NZ626306B2 - Substituted pyrazolo[1,5-a] pyridine as tropomyosin receptor kinase (trk) inhibitors - Google Patents

Substituted pyrazolo[1,5-a] pyridine as tropomyosin receptor kinase (trk) inhibitors Download PDF

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NZ626306B2
NZ626306B2 NZ626306A NZ62630612A NZ626306B2 NZ 626306 B2 NZ626306 B2 NZ 626306B2 NZ 626306 A NZ626306 A NZ 626306A NZ 62630612 A NZ62630612 A NZ 62630612A NZ 626306 B2 NZ626306 B2 NZ 626306B2
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pyrazolo
pyridine
pyrrolidin
carboxamide
fluoro
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NZ626306A
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NZ626306A (en
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Shahadat Ahmed
Prasanna M Dattatreya
Nanjegowda Jagadeesh Mavinahalli
Vidyadhar Paradkar
Pradip Kumar Sasmal
Ashok Tehim
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Dr Reddy's Laboratories Ltd
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Priority claimed from PCT/IB2012/003012 external-priority patent/WO2013088256A1/en
Publication of NZ626306A publication Critical patent/NZ626306A/en
Publication of NZ626306B2 publication Critical patent/NZ626306B2/en

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Abstract

Disclosed are substituted pyrazolo[1,5-a]pyridine compounds of formula (I), wherein the substituents are as defined in the specification. The compounds are useful for treating conditions diseases and/or disorders treatable or preventable by inhibition of Trk kinase activity, such as pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibrosis, neurodegenerative disease, a disease, disorder, or injury relating to dysmyelination or demyelination or certain infectious diseases such as Trypanosoma Cruzi infection. Examples of compounds or formula (I) are: N-(N-ethyl-N-methylsulfamoyl)-5-(2-(8-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)pyrrolidin-1-yl)pyrazolo[1,5-a ]pyridine-3-carboxamide (R)-5-(2-(2,5-difluorophenyl) pyrrolidin-1-yl)-N -((3,5-dimethylisoxazol-4-yl)sulfonyl)pyrazolo [1,5-a]pyridine-3-carboxamide on, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibrosis, neurodegenerative disease, a disease, disorder, or injury relating to dysmyelination or demyelination or certain infectious diseases such as Trypanosoma Cruzi infection. Examples of compounds or formula (I) are: N-(N-ethyl-N-methylsulfamoyl)-5-(2-(8-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)pyrrolidin-1-yl)pyrazolo[1,5-a ]pyridine-3-carboxamide (R)-5-(2-(2,5-difluorophenyl) pyrrolidin-1-yl)-N -((3,5-dimethylisoxazol-4-yl)sulfonyl)pyrazolo [1,5-a]pyridine-3-carboxamide

Description

PCT/IB20121003012 Substituted pyrazolo[1,5~a}pyridine as Tropomyosin Receptor Kinase (Trk) Inhibitors TECHNICAL FIELD The present application relates to a series of substituted pyrazolo[l,5—a]pyridine compounds. The present application is further directed to use such compounds as tropomyosin receptor kinase (Trk) family protein kinase inhibitors. The present application also describes method of making such compounds and pharmaceutical compositions comprising such compounds.
BACKGROUND TrkA, TrkB and TrkC, which make up the the Trk receptor family, are high y receptor tyrosine s activated by a group of soluble growth factors called neurotrophins (NT) (Curr Opin Neurobiol, 2001, 11, 272—280).
Inhibitors of the Trk/neurotrophin y have been demonstrated to be effective in numerous animal models of pain. For example, sustained blockade of rophin receptors TrkA, TrkB and TrkC reduces non-malignant skeletal pain (Bone, 2011, 48(2), 389—398). Administration ofNGF receptor (TrkA) inhibitor K252a showed significant suppression of mechanical lgesia (relevant to the pathogenesis of myofascial pain syndrome (MPS)) in animal models (J. Pain, Article in Press, 2011, 12(10), 068). Antagonistic NGF and TrkA antibodies have been shown to be efficacious in inflammatory and neuropathic pain animal models (Neuroscience, 1994, 62,327—331; J. Pain, 2004, 5, 157—163; Nat. Med, 1995, 1, 774— 780; Pain, 2005, 116, 8-16; Pain, 2003, 105, 489-497) and neuropathic pain animal models (Eur. J. Neurosci., 1999, 11, 837-846; Pain, 1999, 79, 265-274 ; Pain, 1999, 81, 245255; Neurosci. Lett., 2003, 336, 0).
NGF secreted by tumor cells and tumor ng hages has been shown to directly stimulate TrkA located on peripheral pain fibers. It has also been demonstrated in s tumor models in both mice and rats that neutralizing NGF with a monoclonal antibody inhibits cancer d pain. Further, activation of the BDNF/TrkB pathway has been implicated in numerous studies as a modulator of s types of pain including inflammatory pain (J. Physiol. 2005, 569:685—95), neuropathic pain (Proc. Natl. Acad. Sci. USA 1999, 96:7714-18) and surgical pain (Molecular Pain, 2008, 4(28), l-ll). Since TrkA kinase has been demonstrated to serve as a mediator ofNGF driven biological responses, inhibitors ofTrkA and/or other Trk kinases may provide an effective treatment for various pain conditions.
Inhibition of the neurotrophin/Trk pathway with NGF antibodies or non- selective small molecule inhibitors of Trk A, B and C has been shown to be effective in treatment of pre-clinical models of inflammatory es such as asthma (Pharmacol.
Therapeut, 2008, 117(1), 52—76), interstitial cystitis (.1. Urology, 2005, 173(3), 1016— 21), inflammatory bowel diseases including ulcerative colitis and Crohn's disease (Gut, 2000, 46(5), 670—678) and inflammatory skin diseases such as atopic dermatitis (Arc Dermatol Res., 2006, 298(1), , eczema and psoriasis (J. Investig Dermatol., 2004, 122(3), 812~819).
The current treatment regimes for pain ions utilize several classes of compounds. The opiates apart from being potentially addictive have several e effects such as , constipation, dose-related respiratory depression. Nonsteroidal anti—inflammatory analgesics (NSAID) also have drawbacks such as gastric ulceration, dyspepsia and insufficient y in treating severe pain. ingly, there is a continuing need for new and more effective treatments for the relief of pain, especially chronic pain. Several classes of small molecule inhibitors of Trk kinases said to be useful for treating pain or cancer are known (Expert Opin. Ther. Patents, 2009, 19(3), 305-319).
U.S. Publication No. 20110195948 describes substituted pyrazolo[1,5— a]pyrimidine compounds as Trk kinase tors.
JP Publication No. 2003231687 describes a series of lyl sed cyclic compounds as Trk inhibitors.
PCT Publication No. 427 describes compounds containing a 1,4,5,6— tetrahydropyrrolo[3,4—c]pyrazoie bicyclic scaffold as TrkA inhibitors.
PCT ation No. 2004011461 describes a series of isothiazole derivatives as Trk inhibitors.
SUMMARY The present ations relates to pyrazolo[l,5-a]pyridine compounds of formula (I), SQIN\ \ A Rb C R1 O (1) their phannaceutically acceptable salts, pharrnaceutically acceptable solvates or stereoisomers thereof, wherein (R2)m (R2)m 0// Mi‘/ 8“,},, O 8W},, /4 /V/ A is (R3)n or (R3)n ; X1 is CH or N; Rl represents hydrogen or —(C1-C6)alkyl; R2 is independently selected from hydrogen, halogen, cyano, -(C.-C6)alkyl, - 1-C6)alkyl-, -halo(C1-C6)alkoxy-, phenyl optionally substituted with 1 to 3 halogens or an optionally substituted -O—heterocycly1 wherein the optional substituent is selected from alkyl, -ORi or - C(0)N<Ri)2; when X1 is CH, optionally two st present on any two adjacent carbon atoms combine to form a 5 to 7 membered heterocyclic ring; R3 is independently selected from halogen, cyano, —ORi—, -C(O)N(Ri)2 or two R35 together with the carbon atom they are attached form a (C3- C7)cycloalkyl group spiro ed to idine; or two R3 when they are attached to nt carbon atoms form a (C3-C7)cycloalkyl ring fused to the pyrrolidine; R21 is selected from (i) a group selected from optionally substituted -(C1-C6)alkyl, -hydroxy(C1-C6)alky1- or 6)alkyl-(C1-C6)alkoxy wherein the optional substituent is selected from cyano, halogen or -(C6- C12)aryla (ii) an optionally substituted -(C3~C10)Cycloalky1 wherein the al substituent is selected from cyano, -(C]—C6)alkyl, hydroxyl, halogen or -RS, (iii) an optionally substituted -(C6-C12)ary1 wherein the optional substituent is selected from cyano, hydroxyl, halogen, -(C1— C6)alky1 or -Rr (iv) an optionally substituted 5 to 10 membered heterocyclyl wherein the optional tuent is selected from cyano, hydroxyl, halogen or —(C1—C6)alkyl, (V) an ally tuted 5 to 10 membered heteroaryl wherein the optional substituent is selected from cyano, oxo (=0), hydroxyl, halogen, -(C1-C6)alkyl, —(C1-C6)alkoxy, —NR°Rd or «Rf, (vi) ~NR4R5, (Vii) -(C1—C6)alkyl-(C6-C12)aryl; Rb represents hydrogen or halogen; R4 is selected from hydrogen, —(C1-C6)alkyl, -(C3-C10)cycloalky1, -hydroxy(C1- C6)alkyl-, -alkoxy(C1-C6)alkyl-,I -halo(C1-C6)alkyl- or -(C1-C6)alkyl- (C3-C10)cycloalkyl; R5 is selected from hydrogen or -(C1—C6)alkyl or —(C1—C6)alky1-(C3- C10)cycloalky1; atively R4 and R5 together with the en atom to which they are attached may form an optionally substituted 5 to 10 membered heterocyclic ring optionally containing 1-2 additional heteroatoms or groups selected from ~O—, -S—, —N—, —C(=O)-, —S(=O)- or —S(=O)2-, wherein the optional substituent is selected from hydroxyl, -(C1- yl, —C(=O)—(C1—C6)alkyl, mesyl or COORC; Rc and Rd are ndently selected from hydrogen or -(C1‘-C6)alky1; Re is selected from en or alkyl; Ri is hydrogen, -(C1-C6)alky1, ~halo(C1-C6)alkyl-, -(C1-C6)alky1-(C1—C6)alkoxy, —(C3—C10)cycloalkyl, optionally tuted —(C1-C6)alkyl-(C3- C10)cycloalkyl wherein the optional substituent is halogen or -(C1- C6)alkyl substituted with l to 3 hydroxy groups; 2012/003012 Rr is independently selected from a 5 to 10 membered heterocyclyl or a 5 to 10 membered heteroaryl, wherein optional substituent is selected from hydroxyl, halogen, -(C1-C5)alkyl or -(C1-C5)alkoxy; RS is an optionally susbtituted -(C1-C5)alkyl-(C6-C10)aryl, wherein the optional substituent is halogen; m is independently represents 0, l, 2, 3 or 4; and n is independently represents 0, l, 2, or 3.
The present application further s to methods of treating or preventing conditions, diseases and/or disorders associated with abnormal or deregulated Trk kinase activity by stereing ive amount of a compound of formula (I), to a patient in need thereof.
One aspect of the present ation provides s of treating or preventing conditions, diseases and/or disorders associated with abnormal or deregulated TrkA kinase activity by administereing effective amount of a compound of formula (I), to a patient in need thereof.
One aspect of the present application provides conditions. diseases and/or disorders ble or preventable by inhibition of Trk kinase activity, such as pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, fibrosis, neurodegenerative e or a disease, disorder or injury relating to dysmyelination or demyelination by administering a therapeutically effective amount of compound of formula (I), to a patient in need thereof.
The present application also s to pharmaceutical itions comprising ive amount of a compound of formula (I), and a pharmaceutically acceptable carrier or diluent, and the use of such itions in the treatment and/or prevention of diseases associated with inhibiting TrkA in a patient in need thereof, such as pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, fibrosis, neurodegenerative e, a disease, disorder, or injury relating to dysmyelination or demyelination or certain infectious diseases such as osoma cruzi infection W0 2013(088256 DETAILED DESCRIPTION As used herein, ‘halogen or halo’ group refers to fluorine, chlorine, bromine or As used herein, ‘(C 1-C6)alkyl’ refers to linear or branched alkyl group with l to 6 carbon atoms. Exemplary (C1—C5)alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, opyl, n-butyl, iso—butyl, t-butyl, yl, iso-pentyl and the like.
(C1-C3)alkyl refers to linear or ed alkyl group having one to three carbon atoms such as , ethyl propyl or iso—propyl.
As used , ‘hydroxy(C1-C6)alkyl’ refers to a group wherein at least one en atom of an (C1—C6)alkyl group is replaced by a hydroxyl group. (C1-C6)alkyl group is as defined above. Representative examples of hydroxy(C1—C5)alkyl groups include one or more of, but are not limited to hydroxymethyl, hydroxyethyl and the like. Unless otherwise specified, a hydroxy(C1-C6)alkyl group is having 1 to 6 carbon atoms. As used herein, C1—C5)alkyl’, in each occurrence, ndently means at least one hydrogen atom of an )alkyl group is replaced by a halogen group.
Halogen and (C1-C6)alkyl group are as defined above. Representative es of halo(C1-C6)alkyl groups include one or more of, but are not limited to fluoromethyl, difluoromethyl, fluroethyl, difluroethyl, trifluloethyl, fluoropropyl, difluoropropyl, trifluoropropyl and the like.
As used herein ‘(C3-C10)cycloalkyl’ refers to a cyclic alkyl group which may be mono, bicyclic, polycyclic, or a fused/bridged ring system having 3 to 10 carbon atoms.
Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Typical bridged cycloalkyls include, but are not limited to adamantyl, noradarnantyl, bicyclo[1.l.0]butanyl, norbornyl(bicyclo[2.2. l]heptanyl), and the like.
As used herein, two R3s when they are attached two adjacent carbon atoms form (C3—C7)cycloalkyl Spiro attached to pyrrolidine are selected from cyclopropyl, cyclobutyl and the like.
As used herein, ‘(C1~C6)alkyl-(C3—C10)cycloalkyl’ refers to a group wherein (C1- C5)alkyl group is optionally substituted with t one (C3—C10)cycloalkyl, wherein (C1-C6)alkyl and (Cg-C10)cycloalkyl are as defined above. Exemplary (C 1-C6)alkyl—(C3- C10)cycloalkyl groups include methyl-cyclobutyl, ethyl-clcobutyl and the like. 2012/003012 As used herein, ‘(CI-C6)alkoxy’ refers to an —O-(C1—C6)alkyl group, wherein (C1-C5)alkyl group is as defined above. Exemplary (C1—C6)alkoxy groups include methoxy, ethoxy, n-propoxy, iso—propoxy, n-butoxy, iso-butoxy, xy, and the like.
(C1—C3)alkoxy refers to an alkoxy group having one to three carbon atoms, such as methoxy, , propoxy or poxy.
As used herein, ‘halo(C1-C5)alkoxy’ refers to a group wherein atleast one hydrogen atom of an (C1—C6)alkoxy group is replaced by a halogen group. Halogen and (C1—C6)alkoxy group are as defined above. Representative examples of halo(C1— C5)alkoxy groups include one or more of, but are not limited to fluoromethoxy, difluorornethoxy, fluroethoxy, difluroethoxy, trifluloethoxy, fluoropropoxy, difluoropropoxy, trifluoropropoxy and the like.
As used herein, “(C6-C12)aryl’ refers to a monocyclic or clic ic ring system having 6 to 12 carbon atoms. Exemplary aryl groups include, but are not limited to, phenyl, yl, and the like.
As used herein, ‘aralkyl’ refers to an (C1-C5)alkyl group substituted with atleast one (Cg-(:12)an group, wherein (C1—C5)alkyl and z)aryl groups are as defined above. Exemplary aralkyl groups include, but are not limited to, benzyl, ethyl- phenyland the like. (C1-C3)alkyl-(C6-C12)aryl groups refers to an (C1-C3)alkyl group substituted with atleast one (C6—C12)aryl group, wherein (C1-C3) represents an alkyl group having 1 to 3 carbon atoms and (C5-C12)aryl group is as defined above.
Exemplary )alkyl-(C6—C12)aryl groups include methyl—phenyl, ethyl-phenyl and the like.
As used herein, ‘5 to 10 membered heterocyclyl’ ‘ or 5 to 10 membered cyclic ring’ refers to a monocyclic or polycyclic ring system, having at least one heteroatom or heterogroup selected from O, N, S, SO, $02, or CO. Exemplary heterocyclyl or heterocyclic ring groups include, but not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, ydro-ZH-pyranyl, morpholinyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, ydro-2H-thiopyranyl, thiazolidinyl, 1,3-dioxolanyl, l,4~dioxanyl, l-oxidotetrahydro-2H-thiopyranyl, 1,1- dioxidotetrahydro-ZH-thiopyranyl , hexahydropyrrolo[3 ,4-c]pyrrol-2(l H)-yl , 2,5-diazabicyclo[2.2. l ]heptanyl, azepanyl and the like.
As used herein, ‘5 to 7 membered heterocyclyl’ ‘ or 5 to 7 membered heterocyclic ring’ refers to a monocyclic ring system, having at least one heteroatom or heterogroup selected from O, N, S, SO, $02, or CO. Exemplary heterocyclyl or cyclic ring groups include, but not limited to, 1,4-dioxane, 1,4-dioxepane and the like.
As used , ‘5 to 10 membered heteroaryl group’ refers to a monocyclic or polycyclic ring system, rated, ic or non—aromatic; having at least one atom or heterogroup selected from -O- —N- — , , —S- , -S(=O)—, -S(=O)z, or C(=O)—. Exemplary heteroaryl ring groups, aromatic or non-aromatic rings, include, but not limited to, furanyl, oxazolyl, isoxazole, olyl, lyl, thiophenyl, thiazolyl, pyridinyl, thiazinyl, pyrazinyl, pyrazolyl, tetrazolyl, imidazothiazolyl, l, yl, isoxazole, imidazolyl, oxadiazolyl, triazolyl, lyl, pyridinyl, thiazinyl, pyrazinyl, pyrazolyl, tetrazolyl, imidazothiazolyl, indolizidinyl, indolinyl, oxoindolinyl, indolyl, oxoindolyl, quinolinyl, 3,4-dihydroisoquinolin-2(lH)~yl, quinoxalinyl, benzoxazolyl, benzo[d]isoxazolyl, benzo[d}thiazolyl, benzo[d][l,3]dioxolyl, 1H- benzo[d][l,2,3]triazolyl, 2H—indazoly1, lH—indazolyl, quinoxalin—2—yl, lH— benzo[d]imidazoly1, pyrazolo[l,5-a]pyridinyl, obenzo[b][1,4]dioxiny1, (5,6,7,8- tetrahydroimidazo[l,2-a]pyridin—7-yl), 4,5,6,7-tetrahydropyrazolo[l,5—a]pyrazinyl, 5,6— dihydroimidazo[l ,2-a]pyrazin—7(8H)—yl), 5,6,7,8-tetrahydroimidazo[1 ,2-a]pyrazinyl, Hexahydropyrrolo [1, 2-a] pyrazin-2(1H)-y1, 5,6-dihydr0-[l,2,4]triazolo[4,3- a]pyraziny1, pyrazolo[l,5a]pyridinyl and the like.
The Trk's are made up of three family members TrkA, TrkB and TrkC that bind to and mediate the the signal transduction derived from the Neurotrophins. Inhibitors of the Trk/neutrophin pathway have been demonstrated to be highly effective in numerous pre-clinical animal models of pain. The nds of the invention are modulators of the Trk receptors, particularly TrkA.
As used herein, the term TrkA refers to one of Trk‘s high affinity binding protein kinase receptors that are activated by Neurotrophins (NT), a group of soluble growth factors Nerve Growth Factor (NGF), Brain—Derived Neurotrophic Factor (BDNF) and Neurotrophin 3-5 (NT 3—5).
‘Optionally substituted’ means that the substitution is optional and therefore it is possible for the designated atom or group to be unsubstituted. In the event a substitution is desired, then such substitution means that any number of hydrogens on the designated atom is ed with a selection from the indicated group, provided that the normal valence of the designated atom is not exceeded, and that the substitution results in a stable compound. For example, in formula (I) when a substituent is oxo (ire, =0), then two hydrogens on the atom are replaced and when the substitution is fluoro, then one hydrogen on the atom is ed and the like. When more than one substituent is present on an atom or group, the chosen substituents are independent of each other (ie same or different).
As used herein and in the appended claims, the ar forms “ n u a an”, and “the” include plural reference unless the context clearly indicates otherwise.
As used herein, the term 'subject' or ‘patient’ means mammals, such as humans and other animals, including horses, dogs, cats, rats, mice, sheep, pigs, s, chimpanzees or other apes or primates. In exemplary embodiments, the subject may include subjects for which treatment and/or prevention of the conditions described herein would be beneficial.
For ease of reference, in this ation it will be described in terms of administration to human subjects. It will be tood, however, that such descriptions are not limited to administration to humans, but will also include administration to other animals unless explicitly stated otherwise.
A ‘therapeutically effective amount’ is the amount of compound of the present application that is effective in generating biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or rate symptoms, ate conditions, slow or delay disease progression, or prevent a disease.
In one embodiment, the term ‘a therapeutically effective amount’ refers to the amount of the compound of the present ation that, when administered to a subject, is ive in (i) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease ed by TrkA, TrkB and/or TrkC, associated with TrkA, TrkB and/or TrkC activity or characterized by activity (normal or abnormal) of TrkA, TrkB and/or TrkC; (ii) reducing or inhibiting the activity of TrkA, TrkB and/or TrkC; or (iii) reducing or inhibiting the expression of TrkA, TrkB and/or TrkC.
In another embodiment, the term "a therapeutically effective amount" refers to the amount of the nd of the t invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is ive to at least partially reducing or inhibiting the activity of TrkA, TrkB and/or TrkC; or at least partially reducing or inhibiting the expression of TrkA, TrkB and/or TrkC.
The terms 'treating' or 'to treat‘ means to alleviate symptoms, ate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms. The term 'treatment' includes alleviation, ation of causation of or prevention of any of the diseases or disorders bed above. The compounds described herein are typically administered in admixture with one or more pharmaceutically acceptable excipients or carriers in the fonn of a pharmaceutical composition. A 'composition' may n one compound or a mixture of compounds.
A aceutical composition‘ is any composition useful in producing at least one physiological response in a subject to which such pharmaceutical composition is stered.
The term antially pure’ means that the isolated material is at least 80% pure, preferably 90% pure, more preferably 95% pure, and even more preferably 99% pure as measured by a le analytical techniques known in the art.
Unless defined ise, all cal and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.
One or more compounds of formula (I) can be supplied in the form of a therapeutic composition that is within the scope of the present application.
The term ‘Pharrnaceutically acceptable salts’ refers to any acid or base salt, pharmaceutically acceptable solvates, or any complex of the compound that, when administered to a recipient, is capable of providing (directly or indirectly) a compound as described herein. It should be appreciated, however, that salts that are not pharmaceutically able also lie within the scope of the application. The preparation of salts can be carried out using known methods.
For example, pharmaceutically able salts of compound of formula (I) contemplated refers to salts prepared from acids or bases including inorganic or organic acids and inorganic or organic bases by conventional chemical methods using a compound of formula (1). Generally, such salts may be prepared, for example, by making free base of the compounds and reacting with a stoichiometric quantity of the appropriate acid and vice-versa in water or in an organic solvent, or in a mixture of the two. The comounds of the present applications may form mono, di or tris salts.
When the compound of formula (I) is basic, salts may be ed from acids, including inorganic or organic acids (acid addition salts). Examples of such acids e, but not limited tofonnic, acetic, trifluoroacetic, propionic, succinic, glycolic, PCT/IBZOlZ/003012 gluconic, lactic, malic, tartaric, , ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p—hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),nitric, hydrochloride, hydrobromide, isoethionic, hydroiodide, phosphoric, sulfuric, succinic, tartaric, methanesulfonic, ethanesulfonic, benzenesulfonic, benzoic, mucic, pantothenic, p—toluenesulfonic, camphorsulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, B—hydroxybutyric, galactaric, and galacturonic acid, and the like.
Salts formed from nic bases include sodium, potassium, lithium, calcium, copper, magnesium, manganic salts, ous, zinc, aluminum, ammonium, ferric, ferrous and the like.
Salts derived from organic bases include salts of y, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N—dibenzylethylene—diamineS diethylamine, 2—diethylaminoethanol, 2— dimethylaminoethanol, ethanolamine, ethylenediamine, N—ethylmorpholine, N— ethylpiperidine, glucamine, glucosamine, histidine, amine, isopropylamine, , giucamine, morpholine, piperazine, piperid e, polyamine resins, procaine, purines, omine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
‘Pharmaceutically acceptabl salts’ in the solid form may exist in more than one crystal structure, and may also be in the form of es.
The term ‘stereoisomers’ is a general term used for all isomers of an individual molecule that differ only in the orientation of their atoms in space. Where the compounds according to the present application possess one or more asymmetric centers and compounds with tric centers give rise to enantiomers, diastereomers or both as pure or partially purified compounds. It is to be understood that all stereoisomeric forms of the nds of the invention, including but not d to, diastereomers, enantiomers and atropsiomers, as well as mixtures thereof such as forms, are included in the scope of the t ation. Preparation of such stereoisomeric forms of compound of formula (l), may be achieved by appropriate modification of the methodology known in the art. Their absolute stereochemistry may be determined by the suitable methods. If required, racemic mixtures of the compound of a (I) may be separated to isolate individual enantiomers or diastereomers.
Such separation can be carried out by methods known in the art, such as the coupling of a racemic mixture of compound of formula (I) to an omerically pure compound to form a diastereomeric mixture, followed by tion of the individual diastereomers by standard methods, such as onal crystallization or tography. The coupling on is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated ly by chromatographic methods using chiral stationary phases, which s are well known in the art. Alternatively, any enantiomer or diastereomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or known reagents.
For any particular compound disclosed herein, wherein the stereochemistry of any particular chiral atom is not ed, then all stereoisomers are contemplated and included as the compounds of the application. Where stereochemistry is specified by a solid wedge or a dashed wedge bond or dashed line representing a particular ration then that stereoisomer is so specified and defined. Following the standard chemical literature description practice and as used herein, a full wedge bond means above the ring plane, and a dashed wedge bond or dashed line means below the ring plane.
Pharmaceutically acceptable solvates of compound of formula (I) may be hydrates or sing other solvents of crystallization such as alcohols.
Pharmaceutically acceptable solvates of compound of formula (I) may be prepared by conventional methods such as dissolving the compounds of formula (I) in solvents such as water, methanol, ethanol etc., preferably water and recrystallizing by using different crystallization techniques.
In the formulae depicted herein, a bond to a substituent and/or a bond that links a molecular fragment to the remainder of a compound may be shown as intersecting one or more bonds in a ring structure, This indicates that the bond may be attached to any one of the atoms that constitutes the ring structure, so long as a hydrogen atom could ise be present at that atom. Where no particular substituent(s) is identified for a particular position in a structure, then en(s) is present at that position.
Reference will now be made in detail to the embodiments of the invention, one or more examples of which are set forth below. Each example is provided by way of explanation of the invention, and not by way of limitation of the invention. In fact, it will be apparent to those skilled in the art that various modification and variations can be made in the present ion without departing from the scope or spirit of the invention. For instance, features illustrated or bed as part of one embodiment can be used on another embodiment to yield a still further embodiment. Thus it is intended that the present invention cover such ations and variations as come Within the scope of the appended claims and their equivalents. Other objects, features, and aspects of the present invention are disclosed in, or are obvious from, the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only, and is not to be construed as limiting the broader aspects of the present application.
Thus in accordance of this application there is provided a series of substituted pyrazolo[1,5-a]pyridine derivatives having the general a (I), / ,N Rb 4Q H O N'-S—Ra R1 O (1) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, n (R2)m (R2)m 9‘ o f. QtI, (R3)n or (R3)n ;x1 is CH or N; RI represents en or 6)alkyl; R2 is independently selected from hydrogen, halogen, cyano, -(C1-C6)alkyl, — halo(C1—C6)alkyl-, -halo(C1-C6)alkoxy—, phenyl optionally substituted with 1 to 3 halogens or an optionally substituted -O-heterocyclyl wherein the optional substituent is ed from alkyl, -ORi or - C(0)N(Ri>2; when X1 is CH, optionally two R23 present on any two adjacent carbon atoms combine to form a 5 to 7 membered heterocyclic ring; R3 is independently selected from halogen, cyano, —ORi , -C(O)N(Ri)2 or two R3s together with the carbon atom they are attached form a (C3— C7)cycloalky1 group Spiro attached to pyrrolidine; or two R3 when they are ed to adjacent carbon atoms form a (C3—C7)cycloa1kyl ring fused to the pyrrolidine; Ra is selected from (i) a group selected from optionally substituted -(C1—C6)alkyl, l0 -hydroxy(C1-C6)alkyl- or ~(C1~C6)a1kyl-(C1—C6)alkoxy wherein the al substituent is selected from cyano, halogen or —(C6— C12)aryl, (ii) an optionally substituted ~(C3-Cio)cycloalky1 wherein the optional substituent is selected from cyano, -(C1-C6)alkyl, hydroxyl, halogen or Rs, (iii) an optionally substituted —(C6-C12)aryl wherein the optional substituent "is selected from cyano, hydroxyl, n, -(C1— C6)alkyl or -Rr (iv) an optionally tuted 5 to 10 ed heterocyclyl wherein the al substituent is selected from cyano, hydroxyl, halogen or —(C1—C6)a1kyl, (V) an optionally substituted 5 to 10 membered heteroaryl wherein the optional substituent is ed from cyano, 0x0 (=0), hydroxyl, halogen, ~(C1-C6)alkyl, —(C1—C6)alkoxy, —NR°Rd or —Rr, (Vi) —NR4R5, (vii) -(C1—C6)a1kyl—(C6~C12)aryl; Rb represents hydrogen or halogen; R4 is selected from hydrogen, -(C1-C6)alky1, -(C3-C10)cycloalkyl, —hydroxy(C1- y1-, -a1koxy(C1—C6)alkyl, -halo(C1-C6)a1kyl or -(C1-C6)alkyl— (C3—C10)cycloalkyl; R5 is selected from hydrogen or -(C1-C6)alky1 or -(C1-C6)alkyl-(C3- C10)cycloalky1; Alternatively R4 and R5 together with the nitrogen atom to which they are attached may form an optionally substituted 5 to 10 membered heterocyclic ring optionally containing 1-2 additional heteroatoms or groups selected from -O-, -S-, -N—, -C(=O)-, -S(=O)- or -S(=O)2-, wherein the optional substituent is selected from hydroxyl, -(C1— C6)alkyl, —C(=O)-(C;-C6)alkyl, mesyl or COORC; RC and Rd are independently selected from hydrogen or -(C1-C6)alkyl; Re is selected from hydrogen or alkyl; Ri is en, ~(C1—C6)alkyl, C1—C6)alkyl, -(C1-C6)alkyl—(C1—C6)alkoxy, — (C3-C10)Cycloalkyl, optionally substituted ~(C1-C6)a1kyl-(C3— Cm)cycloalkyl wherein the optional substituent is halogen or -(C1— C6)a1ky1 substituted with 1 to 3 hydroxy groups,; Rr is independently ed from a 5 to 10 membered heterocyclyl or a 5 to 10 membered heteroaryl, wherein al substituent is selected from hydroxyl, halogen, -(C1—C6)alky1 or -(C1-C6)alkoxy; RS is an optionally tuted -(C1-C6)a1kyl-(C6—C10)aryl, wherein the optional substituent is halogen; m is independently represents 0, 1, 2, 3 or 4; and n is independently ents 0, 1, 2, or 3.
In one embodiment, there is ed a compound of formula (1), R1 0 (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates or isomers thereof, wherein A is (R3)n ; X1 is CH or N; RI represents hydrogen or ~(C1-C6)alkyl; R2 is independently selected from hydrogen, halogen, cyano, —(C1—C6)a1kyl, ~ halo(C1-C6)a1kyl—, C1-C6)alkoxy—, phenyl optionally substituted with l to 3 halogens or an optionally substituted erocyclyl wherein the al substituent is selected from alkyl, -ORi or - C(O)N<Ri)2; when X1 is CH, optionally two R25 present on any two adjacent carbon atoms combine to form a 5 to 7 membered heterocyclic ring; R3 is independently ed from halogen, cyano, —ORi , —C(O)N(Ri)2 or two R33 together with the carbon atom they are attached form a (C3— C7)cycloalkyl group spiro attached to pyrrolidine; or two R3 when they are attached to adjacent carbon atoms form a (C3-C7)cycloalkyl ring fused to the pyrrolidine; R21 is selected from (i) a group selected from ally substituted 6)alky1, —hydroxy(C1-C6)alkyl— or -(C1-C6)alkyl-(C1—C6)alkoxy wherein the optional substituent is selected from cyano, halogen or -(C6- C12)aryl, (ii) an optionally substituted -(C3-C10)cycloalkyl wherein the optional substituent is selected from cyano, —(C1-C6)a1kyl, hydroxyl, n or —RS, (iii) an optionally substituted -(C6—C12)aryl wherein the optional substituent is selected from cyano, hydroxyl, halogen, —(C1— C6)alkyl or —Rr (M an optionally tuted 5 to 10 membered heterocyclyl n the optional substituent is ed from cyano, hydroxyl, halogen or -(C1—C6)alkyl, (V) an optionally substituted 5 to 10 membered heteroaryl wherein the optional substituent is selected from cyano, 0x0 (=0), hydroxyl, halogen, —(C1—C6)alkyl, —(C1—C6)alkoxy, —NR°Rd or —R“, (Vi) -NR4R5, (vii) -(C1-C6)alkyl—(C6—C12)aryl; Rb represents hydrogen or halogen; R4 is selected from hydrogen, —(C1-C6)alkyl, -(C3-C10)cycloalkyl, -hydroxy(C1— C6)alky1, —alkoxy(C1-C6)alkyl—, —halo(C1-C6)alky1- or -(C1-C6)alky1- (Cg-Clo)cycloalkyl; R5 is selected from hydrogen or -(C1-C6)alkyl or -(C1-C6)alkyl-(C3- C10)cycloalkyl; Alternatively R4 and R5 together with the nitrogen atom to which they are attached may form an optionally substituted 5 to 10 membered heterocyclic ring optionally containing 1-2 additional heteroatoms or groups selected from -O-, -S-, -N—, -, -S(=O)- or —S(=O)2-, wherein the optional substituent is selected from hydroxyl, ~(C1- C6)alkyl, -C(=O)-(C1-C6)alkyl, mesyl or COORC; Rc and Rd are independently ed from hydrogen or ~(C1~C6)alkyl; Re is selected from hydrogen or alkyl; Ri is hydrogen, -(C1-C6)alky1, —halo(C1-C6)alkyl, —(C1—C6)alkyl-(C1-C6)alkoxy, — (C3—C10)cycloalky1, optionally substituted —(C1—C6)alkyl-(C3— C10)cycloalkyl wherein the optional substituent is n or -(C1— C6)a1kyl substituted with 1 to 3 hydroxy ,; Rr is independently selected from a 5 to 10 ed heterocyclyl or a 5 to 10 membered heteroaryl, wherein optional substituent is selected from hydroxyl, n, ~(C1-C6)alkyl or -(C1-C6)alkoxy; R8 is an optionally tuted —(C1~C6)alkyl—(C6—C10)aryl, wherein the optional substituent is halogen; m is independently represents 0, 1, 2, 3 or 4; and n is independently represents 0, l, 2, or 3.
In another embodiment, the compounds of formula (I) are represented as nds of formula (la), (R2)m b C\ ’ R O// N 43:0 0 \a R (Ia) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, wherein the values of all the variables are as described for compound of formula (I).
In r embodiment, compounds of formula (I) are represented as compounds of formula (Ib), Rb C‘ O// N\S o”\;0 R (1b) their pharmaceutically acceptable salts, pharmaceutically able solvates or stereoisomers thereof, wherein the values of all the les are as bed for compound of formula (I).
In another embodiment, compounds of formula (I) are represented as compounds of formula (Ic), N/—\_/(R)m2 \ / / N’N\ their pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, wherein the values of all the variables are as described for compound of formula (I).
In another ment, nds of formula (I) are represented as compounds offormula (Id), 2>m/ N’N\ (R) \ \ O“ WokeVR R1 (1d) their pharmaceutically acceptable salts, pharrnaceutically acceptable solvates or stereoisomers thereof, wherein the values of all the variables are as described for compound of formula (I).
W0 2013I088256 In another embodiment, compounds of formula (I) are represented as compounds of formula (Ie), / ,N F \ Rb qC‘NH 0 ‘s0 o¢3\ R3 (16) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, wherein the values of all the variables are as described for compound of formula (I).
In another embodiment, compounds of a (I) are represented as compounds of formula (If), F a \ (R): \ Rb oC‘NH Ra (If) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, wherein the values of all the variables are as described for nd of formula (I).
In another ment, compounds of formula (I) are represented as compounds of formula (1g), (R2)m Rb 40mm O‘SFO N~R5 R4 Us) wherein the values of all the variables are as bed for nd of formula (I).
In another embodiment, compounds of formula (I) are represented as compounds of formula (1h), WO 88256 (R2)m d\E / ,N CR‘. \ ‘ Rb /,C~NH O \ jo 4/N‘R5 R (1h) wherein the values of all the les are as described for compound of formula (I).
In r embodiment, compounds of formula (I) are represented as compounds of formula (Ii), (R2)m their pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, wherein the values of all the variables are as described for compound of a (I).
In another embodiment, compounds of formula (I) are represented as compounds of formula (lj), (R2)m N’/\ \ (R \ Rb /,C~NH 4/N‘R5 R (U) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, wherein the values of all the variables are as described for compound of formula (I).
WO 2013088256 PCTIIB2012/003012 In another embodiment, nds of formula (I) are represented as compounds of a (1k), _/<R2)m «i: \ / / N,N\ O \ \ O R3 their pharmaceutically acceptable salts, pharmaceutically able solvates or stereoisomers thereof, wherein wherein the values of all the variables are as bed for compound of formula (I).
In another embodiment, compounds of formula (I) are represented as compounds of formula (Ikk), R1 (Ikk) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers f, wherein wherein the values of all the variables are as described for compound of formula (I).
In another embodiment, compounds of formula (I) are represented as compounds offormula (II), (Rem their pharmaceutically acceptable salts, pharmaceutically able solvates or stereoisomers thereof, wherein R3 is fluorine, n is l or 2, and the values of all other variables are as described for compound of formula (I).
In another embodiment, compounds of formula (I) are represented as compounds of formula (1m), (R2)m \’ / N/N\ (R)? \ \ (R3)n/\/J Rb H their pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, wherein R3 is fluorine, n is l or 2, and the values of all other variables are as described for compound of formula (I).
In one embodiment of formula (Ia), R1 is hydrogen, Ra is 6)alkyl or an optionally substituted -(C3-C10)eycloalkyl group, wherein the optional substituent independently selected from cyano, -(C1—C6)alkyl, hydroxyl, halogen or -R5.
In one embodiment of a (la), R1 is hydrogen, Rd is an ally substituted —(C6-C12)aryl, wherein the optional substitent is selected from cyano, hydroxyl, halogen, -(C1-C6)alky1 or -R".
In one embodiment of formula (Ia), R1 is en, R‘1 is an optionally substituted 5 to 10 membered heterocyclyl optionally substituted with 1 to 3 substituents independently selected from cyano, hydroxyl, halogen or —(C1—C6)alkyl.
In one ment of formula (la), R1 is hydrogen, Ra is —NR4R5.
In one embodiment of formula (Ia), Ra is an optionally substituted 5 to 10 ed aryl, whrein the optional substituent is selected from cyano, OX0 (=0), hydroxyl, halogen, -(C1-C6)alkyl, -(C1—C6)alkoxy, -NR°Rd or -R‘.
In another embodiment, the compound of formula (la) of the above embodiments is defined as compound of formula (lb).
In certain embodiments of formula (lb), as defined above, R2, in each occurrence, independently ents halogen, cyano or haloalkyl; m is 1 or 2.
In certain embodiments of formula (lb), as defined above, R1 is en.
In certain embodiment of formula (1b), R4 and R5, independently represents methyl, ethyl or propyl.
In certain embodiment of formula (lb), Ra, independently represents , ethyl, propyl, isopropyl, butyl or tert-butyl.
In one embodiment of formula (10), R1 is hydrogen, R21 is -(C1-C6)alkyl or ally substituted -(C3-Cm)cycloalkyl, wherein the optional substituent is independently selected from cyano, -(C1—C6)alkyl, hydroxyl, halogen or -RS.
In one embodiment of formula (10), R1 is hydrogen, R“1 is optionally substituted —(C6-C12)aryl, wherein the optional substituent is selected from cyano, hydroxyl, halogen, -(C1-C6)alkyl or —Rr.
In one embodiment of formula (10), R1 is hydrogen, Ra is an optionally tuted 5 to 10 membered cyclyl, wherein the al substituent is selected from cyano, hydroxyl, halogen or —(C1-C6)alkyl.
In one embodiment of a (Ic), R1 is hydrogen, Ra is -NR4R5.
In one embodiment of formula (Ic), Ra is an optionally substituted 5 to 10 membered aryl, wherein the optional substituent is selected from cyano, oxo (=0), hydroxyl, halogen, ~(C1—C6)alkyl, ~(C1-C6)alkoxy, —NR°Rd or —Rt.
In another embodiment, the compound of formula (10) of the above embodiments is defined as nd of formula (Id).
In certain embodiments of formula (Id), as defined above, R2, in each occurrence, independently represents halogen, cyano or haloalkyl; m is 1 or 2.
In certain embodiments of a (Id), as defined above, R1 is en.
In certain embodiment of a (Id), R4 and R5, independently represents methyl, ethyl or propyl.
In n embodiment of formula (Id), Ra, independently represents methyl, ethyl, propyl, isopropyl, butyl or tert—butyl.
In one embodiment of formula (10), R1 is hydrogen, Ra is -(C1—C6)alkyl or optionally substituted —(C3~C10)cycloalkyl, wherein the optional substituent is independently selected from cyano, —(C1—C6)alkyl, hydroxyl, halogen or —RS.
In one embodiment of a (10), R1 is hydrogen, Ra is optionally substituted —(C6—C12)aryl, wherein the optional substituent is selected from cyano, hydroxyl, halogen, ~(C1-C6)alkyl or -Rr.
In one embodiment of formula (16), R1 is hydrogen, R21 is an optionally tuted 5 to 10 membered heterocyclyl, wherein the optional substituent is selected from cyano, hydroxyl, halogen or -(C1-C6)alkyl.
WO 88256 In one embodiment of formula (Ie), R1 is hydrogen and Ra is —NR4RS In one embodiment of formula (le), Ra is an optionally substituted 5 to 10 membered heteroaryl, wherein the optional tutent is selected from cyano, oxo (=0), hydroxyl, halogen, -(C1-C5)alkyl, -(C1—C6)alkoxy, -NR°Rd or -R‘.
In another embodiment, the compound of formula (le) of the above embodiments is defined as compound of formula (It).
In certain embodiments of formula (If), as defined above, R2, in each occurrence, ndently represents halogen, cyano or haloalkyl; m is 1 or 2.
In certain embodiments of formula (If), as defined above, R1 is hydrogen.
In certain embodiment of formula (If), R4 and R5, independently represents methyl, ethyl or propyl.
In certain embodiment of formula (If), Ra, independently represents methyl, ethyl, propyl, isopropyl, butyl or tert—butyl.
In another embodiment, the compound of formula (lg) of the above embodiment is defined as compound of formula (Ih).
In certain embodiments of a (1h), as defined above, R2, in each occurrence, ndently represents halogen, cyano or kyl and m is 1 or 2.
In certain embodiments of formula (Ih), as defined above, R1 is hydrogen.
In certain embodiment of formula (Ih), R4 and R5, ndently represents methyl, ethyl or .
In another embodiment, the compound of formula (Ii) of the above embodiments is defined as compound of formula (Ij).
In certain embodiments of formula (Ij), as defined above, R2, in each occurrence, independently represents halogen, cyano or haloalkyl and m is I or 2.
In certain embodiments of formula (Ij), as defined above, R1 is hydrogen.
In certain embodiment of formula (Ij), R4 and R5, independently represents methyl, ethyl or propyl.
In certain embodiments of formula (I), (la), (lb), (lc), (Id), (le), (If), (lg), (1h), (Ii), (11‘) and (1k), Rb is hydrogen.
In n embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) and (1k), Rb is fluorine.
In certain embodiments of formula (I), (la), (1b), (10), (Id), (Ie), (It), (lg), (1h), (Ii), (Ij) and (Ik), wherein R2, in each ence, independenty represents fluorine.
In certain embodiments of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (lg), (1h), (Ii), (Ij) and (Ik), wherein R3, in each occurrence, independenty represents e.
The compounds of formula (I) can also exist in the form of pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof In another embodiment, the present application provides compounds of formula (9i), / ,N A (9i) F OEt or its stereoisomers thereof, wherein the values of all the variables are as described for compound offormula (I).
In another embodiment, the present application provides compounds of formula (9n), / N’N\ A (9ii) F OEt (R2)m (Eno / 0 , /Cf" or its stereoisomers thereof, wherein A represents (R3)n and values of all other variables are as described for nd of formula (I).
In r embodiment, the present ation provides nds of formula (101), / ,N \ '\ (10:) F OH or its stcrcoisomcrs thcrcof, whcrcin the values of all the lcs are as dcscribcd for compound of formula (I).
In another embodiment, the present application provides compounds of formula ( lOii), (1WD (R2)m (in x O <}\NE%, or 1ts steremsomers thereof, wherein A represents ( )n and values of all other variables are as described for compound of formula (I).
In another embodiment, the present application provides nds of formula (13% W(R3)n (En [‘\ o ’\ (R2)m or its stereoisomers thereof, wherein the values of all variables are as described for compound of a (I).
The present application relates to the compounds of formula (I), which are inhibitors of TrkA, TrkB and/or TrkC kinase activity, for the treatment or prevention of diseases or conditions or disorders associated with TrkA, TrkB and/or TrkC kinase activity.
One embodiment of the present application further es methods of treating or preventing conditions, es and/or ers associated TrkA, TrkB and/or TrkC kinase activity, wherein the method includes administration of a therapeutically effective amount of a compound formula (I), to a patient in need thereof.
One embodiment of the present application provides conditions. diseases and/or disorders treatable or preventable by inhibition of Trk kinase activity, such as pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, , psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, tive s, Crohn’s disease, fibrosis, neurodegenerative disease; a disease, disorder or injury ng to lination or demyelination or infectious diseases such as Trypanosoma cruzi infection by administering a therapeutically effective amount of compound of formula (I), to a patient in need thereof.
One embodiment of the present application further es methods of treating or preventing conditions, diseases and/or ers associated TrkA, wherein the method includes administration of a eutically effective amount of a compound formula (I), to a patient in need thereof.
In another embodiment, there is provided a method of treating or preventing pain or pain disorder in a patient in need of such a treatment comprising the administration of a therapeutically ive amount of the compound of formula (I), to said patient.
In r embodiment, pain includes chronic and acute pain but is not limited to, pain related to cancer, surgery, bone fracture, skeletal pain caused by tumor metastasis, rthritis, psoriatic arthritis, rheumatoid arthritis, interstitial cystitits, chronic pancreatitis, visceral pain, inflammatory pain, migraine, chronic lower back pain, bladder pain syndrome and neuropathic pain.
In one embodiment, there is provided a method of binding TrkA protein in a patient in need of such a treatment comprising the administration of a therapeutically effective amount of the compound of formula (I) to said patient The t application further relates to use of compound of formula (I) for treating or preventing conditions, diseases and/or disorders associated with abnormal or deregulated Trk kinase ty.
One aspect of the present ation provides use of compound of formula (I) for treating or preventing conditions, diseases and/or disorders associated with abnormal or lated TrkA kinase activity, in a patient in need f.
In r embodiment, there is provided an use of the compound for formula (I) for treating or preventing pain or pain disorder in a patient in need of such a treatment, comprising the administration of a therapeutically effective amount of the nd offormula (I), to said patient.
In another ment of the present application, pain es chronic and acute pain but is not limited to, pain related to cancer, surgery, bone fracture, skeletal pain caused by tumor metastasis, osteoarthritis, visceral pain, inflammatory pain and neuropathic pain.
WO 88256 In yet another embodiment, the compounds of the present application may be useful for the pain disorders include athic pain (such as postherpetic neuralgia, nerve injury, the "dynias", e.g., vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, painful traumatic mononeuropathy, painful polyneuropathy); central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system); postsurgical pain syndromes (cg, postmastectomy syndrome, postthoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis), repetitive motion pain, denial pain, cancer pain, myofascial pain lar injury, fibromyalgia); erative pain (general surgery, logical), chronic pain, dysmenorrhea, as well as pain associated with angina, and inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoid arthritis, rheumatic disease, teno— synovitis and gout), headache, migraine and cluster he, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization.
In another embodiment of the above aspect, there is provided a method of treating or preventing pain which comprises administering to said subject a pharmaceutical composition comprising an effective amount of a compound of formula (1).
Another ment of the application provides the use of such compositions in the treatment and/or prevention of diseases associated with inhibition of TrkA, such as pain, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, neurodegenerative disease, a e, disorder, or injury relating to lination or demyelination or certain infectious diseases such as Trypanosoma crurzi infection.
In another embodiment, the compounds of formula (I) are useful in ng or preventing neurodegenerative disease.
In one embodiment, neurodegenerative disease is Parkinson’s disease or Alzheimer’s e.
In another , the present ation provides a method of treating or preventing neurodegenerative disease.
In one embodiment, neurodegenerative e, as described above, is Parkinson’s disease or Alzheimer’s disease.
W0 2013,1088256 In another embodiment, the present application provides method of treating or preventing certain infectious diseases, for example Trypanosoma cruzi ion, by administering ive amount of compound of formula (I) to a patient in need thereof.
In another embodiment, the present application provides method of treating or preventing Trypanosoma cruzi infection by administering effective amount of compound of formula (I), to a patient in need thereof.
In another embodiment, certain compounds of formula (I) posseses Rat liver microsome (RLM) stability (half life in minutes) >30, specifically >60, more specifically >80, still r more cally >90.
In another embodiment, certain compounds of formula (I) posseses Human liver microsome (HLM) stability (half life in s) >30, specifically >60, more specifically >80, still further more specifically >90.
In one embodiment of the present application, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula (I) and pharmaceutically acceptable carrier.
Another embodiment of the present application provides a method of stering Trch inhibitors in a subject (i.e., a patient), which ses administering to said subject (i.e., a patient) a pharmaceutical composition comprising a therapeutically ive amount of a compound of formula (I). As used herein the term ct” and “patient” can be the same and can be used hangeably.
In another embodiment, there is provided a method of inhibiting TrkA comprising administering to said subject a pharmaceutical composition comprising an effective amount of a compound of a (1). ln an embodiment, specific compounds of formula (1) without any limitation are enumerated below (List- 1 ): (2-(2 ,5—difluorophenyl)pyrrolidin- l -yl)-N—-((4—fluorophenyl)sulfonyl)pyrazo10 [1,5-a]pyridinecarboxamide, (R)-N—(tert-butylsulfonyl)—5-(2-(2,5-difluorophenyl) pyrrolidin~ l ~yl)pyrazolo[l ,5 -a] pyridine-3—carboxamide, (R)(2-(2,5~difluorophenyl)pyrrolidinyl)-N-(ethylsulfonyl)pyrazolo[ l ,5 -a] pyridinecarboxamide, (R)-N—((3-cyanophenyl)sulfonyl)—5-(2-(2,5-difluorophenyl)pyrrolidin-l —yl)pyrazolo {LS-a] pyridinecarboxamide, (R)-N-(cyclopropylsulfonyl)—5-(2-(2,5-difluorophenyl)pyrrolidinyl)pyrazolo[1 ,5— a]pyridinecarboxamide, (R)(2—(2,5-difluoropheny1)pyrrolidin-1 ~yl)-N-(methylsulfonyl)pyrazolo[1 ,S—a] pyridine—3-carboxamide, (R)(2-(2,5—diflu0ropheny1)pyrrolidinyl)-N—(isopropylsulfonyl)pyrazolo[1 ,S-a] pyridine—3—carboxamide, —2—(2,5—difluoropheny1)pyrrolidiny1)—N—((4—((S)—3~hydroxypyrrolidin— 1—y1) phenyl) sulfonyl)pyrazolo[1, 5-a]pyridine—3 ~carboxamide, (R)-N—((3 pheny1)su1fony1)-5 -(2-(2,5—difluorophenyl)pyrrolidin—1~yl)-N- methyl pyrazolo[1,5—a]pyridinecarboxamide, (R)-5~(2-(2,5-difluoropheny1)pyrrolidin—1-y1)~N—(propylsulfony1)pyrazolo[1 5 S-a] pyridine-3—carboxamide, (R)—5—(2~(2,5-difluoropheny1)pyrrolidin— 1 —y1)—N—((3 ,5—dimethy1isoxazol—4—yl) yl) lo [1, 5—31] pyridinecarboxamide, (R)-N-(cyclohexylsu1fonyl)—5~(2—(2,5-diflu0rophenyl)pyrrolidin~1-yl)pyrazolo[1,S-a] pyridinecarboxamide, (R)-N-(cyclopentylsulfonyl)(2—(2, 5—difluorophenyl)pyrrolidinyl)pyrazolo [1 ,5- a] pyridine-3—carboxamide, (R)—5—(2-(2,5-difluorophenyl)pyrrolidin- 1-y1)~N~(isobutylsu1fonyl) pyrazolo[1 , 5-21] pyridine -3—carb0xamide, (R)(2-(2,5-difluorophenyl) pyrrolidin-l—yl)—N—((1, 2-dimethyl-1H—imidazolyl) sulfonyl) pyrazolo [1, 5-21] pyridinecarboxamide, (R)—5-(2-(2, 5—difluorophenyl) pyrrolidin—l-y1)—N—((1, 2—dimethyl—lH-imidazol—S-yl) sulfonyl) pyrazolo [1, 5-21] pyridine-3—carboxamide, (R)(2—(2, 5—difluorophenyl) pyrrolidin—1~y1)~N—(piperidin—4-ylsulfonyl) pyrazolo [1, 5—21] pyridinecarboxamide, (R)—5-(2-(2, 5-diflu0rophenyl) idin-l-yl)-N—((1-methy1~1H-imidazoly1) sulfonyl) pyrazolo [1, S—a] pyridinecarboxamide, (R)—5-(2-(2, 5-difiuorophenyl) pyrrolidin-l -yl)—N—((1 -methyI-1H-pyrazol-5~yl) yl) pyrazolo [1, S-a] pyridine—3-carboxamide, (R)-5—(2-(2, 5-difluorophenyl)pyrrolidin—l-y1)-N-((2, 4-dimethylthiazolyl) yl) pyrazolo [1, S-a] pyridine—3-carboxamide, (R)(2-(2, 5—difluoropheny1) pyrrolidiny1)-N-(( 1 -methy1-2—0xoindolin-5 -y1) sulfonyl) pyrazolo [1, 5-21] pyridinecarboxamide, (R)(2-(2, 5-difluorophenyl) pyrrolidin-l-yl)-N-((tetrahydro-2H-pyran—4-y1) sulf‘onyl) pyrazolo [1, 5-a] pyridine-B-carboxamide, (R)—5—(2-(2, 5—difluoropheny1) pyrrolidin—l—y1)—N—((6~(dimethy1amino) pyridin—3-yl) sulfonyl) pyrazolo [1, 5-21] pyridine-3—carboxamide, —((R)—2-(2, 5-difluorophenyl) pyrrolidinyl)—N—((2-methy1tetrahydrofuran-3—y1) sulfonyl) pyrazolo [1, S—a] pyridine—3—carboxamide, (2, 5-difluorophenyl) idinyl)—N-((6-((S)—3—hyd1‘oxypyrrolidin~1—y1) pyridin—3-yl) sulfony1)pyrazolo [1, 5—21] pyridinecarboxamide, (2—(2, 5—diflu0ropheny1) pmolidin—1—y1)-N-((6—methoxypyridin—3—y1) sulfonyl) lo [1, 5—21] pyridine-3~carboxamide, (R)-N-((6-(1H-1 ,2,4-tria201- 1 —yl)pyridiny1)su1f0ny1)—5 ,5—difluoropheny1) pyrrolidin-l—yl) pyrazolo [1, S—a] pyridine-3~carboxamide, (R)—5-(2-(2, 5—difluor0phenyl) pyrrolidin—l-yl)-N—((1-methyl—1H—pyrazol-4~y1) sulfonyl) lo [1, 5-21] pyridinecarboxamide, (R)—5-(2-(2, 5-difluorophenyl)pyrrolidiny1)-N-((4—morpholinophenyl) sulfonyl) pyrazolo [1, 5-21] ne-S—carboxamide, (R)—5-(2~(2 ,5-difluorophenyl)pyrrolidin- 1—y1)-N-(py1idin—3 fony1)pyrazolo[l ,5 ~ a]pyridine—3-carboxamide, (R)-N-((5-chlorothiophen—Z-yl) sulfonyl)—5-(2-(2, 5-difluorophenyl) pyrrolidin-l-yl) pyrazolo [1, 5—21] pyridine—3—carboxamide, (R)-N-((2, 5—dich10rothiophen-3—yl) sulfony1)—5-(2—(2, 5-difluorophenyl) pyrrolidin— 1-y1) pyrazolo [1, S-a] pyfidinecarboxamide, (R)-N-(cyclobutylsulfony1)~5—(2-(2, 5-difluorophenyl) pyrrolidin-l—yl) pyrazolo [1, -21] pyridine-3—carboxamide, (R)(2—(2,5-difluorophenyl)pyrr01idin—1-y1)—N—((2,3 -dihydrobenzo[b] [ 1 ,4]dioxin~ 6-y1)su1fonyl)pyrazolo[1 ,5-a]pyridine-3—carb0xamide, (R)—N~(benzo[d][1,3]dioxolylsu1fony1)-5—(2-(2,5-difluorophenyl)pyrrolidiny1) pyrazoIoU ,5-a]pyri dinecarboxamide, (R)(2-(2,5-difluoropheny1)pyrrolidiny1)-N-(( 1 -ethylcyclopropy1)sulfonyl) pyrazolo[1,5-a]pyridinecarboxamide, (R)—5-(2-(2,5-difluorophenyl)pyn‘olidin-1 -y1)-N-(neopentylsulfonyl)pyrazolo[1 ,5- a]pyridinecarboxamide, (R)—5-(2-(2,5—diflu0ropheny1)pyrrolidiny1)~N-(( 1 -methy1cyclopropyl)sulfonyl) pyrazolo[1,5-a]pyridine—3-carboxamide, (2-(2,5-di fluorophenyl)pyrroli din—1 -yl)-N-(o-tolylsul fony])pyrazolo[1 ,5 -a] pyridine~3~carboxamide, (R)-N-(benzylsu1fonyl)—5—(2~(2,5—difluorophenyl)pyrrolidiny1)pyrazolo[ 1 ,S—a] pyridine—3-carb0xamide, (R)—5~(2—(2,5—difluoropheny1)pyrrolidin— 1 ~yl)—N—((1—(4—fluorobenzyl)cyclopropyl) sulfonyl)pyrazolo[1 ,5~a]pyridine—3—carboxamide, (R)—N-(tert~butylsu1f0ny1)—5—(2-(5—flu0ro-2~methoxypheny1) pyrrolidin-l -yl) pyrazolo [ 1 , S—a] pyridi11€~3~carboxamide, (R)-N-(tel“c—butylsulfonyl)—5~(2—(3~(diflu0r0methoxy)flu0rophenyl) pyrrolidin— 1 - yl) pyrazolo [1, 5-21] pyridine-S-carboxamide, (R)—N—(tert—butylsu1fony1)-5—(2~(5~fluoropyridin—3-yl) pyrrolidin— 1 —yl) pyrazolo [1 , S—a] pyridinecarboxamide, (R)-N—(tert-butylsulfony1)—5-(2-(2-ethoxy-S-fluorophenyl)pyrrolidin—l razolo [1,5-a]pyridine—3~carboxamide, (R)-N-(tert-butylsu1fony1)(2-(2-(cyclopropylmethoxy)-5 —f1uoropheny1) pyrrolidin-l -yl)pyrazolo[1,5-a]pyridine—3-carboxamide, (R)-N-(tefi—butylsulfonyl)—5-(2-(2-chloro—5-fluorophenyl)pyrrolidin- 1 —yl) pyrazolo[l ,5—a]pyridine—3 xamide, t—butylsulfonyl)—5 -((2R,4R)(2,5-difluorophenyl)hydroxypyrrolidiny1) lo[1 ,5—a]py1idinecarboxamide, (R)-N-(tert-butylsulfonyl)(2-(5-fluoro(2,2,2—trifluoroethoxy)phenyl) pyrrolidin-l-yl)pyrazolo[1 ,5—a]pyridine—3~carboxamide, N~(tert-butylsulfonyl)-5 ~(2—(7—fluoro-2,3—dihydrobenzo[b][1,4]dioxin—5— yl)pyrrolidin—1-y1)pyrazolo[ pyridine—3~carboxamide (Isomer—I), N-(tert-butylsulfonyl)—5~(2—(7—fluor0-2,3—dihydr0benzo [b] [ 1 ,4]di0xin—5— y1)pyrrolidiny1)pyrazolo[ 1 ,5 ~a]pyridine-3 ~carboxamide (Isomer—II), N-(tert-butyl sul fonyD-S —((2R,4S)—2-(2,5-difluorophenyl)flu0r0pyrrolidin-1 - yl)pyrazolo[1,5-a]pyridinecarboxamide (Isomer—I), N-(tert-butylsulfonyl)—5—((2R,4S)(2,5-difluorophenyI)fluoropyrrolidin yl)pyrazolo[1 ,5-a]pyri dine—3-carboxami de (Isom er—H), PCT/IBZOIZ/003012 (R)—N-(tert-butylsu1f0nyl)~5~(2-(4,4'-diflu0ro-[ 1 , 1 '~bipheny1]y1)pyrrolidin— 1 - y1)pyrazolo[1,5~a]pyridinecarboxamide, (S)-N—(tert-butylsulfony1)(2-(2, 5-difluorophenyl)-4, 4-difluoropyrrolidinyl) pyrazolo [1 , S-a] pyridinecarboxamide, (R)—N—(tert-butylsulfonyl)—5~(2—(2, 5—difluoropheny1)—4, 4-difluor0pyrrolidin-1—y1) pyrazolo [1, S-a] pyridine-3—carboxamide, (R)-N—(tert-butylsu1f0ny1)(2—(5—fluor0—2-(2-fluoroethoxy)phenyl)pyrrolidin-1 — y1)pyrazolo[1 ,5—a]pyridine~3-carboxamide, N~(tert—butylsulfonyl)—5-((2R,4R)—2~(2,5~diflu0r0phenyl)~4~fluoropyrr01idin—1— yl)pyrazolo[1,5—a]pyridine-3~carboxamide, N—(tert—butylsulfonyl)—5—((2R)—2—(5~fluoro—2—((tetrahydrofuran—3-y1)oxy)pheny1) pyrrolidin—l-yl)pyrazolo[1,5~a]pyridine-3 -carboxamide, N-(tert-butylsulfonyI)((2R)-2—(5—fluoro—2—((tetrahydrofurany1)oxy)phenyl) pyrrolidin-l-y1)pyrazolo[1,5—a]pyridine~3—carb0xamide, (R)—N~(tert~butylsulfonyl)~5~(2-(2, 5-diflu0ropheny1) pyrrolidin- 1 ~yl)flu0r0 pyrazolo[l, S-a] pyridinecarboxamide, (R)—N—(telt-butylsulfony1)—5—(2—(2-(difluoromethoxy)fluoropheny1) pyrrolidin— 1 — yl)-4—fluoropyrazolo [1, 5-21] necarboxamide, (R)-N—(tel‘r-butylsulfony1)—5—(2—(2-(difluor0methoxy)—5—fluoropheny1) pyrrolidin- l - y1)pyrazolo [1, S—a] pyridine—3 -carboxamide, (R)~N-(tert-butylsulfonyl)~5-(2-(2-flu0ro—5~(2—meth0xyethoxy) phenyl) pyrrolidin yl)pyrazolo [1, S—a] pyridinecarboxamide, (R)-N—(tert-butylsulfonyl)~5—(2-(5-f1u0r0—2—(2~methoxyethoxy) ) pyrrolidin~1- azolo [1, 5-21] pyridine-3—carboxamide, (R)-N-(tert~butylsu1fony1)-5—(2-(3, uoropheny1) pyrrolidin—l—yl) pyrazolo [1, 5- a] pyridinecarboxamide, (R)-N-(tert—butylsulfonyl)(2-(3—fluoro—5-(2-methoxyethoxy)phenyl)pyrrolidin— 1 - y1)pyrazolo[l ,5-a]pyridine~3 —carboxamide, N-(tert—butylsulfonyl)((2R)-2~(3—fluoro((tetrahydrofuran—3—y1)oxy)phenyl) pyrrolidin-1 -yl)pyrazolo[1 yridinecarboxamide, (R)(2-(3, 5-difluoropheny1)pyrrolidiny1)-N-((4-fluorophenyl) sulfonyl) lo [1, S-a] pyridinecarboxamide, —((R)—2-(3, 5-difluorophenyl) pyrrolidin-l -y1)~N-((4-((S)—3-hydr0xypyrrolidin-1—y1) WO 88256 phenyl) sulfonyl) pyrazolo [1, S-a] pyridine—3-carboxamide, (R)—5-(2—(3, 5-difluoropheny1)pyrrolidin-1—yl)—N~(isopropylsulfonyl) pyrazolo [1, 5- a] ne-S-carboxamide, ((6-(]H-1, 2, 4-triazolyl) pyridinyl) yl)(2—(3, 5-difluorophenyl) idin—l—yl) pyrazolo [1, 5—21] pyridine—3—carboxamide, ~((R)—2-(3, 5-diflu0ropheny1) pyrrolidin—1—y1)-N—((6~((S)—3-hydr0xypyrr01idin-1—y1) pyridin-3—yl) sulfony1)pyrazolo [1, 5—21] pyridine—3-carboxamide, —((2R,4S)—2—(2,5~difluorophenyl)-4—fluoropyrrolidin—1—yl)—N-((1—methyl cyclopropyl)su1f0nyl)py1‘azo10 [1 ,5—a]pyridine-3 —carboxamide, (R)~5-(2-(2, 5—diflu0rophenyl) pyrrolidin- 1 —y1)flu0ro-N~(isopropylsulfonyl) pyrazolo [1, 5-21] pyridine—3—carboxamide, (R)—5-(2-(2, 5-difluor0phenyl) pyrrolidin—I—yl)-N-G\J, N-dimethylsulfamoyl) pyrazolo [1, 5-21] pyridine-3—carboxamide, (R)—5—(2-(2,5—difluorophenyl)pyrrolidin— 1 —y1)—N—(N—ethyl—N—methylsulfamoyl) pyrazolofl ,5-a]pyridine—3~carboxamide, ,4S)—2—(2,5-difluorophenyl)fluoropyrrolidin— l-yl)~N-(N,N—dimethyl sulfamoyl)pyrazolo [1 ,5-a]pyridinecarboxamide, —((2R,4S)(2,5—difluorophenyl)fluoropyrrolidin—1-y1)-N-(N-ethyl-N-methyl sulfamoyl)pyrazolo [l ,5-a]pyridine-3—carboxamide, (R)-N—(N—(cyclopropylmethyl)-N-methylsu1famoyl)(2—(2,5-difluoropheny1) pyrrolidin— 1 —y1)pyrazolo[ 1 ,5-a]pyridine-3 -carb0xamide, (R)—N~(N,N —diethylsulfamoyl)—5 —(2-(2,5-difluorophenyl)pyrrolidin— 1 - yl)pyrazolo[1,5—a]pyridine-3—carboxamide, ,4S)—2-(2,5-difluorophenyl}4-flu0r0pyrrolidin-1—y1)-N—(N,N—dimethyl sulfamoyl) pyrazolo{1,5—a]pyridinecarboxamide, -((2R,4S)—2—(2,S-difluorophenyl)~4-fluoropyrrolidin- 1-y1)—N—(N-ethyl~N~ methylsulfamoyl) pyrazolo[1,5-a}pyridine—3—carboxamide, (R)—5-(2-(2,5~difluorophenyl)pyrrolidin—1-y1)-N—(morpholinosulfonyl) pyrazolo[1 ,5 - a]pyridine~3—carboxamide, (R)(2-(2,5-difluorophenyl)pyrrolidin-I -yI)-N-(pyrrolidinylsulf0ny1) pyrazolo[l ,5-a]pyridinecarboxamide, (R)—5-(2-(2,5-difluorophenyl)pyrrolidin— 1 ~y1)-N-((4-methylpiperazin-1 -yl) sulfonyl)pyrazo]0[1 ,5-a]pyridinecarboxamide, W0 2013.1088256 (R)-N-(N,N-diethylsulfamoy1)(2—(5-fluoromethoxypheny1)pyrrolidin— 1 -y1) pyrazolo [1 yfidinecarboxamide, (R)-N-(N,N-diethylsulfamoy1)(2-(5—fluoro(2-fluoroethoxy)pheny1)pyrr01idin— 1 -yl)pyrazolo[ I ,5-a]pyridine-3 -carboxami de, (R)—5~(2-(2,5—difluoropheny1)pyrr01idin— 1 ~y1)—N-(piperidin— 1 —ylsulfonyl) pyraz010[1 ,5—a]pyridine—3 -carb0xamide, (R)-5—(2—(3 ,5—difluoro—Z-methoxypheny1)pyrrolidiny1)-N—(N—ethy1—N-methy1 sulfamoyl)pyrazolo [1 ,5~a]pyridine—3—carboxamide, (R)—N~(N—ethyl-N—methylsulfamoy1)-5—(2-(5~fluoro—2—methoxyphenyl)pyrr0lidin-1 — y1)pyrazolo[1,5-a]pyridine-3 -carb0xamide, (R)—N—(N—ethyl~N~methylsu1famoy1)-5—(2—(5—fluoro~2-(2~flu0roethoxy) pheny1)pyrrolidiny1)pyrazolo[1 ,5-a]pyridine~3~carboxamidea ~2-(2,5-difluor0pheny1)pyrr01idin-1—y1)—N—(((S)-3 -hydroxypyrrolidin—1-yl) sulfony1)pyrazolo[1 ,5—a]pyridine—3—carboxamide, (2-(2,5~difluorophenyl)pyrr01idinyl)—N—sulfamoylpyrazolo[1,5-a]pyridine- 3-carboxamide, (R)—5-(2-(3 ,5 -difluoro-Z—(Z-fluoroeth0xy)phenyl)pyrrolidin—1 ~yl)-N-(N-ethy1—N— methylsulfamoyl)pyrazolo[ 1 ,5-a]pyridine-3 -carboxamide, N-(N-ethyl—N-methylsulfamoy1)-5—(2-(8~flu0ro-3,4-dihydro-2H-benzo[b] [1 ,4] in—6-yl)pyrrolidin— 1—y1)pyrazolo[1 ,5 ~a]pyridinecarboxamide (Diastereomer—I), N-(N—ethyl-N-methylsulfamoyI)-5—(2-(8—flu0r0-3,4-dihydro-2H—benzo[b][1 ,4} dioxepin—6-yl)pyrrolidin— 1 —y1)pyrazolo [1 ,5-a}pyridine—3—carboxamide (Diastereomer—ll), N-(N,N—dimethylsulfamoyl)~5~(2—(7—fluor0—2,3-dihydrobenzo [b] [ 1 xin yl)pyrrolidin—1~y1)pyrazolo[ 1,5 —a]pyridine-3 -carboxamide ereomer—I), N~(N,N—dimethylsulfamoyl)—5—(2—(7-flu0r0~2,3-dihydr0benzo[b][1,4]dioxin—5- y1)pyrrolidinyl)pyrazolo[1,5—a]pyridine—3—carboxamide (Diastereomer—II), N-(N~ethy1~N-methylsu1fam0y1)—5-(2-(7—flu0r0—2,3-dihydrobenzo[b] [1 ,4]di0xin-5 — yl)pyrrolidin-1~y1)pyrazolo[ 1 ,5-a]pyridine—3-carboxamide (Diastereomer—I), N-(N—ethy1—N—methylsulfamoyl)-5~(2-(7-flu0ro-2,3~dihydrobenzo[b] [ 1 ,4]di0xin—5- yl)pyrrolidiny1)pyrazolo[1 ,5 -a]pyridine—3-carboxamide (Diastereomer-H), N-(N-ethyl—N-methylsulfamoy1)—4-fluoro-S-((2R,4S)fluoro(3- henyl)pyrrolidin- 1-y1)pyrazolo[1,5-a]pyridine-3 -carboxamide, N—(N—ethyl -N—methylsulfamoyl)((R)~2-(3-fluoro-5 -(((S)-tetrahydrofi1ran y1)oxy)phenyl)pyrrolidin-1 razolo[ 1 ,5-a]pyridine~3-carboxamide, (R)—5-(2—(3 ,5—diflu0ro((tetrahydro-”H-pyran—4-yl)oxy)phenyl)pyrroh'dinyl)—N- (N-ethyl-N-methylsulfamoy1)pyrazolo[1,5-a]pyridinecarboxamide, (R)(2-(3,5-di fluoro-Z—((tetrahydro-2H-pyranyl)oxy)pheny1)pyrrolidiny| )-N- (N,N—dimethylsulfamoy1)pyrazolo [1 ,5—a]pyridine—3-carboxamide, N-(N—ethyl—N-methylsulfamoyl)~5~((R)—2—(3—fluoro(((R)-tetrahydrofi1ran—3 — y1)oxy)phenyl)pyrrolidinyl)pyrazolo[ 1 ,5—a}pyridinecarboxamid e, 4—fluoro((2R,4S)—4—fluoro—2~(3~fluor0pheny1)pyrrolidin—1—yl)—N—sulfamoy1 pyrazolo[1 yridineca1‘boxamide, N—(N,N-dimethylsulfamoyl)—5-(2-(8-flu0r0-3 ,4-dihydro—2H~benzo[b] [1 ,4]dioxepin- 6~y1)pyrr01idin-1—y1)pyrazolo[1 ,5—a]pyridine-3~carboxamide (Diastereomer—I), N—(N,N-dimethylsulfamoyl)—5-(2-(8-fluor0—3 ,4-dihydro—2H—benzo[b][1,4]dioxepin- 6-y1)pyrrolidin— 1 -yl)pyrazolo [1 ,5-a]pyridine-3—carboxamide (Diastereomer-Z); (R)—5-(2-(2,5~difluoropheny1)pyrrolidin— 1 -y1)—N—(N—isobuty1—N—methyl sulfamoyl)pyra2010 [1 ,5 -a]pyridine—3—carboxamide, (R)-N~(N-ethy1—N—methylsu1famoy1)-4—fluoro—5—(2-(3-fluorophenyl)pyrrolidin-1 - yl)pyrazolo [l ,5-a]pyridineoarboxamide, (R)-N-(N,N-dimethylsulfamoyl)—4-fluoro(2-(3-fluoropheny1)pyrrolidinyl) pyrazolo[1 yridine-3~carboxamide, (R)-N—G\I,N~dimethylsu1famoy1)-4—fluoro(2-(3—fluoropheny1)pyrrolidin~ 1 —yl) pyrazolo[1,5—a]pyridine—3—carboxamide, (R)-N~(N—ethy1~N—methylsulfamoyl)fluoro(2-(5 -fluoro—2-((tetrahydro-2H- pyran-4—yl)oxy)pheny1)pyrr01idin- 1 —y1)pyrazo10[ 1 ,5-a]pyridine—3-carboxamide, -((2R)-2—(3-((2,2—dif1uorocyclopropy1)methoxy)—5—fluoropheny1)pyrrolidin—1 -y1)- thy1~N~methylsulfamoyl)pyrazo10[1 ,5~a]pyridine-3—carboxamide, (R)~N—G\I,N—bis(cyclopropylmethyl)sulfamoy1)(2~(2 ,5~difluor0phenyl)pyrrolidin— 1-y1)pyrazolo[1 yridinecarboxamide, N-(N-ethy1-N—methy1su1famoy1)((2R)~2-(5—fluoro—2-((tetrahydrofurany1)oxy) pheny1)pyrrolidin-1 -y1)pyrazolo[1 ,5~a]pyridine-3 -carboxamidc, N-(N-ethyl—N—methylsulfamoyl)-5—((2R)(5-fluoro—2-((tetrahydrofuran-3 —yl)oxy) )pyrrolidiny1)pyrazolo[1,5-a]pyridine—3—carboxamide (Diastereomer—II), N-(tert—butylsulfonyl)(2-(2,5-difluor0pheny1)pyrrolidin—I —yl)pyrazolo[1 ,5-a] W0 2013f088256 pyridinecarboxamide (Racemic mixture); (R)—N~(tert-butylsulfonyl)—5-(2—(3 ,5—difluoro—2-methoxypheny1)pyrrolidin- 1 —y[) pyrazolo[1,5-a]pyridine—3—carboxamide, N-(tert-butylsul fonyl)—4-fluoro((2R,4S)fluoro(3-fluorophenyl)pyrroli din y1)pyrazolo [1 ,5—a]pyridine—3 —carboxamide, 4—fluoro-5—((2R,4S)—4—fluoro—2—(3-fluoropheny1)pyrrolidin- N-(isopropyl sulfony1)pyrazolo[1 ,5-a]pyridinecarboxamide, (R)—N—(tert—butylsu1fonyl)—5—(2—(3 uoro-Z—((tetrahydro—2H—pyran~4—y1)oxy) phenyl)pyrrolidin— 1 —yl)pyrazolo[1 ,5—a]pyridine~3—carboxamide, (R)-N-(tert-butylsulfonyl)(2—(5-fluoro—2-((tetrahydro—ZH-pyrany1)oxy) phenyl)pyrrolidin— 1 —y1)pyrazolo [1 ,5-a]pyridine—3 -Carboxamide, (R)-5—(2-(3 ,5-difluoro((tetrahydro-2H—pyran~4—y1)oxy)pheny1)pyrrolidiny1)—N— (isopropylsu1fony1)pyrazolo [1 ,5 —a]pyridine—3-carboxamide, (R)—4—fluoro—5—(2—(3-fluoropheny1)pyrrolidin— 1 -yl)—N—(isopropylsulfonyl)pyrazolo [1,5—a]py1idine—3~carboxamide, (R)-N—(tefi—butylsu1fony1)—4-fluor0(2—(5 -fluor0-2—((tetrahydro-ZH—pyran—4—y1) oxy)pheny1)pyrrolidiny1)pyrazolo[ 1 yridinecarboxamide, Sodium (tert-butylsulfonyl)(5 -((2R,4S)—2-(2,5—difluorophenyl)-4—fluoropyrrolidin— 1 — yl) pyrazolo[ l ,5-a]pyridinecarbony1)amide, (R)-(tert-butylsulfonyl)(5-(2-(2,5—dif1uorophenyl)pyrrolidin— 1—yl) pyrazolo [1 ,S-a] pyridine-3 -carbony1)amide, Sodium (R)-(tert—butylsu1fony1)(5-(2-(7-fluoro-2,3-dihyd1'obenzo[b][ l ,4]di0xin—5— yl)pyrr01idin—1—yl)pyrazolo[1,5-a]pyridine-3~carbony1)amide, Sodium (tert—butylsulfonleS-((2R,4R)(2,5—difluorophenyl)—4-fluoropyrrolidin yl) pyrazolo[1 ,5—a]pyridine~3-carbony1)amide, Sodium (R)-(5—(2-(2,5 -dif1uorophenyl) pyrrolidin— 1 —yl)pyrazolo[1 yridine-3 - carbonyl) (N,N-dimethylsulfamoy1)amide, Sodium (tert—butylsulfonyl)(5 -(2—(2,5 -diflu0rophenyl)—4,4-difluoropyrrolidin y1)pyrazolo[l ,5-a]pyridinecarbonyl)amide, Sodium (R)—(5-(2-(2,5-difluorophenyl) pyrrolidin-1 -yl)pyrazolo[1 ,5-a]pyridine-3 — carbony1)(( 1-methylcyclopropyl) y1)amide, Sodium (tert-butylsulfonyl)(5-((2R)(2,5-difluorophenyl)fluoropyrrolidin— 1 - y1)pyrazolo [1 ,5-a]pyridine—3—carbony1)amide, Sodium (5-((2R,4S)(2,5-difluorophenyl)—4-fluoropyrrolidinyl)pyrazolo[1 ,5- a]pyridine-3—carbonyl)(N,N-dimethylsulfamoyl)amide, Sodium (tert-butylsulfony1)(4—fluoro((2R,4S)fluoro(3-fluorophenyl) pyrrolidin-1 -yl)pyrazolo[l ,5-a]pyridinecarbonyl)amide, Sodium (R)—(N,N—dimethylsulfamoyl)(4—fluoro—5—(2—(3~fluor0phenyl)pyrrolidin—1 - yl)pyrazolo [l ,5-a]pyridinecarbonyl)amide, Sodium (N—ethyl—N-methylsu1famoy1)(5—((2R)—2—(5~fluoro-2—((tetrahydrofuran—3~ yl)oxy) phenyl)pyrrolidin—l—yl) pyrazolo[1,5—a]pyridine—3—carbony1)amide, Sodium (R)—(5—(2*(2,5—difluor0phenyl) pyrrolidin- 1 ~yl)pyrazolo[1 y1‘idine—3- carbonyl)(o—tolylsulfonyl)amide, Sodium (4—fluoro—5—((2R,4S)—4—fluoro—2~(3—fluorophenyl)pyrrolidin-l—yl) pyrazolo[l ,5-a]pyridinecarbonyl) (isopropylsulfonyl)amide, Sodium (5-((2R,4S)—2-(2,S-difluorophenyl) -4—fluoropyrrolidinyl)pyrazolo[1,5- dine—3-carbonyl)(( 1 —methylcyclopropyl)sulfonyl)amide, or Sodium -(2-(2,5—difluorophenyl) pyrrolidin~l-yl)pyrazolo[1,5-a]pyridine carbonyl)(piperidinylsulfonyl)amide; or a pharmaceutically acceptable salt f, a pharmaceutically acceptable solvate thereof or a stereoisomer thereof.
In one embodiment, compounds of formula (I) are represented as (R)—5~(2—(2,5—difluorophenyl)pyrrolidin— l —((4-fluorophenyl)sulfonyl) lo[l ,S—a] pyridine—3-carboxamide, (R)-N—((3-cyanophenyl)sulfonyl)—5—(2-(2,5-difluoropheny1)pyrrolidin-l~yl)pyrazolo [1 ,S—a] pyridine—3-carboxamide, ~((R)(2, 5—difluorophenyl) pmolidin-l-yl)—N -((4-((S)—3-hydr0xypyrrolidin~1-yl) phenyl) sulfonyl) pyrazolo [1, S—a] pyridinecarboxamide, (R)—N-((3-cyanophenyl) sulfonyl)—5—(2-(2, S-difluorophenyl) pyrrolidin-l-yl)—N— methylpyrazolo [1, 5-a] pyridinecarboxamide, (R)—5-(2-(2, 5~difluor0phenyl) pyrrolidin—l~yl)-N-((4-morpholinophenyl) sulfonyl) pyrazolo [1, S-a] pyridine-S-carboxamide, (2-(2,5-difluorophenyl)pyrrolidiny1)-N-(o-tolylsulfonyl)pyrazolo[1 ,5- a]pyridinecarboxamide, W0 2013f088256 (R)—5-(2-(3, 5-difluorophenyl)pyrrolidin-1—yl)-N-((4-fluorophenyl) sulfonyl) pyrazolo [1, 5-21] pyridinecarboxamide, -((R)(3, 5-difluorophenyl) pyrrolidin— l -y1)-N-((4-((S)—3 -hydroxypyrrolidin- l —yl) phenyl) sulfonyl) pyrazolo [1, 5-21] pyridinecarboxamide, (R)—(5—(2—(2,5—difluorophenyl)pyrrolidin— 1 —yl)pyrazolo[ l ,5—a]pyridine—3— yl) (piperidin— l fonyl)amide, or Sodium(R)—(5—(2-(2,5 -difluorophenyl)pyrrolidin—l—yl)pyrazolo[1,5-a]pyridine carbonyl) (o-tolylsulfonyl)amide; or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof or a isomer thereof.
In one embodiment, compounds of formula (I) are represented as (R)—N—(tert—butylsulfonyl)~5—(2—(2, 5—difluorophenyl) pyrrolidin—l—yl) pyrazolo [1, 5-51] pyridine—3-carboxamide, (R)-5 -(2—(2,5-difluorophenyl)pyrrolidin- 1 ~yl)-N-(ethylsulfonyl)pyrazolo[ l ,5- a]pyridinecarboxamide, (R)—5-(2-(2,5-difluorophenyl)pyrrolidin- l -(methylsulfonyl)pyrazolo[1 ,S-a] pyridine-3~carboxamide, (R)-5—(2—(2, 5-difluorophenyl) pyrrolidin-l-yl)-N-(isopropylsulfonyl) pyrazolo [1, S-a] pyridinecarboxamide, (R)—5 , 5-difluorophenyl) pyrrolidin—l-yl)-N —(propylsulfonyl) pyrazolo [1, 5—21] pyridine—3—carboxamide, (R)(2—(2, 5-difluorophenyl) pyrrolidin-l-yl)-N~(isobutylsulfonyl) pyrazolo [1, 5-21] pyridinecarboxamide, (R)—5 -(2~(2,5~difluorophenyl)pyrrolidin- l —(neopentylsulfonyl)pyrazolo[l,5- dinecarboxamide, (R)—N—(benzylsulfonyl)-5 ~(2-(2,5-difluorophenyl)pyrrolidin- l —yl)pyrazolo[ l ,5— a]pyridine-3—carboxamide, (R)—N-(tert—butylsulfonyl)(2-(5-fluoro—2-methoxyphenyl) pyrroli din-1 -yl) pyrazolo [1, 5-3] pyridinecarboxamide, (R)-N-(tert-butylsulfonyl)~5-(2-(3 -(difluoromethoxy)fluorophenyl) pyrrolidin- l -yl) pyrazolo [l , S-a] pyridinecarboxamide, WO 2013088256 PCT/IBZOIZIOOSOIZ (R)-N-(tert—butylsu1fony1)(2-(5-fluoropyridiny1) pyrrolidin-l-yl) pyrazolo [1, 5—21] pyridine-S-carboxamide, (R)-N-(tert-butylsulfonyl)(2-(2-ethoxyfluoropheny1)pyrrolidiny1)pyrazolo[ 1 ,5 — a] pyridinecarboxamide, (R)—N~(tert—butylsulfony1)—5 —(2—(2—(cyclopropylmethoxy)—5—fluorophenyl)pyrrolidin— 1 ~ yI) pyrazolo[1 ,5-a]pyridi116—3—carboxamide, (R)—N-(tert—butylsu1fony1)-5 -(2—(2—chloro-5—fluoropheny1)pyrrolidin—1 ~y1)pyra2010[1 ,5- dine—3—carboxamide, N—(telt-butylsulfony1)—5—((2R,4R)—2—(2,5—difluorophenyl)~4-hydr0xypyrrolidin~l- y1)pyrazolo[1,5 -a]pyridine-3 -carboxamide, N—(tert—butylsulfonyl)—5—((2R,4S)—2—(2,5—difluoropheny1)—4—f1uoro pyrrolidin— 1 — yl)pyrazolo [1 ,5-a]pyridine—3-carboxamide, (R)—N—(tert-butylsulfony1)-5—(2-(4,4’-difluoro-[1 - , 1'-bipheny1] pyrrolidin— 1 yl)pyrazolo[1 ,5 -a]pyridine—3 xamide, (R)-N—(tert—butylsulfony1)(2-(5 ~fluoro-Z-(2-fluoroethoxy)pheny1)pyrrolidin yl)pyrazolo [1 ,5-a]pyridine—3 -carb0xamide, N-(tert-butylsu1fonyl)-5—((2R)(5-fluoro—2-((tetrahydrofuran—3-y1)oxy)phenyl) pyrrolidiny1)pyrazolo[1 ,5-a]pyridinecarboxamide, N—(tert—butylsulfonyl)~5-((2R)—2~(5~fluoro((tetrahydrofuran—3-y1)0xy)phenyl) pyrrolidin— 1 -y1)pyrazolo[1 ,5—a]pyridine—3-carboxamide, (R)—N—(tert—butylsulfonyI)—5—(2-(2, 5—diflu0r0pheny1) pyrrolidin— 1 -y1)-4—fluoro pyrazolo[1, S—a] pyridine-B—carboxamide, (R)—N-(tert-butylsulfony1)(2-(2-(difluoromethoxy)—5—fluoropheny1) pyrrolidin— 1 —y1)- opyrazolo [1, S-a] pyridine—3-carboxamide, (R)—N-(tert—butylsulfonyl)(2—(2-(difluoromethoxy)—5—fluor0phenyl) pyrrolidin— 1 -y1) lo [1, 5-31] pyridine—3—carboxamide, (R)—N-(tert-butylsu1fonyl)(2—(2-fluor0(2-methoxyethoxy) phenyl) pyrrolidin y1)pyrazolo [1, 5—21] pyridinecarboxamide, (R)-N-(tert—butylsulfony1)(2-(5—flu0ro(2-methoxycthoxy) ) pyrrolidin— 1-yl) pyrazolo [1, S-a] pyridine-3~carboxamide, (tert—butylsulfonyl)(2—(3, 5-difluoropheny1)pyrrolidin-l-yl) pyrazolo [1, S-a] pyridine—3-carboxamide, (R)-N-(tert-butylsulfonyl)(2-(3-fluoro—5 -(2-methoxyethoxy)phenyl)pyrrolidin- 1 — yl)pyrazolo[1 ,5—a]pyridine-3—carboxamide, N-(tert-butylsulfonyl)((2R)—2-(3-fluoro((tetrahydrofuranyl)oxy)pheny1) pyrrolidin-l -yl)pyrazolo[1 ,5-a]pyridinecarboxamide, (R)—5—(2-(3, 5—diflu0rophenyl) pyrrolidin—l—yl)—N—(isopropylsulfony1) pyrazolo [1, S-a] pyridine-3—carboxamide, N-(tert-butylsu1f0ny1)—5—(2-(2,5-dif1uorophenyl)pyrrolidin- 1 —yl)pyrazolo[l ,5- a]pyridine-3—carboxamide (Racemic mixture); (R)-N~(te1‘t—butylsulfonyl)(2-(3 ,5—difluoro-2—methoxyphenyl)pyrr0lidin—1 - yl)pyrazolo [1 ,5-a]pyridine-3 xamide, (R)~N-(tert—butylsulfonyl)~5—(2—(3,5—difluoro—2-((tetrahydro-2H—pyran-4— yl)oxy)phenyl)pyrrolidinyl)pyrazolo[ l ,5-a]pyridine-3 —carboxarnide, (R)-N—(tert—butylsulfonyl)-5~(2—(5-fluoro-2—((tetrahydro-2H-pyran yl)oxy)phenyl)pyrrolidin- 1 ~yl)pyrazolo[ 1 ,5—a]pyridine—3-carboxamide, (2—(3 ,5~difluoro((tetrahydro-2H—pyranyl)oxy)phenyl)pyrrolidin~ l -yl)-N- (isopropylsulfony1)pyrazolo[ 1 ,5-a]pyridinecarboxamide, (R)—4-fluoro(2-(3 —fluorophenyl)pyrrolidinyl)—N—(isopropylsulfonyl)pyrazolo [1 ,5 - dine-3—carboxamide, (R)-N—(tert—butylsulfonyl)—4—fluoro(2—(5~fluoro((tetrahydro-2H—pyran-4~ yl)oxy)phenyl)pyrrolidin— 1 ~yl)pyrazolo[1 ,5—a]pyridine—3 —carboxamide, Sodium(tert—butylsulfonyl)(5—((2R,4R)—2—(2,5~difluorophenyl)~4-fluor0pyrrolidin— 1— y1)pyrazolo[1 ,5ua]pyridine-3~carbonyl)amide, Sodium(tert~butylsulfonyl)(5~((2R,4S)(2,5-difluorophenyl)fluoropyrrolidin—1- y1)pyraz010 [1 ,5~a]pyridinecarbony1)amide, Sodium(R)-(tert—butylsulfonyl)(5-(2-(2,5—difluoropheny1)pyrrolidinyl)pyrazolo[ 1 ,5- a] necarbonyl)amide, or Sodium(R)—(tert—butylsulfonyl)(5-(2—(7—fluoro-2,3-dihydrobenzo [b] [ 1 ,4]dioxin y1)pyrrolidin—1 —yl)pyrazolo [ 1 ,5 —a]pyridinecarbonyl)amide; or a pharmaceutically acceptable salt f, a pharmaceutically acceptable solvate thereof or a isomer thereof.
In one embodiment, compounds of a (I) are represented as (R)-N—(cyclopropylsulfonyl)-5~(2-(2,5 -difluorophenyl)pyrrolidinyl)pyrazolo[1,5- a]pyridinecarboxamide, (R)-N-(cyclohexy1su1fonyl)(2-(2, 5-dif1uoropheny1) pyrrolidin-l-y1)pyrazolo [1, 5- a] pyridinecarboxamide, (R)—N—(cyclopentyl sulfony1)—5—(2-(2, 5—difluorophenyl) pyrrolidin—l—yl) pyrazolo [1 , 5— a] pyridine-3—carboxamide, (R)-N—(cyclobutylsu1fony1)-5—(2—(2, 5—difluoropheny1) pyrrolidin—l-yl) pyrazolo [1, 5-a] pyridine—3 —carboxamide, (R)(2-(2,5~diflu0ropheny1)pyrrolidin— 1 ~y1)-N—((1-ethy1cyclopropyl)sulfonyl) pyrazolo[1,5-a]pyridinecarboxamide, (R)—5—(2—(2,5—difluoropheny1)pyrrolidin—1 —yl)-N-(( 1 — methylcyc10propy1)su1fony1)pyrazolo [1 ,5-a]pyridine—3~carboxamide, (R)-5 -(2—(2,5—difluoropheny1)pyrrolidin— 1 —y1)-N-(( 1 ~(4- fluorobenzyl)oyclopropy1)su1fonyl) pyrazolo[1,5~a]pyridine—3~carboxamide, (R)(2-(2, oropheny1) pyrrolidin—l-y1)-4—fluoro—N—(isopropylsulfonyl)pyrazolo [1, S-a] pyridinecarboxamide, or Sodium(R)—(5-(2-(2,5-difluoropheny1)pyrrolidiny1)pyrazolo[1 ,5 -a]pyridine~3- carbonyl)((1 -methylcyclopropy1) sulfonyl)amide; or a pharmaceutically acceptable salt thereof, a pharmaceutically able solvate thereof or a stereoisomer thereof 1n one ment, compounds of formula (1) are represented as (R)—5—(2-(2,5~difluoropheny1)pyrrolidin—1 ~y1)—N—((3 ,5—dimcthylisoxazol-4—y1)sulfony1) pyrazolo [1, S-a] pyridinecarboxamide, (R)-5—(2-(2,5~dif1uorophenyl) pyrrolidin—l-yl)—N~((1, 2-dimethy1—11imidazol-4—yl) sulfonyl) pyrazolo {1, S-a] ne-3—carboxamide, (R)(2-(2,5-difluoropheny1) idin-l -y1)—N-((1, 2-dimethy1-1H—imidazoly1) sulfonyl) pyrazolo [1, 5-a] necarboxamide, (R)—5-(2—(2,5-difluoropheny1) idin-1—y1)—N-((1-methyl-1H—imidazolyl) sulfony1)py'razolo [1, S-a] necarboxamide, (R)(2-(2,5-difluorophenyl) pyrrolidin-l -y1)-N-((1-methy1- lH-pyrazol-S-yl) sulfonyl) pyrazolo [1, S-a] pyridinecarboxamide, W0 2013(088256 (R)—5-(2-(2, orophenyl) pyrrolidin—l—yl)-N—((2, 4-dimethylthiazol—5—yl) sulfonyl) pyrazolo [1, 5—a] pyridinecarboxamide, (R)(2-(2,5-difluorophenyl)pyrrolidin-1 -yl)-N-((1~methyloxoindolinyl)su1fonyl) pyrazolo [1, 5-a] pyridinecarboxamide, (R)—5 —(2—(2, S—difluorophenyl) pyrrolidin—l—yl)-N—((6—(dimethylamino) pyridin—3—yl) yl) pyrazolo [1, S-a] pyridine-3—carboxamide, -2—(2, S-difluorophenyl) pyrrolidin—l-yl)-N-((6-((S)—3—hydroxypyrrolidin-1—yl) pyridin—3-yl) sulfonyl) pyrazolo [1, S—a] pyridine—3—carboxamide, (R)-5—(2-(2, 5—difluorophenyl) pyrrolidin—l—yl)—N—((6-methoxypyridinyl) yl) pyrazolo [1, 5-a] pyridine—3-carboxamide, (R)—N—((6—( l H— 1 ,2,4—triazol— l ridin—3—yl)sulf0nyl)-5—(2—(2,S—difluor0phenyl) pyrrolidin-l-yl) pyrazolo [1, 5~a] pyridine-3—carboxamide, (R)(2—(2,5-difluorophenyl) pyrrolidin-l—yl)-N—((1—methyl-lH—pyrazolyl) sulfonyl) pyrazolo [1, S—a] pyridine—3—carboxamide, (R)(2-(2,5-diflu0rophenyl)pyrrolidinyl)-N—(pyridin—3 -ylsulfonyl)pyrazolo[l ,5 - a]pyridinecarboxamide ; (R)-N-((5-chlorothiophenyl) sulfonyl)—5-(2—(2, S—difluorophenyl) pyrrolidin-l-yl) pyrazolo [1, S—a] pyridinecarboxamide, (R)—N—((2,5-dichlorothiophen—3-yl) sulfonyl)-5—(2~(2, 5-difluorophenyl) pyrrolidin—l— yl) pyrazolo [1, 5-a] pyn'dinecarboxamide, (R)—5-(2—(2,5-difluorophenyl)pyrrolidin~ 1 ~yl)-N-((2,3-dihydrobenzo[b] [1 ,4]dioxin yl)sulfonyl)pyrazolo [1 ,5—a}pyridine—3 -carboxamide, (R)—N-(benzo[d][1,3]dioxolylsulfonyl)(2—(2,5~difluorophenyl)pyrrolidin—1- y1)pyrazolo[1 ,5-a1pyridine-3 xamide, (R)-N—((6—(lH—1, 2, zol-l-yl) pyridinyl) sulfonyl)-5—(2~(3, 5—difluorophenyl) pyrrolidin~1—yl) pyrazolo [1 , S—a} pyridine—3—carboxamide, or -((R)-2—(3, 5-difluorophenyl) pyrrolidin-l~yl)-N—((6-((S)—3-hydroxypyrrolidin—1~yl) pyridinyl) sulfonyl) pyrazolo [1, 5-a] pyridinecarboxamide; or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof or a stereoisomer f.
In one embodiment, compounds of formula (I) are represented as (R)(2-(2, 5-difluoropheny1) pyrrolidinyl)-N-(piperidinylsu1fonyl) pyrazolo [1, -21] pyridine—3-carboxamide, (R)—5-(2-(2, 5-difluorophenyl) pyrrolidin—1-yl)-N-((tetrahydro-2H—pyranyl) sulfonyl) pyrazolo [1 , S-a] pyridinecarboxamide, —((R)—2—(2, 5—difluorophenyl) pyrrolidin—1—y1)—N—((2-methy1tetrahydrofuran—3—yl) sulfonyl) pyrazolo [1, 5-21] pyridine—S-carboxamide, (R)~5—(2—(2,5-difluorophenyl)pyrrolidin—1 -y1)-N-(morpholinosulfonyl) pyrazolo[1,5- a]pyridine-3—carboxamide, (R)(2-(2,5-difluoropheny1)pyrrolidin-1 -yl)—N-(pyrrolidin— 1 —ylsu1fony1) pyrazolo[1 ,5— a]pyridinecarboxamide, (R)—5-(2-(2,5—difluoropheny1)pyrrolidm—1 —((4—methy1piperazin—1 —y1) yl)pyrazolo [1,5—a]pyridine—3 -carboxamide, (R)-5—(2—(2,5-difluoropheny1)pyrrolidin-1 -y1)-N—(piperidin~ 1 -ylsu1fonyl)pyrazolo[ 1 , 5 - a]pyridine—3 —carboxamide, or -((R)—2—(2,5-difluorophenyl)pyrrolidiny1)-N—(((S)—3 -hydroxypyrr01idin-1—yl) sulfonyl) pyrazolo[1,5 -a]pyridine—3-carboxamide; or a pharmaceutically acceptable salt thereof, a pharmaceutically able solvate thereof or a stereoisomer thereof.
In one embodiment, compounds of formula (I) are represented as (R)—N—(tert—butylsulfonyl)—5—(2-(5~fluoro-2—(2,2,2-trifluoroethoxy)phenyl)pyrr0lidin— 1 — yl) pyrazolo[1,5—a]pyridine—3—carboxamide, N~(tert—butylsu1fony1)—5-(2—(7—fluoro-2,3-dihydrobenzo [b] [ 1 xiny1)pyrrolidin- 1 — yl)pyrazolo [1 ,5—a]pyridinecarboxamide, N-(tert—butylsulfonyl)—5—(2—(7-fluoro~2,3-dihydrobenzo [b] [ 1 ,4}dioxin-5 rrolidin y1)pyrazolo [1 ,5~a]pyridinecarboxamide, N—(tert-butylsulfonyl)((2R,4S)—2-(2,5-difluorophenyl)~4-fluoropyrrolidin yl)pyrazolo[1 ,5—a]pyridinecarboxamide, N—(tert-butylsulfonyl)—5-((2R,4R)-2—(2,5—difluorophenyl)fluoropyrrolidin- 1- yl)pyrazolo[1 ,5-a]pyridinecarboxamide, 4S)(2,5—difluoropheny1)fluoropyrrolidin— 1 -yl)-N-(( 1 -methyl ropyl) sulfony1)pyrazolo [1 ,5 —a]pyridinecarboxamide, ,4S)-2—(2,5-difluorophenyl)—4-fluoropyrrolidin- 1 —yl)-N—(N,N-dimethylsulfamoyl) pyrazolo[l yridinecarboxamide, -((2R,4S)-2—(2,5-difluorophenyl)fluoropyrrolidin—1-yl)-N-(N-ethyl-N- methylsulfamoyl) pyrazolo[1,5-a]pyrid1'necarboxamide, —((2R,4S)—2—(2,5—difluorophenyl)—4—fluoropyrrolidin— 1 —yl)—N~(N,N-dimethylsulfamoyl) pyrazolo[ 1 ,5-a]pyridine-3 xamide, -((2R,4S)—2-(2,5-difluorophenyl)fluoropyrrolidiny1)-N-(N—ethyl-N— methylsulfamoyl) pyrazolo[1,5~a]pyridine—3—carboxamide, N—(N-ethyl-N—methylsulfamoyl)-4—fluoro~5~((2R,4S)—4—fluoro-2~(3— fluoropheny1)pyrrolidinyl)pyrazolo[1 yridine-3 -carboxamide, N—(tert-butylsulfonyl)~4-fluoro—5—((2R,4S)—4—fluoro—2—(3 —fluorophenyl)pyrrolidin—1— yl)pyrazolo [1 ,5-a]pyridine~3—carboxamide, 4-fluoro((2R,4S)—4—flu0ro(3-fluorophenyl)pyrrolidiny1)~N-(isopropylsulfonyl) pyrazolo[1,5—a]pyridine—3 -carboxamide, Sodium(4—flu0r0((2R,4S)—4~fluoro-2—(3-fluorophenyl)pyrrolidin- l -yl)pyrazolo[ 1 ,5- a]pyridine-3 -carbonyl) (isopropylsulfonyl)amide, Sodium(5—((2R,4S)—2—(2,5-difluorophenyl)-4—fluoropyrrolidin- 1 ~yl)pyrazolo [ 1 ,5- a]pyridine-3 -carbonyl)((1-methylcyclopropyl)sulfony1)amide, S0dium(tert-butylsulfonyl)(5-((2R)(2,5-difluorophenyl)—4-fluoropyrrolidin— l — yl)pyrazolo[1 ,5—a]pyridinecarbonyl)amide, Sodium(5—((2R,4S)—2—(2,5—difluorophenyl)—4—fluoropyrrolidin— 1 -yl)pyrazolo[ 1 ,5— a]pyridine—3 nyl)(N ,N~dimethylsulfamoyl)amide, (tert—butylsulfony1)(4-fluoro((2R,4S)-4—fluoro—2-(3-fluorophenyl)pyrrolidiny1)pyrazolo[1 ,5-a}pyridinecarbonyl)amide, or Sodium (tert-butylsulfonyl)(5-(2—(2,5—difluorophenyl)~4,4-difluoropyrrolidin- 1 ~ yl)pyrazolo [1 ,5 —a]pyridinecarbonyl)amide; or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof or a stereoisomer thereof.
In one embodiment, compounds of formula (I) are represented as (R)-5 -(2-(2,5-difluorophenyl) pyrrolidin-l —yl)-N-(N, N- dimethylsulfamoyl)pyrazolo[1 ,S-a] pyridine-3 -carboxamide, WO 88256 (R)—5 ~(2—(2 ,5-diflu0ropheny1)pyrr01idiny1)-N-(N-ethyl—N—methylsulfamoy1)pyrazo10 [1 ,5-a]pyridine-3 -carboxamide, (N—(cyclopropy1methy1)—N—methy1sulfamoyl)(2-(2,5 — difluorophenpryrrolidin-1 -y1)pyrazolo [1 ,5 -a]pyridine-S-carboxamide, (R)~N—(N,N-diethylsulfamoyl)—5~(2—(2,5—difluoropheny1)pyrrolidin— 1 —yl)pyrazolo [ 1 ,5 — a]pyridine—3-carboxamide, (R)—N—(N,N-diethylsulfamoyl)-5 ~(2-(5-f1uorometh0xyphenyl)pyrrolidin-1— y1)pyrazolo[1 ,5—a]pyridine—3—carboxamide, (R)-N-(N,N-diethylsulfamoyl)-5 -(2-(5—fluor0—2-(2—flu0roethoxy)phenyl)pyr1’olidin— 1 - yl) pyrazolo[1 ,5 -a]pyridine-3—carboxamide, (R)—5—(2—(3 ,5—diflu0ro—2~meth0xypheny1)pyrrolidin~ 1 —y1)—N—(N—ethy1—N—methyl sulfam0y1)pyrazolo[1,5-a]pyridine-3 —carboxamide, (R)-N-(N-ethy1—N—methylsulfamoy1)(2-(5—f1uorometh0xypheny1)pyrrolidin— 1 - y1)pyrazolo[1 ,5~a]pyridine—3—carboxamide, (R)—N-(N—ethyl-N-methylsulfamoyl)—5 -(2-(5—fluoro—2-(2— fluoroethoxy)phenyl)pyrr0lidiny1)pyrazolo[1 ,5-a]pyridinecarboxamide, (R)-5 -(2-(3 ,5-diflu0ro(2-fluoroethoxy)phenyl)py1rolidin- 1 —y1)—N—(N-ethyl-N- methylsulfamoyl)pyrazolo[ 1 ,5 -a]pyridine-3~carboxamide, (R)—5-(2—(2,5-difluoropheny1)pyrrolidiny1)-N-su1famoylpyrazo10[ 1 ,5-a]pyridine-3 - carboxamide, N—(N-ethyl—N—methylsu1famoy1)((R)—2—(3~flu0r0—5—(((S)~tetrahydr0furan—3~yl)oxy) pheny1)pyrrolidin— l -y1)pyrazolo[1 yridine-3 -carboxamide, (R)—5—(2-(3 uoro—2~((tetrahydro-2H—pyran—4—yl)oxy)pheny1)pyrrolidiny1)~N—(N— ethyl-N—methy1sulfamoy1)pyrazolo[ 1 ,5-a]pyridine~3~carboxamide, (R)—5-(2~(3 ,5—difluoro-2~((tetrahydro—2H-pyran—4~y1)oxy)pheny1)pyrrolidin— 1 —yl)—N ~ imethylsulfamoy1)pyrazo10[1 ,5-a]pyridine—3—carboxamide, N—(N—ethyl-N—methylsulfamoyl)((R)(3~fluor0(((R)-tetrahydrofi1ran—3- yl)oxy)pheny1)pyrrolidin- 1 —yl)pyrazolo[ 1 ,5-a]pyridine-3—carb0xamide, 4-fluoro((2R,4S)—4-fluoro(3 -fluorophenyl)pyrr01idiny1)-N- sul famoylpyrazolo [1 yri dinecarb0xamide, N-(N,N-dimethylsulfamoyl)—5-(2-(8—fluoro-3 ,4-dihydro-2H-benzo[b] [1 ,4]dioxepin yl)pyrrolidin-1 -yl)pyrazolo[1 ,5-a]pyridine—3-carboxamide (Diastereomer—I), (R)—5-(2—(2,5—difluorophenyl)pyrrolidin—1 -yl)—N-(N—isobutyl—N- methylsulfamoyl)pyrazolo[ 1 ,5-a]pyridine-3—carboxamide, (R)—N—CN-ethyl-N-methylsulfamoyl)-4—fluoro(2-(3-fluor0phenyl)pyrrolidin- l - yl)pyrazolo[1 ,5-a]pyridinecarboxamide, (N,N—dimethylsulfamoyl)—4—fluoro—5—(2—(3 phenyl)pyrrolidin—l — yl)pyrazolo [1 ,5-a]pyridine-3 -carboxamide, (R)~N~(N,N-dimethylsulfamoyl)—4-fluoro-5~(2-(3-fluorophenyl)pyrrolidin—l- yl)pyrazolo[1 ,5—a]pyridine~3~carboxamide, (R)-N—(N-ethyl—N—methylsulfam0y1)—4~fluoro-5—(2—(5—fluoro-2—((tetrahydro-ZH-pyran- 4—yl)oxy)phenyl)pyrrolidin-1 ~yl)pyrazolo[ 1 ,5 idine-3—carboxamide, —((2R)—2—(3~((2,2-difluorocyclopropyl)methoxy)—5—fluorophenyl)pyrrolidin—1~yl)—N— (N~ethyl~N—methylsulfamoy1)pyrazolo[1 ,5—a]pyridine—3-carboxamide, (R)—N—(N,N-bis(cycl0propylmethyl)sulfamoyl)—5-(2-(2,5~difluorophenyl)pyrrolidin- 1- yl)pyrazolo[1,5—a]pyridine~3 ~carb0xamide, N—(N-ethyl—N~methylsulfamoyl)~5~((2R)(5 -flu0r0—2—((tetrahydr0furan—3— yl)oxy)phenyl)pyrrolidin— 1 -yl)pyrazolo[1 ,5-a]pyridinecarboxamide, N-(N-ethy1-N-methylsulfamoyl)((2R)—2—(5 ~fluoro—2-((tetrahydrofuran yl)oxy)pheny1)pyrrolidin- 1 —yl)pyrazolo[ 1 ,5-a]pyridinecarboxamide, Sodium(R)—(N,N-dimethylsulfamoyl)(4—fluoro-S-(2-(3-fluorophenyl)pyrrolidin- l- yl)pyrazolo[1 yridine—3-carbony1)amide, S0dium(N-ethyl-N-methylsulfamoyl)(5—((2R)—2-(5-fluor0—2—((tetrahydrofi1ran—3- yl)oxy) phenyl)pyrrolidin—l-yl) pyrazolo[1,5~a]pyridine-3—carbonyl)amide, or Sodium (R)—(5-(2-(2,5-difluorophenyl) idin- 1—yl)pyrazolo[1 ,5-a]pyridine-3— carbonyl)(N,N-dimethylsulfamoyl)amide; or a pharmaceutically able salt thereof, a pharmaceutically acceptable solvate thereof or a stereoisomer thereof.
In one embodiment, compounds of formula (I) are ented as N-(N-ethyl-N—methylsulfamoyl)(2—(8—fluoro-3,4-dihydro—2H—benzo [b1 [1 ,4]dioxepin- 6-yl)pyrrolidin-l -yl)pyrazolo[1 ,5-a]pyridine—3-carb0xamide (Diastereomer—I), N-(N-ethyl-N-methylsulfamoyl)-5 -(2—(8-f1uoro-3,4-dihydro-2H-benzo[b] [1 ,4]dioxepin- 6-yl)pyrrolidinyl)pyrazolo[l ,5-a]pyridine-3 —carboxamide (Diastereomer-II), W0 88256 N-(N,N-dimethylsulfamoyl)(2-(7—fluoro-2,3—dihydrobenzo[b][1,4]dioxin—5- yl)pyrrolidinyl)pyrazolo[1,5-a]pyridine—3—carboxamide (Diastereomer—I), N-(N,N—dirnethylsulfamoyl)—5-(2-(7-fluoro—2,3-dihydrobenzo[b][1,4]dioxin yl)pyrrolidin-l -yl)pyrazolo[l ,5-a]pyri dine—3-carboxamide (Diastereomer—ll), N-(N~ethyl-N—methylsulfamoyl)—5—(2-(7—fluoro—2,3—dihydrobenzo [b] [l ,4]dioxin—5— yl)pyrrolidinyl)pyrazolo[1,5 -a]pyridine-3 xamide (Diastereomer-I), N—(N—ethyl—N-methylsulfamoyl)(2-(7-fluoro—2,3-dihydrobenzo [b] [ 1 ,4]dioxin—5- yl)pyrrolidin—l—yl)pyrazolo[1,5—a]pyridine—3—carboxamide (Diastereomer—II), or N—(N,N-dimethylsulfamoyl)—5-(2-(8-fluoro~3,4—dihydro-2H~benzo[b] [1 ,4]dioxepin~6— yl)pyrrolidin-1 -yl)pyrazolo[1,5-a]pyridinecarboxamide (Diastereomer—Z); or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof or a stereoisomer thereof.
In another embodiment, there is provided a method of treating or preventing pain or pain disorder in a patient in need of such a treatment comprising the stration of a therapeutically effective amount of the compound of formula (I) enlisted in List-l, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof to said patient.
The present ation further s to methods of treating a patient for diseases or disorders in which the nerve growth factor (NGF) receptor are ed, in particular TrkA, such as such as pain, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, or a disease, disorder, or injury relating to dysmyelination or demyelination, by stering a therapeutically effective amount of compound of formula (I), as enlisted in List-1, to said patient.
In another embodiment, there is provided a method of ng or preventing pain or pain disorder in a patient in need of such a treatment sing the administration of a therapeutically effective amount of the compound of formula (I), as ed in , to said patient.
In another embodiment, pain includes chronic and acute pain but is not limited to, pain related to cancer, surgery, bone fracture, skeletal pain caused by tumor metastasis, osteoarthritis, visceral pain, inflammatory pain and neuropathic pain.
In one embodiment, there is provided a method of g NGF receptor TrkA protein in a patient in need of such a treatment comprising the administration of a therapeutically effective amount of the compound of formula (I), as enlisted in List-1, to said patient.
The present application further relates to use of compound of formulation (1) for treating a t for diseases or disorders in which the NGF receptor are involved, in particular TrkA, such as such as pain, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, or a disease, disorder, or injury relating to dysmyelination or demyelination, by administering a therapeutically effective amount of compound of a (I), as enlisted in List-1, to said patient.
In another embodiment, there is provided an use of the compound for formula (I) for treating or ting pain or pain disorder in a patient in need of such a treatment, comprising the administration of a therapeutically effective amount of the compound of formula (I), as enlisted in List-1, to said patient.
In another embodiment, pain es chronic and acute pain but is not limited to, pain d to cancer, surgery, bone fracture, skeletal pain caused by tumor metastasis, osteoarthritis, al pain, inflammatory pain and neuropathic pain.
In another embodiment of the above aspect, there is provided a method of treating or ting pain which comprises administering to said t a pharmaceutical composition comprising an effective amount of a compound of formula (I), as ed in List-l. r embodiment of the application es the use of such compositions in the treatment or prevention of diseases associated with inhibiting NGF receptor TrkA, such as pain, cancer, restenosis, sclerosis, psoriasis, thrombosis, or a disease, disorder, or injury relating to dysmyelination or demyelination.
One embodiment ofthe present application es intermediates as 2—(7—fluoro-2, 3—dihydrobenzo[b] [1, 4]dioxin—5-yl)pyrrolidine, Ethyl 5-(2-(7~fluor0~2, 3—dihydrobenzo [b] [1, 4] dioxin-S-yl) pyrrolidin—l-yl) pyrazolo [1, 5-a] ne-S-carboxylate (Isomer-I), -(2-(7—fluoro—2, 3~dihydrobenzo [b] [1, 4] dioxin-S—yl) pyrrolidin—l-yl) pyrazolo [1, 5- a] pyridinecarboxylic acid (Isomer—l) Ethyl 5-(2-(7-fluoro-2, 3-dihydrobenzo [b] [1, 4] dioxin-S-yl) pyrrolidin-l-yl) pyrazolo [1, 5-a] pyridinecarboxylate (Isomer-II) W0 2013I088256 -(2-(7-fluoro-2, 3-dihydrobenzo [b] [1, 4] dioxin-S—yl) pyrrolidin-l-yl) pyrazolo [1, 5- a] pyridinecarboxylic acid (Isomer-II) The pharmaceutical composition of a compound of formula (I) may be administered enterally and/or parenterally. Parenteral administration includes subcutaneous, intramuscular, intradermal, intramammary, intravenous, and other administrative methods known in the art. Enteral administration includes solution, tablets, sustained release capsules, enteric coated capsules, syrups, beverages, foods, and other ional supplements. When administered, the present pharmaceutical compositions may be at or near body ature. In some embodiments, the present pharmaceutical compositions may be below body temperatures. In other embodiments, the present pharmaceutical compositions may be above body temperatures.
The compounds of the present invention may be administered in a wide variety of different dosage forms. For example, they may be ed with various pharmaceutically acceptable inert carriers in the form of, but not limited to, tablets, capsules, lozenges, s, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable ons, elixirs, syrups, and the like. Such carriers may include solid diluents or fillers, sterile aqueous media, and various nontoxic organic solvents, etc. Moreover, oral ceutical compositions may be sweetened and/or flavored. In general, the compounds of the invention may be present in such dosage forms at concentration levels ranging from about 0.1 % to about 90% by weight.
In general, compounds of the present invention for ent may be stered to a subject in a suitable effective dose in the range of from about 0.01 to about 100 mg per kilogram of body weight of recipient per day, in some embodiments, in the range of from about 0.5 to about 50 mg per kilogram body weight of recipient per day, in still other ments, in the range of from about 0.1 to about 20 mg per kilogram body weight of ent per day. The ary dose may be suitably administered once daily, or several sub~doses, e.g. 2 to 5 sub—doses, may be administered at riate intervals through the day, or on other appropriate schedules.
An embodiment of the present invention provides the preparation of compounds of formula (I) according to the procedures of the following examples, using appropriate materials. Those d in the art will understand that known variations of the conditions and processes of the ing preparative procedures can be used to prepare these nds. er, by utilizing the procedures described in , one of ordinary skill in the art can prepare additional compounds of the present invention claimed herein. All temperatures are in degrees Celsius (°C) unless otherwise noted.
The following acronyms, abbreviations, teims and definitions have been used throughout the reaction scheme and experimental section.
ACN (Acetonitrile), BINAP bis(diphenylphosphino)—1,l'—binaphthyl), CDC13 (Deuterated chloroform), CD301) (Deuterated methanol), C32C03 (Caesium Carbonate) DCM (Dichloromethane), DIPEA [(N,N-diisopropylethylamine) (Hunig’s base)], DMF (N,N~dimethylformamide), DMSO (Dimethyl sulfoxide), DMAP (Dimethyl amino ne), EtOH (Ethanol), EtOAc (Ethyl acetate), Eth (Triethylamine), EDCl (l-ethyl—3—(3 -dimethylaminopropyl)carbodiimide hydrochloride, HOBt (1-hydroxybenzotriazole), HCl (hydrochloric acid), HATU [O-(- 7-azabenzotriazolyl)-N,N,N’,N’—tetramethyluronium hexafluorophosphate], MeOH nol), LiHMDS (Lithium bis(trimethylsilyl)amide), LiOH um hydroxide), K2C03 (Potassium Carbonate), KOBut (Potassium utoxide), Pd dium), Pd(OAe)2 (Palladium (II) acetate), Pd2(dba)3 (Tris(dibenzylideneacetone)dipalladium(0)), POC13 (Phosphorus oxychloride), NaHC03 (Sodium Bicarbonate), NaOH (Sodium hydroxide), NaZSO4 (Sodium Sulfate), NaBH4 (Sodium borohydride), NH4C1 (Ammonium chloride), TFA (Trifluoroacetic acid), THF (Tetrahydrofiiran), H20 (Water).
Another embodiment of the present invention provides a process for the preparation of compounds of formulae (Ii)—(Iix) represent respectively a sub-group of a compound of formula (I), wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented by Scheme-l : W0 20131088256 HzN-O O NO NHBoc NHBoc / ,N 2 N Rb Rb / O/\ \ \ \ <4) \ \ + l ___..l OZN BocHN / ’ N02 N “I" ‘OONoz OEt (1) (2) ”“2 (5) N-N\ AH / N,” / c (8) / N»: ——> 5' \ —>TFAVHZN —> Rb OEt R” 05" A o o Rb CE (6) (7) 0 (Ram (Ram l I: O r , = \/ \ $513"— 0 A <— \ \ R” ,C 9 A /\J 8‘Ntl5; V] o’ ‘N—s—Ra Rb OH (R3)n (R3),,/ {R1 ('5 0 (Ii) (10) Schemel Compound of formula (3) obtained from compound (1) (prepared according to the procedure described in J. Org. Chem. 2003, 68, 7119-7122) and (2) was reacted with compound (4) to obtain of a (5) where Rb is as defined as before.
A compound of formula (6) can be obtained by ng a compound of formula (5) with. trifluoroacetic acid in dichloromethane at room temperature A nd of formula (7) was obtained from compound of formula (6) by standard Sandmeyer reaction protocol.
A compound of formula (9) was obtained from compound of formula (7) by reaction with compound of formula (8) in the presence of szdbag, BINAP, Eth and CS2C03, in a t such as 1,4-dioxane and the like at a temperature of about 60 to about 80 °C for about 12 to about 16 h where A is as defined before A compound of formula (9) to a (10) can be converted using reagents such as 3M LiOH solution, 5N NaOH solution and the like in presence of a suitable solvent such as THF, THF-MeOH and the like.
A compound of formula (10) to a (I) can be converted by using suitable ts such as HATU, DIPEA or HATU, HOBt, DIPEA or EDCI, HOBt, DIPEA or EDCI, DMAP or EDCI, HOBt, NaH and the like in presence of a suitable solvent such W0 2013I'088256 as DMF, DCM and the like at a ature of about 20 to about 65°C for about 15 to about 18 h.
Another embodiment of the t invention provides a process for the preparation of compounds of formulae (100, (Hi) and (H), wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented by Scheme—2: /N’N\ / ,N \ \ \ \ "(R3)/ Rh b CE R 05* 0 "(R3)/‘// o (10i) (9i) Rio< 3F ,N Rio< EFL o ,N NH(R‘2)SORa \ \ \ \ n(R3)/\/l 00C‘2——s—R8 n(R3)/\JJ/G‘Liofl (Ii) (11i) Scheme—2 A compound of formula (10i) can be obtained from compound of a (9i) by reacting with hydroxyl containing compounds like RiOH where Ri is defined as before under le conditions.
A compound of formula (10i) can be converted to the compound of formula (lli) and subsequently to compound of formula ( 1i) using conditions as mentioned under Scheme—1.
Another embodiment of the present invention provides a process for the preparation of compounds of formulae (lOii), , (lZi) and (liii), wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented by Scheme-3: F F / N’N\ / N’N\ / N»N\ M90 Ho \ Rio \ \ \ \ \ n(R3)/\/’ "(R3)/\’J Rb oEt OEt 0 o “(R3) (10ii) (11ii) (9n) F i /N’N NH(R1)sozRa / N . \ \ \ R'O o N 3/ 1c M "(R) \ owns—Ra0, “023) Rb OH (llli) (12“) Scheme-3 A compound of formula (lOii) can be obtained from compound of formula (9ii) by reacting with BBr3 in a suitable solvent like dichloromethane.
A compound of formula (10ii) can be converted to the compound of a (1 lii) using suitable reaction conditions known in the art.
A compound of formula (llii) can be ted to the compound of formula (12ii) and uently to compound of formula (lii) using conditions as mentioned under Scheme-l.
Another embodiment of the t invention provides a process for the preparation of compounds of a (13), wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented by Scheme-4: OH 0 OH 0H 0 |\ OZN —_" 02N1\OH 02N|\O // ll/ _" // —> // (R2)m (R2)m (R2)m (R2)m (13w) (13i) (13“) (13m) (Rzim N\ l n(R3) O \l‘NBocOI/gm 014% 0% (Enl\ HO[\O Bkb/ H2Nl\0 ‘— o ’i/R) 2m // // // (R2)m (R2)m (R2)m (13m) (13vii) (13vi) (13v) (E1 [\ O '\’ (R2)m (13) Scheme-4 A compound of formula (l3ii) can be obtained from compound of formula, (13i) by nitration in presence of filming nitric acid / acetic acid or a similar nitrating t.
Nitration of the compounds (l3ii) on Dakin oxidation resulted compound of formula (13in), which can be cyclized to compound (13iv) by reacting with a dihalo alkyl in presence of a suitable base and solvent.
Compound of formula (13V) can be obtained by reduction of (l3iv) in presence of a suitable reducing agent, which can then be ted to a compound of a (13Vi) by Sandmeyer reaction with a suitable copper halide.
Compound of formula (l3vi) can be converted to a compound of formula (13vii) by magnesium metal mediated reaction with Boc ted pyrrolidin—2-one derivatives.
Compound of formula (13vii) on TFA de-protection followed by NaBH4 or a suitable reducing agent mediated reduction afforded compound of formula (13).
As used in the examples and preparations that follow, the terms used therein shall have the meanings indicated: "g" or “gm” refers to grams, "mg" refers to milligrams, "pg" refers to micrograms, "mol" refers to moles, "mmol" refers to millimoles, "L" refers to liters, "mL" or "ml" refers to milliliters, "uL" refers to microliters, "mp" or "mp." refers to melting point, "mm of Hg" refers to pressure in millimeters of mercury, "cm" refers to centimeters, "nm" refers to nanometers, "conc." refers to concentrated, "M" refers to molar, "mM" refers to millimolar, "nM" refers to micromolar, "nM" refers to nanomolar, "TLC" refers to thin layer chromatography, "HPLC" refers to high performance liquid chromatography, “anhyd” refers to anhydrous; “aq” refers to aqueous; “min” refers to ; “mins” refers to minutes; “h” or “hr” refers to hour; “d” refers to day; “atm” refers to atmosphere; “sat.” refers to saturated; “ 7, S refers to singlet, “d” refers to doublet; “t” refers to triplet; L‘ 99 q refers to quartet; “m” refers to multiplet; “dd” refers to “doublet of ts”; “br” refers to broad; “bs” refers to broad t, “LC” refers to liquid chromatograph; “MS” refers to mass spectroscopy; “ESI” refers to electrospray ionization; “CI” refers to chemical ionization; “RT” refers to retention time; “M” refers to molecular ion; “NMR” refers to nuclear magnetic resonance spectroscopy; “MHz” refers to megahertz.
EXAMPLES Although the ion has been illustrated by certain of the preceding es, it is not to be construed as being limited thereby; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made t departing from the spirit and scope thereof.
Synthesis of ediates: Int-6: (R)—2-(2,5—difluorophcnyl)pyrrolidinc hydrochloride W0 2013;088256 O 0 N/ \‘o \/\/CI ____.. F CI l F C. | _‘_” Int-3 Int-1 F Int-2 F F i F «— ~ 0 N N and H HCI F F 5' , Int—1 : 4~chloro-N~methoxy-N-methylbutanamide Pyridine (101.28 g, 106.6mL 1281.79 mmol) was added to a solution of NO— dimethylhydroxylamine hydrochloride (50 g, 512.72 mmol) in DCM (800mL) at 0°C and stirring was ued for 15 min. Chlorobutyrylchloride (72.29 g, 512.72 mmol) was then added to this mixture and was stirred continuously at 0°C for 2 h. The reaction mixture was diluted with DCM and the organic layer was washed with water followed by brine. The organic layer was separated; dried over anhydrous sodium sulphate and concentrated under reduced re to afford 79 g of the title compound as a pale brown liquid.
MS (ESI): m/z 166.1(M+H) Int-2: 4—chloro- 1—(2, 5 -difluorophenyl)butan~l ~one 2—Bromo—l,4—difluorobenzene(53.6 g, 277.74 mmol) in THF cooled to -50°C was added to isopropyl magnesium chloride (2M in THF)( 133mL, 266 mmol). The reaction mixture thus obtained was warmed to 0°C and stirred for 1h. The on mixture was cooled again to ~50°C. 4-chloro-N-methoxy-N-methylbutanamide (40 g, 241.52 mmol) in THF (200mL) was added dropwise to this reaction mixture with stirring and the stirring was continued at 0°C for 1h. The reaction mixture was quenched with saturated s NH4C1 solution, extracted with ethylacetate. The c layer collected was washed with water (500 mL) and then with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude liquid residue. The residue thus obtained was purified by column chromatography (using 60—120 silica gel and 5% EtOAc in Hexane as eluent) to afford g of the title compound as a colourless liquid. 1H NMR (300MHz, CDCl3) 5 ppm 7.6-7.53(1H, m), 7.26—7.09(2H, m), 3.7(2H, t) 3.22- 3.14(2H, m), 2.28-2.16(2H, m).
Int-3: (S, E)—N-(4-chloro(2, 5-difluorophenyl) butylidene)methylpropane mide Titanium (IV) ethoxide (54.77 g, 240.13 mmol) was added to a solution of 4— cliloro-1—(2,5-dif1uoropheny1)butan~l-one(35 g, 160.09 mmol) and (S) methylpropane—Z-sulfinamide (29.1 g, 240.13 mmol) in THF(400mL) with stirring. The mixture was stirred continuously at 70°C for 16h. on mixture was then cooled to a temperature of 20-35°C, quenched with ted aqueous NH4C1 solution, diluted with ethylacetate and filtered. The filtrate was washed with water followed by brine solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 44.5 g of the title compound as a colourless liquid.
MS (ESI): m/z 322.3 (M+H) Int-4: (R)—1~((S)~tert-butylsulfinyl)(2, 5—difluorophenyl) pyrrolidine and Int-5: (S)-l— ert-butylsulfinyl)—2~(2, 5-difluorophenyl) pyrrolidine (S,E)—N-(4-chloro-l -(2,5-difluorophenyl)butylidene)-2—methylpropane-2— sulfinamide (44 g, 136.72 mmol) in THF(500mL) was cooled to -78°C and to which was added cold (-78°C) Lithium triethylborohydride(1M in THF) (17.38 g, l65mL, and 134.67 mmol) dropwise and stirring was continued at -78°C for 3h. LiHMDS (1M in THF) (25.26 g, lSOmL, 150 mmol) was then added and stirring was continued at -78°C to 0°C for 2h. The resultant reaction mixture was quenched with saturated NH4C1 solution, diluted with ethylacetate. The ethylacetate layer separated was washed with water followed by brine solution, dried over anhydrous sodium sulphate and trated under reduce pressure to afford the crude residue. The residue thus obtained was purified by column tography twice (using initially with 60—120 silicagel and 15%EtOAC in Hexane as eluent and again with 230-400 silicagel and 12- 14% EtOAc in Hexane as ) to afford 14.5 g of the title compound (R)((S)-tert- butylsulfinyl)~2-(2, 5—difluorophenyl) pyrrolidine as a pale brown liquid. 1H NMR (300MHz, CDCl3) 8 ppm 7.1-6.85(3H, m), 5.0(11-1, t) 3.93-3.85(1H, m), 3.02- 2.94(1H, m), .2(1H, m), 72(3H, m), l.l6(9H, s) and 4 g of the title compound (S)-l—((S)-tert-butylsu1finyl)(2, 5- difluorophenyl) pyrroli dine.
W0 20132’088256 H NMR z, CDClg) 1H NMR z, CDClg) 5 ppm 7.1—6.8(3H, m), 5.42- .2(1H, d, J=7.5Hz), 2.3-2.05(1H, m), 2.0-1.65(4H, m), 1.1(9H, s).
Int-6: (R)(2, 5-difluorophenyl) pyrrolidine hydrochloride 4M HCI solution (in Dioxane) (75mL) was added to stirred solution of (R)—1— ((S)—tert—butylsulfinyl)—2~(2, 5—difluorophenyl) pyrrolidine (15 g, 52.19 mmol) in Dioxane (25mL) and stirring was continued at 20-35°C for 4h. After which the reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by washing with diethyl ether to afford 7.5 g of the title compound as a white solid.
MS (ESI): m/z 184 (M+H) Int—10: 2-(2,5—difluorophenyl)pyrrolidine Boc u, p “ F “ F ““ Int-7 Int8 F Int-10 Int-9 F Int-7: utyl yrrolidinecarboxy1ate Di-tert-butyldicarbonate (154 g, 154mL, 704 mmol) was added to solution of 2- idinone (50 g, 587 mmol) and DMAP (36 g, 293.7 mmol) in acetonitrile (SOOmL) at 0-5°C and stirring was continued at 20—35°C for 2 h. Reaction mixture was concentrated under reduced pressure to afford the residue, which was diluted with EtOAc, washed it with water. dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 73 g ofthe title compound.
Int-8: utyl —difluorophenyl)—2,3 ~dihydro—1H—pyrrole— l ~carboxylate 2.0 M Isopropyl magnesium chloride solution in THF (163mL, 324.3 mmol) was added to a solution of 2-bromo-1,4-difluorobenzene (62.5 g, 324.3 mmol) in THF (350mL) at ~40°C and stirring was continued at 5°C for 1 h. tert—Butyl 2— oxopyrrolidine—1-carboxylate(Step-l)(73 g, 392 mmol) in THF(150mL) was added dropwise to above reaction mixture at —40°C and stirring was continued at 10°C for 2 h.
Reaction mixture was ed with saturated NH4Cl solution, extracted with EtOAc, dried over anhydrous sodium sulphate and concentrated under reduced re to afford 76 g of the title compound.
Int—9: 5-(2,5—dif1uorophenyl)~3 ,4-dihydro—2H—pyrrole WO 88256 TFA (108 g, 940 mmol) was added to a solution of utyl 5-(2,5- difluorophenyl)-2,3-dihydro-1H—pyrrole-l-carboxylate (53 g, 188 mmol) in DCM (300mL) at 0°C and stirring was continued at 20-35°C for 2 h. The reaction mixture was concentrated under reduced re to afford the crude, which was diluted with EtOAc, washed with saturated NaHC03 solution, dried over anhydrous sodium sulphate to afford 28.5 g of the title compound.
MS (ESI): m/z 181.9 (M+H) Int—10: —difluorophenyl)pyrrolidine NaBH4(l2 g, 314.9 mmol) was added to a solution of -diflu01‘ophenyl)- 3,4—dihydro-2H-pyrrole(28.5 g, 157.4 mmol) in a mixture of MeOH2H20 (4:1, 250mL) and stirring was continued at 25-35°C for 2 h. The reaction mixture was quenched with 1N aqueous HCl solution and basified with 2N aqueous NaOH solution. extracted with DCM, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 23 g of the title compound.
MS (ESI): m/z 184 (M+H) Synthesis of ethyl 5-bromofluoropyrazolo[1,5-a]pyridine—3—carboxylate (Int—l4) NHBoc } NHBOCOZN Ethyl propiolate, / F N \ K2C03,THF OINHZTFA MeCN.40°C,6hr “I” 27°C, 24hr Int-11 / N’N\ NaNOZCuBr‘ / N’N\ M. / N’N\ \ \ Aq.HBr RT. 12hr \ \ \ Br \ ._.......__ TFAHZN 4—— BocHN F OEt F CE F 0 CE o 0 Int-14 Int-13 Int-12 Int—1 l : l ~amino((tert—butoxycarbonyl)amino)—3-flu0ropyridin~1~ium—2,4- dinitrophenolate NHBoc I '0 N02 A solution of tert-butyl (3-f1uoropyridin—4-yl)carbamate (25.0 g, 125 mmol) in MeCN (200 ml), was added O-(2, 4-dinitrophenyl) hydroxylamine (26.64 g, 125 mmol) in MeCN (200 ml), drop wise over 30 min at RT, reaction mass was stirred at 40 W0 2013(088256 2012/003012 0C for 12 hrs, reaction mass was concentrated at temperature below 40°C under reduced pressure to afford Int-11 (50 g) which was used in the next step without further purification.
Int-12: Ethyl 5-((tert-butoxyearbonyl)amino)—4-fluoropyrazolo[1,5-a]pyridine-3— carboxylate K2CO3 (36.96 g, 267 mmol) was added to a solution of o-4—((tert- butoxycarbonyl)amino)—3—fluoropyridin~1—iurn 2,4—dinitrophen01ate (50 g, 121 mmol ) in THF (500 mL) at 28°C and continued stirring at same temperature for 30 min. Ethyl late (14.3 g,l45 mmol) was added to above solution and stirring was continued at 28°C for 16hr. Reaction mixture was filtered to remove the salt, filtrate collected was diluted with EtOAc washed it with water ed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude obtained was purified by column purification (using 60—120 silicagel and 10%EtOAc in Hexane as ) to afford the title compound.
MS m/z 323.9 (M+l—l) Int-l3: 3~(ethoxycarbonyl)-4—fluoropyrazolo[1,5-a]pyridinaminium 2,2,2- trifluoroacetate To a solution of ethyl 5-((tert—butoxycarbonyl)amino)~4-fluoropyrazolo[l,5— a]pyridine-3—carboxylate (7 g, 21 mmol) in DCM (60 mL), TFA (12 g, 108 mmol) was added at 0—5 °C drop Wise over a period of 30 min, then stirred at room temperature for 2 hrs, reaction mass was concentrated at temperature below 40 °C under reduced pressure to afford the title compound (7 g) which was used in the next step without further ation, MS m/z 223.2 (M+) Int-14: Ethyl 5-bromofluoropyrazolo[1,5~a]pyridinecarboxylate WO 88256 NaNOz (2.26 g, 32.89 mmol) in water (7 mL) was added dropwise at 0°C to a solution of oxycarbonyl)~4—fluoropyrazolo[1,5-a]pyridin-5—aminium 2,2,2— trifluoroacetate (7 g, 97.5 mmol) in aq.47% HBr (56 mL) and continued stirring at same temperature for 30 min. CuBr (6.29 g, 44 mmol) in aq.47% HBr (56 mL) was added dropwise to above solution at 0°C and stirring was continued at 28°C for lhr.
Reaction mixture was quenched with ice water, extracted into EtOAc washed it with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude obtained was purified by column purification (using 60—120 silicagel and 5%EtOAc in Hexane as eluant) to afford ethyl -bromo~4—fluoropyrazolo[l,5-a]pyridinccarboxylatc. NMR (300 MHz, DMSO-dg) 8 9.45-9.43 (d, 1H), 8.51 (s, 1H), 8.33—8.30 (d, 1H), 4.35-4.28 (m, 2H), 1.36—1.31 (t, 3H).
Int-15 : ylpropanc—2—sulfonamidc Cl—(IS? ___NH3‘9), Meg—é o Ammonia gas was purged into t-butylsulfonyl chloride (500 mg, 3.2 mmol) in THF (5 mL) at —50°C for 15 s and stirring was continued at 20—35 0C for 16 h.
The solid precipitate ed was filtered; the filtrate collected was trated under reduced pressure to afford 350 mg of the title compound. 1H NMR (400 MHz, DMSO— (16) 5 ppm 6.71 (2H, bs), 1.38 (9H, s).
The following amides (Int—16 to Int-19) are prepared following the similar procedure as mentioned in Int—15 using the appropriate sulfonyl chloride.
Intermediate Structure IUPAC name 1,2—dimethyl- 1 H-imidazole-S- sulfonamide l-methyl- 1 H—pyrazole—S— sulfonarnide benzyl 4-sulfamoylpiperidine- 1—carboxylate 6-methoxypyn'dine sulfonamide Int-20: 4—(3—hydroxypyrrolidiny1) benzene sulfonamide “2N-EQO’ii 3 A solution of 4~fluorobenzene sulfonamide (0.39 g, 2.22 mmol) and - hydroxypyrrolidine (0.32 g, 2.67 mmol) in DMSO (2 mL) was heated to 100 °C for 20 h. Reaction was cooled to 25 °C and quenched with cold water. The separated solid was filtered and washed with water and dried to afford ydroxypyrrolidin—l~yl) benzene sulfonamide 0) as a white solid. MS (ESI): m/z 243.1 (M+H).
The sulfonamides Int-21 to Int-23 are synthesized following the procedure as mentioned in Int-20 using the appropriate aryl halides and amines.
Intermediate Structure IUPAC name ESMS (M+H) Int~21 4—morpholinobenzene— m/z 243 sulfonamide Int-22 (S)(3— m/z 244 hydroxypyrrolidim 1 — idine-3— sulfonamide 6—(1H-1,2,4-triazol-l- m/Z 226 yl)pyridine—3- sulfonarnide Int-24: Benzyl eyelopropanesulfonate PCT/132012/003012 Cyclopropyl sulfonyl chloride (2 g, 14.2 mmol) was added drop-wise at 0°C to a solution of Benzyl l (2.1 g, 28.4 mmol) and Pyridine (2.35 g, 29.8 mmol) in DCM (20 mL) and continued stirring at 25°C for 16 h. The reaction mixture was diluted with DCM (100 mL), washed with 1N aqHCl solution followed by water and brine; Organic layer ted was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the Benzyl cyclopropanesulfonate. 1H NMR z, CD30D) 8 ppm 4.3—4.1 (2H, t), 2.7—2.6 (1H, m), 1.8-1.6 (2H, m), 1.6— 1.4 (2H, m), 1.2-1.1 (4H, m), 1.0—0.9 (3H, t).
Int-25 : Benzyl 1—methylcyclopropanesulfonate n-BuLi (0.78 g, 12.25 mmol) was added drop-wise at -78°C to a solution of cyclopropane sulfonate (2.0 g, 11.2 mmol) in THF (20 mL) and continued stirring at the same temperature for 10 min. CH3I (3.98 g, 28.0 mmol) was added at — 78°C, allowed the reaction to warm to 0°C with stirring for 30 min. The reaction mixture was quenched with ice cold water, d with ethylacetate (100 mL), organic layer collected was dried over anhydrous sodium sulphate and trated under reduced pressure to afford the crude. The crude was purified by column tography (using silica gel and 4% ethyl acetate in Hexane as eluent) to afford benzyl l—methylcyclopropane-l-sulfonate (Int-25). 1H NMR (300MHz, CD3OD) 8 ppm 4.2-4.1 (2H, t), 1.7-1.6 (2H, m), 1.4 (3H, s), 1.5-1.3 (2H, m), 1.3-1.2 (2H, m), 1.0-0.9 (2H, m), 0.9 (3H, t).
Int-26: Potassium l-methylcyclopropane-l -su1fonate KSCN (2.48 g, 25.5 mmol) was added to a solution of Benzyl 1- methylcyclopropane—l-sulfonate (4.9 g, 25.5 mmol) in DME/HZO (1:1, 120 mL) and PCT/IBZOIZ/003012 ued stirring at 100°C for 16 h. Reaction mixture was concentrated under reduced pressure and the residue was washed with n-Pentane and dried to afford Potassium 1— methylcyclopropane—l-su1fonate (Int-26) which was used in the next step without further purification.
Int-27: l—Methylcyclopropane— l namide To a solution of Potassium l—methylcyclopropane~1~sulfonate (4.44 g, 25.5 mmol) in THF (50 mL) at 0°C was added POC13 (11.7 g, 76.5 mmol) with stirring maintaining the same temperature for 30 min. DIPEA (9.8 g, 76.5 mmol) was added to above e and continued stirring at 25°C for 2 h. Reaction mixture was ed with ice cold water, extracted into diethyl ether (3x100 mL), dried over anhydrous sodiumsulphatc to afford l-mcthylcyclopropanc -l-sulfonylchloridc in dicthyl other.
The above dried ethereal solution of l-methylcyclopropane-l—sulfonylchloride was cooled to -78°C and purged in with NH3 gas for 30 min. and slowly allowed the on mixture to warm to 25°C with stirring for 16 h. Reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure and the crude thus obtained was washed with n—pentane to afford l—methylcyclopropane-l- sulfonamide (Int—27) as pale brown solid. 1H NMR (300 MHZ, DMSO—d6) 5 ppm 6.7 (2H, s), 1.4 (3H, s), 1.1—1.0 (2H, m) 0.7-0.6 (2H, m).
Int-28 : 1-(4-Fluorobenzyl) ropane— l namide Int-28 The title compound Int—28 was prepared by the similar method as mentioned in Int-27 except in lnt~25, 4-F1uoro benzyl e was used in place of CH3] to afford 1.1 g Oflnt-ZS as pale brown solid. 1H NMR (300MHz, DMSO-d6) 5 ppm 7.3—7.2 (5H, m), 6.9 (2H, s), 3.3 (2H, s) 1.2-1.1 (2H, m), 0.5—0.4 (2H, m).
Int-29: l-ethylcyclopropane-l-sulfonamide Int-29 The title compound Int—29 was prepared by the similar method as mentioned in Int-27 except in Int-25, ethyl iodide was used in place of CH3I to afford 0.9 g of Int-29 as pale brown solid.
Int-30: N—Ethyl-N-methyl sulfamide N l/ / ‘3‘ 0/1 NH; Int-30 N-Ethyl-N—methyl amine (2.95 g, 50 mmol) was added to a solution of Sulfamide (4 g, 41.6 mmol) in 1,4—Dioxane (40 mL) and continued stirring at 110°C for 16 h. Reaction mass was concentrated under reduced pressure to afford the crude, which was purified by column purification (using l alumina and 10-70% ethyl acetate in Hexane as ) to afford N—Ethyl—N—methyl sulfamide 0) as pale yellow oil. 1H NMR (300 MHz, DMSO-dé) 5 ppm 6.7 (2H, s), 3.1-2.3 (2H, m), 2.6 (3H, s), 1.2-1.0 (3H, t).
Following sulfamides Int—31 and Int—35 were made using above method except changing the amine Intermediate ure IUPAC name MS (ESI) (M+H) N,N—Diethylsulfamide m/z 153.07 N,N-Dimethylsulfamide m/z 125.03 Piperidine— l —sulfonamide m/z 165.07 Pyrrolidine-l —sulfonami dc m/z 151.03 2012/003012 line—4-sulfonamide m/z 167.03 Int-39: N-Ethyl-N-cyclopropyl sulfamide H2N\$19 (A___*(300)20 Et3N NaH, DMF, Mel Comm, KA 00 ‘NH2 (A ——-—-—-——> 0 _.__> _—.__., /N\ I, THF, 25°C 25°C,16h /NB°° NHZ NHBOC H20,24h/NH.HCI 1,4-Dloxane,110°c 0,,3\NH2 Int-36 Int-37 Int—38 Int-39 Int-36: Tert—butyl (cyclopropylmethyl) carbamate NHBoc Int-36 Di—tert-butyldicarbonate (6.13 g, 6.46 mL, 28.08 mmol) was added to solution of ropyl methyl amine (2 g, 28.1 mmol), Et3N (2.84 g, 28.1 mmol) and DMAP (0.34 g, 2.8 mmol) in THF (20 mL) at 0-5°C and stirring was continued at 25 °C for 3 h. Reaction mixture was diluted with ethyl acetate and the organic layer was washed with brine, followed by water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford tert-butyl (cyclopropylmethyl) carbamate 6) as pale yellow oil. 1H NMR (300 MHz, DMSO—d6) 8 ppm 7.0-6.7 (2H, bs), 2.9-2.7 (2H, t), 1.3 (9H, s), 0.9-0.8 (1H, bs), 0.4—0.3 (2H, m), 0.1-0.05 (2H, m).
Int-37: Tert-butyl (cyclopropylmethyl) (methyl) carbamate /NBoc Int-37 A solution of tert—butyl propylmethyl)carbamate (4 g, 23.4 mmol) in DMF (35 mL) was added to a suspension ofNaH (60% suspension in mineral oil) (0.58 g, 25.7 mmol) in DMF (5 mL) at 0-5°C, to it was added Iodomethane (2.5 mL, 40 mmol) and ng was continued at 25°C for 16 h. Reaction mixture was quenched with cold water, extracted with ethyl acetate (3x50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was 2012/003012 purified by flash chromatography (Biotage, Column: silica gel 12 g pack size, solid load, Mobile Phase: EtOAc in n—Hexane: 0 to 5% as ) to afford tert-butyl (cyelopropylmethyl)(methyl)carbamate (Int-37) as pale yellow oil. 1H NMR (300 MHz, DMSO-d6) 8 ppm 3.0—29 (2H, d), 2.85 (3H, s), 1.4 (9H, s), 0.9-0.7 (1H, bs), 0.5-0.3 (2H, m), 0.2—0.05 (2H, m).
Int—3 8 : l—Cyclopropyl—N-methylmethanamine hydrochloride /NH.HC| Int-38 ConcHCl (0.6 mL) was added to a solution of tert- butyl(cyclopropylmethyl)(methyl)carbamate (2 g, 10.8 mmol) in H20 (20 mL) at 0—5°C and stirring was continued at 25 °C for 48 h. Reaction mixture was concentrated under reduced re to afford l~Cyclopropyl—N-methylmethanamine hydrochloride (Int- 38) (1424 g cr.). 1H NMR (300 MHz, DMSO—d6) 8 ppm 2.9-2.8 (2H, cl), 2.7 (3H, s), 1.1-1.0 (1H, m), 0.7-0.6 (2H, 111), 0.5-0.3 (2H, m), 0.4—0.3 (2H, m).
Int-39: N~Ethyl-N—cyclopropyl sulfamide N l/ / \S\ 01/ NH2 Int-39 The title compound Int—39 was synthesized by a similar method as that of Int-30 except Int-38 was used in place of N-Ethyl-N—methyl amine to afford N—Ethyl-N— ropyl sulfamide (Int-39) as pale yellow oil. 1H NMR (300MHz, DMSO-d6) 8 ppm 6.7 (2H, s), 2.8—2.7 (2H, d), 2.7 (3H, s), 1.0-0.9 (1H, m), 4 (2H, m), 1 (2H, m).
Int-40: (R)—2-(2-Chloro-5~fluorophenyl) pyrrolidine hydrochloride (Int-40) (R N) H.HC| Int-40 The title compound was prepared by the method similar to that mentioned for Int-6 using 2-chlorofluoro—1-brom0benzene in place of 2,5-dilfuoro-l— bromobenzene to afford the title compound (Int-40) as pale pink solid. MS (ESI): m/z 200.1 (M+H).
Int-41: (R)(5-Fluoromethoxyphenyl) pyrrolidine hydrochloride NH.HC| Int-41 The title nd was ed by the method similar to that mentioned for Int—6 using 2-Bromo-4—fluoro-anisolc in place of 2,5~dilfuorobromobcnzcnc to afford the title compound Int-41 as white solid. MS (ESI): m/z 195.9 (M+H). int-42: 2~Bromo-4—fluoro(2-methoxyethoxy) benzene BEG/F /o\/\Br Br F ———————> HO K2C03, CHacN £9on Int-42 l-bromo—2-methoxyethane (5.49 g, 39.5 mmol) was added to a mixture of 2- bromofluoro phenol (5 g, 26.18 mmol) and K2CO3 (11.5 g, 83.25 mmol) in CH3CN (41.5 mL) and continued stirring at 80°C for 16 hr. The reaction mixture was quenched with 1M aq.NaOl—l solution, extracted with diethyl ether (3x100 mL), dried over anhydrous sodium sulphate and trated under reduced pressure to afford the crude, which was purified by column chromatography (using silica gel and 2% ethyl e in hexane as eluent) to afford the desired compound (Int~42). 1H NMR (300 MHZ, CDC13) 5 ppm 7.3 (1H, m), 6.9 (1H, m), 6.7 (1H, m), 4.1 (2H, t), 3.8 (2H, t), 3.5 (3H, s).
Int-43: (R)—2—(5—Fluoro~2-(2-methoxyethoxy) phenyl) pyrrolidine hloride NH.HC| (R) F /0\/\0 Int-43 The title compound (Int-43) was prepared by the method similar to that mentioned for Int-6 using 2-bromo—4-fluoro(2-methoxyethoxy)benzene 2) in place of 2,5-dilfuorobromobenzene to afford the desired compound (Int-43) as a solid. MS (ESI): m/z 240.2 (M+H).
W0 20131088256 Int—44: (R)—2~(3, 5-Difluorophenyl) pyrrolidine hydrochloride NH.HCl (R) F Int-44 The title compound (Int—44) was ed by the method similar to that mentioned for Int-6 using 3,5-difluorobromobenzene in place of 2,5-dilfuoro-1~ bromobenzene to afford the title compound (Int-44) as white solid. MS (ESI): m/z 184 (M+H).
Int-46: (R)(3~(difluorornethoxy)—5-fluoropheny1)pyrrolidine hydrochloride NH.HCI ESQ0” OCHFZ (R) CIFZCCOZNa OCHFz K2C03,DMF, 100°C "“45 In:46 int-45 : 1-Bromo(difluoromethoxy)—5~fluorobenzene BrUOCHFZ Int-45 To a solution of 3—bromofluorophenol (0.5 g, 2.6 mmol) in DMF (4.5 mL) was added K2C03 (0.9 g, 6.54 mmol) and d at 25 °C for 10 mini Water (0.5 mL) was added to the above mixture followed by on of 2-Chloro—2,2,—difluoroacetic acid sodium salt (0.6 g, 3.93 mmol) and stirring was continued at 100 °C for 3 h. The reaction mixture was cooled to 25 °C and diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by column chromatography (using silica gel and 2% ethyl acetate in Hexane as eluent) to afford the desired compound (Int-45). 1H NMR (400MHz, 5 ppm 7.2-6.9 (2H, 111), 7 (1H, d), 6.7—6.2 (1H, m).
Int-46: (R)—2-(3—(Difluoromethoxy)—5—fluorophenyl)pyrrolidine hydrochloride W0 2013f088256 NH.HCI (R) OCHF2 I M46 The title compound (Int-46) was prepared by the method similar to that mentioned for Int-6, using 1—bromo—3—(difluoromethoxy)—5~fluorobenzene (Int—45) in place of 2,5—dilfuoro-l—bromobenzene to afford the title compound (Int-46) as a thick brown liquid. MS (ESI): m/z 232.2 (M+H).
Int—47: Synthesis of (2R, 4S)—2~(2, uorophenyl)—4—fluoropyrrolidine hydrochloride The title compound was prepared by the method similar to that mentioned in WO2009140128 to afford Int-47 as te solid. MS (ESI): m/z 202.1 (M+H).
Int-48: Synthesis of (R)(2, 5-difluorophenyl)—4, 4-difluoropyrrolidine hydrochloride Int-48 The title compound hit-48 was prepared by following the method similar to that mentioned in 140128. MS (ESI): m/z 220.4 (M+H).
Int-56: Synthesis of 2-(7-fluoro—2, 3-dihydrobenzo [b] [1, 4]dioxin-5~yl)pyr1'olidine OH 0“ HNO; AcOH 02“ 0/7) —_—+02NH2504, H202 H3303, 0H 12Dibromoethane“.02“ %Pdlc M50” H2 o45c 14Dioxane 60°C 48hr K2003, DMF, 80°c, 3hr 25”30c, 3hr F F F Int-49 Int-50 Int-51 0’} "3°“ H2N 0H2504 Nam)2Cums, Br 0 iPngCl, 40°to 27°0 THF, TFA o.27c NaBH4, MeOH:H20 HBrIn water. 2528°C tert-butyl 2—oxopyrrolidine- F 1-carboxylate F N::[——£> MHZ] Int—52 Int»53 Int-54 Int-55 Int—56 : 1~(5~Fluor0hydroxy—3-nitrophenyl) ethanone Int—49 Conc. HN03 (22.49 g, 357 mmol) was added to a solution 1-(5-fluoro-2— hydroxyphenyl) ethanone (50 g, 325 mmol) in acetic acid (300 mL) at 0°C and stirring was continued at 20°C for 3 h. The reaction mixture was ed with ice cold water.
The separated solid was filtered and washed with cold water and dried to afford l-(5— fluoro—Z—hydroxy—3~nitrophenyl) ne (Int—49) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) 5 ppm 12.6 (1H, s), 8.3-8.2 (1H, dd), 8.2-8.1 (1H, dd), 2.7 (3H, s).
Int-50: 5-Fluoro-3—nitrobenzene-1 2-diol 02N OH Int-50 H2804 (50 mL) was added to a on of H3B03 (89.3 g, 1.4 mol) in 1,4- Dioxane (300 mL) at 0 °C and d at 28 0C for l h. 1—(5-fluorohydroxy-3— nitrophenyl) ethanone (50 g, 289 mmol) was added portion wise to the above solution over 1 h, maintaining the temperature at 0°C, after addition was complete, the reaction mixture was warmed to 25 °C and stirred for l6 h. Reaction mixture was quenched with cold water, solid separated was collected by filtration. The solid was suspended in diethyl ether (500 mL) and filtered to remove insoluble nic mass, ether layer was washed with cold water (2 to 3 times) followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced re to afford the crude sticky solid. The crude solid was triturated over n-Hexane and filtered to afford 5-fluoronitrobenzene- 1,2-diol (Int-50) as pale yellow solid. MS (ESI): m/z 171.9 (M—l).
Int-51: 7—Fluoro—5—nitro—2, 3-dihydrobenzo[b] [1, 4] dioxine W0 2013XO88256 PCT/IBZO 12/003012 02N o Int-51 K2C03 (15.27 g, 110.6 mmol) was added to a solution of 5—f1uoro—3— nitrobenzene-1,2—diol (5 g, 28.9 mmol) in DMF (35 mL) followed by the addition of 1,2~Dibromoethane (13.63 g, 6.25 mL, 72.5 mmol) and stirring was continued at 80 0C for 2 h. Reaction mixture was diluted with ethyl acetate, washed with cold water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by MPLC (silica gel, Mobile Phase: ethyl acetate in n— Hexane 0 to 5% as ) to afford 7—fluoronitro—2,3—dihydrobenzo[b] [l,4]dioxine 1) as pale yellow solile NMR (300 MHZ, CDC13) 6 ppm 7.3-7.2 (1H, dd), 6.9- 6.8 (1H, dd), 4.4 (4H, s).
Int-52: 7-Fluoro-2, 3-dihydrobenzo[b] [1, 4] dioxin-S-amine HZN o Int-52 % Pd/C (400 mg) was added to a on of 7—fluoronitro~2,3- obenzo[b][l,4]dioxine (2.0 g, 10 mmol) in methanol (50 mL) and stirring was continued at 25 °C under Hz atmosphere for 3 h. The reaction mixture was filtered over celite bed and washed with ol. The filtrate and the washings were concentrated under reduced pressure to afford 7-fluoro—2,3-dihydrobenzo[b] [1 ,4]dioxinamine (Int— 52) as pale brown liquid. MS (ESI): m/z 170.1 (M+H).
Int-53: 5-Bromofluoro-2, 3-dihydrobenzo[b] [1, 4] dioxine Br “1 Int-53 NaNOz (2.69 g, 39.9 mmol) in water (20 mL) was added slowly at 0 °C to a solution of 7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin~5-amine (4.5 g, 26 mmol) in aq. 47%HBr (20 mL) and continued stirring at same temperature for 30 min. The above diazonium salt solution was added slowly to a solution of CuBr (5.7 g, 39.9 mmol) in aq.47%HBr (25 mL) at 0 °C and stirred at 25 °C for 30 min. Reaction mixture was ed with ice water, extracted with ethyl e (3x50 mL), washed it with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude was purified by column ation (using silica gel and 0—5% ethyl acetate in Hexane as eluent) to afford 5-bromo-7—fluoro—2, 3— dihydrobenzo[b] [1,4] dioxine (Int-53) (5.9 g). 1H NMR (300 MHz, CDC13) 8 ppm 6.9— 6.84 (1H, dd), 6.6—6.5 (1H, dd), 4.3-4.3 (4H, m).
Int—S4: Tert-butyl—Z-(7—fluoro—2,3-dihydrobenzo [b] [l xin—5-yl)—2- hydroxypyrrolidine~ 1 —carboxylate NBoc int-54 A solution of isopropyl ium chloride in THF (2M, 5.39 mL, 10.78 mmol) was added to a solution of 5—bromo-7—fluoro-2, 3-dihydrobenzo[b] [1,4] dioxine (Int-53) (1 g, 4.31 mmol) in THF (10 mL) at —45 °C ise and then allowed it to warm up to 5 °C over a period of 1 h. The reaction mixture was cooled again to -45 °C and a solution of tert-butyl 2—oxopyrrolidine—l—carboxylate (1.6 g, 8.62 mmol) in THF (10 mL) was added drop-wise maintaining the temperature at —45 °C. The reaction mixture was warmed to 25 °C and stirred for l h and then quenched with saturated NH4C1 on (100 mL). The on mixture was extracted with ethyl acetate (3x30 mL) and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure and purified by column chromatography (using silica gel and % ethyl acetate Hexane as eluent) to afford tert—butyl 5-(7—fluoro—2,3— dihydrobenzo[b][l,4]dioxin-5—yl)~2,3-dihydro—1H-pyrrole-l-carboxylate (Int-54). MS (ESI) m/z 340 (M-+l).
Int—55: 5-(7~Fluoro-2, 3-dihydrobcnzo[b] [1, 4] dioxinyl)-3, 4—dihydro—2H—pyrrolc W0 2013.!088256 Int-55 TFA (0.09 mL, 1.18 mmol) was added to a on of tert—butyl 5-(7-fluoro— 2,3-dihydrobenzo[b][l,4]dioxiny1)-2,3—dihydro~1H-pyrrole-l-carboxylate (0.04 g, 0.117 mmol) in DCM (5 mL) at 0°C and stirring was continued at 25°C for 3 h.
Reaction mixture was concentrated under reduced pressure to afford the crude, which was diluted with ethyl acetate, washed with ted NaHC03 solution, dried over ous sodium sulphate to afford 5—(7-fluoro-2,3~dihydrobcnzo[b][1,4]dioxinyl)- 3,4—dihydro-2H~pyrrole (Int—55). MS (ESI) m/z 222 (M+H) Int-56: 2—(7—Fluoro-2, 3-dihydrobenzo[b][1,4]dioxinyl)pyrrolidine F\§:j Int-56 NaBH4 (0.25 g, 6.69 mmol) was added to a solution of 5-(7—fluoro—2,3- dihydrobenzo [b][l,4]dioxin—5-yl)—3,4—dihydro—2H—pyrrole (1nt~55) (0.8 g, 3.34 mmol) in a mixture of MeOH and H20 (3:1, 20 mL) and was stirred at 25°C for 2 h. Reaction mixture was ed with 1N s HCl solution (50 mL) and basified with 2N aqueous NaOH solution to pH Sand extracted with DCM (3x20 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2-(7-fluoro~2, drobenzo[b] {1,4]dioxinyl)pyrrolidine (Int—56).. MS (ESI) m/z 224.5 (M+H).
Above enatiomeric mixture was separated in a prerprative chiral HPLC column (Chiral pak IC (10 mmx250mmx5u) flow: 7 mL/min; 95:5 :: Hexane:0.1% ethanolamine in EtOH (isocratie) to afford two isomer, 240 mg (Int-56A) and 233 mg (Int-56B) F 01 F 01 O O NH NH Int-56A Int-56B [somer-l lsomer-ll Int—57: (4R)—4—((tert—butyldimethylsilyl) —(2, 5—difluorophenyl) pyrrolidine hydrochloride OTBDMS F (R) H.HCI Int-57 TFA (0.27 mL, 0.414 g, 3.63 mmol) was added to a solution of (4R)-tert-butyl 4—((tert—butyldimethylsilyl) oxy)—2—(2, 5—difluoropheny1) pyrrolidine—l—carboxylate (0.5 g, 1.21 mmol) in DCM (10 mL) at 0°C and stirring was continued at 28°C for 2hr.
Reaction mixture was concentrated under reduced pressure to afford (4R)((tert- imethylsilyl) oxy)(2, 5-difluorophenyl) pyrrolidine hydrochloride 7).
MS(ESI) m/z 200(M-TBDMS + 1, free base) Int—5 8: Ethyl 5—((4R)(2, 5-difluoropheny1)—4-hydroxypyrrolidiny1) pyrazolo [1, 5— a] pyridine—3—carboxylate “0‘ Int-58 The title compound (Int-58) was ed by the method similar to that mentioned for Int—84, by using ethyl 5—bromopyrazolo [1, 5a] ne—3—carboxylate and (4R)—4—((tert-butyldimethylsilyl) oxy)—2-(2, 5-difluoropheny1) idine hydrochloride (Int-57) to afford (0.26 g, crude) as white solid after in situ deprotection ofOTBDMS group to hydroxyl moiety. MS (ESI) m/z 388.1(M+H) Int-59: Ethyl 5-((4R)-4—((tert-butyldimethylsilyl) oxy)(2, 5-difluorophenyl) pyrrolidin-l-yl) pyrazolo [1, 5—21] pyridinecarboxylate WO 2013088256 F /N\ N\ \ _ oOEt TBDMSGYR) Int-59 TBDMSCI (0.093 g, 0.62 mmol) was added at 0°C to a solution of Ethyl 5— 2—(2, 5—dif1uoropheny1)—4—hydroxypyrrolidin-1~yl) pyrazolo[1, 5—a] pyridine—3— carboxylate (Int-58) (0.2 g, 0.52 mmol) in DMF (5 mL) followed by Imidazole (0.1 g, 1.55 mmol) and continued stirring at 28°C for lhr.The reaction mixture quenched with ice water, extracted into DCM, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 5-((4R)—4-((tert-butyldimethylsilyl) oxy)(2, 5- difluorophenyl) pyrrolidin—l-yl) pyrazolo [1, S-a] pyridine-3—carboxylate (Int-59) (0.28 g, Crude) as Brown oil.
Int-60: Ethyl 5-((2R, 4R)((tert-butyldimethylsilyl) oxy)(2, 5-difluorophenyl) pyrrolidin-l-yl) pyrazolo [1, S-a] pyridine-3 —carboxylate (Isomer-I) F : N’N\ =(R) TBDM85(R) Int-60 The diastereomeric mixture (Int-59) obtained was purified by Flash tography (Biotage, Column: Silicagel 25g pack size, Mobile Phase: EtOAc in n-Hexane: 0 to 12% as eluant) to afford ethyl , ((tert-butyldimethylsilyl) oxy)—2-(2, 5-difluorophenyl) pyrrolidin—l—yl) lo [1, 5—a] pyridine-3—carboxylate (Isomer—I) (Int—60) as yellow solid. MS(ESI) m/z M+H) and Int-61: Ethyl 5-((2S, 4R)~4-((tert—butyldimethylsilyl) -(2, 5-difluorophenyl) pyrrolidin-l-yl) pyrazolo [1, 5—a] pyridinecarboxylate (Isomer—II) TBDMSdm) Int-61 as yellow solid. MS(ESI) m/z 502(M+H) Int-62: , 4R)(2, 5-difluorophenyl)—4-hydroxypyrrolidin-l-yl) pyrazolo [1, 5-3] pyridine-3—carboxylic acid “6"” Int-62 1M aq. solution of LiOHHzO (0.4 mL) was added to a d solution of ethyl -((2R, 4R)-4—((tert—butyldimethylsilyl) oxy)—2-(2, 5—difluorophenyl) pyrrolidin~l-yl) pyrazolo [1, 5-21] pyridine-3—carboxylate (Isomer-I) (Int-60) (0.07 g, 0.14 mmol) in EtOH (5 mL) and the stirring was continued at 90°C for 8h. The reaction e was concentrated under reduced pressure to afford the crude product. The crude product thus obtained was diluted with cold water, acidified with citric acid solution, filtered the solid precipitated to afford 5—((2R, 4R)—2—(2, 5—difluorophenyl)—4-— hydroxypyrrolidin-l-yl) pyrazolo [1, 5—a} pyridine—3—carboxylic acid (Int-62) as yellow solid. MS (ESI): m/z 360(M+H).
Int-63: Ethyl 5-(2-(7—fluoro—2, 3—dihydrobcnzo [b] [1, 4] dioxin-S-yl) pyrrolidin—l~yl) pyrazolo [1, 5~a] ne-3—carboxylate (Isomer—I) Eo F N \ \ Int-63 C025: The title compound (Int—63) was prepared by the method similar to that for Int- 84 using 2-(7-fluoro-2, 3-dihydrobenzo[b] [1, 4] yl)pyrrolidine (Ont—56A) and Ethyl opyrazolo [1, 5-a] pyridine-S-carboxylate to afford as pale brown solid. LCMS (ESI): m/z 412.85(M+H).
Int-64: 5—(2—(7-fluoro—2, 3-dihydrobenzo [b] [1, 4] dioxin-S-yl) pyrrolidin~1-yl) pyrazolo [1, 5-a] pyridine-3—carboxylic acid (Isomer—I) EO F N \ \\ 0 OH Int-64 The title compound (Int—64) was prepared by the method similar to that of Int— 85 employing Int-63 to afford as white solid. LCMS (ESI): m/z 384.2(M+H).
Int-65: Ethyl 5-(2-(7—fluoro-2, 3—dihydrobenzo [b] [1, 4] dioxin—S-yl) pyrrolidin-l-yl) pyrazolo [1, S—a] ne—3—carboxylate r—H) Eo F \ ‘ N \ Int 65 C023 The title compound (Int-65) was prepared by the method similar to that of Int— 84 using uoro-2, drobenzo[b] [1 , 4] dioxin-S-yl) pyrrolidine (Int—568)) and Ethyl 5—bromopyrazolo [1, S—a] pyridine-3—carboxylate to afford as pale brown solid.
LCMS (ESI): m/z 412.85(M+H).
Int—66: 5—(2-(7—fluoro—2, 3-dihydrobenzo [b] [1 , 4] dioxin-S-yl) pyrrolidin—l-yl) pyrazolo [1, S—a] pyridine—3—carboxylic acid (Isomer-II) Eo F N \ \\ Int-66 0 OH The title compound (Int-66) was prepared by the method similar to that of Int— 64 employing Int-65 to afford as white solid. LCMS (ESI): m/z M+H).
Int-67: Ethyl 5—((2R, 4S)—2-(2, 5-dif1uorophenyl)-4—fluoropyrrolidin~1-yl) pyrazolo [1, S-a] pyridinecarboxylate The title compound (Int—67) was prepared by the method similar to that for Int- 84 using (2R, 4S)—2-(2,5-difluorophenyl)—4-fluoropyrrolidine hydrochloride (Int—47) and Ethyl 5—bromopyrazolo [1, 5—a] pyridine-3—carboxylate to afford as yellow solid.
LCMS (ESI): m/z 390.8 (M+H).
Int-68: 5—((2R, 4S)—2-(2, 5-difluorophenyl)—4-fluor0pyrrolidin—1~yl) pyrazolo [1, 5-a] pyridine-3—carboxylie acid O/ ,N F 2 \ F Int-680 The title compound (Int-68) was prepared by the method similar to that of Int- 85 employing Int—67 to afford as white solid. LCMS (ESI): m/z 362.8 (M+H).
Int-69: (R)-Ethyl 5—(2-(2-chlorofluorophenyl) pyrrolidin~1-yl) pyrazolo [1, 5-a] pyridine—3-carboxylate O/ a” CI =._ N\\ O“ \ OEt Int-69 0 A mixture of ethyl 5—bromopyrazolo [1, 5a] pyridine-3—carboxy1ate (1.3 g, 4.85 mmol), (R)(2-chlorofluor0phenyl) pyrrolidine hydrochloride (Int-40) (1.13 g, 4.85 mmol) and K3PO4 (3.08 g, 14.5 mmol) in 1, 4—Dioxane (20 mL) was degassed with argon gas for 15 min. Pd2(dba)3 (0.313 g, 0.34 mmol) and BINAP (0.24 g, 0.39 mmol) were added to the above mixture and stirring was ued at 100°C for 2h.
After completion of the on, the reaction mixture was cooled and filtered over a celite bed. The celite bed was washed with ethylaeetate. The filtrate thus obtained was further washed with water, dried over ous sodium sulphate and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography (using silica gel and 20% EtOAc in Hexane as eluant) to afford (R)- Ethyl 2—chlorofluorophenyl)pyrrolidinyl)pyrazolo [1 ,5-a]pyridine ylate (Int-69) as a white solid. MS (EST): m/z 388.1 (M+H).
Int-70: (R)aEthyl 5-(2—(4,4'—difluoro—[1 ,1 '—bipheny1]—2—yl)pyrrolidin—1—yl)pyrazolo[1,5— dinecarboxylate =_ /N\,N F0G” GE Int-70 O C32C03 (0.75 g, 2.32 mmol) in 1,4—Dioxane (10 mL) was degassed with argon gas for 15 min. Pd(OAc)2 (0.052 g, 0.23 mmol) and X—Phos (0.22 g, 0.45 mmol) were added to the above mixture and degassed with argon gas for 15 min. (R)-Ethyl 2- chloro—5—fluorophenyl) pyrrolidin—l—yl) pyrazolo [1, 5—a] pyridine—S—carboxylate (Int— 69) (0.3 g, 0.77 mmol) ed by 4-F1uorophenylboronic acid (0.54 g, 3.87 mmol) and again ed with argon gas for 15 min. KI (0.025 g, 0.25 mmol) was added to the above mixture and stirring was continued at 100°C for 20h. The reaction mixture was cooled to 28°C, diluted with EtOAc, filtered through whatman filter paper filtrate collected was washed with water, dried the organic layer over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product, which was purified by Flash Chromatography (Biotage, Column: Silicagel 12g pack size, Mobile Phase: EtOAc in n—Hexane: 0 to 15% as eluant) to afford (R)—Ethyl 5—(2-(4, 4‘- difluoro-[L 1'—biphenyl]—2—yl) pyrrolidin-l-yl) pyrazolo [1, 5—a] pyridineearboxylate (Int-70) as off white sticky mass. MS (ESI): m/z 448.8(M+H).
Int—71: (R)-5—(2-(4, 4'-difluoro-[1, 1'—biphenyl]—2-yl) pyrrolidin-l—yl) pyrazolo [1, 5-a] pyridine—3-carboxylic acid =. /N\ F O@\\ OH Int-71 O The title compound (Int-71) was prepared by the method similar that of Int-85 employing Int—70 to afford as white solid. MS (1381): m/z 420.2 (M+H).
Int-72: Ethyl 5-(2-(2, 5-difluorophenyl)-4, 4-difluoropyrrolidin—1-yl) pyrazolo [1, 5-a] pyridine—3—carboxylate The title compound (Int-72) was prepared by the method similar to that for Int— 84 using (R)—2—(2, 5—difluorophenyl)-4, oropyrrolidine hydrochloride and Ethyl —bromopyrazolo [1, 5—a] pyridine~3—carboxylate to afford as yellow solid. LCMS (ESI): m/z 408.1 (M+H).
Int-73: 5—(2-(2, 5—difluorophenyl)—4, 4-difluoropyrrolidin—l—yl) pyrazolo [1, S-a] pyridine—3—carboxylic acid F The title nd (Int—73) was prepared by the method similar to that of Int- 85 employing Int—72 to afford as White solid. LCMS (ESI): m/z 379.8(M+H).
Int-74: Ethyl 5—((2R, 4R)(2, orophenyl)~4-fluoropyrrolidin—l—yl) pyrazolo [1, —a] ne-3—carboxylate F 2' N’N\ -(R) (R); O 1 5 F Int-74 The title compound (Int-74) was ed by the method similar to that for Int- 84 using (2R, 4R)(2,5—difluorophenyl)—4-fluoropyrrolidine hydrochloride (Int-48) and Ethyl 5-bromopyrazolo [1,5-a] pyridinecarboxylate to afford as yellow liquid.
LCMS (ESI): m/z 390.2 (M+H).
Int-75: 5-((2R, 4R)(2, 5—difluorophenyl)fluoropyrrolidin—1-y1) pyrazolo [1, 5-a] pyridinecarboxylie acid W0 20131088256 Pg / N‘N\ (R);CW!Int—75 ° The title compound (Int—75) was preparcd by the method similar to that of Int— 85 using Int-74 to afford as off white solid. LCMS (ESI): m/z 362.2 (M+H).
Int-76: (R)—ethyl 5-(2—(5-fluoro-2~hydroxyphenyl) pyrrolidin—1—yl) pyrazolo [1, 5-a] pyridinecarboxylate HO 3 N\\ C? \ OEt Int—76 To a stirred solution of (R)—ethyl 5-(2-(5-fluoromethoxyphenyl)pyrrolidin yl)pyrazolo[1,5—a]pyridine—3~carboxylate (synthesized similar to that of Int—84 using intermediate 41) (1.2 g, 3.13 mmol) in 25 mL of DCM, 1.0M Borontribromide (15.6 mi, 39.2 g, 15.65 mmol) was added at -70°C and stirred at -70°C to room temperature during 16h. Reaction mass was quenched with 5 mL of ice cooled water and stirred for min. The reaction e was diluted with DCM (50 mL) and the c layer was washed with water followed by brine. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford of the title compound 6) as off white solid. MS (1381): m/z 370.3 (M+H).
Int-78: (2-(2—ethoxy—5~fluorophenyl)pyrrolidin— l -yl)pyrazolo[ l ,5-a]pyridine—3- carboxylic acid F F HOQ / A! m/Q / gnaw m3Q \ \ K2003,ACN \ \\ ——> \ N /\ o/\ O C \ OH Int-76 Int-77 Int-73O Int-77: (R)—ethy15—(2—(2-ethoxyfluorophenyl)pyrrolidin— l —yl)pyrazolo[l ,5- a]pyridinecarboxylate Iodoethane (0.17 g, 1.08 mmol) was added to a mixture of (R)-ethyl 5- 2—hydroxyphenyl)pyrrolidinyl)pyrazolo[ 1 ,5—a]pyridine—3—carboxylate (Int—76) (0.2 g, 0.54 mmol) and K2C03 (0.23 g, 1.62 mmol) in CH3CN (10 mL) and continued stirring at 80°C for 16 h. The reaction mixture was diluted with ethyl e (100 mL), washed with water and dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by column chromatography (using silica gel and 2% ethyl acetate in hexane as eluent) to afford the desired compound 7). MS (ESI): m/z 398.1 (M+H).
Int—78: (R)(2—(2-ethoxy—5-fluorophenyl)pyrrolidinyl)pyrazolo[1 ,5-a]pyridine—3— carboxylic acid 1M aq. solution of LiOHHzO (0.4 mL) was added to a d solution of (R)— ethyl 5—(2—(2—ethoxy—5 —fluorophenyl)pyrrolidin~ l ~yl)pyrazolo[ 1 ,5-a]pyridine carboxylate (Int-77) (0.12 g, 0.32 mmol) in ethanol (5 mL) and the stirring was continued at 90°C for 8h. The reaction e was concentrated under reduced pressure to afford the crude, which was diluted with cold water (20 mL) and acidified with 2N HCl solution to pH=2, solid precipitated out was filtered and dried to afford the d compound (Int—78) as yellow solid. MS (ESI): m/z 370.3 (M+H).
The following intermediates 9 to Int—83) were prepared by a method substantially similar to that mentioned for Int-78 except a suitable alky halides or O- mesylates was used in place of ethyl iodide in Int-77.
Intermediate Structure IUPAC name MS (ESI) (M+H) Int-79 (2—(5—fluoro—2- (2,2,2—trifluoroethoxy) phenyl)pyrrolidin—1- yl)pyrazolo[1,5— a]pyridine—3—carboxylic acid -((2R)~2-(5—fluoro-2— ((tetrahydrofuran—3- yl)oxy)phenyl)pyrrolidin- 1-yl)pyrazolo[1 ,5- a]pyridinc—3—carboxylic methoxy)—5—fluoro pheny1)pyrroiidin— 1 — y1)pyrazolo[1,5— a]pyridine—3-carboxylic acid (R)—5-(2~(5-flu0r0(2— m/z 388.1 fluoroethoxy)phenyl)pyrr oiidin— 1 —y1)pyrazolo[1 ,5- a]pyridine~3-carboxylic acid (R)(2-(5—fluoro-2—(2- yethoxy)phenyl)p ytrolidin—l -y1)pyrazolo [1 ,5-a]pyridine—3- carboxylic acid Int-84: (R)—ethyl 5-(2-(2, 5-difluorophenyl) pyrrolidin-l-yl)pyrazolo[1,5a]pyridine~3- carboxylate / N’N\ F /\ F Int-84 A mixture of ethyl opyrazolo[1,5a]pyridine-3—carboxylate (2 g, 7.49 mmol), (R)(2, 5-difluorophenyl) pyrrolidine hydrochloride (Int-6) (1.65 g, 7.49 mmol) and CSZCO3 (7.3 g, 22.47 mmol) in 1,4-Dioxane(35mL) was degassed with argon gas for 15min. Pd2(dba)3 (480 mg, 0.52 mmol) and BINAP (380 mg, 0.59 mmol) were added to the above mixture and stirring was continued at 100°C for 2h. After WO 88256 completion of the reaction, the reaction mixture was cooled and filtered over a celite bed. The celite bed was washed with ethylacetate. The filtrate thus obtained was further washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography (using silica gel 60—120, and 30% EtOAc in Hexane as eluent) to afford 1.8 g of the title compound as a yellow solid. 1H NMR (300MHz, CDC13) 5 ppm 8.21-8.18(2H, m), 7.12-7.02(1H, m), 6.98—6.86(1H, m), .66(1H, In), 6.28—6.2(1H, m), 5.15(lH, d, J=8Hz), 6.16—6.l3(1H, m), .11(1H, d, J=8.1Hz), .27(2H, m), 3.84(1H, t) 3.60-3.5(1H, m), 2.52—2.4(1H, m), 2.2—2.0(3H, m), .3(3H, m).
MS (ESI): m/z 372 (M+H).
Int-85: (R)(2-(2, 5-difluorophenyl) pyrrolidin-l-yl) pyrazolo[1,5a]pyridine—3- carboxylic acid /N\,N LiOHHzO (0.679 mg, 16.2 mmol) in water (SmL) was added to a stirred solution of Int—84 (1.8 g, 4.85 mmol) in EtOH (30mL) and the stirring was continued at reflux temperature for 12-16 h. The on mixture was trated under reduced pressure to afford the crude product. The crude product thus obtained was diluted with cold water, acidified with 2N aqueous HCl solution, filtered the solid precipitate to afford 1.2 g of the title compound as an off white solid.
MS (ESI): m/z 344(M+H).
Int 87: 5—(2-(2, 5~difluorophenyl) idin-l-yl) pyrazolo[l,5a]pyridine—3—carboxylic acid Int-86: Ethyl 5—(2—(2,5-difluorophenyl)pyrrolidin- l —yl)pyrazolo[l ,5-a]pyridine—3— carboxylate The title compound was prepared by a procedure ntially similar as for Int— 84, using Int-10 in place of Int-6 to afford the crude. The crude nd was purified by column chromatography (using silica gel 60-120, and 5% EtOAc in Hexane as ) to afford 135 mg of the title compound. 1H NMR z, DMSO-da) 5 ppm 8.52-8.50(1H, d, J=7.6Hz), 8.12(1H, s), 7.4- 7.3(1H, m), 7.2—7.1(1H, m), 6.95-6.9(1H, m), 6.7(1H, s), 6.55(1H, bs), 5.12(lH, d, J=7.6Hz), 4.2-4.27(2H, m), 3.94—3.84(1H, t), 3.55-3.40(1H, m), 2.52-2.40(1H, m), .85(3H, m), l.3-1.15(3l-l, m), MS (E81): 372 (M+H). : 5-(2-(2, 5-difluoropheny1) pyrrolidin-l-yl)pyrazolo[l,5a]pyridine—3-carboxylic acid 5N aqueous solution ofNaOH (2mL) was added to stirred solution of Int-86 (50 mg, 0.134 mmol) in a mixture of MeOH(4mL) and THF(4mL) and continued stirring at 80°C for 4h. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product thus ed was diluted with cold water, acidified with concentrated HCl solution to obtain a solid precipitate. This solid itate was filtered and dried well to afford 18 mg of 5-(2~(2,5- difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5—a]pyridine—3~carboxylic acid as off white solid. 1H NMR (400MHz, DMSO-ds) 5 ppm ll.82(lH, s), 8.46(1H, d, J=7.6Hz), 8.08(1H, s), 7.40-7.30(1H, m), 7.20-7.10(1H, m), 6.95-6.88(1H, m), 6.67(1H, s), 6.39(1H, s), .15(lH, d, J=8Hz), 3.80-3.70 00(1H, t, J=8Hz), 3.50-3.30(1H, m), 2.44(1H, m), 2.10- 1.85(3H, m).
W0 2013f088256 MS (ESI): m/z 344,2 (M+H).
Int-89: (R)(2-(5 —(difluoromethoxy)fluorophenyl)pyrrolidinyl)pyrazolo[1 ,5- a]pyridineearboxylic acid F\( F\( Pg “—H O / ,N F ' N\ @HHCI o/\ Int-88 Int-89 Int—88: (R)(5-(difluoromethoxy)—2-fluorophenyl) idine hydrochloride This compound was prepared by the method substantially similar to the preparation of Int-6 using o(difluoromethoxy)-l-fluorobenzene (J. Med.
Chem. 2003, 46, 1016-1030).
Int-89: (R)—Ethyl 5~(2—(5-(difluoromethoxy)—2-fluorophenyl) pyrrolidin-l -yl) pyrazolo[1 ,5—a]pyridine—3 -earboxylate The title compound was prepared by the method substantially similar to that for Int~84, to afford the crude, which was purified by column chromatography (using silica gel 60-120, and 5% EtOAc in Hexane as eluent) to afford 140 mg of the title compound.
MS (ESI): m/z 420 (M+H).
Int-90: (R)(2-(5-(difluoromethoxy)—2-fluorophenyl)pyrrolidinyl)pyrazolo[l ,5- a]pyridine—3—carboxylic acid The title compound was prepared by the method substantially similar to that for Int—85, to afford 85 mg of the title nd. 1H NMR (300MHz, DMSO—d6) 5 ppm 11.9(1H, bs,), 8.47-8.45(1H, d, J=7.5Hz), 8.08(lH, s), 7.37-7.30(lH, t), 7.20-7il0(lH, m), .85(ll—l, m), .87(lH, t, OCHFZ) H, bs), 6.45-6.35(1H, m), 5.16—5.14(1H, d, J=7.5Hz), 3.90-3.80(1H, t), 3.55~3.45(2H, m), 2.08-1.85(3H, m).
MS (ESI): m/z 392.1 (M+H).
Int—91 (R)—5—(2—(3 uorophenyl)pyrrolidin— 1 -yl)pyrazolo [ l ,5—a]pyridine—3— carboxylic acid Ffi / N ,N 2 \ ‘ \ O“ OH Title compound was prepared by a method substantially similar to that of Int—84 using ethyl 5-bromopyrazolo[l ,5a]pyridinecarboxylate and (R)—2—(3, 5— Difluorophenyl) pyrrolidine hydrochloride (Int-44), followed by hydrolysis similar to that of Int-85 to afford a white solid.
MS (ESI): m/z 344.2 (M+H).
Synthesis of compounds of Formula 1 Examplc~1: (R)~5—(2-(2,5—difluorophcnyl)pyrrolidin—1-yl)—N~((4-fluorophcnyl)sulfonyl) pyrazolo[1 ,5-a]pyridinecarboxamide EDCI (111 mg, 0.5 mmol) was added to a solution of (R)(2-(2,5— difluorophenyl)pyrrolidinyl)pyrazolo[1,5-a]pyridine—3-carboxylic acid (100 mg, 0.29 mmol) in DCM (4 mL) followed by DMAP (36 mg, 0.29 mmol) and 4- fluorobenzenesulfonamide (56 mg, 0.31 mmol) and stirring was continued at 20—35°C for 20h. on mixture was quenched with water, extracted into EtOAc, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude. The crude nd was purified by Preparative HPLC nz 21.2 x 150 x Sum, Zorbax, Eclipse,C—18, Mobile phase—A: Water, BzACN, Gradient(Time/%B): 0/30, 2/40, 10/80 and Flow rate:20mL/min] to afford 9.3 mg of the title compound. 1H NMR z, CDCl3) 5 ppm 8.29 (1H, bs), 8.22—8.20(2H, m), H, d, J=7.6Hz), 8.00(1H, s), 7.26-7.20(2H, m), 7.14-7.04(2H, m), 6.96—6.88(1H, m), 6.61(1H, m), 6.18(1H, d, J=7.6Hz), 5.12-5.11(1H, d, , 3.80—3.74(1H, m), 3.6- 3.5(1H, m), 2.5-2.4(1H, m), 2.15-2.0(3H, m).
MS (E81): m/z 501.8 (M+H).
Example-2: (R)—N-(tert—butylsulfonyl)-5~(2-(2, S—difluorophenyl) pyrrolidin-l—yl) pyrazolo [1, 5-a] pyridinecarboxamide D -N F? /N\ Q”‘ \ O ,\850,c To a stirred solution of (R)—5—(2-(2, S—difluorophenyl) pyrrolidin-l—yl) pyrazolo [1, 5-a] pyridine-3~carboxylic acid (170 mg, 0.49 mmol) in dry DCM (10 mL) was added EDCI (288 mg, 1.5 mmol) followed by DMAP (0.18 g, 1.4 mmol) and stirring was ued at 25°C for 2 h. To the reaction mixture was added tert—butyl sulfonamidc (67 mg, 0.49 mmol) and the stirring was continued at 25°C for 72 h.
Reaction mixture was diluted with DCM (50 mL) and the organic layer was washed with saturated aqueous Kl-lSO4 solution followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by combiflash chromatography followed by re-erystalisaiton from EtOH to afford (R)-N—(tert~butylsulfonyl)(2-(2, 5-difluorophenyl) pyrrolidin—l-yl) pyrazolo [1, 5-21] pyfidinecarboxarnide as white solid. MS (ESI): m/z 463.2 (M+H).
Example-3: (2-(2,5-difluorophenyl)pyrrolidinyl)—N- (ethylsulfonyl)pyrazolo[l ,5—a]pyridine—3—carboxamide The title compound was prepared by the method ntially similar to that ned in Example-2 using Ethanesulfonamide to afford the crude. The crude compound was purified by Preparative HPLC [Columnz 21.2 x 150 x Sum, Zorbax, Eclipse,C-l8, Mobile phase-A: 0.1%TFA in Water, B:ACN, Gradient(Time/%B): 0/30, 2/40, 5/80 and Flow rate:20 mL/min] to afford 12 mg of the title nd. 1H NMR (300 MHz, CD3OD) 6 ppm .29 (2H, m), 7.22-7.12 (1H, m), 7.08-6.96 (2H, m), 6.8—6.72 (1H, m), 6.50 (1H, m), 5.2-5.18 (1H, d, J=6.8Hz), 3.9—3.82 (1H, m), 3.6-3.48 (3H, m), 2.5 (1H, m), 2.1820 (3H, m), 1.4-1.3 (3H, t).
MS (1381): m/z 434.8 (M+H).
Example-4: (R)—N—((3-cyanophenyl)sulfonyl)—5-(2—(2,S—difluorophenyl)pyrrolidin— 1- yl)pyrazolo [1,5-a]pyridine~3—carboxamide The title compound was prepared by the similar coupling method as mentioned in Example-2, using 3-cyanobenzenesulfonamide to afford the crude. The crude purified by Preparative HPLC [Column: 21.2 X 150 x Sum, Zorbax, XDB, C—18(#22), Mobile phase-A: 0,1%TFA in water, BzACN, Gradient (Time/%B): 0/30, 5/40, 6/80 and flow rate : 20 mL / min] to afford 46 mg of the title compound. 1H NMR (400 MHz, DMSO-ds) 5 ppm 12.05 (1H, s), 8.51 (1H, s), 8.42-8.45 (1H, d, J=7.6Hz), 8.37 (1H, s), 8.30-8.18 (2H, m), 7.89-7.85 (1H, t), 7.36-7.28 (ll-l, m), 7.18- 7.10 (1H, m), 6.90—6.75 (2H, m), 6.39 (1H, bs), 5.14—5.13 (1H, d, J=7.2Hz), 3.83-3.81 (1H, t), 3.48—3.38 (1H, m), 2.50—2.42 (1H, m), 2.10-1.85 (3H, m).
MS (ESI): m/z 507.8 (M+H).
Example-5: (R)-N-(cyclopropylsulfonyl)—5-(2—(2,5—dif1uorophenyl)pyr1'01idin— 1 - yl)pyrazolo[1,5-a]pyridine-3~carboxamide The title compound was prepared by a coupling method ntially similar to that mentioned in e-2 using cyclopropane amide in place of 4- fluorobenzenesulfonamide to afford the crude. The crude was purified by Preparative HPLC n: 19 x 150 x Sum, Zcrbax, XDB, C—18(#22), Mobile A: 0.1%TFA in water, B:ACN, Gradient (Time / %B): 0/30, 2/40, 10/80 and flow rate : 20mL / min] to afford 8 mg of the title compound. 1H NMR (400 MHz, DMSO-dg) 5 ppm 8.51-8.49 (2H, m), 7.40-7.30 (1H, m), .12 (1H, m), 6.956.85 (2H, m), 6.46—6.40 (1H, bs), 5.20-5.15 (1H, d, J=7.6Hz), 3.92-3.85 (1H, m), 3.50-3.42 (1H, m), 3.18-3.10 (1H, m), 2.50—2.41 (1H, m), 2.10-1.85 (3H, m), 1.14—1.02 (4H, m).
MS (ESI): m/z 446.8 (M+H).
Example-6: (R)-5—(2—(2,5~difluorophenyl)pyrrolidin-1—yl)—N— (methylsulfonyl)pyrazolo[1,S-a] pyridinecarboxamide WO 88256 The title compound was prepared by the similar coupling method as mentioned in Example-2, using Methane sulfonamide to afford the crude, The crude was purified by Preparative HPLC [Column: 19 X 150 x Sum, Xbridge, C—18(#22), Mobile phase—A: 0.1%TFA in water, B2ACN, Gradient (Time / %B): 0/40, 2/40, 7/60 and flow rate : 15 mL / min] to afford 16 mg of the title compound. 1H NMR (400 MHz, s) 8 ppm 8.54—8.46 (2H, m), 7.38~7.30 (1H, m), 7.20—7.12 (1H, m). 6.96-6.64 (2H, m), 6.48-6.40 (1H, bs), 5.17—5.16 (1H, d, J=8.4Hz)_, 3.89-7.81 (1H, t), 350-340 (1H, m), 3.33 (3H, s), .45 (1H, m), 2.10-1.88 (3H, m).
MS (ESI): m/z 421.2 (M+H).
Example-7 to Example—41 were synthesized following a procedure ntially r to Example-2 except appropriate sulfonamide was used in place of tert-butyl sulfonamide to afford the desired product.
Example Structure IUPAC name MS(ESI) No. M+H 7 F 0 (R)—5—(2~(2, 5—difluorophenyl) m/z 449.3 / N’N pyirolidin—l -yl)-N-(lSOpI‘Opyl F 2' \ \\ 0\ >\ sulfonyl) pyrazolo [1, S—a] pyridine—3-carboxamide WO 88256 —((R)—2—(2, 5-difluorophenyl) m/z 568.2 pyrrolidin—l-y1)-N—((4-((S)-3— hydroxypyrrolidiny1) phenyl) sulfonyl) pyrazolo [1, 5-21] pyridine—3—carboxamide (R)-N—((3—cyanophenyl) sulfonyl)-S-(Z-(Z, 5—difluoro phenyl) pyrrolidin—l-yl)~N~ methylpyrazolo [1, 5-21] ne—3-carboxamidc (R)(2-(2, 5-diflu0rophenyl) pyrrolidin-l—y1)-N-(propy1 yl) pyrazolo [1, S-a] pyridine—3—carboxamide (R)(2-(2, 5-difluor0phenyl) pyrrolidin—l -yl)—N—((3 , 5— dimethylisoxaz01—4—yl) sulfonyl) pyrazolo [1, 5—21] pyridine—3- carboxamidc 12 (R)—N-(cyclohexy1 sulfonyl)—5- m/z 489.3 (2—(2, 5-difluorophenyl) pyITolidin-l-yl) pyrazolo [1, 5-21] pyridinecarboxamide 13 (R)-N-(cyclopentyl sulfonyl)~5- m/z 475.1 (2—(2, 5-difluorophcnyl) pyrrolidin-l—yl) lo [1, 5-21] pyridine—3-carboxamide 14 (R)~5-(2-(2, 5-difluoropheny1) m/z 463.1 pyrrolidin—l -y1)-N-(isobutyl sulfonyl) pyrazolo [1, 5-21] pyridinecarboxamide (R)—5-(2-(2 , 0r0pheny1) pyrrolidin-l-y1)-N-((1, 2— dimethyl—1H-imidazolyl) sulfonyl) pyrazolo [1, 5-31] pyridinecarboxamide 16 (R)—5-(2-(2, 5-difluoropheny1) m/z 501.1 pyrrolidin-l—y1)-N-((1 , 2- dimethy1— 1 H—imidazol-S-y1) sulfonyl) pyrazolo [1, S-a] pyridinecarboxamide WR)—5—(2-(2, S—difluorophenyl) m/z 490.1—l pyrrolidin—l-y1)—N-(piperidin-4~ ylsulfonyl) pyrazolo [1, 5-a] pyridinecarboxamide 18 (R)(2-(2, 0r0phenyl) m/z 487.3 pyrrolidin— 1 -y1)—N—((1 -methy1— 1 H-imidazol~4-y1) sulfonyl) pyrazolo [1, 5-a] pyridine—3— carboxamide 19 (R)(2-(2, 5-difluoropheny1) m/z 487.4 pyrrolidiny1)-N—(( 1 -methyl- 1H-pyrazol-5—y1) sulfonyl) lo [1, S—a] pyridine-3~ carboxamide (R)(2—(2, 5-difluor0pheny1) m/z 518.0 pyrrolidin- 1 —y1)-N-((2, 4- dimethylthiazol-S-yl) sulfonyl) lo [1, 5—a] ne—3- carboxamide 21 (R)-5—(2-(2, S—difluorophenyl) m/z 552.1 pyrrolidin- 1 —y1)—N—(( 1 -methy1—2- oxoindolin—S—yl) sulfonyl) pyrazolo [1, 5-a] pyridine carboxamide Tim—54242, 5-difluorophenyl) m/z 491.2 idiny1)-N—((tetrahydro- 2H-pyrany1) sulfonyl) pyrazolo [1, 5-a] pyridine carboxamide (R)(2-(2, 5-difluor0phenyl) m/z 527.1 1 idin— 1 —y1)-N-((6- (dimethylamino) pyridin—3—y1) sulfonyl) pyrazolo [1, 5-a] pyridine-3—carboxamide -((R)—2—(2, S—difluorophenyl) m/z 491.1 pyrrolidin-l—yl)-N—((2- methyltetrahydrofuran-3 -yl) sulfonyl) pyrazolo [1, S-a] pyridine—3 ~carboxamide -((R)(2, 5~diflu0rophenyl)Tm/z 569.1 pyrrolidin—l-y1)-N—((6-((S)—3— hydroxypyrrolidin— 1 -y1) pyridin— 3-y1) sulfonyl) pyrazolo [1, S—a] pyridine—3-carboxamide (R)—5-(2—(2, 5-difluorophenyl) pyrrolidin—l-yl)-N-((6— methoxypyridin-S-yl) sulfonyl) pyrazolo [1, 5-21] pyridine carboxamide (R)-N-((6—(1H—1,2,4-triazol y1)pyridin-3~y1)sulfonyl)—5-(2— (2,5-difluorophenyl) pyrroh'din- 1—y1) pyrazolo [1, S-a] pyridine- 3—carboxamide (R)(2-(2, oropheny1) m/z 487.1 pyrrolidin-l -y1)-N—((1 -methyl- azolyl) sulfonyl) pyrazolo [1, 5-a] pyridine amide (R)(2-(2, 5-difluorophenyl) pyrrolidin—l—yI)—N-((4- morpholinophenyl) sulfonyl) pyrazolo [1, S-a] pyridine-3— carboxamide (2—(2,5—difluorophenyl) m/z 484.1 pyrrolidin—l-yl)—N—(pyridin—3~ ony1)pyrazolo[1 ,5- a]pyridinecarboxamide 31 (R)-N—((5—chlorothiophen—2—yl) m/z 523.0 sulfony1)(2-(2, 5—difluoro phenyl) pyrrolidin—l-yl) pyrazolo [1, 5-21} pyridine-3—carboxamide 32 (R)-N—((2, 5-dichlorothiophen-3— m/z 556.7 yl) sulfony1)—5-(2—(2, 5_ F N“ ‘ difluorophenyl) pyrrolidin— 1 —yl) C“ \ NH pyrazolo [1, S-a] pyridine carboxamide 33 (R)—N~(cyclobutylsulfonyl)-5~(2- m/z 461.1 (2, 5—difluor0phenyl) pyrrolidin— 1-y1) pyrazolo [1, 5~a] pyridine— 3—carboxamidc Q (R)-5—(2—(2,5— m/z 541.1 difluoropheny1)pyrrolidin—1-y1)- F \ N—((2,3—dihydrobenzo [b] [1 ,4] yl)su1fonyl)pyrazolo [1 ,5-a]pyridine-3 -carb0xamide (R)—N-(benzo[d][1,3]dioxol—5- m/z 527.1 ylsulfonyl)~5-(2-(2,5— ophenyl)pyrrolidin—1- yl)pyrazolo[1,5-a]pyridine—3- carboxamide 36 (2-(2,5-diflu0rophenyl) m/z 475.4 pyrrolidin—1~y1)-N—((1 - ethylcyclopropy1)sulfonyl) pyrazoloU ,5—a]pyridine-3— OK carboxamide 37 J’Eys-(z—(zfi- m/z 477.4 difluorophenyl)pyrrolidin-l -yl)- N-(neopentylsulfonyl) pyrazolo[1,5-a]pyridine carboxamide 38 (R)—5-(2~(2,5— m/z 461.1 difluorophenyl)pyrrolidin—1 —yl)— N-((1—methylcyclopropyl) sulfonyl) pyrazolo[l ,5—a] pyridine-3—carboxamide 39 (R)—5~(2-(2,5-diflu0rophenyl) m/z 498.05 pyrrolidin—l-yl)-N—(o— tolylsulfony1)pyrazolo[1 ,5 - a]pyridine—3-carboxamide (benzylsu1fonyl)—5-(2- (2,5—difluorophenyl)pyrrolidin- l—y1)pyrazolo[ 1 ,5-a]py1'idine carboxamide (R)—5—(2~(2,5— ophenyl)pyn‘olidin— 1 —yl)— N-((1-(4-fluorobenzyl) cyclopropyl) sulfonyl) pyrazolo[1,5—a]pyridine-3— carboxamide (R)-N—(tert—butylsulfonyl)—5-(2— (S-fluoro-Z-methoxyphenyl) pyrrolidin—l-yl) pyrazolo [1, 5—21] pyridinecarboxamide (R)-N-(tert—butylsulfonyI)(2- (3—(diflu0romethoxy)—5- fluorophenyl) idin— 1 —y1) pyrazolo [1, 5-a] pyridine-3— carboxamide 44 (R)—N-(tert—butylsulfonyl)(2- m/z 446.1 (5-flu0ropyridin—3-y1) pyrrolidin—l-yl) pyrazolo [1, S-a] pyridinecarboxamide W0 20131088256 45 (R)—N—(tert—butylsulfonyl)(2- m/z 488.9 (2—ethoxy—5—fluorophenyl) pyrrolidin—l 1'azolo [1,5- dinecarboxamide 46 (R)—N-(tert—butylsulfonyl)(2— m/z 51 4.8 (2—(cyclopropylmethoxy)~5— fluorophenyl) pyrrolidin—l— y1)pyrazolo[1,5-a]pyridine—3- carboxamide 47 (R)—N-(tert—butylsu1fonyl)(2- m/z 479.1 (2—chlorofluorophenyl) pyrrolidin-l-y1)pyrazolo[1 ,5— a]pyridinecarboxamide 48 F N—(tert—butylsulfonyl)—5— m/z 478.9 ((2R,4R)(2,5-difluorophenyl)- \ \ 4-hydroxypyrrolidin— 1 - CIN NH y1)pyrazolo[1,5-a]pyridine—3- carboxamide 49 F (R)-N-(tert~butylsulfonyl)(2— m/z 542.7 OD? / N’N\ (5-flu0r0—2-(2,2,2— Ff —' N trifluoroethoxy)phenyl) o \ pyrrolidin-l-yl)pyrazolo[1,5- )v a]pyridine—3—carboxamide 50 N—(tert-butylsulfony1)(2-(7- m/z 503.4 (Isomep O fluoro—2,3—dihydrobenzo N \ N:N\ 4]dioxinyl)pyrrolidin azolo[1,5-a]pyridine carboxamide 1 fi-(tert—butylsulfonyl)—5—(2—(7— (Isomer- fluoro-2,3—dihydr0benz0 N \ ”31‘ 4}dioxinyl)pyrrolidin—l- y1)pyrazolo[1 ,5—a]pyridine—3— carboxamide 52 N—(tert~butylsulfonyl)-5— m/z 481.2 (Isomer- ((2R,4S)—2—(2,5-difluor0phenyl)~ I) 4—fluoropyrrolidin yl)pyrazolo[1,5-a]pyridine—3- carboxamide 53 N-(tert-butylsulfonyl)~5— m/z 481.3 (Isomer- % / N’N ((2R,4S)—2~(2,5—difluorophenyl)- II) F 4—flu0ro pyrrolidin—l-yl) O NH pyrazolofi ,5-a]pyridine carboxamide 54 (R)-N-(tert-butylsu1fonyl)(2- m/z 539.1 (4,4'~difluoro—[1 , 1 '—bipheny1]—2~ yl)pyrrolidin~1-y1)pyrazolo[1,5— a]pytidinecarboxamide (S)-N—(tert-butylsulfonyl)(2~ m/z 499.25 (2, 5—difluoropheny1)—4, 4- difluoropyrrolidin- 1-y1) pyrazolo [1, 5-51] pyridinecarboxamide (R)—N—(tert-butylsulfonyl)—5—(2- m/z 499.45 (2, 5-difluor0phenyl)—4, 4- difluoropyrrolidin- 1-y1) pyrazolo [1, 5-21} pyridine-3—carboxamide (R)-N-(tert-butylsulfonyl)-5~(2— m/z 507.1 r0(2-fluoroethoxy) phenyl)pyrrolidin— 1 -yl) pyrazoloU ,5-a]pyridine carboxamide N—(tert—butylsulfonyl)—5— m/z 481.1 ((2R,4R)(2,5-diflu0rophenyl)- 4—fluoropyrrolidin—1-yl) pyrazolofl yridine-3 - carboxamide N~(tert-butylsulf0nyl)((2R)~2— m/z 531.6 (5-flu0ro—2-((tetrahydrofuran—3- y1)oxy)pheny1) pyrrolidin y1)pyrazolo [1 ,5 idine carboxamide WO 88256 N—(tert-butylsulfonyl)—5-((2R)—2- { \ Q / -N O N (5—fluoro-2—((tetrahydrofuran - )phenyl) pyrrolidin (R)—N—(tert—butylsulfonyl)—5~(2— (2, 5-difluorophenyl) pyrrolidin— 1-y1)flu0r0 pyrazolofl, S-a] ne-3—carboxamide (R)—N—(tefi-butylsulfonyl)~5-(2- (2—(difluor0methoxy)—5- fluorophenyl) pyrrolidinyl) fluoropyrazolo [1, 5-a] pyridine- 3-carboxamide (R)-N-(tert-butylsulfonyl)—5—(2— (2—(difluoromethoxy) fluorophenyl) pyr’rolidinyl) NH pyrazolo [1, 5—a] pyridine—3— ofis’ carboxamide / N’N\ 'Jfimq—(ten—buty1su1fony1)—5—(2— (2-fluoro—5-(2—methoxyethoxy) o 1410 phenyl) pytrolidin-l-yl)pyrazolo [1, S—a] pyridine-3—carboxamide Q (tert—butylsulfonyl)(2- m/z 519.1 / N’N (5—fluoro(2—methoxyethoxy) N phenyl)py11‘olidiny1)pyrazolo [1, 5-21] pyridine—3-carboxamide FU (R)—N—(tert—butylsulfonyl)(2- m/z 463.1 N’N (3, 5—difluoropheny1) pyrrolidin— 1—y1) pyrazolo [1, 5-a] pyridine— 3—carb0xamide 67 (tert—butylsulfonyl)(2- m/z 519.2 (3-fluoro(2-methoxyethoxy) pheny1)pyrrolidin-1 —y1) pyrazolo[1 ,5-a]pyridine carboxamide 68 N—(tert—butylsulfonyl)—5—((2R) m/z 531.2 (3—fluor0—5—((tetrahydrofi1ran—3 — )phenyl) pyrrolidin-l- NH y1)pyrazolo[1,5-a]pyridine~3- carboxamide 69 (R)—5-(2—(3, 5-difluorophenyl) m/z 501 pyrrolidin-l -y1)-N-((4—fluoro phenyl) sulfonyl) pyrazolo [1, 5— a] pyridine-3 —carb0xamide 2012/003012 —((R)(3, 5-difluorophenyl) m/z 568.1 pyrrolidin—l—y1)-N—((4-((S)—3- hydroxypyrrolidin- 1 —yl) phenyl) sulfonyl) pyrazolo [1, 5-a] pyridine—3—carboxamide (R)~5-(2-(3, orophenyl) m/z 449.1 pyrrolidin—l ~y1)-N—(isopropy1 sulfonyl) pyrazolo [1, 5-a] pyridine—3—carboxamide (R)~N-((6—( 1H-1 , 2, 4-triazol— 1 - m/z 551.1 y1) pyridinyl) yl)—5-(2- (3, 5—difluorophcnyl) pyrrolidin- 1-y1) pyrazolo [1, 5-21] pyridine- 3-carboxamide —((R)—2-(3, 5-difluoropheny1) pyrrolidin—l -y1)—N-((6-((S)—3- hydroxypyrrolidinyl) pyridin— 3-yl) sulfonyl) pyrazolo [1, 5—21] py1idine—3-carboxamide -((2R,4S)—2—(2,5-difluoro phenyl)—4-fluoro pyrrolidin— l — yl)—N-((1-methylcyclopropyl) sulfonyl)pyrazolo [1 ,5- a]pyridine—3-carboxamide 75 (Rl-S-(Z-(Z, orophenyl) m/z 467.2 pyrrolidin—l -y1)-4—fluoro-N- (isopropylsulfonyl) pyrazolo [1, S-a] pyridinecarboxamide Example-76: (R)—5—(2-(2, 5-difluorophenyl) pyrrolidin-l-yl)-N-(N, N— dimethylsulfamoyl) pyrazolo [1, 5-a] pyridine-3—carboxamide F’: /N\-N obi” 0 f0 To a stirred solution of (R)-5—(2-(2, S-difluorophenyl) pyrrolidin—l-yl) pyrazolo [1, 5-a] pyridine—3—carboxylic acid (0.1 g, 0.29 mmol) in DCM (20 mL), added EDCI (0.084 g, 0.43 mmol) ed by DMAP (0.18 g, 1.4 mmol) and ng was continued at 28°C for 16hr . To the above reaction added 1,1,-dirnethyl sulfamide (0.09 g, 0.69 mmol), ng was continued at 28°C for 48hr. Reaction mixture was diluted with DCM, washed it with saturated KHSO4 solution followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced re to afford the crude. The crude ed was purified by preparative HPLC (AG/AD/PP/Cl8-25/033, Flow rate: 20mL/min., Mobile phase: 0.1%TFA in water (A) : ACN (B), Gradient — Time : %B = 0 : 20, 2 : 30, 10 : 70) to afford (R)—5-(2-(2, 5-difluorophenyl) pyrrolidin— l-yl)-N-(N, N-dimethylsulfamoyl) pyrazolo [1, S-a] pyridinecarboxamide as pale pink solid. MS (ESI): m/z 450.3(M+H). lHNMR (300MHz, DMSO-d6) : 8 ppm 11.2(1H, s), 8.6—8.4(2H, m), 7.2-7.1(1H, m), 7.1-7.05(1H, m,), 7.0—6.8(2H, m), 6.5- 6.3(1H, d), 5.25—5.08(1H, d), 3.95-3.75(1H, m), 3.55-3.4(1H, m), 2.84(6H, s), 2.15— 2.85(3H, m).
Following acylsulfamides e-77 to Example-l l6 were synthesized by a similar procedure as that of e—76.
Example F (R)-5~(2-(2,S—difluorophenyl) m/z {3 /N'”\ idin-l-yl)—N—(N-ethyl- 463.8 77 1 \-- F ’. N—methylsulfamoyl) ON N\H/O o ¢S’ pyrazolo{ 1 ,5~a]pyridine-3— O \N / fi\ amide 78 F 5-((2R,4S)(2,5-difluo m/z 0’ / ,N rophenyl)—4—fluoropyrrolidin- 468.1 F : \ \ 1 ~yl)-N—(N,N—dimethy1 Q \ NH sulfamoyl)pyrazolo [1 ,5- F O=S‘—O\, a]pyridinecarboxamide 79 F 5-((2R,4S)(2,5~diflu0ro m/z FQ phenyl)fluoropyrrolidin-l— 482.1 / N’N\ yl)~N-(N-ethy1—N—methyl NH sulfamoyl)pyrazolo[1 ,5— O \, F 050 a]pyridinecarboxamide (R)~N—(N- m/z ’/ (cyclopropylmethyl)—N— 490.6 F \ C“' \ methylsulfamoyl)(2-(2,5 - O N\Ho difluorophenyl) pyrrolidin o‘fi’ yl)pyrazolo [1 ,5~a]pyridine carboxamide (R)-N-(N=N- diethylsulfamoyl)~5—(2—(2,5- difluorophenyl) pyrrolidin yl)pyrazolo[1 ,5-a]pyridine carboxamide ~((2R,4S)-2—(2,5-difluoro phenyl)f1uoropyrrolidin—1— yl)—N_(N7N" dimethylsulfamoyl) pyrazolo{l ,5-a]pyridine—3- carboxamide —((2R,4S)—2-(2,5—difluoro phenyl)—4-fluoropyrrolidin yl)-N-(N-ethy1-N- methylsulfamoyl) pyrazolo[1 ,5 -a]pyridine carboxamide (R)-5—(2-(2,5—diflu0rophenyl) pyrrolidin— 1 —y1)—N- (morpholino yl) pyrazolo{ 1 ,S-a] ne carboxamide (R)—5—(2-(2,S—difluorophenyl) pyrrolidin-l N-(pyrrolidin— 1-ylsu1fonyl) pyrazolo[1,5- a]pyridinecarboxamide (R)-5—(2—(2,5-difluorophenyl) pyrrolidin— 1 —((4- methylpiperaziny1) sulfony1)pyrazolo [1 ,5- a]pyridine-3—carboxamide (R)-N-(N,N- diethylsulfamoyl)—5-(2-(5- fluoromethoxy pheny1)pyrrolidin— 1 —yl) pyrazolo [1 ,5 -a]pyridine amide (R)-N-(N,N- diethylsulfamoy1)—5—(2—(5— fluoro-Z-(Z-fluoro ethoxy)pheny1)pyrr01idin y1)pyrazolo[1,5 -a]pyridine carboxamide (2—(2,5~diflu0rophenyl) pyrrolidiny1)-N—(piperidinylsu1fony1) pyrazolo[ 1 ,S—a] pyridine—S—carboxamide (R)-5—(2-(3,5-difluor0—2- methoxyphenyl)pyrrolidin—1- yl)—N-(N—ethy1-N-methyl sulfamoyl)pyrazolo[1,5- a]pyridinecarboxamide 91 F ] (R)-N—(N-ethyl-N— m/z Q N methylsulfamoyl)(2-(5- 476.55 \ N’ O : \ \ \ fluoro-Z-methoxyphenyl) pyrrolidin-l-y1)pyrazolo[1,5— O NH O;s\¢0 dine~3-carb0xamide 92 F (R)~N—(N—ethyl—N—methyl F l—m/z E Q N sulfamoyl)—5—(2—(5—fluoro—2— 508.6 / N’ O - \ \ \ (2-fluoroethoxy) pheny1)pyrrolidin—1- O NH ofisgo y1)pyrazolo[1,5-a]pyn'dine l— / \\ carboxamide \ L 93 F 5—((R)—2—(2,5—difluor0phenyl) 111/2 0 pyrrolidin-1—y1)-N-(((S) 492.3 F N’N\ \ \ hydroxypyrrolidin-l-yl) sulfonyl)pyrazolo[1,5-a] O NH ofisf’o pyridinecarboxamide @014 94 F (R)(2-(3,5-difluoro-2—(2-—1 m/z 7 N fluoroethoxy)phenyl)pyrrolidi 525.8 / N’ F\/\0 — \ \ \ n-l—yl)-N—(N-ethyl-N— methylsulfamoyl)pyrazolo[ 1 ,5 O N\H ofisfo —a]pyridinecarboxamide /N\\ 95 O H O (R)~5-(2-(2,5-difluorophenyl) m/z 422.3 / (gs/NW idiny1)—N—sulfamoyl F \ N‘N/ pyrazolo[1,5-a]py1idine carboxamide N—(N—ethyl-N— m/z methylsulfamoyl)—5—(2-(8— 518.2 3,4—dihydro-2H— benzo[b][1,4]dioxepin—6—yl) pyrrolidin-l—y1)pyrazolo[1,5- a]pyridine-3 -carboxamide (Diastereomer—I) N-(N—ethyl-N— m/z methylsulfamoyl)—5—(2—(8— 518.2 fluor0—3 ,4-dihydro-2H- benzo[b][1,4]di0xepin—6-yl) pyrrolidin-1—y1)pyrazolo[1,5- a]pyridinecarb0xamide (Diastereomer—II) N-(N,N-dimethylsu1famoyl)- m/z —(2—(7—flu0r0-2,3- 490.2 dihydrobenzo [b][1,4]dioxin— -y1)pyrrolidin- 1 — y1)pyrazolo[1,5—a]pyridine—3 — carboxamide (Diastereomer—I) N—(N,N-dimethylsu1famoyl)— m/z -(2-(7-flu0r0—2,3 — 489.8 dihydrobenzo [b][ 1 xin— —y1)py1T01idin—1- yl)pyrazolo[1,5-a]pyridine amide (Diastereomer— N—(N—ethyl-N— m/z methylsulfamoyl)-5—(2—(7- 504.1 fluoro—2,3-dihydrobenzo [b][1,4]dioxiny1)pyrrolidin— 1-yl)pyrazolo[l,5-a]pyridine— 3-carboxamide (Diastereomer— N-(N-ethyl-N- m/z methylsulfamoyl)(2-(7- 504.1 fluoro-2,3-dihydrobenzo [b][1 xin—5-y1)pyrrolidin— 1-y1)pyrazolo[1,5-a]pyridine— 3—carboxamide (Diastereomj N-(N—ethyl—N— m/z methylsulfamoyl)—4—fluoro-5— 481.8 ((2R,4S)—4—fluoro—2~(3- fluorophenyl)pyrrolidin y1)pyrazolo[ 1 yridine-3 — carboxamide N—(N-ethyl—N— m/z ‘1 methylsulfamoyl)-5—((R)(3- 532.4 fluoro(((S)-tetrahydrofuran- 3 ~yl)oxy) phenyl)pyrrolidin-1~ yl) pyrazolo[1,5—a]pyridine carboxamide (R)(2-(3,5—difluoro m/z ((tetrahydro—ZH-pyran_4_ 564.2 y1)0xy)phenyl)pyrrolidin—1— yl)‘N‘(N~€thyl—N-methy1 sulfamoy1)pyrazolo[ 1,5- a]pyridine-3 xamide 105 (R)-5—(2—(3,5—difluoro m/z ((tetrahydro—ZH-pyran—4-yl) 549.8 / oxy)phenyl)pyrrolidinyl)- N-(N,N-dimethylsulfamoyl) pyrazolo[ l ,5-a]pyridine—3— carboxamide 106 1 O N O» N-(N~ethyl-N-methy1 111/2 i ;N@(gs/LIX sulfamoy1)((R)(3-fluoro- 532.4 \ N‘N/ 5-(((R)-tetrahydrofuran-3— O y1)0xy)pheny1)pyrrolidin (S F yl)pyrazolo[1 yn'dine—3- o carboxamide 107 F 4—fluor0-5—((2R,4S)fluoro— m/z 0 2—(3-flu0r0phenyl)pyrrolidin— 539.7 / N ’ \ F sulfamoylpyrazolo[1,5— O n’ *0 F a]pyridinecarboxamide 108 \N _, N—(N,N-dimethy1sulfamoyl)-T 111/2 0 oiSlzo 5-(2—(8-fluoro-3,4-dihydro- 503.8 N 2H—benzo[b] [ 1 ,4] dioxepin—6- 0 / ( / \ N \ N/ rolidin 0 y1)pyrazolo[ 1,5-a]pyridine carboxamide (Diastereomer—I) [— 109 \N/ N-(N,N—dimethyl sulfamoyl)— I_m/z 1 o 0°,Slco 5-(2—(8—fluor0-3,4-dihydr0— 504.1 0 / 2H-benzo[b][1,4]dioxepin—6- ( / \ N . N/ yI) pyrrolidin-1~ 0 y1)pyrazolo[1,5-a]pyridine carboxamide (Diastereomer—Z) 1 10 _I F (R)(2-(2,5-difluorophenyl) m/z O/ N pyrrolidin— 1—yl)—N—(N- 491.8 F (R? \ \ \ isobutyl—N- NH methylsulfamoyl)pyrazolo [1,5-a]pyridine-3~carb0xamide L . 111 F (R)—N—(N—ethy1-N—methyl m/z sulfamoy1)fluoro(2-(3— 464.2 (R)? \ \ \ O \N \/ fluoropheny1)pyrrolidin- 1- C!N \‘ ' F N’S\‘Q azolo[1,5-a]pyridine carboxamide 112 F (R)-N-(N,N— m/z G dimethylsulfamoyl) -4—fluoro~ 450.1 / N ‘ N : \ \ (R \ \ ,N\ 5—(2—(3 —fluoro N 0“ F N’S“O pheny1)pyrr01idin~ 1 — y1)pyrazolo [1,5—a]pyridine carboxamide 1 13 F (R)-N-(N,N— m/z g dimethylsulfamoyl) r0- 450.1 / N ’ N : \ \ (R \ \ 0‘ 5—(2—(3 —fluoro ‘ ,N \ N s \ .
F N’ ‘0 phenyl)pyrr011d1n. y1)pyrazolo [1 yridine carboxamide 1 14 F (R)-N—(N—ethy1—N-methy1 m/z (j 0 546.2 / N sulfamoy1)-4—fluoro-5—(2—(5— O (R)? \ \ fluoro-2—((tetrahydro~2H- ClN Pyran‘4‘ 0 NH 0:3“O yl)oxy)phenyl)pyrrolidin—1— y1)pyrazolo[1,5-a]pyridine—3— carboxamide 115 A 5—((2R)—2—(3 —((2,2—diflu0r0 m/z cyclopropyl)methoxy)—5— 552.40 fluorophenyl)pyrrolidinyl)- N-(N-ethyl-N—methyl sulfam0y1)pyra2010[1,5— a]pyridinecarboxamide Examples 116 to Example 127 were synthesized following a procedure similar to Example-2, except that an appropriate acid counter part was used in place (R)—5-(2—(2,5- difluorophenyl) pyrrolidin—l-y1)pyrazolo[1,5-a]pyridinecarboxylic acid and appropriate sulfonamides were used in place t-butylsulfonamide to afford the desired t.
Example F (N,N— m/z 529.8 bis(cyclopropylmethyl)sulfamo / N 116 N’ F , \ (R) 1 \ \ y1)-5~(2-(2,5-d1fluorophenyl) CIN NH pyrrolidin— 1—y1)pyrazolo[ 1 ,5- 0 o‘sfo a]pyridinecarboxamide 117 F ‘1 N—(N-ethyl—N—methyl m/z 532.1 (Diastere * .N 0 N sulfamoyl)—5—((2R)-2—(5-fluoro— O :(R) \ \ ) \ G1 \ Cos/N 2-((tetrahydrofuran-3— N’ *0 H yl)0xy)phenyl)pyrrolidin—1- yl)pyrazolo[1,5-a]pyridine—3- l_ carboxamide 118 F N—(N—ethyl-Nvmethyl m/z 532.2 0/ \ O (:1 N.N\ sulfamoyl)~5-((2R)-2—(5—fluor0- . O¢S,NJ 2—((tetrahydrofuran—3—yl)0xy) (Dlastere CI N' *0 H phenyl)pyrrolidin-1—yl) pyrazolo[l,5-a]pyridine-3— carboxamide 119 N-(tert—butylsulfonyl)-5—(2—(2,5- difluorophenyl)pyrrolidin-1— yl)pyrazolo[1,5-a]pyridine-3 — carboxamide (Racemic mixture) (R)-N-(tert—butylsulfonyl)—5-(2- m/z 493.3 (3,5-difluoro-2—methoxy phenyl)pyrrolidiny1) pyrazolo[1,5-a]pyridine carboxamide 121 N—(tert—butylsulfonyl)—4-fluoro- m/z 481.05 —((2R,4S)fluoro-2—(3~ fluorophenyl)pyrrolidin y1)pyrazolo[1,5-a]pyridine~3— carboxamide 122 4-fluoro-5—((2R,4S)-4—fluoro (3 -fluor0pheny1)pyrrolidin— 1 - y1)—N—(isopropylsulfonyl) lo[1,5-a]pyridine carboxamide (R)-N-(tert-butylsu1fonyl)—5-(2- m/z 563.50 (3 ,5—difluoro—2-((tetrahydro—2H— pyran—4-yl)oxy)pheny1) pyrrolidin— 1—y1)pyrazolo[ 1 ,5- a]pyridine—3-carb0xamide 124 (R)-N-(tert-butylsulfonyl)-5—(2— m/z 545.50 (5~fluoro—2—((tetrahydro~2H— 4-y1)oxy)phenyl) pyrrolidin-l—y1)pyrazolo[1,5- a]pyridine-3—carboxamide 125 F (R)(2—(3,5-difluoro-2— m/z 549.2 CupF / N’N\ ((tetrahydro-2H—pyran—4— O1 \ \ )phenyl)pyrrolidin—1-yl)- O ’Nél'io N-(isopropylsulfonyl) 0% pyrazolo[1,5—a]pyridine-3~ carboxamide 126 F (R)-4—fluoro—5—(2—(3- m/z 449.2 fluorophenyl)pyrrolidin-1~yl)- — N’N\ . \ \ 003% N—(isopropylsulfonyl) F N’ *0 pyrazolo[l,5~a]pyridine—3- carboxamide. 127 F (R)-N—(tert—butylsulfonyl)—4— m/z 532.2 ogo/O/ / N’N\ fluoro-S—(2-(5-fluoro-2— C \ \ N ((tetrahydro-2H—pyran—4- F NH O yl)oxy)phenyl)py1rolidin :54) yl)pyrazolo[ l yridine-3 - carboxamide General rocedure for salt 3 thesis: Above es 1-127 can be converted to a pharmaceutically acceptable salt by ng with a suitable salt, by reacting a solution of the compound (1-127) with suitable salt. For example a solution of the compound of (1-127)(1 eq) in water sodium hydroxide or potassium hydroxide or calcium hydroxide (1M, 1 eq.) can be added drop wise and to be stirred for l h at 25°C-100°C. Reaction mixture shall be cooled and filtered and the filtrate to be concentrated to get required salt as white powder compound.
Illustrative examples of the salts prepared are as given below: HNMR (400 MHz, DMSO-D6) a 8.4-8.3 (d, 1H), 7.95 (s, 1H), 7.3— 7.2 (m, 1H), 7.2-7.09 (m, 3H), 6.6 (dd, 1H), 55549 (d, IH), 5.3—5.2 (m, 1H), 4.15—4.0 (m, 1H), 3.8-3.65 (m, 1H), 2.95-2.8 (m, 1H), 2.3—2.1 Sodium (tert~butylsu1fonyl)(5-((2R,4S)—2- (m, 1H), 1.25 (s, 9H); (2,5—difluor0phenyl)—4-flu0ropyrrolidin~ 1 - azolo[1,5-a]pyridine-3 — LCMS (ESI) m/z 481.1 carbonyl)amide VHFMR (400 MHz, DMSO-D6) a 8.35—8.333 7.93 N/N\ (d, 1H), (s, 1H), \ \ O\\ ,,O 7.32—7.27 (m, 1H), 7.15—7.10 (m, 1H), 7.04 (s, 1H), 6.84—6.79 (m, O ‘NaKNI 1H), 6.28-6.26 (dd, 1H), 5.07—5.05 Sodium(R)-(tert-butylsulfonleS-(2-(2,5- (dd, 1H), .76 (m, 1H), 3.40— difluoropheny1)pyn'olidin- 1— 3.38 (m, 1H), 2.46-2.42 (m, 1H), yl)pyrazolo[1,5-a]pyridine-3 — 2.04—2.02 (m, 1H), 1.93-1.85 (m, carbony1)amide 2H), 1.25 (s, 9 H); LC—MS (API) 463.1 H NMR (400 MHz, DMSO-d6) 5 ppm 8.31—8.29 (1H, d), 7.91 (1H, s), 7.10 (1H, s), 6.66-6.62 (1H, dd), 6.25—6.22 (1H, dd), 6.13—6.12 (1H, m), .99 (1H, d), .28 (4H, m), 3.72-3.68 (1H, t), 2.36- 2.31 (1H, m), 2.02—1.99 (1H, m), 1.93—1.87 (2H, m), 1.28 (9H, s); Sodium (R)-(tert—butylsulfony1)(5~(2-(7- MS (ESI): m/z 502.8 fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5— y1)pyrrolidin—1-yl)pyrazolo[1,5—a]pyridine- 3-carbony1)amide ‘H NMR (400 MHz, DMSO-dflfl o 'Na+ N\ 30 ppm 8.42-8.40 (1H, d), 8.00-7.90 N ,S F // 0’ >< (1H, s), 730729 (1H, dt), 7.17— \ N\N 7.09 (1H, m) 7.04 (1H, s), 6.82- F 6.80 (1H, m), 6.40-6.30 (1H, d), .59—5.46 (1H, m), 5.19-5.16 ' (1H, Sodlum butysulfonyl)(1 5-((2R,4R)-2— (1), 4.03—4.96 (1H, m), 3.85-3.73 (2,5—d1flu0rophenyl)fluoropyrrohdln—1- (1H, m), 2.88—2.66 ( 1H, m), 2.3?” yl)pyrazo OU’ my“ mel 5— 'd' -3— 2.24(1H, m), 1.22 (9H, s); carbony1)amide MS (ESI): m/Z 481.5 132 F _1H NMR (400 MHz, DMSO—dg) 5 O/ N’N\ ppm 8.35-8.33 (1H, d), 7.91 (1H, F =. \ \ s), 7.33-7.27(1H, m), 7.15—7.10 C/N N‘Na‘“ (1H, m), 7.06 (1H, s), 6.85-6.81 O ofifi’o‘ , (1H, m), .29 (1H, d), 5.06— / 5.04 (1H, d), 3.83-3.79 (1H, t), . 3.44-3.38 (1H, q), 2.06—2.02 (1H, Sodlum (R)—(5-(2-(2,5-d1fluorophenyl)_ . . . ' m), 1.93—1.85 (2H, m); pyrrohd1n—1-yl)pyrazolo[1,5—a]pyr1d1ne-3~ carbonyl)(N,N—dimethy1sulfamoyl)amide MS (ESI): m/z 449.8 1 1H 133 F F NMR (400 MHz, DMSO-dG) 5 o ‘Na” N\ 00 ppm 8.44-8.42 (1H, d), 7.95 (1H, N ,/S / / O K F s), 7.36-7.30 (1H, m), 7.19-7.15 \ N\N/ (1H, m), 7.05-7.04 (1H, d), 7.00- F 6.95 (1H, m), 6.37—6.35 (1H, dd), .35—5.32 (1H, d), 4.25—4.23 (1H, Sodium (ten—butylsulfonleS~(2—(2,5— m), .93 (1H, m), 1.21 (9H, 5); difluorophenyl)-4,4—difluoropyrrolidin- 1 — MS (ESI): m/z 499.1 yl)pyrazolo[1,5-a]pyridine carbony1)amide 0 ‘Na” ‘H NMR (400 MHz, DMSO—dé) 5 N 6’s,i; ppm 8.32-8.30 (1H, d), 7.93 (1H, F / \ N‘N s), 7.32-7.26 (1H, m), 7.15-7.10 (2H, m), 6.90-6.80 (1H, m), 6.22- 6.21 (1H, d), 5.11—5.09 (1H, d), Sodium 3‘79'3'78 (1H’ m), (R)—(5~(2-(2,5—diflu0ropheny1) 2‘04'1'88 (3H’ idin— 1-y1)pyrazolo[ 1 ,5~a]pyfidine~3 — m), 1.14 (2H, m), 0.50 (2H, m); MS carbony1)((1 -methylcyclopropyl) (ESI): m/z 461.8 sulfonyl)amide F 1H NMR (400 MHz, DMSO-ds) 5 D ppm .40 (1H, d), 7.95 (1H, / N F - \ \ \ s), 7.33—7.27 (1H,m),7.15-7.10 QN N-Na+ (1H, m), 7.05 (1H, s), 6.84-6.81 O 058“) F (1H, m), 6.36-6.35(1H, d), 5.59— .46 (1H, m), 5.18-5.16 (1H, d), 4.06-3.96 (1H, m), 3.85—3.73 (1H, Sodium (tert-butylsulfonleS-((2R) dd), .76 (1H, m), 2.32-2.25 (2,5-difluorophenyl)fluoropyrrolidin— 1 - (1H, m), 1.22 (9H, 5); MS (ESI): yl)pyrazolo[1,5—a]pyridine-3 - m/z 480.8 carbonyl)amide 1:? WNMR (400 MHz, DMSO—d6) 5 O 11W 7.93 ppm 8.35—8.34 (1H, d), (1H, / / 0:83"; F \ N‘N/ / s), .25 (1H, m), 7.16—7.13 (2H, m), 7.10—7.04 (1H, m), 6.34- F 6.32 (1H, dd), 5.56~5.43 (1H, m), .23-5.18 (1H, t), 4.16~4.03 (1H, Sodium (5-((2R,4S)—2-(2,5-difluoro m), 3.81—3.72 (1H, m), 2.92-2.81 phenyl)flu0ropy1“rolidin- 1— (1H, m), 2.52—2.44 (6H, s), 2.17— yl)pyrazolo[1,5—a]pyn'dine—3- 2.11 (1H,m); carbony1)(N,N-dimethylsulfamoy1)amide MS (ESI): m/z 468.8 137 F’: o _1 TENMR (400 MHz, é) 5 _| F 'Na:O ppm 8.77-8.75 (1H, d), 7.92 (1H, / 0087; s), 7.34-7.28 (2H, m), 7.17-7.12 \ N \ N (2H, m), 7.03-6.98 (1H, m), 5.51- F 5.38 (1H,m), 5.11—5.07 (1H,m), 4.31-4.18 (1H, m), 3.70-3.62 (1H, Sodlum’ (tert bu ylsul ony1)(t f 4-flu010 5‘ - - - m), 2.85-2.76 (1H, m), 2.48-1.99 ((2R,4S) 4 fluoro- - -2—(3 -fluoropheny)1 ( 1H, m), 1.25 (9H, s); pyrrolidin—1—y1)pyrazolo[1,5—a]pyridine—3- yl)amide M3 (E31): 111/2 481-8 138 F jH NMR (400 MHz, DMSO-dé) a O N’N\ ppm 8.68—8.66 (1H, d), 7.92 (1H, \ \ s), 7.35-7.29 (2H, m), 7.07—6.98 C/N F N'Na“ (3H, m), 5.09-5.08 (1H, m), 3.88— 0:3/0\ , 3.86 (1H, m), 3.55—3.52 (1H, m), / 2.56 (6H, s), 2.00—1.89 (2H, m), 1.86-1.84 (1H, m); MS (ESI): m/z Sodium (R)-(N,N—dimethylsulfamoyl)(4- 449 8. fluoro—S-(Z-(3-flu0rophenyl)pyrrolidin azolo[1,5—a]pyridine—3~ carbony1)amide 139 F 1H NMR (400 MHz, DMSO—d6) 5 ppm .29 (1H, d), 7.90 (1H, \ s), 7.08-7.03 (3H, m), 6.70-6.67 C” \ N'Na“ (1H, m), 6.10 (1H, bs), 5.16 (1H, m), 4.99—4.97 (1H, m), 3.94-3.88 /N\\ (2H, m), 3.85—3.73 (3H, m), 3.39— Sodium (N—ethyl-N-methylsulfam0y1)(5- 3.37 (2H, m), 2.98-2.92(2H, m), ((2R)-2—(5-flu0ro-2—((tetrahydrofuran 2.54 (3H, s), 2.40—2.32 (2H, m), yl)oxy)phenyl)pyrrolidin— 1—y1) 2.28-2.23 (1H, m), 2.14—2.00 (1H, pyrazolo[1 ,5 -a]pyridine-3—carbony1)amide m), 1.86-1.84(2H, m), 1.05-1.01 (3H, t); MS (ESI): m/z 531.8 H NMR (400 MHz, DMSO-dg) 6 ppm 8.30-8.29 (1H, d), 7.90 (1H, F 2 \ \ s), 7.90-7.80 (1H, d), .03 O‘ \ (7H, 111), 690-81 (1H, m), 6.18 (1H, o 1922; Gas; bs), 5.10—5.05 (1H, 111), 374-370 (2H, m), 2.01-1.89 (4H, m); MS (ESI): m/z 497.1 Sodium (R)-(5-(2~(2,5-difluorophenyl) din—1—y1)pyrazolo[1,5-a]pyridine—3- carbonyl)(o—tolylsulfonyl)amide 1H NMR (400 MHz, DMSO~d6) 5 ppm 8.76-8.74 (1H, d), 7.91 (1H, s), 7.51—7.49 (1H, d), 7.32 (2H, bs), 7.24—7.22 (1H, d), 7.03—7.00 (1H, m), 5.52—5.39 (1H, m), 5.02-4.98 (1H, m), 4.38-4.24 (1H, m), 3.71- Sodium (4—fluoro-5—((2R,4S)-4—flu0ro~2~ 3.63 (1H, m), 3.50—3.42 (1H, m), (3 —fluoropheny1)pyn‘olidiny1) 2.80-2.73 (1H, m), .06 (1H, pyrazolo[1,5-a]pyn'dine—3-carbonyl) m), 1.15—1.11 (6H, d); (isopropylsulfonyl)amide MS (ESI): m/z 467.35 F ”‘HNMR (400 MHz, DMSO—dé) 5 ’—. o 'Na+ N\ //O ppm 8.33-8.31 (1H, d), 7.93 (1H, / / O F 03$ 3), 7.30725 (1H, m), 7.16-7.11 \ N\N/ (3H, m), 6.28—6.27 (1H, d), 5.58- F 5.44 (1H, m), 5.25—5.21 (111,1), 4.15—4.04 (1H, m), 3.79—3.71 (1H, Sodium (5—((2R,4S)(2,5—difluorophenyl) m), 2.88—2.80 (1H, 111), 292—212 fluoropyrrolidiny1)pyrazolo[1,5— (1H, m), 1.38 (3H, s) 1.16 (2H, m), a]pyridine-3 nyl)((1- 0.51 (2H, m); methylcyclopropyl)sulfonyl)amide MS (ESI): m/z 479.40 [— 143 F ‘L‘H NMR (400 MHz, ot} D N ppm 8.30-8.28 (1H, d), 7.93 (1H, / N’ F , ( \ \ s), 7.33—7.27 (1H, m), 7.21 (1H, C)N N-Na+ bs), 7.16-7.10 (1H, m), 6.89-6.85 O Oaseo (1H, m), 6.15-6.14(1H, d), 5.13- O 5.11 (1H, d), 3.82-3.79 (1H, t), 3.44—3.38 (1H, q), 3.02 (4H, t), 2.04-1.89 (3H, m), 1.53—1.51 (4H, Sodium (R)-(5~(2—(2, 5-difluorophenyl) m), 1.43—1.42 (2H, m); MS (ESI): idin- 1-yl)pyrazolo[1,5—a]pyridine-3 - m/z 489.8 carbonyl)(piperidin— 1 fonyl)amide Example-144 Determination of in vitro TrkA inhibitory activity using TR-FRET assay Compounds were screened in the TR—FRET assay with TrkA kinase. 5 ng of TrkA [Upstate, USA] kinase was used for assay. The compound was incubated with the kinase for 30 minutes at 20-3 5°C. After the incubation, substrate mix [40 11M Ultra light poly GT (Perkin Elmer, USA) and 500 uM ATP] was added. The above reaction was stopped by the addition of 40mM EDTA after 30 minutes. The Eu-labelled ospho-tyrosine antibody [Perkin Elmer, USA] was added at 0.5 nM and the fluorescence emission at 615nm/665nm [excitation at 340nm] was measured. The nds were initially screened at IOOnM, luM and lOuM concentrations. The potent compounds with >25% inhibition at luM of TrkA were taken for the full dose se studies. The final DMSO concentration in the assay was 1%. For IC50 determination, l/3rd serial dilution was made from the 20mM DMSO stock solution. 2 ul of these were erred to the test wells containing 20 pl reaction mixture [Total reaction volume 22 ul]. The fluorescence was measured in Perkin Elmer Wallac 1420 Multilabel Counter Victor 3. The ICso was determined by fitting the dose response data to a sigmoidal curve fitting equation using ad Prism software version 5.
Using this protocol, various compounds as described herein and further as exemplified above, were found to exhibit inhibitory effect on TrkA (Table 2).
Examples 2, 7, 8, 9, 10, 25, 31, 39, 40, 41, 52,57, 59, 65, 70, 73, 74, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 87, 88, 89,90, 91, 94, 128, 132, 136, 137, 138, 139, 140, 141, 142 and 143, as described , exhibited a TrkA inhibition in-vitro IC50 values less than or equal to about 50 nM; Examples 4, 26, 34, 35, 38, 44, 45, 46, 47, 60, 63 and 134, as described herein, exhibited a TrkA inhibitory ty in—vitro ICso values between about 50 nm and about 100 nM; Examples 1, 3, 5, 6, 11, 12, 13, 14, 19, 20, 22, 23, 24, 27, 28, 29, 32, 33, 36, 37, 43, 49, 50, 54, 56, 61, 62, 66, 71, 72, 75, 86, 93, 130 and 133, as described , exhibited a TrkA tory activity in—Vitro ICSO values between about 100 nm to about 500 nm; Examples 15, 21, 30, 48, 58, 67, 68, 69 and 131, as described herein, exhibited a TrkA inhibitory activity in—vitro IC50 values between about 500 nm to about 1 MM; Examples 16, 17, 18, 51, 53, 55 and 135, as described herein, exhibited a TrkA inhibitory activity in—vitro ICso values between about 1 ,uM to about 10 uM.
Example—145 ity Protocol: Metabolic stability using Rat Liver omes (RLM) and Human Liver Microsomes (HLM).
This assay was performed using pooled male rat liver microsomes (In-house prepared as per SOP), Pooled Human liver microsomes (XENOTECH; Batch No— H0630- 1110189)). The 100 pl reaction contains the compounds at 1 uM, 0.3mg/ml microsomal protein and both the tors (lmM NADPH) in buffer and the mixture was ted at different time points (0, 15, 30, 45, 60, & 90 minutes). The reaction was d by the addition of equal volume of acetonitrile containing internal standard (Telmesartin). The precipitated protein was removed by centrifugation and the supernatant were analyzed LC/MS-MS method. The percent parent compound remaining was quantified by analysis using following formula (% parent compound remaining = (peak area at Time x /peak area at T0) X 100. The intrinsic clearance was calculated using the following formula.
CLimpp : (0.693/in vitro 11/ 2) (incubation volume/mg of microsomal protein) (45 mg microsomal protein]gram of liver) (20“ g of liver/kg body weight) a: 20 and 45 g of liver/kg of body weight were used for human and rat, tively (Lu C et al., DMD, 2006).
Bio-analysis: It was performed in Multiple Reaction Monitoring mode ive mode) using Applied Biosystems API 4000 coupled to Agilent Technologies 1100 series HPLC on a reverse phase column (Zorbax Eclipse XDB C18, 50 X 4.6 mm, 5 um). Celecoxib used as internal standard both in in—Vitro and o experiments. Mobile phase used 0.05% monofluoro acidic water and acetonitrile (10:90) with a flow rate of 0.6mI/minute.
The injection volume was kept as 10 ul.
Examples 1, 2, 3, 4, 10, 24, 25, 26, 35, 38, 39, 40, 42, 43, 45, 46, 50, 52, 57, 59, 65, 74, 75, 76, 77, 78, 79, 91, 97, 102, 106, 107, 121, 122 and 124 as described herein, exhibited metabolic ity half life (in minutes) of >80, by using Human Liver Microsomes, Example—146: Apparent s Solubility Assay: The 10mM DMSO solution of test nds or reference standards were added to Dulbeco’s phosphate buffer saline pH 7.4 (DPBS) and DMSO in a 96 deep-well plate generate theoretical concentration of 200 uM. The solutions were brated by shaking (200 rpm, lka plate shaker) for 16 hours at 25 OC. Undissolved compound was removed by centrifugation, and the supernatant was analyzed by HPLC—UV. The assays were med in duplicates. Aqueous solubility was calculated using the equation: Aqueous solubility = 200 uMXPApBS/PADMSQ Whereas PAsz and PADMSQ are the peak areas from the analyses of test compound in PBS with 2% DMSO and of test compound in 100% DMSO, respectively.
Although the present application has been illustrated by certain of the preceding es, it is not to be construed as being limited thereby; but rather, the present application encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof. For example, the following compounds, their pharmaceutically acceptable salts, phannaceutically acceptable solvates or stereoisomers f are also included in the scope of the present application.
F - \ F : \ O \ ‘ C“ \ \ G“ \ \‘ 0 0 / \/\N,3¢Oo “N 4H?“ "3H ,‘Sgo otsfio \\ N \\ / O / l\\l O ¢ F [0: : .F F D/ ,N N 0 \ § / N/N / a N’N\ N ::N \ \\ \ \ O oeifi‘N/ NH o N“ 0 OlslN/ O) O§S\§O /N\/ '0') 2012/003012 k “F” / GOQ, \ ,9 Z//‘z o E»?cm< o UK / o Z z\ 6’ i: I \ oflow-n \ \ / /N\/ F 0,SN\/, 2:0 Q o 0 ’N F o F o =. \ :f 9‘N \ \ / N’N " NH N’N F 00:34) CN \ N \ \‘ o NH 0 NH 0:850 0/330 W0 088256 oséso OO/éfioNH o NH /\\ ’\ 0; $0 /N\/ ‘3 (‘NO F F W G / D/ ,N N N F ’=-<R> \ F . 5(a) E / N’N O \ \ < :N \ \ ON C{\S,NH KL? 0 HN’\‘O / I§‘fi o NH J O ossfio F F F i 3 / ,N D N\\ / ,N D/ ,N F 2:01) F :30" N\\ F 2““) \ \ \ N\\ o NU N N N “s’ 0 o N o HN HM O H N,“ \O / o / {UP {UP (OI) F o = / o - o A: _ 3(R) / HR) N’N 50?) / ’N N \ \ \ N \ \\ N \ \ oMo %,o 0\,O F3) z \ Fs) / 0 N, O N,S‘ N,s H N H ,N’\ O H >§ =2 R( )N \ F ‘ \ \ O \ :=(R) ‘ 0 “l” o G G NH 048" O O Oz‘szo / \ N’‘sfio N\/ \\ / HO 0 WO 88256 {UP0 _ / E NzN QN \ \\ Q\ o F ’/ F ’8 [0 F / / N Hg N’N\ \ QN \ \\ E<R>N \ Og‘N‘ N qééo is; F F O F ’ Q 0 O E x, F(S) (S) n F F F H \ % D m N O‘S'N F ’2(R) \ \ 0‘ F N “o o 35:0 F(S) H F N F(S) 0 H F F (RIGQiO‘SNJ/ N'N 0/ / N’N F “g \ \ F =_ \ \ 9 \IN“ , o O ”.0 9:(R)N \ \ F F F(S) F(S> O F F

Claims (28)

  1. What is claimed is 1.
  2. A compound of formula (I), / /N RID 4Q H O N—§-Ra R O1 (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, wherein (R2)m (R2)m X1A‘/\ O ( ‘/x o GOD N; N A is (Rah/J or (Rm/VI ;X1 is CH or N; R1 represents hydrogen or ~(C1-C6)alkyl; R2 is independently selected from hydrogen, halogen, cyano, —(C1—C6)alkyl, — halo(C1-C6)alkyl—, C1-C6)alkoxy-, phenyl optionally substituted with l to 3 halogens or an optionally substituted erocyclyl wherein the optional substituent is selected from alkyl, -ORi or —C(O)N(Ri)2; when X1 is CH, optionally two R23 present on any two adjacent carbon atoms combine to form a 5 to 7 membered heterocyclic ring; R3 is independently selected from n, cyano, -ORi , -C(O)N(Ri)2 or two R3s together with the carbon atom they are ed form a (C3—C7)cycloalkyl group spiro attached to pyrrolidine; or two R3 when they are attached to nt carbon atoms form a (C3-C7)cycloalkyl ring fused to the pyrrolidine; Ra is selected from (i) a group selected from optionally substituted -(C1-C6)alkyl, —hydroxy(C1—C6)alkyl— or —(C1-C6)alkyl-(C1-C6)alkoxy wherein the optional substituent is ed from cyano, halogen or -(C6-C12)aryl, (ii) an optionally substituted -(C3-C10)cycloalkyl wherein the al substituent is selected from cyano, -(C1-C6)a1ky1, hydroxyl, halogen or -RS, (iii) an optionally substituted -(C6-C12)ary1 wherein the optional substituent is selected from cyano, hydroxyl, halogen, -(C1-C5)alkyl or -Rr (M an optionally tuted 5 to 10 membered heteroeyclyl n the optional substituent is selected from cyano, hydroxyl, halogen or — (CI‘C6)a1ky1: (V) an optionally substituted 5 to 10 ed heteroaryl wherein the optional tuent is selected from cyano, 0x0 (=0), hydroxyl, halogen, —(C1-C6)alkyl, —(C1—C6)alkoxy, —NR°Rd or ‘Rr, (Vi) —NR4R5, (Vii) '(CI’C6)alky1‘(C6‘C12)ary1; Rb ents hydrogen or halogen; R4 is selected from hydrogen, -(C1-C6)a1ky1, -(C3—Cio)cycloalkyl, —hydroxy(C1- C6)alky1-, —a1koxy(C1-C6)alky1-, ~halogen(C1—C6)alky1 or -(C1-C6)alky1- (C3-C10)cycloalkyl; R5 is selected from hydrogen or —(C1—C6)alkyl or ~(C1-C6)alky1-(C3-C10)cycloalkyl; Alternatively R4 and R5 together with the nitrogen atom to which they are attached may form an optionally substituted 5 to 10 membered heterocyclic ring optionally containing 1-2 additional heteroatoms or groups selected from - 0-, —S—, -N-, —, — or —S(=O)2—, wherein the optional substituent is selected from hydroxyl, -(C1—C6)alkyl, -C(=O)—(C1-C6)alkyl, mesyl or COORe; Rc and Rd are independently selected from hydrogen or —(C1-C6)alkyl; Re is selected from hydrogen or alkyl; Ri is hydrogen, ~(C1-C6)alkyl, -halo(C1-C6)alkyl, -(C1—C6)alky1-(C1—C6)alkoxy, ~(C3— cloalky1, optionally substituted —(C1-C6)alkyl-(C3-C10)cycloalkyl wherein the optional substituent is halogen or 6)alkyl substituted with 1 to 3 hydroxy groups; Rr is independently selected from a 5 to 10 ed cyclyl or a 5 to 10 membered heteroaryl, wherein optional substituent is selected from hydroxyl, halogen, -(C1-C6)a1kyl or -(C1-C5)alkoxy; RS is an optionally substituted -(C1—C6)alkyl—(C6-C10)aryl, wherein the optional substituent is halogen; m is independently represents 0, 1, 2, 3 or 4; and n is independently ents 0, 1, 2, or
  3. 3. The compound according to claim 1, wherein A is (R3)n ; X1 is CH or N. The compound according to claim 1, having the formula (la) Rb C\ O// N\S O//\\O Ra (Ia) their ceutically acceptable salts, pharrnaceutically acceptable solvates or stereoisomers thereof.
  4. 4. The compound according to claim 1, having the formula (lb) ()R \ N R1 b C\ ' R O// l\\l 48:0 Ra (1b) their pharmaceutically acceptable salts, phaimaceutically acceptable solvates or stereoisomers thereof, wherein the values of all the variables are as described for compound of a (lb).
  5. The nd according to claim 1, having a formula selected from N/=/(R)m2 \ / / N’N\ N (Ea Rb O//C\l.\l’ O R‘ (Io), [VF/(Rh2 \ / / N/N\ N Cece ,Sco Rb O//C">lR‘ (Id), / /N F \ Rb oC‘NHO 0‘?” Ra (Ie), Rb /,C‘NH O \ N or? b C\ ’ ‘0 R // N or pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof.
  6. The nd ing to claim 1, having the formula (11) (R2)m \ / N/N\ (Ran/VI Rb C~ 0” £10 their pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, wherein R3 is fluorine, n is l or 2.
  7. 7. The compound according to claim 1, having the formula (1m) (R2)m O\, / N I N\ (Rf- \ \ (R3 /\/l)n Rb /,C‘NH O ,gao Ra (1m) their pharmaceutically acceptable salts, ceutically acceptable solvates or stereoisomers thereof.
  8. 8. The nd according to claim 1, wherein Rb is hydrogen or e, or wherein R. 2 . . . . . 13 fluorme or wherein R31s fluorine.
  9. 9. A compound which is (R)—5-(2—(2,5—difluoropheny1)pyrrolidin—1-y1)—N-((4-fluorophenyl)sulfonyl)pyrazolo [1, 5-a]pyridine-3 -carboxamide, (R)-N-(tert-butylsulfonyl)-5—(2-(2,5-difluorophenyl) pyrrolidin— yrazolo[ l ,5-a] pyridinecarboxamide, (R)-5—(2-(2,5—difluorophenyl)pyrrolidin—1~yl)—N-(ethylsulfonyl)pyrazolo[1,S-a] pyridinecarboxamide, (R)-N-((3—cyanophenyl)sulfony1)—5-(2-(2,5—difluorophenyl)py1rolidin— 1 —yl)pyrazolo [1,5—a] pyridinecarboxamide, (R)—N—(cyclopropylsulfonyl)—5—(2—(2,5~difluorophenyl)pyrrolidin~1—yl)pyrazolo[1,5— a]pyridine—3-carboxamide, (R)—5-(2—(2,5-difluorophenyl)pyrrolidin— l —yl)-N—(methylsulfonyl)pyrazolo[ 1 ,S—a] pyridine—3-carboxamide, (R)(2-(2,5—difluorophenyl)pyrrolidin—1-yl)—N-(isopropylsulfonyl)pyrazolo[1, S-a] pyridine—3—carboxamide, 5—((R)—2-(2,5—difluorophenyl)py1rolidinyl)—N—((4-((S)—3 ~hydroxypyrrolidin—1—yl) phenyl) sulfonyl)pyrazolo[1, 5-a]pyridinecarboxamide, (R)-N-((3 -cyanophenyl)sulfonyl)(2-(2,5-difluorophenyl)pyrrolidin—1-yl)-N- methyl pyrazolo[1 ,5—a]py1'idine-3 -carboxamide, (R)(2-(2,5-difluorophenyl)pyrrolidiny1)-N-(propy1sulfonyl)pyrazolo[ 1 , 5-a] pyridinecarboxamide, (R)(2-(2,5—difluorophenyl)pyrrolidin~1—y1)—N-((3 ,5-dimethylisoxazolyl) sulfonyl) pyrazolo [1, S—a] pyridinecarboxamide, (R)-N—(cyclohexy1sulfony1)—5-(2—(2,5-difluoropheny1)pyrrolidin—1—y1)pyrazolo[1,5—a] pyridine—3—carboxamide, (R)—N-(cyc10penty1sulfonyl)(2—(2, 5~diflu0ropheny1)pyrrolidin~1-yl)pyrazolo[ 1,5- a] pyridine-3 —carboxamide, (R)—5—(2-(2,5-difluor0pheny1)pyrrolidin— 1 -y1)—N~(isobuty1sulfonyl) pyrazolo[1, 5-a] pyridine —3 -carboxamide, (R)(2~(2,5—difluorophenyl) pyrrolidin—l-yl)-N—((1, 2-dimethyl—1H-imidazol—4-y1) sulfonyl) pyrazolo [1, 5—a] pyfidinecarboxamide, (R)-5—(2-(2, 5—difluor0phenyl) pyrrolidin—l-yl)—N—((1, 2-dimethyl-1H—imidazolyl) sulfonyl) pyrazolo [1, 5—a] pyridinecarboxamide, (2-(2, S—difluorophenyl) pyrrolidiny1)-N-(piperidinylsulfonyl) pyrazolo [1, 5—a] pyridinecarboxamide, (R)(2—(2, S—difluorophenyl) pyrrolidin—1~y1)~N—((1—methyl-1H-imidazol—4—yl) y1)pyrazolo [1, 5—a] pyridine—3—carboxamide, (R)—5~(2—(2, 5-difluor0phenyl) pyrrolidin—l—y1)-N—((1-methy1—1H—pyrazol—5~yl) sulfonyl) pyrazolo [1, 5—a] pyridine—3-carboxamide, (R)-5—(2-(2, 0rophenyl) pyrrolidin-l-y1)-N-((2, 4—dimethylthiazol—5-yl) sulfonyl) pyrazolo [1, 5-a] necarboxamide, (R)(2-(2, 5—difluoropheny1) pymolidin—1—y1)-N-((1-methyl0xoindolin-5~y1) sulfony1)pyrazolo [1, 5—a] pyridine-3—carboxamide, (R)(2-(2, orophenyl) pyrrolidin—1—y1)—N-((tetrahydro—2H—pyran—4-yl) sulfony1)pyrazolo [1, 5—a] pyridine—3—carboxamide, (R)(2-(2, S—difluorophenyl) pyrrolidin-l-y1)—N-((6—(dimethylamino) nyl) sulfony1)pyrazolo [1, S-a] ne—3—carboxamide, 5-((R)(2, 5-difluor0pheny1) pyrrolidin— 1 -y1)-N-((2-methyltetrahydrofi1ran—3—y1) sulfonyl) pyrazolo [1 , 5-a] pyridine—3 -carboxamide, 5—((R)(2, orophenyl) pyrrolidin-1—yl)-N-((6-((S)hydroxypyrrolidiny1) pyridinyl) sulfonyl) pyrazolo [1 , 5-a] pyridinecarboxamide, (R)-5—(2—(2, 5 -difluorophenyl) pyrrolidin—1-y1)-N—((6-meth0xypyridin-3 —yl) sulfonyl) pyrazolo [1, 5-a] ne-3 —carb0xamide, (R)-N—((6-(1H-1 riazol-1—y1)pyridin—3—y1)sulfony1)—5~(2—(2,5-difluor0phenyl) pyrrolidin- 1 —yl) pyrazolo [1 , 5-a] pyridinecarboxamide, (R)-5—(2-(2, S-difluorophenyl) pyrrolidin- 1 —y1)—N—(( 1 -methyl— 1H-pyrazoly1) sulfonyl) pyrazolo [1 , 5—a] pyridine-3—carboxamide, (R)~5-(2—(2, S-difluorophenyl) pyrrolidin—l-y1)-N-((4—m0rpholinophenyl) sulfonyl) pyrazolo [1, S-a] pyridine—3-carboxamide, (R)—5-(2-(2,5-difluoropheny1)pyn‘olidin— N—(pyn'din-3 —ylsu1f0nyl)pyrazolo[1,5 - a]pyridine—3-carboxamide, (R)—N—((5—chlorothiophen—2-yl) sulfonyl)—5—(2-(2, 5—difluorophenyl) idin— 1 -y1) pyrazolo [1, 5-a] pyn'dinecarb0xamide, (R)—N—((2, 5-dichlorothiophen—3 -y1) sulfonyl)(2-(2, 5—diflu0rophenyl) idin- 1-y1) pyrazolo [1, 5-a] pyridinecarb0xamide, (R)—N-(cyclobutylsulf0ny1)(2—(2, 5-difluor0phenyl) pyrrolidin— 1 -yl) pyrazolo [1, 5—a] pyfidinecarboxamide, (R)—5—(2-(2,5—diflu0ropheny1)pyrrolidin- 1 —y1)—N—((2,3 ~dihydrobenzo[b][1,4]di0xin— 6-y1)su1fonyl)pyrazolo[1,5—a]pyridine—3~carboxamide, (R)—N—(benzo [d] [1 ,3]dioxol—S-ylsu1f0nyl)—5-(2—(2,5—difluorophenyl)pyrrolidin— 1—y1) pyraz010[1 ,5—a]pyridine—3 -carb0xamide, (R)-5—(2—(2,5-difluorophenyl)pyrrolidin~1—yl)—N-((1-ethylcyclopropyl)sulfonyl) pyrazolo[1,5—a]pyridine—3-carboxamide, (R)(2-(2,S—difluorophenyl)pyrrolidin—1-y1)-N-(neopentylsulfonyl)pyrazolo[1,5— a]pyfidine—3—carboxamide, (R)—5-(2-(2,5-difluorophenyl)pyrr01idin~ 1 -y1)-N-(( 1 lcyclopropyl)sulfony1) pyrazolo[1,5-a]pyridine—3-carboxamide, (R)—5-(2-(2,5—difluorophenyl)pyrrolidin—1—yl)-N-(o-tolylsulfony1)pyrazolo[ 1,5-a] pyridinecarb0xamide, (R)-N—(benzylsulfonyl)(2-(2,5 -difluoropheny1)pyrrolidinyl)pyrazolo[1,5—a] pyridine-3—carboxamide, (R)(2—(2,5-diflu0rophenyl)pyrr01idin(( 1 -(4-fluorobenzy1)cyc10pr0py1) sulfony1)pyrazolo[1,5—a]pyridine—3~carboxamide, (R)-N—(tert-butylsulfony1)—5-(2-(5—flu0ro-2—methoxyphenyl) pyrrolidin— 1-y1) pyrazolo [1, 5—a] pyridine—B—carboxamide, (R)-N—(tert—butylsu1f0nyl)(2-(3—(diflu0romethoxy)-5—fluorophenyl) pyrrolidin yl) pyrazolo [1, 5—a] pyridine—B-carboxamide, (R)-N-(tert~buty1su1fonyl)~5—(2—(5-fluoropyridin-3 ~y1) pyrrolidin— 1 —yl) pyrazolo [1 , S-a] pyridinecarboxamide, (R)-N~(tert-butylsulfonyl)(2-(2—ethoxy—S~flu0r0pheny1)pyrrolidinyl)pyrazolo ]pyridine—3—carboxamide, (tert-butylsu1fony1)~5~(2-(2-(cyclopropylmethoxy)fluoropheny1) idin— 1 —y1)pyrazolo[ 1 yridine-3 -carboxamide, (R)—N-(tert-buty1sulfony1)(2-(2-chloro-S-fluoropheny1)pyrrolidin-1—yl) pyrazolo[1,5-a]py1idinecarboxamide, N-(tex’t-butylsulfonyl}5—((2R,4R)(2,5-difluorophenyl)-4—hydroxypy1rolidin- 1 —y1) pyrazolo[1,5-a]pyridinecarboxamide, (R)~N-(tert—butylsulfony1)—5-(2-(5—flu0r0(2,2,2—trifluoroethoxy)phenyl) pyrrolidin— 1 —y1)pyrazolo[ 1 ,5~a]pyridine—3~carboxamide, N—(tert—butylsulfonyl)(2-(7—fluor0-2,3—dihydrobenzo[b][1,4]dioxin—5- y1)pyrr01idin—l-yl)pyrazolo[1,5—a]pyridine—3—carboxamide (Isomer-I), N-(tett-butylsulfonyl)—5—(2-(7-fluoro-2,3 —dihydr0benzo[b][1,4]dioxin—5- y1)pyrr01idin—1—y1)pyrazolo[1,5—a]pyridine—3-carboxamide (Isomer—II), N-(tert—butylsulfonyl)((2R,4S)-2—(2,5-difluor0phenyl)—4-fluor0pyrrolidin y1)pyrazolo[1,5—a]pyridinecarb0xamide (Isomer—I), N—(tert-butylsulfonyl)-5 -((2R,4S)-2—(2,5-difluoropheny1)~4-fluoropyrrolidin y1)pyrazolo[1,5-a]pyridine—3—carboxamide (Isomer—II), (R)-N-(tert-buty1sulfony1)(2-(4,4'—difluor0-[ 1, 1'-bipheny1]y1)pyrr01idin-1— yl)pyrazolo[1,5-a]pyridine—3~carb0xamide, (S)-N—(tert—butylsulfonyl)(2-(2, 5-difluoropheny1)-4, oropyrrolidinyl) pyrazolo [1, S-a] pyridinecarboxamide, (R)—N—(tert—buty1sulfony1)(2-(2, 5-difluoropheny1)—4, 4-difluoropyrrolidiny1) pyrazolo [1, 5-a] pyridine—3-carboxamide, (R)-N-(tert-butylsulfony1)(2-(5—fluoro—2-(2-fluor0ethoxy)phenyl)pyrrolidin— 1- yl)pyrazolo[1 ,5—a]pyridine—3 xamide, N—(tert-butylsulfonyl)—5-((2R,4R)—2—(2,5—diflu0rophenyl)—4-flu0r0pyrrolidin yl)pyrazolo[1,5-a]pyridinecarboxamide, N—(tert-butylsulfonyl)~5~((2R)—2—(5-fluoro—Z-((tetrahydrofuran—3 -y1)oxy)phenyl) pyrrolidin~1-yl)pyrazolo[1,5—a]pyridine-3—carboxamide, N—(tert-butylsulfonyl)—5-((2R)-2—(5—fluor0—2—((tetrahydr0furan-3—y1)0xy)phenyl) pyrrolidin-l—yl)pyrazolo[1,5—a]pyridine—3—carboxamide, (R)-N-(tert—butylsulfonyl)—5-(2-(2, 5-difluorophenyl) pyrrolidin—l—yl)—4—fluoro pyrazolo[1, 5—a] pyridinecarboxamide, (tert-butylsulfonyl)—5—(2-(2-(difluoromethoxy)fluorophenyl) pyrrolidin yl)—4-fluoropyrazolo [1, 5—a] pyfidine-3—carboxamide, (R)-N-(teIT-butylsu1fonyl)(2-(2—(difluoromethoxy)—5-fluorophenyl) pyrrolidin— 1 — yl) pyrazolo [1, S—a] pyridine—3~carboxamide, (tert—butylsulfonyl)-5—(2—(2-fluoro(2—methoxyethoxy) phenyl) pleOIidin-l- yl)pyrazolo [1, 5—a] pyridine—3—carboxamide, (tert-butylsulfonyl)—5—(2-(5-flu0r0~2~(2—methoxyethoxy) phenyl) pyrrolidin—l— yl) pyrazolo [1, S-a] pyridine—3—carboxamide, (R)—N~(tert—butylsu1f0ny1)-5~(2-(3, 5—diflu0ropheny1) pyrrolidin-l—yl) pyrazolo [1, 5- a] pyridine—3—carboxamide, (R)-N—(tert—butylsulfonyl)-5—(2—(3 -flu0ro—5—(2-methoxyethoxy)phenyl)pylrolidin— 1 — azolo[1,5 -a]pyn'dine-3 -carboxamide, N-(tert—butylsulfonyl)((2R)(3 -fluor0—5-((tetrahydrofurany1)0xy)phenyl) pyrrolidin—l-y1)pyrazolo[1,5-a]pyridinecarboxamide, (R)(2-(3, S-difluorophenyl) pyrrolidin-1—y1)-N-((4-fluorophenyl) sulfonyl) lo [1, 5—a] pyridine-3 —carboxamide, 5-((R)(3, 5-difluoropheny1) pyrrolidiny1)-N-((4-((S)-3 -hydroxypyrrolidin- 1 —yl) phenyl) sulfonyl) lo [1 , S—a] ne-3 -carboxamide, (R)-5—(2—(3, S-difluorophenyl) pyn‘olidiny1)-N-(isopropylsulfonyl) pyrazolo [1 , 5— a] pyridine-3 -carb0xamide, (R)-N—((6—( 1H— 1 , 2, 4-triazol~ 1 ~y1) pyridin-3 -y1) sulfony1)(2-(3 , S—difluorophenyl) pyrrolidin- 1 —yl) lo [1, 5-a] ne—3—ca1‘b0xamide, 5-((R)—2-(3 , S—difluorophenyl) pyrrolidin— 1 —y1)—N—((6—((S)-3 -hydroxypyrrolidin— 1-y1) pyridin~3~yl) sulfonyl) pyrazolo [1 , 5—a] pyridine—3 —carboxamide, 5-((2R,4S)~2-(2,5-difluorophenyl)-4~fluoropyrrolidin- 1-y1)—N—((1—methy1 cyclopropyl)sulfony1)pyrazolo[1 yridine-3 -carb0xamide, (R)—5-(2-(2, oropheny1) pyrrolidiny1)—4-fluor0—N—(isopropylsulfonyl) pyrazolo [1, 5—a] pyridinecarboxamide, (R)—5—(2—(2, 5-difluoropheny1) pyrrolidin— 1 -y1)-N—(N, N-dimethylsulfamoyl) pyrazolo [1, 5—a] pyfidine-3—carboxamide, (R)(2-(2, 5-difluorophenyl)pyrrolidin—1-y1)-N-(N-ethyl-N—mcthylsulfamoyl) pyrazolo[1,5-a]pyridinecarboxamide, 5-((2R,4S)(2,5-diflu0ropheny1)~4—flu0ropyrrolidinyl)-N-(N,N-dimethyl oyl)pyrazolo[1,5-a]pyridinecarboxamide, 5-((2R,4S)—2—(2,5—difluor0pheny1)-4—fluoropyrrolidin— 1 —yl)-N—(N—ethyl—N—methyl sulfamoy1)pyrazolo[1,5—a]pyridine~3-carboxamide, (R)—N—(N—(cyclopropy1methyl)—N-methylsulfamoy1)—5~(2—(2,5—difluor0phenyl) pyrrolidin- 1 —y1)pyrazolo[ 1 ,5—a]pyridine—3 —carboxamide, (R)-N—(N,N-diethy1sulfam0y1)(2—(2,5—diflu0r0phenyl)pyrrolidin— 1 - y1)pyrazolo[1,5-a]pyridine-3—carb0xamide, 5—((2R,4S)(2,5—diflu0ropheny1)~4-fluor0pyrrolidin—1—y1)—N-(N,N-dimethy1 sulfamoyl) pyrazolo[1,5 -a]pyridine-3 -carb0xamide, 5—((2R,4S)—2—(2,5 -difluorophenyl)fluoropyrrolidiny1)—N-(N—ethy1-N- methylsulfamoyl) pyrazolo[1,5—a]pyridinecarboxamide, (R)(2-(2,5—difluorophenyl)pyrrolidin-1—yl)—N—(morph01inosu1fonyl) pyrazolo[ 1 , 5- dine—3—carboxamide, (R)—5—(2-(2,5—difluorophenyl)pyn'olidiny1)-N—(pyrrolidinylsulfonyl) pyrazolo[1,5-a]pyridine—3-carboxamide, (R)—5-(2—(2,5—difluorophenyl)pyrrolidin~ I —y1)-N-((4-methylpiperazin- l —y1) sulfonyl)pyrazolo[1,5—a]pyfidine-3—carboxamide, (R)-N—(N,N—diethylsulfamoy1)-5—(2-(5—fluoro-2—meth0xyphenyl)pyrrolidiny1) pyrazolo[1,5-a]pyridinecarb0xamide, (R)—N—(N,N~diethylsulfamoyl)-5—(2-(5—fluoro—2-(2-fluoroethoxy)phenyl)pyrrolidin~ 1—y1)pyrazolo[1,5-a]pyn'dine—3-carboxamide, (R)—5—(2-(2,5-difluoropheny1)pyrrolidin- 1-y1)-N—(pipen'din-1 —ylsu1f0nyl) pyrazolo[1,5-a]pyridine—3—carboxamide, (R)(2-(3,S—difluoromethoxyphenyl)pyrrolidin- 1-y1)—N—(N—ethy1-N-methy1 sulfamoyl)pyrazolo[1,5—a]pyridine-3—carboxamide, (R)—N—(N-ethy1-N—methylsulfamoy1)(2—(5~fluoromethoxyphenyl)pyrrolidin— 1- azolo[1,5—a]pyridine—3—carboxamide, (R)-N-(N-ethyl-N-1nethy1su1famoy1)—5-(2-(5-fluoro-2—(2-fluoroethoxy) phenyl)py1*rolidin— 1 —yl)pyrazolo[ 1 ,5-a]pyridine—3 -carboxamide, 5-((R)-2—(2, 5—difluorophenyl)pyn'01idin— 1 -y1)-N—(((S)—3 -hydroxypyrrolidin—1—y1) sulfony1)pyrazolo[1, 5~a]pyridine—3-carboxamide, (R)(2—(2,5—diflu0rophenyl)pyrrolidinyl)-N-sulfamoylpyrazolo[ 1 ,5-a]pyn'dinecarboxamide, (R)(2—(3 ,5—difluoro-2—(2—fluoroethoxy)phenyl)pyrr01idiny1)-N~(N~ethy1—N— methylsulfamoyl)pyrazolo[1,5-a]pyridine—3—carb0xamide, N—(N-ethyl—N-methylsulfam0y1)(2—(8—flu0ro-3 ,4—dihydro-2H—benzo[b][ 1 ,4] dioxepinyl)pyrrolidin—1-yl)pyrazolo[1,5—a]pyridine—3-carboxamide (Diastereomer—I), thyl-N—methylsulfamoyl)-5—(2-(8-fluoro-3 ,4-dihydro-2H-benzo[b][1 ,4] dioxepinyl)pyrrolidin- yrazolo[1,5-a]pyridine—3—carboxamide (Diastereomer-H), N—(N,N-dimethylsulfamoy1)—5~(2-(7-fluoro~2,3—dihydrobenzo[b] [ 1 ,4]di0xin-5— yl)pyrrolidiny1)pyrazolo[1,5-a]pyridinecarboxamide (Diastereomer-I), N-(N,N—dimethylsulfamoyl)(2-(7-fluoro-2,3-dihydrobenzo[b] [ 1 ,4]dioxin yl)pyrrolidin~1—y1)pyrazolo[ 1 ,5—a]pyridine-3 -carb0xamide (Diastereomer—II), thyl-N-methylsu1famoy1)(2-(7-fluoro-2,3—dihydrobenzo[b][1,4]dioxin—5 - y1)pyrrolidiny1)pyrazolo[1,5-a]pyridine-3—carboxamide (Diastereomer—I), N—(N—ethyl-N—methylsulfamoyl)—5—(2-(7-fluoro—2,3—dihydr0benzo[b][1,4]di0xin—5- y1)pyrrolidin—1—yl)pyrazolo[1,5—a]pyridine-3—carboxamide ereomer—II), N-(N—ethyl—N—methy1su1famoyl)~4—fluoro((2R,4S)—4—flu0r0—2—(3— fluorophenyl)pyrrolidin-1—y1)pyrazolo[1 ,5—a]pyridinecarboxamide, N—(N—ethyl—N-methylsulfamoyl)—5«((R)—2—(3-fluoro—5—(((S)~tetrahydr0furan-3 - y1)0xy)phenyl)pyrrolidin~1~y1)pyrazolo[1 ,5~a]pyridine-3 ~carboxamide, (R)(2—(3 ,5-difluoro~2—((tetrahydro—2H-pyran-4—yl)oxy)pheny1)pyrrolidin— 1 -y1)—N— (N~ethy1—N—methy1su1famoy1)pyrazolo[ 1 ,5 -a]pyridine-3 —carb0xamide, (2-(3 ,5-difluor0((tetrahydro—2H-pyran«4~y1)0xy)phenyl)pyrrolidin— 1 -y1)-N- (N,N-dimethylsulfamoy1)pyrazolo[ 1 ,5 -a]pyridinecarboxamide, N—(N—ethy1-N—methylsu1fam0y1)((R)(3-fluoro(((R)-tetrahydrofuran-3 — yl)oxy)phenyl)pyrrolidin—1—yl)pyrazolo[1,5-a]pyridine—3-carb0xamide, 4-fluor0-5—((2R,4S)fluoro(3-fluorophenyl)pyrr01idiny1)-N-su1famoy1 pyrazolo[ l ,5—a]pyridine-3 ~carb0xamide, N—(N,N-dimethylsulfamoy1)~5—(2—(8—fluoro-3,4—dihydro-2H—benzo[b] [ 1 ,4]dioxepin— yrrolidin—1—y1)pyrazolo[1,5-a]pyridine~3—carb0xamide (Diastereomer-I), N-(N,N—dimethylsulfamoyl)—5-(2-(8—fluor0—3,4-dihydro~2H-benzo[b] [ 1 ,4]dioxepin- 6-y1)pyrrolidinyl)pyrazolo[ 1 ,5~a]pyridine—3 ~carboxamide (Diastereomer—Z); (2-(2,5—difluorophenyl)pyrr01idin~1-y1)-N—(N—isobuty1-N—methyl sulfam0y1)pyrazolo[1,5~a]pyridine—3—carboxamide, (R)—N-(N—ethyl-N-methylsulfamoy1)—4-fluoro—5 —(2—(3—fluorophenyl)pyrrolidin- 1 — y1)pyrazolo[1,5-a]pyridinecarboxamide, (R)—N—(N,N-dimethylsulfamoy1)—4—fluor0(2-(3—fluoropheny1)pyrrolidin— 1 —y1) pyrazolo[1,5-a]pyridine—3—carb0xamide, (R)-N-(N,N—dimethylsulfamoy1)-4—fluoro-5—(2—(3-fluorophenyl)pyrrolidin—1—yl) pyrazolo[1,5-a]pyridinecarboxamide, (R)-N-(N-ethy1-N-methylsulfamoy1)—4—fluoro-5 -(2—(5 -fluoro-Z-((tetrahydro-2H- py1‘any1)oxy)phenyl)pyrrolidin- 1 —yl)pyrazolo[ 1 ,5~a]pyridine-3 -carboxamide, 5-((2R)(3 —((2,2—difluorocyclopropy1)methoxy)fluorophenyl)pyrrolidinyl)- N-(N-ethy1—N~methylsulfamoy1)pyrazolo[ 1 yridinecarboxamide, (R)—N—(N,N-bis(cyclopropylmethyl)su1famoyl)-5 -(2-(2,5—difluoropheny1)pyrrolidin— 1-y1)pyrazolo[1,5-a]pyridine—3~carboxamide, N—(N-ethyl-N—methylsu1famoyl)—5—((2R)—2-(5-fluoro—2-((tetrahydrofuran—3-yl)oxy) pheny1)pyrrolidin—1-y1)pyrazolo[ 1 ,5-a]pyridine—3 —carboxamide, N—(N—ethyl—N—methylsulfamoy1)—5-((2R)~2-(5—fluoro—2—((tetrahydrofuran—3 —yl)oxy) phenyl)pyrrolidin—1—yl)pyrazolo[1,5—a]pyridine—3-carboxamide (Diastereomer—II), N-(tert—butylsulfonyl)—5—(2—(2,5—difluoropheny1)pyrrolidin- 1-y1)pyrazolo[1,5—a] necarboxamide ic mixture); (R)~N—(tert-buty1sulfonyl)~5~(2-(3 ,5-difluoro—2—methoxyphenyl)pyrrolidiny1) pyrazolo[1,5-a]pyridine-3~carboxamide, t-butylsulfonyl)—4-fluoro((2R,4S)—4—fluoro-2—(3-fluorophenyl)pyrrolidin y1)pyrazolo[1,5-a]pyn'dine—3—carboxamide, 4-flu0r0((2R,4S)fluoro(3-fluoropheny1)pyrrolidiny1)-N—(isopropy1 sulfony1)pyrazolo[1 ,5-a]pyridine—3-carboxamide, (R)—N—(tert-butylsulfonyl)—5-(2-(3 ,5—difluoro-2—((tetrahydro-2H—pyran-4—y1)oxy) phenyl)pyrrolidin—1—y1)pyrazolo[1,5—a]pyridine~3-carboxamide, (R)-N—(tert—butylsulfonyl)(2—(5~fluoro((tetrahydro-2H—pyranyl)oxy) phenyl)pyrrolidin—1~y1)pyrazolo[ 1 ,5 —a]pyridine—3 -carboxamide, (2-(3 ,5~difluoro—2-((tetrahydro~2H-pyran-4—y1)oxy)phenyl)pyrrolidin- 1 —y1)—N— (isopropylsulfonyl)pyrazo10[1,5—a]pyridine—3—carb0xamide, (R)-4—fluoro-5~(2-(3 -fluorophenyl)py1’rolidinyl)~N—(isopropylsulfonyl)pyrazolo [1, 5—a]pyridine—3-carboxamide, (R)—N-(tert—buty1su1fonyl)—4-fluoro-5—(2—(5—fluoro-Z—((tetrahydro-2H-pyran—4-y1) oxy)phenyl)pyrrolidin-1—yl)pyrazolo[1,5 -a]pyridine-3 ~carboxamide, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof or a stereoisomer thereof.
  10. 10. A pharmaceutical composition comprising at least one compound as d in any one of claims 1 to 9 and at least one pharmaceutically acceptable excipient.
  11. 11. The compound of any one of claims 1 to 9 for use in inhibiting tropomyosin receptor kinase A (TrkA); or for use in the treatment or prevention of conditions, diseases and/or disorders associated with al or deregulated TrkA kinase activity by administering effective amount of the compound; or for use in the treatment or prevention of, diseases and/or disorders treatable or preventable by inhibition of Trk kinase activity, such as pain, ation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, fibrosis, neurodegenerative disease, a disease, disorder, or injury relating to dysmyelination or demyelination or certain infectious diseases such as Trypanosoma Cruzi infection by stering a therapeutically effective amount of the nd; or for use in treating pain comprising administeringto a patient in need f, therapeutically effective amount of a nd.
  12. 12. A nd according to claim 11, wherein the pain includes chronic and acute pain or wherein the pain is related to cancer, surgery, bone fracture, skeletal pain caused by tumor asis, osteoarthritis, psoriatic arthritis, rheumatoid arthritis, interstitial cystitis, chronic pancreatitis, al pain, inflammatory pain, migraine, chronic lower back pain, r pain syndrome and neuropathic pain.
  13. 13. A compound of claim 1 having TrkA inhibitory activity using TR-FRET assay of less than about 1 [.LM.
  14. 14. The compound according to claim 1, which is Sodium (tert-butylsulfonyl)(5-((2R,4S)(2,5-difluorophenyl)fluoropyrrolidin— l—yl) pyrazolo[1,5-a]pyridinecarbonyl)amide, Sodium(R)-(tert-butylsulfonyl)(5-(2-(2,5-difluorophenyl)pyrrolidin- l -y1) pyrazolo [1 ,5-a] pyridinecarbonyl)amide, Sodium ert-butylsulfony1)(5-(2-(7-fluoro—2,3 ~dihydrobenzo[b][1,4]dioxin—5— yl)pyrrolidiny1)pyrazolo[1,5-a]pyridine—3 -carbonyl)amide, Sodium butylsulfonleS—((2R,4R)—2—(2,5—difluoropheny1)-4—fluoropyrrolidiny1) pyrazolo[1,5—a]pyridine—3 -carbonyl)amide, Sodium (R)—(5-(2—(2,5~difluoropheny1) pyrrolidiny1)pyrazolo[ 1 ,5-a]pyridine—3 - carbonyl) imethylsulfamoyl)amide, Sodium (tert—butylsulfonleS—(2—(2,5-difluoropheny1)-4,4-difluoropyrrolidin— 1 — yl)pyrazolo[1,5—a]pyridine-3 —carbonyl)amide, Sodium (R)—(5-(2-(2,5~difluoropheny1) pyrrolidinyl)pyrazolo[1,5~a]pyridine-3 - carbony1)(( 1 —methylcyclopropyl) sulfony1)amide, Sodium (tert-butylsulfonyl)(5—((2R)-2—(2,5-difluorophenyl)—4-fluoropyrrolidin— 1 - yl)pyrazolo [1,5—a]pyridine~3 ~carbonyl)amide, Sodium (5—((2R,4S)—2-(2,5~difluorophenyl)-4—fluoropyrrolidin- 1-y1)pyrazolo[ 1, 5- a]py1idinc—3—carbonyl)(N,N-dimethylsulfamoyl)amide, Sodium (tert—butylsulfony1)(4—fluoro((2R,4S)-4—fluoro(3-fluor0phenyl) pyrrolidin— 1 -yl)pyrazolo[ l ,5-a]pyridine-3 —carbony1)amide, Sodium (R)-(N,N—dimethylsu1famoyl)(4—fluoro-5 -(2—(3~fluoropheny1)pyrrolidin- 1 — y1)pyrazolo [ 1,5-a]pyridine—3~carbonyl)amide, Sodium (N—ethyl-N—methy1sulfamoyl)(5«((2R)—2-(5—fluoro—2—((tetrahydrofuran—3 - yl)oxy) phenyl)pyrrolidin-1—yl) lo[1 yridine—3 ~carbony1)amide, Sodium (R)—(5—(2—(2,5~difluoropheny1) pyrrolidin— 1 -y1)pyrazolo[1 ,5—a]pyridine-3 — carbonyl)(o—t0lylsulfonyl)amide, Sodium (4-fluoro-5—((2R,4S)fluoro-2—(3~fluorophenyl)pyrrolidin— 1 —yl) pyrazolo[ 1 ,5—a]py1idinc—3 ~carbonyl) (isopropylsulfonyl)amide, Sodium (5—((2R,4S)-2—(2,5-difluorophenyl) —4—fluoropyrrolidin—1-y1)pyrazolo[1,5— a]pyridine-3 —carbonyl)(( 1-mcthylcyclopropyl)sulfony1)amide, or Sodium (R)—(5-(2-(2,5—difluorophenyl) pyrrolidin- 1-y1)pyrazolo[1 ,5-a]pyridine—3 - carbonyl)(piperidin— 1 -ylsu1fony1)amide.
  15. 15. A compound which is (R)—5~(2-(2,5-diflu0rophenyl)pyrrolidin~1~y1)-N-(N—(2-methoxyethyl)-N- sulfamoyl)pyrazolo[1,5-a]pyridineCarboxamide; (R)-N—(N-cyclopropyl-N-methylsu1famoy1)(2-(2 ,5-difluoropheny1)pyrrolidin y1)pyrazolo[1,5-a]pyridine-3—carb0xamide; (R)-N—(N—ethyl—N-methylsulfamoyl)(2-(5-fluoro-2~methy1phenyl)pyrrolidin y1)pyrazolo[ 1 ,5-a]pyridine-3 —carboxamide; (R)—N—(N—ethyl-N—methylsulfamoyl)(2-(7-fluoro—2,3-dihydr0benzo[b] [ 1 ,4]dioxin-5 — y1)pyrrolidin—1—y1)pyrazolo[1,5-a]pyridine—3 ~carboxamide; N—(teI’c—butylsulfonyl)-5 -((2R,4S)-4—flu0r0(3 —fluoro((tetrahydro—2H~pyran~4~ yl)0xy)phenyl)pyrr01idiny1)pyrazolo[1,5-a]pyridine-3—carboxamide; N-(N—ethyl~N—methylsu1fam0y1)—5—((2R,4S)—4-fluoro-2—(3~fluor0~5—((tetrahydr0-2H-pyran— 4-yl)oxy)pheny1)pyrr01idin- 1 —y1)pyrazolo[ 1 ,5-a]pyridine—3 -carboxamide; —butylsulfonyl)-5—((2R,4S)-4—flu0r0—2—(5—fluoro((tetrahydro-ZH—pyran )pheny1)pyrrolidiny1)pyrazolo[1,5-a]pyridine—3—carboxamide; N-(N-ethyl-N-methylsulfamoy1)((2R,4S)—4~fluor0-2—(5—fluoro((tetrahydro-2H—pyran— 4-yl)oxy)phenyl)pyrrolidin—1—yl)pyrazolo[1 ,5-a]pyridinecarb0xamide; 5~((2R,4S)—4-fluoro—2—(5 ~fluoro((tetrahydro-2H—pyran—4—yl)0xy)phenyl)pyrrolidiny1)— N-(isopropylsulfonyl)pyrazolo[1 ,5-a]pyridine~3~carb0xamide; ,4S)—2-(2—(cyclopropy1meth0xy)—5—fluorophenyl)fluoropyrrolidin- 1—yl)-N~(N— ethyl—N-methy1su1famoy1)pyrazolo[1 ,5—a]pyridine-3—carboxamide; N—(tert—butylsulfonyl)-5 -((2R,4S)-4—fluoro—2—(5—flu0r0—2—((tetrahydrofuran—3 — y1)oxy)phenyl)py1T01idiny1)pyrazolo{1,5—a]pyridinecarboxamide; N-(N—ethyl—N-methylsulfamoyl)((2R,4S)-4—fluoro~2—(5—fluoro—2—((tetrahydrofuran—3 — y1)0xy)phenyl)pyrrolidin—1~y1)pyrazolo[1,5—a]pyridine—3~carboxamide; 5—((2R,4S)(2—(cyclopropylmethoxy)~5-flu0ropheny1)—4-flu0ropyrrolidin-1—yl)—N~(N— ethyl-N—methylsulfamoy1)-4—fluoropyrazolo[ 1 ,5—a]pyridine—3-carb0xamide; N—(tert—butylsulfonyl)—5—((2R,4S)-2—(2—(cyclopropylmethoxy)—5~fluorophenyl)—4- fluoropyrrolidin-l—y1)pyrazolo[1 ,5-a]pyridine-3 -carboxamide; (R)—5~(2-(2,5-difluoropheny1)pyrr01idin-1~y1)—N—(N~ethylsu1famoy1)pyrazolo[1,5- a]pyridinecarboxamide; (R)(2-(2,5-diflu0rophenyl)py1rolidin—1~y1)-N-(N—methylsulfamoy1)pyrazolo[1,5- a]pyridinecarboxamide; (R)(2—(2,5-difluorophenyl)pyrrolidin- 1 ~yl)-N-(N-(2—fluoroethy1)-N- methylsulfamoyl)pyrazolo[1,5—a]pyridinecarboxamide; (R)—5-(2-(2,5—difluoropheny1)pyrrolidin~ 1 —y1)—N—(N—(2-hydroxyethy1)-N— methylsulfamoyl)pyrazolo[1,5—a]pyridine~3—carboxamide; (R)—N—(azetidin— 1 —ylsu1fony1)—5 —(2-(2,5—difluoropheny1)pyrr01idin-1—yl)pyrazolo[1 ,5— a]pyridine-3—carboxamide; t—butylsulfonyl)~5-((2R,4S)fluoro-2~(7—fluoro—2,3—dihydrobenzo[b] [ 1 ,4]dioxin—5- y1)pyrrolidin—1—yl)pyrazolo[1,5—a]pyridine—3—carboxamide; (R)-N—(N—(Z-cyanoethy1)—N~methy1sulfamoy1)—5-(2—(2,5—difluorophenyl)pyrrolidin— 1 - y1)pyrazolo[1 ,5 -a]pyridine—3 -carboxamide; N—(tert-butylsulfonyI)fluoro~5-((2R,4S)fluoro—2—(7—fluoro—2,3 — dihydrobenzo[b][1,4]dioxin—5-yl)pyrrolidin-1—yl)pyrazolo[1, 5-a]pyridine—3 - carboxamide; or —dimethylsulfamoy1)fluoro((2R,4S)—4-fluoro(3-fluorophenyl)pyrrolidin y1)pyrazolo[1,5-a]pyridine-3—carboxamide; or a phalmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof or a stereoisomer thereof.
  16. 1 6. The compound which is N—(N—ethyl-N—methylsulfamoyl)((2R)—2-(7-fluoro—3~(fluoromethyl)—2,3~ obenzo[b][1,4]dioxin~5-yl)pyrrolidiny1)pyrazolo[1,5—a]pyridine—3- carboxamide; (R)—N—(N-ethy1~N-methylsulfamoyl)-5~(2—(3—fluor0pheny1)pyrrolidinyl)pyrazolo[ 1 ,5— a]pyridine—3-carboxamide; 5-((2R,4S)—4-fluor0—2-(3-fluoro((tetrahydro-2H—pyran—4-y1)oxy)pheny1)pyrrolidin- 1-yl)~ N-(isopropylsulfonyl)pyrazolo[1,5—a]pyridine—3—carboxamide; 5-((2R,4S)(3-(cyclopropy1methoxy)-5—fluorophenyl)—4—fluoropyrrolidin— 1 -y1)-N-(N— ethyl—N—methylsulfamoyl)pyrazolo[1,5-a]pyridinecarboxamide; N—(tert—butylsulfonyl)—5 4S)-2—(2—cyclopr0poxy-5 —fluorophenyl)~4—fluoropyrrolidin— 1-y1)pyrazolo [1 ,5-a]pyridine—3 xamide; 5-((2R,4S)—2-(2-cyclopropoxy—5-fluoropheny1)—4—fluor0pyrrolidin- 1-y1)-N-(N-ethy1-N— methylsulfamoyl)pyrazolo[1,5~a]pyridine~3-carb0xamide; N—(N-ethyl-N-methy1su1famoyl)—4~fluoro—5—((2R,4S)—4—fluoro—2—(5—flu0ro-2— ((tetrahydrofilran-3 ~y1)oxy)phenyl)pyrrolidiny1)pyrazolo[1 ,5—a]pyridine-3 - carboxamide; 5—((ZR,4S)—2-(2—cyclopropoxy—5—fluoropheny1)~4—flu0ropyrrolidin— 1 -y1)—N-(N-ethy1-N- methylsulfamoyl)—4-fluor0pyrazolc[ 1 ,5-a]pyridine-3~carboxamide; (R)-N—(N-ethy1—N—methylsu1famoy1)—5-(2—(8-fluoro-2,3—dihydrobenzo[b][ 1 ,4]dioxin y1)pyrrolidin—1-y1)pyrazolo[ 1,5-a]pyridine-3 -carboxamide; (R)(2—(8—flu0r0-2,3 -dihydrobenzo[b][1,4]dioxin—6~y1)pyrrolidin—1-y1)-N- opylsulfony1)pyrazolo[ 1 ,5—a]pyridine~3-carboxamide; N—(tert-butylsulfonyl)—5—(2—(8-flu01‘0~2,3 ~dihydrobenzo[b] [ 1 ,4]dioxin—6-yl)pyrrolidin azolo[1,5—a]pyn'dine—3—carboxamide; N-(tert-butylsulfonyl)-5 -(2-(9-fluoro-3 ,4-dihydro—2H-benzo[b] [ 1 ,4]dioxepin—7- y1)pyrr01idin- 1 —y1)pyrazolo[ 1 ,5—a]pyridine-3 -carboxamide; N—(N,N—dimethylsulfamoyl)-5—(2-(8-fluoro—2,3—dihydrobenzo[b][1,4]dioxin r01idin—1~y1)pyrazolo[1,5-a]pyridinecarboxamide; (R)—N—(N,N-dimethylsulfamoyl)-5—(2-(9-fluor0—3 ,4-dihydro—2H-benzo[b][ 1 ,4]dioxepin y1)pyrrolidin—1-yl)pyrazolo[ 1 , 5—a]pyn‘dine—3 xamide; N—(tert—butylsulfonyl)—5~((2R,4S)—4-fluoro—2—(6—flu0robenzo[d][ 1 ,3 ]dioxol-4—yl)pyrrolidin- 1-yl)pyrazolo[1,5—a]pyridine—3~carboxamide; N—(N—ethyl-N-methylsu1famoy1)—5—((2R,4S)—4~flu0r0~2~(6—fluorobenzo[d][ 1 ,3]diox01—4— yl)pyrrolidiny1)pyrazolo[1,5-a]pyridine~3~carboxamide; (R)—5—(2—(2,5~diflu0rophenyl)pyrrolidin— 1 —y1)—N~(N—(( 1 — (hydroxymethyl)cyclobuty1)methy1)-N—methylsu1famoyl)pyrazolo[ 1 ,5—a]pyridine— 3~carboxamide; (R)-N-(N-ethyl-N-methylsu1famoyl)(2-(5-fluoro-Z—((4—methyltetrahydr0-2H-pyran-4— y1)oxy)phenyl)pyrrolidinyl)pyrazolo[1,5-a]pyridine-3 -carboxamide; (R)—N—(tert-butylsulfonyl)—5-(2-(5-fluoro-2—((4—methyltetrahydro-2H—pyran—4— yl)oxy)phenyl)pyrrolidinyl)pyrazolo[1 ,5-a]pyridine-3 -carboxamide; (2-(5-fluoro—2-((4-methyltetrahydro-2H-pyranyl)oxy)phenyl)pyrrolidin— 1 -yl)—N- (isopropylsulfonyl)pyrazolo[1,5—a]pyridine—3 -carboxamide; N-(tert-butylsulfonyl)fluoro—5—((2R,4S)flu0ro(6—fluorobenzo[d][1,3]dioxol—4- yl)pyrrolidinyl)pyrazolo[1,5—a]pyridinea3—carboxamide; N-(tert-butylsulfonyl)—5—((2R,4S)fluoro—2-(6—fluorobenzo[d][ l 3 ]dioxolyl)pyrrolidin— 1-yl)pyrazolo[l ,5—a]pyridine—3 —carboxamide; N—(N—ethyl—N—methylsulfamoyl)-5—((2R,4S)~4-fluoro—2-(6-fluorobenzo[d] [ 1 ,3]dioxol—4- yl)pyrrolidin—1-yl)pyrazolo[l,5-a]pyridine—3—carboxamide; tidin—1-ylsulfony1)fluoro((2R,4S)~4—fluoro—2-(3—fluorophenyl)pyrrolidin— l — yl)pyrazolo[ l ,5—a]pyridine—3 —carb0xamide; 4—fluoro—5—((2R,4S)fluor0~2-(3-fluorophenyl)pyrrolidin- l —yl)-N—(N-isobutyl—N- methylsulfamoyl)pyrazolo[ l yridine-3—carboxamide; N-(tert-butylsulfonyl)-5—((2R,4S)(2,5-difluorophenyl)~4—flu0ropyrrolidin- l —yl) fluoropyrazolo[1,5-a]pyridinecarboxamide; 5 -((2R,4S)(2,5—difluorophenyl)~4—fluoropyrrolidin—1-yl)fluoro-N— (isopropylsulfonyl)pyrazolo[ l ,5—a]py1‘idine-3—carboxamide; ,4S)—2-(2,5-diflu0rophenyl)fluoropyrrolidin— l ~yl)~N—(N—ethyl—N— methylsulfamoyl)—4-fluoropyrazolo[ l , 5—a]pyridine—3-carboxamide; 5~((2R,4S)—2-(2,5-difluorophenyl)—4—fluoropyrrolidin—1~yl)-N—(N,N-dimethylsulfamoyl)-4— fluoropyrazolo[ 1 ,5—a]pyridine—3—carboxamide; N—(azetidin~1-ylsulfonyl)—5-((2R,4S)(2,5—difluorophenyl)-4—fluoropyrrolidinyl)-4— fluoropyrazolo[ 1 ,5—a]pyridine-3 ~carboxamide; 5—((2R,4S)(2,5~difluorophenyl)fluoropyrrolidin— l -yl)-4—fluoro-N—(N—isobutyl-N— methylsulfamoyl)pyrazolo[ l ,5—a]pyn'dine—3—carb0xamide; or 5—((2R,4S)—2-(2,5—diflu0rophenyl)~4-flu0ropyrrolidin—1—yl)fluoro-N— oylpyrazolo[ l , ridine-3 —carboxamide; or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof or a stereoisomer thereof.
  17. 17. A pharmaceutical composition comprising at least one compound as claimed in any one of claims 15 or 16 and at least one ceutically acceptable excipient.
  18. 18. The compound of claims 15 or 16 for use in the treatment ofpain comprising administering an effective amount of compound.
  19. 19. A pharmaceutical composition comprising at least one compound as claimed in any one of the claims 15 or 16 and at least one pharmaceutically acceptable excipient.
  20. 20. The compound of claims 15 or 16 for use in inhibiting tropomyosin receptor kinase A (TrkA) in a patient; or for use in the treatment or prevention of conditions, es and/or disorders associated with abnormal or deregulated TrkA kinase activity; or for use in the ent or prevention of conditions, diseases and/or disorders treatable or preventable by inhibition of Trk kinase activity, pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, fibrosis, neurodegenerative disease; a disease, disorder, or injury relating to dysmyelination or demyelination or certain infectious diseases, osoma Cruzi infection; or for use in the treatment of pain.
  21. 21. A compound for use according to claim 20, wherein pain includes chronic and acute pain, or wherein the pain is related to cancer, surgery, bone fracture, skeletal pain caused by tumor metastasis, osteoarthritis, tic arthritis, rheumatoid arthritis, titial cystitis, chronic pancreatitis, Visceral pain, inflammatory pain, ne, chronic lower back pain, bladder pain syndrome and athic pain.
  22. 22. A compound of claims 19 or 20 having TrkA tory ty using TR—FRET assay of less than about 1 ,uM.
  23. 23. The use of a compound according to any one of claims 1-9 and 14-18 in the manufacture of a medicament for the treatment of inhibiting yosin receptor kinase A (TrkA) in a patient; or for use in the ent or prevention of conditions, diseases and/0r disorders associated with abnormal or deregulated TrkA kinase activity; or for use in the treatment or prevention of conditions, diseases and/or disorders treatable or preventable by tion of Trk kinase ty, pain, ation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, tive colitis, Crohn’s disease, fibrosis, neurodegenerative disease; a e, disorder, or injury relating to dysmyelination or demyelination or certain infectious diseases, Trypanosoma Cruzi infection; or for use in the treatment of pain.
  24. 24. The use according to claim 23, wherein the pain chronic and acute pain, or wherein the pain is d to cancer, surgery, bone fracture, skeletal pain caused by tumor metastasis, osteoarthritis, psoriatic arthritis, rheumatoid arthn'tis, interstitial cystitis, chronic pancreatitis, Visceral pain, inflammatory pain, migraine, chronic lower back pain, bladder pain syndrome and neuropathic pain.
  25. 25. The use according to any one of claims 23 or 24, wherein the compound has TrkA inhibitory activity using TR-FRET assay of less than about 1 MM.
  26. 26. A compound according to any one of claims l, 9, 15 to 18, substantially as herein described with reference to any one of the es and/or figures.
  27. 27. The use according to claim 23, substantially as herein described with reference to any one of the examples and/or figures.
  28. 28. A pharmaceutical according to claim 17, substantially as herein bed with reference to any one of the examples and/or figures.
NZ626306A 2011-12-12 2012-12-12 Substituted pyrazolo[1,5-a] pyridine as tropomyosin receptor kinase (trk) inhibitors NZ626306B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN4329/CHE/2011 2011-12-12
IN4329CH2011 2011-12-12
PCT/IB2012/003012 WO2013088256A1 (en) 2011-12-12 2012-12-12 Substituted pyrazolo[1,5-a] pyridine as tropomyosin receptor kinase (trk) inhibitors

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NZ626306A NZ626306A (en) 2015-05-29
NZ626306B2 true NZ626306B2 (en) 2015-09-01

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