinylcarbamate (0.584 g, 47%).
] Step F: Preparation of tert-butyl ]3R [fluoro]]R[-2,2,2-trifluoro]6- hydrazinylpyridinyl[ethyl[pyrrolidinylcarbamate: Prepared as described in Example 9B, Step E, substituting tert—butyl (3R)((R)(6-chloropyridinyl)-2,2,2-trifluoroethyl)- 4-fiuoropyrrolidinylcarbamate (0.565 g, 98%).
Step G: Pre aration of 3R fiuoro R -2 2 2-trifiuoro 3- 6-fluoro methox n l - 1 2 4 triazolo 4 3-a ridin l eth l inamine dihydrochloride: Prepared as described in Example 9B, Step F, using tert—butyl (3R) fluoro((R)-2,2,2-trifiuoro(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate in place of utyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridinyl)ethyl)pyrrolidin yl)carbamate and substituting 6-fluoromethoxyquinolinecarbaldehyde for 8- yquinolinecarbaldehyde. LCMS APCI (+) m/z 479 (M + H).
Example 163 F3CI,' NH2 N/ H \ N N / 2- 6- R S amino rrolidin l -2 2 2-trifluoroeth l - 1 2 4 triazolo 4 3-a ridin lfluoro nol h drochloride (S)- l -((R)- l -(3 -(8-(cyclopropylmethoxy)fluoroquinolinyl)- [1,2,4]triazolo [4,3-a]pyridinyl)—2,2,2-trifluoroethyl)pyrrolidinamine hydrochloride (Example 158; 200 mg, 0.400 mmol) was stirred in 5-6N HCl (2 mL) in IPA in a sealed tube at 60°C for 14 hours. The reaction mixture was concentrated under d pressure to provide 2-(6-((R)((S)aminopyrrolidinyl)-2,2,2-trifiuoroethyl)-[1,2,4]triazolo[4,3- a]pyridinyl)fluoroquinolinol hydrochloride (128 mg, 71.8 % yield) as a solid. LCMS APCI (+) m/z 447 (M+H). e 164 dQ’2 HCI/ N Prepared as described in Example 114 using (1-(6-fluoromethquuinolin yl)cyclopropyl)methanol in place of (1-(2-methquuinolinyl)cyclopropyl)methanol in Step A. LCMS APCI (+) m/z 501(M+H).
Example 165 F39. 9’NH2 / \ 2HCI / N N. / N N \ | O\ Prepared as described in Example 112 using methyl 2-(6-fluoro methquuinolinyl)acetate in place of methyl 2-(2-methquuinolinyl)acetate in Step A.
LCMS APCI (+) m/z 515(M+H). e 166 F39- N3NH2 d 2HCI / N F N‘N/ N\ O\ Step A: Pre n of tert—butl 3-bromofluoro hen lcarbamate: A solution of 3-bromofluorobenzoic acid (6.86 g, 31.32 mm 1), triethylamine (5.24 mL, 37.59 mmol) and DPPA (7.45 mL, 34.46 mmol) in t—BuOH (30 mL) was stirred at reflux for hours. After cooling to t temperature, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with brine, dried (sodium sulfate), d and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate) to give tert—butyl 3-bromo fluorophenylcarbamate (6.0 g, 66.0%) as an oil.
Step B: ation of 7-bromofluoromethylguinoline: A solution of tert—butyl 3-bromofluorophenylcarbamate (6.0 g, 20.7 mmol) in 4N HCl (30 mL) in dioxane was d at ambient ature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in 6 N HCl (100 mL) and (E)—butenal (2.96 ml, 36.2 mmol) was added dropwise at 106 °C. The reaction was stirred at 106 °C for 2 hours. After cooling to ambient temperature, the reaction mixture was basifled with ammonium hydroxide to about pH 12, extracted with DCM (2 x 100 mL), dried (sodium sulfate), filtered and concentrated under reduced re. The residue was ed by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 7-bromofluoro methquuinoline (2.99 g, 60.2%) as a solid.
Step C: Pre aration of S -l- R -2 2 2-trifluoro-l- 3- 8-fluoro 2- methox eth l uinolin l- 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine dihydrochloride: Prepared as described in Example 105 using ofluoro methquuinoline in place of 8-bromomethquuinoline in Step A. LCMS APCI (+) m/z 489(M+H).
Example 167 “3’NH2 / \ 2HC| / N F N / N o\ a 6- leth l rrolidinamine dih drochloride ] Step A: Pre aration of 2-fluoromethox benzoic acid: A suspension of 2- fluorohydroxybenzoic acid (12.0 g, 76.9 mmol) and potassium carbonate (23.4 g, 169 mmol) in acetone (154 mL) was stirred at ambient temperature for 1 hour. To the mixture was added dimethyl sulfate (21.8 mL, 231 mmol) and the mixture stirred at ambient temperature for 30 minutes then heated at reflux for 4 hours. The e was cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue was dissolved in anhydrous THF (154 mL) and the solution cooled to 0 CC in an ice bath. To this solution was added LiOH-HZO (12.9 g, 307 mmol) followed by water (30 mL) and the resulting mixture stirred at ambient temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue partitioned between water and ethyl acetate and the layers separated. The aqueous layer was acidified with 1N HCl solution and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgSO4), filtered and trated under reduced pressure to afford 2-fluoromethoxybenzoic acid (12.31 g, 94%).
Step B: ation of tert—butyl 2-fluoromethoxyphenylcarbamate: A solution of 2-fluoromethoxybenzoic acid (2.50 g, 14.69 mmol) and DIEA (3.07 mL, 17.63 mmol) in a mixture of toluene (12 mL) and t—BuOH (12 mL) was stirred over 4A molecular sieves (3 g) for 1 hour at ambient temperature, followed by addition of diphenyl phosphoryl azide (3.9 mL, 17.63 mmol) and the e heated at reflux for 18 hours. The cooled reaction mixture was filtered and the filtrate concentrated under reduced pressure. The e was dissolved in ethyl acetate (50 mL) and washed with 1N HCl on, saturated sodium bicarbonate on, water and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; 2.5% ethyl acetate/hexanes) to afford tert—butyl 2-fluoromethoxyphenylcarbamate (2.27 g, ld).
Step C: Preparation of 8-fluoromethoxymethylguinoline: A solution of utyl 2-fluoromethoxyphenylcarbamate (2.27 g, 9.41 mmol) in methanol (5 mL) was treated with 4N HCl in 1,4-dioxane (30 mL) for 2 hours. The solvent was removed under reduced pressure and the residue stirred in aqueous 6N HCl (20 mL) at 106 0C. A solution of crotonaldehyde (1.56 mL, 18.8 mmol) in n-BuOH (2 mL) was added se from an addition filnnel over 20 minutes and the resulting mixture was heated at reflux for an additional 2 hours. The on was cooled to ambient ature and the mixture carefully pH ed to 9 with ammonium hydroxide. The mixture was extracted with dichloromethane and the combined dichloromethane extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes) to afford omethoxy methquuinoline (1.20 g, 6.28 mmol, 67%).
Step D: Preparation of 8-fluoromethoxyguinolinecarbaldehyde: Prepared as described in Example 37, Step B, using 8-fiuoromethoxymethquuinoline (0.60 g, 3.14 mmol) in place of 8-ethylmethquuinoline (0.43 g, 79%).
WO 54274 2012/026572 Step E: Pre aration of R -2 2 2-trifluoro 3- 8-fluoro methox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine ochloride: Prepared as described in Example 9B using tert—butyl (S)-l-((R)-2,2,2- trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate and substituting 8- fluoromethoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 461 (M + H).
Example 168 (\fg2HC|/ N N F l eth l inamine dih oride Prepared as described in Example 9B using 8-fluoroquinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 431(M+H).
Example 169 F39, S’F 2 HCI / ow N/ N O \ / N N \ fluorometh l R -2 2 2-trifluoro 3- 8-methox uinolin l - 1 2 4 triazolo 4 3- a ridin leth l inamine Step A: Pre aration of tert—but l 3- fluorometh l -l- R -2 2 uoro-l- 3- 8-methox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidin lcarbamate: Prepared as described in Example 9B using tert—butyl 3-(fluoromethyl)-l-((R)-2,2,2-trifluoro- 1-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate (Example 154; 0.20 g, 0.491 mmol) in place of tert—butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin yl)ethyl)pyrrolidineylcarbamate and 8-methoxyquinolinecarbaldehyde (0.092 g, 0.491 mmol) in Step E (0.229 g, 81 %). LCMS APCI (+) m/z 575 (M + H).
Step B: Isolation of Stereoisomer of ut l 3- fluorometh l-l- R - 2 2 2-trifluoro 3- 8-methox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l pyrrolidinylcarbamate: The racemic material from Step A was purified by Chiral HPLC (IC, Chiral Technologies) 20% EtOH: 80% hexanes, to provide the first eluting peak as a single stereoisomer (99% e.e.), designated (S) by Proton NMR analysis of the Mosher amide.
Step C: Pre aration of fluorometh l R -2 2 2-trifluoro 3- 8- methox uinolin l- 12 4 triazolo 4 3-a ridin l eth l rrolidinamine: Prepared as described in Example 9B, Steps F and G, using (S)-tert—butyl 3-(fluoromethyl)((R)- 2,2,2-trifluoro(3 thoxyquinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate in Step F. LCMS APCI (+) m/z 475 (M + H).
Example 170 F39. F 2HCI N "’NH2 / N R 3- fluorometh l R -2 2 2-trifluoro 3- 8-methox uinolin l - 1 2 4 triazolo 4 3- a ridin leth l rrolidinamine Step A: Isolation of Stereoisomer R of tert—but l 3- fluorometh l R - 2 2 2-trifluoro 3- 8-methox uinolin l - 1 2 4 triazolo 4 3-a ridin yl[pmolidinylcarbamate: The c material from Example 169 was purified by Chiral HPLC l Technologies) IC 20% EtOH: 80% hexanes, to provide the second eluting peak as a single stereoisomer (99% ee), designated (R) by Proton NMR analysis of the Mosher amide.
] Step B: Preparation of [R2gfluoromethyl]—1-][R[-2,2,2-trifluoro]3-]8- methox n l- 12 4 triazolo 4 3-a ridin l eth l rrolidinamine: Prepared as described in Example 9B, Steps F and G, substituting (R)-tert—butyl 3-(fluoromethyl) ((R)-2,2,2-trifluoro(3 -(8-methoxyquinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate. LCMS APCI (+) m/z 475 (M + H).
Example 171 Step A: Pre aration of 8-fluorometh l l-meth l-1H- razol ylzguinoline: A solution of 7-bromofluoromethquuinoline (0.15 g, 0.63 mmol), 1- methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (0.26 g, 1.25 mmol), PdC12(dppf)*dcm (0.051 g, 0.063 mmol), CsF (0.247 g, 1.62 mmol) and triethylamine (0.13 mL, 0.94 mmol) in IPA (3 mL) was heated at 100 °C in a sealed tube for 6 hours. After cooling to t temperature, water (10 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine, dried m sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ethyl acetate) to give omethyl(1-methyl-1H-pyrazolyl)quinoline (0.132 g, 87.6%) as a solid.
Step B: Pre aration of S R -2 22-trifluoro 3- 8-fluoro 1-meth l- 1H- razol l uinolin l - 1 2 4 lo 4 3-a ridin-6 l eth l rrolidinamine tri-hydrochloride: Prepared as described in Example 37, Steps B-C, using 8-fluoromethyl- 7-(1-methyl-1H-pyrazolyl)quinoline in place of lmethquuinoline in Step B.
LCMS APCI (+) m/z 511(M+H).
Example 172 F301 UNH2 a 2HCI / N F N\/ N 2 2 2-trifluoroeth l rrolidinamine dih drochloride Step A: Pre aration of 7-c clo ro orometh l uinoline: A solution of 7-bromofluoromethquuinoline (0.15 g, 0.63 mmol), Pd(PPh3)4 (0.072 g, 0.063 mmol) and 0.5 M cyclopropylzinc(II) bromide (2.50 ml, 1.25 mmol) in THF was stirred at reflux for 12 hours. After cooling to ambient temperature, ethyl acetate (20 mL) and water (5 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel e/ethyl acetate 2:1) to give 7-cyclopropylfluoro methquuinoline (0.10 g, 80.3%) as a solid.
Step B: Pre aration of S 1 2 4 triazolo 4 3-a idin l -2 2 2-trifluoroeth l rrolidinamine dih drochloride: Prepared as described in Example 37, Steps B-C, using 7-cyclopropylfluoro methquuinoline in place of 8-ethylmethquuinoline in Step B. LCMS APCI (+) m/z 471(M+H).
Example 173 / NQ,NH2 3HCI / / N N\ N\ / I N /N S -l- R -2 2 2-trifluoro-l- 3- 6-fluoro l-meth l-lH- razol l u1nolin l - l 2 4 triazolo 4 3-a r1d1n l eth l rrolid1nam1ne tr1-h drochlor1de Prepared as described in Example 171, using 7-bromofluoro methquuinoline in place of 7-bromofluoromethquuinoline in Step A. LCMS APCI (+) m/z 5 l 1(M+H).
Example 174 l -2 2 2-trifluoroeth l rrolidinamine h drochloride Step A: Pre n of 8-chlorometh l uinolinol: 2-Methquuinolinol (200 mg, 1.26 mmol) was added to a solution of l-chloropyrrolidine-2,5-dione (168 mg, 1.26 mmol) and zirconium(IV) chloride (14.6 mg, 0.0628 mmol) in DCM (10 mL) and the reaction was stirred at ambient temperature for 24 hours. The reaction was diluted with chloroform (30 mL) and washed with an aqueous sodium carbonate solution followed by brine. After drying (MgSO4), the on was filtered and concentrated under reduced pressure and the residue was ed by reverse phase chromatography (SP4, 25 M, g with a gradient of water/ACN 90:10 to 0:100, 30 column s) to yield 8-chloro uinolinol (134 mg, 55.1 % yield) as a thick oil.
Step B: Preparation of 8-chloro12-methoxyethoxy1methylguinoline: 8- chloromethquuinolinol (80 mg, 0.41 mmol), potassium carbonate (171 mg, 1.2 mmol) and l-bromomethoxyethane (115 mg, 0.83 mmol) in acetone (10 mL) were d at 70 °C in a sealed tube for 20 hours. After dilution with water (50 mL) the reaction was extracted with DCM. The DCM phases were concentrated under reduced pressure and the residue purified by e phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 8-chloro(2-methoxyethoxy) methquuinoline as a solid.
Step C: Pre aration of S R 3- 8-chloro 2-methox ethox uinolin l - 1 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidinamine hydrochloride: Prepared following Steps B-E of Example 117, substituting 2,8- dimethquuinolinol with 8-chloro(2-methoxyethoxy)methquuinoline in Step B.
LCMS APCI (+) m/z 521 (M+H).
Example 175 F3C/,' orNH2 dN/ CI N ,N/ /N| o\ S R 3- 8-chloromethox uinolin l - 1 2 4 triazolo 4 3-a ridin l -2 2 2- trifluoroeth l inamine h drochloride ed as in Example 174, substituting 1-bromomethoxyethane in Step B with iodomethane. LCMS APCI (+) m/z 477 (M+H).
Example 176 F30: . NQ’NH2 / \ 2HC| / N N\ / N 2 2 2-trifluoroeth l rrolidinamine dih drochloride Prepared as bed in Example 172, using 7-bromofluoro methquuinoline in place of ofluoromethquuinoline in Step A. LCMS APCI (+) m/z 471(M+H).
Example 177 F301 dNgNHZ2HC|/ N N\N/ N\ 2 2 2-trifluoroeth l rrolidinamine dih drochloride Prepared as described in Example 172, using 8-bromofluoro methquuinoline in place of 7-bromofluoromethquuinoline in Step A. LCMS APCI (+) m/z 471(M+H).
Example 178 “3’NH2 / 2HC| N/ N F R 3- 6 8-difluoromethox uinolin l - 1 2 4 triazolo 4 3-a r1d1n 1- 2 2 2-trifluoroeth l rrolidinamine dih drochloride Step A: Pre n of 6 8-difluoromethox uinolinecarbaldeh de: Prepared as described in Example 167, Steps A-D, using 2,4-difluoromethoxybenzoic acid (5.0 g, 26.58 mmol) in place of omethoxybenzoic acid in Step B (0.942 g, 65%).
] Pre aration of S R 3- 6 8-difluoromethox n l - 1 2 4 triazolo 4 3-a idin-6I _. IL) N ’F’5:?H.mso"9o ("DH:r _. rrolidinamine dih drochloride: Prepared as described in Example 9B, Steps F and G, using tert-butyl (S)((R)-2,2,2- trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate and fluoro methoxyquinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F.
LCMS APCI (+) m/z 479 (M + H).
Example 179 F39.
NO’NH2 / \ 2HC| N/ N F N N\ O\/\O/ ] Step A: Pre aration of 8-fluoromethox meth l uinoline: Prepared as described in Example 167, Steps A-C (1.20 g, 67%).
Step B: Preparation of 8-fluoromethylguinolinol: A solution of 8- fluoromethoxymethquuinoline (0.57 g, 2.96 mmol) was stirred in dichloromethane (5 mL) and treated with a 1M solution of BBr3 in dichloromethane (15 mL). The resulting mixture was heated at reflux for 16 hours, then poured into crushed ice and d with a 6N NaOH solution to pH 14. The organic layer was separated and the aqueous layer was further extracted with dichloromethane. The organic layer was pH ed to 6 with aqueous 6N HCl and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to afford o methquuinolinol in quantitative yield.
Step C: Preparation of 8-fluorog2-methoxyethoxy[methylguinoline: To a mixture of omethquuinolinol (0.30 g, 1.69 mmol) and potassium carbonate (0.70 mg, 5.08 mmol) in acetone (7 mL) was added 1-bromomethoxyethane (0.47 g, 3.39 mmol) and the mixture heated at 70 0C for 18 hours. Additional bromomethoxyethane (0.150 mL) and potassium carbonate (0.35 g) were added and heating was continued for 16 hours. The mixture was partitioned between water and ethyl acetate and the layers were separated. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 25M; 25% ethyl acetate: s) to afford 8-fluoro(2-methoxyethoxy)methquuinoline (0.217 g, 54 %).
Step D: Pre aration of 8-fluoro 2-methox ethox uinoline carbaldehyde: Prepared as bed in Example 37, tuting 8-fluoro(2- methoxyethoxy)methquuinoline (0.216 g, 0.918 mmol) in Step B (0.20 g, 87%).
Step E: Pre n of R -2 2 2-trifluoro 3- 8-fluoro 2- methox ethox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine ochloride: ed as described in Example 9B, Steps F and G, using tert-butyl (S) ((R)-2,2,2-trifluoro(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate and 8-fluoro- 7-(2-methoxyethoxy)quinolinecarbaldehyde in place of 8-methoxyquinoline carbaldehyde in Step F. LCMS APCI (+) m/z 505 (M + H).
Example 180 Step A: Pre aration of R fluoro1-methox ro an lox methylguinoline: Prepared as described in Example 140, Step A, using 8-fiuoro WO 54274 methquuinolinol (0.30 g, 1.69 mmol) in place of 2-methquuinolinol and using (S) ypropanol (0.196 g, 46%).
Step B: Preparation of ]R[fluoro]1-methox1propanyloxy[guinoline- aldehyde: Prepared as described in Example 37, Step B, using (R)fluoro(1- methoxypropanyloxy)methquuinoline (0.195 g, 0.782 mmol) to provide 0.141 g (69%) of the desired product.
Step C: Pre n of R -2 2 2-trifluoro 3- 8-fluoro R methox ro an lox uinolin l- 12 4 triazolo 4 3-a ridin-6 leth l rrolidin amine dihydrochloride: Prepared as described in Example 9B, Steps F and G, using tert-butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate and (R)fluoro(1-methoxypropanyloxy)quinolinecarbaldehyde in Step F. LCMS (APCI) (+) m/z 519 (M + H).
Example 181 " Nd 2HCI / \ N, / N N \ Prepared as described in Example 9B, Steps E-G, using tert—butyl (3R,4R)—1- ((R)— 1 -(6-chloropyridin-3 -yl)-2,2,2-trifluoroethyl)hydroxypyrrolidinylcarbamate in place of tert—butyl ((R)(6-chloropyridin-3 -yl)-2,2,2-trifluoroethyl)pyrrolidin-3 - ylcarbamate in Step E, and substituting 6-fluorocyclopropquuinolinecarbaldehyde for 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 487(M+H).
Example 182 1. NQ’NH2 / \ 2HCI / N CI N\ / N l eth l rrolidinamine dih drochloride Prepared as described in Example 9B, Steps F and G, using 8-chloroquinoline- aldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 447(M+H). e 183 dgN 2 HCI / N l eth l rrolidinamine dih drochloride ] Step A: Pre aration of 2 th l uinoline: Prepared as described in Example 37, Step A, using o-toluidine (8.0 g, 74.7 mmol) in place of 2-ethylaniline (5.72 g, 49%).
] Step B: Preparation of 8-methylguinolinecarbaldehyde: Prepared as described in Example 37, Step B, using 2,8-dimethquuinoline (5.72 g, 36.4 mmol) in place of 8-ethylmethquuin0linepyrrolidinylcarbamate in Step B (5.47 g, 88%).
] Step C: Pre aration of -l- R -2 2 2-trifluoro-l- 3- 8-meth l uinolin l - l 2 4 triazolo 4 3-a idin l eth l rrolidinamine dih drochloride: Prepared as described in Example 9B, Steps F and G, using 8-methquuinolinecarbaldehyde and tert- butyl (S)- l -((R)-2,2,2-triflu0r0- l -(6-hydrazinylpyridin-3 -yl)ethyl) pyrrolidine-3 -ylcarbamate.
APCI (+) m/z 427 (M + H).
Example 184 F3Q— NQ’NH2 / \ 2HCI N/ N \N/ N\ 6- leth l rrolidinamine dih drochloride Step A: Pre aration of 6-fluoro-2 8-dimeth l uinoline: Prepared as described in Example 37, Step A, using 4-flu0r0-2,methylaniline in place of 2-ethylaniline, to afford 6- fluor0-2,8-dimethquuinoline (21 g, 98%).
Step B: Preparation of 6-fluoromethylguinolinecarbaldehyde: Prepared as bed in Example 37, Step B, using 6-fluoro-2,8-dimethquuinoline (5.62 g, 32.1 mmol) in place of lmethquuinoline (3.08 g, 51%).
Step C: Pre aration of R -2 2 2-trifiuoro 3- 6-fiuoro meth l uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidinamine dihydrochloride: Prepared as bed in Example 9B, Steps F and G, using tert-butyl (S) ((R)-2,2,2-trifluoro(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate and using 6- fluoromethquuinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 445 (M + H).
Example 185 F3Q— ’ “3’NH2 /\ 2HCI N/ N \N/ N\ Step A: Pre aration of 1- methox meth l nitrobenzene: To a solution of (2-nitrophenyl)methanol (5.13 g, 33.50 mmol) in DCM (75 mL) was added 3.35 N NaOH (75 mL, 251.2 mmol) in water at ambient temperature and stirred at ambient temperature for 10 minutes. Me2S04 (6.38 ml, 67.0 mmol) and tetrabutylammonium hydrogen sulfate (0.57 g, 1.68 mmol) were added and the mixture stirred vigorously for 20 hours at ambient temperature. The reaction mixture was d with DCM (100 mL) and organic layer was separated, washed with brine, dried m sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give hoxymethyl)nitrobenzene (5.12 g, 91.4%) as an oil.
Step B: Preparation of 2-[methoxymethyl[aniline: A solution of 1- (methoxymethyl)nitrobenzene (4.30 g, 25.7 mmol) and PtOz (0.29 g, 1.29 mmol) in MeOH (30 mL) was charged with 1 atmosphere en and stirred at ambient ature for 1 hour. Charcoal (5 g) was added and the reaction mixture was stirred for 10 minutes. The solid was removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure to give 2-(methoxymethyl)aniline (3.42 g, 96.9%) as a solid.
Step C: ation of 8-]methoxymethyl [methylguinoline: Prepared as described in Example 37, Step A, using 2-(methoxymethyl)aniline in place of 2-ethylaniline.
] Step C: Pre aration of S -l- R -2 2 2-trifiuoro-l- 3- 8- methox meth l uinolin l - l 2 4 triazolo 4 3-a ridin l eth l inamine ochloride: ed as described in Example 37, Steps B-C, using 8-(methoxymethyl)- 2-methquuinoline in place of 8-ethylmethquuinoline in Step B. LCMS APCI (+) m/z 457(M+H).
Example 186 Whig;' NH2 2HC| /%OH a ridin l uinolin lox ro an-l-ol dih drochloride Step A: Pre aration of -l- tert—but ldimeth lsil lox ro anol: A solution of (S)-propane-l,2-diol (1.9 mL, 26 mmol), tert-butyldimethylsilyl chloride (4.87 g, 32 mmol), and imidazole (4.5 g, 66 mmol) in anhydrous dimethylformamide (6.6 mL, 26 mmol) was allowed to stir at ambient temperature for 12 hours. The reaction mixture was poured into ethyl acetate (50 mL) and washed sequentially with saturated aqueous sodium bicarbonate (30 mL) and water (30 mL). The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (5.2 g, 104%) which was used without filrther purification.
Step B: Pre n of R l- tert—but ldimeth lsil lox ro an lox 2-methylguinoline: To a on of 2-methquuinolinol (0.40 g, 2.5 mmol) in tetrahydrofuran (2.1 mL, 2.5 mmol) was added triphenylphosphine (1.6 g, 6.3 mmol), diethyl azodicarboxylate (0.63 mL, 4.0 mmol), and (S)-l-(tert—butyldimethylsilyloxy)propanol (0.62 g, 3.3 mmol). The resultant mixture was allowed to stir at ambient ature for 24 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2 x 20 mL). The combined organic extracts were dried over magnesium e and concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel % ethyl acetate/hexanes) to provide the title compound (0.33 g, 40%).
Step C: Pre n of R l- tert—but ldimeth lsil lox ro an yloxy[guinolinecarbaldehyde: To a solution of (R)(l-(tert—butyldimethylsilyloxy) propanyloxy)methquuinoline (0.33 g, 1.0 mmol) in dioxane (40 mL) and water (0.4 mL) was added selenium dioxide (0.13 g, 1.2 mmol) and the ant mixture heated at reflux for 1 hour. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (10% ethyl acetate/hexanes) providing the title compound (0.29 g, 84%).
Step D: Pre aration of tert—but l R 3- 8- R tert- but ldimeth lsil lox ro an lox n l- 124triazolo 4 3-a ridin l- 2,2,2-trifluoroethyl[pyrrolidinylcarbamate: A solution of tert—butyl (S)((R)-2,2,2- trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate (Example 9B, Steps A- E; 0.32 g, 0.84 mmol) and (1-(tert—butyldimethylsilyloxy)propanyloxy)quinoline carbaldehyde (0.29 g, 0.84 mmol) in ethanol (4.2 mL, 0.84 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (4.2 mL) and iodosobenzene diacetate (0.30 g, 0.92 mmol) was added. The on mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under d pressure. The residue was purified by reverse phase chromatography on C18 (0- 100% acetonitrile/water) to give the title nd (0.29 g, 49%).
Step E: Pre aration of R 2- 6- R amino rrolidin-l- l -2 2 2- trifluoroeth l- 12 4 triazolo 4 3-a ridin l uinolin lox ro anol dih dro- chloride: To a solution of tert—butyl (S)((R)(3-(8-((R)(tert- butyldimethylsilyloxy)propanyloxy)quinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridinyl)— 2,2,2-trifluoroethyl)pyrrolidinylcarbamate (0.29 g, 0.41 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (2 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was d by reverse phase tography on C18 (0-80% acetonitrile/water). The al ed after purification was dissolved in methanol (0.5 mL) and added dropwise to hydrochloric acid (2M in l ether; 5 mL). The resulting salt was collected by vacuum filtration to provide the title nd (0.17 g, 73%). LCMS APCI (+) m/z 487 (M+H).
Example 187 ‘ “3’NH2 / 2HC| / N N. / W 2- 6- R amino rrolidin-l- l -2 2 2-trifiuoroeth l - 1 2 4 triazolo 4 3- a |pyridinyl [guinolinyloxy [propanol dihydrochloride Step A: Preparation of [é[]2-methylguinolinyloxy[propanol: A mixture of 2-methquuinolinol (0.50 g, 3.1 mmol), cesium carbonate (3.1 g, 9.4 mmol), and S—(-)-propylene oxide (0.66 mL, 9.4 mmol) in dimethylformamide (3.7 mL, 3.1 mmol) was vigorously stirred at 80 0C for 12 hours. The cooled reaction mixture was diluted with water (30 mL) and d at ambient temperature for 30 minutes. The solids which formed were collected by vacuum filtration providing the title compound (0.36 g, 53%) which was used without filrther purification.
Step B: Pre aration of 2-h drox ro ox uinolinecarbaldeh de: To a on of (S)(2-methquuinolinyloxy)propanol (0.15 g, 0.69 mmol) in dioxane (10 mL) and water (0.1 mL) was added um dioxide (0.092 g, 0.83 mmol) and the resultant e heated at reflux for 2.5 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane, and the filtrate was concentrated under d pressure. The residue was purified by normal phase chromatography on silica gel (20-40% ethyl acetate/hexanes) providing the title compound (0.091 g, 57%).
Step C: Pre aration of tert—but l R trifiuoro 3- 8- h drox ro ox uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidin ylcarbamate: A solution of tert—butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin yl)ethyl)pyrrolidinylcarbamate (0. 1 6 g, 0.3 9 mmol) and (S)(2- hydroxypropoxy)quinolinecarbaldehyde (0.91 g, 0.39 mmol) in l (2.0 mL, 0.39 mmol) was d to stir at t temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (2.0 mL) and iodosobenzene diacetate (0.14 g, 0.43 mmol) was added. The on mixture was stirred at t temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium e, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (0-100% acetonitrile/water) to give the title compound (0.11 g, 49%).
Step D: Pre aration of trifluoroeth l- 12 4 triazolo 4 3-a ridin l uinolin lox ro anol dih dro- chloride: A solution of utyl (S)((R)-2,2,2-trifluoro(3-(8-((S)hydroxypropoxy) quinolinyl)-[1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate (0.11 g, 0.19 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (2 mL) was stirred at ambient temperature for 30 minutes. The reaction e was concentrated under reduced pressure.
The residue was by reverse phase chromatography on C18 (0-80% acetonitrile/water). The material isolated after purification was dissolved in methanol (0.5 mL) and added dropwise to hydrochloric acid (2M in diethyl ether; 5 mL). The ing salt was collected by vacuum filtration to provide the title compound (0.026 g, 25%). LCMS APCI (+) m/z 487 (M+H).
Example 188 F3C 0H "'N "’NH2 / \ J\ / N N/ N\ 2 HCI R amino R -2 2 2-trifluoro 3- 8-iso ro ox uinolin l - 1 2 4 triazolo 4 3- a ridin leth l rrolidin lmethanol dih drochloride ] Step A: Pre aration of S -meth l 3- benz lox carbon lox tert- butoxycarbonylamino[propanoate: A solution of N—(tert-butoxycarbonyl)-L-serine methyl ester (25.0 g, 114 mmol) in DCM (570 mL) was cooled to -50 0C. Pyridine (23.0 mL, 285 mmol) was added. CBZ-Cl (18.9 mL, 125 mmol) was added dropwise over 1 hour. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was then diluted with DCM, washed with 10% citric acid and brine, dried and concentrated under reduced pressure. The residue was d by flash tography on silica gel (5:1 hexanes/EtOAc) to give (S)-methyl 3-(benzyloxycarbonyloxy)(tert- butoxycarbonylamino)propanoate (36.0 g, 89%).
Step B: Preparation of methyl 2-1tert-butoxycarbonylamino[acglate: A mixture of (S)-methyl 3-(benzyloxycarbonyloxy)(tert-butoxycarbonylamino)propanoate (36.0 g, 102 mmol), K2C03 (28.2 g, 204 mmol) and DMF (204 mL) was heated at 65 0C for 1 hour. After cooling, the reaction mixture was ioned n ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and trated under reduced pressure. The residue was purified by flash tography on silica gel (10:1 hexanes/EtOAc) to give methyl 2-(tert— butoxycarbonylamino)acrylate (16.5 g, 81%) as a colorless oil, which was used directly in the next step.
Step C: Preparation of methyl l-benzylgtert-butoxycarbonylamino1 pyrrolidinecarboxylate: To a solution of methyl 2-(tert-butoxycarbonylamino)acrylate (16.5 g, 82.0 mmol) and N—(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (19.5 g, 82.0 mmol) in DCM (400 mL) was added dropwise TFA (0.32 mL) at 0 0C under nitrogen.
The on mixture was allowed to warm to t temperature and stirred ght. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHC03 and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3% MeOH in DCM) to give methyl yl(tert- butoxycarbonylamino)pyrrolidinecarboxylate (21.7 g, 79%).
] Step D: Pre aration of tert-but l 1-benz 1 h drox meth l rrolidin amate: To a solution of methyl 1-benzyl(tert-butoxycarbonylamino)pyrrolidine carboxylate (21.7 g, 64.9 mmol) in THF (320 mL) was added dropwise a on of LiAlH4 in THF (1.0 M, 55.2 mL, 55.2 mmol) at -78 0C under nitrogen. The reaction mixture was warmed to 0 0C for 5 minutes and then quenched by dropwise addition of water (2.1 mL) followed by 15% NaOH (2.1 mL) and water (6.3 mL). The on mixture was stirred at ambient temperature for 15 minutes and then filtered through Celite®. The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel (4% MeOH in DCM) to give tert-butyl 1-benzyl(hydroxymethyl)pyrrolidinylcarbamate (11.2 g, 56%) as a colorless oil.
Step E: Isolation of R -tert-but l 1-benz l h drox meth l rrolidin ylcarbamate: The omerically pure (R)-tert-butyl 1 -benzyl-3 - (hydroxymethyl)pyrrolidinylcarbamate (3.95 g) was separated from racemic tert-butyl 1- benzyl(hydroxymethyl)pyrrolidinylcarbamate (11.0 g, 35.9 mmol) by chiral SFC (for analysis: Rt of the (R) enantiomer = 4.22 min; Rt of the (S) enantiomer = 6.45 min; Chiralpak AD-H 4.6mm x 150 mm, 85/15 heptane/EtOH (with 0.2% DEA) at 1.5 mL/min. For preparative SFC: AD-H 21 mm x 250 mm, 8% EtOH with 0.1% DEA at 65 mL/min).
Step F: Pre aration of R -tert-but l 3- h drox meth l rrolidin ylcarbamate: A mixture of (R)-tert-butyl 1-benzyl(hydroxymethyl)pyrrolidin ylcarbamate (387 mg, 1.26 mmol), 10% Pd/C (134 mg, 0.126 mmol), ammonium formate (398 mg, 6.32 mmol) and MeOH (10 mL) was heated at reflux under nitrogen for 3 hours.
After g, the reaction mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was taken up in DCM and filtered through Celite again. Removal of the solvent gave (R)-tert-butyl 3-(hydroxymethyl)pyrrolidin ylcarbamate (260 mg, 95%), which was used in the next Step t filrther purification.
Step G: Pre aration of R amino R -2 2 2-trifluoro 3- 8-iso ro ox uino- lin l - 1 2 4 triazolo 4 3-a 6 leth l rrolidin lmethanol dih drochloride: Prepared as described in Example 9B, Steps D-G, using (R)-tert-butyl 3-(hydroxymethyl) pyrrolidinylcarbamate in place of (S)-tert—butyl pyrrolidinylcarbamate in Step D, and substituting ropoxyquinolinecarbaldehyde for 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 501 (M+H).
Example 189 F3C 0“ "IN ”INHZ N/ N \ / 2 HCI N |N\ R amino R 3- 8-tert-but l uinolin l - 1 2 4 triazolo 4 3-a ridin l -2 2 2- trifiuoroeth l rrolidin lmethanol dih oride Prepared as described in Example 9B, Steps D-G, using (R)-tert-butyl 3- xymethyl)pyrrolidinylcarbamate in place of (S)-tert—butyl pyrrolidinylcarbamate in Step D, and substituting 8-tert-butquuinolinecarbaldehyde for 8-methoxyquinoline carbaldehyde in Step F. LCMS APCI (+) m/z 499 (M+H).
Example 190 6N3,NH22HCI/ N N N/ N\ N //3\ Step A: Pre aration of 7-bromo-2 8-dimeth l uinoline: Prepared as described in e 37, Step A, using 3-Bromomethylaniline (8.49 g, 45.6 mmol) in place of laniline (5.94 g, 55%).
Step B: Pre aration of 2 8-dimeth l 4-meth l-1H- razol-l- l uinoline: A mixture of 7-Bromo-2,8-methylaniline (2.00 g, 8.47 mmol), 4-methyl-1H-pyrazole (1.04 g, 1.02 mL, 12.71 mmol), C82C03 (5.52 g, 16.94 mmol) and CuO (0.067 g, 0.847 mmol) and Fe(acac)3 (0.90 g, 2.54 mmol) in anhydrous DMF (10 mL) was stirred at 116 0C in an oil bath for 24 hours. The mixture was cooled to ambient temperature and ioned between water (50 mL) and EtOAc (150 mL). The solids were removed by filtration and the layers were separated. The organic layer was washed with brine and dried (MgSO4), filtered and concentrated under reduced pressure. The residue was d by column chromatography (Biotage 40M; 7% ethyl acetate/hexanes) to afford 2,8-dimethyl(4-methyl-1H-pyrazol yl)quinoline (1.96 g, 97%).
Step C: Pre aration of 8-meth l 4-meth l-1H- razol-l- l uinoline carbaldehyde: Prepared as described in Example 37, Step B, using 2,8-dimethyl(4-methyl- azolyl)quinoline (1.96 g, 8.26 mmol) in place of 8-ethylmethquuinoline (1.79 g, 86%).
Step D: Pre n of 1H- razol-l- l uinolin l - 1 2 4 triazolo 4 3-a ridin-6I ('DH{27‘ ..Q.,_..P L.” a:EB('9 Prepared as bed in Example 9B, Step F, using tert—butyl (S)((R)-2,2,2-trifluoro(6- hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate and substituting 8-methyl(4- methyl- 1 H-pyrazolyl)quinolinecarbaldehyde for 8-methoxyquinolinecarbaldehyde.
LCMS APCI (+) m/z 507 (M + H). e 191 F30”: NQ’NH2 d 2 HCI/ N\/W‘N N \ R -2 2 2-trifiuoro 3- 8-meth l 1-meth l-1H- razol l uinolin l - Step A: Pre aration of 2 8-dimeth l 4-meth l-1H- razol-l- l ne: In a sealed tube a mixture of 7-bromo-2,8-dimethquuinoline (0.60 g, 2.54 mmol), 1-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (1.06 g, 5.08 mmol), PdC12(dppf)*dcm (0.208 g, 0.254 mmol), CsF (1.00 g, 6.61 mmol) and ylamine (0.531 mL, 3.81 mmol) in isopropyl alcohol (17 mL) was heated at 100 0C on an oil bath for 6 hours.
The mixture was cooled to ambient temperature and partitioned between water (25 mL) and ethyl acetate (50 mL). The solids were removed by filtration through a pad of Celite and washed with additional ethyl acetate. The layers were separated and the organic layer washed with brine and dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography ge 25M; 25% ethyl acetate/hexane) to afford 2,8-dimethyl(4-methyl-1H-pyrazolyl)quinoline (0.60 g, 91%).
Step B: Pre aration of 8-meth l 4-meth l-1H- razol-l- l uinoline carbaldehyde: ed as described in Example 37, using 2,8-dimethyl(1-methyl-1H- pyrazolyl)quinoline (0.60 g, 2.53 mmol) in place of 8-ethylmethquuinoline in Step B (0.507 g, 80%).
] Step C: Pre aration of lH- razol l uinolin l - l 2 4 lo 4 3-a ridin-6I ('DH{27‘ ..Q.,_..? L.” D Prepared as described in Example 9B, Step F, using tert-butyl (S)-l-((R)-2,2,2-trifluoro-l-(6- hydrazinylpyridin-3 -yl)ethyl)pyrrolidinylcarbamate and 8-methyl(l -methyl- 1 H- pyrazolyl)quinolinecarbaldehyde. LCMS APCI (+) m/z 507 (M + H).
Example 192 '— NQ’NH2 W 2 CH(O)OH . / o -l- R -2 2 2-trifluoro-l- 3- 8- 3-meth loxetan l methox uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidinamine diformate Step A: Pre aration of tert—but l -l- R trifluoro-l- 3- 8- 3- meth loxetan l methox uinolin l - l 2 4 lo 4 3-a ridin yl[ethyl[pyrrolidinylcarbamate: Prepared according to the method of Example 140, Steps A-C, substituting (3-methyloxetanyl)methanol for (S)-l-methoxypropanol in Step A.
] Step B: Pre aration of -l- R -2 2 uoro-l- 3- 8- 3-meth loxetan l methox uinolin l - l 2 4 triazolo 4 3-a ridin-6I ('DH{27‘ 5EQ.,_..?L.”a:EB('D diformate: tert—Butyl (S)- l -((R)-2,2,2-trifluoro- l -(3 -(8-((3 -methyloxetan-3 - yl)methoxy)quinolinyl)-[ l ,2,4]triazolo [4,3 -a]pyridin—6-yl)ethyl)pyrrolidin-3 -ylcarbamate (0.032 g, 0.053 mmol) was dissolved in formic acid (0.53 mL, 0.053 mmol) and stirred at ambient temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) to give the title compound (0.025 g, 75%). LCMS APCI (+) m/z 513 (M+H).
Example 193 N/ N O/ \N/ |N\ Diastereomer l of 3-meth l-l- R -2 2 2-trifluoro-l- 3- 8-methox uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidinol h drochloride Prepared as described in Example 9B, Steps F-G, using 3-methyl-l-((R)-2,2,2- trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinol Diastereomer 1 (Preparation F) in place of tert-butyl (S)-l-((R)-2,2,2-trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidin ylcarbamate in Step F. MS APCI (+) m/Z 458 (M+l) detected.
Example 194 F30, = NQAOH N/ N O/ Diastereomer 2 of 3-meth l-l- R -2 2 2-trifluoro-l- 3- 8-methox uinolin l - l 2 4 lo 4 3-a ridin l eth l inol h drochloride Prepared as described in Example 9B, Steps F-G, using 3-methyl-l-((R)-2,2,2- trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinol Diastereomer 2 (Preparation F) in place of tert-butyl (S)-l-((R)-2,2,2-trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidin ylcarbamate in Step F. MS APCI (+) m/z 458 (M+l) detected e 195 F30. HCI / Gm / N N/ N\ Diastereomer l of l- R -l- 3- 8-tert-but l uinolin l - l 2 4 triazolo 4 3-a ridin-6I ,_. I 2 2 2-trifluoroeth l meth l rrolidinol h drochloride ] Prepared as described in Example 9B, Steps F-G, using 3-methyl-l-((R)-2,2,2- trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinol Diastereomer 1 (Preparation F) in place of tert-butyl (S)-l-((R)-2,2,2-trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidin ylcarbamate and substituting 8-tert-butquuinolinecarbaldehyde for oxyquinoline carbaldehyde in Step F. MS APCI (+) m/z 484 (M+l) detected.
Example 196 qu HCI Cf/ N Diastereomer 2 of1- R -l- 3- 8-tert-but l uinolin l - l 2 4 triazolo 4 3-a 6- l - 2 2 2-trifluoroeth l meth l rrolidinol h drochloride Prepared as described in Example 9B, Steps F-G, using yl-l-((R)-2,2,2- trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinol reomer 2 (Preparation F) in place of tert-butyl (S)-l-((R)-2,2,2-trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidin ylcarbamate and substituting 8-tert-butquuinolinecarbaldehyde for 8-methoxyquinoline carbaldehyde in Step F. MS APCI (+) m/z 484 (M+l) detected.
Example 197 F3C 0H "’N NH2 / N N/ |N\ 2HC| 3-amino-l- R -2 2 2-trifluoro-l- 3- 8-iso ro ox uinolin l - l 2 4 triazolo 4 3- a ridin leth l rrolidin lmethanol dih drochloride Prepared as described in Example 9B, Steps D-G, using tert-butyl 3- (hydroxymethyl)pyrrolidinylcarbamate in place of (S)—tert—butyl pyrrolidinylcarbamate in Step D, and substituting 8-isopropoxyquinolinecarbaldehyde for 8-methoxyquinoline carbaldehyde in Step F. LCMS APCI (+) m/z 501 (M+H).
Example 198 " 0% d CH(O)OH N/ N -l- R -2 2 uoro-l- 3- 7- 3-meth loxetan l methox uinolin l - l 2 4 triazolo 4 3-a ridin l eth l inamine diformate Prepared according to the method of e 192, substituting 2- methquuinolinol for 2-methquuinolinol. LCMS APCI (+) m/Z 513 (M+H).
Example 199 F3C HCI N/ |N\ 3-meth l-l- -2 2 2-trifluoro-l- 3- 8-iso ro ox uinolin l - l 2 4 triazolo 4 3- a ridin leth l rrolidinol h drochloride Diastereomerl Prepared as described in Example 9B, Steps F-G, using Diastereomer l of 3- ((S)-2,2,2-trifluoro- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ol (Preparation E, Step H) in place of tert—butyl (S)-l-((R)-2,2,2-trifluoro-l-(6-hydrazinylpyridin yl)ethyl)pyrrolidinylcarbamate, and substituting 8-isopropoxyquinolinecarbaldehyde for 8-methoxyquinolinecarbaldehyde. MS APCI (+) m/Z 486 (M+l) detected.
Example 200 F3C HCI / m\ N/ N I “N \N/ |N\ 3-meth l-l- S -2 2 2-trifluoro-l- 3- 7- l-meth l-lH- razol l uinolin l - ] Prepared as described in Example 9B, Steps F and G, using reomer l of 3 -methyl((S)-2,2,2-trifluoro- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ol (Preparation E, Step H) in place of tert—butyl ((R)-2,2,2-trifluoro-l-(6-hydrazinylpyridin yl)ethyl)pyrrolidin—3-ylcarbamate, and substituting 7-(l-methyl-lH-pyrazolyl)quinoline carbaldehyde for 8-methoxyquinolinecarbaldehyde. MS APCI (+) m/Z 508 (M+l) detected.
Example 201 F3C HCI / NQLOH \ / N/ N l N\N N/ N\ / ] Prepared as described in Example 9B, Steps F-G, using Diastereomer 2 of 3- methyl((S)-2,2,2-trifluoro- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ol (Preparation E, Step I) in place of tert-butyl ((R)-2,2,2-trifluoro-l-(6-hydrazinylpyridin yl)ethyl)pyrrolidin—3-ylcarbamate, and substituting 7-(l-methyl-lH-pyrazolyl)quinoline carbaldehyde for 8-methoxyquinolinecarbaldehyde. MS APCI (+) m/Z 508 (M+l) detected.
Example 202 Diastereomer l of 3-meth l-l- S -2 2 2-trifluor0-l- 3- 6-flu0r0is0 r0 0x uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidinol h drochloride Prepared as described in Example 9B, Steps F-G, using Diastereomer l of 3- methyl((S)-2,2,2-trifluor0- l drazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ol (Preparation E, Step H) in place of tert—butyl (S)-l-((R)-2,2,2-trifluor0-l-(6-hydrazinylpyridin yl)ethyl)pyrrolidinylcarbamate, and substituting 6-flu0r0is0pr0p0xyquinoline carbaldehyde for 8-meth0xyquinolinecarbaldehyde. MS APCI (+) m/Z 504 (M+l) detected.
Example 203 Diastereomer 2 of 3-meth l-l- S -2 2 2-trifluor0-l- 3- 6-flu0r0is0 r0 0x uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidinol h drochloride Prepared as described in Example 9B, Steps F-G, using Diastereomer 2 of 3- ((S)-2,2,2-trifluor0- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ol (Preparation E, Step I) in place of tert-butyl (S)-l-((R)-2,2,2-trifluor0-l-(6-hydrazinylpyridin yl)ethyl)pyrrolidinylcarbamate, and substituting 0is0pr0p0xyquinoline carbaldehyde for 8-meth0xyquinolinecarbaldehyde. MS APCI (+) m/Z 504 (M+l) Example 204 2 HCI ] Step A: Pre aration of tert- 2- l - l 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidin lcarbamate: Prepared according to the method of Example 113, Steps A-C, substituting 3-bromo fluoroaniline for 4-fluoromethoxyaniline in Step A.
Step B: Pre aration of tert—but l 3 1R 3- 7- 13-dimeth l-1H— razol-S- l fluoro uinolin l - l 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l pyrrolidinylcarbamate: A mixture of tert—butyl (S)-l-((R)(3-(7-bromofluoroquinolin- 2-yl)—[ l ,2,4]triazolo[4,3-a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidinylcarbamate (0. 10 g, 0.16 mmol), 1,3-dimethyl(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-lH—pyrazole (0.073 g, 0.33 mmol) and cesium fluoride (0.065 g, 0.43 mmol) in 2-propanol (3.3 mL, 0.16 mmol) was ed with en. ining a nitrogen here, triethylamine (0.034 mL, 0.25 mmol) and dichloro[l,l ’-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.013 g, 0.016 mmol) were added, and the vessel sealed and heated at 100 CC for 17 hours. After cooling, the reaction e was diluted with ethyl acetate (10 mL), filtered through a plug of Celite®, and concentrated under reduced pressure.
Purification of the residue by reverse phase tography on a C18 column (0-100% acetonitrile/water) provided the title compound (0.074 g, 72%).
Step C: Pre aration of 3 1R 3- 7- l 3-dimeth l-lH- razol-S- l - 6-fluoro uinolin l - l 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidin amine dihydrochloride: Prepared according to the method of Example 1, Step F, substituting tert—butyl (3S)((1R)(3 -(7-(l ,3 -dimethyl- 1H-pyrazol-5 -yl)—6-fluoroquinolinyl)- ]triazolo[4,3-a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidinylcarbamate for tert-butyl (3S)-l-(2,2,2-trifluoro(3 -(8-methoxyquinolinyl)-[1 ,2,4]triazolo[4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate. LCMS APCI (+) m/Z 525 (M+H).
Example 205 ’—. NO,NH2 Cf 2 HCI / N N\ 3 1R 3- 7- eth l-lH- razol lfluoro uinolin l- l 2 4 triazolo 4 3-a 6- l -2 2 2-trifluoroeth l rrolidinamine dih drochloride Prepared according to the method of Example 204, substituting l,3-dimethyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-lH-pyrazole for l,3-dimethyl(4,4,5,5- tetramethyl-l,3,2-dioxaborolanyl)-lH-pyrazole in Step B. LCMS APCI (+) m/Z 525 (M+H).
Example 206 NO,NH2 Cf 2 HCI / N N\ l 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidinamine dih drochloride Prepared according to the method of e 204, substituting l,5-dimethyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-lH-pyrazole for l,3-dimethyl(4,4,5,5- tetramethyl-l,3,2-dioxaborolanyl)-lH-pyrazole in Step B. LCMS APCI (+) m/Z 525 (M+H).
Example 207 F3C HCI / CM 3-meth l-l- -2 2 2-trifluoro-l- 3- 8-iso ro ox uinolin l - l 2 4 triazolo 4 3- a ridin l eth l rrolidinol h drochloride Diastereomer 2 Prepared as described in Example 8, using Diastereomer 2 of 3-methyl-l-((S)- trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinol (Preparation E, Step I) in place of tert-butyl ((R)-2,2,2-trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidin ylcarbamate, and substituting 8-isopropoxyquinolinecarbaldehyde for 8- methoxyquinolinecarbaldehyde. MS APCI (+) m/Z 486 (M+l) detected. e 208 F301 dQ’2 HCI/ N N OH N\/ N l uinolinol dih oride ((R)(3-(8-(cyclopropylmethoxy)quinolinyl)-[1,2,4]triazolo[4,3- a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidinamine dihydrochloride (Example 11; 0.040 g, 0.074 mmol) in 5 N HCl (0.294 mL, 1.47 mmol) in IPA was stirred at 56 °C for 20 hours.
The solvent was removed and ACN (5 mL) was added. The resulting solid was ted by ion to give 2-(6-((R)((S)-3 -aminopyrrolidinyl)-2,2,2-trifluoroethyl)- [1,2,4]triazolo[4,3-a]pyridinyl)quinolinol as the di-HCl salt (0.032 g, 86.7%) as a solid.
Example 209 ' NQ’NH2 / \ 2 HCI / N o \N/ N\ NJ\ I/ H Step A: Pre aration of 2 8-dimeth l uinolinecarbox lic acid: A 250 mL round-bottomed flask was charged with 7-bromo-2,8-dimethquuinoline (2.0 g, 8.47 mmol), potassium 2-ethoxyoxoacetate (1.98 g, 12.7 mmol) and dcpp-2HBF4 (0.311 g, 0.508 mmol) in anhydrous NMP (28 mL) and nitrogen was bubbled into the mixture for 10 minutes, followed by the addition of Pd(TFA)2 (0.085 g, 0.254 mmol). The mixture was heated at 150 0C in an oil bath under a nitrogen atmosphere for 18 hours. The reaction mixture was cooled to ambient temperature and treated with a 2N NaOH solution (20 mL), and the mixture stirred at ambient temperature for 18 hours. The mixture was diluted with water (100 mL) and washed with ethyl acetate (180 mL). The s layer was adjusted to pH 3 with 6N HCl and extracted with a 10% IPA-ethyl acetate solution. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The e was purified by reverse phase chromatography ge SP4, 40M, C-18; 0-40% MeCN-H20) to afford 2,8-dimethquuinolinecarboxylic acid (0.921 g, 54% yield).
Step B: Preparation of N—isop_rop_yl-2,8-dimethylguinolinecarboxamide: A mixture of 2,8-dimethquuinolinecarboxylic acid (0.20 g, 0.994 mmol), pylamine (0.102 mL, 1.19 mmol) and HATU (0.491 g, 1.29 mmol) in anhydrous MeCN (5 mL) under a nitrogen atmosphere was cooled to 0 0C in an ice bath. To the cooled mixture was added dropwise DIEA (0.69 mL, 3.98 mmol) and the resulting mixture d at ambient temperature for 18 hours. The mixture was diluted with water, neutralized with aqueous 1N HCl and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Biotage SP4, 25M C-18, 5-60% MeCN-H20) to afford N—isopropyl-2,8-dimethquuinolinecarboxamide (0.223 g, 93%).
Step C: Preparation of 2-formyl-N—isopropylmethylguinoline carboxamide: Prepared as described in Example 37, Step B, using ropyl-2,8- dimethquuinolinecarboxamide (0.219 g, 0.904 mmol) in place of 8-ethyl methquuinoline in Step B (0.21 g, 90%).
Step D: Pre aration of 2- 6- R amino rrolidin l trifluoroeth l- 12 4 triazolo 4 3-a ridin l -N—iso ro lmeth l uinoline carboxamide dihydrochloride: Prepared as described in Example 9B, Steps F and G, using tert-butyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 - amate and substituting 2-formyl-N-isopropylmethquuinolinecarboxamide in Step F. LCMS APCI (+) m/z 512 (M + H).
Example 210 _ NqNH2 d 2HC| / N Step A: Isolation of the stereoisomer of tert—but 1 3R fiuoro R - 2 2 2-trifluoro 3- 6-fluoromethox uinolin l - 1 2 4 triazolo 4 3-a ridin yl[ethyl[pmolidinylcarbamate: The racemic al from Example 162 was d by Chiral SFC (For analysis: OD-H, Chiral Technologies 4.6 mm x 150 mm, 10-90% EtOH: hexanes, 0.80 mL/min. For preparative OD-H: Chiral Technologies, 20 mm x 250 mm, 30% EtOH, 50 mL/min). Isolation of the first eluting peak provided as a single stereoisomer (99% e.e.), ated as the (S) enantiomer by Proton NMR analysis.
Step B: Pre aration of 3R 4 fluoro-l- R -2 2 2-trifluoro-l- 3- 6-fluoro- 7-methox uinolin l - l 2 4 triazolo 4 3-a ridin-6 l eth l rrolidinamine dihydrochloride: Prepared as described in Example 9B, Step G, from tert—butyl (3R,4S) fluoro- l 2,2,2-trifluoro- l -(3 -(6-fluoromethoxyquinolinyl)-[ l ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinylcarbamate. LCMS APCI (+) m/z 479 (M + H).
Example 211 NQ’NH2 / N N\ / N O\ Step A: Isolation of the R isomer of tert—but 1 3R fluoro-l- R - 2 2 2-trifluoro-l- 3- 6-fluoromethox uinolin l - l 2 4 triazolo 4 3-a ridin yl[ethyl[pmolidinylcarbamate: The c material from Example 162, was purified by Chiral SFC (For analysis: OD-H, Chiral Technologies 4.6 mm x 150 mm, 10-90% EtOH: hexanes, 0.80 mL/min. For preparative OD-H, Chiral Technologies, 20 mm x 250 mm, 30% EtOH, 50 mL/min), to provide the second eluting peak as a single isomer (99% ee), designated as the (R) enantiomer by Proton NMR is.
Step B: Pre aration of 3R 4R fluoro-l- R -2 2 2-trifluoro-l- 3- 6-fluoro- 7-methox uinolin l - l 2 4 triazolo 4 3-a 6- l eth l rrolidinamine dih dro- chloride: Prepared as described in Example 9B, Step G, from tert—butyl (3R,4R)fluoro-l- ((R)-2,2,2-trifluoro- l -(3 oromethoxyquinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate. LCMS APCI (+) m/z 479 (M + H).
Example 212 F39. “3’NH2 d 2HC| / N N\ / W \ R -2 2 2-trifluoro 3- 8- methox ro ox uinolin l - 1 2 4 triazolo 4 3- a 6- leth l rrolidinamine dih drochloride Prepared according to the method of e 140, substituting (S) methoxypropan-l-ol for (S)methoxypropanol. LCMS APCI (+) m/Z 501 (M+H).
Example 213 Step A: Pre n of tert 2- l - 1 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidin lcarbamate: Prepared as described in Example 9B, Step F, using tert-butyl (S)((R)-2,2,2-trifluoro(6- hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate (0.80 g, 2.13 mmol) and 7-bromo methquuinolinecarbaldehyde (0.533 g, 2.13 mmol) in place of 8-methoxyquinoline carbaldehyde to provide tert-butyl (S)-l-((R)-l-(3-(7-bromomethquuinolinyl)- [1,2,4]triazolo[4,3-a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidinylcarbamate (1.01 g, 79%).
Step B: Pre aration of tert-but l R 3- 7- 1 3-dimeth l-1H- razol- - l meth l uinolin l - 1 2 4 triazolo 4 3-a 6- l -2 2 2- trifluoroethyl[pyrrolidinylcarbamate: Prepared as described in Example 191, using tert- butyl (S)((R)(3-(7-bromomethquuinolinyl)— [1 riazolo [4,3 -a]pyridinyl)- 2,2,2-trifluoroethyl)pyrrolidinylcarbamate in place of 7-bromo-2,8-dimethquuinoline and substituting 1 ,3 -dimethyl-5 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolanyl)-1H-pyrazole in Step A. LCMS APCI (+) m/z 621 (M + H).
Step C: Pre aration of 3 meth l uinolin l - 1 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l olidin amine dihydrochloride: Prepared as described in Example 9B, Step G substituting tert-butyl (S)((R)(3 ,3 -dimethyl-1H-pyrazol-5 -yl)methquuinolinyl)—[1,2,4]triazolo[4,3 - a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidinylcarbamate. LCMS APCI (+) m/z 521 (M + H).
Example 214 d3}IN NH2 2HC| /N /N\ Step A: Pre aration of tert-but l - l meth l uinolin l - 1 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l pyrrolidinylcarbamate: Prepared as described in Example 191, using tert-butyl (S)((R)— l-(3 -(7-bromomethquuinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)—2,2,2- trifluoroethyl)pyrrolidin-3 -ylcarbamate in place of 7-bromo-2,8-dimethquuinoline and using 1,5-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—1H-pyrazole in Step A. LCMS APCI (+) m/z 621 (M + H).
Step C: Pre n of 3 meth l n l - 1 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l olidin amine dihydrochloride: ed as described in Example 9B, Step G, using tert—butyl (S)-l- ((R)(3-(7-(1,5-dimethyl-1H-pyrazolyl)—8-methquuinolinyl)—[1,2,4]triazolo[4,3- dinyl)-2,2,2-trifluoroethyl)pyrrolidinylcarbamate. LCMS APCI (+) m/z 521 (M + H).
CExample 215 l -2 2 2-trifluoroeth l rrolidinamine dih drochloride Step A: Pre n of 7- omethox fluorometh l uinoline: A heterogeneous solution of 6-fluoromethquuinolinol (0.30 g, 1.7 mmol) in dichloromethane (2.3 mL, 1.7 mmol) was added to a solution of potassium hydroxide (0.48 g, 8.5 mmol) in water (1.4 mL, 1.7 mmol) at 0 CC followed by addition of tetrabutylammonium bromide (0.055 g, 0.17 mmol). While at 0 oC, chlorodifluoromethane gas was bubbled through the mixture for 10 minutes, followed by 45 minutes of stirring at 0 0C. This process was repeated three times. The reaction e was diluted with water (10 mL) and dichloromethane (20 mL) and the aqueous layer fiarther extracted with dichloromethane (2 x mL). The combined c ts were washed with 1M sodium hydroxide (10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The e was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) yielding the title compound (0.12 g, 30%).
Step B: Pre aration of 2- l - 1 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidinamine dihydrochloride: Prepared according to the method of Example 140, substituting 7- (difluoromethoxy)fluoromethquuinoline for (R)(1-methoxypropanyloxy) methquuinoline. LCMS APCI (+) m/Z 497 (M+H). e 216 2HC| F30 5 / gm \ k / N O N\ / N ] Prepared as described in Example 8 using (S)-tert-butyl 3-methylpyrrolidin ylcarbamate (from Preparation A) in place of (S)-tert-butyl pyrrolidinylcarbamate, and substituting 6-fluoroisopropoxyquinolinecarbaldehyde for 8-methoxyquinoline carbaldehyde. MS APCI (+) m/z 503 (M+l) detected.
Example 217 2HC| / NQiNHZ WO 54274 ed as described in Example 8, using (S)-tert—butyl 3-methylpyrrolidin ylcarbamate (Preparation A) in place of (S)-tert-butyl pyrrolidinylcarbamate. MS APCI (+) m/z 457 (M+l) detected.
Example 218 F3C : / NQLNHZ meth l-l- -2 2 2-trifluoro-l- 3- 6-fluoromethox uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidinamine Step A: Pre aration of tert-but l -l- -l- 6-chloro ridin l trifluoroeth l meth l rrolidin lcarbamate: Prepared as described in Example 1, Step C, using (S)-tert-butyl 3-methylpyrrolidinylcarbamate (Preparation C) in place of (S)-tert- butyl pyrrolidinylcarbamate.
Step B: Pre aration of tert-but l meth l-l- trifluoro-l- 6- h drazin l ridin leth l rrolidin mate: Prepared as bed in Example 1, Step D, using tert-butyl (S)-l-((S)-l-(6-chloropyridinyl)-2,2,2-trifluoroethyl) methylpyrrolidinylcarbamate in place of tert-butyl (3S)-l-(l-(6-chloropyridinyl)-2,2,2- trifluoroethyl)pyrrolidinylcarbamate.
Step C: Pre aration of tert-but l meth l-l- -2 2 uoro-l- 6- E - 2- 6-fluoromethox n lmeth lene h drazin l ridin leth l rrolidin ylcarbamate: To a solution of tert-butyl (S)methyl-l-((S)-2,2,2-trifluoro-l-(6- hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate (1.00 g, 2.57 mmol) in DCM (15 mL) was added 6-fluoromethoxyquinolinecarbaldehyde (0.5269 g, 2.568 mmol) and the reaction mixture was stirred at ambient temperature overnight. The reaction was concentrated under reduced pressure and the residue purified by chromatography (C18, 300 g, 10% MeCN/water to 95% MeCN/water over 25 column s) to give tert-butyl (S) methyl((S)-2,2,2-trifluoro- l -(6-((E)((6-fluoromethoxyquinolin hylene)hydrazinyl)pyridinyl)ethyl)pyrrolidinylcarbamate (1.132 g, 1.963 mmol, 76.45 % yield).
Step D: Pre aration of tert-but l meth l-l- -2 2 2-trifluoro-l- 3- 6- fluoromethox uinolin l - l 2 4 triazolo 4 3-a ridin l eth l in - mate: To a solution of tert-butyl (S)methyl-l-((S)-2,2,2-trifluoro-l-(6-((E)—2-((6-fluoro methoxyquinolinyl)methylene)hydrazinyl)pyridinyl)ethyl)pyrrolidinylcarbamate (1.130 g, 1.960 mmol) in DCM (10 mL) was added iodobenzene diacetate (0.6312 g, 1.960 mmol) and stirred ght at ambient temperature The reaction was concentrated under reduced pressure and the residue was purified by chromatography (C18, 300 g, 10% MeCN/water to 95% MeCN/water over 25 column volumes) to give tert-butyl (S)methyl- 1-((S)-2,2,2-trifiuoro(3 -(6-fiuoromethoxyquinolinyl)-[1,2,4]triazolo[4,3 idin yl)ethyl)pyrrolidinylcarbamate (0.906 g, 1.577 mmol, 80.46 % yield) Step E: Pre aration of h l trifiuoro 3- 6-fiuoro methox uinolin l - 1 2 4 lo 4 3-a ridin-6 lethl rrolidinamine: To a solution of tert-butyl methyl((S)-2,2,2-trifiuoro(3-(6-fiuoromethoxyquinolin yl)-[1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate (0.900 g, 1.57 mmol) in DCM (8 mL) was added 4M HCl in dioxane (2 mL) and the reaction stirred for 2.5 hours.
The reaction was diluted DCM (100 mL) and washed with ted N32C03 (25 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by normal phase tography (5% [10%NH4OH]/DCM) to give (S)methyl((S)-2,2,2- trifiuoro(3 -(6-fiuoromethoxyquinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinamine (0.690 g, 1.45 mmol, 92.8 % yield) MS APCI (+) m/z 475 (M+1) detected.
Example 219 NQ’NH2 d 2 HCI 2- 2- 6- R amino rrolidin-l- l -2 2 2-trifiuoroeth l - 1 2 4 triazolo 4 3- a ridin l uinolin lox ethanol dih drochloride Step A: Pre aration of 2- 2-meth l uinolin lox eth te: Amixture of 2-methquuinolinol (0.30 g, 1.9 mmol), 2-bromoethyl acetate (0.8.2 mL, 7.6 mmol) and potassium carbonate (1.6 g, 12 mmol) in acetone (7.5 mL, 1.9 mmol) was heated at 70 °C for 12 hours. The cooled reaction mixture was diluted with water (10 mL) and extracted with romethane (3 x 20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was d by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) to provide the title compound (0.29 g, 63%).
Step B: Preparation of 2-]2-formylguinolinyloxy[ethyl acetate: To a solution of 2-(2-methquuinolinyloxy)ethyl acetate (0.29 g, 1.2 mmol) in dioxane (20 mL) and water (0.20 mL) was added selenium dioxide (0.16 g, 1.4 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title compound (0.30 g, 99%).
Step C: Pre aration of 2- 2- 6- R tert- butox carbon lamino rrolidin l -2 2 2-trifiuoroeth l - 1 2 4 triazolo 4 3-a 3- yl[guinolinyloxy[ethyl acetate: A solution of tert—butyl (S)((R)-2,2,2-trifiuoro(6- hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate (0.48 g, 1.2 mmol) and 2-(2- methquuinolinyloxy)ethyl e (0.30 g, 1.2 mmol) in ethanol (5.8 mL, 1.2 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in romethane (5.8 mL) and iodosobenzene ate (0.41 g, 1.3 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and trated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column % acetonitrile/water) to give the title nd (0.47 g, 66%).
Step D: Preparation of tert-but l R -2 2 2-trifiuoro 3- 8- 2- h drox ethox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l olidin amate: To a solution of 2-(2-(6-((R)((S)(tert—butoxycarbonylamino)pyrrolidin yl)-2,2,2-trifiuoroethyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridin-3 -yl)quinolinyloxy)ethyl e (0.47 g, 0.76 mmol) in ol (5 mL) was added lithium hydroxide (2M; 1.9 mL, 0.76 mmol) and the mixture allowed to stir at ambient temperature for 1 hour. The reaction mixture was extracted with dichloromethane (2 x 30 mL). The combined organic extracts were dried over ium sulfate, filtered and concentrated under reduced re. The residue was purified by reverse phase chromatography on C18 (0-100% acetonitrile/water) to provide the title compound (0.40 g, 92%).
Step E: Pre aration of 2- 2- 6- R amino rrolidin l trifiuoroeth l- 12 4 triazolo 4 3-a ridin l uinolin lox ethanol dih drochloride: To a solution of tert—butyl (S)((R)-2,2,2-trifiuoro(3-(8-(2-hydroxyethoxy)quinolinyl)- [1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate (0.40 g, 0.70 mmol) in romethane (1 mL) was added hydrochloric acid (5-6M in 2-propanol; 7.0 mL, 0.61 mmol). The reaction mixture was stirred at ambient temperature for 30 s. The solvent was removed under reduced pressure, and the resulting solid was suspended in itrile (3 mL) and stirred at ambient temperature for 5 minutes. The resulting solid was collected by vacuum filtration to give the title compound (0.38 g, 99%). LCMS APCI (+) m/z 473 (M+H).
Example 220 N NH2 / N N/ [N O\/ trifiuoroeth lmeth l rrolidinamine Step A: Pre aration of tert-but l 6-chloro 3- l trifluoroeth l h l rrolidin lcarbamate: Prepared as described in Example 1, Step C, using (S)-tert-butyl 3-methylpyrrolidinylcarbamate (Preparation C) in place of (S)-tert- butyl pyrrolidinylcarbamate.
Step B: Preparation of tert-butyl ]§[methyl-l-]]§[-2,2,2-trifiuoro]6- inylpyridinyl[ethyl[pyrrolidinylcarbamate: Prepared as described in Example 1, Step D, using tert-butyl (S)((S)(6-chloropyridinyl)-2,2,2-trifiuoroethyl) methylpyrrolidinylcarbamate in place of tert-butyl -(1-(6-chloropyridinyl)-2,2,2- trifiuoroethyl)pyrrolidinylcarbamate.
Step C: Pre aration of tert-but l fiuoro n lmeth lene h drazin l ridin l-2 2 2-trifiuoroeth l methylpyrrolidinylcarbamate: To a solution of tert-butyl (S)methyl((S)-2,2,2- trifiuoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate (Example 122, Steps A and B; 5.113 g, 13.13 mmol) in ethanol (25 mL) was added 7-ethoxyfluoroquinoline carbaldehyde (2.878 g, 13.13 mmol) and stirred overnight at ambient temperature. The precipitate was filtered to give desired product as a pale yellow solid (5.276 g). The filtrate was subjected to chromatography (C18, 300 g, 75 mL/min, 10% MeCN/H20 to 95% MeCN over 25 column volumes) and combined with the filtered t to give tert-butyl (S)((S)(6-((E)((7-ethoxyfiuoroquinolinyl)methylene)hydrazinyl)pyridin-3 -yl)-2,2,2- trifluoroethyl)methylpyrrolidinylcarbamate (6.322 g, 10.70 mmol, 81.53 % yield).
Step D: Pre aration of tert-but l 3- 7-ethox fluoro uinolin l - 1 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l meth l rrolidin ylcarbamate: A solution of tert-butyl (S)((S)(6-((E)((7-ethoxyfluoroquinolin yl)methylene)hydrazinyl)pyridinyl)-2,2,2-trifluoroethyl)methylpyrrolidin ylcarbamate (6.320 g, 10.70 mmol) and iodobenzene diacetate (3.447 g, 10.70 mmol) in DCM (50 mL) was stirred overnight at ambient temperature. The reaction was concentrated under reduced pressure and the residue subjected to chromatography (10% ethyl acetate/hexanes to 50% ethyl acetate/hexanes over 4 column volumes) to give tert-butyl (S)- 1-((S)(3-(7-ethoxyfluoroquinolinyl)-[1,2,4]triazolo[4,3-a]pyridinyl)-2,2,2- trifiuoroethyl)methylpyrrolidinylcarbamate (5.406 g, 9.18 mmol, 85.83 % yield).
Step E: Pre aration of 1 2 4 lo 4 3-a ridin l -2 2 2-trifiuoroeth l meth l rrolidinamine: A solution of utyl (S)((S)(3-(7-ethoxyfluoroquinolinyl)-[1,2,4]triazolo[4,3- dinyl)-2,2,2-trifluoroethyl)methylpyrrolidinylcarbamate (5.406 g, 9.185 mmol) in DCM (40 mL) was added 4M HCl in dioxane (22.96 mL, 91.85 mmol) and d at ambient temperature for 1.5h. The filtered precipitate was dissolved in water and basified (1N NaOH), extracted with ethyl acetate (3 x 200 mL), washed with brine (200 mL), dried (MgSO4), filtered concentrated under reduced pressure and the residue d by flash chromatography (1 column volume DCM, increasing to 10% ol/DCM over 2 column volumes, holding for 3 column volumes, then switching to 10% [10% NH4OH/Methanol]/DCM for 7 column volumes) to give ((S)—1-(3-(7-ethoxy fluoroquinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2-trifluoroethyl)-3 - methylpyrrolidinamine (4.13 g, 8.45 mmol, 92.05 % yield). MS APCI (+) m/z 489 (M+1) detected. Specific rotation: D = -0.870 (c = 1.02, MeOH).
Example 221 F3C : Prepared as described in Example 9B, Steps D-G, using (S)-tert-butyl 3- methylpyrrolidinylcarbamate (Preparation B) in place of rt-butyl pyrrolidin ylcarbamate in Step D and using (R)fluoro(l-methoxypropanyloxy)quinoline carbaldehyde in place of oxyquinolinecarbaldehyde in Step F. MS APCI (+) m/z 533 (M+l) detected.
Example 222 / NQiNHZ Prepared as described in Example 9B, Steps D-G, using (S)-tert-butyl 3- methylpyrrolidinylcarbamate (Preparation A) in place of (S)-tert-butyl pyrrolidin ylcarbamate in Step D and using 7-(l-methyl-lH-pyrazolyl)quinolinecarbaldehyde in place of oxyquinolinecarbaldehyde in Step F. MS APCI (+) m/z 507 (M+l) detected.
Example 223 2 HCI trifluoroeth th l rrolidinamine dih drochloride Prepared as described in Example 9B, Steps D-G, using (S)-tert-butyl 3- methylpyrrolidinylcarbamate (Preparation A) in place of (S)-tert-butyl pyrrolidin ylcarbamate in Step D and using 7-cyclopropquuinolinecarbaldehyde in place of 8- methoxyquinolinecarbaldehyde in Step F. MS APCI (+) m/z 467 (M+l) detected. e 224 a ridin l uinolin lmeth lbutanol dih drochloride Step A: Preparation of hyl 3methylguinolinyl)butenoate: A solution of 8-bromomethquuinoline (2.00 g, 9.01 mmol), (E)-ethyl enoate (3.36 mL, 27.0 mmol), N—cyclohexyl-N-methylcyclohexanamine (5.79 mL, 27.0 mmol), and Pd(PtBu3)2 (0.23 g, 0.45 mmol) in dioxane (10 mL) was stirred at reflux for 20 hours. After cooling to ambient temperature, water (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), d and concentrated under reduced pressure. The residue was purified by C-l8 reverse phase flash chromatography (Biotage SP4 unit, C-18 40M column, 0-100% CHgCN/water gradient; 30 column volumes) to give (Z)-ethyl 3-(2-methquuinolinyl)butenoate (0.81 g, 35.2%) as a solid.
Step B: Preparation of ethyl 3-methyl12-methylguinolinyl)butanoate: To a mixture of Cu(I)I (2.42 g, 12.7 mmol) in ether (5 mL) was added a solution of 1.6 M MeLi (15.9 ml, 25.4 mmol) in ether at 0 °C and the mixture was d at 0 °C for 10 minutes. The solvent was removed under reduced pressure and cold DCM (10 mL) was added. The solvent was removed under reduced pressure. Cold DCM (40 mL) was added and the mixture was cooled to -78 °C. TMSCl (1.54 mL, 12.7 mmol) was added, followed by a solution of (Z)- ethyl 3-(2-methquuinolinyl)butenoate (0.81 g, 3.17 mmol) in DCM (10 mL). The on mixture was warmed to 0 °C and stirred at 0 °C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution. The organic layers was separated, washed with brine, dried (sodium e), d and concentrated under reduced pressure.
The residue was d by flash chromatography on silica gel (7:1 hexane/ethyl acetate) to give ethyl 3-methyl(2-methquuinolinyl)butanoate (0.66 g, 76.8%) as an oil.
Step C: Preparation of 3-methylg2-methylguinolinyl)butan-l-ol: To a solution of ethyl 3-methyl(2-methquuinolinyl)butanoate (0.66 g, 2.43 mmol) in THF (3 mL) was added 1.0 N LAH (3.65 mL, 3.65 mmol) in THF at 0 °C and stirred at 0 °C for 3 2012/026572 hours. Sodium sulfate decahydrate (2.0 g) was added and stirred at ambient temperature for minutes. The solid was removed by filtration and washed with ethyl acetate (30 mL). The filtrate was concentrated under d re to give 3-methyl(2-methquuinolin yl)butanol (0.56 g, 100%) as a solid.
Step D: Pre aration of 3- 2- 6- R S amino rrolidin l -2 2 2- trifiuoroeth l - 1 2 4 triazolo 4 3-a 3- l uinolin l meth lbutan-l-ol dihydrochloride: Prepared as described in Example 114, Steps A-B, using 3-methyl(2- methquuinolinyl)butanol in place of (1-(2-methquuinolinyl)cyclopropyl)methanol in Step A. LCMS APCI (+) m/z 499(M+H).
Example 225 / ,HNQ’NHZ N\/ N a ridin l uinolin l ro anol Step A: Pre aration of meth l2-meth l uinolinecarbox late: To a stirred solution of 2-methquuinolinecarboxylic acid (0.830 g, 4.43 mmol) in MeOH (20 mL) was added dropwise chlorotrimethylsilane (2.41 g, 22.2 mmol). The reaction mixture was heated at reflux overnight. After cooling, the reaction was concentrated under reduced pressure. The residue was dissolved in water and d by dropwise addition of ted aqueous NaHC03 solution. The e was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 hexane/EtOAc) to give methyl 2-methquuinoline- 8-carboxylate (0.290 g, 33%).
Step B: Preparation of 2methylguinolinyl[propanol: To a d solution of methyl 2-methquuinolinecarboxylate (0.290 g, 1.44 mmol) in THF (1 mL) was added dropwise a solution of MeMgBr in ether (3.0 M, 1.44 mL, 4.32 mmol) at -15 0C under nitrogen. The reaction mixture was stirred at -15 CC for 30 minutes and then ed by the addition of saturated aqueous NH4C1 solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated under d pressure. The residue was purified by flash chromatography on silica gel (1:1 hexanes/EtOAc) to give 2-(2-methquuinolinyl)propanol (0.260 g, 90%).
Step C: Preparation of 8-]2-hydroxypropanyl1guinolinecarbaldehyde: Prepared as described in Example 5, Step B, using 2-(2-methquuinolinyl)propanol in place of 8-(cyclopropylmethoxy)methquuinoline.
Step D: Pre n of tert-but l S -l- R -2 2 2-trifluoro-l- 3- 8- 2- h drox ro an l uinolin l- l 24 triazolo 4 3-a ridin leth l rrolidin ylcarbamate: Prepared as described in Example 9B, Step F, using ydroxypropan yl)quinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde.
Step E: Pre aration of 2- 2- 6- R -l- S amino rrolidin-l- l trifluoroeth l- 12 4 triazolo 4 3-a 3- l uinolin l ro anol: A mixture of tert-butyl (S)— l 2,2,2-trifluoro- l -(3 -(8-(2-hydroxypropanyl)quinolinyl)-[ l ,2,4] triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate (56 mg, 0.098 mmol), DCM (l mL) and 4N HCl in dioxane (0.3 mL) was stirred at ambient temperature for 3 hours.
Removal of the solvents gave the crude product, which was purified by e phase preparative HPLC (5-95% acetonitrile/water) to give the product as a bis TFA salt. The combined fractions were basified by saturated aqueous NaHC03 solution and extracted with EtOAc. The organic layers were washed with brine, dried and concentrated under reduced pressure to give 2-(2-(6-((R)- l -((S)—3 -aminopyrrolidin- l -yl)-2,2,2-trifluoroethyl)- ]triazolo[4,3-a]pyridinyl)quinolinyl)propanol (14 mg, 30%). LCMS APCI (+) m/z 471 (M+H).
Example 226 F39— NH 2 / NO’ \ 2HCI / N Prepared according to the method of e 119, Steps A-G, substituting l,l,l-trifluoroiodoethane for 2-iodopropane in Step C. FIA-MS APCI (+) m/z 529 (M+H).
Example 227 d“?—. NH2 2 HCI /N O/\/\ R -2 2 2-trifluoro 3- 8- 2-methox ethox n l - 1 2 4 triazolo 4 3- a ridin leth l rrolidinamine dih oride Prepared according to the method of Example 148, substituting 2- methquuinolinol for 2-methquuinolinol. FIA-MS APCI (+) m/Z 487 (M+H).
Example 228 = NO’NH / \ i 2 HCI / N O F l -2 2 2-trifluoroeth l rrolidinamine dih drochloride Step A: Pre aration of 8- difluoromethox fluorometh l uinoline: To a mixture of 6-fluoromethquuinolinol (0.15 g, 0.85 mmol) and potassium carbonate (4.2 g, 30 mmol) in itrile (3.4 mL, 0.85 mmol) and water (3.4 mL, 0.85 mmol) was added ro-2,2-difluoroacetophenone (0.62 mL, 4.2 mmol). The vessel was sealed and the e was heated at 80 CC for 4 hours. The cooled on mixture was extracted with diethyl ether (2 x 30 mL), and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure at ambient temperature The ing residue was purified by reverse phase tography on a C18 column (0-100% acetonitrile/water). Aqueous fractions containing the product were combined and extracted with diethyl ether (2 x 100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure at ambient temperature providing the title compound. Presence of water was noted and the material taken on as is assuming theoretical yield obtained (0.19 g, 100%).
Step B: Pre aration of 2- l - 1 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidinamine dihydrochloride: Prepared ing to the method of Example 140, substituting 8- 2012/026572 (difiuoromethoxy)fluoromethquuinoline for (R)(l-methoxypropanyloxy) methquuinoline. FIA-MS APCI (+) m/Z 497 (M+H).
Example 229 F30, = NH 2 / \ 2HCI / N O/\/\OH Nt / N N\ Step A: Pre aration of tert—but l -l- R -l- 3- 8- 3- tert- but ldimeth lsil lox ro ox fluoro n l- l 24 lo 4 3-a ridin l- 2,2,2-trifluoroethyl)pvrrolidinylcarbamate: Prepared according to the method of Example 148, substituting omethquuinolinol for 2-methquuinolinol and (3- bromopropoxy)(tert—butyl)dimethylsilane for l-bromomethoxyethane.
Step B: Pre aration of 3- 2- 6- R -l- amino rrolidin-l- l roeth l- 12 4 triazolo 4 3-a ridin l fluoro uinolin lox ro an-l-ol dihydrochloride: A solution of tert—butyl (S)-l-((R)-l-(3-(8-(3 -(tert—butyldimethyl silyloxy)propoxy)—6-fiuoroquinolinyl)—[ l ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2-trifiuoro ethyl)pyrrolidinylcarbamate (0.18 g, 0.24 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (2 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The e was purified by reverse phase tography on a C18 column (0-80% acetonitrile/water). The material isolated after purification was dissolved in methanol (0.5 mL) and added dropwise to hydrochloric acid (2M in diethyl ether; 5 mL). The resulting salt was collected by vacuum filtration to provide the title compound (0.12 g, 84%). FIA-MS APCI (+) m/Z 505 (M+H).
Example 230 To a stirred solution of (R)(2-(6-((R)((S)aminopyrrolidinyl)-2,2,2- trifluoroethyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridin-3 -yl)quinolinyloxy)propanol dihydro chloride (40 mg, 0.082 mmol) in MeOH (0.8 mL) was added DIEA (43 uL, 0.25 mmol).
Cyclopropanecarbaldehyde (8.0 uL, 0.10 mmol) and hyl orthoformate (90 uL, 0.82 mmol) were added. The reaction was allowed to stir at ambient temperature overnight.
NaBH4 (6.2 mg, 0.16 mmol) was added. After stirring for 30 minutes, the reaction was quenched by the addition of a saturated aqueous NH4C1 on. The mixture was partitioned between DCM and water. The s phase was extracted with DCM. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (5-95% itrile/water) to give the bis-TFA salt. The combined fractions were basified by ted aqueous NaHC03 solution and extracted with EtOAc. The organic layers were washed with brine, dried and trated under reduced pressure to give the free base, which was treated with 4N HCl in dioxane to give 2-(2-(6-((R)((S)-3 -aminopyrrolidinyl)-2,2,2-trifluoroethyl)- ]triazolo[4,3-a]pyridinyl)quinolinyl)propanol dihydrochloride (39 mg, 88%) as a yellow solid. LCMS APCI (+) m/z 541 (M+H).
Example 231 / ”INQ’ /\/OH / N ~ / N N \ | 2HC| 2- 2- 6- R S amino rrolidin l -2 2 2-trifluoroeth l - 1 2 4 triazolo 4 3- a ridin l uinolin l ro anol dih drochloride To a stirred solution of (R)(2-(6-((R)((S)aminopyrrolidinyl)-2,2,2- trifluoroethyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridin-3 -yl)quinolinyloxy)propanol (Example 1 86; 36 mg, 0.074 mmol) in itrile (1 mL) was added acetone (33 uL, 0.44 mmol).
NaBHgCN (9.3 mg, 0.15 mmol) was added followed by 1 drop of AcOH. The reaction was stirred at ambient temperature for 15 minutes and then quenched by the on of saturated s NaHC03 solution. The mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to give the bis-TFA salt. The combined ons were basif1ed by saturated aqueous NaHC03 solution and extracted with EtOAc.
The organic layers were washed with brine, dried and concentrated under reduced pressure to give the free base, which was treated with 4N HCl in dioxane to give 2-(2-(6-((R)-l-((S) aminopyrrolidin- l -yl)-2,2,2-trifluoroethyl)-[ l ,2,4]triazolo [4,3 -a]pyridin-3 -yl)quinolin yl)propanol dihydrochloride (26 mg, 67%) as a yellow solid. LCMS APCI (+) m/z 529 (M+H).
Example 232 F301 ' ow d 2 HCI / N N~N/ N\ OVCF3 Prepared according to the method of Example 226, tuting 6-fluoro methquuinolinol for omethquuinolinol. FIA-MS APCI (+) m/Z 529 (M+H).
Example 233 / N O/\/\O/ Step A: Pre aration of 6-fluoro 3-methox ro ox meth l uinoline: Triphenylphosphine (0.74 g, 2.8 mmol) was dissolved in tetrahydrofuran (0.94 mL, 1.1 mmol) and diisopropyl azodicarboxylate (0.35 mL, 1.8 mmol), 3-methoxypropan-l-ol (0.14 mL, 1.5 mmol) and 6-fluoromethquuinolinol (0.20 g, 1.1 mmol) were added. The vessel was sealed and the mixture was stirred at 50 0C for 12 hours. The cooled reaction e was d with water (10 mL) and extracted with dichloromethane (2 x 20 mL).
The combined organic extracts were dried over magnesium sulfate, d and concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (10-50% ethyl acetate/hexanes) to provide the title compound (0.22 g, 77%).
Step B: Pre aration of 6-fluoro 3-methox ro ox uinoline carbaldehyde: To a on of 6-fluoro(3-methoxypropoxy)methquuinoline (0.22 g, 0.87 mmol) in dioxane (20 mL) and water (0.2 mL) was added selenium dioxide (0.12 g, 1.0 mmol) and the resultant mixture was heated at reflux for 5 hours. The cooled reaction e was filtered through a plug of Celite®, washing the solids with dichloromethane.
The filtrate was concentrated under reduced pressure and the residue was purified by normal phase chromatography on silica gel (10-30% ethyl acetate/hexanes) to provide the title compound (0.20 g, 89%).
Step C: Pre aration of tert- 3-methox ro ox n l- 12 4 triazolo 4 3-a ridin leth l rrolidin amate: A solution of utyl (S)((R)-2,2,2-trifluoro(6-hydrazinylpyridin yl)ethyl)pyrrolidinylcarbamate (0.15 g, 0.36 mmol) and 6-fiuoro(3- methoxypropoxy)quinolinecarbaldehyde (0.095 g, 0.36 mmol) in ethanol (1.8 mL, 0.36 mmol) was d to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (1.8 mL) and iodosobenzene diacetate (0.13 g, 0.39 mmol) was added. The reaction e was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) to give the title compound (0.12 g, 55%).
Step D: Pre aration of R -2 2 2-trifiuoro 3- 6-fiuoro 3- methox ro ox uinolin l - 1 2 4 triazolo 4 3-a ridin leth l rrolidinamine dihydrochloride: To a solution of tert—butyl (S)((R)-2,2,2-trifiuoro(3-(6-fiuoro(3- methoxypropoxy)quinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - ylcarbamate (0.12 g, 0.19 mmol) in dichloromethane (1 mL) was added hydrochloric acid (5- 6M in 2-propanol; 6.5 mL, 0.19 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the solid obtained was suspended in acetonitrile (3 mL) and stirred at t temperature for 5 s. The solid formed was ted by vacuum filtration to give the title nd (0.095 g, 80%). FIA-MS APCI (+) m/z 519 (M+H).
Example 234 {{NQ’3’: NH2 2HC| / N N/ N\ I N/ N\ WO 54274 a: EQ.I—I? b.) I CI—IBOrE 00 I IZ .2Q.E.('DH,{27‘ 5‘O('DH,a:E.O.('D 7‘ a.OOEOHH.O.('D Prepared as described in Example 30, using methyl 2-(2-methquuinolin yl)acetate in place of methyl 2-methquuinolinecarboxylate in Step C, substituting tert- butyl (S)- l -((R)—2,2,2-trifluoro- l -(6-hydrazinylpyridinyl)ethyl)pyrrolidin-3 -ylcarbamate for tert—butyl (3 S)- l -(2,2,2-trifluoro- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 - ylcarbamate in Step D, and substituting dimethylamine for propanamine in Step E. LCMS APCI (+) m/z 498 (M+H).
Example 235 F3c1 ”3’NH2 d 2 HCI / N N/\ N./ H Prepared as described in Example 30, using methyl ethquuinolin yl)acetate in place of methyl 2-methquuinolinecarboxylate in Step C, tuting tert- butyl (S)- l -((R)—2,2,2-trifluoro- l drazinylpyridinyl)ethyl)pyrrolidin-3 -ylcarbamate for tert—butyl (3 S)- l -(2,2,2-trifluoro- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 - ylcarbamate in Step D, and substituting ethyl amine for propanamine in Step E. LCMS APCI (+) m/z 498 (M+H).
Example 236 / Fsc"'NQ’NH2\ / N N~N/ |N\ OH F 2 HCI 2- 2- 6- R -l- S amino rrolidin-l- l -2 2 2-trifluoroeth l - l 2 4 triazolo 4 3- a 3- l uinolin l ro anol dih drochloride Step A: Pre aration of l- 6-fluorometh l uinolin lmeth l ro an o_l: To a stirred solution of methyl 2-(6-fluoromethquuinolinyl)acetate (0.650 g, 2.79 mmol) in toluene (14 mL) was added dropwise a solution of MeMgBr in ether (3.0 M, 2.79 mL, 8.36 mmol) at 0 CC under nitrogen. The reaction mixture was stirred at t temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl solution. The reaction mixture was extracted with EtOAc. The ed organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:2 hexanes/EtOAc) to give l-(6-fluoro- 2-methquuinolinyl)—2-methylpropanol (0.202 g, 31%).
Step B: Preparation of 8-[2-hydrox1propanyl[guinolinecarbaldehyde: Prepared as described in Example 5, Step B, using l-(6-fluoromethquuinolinyl) methylpropanol in place of 8-(cyclopropylmethoxy)methquuinoline.
Step C: Pre aration of 2- 2- 6- R -l- S amino rrolidin-l- l trifluoroeth l- 12 4 triazolo 4 3-a ridin l uinolin l ro anol dih oride: Prepared as described in Example 9B, Steps F-G, using ydroxypropanyl)quinoline- 2-carbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 503 (M+H).
Example 237 / NQ’NHZ N/ N \N/ |N\ OH F 2HCI Prepared as described in Example 9B, Steps B-G, using dichloro{(R)-(+)—2,2'- bis[di(3 ,5 -xylyl)-phosphino- l , l '-binaphthyl} [(2R)-(-)- 1 , l-bis(4-methoxyphenyl)—3 -methyl- tanediamine in place of dichloro{(S)-(-)-2,2'-bis[di(3,5-xylyl)-phosphino-l,l'- binaphthyl} [(2S)-(+)-l,l-bis(4-methoxyphenyl)methyl-l,2-butanediamine in Step B, and substituting 8-(2-hydroxypropanyl)quinolinecarbaldehyde for oxyquinoline carbaldehyde in Step F. LCMS APCI (+) m/z 503 (M+H).
Example 238 F30, = NH 2 / \ g 2HCI N/ N\ Step A: Pre aration of tert—but l R 3- 8- R tert—but ldi hen l sil lox ro an lox ro uinolin l - 1 2 4 triazolo 4 3-a ridin 1-2 2 2- trifluoroethyl[pyrrolidinylcarbamate: Prepared according to the method of Example 148, Steps A-C, substituting 6-fluoromethquuinolinol for 2-methquuinolinol and (S) (tert—butyldiphenylsilyloxy)propanol for 1-bromomethoxyethane in Step A.
Step B: Pre aration of R 3- 8- R tert—but ldi hen l sil lox ro an lox ro n l - 1 2 4 triazolo 4 3-a ridin 1-2 2 2- trifluoroethyl[pyrrolidinamine: A solution of tert—butyl (S)((R)(3-(8-(3-(tert— butyldimethylsilyloxy)propoxy)fluoroquinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)- 2,2,2-trifluoroethyl)pyrrolidinylcarbamate (0.098 g, 0.12 mmol) in romethane (1 mL) and trifluoroacetic acid (2 mL) was stirred at ambient temperature for 30 minutes.
Reaction mixture concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) to provide the title compound (0.045 g, 52%).
Step C: Pre aration of R 2- 6- trifluoroeth l- 12 4 triazolo 4 3-a 3- l fluoro uinolin lox ro anol ochloride: A solution of (S)((R)(3-(8-((R)(tert-butyldiphenylsilyloxy)propan- 2-yloxy)fiuoroquinolinyl)—[ 1 ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2-trifiuoroethyl)pyro lidinamine (0.045 g, 0.061 mmol) in tetrahydrofuran (0.5 mL) and tetrabutylammonium fluoride (1M in tetrahydrofuran; 0.18 mL) was stirred at t temperature for 90 minutes.
The reaction mixture concentrated under reduced pressure. The residue was by reverse phase chromatography on a C18 column (0-100% acetonitrile/water). The material isolated after purification was ved in methanol (0.5 mL) and added se to hydrochloric acid (2M in diethyl ether; 3 mL). The resulting salt was collected by vacuum filtration to provide the title compound (0.010 g, 30%). FIA-MS APCI (+) m/z 505 (M+H).
Example 239 / NQ’NH2 \ 2HC| / N a 6- leth l rrolidinamine dih drochloride Prepared according to the method of Example 113, substituting 3- (trifluoromethoxy)aniline for 4-fluoromethoxyaniline in Step A. FIA-MS APCI (+) m/Z 497 (M+H).
Example 240 2HCI / N N\/ N Prepared as described in Example 9B, Steps F-G, using (R)-tert-butyl 3- methylpyrrolidinylcarbamate (from Preparation A) in place of (S)-tert-butyl pyrrolidin ylcarbamate. MS APCI (+) m/z 457 (M+l) detected.
Example 241 2HCI / N\/:/'/"NH2 / N Prepared as described in Example 9B, Steps F-G, using (R)-tert-butyl 3- methylpyrrolidinylcarbamate (Preparation A) in place of (S)-tert-butyl idin ylcarbamate and using omethoxyquinolinecarbaldehyde in place of 8- methoxyquinolinecarbaldehyde. MS APCI (+) m/z 475 (M+l) ed.
Example 242 .,, 2 / N Step A: Pre aration of +/- benz l 3- tert-butox carbon lamino ethylpyrrolidine-l-carboxylate: Prepared as described in International Publication No. WC 2009/140320A1, Example D, Steps A-D, using ethyl iodide in place of methyl iodide.
Step B: Separation of enantiomers: benzyl 3-1tert-butoxycarbonylamino2 ethylpyrrolidine-l-carboxylate enantiomer 1 and benzyl 3-]tert-butoxycarbonylamino[ yrrolidine-l-carboxylate enantiomer 2: A racemic mixture of benzyl 3-(tert- butoxycarbonylamino)ethylpyrrolidinecarboxylate (0.280 g, 0.8 mmol) was separated via preparative supercritical fluid chromatography under the following conditions: Column: IC 20 mm x 250 mm; flow rate: 50 mL/min; mobile phase A: supercritical C02; mobile phase B: isopropyl alcohol; gradient: isocratic 10% isopropyl alcohol 90% supercritical C02; UV detection wavelength: 212 nm. Peak one: retention time: 4.34 minutes; recovery: Enantiomer 1 of benzyl t-butoxycarbonylamino)ethylpyrrolidine-l-carboxylate (0.120 g, 0.3 mmol). Peak two: retention time: 8.34 s; recovery: Enantiomer 2 of benzyl t— carbonylamino)ethylpyrrolidine-l-carboxylate (0.116 g, 0.3 mmol).
Step C: Preparation of Enantiomer 1 of tert-bu‘ng 3-ethylp_yrrolidin ylcarbamate: Prepared as described in International Application No. WC 2009/140320Al, Example D, Step E, using Enantiomer 1 of benzyl 3-(tert-butoxycarbonylamino) ethylpyrrolidine-l-carboxylate in place of racemic benzyl 3-(tert-butoxycarbonylamino) methylpyrrolidinecarboxylate.
Step D: ed as described in Example 9B, Steps F-G, using Enantiomer 1 of tert-butyl 3-ethylpyrrolidinylcarbamate in place of (S)-tert—butyl pyrrolidin amate in Step D. LCMS APCI (+) m/z 471 (M+H).
Example 243 Prepared as bed in Example 9, Steps D-G, using Enantiomer 1 of tert- butyl 3-ethylpyrrolidinylcarbamate (Example 242) in place of rt—butyl pyrrolidin ylcarbamate in Step D, and substituting 7-ethoxyfluoroquinolinecarbaldehyde for 8- methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 503 (M+H).
WO 54274 Example 244 /N o/ ~ / N N \ | 2HCI Diastereomer 2 of 3-eth l S -2 2 2-trifluoro 3- 8-methox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine dih drochloride Step A: Pre aration of +/- benz l 3- tert-butox carbon lamino ethylpyrrolidine-l-carboxylate: Prepared as described in International Publication No. WC 2009/140320A1, Example D, Steps A-D, using ethyl idodide in place of methyl idodide.
] Step B: Se aration of enantiomers: benz l 3- utox carbon lamino eth l rrolidinecarbox late enantiomer 1 and benz l 3- tert-butox carbon lamino ethylpyrrolidinecarboxylate enantiomer 2: A racemic mixture of benzyl 3-(tert- butoxycarbonylamino)ethylpyrrolidinecarboxylate (0.280 g, 0.8 mmol) was separated via preparative supercritical fluid chromatography under the following conditions: Column: IC 20 mm x 250 mm; flow rate: 50 mL/min; mobile phase A: ritical C02; mobile phase B: isopropyl alcohol; gradient: isocratic 10% isopropyl alcohol 90% supercritical C02; UV detection wavelength: 212 nm. Peak one: ion time: 4.34 minutes; recovery: Enantiomer 1 of benzyl 3-(tert-butoxycarbonylamino)ethylpyrrolidinecarboxylate (0.120 g, 0.3 mmol). Peak two: retention time: 8.34 s; recovery: Enantiomer 2 of benzyl t— butoxycarbonylamino)ethylpyrrolidinecarboxylate (0.116 g, 0.3 mmol).
Step C: Preparation of Enantiomer 2 of tert-buth 3-ethylp_yrrolidin ylcarbamate: Prepared as described in International Application No. WC 2009/140320Al, Example D, Step E, using Enantiomer 2 of benzyl 3-(tert-butoxycarbonylamino) ethylpyrrolidinecarboxylate in place of racemic benzyl 3-(tert-butoxycarbonylamino) methylpyrrolidine- 1 xylate.
Step D: Prepared as described in Example 9B, Steps B-G, using dichloro{(R)- (+)-2,2'-bis [di(3 ,5 -xylyl)-phosphino-1,1'-binaphthyl} [(2R)-(-)-1,1-bis(4-methoxyphenyl)-3 - methyl-1,2-butanediamine in place of dichloro{(S)-(-)-2,2'-bis[di(3,5-xylyl)-phosphino-1,1'- binaphthyl}[(2S)-(+)-1,1-bis(4-methoxyphenyl)methyl-1,2-butanediamine in Step B, and substituting omer 2 of tert-butyl 3-ethylpyrrolidinylcarbamate ration J) for (S)—tert—butyl pyrrolidinylcarbamate in Step D. LCMS APCI (+) m/z 471 (M+H).
Example 245 / N N\ I N O N \ \/ I 2HCI Prepared as described in Example 9B Steps B-G, using dichloro{(R)-(+)—2,2'- (3 ,5 -xylyl)-ph0sphino- l , l '-binaphthyl} (-)- 1 , l-bis(4-meth0xyphenyl)—3 -methyl- l,2-butanediamine in place of dichloro{(S)-(-)-2,2'-bis[di(3,5-xylyl)-ph0sphin0-l,l'- binaphthyl}[(2S)-(+)-l,l-bis(4-methoxyphenyl)—3-methyl-l,2-butanediamine in Step B, substituting Enantiomer 2 of tert-butyl 3-ethylpyrrolidinylcarbamate (Example 244) for (S)—tert—butyl pyrrolidinylcarbamate in Step D, and substituting xy fluoroquinolinecarbaldehyde for 8-meth0xyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 503 (M+H).
Example 246 F3Q NH2 dN\/:/,'"II 2 HCI/ N O/ S meth l-l- R -2 2 2-triflu0r0-l- 3- ox uinolin l - l 2 4 triazolo 4 3- a ridin leth l rrolidinamine dih drochloride Prepared as described in Example 9B, Steps D-G, using (S)-tert-butyl 3- methylpyrrolidinylcarbamate (Preparation A) in place of (S)-tert—butyl pyrrolidin ylcarbamate in Step D. LCMS APCI (+) m/z 457 (M+H).
Example 247 Fgc; NH2 dg2 HCI/ N trifluoroeth lmeth l rrolidinamine dih drochloride Prepared as described in Example 9B, Steps D-G, using (S)-tert-butyl 3- methylpyrrolidinylcarbamate (Preparation A) in place of (S)-tert—butyl pyrrolidin ylcarbamate in Step D, and substituting 7-ethoxyfluor0quinolinecarbaldehyde for 8- methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 489 (M+H).
Example 248 Prepared as described in Example 9B, Steps D-G, using (S)-tert—butyl 3- methylpyrrolidinylcarbamate (Preparation A) in place of (S)-tert—butyl idin ylcarbamate in Step D, and substituting 6-fluor0meth0xyquin0linecarbaldehyde for 8- methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 475 (M+H).
Example 249 / NO’NH2 N/ N \N/ N\ o\/ I 2 HCI trifluoroeth l rrolidinamine dih drochloride ] Prepared as described in Example 9B, Steps A-G, using dichloro{(R)-(+)-2,2'- bis[di(3 ,5 )-ph0sphino- l , l '-binaphthyl} [(2R)-(-)— 1 , l-bis(4-meth0xyphenyl)—3 -methyl- l,2-butanediamine in place of ro{(S)-(-)-2,2'-bis[di(3,5-xylyl)-ph0sphin0-l,l'- binaphthyl} [(2S)-(+)—l,l-bis(4-meth0xyphenyl)methyl-l,2-butanediamine in Step B, and substituting 7-eth0xyfluoroquinolinecarbaldehyde for 8-meth0xyquinoline carbaldehyde in Step F. LCMS APCI (+) m/z 475 (M+H).
Example 250 dat/ NH2 N o/ Prepared as described in Example 9B, Steps B-G, using dichloro{(R)—(+)—2,2'- (3 ,5 )-ph0sphino- l , l '-binaphthyl} [(2R)-(-)— 1 , l-bis(4-meth0xyphenyl)—3 -methyl- l,2-butanediamine in place of dichloro{(S)-(-)-2,2'-bis[di(3,5-xylyl)-ph0sphin0-l,l'- binaphthyl} [(2S)-(+)—l,l-bis(4-meth0xyphenyl)methyl-l,2-butanediamine in Step B, and substituting Enantiomer l of tert-butyl 3-ethylpyrrolidinylcarbamate (from Preparation J) for (S)-tert—butyl idinylcarbamate in Step D. LCMS APCI (+) m/z 471 (M+H).
Example 251 ed as described in Example 9B Steps B-G, using dichloro{(R)-(+)—2,2'- bis[di(3 ,5 -xylyl)-ph0sphino- l , l '-binaphthyl} [(2R)-(-)— 1 , l-bis(4-meth0xyphenyl)—3 -methyl- l,2-butanediamine in place of dichloro{(S)-(-)-2,2'-bis[di(3,5-xylyl)-ph0sphin0-l,l'- binaphthyl}[(2S)-(+)-l,l-bis(4-methoxyphenyl)—3-methyl-l,2-butanediamine in Step B, substituting Enantiomer l of tert-butyl 3-ethylpyrrolidinylcarbamate ration J) for (S)—tert—butyl pyrrolidinylcarbamate in Step D, and substituting 7-eth0xy fluoroquinoline-Z-carbaldehyde for 8-meth0xyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 503 (M+H).
Example 252 d at/ .,, NH2 N 0/ | 2HCI Diastereomer 2 of 3-eth l-l- R -2 2 uoro-l- 3- 8-methox uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidinamine dih drochloride Prepared as described in Example 9B, Steps D-G, using Enantiomer 2 of tert- butyl 3-ethylpyrrolidinylcarbamate (Preparation J) in place of (S)-tert—butyl pyrrolidin ylcarbamate in Step D. LCMS APCI (+) m/z 471 (M+H). e 253 Prepared as described in Example 9B, Steps D-G, using Enantiomer 2 of tertbutyl 3-ethylpyrrolidinylcarbamate (from Preparation J) in place of rt—butyl pyrrolidinylcarbamate in Step D, and substituting 7-ethoxyfluoroquinoline carbaldehyde for 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 503 (M+H).
Example 254 1 NH2 2HCI Prepared according to the method of Example 219 substituting 6-fluoro methquuinolinol for 2-methquuinolinol in Step A. FIA-MS APCI (+) m/z 491 (M+H).
Example 255 / 'IINgNHZ / N \N/ N\ O\/ l 2 HCI S -l- R -l- 3- 7-ethox uinolin l - l 2 4 triazolo 4 3-a ridin l -2 2 2- trifluoroethyl [pyrrolidinamine dihydrochloride Step A: Preparation of xymethylguinoline: To a stirred mixture of quuinolinol (400 mg, 2.51 mmol), CSZC03 (2.46 g, 7.54 mmol) and NMP (12 mL) was added bromoethane (0.563 mL, 7.54 mmol). The reaction mixture was stirred at ambient ature overnight. The on was partitioned between ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2:1 to 5:1 hexanes:EtOAc) to give 7-ethoxymethquuinoline (416 mg, 88%).
Step B: Preparation of 7-ethoxyguinolinecarbaldehyde: Prepared as described in Example 5, Step B, using 7-ethoxymethquuinoline in place of 8- (cyclopropylmethoxy)methquuinoline.
Step C: Pre aration of S -l- R -l- 3- 7-ethox uinolin l - l 2 4 triazolo 4 3-a idin l -2 2 2-trifluoroeth l rrolidinamine dih drochloride: Prepared as described in Example 9B, Steps F-G, using 7-ethoxyquinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 457 (M+H).
Example 256 / NQ’NHZ N\ O\/ I 2 HCI S -l- S -l- 3- 7-ethox uinolin l - l 2 4 triazolo 4 3-a r1d1n l -2 2 2- trifluoroeth l rrolidinamine dih drochloride ] Prepared as described in Example 9B, Steps B-G, using dichloro{(R)-(+)-2,2'- bis[di(3 ,5 -xylyl)-phosphino- l , l phthyl} [(2R)-(-)- 1 , l-bis(4-methoxyphenyl)-3 l- l,2-butanediamine in place of dichloro{(S)-(-)-2,2'-bis[di(3,5-xylyl)-phosphino-l,l'- binaphthyl} (+)-l,l-bis(4-methoxyphenyl)methyl-l,2-butanediamine in Step B, and substituting 7-ethoxyquinolinecarbaldehyde for 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 475 (M+H).
Example 257 F3C f / \ H / N 2 HCI 7-eth0x 6- 1R -2 2 2-trifluor0-l- l 7-diazas iro 4.4 nonan l eth l - l 2 4 lo 4 3-a ridin l uinoline dih drochloride Prepared as described in Example 9B, Steps B-G, using tert-butyl 1,7- diazaspir0[4.4]n0nane-l-carb0xylate in place of (S)-tert—butyl pyrrolidinylcarbamate in Step D, and substituting 7-ethoxyquinolinecarbaldehyde for 8-methoxyquinoline dehyde in Step F. LCMS APCI (+) m/z 497 (M+H).
Example 258 7-eth0x 6- 1S -2 2 2-triflu0r0-l- l 7-diazas iro 4.4 nonan l eth l - l 2 4 triazolo 4 3-a ridin l uinoline dih drochloride Prepared as described in Example 9B, Steps B-G, using dichloro{(R)—(+)—2,2'- bis[di(3 ,5 -xylyl)-ph0sphino- l , l '-binaphthyl} [(2R)-(-)- 1 , l-bis(4-meth0xyphenyl)—3 -methyl- l,2-butanediamine in place of dichloro{(S)-(-)-2,2'-bis[di(3,5-xylyl)-ph0sphin0-l,l'- binaphthyl} [(2S)-(+)-l,l-bis(4-meth0xyphenyl)—3-methyl-l,2-butanediamine in Step B, substituting utyl l,7-diazaspiro[4.4]n0nane-l-carboxylate for rt—butyl pyrrolidin- 3-ylcarbamate in Step D, and substituting 7-ethoxyquinolinecarbaldehyde for 8- methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 497 (M+H).
Example 259 ’ New d CH(O)OH N o Step A: Preparation of ethyl 2fluoromethylguinolinyloxy[acetate: Prepared according to the method of Example 219, Step A, substituting ethyl 2-bromoacetate for 2-bromoethyl acetate.
Step B: Pre aration of l- 6-fluorometh l uinolin lox methylpropanol: To a solution of ethyl 2-(2-methquuinolinyloxy)acetate (0.74 g, 3.0 mmol) in l ether (15 mL, 3.0 mmol) was lly added methylmagnesium e (3M in diethyl ether; 2.5 mL) by dropwise addition. The reaction mixture was allowed to stir at ambient temperature for 2 hours. The reaction mixture was poured into ammonium chloride (saturated aqueous; 50 mL) and extracted with dichloromethane (1 x 30 mL). The c extract was dried over ium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0- 100% acetonitrile/water) ing the title compound (0.41 g, 60%).
Step C: Pre n of l- 2- 6- R -l- amino rrolidin-l- l trifluoroeth l - l 2 4 triazolo 4 3-a ridin-3 I IC?“ :3COHO C,_.BOrP 00 I 5‘N I'F’B('DH{27‘ HO a:P 2-ol formate: Prepared according to the method of Example 140 substituting 1-(6-fluoro methquuinolinyloxy)methylpropanol for (R)(l-methoxypropanyloxy) methquuinoline. FIA-MS APCI (+) m/Z 519 (M+H).
Example 260 / NQZNHZ \ 2 HCI Step A: Pre aration of 7- 2-methox ethox meth l uinoline: To a d mixture of 2-methquuinolinol (300 mg, 1.88 mmol), C82C03 (1.84 g, 5.65 mmol) and NMP (10 mL) was added 1-bromomethoxyethane (0.786 g, 5.65 mmol). The on mixture was stirred at ambient temperature overnight. The reaction was partitioned between ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2:1 to 1:2 hexanes/EtOAc) to give 7-(2-methoxyethoxy)methquuinoline (235 mg, 57%).
Step B: Preparation of 7methoxyethoxy[guinolinecarbaldehyde: To a solution of 7-(2-methoxyethoxy)methquuinoline (235 mg, 1.08 mmol) in dioxane (3 mL) and water (0.03 mL) was added SeOz (132 mg, 1.19 mmol). The reaction mixture was heated at reflux for 2 hours. After cooling to t temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure and The residue was purified by flash chromatography on silica gel (4:1 hexanes/EtOAc) to give 7-(2-methoxyethoxy)quinolinecarbaldehyde (195 mg, 78%) as a white solid.
Step C: Pre aration of tert-but l S h l S -2 2 2-trifluoro 3- 7- ox ethox uinolin l - 1 2 4 triazolo 4 3-a ridin-6 l eth l rrolidin ylcarbamate: A mixture of utyl (S)methyl((S)-2,2,2-trifluoro(6- hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate (53 mg, 0.14 mmol), 7-(2- methoxyethoxy)quinolinecarbaldehyde (30 mg, 0.13 mmol) and EtOH (1.4 mL) was stirred at ambient ature ght. The solvent was removed under reduced pressure.
The residue was dissolved in DCM (1.4 mL) and iodosobenzene diacetate (54 mg, 0.17 mmol) was added. The reaction mixture was stirred at ambient temperature overnight and then loaded to a silica gel column eluting with 1:2 to 3:1 hexanes to give tert-butyl (S)-3 -methyl((S)-2,2 ,2-trifluoro(3 -(7-(2-methoxyethoxy)quinolinyl)- [1 ,2,4]triazolo [4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate (72 mg, 92%).
Step D: Pre aration of S meth l S -2 2 2-trifluoro 3- 7- 2- methox ethox uinolin l - 1 2 4 triazolo 4 3-a ridin-6 l eth l rrolidinamine dihydrochloride: A mixture of tert-butyl (S)methyl((S)-2,2,2-trifluoro(3-(7-(2- methoxyethoxy)quinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - ylcarbamate (72 mg, 0.12 mmol), DCM (1 mL) and 4N HCl in dioxane (0.3 mL) was stirred at ambient temperature overnight. Removal of the solvents under reduced pressure gave (S)methyl((S)-2,2,2-trifluoro(3 -(7-(2-methoxyethoxy)quinolinyl)- [1 ,2,4]triazolo [4,3 - dinyl)ethyl)pyrrolidinamine dihydrochloride (65 mg, 95%) as a yellow solid.
LCMS APCI (+) m/z 501 (M+H). c rotation: [(1]st = -0.890 (c = 0.97, MeOH).
Example 261 / F3CWNQ€NH2\ I 2 HCI / N N‘N/ N\ O\/\O/ Prepared as described in e 9B, using (S)—tert-butyl 3-methylpyrrolidin- 3-ylcarbamate in place of (S)-tert—butyl pyrrolidinylcarbamate in Step D, and substituting 7-(2-meth0xyeth0xy)quinolinecarbaldehyde for 8-meth0xyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 501 (M+H).
Example 262 trifluoroeth lmeth l rrolidinamine dih oride ed as described in Example 260, Steps C-D, using 7-ethoxyquinoline carbaldehyde in place of 7-(2-meth0xyeth0xy)quinolinecarbaldehyde in Step C. LCMS APCI (+) m/z 471 (M+H).
Example 263 5N3, OCH(O)OH -l- R -22 2-triflu0r0-l- 3- 8- l-methox meth 1 r0 an lox uinolin l- l 2 4 triazolo 4 3-a ridin l eth l inamine formate Prepared according to the method of Example 192, substituting l-methoxy methylpropanol for (3-methyloxetanyl)methanol. FIA-MS APCI (+) m/Z 515 (M+H).
Example 264 ’ NH2 / NO, \ CH(O)OH / N Ohm -l- R -2 2 2-triflu0r0-l- 3- 6-flu0r0 l-methox meth 1 r0 an lox uinolin Prepared according to the method of Example 192, tuting l-methoxy methylpropanol for (3-methyloxetanyl)methanol and 6-flu0romethquuinolinol for 2-methquuinolinol. FIA-MS APCI (+) m/Z 533 (M+H).
Example 265 a ridin l uinolin lethanol dih drochloride Prepared as described in Example 114, using 2-(2-methquuinolinyl)ethanol in place of (l-(2-methquuinolinyl)cyclopropyl)methanol in Step A. LCMS APCI (+) m/z 457(M+H).
Example 266 F39 NH2 N\ / N N\ S\/ S -l- R -l- 3- 7- eth lthio uinolin l - l 2 4 lo 4 3-a ridin l -2 2 2- trifluoroeth l rrolidinamine h drochloride Step A: Pre n of tert-but l S -l- R -l- 3- 7-br0m0 uinolin l- l 2 4 triazolo 4 3-a ridin l -2 2 2-trifluor0eth l rrolidin lcarbamate : Prepared as described in e 2, Steps A-B, substituting utyl (S)-l-((R)-2,2,2-trifluoro-l-(6- hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate for tert-butyl (3 S)-l-(2,2,2-triflu0r0-l- (6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate.
Step B: Pre aration of tert-but l S -l- l 2 4 triazolo 4 3-a idin l -2 2 2-trifluor0eth l rrolidin lcarbamate: A e of szdbag-CHClg (13.1 mg, 0.0127 mmol), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphine) (14.7 mg, 0.0254 mmol), tert-butyl ((R)(3-(7- bromoquinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidin-3 - ylcarbamate (150 mg, 0.254 mmol), ethanethiol (31.5 mg, 0.507 mmol), DIEA (98.3 mg, 0.761 mmol) in dioxane was heated to 150°C under microwave irradiation for 1 hour. After cooling, the reaction was trated under reduced pressure and purified by chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 30 column volumes) to yield utyl (S)-l-((R)(3-(7-(ethylthio)quinolinyl)-[1,2,4]triazolo[4,3- a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidinylcarbamate (95 mg, 65.4 % yield) as an oil.
] Step C: Pre aration of S -l- R -l- 3- 7- eth lthio uinolin l- 1 2 4 triazolo 4 3-a ridin-6 l -2 2 2-trifluoroeth l rrolidinamine h drochloride: tert- Butyl (S)((R)(3 -(7-(ethylthio)quinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2- trifluoroethyl)pyrrolidinylcarbamate (95 mg, 0.17 mmol) was stirred in TFA for 30 minutes. The on was trated to dryness, then diluted in 1 mL of methanol and added dropwise into 4N HCl in ether. The resulting precipitate was filtered and dried under vacuum to yield (S)((R)(3-(7-(ethylthio)quinolinyl)-[1,2,4]triazolo[4,3-a]pyridin yl)-2,2,2-trifluoroethyl)pyrrolidinamine (56 mg, 71 % yield) hydrochloride as a solid.
LCMS APCI (+) m/z 473 (M).
Example 267 a ridin l uinolin lthio ethanol h drochloride Prepared as in Example 266, substituting ethanethiol in Step A with 2- mercaptoethanol. LCMS APCI (+) m/z 489 (M+H).
Example 268 F3C”. N H 2 N\/mmN 8 S R -2 2 uoro 3- 7- iso ro lthio uinolin l - 1 2 4 triazolo 4 3-a ridin- 6- l eth l rrolidinamine h drochloride Prepared as in Example 266, substituting thiol in Step A with propane- 2-thiol. LCMS APCI (+) m/z 487 (M+H).
Example 269 F39. aNgNH2 HCI/ N N\ / N O\ a ridin leth l rrolidinamine dih drochloride ed as described in Example 153 using 3-bromoaniline in place of 3- bromofluoroaniline in Step A. LCMS APCI (+) m/z 47l(M+H). e 270 —. ND’NH / \ CH(O)OH / N OACN N\ / N N\ 2- 2- 6- R amino rrolidin l -2 2 2-trifluoroeth l - 1 2 4 triazolo 4 3- a 3- l uinolin lox acetonitrile formate ] Step A: Pre aration of tert—but l R 3- 8- c anomethox uinolin- 2- l - 1 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidin lcarbamate: Prepared according to the method of Example 219, Steps A-D, substituting 2-iodoacetonitrile for 2-bromoethyl acetate in Step A.
Step B: Pre aration of 2- 2- 6- R amino rrolidin l -2 2 2- trifluoroeth l- 12 4 triazolo 4 3-a ridin l uinolin lox acetonitrile formate: Prepared according to the method of Example 192, tuting tert—butyl (S)((R)—1-(3-(8- (cyanomethoxy)quinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2- trifluoroethyl)pyrrolidinylcarbamate for tert—butyl (S)((R)—2,2,2-trifluoro(3-(8-((3- methyloxetanyl)methoxy)quinolinyl)-[1 ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidin—3-ylcarbamate in Step A. FIA-MS APCI (+) m/Z 468 (M+H).
Example 271 F30r ng/EC:\_ NH2 2HC| / N Step A: Pre aration of 8- 1 3-dimethox ro an lox meth l uinoline: To a solution of 2-methquuinolinol (4.10 g, 25.76 mmol), PPh3 (16.89 g, 64.39 mmol) and 1,3-dimethoxypropanol (4.02 g, 33.48 mmol) in THF (20 mL) was added DIAD (8.40 mL, 41.21 mmol) dropwise at ambient temperature. The reaction mixture was stirred at room temperature for two days. 4 N HC1 (7.73 mL, 30.91 mmol in , water (20 mL), and ethyl acetate (50 mL) were added. The aqueous layer was separated and washed with ethyl acetate.
The aqueous layer was neutralized with ammonium hydroxide to about pH 9 and extracted with ethyl acetate (50 mL). The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under d pressure. The residue was purified by flash chromatography on silica gel (1:2 hexane/ethyl acetate) to give 8-(l,3- dimethoxypropanyloxy)methquuinoline (6.00 g, ) as an oil.
Step B: Pre aration of S R 3- 8- 13-dimethox ro an lox uinolin l - 1 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidin amine ochloride: Prepared as described in e 37, Steps A-C, using 8-(l,3- dimethoxypropanyloxy)methquuinoline in place of 8-ethylmethquuinoline in Step B. LCMS APCI (+) m/z 531(M+H).
Example 272 2HC| / N O/X Prepared as described in e 9B, Steps A-G, using (R)-tert-butyl 3- methylpyrrolidinylcarbamate Preparation B) in place of rt-butyl pyrrolidin 2012/026572 ylcarbamate in Step D and using 8-(2-hydroxymethylpropoxy)quinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. MS APCI (+) m/z 515 (M+1) detected.
Example 273 F3C1 NH2 cf/ NC!» N S/\ N N\ S R 3- 8- eth lthio uinolin l - 1 2 4 triazolo 4 3-a ridin l -2 2 2- trifluoroeth l rrolidinamine h drochloride Step A: Pre aration of tert-but l S R 3- 8-bromo uinolin l- 1 2 4 triazolo 4 3-a 6- l -2 2 2-trifluoroeth l in lcarbamate: Prepared as described in Example 9B, Steps A-G, using 8-bromoquinolinecarbaldehyde (WO 2010/022081) in place of 8-methoxyquinolinecarbaldehyde in Step F.
Step B: Pre aration of tert-but l S R 3- 8- eth lthio uinolin l - 1 2 4 triazolo 4 3-a ridin l -2 2 2-trifluoroeth l rrolidin lcarbamate: szdbag'CHClg (8.75 mg, 0.00845 mmol), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphine) (9.78 mg, 0.0169 mmol), tert-butyl (S)((R)(3-(8- uinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidin-3 - ylcarbamate (100 mg, 0.169 mmol), thiol (31.5 mg, 0.507 mmol) and l-N- pylpropanamine (131 mg, 1.01 mmol) in dioxane were heated to 150°C under microwave irradiation for 1 hour. After cooling, the reaction was concentrated under reduced pressure and purified by chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 30 column volumes) to yield tert-butyl ((R)(3-(8-(ethylthio)quinolin- 2-yl)-[1,2,4]triazolo[4,3-a]pyridinyl)-2,2,2-trifluoroethyl)pyrrolidinylcarbamate (60 mg, 62.0 % yield) Step C: Pre aration of S R 3- 8- eth lthio uinolin l- 1 2 4 triazolo 4 3-a 6 l -2 2 2-trifluoroeth l rrolidinamine h drochloride: tert- butyl (S)((R)(3 -(8-(ethylthio)quinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)-2,2,2- trifluoroethyl)pyrrolidinylcarbamate (55 mg, 0.096 mmol) was stirred in TFA for 30 minutes. The reaction was concentrated to dryness, and the residue was diluted in 1 mL of methanol and added dropwise into 4N HCl in ether. The resulting precipitate was filtered and dried under vacuum to yield (S)((R)(3-(8-(ethylthio)quinolinyl)-[1,2,4]triazolo[4,3- dinyl)—2,2,2-trifluoroethyl)pyrrolidinamine (16 mg, 35 % yield) hydrochloride as a solid. LCMS APCI (+) m/z 473 (M+H).
Example 274 / ,HNQ’NHZ 2HCI / N N\ / N N\ O\/\O/\ trifluoroeth l rrolidinamine dih drochloride Step A: Pre aration of 7- 2-ethox ethox uinolinecarbaldeh de: ed as described in Example 260, Step A to B, using 1-bromoethoxyethane in place of 1- bromomethoxyethane in Step A.
Step B: Pre aration of S R 3- 7- 2-ethox ethox uinolin l- 1 2 4 triazolo 4 3-a idin l -2 2 2-trifluoroeth l inamine dih drochloride: ed as described in Example 9B, Steps F-G, using 7-(2-ethoxyethoxy)quinoline carbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 501 (M+H).
Example 275 / ”NQ’NHZ 2 HCI N/ N \N/ N\ O\/\/O\ a ridin leth l rrolidinamine dih drochloride Step A: Pre aration of 7- 3-methox ro ox uinolinecarbaldeh de: ed as described in Example 260 Step A to B using 1-bromomethoxypropane in place of 1-bromomethoxyethane in Step A.
Step B: Pre aration of S R -2 2 2-trifluoro 3- 7- 3- methox ro ox uinolin l - 12 4 triazolo 4 3-a ridin l eth l inamine dihydrochloride: Prepared as described in Example 9B, Steps F-G, using 7-(3- methoxypropoxy)quinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 501 (M+H).
Example 276 ‘ ”3’NH2 d CH(O)OH / N N. / 0%\ R -2 2 2-trifluoro 3- 8- 2-methox meth l ro ox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l inamine formate Step A: Pre aration of 8- 2-methox meth l ro ox meth l uinoline: To a mixture of sodium hydride (60% in mineral oil; 0.013 g, 0.32 mmol) in anhydrous dimethylformamide (1.4 mL, 0.22 mmol) was added dropwise a solution of 2-methyl(2- methquuinolinyloxy)propanol (Example 259; 0.050 g, 0.22 mmol) in ous dimethylformamide (1.4 mL, 0.22 mmol). The mixture was allowed to stir at ambient temperature for 30 minutes before by addition of iodomethane (0.054 mL, 0.86 mmol), and the resultant mixture allowed to stir at ambient temperature for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic ts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) providing the title compound (0.038 g, 73%).
Step B: methox h l ro ox uinolin l - 1 2 4 triazolo 4 3-a 6I _. (DH:r _. oaO.H? 3-ylcarbamate: ed according to the method of Example 140, Steps B-C , substituting ethoxymethylpropoxy)methquuinoline for (R)(1-methoxypropanyloxy) methquuinoline in Step B.
Step C: Pre aration of R -2 2 2-trifluoro 3- 8- 2-methox meth l ro ox uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidinamine formate: Prepared according to the method of e 192, Step B, substituting tert—butyl (S)((R)-2,2,2-trifluoro(3-(8-(2-methoxymethylpropoxy)quinolinyl)- [1,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate for utyl (S)((R)— 2,2,2-trifluoro(3 -(8-((3 -methyloxetan-3 -yl)methoxy)quinolinyl)-[1 ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinylcarbamate. FIA-MS APCI (+) m/Z 515 (M+H).
WO 54274 Example 277 / HZ Step A: Pre aration of R 2-meth l uinolin lox ro anol: To a stirred mixture of 2-methquuinolinol (0.400 g, 2.51 mmol), C82C03 (2.46 g, 7.54 mmol) and DMF (16 mL) was added (R)methyloxirane (0.438 g, 7.54 mmol). The reaction mixture was heated at 80 CC for 2 hours. After cooling, the reaction mixture was partitioned between ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash tography on silica gel (1% MeOH in EtOAc) to give (2-methquuinolinyloxy)propanol (0.471 g, 86%).
Step B: Preparation of gR2g2-methoxyprop_oxy2methylguinoline: To a stirred suspension of NaH (60% dispersion in oil, 95 mg, 2.4 mmol) in DMF (8 mL) was added dropwise a solution of (R)(2-methquuinolinyloxy)propanol (344 mg, 1.58 mmol) in DMF (4 mL) at 0 CC under nitrogen. The reaction mixture was stirred at 0 °C for 30 minutes. Mel (0.198 mL, 3.17 mmol) was added dropwise. The reaction was stirred at ambient ature overnight. The reaction mixture was partitioned n EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexanes/EtOAc) to give (R)(2- methoxypropoxy)methquuinoline (185 mg, 51%).
Step C: Pre aration of R ox ro ox uinolinecarbaldeh de: Prepared as bed in Example 5, Step B, using (R)(2-methoxypropoxy) methquuinoline in place of 8-(cyclopropylmethoxy)methquuinoline.
Step D: Pre aration of S R -2 2 2-trifluoro 3- 7- R methox ro ox uinolin l - 12 4 triazolo 4 3-a 6- l eth l rrolidinamine dihydrochloride: Prepared as described in Example 9B, Steps F-G, using (R)(2- methoxypropoxy)quinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 501 (M+H).
Example 278 / "'NQ’NHZ N/ N \/ 0 N X IN\ OH l- 2- 6- R -l- S n0 in-l- l -2 2 2-triflu0r0eth l - l 2 4 triazolo 4 3- Step A: Pre aration of 2-meth l-l- 2-meth l uinolin lox r0 anol: Prepared as described in Example 277, Step A, using 2,2-dimethyloxirane in place of (R) methyloxirane.
Step B: Pre aration of 7- 2-h drox meth 1 r0 0x uinoline carbaldehyde: Prepared as bed in Example 5, Step B, using 2-methyl-l-(2- uinolinyloxy)propanol in place of 8-(cyclopropylmethoxy)—2-methquuinoline.
Step C: Pre aration of l- 2- 6- R -l- S amino rrolidin-l- l trifluoroeth l- 12 4 triazolo 4 3-a ridin l uinolin lox meth 1 r0 anol dihydrochloride: Prepared as described in Example 9B, Steps F-G, using 7-(2-hydroxy methylpropoxy)quinolinecarbaldehyde in place of oxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 501 (M+H).
Example 279 trifluoroeth l rrolidin lmethanamine h drochloride ] Prepared as in Example 133, replacing tert-butyl (S)-l-((R)-2,2,2-triflu0ro-l- (6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in Step C with tert-butyl ((S)-l- ((R)-2,2,2-triflu0r0- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -yl)methylcarbamate.
LCMS APCI (+) m/z 489 (M+H).
Example 280 roeth 1 rrolidin lmethanamine h drochloride Prepared as in Example 133, replacing tert-butyl ((R)-2,2,2-triflu0ro-l- (6-hydraziny1pyridiny1)ethy1)pyrr01idinylcarbamate in Step C with tert-butyl ((R)-l- ((R)-2,2,2-triflu0r0- l -(6-hydraziny1pyridin-3 -y1)ethy1)pyrr01idin-3 -y1)methylcarbamate.
LCMS APCI (+) m/z 489 (M+H).
Example 281 a 6- leth 1 rrolidinamine h drochloride ] Prepared as in Example 275, substituting l-bromomethoxypropane in Step A with (2-chloroethy1)(methy1)sulfane. (LCMS APCI (+) m/z 489 (M+H). (LCMS APCI (+) m/z 489 (M+H).
Example 282 trifluoroeth 1 rrolidinamine h drochloride Prepared as in Example 133, replacing tert-butyl (S)-l-((R)-2,2,2-triflu0ro-l- (6-hydraziny1pyridiny1)ethy1)pyrr01idinylcarbamate in Step C with tert-butyl (R)-l- ((R)-2,2,2-triflu0r0- l -(6-hydraziny1pyridin-3 -y1)ethy1)pyrr01idin-3 -y1carbamate. (LCMS APCI (+) m/z 475 (M+H).
Example 283 F3C’ '- NH2 dgN CH(O)OH a ridin l uinolin lox ro anol formate Step A: Pre aration of tert—but l -l- R trifluoro-l- 3- 8- R h drox ro ox uinolin l- 12 4 triazolo 4 3-a ridin leth l rrolidin ylcarbamate: Prepared according to the method of Example 187, substituting R-(+)- propylene oxide for S—(-)-propylene oxide.
Step B: Pre aration of -l- R -2 2 2-trifluoro-l- 3- 8- ox meth l ro ox uinolin l- l 2 4 triazolo 4 3-a ridin leth l rrolidinamine formate: ed according to the method of Example 192, Step B, substituting utyl (S)- l -((R)-2,2,2-trifluoro- l -(3 -(8-((R)hydroxypropoxy)quinolinyl)-[ l ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinylcarbamate for tert—butyl (S)-l-((R)-2,2,2-trifluoro-l-(3-(8- ((3 -methyloxetanyl)methoxy)quinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridinyl)ethyl) pyrrolidinylcarbamate. FIA-MS APCI (+) m/Z 487 (M+H).
Example 284 F3C NH2 / 0/ 2 HCI / N N/ N\ O\ Prepared as bed in Example 9B, using dichloro{(R)-(+)-2,2'-bis[di(3,5- xylyl)-phosphino- l , l phthyl} [(2R)-(-)- 1 , l -bis(4-methoxyphenyl)-3 -methyl- 1 ,2- butanediamine in place of dichloro {(S)—(-)-2,2'-bis [di(3 ,5 -xylyl)-phosphino- l l '- binaphthyl}[(2S)-(+)-l,l-bis(4-methoxyphenyl)methyl-l,2-butanediamine in Step B, substituting (S)-tert—butyl 3-methylpyrrolidinylcarbamate for (S)-tert—butyl pyrrolidin amate in Step D, and tuting 6-fluoro(2-methoxyethyl)quinoline carbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 503 (M+H).
Example 285 / "'NQ’NHZ a ridin lfluoro uinolin lox eth lisobut rate Step A: Pre aration of 7- 2- tert-but ldimeth lsil lox ethox fluoro methylguinoline: To a d e of 2-methquuinolinol (1.54 g, 8.69 mmol), C82C03 (8.50 g, 26.1 mmol) and NMP (43 mL) was added moethoxy)(tertbutyl )dimethylsilane (6.24 g, 26.1 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was partitioned between ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2:1 hexanes/EtOAc) to give 7-(2-(tertbutyldimethylsilyloxy )ethoxy)fluoromethquuinoline (2.75 g, 94%).
Step B: Pre n of 7- 2- tert-but ldimeth lsil lox ethox fluoroguinolinecarbaldehyde: To a solution of 7-(2-(tert-butyldimethylsilyloxy)ethoxy)- 6-fluoromethquuinoline (2.74 g, 8.17 mmol) in dioxane (24 mL) and water (0.24 mL) was added SeOz (0.997 g, 8.98 mmol). The reaction mixture was heated at reflux for 4 hours.
After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure and The residue was d by flash tography on silica gel (4:1 hexanes/EtOAc) to give 7-(2-(tert— butyldimethylsilyloxy)ethoxy)fluoroquinolinecarbaldehyde (2.69 g, 94%).
Step C: Pre aration of tert-but l S meth l S -2 2 2-trifluoro 3- 7- 2-methox ethox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidin ylcarbamate: A mixture of tert-butyl (S)methyl((S)-2,2,2-trifluoro(6- hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate (1.50 g, 4.01 mmol), 7-(2-(tert- butyldimethylsilyloxy)ethoxy)fluoroquinolinecarbaldehyde (1.40 g, 4.01 mmol) and EtOH (30 mL) was stirred at t temperature overnight. The solvent was d under reduced pressure. The residue was dissolved in DCM (30 mL) and iodobenzene diacetate 2012/026572 (1.68 g, 5.21 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The mixture was partitioned between EtOAc and saturated aqueous NaHC03 solution. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and trated under reduced pressure. The residue was purified by flash chromatography on silica gel ) to give tert-butyl (S)methyl-l-((S)-2,2,2- trifluoro-l -(3 -(7-(2-methoxyethoxy)quinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridin yl)pyrrolidinylcarbamate (1.45 g, 51%).
Step D: Pre aration of tert-bu l S -l- R -2 2 2-trifluoro-l- 3- 6-fluoro 2- h drox ethox uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidin ylcarbamate: To a d solution of tert-butyl (S)methyl-l-((S)-2,2,2-trifluoro-l-(3-(7- hoxyethoxy)quinolinyl)-[ l ,2,4]triazolo [4,3 idinyl)ethyl)pyrrolidin-3 - ylcarbamate (1.37 g, 1.94 mmol) in THF (100 mL) was added tetrabutylammonium fluoride trihydrate (1.84 g, 5.83 mmol). The reaction e was stirred at ambient temperature for 2 hours. The e was partitioned between saturated aqueous NH4Cl solution and EtOAc.
The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash tography on silica gel (3% MeOH in EtOAc) to give tert-butyl (S)-l- ((R)-2,2,2-trifluoro- l -(3 -(6-fluoro(2-hydroxyethoxy)quinolinyl)-[ l ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinylcarbamate (1.01 g, 88%) as a white solid.
Step E: Pre aration of 2- 2- 6- R -l- S tert- butox carbon lamino rrolidin-l- l -2 2 2-trifluoroeth l - l 2 4 triazolo 4 3-a ridin yl1fluoroquinolinyloxy[ethyl isobutyrate: To a stirred on of tert-butyl (S)-l-((R)- 2,2,2-trifluoro- l -(3 -(6-fluoro(2-hydroxyethoxy)quinolinyl)- [l ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinylcarbamate (80 mg, 0.14 mmol) in DCM (1 mL) and Et3N (0.057 mL, 0.41 mmol) was added dropwise isobutyryl chloride (0.036 mL, 0.34 mmol) at 0 CC under nitrogen. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHC03 solution and brine, dried and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to give 6-((R)- l-((S)-3 -(tert-butoxycarbonylamino)pyrrolidin- l -yl)-2,2,2-trifluoroethyl)-[ l ,2,4]triazolo [4,3 - a]pyridinyl)fluoroquinolinyloxy)ethyl isobutyrate (75 mg, 84%).
Step F: Pre aration of 2- 2- 6- R -l- S amino rrolidin-l- l trifluoroeth l- 12 4 triazolo 4 3-a ridin l fluoro uinolin lox eth l isobut rate: A mixture of 6-((R)- l -((S)-3 -(tert-butoxycarbonylamino)pyrrolidin- l -yl)-2,2,2- 2012/026572 trifluoroethyl)-[ 1 ,2,4]triazolo[4,3-a]pyridinyl)fluoroquinolinyloxy)ethyl isobutyrate (75 mg, 0.11 mmol), DCM (1 mL) and 4N HC1 in dioxane (0.3 mL) was stirred at ambient temperature for 3 hours. The solvents were removed under reduced pressure. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to give the product as the A salt. The combined fractions were basified by saturated s NaHC03 solution and extracted with EtOAc. The organic layers were washed with brine, dried and concentrated under reduced pressure to give 6-((R)((S)aminopyrrolidinyl)- 2,2,2-trifluoroethyl)- [1 riazolo [4,3 -a]pyridin-3 -yl)fluoroquinolinyloxy)ethyl isobutyrate (49 mg, 77%) as a white solid. LCMS APCI (+) m/z 561 (M+H).
Example 286 / ,"NQ’NHZ N/ N \ /moo” 2- 2- 6- R S amino rrolidin-l- l -2 2 2-trifluoroeth l - 1 2 4 triazolo 4 3- Step A: Pre aration of 2- 2- 6- R S tert- butox carbon lamino rrolidin-l- l -2 2 2-trifluoroeth l - 1 2 4 triazolo 4 3-a ridin yl2fluoroguinolinyloxy[ethyl isobutyrate: To a stirred on of tert-butyl (S)((R)- 2,2,2-trifluoro(3-(6-fluoro(2-hydroxyethoxy)quinolinyl)- [1 ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinylcarbamate (Example 123, Step A; 100 mg, 0.169 mmol) and DMAP (21 mg, 0.17 mmol) in ne (1 mL) was added dropwise pivalic anhydride (0.063 mL, 0.34 mmol) at 0 °C under nitrogen. The reaction mixture was warmed to ambient temperature and heated at 60 0C for 3 hours. After cooling, the solvent was evaporated under reduced pressure. The residue was taken up in EtOAc, washed with saturated aqueous NaHC03 solution and brine, dried and concentrated under reduced re. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to give 2-(2-(6-((R)- 1-((S)-3 -(tert-butoxycarbonylamino)pyrrolidinyl)-2,2,2-trifluoroethyl)-[1 ,2,4]triazolo [4,3 - a]pyridinyl)fluoroquinolinyloxy)ethyl yrate (92 mg, 81%).
Step B: Pre aration of 2- 2- 6- R S amino rrolidin-l- l -2 2 2- trifluoroeth l- 12 4 triazolo 4 3-a ridin lfluoro n lox eth l ivalate: A mixture of 2-(2-(6-((R)((S)-3 -(tert-butoxycarbonylamino)pyrrolidinyl)-2,2,2- trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridinyl)fluoroquinolinyloxy)ethyl isobutyrate (92 mg, 0.14 mmol), DCM (1 mL) and 4N HCl in dioxane (0.3 mL) was stirred at ambient temperature for 3 hours. The ts were removed under reduced re. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to give the t as the bis-TFA salt. The combined fractions were basified by saturated aqueous NaHC03 solution and extracted with EtOAc. The organic layers were washed with brine, dried and trated under reduced pressure to give 2-(2-(6-((R)((S)aminopyrrolidinyl)- 2,2,2-trifluoroethyl)- [1 ,2,4]triazolo [4,3 -a]pyridin-3 -yl)fluoroquinolinyloxy)ethyl pivalate (66 mg, 84%) as a white solid. LCMS APCI (+) m/z 575 (M+H).
Example 287 / HZ 2 HCI / N E N\ 3 N/ N\ o\/\O/ a ridin leth l rrolidinamine dih drochloride Step A: Pre aration of S 2-methox ro ox meth l uinoline: To a stirred solution of 2-methquuinolinol (1.00 g, 6.28 mmol), PPh3 (4.12 g, 15.7 mmol) and (S)methoxypropanol (0.679 g, 7.54 mmol) in THF (60 mL) was added dropwise diisopropyl azodicarboxylate (2.05 mL, 10.1 mol) at 0 CC under nitrogen. The reaction mixture was stirred at ambient temperature overnight. The reaction was then heated at 50 CC for additional 2 hours. After cooling, to the on were added 4N HCl (3.1 mL), water (100 mL) and EtOAc (200 mL). The aqueous layer was separated and washed with EtOAc (100 mL). The s was neutralized with ammonium hydroxide to about pH 9, extracted with EtOAc, washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:1 hexane/EtOAc) to give (S)(2- methoxypropoxy)methquuinoline (0.738 g, 51 %).
Step B: Pre n of S 2-methox ro ox uinolinecarbaldeh de: Prepared as described in Example 5, Step B, using (S)(2-methoxypropoxy) methquuinoline in place of 8-(cyclopropylmethoxy)methquuinoline.
Step C: Pre n of S R -2 2 2-trifluoro 3- 7- S methox ro ox uinolin l - 12 4 lo 4 3-a ridin l eth l rrolidinamine dihydrochloride: Prepared as described in Example 9B, Steps F-G, using (S)(2- methoxypropoxy)quinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 501 (M+H).
Example 288 / ,HNQ’NHZ N/ N \ /NWOV\O 2- 2- 6- R -l- S amino rrolidin-l- l -2 2 2-trifluoroeth l - l 2 4 triazolo 4 3- a ridin lfluoro uinolin lox eth l2-eth oate Prepared as described in e 286 using 2-ethylbutanoyl chloride in place of pivalic anhydride in Step A. LCMS APCI (+) m/z 589 (M+H).
Example 289 / ,HNQ’NHZ N/ N N N\ O\/\O 2- 2- 6- R -l- S amino rrolidin-l- l -2 2 2-trifluoroeth l - l 2 4 triazolo 4 3- a ridin lfluoro uinolin lox eth l2 2-dimeth lbutanoate Prepared as described in e 286 using dimethylbutanoyl chloride in place of pivalic anhydride in Step A. LCMS APCI (+) m/z 589 (M+H).
Example 290 a ridin lfluoro uinolin lox eth l2-aminometh lbutanoate Step A: Pre aration of S 2- 6- R -l- S tert- butox carbon lamino in-l- l -2 2 2-trifluoroeth l - l 2 4 triazolo 4 3-a 3- lfluoro uinolin lox eth l 2- tert—butox carbon lamino meth lbutanoate: To a d solution of tert-butyl (S)-l -((R)-2,2,2-trifluoro- l -(3 -(6-fluoro(2- hydroxyethoxy)quinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - 2012/026572 ylcarbamate (Example 123, Step A; 100 mg, 0.169 mmol) and (S)—2-(tertbutoxycarbonylamino )methylbutanoic acid (44.1 mg, 0.203 mmol) in DCM (2 mL) was added DMAP (41.4 mg, 0.339 mmol) and DCC (41.9 mg, 0.203 mmol) under nitrogen. The reaction mixture was stirred at ambient temperature for 4 hours and then poured into water.
The mixture was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHC03 solution and brine, dried, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to give (S)(2-(6-((R)((S)(tert-butoxycarbonylamino)pyrrolidin yl)-2,2,2-trifluoroethyl)—[ 1 ,2,4]triazolo[4,3-a]pyridinyl)fluoroquinolinyloxy)ethyl 2- (tert-butoxycarbonylamino)methylbutanoate (110 mg, 82%).
Step B: Pre aration of S 2- 6- R S amino rrolidin-l- l -2 2 2- trifluoroeth l- 12 4 triazolo 4 3-a ridin l fluoro uinolin lox eth l 2-amino butanoate: Prepared as described in Example 286, Step B, using (S)(2-(6-((R) ((S)-3 -(tert—butoxycarbonylamino)pyrrolidinyl)-2,2,2-trifluoroethyl)- [1 ,2,4]triazolo [4,3 - a]pyridinyl)fluoroquinolinyloxy)ethyl 2-(tert-butoxycarbonylamino) methylbutanoate in place of 2-(2-(6-((R)((S)(tert-butoxycarbonylamino)pyrrolidin yl)-2,2,2-trifluoroethyl)—[ 1 ,2,4]triazolo [4,3 idin-3 -yl)fluoroquinolinyloxy)ethyl isobutyrate in Step B. LCMS APCI (+) m/z 590 (M+H).
Example 291 / N\C-NQ’NHZ CH(O)OH \O/\/O\ R -2 2 2-trifluoro 3- 8- R methox ro ox uinolin l - 1 2 4 triazolo 4 3- ridin leth l rrolidinamine e ] Step A: Pre aration of R 2-meth l n lox ro anol: Prepared according to the method of Example 187, Step A, substituting R-(+)—propylene oxide for S—(-)—propylene oxide.
Step B: Pre aration of R 2-methox ro ox h l uinoline: Prepared according to the method of Example 276, Step A, substituting (R)(2- uinolinyloxy)propanol for 2-methyl(2-methquuinolinyloxy)propanol.
Step C: Pre aration of tert—but l R trifluoro 3- 8- R methox ro ox uinolin l - 1 2 4 triazolo 4 3-a ridin leth l rrolidin amate: Prepared according to the method of Example 140, Steps B-C, substituting (R)- 8-(2-methoxypropoxy)—2-methquuinoline for (R)(1-methoxypropanyloxy) methquuinoline in Step B.
Step D: Pre aration of R -2 2 uoro 3- 8- R methox ro ox n l - 1 2 4 triazolo 4 3-a ridin leth l rrolidinamine formate: Prepared according to the method of e 192, Step B, substituting tert—butyl (S)((R)-2,2,2-trifluoro(3 -(8-((R)methoxypropoxy)quinolinyl)-[ 1 ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinylcarbamate for tert—Butyl (S)((R)-2,2,2-trifluoro-l-(3- (8-((3 -methyloxetan-3 -yl)methoxy)quinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidin—3-ylcarbamate. FIA-MS APCI (+) m/Z 501 (M+H).
Example 292 F30 .\\N H2 trifluoroeth l rrolidinamine h drochloride Prepared as in Example 133 replacing tert-butyl (S)-l-((R)-2,2,2-trifluoro (6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in step C with utyl (R)((S)- 2,2,2-trifluoro(6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate. (LCMS APCI (+) m/z 475 (M+H).
Example 293 F306 .\\N H2 ‘ NC" trifluoroeth th l rrolidinamine h drochloride Prepared as in Example 133 replacing tert—butyl (S)-l-((R)-2,2,2-trifluoro (6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in step C with tert-butyl (R) methyl((R)-2,2,2-trifluoro(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate.
(LCMS APCI (+) m/z 489 (M+H).
Example 294 F30 0‘.\‘ N H2 trifluoroeth th l rrolidinamine h oride Prepared as in Example 133 replacing tert—butyl ((R)-2,2,2-triflu0ro-l- (6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in step C with tert-butyl (R) methyl((S)-2 rifluor0- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate.
(LCMS APCI (+) m/z 489 (M+H).
Example 295 trifluoroeth l rrolidin lmethanamine h drochloride Prepared as in Example 133 replacing tert—butyl (S)-l-((R)-2,2,2-triflu0ro-l- (6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in step C with tert-butyl ((S)-l- ((S)-2,2,2-triflu0r0- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidinyl)methylcarbamate (Prepared as described in Example 1, Steps A-F, using (R)-tert-butyl pyrrolidin ylmethylcarbamate in place of (S)—tert-butyl pyrrolidinylcarbamate in Step C). (LCMS APCI (+) m/z 489 (M+H).
Example 296 roeth l rrolidin lmethanamine h drochloride Prepared as in Example 133 replacing tert-butyl (S)-l-((R)-2,2,2-triflu0ro-l- (6-hydrazinylpyridinyl)ethyl)pyrrolidinylcarbamate in step C with tert-butyl ((R)-l- ,2,2-triflu0r0- l drazinylpyridin-3 -yl)ethyl)pyrrolidinyl)methylcarbamate (Prepared as described in Example 1, Steps A-F, using (S)—tert-butyl pyrrolidin ylmethylcarbamate in place of (S)—tert-butyl pyrrolidinylcarbamate in Step C. (LCMS APCI (+) m/z 489 (M+H).
Example 297 2 HCI Prepared as described in Example 260, Steps C-D, using 7-(2-hydroxy propoxy)quinolinecarbaldehyde in place of 7-(2-meth0xyeth0xy)quinoline carbaldehyde in Step C. LCMS APCI (+) m/z 515 (M+H).
Example 298 / NQZNHZ \ 2 HCI Prepared as described in Example 260, Steps C-D, using 6-fluoro(2- methoxyethoxy)quin0linecarbaldehyde in place of 7-(2-meth0xyeth0xy)quin0line dehyde in Step C. LCMS APCI (+) m/z 519 (M+H).
Example 299 2HC| / N 2 2 2-trifluoroeth l methox rrolidinamine dih drochloride ] Step A: Pre aration of 3R 4R -tert-but l 3-azidomethox rrolidine carboxylate: To a solution of (3R,4R)-tert-butyl 3-azidohydroxypyrrolidinecarboxylate (2.00 g, 8.76 mmol) and Mel (1.64 mL, 26.3 mmol) in DMF (20 mL) was added 60% NaH (0.701 g, 17.5 mmol) at 0 °C. The mixture was warmed to ambient ature and stirred at ambient temperature for 1 hour. Water (20 mL) and ether (40 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash tography on silica gel (3:1 hexane/ethyl acetate) to give (3R,4R)-tert-butyl 3-azidomethoxypyrrolidinecarboxylate (2.04 g, 96.1%) as thick oil.
Step B: Preparation of g3R,4R)—tert-butyl 3-1benzyloxycarbonylamino1 methoxypyrrolidinecarboxylate: A mixture of (3R,4R)-tert—butyl 3-azido methoxypyrrolidinecarboxylate (2.04 g, 8.420 mmol) and PtOz (0.096 g, 0.42 mmol) in MeOH (100 mL) was charged with hydrogen (1 atmosphere) and stirred at ambient temperature for 2 days. Charcoal (2 g) was added to the solution and. The catalyst was removed by filtration and washed with MeOH (20 mL). The t was removed and dried to give (3R,4R)-tert—butyl 3-aminomethoxypyrrolidinecarboxylate. It was dissolved in dioxane (10 mL) and water (10 mL). Na2C03 (1.34 g, 12.63 mmol) was added, followed by Cbz-Cl (1.87 mL, 12.63 mmol) at ambient temperature. The reaction e was stirred at ambient temperature for 3 hours. Ethyl acetate (50 ml) was added. The organic layer was ted, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (1:1 hexane/ethyl acetate) to give )-tert—butyl 3-(benzyloxycarbonylamino) methoxypyrrolidinecarboxylate (2.90 g, 98.3% yield) as oil.
Step C: Pre n of benz l benz 1 3R 4R methox rrolidin ylcarbamate: To a solution of )-tert-butyl 3-(benzyloxycarbonylamino) methoxypyrrolidinecarboxylate (2.90 g, 8.28 mmol) in DCM (20 mL) was added 4 N HCl (20.69 mL, 82.76 mmol) in dioxane. The reaction mixture was stirred at t temperature for 2 hours. The t was removed under reduced pressure. Saturated bicarbonate (20 mL) and DCM (50 mL) were added. The organic layer was separated, dried (sodium sulfate), filtered and concentrated under reduced pressure to give benzyl (3R,4R) methoxypyrrolidinylcarbamate (2.0 g, 96.6%) as oil.
Step D: Pre aration of benz l tert-but 1 3R 4R R -l- 6-chlor0 ridin yl[-2,2,2-trifluor0ethyl[meth0x1pyrrolidinylcarbamate: Prepared as described in Example 145, Steps C-D, using tert—butyl (3R,4R)—4-meth0xypyrrolidinylcarbamate in place of benzyl (3R,4R)hydr0xypyrrolidinylcarbamate in Step C.
Step E: Pre aration of 3R 4R l 2 4 triazolo 4 3-a ridin l -2 2 2-trifluor0eth l meth0x inamine dihydrochloride: Prepared as described in Example 9B, Steps E-G, using tert—butyl (3R,4R)- l -((R)- l -(6-chlor0pyridin-3 -yl)-2,2,2-trifluor0ethyl)meth0xypyrrolidinylcarbamate in place of tert—butyl (S)-l-((R)-l-(6-chlor0pyridinyl)-2,2,2-triflu0r0ethyl)pyrrolidin ylcarbamate in Step E, and substituting 7-ethoxyfluor0quinolinecarbaldehyde for 8- yquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 505(M+H).
Example 300 F3C NH2 N "'u / 2HCI / N N/ N\ O\ Prepared as described in Example 9B, using (R)-l-(6-chloropyridinyl)— 2,2,2-triflu0r0ethanol in place of (S)-l-(6-chlor0pyridinyl)-2,2,2-triflu0roethanol in Step C, substituting (S)-tert-butyl 3-methylpyrrolidinylcarbamate for (S)-tert—butyl pyrrolidin- 3-ylcarbamate in Step D, and tuting 7-(2-methoxyethyl)quin0linecarbaldehyde in place of 8-meth0xyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 485 (M+H).
Example 301 2 HCI ochloride Step A: Pre aration of l— 6-fluorometh l uinolin lox propan-Z-ol: Prepared as bed in Example 277, Step A, using 2,2- dimethyloxirane in place of (R)methyloxirane, and substituting omethquuinolin- 7-ol for 2-methquuinolinol.
Step B: Preparation of 6-fluorog2-hydroxy—2-methylp_rop_oxy[guinoline carbaldehyde: Prepared as described in Example 5, Step B, using l-(6-fluoro methquuinolinyloxy)methylpropanol in place of 8-(cyclopropylmethoxy) methquuinoline.
Step C: Pre n of l- 2- 6- S S aminometh l rrolidin-l- l- 2 2 2-trifluoroeth l - l 2 4 triazolo 4 3-a ridin l fluoro n lox methylpropanol dihydrochloride: Prepared as described in Example 260, Steps C-D, using o(2-hydroxymethylpropoxy)quinolinecarbaldehyde in place of 7-(2- methoxyethoxy)quinolinecarbaldehyde in Step C. LCMS APCI (+) m/z 533 (M+H).
Example 302 / ,UNQ’NHZ 2 HCI Prepared as bed in Example 9B, Steps F-G, using 6-fluoro(2- hydroxymethylpropoxy)quinolinecarbaldehyde in place of 8-methoxyquinoline carbaldehyde in Step F. LCMS APCI (+) m/z 519 (M+H).
Example 303 To a stirred solution of (S)-l-((R)-2,2,2-trifluoro-l-(3-(8-((R)-lmethoxypropanyloxy )quinolinyl)—[ l ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - amine (Example 140; 0.200 g, 0.400 mmol), formaldehyde (37 wt% in water, 0.565 mL, 7.59 mmol) and glacial acetic acid (0.041 mL, 0.719 mmol) in methanol (2 mL) cooled on an ice- water bath, was added slowly sodium cyanoborohydride (0.075 g, 1.20 mmol) and the e stirred for 2 hours. The mixture was neutralized with 1N NaOH solution and ted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was d by column chromatography (Biotage, 25M, 1% methanol/dichloromethane). The isolated product was stirred in 4N HCl in 1,4-dioxane for 45 minutes and concentrated under reduced pressure. The residue was stirred with acetonitrile and evaporated under reduced pressure until a solid was obtained. The solid stirred in acetonitrile, filtered and dried under vacuum to afford (S)-N,N—dimethyl((R)-2,2,2-trifluoro(3 -(8-((R)methoxypropan yloxy)quinolinyl)-[1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidinamine dihydrochloride. LCMS APCI (+) m/z 529 (M+H).
Example 304 F3C :3 / NQ‘NHZ N/ N g N/ [N\ O\/\O/ S meth l S -2 2 2-trifluoro 3- 7- S methox ro ox uinolin l - 1 2 4 lo 4 3-a ridin l eth l rrolidinamine Prepared as bed in e 9B, Steps D-G, using (S)-tert-butyl 3- methylpyrrolidinylcarbamate (Preparation B) in place of (S)-tert-butyl idin ylcarbamate in Step D and using (S)(2-methoxypropoxy)quinolinecarbaldehyde (Example 287, Steps A-B) in place of 8-methoxyquinolinecarbaldehyde in Step F. MS APCI (+) m/z 515 (M+1) detected.
Example 305 F3C : / NQLNHZ S meth l S -2 2 2-trifluoro 3- 7- R methox ro ox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine Prepared as described in e 9B, Steps D-G, using (S)-tert-butyl 3- methylpyrrolidinylcarbamate (Preparation B) in place of (S)-tert-butyl pyrrolidin ylcarbamate in Step D and using (R)—7-(2-methoxypropoxy)quinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F. MS APCI (+) m/z 515 (M+1) detected. e 306 F30 5‘ / NQ‘NHZ N\/ /N N N \ O\/\ /\ S S 3- 7- x ethox uinolin l - 1 2 4 triazolo 4 3-a ridin-6I ,_. IN N ’F’ trifluoroeth lmeth l rrolidinamine Prepared as described in Example 9B, Steps D-G, using (S)-tert-butyl 3- methylpyrrolidinylcarbamate (Preparation B) in place of (S)-tert-butyl pyrrolidin amate in Step D and using 7-(2-ethoxyethoxy)quinolinecarbaldehyde in Step F. MS APCI (+) m/z 515 (M+1) detected. e 307 '6 3 HCI 3-amine trihydrochloride 3] Step A: Pre aration of tert-but l S R 3- 8-tert-but l uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidin lcarbamate: Enantiomerically pure tert—butyl (S)-l-((R)(3 -(8-tert—butquuinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamatewas was isolated from the racemate tert-butyl (3 S)-l-(l-(3- (8-tert—butquuinolinyl)- [1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 -ylcarbamate (prepared as in Example 307, Steps A-F) by chiral SFC (Supercritical Fluid Chromatography). Conditions for preparative tography: Chiralpak IC (Chiral Technologies) 20 mm x 250 mm, 50% MeOH at 50 mL/min. Outlet pressure: 100 bar.
Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes/10% (1:1 MeOH/EtOH) at 1.0 mL/min, >99% d.e. (R,S)—diastereomer).
Step B: Pre n of tert—but l S R 3- -but l uinolin—2- l- 12 4 triazolo 4 3-a ridin leth l rrolidin lcarbamate trih drochloride: To a solution of tert—butyl (S)((R)(3-(8-tert-butquuinolinyl)-[1,2,4]triazolo[4,3-a]pyridin- 6-yl)ethyl)pyrrolidinylcarbamate (0.197 g, 0.383 mmol) in DCM (1 mL) was added 4 N HCl (1.92 mL, 7.66 mmol) in IPA. The mixture was stirred at ambient ature for 1 hour. The solvent was removed under reduced pressure and ether (5 mL) was added. The suspension was stirred at ambient temperature for 10 minutes and the solid formed was collected by ion to give (S)((R)(3-(8-tert—butquuinolinyl)-[1,2,4]triazolo[4,3- a]pyridinyl)ethyl) pyrrolidinamine (0.186 g, 92.8%) as solid. LCMS APCI (+) m/z 415 (M+H).
Example 308 "lj 3 HCI U) I p—I I U) I p—I I DJ I 00 4.?N‘T‘U‘E, ,_I CH.BOE?NI ,_I I p—I N J; z—rE. a:NO ,_IO J; L.”a: HI—l C?“ leth l rrolidin- 3-amine trihydrochloride Step A: Pre aration of tert—but l S S 3- 8-tert—but l uinolin l - 1 2 4 lo 4 3-a ridin l eth l rrolidin lcarbamate: Enantiomerically pure tert—butyl (S)((S)(3 -(8-tert—butquuinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate was isolated from the racemate tert—butyl (3S)(1-(3-(8- tert—butquuinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 -ylcarbamate (prepared as in Example 17, Steps A-F) by chiral SFC (Conditions for preparative chromatography: Chiralpak IC, Chiral Technologies 20 mm x 250 mm, 50% MeOH at 50 mL/min. Outlet pressure: 100 bar). Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% s/10% (1:1 tOH) at 1.0 mL/min, 99.2% d.e. (S,S)— diastereomer).
Step B: Pre aration of tert—but l S S 3- 8-tert-but l uinolin l - 12 4 triazolo 4 3-a 6- leth l rrolidin lcarbamate trih drochloride: To a solution of tert—butyl (S)((S)(3-(8-tert-butquuinolinyl)-[1,2,4]triazolo[4,3-a]pyridin- 6-yl)ethyl)pyrrolidinylcarbamate (0.203 g, 0.39 mmol) in DCM (1 mL) was added 4 N HCl (1.97 mL, 7.89 mmol) in IPA. The mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure and ether (5 mL) was added. The suspension was stirred at ambient temperature for 10 minutes and the solid formed was collected by filtration to give (S)((S)(3-(8-tert—butquuinolinyl)—[1,2,4]triazolo[4,3- a]pyridinyl)ethyl) pyrrolidinamine (0.204 g, 98.7%) as solid.
Example 309 [11$ 3 HCI leth l rrolidinamine trih drochloride Step A: Pre aration of 1- o ridin l ethanone: To a on of 6- fluoronicotinonitrile (5.00 g, 41.0 mmol) in THF (50 mL) was added 1 N methylmagnesium bromide (16.4 mL, 49.1 mmol) in THF at 0 °C. After addition, the mixture was warmed to ambient temperature and stirred at ambient temperature for 4 hours. ted sodium bicarbonate solution (50 mL) and ether (100 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under d pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 1-(6-fiuoropyridinyl)ethanone (0.85 g, 14.9%) as solid.
Step B: Pre aration of ut 1 3S 1- 6-fiuoro ridin yl)ethyl)pflOlidinylcarbamate: To a solution of (S)-tert—butyl pyrrolidinylcarbamate (0.94 g, 5.04 mmol), 1-(6-fiuoropyridinyl)ethanone (0.35 g, 2.52 mmol) in THF (10 mL) was added tetraisopropoxytitanium (1.48 mL, 5.04 mmol) and the reaction mixture was stirred at ambient temperature for 18 hours. Ethanol (2 mL) and NaBH4 (0.38 g, 10.1 mmol) were added and the mixture was stirred at ambient temperature for 2 hours. Water (10 mL), concentrated ammonium (2 mL) and ethyl e (20 mL) were added. The c layer was separated, washed with brine, dried (sodium e), filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (1:1 hexane/ethyl acetate) to give utyl (3S)(1-(6-fluoropyridinyl)ethyl)pyrrolidin- 3-ylcarbamate (0.343 g, 44.0% ) as solid. 9] Step C: Pre aration of tert- l - 1 2 4 triazolo 4 3-a ridin-6 leth l rrolidin lcarbamate: Prepared as described in Example 1, Steps D-E, using tert—butyl (3 S)(1-(6-fluoropyridinyl)ethyl)pyrrolidin ylcarbamate in place of tert—butyl (3 S)- l -( l -(6-chlor0pyridin-3 -yl)-2,2,2— trifluoroethyl)pyrr0lidinylcarbamate in Step D and substituting 7-eth0xy fluoroquinoline-Z-carbaldehyde for 8-methoxyquinolinecarbaldehyde in Step E.
Step D: Pre aration of S -l- 12 4 triazolo 4 3-a - leth l rrolidinamine trih drochloride: ed as described in Example 307 using tert—butyl (3 1-(3-(7-ethoxyfluoroquinolinyl)- [l,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinylcarbamate in place of tert—butyl (3 S)-l- (l-(3 -(8 -tert—butquuinolinyl)—[ l ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - ylcarbamate in Step A. LCMS APCI (+) m/z 421 (M+H).
Example 310 “/‘j 3 HCI leth l rrolidinamine trih drochloride [00101 1] Prepared as described in Example 308 using tert—butyl (3 S)- l -(l-(3-(7-ethoxy- 6-flu0r0quinolinyl)-[ l ,2,4]triazolo [4,3 idinyl)ethyl)pyrrolidin-3 -ylcarbamate in place of tert—butyl (3 S)-l-(l-(3-(8-tert—butquuinolinyl)-[l,2,4]triazolo[4,3-a]pyridin yl)ethyl)pyrrolidinylcarbamate in Step A. LCMS APCI (+) m/z 421 (M+H). e 311 F3C NH2 / cw 2HC| N/ N N/ |N\ o\ l 2 4 triazolo 4 3-a ridin l eth l rrolidinamine Prepared as described in Example 9B, using (R)-l-(6-chloropyridinyl)— trifluor0ethanol in place of (S)-l-(6-chlor0pyridin—3-yl)—2,2,2-trifluoroethanol in Step C, substituting (S)-tert—butyl 3-methylpyrrolidinylcarbamate for (S)-tert—butyl pyrrolidin- 3-ylcarbamate in Step D, and substituting 6-fluoro(2-methoxyethyl)quinoline WO 54274 carbaldehyde in place of 8-meth0xyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 485 (M+H).
Example 312 2HC| F30 D / NgiNHZ a ridin leth l rrolidinamine Prepared as described in Example 217, using (S)-tert-butyl 3- methylpyrrolidinylcarbamate (Preparation D) in place of (S)-tert-butyl pyrrolidin ylcarbamate, and 7-methoxyquinolinecarbaldehyde in place of 7-meth0xyquinoline carbaldehyde. MS APCI (+) m/z 457 (M+l) detected.
Example 313 a ridin lfluor0 uinolin lox eth lbenzoate 4] ed as described in Example 286 using l chloride in place of pivalic anhydride in Step A. LCMS APCI (+) m/z 595 (M+H).
Example 314 2HC| S meth l-l- S -2 2 2-triflu0r0-l- 3- 7-is0 r0 0x uinolin l - l 2 4 triazolo 4 3- a ridin leth l rrolidinamine Prepared as bed in Example 217, using (S)-tert-butyl 3- methylpyrrolidinylcarbamate (Preparation D) in place of (S)-tert-butyl pyrrolidin ylcarbamate, and 7-isopropoxyquinolinecarbaldehyde in place of 7-methoxyquinoline carbaldehyde. MS APCI (+) m/z 486 (M+l) detected.
Example 315 2HC| F3C 5 / Ow / N S meth l S -2 2 uoro 3- 7- R methox ro an l ox uinolin l - 1 2 4 triazolo 4 3-a 6- l eth l rrolidinamine Prepared as described in Example 217, using (S)-tert-butyl 3- methylpyrrolidinylcarbamate (Preparation D) in place of (S)-tert-butyl pyrrolidin ylcarbamate, and 7-(R)(methoxypropanyl)quinolinecarbaldehyde in place of 7- methoxyquinolinecarbaldehyde. MS APCI (+) m/z 515 (M+l) detected.
Example 316 {(17NH2N N\//N O l eth l rrolidinamine Step A: Pre aration of dieth l 2- 2-meth l uinolin l malonate: A mixture of 7-bromomethquuinoline (2.00 g, 9.01 mmol), Cu(I)I (0.172 g, 0.90 mmol), picolinic acid (0.222 g, 1.80 mmol), C82C03 (8.80 g, 27.0 mmol) and diethyl malonate (2.73 mL, 18.0 mmol) in dioxane (25 mL) was stirred at 100 0C for hours. After cooling to ambient temperature, ethyl acetate (30 mL) and water (15 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (3:2 hexane/ethyl e) to give l 2-(2-methquuinolinyl)malonate (0.7 g, 2.32 mmol, 26 % yield) as oil.
Step B: Preparation of 2-[2-methylguinolinyl[propane-l,3-diol]: To a solution of 1.0 N LAH (15.3 mL, 15.3 mmol) in THF was added l 2-(2- methquuinolinyl)malonate (1.15 g, 3.82 mmol) in Ether (30 mL) slowly at 0 CC. The reaction e was stirred at 0 0C for 2 hours. Sodium sulfate decahydrate (2.0 g) was added and stirred at ambient temperature for 30 minutes. The solid was removed by filtration and washed with ethyl acetate (50 mL). The filtrate was concentrated and the e ed was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 40M column, 0-70% CH3CN/water gradient; 30 CV) to give 2-(2-methquuinolin yl)propane-1,3-diol (0.34 g, 1.56 mmol, 41.0% yield) as a solid.
Step C: ation of 2-methyl[oxetanyl[guinoline: To a solution of 2- (2-methquuinolinyl)propane-l,3-diol (0.100 g, 0.46 mmol) and PPh3 (0.241 g, 0.921 mmol) in toluene (10 mL) was added zinc(II) dimethylcarbamodithioate (0.211 g, 0.690 mmol) and DEAD (0.145 ml, 0.921 mmol). The resulting mixture was stirred at ambient temperature for 30 hours. The solvent was removed under reduced pressure, and water (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried m sulfate), filtered and trated under d pressure. The residue obtained was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-90% CHgCN/water gradient; 25 CV)) to give 2-methyl(oxetan yl)quinoline (0.020 g, 0.100 mmol, 22% yield) as a solid.
Step D: Preparation of 7-[oxetanyl[guinolinecarbaldehyde: 2-Methyl (oxetanyl)quinoline (0.020 g, 0.100 mmol) was dissolved in dioxane (5 mL) and water (0.05 mL). The reaction was treated with SeOz (0.013 g, 0.120 mmol) and the mixture was heated to reflux for 2 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was trated under reduced pressure to give 7-(oxetanyl)quinolinecarbaldehyde (0.020 g, 0.0938 mmol, 93.4 % yield) as a solid.
Step E: Pre aration of tert-but l S -l- R -2 2 2-trifluoro-l- 3- 7- oxetan l n l - l 2 4 triazolo 4 3-a 6 leth l rrolidin lcarbamate: Prepared as described in Example 9B, substituting 7-(oxetanyl)quinolinecarbaldehyde in place of 8-methoxyquinolinecarbaldehyde in Step F.
Step F: Pre aration of S -l- R -2 2 2-trifluoro-l- 3- 7- oxetan l uinolin- 2- l - l 2 4 triazolo 4 3-a ridin l eth l rrolidinamine: A on of tert-butyl (S)- l-((R)-2,2,2-trifluoro- l -(3 -(7-(oxetan-3 -yl)quinolinyl)-[ l ,2,4]triazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinylcarbamate (0.015 g, 0.026 mmol) in formic acid (0.51 ml, 13.2 mmol) was stirred at ambient temperature for 10 hours. The t was removed under reduced pressure to give (S)((R)-2,2,2-trifluoro(3 -(7-(oxetan-3 -yl)quinolinyl)- [l,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinamine (0.012 g, 0.026 mmol, 97 % yield) as a formic acid salt. LCMS APCI (+) m/z 469(M+H).
Example 317 / N94” \/ N OH 2- 2- 6- S S aminometh l rrolidin-l- l -2 2 2-trifluoroeth l - 1 2 4 triazolo 4 3-a ridin l uinolin 1 l Step A: Pre n of meth l 2- 2-meth l uinolin lacetate: 2-(3- aminophenyl)acetic acid (11.0 g, 72.8 mmol) was dissolved in 6 N HCl (200 mL) and heated to reflux. (E)—butenal (11.9 mL, 146 mmol) was added dropwise over 10 minutes. The reaction was heated at reflux for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with sodium hydroxide to pH~12 and ether (100 mL) was added. The aqueous layer was ted, acidified with saturated potassium hydrogen sulfate to , extracted with 3:1 IPA (3x300 mL), dried (sodium sulfate) and concentrated to give a solid. The solid was dissolved in MeOH (200 mL). The residue was suspended in ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated, washed with brine, dried m sulfate) and concentrated. The residue obtained was purified by flash chromatography (5:1 DCM:ethyl acetate ) to give methyl 2-(2- methquuinolinyl)acetate as a solid. 4] Step B: Preparation of 2-]2-methylguinolinyl[ethanol: methyl 2-(2- methquuinolinyl)acetate (5.78 g, 26.9 mmol) in THF (50 mL) was added 1M LAH (40.3 mL, 40.3 mmol) in THF at 0 OC, followed by stirring at 0 0C for 3 hours. Sodium sulfate decahydrate (10.0 g) was added and stirred at ambient temperature for 30 minutes. The solid was removed by filtration and washed with ethyl acetate (100 mL). The filtrate was concentrated and the residue obtained was purified by flash chromatography (ethyl acetate) on silica gel to give 2-(2-methquuinolinyl)ethanol (2.35 g, 12.6 mmol, 47% yield) as a solid.
Step C: Preparation of 7-]2-hydroxyethyl[guinolinecarbaldehyde: 2-(2- methquuinolinyl)ethanol (0.220 g, 1.17 mmol) was dissolved in dioxane (5 mL) and water (0.05 mL). The reaction was treated with SeOz (0.156 g, 1.41 mmol) and the mixture was heated to reflux for 2 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was trated and the residue was purified by flash chromatography on silica gel (ethyl acetate/hexanes 5:1) to give 7-(2- hydroxyethyl)quinolinecarbaldehyde (0.21 g, 1.04 mmol, 89 % yield) as a solid.
Step E: Pre aration of tert-but l S R -2 2 2-trifiuoro 3- 7- oxetan l uinolin l - 1 2 4 triazolo 4 3-a ridin-6 leth l rrolidin lcarbamate: Prepared as bed in Example 9B, using (R)(6-chloropyridinyl)-2,2,2-trifiuoroethanol in place of (S)(6-chloropyridinyl)-2,2,2-trifiuoroethanol in Step C, substituting (S)-tertbutyl 3-methylpyrrolidinylcarbamate for (S)-tert—butyl idinylcarbamate in Step D, and substituting 7-(2-hydroxyethyl)quinolinecarbaldehyde in place of 8- methoxyquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z H).
Example 318 ’—. ”3’NH2 Cf ZHCI / "”IO\ / N 3R 4R hox R -2 2 2-trifiuoro 3- 7- 2-methox ethox uinolin l - 1 2 4 triazolo 4 3-a ridin l eth l rrolidinamine Prepared as described in Example 299, substituting 7-methoxyethoxyquinolinecarbaldehyde for hoxyfiuoroquinolinecarbaldehyde in Step F. LCMS APCI (+) m/z 517(M+H).
Example 319 / ”lNgNHZ Step A: Pre aration of cis- 1S 2R tert- butyldimethylsilyloxy[cyclopentanol: To a stirred solution of cis-cyclopentane-l,2-diol (2.30 g, 22.5 mmol) and imidazole (3.07 g, 45.0 mmol) in DMF (80 mL) was added dropwise tert- WO 54274 butyldimethylsilyl chloride (3.39 g, 22.5 mmol) in DMF (30 mL) at 0 CC under nitrogen. The reaction mixture was d at ambient ature overnight. The on was partitioned between ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (hexanes:EtOAc, 25:1) to give cis-(lS,2R)(tert— butyldimethylsilyloxy)cyclopentanol (3.02 g, 62%).
Step B: Pre n of trans 2- tert- but ldimeth lsil lox c clo ent lox meth l uinoline: Prepared as bed in Example 140, Step A, using cis-(lS,2R)—2-(tert-butyldimethylsilyloxy)cyclopentanol as a replacement for (S)methoxypropanol, and substituting 2-methquuinolinol for 2- methquuinolinol.
Step C: Preparation of transmethylguinolinyl[oxy]cyclop_entanol: To a stirred solution of crude trans((2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy) methquuinoline (3.0 g, 8.4 mmol) in THF (10 mL) was added 1.0 M TBAF in THF (17 mL, 17 mmol). After stirring at ambient temperature for 1 hour, saturated aqueous NH4Cl was added to the reaction mixture. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (2% MeOH in EtOAc) to give trans((2-methquuinolin yl)oxy)cyclopentanol (0.065 g, 3% for two .
Step D: Preparation of transhydroxycyclopentyl[oxyzguinoline carbaldehyde: ed as described in Example 5, Step B, using trans((2- methquuinolinyl)oxy)cyclopentanol in place of 8-(cyclopropylmethoxy) methquuinoline.
Step E: Preparation of trans-tert-butyl 1-]]1R[-2,2,2-trifluoro]3-]7- 2-h drox c clo ent lox uinolin l - 1 2 4 triazolo 4 3-a ridin yl[ethyl[pyrrolidinyl[carbamate: Prepared as described in e 9 (Method B) Step F, using trans((2-hydroxycyclopentyl)oxy)quinolinecarbaldehyde in place of 8- methoxyquinolinecarbaldehyde.
Step F: Preparation of diastereomer 1 of trans-tert-butyl [138111 1R]—2,2,2- trifluoro-l- 3- 7- 2-h drox c clo ent lox uinolin l- 12 4 triazolo 4 3-a ridin yl[ethyl[pmolidin—3-yl[carbamate: Diastereomer 1 of trans-tert-butyl ((3S)((1R)-2,2,2- trifluoro(3 -(7-((2-hydroxycyclopentyl)oxy)quinolinyl)-[1 riazolo [4,3 -a]pyridin yl)ethyl)pyrrolidinyl)carbamate (26 mg, 99.64% purity) was separated from trans-tert- butyl 1-benzyl(hydroxymethyl)pyrrolidinylcarbamate (68 mg) by chiral SEC.
Conditions for analytical chromatography: Rt = 9.915 min; Chiral Technologies CHIRALPAK® IC 4.6 x 150 mm, 70/30 heptane/EtOH at 0.8 . Conditions for preparative chromatography: Chiral Technologies CHIRALPAK® 1B 21 mm x 250 mm, % EtOH at 75 ).
Step G: Pre aration of diastereomer 1 of trans 2- 6- R-l- S amino rrolidin l -2 2 2-trifluoroeth l - 1 2 4 triazolo 4 3-a 3- l uinolin yl[oxy[cyclop_entanol di-hydrochloride: Prepared as described in Example 9 (Method B) Step G using diastereomer 1 of tert-butyl ((3S)—1-((1R)-2,2,2-trifluoro(3-(7-((2- ycyclopentyl)oxy)quinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - bamate as a replacement for tert—butyl (S)((R)-2,2,2-trifluoro(3-(8- methoxyquinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 -ylcarbamate.
LCMS APCI (+) m/z 513 (M+H).
Example 320 / g Step A: Pre aration of diastereomer 2 of trans-tert-but 1 3S 1R -2 2 2- trifluoro-l- 3- 7- 2-h drox c clo ent lox uinolin l- 12 4 triazolo 4 3-a ridin yl [ethyl [pmolidin—3 -yl [carbamate: The diastereomer 2 of trans-tert-butyl ((3 S)((1R)- 2,2,2-trifluoro(3 -(7-((2-hydroxycyclopentyl)oxy)quinolinyl)- [1 ,2,4]triazolo [4,3 - a]pyridinyl)ethyl)pyrrolidinyl)carbamate (30 mg, 100% purity) was separated from trans-tert-butyl 1-benzyl(hydroxymethyl)pyrrolidinylcarbamate (68 mg) by chiral SFC.
Conditions for analytical chromatography: Rt = 11.294 min; Chiral Technologies CHIRALPAK® IC 4.6 x 150 mm, 70/30 heptane/EtOH at 0.8 . Conditions for preparative chromatography: Chiral Technologies CHIRALPAK® 1B 21 mm x 250 mm, % EtOH at 75 mL/min).
Step B: Pre aration of diastereomer 2 of trans 2- 6- R-l- S amino rrolidin l -2 2 2-trifluoroeth l - 1 2 4 triazolo 4 3-a 3- l uinolin yl[oxy[cyclop_entanol di-hydrochloride: Prepared as described in Example 9 (Method B) Step G using diastereomer 2 of trans-tert-butyl ((3S)—1-((1R)-2,2,2-trifluoro(3-(7-((2- hydroxycyclopentyl)oxy)quinolinyl)-[ 1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - yl)carbamate as a replacement for tert—butyl (S)((R)-2,2,2-trifluoro(3-(8- methoxyquinolinyl)—[ 1 ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 -ylcarbamate.
LCMS APCI (+) m/z 513 (M+H).
Example 321 ‘ 9:ON .
("DH5‘ON CH5OE?NI ,_. I I—I N J; S.a:NO ,_.O J; L.” a: EQ.I—l? O\ I ,_. ("DH5‘ I—‘ .I—l?L.” yl [carbamate To a solution of 2-((2-(6-((R)((S)aminopyrrolidinyl)-2,2,2- trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridinyl)fluoroquinolinyl)oxy)ethanol (125 mg, 0.255 mmol) in DMF (1.5 mL) was added a solution of (5-methyloxo-1,3-dioxol yl)methyl 4-nitrophenyl carbonate (prepared according to procedures described in J. Med.
Chem. 1999, 42, 3994-4000, 71.2 mg, 0.255 mmol) in DMF (1 mL). The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction was ioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by flash tography on silica gel (DCM:MeOH, 70:1 to 40:1) to give (5-methyloxo-1,3- dioxolyl)methyl ((S)— 1 -((R)-2,2,2-trifluoro(3 oro(2-hydroxyethoxy)quinolin ,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinyl)carbamate (131 mg, 80%). LCMS APCI (+) m/z 647 (M+H).
Example 322 / N3NH2 Step A: Preparation of g S[methoxypropyl 4-methylbenzenesulfonate: To a stirred on of (S)methoxypropanol (1.00 g, 11.1 mmol) in DCM (50 mL) was added Eth (2.33 mL, 16.6 mmol). A solution of toluene sulfonyl chloride (2.54 g, 13.3 mmol) in DCM (20 mL) was added dropwise at 0 CC under nitrogen. The reaction mixture was allowed to warm to t temperature and was stirred overnight. The reaction was diluted with DCM, washed with saturated aqueous NaHC03 and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (hexanes:EtOAc, 10:1 to 4:1) to give (S)methoxypropyl 4-methylbenzenesulfonate (2.03 g, 75%).
Step B: Pre aration of S ro 2-methox ro ox methylguinoline: To a stirred mixture of 6-fluoromethquuinolinol (0.200 g, 1.13 mmol), C82C03 (0.552 g, 1.69 mmol) and NMP (2.3 mL) was added (S)—2-methoxypropyl 4- methylbenzenesulfonate (0.303 g, 1.24 mmol). The on mixture was heated at 80 CC for 1 hour. After cooling, the reaction was partitioned between toluene and water. The aqueous layer was extracted with toluene. The combined organic layers were washed with water and brine, dried and concentrated to give the crude product, which was used in the next step without further purification.
Step C: Pre aration of S ro 2-methox ro ox uinoline carbaldehyde: To a solution of crude (S)fluoro(2-methoxypropoxy)methquuinoline (0.281 g, 1.13 mmol) in dioxane (4 mL) and water (0.04 mL) was added SeOz (0.138 g, 1.24 mmol). The reaction mixture was heated at reflux for 3 hours. After cooling, the mixture was filtered h Celite®. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (hexanes:EtOAc, 4:1) to give (S)—6-fluoro(2- methoxypropoxy)quinolinecarbaldehyde (0.251 g, 85% for two steps) as a solid.
Step D: Pre aration of S meth l S -2 fluoro 3- 6-fluoro S hox ro ox uinolin l - 1 2 4 triazolo 4 3-a ridin-6 leth l rrolidin amine di-hydrochloride: Prepared as bed in Example 260 using fluoro(2- methoxypropoxy)quinolinecarbaldehyde as a replacement for 7-(2- methoxyethoxy)quinolinecarbaldehyde in step B. LCMS APCI (+) m/z 533 (M+H). 2012/026572 Example 323 ’ NQ’NH2 / N Prepared as described in Example 9 (Method B) using (S)fluoro(2- methoxypropoxy)quinolinecarbaldehyde as a replacement for 8-methoxyquinoline carbaldehyde in Step F. LCMS APCI (+) m/z 519 (M+H).
Example 324 Step A: Pre aration of R -meth lZ-methox ro anoate: To a stirred solution of (R)-methyl 2-hydroxypropanoate (5.00 g, 48.0 mmol) in ether (240 mL) was added AgzO (33.0 g, 144 mmol) and 4A molecular sieves (5 g). Mel (20.0 g, 144 mmol) were added to the mixture. The reaction was stirred at ambient temperature for 5 days. The mixture was filtered through Celite®. The filtrate was concentrated in a cold water bath under reduced pressure (300 mm Hg) to give (R)—methyl 2-methoxypropanoate as a colorless oil, which was used in the next step without filrther purification.
Step B: Preparation of methox1prop_an-l-ol: To a stirred suspension of LiAlH4 (1.5 g, 39 mmol) in ether (50 mL) was added dropwise a on of crude (R)-methyl 2-methoxypropanoate (5.7 g, 48 mmol) in ether (20 ml) under nitrogen. The mixture was heated at reflux for 1 hour and then cooled to 0 oC. The on was quenched by dropwise addition of water (1.5 mL), 15% NaOH aqueous solution (1.5 mL) and water (4.5 mL). The e was diluted with ether and d for 10 minutes. The mixture was filtered h Celite®. The filtrate was concentrated in a cold water bath under reduced pressure (300 mm Hg). The crude product was used in the next step without further purification.
] Step C: Preparation of ]R[methoxypropyl 4-methylbenzenesulfonate: To a stirred solution of crude (R)methoxypropanol (4.30 g, 47.7 mmol) in DCM (200 mL) was added Eth (10.0 mL, 71.6 mmol). A solution of toluene sulfonyl chloride (10.9 g, 57.3 mmol) in DCM (80 mL) was added dropwise at 0 CC under nitrogen. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was d with DCM, washed with ted aqueous NaHC03 solution and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (hexanes:EtOAc, 10:1 to 4:1) to give (R)methoxypropyl 4-methylbenzenesulfonate (6.43 g, 55% for three steps).
Step D: Pre aration of R fluoro 2-methox ro ox methylguinoline: To a stirred mixture of 6-fluoromethquuinolinol (0.200 g, 1.13 mmol), C82C03 (0.552 g, 1.69 mmol) and NMP (2.3 mL) was added (R)methoxypropyl 4- methylbenzenesulfonate (0.303 g, 1.24 mmol). The reaction mixture was heated at 80 CC for 1 hour. After cooling, the reaction was partitioned between toluene and water. The aqueous layer was extracted with e (2x). The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (hexanes:EtOAc, 1:1) to give (R)fluoro(2-methoxypropoxy) uinoline (0.289 g, 103%).
Step E: Pre aration of R fluoro 2-methox ro ox uinoline carbaldehyde: To a solution of (R)fluoro(2-methoxypropoxy)methquuinoline (0.281 g, 1.13 mmol) in e (4 mL) and water (0.04 mL) was added SeOz (0.138 g, 1.24 mmol).
The reaction mixture was heated at reflux for 3 hours. After cooling, the mixture was filtered h Celite®. The filtrate was concentrated. The residue was purified by flash tography on silica gel (hexanes:EtOAc, 4:1) to give (R)fluoro(2- methoxypropoxy)quinolinecarbaldehyde (0.219 g, 74%) as a solid.
Step F: Pre aration of S meth l-l- S -22 2-trifluoro-l- 3- 6-fluoro R methox ro ox uinolin l - l 2 4 triazolo 4 3-a ridin-6 leth l rrolidin amine rochloride: Prepared as described in Example 260 using (R)fluoro(2- methoxypropoxy)quinolinecarbaldehyde as a ement for 7-(2- methoxyethoxy)quinolinecarbaldehyde in Step B. LCMS APCI (+) m/z 533 (M+H). 2012/026572 Example 325 Prepared as described in Example 9 d B) using (R)fluoro(2- methoxypropoxy)quinolinecarbaldehyde as a replacement for 8-methoxyquinoline carbaldehyde in Step F. LCMS APCI (+) m/z 519 (M+H).
Example 326 dNQ’NHZ/ N S -l- R -2 2 2-trifluoro-l- 3- 3-fluoro 2-methox ethox uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidinamine Step A: Pre aration of Z - ethox vin lox trimeth e: LHMDS (301.9 mL, 317.0 mmol) was dissolved in 500 mL of THF, and cooled to -78 0C. Methyl 2- yacetate (28.5 ml, 288 mmol) was then added ise, and the reaction e was allowed to stir for 30 minutes at -78 0C. TMSCl (36.45 mL, 288.2 mmol) was added drop- wise, and the reaction was allowed to warm to ambient temperature. The mixture was then concentrated in vacuo (<20 0C), followed by purification on Celite® plug, and wash the Celite® was washed with petroleum ether. The crude residue was concentrated using a frit adapter (<20 0C), followed by application of a high vacuum with water bath cooling to remove TMSZNH, affording (Z)—(l,2-dimethoxyvinyloxy)trimethylsilane (36 g, 70.87 % yield) as a light yellow oil.
Step B: Pre aration of Z -meth l 2-fluoromethox ac late: (Z)-(l,2- Dimethoxyvinyloxy)trimethylsilane (6.00 g, 34.0 mmol) was dissolved in 200 mL of Hexanes and cooled to -78°C, followed by addition of KOtBu (7.64 g, 68.1 mmol).
Dichlorofluoromethane (3.50 g, 34.0 mmol) was added over 3 minutes directly to the cooled solution. The reaction was then allowed to warm to ambient temperature over 2 hours. The reaction was then poured through Celite®, washed with EtzO, and the combined organics concentrated in vacuo (20 0C). The crude material was then purified by flash column chromatography (10-20% ethyl acetate/Hexane) to afford (Z)—methyl o methoxyacrylate (1.90 g, 41.6% yield) as a yellow oil. The (E) stereoisomer (360 mg) was also isolated.
Step C: Preparation of 3-fluoromethoxyguinolin-2g1H)-one: To a solution of 3-methoxyaniline (1.718 mL, 15.29 mmol) in THF(12 mL) was added 2.5 N n-BuLi (5.965 mL, 14.91 mmol) in hexane at 0 C. The reaction mixture was stirred at 0 C for 5 minutes. thyl 3-fluoromethoxyacrylate (1.00 g, 7.457 mmol) in THF (10 mL) was added. The mixture was stirred at 0 0C for one hour. 1 N HCl (20 mL) and ether (30 mL) were added. The organic layer was separated, washed with water, saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give an oil. Sulfiaric acid (70%; 8 mL) was added. The mixture was stirred at 56 0C (bath) for 2 hours. After cooling to ambient temperature, ice (20 g) and water (50 mL) were added. The mixture was d at t temperature for 10 s. The solid was collected by filtration and washed with water to give 3-fluoromethoxyquinolin-2(1H)—one (1.40 g, 7.247 mmol, 97.19 % yield) as a solid.
Step D: Preparation of 2-chlorofluoromethoxyguinoline: A mixture of 3- fluoromethoxyquinolin-2(1H)-one (1.40 g, 7.25 mmol) and POC13 (13.3 ml, 145 mmol) was stirred at 110 C (bath) for 1 hour. The POC13 was d under reduced re. Ethyl acetate (30 mL) and saturated sodium bicarbonate (30 mL) were added and d for 10 minutes. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude residue was purified by flash tography on silica gel (10:1 hexane/ethyl acetate) to give rofluoro methoxyquinoline (0.55 g, 2.60 mmol, 36% yield) as white solid.
Step E: Preparation of -fluoromethoxymethylguinoline: To a sion of Cu(I)Br (1.49 g, 10.4 mmol) in THF (30 mL) was added 3M MeMgBr (6.93 ml, 20.8 mmol) in ether at -78 0C. After stirring at -78 0C for 5 minutes, 2-chlorofluoro methoxyquinoline (0.55 g, 2.60 mmol) in THF (10 mL) was added. The reaction mixture was stirred at -78 CC for 1 hour, then allowed to warm to ambient temperature and stirred for 20 hours. Ammonium hydroxide (10 mL) was added slowly. The mixture was stirred at ambient temperature for 10 minutes, then passed through a pad of Celite® and washed with ether (50 mL). The filtrated was washed with brine (20 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography 3:1 hexane/ethyl acetate to give 3-fluoromethoxymethquuinoline (0.255 g, 1.33 mmol, 51.3% yield) as a solid.
] Step F: Preparation of omethylguinolinol hydrobromide: To a solution of 3-fluoromethoxymethquuinoline (0.255 g, 1.33 mmol) in DCM (5 mL) was added BBr3 (6.67 mL, 6.67 mmol) at 0 oC. The mixture was d at 0 0C for 2 hours and at ambient temperature for 3 hours. Methanol (10 mL) was added slowly and the resulting mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure. The resulting solid was ded in 1:1 ether/hexane and stirred at t temperature for 10 minutes. The solid was collected by filtration to give 3-fluoro methquuinolinol hydrobromide (0.37 g, 1.43 mmol, 107% yield) as a solid.
Step G: Preparation of 3-fluorog2-methoxyethoxy[methylguinoline: To a suspension of 3-fluoromethquuinolinol hydrobromide (0.37 g, 1.43 mmol) and C82C03 (1.08 g, 3.31 mmol) in NMP (6 mL) was added 1-bromomethoxyethane (0.230 g, 1.66 mmol). The reaction mixture was stirred at ambient temperature for 24 hours. Water (10 mL) and toluene (20 mL) were added. The organic layer was separated, washed with brine, dried m sulfate), filtered and concentrated under reduced pressure. The residue ed was purified by flash chromatography on silica gel (2:1 /ethyl acetate) to give 3-fluoro (2-methoxyethoxy)methquuinoline (0.234 g, 0.995 mmol, 90.1% yield).
Step H: Pre aration of 3-fluoro 2-methox ethox uinoline carbaldehyde: A solution of 3-fluoro(2-methoxyethoxy)methquuinoline (0.234 g, 0.995 mmol) and SeOz (0.132 g, 1.19 mmol) in dioxane (10 mL) and water (0.1 mL) was stirred at 102 °C (bath) for 5 hours. The solid was removed by filtration. The filtrated was concentrated under reduced pressure. The residue obtained was purified by flash chromatography (1:1 hexane/ethyl acetate) to give 3-fluoro(2-methoxyethoxy)quinolinecarbaldehyde (0.24 g, 0.963 mmol, 97% yield) as a solid.
Step 1: Pre aration of tert-but 1 3S 1R -2 2 uoro 3- 3-fluoro 2-methox ethox uinolin l - 1 2 4 triazolo 4 3-a ridin-6 l eth l rrolidin ylcarbamate: A e of tert-butyl (S)((R)—2,2,2-trifluoro(6-hydrazinylpyridin yl)ethyl)pyrrolidinylcarbamate (0.080 g, 0.20 mmol) and 3-fluoro(2- methoxyethoxy)quinolinecarbaldehyde (0.051 g, 0.20 mmol) in EtOH (10 mL) was stirred at ambient temperature for 3 hours. The solvent was removed. The residue obtained was dissolved in DCM (10 mL) and nzene diacetate (0.078 g, 0.24 mmol) was added. The mixture was stirred at ambient temperature for 2 hours. The solvent was removed under reduced re. The e obtained was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-l8 25M column, 10-90% CHgCN/water gradient; 25 CV)) to give tert-butyl (3 S)- l -(( l ,2-trifluoro- l -(3 -(3 -fluoro(2- methoxyethoxy)quinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - amate (0.096 g, 0.159 mmol, 78% yield) as a solid.
Step J: Pre aration of 3S 1R -2 2 2-trifluoro-l- 3- 3-fluoro 2- methox ethox uinolin l - l 2 4 triazolo 4 3-a ridin-6 leth l rrolidinamine: To a solution of tert-butyl (3 S)- l -(( l R)-2,2,2-trifluoro- l -(3 -(3 -fluoro(2- methoxyethoxy)quinolinyl)- [l ,2,4]triazolo [4,3 -a]pyridinyl)ethyl)pyrrolidin-3 - ylcarbamate (0.096 g, 0.159 mmol) in DCM (0.5 mL) was added 5 N HCl (0.530 mL, 2.65 mmol) in IPA. The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed under reduced re. The crude residue was suspended in ACN (5 mL) and stirred at ambient temperature for 10 minutes. The solid was collected by filtration to give (3 S)- l -(( l ,2-trifluoro- l -(3 -(3 -fluoro(2-methoxyethoxy)quinolinyl)- [l,2,4]triazolo[4,3-a]pyridinyl)ethyl)pyrrolidinamine (0.078 g, 0.135 mmol, 85% yield) as a solid. LCMS APCI (+) m/z H).
Example 327 dbl NH2 N\/ /N N o N \ \/\O/ S meth l-l- R -2 2 2-trifluoro-l- 3- 3-fluoro 2-methox ethox uinolin l - l 2 4 triazolo 4 3-a ridin l eth l rrolidinamine Prepared as described in Example 327, substituting tert-butyl ((S)methyl-l- ,2,2-trifluoro-l-(6-hydrazinylpyridinyl)ethyl)pyrrolidinyl)carbamate for 8-tert- butyl (S)- l -((R)-2,2,2-trifluoro- l -(6-hydrazinylpyridin-3 -yl)ethyl)pyrrolidin-3 -ylcarbamate in Step I. LCMS APCI (+) m/z 5 l9(M+H).
Example 328 {Vor N/ N \ 5L S -l- R -2 2 2-trifluoro-l- 3- 3-fluoro R hox ro ox uinolin l - l 2 4 lo 4 3-a ridin l eth l rrolidinamine Step A: Pre aration of R fluoro 2-methox ro ox methylguinoline: To a suspension of (R)methoxypropyl 4-methylbenzenesulfonate (0.0530 g, 0.217 mmol) and C82C03 (0.212 g, 0.651 mmol) in NMP (6 mL) was added (R) methoxypropyl 4-methylbenzenesulfonate (0.053 g, 0.22 mmol). The reaction mixture was stirred at 100 CC for 2 hours. After cooling to the ambient temperature, water (10 mL) and toluene (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium e), filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (3:1 hexane/ethyl acetate) to give (R)fluoro- 7-(2-methoxypropoxy)—2-methquuinoline (0.030 g, 0.120 mmol, 56% yield) as a solid. 2] Step B: Pre aration of R fluoro 2-methox ro ox uinoline carbaldehyde: A on of (R)fluoro(2-methoxypropoxy)methquuinoline (0.030 g, 0.120 mmol) and 8602 (0.0160 g, 0.144 mmol) in dioxane (10 mL) and water (0.1 mL) was stirred at 102 CC (bath) for 5 hours. The solid was d by filtration. The mother liquor was concentrated under reduced pressure. The e obtained was purified by flash chromatography 2.5 : 1 hexane/ethyl acetate to give (R)fiuoro(2- methoxypropoxy)quinolinecarbaldehyde (0.024 g, 0.091 mmol, 76% yield) as a solid.
Step C: Pre aration of S R -2 2 uoro 3- 3-fiuoro R methox ro ox uinolin l - 1 2 4 triazolo 4 3-a ridin-6I ('DH{27‘ 5EQ.,_..RL.”a:EB('D Prepared as bed in Example 327, substituting (R)fluoro(2- methoxypropoxy)quinolinecarbaldehyde for 3-fluoro(2-methoxyethoxy)quinoline carbaldehyde in Step I. LCMS APCI (+) m/z 519 (M+H).

Claims (46)

What is claimed
1. A compound of general Formula I N R1 N R2 and stereoisomers, pharmaceutically acceptable salts and solvates thereof, wherein: R1 is H, n, CN, OH, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl (optionally substituted with hydroxy), di(1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, fluoro(1- 6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, hydroxy(2-6C)alkoxy, cyano(1- 6C)alkoxy, (1-3C alkoxy)(2-6C)alkoxy, di(1-3C alkoxy)(2-6C)alkoxy, (3-6C lkyl)methoxy, oxetanylmethoxy (optionally substituted with methyl), (1-6C alkyl)sulfanyl, -C(=O)NRaRb, -CH2C(=O)NRcRd, or cycloalkyl optionally substituted with -CH2OH or -CH2O(1-4C alkyl); Ra, Rb, Rc and Rd are ndently selected from H and (1-4C)alkyl; R2 is H, halogen, CN, OH, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy (optionally substituted with (1-6C alkyl)C(=O)O-, amino(1-6C alkyl)C(=O)O-, or phenyl(C=O)O-), fluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-3C alkoxy)(2-6C)alkoxy, (3-6C cycloalkyl)methoxy, (3- 6C)cycloalkoxy (optionally tuted with OH), oxetanylmethoxy (optionally substituted with methyl), ydropyranyloxy, (1-6C alkyl)sulfanyl, y(2-6C alkyl)sulfanyl, (1- 3C alkylsulfanyl)(2-6C)alkoxy,-COOH, hetAr1, -C(=O)NReRf, -NReC(=O)Rf, oxetanyl, or cyclopropyl optionally tuted with -CH2OH or -CH2O(1-6C alkyl); or R1 and R2 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having 1 - 2 ring heteroatoms independently selected from O and N, wherein said ring is optionally substituted with (1-4C)alkyl; hetAr1 is a 5-6 membered heteroaryl ring having one or two ring en atoms and optionally substituted with one or more groups selected from (1-6C)alkyl; Re and Rf are independently H, (1-6C)alkyl or cyclopropyl ally tuted with (1-4C)alkyl; R3 is H, halogen or (1-6C)alkyl; R4 is R5 is CF3, CH2F, CHF2, methyl or ethyl; R5a is H or methyl; or R5 and R5a together with the atom to which they are attached form a cyclopropyl ring; R6 is H, NH2, OH, (1-6C alkyl)NH-, fluoro(1-6C alkyl)NH-, hydroxy(1-6C NH- , (3-6C cycloalkyl)CH2NH-, (1-6C alkyl)C(=O)NH-, (1-6C alkyl)OC(=O)NH- (optionally substituted with 5-methyloxo-1,3-dioxolyl) or amino(1-6C)alkyl-; R7 is H, (1-6C)alkyl, fluoro(1-6C)alkyl or hydroxy(1-6C)alkyl; or R6 and R7 together with the atom to which they are ed form a 5-6 membered spirocyclic heterocycle having a ring nitrogen atom; R8 is H, halogen, OH, or (1-6C)alkoxy, or R6 and R8 together with the carbon atoms to which they are attached form a cyclopropyl ring optionally substituted with NH2; R9 is H, or R6 and R9 together form a linking group having the formula - which links the carbon atoms to which they are attached; and R10 is H or n.
2. A compound according to claim 1, wherein: R1 is H, halogen, CN, OH, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl (optionally substituted with hydroxy), di(1-3C alkoxy)(1-6C)alkyl, alkoxy, fluoro(1- oxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, hydroxy(2-6C)alkoxy, cyano(1- 6C)alkoxy, (1-3C alkoxy)(2-6C)alkoxy, di(1-3C alkoxy)(2-6C)alkoxy, (3-6C cycloalkyl)methoxy, oxetanylmethoxy (optionally substituted with ), (1-6C alkyl)sulfanyl, -C(=O)NRaRb, -CH2C(=O)NRcRd, or (3-6C)cycloalkyl optionally substituted with -CH2OH or -CH2O(1-4C alkyl); Ra, Rb, Rc and Rd are independently selected from H and (1-4C)alkyl; R2 is H, halogen, CN, OH, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, y(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy (optionally substituted with (1-6C alkyl)C(=O)O- or 1-6C alkyl)C(=O)O-), fluoro(1- 6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-3C alkoxy)(2-6C)alkoxy, (3-6C cycloalkyl)methoxy, oxetanylmethoxy nally substituted with ), tetrahydropyranyloxy, (1-6C alkyl)sulfanyl, hydroxy(2-6C sulfanyl, (1- 3C alkylsulfanyl)(2-6C)alkoxy,-COOH, hetAr1, -C(=O)NReRf, -NReC(=O)Rf, or cyclopropyl optionally substituted with -CH2OH or 1-6C alkyl); or R1 and R2 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having 1 - 2 ring heteroatoms independently selected from O and N, wherein said ring is optionally substituted with (1-4C)alkyl; hetAr1 is a 5-6 membered heteroaryl ring having one or two ring nitrogen atoms and optionally substituted with one or more groups selected from (1-6C)alkyl; Re and Rf are independently H, (1-6C)alkyl or cyclopropyl optionally substituted with (1- 4C)alkyl; R3 is H, halogen or (1-6C)alkyl; R4 is R5 is CF3, CH2F, CHF2, methyl or ethyl; R5a is H or methyl; or R5 and R5a together with the atom to which they are attached form a cyclopropyl ring; R6 is H, -NH2, OH, (1-6C alkyl)NH-, fluoro(1-6C alkyl)NH-, hydroxy(1-6C alkyl)NH-, (3-6C cycloalkyl)CH2NH-, (1-6C alkyl)C(=O)NH-, (1-6C alkyl)OC(=O)NH- or amino(1-6C)alkyl-; R7 is H, (1-6C)alkyl, (1-6C)alkyl or hydroxy(1-6C)alkyl; or R6 and R7 together with the atom to which they are attached form a 5-6 membered yclic heterocycle having a ring nitrogen atom; R8 is H, halogen, OH, or (1-6C)alkoxy, or R6 and R8 er with the carbon atoms to which they are attached form a cyclopropyl ring optionally substituted with NH2; R9 is H, or R6 and R9 together form a linking group having the formula - which links the carbon atoms to which they are attached; and R10 is H.
3. A compound of claim 1 or 2, wherein R1 is selected from H, (1-6C)alkyl, cycloalkyl optionally tuted with -CH2OH or -CH2O(1-4C alkyl), (1-6C)alkoxy, trifluoro(1-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-3C alkoxy)(2-6C)alkoxy, and cycloalkylmethoxy.
4. A compound of claim 3, wherein R1 is selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, , isopropoxy, trifluoromethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy, oxypropoxy, 3-methoxypropoxy, 2-ethoxyethoxy, 1,3-dimethoxypropanyloxy and cyclopropylmethoxy.
5. A compound of claim 4, wherein R1 is H.
6. A compound of claim 4, n R1 (1-3C alkoxy)(2-6C)alkoxy.
7. A compound of claim 1, wherein R1 is selected from halogen, CN, OH, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, cyano(1- 6C)alkyl, di(1-3C alkoxy)(1-6C)alkyl, fluoro(1-6C)alkoxy, ro(1-6C)alkoxy, oro(1- 6C)alkoxy, cyano(1-6C)alkoxy, di(1-3C alkoxy)(2-6C)alkoxy, oxetanylmethoxy nally substituted with methyl), (1-6C alkyl)sulfanyl, -C(=O)NRaRb, and -CH2C(=O)NRcRd.
8. A compound according to any of claims 1-7, wherein R2 is selected from H, (1-3C alkoxy)(1-6C)alkyl, hydroxy(2-6C)alkoxy, and (1-6C)alkoxy which is optionally substituted with (1-6C alkyl)C(=O)O- or amino(1-6C alkyl)C(=O)O-.
9. A compound according to claim 8, wherein R2 is selected from H, 2-methoxyethoxy, 3-methoxypropoxy, 2-methoxypropoxy, 2-ethyoxyethoxy, and 2-hydroxyethoxy.
10. A compound according to claim 9, wherein R2 is H.
11. A compound according to any of claims 1-7, wherein R2 is selected from halogen, CN, OH, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, oro(1-6C)alkyl, hydroxy(1-6C)alkyl, fluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, (1-3C alkoxy)(2-6C)alkoxy, (3-6C cycloalkyl)methoxy, oxetanylmethoxy nally substituted with ), tetrahydropyranyloxy, (1-6C alkyl)sulfanyl, hydroxy(2-6C alkyl)sulfanyl, (1- 3C alkylsulfanyl)(2-6C)alkoxy, -COOH, hetAr1, -C(=O)NReRf, -NReC(=O)Rf, and cyclopropyl optionally substituted with -CH2OH or -CH2O(1-6C alkyl).
12. A compound according to claim 1 or 2, wherein R1 and R2 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having 1 to 2 ring atoms independently selected from O and N, wherein said ring is optionally substituted with (1-4C)alkyl.
13. A compound according to any of claims 1-12, n R3 is selected from H, F and methyl.
14. A compound according to claim 13, wherein R3 is H.
15. A compound according to claim 13, wherein R3 is F.
16. A compound according to any of claims 1-15, wherein R5 is CF3, CH2F, CHF2, methyl or ethyl and R5a is H.
17. A compound according to claim 16, wherein R5 is CF3 and R5a is H.
18. A compound according to any of claims 1-15, wherein R5 is CF3, CH2F, CHF2, methyl or ethyl and R5a is methyl.
19. A compound according to claim 15, wherein R5 is methyl, and R5a is H.
20. A compound according to any of claims 1-19, wherein R6 is selected from H, NH2, OH, CH3NH-, (CH3)2CHNH-, FCH2CH2NH-, HOCH2CH2NH-, (cyclopropyl)CH2NH-, CH3C(=O)NH-, (CH3)3COC(=O)NH- and NH2CH2-.
21. A compound according to claim 20, wherein R6 is NH2.
22. A nd according to any of claims 1-21, wherein R7 is selected from H, methyl, ethyl, FCH2- and HOCH2-.
23. A compound ing to claim 22, wherein R7 is H.
24. A compound according to claim 23, wherein R7 is methyl.
25. A compound according to any of claims 1-19, wherein R6 and R7 together with the atom to which they are attached form a 5-6 membered spirocyclic heterocycle having a ring nitrogen atom.
26. A compound according to any of claims 1-25, wherein R8 is selected from H, F, OH or -OMe.
27. A compound according to claim 26, wherein R8 is H.
28. A compound ing to any of claims 1-19, wherein R6 and R8 er with the carbon atoms to which they are attached form a cyclopropyl ring optionally substituted with NH2.
29. A compound according to any of claims 1-28, wherein R9 is H.
30. A compound according to any of claims 1-19, wherein R6 and R9 er form a g group having the a -CH2NH- which links the carbon atoms to which they are attached.
31. A compound according to any of claims 1-30, wherein R10 is H.
32. A compound according to any of claims 1 or 3-30, wherein R10 is fluoro.
33. A compound of claim 1, selected from any one of es 1-328.
34. A ition comprising a nd according to any of claims 1-33 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
35. A nd of Formula I as defined in any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory or autoimmune disease.
36. A compound as defined in claim 35, wherein the inflammatory or autoimmune disease is multiple sclerosis, lupus, inflammatory bowel disease or rheumatoid arthritis.
37. A compound of Formula I as defined in any one of claims 1 to 33 or a pharmaceutically acceptable salt f, for use in the treatment of cancer.
38. Use of a nd of Formula I as defined in any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a PIM-1 and/or PIM-2 and/or PIM-3 kinase-mediated condition in a mammal.
39. Use of a compound of Formula I as defined in any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the ent of an inflammatory or autoimmune disorder in a mammal.
40. The use as defined in claim 39 wherein the inflammatory or autoimmune disease is multiple sis, lupus, inflammatory bowel disease or rheumatoid arthritis.
41. Use of a compound as defined in any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof in the cture of a medicament for the treatment of cancer in a patient in need thereof.
42. A process for the preparation a compound of claim 1, which comprises: (a) reacting a corresponding compound of formula II or a protected derivative where R4 is as defined for Formula I, with a corresponding compound having the formula III or a protected derivative thereof where R1, R2 and R3 are as defined for Formula I, in the ce of an organo hypervalent iodine reagent; or (b) for a compound of Formula I where R2 is hetAr1 or a cyclopropyl ring optionally substituted with -CH2OH or -CH2O(1-6C , reacting a corresponding compound having the formula IV or a protected derivative thereof: where R1, R3 and R4 are as defined for Formula I, with a reagent having the formula tively, where hetAr1 is as defined for Formula I, Cyc is cyclopropyl optionally substituted with -CH2OH or 1-6C alkyl), and Rx and Ry are H or (1-6C)alkyl, or Rx and Ry together with the atoms to which they are connected form a 5-6 membered ring ally substituted with 1-4 substituents selected from (1-3C alkyl), wherein said reaction takes place in the presence of a palladium catalyst and optionally in the presence of a base and a ligand; or (c) for a nd of Formula I where R2 is -NReC(=O)Rf, reacting a corresponding compound having the formula IV or a protected derivative thereof: where R1, R3 and R4 are as defined for Formula I, with a reagent having the formula HNReC(=O)Rf in the presence of a base and a metal catalyst; or (d) for a compound of a I where R2 is (1-6C alkyl)sulfanyl or hydroxy(2-6C alkyl)sulfanyl, reacting a corresponding compound having the formula IV or a ted derivative thereof: where R1, R2, R3 and R4 are as defined for Formula I, with a reagent having the a HS(1-6C alkyl) or HS(1-6C OH, respectively, in the presence of a base; or (e) for a compound of a I where R2 is -C(=O)NReRf, coupling a corresponding compound having the formula V or a protected derivative thereof: where R1, R3 and R4 are as defined for Formula I, with a reagent having the formula HNReRf, where Re and Rf are as defined for Formula I, in the presence of a base and a ng t; or (f) for a compound of Formula I where R1 is -CH2C(=O)NRcRd, coupling a corresponding compound having the formula VI or a protected derivative thereof where R2, R3 and R4 are as defined for Formula I, with a reagent having the formula HNRcRd, where Rc and Rd are as defined for Formula I, in the presence of a base and a coupling reagent; or (g) for a compound of Formula I where R2 is (1-6C)alkoxy substituted with (1-6C alkyl)C(=O)O-, coupling a corresponding compound having the formula VII or a protected derivative thereof where R1, R3 and R4 are as defined for Formula I, with a (1-6C)alkyl acid anhydride or a (1- 6C)alkyl acid chloride in the presence of a base; or (h) for a compound of a I where R2 is (1-6C)alkoxy substituted with amino(1- 6C alkyl)C(=O)O-, coupling a corresponding compound having the formula VII or a protected tive thereof where R1, R3 and R4 are as d for Formula I, with a compound having the formula P1NH(1-6C alkyl)C(=O)OH where P1 is H or an amine protecting group, in the presence of a base and a coupling reagent; or (i) f or a compound of Formula I where R4 is a moiety having the structure where R5, R5a, and R7 are as defined for a I, R8 is H, halogen, OH, or (1-6C)alkoxy, and R9 is H, reacting a corresponding compound having the formula VIII VIII where R1, R2, R3, R5, R5a, and R7 are as defined for Formula I, R8 is H, halogen, OH, or (1- 6C)alkoxy, and R9 is H, with a (1-6C)alkylcarboxylic acid anhydride or a (1- 6C)alkylcarboxylic acid chloride in the presence of a base; or (j) for a compound of a I where R4 is a moiety having the structure where R5, R5a, and R7 are as defined for Formula I, R8 is H, halogen, OH, or (1-6C)alkoxy, and R9 is H, reacting a corresponding compound having the a VIII VIII where R1, R2, R3, R5, R5a and R7 are as defined for Formula I, R8 is H, halogen, OH, or (1- 6C)alkoxy, and R9 is H, with a (1-6C)aldehyde or a protected (1-6C)aldehyde in the presence of a catalyst and a base followed by treatment with a reducing agent; or (k) for a compound of Formula I where R4 is a moiety having the structure where R5, R5a, and R7 are as defined for a I, R8 is H, halogen, OH, or (1-6C)alkoxy, and R9 is H, ng a corresponding compound having the formula VIII VIII where R1, R2, R3, R5, R5a, and R7 are as defined for Formula I, R8 is H, halogen, OH, or (1- 6C)alkoxy, and R9 is H, in the presence of a reagent having the formula (1-5C alkyl) and a reducing agent; or (l) for a compound of Formula I where R4 is a moiety having the structure where R7 is as defined for Formula I, R8 is H, halogen, OH, or (1-6C)alkoxy, R9 is H, and P2 is H or an amine protecting group, reacting a corresponding compound having the formula IX where R1, R2, and R3 are as defined for Formula I, in the presence of a Lewis acid, followed by ent with a reducing agent; and removing any ting group or groups and, if desired, forming a salt.
43. A compound having the formula II-A II-A including enantiomers and diastereomers thereof, where P3 is H or an amine protecting group and R7 is H, (1-6C)alkyl, fluoro(1-6C)alkyl or hydroxy(1-6C)alkyl.
44. A compound of claim 43, n R7 is H or (1-6C)alkyl.
45. A compound of claim 44, wherein R7 is H or .
46. A compound of Formula I as defined in any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof for use in the treatment of a PIM-1 and/or PIM-2 and/or PIM-3 kinase-mediated condition in a mammal.
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