AU2019275599A1 - Substituted pyrazolo[1,5-a]pyrimidine compounds as TRK kinase inhibitors - Google Patents

Abstract

[00529] Compounds of Formula (I) in which R, R 2, R, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor.

Description

SUBSTITUTED PYRAZOLO[l,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS

This application is a divisional of Nos. 2017268517, 2015200511 and 2009308465, the entire contents of which are hereby incorporated by way of reference.

[0001] The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to a process for making the compounds and to the use of the compounds in therapy. More particularly, it relates to certain substituted pyrazolo[l,5-a]pyrimidine compounds which exhibit Trk family protein tyrosine kinase inhibition, and which are useful in the treatment of pain, inflammation, cancer, and certain infectious diseases.

[0002] The current treatment regimes for pain conditions utilize several classes of compounds. The opioids (such as morphine) have several drawbacks including emetic, constipatory and negative respiratory effects, as well as the potential for addictions. Nonsteroidal anti-inflammatory analgesics (NSAIDs, such as COX-1 or COX-2 types) also have drawbacks including insufficient efficacy in treating severe pain. In addition, COX-1 inhibitors can cause ulcers of the mucosa. Accordingly, there is a continuing need for new and more effective treatments for the relief of pain, especially chronic pain.

[0003] Trk's are the high affinity receptor tyrosine kinases activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family has three members —TrkA, TrkB and TrkC. Among the neurotrophins are (i) nerve growth factor (NGF) which activates TrkA, (ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activate TrkB and (iii) NT3 which activates TrkC. Trk’s are widely expressed in neuronal tissue and are implicated in the maintenance, signaling and survival of neuronal cells (Patapoutian, A. et al., Current Opinion in Neurobiology, 2001, 11, 272-280).

[0004] Inhibitors of the TrlUneurotrophin pathway have been demonstrated to be effective in numerous pre-clinical animal models of pain. For example, antagonistic NGF and TrkA antibodies (for example, RN-624) have been shown to be efficacious in inflammatory and neuropathic pain animal models and in human clinical trials (Woolf, C.J. et al. (1994) Neuroscience 62,327-331; Zahn, P.K. et al. (2004) J. Pain 5, 157-163; McMahon, S. B. et al., (1995) Nat. Med. 1, 774-780; Ma, Q. P. and Woolf, C. J. (1997) Neuroreport 8, 807810; Shelton, D. L. et al. (2005) Pain 116, 8-16; Delafoy, L. et al. (2003) Pain 105, 489497; Lamb, K. et al. (2003) Neurogastroenterol. Motil. 15, 355-361; Jaggar, S. 1. et al. (1999) Br. J. Anaesth. 83, 442-448). Additionally, recent literature indicates after inflammation, BDNF levels and TrkB signaling is increased in the dorsal root ganglion (Cho, L. et al. Brain Research 1997, 749, 358) and several studies have show antibodies that

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2019275599 04 Dec 2019 decrease signaling through the BDNF/TrkB pathway inhibit neuronal hypersensitization and the associated pain (Chang-Qi, L et al. Molecular Pain 2008, 4:27).

[0005] In addition, it has been shown that tumor cell sand tumor invading macrophages directly stimulates TrkA located on peripheral pain fibers. Using various tumor models in both mice and rats it was demonstrated that neutralizing NGF with a monoclonal antibody inhibits cancer related pain to a degree similar or superior to the highest tolerated dose of morphine. In addition, activation of the BDNF/TrkB pathway has been implicated in numerous studies as a modulator of various types of pain including inflammatory pain (Matayoshi, S., J. Physiol. 2005, 569:685-95), neuropathic pain (Thompson, S.W., Proc. Natl. Acad. Sci. USA 1999, 96:7714-18) and surgical pain (Li, C.-Q. et al., Molecular Pain, 2008, 4(28), 1-11). Because TrkA and TrkB kinases may serve as a mediator of NGF driven biological responses, inhibitors of TrkA and/or other Trk kinases may provide an effective treatment for chronic pain states.

[0006] Recent literature has also shown that overexpression, activation, amplification and/or mutation of Trk's are associated with many cancers including neuroblastoma (Brodeur, G. M., Nat. Rev. Cancer 2003, 3, 203-216), ovarian cancer (Davidson. B., et al., Clin. Cancer Res. 2003, 9, 2248-2259), breast cancer (Kruettgen et al, Brain Pathology 2006, 16: 304310), prostate cancer (Dionne et al, Clin. Cancer Res. 1998, 4(8): 1887-1898), pancreatic cancer (Dang et al, Journal of Gastroenterology and Hepatology 2006, 21(5): 850-858), multiple myeloma (Hu et al, Cancer Genetics and Cytogenetics 2007, 178: 1-10), astrocytoma amd medulloblastoma (Kruettgen et al, Brain Pathology 2006, 16: 304-310) glioma (Hansen et al, Journal of Neurochemistry 2007, 103: 259-275), melanoma (Truzzi et al, Journal of Investigative Dermatology 2008, 128(8): 2031-2040, thyroid carcinoma (Brzezianska et al, Neuroendocrinology Letters 2007, 28(3), 221-229.), lung adenocarcinoma (Perez-Pinera et al, Molecular and Cellular Biochemistry 2007, 295(1 &2), 19-26), large cell neuroendocrine tumors (Marchetti et al, Human Mutation 2008, 29(5), 609-616), and colorectal cancer (Bardclli, A., Science 2003, 300, 949). In preclinical models of cancer, Trk inhibitors are efficacious in both inhibiting tumor growth and stopping tumor metastasis. In particular, non-selective small molecule inhibitors of Trk A, B and C and Trk/Fc chimeras were efficacious in both inhibiting tumor growth and stopping tumor metastasis (Nakagawara, A. (2001) Cancer Letters 169:107-114; Meyer, J. et al. (2007) Leukemia, ί10; Pierottia, M.A. and Greco A., (2006) Cancer Letters 232:90-98; Eric Adriaenssens, E. et al. Cancer Res (2008) 68:(2) 346-351) (Truzzi et al, Journal of Investigative Dermatology

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2008, 128(8): 2031-2040. Therefore, an inhibitor of the Trk family of kinases is expected to have utility in the treatment of cancer.

[0007| In addition, inhibition of the neurotrophin/Trk pathway has been shown to be effective in treatment of pre-clinical models of inflammatory diseases. For example, inhibition of the neurotrophin/Trk pathway has been implicated in preclinical models of inflammatory lung diseases including asthma (Freund-Michel, V; Frossard, N.; Pharmacology & Therapeutics (2008), 117(1), 52-76), interstitial cystitis (Hu Vivian Y; et. al. The Journal of Urology (2005), 173(3), 1016-21), inflammatory bowel diseases including ulcerative colitis and Crohn’s disease (Di Mola, F. F, et. al., Gut (2000), 46(5), 670-678) and inflammatory skin diseases such as atopic dermatitis (Dou, Y.-C.; et. al. Archives of Dermatological Research (2006), 298(1), 31-37), eczema and psoriasis (Raychaudhuri, S. P.; et. al. Journal of Investigative Dermatology (2004), 122(3), 812-819).

[0008] The neurotrophin/Trk pathway, particularly BDNF/TrkB, has also been implicated in the etiology of neurodegenerative diseases including multiple sclerosis, Parkinson’s disease and Alzheimer’s disease (Sohrabji, Farida; Lewis, Danielle K. Frontiers in Neuroendocrinology (2006), 27(4), 404-414). Modulation of the ncutroph in/Trk pathway may have utility in treatment of these and related diseases.

[0009] The TrkA receptor is also thought to be critical to the disease process in the infection of the parasitic infection of Typanosoma cruzi (Chagas disease) in human hosts (de Melo-Jorge, M. et al. Cell Host & Microbe (2007), 1(4), 251-261). Thus, TrkA inhibition my have utility in treating Chagas disease and related protozoan infections.

[0010] Trk inhibitors may also find use in treating disease related to an imbalance of the requlation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases. Bone metastases are a frequent complication of cancer, occurring in up to 70 percent of patients with advanced breast or prostate cancer(l) and in approximately 15 to 30 percent of patients with carcinoma of the lung, colon, stomach, bladder, uterus, rectum, thyroid, or kidney. Osteolytic metastases can cause severe pain, pathologic fractures, lifethreatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes. For these reasons, bone metastasis is a serious and costly complication of cancer. Therefore, agents that can induce apoptosis of proliferating osteoblasts would be highly advantageous. Expression of TrkA and TrkC receptors has been observed in the bone forming area in mouse models of bone fracture (K. Asaumi, et aL, Bone (2000) 26(6) 625633). In addition, localization of NGF was observed in almost all bone forming cells (K.

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Asaumi, et al.). Recently, it was demonstrated that a pan-Trk inhibitor inhibits the tyrosine signaling activated by neurotrophins binding to all three of the Trk receptors in human hFOB osteoblasts (J. Pinski, et al., (2002) 62, 986-989). These data support the rationale for the use of Trk inhibitors for the treatment of bone remodeling diseases, such as bone metastases in cancer patients.

[0011] 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)).

[0012] International Patent Application Publications WO 2006/115452 and WO 2006/087538 describe several classes of small molecules said to be inhibitors or Trk kinases which could be useful for treating pain or cancer.

[0013] Pyrazolo[l,5-a]pyrimidine compounds are known. For example, International Patent Application Publication WO 2008/037477 discloses pyrazolo[l,5-a]pyrimidine compounds bearing an alkyl, aryl or heterocyclic group at the 3-position. These compounds are asserted to be P13K and/or mTOR Lipid Kinase inhibitors.

[0014] International Patent Application Publication WO 2008/058126 discloses pyrazolo[l,5-a]pyrimidine compounds bearing a phenyl group at the 3-position. These compounds are asserted to be Pim-kinase inhibitors.

[0015] U.S. Publication US 2006/0094699 discloses pyrazolo[l,5-a]pyrimidine compounds bearing a -C(=O)NH-phenyl, -C(=O)(4-methylpiperidinyl) or -C(=O)NMe(CH2-trimethylpyrazolyl) group at the 3-position for use in combination therapy with a glucocorticoid receptor agonist.

[0016] It has now been found that certain pyrazolo[l,5-a]pyrimidinc compounds bearing an aryl or heteroaryl-substituted heterocyclic group at the 5-position and a group having the formula NR’C(=O)R² at the 3-position, wherein R^l and R² are as defined herein, are inhibitors of Trk kinases, in particular inhibitors of TrkA and/or TrkB, which are useful for treating disorders and diseases which can be treated by inhibiting TrkA and/or TrkB kinases, such as pain, including chronic and acute pain, or cancer. Certain compounds which are dual inhibitors of TrkA and TrkB may be useful in the treatment of multiple types of pain including inflammatory pain, neuropathic pain, surgical pain, and pain associated with cancer, surgery and bone fracture. Selectivity for TrkA and/or TrkB is particularly desirable in compounds for use in treating pain. In addition, compounds of the invention may be useful for treating cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

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2019275599 04 Dec 2019 [0017] Accordingly, one embodiment of this invention provides a compound of the general Formula I:

[0018] or a pharmaceutically acceptable salt thereof, wherein:

[0019] R¹ is H or (1-6C alkyl);

[0020] R² is NR^bR^c, (l-4C)alkyl, (l-4C)fluoroalkyl, CF3, (l-4C)hydroxyalkyl, -(1-4C alkyljhetAr¹, -(1-4C alkyl)NH2, -(1-4C alkyl)NH(l-4C alkyl), -(1-4C alkyl)N(l-4C alkyl)₂, hetAr², hetCyc¹, hetCyc², phenyl which is optionally substituted with NHSO2(1-4C alkyl), or (3-6C)^ecycloalkyl which is optionally substituted with (1-4C alkyl), CN, OH, OMc, NH2, NHMe, N(CH₃)₂. F, CF₃, CO₂(1-4C alkyl), CO₂H, C(=O)NR^eR^f or C(=O)OR^S;

[0021] R^b is H or (1-6C alkyl);

[0022] R^c is H, (l-4C)alkyl, (l-4C)hydroxyalkyl, hetAr³, or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, CF₃ and -0(1-4C alkyl), [0023] or NR^bR^c forms a 4 membered heterocyclic ring having a ring nitrogen atom wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, -OC(=O)(1-4C alkyl), NH₂, -NHC(=O)O(1-4C alkyl) and (l-4C)hydroxyalkyl, [0024] or NR^bR^L forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO₂, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF₃, (l-4C)alkyl, CO₂(1-4C alkyl), CO₂H, NH₂, NHC(=O)O(1-4C alkyl) and oxo, [0025] or NR^bR^c forms a 7-8 membered bridged heterocyclic ring having a ring nitrogen atom and optionally having a second ring heteroatom selected from N and O, wherein said ring is optionally substituted with CO₂(1-4C alkyl);

[0026] hetAr¹ is a 5-membered heteroaryl ring having 1-3 ring nitrogen atoms;

[0027] hetAr² is 5-6 membered heteroaryl ring having at least one nitrogen ring atom and optionally having a second ring heteroatom independently selected from N and S,

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2019275599 04 Dec 2019 wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from (1-4C alkyl), halogen, -(1-4 C)alkoxy, and NH(1-4C alkyl);

[0028] hetCyc¹ is a carbon-linked 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from (1-4C alkyl), and CO₂(1-4C alkyl);

[0029] hetCyc² is a pyridinone or pyridazinone ring which is optionally substituted with a substituent selected from (l-4C)alkyl;

[0030] hctAr' is a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from (l-4C)alkyl;

[0031] R^e is H or (1 -4C)alkyl;

[0032] R^f is H, (l-4C)alkyl, or (3-6C)cycloalkyl;

[0033] or NR^eR^f forms a 5-6-membered azacyclic ring optionally having an additional ring heteroatom selected from N and O, wherein the azacyclic ring is optionally substituted with OH;

[0034] R^g is H or (1 -6C)alkyl;

[0035] Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4C)alkoxy, CF3 and CHF₂, or (ii) a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more halogen atoms;

[0036] X is null, -CH₂-, -CH₂CH₂-, -CH₂O- or -CH₂NR^d-;

[0037] R^d is H or (1-4C alkyl);

[0038] R³ is H or (1-4C alkyl);

[0039] each R⁴ is independently selected from halogen, (l-4C)alkyl, OH, (14C)alkoxy, NH₂, NH(1-4C alkyl) and CH₂OH; and [0040] n is 0, 1,2, 3, 4, 5 or 6.

[0041] In certain embodiments of Formula I, R² is selected from any of the values described above, other than C(=O)NR^eR^f or C(=O)OR^g.

[0042] In certain embodiments of Formula I, R¹ is hydrogen.

[0043] In certain embodiments of Formula I, R¹ is (l-6C)alkyl. A particular example is methyl.

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2019275599 04 Dec 2019 [0044] Tn certain embodiments of Formula I, R² is a group having the formula NR^bR^c, such that the group at the 3 position of the pyrazolo[l,5-a]pyrimidine core of Formula I has the formula -NR¹C(=O)NR^bR^c.

[0045] In certain embodiments, R^b is H or (1-6C alkyl).

[0046] In certain embodiments, R^b is H. In certain embodiments, R^b is (1-6C alkyl), for example Me.

[0047] In certain embodiments, R² is NR^bR^c where R^c is H, (l-4C)alkyl, (14C)hydroxyalkyl, hetAr³, or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, CF₃ and -0(1-4C alkyl).

[0048] In certain embodiments, R² is NR^bR^c, where R^e is hydrogen. In particular embodiments, the group represented by NR^bR^c is NH₂.

[0049] In certain embodiments, R² is NR^bR^c, where R^c is (l-4C)alkyl. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and the like. In particular embodiments, the group represented by NR^bR^c includes NHMe, NMe2 and NH(t-butyl). [0050] In certain embodiments, R² is NR^bR^c, where R^c is (1-4C)hydroxyalkyl. Examples include CH2CH₂OH and CH₂CH₂CH₂OH. In particular embodiments, the group represented by NR^bR^c includes NMc(CH₂CH₂OH).

[0051] In certain embodiments, R² is NR^bR^c, where R^c is hetAr³, and hetAr³ is an optionally substituted 5-6 membered heteroaryl ring having 1-2 ring heteroatoms independently selected fromN and O. An example of hetAr³ includes an isoxazolyl ring. In certain embodiments, hetAr³ is unsubstituted. In other embodiments, hetAr³ is substituted with one or more substituents independently selected from (l-4C)alkyl, for example one or more substituents independently selected from methyl and ethyl. Examples of hetAr³ include dimethylisoxazolyl. In particular embodiments, the group represented by NR^bR^c includes the group having the structure:

[0052] In certain embodiments, R² is NR^bR^e, where R^e is a phenyl group optionally substituted with one or more substituents independently selected from halogen, CN, CF₃ and 0-(1-4C alkyl). Examples of R^c include phenyl, fluorophenyl, chlorophenyl, cyanophenyl, methoxyphenyl, trifluoromethylphenyl, dichlorophenyl, and trimethoxyphenyl. More

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In particular embodiments, the group represented by NR^bR^c includes the structures:

OMe

OMe

OMe [0053] In certain embodiments, R² is NR^bR^c where R^c is selected from H, Me, t-butyl, CH2CH2OH and CH2CH2CH2OH, dimethylisoxazolyl, phenyl, fluorophenyl, chlorophenyl, cyanophenyl, methoxyphenyl, trifluoromethylphenyl, dichlorophenyl, and trimethoxyphenyl. More particular examples include 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3cyanophenyl, 4-cyanophenyl, 4-methoxyphenyl, 2-4-dichlorophenyl, 3(trifluoromethyl)phenyl, 3,5-dichlorophenyl, and 3,4,5-trimethoxyphenyl. In one embodiment, R^b is H. In one embodiments, R^b is (1-6C alkyl), for example methyl.

[0054] In certain embodiments, R² is -NR^bR^c, wherein:

[0055] (i) NR^bR^c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, -OC(=O)(1-4C alkyl), NH2, NHC(=O)O(1-4C alkyl) and (l-4C)hydroxyalkyl, or [0056] (ii) NR^bR^c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO2, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF₃, (l-4C)alkyl, CO2(1-4C alkyl), CO2H, NH₂, NHC(=O)O(1-4C alkyl) and oxo, or [0057] (iii) NR^bR^c forms a 7-8 membered bridged heterocyclic ring having a ring nitrogen atom and optionally having a second ring heteroatom selected from N and O, wherein said ring is optionally substituted with CO2(1-4C alkyl).

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2019275599 04 Dec 2019 [0058] in certain embodiments, R² is -NR^bR^c, wherein -NR^bR^c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), -O(1-4C alkyl), -OC(=O)(1-4C alkyl), NH₂, -NHC(=O)O(1-4C alkyl) and (l-4C)hydroxyalkyl. Examples include azctidinyl rings optionally substituted with one or more substituents independently selected from F, OH, methyl, OMe, OC(=O)C(CH3)₂, NH₂, -NHC(=O)OC(CH₃)₃ and CH₂OH. Particular examples of R² when represented by -NR^bR^c, wherein -NR^bR^c forms a 4 membered heterocyclic ring, include the structures:

H [0059] In certain embodiments, R² is -NR^bR^c, wherein -NR^bR^c forms a 4 membered azcyclic ring optionally substituted with one or two substituents independently selected from OH, (1-4C alkyl), and -0(1-4C alkyl), for example OH, Me and OMe.

[0060] In certain embodiments, R² is -NR^bR^c, wherein -NR^bR^c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO₂, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF₃, (l-4C)alkyl, CO₂(1-4C alkyl), CO₂H, NH₂, NHC(=O)O(1-4C alkyl) and oxo. Examples include optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and piperidinesulfone rings. Examples of substituents on the 5-6 membered heterocyclic ring include OH, F, NH₂, CO₂H, CO₂Et, NHCO₂C(CH₃)₃, CF₃, methyl, ethyl, isopropyl, CO₂C(CH₂)₃ and oxo. In one embodiment, the heterocyclic ring is optionally substituted with one or two of said substituents. Particular examples of R² when represented by -NR^bR^c, wherein -NR^bR^c forms a 5-6 membered heterocyclic ring, include the structures:

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[0061] In certain embodiments, R² is -NR^hR^c, wherein -NR^bR^c forms a 5-membered heterocyclic ring optionally substituted with one or two substituents independently selected from OH and (1-4C) alkyl, for example OH and Me. In certain embodiments, -NR^bR^c forms an azacyclic ring optionally substituted with one to two substituted independently selected from OH and Me.

[0062] In certain embodiments, R² is -NR^bR^c, wherein -NR^bR^c forms a 6-membered heterocyclic ring optionally substituted with one or two substituents independently selected from OH and (1-4C) alkyl, for example OH and Me.

[0063] In certain embodiments, R² is -NR^bR^c, wherein NR^bR^c forms a 7-8 membered bridged heterocyclic ring having a ring nitrogen atom and optionally having a second ring heteroatom selected from N and O, wherein said ring is optionally substituted with CO2(1-4C alkyl). Examples of bridged heterocyclic rings include diazabicyclooctane rings such as 3,8diazabicyclo[3.2.1]octane and oxa-azabicyclo[2.2.1]heptane rings, which are optionally substituted with CO2(1-4C alkyl), such as CO2C(CH₃)₃. Particular examples of R² when represented by -NR^bR^c, wherein -NR^bR^c forms a 7-8 membered bridged heterocyclic ring, include the structures:

[0064] In certain embodiments, R² is selected from (l-4C)alkyl, (l-4C)fluoroalkyl, CF₃, -(l-4C)hydroxyalkyl, (1-4C alkyljhetAr¹, and -(1-4C alkyl)NH(l-4C alkyl).

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L0065J in certain embodiments, R² is (l-4C)alkyl. Particular examples include methyl, isopropyl and tert-butyl.

[0066] In certain embodiments, R² is (l-4C)fluoroalkyl. A particular example includes CF(CH₃)₂.

[0067] In certain embodiments, R² is CF3.

[0068] In certain embodiments, R² is (l-4C)hydroxyalkyl. Particular examples include C(CH₃)₂OH and C(CH₃)₂CH₂OH.

[0069] In certain embodiments, R² is -(1-4C alkyljhetAr¹, where hetAr¹ is a 5membercd hetcroaryl ring having 1-3 ring nitrogen atoms. An example of hetAr¹ is a triazolyl ring, such as 1,2,4-triazolyl. Examples of the (l-4C)alkyl portion include methylene, ethylene, dimethylmethylene, and the like. A particular value for R² when represented by -(1-4C alkyljhetAr¹ is the structure:

[0070] In certain embodiments, R² is -(1-4C alkyl)NH(l-4C alkyl). Examples include groups having the formula (1-4C alkyl)NHCH₃. A particular value include C(CH₃)₂NHCH3.

[0071] In certain embodiments, R² is selected from methyl, isopropyl, tert-butyl, CF(CH₃)₂, CF₃, C(CH₃)₂OH and C(CH₃)₂CH₂OH, 2-(l,2,4-triazolyl)propan-2-yl, and -C(CH₃)₂NHCH₃.

[0072] Tn certain embodiments, R² is (3-6C cycloalkyl) which is optionally

CO₂(1-4C alkyl) or CO₂H. Particular examples of R² include substituted with (l-4C)alkyl, CN, OH, OMe, NH₂, NHMe, N(CH₃)_2! F, CF₃, CO₂(1-4C alkyl) or CO₂H. In certain embodiments, R² is a cyclopropyl ring optionally substituted with (1-4C alkyl), CN, OH, CF₃, the structures:

CN

OH cf₃

CO₂Me co₂h [0073]

In certain embodiments R² is (3-6C cycloalkyl) include cyclopropyl, cyclobutyl and cyclopentyl rings optionally substituted with (1-4C alkyl), CN, OH, CF₃, CO₂(1-4C alkyl) or CO₂H. Examples include cyclobutyl and cyclopentyl rings optionally substituted with OH. Further examples of R² include the structures:

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[0074] In certain embodiments, R² is selected from hetAr², hetCyc¹, and hetCyc². [0075] In certain embodiments, R² is hetAr². Examples of hetAr² include pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, imidazolyl and thiazolyl rings optionally substituted with one or more substituents independently selected from (1-4C alkyl), halogen, (l-4C)alkoxy and NH(1-4C alkyl). Particular examples of substituents for hetAr² include methyl, ethyl, chloro, OMe, and NHCH(CH3)2. In certain embodiments, hetAr² is optionally substituted with 1 or 2 of said substituents. Particular values of R² when represented by hetAr² include the structures:

[0076] In certain embodiments, R² is hetCyc¹. Examples of hetCyc¹ include carbon linked azetidinyl, pyrrolidinyl and piperidinyl rings optionally substituted with one or more substituents independently selected from (1-4C alkyl), CO₂H and CO₂(1-4C alkyl).

Examples of substituents include methyl, ethyl, propyl, CO₂Me, CO₂Et and CO₂C(CHj)3. In one embodiment, hetCyc¹ is optionally substituted with one or two of said substituents. Particular values for R² represented by hetCyc¹ include the structures:

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[0077] In certain embodiments, R² is hetCyc². Examples include a pyridinone or pyridazinone ring which is optionally substituted with a substituent selected from (l-4C)alkyl such as a methyl or ethyl group. Particular values of R² when represented by hetCyc² include the structures:

[0078] In certain embodiments, R² is selected from (i) pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, imidazolyl and thiazolyl rings optionally substituted with one or more substituents independently selected from (1-4C alkyl), halogen, (l-4C)alkoxy and NH(1-4C alkyl); (ii) carbon-linked azetidinyl, pyrrolidinyl and piperidinyl rings optionally substituted with one or more substituents independently selected from (1-4C alkyl), CO2H and CC>2(1-4C alkyl); and (iii) a pyridinone or pyridazinone ring which is optionally substituted with a substituent selected from (l-4C)alkyl.

[0079] In certain embodiments, R² is selected from the structures:

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O

[0080] In certain embodiments, R² is phenyl which is optionally substituted with an

NHSO2(1-4C alkyl) group such a methancsulfonamido or an ethanesulfonamido group. Particular values for R² include the structures:

[0081] In certain embodiments, R² is C(=O)NR^eR^f or C(=O)OR^g.

[0082] In certain embodiments, R² is C(=O)NR^cR^f. In certain embodiments, R^s is H or (l-4C)alkyl and R^f is H, (l-4C)alkyl, or (3-6C)cycloalkyl. Particular values for R² include C(=O)NH₂, C(=O)NMe, C(=O)NMe₂ and C(=O)NH-cyclopropyl.

[0083] In certain embodiments R² is C(=O)NR^eR^f, where NR^eR^f forms a 4-6membered azacyclic ring optionally having an additional ring heteroatom selected from N and O, wherein the azacyclic ring is optionally substituted with OH. Particular values for R² include the structures:

[0084] In certain embodiments where R² is C(=O)OR^g. Particular examples include C(=O)OH and C(=O)Me.

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2019275599 04 Dec 2019 [0085] Referring now to the substituents on the ring at the 5-position of Formula I, in one embodiment Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4C)alkoxy, CF₃ and CHF₂. In one embodiment, Y is phenyl optionally substituted with one or more substituents independently selected from F, Cl, OMe, CF₃ and CHF₂. In certain embodiments, Y is phenyl optionally substituted with one or two of said substituents. Particular values for Y include phenyl, 3-fluorophenyl, 2,5difluorophenyl, 2-chloro-5-fluorophenyl, 2-methoxyphenyl, 2-methoxy-5-fluorophenyl, 2trifluoromethyl-5-fluorophenyl, 2-difhioromethyl-5-fluorophenyl and 3-chloro-5fluorophenyl.

[0086] In one embodiment, Y is a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S and optionally substituted with one or more halogen atoms. Examples include pyridyl and thienyl groups optionally substituted with one or more halogen atoms, for example one or more fluoro atoms. Particular values for Y include 2pyridyl, 3-pyridyl, 5-fluoropyrid-3-yl and 2-thienyl.

[0087] In one embodiment, the Y group has the absolute configuration shown in Figure la:

la [0088] With reference to the R³ substituent, in one embodiment R³ is H. In one embodiment, R³ is (l-4C)alkyl, for example, methyl, ethyl, propyl, isopropyl or butyl. Particular values for R³ include hydrogen and methyl.

[0089] With reference to the R⁴ substituent, in one embodiment R⁴ is halogen. Particular examples are fluoro and chloro.

[0090] In one embodiment, R⁴ is (l-4C)alkyl, such as methyl, ethyl, propyl, isopropyl, or butyl. A particular example is methyl.

[0091] In one embodiment, R⁴ is OH.

[0092] In one embodiment, R⁴ is (1-4 Qalkoxy, for example OMe and OEt.

[0093] In one embodiment, R⁴ is NH₂.

[0094] In one embodiment, R⁴ is NH(1-4C alkyl), for example NHMe, NHEt, NHPr,

NHiPr or NHBu. A particular example is NHMe.

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2019275599 04 Dec 2019 [0095J in one embodiment, R⁴ is CH₂OH.

[0096] In one embodiment, each R⁴ is independently selected from F, Cl, OH, OMe, NH₂, Me, CH₂OH and NHMe.

[0097] In one embodiment, n is 0, 1, 2, 3 or 4. In one embodiment, n is 0, 1, 2 or 3. In one embodiment, n is 0, 1 or 2.

[0098] With continued reference to the ring at the 5-position of Formula I, in certain embodiments, X is null, -CH₂- or -CH₂CH₂-.

[0099] In one embodiment X is null, such that the heterocyclic ring at the 5-position of Formula I has the structure:

[00100] where R³, R⁴, Y and n are as defined herein. In one embodiment, Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (14C)alkoxy, CF3 and CHF₂. In one embodiment, Y is 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more halogen atoms. In one embodiment, R³ is hydrogen. In another embodiment, R³ is methyl. A particular example of the ring at the 5-position of Formula I when X is null includes the structures:

F F

[00101] In one embodiment, X is CH₂, such that the heterocyclic ring at the 5-position of Formula I has the structure:

(R⁴)n [00102] where R³, R⁴, Y and n are as defined herein. In one embodiment Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (1

4C)alkoxy, CF3 and CHF₂. In one embodiment, Y is a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally

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2019275599 04 Dec 2019 substituted with one or more halogen atoms. In one embodiment, R³ is hydrogen. In another embodiment, R³ is methyl. In one embodiment, each R⁴ is independently selected from F, Cl, Me, OH, OMe, NH₂, NHMe, CH2OH, CHF₂ and CF3. In one embodiment, n is 0, 1 or 2. Particular examples of the ring at the 5-position of Formula I when X is CH₂ include the structures:

ci

[00103] In one embodiment, X is CH₂CH₂, such that the heterocyclic ring at the 5position of Formula I has the structure:

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[00104] where R³, R⁴, Y and n are as defined herein. In one embodiment, phenyl optionally substituted with one or more substituents independently selected from halogen, (1

4C)alkoxy, CF₃ and CHF₂. In one embodiment, Y is a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more halogen atoms. In one embodiment, R³ is hydrogen. In another embodiment, R³ is methyl. In one embodiment, n is 0, 1 or 2. In one embodiment, n is 0. Particular examples of the ring at the 5-position of Formula I when X is CH₂CH₂ include the structures:

[00105] In one embodiment, X is -CH₂O-. In one embodiment, the heterocyclic ring at the 5-position of Formula I has the structure:

[00106] where R³, R⁴, Y and n are as defined herein. In one embodiment, Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (1

4C)alkoxy, CF₃ and CHF₂. In one embodiment, Y is phenyl optionally substituted with one or more substituents independently selected from F and (l-4C)alkoxy. In one embodiment,

Y is a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more halogen atoms. In one embodiment, R³ is hydrogen. In another embodiment, R³ is methyl. In one embodiment, n is

0, 1 or 2. Particular examples of the ring at the 5-position of Formula I when X is -CH₂Oincludc the structures:

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[00107] In one embodiment, X is -CH₂NR^d-. In one embodiment, the heterocyclic ring at the 5-position of Formula I has the structure:

R^d [00108] where R³, R⁴, Y, R^d and n are as defined herein. In one embodiment, R^d is H. In one embodiment, R^d is (1-4C alkyl), for example methyl, ethyl, propyl, isopropyl, or butyl. A particular example is methyl. In one embodiment, Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4C)alkoxy, CF? and CHF₂.

In one embodiment, Y is a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more halogen atoms. In one embodiment, n is 0. Particular examples of the ring at the 5-position of Formula I when X is -CH₂NR^d- include the structures:

[00109] Compounds of Formula I include compound of Formula lb, wherein [00110] R¹ is H or (1-6C alkyl);

[00111] R²isNR^bR^c;

[00112] NR^bR^c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 Qalkoxy, -OC(=O)(1-4C alkyl), NH₂, -NHC(=O)O(1-4C alkyl) and (l-4C)hydroxyalkyl, [00113] or NR^bR^c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N,

O and SO₂, wherein the heterocyclic ring is optionally substituted with one or more

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2019275599 04 Dec 2019 substituents independently selected from OH, halogen, CF₃, (l-4C)alkyl, CO2(1-4C alkyl), CO₂H, NH₂, NHC(=O)O(1-4C alkyl) and oxo;

[00114] Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4C)alkoxy, CF₃ and CHF₂;

[00115] X is null, -CH₂-, or -CH₂CH₂-;

[00116] R³ is H or (1-4C alkyl);

[00117] each R⁴ is independently selected from halogen, (l-4C)alkyl, OH, (1-4 Qalkoxy, NH₂, NH(1-4C alkyl) and CH₂OH; and [00118] n is 0,1, or 2.

[00119] In one embodiment of Formula lb, Y is phenyl optionally substituted with one or more halogen atoms. In one embodiment of Formula lb, Y is phenyl optionally substituted with one or two fluorine atoms.

[00120] Tn one embodiment of Formula lb, NR^bR^c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 Qalkoxy, -OC(=O)(1-4C alkyl), NH2, -NHC(=O)O(1-4C alkyl) and (l-4C)hydroxyalkyl, or (ii) NR^bR^c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO2, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF₃, (l-4C)alkyl, CO₂(1-4C alkyl), CO₂H, NH₂, NHC(=O)O(14C alkyl) and oxo.

[00121] In one embodiment of Formula lb, NR^bR^c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO₂, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF₃, (14C)alkyl, CO₂(1-4C alkyl), CO₂H, NH₂, NHC(=O)O(1-4C alkyl) and oxo.

[00122] In one embodiment of Formula lb, n is zero or one.

[00123] In one embodiment of Formula lb, R³ is hydrogen.

[00124] Compounds of Formula lb include compounds of Formula Ic wherein:

[00125] R¹ is H or (1-6C alkyl);

[00126] R² is NR^bR^c;

[00127] NR^bR^c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said heterocyclic ring is optionally substituted with one or more substituents

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2019275599 04 Dec 2019 independently selected from halogen, OH, (1-4C alkyl), (1-4 Qalkoxy, -OC(=O)(1-4C alkyl), NH2, -NHC(=O)O(1-4C alkyl) and (l-4C)hydroxyalkyl;

[00128] Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4C)alkoxy, CF₃ and CHF₂;

[00129] X is -CH₂-;

[00130] R³ is H or (1-4C alkyl);

[00131] each R⁴ is independently selected from halogen, (l-4C)alkyl, OH, (1-4 Qalkoxy, NH₂, NH(1-4C alkyl) and CH₂OH; and [00132] n is 0,1, or 2.

[00133] In one embodiment of Formula Ic, the heterocyclic ring formed by NR^bR^c is optionally substituted with one or two substituents independently selected from F, OH, methyl, OMe, OC(=O)C(CH₃)₂, NH₂, -NHC(=O)OC(CH₃)₃ and CH₂OH.

[00134] In one embodiment of Formula 1c, the heterocyclic ring formed by NR^bR^c is 4 membered azcyclic ring optionally substituted with one or two substituents independently selected from OH, (1-4C alkyl), and -O(1-4C alkyl), for example OH, Me and OMe.

[00135] In one embodiment of Formula Ic, Y is phenyl optionally substituted with one or more halogen atoms. In one embodiment of Formula Ic, Y is phenyl optionally substituted with one or two fluorine atoms.

[00136] Compounds of Formula lb also include compounds of Formula Id wherein: [00137] R¹ is H or (1-6C alkyl);

[00138] R² is NR^bR^c;

[00139] NR^bR^e forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO₂, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF₃, (l-4C)alkyl, CO₂(1-4C alkyl), CO₂H, NH₂, NHC(=O)O(1-4C alkyl) and oxo;

[00140] Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4C)alkoxy, CF₃ and CHF₂;

[00141] X is -CH₂-;

[00142] R³ is H or (1-4C alkyl);

[00143] each R⁴ is independently selected from halogen, (1-4C)all<yl, OH, (1-4 Qalkoxy, NH₂, NH(1-4C alkyl) and CH₂OH; and [00144] n is 0,1, or 2.

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2019275599 04 Dec 2019 [00145] in one embodiment of Formula Id, the heterocyclic ring formed by NR^bR^c is optionally substituted with one or two substituents independently selected from OH, F, NH₂, CO₂H, CO₂Et, NHCO₂C(CH₃)₃, CF₃, methyl, ethyl, isopropyl, CO₂C(CH₂)₃ and oxo.

[00146] In one embodiment of Formula Id, the heterocyclic ring formed by NR^ is a 5-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from OH, F, NH₂, CO₂H, CO₂Et, NHCO₂C(CH3)3, CF3, methyl, ethyl, isopropyl, CO₂C(CH₂)₃ and oxo.

[00147] In one embodiment of Formula Id, the heterocyclic ring formed by NR^bR^c is a membered azacyclic ring optionally substituted with one or more substituents independently selected from OH, F, NH₂, CO₂H, CO₂Et, NHCO₂C(CH₃)3, CF₃, methyl, ethyl, isopropyl, CO₂C(CH₂)₃ and oxo.

[00148] In certain embodiments of Formula Id,, -NR^bR^c forms a 5-membered azacyclic ring optionally substituted with one to two substituted independently selected from OH and Me.

[00149] In one embodiment of Formula Id, the heterocyclic ring formed by NR^bR^c is a membered azacyclic ring optionally substituted with one or more substituents independently selected from OH, F, NH₂, CO₂H, CO₂Et, NHCO₂C(CH3)₃, CF₃, methyl, ethyl, isopropyl, CO₂C(CH₂)3 and oxo.

[00150] In one embodiment of Formula Id, the heterocyclic ring formed by NR^l’R^t is a 6 membered azacyclic ring optionally substituted with one or two substituents independently selected from OH and (1-4C) alkyl, for example OH and Me.

[00151] In one embodiment of Formula Id, Y is phenyl optionally substituted with one or more halogen atoms. In one embodiment of Formula Id, Y is phenyl optionally substituted with one or two fluorine atoms.

[00152] In one embodiment of Formula Ic or Id, n is zero or one.

[00153] In one embodiment of Formula 1c or Id, R³ is hydrogen.

[00154] In one embodiment of Formula Ic or Id, R¹ is hydrogen.

[00155] Compounds of Formula I include compound of Formula le, wherein:

[00156] R¹ is H or (1-6C alkyl);

[00157] R²isNR^bR^c;

[00158] NR^bR^c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said heterocyclic ring is optionally substituted with one or more substituents

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2019275599 04 Dec 2019 independently selected from halogen, OH, (1-4C alkyl), (1-4 Qalkoxy, -OC(=O)(1-4C alkyl), NH₂, -NHC(=O)O(1-4C alkyl) and (l-4C)hydroxyalkyl, [00159] or NR^bR^c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO₂, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF3, (l-4C)alkyl, CO₂(1-4C alkyl), CO₂H, NH₂, NHC(=O)O(1-4C alkyl) and oxo;

[00160] Y is a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more halogen atoms; [00161] X is null, -CH₂-, or -CH₂CH₂-;

[00162] R³ is H or (1-4C alkyl);

[00163] each R⁴ is independently selected from halogen, (l-4C)alkyl, OH, (1-4 Qalkoxy, NH₂, NH(1-4C alkyl) and CH₂OH; and [00164] n is 0,1, or 2.

[00165] Compounds of Formula I include compounds of Formula If, wherein:

[00166] R¹ is H or (1-6C alkyl);

[00167] R² is (l-4C)alkyl, (l-4C)fluoroalkyl, CF3, (l-4C)hydroxyalkyl, -(1-4C alkyljhetAr¹, -(1-4C alkyl)NH2, -(1-4C alkyl)NH(l-4C alkyl), -(1-4C alkyl)N(l-4C alkyl)₂, hetAr², hetCyc¹, hetCyc², phenyl which is optionally substituted with NHSO₂(1-4C alkyl), or (3-6C)cycloalkyl which is optionally substituted with (1-4C alkyl), CN, OH, OMe, NH₂, NHMe, N(CH₃)₂, F, CF₃, CO₂(1-4C alkyl), CO₂H, C(=O)NR^eR^f or C(=O)OR^g;

[00168] hetAr¹ is a 5-membered heteroaryl ring having 1-3 ring nitrogen atoms;

[00169] hetAr² is 5-6 membered heteroaryl ring having at least one nitrogen ring atom and optionally having a second ring heteroatom independently selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from (1-4C alkyl), halogen, -(1-4 Qalkoxy, and NH(1-4C alkyl);

[00170] hetCyc¹ is a carbon-linked 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from (1-4C alkyl), and CO₂(1-4C alkyl);

[00171] hetCyc² is a pyridinone or pyridazinone ring which is optionally substituted with a substituent selected from (l-4C)alkyl;

[00172] R^e is H or (l-4C)alkyl;

[00173] R^f is H, (l-4C)alkyl, or (3-6C)cycloalkyl;

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2019275599 04 Dec 2019 [00174] or NR^eR^f forms a 5-6-membered azacyclic ring optionally having an additional ring heteroatom selected from N and O, wherein the azacyclic ring is optionally substituted with OH;

[00175] R^g is H or (l-6C)alkyl;

[00176] Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4C)alkoxy, CF₃ and CHF₂, or (ii) a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more halogen atoms;

[00177] X is null, -CH₂-, -CH₂CH₂-;

[00178] R^d is H or (1-4C alkyl);

[00179] R³ is H or (1-4C alkyl);

[00180] each R⁴ is independently selected from halogen, (l-4C)alkyl, OH, (14C)alkoxy, NH₂, NH(1-4C alkyl) and CH₂OH; and [00181] n is 0, 1,2, 3,4, 5 or 6.

[00182] In one embodiment of Formula If, Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF₃ and CHF₂.

[00183] In one embodiment of Formula If, Y is a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more halogen atoms.

[00184] In one embodiment of Formula If, R² is selected from (l-4C)alkyl, (14C)fluoroalkyl, CF₃, -(l-4C)hydroxyalkyl, (1-4C alkyljhetAr¹, and -(1-4C alkyl)NH(l-4C alkyl) [00185] In one embodiment of Formula If, R² is selected from methyl, isopropyl, tertbutyl, CF(CH₃)₂, CF₃, C(CH₃)₂OH and C(CH₃)₂CH₂OH, 2-(l,2,4-triazolyl)propan-2-yl, and -C(CH₃)₂NHCH₃.

[00186] In one embodiment of Formula If, R² is a cyclopropyl, cyclobutyl and cyclopentyl ring optionally substituted with (1-4C alkyl), CN, OH, CF₃, CO₂(1-4C alkyl) or CO₂H.

[00187] In one embodiment of Formula If, R² is selected from hetAr², hetCyc¹, and hetCyc².

[00188] In one embodiment of Formula If, R² is selected from (i) pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, imidazolyl and thiazolyl rings optionally substituted with one or more substituents independently selected from (1-4C alkyl), halogen, (l-4C)alkoxy and NH(1-4C

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2019275599 04 Dec 2019 alkyl); (ii) carbon-linked azetidinyl, pyrrolidinyl and piperidinyl rings optionally substituted with one or more substituents independently selected from (1-4C alkyl), CO₂H and CO₂(1-4C alkyl); and (iii) a pyridinone or pyridazinone ring which is optionally substituted with a substituent selected from (l-4C)alkyl.

[00189] In one embodiment of Formula If, R² is C(=O)NR^eR^f or C(=O)OR^g.

[00190] Compounds of Formula I include compound of Formula Ig, wherein [00191] R^l is H or (1-6C alkyl);

[00192] R² is NR^bR^c;

[00193] R^b is H or (1-6C alkyl);

[00194] R^c is H, (l-4C)alkyl, (l-4C)hydroxyalkyl, hetAr³, or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, CF₃ and -0(1-4C alkyl);

[00195] hetAr' is a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from (l-4C)alkyl;

[00196] Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4C)alkoxy, CF₃ and CHF₂, or (ii) a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more halogen atoms;

[00197] X is null, -CH₂-, or -CH₂CH₂-;

[00198] R^d is H or (1-4C alkyl);

[00199] R³ is H or (1-4C alkyl);

[00200] each R⁴ is independently selected from halogen, (l-4C)alkyl, OH, (14C)alkoxy, NH₂, NH(1-4C alkyl) and CH₂OH; and [00201] n is 0, 1,2, 3,4, 5 or 6.

[00202] In one embodiment of Formula Ig, Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4C)alkoxy, CF? and CHF₂.

[00203] In one embodiment of Formula Ig, Y is a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more halogen atoms.

[00204] In one embodiment of Formula Ig, R^c is selected from H, Me, t-butyl, CH₂CH₂OH and CH₂CH₂CH₂OH, dimethylisoxazolyl, phenyl, fluorophenyl, chlorophenyl, cyanophenyl, methoxyphenyl, trifluoromethylphenyl, dichlorophenyl, and trimethoxyphenyl.

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More particular examples include 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-cyanophenyl, 4-cyanophenyl, 4-methoxyphenyl, 2-4-dichlorophenyl, 3-(trifluoromethyl)phenyl, 3,5-dichlorophenyl, and 3,4,5-trimethoxyphenyl.

[00205] In one embodiment of Formula Ig, n is 0, 1 or 2.

[00206] It will be appreciated that certain compounds according to the invention may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic or diastereomeric mixture, or in an enantiomerically pure form. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.

[00207] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. [00208] It will also be appreciated that certain compounds of Formula I may be used as intermediates for further compounds of Formula I.

[00209] The compounds of Formula I include pharmaceutically acceptable salts thereof. In addition, the compounds of Formula T also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula I and/or for separating enantiomers of compounds of Formula I. Examples of particular salts include hydrogen sulfate salts, hydrochloride salts and tri fluoroacetate salts.

[00210] It will further be appreciated that the compounds of Formula I and their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention.

[00211] The compounds of Formula 1 also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds of the invention include compounds wherein one or more hydrogen atoms are replaced deuterium or tritium, or one or more carbon atoms are replaced by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

[00212] The term (1-4C) alkyl as used herein refers to saturated linear or branchedchain monovalent hydrocarbon radicals of one to four carbon atoms, respectively. Examples

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2019275599 04 Dec 2019 include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-l -propyl, 2-butyl, and 2-methyl-2-propyl.

[00213] The term (1-4C) alkoxy as used herein refers to saturated linear or branchedchain monovalent radicals of one to four carbon atoms, respectively, wherein the radical is on the oxygen atom.

[00214] The term (l-4C)hydroxyalkyl as used herein refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one to four carbon atoms, respectively, wherein one of the hydrogen atoms is replaced with an OH group.

[00215] The term halogen includes fluoro, chloro, bromo and iodo.

[00216] According to another aspect, the present invention provides a process for the preparation of a compound of Formula I or a pharmaceutically acceptable salt thereof as defined herein which comprises:

[00217] (a) for a compound of Formula I wherein R² is NR^bR^c, reacting a corresponding compound of formula II

X

II [00218] with a compound having the formula HNR^bR^c in the presence of a coupling reagent; or [00219] (b) for a compound of Formula I wherein R² is NR^bR^c and R^b is H, reacting a corresponding compound of formula II with a compound having the formula O=C=N-R^C; or [00220] (c) for a compound of Formula I wherein R is hetAr or a phenyl ring which is optionally substituted with NHSO₂(1-4C alkyl) , reacting a corresponding compound of Formula II with a corresponding compound having the formula HOC(=O)R² in the presence of a coupling reagent and a base; or [00221] (d) for a compound of Formula I wherein R² is (l-4C)alkyl, (14C)fluoroalkyl, CF3, (l-4C)hydroxyalkyl, or (3-6C)cycloalkyl which is optionally substituted with (1-4C alkyl), CN, OH, CF3, CO2(1-4C alkyl) or CO2H, reacting a corresponding compound of Formula II with a corresponding compound having the formula (R²CO)2O in the presence of a base; or [00222] (e) for a compound of Formula I wherein R² is (l-4C)alkyl, (14C)fhioroalkyl, CF₃, (l-4C)hydroxyalkyl, or (3-6C)cycloalkyl which is optionally substituted

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2019275599 04 Dec 2019 with (1-4C alkyl), CN, OH, CF₃, CO2(1-4C alkyl) or CO₂H, reacting a corresponding compound of Formula II with a corresponding compound having the formula HOC(=O)R² in the presence of a coupling reagent and a base; or [00223] (f) for a compound of Formula I wherein R² is C(=O)NR^eR^f, reacting a compound of formula VII

[00224] with a compound having the formula HNR^eRⁱ in the presence of a base; or [00225] (g) for a compound of Formula I wherein R is C(=O)OR^g, reacting a compound of Formula II with methyl 2-chloro-2-oxoacetate, and treating with an alkali hydroxide to prepare a compound of formula I where R^s is H; and [00226] removing or adding any protecting groups if desired, and forming a salt if desired.

[00227] Referring to methods (a) and (e), examples of suitable coupling reagents include CDI (carbonyl diimidazole), phosgene, and bis(trichloromethyl) carbonate. The reaction is optionally performed in the presence of a tertiary amine base, such as DIEA (diisopropylethylamine). Suitable solvents include dichloromethane, dichloroethane, THF, and DMF. The reaction is conveniently performed at ambient temperature.

[00228] Compounds of formula II

X

II [00229] can be prepared by reducing a corresponding compound of formula III

X

III [00230] under standard reducing conditions, for example reacting a compound of formula II with zinc dust under acidic conditions, such as in the presence of NH4CI (saturated

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2019275599 04 Dec 2019 aqueous), HO, or acetic acid. Another example of such standard reducing conditions includes reacting compounds of formula III under a hydrogen atmosphere in the presence of a precious metal catalyst to corresponding compounds of formula II.

[00231] Compounds of Formula III can be prepared by nitrating a corresponding compound having the formula IV

X

IV [00232] using standard nitrating conditions known in the art, for example by reacting a corresponding compound of Formula IV with nitric acid in the presence of an activating agent such as TFA or concentrated sulfuric acid.

[00233] Compounds of the formula IV can be prepared by coupling a corresponding compound of Formula V

[00234] where Z is a leaving group or atom, such as a halogen (for example Cl), with a corresponding compound having the formula VI

R³

X

VI [00235] where R³, R⁴, η, X and Y are as defined herein, in a suitable solvent such as an alcohol (for example n-butanol or isopropanol), at elevated temperatures, for example at temperatures between 100 and 180 °C, for example at a temperature of about 140 °C. Compounds of Formula V are commercially available or can be prepared by standard methods known in the art.

[00236] Compounds of Formula 11 and III are also believed to be novel and provide a further embodiment of this invention.

[00237] Referring to method (b), suitable solvents include dichloromethane, dichloroethane, THF, and DMF. The reaction is conveniently performed at ambient temperature.

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2019275599 04 Dec 2019 [00238] Referring to method (c), suitable coupling reagents include HATU, HBTU, TBTU, DCC (N,N'-dicyclohexylcarbodiimide), DIEC (1-(3-dimethylaminopropy 1)-3ethylcarboiimide) and any other amide coupling reagents well known to persons skilled in the art. Suitable bases include tertiary amine bases such as diisopropylethylamine (DIEA) and tricthylaminc. Suitable solvents include DMF and CH₃CN. The reaction is conveniently performed at temperatures between 0 °C and ambient temperature.

[00239] Referring to method (d), suitable bases include amine bases such as pyridine or triethylamine, and suitable coupling reagents include HATU, HBTU, TBTU, DCC (N,N'dicyclohexylcarbodiimide), DIEC (l-(3-dimethylaminopropyl)-3-ethylcarboiimide) and any other amide coupling reagents well known to persons skilled in the art. Suitable solvents include dichloromethane and dichloroethane. The reaction is conveniently performed at temperatures between 0 °C and ambient temperature.

[00240] The ability of compounds to act as TrkA inhibitors may be demonstrated by the assays described in Examples A and B. The ability of compounds to act as TrkB inhibitors may be demonstrated by the assay described in Example B.

[00241] Compounds of Formula I are useful for treating chronic and acute pain, including pain associated with cancer, surgery, and bone fracture. Certain compounds which are inhibitors of TrkA and/or TrkB may be useful in the treatment of multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fracture.

[00242] Compounds of Formula I are also useful for treating cancers including neuroblastoma, ovarian, pancreatic and colorectal cancer.

[00243] Compounds of Formula I are also useful for treating inflammation and certain infectious diseases.

[00244] In addition, compounds of Formula I may also be used to treat interstitial cystitis (IC), painful bladder syndrome (PBS), urinary incontinence, asthma, anorexia, atopic dermatitis, and psoriasis.

[00245] Compounds of Formula I may also be used to treat demyelination and dysmyelination by promoting myelination, neuronal survival, and oligodendrocyte differentiation via blocking Sp35-TrkA interaction.

[00246] Compounds of Formula I which are dual inhibitors of TrkA and TrkB may be useful in the treatment of multiple types of pain including inflammatory pain, neuropathic pain, surgical pain and pain associated with cancer.

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2019275599 04 Dec 2019

100247] Compounds of Formula I may be of therapeutic value for the useful in the treatment of bone-related diseases (such as those involving bone resorption). Examples of bone-related diseases include metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, ankylosing spondylitis, Paget's disease, and periodontal disease. The osteoporosis may be attributed to (1) menopause in women, (2) aging in men or women, (3) suboptimal bone growth during childhood and adolescence that resulted in failure to reach peak bone mass, and/or (4) bone loss secondary to other disease conditions, eating disorders, medications and/or medical treatments.

[00248] Other osteolytic diseases that can be treated according to the present invention are more localized. A particular example is metastatic tumor-induced osteolysis. In this condition, bone cancers or bone metastases induce localized osteolysis that causes pain, bone weakness and fractures. Such localized osteolysis also permits tumors to grow larger by creating more space for them in the bone and releasing growth factors from the bone matrix. Cancers presently known to cause tumor-induced osteolysis include hematological malignancies (e.g., myeloma and lymphoma) and solid tumors (e.g., breast, prostate, lung, renal and thyroid), all of which the present invention contemplates treating.

[00249] As used herein, the term treatment includes prophylaxis as w ell as treatment of an existing condition.

[00250] Accordingly, another aspect of this invention provides a method of treating diseases or medical conditions in a mammal, wherein said disease or condition is treatable with an inhibitor of TrkA and/or TrkB, comprising administering to said mammal one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent said disorder. In a particular embodiment, the invention provides a method of treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[00251] In another embodiment, the invention provides a method of treating osteolytic disease in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[00252] The compounds of the present invention can be used in combination with one or more additional drugs that work by the same or a different mechanism of action. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate

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2019275599 04 Dec 2019 administration of the individual components of the treatment. Examples include antiinflammatory compounds, steroids (e.g., dexamethasone, cortisone and fluticasone), analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), and opioids (such as morphine), and chemotherapeutic agents.

[00253] In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other component(s) of such conjoint treatment in addition to compositions of the present invention may be, for example, surgery, radiotherapy, chemotherapy, signal transduction inhibitors and/or monoclonoal antibodies.

[00254] Accordingly, the compounds of Formula I may be administered in combination with one or more agents selected from mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, intercalating antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, cytostatic agents anti-androgens, targeted antibodies, HMG-CoA reductase inhibitors, and prenyl-protein transferase inhibitors.

[00255] The phrase effective amount means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat or prevent a particular disease, condition, or disorder which can be treated with an inhibitor of TrkA and/or TrkB, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[00256] The amount of a compound of Formula I that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.

[00257] As used herein, the term mammal refers to a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.

[00258] Compounds of the invention may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. rectally or orally), the nose, lungs, musculature or vasculature, or transdermally or dermally. Compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions,

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2019275599 04 Dec 2019 suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion. Such compositions form a further aspect of the invention.

[00259] According to another aspect, the present invention provides a pharmaceutical composition, which comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, as defined hereinabove. In one embodiment, the pharmaceutical composition includes the compound of Formula I together with a pharmaceutically acceptable diluent or carrier.

[00260] According to another aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in therapy, such as the treatment of a condition treatable with an inhibitor or TrkA and/or TrkB, such as a TrkA and/or TrkB mediated condition, such as one or more conditions described herein.

[00261] According to a further aspect, the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, in the treatment of a condition that can be treated with an inhibitor of TrkA and/or TrkB, such as a TrkA and/or TrkB mediated condition, such as a condition as defined hereinabove. In one embodiment, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection.

[00262] In one embodiment, a compound of the invention is selected from any one of: [00263] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3y 1)-3 -hydroxyazetidine-1 -carboxamide;

[00264] (R)-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-l, 1 -dimethylurea;

[00265] (R)-l-tert-butyl-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3 -yljurea;

[00266] (R)-l -(5-(2-(2,5-difluorophenyl)pyrrolidin-l -yl)pyrazolo[l ,5-a]pyrimidin-3y 1)-3 -phenylurea;

[00267] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yljisobutyramide;

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2019275599 04 Dec 2019 [00268] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)- l-methyl-6-oxo-l,6-dihydropyridazine-3-carboxamide;

[00269] (R)-N-(5-(4,4-difluoro-2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-hydroxyazetidine-l-carboxamide;

[00270] (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-hydroxyazetidine-l-carboxamide;

[00271] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)morpholine-4-carboxamide;

[00272] N-(5-(2-(3-fluorophenyl)-2-methylpyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3y 1)-3 -hydroxyazetidine-1 -carboxamide;

[00273] (R)-N-(5-(2-(3-chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-hydroxyazetidine-l-carboxamide;

[00274] (R)-N-(5-(2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-hydroxyazetidine-l-carboxamide;

[00275] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)morpholine-4-carboxamide;

[00276] (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin3-yl)-3-hydroxypyrrolidine-1 -carboxamide;

[00277] (3R,4R)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3 -y 1)-3,4-dihydroxypyrrolidine-1 -carboxamide;

[00278] (R)-N-(5-(2-(2,5-difluorophcnyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-3-methoxyazetidine-1-carboxamide;

[00279] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3y 1)-3 -hydroxy-3-methylazetidine-1 -carboxamide;

[00280] (R)-l -(5-(2-(2,5-difluorophenyl)pyrrolidin- l-yl)pyrazolo[ 1,5-a]pyrimidin-3yl)-3-(4-fluorophenyl)urea;

[00281] (R)-l-(4-chlorophenyl)-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo[ 1,5-a]pyrimidin-3-yl)urea;

[00282] (R)-l-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-3-(4-methoxyphenyl)urea;

[00283] (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-methoxyazetidine-1 -carboxamide;

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2019275599 04 Dec 2019 [00284J (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l -yl)pyrazolo[l ,5a]pyrimidin-3-yl)-3-hydroxy-3-methylazetidine-l-carboxamide;

[00285] (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)morpholine-4-carboxamide;

[00286] (S)-tert-butyl 4-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-l yl)pyrazolo [ 1,5-a]pyrimidin-3 -ylcarbamoyl)-2-methylpiperazine-1 -carboxylate;

[00287] (S)-N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1 -yl)pyrazolo[ 1,5a]pyrimidin-3-yl)-3-methylpiperazine-l-carboxamide;

[00288] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-4-isopropylpiperazine-1 -carboxamide;

[00289] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-4-ethylpiperazine-1 -carboxamide;

[00290] (R)-N -(5-(2-(2,5-difluorophenyl)pyrrolidin-l -yl)pyrazolo[l, 5-a]pyrimidin-3yl)-4-methylpiperazine-1 -carboxamide;

[00291] N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3y 1)-3,5 -dimethylpiperazine-1 -carboxamide;

[00292] (S)-tert-butyl 4-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l ,5a]pyrimidin-3 -ylcarbamoyl)-2-methylpiperazine-1 -carboxylate;

[00293] (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidm-l-yl)pyrazolo[l,5-a]pyrimidm3-yl)-3-methylpiperazine-1 -carboxamide hydrochloride;

[00294] (R)-N-(5-(2-(3-fluorophcnyl)pyrrolidm-l-yl)pyrazolo[l,5-a]pyrimidm-3-yl)3-hydroxyazetidine-l-carboxamide;

[00295] (R)-methyl 1-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-ylcarbamoyl)cyclopropanecarboxylate;

[00296] (R)-l -(5-(2-(2,5-difluorophenyl)pyrrolidm- l-yl)pyrazolo[ 1,5-a]pyrimidin-3ylcarbamoyl)cyclopropanecarboxylic acid;

[00297] (S)-N-(5-((R)-2-(3-chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1 -carboxamide;

[00298] (R)-N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide;

[00299] (S)-N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-lyl)pyrazolo [ 1,5-a]pyrimidin-3 -y 1)-3 -hydroxypyrrolidine-1 -carboxamide;

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2019275599 04 Dec 2019 [00300J (R)-N-(5-(2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-l -yl)pyrazolo[l ,5a]pyrimidin-3-yl)-4-hydroxypiperidine-1 -carboxamide;

[00301] (R)-N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-l-carboxamide;

[00302] (S)-N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-l-carboxamide;

[00303] (R)-N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1 -carboxamide;

[00304] (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidm-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-4-hydroxypiperidine-1 -carboxamide;

[00305] (R)-N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidm-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-hydroxypiperidine-1 -carboxamide;

[00306] (S)-N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1 -yl)pyrazolo[ 1,5a]pyrimidm-3-yl)-3-hydroxypiperidine-1 -carboxamide;

[00307] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)pivalamide;

[00308] (R)-tert-butyl 3-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l ,5a]pyrimidin-3-yl carbamoyl )azcti d i nc-1 -carboxylate;

[00309] (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)azetidine-3-carboxamide;

[00310] (R)-tcrt-butyl 4-(5-(2-(2-chloro-5-fluorophcnyl)pyrrolidin-l-yl)pyrazolo[l ,5a]pyrimidin-3-ylcarbamoyl)-4-methylpiperidine-1 -carboxylate;

[00311] (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1 -yl)pyrazolo[ 1,5a]pyrimidin-3-yl)-4-methylpiperidine-4-carboxamide;

[00312] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-2-hydroxy-2-methylpropanamide;

[00313] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-1 -(trifluoromethyl)cyclopropanecarboxamide;

[00314] (R)-1 -cyano-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1 -yl)pyrazolo[ 1,5a]pyrimidin-3-yl)cyclopropanecarboxamide;

[00315] (R)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-2-methylpyrrolidine-2-carboxamide;

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2019275599 04 Dec 2019 [00316] (R)-N-(5-(2-(2,5-difhiorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-2-fluoro-2-methylpropanamide;

[00317] (R)-N-(5-(2-(2,5-di fl uorophcny I )py rro lidin-1 -yl)pyrazolo [ 1,5-a]pyrimidin-3 yl)-2-(isopropylamino)thiazole-4-carboxamide;

[00318] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l ,5-a]pyrimidin-3yl)-2-methyl-2-( 1 Η-1,2,4-triazol-1 -yl)propanamide;

[00319] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)pyrazine-2-carboxamide;

[00320] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-5-methylpyrazine-2-carboxamide;

[00321] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)picolinamide;

[00322] (R)-N -(5-(2-(2,5-difluorophenyl)pyrrolidin-l -yl)pyrazolo[l, 5-a]pyrimidin-3yl)-6-methylpicolinamide;

[00323] (R)-5-chloro-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)picolinamide;

[00324] (R)-4-chloro-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)picolinamide;

[00325] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidm-l-yl)pyrazolo[l,5-a]pyrimidin-3y 1)-3 -methylpicolinamide;

[00326] (R)-N-(5-(2-(2,5-difluorophcnyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-3-hydroxy-2,2-dimethylpropanamide;

[00327] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-1 -hydroxy cyclopropanecarboxamide;

[00328] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-2-methyl-2-(methylamino)propanamide;

[00329] (R)-N-(5-(2-(2,5-difhiorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)pyrimidine-2-carboxamide;

[00330] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)picolinamide;

[00331] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)3-methylpicolinamide;

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2019275599 04 Dec 2019 [00332] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)1 -methyl-2-oxo-1,2-dihydropyridine-4-carboxamide;

[00333] (R)-6-chloro-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)picolinamide;

[00334] (R)-4-(ethylsulfonamido)-N-(5-(2-(3-fluorophenyl)pyrrolidin-lyl)pyrazolo[ 1,5-a]pyrimidin-3-yl)benzamide;

[00335] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidm-3-yl)1 -methyl-1 H-pyrazole-3 -carboxamide;

[00336] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)lH-pyrazole-3-carboxamide;

[00337] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidm-l-yl)pyrazolo[l,5-a]pyrimidm-3-yl)6-methoxypicolinamide;

[00338] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidm-l-yl)pyrazolo[l,5-a]pyrimidm-3yl)nicotinamide;

[00339] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidm-l-yl)pyrazolo[l,5-a]pyrimidm-3yl)isonicotinamide;

[00340] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1 -yl)pyrazolo[ 1,5-a]pyrimidin-3-yl)6-methylnicotinamide;

[00341] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidm-3-yl)-

2- methoxynicotinamide;

[00342] (R)-N-(5-(2-(3-fluorophcnyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-

3- methylisonicotinamide;

[00343] (S)-N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1 -yl)pyrazolo[ 1,5a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1 -carboxamide;

[00344] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)5-methylpyrazine-2-carboxamide;

[00345] (R)-N-(5-(2-(3-fluorophenyl)pyrrolidm-l-yl)pyrazolo[l,5-a]pyrimidm-3-yl)1 -methyl-1 H-imidazole-2-carboxamide;

[00346] (S)-N-(5-((R)-2-(5-fluoro-2-(trifluoromcthyl)phenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide;

[00347] (R)-N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-lyl)pyrazolo [ 1,5-a]pyrimidin-3 -y 1)-3 -hydroxypyrrolidine-1 -carboxamide;

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2019275599 04 Dec 2019 [00348] (R)-N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidm-lyl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-l-carboxamide;

[00349] (S)-N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-l-carboxamide;

[00350] (S)-N-(5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-l -yl)pyrazolo[l ,5a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1 -carboxamide;

[00351] (R)-N-(5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1 -carboxamide;

[00352] (S)-N-(5-((R)-2-(5-fluoro-2-mcthoxyphcnyl)pyrrolidin-l -yl)pyrazolo[ 1,5a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1 -carboxamide;

[00353] (S)-N-(5-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-l -yl)pyrazolo[ 1,5a]pyrimidin-3-yl)-3-hydroxypiperidine-1 -carboxamide;

[00354] (1 S,4S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l -yl)pyrazolo[ 1,5a]pyrimidm-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxamide;

[00355] (R)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1 -carboxamide;

[00356] (1S ,3R)-N-(5 -((R)-2-(2,5 -difluorophenyl)pyrrolidin-1 -y I )py razo Io [1,5a]pyrimidin-3-yl)-3-hydroxycyclopentanecarboxamide;

[00357] (lS,3S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-hydroxycyclopentanecarboxamide;

[00358] (R)-N-(5-(2-(2,5-difluorophcnyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-3-hydroxycyclobutan ecarboxamide;

[00359] (R)-N¹-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-N²,N²-dimethyloxalamide;

[00360] (R)-N¹-(5-(2-(2,5-difluorophenyl)pyrrolidin-l -yl)pyrazolo[ 1,5-a]pyrimidin-3yl)-N²-methyloxalamide;

[00361] (R)-N¹-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)oxalamide;

[00362] (R)-N¹-cyclopropyl-N2-(5-(2-(2,5-difluorophcnyl)pyrrolidin-lyl)pyrazolo[l ,5-a]pyrimidin-3-yl)oxalamide;

[00363] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-2-(3-hydroxyazetidin-1 -yl)-2-oxoacetamide;

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2019275599 04 Dec 2019 [00364] N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l ,5-a]pyrimidin-3yl)-2-((S)-3-hydroxypyrrolidin-l-yl)-2-oxoacetamide;

[00365] (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3yl)-2-morpholino-2-oxoacetamide;

[00366] (R)-methyl 2-(5-(2-(2,5-difluorophenyl)pyrrolidin-l -yl)pyrazolo[l ,5a]pyrimidin-3-ylamino)-2-oxoacetate;

[00367] (R)-2-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3ylamino)-2-oxoacetic acid;

[00368] and salts thereof.

[00369] Particular examples of salts of the above compounds include hydrogen sulfate salts, hydrochloride salts and trifluoroacetate salts.

Examples [00370] The following examples illustrate the invention. In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge, and were used without further purification unless otherwise indicated. Tetrahydrofuran (THF), dichloromcthane (DCM, methylene chloride), toluene, and dioxane were purchased from Aldrich in Sure/Seal™ bottles and used as received.

[00371] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.

[00372] Column chromatography was done on a Biotage system (Manufacturer: Dyax Corporation) having a silica gel or C-18 reverse phase column, or on a silica SepPak cartridge (Waters).

[00373] Acronyms found in the examples have the following meanings:

CDI	carbonyldiimidazole
DIEA	diisopropylethylamine
DCM	dichloromethane
DME	dimethoxyethane
DMF	dimethylformamide
DMSO	dimethylsulfoxide
HATU	O-(7-azabenzotriazol-1 -yl)-1,1,3,3-tetramethyluronium hcxafluorophosphate
PS-DMAP	polystyrene-bound dimethylaminopyridine
TFA	trifluoroacetic acid

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Example A

TrkA ELISA assay [00374] An enzyme-linked immunosorbant assay (ELISA) was used to assess TrkA kinase activity in the presence of inhibitors. Immulon 4HBX 384-well microtiter plates (Thermo part #8755) were coated with a 0.025 mg/mL solution of poly (Glu, Ala, Tyr; 6:3:1; Sigma P3899). Various concentrations of test compound, 2.5 nM TrkA (Invitrogen Corp., histidine-tagged recombinant human TrkA, cytoplasmic domain), and 500 μΜ ATP were incubated for 25 minutes at ambient temperature in the coated plates while shaking. The assay buffer consisted of 25 mM MOPS pH 7.5, 0.005% (v/v) Triton X-100 and 5 mM MgCL. The reaction mixture was removed from the plate by washing with PBS containing 0.1% (v/v) Tween 20. The phosphorylated reaction product was detected using 0.2 pg/mL of a phosphotyrosine specific monoclonal antibody (clone PY20) conjugated to horseradish peroxidase in conjunction with the TMB Peroxidase Substrate System (KPL). After the addition of IM phosphoric acid, the chromogenic substrate color intensity was quantitated via absorbance at 450 nm. IC50 values were calculated using either a 4 or 5-parameter logistic curve fit.

[00375] In this assay, compounds of the invention had an average IC50 below 1000 nM. Certain compounds had an average IC50 below 100 nM. Table 1 provides specific IC50 values for compounds of this invention when tested in this assay.

Table 1

Example No.	TrkA Elisa Enzyme IC50 (nM)
1	20.7
2	15.8
3	22.2
4	5
5	12.1
6	19.2
7	77.5
8	13.7
9	820.8
10	187.9
11	171
12	26.5
13	32.2
14	9.7
15	13.3

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Example No.	TrkA Elisa Enzyme IC50 (nM)
16	27.5
17	19.7
18	4.6
19	10.1
20	4.8
21	27.9
22	11.5
23	41.7
24	55
25	82.3
26	45
27	106.7
28	57.4
29	98
30	153.7
31	88.3
32	115.6
33	4.7
34	98.2
35	20.2
36	18
37	8.7
38	85.5
39	25.7
40	30.8
41	4.1
42	28.3
43	11.7
44	13.4
45	6.3
46	37.3
47	190.3
48	15.3
49	29.2
50	12.4
51	5.2
52	4.2
53	31
54	14.2
55	3.1
56	14.4
57	2.2
58	3.1
59	1.7
60	4.2

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Example No.	TrkA Elisa Enzyme IC50 (nM)
61	4
62	4
63	1.7
64	7.5
65	16.5
66	52.5
67	3
68	4
69	6.2
70	55.6
71	3.5
72	45.5
73	8.5
74	15.3
75	7.4
76	53.3
77	71.8
78	47
79	5.7
80	320.2
81	8
82	6.6
83	35.4
84	3.2
85	5.7
86	14
87	14.6
88	156.1
89	896.1
90	11.3
91	10.2
92	107.4
93	28.5
94	20.3
95	42.5
96	27.4
97	47.45
98	7.65
99	4.65
100	15.85
101	10.1
102	12.75
103	82.4
104	7.65
105	4.7

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Example B

TrkA and TrkB Omnia Assay [00376] Trk enzymatic selectivity was assessed using Omnia™ Kinase Assay reagents from Invitrogen Corp. Enzyme (either TrkA or TrkB from Invitrogen Corp.) and test compound (various concentrations) were incubated for 10 minutes at ambient temperature in a 384-well white polypropylene plate (Nunc catalog# 267462). Omnia Tyr Peptide #4 (for TrkA) or #5 (for TrkB), as well as ATP, were then added to the plate. Final concentrations were as follows: 20 nM enzyme, 500 μΜ of ATP for TrkA assay or 1 mM ATP for TrkB assay, 10 μΜ peptide substrate. The assay buffer consisted of 25 mM MOPS pH 7.5, 0.005% (v/v) Triton X-100 and 5 mM MgCl₂. The production of phosphorylated peptide was monitored continuously for 70 minutes using a Molecular Devices FlexStation II³⁸⁴ microplate reader (excitation = 360 nm; emission = 485 nm). Initial rates were calculated from the progress curves. IC50 values were then calculated from these rates using either a 4 or 5-parameter logistic curve fit.

[00377] In this assay, compounds of the invention had an average IC50 below 1000 nM. Certain compounds had an average IC50 below 100 nM.

Preparation A

F

Preparation of (R)-2-(2,5-difluorophenyl)pyrrolidinc [00378] Step A: Preparation of (R)-tert-butyl 2-('2,5-difluoror)henvl)nvrrolidine-lcarboxylate: A solution of tert-butylpyrrolidine-1-carboxylate (20 g, 116.8 mmol) and (-)sparteine (32.9, 140 mmol) in MTBE (360 mF) was cooled to -78 °C, and sec-BuEi (100 mF, 140 mmol, 1.4 M in cyclohexane) was introduced dropwise via cannula, keeping the internal temperature under -70 °C. The resulting solution was stirred for 3 hours at -78 °C, followed by addition of a solution of ZnCl₂ (93.4 mF, 93.4 mmol, IM in Et₂O) drop-wise with rapid stirring, keeping the internal temperature below -65 °C. The resulting light suspension was stirred at -78 °C for 30 minutes and then warmed to ambient temperature. The resulting mixture was charged with 2-bromo-l,4-difluorobenzenc (14.5 mL, 128 mmol), followed by Pd(OAc)₂ (1.31 g, 5.8 mmol) and i-Bu3P-HBF4 (2.03 g, 7.0 mmol) in one portion. After stirring overnight at ambient temperature, 10.5 mL of NH4OH solution was added and the reaction was stirred for another hour. The resulting slurry was filtered through

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CELITE and washed with Et₂O (1 L). The filtrate was washed with HCI (0.5 L, IM aq.) and brine. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5-10% EtOAc/hexanes to give product (R)-tertbutyl 2-(2,5-difluorophenyl)pyrrolidine-l-carboxylate as yellow oil (23.9 g, 72% yield).

[00379]

Step B: Preparation of (R)-2-(2.5-difluorophcnyl)pvrrolidine: To (R)-tcrt butyl 2-(2,5-difluorophenyl)pyrrolidine-l-carboxylate (23.9 g, 84.4 mmol) was added 56.2 mL 4N HCI (dioxane). After stirring at ambient temperature for 2 hours, 200 mL of ether was added and the mixture was stirred for 10 minutes. The resulting slurry was filtered, yielding the hydrochloride salt of the product as a white solid (17.2 g). To obtain the free base, the HCI salt product was dispersed in a mixture of EtOAc (200 mL) and NaOH solution (100 mL, 2 N aq.) The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were filtered and concentrated to give the desired product as a liquid (13.2g, 85% yield).

[00380] Step C: Determination of Enantiomeric Excess (ee%) of (R)-2-(2,5difluoronhenvDpyrrolidine: To an ethanol solution of (R)-2-(2,5-difluorophenyl)pyrrolidine was added excess N-(2,4-dinitro-5-fluorophenyl)-L-alanine amide (FDAA, Marfey’s reagent). The mixture was heated to reflux for approximately two minutes. After cooling to ambient temperature, the reaction mixture was diluted with acetonitrile and injected onto HPLC (YMC ODS-AQ 4.6 * 50 mm 3 pm 120A column; mobile phase: 5-95% solvent B in A; solvent A: H₂O/ 1% IP A/ 10 mM ammonium acetate, and solvent B: ACN/1% IPA/10 mM ammonium acetate; flow rate: 2 mL/rnin) to determine the enantiomeric excess of the product by calculating the peak areas of the two diastereomeric derivatives formed. A 1:1 racemic sample was prepared according the same procedure described herein, replacing (R)2-(2,5-difluorophenyl)pyrrolidine with (rac)-2-(2,5-difluorophenyl)pyrrolidine. The ee% of the product obtained as described above was determined to be > 93%.

Preparation B

Preparation of (R)-5-(2-(2,5-difluorophenvl)pvrrolidin-l-vl)pvrazolo[l,5-a]pyrimidin-3amine

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2019275599 04 Dec 2019 [00381] Step A: Preparation of (R)-5-(2-(2.5-difluorophcnvl)nyrrolidin-lyDpyrazolol 1,5-alpyrimidine: In a pressure reaction tube was added 5-chloropyrazolo[l,5a]pyrimidine (4.2 g, 27 mmol), (R)-2-(2,5-difluorophenyl)pyrrolidine (Preparation A; 5.3 g, 29 mmol), anhydrous n-butanol (5 ml, 55 mmol), and DIEA (9.5 ml, 55 mmol). The yellowish suspension was sealed and heated in an oil bath (160 °C) overnight. The reaction was cooled to ambient temperature, diluted with EtOAc (250 mL), and filtered, rinsing the solid with EtOAc. The filtrate (330 mL) was washed with water (2 x 150 mL), brine (100 mL), concentrated, and purified by silica chromatography, eluting with 2:1 EtOAc/hexanes to give the product as a bright yellowish solid (5.6 g, 68% yield).

[00382] Step B: Preparation of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)-3nitropyrazolol 1,5-alpyrimidine: (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidine (3.3 g, 10.99 mmol), was dissolved in 25 mL TFA at ambient temperature to give a clear yellowish solution, then nitric acid (3.434 mL, 54.94 mmol) was added drop-wise to the solution with rapid stirring. After addition, the reaction mixture was stirred for another 15 minutes at ambient temperature, then quenched by pouring onto ice with rapid stirring. The resulting yellowish suspension was filtered, rinsed with water, then the solid was triturated with MeOH (50 mL, with brief sonication), and vacuum-filtered, giving the pure product as a fine off-white powder (2.2 g, 58% yield).

[00383] Step C: Preparation of (R)-5-(2-(2.5-difkioronhcnyl)pyriOlidin-lvDpyrazoloI 1,5-a1pyrimidin-3 -amine: To a yellowish solution of (R)-5-(2-(2,5difluorophenyl)pyrrolidin-l-yl)-3-nitropyrazolo[l,5-a]pyrimidine (2.3 g, 6.66 mmol), in a 1:1 mixture of MeOH/DCM (30 mL/30 mL) was added Zn dust (4.36 g, 66.6 mmol) [<10 micron, Aldrich] while stirring. Saturated NH4CI aqueous solution (30 mL) was added dropwise to this suspension with rapid stirring. After NH4CI addition was complete, the reaction mixture was allowed to cool to ambient temperature and stirred for another 15 minutes. The reaction was diluted with DCM (50 mL) and filtered through a GF/F paper, rinsing the wet cake with DCM. The organic layer of the filtrate was separated, and the aqueous layer was extracted with DCM (2 x 50 mL). The organic layers were combined, washed with brine (100 mL), dried over Na₂SO4, and concentrated, to provide the basically pure product as a brownish foamy solid (2.08 g, 99% yield), which was used without further purification.

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Example 1

(R )-N-(5 -(2-(2,5-difl uorophcny I toyrrol i di η-1 -y I )r> yrazo Io [ 1,5-a] pyri m i di n-3-y I )-3 hydroxyazetidine-1 -carboxamide [00384] To a DCM (1.0 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyirolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol), was added CDI (39 mg, 0.24 mmol) at ambient temperature in one portion. After stirring two hours, azetidin-3ol hydrochloride (35 mg, 0.32 mmol) [purchased from Oakwood] was added in one portion, followed by addition of DIEA (0.083 mL, 0.48 mmol). After stirring for 5 minutes, the reaction was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 48% acetonitrile/water to yield the final product as a yellowish foamy powder (66 mg, 100% yield). MS (apci) m/z = 415.2 (M+H).

Example 1A

(R)-N-(5 -(2-(2,5 -difluorophenvDpyrro lidin-1 -vDpyrazolo [ 1,5-a]pvrimidin-3 -yl)-3 hydroxyazetidine-1 -carboxamide sulfate [00385] To a solution of (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l -yl)pyrazolo[l ,5a]pyrimidin-3-yl)-3-hydroxyazetidine-l-carboxamide (44 mg, 0.11 mmol) in methanol (3 mL) at ambient temperature was added sulfuric acid in methanol (531 pL, 0.11 mmol). The resulting solution was stirred for 30 minutes then concentrated to provide (R)-N-(5-(2-(2,5difluorophenyl)pyrrolidin-1 -yl)pyrazolo [ 1,5 -a]pyrimidin-3-yl)-3 -hydroxyazetidine-1 carboxamide sulfate (38 mg, 0.074 mmol, 70 % yield) as a yellow solid.

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Example IB

(R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[L5-a1pyrimidin-3-y 1)-3hydroxyazetidine-1 -carboxamide hydrochloride [00386] To a methanol (1 mL) solution of (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidinl-yl)pyr^az^ol^o[l,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-l-carboxamide (5.2 mg, 0.013 mmol) was added HC1 as a solution is dioxane (30 llL). After 30 minutes, the reaction was concentrated to provide (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-hydroxyazetidine-l-carboxamide hydrochloride (5.7 mg, 0.013 mmol, 101 % yield) as a yellow solid.

Example 2

(R)-3-(5-(2-(2,5-difluoror)henvl)pvrrolidin-l-vl)nvrazolo[L5-a1r>vrimidin-3-vl)-Lldimethylurea [00387] To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difhiorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, dimethylamine (0.095 mL -< 2N THF, 0.19 mmol) was added in one portion. The reaction was stirred for 5 minutes, then concentrated, and the residue was directly purified by reversephase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a yellowish foamy powder (33 mg, 90% yield). MS (apci) m/z = 387.2 (M+H).

Example 2A

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2019275599 04 Dec 2019 (R)-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-l -yllpyrazolol 1,5-a |pyrimidin-3-vl)-1,1 dimethylurea hydrochloride [00388] To a methanol (1 mL) solution of (R)-3-(5-(2-(2,5-difluorophenyl)pyrrolidinl-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-l,l-dimethylurea (8.5 mg, 0.022 mmol) was added HCI as a solution is dioxane (30 pL). After 30 minutes, the reaction was concentrated to provide (R)-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-l,ldimethylurea hydrochloride (6.7 mg, 0.016 mmol, 72 % yield) as a yellow solid.

Example 3

(R)-l-tert-butyl-3-(5-(2-(2.5-difluoror)henyl)pyrrolidin-l-yl)pyrazolori,5a]pyrimidin-3 -yllurea [00389] To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difhiorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol) was added 2isocyanato-2-methylpropane (9.4 mg, 0.095 mmol) at ambient temperature drop-wise, followed by addition of DIEA (0.028 mL, 0.16 mmol). The reaction was stirred for 4 hours then concentrated, and the residue was directly purified by reverse-phase column chromatography, eluting with 5 to 65% acetonitrile/watcr to yield the final product as a paleyellowish solid (27 mg, 82% yield). MS (apci) m/z = 415.1 (M+H).

Example 4

(R)-l-(S-Q-^.S-difluorophenyllpyrrolidin-l-yllpyrazolol l,5-a1pyrimidin-3-yf)-3phenylurea [00390] To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol) was added isocyanatobenzene (19 mg, 0.16 mmol) at ambient temperature drop-wise. The reaction was stirred for 5 minutes then concentrated, and the residue was directly purified by reverse-phase

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2019275599 04 Dec 2019 column chromatography, eluting with 5 to 60% acetonitrile/water to yield the final product as a pale-yellowish solid (30 mg, 87% yield). MS (apci) m/z = 435.2 (M+H).

Example 4A

(R)-l-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-alpyrimidin-3-yl)-3phenylurea sulfate [00391] To a solution of (R)-l-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5

a]pyrimidin-3-yl)-3-phenylurea (10.1 mg, 0.0232 mmol) in methanol (0.5 mL) at ambient temperature was added sulfuric acid in methanol (232 liL, 0.0232 mmol) . The resulting solution was stirred for 30 minutes then concentrated to provide (R)-1-(5-(2-(2,5difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-phenylurea sulfate (12 mg, 0.0225 mmol, 96.9 % yield) as a yellow solid.

Example 5

\ I ,2-,

V-1 ΗΝ--γ

YY^F λ' (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[L5-a1pyrimidin-3vDisobutyramide [00392] A DCM (0.5 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 20 mg, 0.063 mmol) was cooled in an ice bath, followed by addition of isobutyric anhydride (11.0 mg, 0.070 mmol) and pyridine (10 mg, 0.12 mmol) drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 1 hour. The reaction mixture was directly purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the final product as a yellowish foamy solid (17 mg, 71%). MS (apci) m/z = 386.2 (M+H).

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Example 6

(R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolon,5-a1pyrimidin-3-yl)-lmethvl-6-oxo-l,6-dihydropvridazine-3-carboxamide [00393] Step A: Preparation of______(R)-5-(2-(3-fluorophenyl)pyrrolidin-1 ylIpyrazolol 1.5-a1pyrimidin-3-amine: Prepared according to the method of Preparation B, substituting (R)-2-(2,5-difluorophenyl)pyrrolidine in Step A with (R)-2-(3fluorophenyl)pyrrolidine.

[00394] Step B: Preparation of (R )-2-(3-fl uorophcnyl (pyrrol id inc: Prepared by the method of Preparation A, substituting 2-bromo-1,4-difluorobenzene with l-bromo-3fluorobenzene in step A.

[00395] Step C: Preparation of______(R)-N-(5-(2-(3-fluorophenvl)pvrrolidin-1 vl)pvrazolori,5-a1pyrimidin-3-vl)-l-methvl-6-oxo-l,6-dihydropyridazine-3-carboxamide: To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine (30 mg, 0.10 mmol), l-methyl-6-oxo-l,6-dihydropyridazine-3-carboxylic acid (34 mg, 0.22 mmol), and HATU (84 mg, 0.22 mmol) was added 0.8 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.053 mL, 0.30 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The resulting fine yellowish suspension from the reaction mixture was filtered, rinsed with first DMF and then ether, to provide the final product as a yellowish solid (14.4 mg, 33% yield). MS (apci) m/z = 434.2 (M+H).

Example 7

(R)-N-(5-(4,4-difluoro-2-(3-fluoronhenvl)pvrrolidin-l -yllpyrazolol 1,5-a1nvrimidin-3 yl)-3 -hy droxyazetidine-1 -carboxamide

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2019275599 04 Dec 2019 [00396] Steps A1-A6: Preparation of (R)-4,4-difluoro-2-(3-fluoronhenvl)-nvrrolidme: [00397] Step Al. Preparation of (R )-3-('tert-butyl dimethyls! I y lox v )-5-/3fl uorophcny I )-3,4-d ih ydro-2 H-p vrro Ic: (3-Fluorophenyl)magnesium bromide (203.2 mL x 0.5 M ether, 102 mmol) was slowly added (via syringe) to a solution of (R)-3-(tertbutyldimethylsilyloxy)-4-chlorobutanenitrile (9.5 g, 40.6 mmol) in 120 mL of MTBE. The reaction was stirred for two hours and then DME (35 ml) was slowly added over 15 minutes, followed by EtOH (23 mL). After stirring for overnight, brine and 1 M NaOH (50 mL each) were added to the reaction. After stirring for one hour, the reaction mixture was filtered through Celite, rinsing the solid with EtOAc. The filtrate was washed with 1 N NaOH and brine, filtered through Phase Separator filter paper, and concentrated, yielding the crude product, which was carried to the next step without further purification (12.8 g, 107% yield).

[00398] Step A2. Preparation of (3R.5R)-5-(3-fluorophenyl)pvrrolidin-3-ol: (R)-3(tert-butyldimethylsilyloxy)-5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole (5.0 g, 17.0 mmol) was dissolved in 50 mL methanol and 10 mL AcOH and cooled to -40 °C. NaBH₄ (1.6 g, 43 mmol) was slowly added in small portions. The reaction was allowed to warm to ambient temperature. Most of the solvent was removed by rotary evaporation. The reaction was taken up in 200 mL of EtOAc, washed with 1 N NaOH, and filtered through Phase Separator filter paper, and concentrated. The crude product was taken up in 20 mL of 2 N HC1 in dioxane. The reaction was concentrated, taken up in 200 mL of EtOAc, washed with 1 N NaOH, filtered, and concentrated, yielding the crude product, which was carried to the next step without further purification (2.93g, 95% yield).

[00399] Step A3. Preparation of (2R,4R)-tert-butvl 2-(3-fluorophenvD-4hydroxypyrrolidine-1 -carboxylate: To a mixture of (3R,5R)-5-(3-fluorophenyl)pyrrolidin-3ol (3.4 g, 18.8 mmol), di-tert-butyl dicarbonate (4.91 g, 22.5 mmol), and PS-DMAP (2.29 g, 18.8 mmol) were added 100 mL DCM and 50 mL THF, and the reaction was left to stand for one week with periodic sonication treatment. The mixture was filtered, concentrated, and purified by silica column chromatography, eluting with 2-10% MeOH/DCM to yield the pure product (4 g, 76% yield).

[00400] Step A4. Preparation of (R)-tert-butyl 2-(3-fluorophenvl)-4-oxopyrrolidine1-carboxylate: (2R,4R)-tert-Butyl 2-(3-fluorophenyl)-4-hydroxypyrrolidine-1 -carboxylate (1.4 g, 4.98 mmol) and Dess-Martin periodinanc (2.53 g, 5.97 mmol) were mixed in 50 mL DCM and stirred at ambient temperature overnight. For workup, 20 mL IN NaOH was added to reaction, and stirred for 30 minutes, followed by addition of 20 mL brine. The

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2019275599 04 Dec 2019 reaction mixture was extracted with several portions of DCM. The combined organic extracts were filtered through a Phase Separator filter paper, concentrated, and purified by reverse phase chromatography, eluting with 20-70% acetonitrile/water to yield the product as yellow oil (600 mg, 43% yield.) [00401] Step A5. Preparation of (R)-tcrt-butyl 4.4-difluoro-2-(3fluorophenyDpyrrolidine-1 -carboxylate: (R)-tert-butyl 2-(3-fluorophenyl)-4-oxopyrrolidine1-carboxylate (200 mg, 0.72 mmol) and Bis(2-methoxyethyl)aminosulfur trifluoride (238 mg, 1.07 mmol) were mixed in 25 mL DCM and stirred at ambient temperature overnight. For workup, 5 mL IN NaOH was added and the reaction stirred for 30 minutes. The reaction was filtered through Celite, rinsing with DCM. Brine (2 mL) was added to the filtrate and the mixture was filtered through a Biotage Phase Separator frit, washing with several portions of DCM. The combined organic extracts were concentrated and purified by reverse phase chromatography, eluting with 20-90% acetonitrile/water to yield the product as clear oil (180 mg, 83%).

[00402] Step A6. Preparation of (R)-4,4-difluoro-2-('3-fluorophenvl)pyrrolidine: To (R)-tert-butyl 4,4-difluoro-2-(3-fluorophenyl)pyrrolidine-l-carboxylate (180 mg, 0.6 mmol) in a pressure reaction tube was added a solution of HC1 (2 mL, 4 N dioxane, 8 mmol), then the reaction was sealed and heated at 60 °C for 4 hours. For workup, the reaction was poured into a mixture of ice and 1 M NaOH, and extracted with several portions of EtOAc. The combined organic extracts were filtered through a Phase Separator filter paper and concentrated, yielding the final product as clear oil, which was used in the next step without further purification.

[00403] Step B: Preparation of fR)-5-(4,4-difluoro-2-(3-fluorophenyl)pyrrolidin-lvl)pyrazolo[ 1,5-a1pyrimidin-3-amine: Prepared according to the method of Preparation B, substituting (R)-2-(2,5-difluorophenyl)pyrrolidine in Step 1 with (R)-4,4-difluoro-2-(3fluorophenyl)-pyrrolidine.

[00404] Step C: Preparation of (R)-N-(5-(4.4-difluoro-2-(3-fluorophenyl)pyrrolidin-lyl)pyrazolo[ 1,5-a1pvrimidin-3-vl)-3-hvdroxvazetidine-1 -carboxamide: To a DCM (0.7 mL) solution of (R)-5-(4,4-difluoro-2-(3-fluorophenyl)pyrrolidm-l-yl)pyrazolo[l,5-a]pyrimidin3-amine (25 mg, 0.074 mmol), was added CDI (18 mg, 0.11 mmol) at ambient temperature in one portion. After stirring two hours, azetidin-3-ol hydrochloride (16 mg, 0.15 mmol) was added in one portion, followed by addition of DIEA (0.039 mL, 0.22 mmol). The reaction was stirred overnight, then concentrated, and the residue was directly purified by reverseWO 2010/048314

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2019275599 04 Dec 2019 phase column chromatography, eluting with 0 to 45% acetonitrile/water to yield the final product as a yellowish oil (15 mg, 48% yield). MS (apci) m/z = 433.1 (M+H).

Example 8

OH (R)-N-(5-(2-(2-chloro-5-fluorophenvl)pvrrolidin-l-vl)pyrazolo[l,5-a]pyrimidin-3-vl)-3hydroxyazetidine-1 -carboxamide [00405] Step A: Preparation of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-lvl)pyrazolo[ 1,5-a]pyrimidin-3-amine: Prepared according to the method of Preparation B, substituting (R)-2-(2,5-difluorophenyl)pyrrolidine in Step 1 with (R)-2-(2-chloro-5fluorophenyl)pyrrolidine.

[00406] Step B: Preparation of (R)-2-(2-chloro-5-fluorophenyl)pyrrolidinc: Prepared by the method of Preparation A, substituting 2-bromo-l,4-difluorobenzene with 2-bromo-lchloro-4-fluorobenzene in Step A.

[00407] Step C: Preparation of (R)-N-(5-(2-(2-chloro-5-fluorophcnyl)pyiTOlidin-lyl)pyrazolo[ 1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1 -carboxamide: To a DCM (0.8 mL) solution of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrroHdin-l-yl)pyrazolo[l ,5-a]pyrimidin-3amine (30 mg, 0.090 mmol) was added CDI (29 mg, 0.18 mmol) at ambient temperature in one portion. After stirring two hours, azetidin-3-ol hydrochloride (20 mg, 0.18 mmol) was added in one portion, followed by addition of DIEA (0.047 mL, 0.27 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 50% acetonitrile/water to yield the final product as a yellowish foamy powder (33 mg, 85% yield). MS (apci) m/z = 431.1 (M+H).

Example 8A

(R)-N-(5-(2-(2-chloro-5-fluorophenyl)pvrrolidin-l-vl)pyrazolo[l,5-a]pvrimidin-3-vl)-3 hydroxyazetidine-1 -carboxamide

OH

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2019275599 04 Dec 2019 [00408] To a solution of (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-l-carboxamide (11.1 mg, 0.0258 mmol) in methanol (1 mL) at ambient temperature was added sulfuric acid in methanol (258 liL, 0.0258 mmol). The resulting solution was stirred for 30 minutes then concentrated to provide (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1 -yl)pyrazolo[ 1,5-a]pyrimidin-3yl)-3-hydroxyazetidine-1-carboxamide sulfate (10 mg, 0.0189 mmol, 73.4 % yield) as a yellow solid.

Example 9

^•o (R)-N-(5-(2-(3-fluorophenvl)pyrrolidin-l-yl)pvrazolo[l,5-a1pyrimidin-3vl)morpholine-4-carboxamide [00409] Step A: Preparation of (R)-5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[ 1,5a]nvrimidin-3-amine: Prepared according to the method of Preparation B, substituting (R)-2(2,5-difluorophenyl)pyrrolidine in Step A with (R)-2-(3-fluorophenyl)pyrrolidine.

[00410] Step B: Preparation of (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-lyl)pyrazolo[ 1,5-a1pvrimidin-3-vf)morr>holine-4-carboxamide: To a DCM (0.8 mL) solution of (R)-5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine (50 mg, 0.17 mmol) was added CDI (41 mg, 0.25 mmol) at ambient temperature in one portion. After stirring two hours, morpholine (22 mg, 0.25 mmol) was added in one portion. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 54% acetonitrile/water to yield the final product as a yellowish foamy powder (69 mg, 100% yield). MS (apci) m/z = 411.2 (M+H).

Example 10

OH

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N-(5-(2-(3-fluorophenyl)-2-methylpyrrolidin-l -yllpyrazolol 1,5-a1pyrimidin-3-yl)-3hydroxyazetidine-1 -carboxamide [00411] Step A: Preparation of tert-butyl 4-(3-fl uorophcny I )-4-oxobuty I carbamate: In a round-bottomed flask was charged ten-butyl 2-oxopyrrolidine-l-carboxylate (2.2 g, 11.9 mmol) and THF (25 mL). The mixture was cooled down to -78 °C first, followed by slow addition of (3-fluorophenyl)magnesium bromide (17.8 mL, 17.8 mmol, 1.0 M solution in THF) over 15 minutes. The mixture was stirred for 3 hours, during which time the bath temperature rose from -78 °C to -10 °C. The reaction was quenched by drop-wise addition of IN HC1 (2 mL) and warmed up to ambient temperature, followed by addition of EtOAc and water. After separating the organic layer, the aqueous layer was extracted with EtOAc three times. The combined organic layers was dried over Na₂SO4 and concentrated to yield the product as a clear oil.

[00412] Step B: Preparation of 5-(3-fluorophenvl)-3,4-dihydro-2H-pyrrole: Crude tert-butyl 4-(3-fluorophenyl)-4-oxobutylcarbamate was dissolved in 10 mL CH₂C1₂ first, followed by addition of 10 mL 4N HC1 (dioxane). The reaction was stirred at ambient temperature for 4 hours and filtered, giving the HC1 salt of the desired product as a white solid (~ 2 g). To obtain the free base product, EtOAc and saturated NaHCO; (aq.) solution were added to the HC1 salt of the product. After separating the organic layer, the aqueous layer was extracted with EtOAc three times. The combined organic extracts was dried over Na₂SO4 and concentrated to yield 5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole (1.46g, 75%).

[00413] Step C: Preparation of 2-(3-fluorophenyl)-2-methylpyrrolidine: A solution of 5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole (6.1 g, 37.4 mmol) in 100 mL THF was cooled to -78 °C, and boron trifluoride diethyl etherate (9.47 mL, 74.8 mmol) was added drop-wise over 5 minutes. The resulting cloudy reaction mixture was stirred at -78 °C for 40 minutes. MeLi (1.6 M in diethyl ether, 46.7 mL, 74.8 mmol) was added drop-wise over 10 minutes. The mixture was stirred at -78 °C for another 2 hours, then warmed up to ambient temperature overnight. For workup, water and EtOAc were added to the reaction mixture, and the aqueous layer was acidified with HC1 solution. After separating and discarding the organic layer, the aqueous layer was basified with NaOH (6 N, aq.) to pH = 12 and extracted twice with EtOAc. The combined organic extracts was dried over Na₂SO4 and concentrated to get a mixture of the desired product (2-(3-fluorophenyl)-2-methylpyrrolidine) and starting material (4.3 g, 1.3:1 of the desired product:starting material, 37% yield). The crude product was used in the next step without any further purification.

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2019275599 04 Dec 2019 [00414] Step D: Preparation of 5-(2-(3-fluorophenvl)-2-methylpvrrolidin-1 y 1 Ipyrazolol 1,5-a1pyrimidin-3-amine: Prepared according to the method of Preparation B, substituting (R)-2-(2,5-difluorophenyl)pyrrolidine in Step 1 with 2-(3-fluorophenyl)-2methylpyrrolidine.

[00415] Step E: Preparation of N-(5-(2-(3-fluorophenvl)-2-methylpvrrolidin-lyllpyrazolol 1,5-a1pyrimidin-3-yF)-3-hydroxyazetidine-1 -carboxamide: To a DCM (0.7 mL) solution of 5-(2-(3-fluorophenyl)-2-methylpyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine (25 mg, 0.08 mmol) was added CDI (20 mg, 0.12 mmol) at ambient temperature in one portion. After stirring one hour, azetidin-3-ol hydrochloride (20 mg, 0.12 mmol) was added in one portion, followed by addition of DIEA (0.028 mL, 0.16 mmol). The reaction was stirred for 30 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a yellowish oil (18 mg, 55% yield). MS (apci) m/z = 411.2 (M+H).

Example 11

F °^H (R )-N-(5-(2-(3-chloro-5-fluorophcny! (pyrrol idin-1 -yllpyrazolol 1,5-a1pyrimidin-3yl)-3 -hydroxyazetidine-1 -carboxamide [00416] Step A: Preparation of (RlG-G-G-chloro-S-fluorophenyllpyrrolidin-lyl)pyrazolo[ 1,5-a]pyrimidin-3-amine: Prepared according to the method of Preparation B, substituting (R)-2-(2,5-difluorophenyl)pyrrolidine in Step A with (R)-2-(3-chloro-5fluorophenyl)pyrrolidine.

[00417] Step B: Preparation of (R)-2-(3-chloro-5-fluorophenyf)pyrrolidine: Prepared by the method of Preparation A, substituting 2-bromo-l,4-difluorobenzene with l-bromo-3chloro-5-fluorobenzene in step A.

[00418] Step C: Preparation of (R)-N-(5-i2-(3-chloro-5-fluorophenyl)pyrrolidin-lyflpyrazolol 1,5-alpyrimidin-3-vl)-3-hydroxyazetidine-1 -carboxamide: To a DCM (0.7 mL) solution of (R)-5-(2-(3-chloro-5-fluorophenyl)pyrrolidin-1 -yl)pyrazolo[ 1,5-a]pyrimidin-3amine (20 mg, 0.06 mmol, prepared as described in the following paragraph), was added CDI (20 mg, 0.12 mmol) at ambient temperature in one portion. After stirring two hours, azetidinWO 2010/048314

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3-ol hydrochloride (20 mg, 0.18 mmol) was added in one portion, followed by addition of DIEA (0.032 mL, 0.18 mmol). The reaction was stirred overnight before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a solid (29 mg, 74% yield). MS (apci) m/z = 431.2 (M+H).

Example 12

OH (R)-N-(5-(2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1 -yDpyrazolol 1,5al pvrimidin-3 -vD-3-hydroxyazetidine-1 -carboxamide [00419] Step A: Preparation of (R)-5-(2-(2-(difluoromethyl)-5fluorophenyPpyrrolidin-1 -yDpyrazolo [ 1,5-a1pyrimidin-3 -amine: Prepared according to the method of Preparation B, substituting (R)-2-(2,5-difluorophenyl)pyrrolidine in Step A with (R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidine.

[00420] Step B: Preparation of (R)-2-(3-chloro-5-fluorophenyl)pyrrolidine: Prepared by the method of Preparation A, substituting 2-bromo-l,4-difluorobenzene with 2-bromo-l(difluoromethyl)-4-fluorobcnzcne in step A.

[00421] Step C: Preparation of (R)-N-(5-(2-(2-(difluoromethvl)-5-fluorophenyl) pyrro lidin-1 -vPpyrazolo[ 1,5-a]pvrimidin-3-vD-3-hydroxyazetidine-1 -carboxamide: To a DCM (0.6 mL) solution of (R)-5-(2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (10 mg, 0.028 mmol, prepared as described in the following paragraph), was added CD! (9 mg, 0.056 mmol) at ambient temperature in one portion. After stirring two hours, azetidin-3-ol hydrochloride (6 mg, 0.056 mmol) was added in one portion, followed by addition of DIEA (0.015 mL, 0.084 mmol). The reaction was stirred overnight before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 50% acetonitrile/water to yield the final product as a solid. MS (apci) m/z = 447.2 (M+H).

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Example 13

F (R)-N-(5-(2-(2,5-difluorophenyl)pvrrolidin-l-vl)pyrazolori.5-a1pyrimidin-3yl)morpholine-4-carboxamide [00422] To a DCM (0.8 ml) solution of (R)-5-(2-(2,5-difluorophenyl)pyirolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, morpholine (17 mg, 0.19 mmol) was added in one portion. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 55% acetonitrile/water to yield the final product as a yellowish foamy powder (37 mg, 91% yield). MS (apci) m/z = 429.2 (M+H).

Example 14

(S)-N-(5-((R)-2-(2,5-difluorophenvl)pvrrolidin-l-vl)pvrazolo[l,5-a1pyrimidin-3-vl)3-hvdroxypyrrolidine-1 -carboxamide [00423] To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, (S)pyrrolidin-3-ol (17 mg, 0.19 mmol) [purchased from Suven Life Sciences] was added in one portion. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 50% acetonitrile/water to yield the final product as a yellowish foamy powder (30 mg, 74% yield). MS (apci) m/z = 429.2 (M+H).

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Example 14A

(S)-N-(5-((R)-2-(2.5-difluorophenvl)pvrrolidin-l-vl)pyrazolori.5-a1pvrimidin-3-vll3-hydroxypyrrolidine-l-carboxamide sulfate [00424] To a solution of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide (4.5 mg, 0.011 mmol) in methanol (1 mL) at ambient temperature was added sulfuric acid in MeOH (105 pL, 0.011 mmol). The resulting solution was stirred for 30 minutes then concentrated to provide (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[ 1,5-a]pyrimidin-3-yl)3-hydroxypyrrolidine-l-carboxamide sulfate (5.2 mg, 0.0099 mmol, 94 % yield) as a yellow solid.

Example 15

(3R,4R)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a1pyrimidin-3vl)-3,4-dihydroxypyrrolidine-1 -carboxamide [00425] To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 26 mg, 0.08 mmol) was added CDI (27 mg, 0.16 mmol) at ambient temperature in one portion. After stirring two hours, (3R,4R)pyrrolidine-3,4-diol (17.3 mg, 0.16 mmol) [obtained from benzyl de-protection of commercially available (3R,4R)-l-benzylpyrrolidine-3,4-diol] was added in one portion. A few drops of DMSO were added to obtain a clear reaction solution. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 45% acetonitrile/water to yield the final product as a yellowish foamy powder (27 mg, 74% yield). MS (apci) m/z = 445.2 (M+H).

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Example 16

(R)-N-(5-(2-(2.5-difluorophenyl)pyrrolidin-l-yllpyrazolol 1.5-a1pyrimidin-3-yl)-3methoxyazetidine-1 -carboxamid e [00426] To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, 3methoxyazetidine 2,2,2-trifluoroacetate (38 mg, 0.19 mmol) [obtained from N-de-protection of commercially available tert-butyl 3-methoxyazetidine-l-carboxylate using TFA in DCM] was added in one portion, followed by addition of DIEA (0.050 mL, 0.29 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reversephase column chromatography, eluting with 0 to 55% acetonitrile/water to yield the final product as a yellowish foamy powder (34 mg, 83% yield). MS (apci) m/z = 429.2 (M+H).

Example 16A

/° (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yllpyrazolol 1.5-a1pyrimidin-3-yl)-3methoxyazetidine-1 -carboxamide sulfate [00427] To a solution of(R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-methoxyazetidine-l-carboxamide (6.2 mg, 0.014 mmol) in methanol (1 mL) at ambient temperature was added sulfuric acid in methanol (145 pL, 0.014 mmol). The resulting solution was stirred for 30 minutes then concentrated to provide (R)-N-(5-(2-(2,5difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-methoxyazetidine-lcarboxamide sulfate (7.2 mg, 0.014 mmol, 94 % yield) as a yellow solid.

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Example 17

HO (R )-N-(5 -(2-(2.5 -difluorophenvDpyrrolidin-1 - yl )p yrazo Ιο Γ1,5-al pyri m i di n-3-y I )-3 hydroxy-3-methylazetidine-1 -carboxamide [00428] To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1yl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, 3methoxyazetidine 3-methylazetidin-3-ol hydrochloride (26 mg, 0.19 mmol) [obtained from N-de-protection of commercially available l-benzhydryl-3-methylazetidin-3-ol under hydrogenation conditions facilitated by Pd(OH)₂ in EtOH and 1% TFA] was added in one portion, followed by addition of DIEA (0.050 mL, 0.29 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 50% acetonitrile/water to yield the final product as a yellowish foamy powder (27 mg, 66% yield). MS (apci) m/z = 429.2 (M+H).

Example 17A

HO (R)-N-(5 -(2-(2.5 -difluorophenyDpyrrolidin-1 -yDpyrazolo Γ1.5-a1pyrimidin-3 -yl)-3 hvdroxv-3-methvlazetidine-1 -carboxamide sulfate [00429] To a solution of (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidm-3-yl)-3-hydroxy-3-methylazetidine-l-carboxamide (3.1 mg, 0.0072 mmol) in methanol (1 mL) at ambient temperature was added sulfuric acid in methanol (145 iiL, 0.014 mmol). The resulting solution was stirred for 30 minutes then concentrated to pro vide(R)-N-(5 -(2-(2,5 -difluorophenyl)pyrro lidin-1 -yl)pyrazolo [ 1,5 -a]pyrimidin-3 -yl)-3 hydroxy-3-methylazetidine-l-carboxamide sulfate (3.3 mg, 0.0063 mmol, 87 % yield) as a yellow solid.

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Example 17B

HO (R)-N-(5-(2-(2,5-difhiorophenyl)pyrrolidin-l-yl)pyrazolori,5-a1pyriniidin-3-y 1)-3hydroxy-3 -methylazetidine-1 -carboxamide hydrochloride [00430] To a methanol (1 mL) solution of (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin1 -yl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxy-3-methylazetidine-l-carboxamide (10.2 mg, 0.0238 mmol) was added HC1 as a solution is dioxane (30 pL). After 30 minutes, the reaction was concentrated to provide (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-yl)-3-hydroxy-3-methylazetidine-l-carboxamide hydrochloride (8.3 mg, 0.0179 mmol, 75.0 % yield) as a yellow solid.

Example 18

F (R)-1 -(5 -(2-(2.5 -difluorophenyDpyrro lidin-1 -yDpyrazolo Γ1,5-al pyri m i di n-3 - yi )-3-(4fluorophenyllurea [00431] To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol) was added 1fluoro-4-isocyanatobenzene (13 mg, 0.095 mmol) at ambient temperature drop-wise, followed by addition of D1EA (0.028 mL, 0.16 mmol). The reaction was stirred for 90 minutes before it was concentrated and directly purified by column chromatography on silica, eluting with 3:1 EtOAc/hexanes to yield the final product as a solid (30 mg, 84% yield). MS (apci) m/z = 453.2 (M+H).

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Example 19

F (R)-1 -(4-ch lorophcny I )-3-(5-(2-(2,5 -difluorophcnyI (pyrrol idin-1 -yl (pvrazolo [1,5alpyrimidin-3 -yllurea [00432] Prepared by the method as described in Example 18, substituting l-fluoro-4isocyanatobenzene with l-chloro-4-isocyanatobenzene, giving the final product as a fine white solid (33 mg, 89%). MS (apci) m/z = 469.1 (M+H).

Example 20

F (R)-1 -(5 -(2-(2,5 -difluorophenyDpyrro lidin-1 -yDpyrazolo [ 1,5-a1pyrimidin-3 -yl)-3 -(4methoxyphcnvDurca [00433] Prepared by the method as described in Example 18, substituting l-fluoro-4isocyanatobenzene with l-methoxy-4-isocyanatobenzene, and eluting with first 4:1 EtOAc/hexanes and then 100% EtOAc during silica column chromatography purification step, giving the final product as a fine white solid (34 mg, 92%). MS (apci) m/z = 465.2 (M+H).

Example 21

/° (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[1.5-a1pyrimidin-3-yl)3-methoxyazetidine-1 -carboxamide

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2019275599 04 Dec 2019 [00434] Step A: Preparation of (R)-5-(2-(2-chloro-5-fluorophcnyl)pyrrolidin-lyI )pyrazolo[ 1,5-a]pyrimidin-3-amine: Prepared according to the method of Preparation B, substituting (R)-2-(2,5-difluorophenyl)pyrrolidine in Step A with (R)-2-(2-chloro-5fluorophenyl)pyrrolidine.

[00435] Step B: Preparation of (R)-N-(5-(2-(2-chloro-5-fluorophenvl)pvrrolidin-1 yI )pyrazoIo[ 1,5-a] pyrimidin-3 -yl)-3-methoxyazetidine-1 -carboxamide: To a DCM (0.8 mL) solution of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1 -yl)pyrazolo[ 1,5-a]pyrimidin-3amine (30 mg, 0.090 mmol) was added CDI (29 mg, 0.18 mmol) at ambient temperature in one portion. After stirring for two hours, 3-methoxyazetidine 2,2,2-trifluoroacetate (36 mg, 0.18 mmol) [obtained from N-de-protection of commercially available tert-butyl 3methoxyazetidine-1 -carboxylate using TFA in DCM] was added in one portion, followed by addition of DIEA (0.047 mL, 0.27 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the final product as a yellowish foamy powder (36 mg, 89% yield). MS (apci) m/z = 445.2 (M+H).

Example 22

HO (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[1.5-a]pyrimidin-3-yl)3-hvdroxv-3-methylazetidine-l-carboxamide [00436] To a DCM (0.8 mL) solution of (R.)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin- l-yl)pyrazolo[l,5-a]pyrimidin-3-amine (Example 8, Step A; 22 mg, 0.066 mmol) was added CDI (22 mg, 0.13 mmol) at ambient temperature in one portion. After stirring two hours, 3methoxyazetidine 3-methylazetidin-3-ol hydrochloride (18 mg, 0.13 mmol) was added in one portion, followed by addition of DIEA (0.035 mL, 0.20 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 50% acetonitrile/water to yield the final product as a yellowish foamy powder (21 mg, 71% yield). MS (apci) m/z = 445.2 (M+H).

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Example 23

(R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrro lidin-1-yDpyrazolori,5-a1pyrimidin-3vl)mort)holine-4-carboxamide [00437] Prepared according to the method of Example 22, replacing (R)-5-(2-(2chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine with morpholine to yield the product as a yellowish foamy powder (26 mg, 76% yield). MS (apci) m/z = 445.1 (M+H).

Example 24

(S)-tert-butyl 4-(5-((R)-2-(2-chtoro-5-fhiorophenvl)pvrrolidin-l-vl)rwrazotori.5-a1r>vrimidin3-ylcarbamoyl)-2-methylpiperazine-1 -carboxylate [00438] Prepared according to the method of Example 22, replacing (R)-5-(2-(2chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine with (S)-tert-butyl

2-methylpiperazine-1 -carboxylate to yield the product as a yellowish foamy powder (47 mg, 80% yield). MS (apci) m/z = 558.1 (M+H).

Example 25

H

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2019275599 04 Dec 2019 (S)-N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yDpyrazolo[L5-a1pyrimidin-3-yl)-3methylpiperazine-1 -carboxamide hydrochloride [00439] To (S)-tert-butyl 4-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-lyl)pyrazolo [ 1,5-a]pyrimidin-3 -ylcarbamoyl)-2-methylpiperazine-1 -carboxylate (Example 24; 47 mg, 0.084 mmol), was added 1 mL 4 N HC1 (dioxane) solution and stirred at ambient temperature for 10 minutes. The reaction was concentrated, treated with ether, and filtered, giving the final product HC1 salt as a fine beige powder. MS (apci) m/z = 458.1 (M+H).

Example 26

(R)-N-(5 -(2-(2,5 -difluorophenyDpyrro lidin-1 -yDpyrazolo [ 1,5 -alpyrimidin-3 -y 1)-4isopropylpiperazine-1 -carboxamide [00440] To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, 1isopropylpiperazine (24 mg, 0.19 mmol) was added in one portion. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 45% acetonitrile/water to yield the final product as a yellowish foamy powder (40 mg, 90% yield). MS (apci) m/z = 470.1 (M+H).

Example 27

(R)-N-(5 -(2-(2,5 -difluorophenyDpyrro lidin-1 -vDpyrazolo [ 1,5-a1pyrimidin-3 -y 1)-4 ethylpiperazine-1 -carboxamide

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2019275599 04 Dec 2019 [00441] Prepared by the method as described in Example 26, substituting 1isopropylpiperazine with 1-ethylpiperazine, giving the final product as a yellowish solid (40 mg, 92%). MS (apci) m/z = 456.1 (M+H).

Example 28

(R)-N-(5 -(2-(2,5 -difluorophenvDpyrro lidin-1 -vDpyrazolo [1,5-a1pyrimidin-3 -yl)-4methylpiperazine-1 -carboxamide

Prepared by the method as described in Example 26, substituting 1-isopropylpipcrazine with

1-methylpiperazine, giving the final product as a yellowish solid (38 mg, 90%). MS (apci) m/z = 442.2 (M+H).

Example 28A

(R. )-N-(5 -(2-(2.5 -difluoronhcnvDnvrro lidin-1 -vDnvrazolo Γ1.5-a1nvrimidin-3 -vl)-4methylpiperazine-1 -carboxamide hydrochloride [00442] To a methanol (1 mL) solution of (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidinl-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-4-methylpiperazine-l-carboxamide was added HC1 as a solution is dioxane (30 uL). After 30 minutes, the reaction was concentrated to provide (R)N-(5-(2-(2,5-difluorophenyl)pyrroHdin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-4methylpiperazine-1 -carboxamide hydrochloride as a yellow solid.

Example 29

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N-(5-((R)-2-(2,5-dif1uoronhcnyl)nvrrolidin-l-yl)nvrazolo| 1,5-a|pvrimidin-3-vl)-3.5dimcthy Ipincrazine-1 -carboxamide [00443] Prepared by the method as described in Example 26, substituting 1isopropylpiperazine with 2,6-dimethylpiperazine [predominantly cis, Aldrich], giving the final product as a yellowish solid (34 mg, 78%). MS (apci) m/z = 456.2 (M+H).

Example 30

(S)-tert-butyl 4-(5 -((R)-2-(2.5 -difluorophenyDpyrrolidin-1 -yDpyrazolo [1,5alpyrimidin-3 -ylcarbamovD-2-methylpiperazine-1 -carboxylate [00444] Prepared by the method as described in Example 26, substituting 1isopropylpiperazinc with (S)-tert-butyl 2-methylpiperazinc-1-carboxylate, giving the final product as a yellowish solid (47 mg, 90%). MS (apci) m/z = 542.2 (M+H).

Example 31

H (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolori,5-a1pyrimidin-3-yl)-

3-methylpiperazine-1 -carboxamide hydrochloride [00445] To (S)-tert-butyl 4-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo [ 1,5-a]pyrimidin-3 -ylcarbamoyl)-2-mcthylpiperazine-1 -carboxylate (Example 30; 47 mg, 0.087 mmol), was added 1 mL 4 N HC1 (dioxane) solution and stirred at ambient temperature for 1 hour. The reaction was concentrated, treated with ether, and filtered, giving the final product HC1 salt as a fine yellowish powder. MS (apci) m/z = 442.2 (M+H).

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Example 32

OH (R)-N-(5-(2-(3-fluoronhcnvl)nyriOlidin-1-ylInvrazolor1,5-alr>yrimidiri-3-yl)-3hydroxyazetidine-1 -carboxamide [00446] To a DCM (0.8 mL) solution of (R)-5-(2-(3-fluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Example 6, Step A; 50 mg, 0.17 mmol) was added CDI (41 mg, 0.25 mmol) at ambient temperature in one portion. After stirring two hours, azetidin3-ol hydrochloride (28 mg, 0.25 mmol) was added in one portion, followed by addition of DIEA (0.059 mL, 0.34 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 55% acetonitrile/water to yield the final product as a yellowish foamy powder (64 mg, 96% yield). MS (apci) m/z = 397.2 (M+H).

Example 33

(R)-methyl l-(5-(2-(2,5-difluorophenvl)pvrrolidin-l-yl)pyrazolo[l,5-a1pvrimidin-3ylcarbamoyllcyclopropanecarboxylate [00447] To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-amine (Preparation B; 43 mg, 0.14 mmol), 1(methoxycarbonyl)cyclopropanecarboxylic acid (24 mg, 0.16 mmol), and HATU (62 mg, 0.16 mmol) was added 0.7 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.053 mL, 0.30 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 10 minutes. The reaction mixture was diluted with EtOAc (15 mL), washed with water, brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 72%

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2019275599 04 Dec 2019 acetonitrile/water to yield the final product as a yellowish foamy powder (36 mg, 60% yield). MS (apci) m/z = 442.2 (M+H).

Example 34

(R)-1 -(5-(2-(2.5-difl uoro phcnyl)py rrol i di η-1 -vDpyrazolo [1,5 -alpyrimidin-3 ylcarbamoylfcyclopropanecarboxylic acid [00448] (R)-methyl 1 -(5-(2-(2,5-difluorophenyl)pyrrolidin-l -yl)pyrazolo[l ,5a]pyrimidin-3-ylcarbamoyl)cyclopropanecarboxylate (Example 33; 24 mg, 0.054 mmol), was dissolved in a mixture solvent of THF/MeOH/water (0.3/0.3/0.2 mL), followed by addition of lithium hydroxide monohydrate (6 mg, 0.14 mmol). After stirring at ambient temperature for five hours, the reaction mixture was diluted with water (15 mL), acidified with 1 N HC1 (aq.) to pH ~ 3, and filtered, giving the final product as a fine white solid (19 mg, 82% yield). MS (apci) m/z = 428.2 (M+H).

Example 35

F (S)-N-(5-((R)-2-(3-chloro-5-fluorophenyl)pvrrolidin-l-yl)pyrazolori,5-a1pyrimidin3 -vD-3-hydroxypyrrolidine-1 -carboxamide [00449] To a DCM (0.6 mL) solution of (R)-5-(2-(3-chloro-5-fluorophenyl)pyrrolidinl-yl)pyrazolo[l,5-a]pyrimidin-3-amine (Example 11, Step A; 20 mg, 0.06 mmol), was added CDI (20 mg, 0.12 mmol) at ambient temperature in one portion. After stirring two hours, (S)pyrrolidin-3-ol (16 mg, 0.18 mmol) was added in one portion. The reaction was stirred overnight before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a solid (50 mg, 83% yield). MS (apci) m/z = 445.2 (M+H).

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Example 36 _F 'OH (R)-N-(5-((R)-2-(2-(difluoromethvl)-5-fluorophenvl)pvrrolidin-l -yllnyrazolor 1,5a1pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide [00450] Step A: Preparation______of______(R)-5-('2-(2-(difluoromcthyl)-5fl uorophcn yl In yrro 1 i di n-1 -yl In yrazoloΓ1,5-a1pyrimidin-3 -amine: Prepared according to the method of Preparation B, substituting (R)-2-(2,5-difluorophenyl)pyrrolidine in Step 1 with (R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidine.

[00451] Step B: Preparation of (R)-N-(5-((R)-2-(2-(difluoromethyl]-5fl uorophcn yl )py rro I i di n-1 - yl In yrazolo [ 1,5-a] n yri m i di n-3 - yl )-3 -hydro xypyrrolidine-1 carboxamide: To a DCM (0.6 mL) solution of (R)-5-(2-(2-(difluoromethyl)-5fluorophenyl)pyrrolidin-l-yl)pyrazolo[l ,5-a]pyrimidin-3-amine (10 mg, 0.028 mmol, prepared as described in the following paragraph), was added CDI (9 mg, 0.056 mmol) at ambient temperature in one portion. After stirring two hours, (S)-pyrrolidin-3-ol (8 mg, 0.084 mmol) was added in one portion. The reaction was stirred overnight, then concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 50% acetonitrile/water to yield the final product as a solid (9 mg, 69%). MS (apci) m/z = 461.2 (M+H).

Example 37

(S)-N-(5-((R)-2-(2-(difluoromethyl]-5-fluorophenyl]pyrrolidin-1 -yl )pyrazolol 1,5a1pyrimidin-3-yl)-3-hydro xypyrrolidine-1 -carboxamide [00452] Prepared by the method as described in Example 36, substituting (S)pyrrolidin-3-ol with (R)-pyrrolidin-3-ol, giving the final product as a solid (12 mg, 89%). MS (apci) m/z = 461.2 (M+H).

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Example 38

(R)-N-(5-(2-(2-(d i fl uoromcthy I )-5 -fluorophenyllpyrrolidin-1 - yl )py razolo [1,5a] pyri m i di n-3-yl )-4-h ydrox ypi peri di nc-1 -carboxamide [00453] Prepared by the method as described in Example 36, substituting (S) pyrrolidin-3-ol with pipcridin-4-ol, giving the final product as a solid (11 mg, 80%). MS (apci) m/z = 475.2 (M+H).

Example 39

OH

F (R)-N-(5-((R')-2-(2-(difluoromethvl)-5-fluorophenvDpvrrolidin-1 -yl )pyrazolo[ 1,5al pyri m i di n-3-yl )-3 -hydroxypiperidine-1 -carboxamide [00454] Prepared by the method as described in Example 36, substituting (S)pyrrolidin-3-ol with (R)-piperidin-3-ol hydrochloride (followed by addition of 3 equivalents of DIEA), giving the final product as a solid (10 mg, 74%). MS (apci) m/z = 475.2 (M+H).

Example 40

OH

F (S)-N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenvl)pyrrolidin-1 -yl )pyrazolo[ 1,5 al pyri m i di n-3-y I )-3 -hydroxypiperidine-1 -carboxamide [00455] Prepared by the method as described in Example 36, substituting (S)pyrrolidin-3-ol with (S)-piperidin-3-ol hydrochloride (followed by addition of 3 equivalents of DIEA), giving the final product as a solid (11 mg, 80%). MS (apci) m/z = 475.2 (M+H).

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Example 41

(R)-N-(5-((R)-2-(2-chloro-5-fluorophenvl)pvrrolidin-l-vl)pvrazolorL5 a1pvrimidin-3-vl)-3-hydroxypyrrolidinc-1 -carboxamide [00456] To a DCM (0.8 mL) solution of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidinl-yl)pyraz^ol°[L5-a]pyrimidm-3-amine (10 mg, 0.030 mmol, prepared as described in Example 8) was added CDI (10 mg, 0.06 mmol) at ambient temperature in one portion. After stirring two hours, (S)-pyrrolidin-3-ol (5 mg, 0.06 mmol) was added in one portion. The reaction was stirred at ambient temperature for 20 hours before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 50% acetonitrile/water to yield the final product as a solid (9 mg, 67% yield). MS (apci) m/z = 445.2 (M+H).

Example 42

OH (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a1pyrimidin-3-yl)4-hvdroxvniperidine-1 -carboxamide [00457] Prepared by the method as described in Example 41, substituting (S)pyrrolidin-3-ol with piperidin-4-ol, giving the final product as a solid (8 mg, 60%). MS (apci) m/z = 459.2 (M+H).

Example 43

F 'OH

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2019275599 04 Dec 2019 (R )-N-(5-((R)-2-(2-chloro-5-fluoronhenvl)pvrrolidin-l-vl )pyrazolo| 1.5-a|pyrimidin3-yl )-3-hvdroxypiperidine-1 -carboxamide [00458] Prepared by the method as described in Example 41, substituting (S)pyrrolidin-3-ol with (R)-piperidin-3-ol hydrochloride (followed by addition of 3 equivalents of DIEA), giving the final product as a solid (9.4 mg, 69%). MS (apci) m/z = 459.1 (M+H).

Example 44

(S)-N-(5-((R)-2-(2-chloro-5-fluorophenvl)pvrrolidin-1 -yllnvrazolor 1,5-alpyrimidin3-yl)-3-hydroxypiperidine-1 -carboxamide [00459] Prepared by the method as described in Example 41, substituting (S)pyrrolidin-3-ol with (S)-piperidin-3-ol hydrochloride (followed by addition of 3 equivalents of DIEA), giving the final product as a solid (9.3 mg, 68%). MS (apci) m/z = 459.2 (M+H).

Example 45 Γΰ Z^N ₀ \J HN—Z

YY^F V (R)₂N₌(52(2₌(2₁52diflnorophonyl)pynOlidinMj_;ylj^yrazqlO]X52a]pyriniidin-32 vDpivalamide [00460] A DCM (0.5 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 20 mg, 0.063 mmol) was cooled in an ice bath, followed by addition of pivalic anhydride (26 mg, 0.14 mmol) and pyridine (12 mg, 0.14 mmol) drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 1 hour. The reaction mixture was directly purified by reverse-phase column chromatography, eluting with 5 to 65% acetonitrile/water to yield the final product as a yellowish foamy solid (19 mg, 75%). MS (apci) m/z = 400.2 (M+H).

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Example 46

(R)-tcrt-biityl 3-(5-(2-(2-chloro-5-fluorophenvl)pvrrolidin-l-vl)pvrazolo[1.5alpyrimidin-3-yl carbamoyl jazetid i n c-1 -carboxylate [00461] To a mixture of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Example 8, Step A; 20 mg, 0.06 mmol), l-(tertbutoxycarbonyl)azetidine-3-carboxylic acid (15 mg, 0.072 mmol), and HATU (28 mg, 0.072 mmol) was added 0.6 mL acetonitrile to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.032 mL, 0.18 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was directly purified by reverse-phase column chromatography, eluting with 5 to 70% acetonitrilc/watcr to yield the final product as an off-white solid (19 mg, 61% yield). MS (apci) m/z = 515.0 (M+H).

Example 47

(R)-N-(5-(2-(2-chloro-5-fluorophenvl)pvrrolidin-l-vl)pvrazolo[L5-a1pvrimidin-3yl)azetidine-3 -carboxamide trifluoroacetate [00462] To (R)-tert-butyl 3-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-ylcarbamoyl)azetidinc-l-carboxylate (Example 46; 17 mg, 0.033 mmol), was added 0.5 mL 50% TFA solution in DCM and stirred at ambient temperature for 10 minutes. The reaction was concentrated, treated with ether, and filtered, giving the final product (TFA salt) as a fine beige powder (12 mg, 88% yield). MS (apci) m/z = 415.2 (M+H).

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Example 48

(R)-tcrt-butyl 4-('5-(2-('2-chloro-5-fluoronhenvl)nyrrolidin-l-yl)nyrazolon,5alpyrimidin-3 -y I carbamoyl )-4-mcthyl pipcri di nc-1 -carboxylate [00463] To a mixture of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amme (Example 8, Step A; 25 mg, 0.075 mmol), l-(tertbutoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (22 mg, 0.090 mmol), and HATU (34 mg, 0.090 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.039 mL, 0.23 mmol) was added to the reaction dropwise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was directly purified by reverse-phase column chromatography, eluting with 5 to 80% acetonitrile/water to yield the final product as a yellowish powder (28 mg, 67% yield). MS (apci) m/z = 557.1 (M+H).

Example 49

(R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidin-3-yl)4-methvlnincridine-4-carboxamide hydrochloride [00464] To (R)-tert-butyl 4-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-ylcarbamoyl)-4-methylpiperidine-l-carboxylate (Example 48; 28 mg, 0.05 mmol), was added 1 mL 4 N HC1 solution in dioxane and stirred at ambient temperature for 10 minutes. The reaction was concentrated, treated with ether, and filtered, giving the final product (HC1 salt) as a fine beige powder. MS (apci) m/z = 457.1 (M+H).

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Example 50

(R)-N-(5-(2-(2,5-difluoror)henvl)r)vrrolidin-l -yl)nvrazolo[l ,5-a1r)yrimidin-3-vl)-2hydroxy-2-methylpropanamide [00465] To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), 2-hydroxy-2-methylpropanoic acid (10 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL acetonitrile to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was concentrated, re-dissolved in methanol, and purified by reverse-phase column chromatography, eluting with 5 to 55% acetonitrile/water to yield the final product as an off-white solid (21 mg, 66% yield). MS (apci) m/z = 402.2 (M+H).

Example 51

(R)-N-(5 -(2-(2,5 -difluorophenyDpyrrolidin-1 -yDpyrazolo [ 1,5-a1pyrimidin-3 -yl)-1 (trifhioromethvPcvclonronanecarboxamide [00466] To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), 1(trifluoromethyl)cyclopropanecarboxylic acid (15 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 72% acetonitrile/water to yield the final product as a beige solid (23 mg, 63% yield). MS (apci) m/z = 452.2 (M+H).

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Example 52

(R)- l-cyano-N-(5-(2-(2,5-di fl uorophenvl)pvrrolidin-l-vl)r)vrazolo[l ,5-a] pyrimidin-3vDcyclopropanecarboxamide [00467] Prepared by the method as described in Example 51, substituting 1(trifluoromethyl)cyclopropanecarboxylic acid with 1-cyanocyclopropanecarboxylic acid, to provide the final product as a white solid (18 mg, 56% yield). MS (apci) m/z = 409.2 (M+H).

Example 53

(R)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)2-methylpyrrolidine-2-carboxamide [00468] To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), (R)-l-(tert-butoxycarbonyl)-2methylpyrrolidine-2-carboxylic acid (22 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was diluted with EtOAc (15 rnL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 68% acetonitrile/water to yield the N-Boc-protected product, (R)-tert-butyl 2-(5-((R)-2-(2,5d ifl uorophcny l)py rrol i din-1 -yl)pyrazolo [ 1,5 -a]pyrimidin-3-ylcarbamoyl)-2methylpyrrolidine-1 -carboxylate, as a beige solid (32 mg, 73% yield). The de-protection was carried out by adding 1 rnL 4 N HC1 solution in dioxane to the above protected product. After 1 hour at ambient temperature, the reaction mixture was concentrated, treated with ether (1 mL), and filtered, giving the final product as an off-white solid. MS (apci) m/z = 427.2 (M+H).

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Example 54

(R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-l -yllpyrazolol 1,5-a1pyrimidin-3-yl)-2fluoro-2-methylpropanamide [00469] Prepared by the method as described in Example 51, substituting 1(trifluoromethyl)-cyclopropane-carboxylic acid with 2-fluoro-2-methylpropanoic acid, to provide the final product as a pale-yellowish solid (25 mg, 77% yield). MS (apci) m/z = 404.2 (M+H).

Example 55

HN

(R)-N-(5 -(2-(2,5 -difluoro phenyl) pyrrolidin-1 -yllpyrazolo 11,5-a] pyrimidin-3 -y 1)-2(isopropylaminolthiazole-4-carboxamide [00470] Prepared by the method as described in Example 51, substituting 1(trifluoromcthyl)-cyclopropane-carboxylic acid with 2-(isopropylamino)thiazolc-4carboxylic acid hydrobromide, to provide the final product as a beige solid (34 mg, 89% yield). MS (apci) m/z = 484.2 (M+H).

Example 56

(R)-N-(5-(2-(2,5-difluorophenvl)pvrrolidin-l-vl)pvrazololl,5-a1pyrimidin-3-vl)-2methyl-2-( 1 Η-1,2,4-triazol-1 -yl)propanamide

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2019275599 04 Dec 2019 [00471] Prepared by the method as described in Example 51, substituting 1(trifluoromethyl)-cyclopropane-carboxylic acid with 2-methyl-2-(lH-l,2,4-triazol-lyl)propanoic acid, to provide the final product as a pale-yellowish solid (26 mg, 72% yield). MS (apci) m/z = 453.1 (M+H).

Example 57

(R)-N-(5-(2-(2.5-difluorophenyl)pyrrolidin-l-yl)pyrazolori.5-a1pyrimidin-3vl)pyrazine-2-carboxamide [00472] To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), pyrazine-2-carboxylic acid (12 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 10 minutes. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 65% acetonitrile/water to yield the final product as a yellowish solid (31 mg, 93% yield). MS (apci) m/z = 422.2 (M+H).

Example 58

(R )-N-(5 -(2-(2,5 -difluorophenvDpyrrolidin-1 -vBpyrazolo [ 1,5-a1pyrimidin-3 -yl)-5 methylpyrazine-2-carboxamidc [00473] Prepared by the method as described in Example 57, substituting pyrazine-2carboxylic acid with 5-methylpyrazine-2-carboxylic acid, to provide the final product as a yellowish solid (9 mg, 26% yield). MS (apci) m/z = 436.2 (M+H).

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Example 59

(R)-N-(5-(2-(2.5-difliioronhcnvl)iwrrolidin-l-Yl)nvrazolori.5-alr>vrimidin-3yppicolinamide [00474] Prepared by the method as described in Example 57, substituting pyrazine-2carboxylic acid with picolinic acid, to provide the final product as a yellowish solid (31 mg, 93% yield). MS (apci) m/z = 421.2 (M+H).

Example 60

(R)-N-(5-(2-(2,5-difluorophenyr)pyrrolidin-l-yr)pyrazolori,5-a1pyrirmdin-3-yl)-6methylpicolinamide [00475] Prepared by the method as described in Example 57, substituting pyrazine-2carboxylic acid with 6-methylpicolinic acid, to provide the final product as a yellowish solid (30 mg, 87% yield). MS (apci) m/z = 435.2 (M+H).

Example 60A

(R)-N-(5-(2-(2,5-difluorophenvl)pvrrolidin-l-yl)pyrazolori,5-a1pyrimidin-3-yl)-6methylpicolinamide hydrochloride [00476] To a methanol (1 mL) solution of (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidinl-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-methylpicolinamide (10.3 mg, 0.0237 mmol) was added HC1 as a solution is dioxane (30 pL). After 30 minutes, the reaction was concentrated

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Example 61

Cl (R)-5-chloro-N-(5-(2-(2,5-difluorophenyPpyrrolidin-l-yPpyrazolo[l,5-a1pyrimidin-3vDnicolinamide [00477] Prepared by the method as described in Example 57, substituting pyrazine-2carboxylic acid with 5-chloropicolinic acid, to provide the final product as a yellowish solid (24 mg, 67% yield). MS (apci) m/z = 455.2 (M+H).

Example 62

Cl (R)-4-chloro-N-(5-(2-(2.5-difluoronhenvPpvrrolidin-l-vl)nvrazolo[1.5-a1nvrimidin-3yDpicolinamide [00478] Prepared by the method as described in Example 57, substituting pyrazine-2carboxylic acid with 4-chloropicolinic acid, to provide the final product as a beige solid (30 mg, 83% yield). MS (apci) m/z = 455.2 (M+H).

Example 63

(R)-N-(5 -(2-(2,5 -difluorophenvPpyrrolidin-1 -vPpyrazolo [ 1,5-a1r>yrimidin-3 -yl)-3 methylpicolinamide

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2019275599 04 Dec 2019 | (10479] Prepared by the method as described in Example 57, substituting pyrazine-2carboxylic acid with 3-methylpicolinic acid, to provide the final product as a beige solid (33 mg, 96% yield). MS (apci) m/z = 435.2 (M+H).

Example 64

HO (R)-N-(5 -(2-(2,5 -difluorophenvDpyrrolidin-1 -vDpyrazolo [1.5-a]pvrimidin-3 -yl)-3 hydroxy-2,2-dimethylpropanamide [00480] Prepared by the method as described in Example 57, substituting pyrazine-2carboxylic acid with 3-hydroxy-2,2-dimethylpropanoic acid, to provide the final product as a pale-yellowish solid (22 mg, 66% yield). MS (apci) m/z = 416.2 (M+H).

Example 65

(R)-N-(5 -(2-(2,5 -difluorophenyDpyrrolidin-1 -yDpyrazolo [ 1,5-a1pyrimidin-3 -yl)-1 hydroxycyclopropanecarboxamide [00481] Prepared by the method as described in Example 57, substituting pyrazine-2carboxylic acid with 1 -hydroxycyclopropanecarboxylic acid, to provide the final product as a beige solid (6 mg, 16% yield). MS (apci) m/z = 400.2 (M+H).

Example 66

(R)-N-(5-(2-(2,5-difluorophenyPpyrrolidin-l-yPpyrazolo[l,5-a1pyrimidin-3-yP-2methyl-2-(methylamino)propanamidc

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2019275599 04 Dec 2019 [00482] Prepared by the method as described in Example 57, substituting pyrazine-2carboxylic acid with 2-methyl-2-(methylamino)propanoic acid hydrochloride, to provide the final product as a solid (2 mg, 6% yield). MS (apci) m/z = 415.1 (M+H).

Example 67

(R)-N-(5-i2-(2,5-difluorophenyl)pyrrolidm-l-yl)pyrazolori,5-a]pyrimidin-3yl)pyrimidiric-2-carboxamidc [00483] To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), pyrimidine-2-carboxylic acid (12 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL DMF. A few drops of DMSO were added to obtain a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for one hour, then at 80 °C for 16 hours. Reaction did not reach completion before workup. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the final product as a light yellowish solid (3 mg, 9% yield). MS (apci) m/z = 422.2 (M+H).

Example 68

(R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolorL5-a1pyrimidin-3vDpicolinamide [00484] To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-amine (Example 6, Step A; 30 mg, 0.1 mmol), picolinic acid (15 mg, 0.12 mmol), and HATU (46 mg, 0.12 mmol) was added 0.7 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.053 mL, 0.3 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 10

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2019275599 04 Dec 2019 minutes. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 70% acetonitrile/water to yield the final product as a yellowish solid (35 mg, 86% yield). MS (apci) m/z = 403.2 (M+H).

Example 69

(R)-N-(5-(2-(3 -fluorophenyllpyrro lidin-1 -yllpyrazolo 11.5-a1pyrimidin-3 -yl)-3 methylpicolinamide [00485] Prepared by the method as described in Example 68, substituting picolinic acid with 3-methylpicolinic acid, to provide the final product as a solid (35 mg, 83% yield). MS (apci) m/z = 417.2 (M+H).

Example 70

(R)-N-(5-(2-(3-fluorophenvl)pvrrolidin-l-vl)pvrazolo[l,5-a1r)vrimidin-3-vl)-lmethyl-2-oxo-1.2-dihydropyridine-4-carboxamide [00486] Prepared by the method as described in Example 68, substituting picolinic acid with l-methyl-2-oxo-l,2-dihydropyridine-4-carboxylic acid, to provide the final product as a yellowish solid (18 mg, 41% yield). MS (apci) m/z = 433.2 (M+H).

Example 71

(R)-6-chloro-N-(5-(2-(2,5-difluorophenyl)nvrrolidin-l-vl)pyrazolon,5-a1pvrimidin-3 yllpicolinamide

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2019275599 04 Dec 2019 [00487] Prepared by the method as described in Example 68, substituting (R)-5-(2-(3fluorophenyl)pyrrolidin-l -yl)pyrazolo[ 1,5-a]pyrimidin-3-amine with (R)-5-(2-(2,5d ifl uorophcny l )py rrol i di η-1 -yl)pyrazolo [ 1,5 -a]pyrimidin-3-amine(Preparation B), and substituting picolinic acid with 6-chloropicolinic acid, to provide the final product as a yellowish solid (9.1 mg, 31% yield). MS (apci) m/z = 455.2 (M+H).

Example 72

O* /NH

(R)-4-(ethvlsulfonamido)-N-(5-(2-(3-fluorophenvl)pvrrolidin-l-vl)pvrazolo[l,5alpyrimidin-3 -yDbenzamide [00488] Prepared by the method as described in Example 68, substituting picolinic acid with 4-(ethylsulfbnamido)benzoic acid, to provide the final product as a yellowish solid (32 mg, 62% yield). MS (apci) m/z = 509.2 (M+H).

Example 73

(R)-N-(5-(2-(3-fluorophenvl)pvrrolidin-l-vl)pvrazolo[l,5-alpyrimidin-3-vl)-lmethyl-lH-pyrazole-3-carboxamide [00489] Prepared by the method as described in Example 68, substituting picolinic acid with 1-methyl-lH-pyrazole-3-carboxylic acid, to provide the final product as a yellowish solid (32 mg, 78% yield). MS (apci) m/z = 406.3 (M+H).

Example 74

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2019275599 04 Dec 2019 (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l -yllpyrazolol 1,5-a1pyrimidin-3-yl)-l HPvrazole-3-carboxamide [00490] Prepared by the method as described in Example 68, substituting picolinic acid with lH-pyrazole-3-carboxylic acid, to provide the final product as a yellowish solid (14 mg, 35% yield). MS (apci) m/z = 392.2 (M+H).

Example 75

(R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a1pyrimidin-3-yl)-6methoxypicolinamide [00491] Prepared by the method as described in Example 68, substituting picolinic acid with 6-methoxypicolinic acid, to provide the final product as a yellowish solid (28 mg, 64% yield). MS (apci) m/z = 433.2 (M+H).

Example 75A

(R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazoloH,5-a1pyrimidin-3-yl)-6methoxypicolinamide hydrochloride [00492] To a methanol (1 mL) solution of (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-yl)-6-methoxypicolinamide (10.1 mg, 0.0234 mmol) was added HC1 as a solution is dioxane (30 pL). After 30 minutes, the reaction was concentrated to provide (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-6methoxypicolinamide hydrochloride as a yellow solid.

Example 76

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2019275599 04 Dec 2019 (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1 -vl )nvrazolo| 1,5-a1pyrimidin-3vDnicotinamide [00493] To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-amine (Example 6, Step A; 30 mg, 0.1 mmol), nicotinic acid (25 mg, 0.2 mmol), and HATU (77 mg, 0.2 mmol) was added 0.7 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.053 mL, 0.3 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 3 hours. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 57% acetonitrile/water to yield the final product as a yellowish solid (30 mg, 74% yield). MS (apci) m/z = 403.2 (M+H).

Example 77

(R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazok>ri,5-a1pyrimidin-3vDisonicotinamide [00494] Prepared by the method as described in Example 76, substituting nicotinic acid with isonicotinic acid, to provide the final product as a yellowish solid (20 mg, 49% yield). MS (apci) m/z = 403.2 (M+H).

Example 78

(R)-N-(5-(2-(3-fluoror>henvl)pvrrolidin-l-vl)pyrazolo[l,5-a1pyrimidin-3-vl)-6methylnicotinamide [00495] Prepared by the method as described in Example 76, substituting nicotinic acid with 6-methylnicotinic acid, to provide the final product as a yellowish solid (27 mg, 64% yield). MS (apci) m/z = 417.2 (M+H).

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Example 79

(R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[1.5-a1pyrimidin-3-yl)-2methoxynicotinamid e [00496] Prepared by the method as described in Example 76, substituting nicotinic acid with 2-methoxynicotinic acid, to provide the final product as a yellowish solid (32 mg, 73% yield). MS (apci) m/z = 433.2 (M+H).

Example 80

(R )-N-(5-(2-(3 -fluorophcnyllpyrro lidin-1 - yl )n yrazolo [ 1.5-a1pyrimidin-3 -yD-3 methylisonicotinamide [00497] Prepared by the method as described in Example 76, substituting nicotinic acid with 3-methylisonicotinic acid, to provide the final product as a yellowish solid (22 mg, 52% yield). MS (apci) m/z = 417.2 (M+H).

Example 81

(S)-N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-l-yl)pyrazolori,5-a1pyrimidin3 -vD-3-hydroxynvrrolidine-1 -carboxamide [00498] To a DCM (0.8 mL) solution of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin- l-yl)pyrazolo[l,5-a]pyrimidin-3-amine (Example 8, Step A; 30 mg, 0.09 mmol) was added CDI (29 mg, 0.18 mmol) at ambient temperature in one portion. After stirring two hours, (S)pyrrolidin-3-ol (15.8 mg, 0.181 mmol) was added in one portion. The reaction was stirred

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2019275599 04 Dec 2019 for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 53% acetonitrile/water to yield the final product as a yellowish foamy powder (33 mg, 81% yield). MS (apci) m/z = 445.2 (M+H).

Example 82

(R)-N-(5 -(2-(3 -fluorophenyDpyrro lidin-1 - yl )n yrazol o [ 1,5-al p yrim id i n-3 -yl)-5 methylpyrazine-2-carboxamide [00499] To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-amine (Example 6, Step A; 50 mg, 0.17 mmol, prepared as described in a previous example), 5-methylpyrazine-2-carboxylic acid (46 mg, 0.34 mmol), and HATU (128 mg, 0.34 mmol) was added 0.7 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.088 mL, 0.5 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 2 hours. The reaction mixture was directly filtered, rinsing with acetonitrile and then with ether, to provide the final product as a beige solid (44 mg, 63% yield). MS (apci) m/z = 418.2 (M+H).

Example 83

(R)-N-(5-(2-(3-fluorophenyF)pyrrolidin-l-yl)pyrazolo|T,5-a]pyrimidin-3-yl)-lmethyl-1 H-imidazole-2-carboxamide [00500] To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5a]pyrimidin-3-amine (Example 6, Step A; 40 mg, 0.13 mmol, prepared as described in a previous example), 1-methyl-lH-imidazole-2-carboxylic acid (34 mg, 0.27 mmol), and HATU (102 mg, 0.27 mmol) was added 1.0 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.07 mL, 0.4 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 10 minutes. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each),

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2019275599 04 Dec 2019 concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 65% acetonitrile/water to yield the final product as a yellowish solid (37 mg, 68% yield). MS (apci) m/z = 406.2 (M+H).

Example 84

(S)-N-( 5 -((R)-2-( 5 -fluoro-2-(trifluoromethyl)phenvl)pyrrolidin-1 -yl )p yrazo lol 1,5alpyrimi din-3 -y I )-3 -hydroxypyrro I idine-1 -carboxami de [00501] Step A: Preparation_______of_______(R)-5-(2-(5-fluoro-2(trifluoromethvDphenvDpyrrolidin-l -yl)pyrazolo[ 1,5-a]pyrimidin-3-amine: Prepared according to Preparation B, substituting (R)-2-(2,5-difluorophenyl)pyrrolidine in Step 1 with (R)-2-(5-fluoro-2-(trifluoromethyl)phenyl) pyrrolidine.

[00502] Step B: Preparation of (R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidine: Prepared by the method of Preparation A, substituting 2-bromo-l,4-difluorobenzene with 2bromo-4-fluoro-1 -(trifluoromethyl)benzene in Step A.

[00503] Step C: Preparation of (S)-N-(5-((R)-2-(5-fluoro-2(trifluoromethyl)phenyDpyrrolidin-l -yl)pyrazolo[ 1,5-a]pyrimidin-3-yl)-3hydroxypyrrolidine-l-carboxamide: To a DCM (1 rnL) solution of (R)-5-(2-(5-fluoro-2(trifluoromethyl)phenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine (25 mg, 0.068 mmol) was added CDI (22 mg, 0.14 mmol) at ambient temperature in one portion. After stirring for two hours, (S)-pyrrolidin-3-ol (18 mg, 0.21 mmol) was added in one portion. The reaction was stirred overnight before it was concentrated and directly purified by reversephase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a yellowish solid (28 mg, 86% yield). MS (apci) m/z = 479.2 (M+H).

Example 85

(R)-N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-l-yl)pyrazolo[ 1,5

a]pvrimidin-3-vl)-3-hvdroxvpvrrolidine-1 -carboxamide

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2019275599 04 Dec 2019 [00504] Prepared by the method as described in Example 84, substituting (S)pyrrolidin-3-ol in Step C with (R)-pyrrolidin-3-ol, giving the final product as a yellowish solid (26 mg, 79%). MS (apci) m/z = 479.2 (M+H).

Example 86

(R)-N-(5-((R)-2-(5-fluoro-2-(trifliioromcthyl)phcnvl)Pvrrolidin-l-yl)pyrazolori,5a]pyrimidin-3 -yl)-3 -hydroxypiperidine-1 -carboxamide [00505] Prepared by the method as described in Example 84, substituting (S)pyrrolidin-3-ol in Step C with (R)-piperidin-3-ol, giving the final product as a yellowish solid (37 mg, 91%). MS (apci) m/z = 493.2 (M+H).

Example 87

(S)-N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidm-1 -yl jpyrazolofl ,5alpyrimidin-3 -yl)-3 -hydroxypiperidine-1 -carboxamide [00506] Prepared by the method as described in Example 84, substituting (S)pyrrolidin-3-ol in Step C with (S)-piperidin-3-ol, giving the final product as a yellowish solid (39 mg, 97%). MS (apci) m/z = 493.2 (M+H).

Example 88

OH (S)-N-(5-((R)-2-(5-fluoropvridin-3-vl)pvrrolidm-l-vl)pvrazolori.5-a1pvrimidin-3-vl)

3-hydroxypyrrolidine-1 -carboxamide

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2019275599 04 Dec 2019 [00507] Step A: Preparation of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-lyDpyrazolol 1,5-a1pyrimidin-3-amine: Prepared according to Preparation B, substituting (R)-

2-(2,5-difluorophenyl)pyrrolidine in Step 1 with (R)-3-fluoro-5-(pyrrolidin-2-yl)pyridine.

[00508] Step B: Preparation of (R)-3-fluoro-5-(pyrrolidin-2-yl)pyridine: Prepared by the method of Preparation A, substituting 2-bromo-l,4-difluorobenzene with 3-bromo-5fhioropyridine in Step A.

[00509] Step C: Preparation of (S)-N-(5-((R)-2-(5-fluoropvridin-3-yl)pyrrolidin-lyl )p yrazo Io[ 1,5-al pyri m i di n-3-yl )-3-hydroxypyrrolidine-1 -carboxamide: To a DCM (1 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine (25 mg, 0.084 mmol) was added CDI (27 mg, 0.17 mmol) at ambient temperature in one portion. After stirring for two hours, (S)-pyrrolidin-3-ol (15 mg, 0.17 mmol) was added in one portion. The reaction was stirred overnight before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 40% acetonitrile/water to yield the final product as a solid (27 mg, 78% yield). MS (apci) m/z = 412.2 (M+H).

Example 89

(R)-N-(5-((R)-2-(5-fluoropyridin-3-yl)pvrrolidm-l-yl)pvrazolo[l,5-a1pyrimidin-3-yl)-

3-hydroxypyrrolidine-1 -carboxamide [00510] Prepared by the method as described in Example 88, substituting (S)pyrrolidin-3-ol in Step C with (R)-pyrrolidin-3-ol, giving the final product as a solid (28 mg, 81 %). MS (apci) m/z = 412.2 (M+H).

Example 90

OH (S)-N-(5 -((R)-2-(5-fluoro-2-methoxvphenyl)pyrrolidin-1 -vDpyrazolo [1,5a1pyrimidin-3-yl)-3-hydroxypyrrolidine-1 -carboxamide

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2019275599 04 Dec 2019 [00511] Step A: Preparation of (R)-5-(2-(5-fluoro-2-mcthoxyphcnvl)pyrrolidin-lyI )pyrazolo[ 1,5-a1pyrimidin-3-amine: Prepared according to Preparation B, substituting (R)2-(2,5-difluorophenyl)pyrrolidine in Step 1 with (R)-2-(5-fluoro-2methoxyphenyl)pyrrolidine.

[00512] Step B: Preparation of (R)-2-(5-fluoro-2-methoxvphenvl)pvrrolidine: Prepared by the method of Preparation A, substituting 2-bromo-l,4-difluorobenzene with 2bromo-4-fluoro-1 -methoxybenzene in Step A.

[00513] Step C: Preparation of (S)-N-(5-((R)-2-(5-fluoro-2methoxyphenyDpyrrolidin-1 -yl )pyrazolo[ 1.5-a1pyrimidin-3-yl)-3-hydroxypyrrolidine-l carboxamide: To a DCM (5 mL) solution of (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrro lidinl-yl)py^raz°l°[l_;5-a]pyrimidin-3-amine (25 mg, 0.076 mmol) and DIEA (0.04 mL, 0.23 mmol) was added CDI (25 mg, 0.15 mmol) at ambient temperature in one portion. After stirring for one hour, (S)-pyrrolidin-3-ol (20 mg, 0.23 mmol) was added in one portion. The reaction was stirred overnight before it was concentrated and directly purified by reversephase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a yellowish solid (28 mg, 83% yield). MS (apci) m/z = 441.2 (M+H).

Example 91

(S)-N-(5-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-l-yl)pvrazolo[l,5alpyrimidin-3 -vl)-3 -hydroxypiperidine-1 -carboxamide [00514] Prepared according to the method as described in Example 90, substituting (S)-pyrrolidin-3-ol in Step C with (S)-piperidin-3-ol, giving the final product as a yellowish solid. MS (apci) m/z = 455.2 (M+H).

Example 92

Ο H

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2019275599 04 Dec 2019 (1 S,4S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolor 1,5-a1pyrimidin-3vl)-2-oxa-5-azabicvclo[2.2.11heptane-5-carboxamide [00515] To a DCM (1.0 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol) was added CDI (51 mg, 0.32 mmol) at ambient temperature in one portion. After stirring 90 minutes, (lS,4S)-2oxa-5-azabicyclo[2.2.1]heptane hydrochloride (43 mg, 0.32 mmol) was added in one portion, followed by DIEA (0.083 mL, 0.48 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a pale-yellowish powder (60 mg, 86% yield). MS (apci) m/z = 441.2 (M+H).

Example 93

(R)-N-(5-((R)-2-(2,5-difhiorophenvl)pvrrolidin-l-vl)pvrazolo[l,5-a1pvrimidin-3-vl)3-hydroxypyrrolidine-1 -carboxamide [00516] Prepared by the method as described in Example 92, substituting (lS,4S)-2oxa-5-azabicyclo[2.2.1]heptane hydrochloride with (R)-pyrrolidin-3-ol. The crude material was purified by reverse-phase column chromatography with 5 to 50% acetonitrile/water eluent, giving the final product as a solid (89 mg, 66% yield). MS (apci) m/z = 429.2 (M+H).

Example 94

(1 S,3R)-N-(5-((R)-2-(2,5-difluoror>henvl)r>vrrolidin-l -yl)r>yrazolo[ 1,5-alr>vrimidin-3-yl)-3hydroxycyclopentanecarboxamide [00517] A DMA (1 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol), (lS,3R)-3hydroxycyclopentanecarboxylic acid (23 mg, 0.17 mmol) [purchased from AFTD Therapeutics Inc.] and 2-(lH-benzo[d][l,2,3]triazol-l-yl)-l,l,3,3-tetramethyluronium

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2019275599 04 Dec 2019 tetrafluoroborate (TBTU) (56 mg, 0.17 mmol) was first cooled in an ice-water bath, then DIEA (0.083 mL, 0.48 mmol) was added to reaction drop-wise. Ice bath was then removed and the reaction was stirred at ambient temperature for 1 hour to reach completion. The reaction mixture was diluted with water (10 mL) and vacuum-filtered, yielding the crude product as a beige solid. The crude was purified by reverse phase column chromatography, eluting with 5 to 57% acetonitrile/water to yield the final product as a solid (20 mg, 30% yield). MS (apci) m/z = 428.2 (M+H).

Example 95

(Ί S.3S)-N-(5-((R )-2-(2.5-difluoronhcnyl )r>vnOlidin-l-vl)nvrazolol 1.5-a1r>yrimidin-3-vl )-3hydroxycyclopentanecarboxamide [00518] Prepared by the same method as described in Example 94, substituting (lS,3R)-3-hydroxycyclopentanecarboxylic acid with (lS,3S)-3hydroxycyclopentanecarboxylic acid (23 mg, 0.17 mmol) [purchased from AFID Therapeutics Inc.] The crude product was purified by reverse phase column chromatography, eluting with 5 to 53% acetonitrile/water to yield the final product as a solid (35 mg, 52% yield). MS (apci) m/z = 428.2 (M+H).

Example 96

OH (R)-N-(5-(2-(2,5-difluoror)henyl)pyrrolidl·n-l-yl)pyrazolo[l,5-a1pyrimidin-3-yl)-3hydroxycyclobutanecarboxamide [00519] Prepared by the same method as described in Example 94, substituting (lS,3R)-3-hydroxycyclopentanecarboxylic acid with 3-hydroxycyclobutanecarboxylic acid (20 mg, 0.17 mmol) [purchased from Parkway Scientific], The crude product was purified by

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2019275599 04 Dec 2019 reverse phase column chromatography, eluting with 5 to 53% acetonitrile/water to yield the final product as a solid (8 mg, 12% yield). MS (apci) m/z = 414.2 (M+H).

Example 97

(R)-N¹-(5-(2-(2,5-difluorophenvl)pvrrolidin-l-vl)pvrazolori,5-a1pyrimidin-3-vl)-N²,N²dimethyloxalamide [00520] To a DCM (1 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-lyl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol) was drop-wise added methyl 2-chloro-2-oxoacetate (19.4 mg, 0.159 mmol), followed by DIEA (0.0829 mL, 0.476 mmol). After the mild exothermal subsided and the reaction cooled back to ambient temperature, dimethylamine (0.8 mL, 1.6 mmol) [2M, THF] was added. The reaction was heated to gentle reflux for a few minutes, allowed to cool back to ambient temperature and stirred for 1 hour to reach completion. The reaction was concentrated and directly purified by reverse phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the final product as a pale-yellowish solid (48 mg, 73% yield). MS (apci) m/z = 415.1 (M+H).

Example 98

(R)-N¹-(5-(2-(2,5-difluorophenvl)pvrrolidin-l-vl)pvrazolori,5-a1pvrimidin-3-vl)-N²methyloxalamide [00521] Prepared by the same method as described in Example 97, substituting dimethylamine with methanamine (2M, THF), and the reaction was carried out at room temperature instead of at reflux. The erode product was purified by reverse phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the final product as a white solid (50 mg, 79% yield). MS (apci) m/z = 401.1 (M+H).

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Example 99

(R)-N¹-(5-(2-(2,5-difluorophenyl')pyrrolidin-l-yl)pyrazolori.5-a1pyrimidin-3-yl)oxal amide [00522] Prepared by the same method as described in Example 97, substituting dimethylamine with ammonia (7 M, methanol), and the reaction was carried out at 50 °C overnight. The crude product was purified by reverse phase column chromatography, eluting with 5 to 55% acetonitrile/water to yield the final product as a white solid (50 mg, 82% yield). MS (apci) m/z = 387.1 (M+H).

Example 100

('R)-N¹-cyclopropyl-N2-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a1pyrimidin

3-vl)oxalamide [00523] Prepared by the same method as described in Example 97, substituting dimethylamine with cyclopropanamine, and the reaction was carried out at ambient temperature instead of at reflux. The crude product was purified by reverse phase column chromatography, eluting with 5 to 65% acetonitrile/water to yield the final product as a white solid (50 mg, 74% yield). MS (apci) m/z = 427.2 (M+H).

Example 101

OH (R)-N-(5-(2-(2,5-difluorophenvl)pvrrolidin-l-vl)pvrazolo[l,5-a1pvrimidin-3-yl)-2-(3hydroxyazetidin-1 -yl)-2-oxoacetamide [00524] Prepared by the same method as described in Example 97, substituting dimethylamine with azetidin-3-ol, and the reaction was carried out at 50 °C overnight. The

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100 crude product was purified by reverse phase column chromatography, eluting with 5 to 55% acetonitrile/water to yield the final product as a pale-yellowish solid (53 mg, 75% yield). MS (apci) m/z = 443.1 (M+H).

Example 102

N-(5-((R)-2-(2,5-difluorophenvl)pvrrolidin-l-vl)pvrazolori.5-a1pvrimidin-3-yl)-2-((S)-3hydroxypyrrolidin-1 -yl )-2-oxoacetamide [00525] Prepared by the same method as described in Example 97, substituting dimethylamine with (S)-pyrrolidin-3-ol, and the reaction was carried out at ambient temperature for 1 hour instead of at reflux. The crude product was purified by reverse phase column chromatography, eluting with 5 to 55% acetonitrile/water to yield the final product as a pale-yellowish solid (54 mg, 75% yield). MS (apci) m/z = 457.2 (M+H).

Example 103

(R)-N-(5-(2-(2,5-difluorophenvl')pvrrolidin-l-yl)pvrazolori,5-a1pvrimidin-3-vl)-2morpholino-2-oxoacetamide [00526] Prepared by the same method as described in Example 97, substituting dimethylamine with morpholine, and the reaction was carried out at 50 °C for 1 hour. The crude product was purified by reverse phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the final product as a pale-yellowish solid (52 mg, 72% yield). MS (apci) m/z = 457.1 (M+H).

Example 104

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2019275599 04 Dec 2019 (R)-methyl 2-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[ 1,5-a1pyrimidin-3ylamino)-2-oxoacetatc [00527] A DCM (5 mL, 0.7928 mmol) solution of (R)-5-(2-(2,5difLuorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 250 mg, 0.7928 mmol) and D1EA (0.2071 mL, 1.189 mmol) was first cooled in an ice-water bath, then methyl 2-chloro-2-oxoacetate (0.07657 mL, 0.8325 mmol) was added to reaction drop-wise. Ice bath was removed and the reaction was stirred at ambient temperature for approx. 10 minutes to reach completion. The reaction was washed with 10% citric acid (aqueous). The aqueous layer was back-washed with DCM. The combined organic layer was washed with 1:1 water/brine, dried (Na₂SO₄) and concentrated. The crude oil residue was directly purified by silica chromatography, eluting with EtOAc/hexanes 1:1 to 2:1, yielding the final product as a pale-yellowish foamy powder (270 mg, 85% yield). MS (apci) m/z = 402.2 (M+H).

Example 105 \__1

YV^F /r^0H vAJ ⁰ (R)-2-(5-(2-(2,5-difluorophenyl)r>vrrolidin-l-vl)pvrazolori,5-a]pvrimidin-3-vlamino)-2oxoacetic acid [00528] (R)-methyl 2-(5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l ,5a]pyrimidin-3-ylamino)-2-oxoacetate (Example 104; 100 mg, 0.249 mmol) was dissolved in a mixture solvent of THF:MeOH:water (2:2:1, 1 mL), followed by addition of LiOH-H₂O (31.4 mg, 0.747 mmol). The reaction was stirred at ambient temperature for 10 minutes to reach completion. The reaction was concentrated, re-dissolved in water (20 mL) and acidified with 6 N HC1. The precipitate was vacuum-filtered, rinsed with water, heptane, and dried on high vacuum, giving the final product as a fine pale-yellowish powder (50 mg, 52% yield). MS (apci negative) m/z = 386.1 (M-H).

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102

1. A compound having the general formula I

or a pharmaceutically acceptable salt thereof, wherein:

R¹ isHor(l-6C alkyl);

R² is NR^bR^c, (l-4C)alkyl, (l-4C)fluoroalkyl, CF3, (l-4C)hydroxyalkyl, -(1-4C alkylfhetAr¹, -(1-4C alkyl)NH2, -(I-4C alkyl)NH(l-4C alkyl), -(1-4C alkyl)N(l-4C alkyl)₂, hetAr², hetCyc¹, hetCyc², phenyl which is optionally substituted with NHSO₂(14C alkyl), or (3-6C)cycloalkyl which is optionally substituted with (1-4C alkyl), CN, OH, OMe, NH₂, NHMe, N(CH₃)₂, F, CF₃, CO₂(1-4C alkyl), CO₂H, C(=O)NR“R^r or C(=O)OR^S;

R^b isHor(l-6C alkyl);

R^c is H, (1 -4C)alkyl, (1 -4C)hydroxyalkyl, hetAr, or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, CF₃ and -0(1 -4C alkyl), or NR^bR^c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, -OC(=O)(1-4C alkyl), NH₂, -NHC(=0)0(MC alkyl) and (l-4C)hydroxyalkyl, or NR^bR^c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring hctcroatom or group selected from N, O and SO₂, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF₃, (l-4C)alkyl, CO₂(1-4C alkyl), CO₂H, NH₂, NHC(=O)O(1-4C alkyl) and oxo, or NR^bR^c forms a 7-8 membered bridged heterocyclic ring having a ring nitrogen atom and optionally having a second ring hctcroatom selected from N and O, wherein said ring is optionally substituted with CO₂(1-4C alkyl);

hetAr¹ is a 5-membcrcd hctcroaryl ring having 1-3 ring nitrogen atoms;

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103 hctAr² is 5-6 membered hetcroaryl ring having at least one nitrogen ring atom and optionally having a second ring hctcroatom independently selected from N and S, wherein said hetcroaryl ring is optionally substituted with one or more substituents independently selected from (1-4C alkyl), halogen, -(1-4 Qalkoxy and NH(1-4C alkyl);

hetCyc¹ is a carbon-linked 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from (1-4C alkyl), and CO₂(1-4C alkyl);

hetCyc² is a pyridinone or pyridazinone ring which is optionally substituted with a substituent selected from (1 -4C)alkyl;

hctAr is a 5-6 membered hetcroaryl ring having 1-2 ring hctcroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from (1 -4C)alkyl;

R^e is H or (l-4C)alkyl;

R^f is H, (l-4C)alkyl, or (3-6Qcycloalkyl;

or NR^UR⁽ forms a 4-6-membered azacyclic ring optionally having an additional ring hetcroatom selected from N and O, wherein the azacyclic ring is optionally substituted with OH;

R^s is H or (l-6C)alkyl;

Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4C)alkoxy, CF₃ and CHF₂, or (ii) a 5-6 membered heteroaryl ring having a ring hctcroatom selected from N and S, wherein said hetcroaryl ring is optionally substituted with one or more halogen atoms;

X is null, -CH₂-, -CH₂CH₂-, -CH₂O-, or -CH₂NR^d-;

R^d isHor(l-4C alkyl);

R'is H or (1-4C alkyl);

each R⁴ is independently selected from halogen, (l-4C)alkyl, OH, (1-4 Qalkoxy, NH₂, NH(1-4C alkyl) and CH₂OH; and n is 0, 1,2,3,4, 5 or 6.

2. A compound of 1, wherein R² is NR^bR^c, (l-4C)alkyl, (14C)fluoroalkyl, CF3, (l-4C)hydroxyalkyl, -(1 -4C alkylJhetAr¹, -(1-4C alkyl)NH2, -(1-4C alkyl)NH(l-4C alkyl), -(1-4C alky 1)N( 1-4C alkyl)₂, hctAr², hetCyc¹, hetCyc², phenyl which is optionally substituted with NHSO₂(1-4C alkyl), or (3-6C)cycloalkyl which is

104

2019275599 04 Dec 2019 optionally substituted with (1-4C alkyl), CN, OH, OMc, NH₂, NHMe, N(CH₃)₂. F, CF₃, CO₂(1-4C alkyl) orCO₂H.

3. A compound of 1 or 2, wherein R² is NR^bR^e.

4. A compound according to any of claims 1-3, wherein:

NR^bR^c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, -OC(=O)(1-4C alkyl), NH₂, -NHC(=O)O(1-4C alkyl) and (l-4C)hydroxyalkyl, or NR^bR^c forms a 5-6 membered heterocyclic ring having a ring hctcroatom which is nitrogen and optionally having a second ring hctcroatom or group selected from N, O and SO₂, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF₃, (l-4C)alkyl, CO₂(1-4C alkyl), CO₂H, NH₂, NHC(=O)O(1-4C alkyl) and oxo, or NR^bR^c forms a 7-8 membered bridged heterocyclic ring having a ring nitrogen atom and optionally having a second ring heteroatom selected from N and O, wherein said ring is optionally substituted with CO₂(i-4C alkyl).

5. A compound according to any of 1-3, wherein:

R^c is H, (l-4C)alkyl, (l-4C)hydroxyalkyl, hetAr, or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, CF₃ and -O(1-4C alkyl).

6. A compound of 1 or 2, wherein R² is (1 -4C)alkyl, (l-4C)fluoroalkyl, CF₃, -(1-4C alkyDhetAr¹ or -(1-4C alkyl)NH(l-4C alkyl).

7. A compound of

8. A compound of with NHSO₂(1-4C alkyl).

9. A compound of or 2, wherein R² is hetAr², hetCyc¹ or hetCyc². lor 2, wherein R² is phenyl optionally substituted or 2, wherein R² is (3-6C)cycloalkyl which is optionally substituted with (1-4C alkyl), CN, OH, CF₃, CO₂(1-4C alkyl) or CO₂H.

10. A compound of claim 1, wherein R² is C(=O)NR^cR^f or C(=O)OR^S.

11. A compound according to any of claims 1-10, wherein X is null, -CH₂- or -CH₂CH₂-.

12. A compound according to 11, wherein X is-CH²-.

13. A compound according to any of 1-10, wherein X is CH₂O-.

14. A compound according to any of 1-10, wherein X is-CH₂NR^d-.

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105

15. A compound according to any of 1-14, wherein Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4Qalkoxy, CF₃ and CHF₂.

16. A compound according to 15, wherein Y is phenyl, 3-fluorophenyl, 2,5-di fluorophenyl, 2-chloro-5-fluorophenyl, 2-methoxyphenyl, 2-methoxy-5fluorophenyl, 2-trifluoromethyl-5-fluorophenyl, 2-difluoromethyl-5-fluorophenyl or 3ch loro-5-fluoropheny I.

17. A compound according to any of 1-14, wherein Y is a 5-6 membered hcteroaryl ring having a ring hetcroatom selected from N and S, wherein said ring is optionally substituted with one or more halogen atoms.

18. A compound according to any of 1-17, wherein Y has the absolute configuration of Figure la:

19. A compound according to any of 1-18, wherein R^J is H.

20. A compound according to claim 1, wherein:

R* isHor(l-6C alkyl);

R² is NR^bR^c;

NR^bR^c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 Qalkoxy, -OC(=O)( 1-4C alkyl), NH₂, -NHC(=O)O(1-4C alkyl) and (l-4C)hydroxyalkyl, or NR^bR^e forms a 5-6 membered heterocyclic ring having a ring hetcroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO₂, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF₃, (l-4C)alkyl, CO₂(1-4C alkyl), CO₂H, NH₂, NHC(=O)O(1-4C alkyl) and oxo;

Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4C)alkoxy, CF₃ and CHF₂;

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X is null, -CH₂-, or -CH₂CH₂-;

R‘isHor(l-4C alkyl·);

each R⁴ is independently selected from halogen, (1 -4C)alkyl, OH, (1-4 C)alkoxy, NH₂, NH(1-4C alkyl) and CH,OH; and n is 0, 1, or 2.

21. A compound according to 20, wherein:

R¹ isHor(l-6C alkyl);

R² is NR^bR^c;

NR^l’R^c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring hctcroatom or group selected from N, O and SO₂, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CFj, (l-4C)alkyl, CO₂(1-4C alkyl), CO?H, NH₂, NHC(=O)O( 1-4C alkyl) and oxo;

Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4C)alkoxy, CF₃ and CHF₂;

X is -CH₂-;

R³ is H or (1-4C alkyl);

each R⁴ is independently selected from halogen, (l-4C)alkyl, OH, (1-4 C)alkoxy, NH₂, NH(1-4C alkyl) and CH₂OH; and n is 0, 1, or 2.

A compound according to 21, wherein the heterocyclic ring formed by NR^bR^c is optionally substituted with one or two substituents independently selected from OH, F, NH₂, CO₂H, CO₂Et, NHCO₂C(CH,)₃, CFj, methyl, ethyl, isopropyl, CO₂C(CH₂)₃ and oxo.

23. A compound according to 22, wherein Y is phenyl optionally substituted with one or more halogen atoms.

24. A compound according to 23, wherein Y is phenyl optionally substituted with one or two fluorine atoms.

25. A compound according 20, wherein:

R¹ is H or (1-6C alkyl);

R² is NR^bR^c;

NR^bR^c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said ring is optionally substituted with one or more substituents independently

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2019275599 04 Dec 2019 selected from halogen, OH, (1-4C alkyl), (1-4 Qalkoxy, -OC(=O)(]-4C alkyl), NH₂, -NHC(=O)O(1-4C alkyl) and (l-4Qhydroxyalkyl;

Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-4Qalkoxy, CF₃ and CHF₂;

X is -CH₂-;

R³ is H or (1-4C alkyl);

each R⁴ is independently selected from halogen, (l-4Qalkyl, OH, (1-4 Qalkoxy, NH₂, NH(1-4C alkyl) and CH₂OH; and n is 0, 1, or 2.

26. A compound according to 25, wherein the heterocyclic ring formed by NR^bR^c is optionally substituted with one or two substituents independently selected from F, OH, methyl, OMc, OC(=O)C(CH.0₂, NH₂, -NHC(=O)OC(CH₅)₃ and CH₂OH.

27. A compound according to substituted with one or more halogen atoms.

28. A compound according to substituted with one or two fluorine atoms.

29. A compound according to any

30. A compound according to

31. A compound according to

32. A compound according to salt or a hydrochloride salt.

33.

as defined in any one of

26, wherein Y is phenyl optionally

27, wherein Y is phenyl optionally of 20-28, wherein n is zero or one.

29, wherein R³ is hydrogen.

30, wherein R¹ is hydrogen.

1, which is a tri fluoroacetate salt, a sulfate

A pharmaceutical composition, which comprises a compound of Formula 1 to 32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

34. A method for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula 1 as defined in any one of 1 to 32, or a pharmaceutically acceptable salt thereof.

35. A method for treating osteolytic disease in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I as defined in any one of 1 to 32, or a pharmaceutically acceptable salt thereof.

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36. A compound of Formula I as defined in any one of 1 to 32, or a pharmaceutically acceptable salt thereof, for use in the treatment of pain, cancer, inflammation, neurodcgcnerative disease orTypanosoma cruzi infection in a mammal.

37. A compound of Formula I as defined in any one of 1 to 32, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteolytic disease in a mammal.

38. A process for the preparation of a compound of 1, which comprises:

(a) for a compound of Formula 1 wherein R² is NR^bR^c, reacting a corresponding compound of formula II

II with a compound having the formula HNR^bR^c in the presence of a coupling reagent; or (b) for a compound of Formula I wherein R² is NR^bR^c and R^b is H, reacting a corresponding compound of formula II with a compound having the formula O=C=N-R^C; or (c) for a compound of Formula I wherein R² is het Ar² or a phenyl ring which is optionally substituted with NHSO₂(l-4C alkyl), reacting a corresponding compound of Formula II with a corrcsponding compound having the formula HOC(=O)R² in the presence of a coupling reagent and a base; or (d) for a compound of Formula I wherein R² is (l-4C)a!kyl, (l-4C)fluoroalkyl, CF3, (l-4C)hydroxyalkyl, or (3-6C)cycloalkyl which is optionally substituted with (1-4C alkyl), CN, OH, CH. CO2( 1-4C alkyl) or CO2H, reacting a corresponding compound of Formula II with a corresponding compound having the formula (R²CO)2O in the presence of a base; or (e) for a compound of Formula I wherein R² is (l-4C)alkyl, (l-4C)fluoroalkyl, CF₃, (l-4C)hydroxyalkyl, or (3-6C)cycloalkyl which is optionally substituted with (1-4C alkyl), CN, OH, CF₂, CO₂(I-4C alkyl) or CO₂H, reacting a corresponding compound of Formula II with a corresponding compound having the formula HOC(=O)R² in the presence of a coupling reagent and a base;

109 (f) for a compound of Formula I wherein R² is Ci^OjNR^R¹, reacting a compound of formula Vll

VII with a compound having the formula HNR^cR^f in the presence of a base; or (g) for a compound of Formula I wherein R² is C(=O)OR^S, reacting a compound of Formula II with methyl 2-chloro-2~oxoacctatc, and treating with an alkali hydroxide to prepare a compound of formula 1 where R® is H; and removing or adding any protecting groups if desired, and forming a salt if desire

Claims (16)

1. Claims

   1. A compound of the formula:

   F

   

   or a pharmaceutically acceptable salt thereof.
2. 2. A compound of the formula:

   

   or a pharmaceutically acceptable salt thereof.
3. 3. A process for preparing the compound of claim 2 comprising reacting a compound of the formula

   F

   

   with nitric acid in the presence of an activating agent.
4. 4. The process of claim 3, wherein the activating agent is TFA.
5. 5. The process of claim 3, wherein the activating agent is concentrated sulfuric acid.
6. 6. A compound of the formula:

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   2019275599 04 Dec 2019

   

   or a pharmaceutically acceptable salt thereof.
7. 7. A process for preparing the compound of claim 6 comprising reacting a compound of the formula:

   

   with zinc dust under acidic conditions.
8. 8. The process of claim 7, wherein acidic conditions comprise reacting in the presence of

   NH4CI (saturated aqueous).
9. 9. The process of claim 7, wherein acidic conditions comprise reacting in the presence of

   HC1.
10. 10. The process of claim 7, wherein acidic conditions comprise reacting in the presence of acetic acid.
11. 11. A process for preparing the compound of claim 6 comprising reacting a compound of the formula:

    

    under a hydrogen atmosphere in the presence of a precious metal catalyst.

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12. 12. A process for preparing (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidine-lyl)pyrazolo[ 1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1 -carboxamide

    

    comprising reacting the compound of claim 6 with (S)-pyrrolidin-3-ol in the presence of a coupling reagent.
13. 13. The process of claim 12, wherein the coupling reagent is selected from carbonyl diimidazole, phosgene, and bis(trichloromethyl) carbonate.
14. 14. The process of claim 12 or 13, wherein the coupling reagent is carbonyl diimidazole.
15. 15. The process of any one of claims 12-14, further comprising forming a salt of (S)-N-(5((R)-2-(2,5-difluorophenyl)pyrrolidine-1 -yl)pyrazolo [ 1,5 -a]pyrimidin-3 -y 1) - 3 hydroxypyrrolidine-1 -carboxamide.
16. 16. The process of claim 15, wherein the salt is (S)-N-(5-((R)-2-(2,5difluorophenyl)pyrrolidine-1 -yl)pyrazolo [ 1,5-a]pyrimidin-3 -y 1)-3 -hydroxypyrrolidine-1 carboxamide sulfate.