macrocyclic compounds such as trk kinase inhibitors, pharmaceutical composition, use of a compound o

专利摘要:
MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS, PHARMACEUTICAL COMPOSITION, USE OF A COMPOUND OF FORMULA I OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, PROCESS FOR THE PREPARATION OF A COMPOUND. The invention relates to compounds of Formula I: I and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R2, R2a, R3, R3a, and Z are as defined herein, are Trk kinase inhibitors and are useful in the treatment of pain, cancer, inflammation, disease, neurodegenerative and certain infectious diseases.
公开号:BR112012029405B1
申请号:R112012029405-9
申请日:2011-05-13
公开日:2021-01-05
发明作者:Steven Wade Andrews；Kevin Ronald Condroski；Julia Haas；Yutong Jiang；Gabrielle R. Kolakowski；Jeongbeob Seo；Hong-Woon Yang；Qian Zhao
申请人:Array Biopharma Inc.；
IPC主号:

专利说明:

[0001] The present invention relates to new compounds, pharmaceutical compositions comprising the compounds, processes for the preparation of the compounds and the use of the compounds in therapy. More particularly, it refers to certain macrocyclic compounds which exhibit inhibition of protein tyrosine kinase of the Trk family, and which are useful in the treatment of pain, cancer, inflammation, neurodegenerative disease and certain infectious diseases.
[0002] Current treatment regimens for pain conditions use several classes of compounds. Opioids (such as morphine) have several disadvantages, including negative emetic, cold and respiratory effects, as well as the potential for addiction. Non-steroidal anti-inflammatory analgesic drugs (NSAIDs, such as types COX-1 or COX-2), also have disadvantages, including insufficient efficacy in treating severe pain and the potential for internal gastrointestinal bleeding. In addition, COX-1 inhibitors can cause mucosal ulcers. Therefore, there is an ongoing need for new and more effective pain relief treatments, especially for chronic pain.
[0003] Trks are high-affinity tyrosine kinase receptors activated by a group of soluble growth factors called neurotrophins (NT). The Trk family of receivers has three members: TrkA, TrkB and TrkC. Among the neurotrophins are (i) nerve growth factor (NGF) that activates TrkA, (ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 that activate TrkB and (iii) NT3 that activates TrkC. Trks are widely expressed in neuronal tissue and are involved in the maintenance of signaling, and the survival of neuronal cells (Patapoutian, A. et al., Current Opinion in Neurobiology, 2001, 11, 272- 280).
[0004] Trk / neurotrophin pathway inhibitors have been shown to be effective in several preclinical animal models of pain. For example, antagonistic NGF and TrkA antibodies such as RN-624 have been shown to be effective in animal models of inflammation and neuropathic pain (Woolf, CJ et al. (1994) Neuroscience 62,327-331; Zahn, PK et al. (2004) J Pain 5, 157-163 ,. McMahon, SB et al., (1995) Nat. Med. 1, 774-780 ;. Ma, QP and Woolf, CJ (1997) Neuroreport 8, 807-810; Shelton, DL et al. Pain (2005) 116, 8-16; Delafoy, L. et al. (2003) Pain 105, 489-497; Lamb, K. et al (2003) Neurogastroenterol. Motil. 15, 355- 361; Jaggar , SI et al (1999) Br. J. Anaesth 83, 442-448) and animal models of neuropathic pain (Ramer, MS and Bisby, MA (1999) Eur. J. Neurosci 11, 837-846; Ro, LS et al. (1999) ,. Pain 79, 265-274 Herzberg, U. et al (1997) Neuroreport 8, 1613-1618 ;. Theodosiou, M. et al (1999) Pain 81, 245-255 ,. Li, L. et al. (2003) Mol Cell Neurosci 23, 232-250; Gwak, YS et al (2003) Neurosci Lett 336, 117-120).
[0005] It has also been shown that NGF secreted by tumor cells and macrophage-invading tumors directly stimulates TrkA located in peripheral pain fibers. Using various tumor models in both mice and rats, neutralization of NGF with a monoclonal antibody has been shown to inhibit cancer-related pain to a degree similar to or greater than the maximum tolerated dose of morphine. In addition, activation of the BDNF / TrkB pathway has been implicated in numerous studies, as a modulator of several types of pain, including inflammatory pain (Matayoshi, S., J. Physiol. 2005, 569: 685-95), neuropathic pain (Thompson, SW, Proc. Natl. Acad. Sci. USA 1999, 96: 7714-18) and surgical pain (Li, C.-Q. et al., Pain Molecular, 2008, 4 (28), 1 -11).
[0006] Recent literature has also shown that overexpression, activation, amplification and / or the mutation of Trk kinases are associated with many cancers, including neuroblastoma (Brodeur, GM, Nat. Rev. Cancer 2003, 3, 203-216) , ovary (Davidson. B., et al, Clin. Cancer Res. 2003, 9, 2248-2259), colorectal cancer (Bardelli, A., Science 2003, 300, 949), melanoma (Truzzi, F., et al ., Dermato-Endocrinology 2008, 3 (1), pp 32-36), head and neck cancer (Yilmaz, T., et al., Cancer Biology and Therapy 2010, 10 (6), pp 644-653), gastric carcinoma (Du, J. et al., World Journal of Gastroenterology 2003, 9 (7) pp 1431-1434), lung carcinoma (Ricci A., et al, American Journal of Respiratory Cell and Molecular Biology 25 (4) , 439 pp - 446), breast cancer (Jin, W., et al., Carcinogenesis 2010, 31 (11), pp 1939-1947), glioblastoma (Wadhwa, S., et al., Journal of Biosciences 2003, 28 (2), pp. 181-188), medulloblastoma (Gruber-Olipitz, M., et al, Journal of Proteome Research 2008 , 7 (5), pp 1932-1944), secretory breast cancer (euthus, DM, et al, Cancer Cell 2002, 2 (5), pp 347-348), salivary gland cancer (Li, Y.-G. , et al, Chinese Journal of Cancer Prevention and Treatment 2009, 16 (6), pp 428-430), papillary thyroid carcinoma (Greco, A., et al., Molecular and Cellular Endocrinology 2010, 321 (1), pp 44-49) and adult myeloid leukemia (Eguchi, M., et al, Blood 1999, 93 (4), pp 1355-1363). In preclinical cancer models, small non-selective molecule inhibitors of TrkA, B and C were effective in inhibiting tumor growth and stopping tumor metastasis (Nakagawara, A. (2001) Cancer Letters 169: 107-114; Meyer , J. et al. Leukemia (2007), 1-10; Pierottia, MA and Greco A., (2006) Cancer Letters 232: 90-98; Eric Adriaenssens, E., et al. Cancer Res (2008) 68: . (2). 346- 351).
[0007] Furthermore, inhibition of the neurotrophin / Trk pathway has been shown to be effective in the treatment of preclinical models of inflammatory diseases with NGF antibodies or inhibitors of small non-selective molecules of TrkA, B and C. 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), 1016-1021), inflammatory bowel diseases including ulcerative colitis and Crohn's disease (Di Mola, FF, 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, SP, et al, J. 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, F., Lewis, K. Danielle, Frontiers in Neuroendocrinology (2006), 27 (4), 404-414).
[0009] It is also believed that the TrkA receptor must be critical to the disease process in the infection of the parasitic infection of Trypanosoma cruzi (Chagas disease) in human hosts (de Melo-Jorge, M., et al, Cell Host & Microbe (2007), 1 (4), 251-261).
[00010] Various classes of small molecule inhibitors of Trk kinases reported to be useful in the treatment of pain or cancer are known (Expert Opin. Ther. Patents (2009) 19 (3)).
[00011] There is still a need, however, for compounds and methods for the treatment of pain, especially chronic pain, as well as the treatment of cancer, inflammation, neurodegenerative diseases and certain infectious diseases. SUMMARY OF THE INVENTION
[00012] It has now been found that macrocyclic compounds that are inhibitors of Trk kinases, in particular inhibitors of TrkA and / or TrkB and / or TrkC, and are useful in the treatment of disorders and diseases such as cancer and pain, including chronic pain and acute. Compounds that are inhibitors of TrkA and / or TrkB may be useful in the treatment of various types of pain, including inflammatory pain, neuropathic pain and pain associated with cancer surgery, and bone fracture. In addition, the compounds of the present invention can be useful in the treatment of inflammation, neurodegenerative diseases and certain infectious diseases.
[00013] Thus, in one aspect the present invention provides new compounds that have general Formula I:

[00014] and the stereoisomers and pharmaceutically acceptable salts and solvates thereof, wherein ring A, ring B, W, m, D, R2, R2a, R3, R3a, and Z are as defined herein.
[00015] In another aspect, the present invention provides new compounds that have the general Formula I:

[00016] or pharmaceutically acceptable salts or solvates thereof, wherein ring A, W, m, R2, R2a, R3, Z, R5 and R6 are as defined herein.
[00017] In another aspect of the invention, pharmaceutical compositions are provided which comprise the compounds of Formula I and a carrier, diluent or excipient.
[00018] In another aspect of the invention, a method is provided for treating or preventing pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases in a mammal, comprising administering to said mammal an effective amount of a compound of Formula I .
[00019] In another aspect of the invention, the use of a compound of Formula I in the manufacture of a medicament for the treatment or prevention of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases is provided.
[00020] In another aspect of the invention, a use of a compound of Formula I is provided in the treatment or prevention of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
[00021] Another aspect provides intermediates for the preparation of compounds of Formula I. In one embodiment, certain compounds of Formula I can be used as intermediates for the preparation of other compounds of Formula I.
[00022] Another aspect includes processes for the preparation, methods of separation and methods of purification of the compounds described herein. DETAILED DESCRIPTION OF THE INVENTION
[00023] One embodiment of the present invention provides compounds of the general Formula I containing a pyrazolo [1,5-a] pyrimidinyl ring and having the structure:

[00024] or pharmaceutically acceptable salts or solvates thereof, where:
[00025] ring A is selected from rings A-1, A-2 and A-3, having the structures:

[00026] where the wavy line marked with 1 indicates the point of attachment of ring A to ring B and the wavy line marked with 2 indicates the point of attachment of ring A to W;
[00027] X is N or CH;
[00028] Y is H or F;
[00029] R1 is H, (1 -3C) alkoxy or halogen;
[00030] ring B is selected from rings B-1 and B-2, which have the structures:

[00031] wherein the wavy line marked with 3 indicates the point of attachment to ring A and the wavy line marked with 4 indicates the point of attachment to the pyrazole ring [1,5-a] pyrimidine of Formula I;
[00032] W is O, NH or CH2, where, when ring A is A-2, then W is CH2;
[00033] m is 0, 1 or 2;
[00034] D is carbon;
[00035] R2 and R2a are, independently, H, F, (1-3 C) alkyl or OH, provided that R2 and R2a are not both OH;
[00036] R3 and R3a are, independently, H, (1-3 C) alkyl or hydroxy (1-3 C) alkyl;
[00037] or D is carbon or nitrogen, R2 and R3 are absent and R2a and R3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 heteroatoms in the ring;
[00038] Z is * -NR4aC (= O) -, * -ONHC (= O) -, * -NR4bCH2-or * -OC (= O) -, where the asterisk indicates the fixation point of Z with the carbon that supports R3;
[00039] R4a is H, (1-6C) alkyl, fluorine (1-6C) alkyl, difluor (1-6C) alkyl, trifluor (1-6C) alkyl, hydroxy (1-6C) alkyl or dihydroxy ( 2-6C alkyl);
[00040] R4b is H, (1-6C) alkyl, fluorine (1-6C) alkyl, difluor (1-6C) alkyl, trifluor (1-6C) alkyl, hydroxy (1-6C) alkyl, dihydroxy ( 2- 6C) alkyl, (1-6C alkyl) C (O) -, (3-6C cycloalkyl) C (O) -, Ar1C (O) -, HOCH2C (O) -, (1-6C alkyl) sulfonyl, (3-6C cycloalkyl) sulfonyl, AR2 (SO2) -, or HO2CCH2- (1-6C alkyl) NH (CO) -;
[00041] Ar1 is phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C) alkyl, and (1-6C) alkoxy;
[00042] Ar2 is phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C) alkyl, and (1-6C) alkoxy; and
[00043] R5 and R6 are, independently, H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.
[00044] In a Formula I modality, ring B is a ring B-2 having the structure:
D is carbon, R2 and R2a are independently (1-3 C) alkyl, and R3 and R3a are independently H, (1-3 C) alkyl or hydroxy (1-3 C) alkyl or
[00045] D is carbon or nitrogen, R2 and R3 and R2a and R3a are absent together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1 - 2 hetero atoms in the ring.
[00046] In a Formula I modality, ring A is an A-1 ring having the structure

[00047] where X, Y and R1 are as defined for Formula I. In a Formula I embodiment, X is CH. In an embodiment, X is N. In an embodiment of Formula I, Y is F. In an embodiment, Y is H. In an embodiment of Formula I, R1 is H. In an embodiment, R1 is (1-3-3) alkoxy . A particular example is methoxy. In one embodiment, R1 is halogen. In one mode, R1 is F.
[00048] Particular examples of ring A, when represented by structure A-1 include the structures:

[00049] In one embodiment, ring A is an A-2 ring having the structure

[00050] where Y is H or F. In one embodiment, Y is F. In one embodiment, Y is H.
[00051] In one embodiment, R1 is H. In one embodiment, R1 is (1-3C) alkoxy. A particular example is methoxy. In one embodiment, R1 is halogen. In one mode, R1 is F.
[00052] Particular examples of ring A when represented by ring A-2 are the structures:

[00053] In a Formula I modality, ring A is an A-3 ring having the structure

[00054] where Y and R1 is as defined for Formula I. In one embodiment, Y is F. In one embodiment, Y is H. In one embodiment, R1 is H. In one embodiment, R1 is (1-3C ) alkoxy. A particular example is methoxy. In one embodiment, R1 is halogen. In one mode, R1 is F.
[00055] Particular examples of ring A when represented by ring A-3 are the structures:

[00056] In a Formula I modality, W is O.
[00057] In one embodiment, W is NH.
[00058] In one embodiment, W is CH2.
[00059] In a Formula I embodiment, D is carbon, R2 and R2a are, independently, H, F, (1-3 C) alkyl or OH (provided that R2 and R2a are not both OH), and R3 and R3a are, independently, H, (1-3C) alkyl or hydroxy (1-3C) alkyl.
[00060] In one embodiment, R2 and R2a are, independently, H, F, methyl or OH, as long as R2 and R2a are not both OH.
[00061] In one embodiment, R2 and R2a are both H.
[00062] In one embodiment, R2 is H and R2a is F.
[00063] In one embodiment, R2 and R2a are both F.
[00064] In one embodiment, R2 is H and R2a is OH.
[00065] In one embodiment, R2 is H and R2a is methyl.
[00066] In one embodiment, R2 and R2a are both methyl.
[00067] In one embodiment, R3 and R3a are, independently, H, (1-3C) alkyl or hydroxy (1-3C) alkyl.
[00068] In one mode, R3a is H. In one mode, R3 is H. In one mode, both R3 and R3a are H.
[00069] In one embodiment, R3a is (1-3C) alkyl. Examples include methyl, ethyl, propyl and isopropyl. In one embodiment, R3 is (1-3C) alkyl. Examples include methyl, ethyl, propyl and isopropyl.
[00070] In one embodiment, R3a is (1-3 C) alkyl and R3 is H. In one embodiment, R3a is a methyl group and R3 is H.
[00071] In one embodiment, both R3 and R3a are (1-3C) alkyl. In one embodiment, R3 and R3a are both methyl.
[00072] In one embodiment, R3 is hydroxy (1-3C) alkyl. Examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl. In one embodiment, R3 is hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl and R3a is H.
[00073] In a Formula I modality, D is carbon or nitrogen, R2 and R3 are absent, and R2a and R3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 heteroatoms ring. In one embodiment, R2a and R3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 nitrogen atoms in the ring. Examples of heteroaryl rings include pyridyl and pyrazolyl rings. Specific examples of heteroaryl rings include the structures:

[00074] In one embodiment, Z is * -NR4aC (= O) -.
[00075] In one embodiment, R4a is H.
[00076] In one embodiment, R4a is (1-6C) alkyl. Examples include methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.
[00077] In one embodiment, R4a is fluorine (1-6C) alkyl. Examples include fluoromethyl and 2-fluorethyl.
[00078] In one embodiment, R4a is difluor (1-6C) alkyl. Examples include difluoromethyl and 2,2-difluorethyl.
[00079] In one embodiment, R4a is trifluor (1-6C) alkyl. Examples include trifluoromethyl and 2,2,2-trifluorethyl.
[00080] In one embodiment, R4a is hydroxy (1-6C alkyl). Examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl.
[00081] In one embodiment, R4a is dihydroxy (2-6C alkyl). An example includes 2,3-dihydroxypropyl.
[00082] In some embodiments, R4a is H or dihydroxy (1-6C alkyl). In one embodiment, R4a is H or Me.
[00083] An example of Z when represented by * -NR4aC (= O) - is * -ONHC (= O) -.
[00084] In one embodiment, Z is * -NR4bCH2-.
[00085] In one embodiment, R4b is H.
[00086] In one embodiment, R4b is selected from (1-6C) alkyl, fluorine (1-6C) alkyl, difluor (1-6C) alkyl, and trifluor (1-6C) alkyl.
[00087] In one embodiment, R4b is (1-6C) alkyl. Examples include methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. In one embodiment, R4b is methyl.
[00088] In one embodiment, R4b fluorine is (1-6C) alkyl. Examples include fluoromethyl and 2-fluorethyl.
[00089] In one embodiment, R4b is difluor (1-6C) alkyl. Examples include difluoromethyl and 2,2-difluorethyl.
[00090] In one embodiment, R4b is alkyl trifluor (1-6C). Examples include trifluoromethyl and 2,2,2-trifluorethyl.
[00091] In one embodiment, R4b is selected from (1-6C alkyl) C (O) -, (3-6C cycloalkyl) C (O) -, Ar1C (O) - and HOCH2C (O) -.
[00092] In one embodiment, R4b is (1-6C alkyl) C (O) -. Examples include CH3C (O) -, CH3CH2C (O) -, CH3CH2CH2C (O) -, and (CH3) 2CHC (O) -. In one embodiment, R4 is CH3C (O) -.
[00093] In one embodiment, R4b is (3-6C cycloalkyl) C (O) -. Examples include cyclopropylC (O) -, cyclobutylC (O) -, cyclopentylC (O) - and cyclohexylC (O) -.
[00094] In one embodiment, R4b is Ar1C (O) -. An example is phenylC (O) -.
[00095] In one embodiment, R4b is HOCH2C (O) -.
[00096] In one embodiment, R4b is selected from (1-6C alkyl) sulfonyl, (3-6C cycloalkyl) sulfonyl, and AR2 (SO2) -.
[00097] In one embodiment, R4b is (1-6C alkyl) sulfonyl. Examples include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
[00098] In one embodiment, R4b is (3-6C cycloalkyl) sulfonyl. Examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl and cyclohexylsulfonyl. In one embodiment, R4 is methylsulfonyl.
[00099] In one mode, R4b is Ar2 (SO2) -. An example is phenylsulfonyl.
[000100] In one embodiment, R4b is HO2CCH2-.
[000101] In one embodiment, R4b is (1-6C alkyl) NH (CO) -. Examples include CH3NHC (O) -, CH3CH2NHC (O) -, CH3CH2CH2NHC (O) -, and (CH3) 2CHNHC (O) -. In one embodiment, R4 is CH3NHC (O) -.
[000102] In one embodiment, R4b is selected from H, methyl, -C (O) CH3, methylsulfonyl, -C (O) CH2OH, -CH2COOH and -C (O) NHCH2CH3.
[000103] In one embodiment, Z is * -OC (= O) -.
[000104] In a Formula I modality, ring B is a ring B-1:

[000105] where R5 and R6 are independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.
[000106] In one embodiment, R5 and R6 are, independently, H, F, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl. In one embodiment, R5 is H and R6 is H, F, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.
[000107] In one embodiment, R5 and R6 are, independently, H, F, OH, (1-3C) alkyl or hydroxy (1-3C) alkyl. In one embodiment, R5 is hydrogen and R6 is H, F, OH, (1-3C) alkyl or hydroxy (1-3C) alkyl.
[000108] In one embodiment, R5 and R6 are, independently, H, F, OH, methyl, ethyl, HOCH2- or -HOCH2CH2. In one embodiment, R5 is hydrogen and R6 is H, F, OH, methyl, ethyl, or HOCH2-HOCH2CH2-.
[000109] In one embodiment, R5 and R6 are, independently, H, F, or methyl. In one embodiment, R5 is H and R6 is H, F, or methyl.
[000110] In one embodiment, R5 is H and R6 is F.
[000111] In one embodiment, R5 is H and R6 is methyl.
[000112] In one mode, R5 and R6 are both H.
[000113] In one mode, R5 and R6 are both F.
[000114] In one embodiment, R5 and R6 are both methyl.
[000115] In one embodiment, ring B is ring B-1 which is optionally substituted by one or two substituents independently selected from OH and F, as long as two OH substituents are not on the same ring carbon atom.
[000116] Particular examples of ring B, when represented by ring B-1 include the structures:

[000117] In a Formula I modality, ring B is a ring B-2 with the formula:

[000118] In one mode, m is 0.
[000119] In one mode, m is 1.
[000120] In one mode, m is 2.
[000121] One embodiment the present invention provides compounds of general formula I or the pharmaceutically acceptable salts or solvates thereof, wherein:
[000122] Ring B is a ring B-1:

[000123] ring A is selected from rings A-1, A-2 and A-3, having the structures:

[000124] wherein the wavy line marked with 1 indicates a point of attachment of ring A to the ring of pyrrolidine of Formula I and the wavy line marked with 2 indicates the point of attachment of ring A to W;
[000125] X is N or CH;
[000126] Y is H or F;
[000127] R1 is H, (1-3C) alkoxy or halogen;
[000128] W is O, NH or CH2, where, when ring A is A-2, then W is CH2;
[000129] m is 0, 1 or 2;
[000130] D is carbon;
[000131] R2 and R2a are, independently, H, F, (1-3 C) alkyl or OH, provided that R2 and R2a are not both OH;
[000132] R3 and R3a are, independently, H, (1-3 C) alkyl or hydroxy (1-3 C) alkyl;
[000133] or R2 and R3 and R2a and R3a are absent together with the atoms to which they are attached form a divalent 5-6 membered heteroaryl ring having 1-2 nitrogen atoms in the ring;
[000134] Z is * -NR4aC (= O) -, * -ONHC (= O) -, * -NR4bCH2- or * -OC (= O) -, where the asterisk indicates the attachment point of Z with the carbon that supports R3;
[000135] R4a is H, (1-6C) alkyl, fluorine (1-6C) alkyl, difluor (1-6C) alkyl, trifluor (1-6C) alkyl, hydroxy (1-6C) alkyl or dihydroxy ( 2-6C alkyl);
[000136] R4b is H, (1-6C) alkyl, fluorine (1-6C) alkyl, difluor (1-6C) alkyl, trifluor (1-6C) alkyl, hydroxy (1-6C) alkyl, dihydroxy ( 2- 6C) alkyl, (1-6C alkyl) C (O) -, (3-6C cycloalkyl) C (O) -, Ar1C (O) -, HOCH2C (O) -, (1-6C alkyl) sulfonyl, (3-6C cycloalkyl) sulfonyl, AR2 (SO2) -, or HO2CCH2- (1-6C alkyl) NH (CO) -;
[000137] Ar1 is phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C) alkyl, and (1-6C) alkoxy;
[000138] Ar2 is phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C) alkyl, and (1-6C) alkoxy; and
[000139] R5 and R6 are independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.
[000140] One embodiment of this invention provides compounds with the General Formula IA

[000141] or pharmaceutically acceptable salts or solvates thereof, where:
[000142] ring A is selected from rings A-1, A-2 and A-3, having the structures:

[000143] wherein the wavy line marked with 1 indicates a point of attachment of ring A to the pyrrolidine ring of Formula I and the wavy line marked with 2 indicates the point of attachment of ring A with W;
[000144] X is N or CH;
[000145] Y is H or F;
[000146] R1 is H, (1-3C) alkoxy or halogen;
[000147] W is O, NH or CH2, where, when ring A is A-2, then, W is CH2;
[000148] m is 0, 1 or 2;
[000149] R2 and R2a are, independently, H, F or OH, as long as R2 and R2a are not both OH;
[000150] R3 is H, (1-3 C) alkyl or hydroxy (C 1-3) -alkyl;
[000151] Z is * -NR4aC (= O) -, * -ONHC (= O) -, * -NR4bCH2- or * -OC (= O) -, where the asterisk indicates the attachment point of Z with the carbon that supports R3;
[000152] R4a is H, (1-6C) alkyl, fluorine (1-6C) alkyl, difluor (1-6C) alkyl, trifluor (1-6C) alkyl, hydroxy (1-6C) alkyl or dihydroxy ( 2-6C alkyl);
[000153] R4b is H, (1-6C) alkyl, fluorine (1-6C) alkyl, difluor (1-6C) alkyl, trifluor (1-6C) alkyl, hydroxy (1-6C) alkyl, dihydroxy ( 2- 6C) alkyl, (1-6C alkyl) C (O) -, (3-6C cycloalkyl) C (O) -, Ar1C (O) -, HOCH2C (O) -, (1-6C alkyl) sulfonyl, (3-6C cycloalkyl) sulfonyl, AR2 (SO2) -, or HO2CCH2- (1-6C alkyl) NH (CO) -;
[000154] Ar1 is phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C) alkyl, and (1-6C) alkoxy;
[000155] Ar2 is phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C) alkyl, and (1-6C) alkoxy; and
[000156] R5 and R6 are, independently, H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.
[000157] In one embodiment, Formula IA includes compounds in which:
[000158] ring A is ring A-1, represented by the structure

[000159] wherein the wavy line marked with 1 indicates a point of attachment of ring A to the pyrrolidine ring of Formula I and the wavy line marked with 2 indicates the point of attachment of ring A with W;
[000160] ring B is ring B-1 represented by the structure:

[000161] wherein the wavy line marked with 3 indicates the point of attachment to ring A and the wavy line marked with 4 indicates the point of attachment to the pyrazole ring [1,5-a] pyrimidine of Formula I;
[000162] X is N or CH;
[000163] Y is H or F;
[000164] R1 is H, (1-3C) alkyl, (1-3C) alkoxy or halogen;
[000165] W is O or H;
[000166] m is 0, 1 or 2;
[000167] R2 and R2a are, independently, H, F or OH, as long as R2 and R2a are not both OH;
[000168] R3 is H, (1-3 C) alkyl or hydroxy (1-3 C) alkyl;
[000169] Z is * -NR4aC (= O) -, * -ONHC (= O) - or * -OC (= O) -, where the asterisk indicates the point of attachment to the carbon that supports R3;
[000170] R4a is H, (1-6C) alkyl, fluorine (1-6C) alkyl, difluor (1-6C) alkyl, trifluor (1-6C) alkyl, hydroxy (1-6C) alkyl or dihydroxy ( 1-6C) alkyl; and
[000171] R5 and R6 are, independently, H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.
[000172] In one embodiment, X is N. In one embodiment, X is CH.
[000173] In one embodiment, Formula IA includes compounds in which:
[000174] ring A is ring A-2 represented by the structure

[000175] wherein the wavy line marked with 1 indicates a point of attachment of ring A to the ring of pyrrolidine of Formula I and the wavy line marked with 2 indicates the point of attachment of ring A with W;
[000176] Ring B is ring B-1 represented by the structure:

[000177] wherein the wavy line marked with 3 indicates the point of attachment to ring A and the wavy line marked with 4 indicates the point of attachment to the pyrazole ring [1,5-a] pyrimidine of Formula I;
[000178] Y is H or F;
[000179] R1 is H, (1-3C) alkyl, (1-3C) alkoxy or halogen;
[000180] m is 0, 1 or 2;
[000181] W is CH2;
[000182] m is 0, 1 or 2;
[000183] R2 and R2a are, independently, H, F or OH, as long as R2 and R2a are not both OH;
[000184] R3 is H, (1-3 C) alkyl or hydroxy (1-3 C) alkyl;
[000185] Z is * -NR4aC (= O) -, where the asterisk indicates the point of attachment to the carbon that supports R3;
[000186] R4a is H, (1-6C) alkyl, fluorine (1-6C) alkyl, difluor (1-6C) alkyl, trifluor (1-6C) alkyl, hydroxy (1-6C) alkyl or dihydroxy ( 1-6C) alkyl; and
[000187] R5 and R6 are independently H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl,
[000188] In one embodiment, Formula IA includes compounds in which:
[000189] ring A is ring A-3 represented by the structure

[000190] wherein the wavy line marked with 1 indicates a fixation point of ring A of the Formula I pyrrolidine ring and the wavy line marked with 2 indicates the fixation point of ring A with W;
[000191] Ring B is ring B-1 represented by the structure:

[000192] wherein the wavy line marked with 3 indicates the point of attachment to ring A and the wavy line marked with 4 indicates the point of attachment to the pyrazole ring [1,5-a] pyrimidine of Formula I;
[000193] Y is H or F;
[000194] R1 is H, (1-3C) alkyl, (1-3C) alkoxy or halogen;
[000195] W is O;
[000196] m is 0, 1 or 2;
[000197] R2 and R2a are, independently, H, F or OH, as long as R2 and R2a are not both OH;
[000198] R3 is H, (1-3 C) alkyl or hydroxy (1-3 C) alkyl;
[000199] Z is * -OC (= O) - or - * - NR4aC (= O) -, where the asterisk indicates the point of attachment to the carbon that supports R3;
[000200] R4a is H, (1-6C) alkyl, fluorine (1-6C) alkyl, difluor (1-6C) alkyl, trifluor (1-6C) alkyl, hydroxy (1-6C) alkyl or dihydroxy ( 1-6C) alkyl; and
[000201] R5 and R6 are, independently, H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl,
[000202] In one embodiment, Formula IA includes compounds in which:
[000203] ring A is ring A-1, represented by the structure

[000204] where the wavy line marked with 1 indicates a point of attachment of ring A to the pyrrolidine ring of Formula I and the wavy line marked with 2 indicates the point of attachment of ring A with W; Ring B is ring B-1 represented by the structure:

[000205] wherein the wavy line marked with 3 indicates the point of attachment to ring A and the wavy line marked with 4 indicates the point of attachment to the pyrazole ring [1,5-a] pyrimidine of Formula I;
[000206] X is N or CH;
[000207] Y is H or F;
[000208] R1 is H, (1-3C) alkyl, (1-3C) alkoxy or halogen;
[000209] W is O;
[000210] m is 0, 1 or 2;
[000211] R2 and R2a are, independently, H, F or OH, as long as R2 and R2a are not both OH;
[000212] R3 is H, (1-3 C) alkyl or hydroxy (1-3 C) alkyl;
[000213] Z is * -NR4bCH2-, where the asterisk indicates the point of attachment to the carbon that supports R3;
[000214] R4b is H, (1-6C) alkyl, fluorine (1-6C) alkyl, difluor (1-6C) alkyl, trifluor (1-6C) alkyl (1-6C alkyl) C (O) -, ( 3-6C cycloalkyl) C (O) -, Ar1C (O) -, HOCH2C (O) -, (1-6C alkyl) sulfonyl, (3-6C cycloalkyl) sulfonyl, AR2 (SO2) -, or HO2CCH2- (1 -6C alkyl) NH (CO) -;
[000215] Ar1 is phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C) alkyl, and (1-6C) alkoxy;
[000216] Ar2 is phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C) alkyl, and (1-6C) alkoxy; and
[000217] R5 and R6 are, independently, H, halogen, OH, (1-6C) alkyl or hydroxy (1-6C) alkyl.
[000218] It should be noted that certain compounds according to the invention can contain one or more centers of asymmetry and can therefore be prepared and isolated as a mixture of isomers, such as a racemic or diastereomeric mixture, or in a enantiomerically or diastereomerically pure. 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, as racemic mixtures, form part of the present invention.
[000219] In one embodiment, compounds of Formula I in which Ring B is a ring B-1 have the absolute configuration of Figure 1-a:

[000220] In one embodiment, compounds of Formula I in which Ring B is a ring B-1 have the absolute configuration of Figure 1-b:

[000221] In the structures presented here, where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included as the compounds of the present invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is thus specified and defined.
[000222] The terms "(1-3C) alkyl" and "(1-6C) alkyl-" as used herein refer to saturated branched or straight chain monovalent hydrocarbon radicals of one to three carbon atoms and one to six carbon atoms, respectively. Examples include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl and hexial.
[000223] The term "fluorine (1-6C) alkyl" as used herein refers to branched or straight chain saturated monovalent hydrocarbon radicals of one to six carbon atoms as defined herein, wherein one of the hydrogens is replaced by a fluorine atom.
[000224] The term "difluor (1-6C) alkyl" as used herein refers to saturated branched or straight chain monovalent hydrocarbon radicals of one to six carbon atoms as defined herein, wherein two of the atoms hydrogen are replaced by fluorine atoms.
[000225] The term "trifluor (1-6C) alkyl" as used herein refers to saturated branched or straight chain monovalent hydrocarbon radicals of one to six carbon atoms as defined herein, wherein three of the carbon atoms hydrogen are replaced by fluorine atoms.
[000226] The term "hydroxy (1-6C alkyl)" as used herein refers to saturated branched or straight chain monovalent hydrocarbon radicals of one to six carbon atoms, where one of the hydrogens is replaced by a hydroxy group (OH).
[000227] The term "dihydroxy (1-6C alkyl)" as used herein refers to branched or straight chain saturated monovalent hydrocarbon radicals of one to six carbon atoms as defined herein, wherein two of hydrogen atoms are replaced by hydroxy groups (OH), as long as the hydroxy groups are not on the same carbon atom.
[000228] The term "(1-6C alkyl) sulfonyl" as used herein refers to a (1-6C alkyl) SO2- group, where the radical is over a sulfur atom and the (1- 6C alkyl) is as defined above. Examples include methylsulfonyl (CH3SO2-) and ethylsulfonyl (-CH3CH2SO2).
[000229] The term "(3-6C cycloalkyl) sulfonyl", as used herein refers to a (3-6C cycloalkyl) SO2- group, wherein the radical is attached to a sulfur atom. An example is cyclopropylsulfonyl.
[000230] The terms "(1-4C) alkoxy" and "(1-6C) alkoxy", as used herein, refer to saturated branched or straight chain monovalent alkoxy, from one to four carbon atoms or one to six carbon atoms, respectively, where the radical is over the oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, and butoxy.
[000231] The term "halogen" includes fluorine, chlorine, bromine and iodine.
[000232] It will also be appreciated that certain compounds of Formula I can be used as intermediates for the preparation of other compounds of Formula I.
[000233] The compounds of Formula I include salts thereof. In certain embodiments, salts are pharmaceutically acceptable salts. In addition, compounds of Formula I include salts of other compounds, which are not necessarily the pharmaceutically acceptable salts, and which may be useful as intermediates for the preparation and / or purification of compounds of Formula I and / or for the separation of enantiomers of compounds of Formula I.
[000234] The term "pharmaceutically acceptable" indicates that the substance or composition is compatible chemically and / or toxicologically, with other ingredients comprising the formulation, and / or with the mammal being treated with it.
[000235] It should also be noted that the compounds of Formula I and their salts can be isolated in the form of solvates, and consequently that any such solvate is included within the scope of the present invention.
[000236] The compounds of the invention may also contain unnatural proportions of atomic isotopes in one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula I, comprises all isotopes and mixtures of isotopes of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically form enriched. For example, when hydrogen is mentioned, it is meant to refer to 1H, 2H, 3H or mixtures thereof, when carbon is mentioned, it is meant to refer to 11C, 12C, 13C, 14C or mixtures thereof , when nitrogen is mentioned, it is meant to refer to 13N, 14N, 15N or mixtures thereof, when oxygen is mentioned, it is meant to refer to 14O, 15O, 16O, 17O, 18O or mixtures thereof, and, when fluoride is mentioned, it is understood to refer to 18F, 19F or mixtures thereof. The compounds according to the present invention, therefore, also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, in which one or more non-radioactive atoms has been replaced by one of its isotopes enriched radioactive substances. Radiolabeled compounds are useful as therapeutic agents, for example, therapeutic agents for cancer, research reagents, for example, test reagents, as well as diagnostic agents, for example, in in vivo imaging agents. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
[000237] The present invention further provides a process for the preparation of a compound of Formula I or a salt thereof as defined in this document, which comprises:
[000238] (a) for a compound of Formula I where Z is * -NHC (= O) -, and ring A, B, W, D, R2, R2a, R3, R3a in are as defined for Formula I, the cyclization of a corresponding compound having formula II

[000239] where P1 is H or a carboxyl protecting group, in the presence of a coupling reagent and a base, or (b) for a compound of Formula I where W is O, ring A is of formula A -1:

[000240] X is N, and ring B, D, Z, Y, R1, R2, R2a, R3, R3a are as defined for Formula I, the cyclization of a corresponding compound that has formula III

[000241] where n is 1, 2, 3 or 4 and L1 is an atom or leaving group, in the presence of a base, or (c) for a compound of Formula I in which W is CH2, ring A is of formula A-2:

[000242] and ring B, Z, D, Y, R1, R2, R2a, R3, R3a and are as defined for Formula I, the cyclization of a corresponding compound that has formula IV

[000243] where L2 is an atom or leaving group, in the presence of a base, or (d) for a compound of Formula I where Z is * -NHC (= O) -, and ring A, ring B, W, D, R2, R2a, R3, R3a and are as defined for Formula I, the cyclization of a corresponding compound that has formula V

[000244] in the presence of a base and a coupling reagent; or (e) for a compound of Formula I in which Z is * -NHCH2-, and ring A, ring B, W, D, R2, R2a, R3, R3a are as defined for Formula I, the cyclization of a corresponding compound having the formula VI

[000245] in the presence of a reducing agent; or (f) for a compound of Formula I in which Z is * -NHCH2-, and ring A, ring B, W, D, R2, R2a, R3, R3a are as defined for Formula I, cyclization of a corresponding compound that has the formula VII

[000246] in the presence of triphenylphosphine; or (g) for a compound of Formula I in ring A, ring B, W, D, m, R2, R2a, R3, and R3a are as defined for Formula I, Z is * - NR4bCH2-, and R4b is (1-6C alkyl) C (O) -, (3-6C cycloalkyl) C (O) -, Ar1C (O) -, HOCH2C (O) -, (1-6C alkyl) sulfonyl, (3-6C cycloalkyl) sulfonyl, (1-6C alkyl) sulfonyl, (3-6C cycloalkyl) sulfonyl, or Ar2 (SO2) -, the coupling of a corresponding compound that has the formula VIII

[000247] with a reagent having the formula (1-6C alkyl) C (O) -L3, (3-6C cycloalkyl) C (O) -L3, Ar1C (O) -L3, HOCH2C (O) -L3, ( 1-6C alkyl) (SO2) - L3, (3-6C cycloalkyl) (SO2) -L3, or Ar2 (SO2) -L3, respectively, where L3 is an outlet atom, in the presence of a base; or (h) for a compound of Formula I in which ring A, ring B, W, D, R2, R2a, R3, R3a in are as defined for Formula I, Z is * - NR4bCH2-, and R4b is ( 1-6C alkyl) NH (CO) -, reacting with a compound having formula VIII

[000248] with a reagent having the formula (1-6C alkyl) N = C = O, in the presence of a base; or (i) for a compound of Formula I where R2 is F, R2a is H, and ring A, ring B, Z, W, D, R3, R3a are as defined for Formula I, reacting with a compound correspondent having the formula IX

[000249] with a fluorination reagent; (j) for a compound of Formula I where W is O, ring A is of formula A-1,

[000250] X is CH, and Y, R1, D, ring B, Z, R2, R2a, R3 and are as defined for Formula I, the cyclization of a corresponding compound having formula X

[000251] where n is 1, 2, 3 or 4 and L1 is an atom or leaving group, in the presence of a base; and
[000252] optionally remove any protecting groups and optionally prepare a salt thereof.
[000253] In an embodiment of the methods described above (a) - (j), ring B is a ring B-1, having the structure:

[000254] D is carbon, R2 and R2a are, independently, H, F, (1-3 C) alkyl or OH (as long as R2 and R2a are not both OH), R3 is H, (1-3 C) alkyl or hydroxy (1-3 C) alkyl., and ring A, W, m, Z, R5 and R6 are as defined for Formula I.
[000255] With reference to method (a), cyclization can be carried out using conventional amide bonding conditions, for example, by treating the carboxylic acid with an activating agent, followed by the addition of the amine in the presence of a base . Suitable activating agents include EDCI, oxalyl chloride, thionyl chloride, HATU, and HOBt. Suitable bases include amine bases, for example, triethylamine, diisopropylethylamine, pyridine, or excess ammonia. Suitable solvents include DCM, DCE, THF and DMF.
[000256] With reference to methods (b) and (c), the output atoms L1 and L2 can be, for example, a halogen atom, such as Br, Cl or I. Alternatively, L1 and L2 can be a leaving group, for example, an arylsulfonyloxy group or an alkylsulfonyloxy group, such as a mesylate group or a tosylate. Suitable bases include alkali metal carbonates, such as sodium carbonate, potassium carbonate or cesium carbonate. Suitable solvents include aprotic solvents, such as ethers (for example, tetrahydrofuran or p-dioxane), DMF or acetone. The reaction can be conveniently carried out at elevated temperatures, for example, 50-150 ° C, for example, 85 ° C.
[000257] With reference to method (d), suitable coupling reagents include HATU, HBTU, TBTU, DCC, DIEC, and any other amide coupling reagents well known to those skilled in the art. Suitable bases include tertiary amine bases, such as triethylamine and DIEA. Suitable solvents include DMF, THF, DCM and DCE.
[000258] With reference to method (e), suitable reducing agents include Me4N (OAc) 3BH, Na (OAc) 3BH and NaCNBH3. Suitable solvents include neutral solvents, such as acetonitrile, THF and DCE. The reaction can be conveniently carried out at room temperature.
[000259] With reference to method (f), in certain embodiments the triphenylphosphine reagent is used in the form of a PPh3 resin bound to polystyrene (sold as PS-PPh3 by Biotage Systems). The reaction is conveniently carried out at room temperature. Suitable solvents include neutral solvents, for example, DCM.
[000260] With reference to method (g), the output atom L3 can be a halogen, for example, Cl or Br. Suitable bases include tertiary amine bases, such as diisopropylethylamine and triethylamine. The reaction is conveniently carried out at room temperature.
[000261] With reference to method (h), suitable bases include tertiary amine bases such as DIEA and triethylamine. The reaction is conveniently carried out at room temperature.
[000262] With reference to method (i), the fluorination reagent can be, for example, bis (2-methoxyethyl) amino sulfur trifluoride (Deoxo-FluorTM) or diethylamino sulfur trifluoride (DAST). Suitable solvents include dichloromethane, chloroform, dichloroethane and toluene. The reaction is conveniently carried out at room temperature.
[000263] With reference to method (j), the base can be, for example, an alkali metal carbonate, such as, for example, sodium carbonate, potassium carbonate or cesium carbonate. Suitable solvents include aprotic solvents, such as ethers (for example, tetrahydrofuran or p-dioxane) or toluene. The reaction can be conveniently carried out at a temperature between room temperature and reflux, for example, 85 ° C.
[000264] The amine groups in the compounds described in any of the above methods can be protected with any suitable amine protecting group, for example, as described in Greene and Wuts, eds. "Protecting Groups in Organic Synthesis", 2nd ed. New York, John Wiley & Sons, Inc., 1991. Examples of amine protecting groups include acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl (BOC), and [2- (trimethylsilyl) ethoxy] methyl (SEM). Likewise, carboxyl groups can be protected with any convenient carboxyl protecting group, for example, as described in Greene and Wuts, eds., "Protecting Groups in Organic Synthesis", 2nd ed. New York, John Wiley & Sons, Inc., 1991. Examples of carboxyl protecting groups include (1-6C) alkyl groups, such as methyl, ethyl and t-butyl. Alcohol groups can be protected with any convenient alcohol protecting group, for example, as described in Greene and Wuts, eds. "Protecting Groups in Organic Synthesis", 2nd ed. New York, John Wiley & Sons, Inc., 1991. Examples of alcohol protecting groups include benzyl ethers, trityl, silyl and the like.
[000265] The compounds of formulas II, III, IV, V, VI, VII, VIII, IX and X are also considered as new and are provided as additional aspects of the present invention.
[000266] The ability of the compounds of the invention to act as inhibitors of TrkA can be demonstrated by the assays described in Examples A and B.
[000267] Certain compounds that are inhibitors of TrkA and / or TrkB may be useful in the treatment of various types of pain, including inflammatory pain, neuropathic pain and pain associated with cancer, surgery, and bone fracture.
[000268] In one embodiment, the compounds of Formula I are useful for treating pain, including chronic and acute pain, in a mammal.
[000269] Acute pain, as defined by the International Association for the Study of Pain, results from disease, inflammation or tissue damage. This type of pain usually comes suddenly, for example, after trauma or surgery, and can be accompanied by anxiety or stress. The cause can usually be diagnosed and treated, and the pain is limited to a certain period of time and severity. In some rare cases, it can become chronic.
[000270] It is widely believed that chronic pain, as defined by the International Association for the Study of Pain, represents the disease itself. It can be made much worse by environmental and psychological factors. Chronic pain persists over a longer period than acute pain and is resistant to most medical treatments, in general, over 3 months or more. It can and often does cause serious problems for patients.
[000271] The compounds of Formula I are also useful in the treatment of cancer in a mammal. Particular examples include neuroblastoma, ovarian, pancreatic, colorectal and prostate cancer.
[000272] The compounds of Formula I are also useful in the treatment of inflammation in a mammal.
[000273] The compounds of Formula I are also useful in the treatment of certain infectious diseases in mammals, such as infection by Trypanosoma cruzi.
[000274] The compounds of Formula I can also be used to treat neurodegenerative diseases in a mammal. Examples of neurodegenerative diseases include demyelination and demyelination. Other examples of neurodegenerative diseases include multiple sclerosis, Parkinson's disease and Alzheimer's disease.
[000275] In addition, the Formula I compounds can also be used to treat interstitial cystitis (HF), painful bladder syndrome (PBS), urinary incontinence, asthma, anorexia, atopic dermatitis, and psoriasis in a mammal.
[000276] Thus, another embodiment of the present invention provides a method for treating or preventing pain in a mammal, comprising administering to said mammal one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an effective amount. to treat or prevent that pain. In one embodiment, pain is chronic pain. In one embodiment, pain is acute pain. In one embodiment, the pain is inflammatory pain. In one embodiment, the pain is neuropathic pain. In one embodiment, pain is pain associated with cancer. In one embodiment, pain is the pain associated with surgery. In one embodiment, pain is pain associated with bone fractures. In one embodiment, the method comprises a method of treating said pain in a mammal. In one embodiment, the method comprises a method for preventing said pain, in a mammal.
[000277] Another embodiment of the present invention provides a method for treating or preventing inflammation in a mammal, comprising administering to said mammal one or more compounds of Formula I or a pharmaceutically acceptable salt thereof, in an amount effective for treat or prevent said inflammation. In one embodiment, the method comprises a method of treating inflammation in said mammal. In one embodiment, the method comprises a method of preventing said inflammation in a mammal.
[000278] Another embodiment of the present invention provides a method for treating or preventing a neurodegenerative disease in a mammal, comprising administering to said mammal one or more compounds of Formula I or a pharmaceutically acceptable salt thereof, in an effective amount. to treat or prevent said neurodegenerative disease. In one embodiment, the neurodegenerative disease is demyelination. In one embodiment, the neurodegenerative disease is demyelination. In one embodiment, the neurodegenerative disease is multiple sclerosis. In one embodiment, the neurodegenerative disease is Parkinson's disease. In one embodiment, the neurodegenerative disease is Alzheimer's disease. Another embodiment of the present invention provides a method for treating or preventing infectious diseases in a mammal, 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 infectious disease. In one embodiment, the infectious disease is Chagas disease. In one embodiment, the method further comprises a method of treating said neurodegenerative disease in a mammal. In one embodiment, the method comprises a method for preventing said neurodegenerative disease in a mammal.
[000279] Another embodiment of the present invention provides a method for treating or preventing cancer in a mammal, 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 cancer. In one embodiment, cancer is neuroblastoma. In one embodiment, cancer is ovarian cancer. In one embodiment, cancer is pancreatic cancer. In one embodiment, cancer is colorectal cancer. In one embodiment, cancer is prostate cancer. In one embodiment, the method comprises a method for treating cancer in a mammal. In one embodiment, the method comprises a method of preventing said cancer in a mammal.
[000280] The compounds of Formula I can be administered individually as a single therapy or they can be administered in addition to one or more other substances and / or treatments that work by the same or a different mechanism of action. Examples include anti-inflammatory compounds, steroids (for example, dexamethasone, cortisone, and fluticasone), analgesics such as NSAIDs (for example, aspirin, ibuprofen, indomethacin, and ketoprofen), and opioids (such as morphine) and chemotherapeutic agents. These agents can be administered with one or more compounds of Formula I, as part of the same dosage forms or separately, through the same routes or different routes of administration and through the same schedules or different schedules according to the standard pharmaceutical practice known to one skilled in the art.
[000281] In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each cancer patient. In medical oncology the other component (s) of such a joint treatment, in addition to compositions of the present invention may be, for example, surgery, radiation therapy, chemotherapy, signal transduction inhibitors and / or monoclonal antibodies.
[000282] Consequently, the compounds of Formula I can 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, inhibitors of signal transduction, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, cytostatic antiandrogen agents, target antibodies, HMG inhibitors -CoA reductase, and prenyl-protein transferase inhibitors. These agents can be administered with one or more compounds of Formula I, as part of the same dosage forms or separately, by means of the same routes or different routes of administration and by means of the same schedules or different schedules according to standard pharmaceutical practice known to one skilled in the art.
[000283] As used herein, the terms "treat" or "treatment" refer to therapeutic, prophylactic, palliative or preventive measures. Beneficial or desired clinical outcomes include, but are not limited to, symptom relief, decrease in disease extent, stabilized (that is, not worsen) disease state, delay or reduced disease progression, amelioration or palliation of disease state , and remission (either partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival, compared to the expected survival if you did not receive treatment. Those in need of treatment include those already with the disease or disorder, as well as those likely to have the condition or disorder, or those in which the condition or disorder is to be prevented.
[000284] In one embodiment, the terms "treatment" or "treating" as used herein, mean a relief, in whole or in part, of the symptoms associated with a disorder or condition, as described herein (for example, various types of pain, including inflammatory pain, neuropathic pain, and cancer-associated pain, surgery, and bone fracture), or reducing or stopping the progression or worsening of these symptoms.
[000285] In one embodiment, the term "prevent" as used herein, means the prevention of the appearance, recurrence or spread, in whole or in part, of the disease or condition, as described herein (for example, various types of pain , including inflammatory pain, neuropathic pain and pain associated with cancer, surgery, and bone fracture), or a symptom thereof.
[000286] The terms "effective amount" and "therapeutically effective amount" refer to an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat or prevent a disease, condition, or particular disorder, (ii) alleviate, alleviate 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. The amount of a Formula I compound that will correspond to such an amount will vary depending on factors such as the particular compound, condition of the disease and its severity, the identity (eg weight) of the mammal in need of treatment, but may , however, be routinely determined by one skilled in the art.
[000287] 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.
[000288] The compounds of the invention can be administered by any convenient route, for example, to the gastrointestinal tract (for example, rectally or orally), the nose, lungs, musculature or vasculature, or transdermally or via the dermal. The compounds can be administered in any convenient form of administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, aerosols, suppositories, gels, emulsions, adhesives, etc. Such compositions may contain conventional components in preparations pharmaceuticals, for example, diluents, vehicles, pH modifiers, sweeteners, bulking agents and also active agents. If parenteral administration is desired, the compositions will be sterile and in a form of solution or suspension suitable for injection or infusion. Such compositions constitute another aspect of the invention.
[000289] The present invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, as defined herein above. In one embodiment, the pharmaceutical composition includes the compound of Formula I together with a pharmaceutically acceptable diluent or carrier.
[000290] The present invention further provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in therapy.
[000291] In one embodiment, the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating pain in a mammal. In one embodiment, pain is chronic pain. In one embodiment, pain is acute pain. In one embodiment, the pain is inflammatory pain. In one embodiment, the pain is neuropathic pain. In one embodiment, pain is pain associated with cancer. In one embodiment, pain is the pain associated with surgery. In one embodiment, pain is pain associated with fractures of the bones.
[000292] In one embodiment, the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in treating inflammation in a mammal.
[000293] In a further aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of a neurodegenerative disease in a mammal. In one embodiment, the neurodegenerative disease is demyelination. In one embodiment, the neurodegenerative disease is demyelination. In one embodiment, the neurodegenerative disease is multiple sclerosis. In one embodiment, the neurodegenerative disease is Parkinson's disease. In one embodiment, the neurodegenerative disease is Alzheimer's disease.
[000294] In one embodiment, the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of infectious diseases in a mammal. In one embodiment, the infectious disease is Chagas disease.
[000295] In one embodiment, the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating cancer in a mammal. In one embodiment, cancer is neuroblastoma. In one embodiment, cancer is ovarian cancer. In one embodiment, cancer is pancreatic cancer. In one embodiment, cancer is colorectal cancer. In one embodiment, cancer is prostate cancer.
[000296] Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating pain in a mammal.
[000297] Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of inflammation in a mammal.
[000298] Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease in a mammal.
[000299] Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of infectious diseases in a mammal.
[000300] Another embodiment of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a mammal. EXAMPLES
[000301] The following examples illustrate the invention. In the examples described below, unless otherwise noted, all temperatures are given in degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, Alfa, Aesar, TCI, Maybridge, Asta Tech, or other suitable suppliers, and were used without further purification unless otherwise indicated. THF, DCM, toluene, DMF and dioxane were purchased from Aldrich in Sure / SealTM bottles and used as received.
[000302] The reactions shown below were generally carried out under a positive pressure of nitrogen or argon, or with a drying tube (unless otherwise indicated) in anhydrous solvents, and the reaction flasks were typically equipped with rubber septa for the introduction of substrates and reagents through a syringe. The glassware was kiln dried and / or heat dried or dried under a stream of dry nitrogen.
[000303] Column chromatography was performed on a Biotage system (Manufacturer: Dyax Corporation) with a silica gel or C-18 reverse phase column, or on a SepPak silica cartridge (Waters), or using column chromatography conventional silica gel flash, unless otherwise specified.
[000304] The abbreviations used here have the following meanings:

Biological Assays Example A ELISA Assay for TrkA
[000305] An enzyme-linked immunosorbent assay (ELISA) was used to assess TrkA kinase activity in the presence of inhibitors. 384-well Immulon 4HBX 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 the test compound, 2.5 nM TrkA (Invitrogen Corp., recombinant human TrkA with histidine tag, cytoplasmic domain), and 500 μM ATP were incubated for 25 minutes at room temperature in the shaker-coated plates. The assay buffer consisted of 25 mM MOPS pH 7.5, 0.005% (v / v) Triton X-100 and 5 mM MgCl2. 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 μg / ml of a phosphotyrosine specific monoclonal antibody (clone PY20) conjugated to horseradish peroxidase, together with the Peroxidase TMB substrate system (KPL). After the addition of 1M phosphoric acid, the color intensity of the chromogenic substrate was quantified through absorbance at 450 nm. IC50 values were calculated using a 4 or 5 parameter logistic curve fit.
[000306] Table 1 shows the mean IC 50 values for the compounds of the invention, when tested in this assay. In Table 1, the letter "A" designates an IC50 value between about 1 and 100 nM, and the letter "B" designates an IC50 value> 100 nM and <3000 nM. Example B TrkA binding assay
[000307] The ability of a compound to bind to TrkA was measured by Invitrogen's LanthaScreenTM Eu kinase binding assay. In this assay, a recombinant human TrkA with His-tag (cytoplasmic domain) from Invitrogen is incubated with Alexa-Fluor® Tracer 236 Invitrogen, biotinylated anti-His, and europium-labeled Streptavidin, compound (2% final DMSO) in buffer ( 25 mM MOPS, pH 7.5, mC Mg125, 0.005% Triton X-100). After a 60-minute incubation at 22 ° C, the reaction was measured using EnVision via TR-FRET dual wavelength detection and the POC was calculated from the emission ratio. The dose-response data for the compounds was adjusted to a 4-parameter logistic model and the IC50 was defined as the concentration of the compound at 50 POC.
[000308] Table 1 shows the mean IC 50 values for the compounds of the invention, when tested in this assay. In Table 1, the letter "A" designates an IC50 value between about 1 and 100 nM, and the letter "B" designates an IC50 value> 100 nM and <3000 nM. Table 1


1 Compound may have been isolated together with the enantiomer and / or one or more diastereomers, in which the additional isomer (s) was believed to constitute <1.5% of the total isolated quantity. Preparation A
(R) -5-fluor-2-methoxy-3- (pyrrolidin-2-yl) -pyridine
[000309] Step A: Preparation of (R) -tert-butyl-2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidine-1-carboxylate: A solution of tert-butyl-pyrrolidine-1-carboxylate ( 4.09 mL, 23.4 mmol) and (-) - Spartein (6.44 mL, 28.0 mmol) in MTBE (50 mL) was cooled to -78 ° C and sec-BuLi (20 mL, 28, 0 mmol, 1.4 M in cyclohexane) was introduced dropwise through a cannula, keeping the internal temperature below -78 ° C. The resulting solution was stirred for 3 hours at -78 ° C, followed by the addition of a solution of ZnCl2 (21.0 mL, 21.0 mmol, 1M in Et2O) dropwise, with rapid stirring, maintaining the temperature temperature below -65 ° C. The resulting clear suspension was stirred at - 78 ° C for 10 minutes and then warmed to room temperature. The resulting mixture was loaded sequentially with 3-bromo-5-fluor-2-methoxypyridine (5.05 g, 24.5 mmol), Pd (OAc) 2 (0.262 g, 1.17 mmol) and t-Bu3P-HBF4 (0.407 g, 1.40 mmol) in one portion. After stirring overnight at room temperature, concentrated NH4OH (1 ml) was added and the reaction was stirred for 1 hour. The resulting suspension was filtered through Celite® and washed with Et2O. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5% EtOAc / hexanes to generate the product (R) -tert-butyl 2- (5-fluor-2-methoxypyridine) -3-yl) - pyrrolidine-1-carboxylate as a yellow oil (4.34 g, 63% yield).
[000310] Step B: Preparation of (R) -5-fluor-2-methoxy-3- (pyrrolidin-2-yl) pyridine: A DCM solution (12 mL) of TFA (11.3 mL, 146 mmol) (R) -tert-butyl 2- (5-fluor-2-methoxy-pyridin-3-yl) -pyrrolidine-1-carboxylate (4.33 g, 14.6 mmol) was added and stirred at temperature room for 1 hour. The reaction was then concentrated, absorbed in EtOAc, then washed with brine and NaHCO3. The organic phase was dried (MgSO4), filtered, and concentrated, and the crude material was purified by column chromatography on silica eluting with 1-2% NH3-MeOH / DCM 7 N to produce (R) -5- fluor-2-methoxy-3- (pyrrolidin-2-yl) pyridine as a liquid (1.40 g, 49% yield).
[000311] The enantiomeric excess (% ee) of (R) -5-fluor-2-methoxy-3- (pyrrolidin-2-yl) pyridine was determined as follows: To a small amount of propan-2-ol solution of ((R) -5-amide fluor-2-methoxy-3- (pyrrolidin-2-yl) -pyridine excess N- (2,4-dinitro-5-fluorophenyl) -L-alanine excess (FDAA, Marfey reagent) The mixture was heated to reflux for approximately two minutes after cooling to room temperature, the reaction mixture was diluted with acetonitrile and analyzed by HPLC (column 120Â 3 μm, 4.6 x 50 mm YMC ODS-AQ; mobile phase: 5-95% solvent B in A; solvent A: H2O / 1% IPA / 10 mM ammonium acetate, and solvent B: ACN / IPA 1% / 10 mM ammonium acetate , flow rate: 2 mL / min) The enantiomeric excess was determined from the peak areas of two formed diastereomeric derivatives. The ee% of the product was determined to be> 93%. Preparation B
(R) -5- (2- (5-fluor-2-methoxypyridine-3-yl) pyrrolidin-1-yl) pyrazolo [1,5- a] pyrimidine-3-carboxylic acid
[000312] Step A: Preparation of ethyl 5-hydroxypyrazole [1,5-a] pyrimidine-3-carboxylate: To a mixture of ethyl 3-amino-1 H-pyrazolo-4-carboxylate (25.0 g, 161 mmol) and (E) -ethyl 3-ethoxyacrylate (35.8 ml, 242 mmol) in DMF (537 ml) cesium carbonate (78.7 g, 242 mmol) was added, and the reaction was heated to 110 ° C for 15 hours. After cooling to room temperature the reaction was acidified with acetic acid to pH 4. The resulting precipitate was filtered, washed with water and EtOAc, to obtain the product as a white solid. To recover the additional product, the filtrate was concentrated, diluted with EtOAc (500 ml) and washed with H2O (5 x 200 ml). The resulting precipitate in the EtOAc layer was filtered and washed with water and EtOAc, to obtain a second batch of product. The two product batches were combined and dried under reduced pressure to generate ethyl 5-hydroxyporazolo [1,5-a] pyrimidine-3-carboxylate as a white solid (33.3 g, 100% yield). MS (apci) m / z = 206.2 (M-H).
[000313] Step B: Preparation of ethyl 5-chloropyrazolo [1,5-a] pyrimidine-3-carboxylate: Ethyl ethyl-5-hydroxypyrazolo [1,5-a] pyrimidine-3-carboxylate (22.7 g , 110 mmol) was suspended in phosphoryl trichloride (100 mL) and heated to reflux. After heating for 2 hours, the reaction mixture was cooled and concentrated to remove excess POCl3. The residue was diluted in DCM (100 ml) and added slowly to a flask containing ice water. The mixture was separated and the aqueous layer was extracted with DCM (2 x 200 ml). The combined organic layers were dried (MgSO4), filtered and concentrated to yield ethyl 5-chloropyrazolo [1,5-a] pyrimidine-3-carboxylate as a pale yellow solid (24.2 g, 97.6% yield) . MS (APCI) m / z = 225.9 (M + H).
[000314] Step C: Preparation of (R) -ethyl 5- (2- (5-fluor-2-methoxypyridin-3-yl) -pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine-3- ethyl carboxylate: A mixture of ethyl 5-chloropyrazolo [1,5-a] pyrimidine-3-carboxylate (0.75 g, 3.32 mmol), (R) -5-fluor-2-methoxy-3- (pyrrolidin-2-yl) pyridine (Preparation A, 0.984 g, 3.66 mmol), DIEA (2.32 mL, 13.3 mmol) and n-butanol (1.11 mL) was sealed in a pressure tube and heated to 90 ° C for 48 hours. The reaction mixture was diluted with EtOAc and washed with water, brine and sat. NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated to produce a dark orange oil. The crude material was purified by silica column chromatography eluting with 50-80% EtOAc / hexanes to produce (R) -ethyl 5- (2- (5-fluor-2-methoxypyridin-3-yl) -pyrrolidin-1 -yl) -pyrazolo [1,5-a] pyrimidine-3-carboxylate (0.72 g, 56.2% yield) as a yellow foamy solid. MS (apci) m / z = 386.0 (M + H).
[000315] Step D: Preparation of (R) -5- (2- (5-fluor-2-methoxypyridine-3-yl) pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine-3-carboxylic acid : To a suspension of (R) -ethyl 5- (2- (5-fluor-2-methoxypyridin-3-yl) -pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine-3-carboxylate (0 , 72 g, 1.868 mmol) in MeOH (9.34 mL) LiOH (1 N, 3.74 mL, 3.74 mmol) was added, and the reaction mixture was heated at 70 ° C for 15 hours. After cooling, the reaction mixture was concentrated and the resulting residue was diluted with water. After acidification with citric acid, the aqueous layer was extracted with DCM. The combined organic phases were dried (MgSO4), filtered and concentrated to produce (R) -5- (2- (5-fluor-2-methoxy-pyridin-3-yl) -pyrrolidin-1-yl) pyrazole [ 1,5-a] -pyrimidine-3-carboxylic (0.67 g, 100% yield) as a yellow solid. MS (apci) m / z = 357.9 (M + H). Preparation C
(R) -4 - ((tert-butyldimethylsilyl) oxy) -2- (5-fluor-2-methoxyphenyl) -pyrrolidin-2,2,2-trifluoracetate
[000316] Steps A to D followed the procedure described by H. Imamura, et al. in Tetrahedron, 2000, 56, 7705.
[000317] Step A: Preparation of (R) -4- (tert-butyldimethylsilyloxy) pyrrolidin-2-one: To a suspension of (R) -4-hydroxypyrrolidin-2-one (purchased from Asta Tech or Aldrich) (5.030 g, 48.26 mmol) in DMF (24 mL) at 0 ° C TBDMS-C1 (7.637 g, 50.67 mmol) was added followed by imidazole (4.978 g, 72.39 mmol). The resulting mixture was warmed to room temperature and stirred for 1 hour, then it was poured into 100 ml of water with stirring. The resulting suspension was filtered and the solids were washed with water and dried under reduced pressure, to produce (R) -4- (tert-butyldimethylsilyloxy) pyrrolidin-2-one (10.14 g, 97.56% yield) which was used directly without further purification.
[000318] Step B: Preparation of (R) -tert-butyl 4- (tert-butyldimethylsilyloxy) - 2-oxopyrrolidine-1-carboxylate: To a solution of (R) -4- (tert-butyldimethylsilyloxy) pyrrolidin-2- one (10.14 g, 47.08 mmol) in MeCN (16 mL) at 0 ° C, DMAP (3.221 g, 26.37 mmol), TEA (3.957 mL, 28.25 mmol), and Boc20 were added sequentially (11.49 g, 52.65 mmol). The resulting mixture was warmed to room temperature and stirred for 48 hours. The reaction mixture was poured into water and extracted with EtOAc (100 ml). The organic layer was washed successively with 1 N aqueous HCl (2 x 50 ml), 1 N aqueous NaOH solution (50 ml), and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to yield (R) -tert-butyl 4- (tert-butyldimethylsilyloxy) -2-oxopyrrolidine-1-carboxylate (13.62 g, 91.69% yield) . 1H NMR (CDC13) δ 4.39 (m, 1H), 3.87 (m, 1H), 3.62 (m, 1H), 2.71 (m, 1H), 2.46 (m, 1H) , 1.53 (s, 9H), 0.88 (s, 9H), 0.08 (d, 6H).
[000319] Step C: Preparation of (R) -tert-butyl 2- (tert-butyldimethylsilyloxy) -4- (5-fluor-2-methoxyphenyl) -4-hydroxybutylcarbamate: To a solution of (R) -tert-butyl 4- (tert-butyldimethylsilyloxy) -2-oxopyrrolidine-1 carboxylate (6.00 g, 19.0 mmol) in THF (36 mL) at 0 ° C, a 0.5 M (5-) bromide solution was added fluor-2-methoxyphenyl) magnesium in THF (50.0 mL, 25.0 mmol). The resulting mixture was stirred at 0 ° C for 30 minutes, then treated with MeOH (60 ml) and NaBH4 (0.966 g, 25.2 mmol). After stirring at 0 ° C for an additional 30 minutes, the reaction mixture was poured into saturated aqueous NH4Cl solution (40 ml) and extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to generate the crude material which was purified by silica column chromatography, eluting with 0-2% MeOH / DCM, to produce (R ) -tert-butyl 2- (tert-butyldimethylsilyloxy) -4- (5-fluor-2-methoxyphenyl) -4-hydroxybutylcarbamate (which was assumed to be a mixture of the sin and anti isomers), (4.81 g, 57 , 0% yield). 1H NMR (CDCl3) δ 7.20 (m, 1H), 6.90 (m, 1H), 6.77 (m, 1H), 5.12 (m, 1H), 4.10 (m, 1H) , 3.82 (m, 3H), 3.29 (m, 2H), 1.71-1.93 (m, 2H), 1.45 (s, 9H), 0.93 (d, 9H), 0.11-0.14 (m, 6H).
[000320] Step D: Preparation of (R) -tert-butyl 4- (tert-butyldimethylsilyloxy) -2- (5-fluor-2-methoxyphenyl) -pyrrolidine-1-carboxylate: To a solution of (R) -tert -butyl 2- (tert-butyldimethylsilyloxy) -4- (5-fluor-2-methoxyphenyl) -4-hydroxybutylcarbamate (4.810 g, 10.84 mmol) in CH2C12 (108 mL) at -60 ° C TEA (4.534 ml, 32.53 mmol) followed by methanesulfonyl chloride (0.9231 ml, 11.93 mmol). The resulting mixture was slowly heated to -5 ° C and poured into a mixture of ice and saturated aqueous NaHCO3 (50 ml). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2 x 50 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to produce crude material which was purified by silica column chromatography, eluting with 2-10% MeOH / DCM, to obtain (R) -tert- butyl 4- (tert-butyldimethylsilyloxy) -2- (5-fluor-2-methoxyphenyl) -pyrrolidine-1-carboxylate (assumed to be a mixture of cis and trans isomers; 2.648 g, 57.38% yield). LC / MS (ES + APCI) m / z = 326.1 (M + H-Boc).
[000321] Step E: Preparation of (R) -4- (tert-butyldimethylsilyloxy) -2- (5-fluor-2-methoxyphenyl) pyrrolidine 2,2,2-trifluoracetate: To a solution of (R) - tert- butyl 4- (tert-butyldimethylsilyloxy) -2- (5-fluor-2-methoxyphenyl) pyrrolidine-1-carboxylate (2.648 g, 6.222 mmol) in CH2Cl2 (26 mL) at 0 ° C, TFA (9.3 ml). The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to generate the crude material which was subjected to azeotropy with toluene-CH2Cl2 (2x) and dried under reduced pressure to produce (R) -4- (tert-butyldimethylsilyloxy) -2- (5-fluor -2-methoxyphenyl) -pyrrolidine 2,2,2-trifluoracetate (assumed to be a mixture of cis and trans isomers; 2.92 g, 106.8% yield), which was used directly without further purification. LC / MS (ES + APCI) m / z = 326.3 (M + H). Preparation D
(R) -5- (2- (5-fluor-2-hydroxyphenyl) -4-hydroxypyrrolidin-1-yl) pyrazolo [1,5- a] pyrimidine-3-carboxylic acid
[000322] Step A: Preparation of (R) -ethyl 5- (4- (tert-butyldimethylsilyloxy) - 2- (5-fluor-2-methoxyphenyl) pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine -3- carboxylate: To a suspension of ethyl 5-hydroxypyrazolo [1,5-a] pyrimidine-3-carboxylate (0.100 g, 0.483 mmol) and BOP reagent (0.320 g 0.724 mmol) in DMF (1 mL) at 0 ° C a solution of (R) -4- (tert-butyldimethylsilyloxy) -2- (5-fluor-2-methoxyphenyl) -pyrrolidine 2,2,2 - trifluoracetate (Preparation C; 0.167 g, 0.483 mmol) in CH2Cl2 ( 1 mL) and N, N-diisopropylethylamine (0.420 mL, 2.41 mmol) sequentially. The resulting mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was diluted with EtOAc (10 ml), and washed with saturated aqueous NaHCO3 and brine. The brine phase was re-extracted with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to generate the crude material which was purified by silica column chromatography, eluting with 0-50% EtOAc / Hexanes to produce (R) -ethyl 5- (4 - (tert-butyldimethylsilyloxy) -2- (5-fluor-2-methoxyphenyl) -pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine-3-carboxylate (as a mixture of cis and trans isomers) (0 , 0487 g, 19.6% yield) LC / MS (ES + APCI) m / z = 515.2 (M + H).
[000323] Step B: Preparation of (R) -ethyl 5- (2- (5-fluor-2-methoxyphenyl) - 4-hydroxypyrrolidin-1-i1) pyrazolo [1,5-a] pyrimidine-3-carboxylate: To a solution of (R) -ethyl 5- (4- (tert-butyldimethylsilyloxy) -2- (5-fluor-2-methoxyphenyl) -pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine-3- carboxylate (as a mixture of cis and trans isomers) (0.0487 g, 0.0946 mmol) in THF (1 mL) at 0 ° C, 1 M TBAF in THF (0.104 mL, 0.104 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. The reaction mixture was diluted with EtOAc (10 ml), washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to produce the crude product (R ) -ethyl 5- (2- (5-fluor-2-methoxyphenyl) -4-hydroxypyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine-3-carboxylate (as a mixture of cis and trans isomers ;. 37.9 mg, 100% yield) LC / MS (ES + APCI) m / z = 401.1 (M + H).
[000324] Step C: Preparation of (R) -ethyl 5- (2- (5-fluor-2-hydroxyphenyl) - 4-hydroxypyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine-3-carboxylate: To a solution of (R) -ethyl 5- (2- (5-fluor-2-methoxyphenyl) -4-hydroxypyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine-3-carboxylate (as a mixture of cis and trans isomers; 0.0379 g, 0.0947 mmol) in CH2Cl2 (1 mL) at 0 ° C 1 M BBr3 in CH2Cl2 (0.473 mL, 0.473 mmol) was added. The resulting mixture was warmed to room temperature for 25 hours, then diluted with CH2Cl2 (10 ml) and poured on a mixture of ice and saturated aqueous NaHCO3 (15 ml). The organic layer was separated and the aqueous layer was acidified with 1N aqueous HCl to pH = 5-6. The aqueous layer was extracted with CH2Cl2 (3x) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to generate a mixture of (R) -5- (2- (5-fluor-2-hydroxyphenyl) acid -4-hydroxypyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine-3-carboxylic (as a mixture of cis and trans isomers) and (R) -ethyl 5- (2- (5-fluor-2- hydroxyphenyl) -4-hydroxypyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine-3-carboxylate (as a mixture of cis and trans isomers). The mixture was dissolved in MeOH-THF (0.25 ml / 0.75 ml) and treated with 1N aqueous LiOH (0.474 ml, 0.474 mmol). The resulting mixture was heated to 50 ° C for 1 hour, then cooled to room temperature and acidified to pH 3-4 with 1N aqueous HCl. The mixture was extracted with EtOAc (3 x 15 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to generate (R) -5- (2- (5-fluor-2-hydroxyphenyl) -4-hydroxy-1-yl) pyrazolo [1,5-5a] crude pyrimidine-3-carboxylic (as a mixture of cis and trans isomers; 33.9 mg, 100% yield). LC / MS (ES + APCI) m / z = 357.1 (MH). Example 1
(6R) -9-fluor-2,11,15,19,20,23-hexaazapentacycle [15.5.2.1711,02'6,020'24] - pentacosa-1 (23), 7,9,17 (24), 18 , 21-hexaene-16,25-dione
[000325] Step A: Preparation of (R) -ethyl 5- (2- (5-fluor-2-oxo-1.2-dihydropyridin-3-1-yl) pyrrolidin-1-yl) pyrazole [1,5-a ] pyrimidine-3-carboxylate: To a mixture of (R) -ethyl 5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine- 3-carboxylate (Preparation B, Step C; 0.92 g, 2.39 mmol) and acetic acid (5.73 g, 95.5 mmol) was added HBr (4.4 ml, 23.9 mmol, 33% in acetic acid). The reaction mixture was heated to 90 ° C for 2 hours. After cooling, the reaction mixture was treated with EtOAc, washed with water, saturated NaHCO3 and brine, then dried (MgSO4), filtered and concentrated. The crude material was purified by silica column chromatography, eluting with 3% MeOH / DCM to yield the desired product (0.605 g, 68% yield). MS (apci) m / z = 372.0 (M + H).
[000326] Step B: Preparation of (R) -ethyl 5- (2- (1- (3- (1,3-dioxoisoindolin-2-yl) propyl) -5-fluor-2-oxo-1,2- dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate: To a DMF (5 mL) suspension of (R) -ethyl 5- (2- (5-fluorine) -2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate (0.20 g, 0.54 mmol) LiH (6 , 8 mg, 0.81 mmol) at 0 ° C, followed first by stirring for 20 minutes, then adding a solution of DMF (1 mL) of 2- (3-bromopropyl) isoindoline-1,3-dione (0 , 29 g, 1.1 mmol). The reaction was warmed to room temperature and stirred for 17 hours. After cooling to 0 ° C the reaction was cooled quickly with ice-water (30 ml) and the aqueous was extracted with EtOAc (3 x 50 ml). The combined organic layers were backwashed with water and brine, dried (MgSO4), filtered and concentrated. The crude material was purified by silica column chromatography, eluting with 2% MeOH DCM to yield the desired product (0.2 g, 66% yield). MS (apci) m / z = 559.0 (M + H).
[000327] Step C: Preparation of (R) -ethyl 5- (2- (1- (3-aminopropyl) -5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl ) pyrazol [1,5-a] pyrimidine-3-carboxylate: To a solution of (R) -ethyl 5- (2- (1- (3- (1,3-dioxoisoindolin-2-yl) propyl) -5 -fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5- a] pyrimidine-3-carboxylate (0.20 g, 0.36 mmol) in MeOH / 1: 1 THF (12 mL) hydrazine-H2O (0.18 g, 3.6 mmol) was added. The reaction mixture was heated to 50 ° C for 24 hours. After cooling, the reaction mixture was poured into water and extracted with DCM (3 x 20 mL). The combined organics were dried (MgSO4), filtered and concentrated to produce the desired product (0.11 g, 72% yield). MS (apci) m / z = 429.0 (M + H).
[000328] Step D: Preparation of (R) -5- (2- (1- (3-aminopropyl) -5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl ) pyrazole [1,5-a] pyrimidine-3-carboxylic: To a solution of (R) -ethyl 5- (2- (1- (3-aminopropyl) -5-fluor-2-oxo-1,2- dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate (0.11 g, 0.26 mmol) in THF / MeOH 3: 1 (8 mL) was added LiOH (1 N, 1.5 mL, 1.5 mmol), and the reaction mixture was heated to 70 ° C for 20 hours. After cooling, the reaction mixture was treated with MeOH, acidified with 1N HCl (1.5 mL), and concentrated to produce the desired product (0.1 g, 100% yield). MS (apci) m / z = 401.1 (M + H).
[000329] Step E: Preparation of (6R) -9-fluor-2,11,15,19,20,23-hexaazapentacycle [15,5,2,17,11,02'6,020'24] pentacosa- 1 ( 23), 7,9,17 (24), 18,21-hexaene-16,25-dione: To a solution of (R) -5- (2- (1- (3-aminopropyl) -5-fluoric acid -2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylic (95 mg, 0.24 mmol) in 1: 2 DMF / DCM (9 mL) EDCI (0.14 g, 0.71 mmol) was added followed by HOBT (96 mg, 0.71 mmol) at room temperature. After stirring for 10 minutes, TEA (0.099 mL, 0.71 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was treated with EtOAc, washed with saturated NH4Cl, saturated NaHCO3, and brine, then dried (MgSO4), filtered, concentrated. The crude material was purified by silica column chromatography, eluting with 4% MeOH / DCM to yield the title product (35 mg, 39% yield). MS (apci) m / z = 383.2 (M + H). Example 2
(6R) -12-oxa-2,16,20,21,24,26- hexaazapentacycle [16,5,2,17'11,02'6,021'25] -hexacous- 1 (24), 7 (26) , 8,10,18 (25), 19,22-heptaen-17-one
[000330] Step A: Preparation of (R) -2-methoxy-6- (pyrrolidin-2-yl) pyridine: Prepared according to the method described in Preparation A, replacing 3-bromo-5-fluor-2-methoxypyridine by 2-bromo-6-methoxypyridine in Step A. MS (apci) m / z = 179.1 (M + H).
[000331] Step B: Preparation of (R) -ethyl 5- (2- (6-methoxypyridin-2-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate: Prepared by the same method as described in Preparation B, Step C, replacing (R) -5-fluor-2-methoxy-3- (pyrrolidin-2-yl) pyridine with (R) -2-methoxy-6- (pyrrolidin-2-yl ) pyridine. MS (apci) m / z = 368.0 (M + H).
[000332] Step C: Preparation of (R) -ethyl 5- (2- (6-oxo-1,6-dihydropyridin-2-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3 -carboxylate: To a mixture of (R) -ethyl 5- (2- (6-methoxypyridin-2-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate (0.46 g , 1.25 mmol) and acetic acid (3.0 g, 50 mmol) HBr (3.1 g, 12.5 mmol, 33% in acetic acid) was added. The reaction mixture was heated to 90 ° C for 2 hours. After cooling, the reaction was diluted with EtOAc, washed with water, saturated NaHCO3, and brine, then dried (MgSO4), filtered and concentrated. The crude material was purified by silica column chromatography, eluting with 4% MeOH / DCM to yield the desired product (0.3 g, 67% yield). MS (apci) m / z = 354.1 (M + H).
[000333] Step D: Preparation of (R) -ethyl 5- (2- (6- (3- (1,3-dioxoisoindolin-2-yl) propoxy) pyridin-2-yl) pyrrolidin-1-yl) pyrazole [1,5- a] pyrimidine-3-carboxylate: To a suspension of (R) -ethyl 5- (2- (6-oxo-1,6-dihydropyridin-2-yl) pyrrolidin-1-yl) pyrazole [ 1.5-a] pyrimidine-3-carboxylate (0.091 g, 0.26 mmol) in DMF (2 mL) LiH (3.2 mg, 0.39 mmol) was added at 0 ° C. After stirring for 20 minutes, a solution of 2- (3-bromopropyl) isoindoline-1,3-dione (0.14 g, 0.52 mmol) in DMF (1 mL) was added, and the reaction was heated to room temperature and stirred for 17 hours. After cooling to 0 ° C, the reaction was cooled quickly with ice-water (30 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated. The crude material was purified by silica column chromatography, eluting with 1.5% MeOH / DCM to yield the desired product (0.117 g, 84% yield). MS (apci) m / z = 541.1 (M + H).
[000334] Step E: Preparation of (R) -ethyl 5- (2- (6- (3-aminopropoxy) pyridin-2-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3- carboxylate: To a solution of (R) -ethyl 5- (2- (6- (3- (1,3-dioxoisoindolin-2-yl) propoxy) pyridin-2-yl) pyrrolidin-1-yl) pyrazole [1 .5-a] pyrimidine-3-carboxylate (0.11 g, 0.20 mmol) in 1: 1 MeOH / THF (12 mL) hydrazine-H2O (0.10 g, 2.0 mmol) was added. The reaction mixture was heated to 50 ° C for 24 hours. After cooling, the reaction mixture was poured into water and then extracted with DCM (3 x 20 mL). The combined organics were dried (MgSO4), filtered and concentrated to produce the desired product (70 mg, 84% yield). MS (apci) m / z = 441.1 (M + H).
[000335] Step F: Preparation of (R) -5- (2- (6- (3-aminopropoxy) pyridin-2-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3- carboxylic: To a solution of (R) -ethyl 5- (2- (6- (3-aminopropoxy) pyridin-2-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate ( 70 mg, 0.17 mmol) in THF / MeOH 3: 1 (8 mL) LiOH (1 N, 1.5 mL, 1.5 mmol) was added and the reaction mixture was heated at 70 ° C for 20 hours. After cooling, the reaction mixture was diluted with MeOH, acidified with 1 N HCl (1.5 ml), and concentrated to produce the desired product (65 mg, 100% yield). MS (apci) m / z = 383.1 (M + H).
[000336] Step G: Preparation of (6R) -12-oxa-2,16,20,21,24,26-hexaazapentacyclo- [16,5,2,17'11,02'6,021'25] hexacosa- 1 (24), 7 (26), 8,10,18 (25), 19,22-heptaen-17-one: To a solution of (R) -5- (2- (6- (3-aminopropoxy) acid pyridin-2-yl) pyrrolidin-1-yl) pyrazol [1,5- a] pyrimidine-3-carboxylic (70 mg, 0.18 mmol) in DMF / DCM 1: 2 (9 mL) was added EDCI ( 110 mg, 0.55 mmol) followed by HOBT (74 mg, 0.55 mmol) at room temperature. After stirring for 10 minutes, TEA (0.077 mL, 0.55 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was diluted with EtOAc, washed with saturated NH4Cl, saturated NaHCO3, and brine, then dried (MgSO4), filtered and concentrated. The crude material was purified by silica column chromatography, eluting with 2% MeOH / DCM to yield the title product (30 mg, 45% yield). MS (apci) m / z = 365.2 (M + H). Example 3
(6R) -9-fluor-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17,5,2,02'6,07'12,022'26] hexacosa-1 (25), 7,9,11,19 (26), 20,23-heptaen-18-one
[000337] Step A: Preparation of (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -N- (3-hydroxypropyl) pyrazole [1,5- a] pyrimidine-3-carboxamide: To a suspension of DMF (2 mL) of (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazole [1 , 5-a] pyrimidine-3-carboxylic (Preparation B, 250 mg, 0.700 mmol) and HATU (319 mg, 0.840 mmol) cooled to 0 ° C 3-aminopropan-1-ol (0.0642 mL, 0.840) was added mmol) drop by drop, resulting in a clear yellowish solution. After adding dropwise DIEA (0.366 mL, 2.10 mmol), the ice bath was removed and the reaction was stirred at room temperature for 1 hour. The reaction was directly purified by reverse phase column chromatography (Biotage SP4 system, column C-18 25 + M, 0 to 54% acetonitrile / water), to provide the product as a white solid (200 mg, 69% yield ). MS (apci) m / z = 415.1 (M + H).
[000338] Step B: Preparation of (R) -N- (3-chloropropyl) -5- (2- (5-fluor-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) pyrazole [1,5- a] pyrimidine-3-carboxamide: A mixture of (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -N- (3-hydroxypropyl) pyrazole [1 , 5-a] pyrimidine-3-carboxamide (20 mg, 0.0483 mmol) in HCl (4N dioxane, 1.2 mL, 4.83 mmol) was heated to 85 ° C overnight. The reaction mixture was concentrated, ground with ether, and filtered, to provide the crude product as a beige solid, which was used directly in the next step without further purification (22 mg, 106% yield). MS (apci) m / z = 419.1 (M + H).
[000339] Step C: Preparation of (6R) -9-fluor-13-oxa-2,11,17,21,22,25-hexaazapentacycle [17,5,2,02'6,07'12 022'26 ] hexacosa- 1 (25), 7,9,11,19 (26), 20,23-heptaen-18-one: A DMF suspension (1 mL) of (R) -N- (3-chloropropyl) - 5- (2- (5-fluor-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (5 mg, 0.012 mmol) and CS2CO3 (4 mg, 0.06 mmol) was heated to 85 ° C overnight. The reaction mixture was filtered through GF / F paper and directly purified by reverse phase column chromatography (Biotage SP4 system, column C-18 12 + M, 5 to 60% acetonitrile / water), to provide the product of the title as white solid (2 mg, 44% yield). MS (apci) m / z = 383.3 (M + H). Example 4
(6R) -9-fluor-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17,5,2,02'6,07'12,022'26] hexacosa-1 (25), 7,9,11,19 (26), 20,23-heptaen-18-one
[000340] Step A: Preparation of N- (2,3-dihydroxypropyl) -5 - ((R) -2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazole [1, 5-a] pyrimidine-3-carboxamide: A mixture of (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazole [1,5-a] pyrimidine-3-carboxylic (Preparation B, 250 mg, 0.700 mmol) and HATU (319 mg, 0.840 mmol) in 1: 1 DMF / DMSO (2 mL) was cooled to 0 ° C, followed first by the dropwise addition of 3-aminopropane-1,2-diol (76.5 mg, 0.840 mmol) and then addition of DIEA (366 μL, 2.10 mmol). The reaction was warmed to room temperature, stirred for 20 minutes, and then directly purified by reverse phase column chromatography (Biotage SP4 System C-18 Cartridge 25 + M, 5 to 50% acetonitrile / water), to provide the product as a white solid (295 mg, 98% yield). MS (apci) m / z = 431.1 (M + H).
[000341] Step B: Preparation of N- (3-chloro-2-hydroxypropyl) -5 - ((R) -2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin- 1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide: A mixture of N- (2,3-dihydroxypropyl) -5 - ((R) -2- (5-fluor-2-methoxypyridin-3 -yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (100 mg, 0.232 mmol) and HCL (4 N, dioxane, 5.8 mL) was sealed in a pressure tube and heated to 85 ° C overnight. After the clear solution was decanted, the crude product was obtained as a brownish oily residue, which was vacuum dried and used directly in the next step without further purification. MS (apci) m / z = 435.0 (M + H).
[000342] Step C: Preparation of (6R) -9-fluor-15-hydroxy-13-oxa- 2,11,17,21,22,25-hexaazapentacycle [17,5,2,02,6,07, 12,022,26] hexacosa- l ('25), 7,9,11,19 ('26), 20,23-heptaen-18-one: A suspension of N- (3-chloro-2-hydroxypropyl) -5 - (((R) -2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (100 mg, 0.23 mmol) and CS2CO3 (375 mg, 1.15 mmol) in DMF (3 niL) was heated to 85 ° C for 2 hours. The reaction mixture was filtered through GF / F paper and directly purified by reverse phase column chromatography (Biotage SP4 System Column C-18 25 + M, 5 to 50% acetonitrile / water), to provide the title product like a white solid. MS (apci) m / z = 399.2 (M + H). Example 5
(6R, 13S) -9-fluor-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo- [15,5,2,17'11,02'6,020'24] pentacosa-1 (23 ), 7,9,17 (24), 18,21-hexaene-16,25-dione
[000343] Step A: Preparation of N - ((S) -3-chloro-2-hydroxypropyl-5 - ((R) -2- (5-fluor-2-oxo-1,2-dihydropyridin-3 -yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide: Prepared according to the method described in Example 3, Steps AB, replacing 3-aminopropan-1-ol in Step A with ( S) -3-aminopropane-1,2-diol MS (apci) m / z = 435.0 (M + H).
[000344] Step B: Preparation of (6R, 13S) -9-fluor-13-hydroxy-2,11,15,19,20,23-hexaazapentacycle [15,5,2,17,11,02'6,020 ' 24] pentacosa- 1 (23), 7,9,17 (24), 18,21-hexaene-16,25-dione: A suspension of N - ((S) -3-chloro-2-hydroxypropyl hydrochloride) -5 - ((R) -2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (40 mg, 0.085 mmol) and CS2CO3 (138 mg, 0.42 mmol) in DMF (0.8 mL) was heated to 85 ° C for 2 hours. The reaction mixture was filtered through GF / F paper and directly purified by reverse phase column chromatography (Biotage SP4 System Column C-18 12 + M, 0 to 40% acetonitrile / water), to provide the title product as to white solid (4 mg, 12% yield). MS (apci) m / z = 399.2 (M + H). Example 6
(6R) -9-fluor-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17,5,2,02'6,07'12,022'26] hexacosa-1 (25), 7,9,11,19 (26), 20,23-heptaen-18-one
[000345] Prepared according to the method described in Example 5 and isolated as a by-product in Step B. The enantiomeric integrity of the chiral center where the HO group resides was found to have eroded unexpectedly (the R / S ratio was about 10: 7) in the final product isolated (6R) -9-fluor-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17,5,2,02,6,07,12,022 , 26] hexacosa-l (25), 7,9,11,19 (26), 20,23-heptaen-18-one, which was obtained as a white solid (5 mg, 15% yield) by chromatography on reverse phase column (Biotage SP4 System Column C-18 12 + M, 0 to 50% acetonitrile / water). MS (apci) m / z = 399.2 (M + H). Example 7
(6R, 15R) -9-fluor-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17,5,2,02'6,07'12,022'26] hexacous - 1 (25), 7,9,11,19 (26), 20,23-heptaen-18-one
[000346] Step A: Preparation of N - (((R) -3-chloro-2-hydroxypropyl) -5- ((R) -2- (5-fluor-2-oxo-1,2-dihydropyridin-3- il) pyrrolidin-1-yl) pyrazol [1,5- a] pyrimidine-3-carboxamide: Prepared according to the method described in Example 3, Steps AB, replacing 3-aminopropan-1-ol in Step A with (R ) -3-aminopropane-1,2-diol. MS (apci) m / z = 435.0 (M + H).
[000347] Step B: Preparation of (6R, 15R) -9-fluor-15-hydroxy-13-oxa- 2,11,17,21,22,25-hexaazapentacycle [17,5,2,02'6, 07'12,022'26] hexacosa- 1 (25), 7,9,11,19 (26), 20,23-heptaen-18-one: A suspension of N - ((R) - 3-chloro-2- hydroxypropyl) -5 - ((R) -2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (30 mg, 0.069 mmol) and CS2CO3 (112 mg, 0.34 mmol) in DMF (0.7 mL) was heated to 85 ° C for 1 hour. The reaction mixture was filtered through GF / F paper and directly purified by reverse phase column chromatography (Biotage SP4 System Column C-18 12 + M, 0 to 50% acetonitrile / water), to provide the title product as a white solid (10 mg, 36% yield). Unlike Example 6, no erosion of the enantiomeric integrity of the chiral center where the HO group resides has been observed for this final product. MS (apci) m / z = 399.2 (M + H). Example 8
(6R, 13R) -9-fluor-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo- [15,5,2,17'11,02'6,020'24] pentacosa-1 (23 ), 7,9,17 (24), 18,21-hexaene-16,25-dione
[000348] Obtained as a by-product of Example 7, Step B and isolated as a white solid (1.2 mg, 4% yield) by reverse phase column chromatography (Biotage SP4 System Column C-18 12 + M, 0 44% acetonitrile / water) of the crude material of Example 7, Step B. MS (apci) m / z = 399.2 (M + H). Example 9
(6R) -9-fluor-13-oxa-2,11,16,20,21,24-hexaazapentacycle [16,5,2,02'6,07'12,021'25] pentacosa- 1 (24), 7 , 9,11,18 (25), 19,22-heptaen-17-one
[000349] Step A: Preparation of (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -N- (2-hydroxyethyl) pyrazole [1,5- a] pyrimidine-3-carboxamide: To a suspension of DMF (1 mL) of acid (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazole [1 , 5-a] pyrimidine-3-carboxylic (Preparation B, 100 mg, 0.28 mmol) and HATU (128 mg, 0.336 mmol) was added DIEA (0.146 mL, 0.840 mmol) at room temperature, followed by a solution of 2-aminoethanol (20.5 mg, 0.336 mmol) in a minimum amount of DMF dropwise at 0 ° C. The reaction was warmed to room temperature and stirred for 30 minutes, then directly purified by reverse phase column chromatography (0 to 70% acetonitrile / water) to yield the product as a white solid (95 mg, 85% yield) . MS (apci pos) m / z = 401.1 (M + H).
[000350] Step B: Preparation of (R) -N- (2-chloroethyl) -5- (2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide: À (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -N- (2-hydroxyethyl ) pyrazole [1,5-a] pyrimidine-3-carboxamide (77 mg, 0.192 mmol) into a pressure reaction tube, hydrogen chloride (4N dioxane, 4.8 mL, 19.2 mmol) was loaded and the suspension The resulting white was heated to 85 ° C overnight. After cooling to room temperature, the reaction mixture was decanted to yield the crude product as a brownish oily residue, which was vacuum dried and directly used in the next step without further purification. MS (apci) m / z = 405.0 (M + H).
[000351] Step C: Preparation of (6R) -9-fluor-13-oxa-2,11,16,20,21,24-hexaazapentacycle [16,5,2,02'6,07'12,021'25] pentacosa- 1 ('24), 7,9,11,18 ('25), 19,22-heptaen-17-one: A suspension of (R) -N- (2-chloroethyl) -5- (2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5- a] pyrimidine-3-carboxamide (78 mg, 0.19 mmol) and CS2CO3 ( 314 mg, 0.96 mmol) in DMF (5 mL) was heated to 85 ° C for 30 minutes. After filtering through GF / F paper, the reaction was diluted with water (40 ml) and NH4Cl (saturated, 5 ml), then extracted with EtOAc (3 x 40 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by reverse phase column chromatography (Biotage SP4 System Column C-18 12 + M, 0 to 73% acetonitrile / water), to provide the title product as a white solid (17 mg, 24% Yield). MS (apci) m / z = 369.2 (M + H). Example 10
(6R) -9-fluor-13-oxa-2,11,18,22,23,26- hexaazapentacycle [18,5,2,02'6,07'12,023'27] heptacous- 1 (26), 9 , 11.20 (27), 21.24-heptaen-19-one
[000352] Step A: Preparation of (R) -N- (4-chlorobutyl) -5- (2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide: Prepared according to the method described in Example 3, Steps AB, replacing 3-aminopropan-1-ol in Step A with 4-aminobutan-1-ol. MS (apci) m / z = 433.0 (M + H).
[000353] Step B: Preparation of (6R) -9-fluor-13-oxa- 2,11,18,22,23,26-hexaazapentacyclo- [18,5,2,02'6 07'12,023'27] heptacosa- 1 (26), 7,9,11,20 (27), 21,24-heptaen-19-one: Prepared according to the method described in Example 3, replacing (R) -N- (3-chloropropyl ) -5- (2- (5-fluor-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide with (R) -N- (4-chlorobutyl ) -5- (2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide in Step C. crude product was purified by reverse phase column chromatography (Biotage SP4 System Column C-18 25 + M, 0 to 80% acetonitrile / water), to provide the title product as a white solid (32 mg, 44%). MS (apci pos) m / z = 397.2 (M + H). Example 11
('6R) -9-fluor-2,11,16,20,21,24-hexaazapentacycle [16,5,2,17'11,02'6,021'25] -hexacous- 1 (24), 7,9 , 18 (25), 19,22-hexaene-17,26-dione
[000354] Obtained as a by-product in Example 10, Step B and isolated as a white solid (4 mg, 6%) by purifying the crude material from Example 10, Step B by reverse phase column chromatography (Biotage SP4 System Column C -18 25 + M, 0 to 50% acetonitrile / water). MS (apci) m / z = 397.2 (M + H). Example 12
(6R) -9-fluor-2,11,13,16,20,21,24- heptaazapentacycle [16,5,2,02'6,07'12,021'25] -pentacosa- 1 (24), 7, 9,11,18 (25), 19,22-heptaen-17-one
[000355] Step A: Preparation of (R) tert-butyl 2- (2-chloro-5-fluorpiridin-3-yl) pyrrolidine-1-carboxylate: A solution of tert-butyl pyrrolidine-1-carboxylate (1 mL 5 , 70 mmol) and (-) - spartin (1.31 mL, 5.70 mmol) in anhydrous MTBE (30 mL) was first cooled to -78 ° C under nitrogen, followed by the addition of sec-butyl lithium (4, 07 mL, 1.4M, 5.70 mmol) dropwise over 15 minutes with a syringe, keeping the temperature below -75 ° C. The pale yellowish solution was stirred at -78 ° C for 3 hours before being treated with zinc chloride (3.80 mL, 1.0 M, 3.80 mmol) dropwise over 15 minutes, keeping the temperature below -73 ° C. The mixture was stirred at -78 ° C for 30 minutes, then placed in a water bath at room temperature and stirred for another hour. At this point a large amount of white precipitate was present. The mixture was treated with 3-bromo-2-chloro-5-fluorpiridine (1.00 g, 4.75 mmol) in MTBE (5 mL), followed by the addition of palladium acetate (53 mg, 0.24 mmol) and tri-t-butylphosphine tetrafluorborate (83 mg, 0.28 mmol). The mixture was allowed to stir at room temperature overnight to reach completion. The mixture was treated with NH4OH (1 ml), stirred for 30 minutes and filtered through GF / F paper, washing with MTBE. The filtrate was washed with 10% citric acid (30 ml) and the aqueous layer was backwashed with MTBE (2 x 30 ml). The combined organic phases were washed with brine (20 ml), dried (MgSO4), and concentrated to produce the crude product as a dark yellowish oil. This crude material was purified on a 50 g Biotage SNAP silica cartridge eluting with 10% EtOAc in hexanes to produce the desired product as a colorless oil (0.5 g, 35% yield). MS (apci) m / z = 201.1 (M + H-Boc).
[000356] Step B: Preparation of (R) -2-chloro-5-fluor-3- (pyrrolidin-2-yl) pyridine dihydrochloride: To a solution of (R) -tert-butyl dioxane (5 mL) 2- (2-chloro-5-fluorpiridin-3-yl) pyrrolidine-1-carboxylate (500 mg, 1.66 mmol) was added HCl (4 N dioxane, 20 mL), followed by stirring at room temperature overnight . The mixture was concentrated and treated with Et2O, then vacuum dried, to provide the product as a white solid (0.36 g, 80% yield). MS (apci) m / z = 201.1 (M + H). The enantiomeric excess (ee%) of the product was determined to be> 92% according to the method described in Preparation A.
[000357] Step C: Preparation of (R) -ethyl 5- (2- (2-chloro-5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate : To a solution of ethyl 5-hydroxypyrazole [1,5-a] pyrimidine-3-carboxylate (Preparation B, Step A, 275 mg, 1.33 mmol) in anhydrous DMF (5 mL) was added (Benzotriazol-1- iloxy) tris (dimethylamino) phosphonium hexafluorphosphate (BOP) (646 mg, 1.46 mmol). The heterogeneous mixture was stirred for 10 minutes before adding DIEA (1.16 mL, 6.6 mmol), followed by addition of (R) -2-chloro-5-fluor-3- dihydrochloride (pyrrolidin-2- il) pyridine (363 mg, 1.33 mmol). The reaction was stirred at room temperature overnight to reach completion. The mixture was partitioned between 10% citric acid (30 ml) and EtOAc (30 ml), and the aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic phases were washed successively with water (20 ml), saturated NaHCO3 (20 ml), water (20 ml) and brine (3 x 20 ml), then dried (Na2SO4) and concentrated to produce the crude product as a sponge Orange. The crude material was purified on a 25 g Biotage SNAP silica cartridge eluting with 1% MeOH / DCM to produce the desired product as a creamy colored foam (0.35 g, 68% yield). MS (apci) m / z = 390.0 (M + H).
[000358] Step D: Preparation of (R) -ethyl 5- (2- (2- (2- (tert-butoxycarbonylamino) ethylamino) -5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazole [1, 5-a] pyrimidine-3-carboxylate: A mixture of Pd2dba3 (7.05 mg, 0.00770 mmol), CS2CO3 (125 mg, 0.385 mmol), rac-Binap (19.2 mg, 0.0308 mmol), (R) -ethyl 5- (2- (2-chloro-5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate (50 mg, 0.128 mmol), and tert-butyl 2-aminoethylcarbamate (24.7 mg, 0.154 mmol) in degassed toluene (1 mL) was first purged with nitrogen, then sealed and subjected to microwave irradiation (120 ° C) for 16 hours. After being cooled to room temperature, the reaction mixture was diluted with EtOAc (10 ml) and washed with water (2 x 5 ml). The organic was dried (Na2SO4) and concentrated. The crude material was purified by reverse phase column chromatography (Biotage SP4 System cartridge C18 12 + M, 5 to 70% acetonitrile / water) to yield the desired product as a white foamy solid (38 mg, 58% yield). MS (apci) m / z = 514.1 (M + H).
[000359] Step E: Preparation of (R) -5- (2- (2- (2- (tert-butoxycarbonylamino) ethylamino) -5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazole acid [1, 5-a] pyrimidine-3-carboxylic: To a solution of (R) -ethyl 5- (2- (2- (2- (tert-butoxycarbonylamino) ethylamino) -5-fluorpiridin-3-yl) pyrrolidin-1- il) pyrazol [1,5-a] pyrimidine-3-carboxylate (38 mg, 0.074 mmol) in THF / MeOH / water (2: 2: 1, 0.7 mL) was added LiOH-H2O (9.3 mg , 0.22 mmol), followed by stirring at 50 ° C for 18 hours. After removing the solvent, a reaction residue was taken up in water (0.5 ml), and acidified with 1 N HCl (0.22 ml) at pH 3. The reaction mixture was extracted with EtOAc (3 x 2 ml ), dried (Na2SO4), filtered and concentrated to provide the desired product, which was used in the next step directly without further purification, assuming the quantitative conversion. MS (apci) m / z = 486.0 (M + H).
[000360] Step F: Preparation of (R) -5- (2- (2- (2-aminoethylamino) -5-fluorpyridin-3-yl) pyrrolidin-1-yl) pyrazole hydrochloride [1,5-a ] pyrimidine-3-carboxylic: A solution of (R) -5- (2- (2- (2- (tert-butoxycarbonylamino) ethylamino) -5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazole [ 1,5-a] pyrimidine-3-carboxylic (31 mg, 0.064 mmol) in HCl (4 N dioxane, 798 μL) and TFA (50% DCM, 2 mL) was stirred at room temperature for 1 hour before being concentrated and dried under high vacuum to provide the desired product as an off-white solid, which was used in the next step directly without further purification, assuming quantitative conversion. MS (apci) m / z = 386.1 (M + H).
[000361] Step G: Preparation of (6R) -9-fluor-2,11,13,16,20,21,24- heptaazapentacyclo- [16,5,2,02'6,07'12,021'25] pentacosa - 1 (24), 7,9,11,18 (25), 19,22-heptaen-17-one: To a solution of DMF (3 mL) of acid (R) -5- (2- (2- (2-aminoethylamino) -5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylic (25 mg, 0.065 mmol) was first added HATU (29 mg, 0.077 mmol ), followed by stirring for five minutes and then the dropwise addition of DIEA (56 μL, 0.32 mmol). After stirring at room temperature overnight, the reaction was directly purified by reverse phase column chromatography (Biotage SP4 System C18 cartridge 25 + M, acetonitrile / water 5 to 45%), to yield the title product as off-white solid. (7 mg, 30% yield). MS (apci) m / z = 368.2 (M + H). Example 13
(6R) -9-fluor-2,11,13,17,21,22,25- heptaazapentacycle [17,5,2,02'6,07'12,022'261] -hexacous- 1 (25), 7, 9,11,19 (26), 20,23-heptaen-18-one
[000362] Step A: Preparation of (R) -ethyl 5- (2- (2- (3- (tert-butoxycarbonylamino) propylamino) -5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazole [1, 5-a] pyrimidine-3-carboxylate: Prepared according to the method described in Example 12, Steps D, replacing tert-butyl 2-aminoethylcarbamate with tert-butyl 3-aminopropylcarbamate. MS (apci) m / z = 528.1 (M + H).
[000363] Step B: Preparation of (6R) -9-fluor-2,11,13,17,21,22,25- heptaazapentacyclo- [17,5,2,02'6,07'12,022'26] hexacosa - 1 (25), 7,9,11,19 (26), 20,23-heptaen-18-one: Prepared according to the method described in Example 12, Steps EG, in three steps, from (R) - ethyl 5- (2- (2- (3- (tert-butoxycarbonylamino) propylamino) -5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate obtained above. The crude product was purified by reverse phase column chromatography (Biotage SP4 System Cartridge C-18 25 + M, 5 to 50% acetonitrile / water), to provide the title product as a white solid (6 mg, 44% yield ). MS (apci pos) m / z = 382.2 (M + H). Example 14
(6R) -9-fluor-13,16-dioxa-2,11,20,21,24- pentaazapentacycle [16,5,2,02'6,07'12,021'251-pentacosa- 1 (24), 7 , 9,11,18 (25), 19,22-heptaen-17-one
[000364] Step A: Preparation of (R) -2-chloroethyl 5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3 -carboxylate: To a suspension of DMF (1 mL) of (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazole [1,5-a] pyrimidine-3-carboxylic (Preparation B, 0.1 g, 0.28 mmol) and HATU (0.128 g, 0.336 mmol) was added DIEA (0.146 ml, 0.840 mmol), followed by 2-chloroethanol (0.0270 g, 0.336 mmol).
[000365] After stirring at room temperature for 30 minutes, the reaction was directly purified by reverse phase column chromatography (Biotage System SP4 C18 25 + M, 5 to 65% acetonitrile / water) to obtain the intermediate (R) -3H- [1,2,3] triazole [4,5-b] pyridin-3-yl 5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazole [1,5- a] pyrimidine-3-carboxylate as the white solid (94.7 mg, 71% yield). This isolated intermediate was dissolved in excess of chloroethanol (1 ml), followed by the addition of drops of DIEA at room temperature and stirred overnight to reach completion. The reaction was directly purified by reverse phase column chromatography (Biotage System SP4 C18 25 + M, acetonitrile / water 5 to 73) to obtain the title product as a white foamy solid (56 mg, 48% yield). MS (apci) m / z = 419.9 (M + H).
[000366] Step B: Preparation of (R) -2-chloroethyl 5- (2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazole [1,5 -a1pyrimidine-3-carboxylate: A mixture of (R) -2-chloroethyl 5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine -3-carboxylate (56 mg, 0.13 mmol) in HQ (4 N dioxane, 2.5 mL, 10 mmol) was sealed in a pressure reaction tube and heated to 100 ° C for 45 minutes. The reaction mixture was cooled and concentrated to yield the product as a yellowish oil, which was used directly in the next step without further purification, assuming the quantitative yield. MS (apci) m / z = 406.0 (M + H).
[000367] Step C: Preparation of (6R) -9-fluor-13,16-dioxa- 2,11,20,21,24-pentaazapentacycle [16,5,2,02'6,07'12,021'25] -pentacosa- 1 (24), 7,9,11,18 (25), 19,22-heptaen-17-one: A mixture of (R) -2-chloroethyl 5- (2- (5-fluor-2 -oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5- a] pyrimidine-3-carboxylate (54 mg, 0.133 mmol) and CS2CO3 (217 mg, 0.665 mmol) in DMF (6 ml) was heated to 90 ° C overnight. The reaction was filtered (GF / F paper) and directly purified by reverse phase column chromatography (Biotage System SP4 C18 25 + M, 5 to 60% acetonitrile / water) to yield a mixture of the desired product and impurities. This mixture was treated with a second column chromatography on Biotage SNAP KP-Sil 10 g, eluting with 10% hexanes / EtOAc to yield the pure title product as a white solid (11 mg, 22% yield). MS (apci pos) m / z = 370.2 (M + H). Example 15
(6R) -9-fluor-14-oxa-2,11,18,19,22- pentaazapentacycle [14,5,2,17'11,02'6,019'23] tetracosa- 1 (22), 7,9 , 16 (23), 17,20-hexaene-15,24-dione
[000368] Obtained as a by-product of Example 14, Step C, and isolated as a white solid (5 mg, 9% yield) by reverse phase column chromatography (Biotage System SP4 Column C-18 25 + M, 5 a 60% acetonitrile / water) of the crude material of Example 14, Step C. MS (apci) m / z = 370.2 (M + H). Example 16
(6R) -9-fluor-13,16-dioxa-2,11,17,21,22,25-hexaazapentacyclo- [17,5,2,02'6,07'12,022'26] hexacosa-1 (25 ), 7,9,11,19 (26), 20,23-heptaen-18- one
[000369] Step A: Preparation of (R) -N- (2-bromoethoxy) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazole [1,5- a] pyrimidine-3-carboxamide: To a mixture of (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine -3-carboxylic (Preparation B, 100 mg, 0.280 mmol) and HATU (128 mg, 0.336 mmol) in DMF (1 mL) was added DIEA (0.146 mL, 0.840 mmol), followed by 0- (2-bromoethyl hydrobromide) ) hydroxylamine (74.2 mg, 0.336 mmol) in one portion. After stirring at room temperature overnight, the reaction mixture was directly purified by reverse phase column chromatography (Biotage System SP4 C-18 25 + M, 5 to 67% acetonitrile / water) to yield the desired product as a solid off-white (91 mg, 68% yield). MS (apci) m / z = 479.0 (M + H).
[000370] Step B: Preparation of (R) -N- (2-chloroethoxy ') - 5- (2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl ) pyrazol [1,5-a] pyrimidine-3-carboxamide: A mixture of (R) -N- (2-bromoethoxy) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin- 1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (70 mg, 0.146 mmol) and HCL (4 N dioxane, 3.65 mL, 14.6 mmol) was sealed in a pressure tube and heated at 90 ° C for 3 hours. The reaction mixture was then cooled, diluted with MeOH, concentrated, and dried under high vacuum to obtain the desired product that was used in the next step directly without further purification, assuming the quantitative conversion.
[000371] Step C: Preparation of (6R) -9-fluor-13,16-dioxa- 2,11,17,21,22,25-hexaazepentacycle [17,5,2,02'6,07'12, 022'26] hexacosa- 1 (25), 7,9,11,19 (26), 20,33-heptaen-18-one: A mixture of (R) -N- (2-chloroethoxy) -5- ( 2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (60 mg, 0.14 mmol) and Cs2C03 (232 mg, 0.71 mmol) in DMF (1.4 mL) was heated to 90 ° C for 20 minutes to reach completion. The reaction mixture was filtered (GF / F paper) and diluted with water (10 ml), then extracted with EtOAc (3 x 10 ml). The organic layers were combined, washed with brine and dried (Na2SO4). The crude material was purified by reverse phase column chromatography (Biotage System SP4 C18 12 + M, acetonitrile / water 5 to 55%) to yield a mixture of the desired final product and impurities. This mixture was again purified by preparative TLC (10% MeOH / DCM) to yield the pure title product as a white solid (1 mg, 1% yield). MS (apci) m / z = 385.1 (M + H). Example 17
(6R, 13R) -9,13-difluor-2,11,15,19,20,23-hexaazapentacyclo- [15.5.2.17'11,02'6,020'24] pentacosa-1 (23), 7,9, 17 (24), 18,21-hexaene-16,25-dione
[000372] A solution of (6R, 13S) -9-fluor-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo- [15,5,2,17,11,02,6,020,24 ] pentacosa- l (23), 7,9,17 (24), 18,21-hexaene-16,25-dione (Example 5; 10 mg, 0.0251 mmol) in a DCM mixture solvent (0, 3 mL) and 3 drops of DMSO was treated with bis (2-methoxyethyl) amino-sulfur trifluoride (7.87 μL, 0.0427 mmol) at 0 ° C, followed by the addition of a DCM solution (0.1 mL ) of ethanol (0.231 mg, 0.00502 mmol), and a mixture was stirred at room temperature overnight. The reaction mixture was poured into NaHCO3 and extracted with DCM, then dried (Na2SO4), filtered and concentrated. The crude material was purified by reverse phase column chromatography (Biotage SP4 System cartridge C18 12 + M, acetonitrile / water 5 to 50%) to yield the title product as beige solid (1.3 mg, 12% yield) . MS (apci) m / z = 401.2 (M + H). Example 18
(6R) -9-fluor-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacycle [17.5.2.02'6.07'12.022'26] hexacosa- 1 (25) 7,9, 11.19 (26), 20.23-heptaen-18-one
[000373] Step A: Preparation of (R) -N- (3-chloropropyl) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -N-methylpyrazole [1 , 5-a] pyrimidine-3-carboxamide: To a suspension of (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazole [1,5- a] pyrimidine-3-carboxylic (Preparation B, 200 mg, 0.56 mmol) and 3-chloro-N-methylpropan-1-amine hydrochloride (177 mg, 1.23 mmol) in DMF (4 mL) was added N-methylmorpholine (0.25 ml, 2.30 mmol), followed by HATU (234 mg, 0.616 mmol). The reaction was stirred at room temperature for 18 hours, then diluted with H2O (10 mL), and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 ml), dried (MgSO4), filtered and concentrated. The crude product was purified by reverse phase column chromatography, eluting with 5 to 60% acetonitrile / water to yield the desired product as a white foamy solid (129 mg, 52% yield). MS (apci) m / z = 447.0 (M + H).
[000374] Step B: Preparation of (R) -N- (3-chloropropyl) -5- (2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) -N-methylpyrazole [1,5-a] pyrimidine-3-carboxamide: A mixture of HCl (4 N dioxane, 4 mL, 16.0 mmol) and (R) -N- (3-chloropropyl) -5- ( 2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -N-methylpyrazol [1,5-a] pyrimidine-3-carboxamide (100 mg, 0.224 mmol) was sealed in a pressure and heated to 90 ° C for 90 minutes. The reaction mixture was then diluted with acetonitrile and concentrated to yield the crude product, which was carried on to the next step without further purification (145mg, 150% yield). MS (apci) m / z = 433.0 (M + H).
[000375] Step C: Preparation of (6R) -9-fluor-17-methyl-13-oxa- 2,11,17,21,22,25-hexaazapentacycle [17,5,2,02'6,07 '12,022'26] hexacosa- 1 (25), 7,9,11,19 (26), 20,23-heptaen-18-one: A mixture of (R) -N- (3-chloropropyl) -5- ( 2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) -N-methylpyrazol [1,5-a] pyrimidine-3-carboxamide (50 mg, 0.12 mmol) and Cs2CO3 (188 mg, 0.58 mmol) in DMF (12 mL) was heated to 90 ° C for 15 minutes to reach completion. The reaction mixture was filtered, rinsed with DMF, and concentrated. The crude material was purified directly by reverse phase column chromatography, eluting with 5 to 60% acetonitrile / water to yield the title product as a pale yellow powder (17 mg, 36% yield). MS (apci) m / z = 397.3 (M + H). Example 19
(6R) -9,15,15-trifluor-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17,5,2,02'6,07'12,022'26] hexacosa-1 (25), 7,9,11,19 (26), 20,23-heptaen-18-one
[000376] Step A: Preparation of (S) -1-amino-3-chloropropan-2-ol hydrochloride: To a solution of benzaldehyde (4.50 g, 42.4 mmol) in EtOH (12 mL) was added aqueous ammonia (4.01 g, 65.9 mmol) in some portions. After stirring for 10 minutes, (S) -2- (chloromethyl) oxirane (3.81 g, 41.2 mmol) was added and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was then heated to 35-40 ° C with a heating mantle for 6 hours, followed by stirring at room temperature for 18 hours. The reaction was concentrated to 5 ml and toluene (5 ml) was added. The mixture was heated to 36 ° C and a solution of concentrated HCl (6.09 g, 61.8 mmol) and water (5.9 mL) was added slowly over 5 minutes to maintain an internal reaction temperature range of 36 - 41 ° C. The biphasic mixture was heated to 42-45 ° C for 3 hours. The organic phase was separated and washed with water (10 ml). The aqueous phases were combined and ethanol (10 ml) was added. The mixture was concentrated to 10 ml, and ethanol (6 x 10 ml) was added, concentrating after each addition. After the last concentration step, the slurry was heated to reflux, cooled to room temperature, and then placed at -20 ° C for 18 hours. The product was collected by vacuum filtration, washed with cold ethanol, and vacuum dried, to provide the product as a white crystalline solid (3.58 g, 60% yield). 1H NMR (d6-DMSO) δ 8.14 (s, 3H), 5.91 (s, 1H), 3.93 (m, 1H), 3.59 (m, 2H), 2.89 (m, 1H), 2.69 (m, 1H).
[000377] Step B: Preparation of N - ((S) -3-chloro-2-hydroxypropyl) -5- ((R) -2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1- il) pyrazol [1,5-a] pyrimidine-3-carboxamide: Prepared according to the method described in Example 18, replacing (5) -1-amino-3-chloropropan-2-ol hydrochloride (98.1 mg , 0.672 mmol) by 3-chloro-N-methylpropan-1-amine hydrochloride in Step A. MS (apci) m / z = 448.9 (M + H).
[000378] Step C: Preparation of (R) -N- (3-chloro-2-oxopropyl) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazole [ 1,5-a] pyrimidine-3-carboxamide: To a solution of N - ((5) -3-chloro-2-hydroxypropyl) -5 - ((R) -2- (5-fluor-2-methoxypyridin- 3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (180 mg, 0.401 mmol) in DCM (3 mL) Dess-Martin periodinane (204 mg, 0.481 mmol) was added . The reaction was stirred at room temperature for 3 hours, then purified directly by reverse phase column chromatography, eluting with 5 to 60% acetonitrile / water to yield the desired product as a white foamy solid (11 mg, 64% yield) ). MS (apci) m / z = 447.0 (M + H).
[000379] Step D: Preparation of (R) -N- (3-chloro-2,2-difluorpropyl) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazole [1,5-a] pyrimidine-3-carboxamide: To a solution of (R) -N- (3-chloro-2-oxopropyl) -5- (2- (5-fluor-2-methoxypyridin-3- il) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (114 mg, 0.255 mmol) in DCM (3 mL) Deoxofluorine (0.103 mL, 0.561 mmol) was added, and the reaction mixture it was stirred at room temperature for 23 hours. The reaction was quenched with saturated NaHCO3 (5 mL), diluted with DCM (5 mL), and stirred for 30 minutes. After phase separation, the aqueous phase was extracted with DCM (10 ml). The combined organic phases were concentrated and purified by reverse phase column chromatography, eluting with 5 to 60% acetonitrile / water to yield the desired product as a white solid (59 mg, 49% yield). MS (apci) m / z = 469.0 (M + H).
[000380] Step E: Preparation of (R) -N- (3-chloro-2,2-difluorpropyl) -5- (2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5- a] pyrimidine-3-carboxamide: Prepared according to the method described in Example 18, replacing (R) -N- (3-chloro-2,2-difluorpropyl) - 5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide by (R) -N- (3-chloropropyl) - 5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) -N-methylpyrazol [1,5-a] pyrimidine-3-carboxamide in Step B. MS (apci) m / z = 455.0 (M + H).
[000381] Step F: Preparation of (6R) -9,15,15-trifluor-13-oxa- 2,11,17,21,22,25-hexaazapentacycle [17.5.2.02'6,07'12,022'26] hexacosa- 1 (25), 7,9,11,19, (26), 20,23-heptaen-18-one: Prepared according to the same method as described in Example 18, replacing (R) -N- ( 3-chloro-2,2-difluorpropyl) -5- (2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine -3-carboxamide by (R) -N- (3 - chloropropyl) -5- (2- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) -N- methylpyrazole [1,5-a] pyrimidine-3-carboxamide in Step C, and heating at 110 ° C for 5 hours, to provide the title product as a pale pink solid (6 mg, 11% yield). MS (apci) m / z = 419.3 (M + H). Example 20
(6R) -9-fluor-13-oxa-2,17,21,22,25-pentazapentacycle [15.5.2.02'6.07'12.022'26] hexacosa- 1 (25), 7,9,11,19 (26 ), 20,23-heptaen-18-one
[000382] Step A: Preparation of (R) -tert-butyl 2- (5-fluor-2-hydroxyphenyl) pyrrolidine-1-carboxylate. This compound was prepared according to the method described in Preparation A, replacing 3-bromo-5-fluor-2-methoxypyridine with 2-bromo-4-fluorophenyl acetate in Step A (3.2 g, 40% yield) . MS (apci) m / z = 182.1 (M + H -Boc).
[000383] Step B: Preparation of (R) -4-fluor-2- (pyrrolidin-2-yl) phenol hydrochloride: To a solution of (R) -tert-butyl 2- (5-fluor-2-hydroxyphenyl) ) pyrrolidine-1-carboxylate (3.2 g, 11.4 mmol) in DCM (20 mL) HCl (4 N dioxane, 5.69 mL, 22.7 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The reaction was concentrated, and the resulting precipitate was taken up in DCM (15 ml) and filtered to yield (R) -4-fluor-2- (pyrrolidin-2-yl) phenol hydrochloride (1.85 g, 90% yield) as a beige solid. MS (apci) m / z = 182.1 (M + H).
[000384] Step C: Preparation of (R) -ethyl 5- (2- (5-fluor-2-hydroxyphenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate: Prepared according with the method described in Preparation B, replacing (R) -4-fluor-2- (pyrrolidin-2-yl) phenol for (R) -5-fluor-2-methoxy-3- (pyrrolidin-2-yl ) pyridine in Step C. The crude material was purified by reverse phase column chromatography (0-65% acetonitrile / H2O) to yield the pure product (686 mg, 80% yield). MS (apci) m / z = 371.0 (M + H).
[000385] Step D: Preparation of (R) -ethyl 5- (2- (2- (3- (1,3-dioxoisoindolin-2-yl) propoxy) -5-fluorophenyl) pyrrolidin-1-yl) pyrazole [ 1,5- a] pyrimidine-3-carboxylate: A suspension of (R) -ethyl 5- (2- (5-fluor-2-hydroxyphenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine- 3-carboxylate (280 mg, 0.756 mmol), 2- (3-bromopropyl) isoindoline-1,3-dione (263 mg, 0.983 mmol) and K2CO3 (104 mg, 0.756 mmol) in DMF (0.4 mL) was stirred at room temperature for 15 hours. The reaction was directly purified by reverse phase column chromatography (5-80% acetonitrile / H2O) to yield (R) -ethyl 5- (2- (2- (3- (1,3-dioxoisoindolin-2-yl) propoxy) -5-fluorophenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate (202 mg, 48% yield) as a clear oil. MS (apci) m / z = 558.0 (M + H).
[000386] Step E: Preparation of (R) -ethyl 5- (2- (2- (3-aminopropoxy) -5-fluorophenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate : (R) -ethyl 5- (2- (2- (3- (1,3-dioxoisoindolin-2-yl) propoxy) -5-fluorophenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine -3-carboxylate (200 mg, 0.359 mmol) and hydrazine monohydrate (115 mg, 3.59 mmol) were combined in MeOH (1 mL) and THF (1 mL) in a sealed container and heated to 60 ° C for 20 minutes. After cooling to room temperature, the reaction was concentrated, followed by the addition of NaOH (1N, 2 mL). The mixture was extracted with DCM, and the combined organic extracts were dried (Na2SO4), filtered and concentrated to yield (R) -ethyl 5- (2- (2- (3- aminopropoxy) -5-fluorophenyl) pyrrolidin-1- il) pyrazol [1,5-a] pyrimidine-3-carboxylate (110 mg, 72% yield). MS (apci) m / z = 428.2 (M + H).
[000387] Step F: Preparation of (6R) -9-fluor-13-oxa-2,17,21,22,25- pentaazapentacycle [17.5.2.02'6,07'12,022'26] hexacosa- 1 (25) , 7,9,11,19 (26), 20,23-heptaen-18-one. (R) -ethyl 5- (2- (2- (3-aminopropoxy) -5-fluorophenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate: (10 mg, 0.023 mmol) and DIEA (8.1 μL, 0.047 mmol) were combined in dry EtOH (0.1 mL) in a sealed container and heated to 200 ° C overnight. The reaction was concentrated and purified by reverse phase column chromatography (0-70% acetonitrile / H2O) to yield the title compound (4.5 mg, 50% yield). MS (apci) m / z = 382.2 (M + H). Example 21
(6R) -9-fluor-13-oxa-2,16,20,21,24- pentaazapentacycle [16,5,2,02'6,07'12,021'251 pentacosa- 1 (24), 7,9, 11.18 (25), 19.22-heptaene
[000388] Step A: Preparation of (R) -4-fluor-2- (1- (pyrazol [1,5- a] pyrimidin-5-yl) pyrrolidin-2-yl) phenol: A mixture of ( R) -4-fluor-2- (pyrrolidin-2-yl) phenol (Example 20, Step B, 1.50 g, 6.89 mmol), DIEA (2.67 g, 20.7 mmol), 5- chloropyrazole [1,5-ajpirimidine (1.11 g, 7.24 mmol) and isopropanol (1 ml) was heated to 120 ° C overnight. The reaction was poured into ether (50 ml) and extracted with NaOH (1N aqueous, 3 x 25 ml). The combined aqueous extracts were brought to pH 4 with concentrated HCl and extracted with DCM. The combined DCM extracts were filtered through the phase separator paper and concentrated to provide (R) -4-fluor-2- (1- (pyrazol [1,5-a] pyrimidin-5-yl) pyrrolidin-2-yl ) phenol (1.82 g, 89% yield) as a beige solid. MS (apci) m / z = 299.4 (M + H).
[000389] Step B: Preparation of ('R-5 - (' 2 - ('5-fluor-2-hydroxyphenylpyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carbaldehyde: After POCl3 (221 μL, 2.41 mmol) was added dropwise to a solution of DMF (4 mL) of (R) -4-fluor-2- (1- (pyrazol [1,5-a] pyrimidin-5-yl) pyrrolidin-2-yl) phenol (600 mg, 2.01 mmol) at room temperature, the reaction was stirred for 5 minutes before NaOH (804 mg, 10.1 mmol) was introduced in. The reaction was stirred for another 10 minutes before of HCL (4 N dioxane, 3 mL) was added, followed by DCM (50 mL). After filtering through Celite®, the reaction was concentrated and purified by reverse phase column chromatography, eluting with 0-70% acetonitrile / H2O to provide (R) -5- (2- (5-fluor-2-hydroxyphenyl) pyrrolidin-1-yl) pyrazol [1,5- a] pyrimidine-3-carbaldehyde (524 mg, 80% yield) as beige solid MS (apci) m / z = 327.2 (M + H).
[000390] Step C: Preparation of (R) -tert-butyl 2- (4-fluor-2- (1- (3-formylpyrazol [1,5-a] pyrimidin-5-yl) pyrrolidin-2-yl) phenoxy) ethylcarbamate: A mixture of (R) -5- (2- (5-fluor-2-hydroxyphenyl) pyrrolidin-1-yl) pyrazol [1,5- a] pyrimidine-3-carbaldehyde (159 mg, 0.487 mmol ), tert-butyl 2-bromoethylcarbamate (13 1 mg, 0.585 mmol), potassium carbonate (202 mg, 1.46 mmol) and DMF (1 mL) were combined in a sealed container and stirred at room temperature overnight and then at 60 ° C for 3 hours. After dilution with DCM (20 mL), the reaction was filtered through Celite®, concentrated and purified by reverse phase column chromatography, eluting with 0-70% acetonitrile / H2O to provide (R) -tert-butyl 2- ( 4-fluor-2- (1- (3-formylpyrazol [1,5-a] pyrimidin-5-yl) pyrrolidin-2-yl) phenoxy) ethylcarbamate (198 mg, 86.6% yield) as a yellowish solid. MS (apci) m / z = 370.4 (M + H - Boc).
[000391] Step D: Preparation of (R) -5- (2- (2- (2-aminoethoxy) -5-fluorphenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carbaldehyde: An HCl (4N dioxane, 80 μL, 0.32 mmol) was added to a DCM solution (2 mL) of (R) -tert-butyl 2- (4-fluor-2- (1- (3-formylpyrazole [ 1,5-a] pyrimidin-5-yl) pyrrolidin-2-yl) phenoxy) ethylcarbamate (198 mg, 0.422 mmol), and the reaction was purged with N2 and stirred at room temperature overnight. After removing the solvent, NaOH (5 mL x IN) was introduced and the reaction mixture was extracted with some portions of DCM in a phase separator tube. The combined organic extracts were concentrated to provide (R) -5- (2- (2- (2-aminoethoxy) -5-fluorphenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carbaldehyde ( 155 mg, 99.5% yield), which was used immediately in the next step. MS (apci) m / z = 352.3 (M + H - H2O).
[000392] Step E: Preparation of (6R) -9-fluor-13-oxa-2,16,20,21,24- pentaazapentacycle [16,5,2,02'6,07'12,021'251pentacosa- 1 ( 24), 7,9,11,18 (25), 19,22-heptaene. Tetramethylammonium triacetoxyborohydride (46.7 mg, 0.629 mmol) was added to a solution of DCM (50 mL) of (R) -5- (2- (2- (2-aminoethoxy) -5-fluorophenyl) pyrrolidin-1- il) pyrazol [1,5-a] pyrimidine-3-carbaldehyde (155 mg, 0.420 mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was then diluted with brine and extracted with some portions of DCM in a phase separator tube, and the combined organic extracts were concentrated and purified by reverse phase column chromatography, eluting with 0-90% acetonitrile-H2O, obtain the title compound (32 mg, 21.6% yield). MS (apci) m / z = 354.2 (M + H). Example 22
1 - [(6R) -9-fluor-13-oxa-2,16,20,21,24-pentaazapentacyclo-] 16,5,2,02'6,07'12,021'25] pentacosa-1 (24) , 7,9,11,18 (25), 19,22-heptaen- 16-yl] etan-1-one
[000393] Acetyl chloride (1.7 mg, 0.021 mmol) was added to a solution of DCM (0.5 mL) of (6R) -9-fluor-13-oxa-2,16,20,21,24 - pentazapentacyclo- [16,5,2,02,6,07,12,021,25] pentacosa- 1 (24), 7,9,11,18 (25), 19,22-heptaene (Example 21, 5,0 mg, 0.014 mmol), followed by DIEA (7.4 μL, 0.042 mmol). After stirring at room temperature overnight, the reaction was concentrated and purified by reverse phase column chromatography eluting with 0-80% acetonitrile / H2O to provide the title product (3.9 mg, 70% yield). MS (apci) m / z = 396.2 (M + H). Example 23
1 - [(6R) -9-fluor-13-oxa-2,16,20,21,24-pentaazapentacyclo-] 16,5,2,02'6,07'12,021'25] pentacosa-1 (24) , 7,9,11,18 (25), 19,22-heptaen- 16-yl] -2-hydroxyethan-1-one
[000394] To a solution of DCM (0.5 mL) of (6R) -9-fluor-13-oxa- 2,16,20,21,24-pentaazapentacyclo- [16,5,2,02,6, 07,12,021,25] pentacosa- 1 (24), 7,9,11,18 (25), 19,22-heptaene (Example 21, 6 mg, 0.017 mmol) 2-chloro-2-oxoethyl acetate was added (3.5 mg, 0.025 mmol), followed by DIEA (8.9 μL, 0.051 mmol). The reaction was stirred at room temperature overnight, then concentrated, and MeOH (0.2 ml) was added followed by sodium hydroxide (6.8 mg, 0.085 mmol). After stirring at room temperature for 5 hours, the reaction was diluted with brine and extracted with some portions of DCM in a phase separator tube. The combined organic extracts were concentrated and purified by reverse phase column chromatography, eluting with 0-70% acetonitrile / H2O, to provide the title product (3.6 mg, 52% yield). MS (apci) m / z = 412.5 (M + H). Example 24
(6R) -9-fluor-13-oxa-2,17,21,22,25-pentaazapentacycle [17,5,2,02'6 07'12,022'26] hexacosa-1 (25), 7,9, 11.19 (26), 20.23-heptaene
[000395] Step A: Preparation of (R) -tert-butyl 3- (4-fluor-2- (1- (3-formylpyrazol [1,5-a] pyrimidin-5-yl) pyrrolidin-2-yl) phenoxy) propylcarbamate: Prepared according to the method described in Example 21, replacing tert-butyl 2-bromoethylcarbamate with tert-butyl 3-bromopropylcarbamate in Step C to produce the desired product (119 mg, 84.5% yield). MS (apci) m / z = 384.2 (M + H - Boc).
[000396] Step B: Preparation of (R) -tert-butyl 3- (4-fluor-2- (1- (3- (hydroxymethyl) pyrazol [1,5-a] pyrimidin-5-yl) pyrrolidin-2 - yl) phenoxy) propylcarbamate: A solution of (R) -tert-butyl 3- (4-fluor-2- (1- (3-formylpyrazol [1,5-a] pyrimidin-5-yl) pyrrolidin-2- il) phenoxy) propylcarbamate (85.0 mg, 0.176 mmol) in MeOH (2 mL) was first cooled to 0 ° C, then NaBH4 (4.04 mg, 0.176 mmol) was introduced, and the reaction was stirred at 0 ° C for 1 hour. The reaction was diluted with brine and extracted with DCM in a phase separator cartridge. The combined organic extracts were concentrated to provide (R) -tert-butyl 3- (4-fluor-2- (1- (3- (hydroxymethyl) pyrazol [1,5-a] pyrimidin-5-yl) pyrrolidin-2 - il) phenoxy) propylcarbamate (86 mg, 101% yield) as a beige solid. MS (apci) m z = 468.1 (M + H - H2O).
[000397] Step C: Preparation of (R) - (5- (2- (2-3-aminopropoxy) -5-fluorophenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidin-3- yl) methanol: (R) -tert-butyl 3- (4-fluor-2- (1- (3- (hydroxymethyl) pyrazol [1,5-a] pyrimidin-5-yl) pyrrolidine-2-yl) phenoxy ) propylcarbamate (80 mg, 0.16 mmol) was dissolved in 2 ml of DCM and treated with HCl (4 N in dioxane, 6.0 mg, 0.16 mmol). The reaction was purged with N2, capped, and stirred at room temperature for 18 hours, then concentrated to provide (R) - (5- (2- (2- (3-aminopropoxy) -5-fluorophenyl) pyrrolidine-1 hydrochloride -yl) pyrazol [1,5-a] pyrimidin-3-yl) methanol (70 mg, 101% yield) as a beige solid. MS (apci) m / z = 368.5 (M + H-H2O).
[000398] Step D: Preparation of (6R) -9-fluor-13-oxa-2,17,21,22,25- pentaazapentacyclo- [17,5,2,02'6,07'12,022'26] hexacosa - 1 (25), 7,9,11,19 (26), 20,23-heptaene. A mixture of (R) - (5- (2- (2- (3-aminopropoxy) -5-fluorphenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidin-3-yl) methanol (50 mg , 0.130 mmol), PS-PPh3 (0.259 mmol) and perchloromethane (200 mg, 1.30 mmol) in DCM (5 mL) was stirred at room temperature overnight. The reaction was filtered, concentrated and purified by reverse phase column chromatography eluting with 0-60% acetonitrile / H2O to yield the title product (27.4 mg, 57.5% yield). MS (apci) m / z = 368.1 (M + H). Example 25
(6R) -9-fluor-16-methanesulfonyl-13-oxa-2,16,20,21,24- pentaazapentacyclo- [16,5,2,02'6,07'12,021'25] pentacosa- l (24 ), 7,9,11,18 (25), 19,22-heptaene
[000399] To a solution of DCM (0.5 mL) of (6R) -9-fluor-13-oxa- 2,16,20,21,24-pentaazapentacyclo- [16,5,2,02,6, 07,12,021,25] pentacosa- 1 (24), 7,9,11,18 (25), 19,22-heptaene (Example 21, 5 mg, 0.0141 mmol) was added DIEA (2.46 μL, 0.0141 mmol), followed by methanesulfonyl chloride (1.10 μL, 0.0141 mmol). The reaction was stirred at room temperature for 1 hour before MeOH (0.1 mL) was added. The reaction was concentrated and purified by reverse phase column chromatography eluting with 0-80% acetonitrile / H2O to provide the title product (3.1 mg, 50.8% yield). MS (apci) m / z = 432.3 (M + H). Example 26
2 - [(6R) -9-fluor-13-oxa-2,16,20,21,24- pentaazapentacycle [16,5,2,02'6,07'12,021'25] pentacosa- 1 (24) , 7,9,11,18 (25), 19,22-heptaen-16-yl] acetic
[000400] An IPA solution (0.1 mL) of (6R) -9-fluor-13-oxa- 2,16,20,21,24-pentaazapentacyclo- [16,5,2,02,6,07 , 12,021,25] pentacosa- 1 (24), 7,9,11,18 (25), 19,22-heptaene (Example 21, 5 mg, 0.014 mmol), 2-bromoacetic acid (2.9 mg, 0.021 mmol) and NaOH (1N, 42 μL, 0.042 mmol) was heated to 60 ° C in a sealed container overnight, then at 120 ° C for 24 hours. After cooling, the reaction mixture was directly purified by reverse phase column chromatography eluting with 0-50% acetonitrile / H2O to yield the title product (3.1 mg, 53% yield). MS (apci) m / z = 412.2 (M + H). Example 27
(6R) -9-fluor-17-methanesulfonyl-13-oxa-2,17,21,22,25-pentaazapentacycle [17,5,2,02'6,07'12,022'26] hexacosa- l (25) , 7,9,11,19 (26), 20,23-heptaene
[000401] Methanesulfonyl chloride (1.69 μL, 0.0218 mmol) was added to a solution of DCM (0.5 mL) of (6R) -9-fluor-13-oxa- 2,17,21,22 , 25-pentaazapentacycle [17,5,2,02,6,07,12,022,26] hexacosa- 1 (25), 7,9,11,19 (26), 20,23-heptaene (Example 24, 4, 0 mg, 0.0109 mmol), followed by DIEA (9.48 μL, 0.0544 mmol). The reaction was stirred at room temperature overnight, concentrated and purified by reverse phase column chromatography eluting with 0-80% acetonitrile / H2O to yield the title compound (2.9 mg, 59.8% yield). MS (apci) m / z = 446.3 (M + H). Example 28
(6R) -N-ethyl-9-fluor-13-oxa-2,17,21,22,25- pentaazapentacycle [17,5,2,02'6,07'12,022'26] hexacosa- l (25) , 7,9,11,19 (26), 20,23-heptaene-17-carboxamide
[000402] To a DCM solution (0.5 mL) of (6R) -9-fluor-13-oxa- 2,17,21,22,25-pentaazapentacycle [17,5,2,02,6,07 , 12,022.26] hexacosa- 1 (25), 7,9,11,19 (26), 20,23-heptaene (Example 24, 4 mg, 0.011 mmol) isocyanatoethane (1.5 mg, 0.022 mmol) was added followed by DIEA (1.9 μL, 0.011 mmol). The reaction was stirred at room temperature overnight, then concentrated and purified by reverse phase column chromatography, eluting with 0-80% acetonitrile / H2O, to yield the title compound (3.5 mg, 73% yield) . MS (apci) m / z = 439.1 (M + H). Example 29
(6R) -N-ethyl-9-fluor-13-oxa-2,16,20,21,24-pentaazapentacyclo- [16,5,2,02'6.07'12,021'25] pentacosa-1 (24), 7,9,11,18 (25), 19,22-heptaene-16-carboxamide
[000403] To a DCM solution (0.5 mL) of (6R) -9-fluor-13-oxa- 2,16,20,21,24-pentaazapentacycle [16,5,2,02,6,07 , 12,021,25] pentacosa- 1 (24), 7,9,11,18 (25), 19,22-heptaene (Example 21, 5.5 mg, 0.016 mmol) isocyanatoethane (1.5 mg, 0.022 mmol), followed by DIEA (1.9 μL, 0.011 mmol). After stirring at room temperature overnight the reaction was concentrated and purified by reverse phase column chromatography, eluting with 0-80% acetonitrile / H2O to yield the title compound (3.3 mg, 50% yield). MS (apci) m / z = 425.4 (M + H). Example 30
(6S) -9-fluor-4,13-dioxa-2,11,17,21,22,25- hexaazapentacycle [17,5,2,02'6,07'12,022'26] hexacosa- 1 (25) , 7 (12), 8,10,19 (26), 20,23-heptaene-3,18-dione
[000404] Step A: Preparation of (S, E) -N - ('2 - (' tert-butyldimethylsilyloxy) ethylidene) -2-methylpropane-2-sulfinamide: To a solution of (S) -2-methylpropane-2 -sulfinimide (3.3 g, 27.2 mmol) in DCM (50 mL) was added 2- (tert-butyldimethylsilyloxy) acetaldehyde (4.98 g, 28.6 mmol) followed by anhydrous copper sulfate (8.69 g, 54.5 mmol). The heterogeneous mixture was stirred at room temperature for 3 days and then filtered through Celite®. The concentrated filtrate and the residue were purified by flash column chromatography, eluting with 10% EtOAc / hexanes, to yield (S, E) -N- (2- (tert-butyldimethylsilyloxy) ethylidene) - 2-methylpropane-2- sulfinamide (5.54 g, 73% yield) as a colorless oil. 1H NMR (CDCl3) δ 7.96 (m, 1H), 4.44 (d, 1H, J = 2.7 Hz), 1.11 (s, 9H), 0.82 (s, 9H), 0 , 00 (s, 6H).
[000405] Step B: Preparation of (S) -N - ('(S) -2 - (' tert-butyldimethylsilyloxy) - 1- (5-fluor-2-methoxypyridin-3-yl) ethyl) -2-methylpropane -2-sulfinamide: To a solution of n-butyl lithium (10.8 mL, 17.3 mmol, 1.6 M in hexanes) in toluene (100 mL) at -78 ° C was added a solution of 3-bromine -5- fluor-2-methoxypyridine (3.27 g, 15.9 mmol) in toluene (5 mL) dropwise, maintaining the internal temperature below -70 ° C. The mixture was stirred at -78 ° C for 1 hour, then treated with a solution of (S, E) -N- (2- (tert-butyldimethylsilyloxy) ethylidene) -2-methylpropane-2-sulfinamide (4.0 g , 14.4 mmol) in toluene (10 mL) dropwise, keeping the internal temperature below -65 ° C. After stirring at -78 ° C for 3 hours the mixture was treated with brine (100 ml) and EtOAc (100 ml) and stirred at room temperature for 20 minutes. The saturated NaHCO3 solution (50 ml) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 ml) and the combined organic phases were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography, eluting with 10% EtOAc / 20% EtOAc / hexanes, to yield (5) -N - ((S) -2- (tert-butyldimethylsilyloxy) -1- (5 -fluor-2-methoxypyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide (1.40 g, 24% yield) mixed with a less polar impurity like a colorless oil. MS (apci) m / z = 405.0 (M + H).
[000406] Step C: Preparation of (S) -2-amino-2- (5-fluor-2-methoxypyridin-3-yl) ethanol dihydrochloride: To a solution of (5) -N - ((5) - 2- (tert-butyldimethylsilyloxy) -1- (5-fluor-2-methoxypyridin-3-yl) ethyl) -2-methylpropane-2-sulfinamide (1.40 g, 3.46 mmol) in methanol (20 mL) 4N HCl / dioxane (8.65 ml, 34.6 mmol) was added. The solution was stirred at room temperature for 16 hours, then concentrated and dried under vacuum to yield (S) -2-amino-2- (5-fluor-2-methoxypyridin-3-yl) ethanol dihydrochloride as a yellow oil that was used without purification, assuming 100% yield. MS (apci) m / z = 186.9 (M + H).
[000407] Step D: Preparation of (S) -4- (5-fluor-2-methoxypyridin-3-yl) oxazolidin-2-one: To a solution of (5) -2-amino-2- ( 5-fluor-2-methoxypyridin-3-yl) ethanol (897 mg, 3.46 mmol) in KOH (10 mL, 24.2 mmol, 2.42 M in water) was added THF (10 mL). The mixture was cooled to 0 ° C and treated with triphosgene (1.03 g, 3.46 mmol). The mixture was allowed to warm to room temperature with stirring for 16 hours then partitioned between EtOAc (50 ml) and water (50 ml), and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 30 ml) and the combined organic phases were washed with brine (20 ml), dried over Na2SO4, filtered and concentrated. The residue was triturated with Et2O, filtered and dried under reduced pressure to yield (S) -4- (5-fluor-2-methoxypyridin-3-yl) oxazolidin-2-one (254 mg, 35% yield) as a White powder. 1H NMR (CDCl3) δ 7.98 (m, 1H), 7.44 (m, 1H), 5.61 (Br S, 1H), 5.13 (m, 1H), 4.83 (m, 1H ), 4.16 (m, 1H), 3.96 (s, 3H).
[000408] Step E: Preparation of (S) -ethyl 5- (4- (5-fluor-2-methoxypyridin-3-yl) -2-oxooxazolidin-3-yl) pyrazol [1,5-a] pyrimidine- 3-carboxylate: To a solution of (5) -4- (5-fluor-2-methoxypyridin-3-yl) oxazolidin-2-one (254 mg, 1.20 mmol) in DMF (10 mL) was added hydride sodium (58 mg, 1.44 mmol, 60% in mineral oil). The mixture was stirred at room temperature for 20 minutes then treated with ethyl 5-chloropyrazole [1,5-a] pyrimidine-3-carboxylate (270 mg, 1.20 mmol) in one portion. The mixture was stirred for 48 hours then treated with saturated NH4Cl solution (30 ml) and extracted with EtOAc (3 x 10 ml). The combined organic phases were washed with water (5 x 10 ml) and brine (10 ml) then dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography, eluting with 20% EtOAc / hexanes to 66% EtOAc / hexanes, to yield (5) -ethyl 5- (4- (5-fluor-2-methoxypyridin-3-yl) - 2-oxooxazolidin-3-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate (311 mg, 65% yield) as a white foam. MS (apci) m / z = 401.9 (M + H).
[000409] Step F: Preparation of (S) -5- (1- (5-fluor-2-methoxypyridin-3-yl) -2-hydroxyethylamino) pyrazol [1,5-a] pyrimidine-3-carboxylic acid: To a solution of (S) -ethyl 5- (4- (5-fluor-2-methoxypyridin-3-yl) - 2-oxooxazolidin-3-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate ( 311 mg, 0.77 mmol) in a 1: 1: 1 mixture of MeOH: THF: H2O (15 mL) was added lithium hydroxide monohydrate (97.6 mg, 2.32 mmol). The mixture was stirred at room temperature for 16 hours and then at 50 ° C for 19 hours, then concentrated to 1/3 volume, diluted with water (30 ml) and acidified to pH 4-5 with 1N HCL. The resulting precipitate was collected by filtration, washed with water and Et2O then dried under reduced pressure to yield (S) -5- (1- (5-fluor-2-methoxypyridin-3-yl) -2-hydroxyethylamino) pyrazole acid [ 1,5-a] pyrimidine-3-carboxylic (121 mg, 45% yield) as a white powder. MS (apci) m / z = 347.9 (M + H).
[000410] Step G: Preparation of (5) -N- (3-chloropropyl) -5- (1- (5-fluor-2-methoxypyridin-3-yl) -2-hydroxyethylamino) pyrazole [1,5-a ] pyrimidine-3-carboxamide: To a suspension of (S) -5- (1- (5-fluor-2-methoxypyridin-3-yl) -2-hydroxyethylamino) pyrazol [1,5-a] pyrimidine-3 - carboxylic (50 mg, 0.14 mmol) in DCM (2 mL) was added HOBt (44 mg, 0.29 mmol) followed by EDCI (83 mg, 0.43 mmol). The heterogeneous mixture was stirred at room temperature for 10 minutes then treated with triethylamine (100 μL, 0.72 mmol) followed by 3-chloro-propylamine hydrochloride (56 mg, 0.43 mmol). The mixture was stirred for 2 hours, then DMF (2 ml) was added and stirring was continued for 48 hours. The mixture was partitioned between saturated NH4Cl solution (20 ml) and EtOAc (20 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 10 ml) and the combined organic phases were washed with water (5 x 10 ml) and brine (10 ml), then dried over Na2SO4, filtered and concentrated to yield (S) -N - (3-chloropropyl) -5- (1- (5-fluor-2-methoxypyridin-3-yl) -2-hydroxyethylamino) pyrazol [1,5-a] pyrimidine-3-carboxamide (60 mg, 99% yield) as a pale yellow foam that was used without further purification. MS (apci) m / z = 423.0 (M + H).
[000411] Step H: Preparation of (S) -N- (3-chloropropyl) -5- (4- (5-fluor-2-methoxypyridin-3-yl) -2-oxooxazolidin-3-yl) pyrazole [1 , 5-a] pyrimidine-3-carboxamide: To a solution of (S) -N- (3-chloropropyl) -5- (1- (5-fluor-2-methoxypyridin-3-yl) -2-hydroxyethylamino) pyrazole [1,5-a] pyrimidine-3-carboxamide (60 mg, 0.14 mmol) in ACN (2 mL) CDI (35 mg, 0.21 mmol) was added. The solution was stirred at room temperature for 16 hours then divided between saturated NH4Cl solution (20 ml) and EtOAc (10 ml) and the separated layers. The aqueous layer was extracted with EtOAc (2 x 10 ml) and the combined organic phases were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluting with 1% MeOH / DCM to yield (S) -N- (3-chloropropyl) -5- (4- (5-fluor-2-methoxypyridin-3-yl) -2 -oxooxazolidin-3-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (37 mg, 58% yield) as a white solid. MS (apci) m / z = 449.0 (M + H).
[000412] Step I: Preparation of (S) -N- (3-chloropropyl) -5- (4- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) -2-oxooxazolidin-3 -yl) pyrazol [1,5-a] pyrimidine-3-carboxamide: A suspension of (S) -N- (3-chloropropyl) -5- (4- (5-fluor-2-methoxypyridin-3-yl) -2-oxooxazolidin-3-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (37 mg, 0.08 mmol) in 4N HCl / dioxane (4 mL) was stirred at 85 ° C for 17 hours and then at room temperature for 48 hours. The resulting solution was concentrated to 1/2 volume, transferred to a sealed tube, treated with 4N HCl / dioxane (2 mL) and stirred at 100 ° C for 2 hours. The heterogeneous mixture was concentrated, dried under reduced pressure and used directly in the next step, assuming 100% yield. MS (apci) m / z = 435.1 (M + H).
[000413] Step J: Preparation of (6S) -9-fluor-4,13-dioxa- 2,11,17,21,22,25-hexaazapentacycle [17,5,2,02'6,07'12,022 ' 26] hexacosa- 1 (25), 7 (12), 8,10,19 (26), 20,23-heptaene-3,18-dione: To a solution of (S) -N- (3-chloropropyl) -5- (4- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) -2-oxooxazolidin-3-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (35 mg , 0.08 mmol) in DMF (3 mL) cesium carbonate (79 mg, 0.24 mmol) was added. The mixture was stirred at 65 ° C for 30 minutes then at room temperature for 48 hours. The mixture was treated with water (30 ml) and extracted with EtOAc (3 x 10 ml). The combined organic phases were washed with water (5 x 10 ml) and brine (10 ml), then dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluting with 2% MeOH / DCM to yield the title compound (13 mg, 41% yield) as an amorphous white solid. MS (apci) m / z = 399.2 (M + H). Example 31
(6S) -9-fluor-4,13-dioxa-2,11,16,20,21,24-hexaazapentacyclo- [16,5,2,02'6,07'12,021'25] pentacosa-1 (24 ), 7 (12), 8,10,18 (25), 19,22-heptaene-3,17-dione
[000414] Step A: Preparation of 5-hydroxypyrazole [1,5- a] pyrimidine-3-carboxylic acid: To a solution of ethyl 5-hydroxypyrazole [1,5- a] pyrimidine-3-carboxylate (Preparation B, Step A; 2.0 g, 9.65 mmol) in a 2: 1 mixture of THF: MeOH, (40 mL) was added lithium hydroxide monohydrate (29 mL, 29.0 mmol, 1.0 M in water ). The solution was stirred at reflux for 16 hours then cooled and concentrated. The residue was dissolved in water (100 ml) and acidified with 6M HCl. The resulting white precipitate was collected by filtration and washed with water and Et2O, then dried under reduced pressure to yield 5-hydroxypyrazole [1,5-a] pyrimidine-3-carboxylic acid (1.18 g, 68% yield) as a white solid. 1H NMR (d6-DMSO) δ 8.50 (d, 2H, J = 7.7 Hz), 8.02 (s, 2H), 6.07 (d, 2H, J = 8.2 Hz).
[000415] Step B: Preparation of 5-chloropyrazole [1,5-a] pyrimidine-3-carbonyl chloride: To a suspension of 5-hydroxypyrazine [1,5-a] pyrimidine-3-carboxylic acid (1,18 g, 6.59 mmol) in DMF (10 mL) at 0 ° C, thionyl chloride (10 mL) was added dropwise over 5 minutes. The mixture was warmed to room temperature, then stirred at 60 ° C for 16 hours. The cooled solution was purged with N2 for 20 minutes, then diluted with 50% EtOAc / hexanes (100 mL) and stirred vigorously for 30 minutes. The organic phase was decanted, treated with Na2CO3 and activated carbon, stirred for 5 minutes then filtered through Celite® and concentrated. The residue was dissolved in toluene (100 ml), treated with activated carbon and filtered through Celite® again. The filtrate was concentrated and dried under reduced pressure to yield 5-chloropyrazol [1,5-a] pyrimidine-3-carbonyl chloride (800 mg, 56% yield) as a creamy colored solid. 1H NMR (CDCl3) δ 8.70 (m, 1H), 8.66 (s, 1H), 7.16 (m, 1H).
[000416] Step C: Preparation of 5-chloro-N- (2-chloroethyl) pyrazol [1,5-alpyrimidine-3-carboxamide: To a suspension of 5-chloropyrazol [1,5-a] pyrimidine-3 -carbonyl (284 mg, 1.31 mmol) in DCM (10 mL) was added DIEA (1.14 mL, 6.57 mmol). The solution was cooled to 0 ° C, then treated with 2-chloroethylamine hydrochloride (183 mg, 1.58 mmol) and stirred for 1 hour. The mixture was partitioned between water (30 ml) and DCM (30 ml) and the layers were separated. The aqueous layer was extracted with DCM (2 x 20 ml) and the combined organic phases were washed with brine (20 ml), dried over Na2SO4, filtered and concentrated to yield 5-chloro-N- (2-chloroethyl) pyrazole [1 , 5-a] pyrimidine-3-carboxamide (290 mg, 85% yield) as a beige solid. MS (apci) m / z = 258.9 (M + H).
[000417] Step D: Preparation of (S) -N- (2-chloroethyl) -5- (4- (5-fluor-2-methoxypyridin-3-yl) -2-oxooxazolidin-3-yl) pyrazole [1 , 5-a] pyrimidine-3-carboxamide: To a solution of (5) -4- (5-fluor-2-methoxypyridin-3-yl) oxazolidin-2-one (prepared according to Example 30; 50 mg , 0.236 mmol) in DMF (1 mL) was added sodium hydride (11 mg, 0.28 mmol, 60% in mineral oil). The mixture was stirred at room temperature for 20 minutes, then treated with 5-chloro-N- (2-chloroethyl) pyrazol [1,5-a] pyrimidine-3-carboxamide (61 mg, 0.236 mmol). The mixture was stirred at 16 hours, and then treated with saturated NH4Cl solution (10 ml) and water (20 ml). The resulting precipitate was collected by filtration, washed with water and Et2O, then dried under reduced pressure to yield (S) -N- (2-chloroethyl) -5- (4- (5-fluor-2-methoxypyridin-3-yl) ) -2-oxooxazolidin-3-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (83 mg, 81% yield) as a beige solid. MS (apci) m / z = 434.9 (M + H).
[000418] Step E: Preparation of (S) -N- (2-chloroethyl) -5- (4- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) -2-oxooxazolidin-3 -yl) pyrazol [1,5-a] pyrimidine-3-carboxamide: A suspension of (S) -N- (2-chloroethyl) -5- (4- (5-fluor-2-methoxypyridin-3-yl) -2-oxooxazolidin-3-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (80 mg, 0.18 mmol) in 5-6N HCl / IPA (2.5 mL) was heated to 90 ° C in a sealed tube for 1.5 hours. The cooled mixture was filtered and the filtrate was concentrated. The residue was concentrated twice from Et2O and dried under reduced pressure to yield (S) -N- (2-chloroethyl) -5- (4- (5-fluor-2-oxo-1,2-dihydropyridin-3 -yl) -2-oxooxazolidin-3-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (63 mg, 82% yield) as a beige solid. MS (apci) m / z = 421.0 (M + H).
[000419] Step F: Preparation of pentacous (6S) -9-fluor-4,13-dioxa- 2,11,16,20,21,24-hexaazapentacycle [16,5,2,02,6,07,12,021,251 - 1 (24), 7 (12), 8,10,18 (25), 19,22-heptaene-3,17-dione: Prepared according to the method of Example 30, Step J, using (5) - N- (2-chloroethyl) -5- (4- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) -2-oxooxazolidin-3-yl) pyrazol [1,5-a] pyrimidine -3-carboxamide in place of (5) -N- (3-chloropropyl) -5- (4- (5-fluor-2-oxo-1,2-dihydropyridin-3-yl) -2-oxooxazolidin-3- il) pyrazol [1,5-a] pyrimidine-3-carboxamide to yield the title compound (14 mg, 24% yield) as a white solid. MS (apci) m / z = 385.1 (M + H). Example 32
(6R) -9-fluor-2,11,16,20,21,24-hexaazapentacycle [16.5.2.02'6.07'12.021'25] - pentacosa-1 (24), 7,9,11,18 (25) , 19,22-heptaen-17-one
[000420] Step A: Preparation of (R) -ethyl 5- (2- (2- (3 - ((tert-butoxycarbonyl) amino) prop-1-in-1-yl) -5-fluorpiridin-3-yl ) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate: (R) -ethyl 5- (2- (2-chloro-5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazole [1,5-a] pyrimidine-3-carboxylate (Example 12, Step C; 153 mg, 0.392 mmol) in DMF (2 mL) tert-butyl prop-2-ynylcarbamate (122 mg, 0.785 mmol) was added, copper (I) iodide (11 mg, 0.0578 mmol), triphenylphosphine (82.4 mg, 0.314 mmol), di-triphenylphosphine palladium (II) chloride (116 mg, 0.165 mmol), and diisopropylamine (99.3 mg, 0.981 mmol). The reaction mixture was sealed and heated to 95 ° C for 8 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with 33% EtOAc / Hexanes to yield the final mixed product. with Ph3P (160 mg, 80.2% yield). MS (apci) m / z = 508.9 (M + H).
[000421] Step B: Preparation of (R) -ethyl 5- (2- (2- (3-aminopropyl) -5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine -3-carboxylate: Ao (R) -ethyl 5- (2- (2- (3- (tert-butoxycarbonylamino) prop-1-ynyl) -5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazole [ 1,5-a] pyrimidine-3-carboxylate (160 mg, 0.315 mmol) in MeOH (10 mL) was added dihydroxipaladium (101 mg, 0.144 mmol). The reaction mixture was stirred under a hydrogen balloon for 6 hours, then filtered through a pad of Celite® and washed with MeOH (30 mL). The filtrate was concentrated and the resulting residue was treated with 4M HCL in dioxane (3 ml). After stirring for 30 minutes, the solution was concentrated to yield the product as an HCl salt (140 mg, 108% yield). MS (apci) m / z = 413.0 (M + H).
[000422] Step C: Preparation of (R) -5- (2- (2- (3-aminopropyl) -5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine -3-carboxylic: (R) -ethyl 5- (2- (2- (3-aminopropyl) -5-fluorpyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine hydrochloride -3-carboxylate (160 mg, 0.356 mmol) in THF / MeOH (2 mL / 1 mL) was added lithium hydroxide (1.1 mL, 2.20 mmol). The reaction mixture was heated to 70 ° C for 5 hours, then concentrated under reduced pressure. Water (10 ml) was added and the mixture washed with Et2O (2 x 5 ml), then neutralized with HCL (1M) at pH = 4. The aqueous solution was extracted with DCM (2 x 10 ml). The organic extract was dried with Na2SO4, filtered and concentrated under reduced pressure to produce the desired crude product (16.0 mg, 11.7% yield). MS (apci) m / z = 385.0 (M + H).
[000423] Step D: Preparation of (6R) -9-fluor-2,11,16,20,21,24-hexaazapentacycle [16,5,2,02'6,07'12,021'25] pentacosa- 1 ( 24), 7,9,11,18 (25), 19,22-heptaen-17-one: To (R) -5- (2- (2- (3- aminopropyl) -5-fluorpiridin-3- acid il) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylic (16 mg, 0.042 mmol) in DMF (5 mL) was added HATU (63 mg, 0.17 mmol) and N-ethyl -N-isopropylpropan-2-amine (22 mg, 0.17 mmol). The reaction mixture was stirred for 3 hours and concentrated under reduced pressure. The crude residue was purified by silica column chromatography using 100% EtOAc to yield the title compound (6.0 mg, 39% yield). MS (apci) m / z = 367.3 (M + H). Example 33
(6R) -9-fluor-15-methyl-2,11,16,20,21,24-hexaazapentacycle [16,5,2,02,6 O7, i2, o21,25] pentacosa-1 (24), 7,9,11,18 (25), 19,22-heptaen-17-one
[000424] Prepared according to the method of Example 37, replacing tert-butyl 2-methylbut-3-in-2-ylcarbamate with tert-butyl but-3-in-2-ylcarbamate in Step B to yield the title compound as a 1: 1 mixture of diastereomers. MS (apci) m / z = 381.2 (M + H). Example 34
(6R, 13R) -9-fluor-13-methyl-2,11,15,19,20,23-hexaazapentacycle [15,5,2,17,11,02,6,020,24] pentacosa- l (23) , 7,9,17 (24), 18,21-hexaene-16,25-dione
[000425] Step A: Preparation of (R) -methyl 5- (2- (5-fluor-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate : To a suspension of (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylic acid (Preparation B ; 5.01 g, 14.0 mmol) in MeOH (150 mL) TMSCHN2 (8.41 mL, 16.8 mmol) was added dropwise. The reaction was stirred for 30 minutes, and then cooled quickly with 1 ml of acetic acid. The solvent was removed under reduced pressure and the residue was dried under high vacuum to produce the methyl ester. To the crude methyl ester was added 4N HCl in dioxane (100 mL) and the reaction was sealed and heated to 90 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM (100 ml) and washed with saturated NaHCO3 (40 ml). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to produce the desired crude product (4.67 g, 93.2% yield). MS (apci) m / z = 357.9 (M + H).
[000426] Step B: Preparation of methyl 5 - ((R) -2- (1 - ((S) -3- (1,3-dioxoisoindolin-2-yl) -2-methylpropyl) -5-fluor-2 -oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate: To a solution of (R) -methyl 5- (2- (5- fluor-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5- a] pyrimidine-3-carboxylate (202 mg, 0.565 mmol) in DMF (5 mL) lithium hydride (22, 5 mg, 2.83 mmol) and (R) -2- (3-bromo-2-methylpropyl) isoindoline-1,3-dione (prepared according to the procedure described in Euro. J. Med. Chem. 2000, 147-156) (239 mg, 0.848 mmol). The reaction was stirred for 2 hours at 70 ° C, and then cooled to room temperature. The reaction mixture was diluted with EtOAc (20 ml) and washed with water (2 x 10 ml). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with 66% EtOAc / Hexanes to yield the product (110 mg, 34.8% yield). MS (apci) m / z = 559.0 (M + H).
[000427] Step C: Preparation of methyl 5 - ((R) -2- (1 - ((R) -3-amino-2-methylpropyl) -5-fluor-2-oxo-1,2-dihydropyridin-3 -yl) pyrrolidin-1-yl) pyrazol [1,5- a] pyrimidine-3-carboxylate: To a solution of methyl 5 - ((R) -2- (l - ((S) -3- (l, 3-dioxoisoindolin-2-yl) -2-methylpropyl) -5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3- carboxylate (110 mg, 0.197 mmol) in MeOH / THF (3 mL / 3 mL) hydrazine (31.6 mg, 0.985 mmol) was added. The reaction was stirred for 14 hours at 50 ° C. After cooling, the reaction mixture was concentrated and the resulting residue was diluted with EtOAc (20 ml) and washed with saturated aqueous NaHCO3 (5 ml), water (2 x 5 ml) and brine (5 ml). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with 10: 1: 0.1 EtOAc / MeOH / H4OH to provide the desired product (65 mg, 77% yield). MS (apci) m / z = 429.2 (M + H).
[000428] Step D: Preparation of (6R, 13R) -9-fluor-13-methyl- 2,11,15,19,20,23-hexaazapentacycle [15,5,2,17'11,02'6,020 ' 24] pentacosa- 1 ('23), 7,9,17 ('24), 18,21-hexaene-16,25-dione: To a solution of methyl 5 - ((R) -2- (1- ( (R) -3-amino-2-methylpropyl) -5-fluor-2-oxo-1,2-dihydropyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate (65 mg, 0.15 mmol) in THF / MeOH (6 mL / 2 mL) lithium hydroxide (455 μL, 0.91 mmol) was added. The reaction was stirred at 70 ° C for 3 hours, then cooled quickly with hydrogen chloride (910 μL, 0.91 mmol). The solvent was removed under reduced pressure and the residue was dried under a high vacuum. To the resulting crude residue was added DMF (10 ml), HATU (115 mg, 0.30 mmol) and N-ethyl-N-isopropylpropan-2-amine (78 mg, 0.61 mmol). The reaction was stirred for 3 hours, and the solvent was removed under reduced pressure. The residue was purified by silica column chromatography, eluting with 10% MeOH / EtOAc to yield the title compound (6.0 mg, 10% yield). MS (apci) m / z = 397.3 (M + H). Example 35
(6R, 13S) -9-fluor-13-methyl-2,11,15,19,20,23-hexaazapentacyclo [15,5,2,17,11,02'6 020,24] pentacosa- 1 (23 ), 7,9,17 (24), 18,21-hexaene-16,25-dione
[000429] Prepared according to the method of Example 34, substituting (5) -2- (3-bromo-2-methylpropyl) isoindoline-1,3-dione (prepared according to the procedure described in Euro. J. Med Chem. 2000, 147-156) for (R) -2- (3-bromo-2-methylpropyl) isoindoline-1,3-dione in Step B. MS (apci) m / z = 397.3 (M + H). Example 36
(6R) -9-fluor-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17,5,2,02'6,07'12,022'26] hexacous -1 (25), 7,9,11,19 (26), 20,23-heptaen-18-one
[000430] Prepared according to the procedure for Example 3, replacing 3-amino-2,2-dimethylpropan-1-ol with 3-aminopropan-1-ol in Step A. MS (apci) m / z = 41 1, 2 (M + H). Example 37
(6R) -9-fluor-15,15-dimethyl-2,11,16,20,21,24-hexaazapentacycle [16,5,2,02'6,07'12,021'25] pentacosa- 1 (24) , 7,9,11,18 (25), 19,22-heptaen-17-one
[000431] Step A: Preparation of (R) -methyl 5- (2- (5-fluor-2- (trifluormethyl-sulfonyloxy) pyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a1 pyrimidine - 3-carboxylate: To a solution of (R) -methyl 5- (2- (5-fluor-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3- carboxylate (Prepared according to Example 34, Step A; 2.31 g, 6.46 mmol) in DMF (20 mL) 1.1.1-trifluor-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide ( 2.54 g, 7.11 mmol) and triethylamine (0.785 g, 7.76 mmol). The reaction was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 33% EtOAc / Hexanes to produce the desired product (2.36 g, 74.6% yield). MS (apci) m / z = 490.0 (M + H).
[000432] Step B: Preparation of (R) -methyl 5- (2- (2- (3- (tert-butoxycarbonylamino) -3-methylbutyl) -5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazole [1,5-a] pyrimidine-3-carboxylate: Ao (R) -methyl 5- (2- (5-fluor-2- (trifluormethylsulfonyloxy) pyridin-3-yl) pyrrolidin-1-yl) pyrazole [1, 5-a] pyrimidine-3-carboxylate (503 mg, 1.03 mmol) in DMF (2 mL) was added tert-butyl 2-methylbut-3-in-2-ylcarbamate (377 mg, 2.06 mmol), copper (I) iodide (39.1 mg, 0.206 mmol), di-triphenylphosphine palladium (II) chloride (144 mg, 0.206 mmol), diisopropylamine (260 mg, 2.57 mmol). The reaction mixture was sealed and heated to 65 ° C for 8 hours. The solvent was removed under reduced pressure. The residue was purified by silica column chromatography, eluting with 66% EtOAc / Hexanes to yield (R) -methyl 5- (2- (2- (3- (tert-butoxycarbonylamino) -3-methylbut-1-inyl) -5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate mixed with Ph3P, which was immediately hydrogenated using dihydroxipaladium on carbon (200 mg, 0.285 mmol) in MeOH ( 20 mL) under an H2 flask for 15 hours. After filtering through a Celite® pad and washing with MeOH, the filtrate was concentrated under reduced pressure and purified by silica column chromatography, eluting with 66% EtOAc / Hexanes to yield the product (166 mg, 30.7% Yield). MS (apci) m / z = 527.1 (M + H).
[000433] Step C: Preparation of (6R) -9-fluor-15,15-dimethyl- 2,11,16,20,21,24-hexaazapentacycle [16,5,2,02,6,07,12,021, 25] pentacosa- 1 (24), 7,9,11,18 (25), 19,22-heptaen-17-one: Ao (R) -methyl 5- (2- (2- (3- (tert- butoxycarbonylamino) -3-methylbutyl) -5-fluorpiridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate (166 mg, 0.315 mmol) in THF / MeOH (3 mL / 1 mL) lithium hydroxide (946 μL, 1.89 mmol) was added. The reaction vessel was sealed and heated to 70 ° C for 3 hours. The reaction mixture was then dried under reduced pressure and HCl (4 ml, 4M in dioxane) was added. The reaction mixture was stirred for one hour, then the solvent was removed and the residue was dried under high vacuum for two hours. To the residue, DMF (8 mL), HOBT-H2O (96.5 mg, 0.630 mmol), EDCI (121 mg, 0.630 mmol) and triethylamine (159 mg, 1.58 mmol) were then added. The reaction mixture was stirred at 45 ° C for 18 hours, then concentrated in vacuo. The residue was purified by silica column chromatography eluting with 5% MeOH / DCM to yield the title compound (60.0 mg, 48.3% yield). MS (apci) m / z = 395.1 (M + H). Example 38
(6R) -9-fluor-13-oxa-2,11,16,17,21,25,26,29-octaazahexacycle [21,5,2,02'6,07'12,016'20,026'30] triathlon- 1 (29), 7,9,11,17,19,23 (30), 24,27- nonaen-22-one
[000434] Step A: Preparation of 1- (2- (tert-butyldiphenylsilyloxy) ethyl) -1H-pyrazol-5-amine: To a suspension of 2- (5-amino-1H-pyrazol-1-yl) ethanol ( 2.07 g, 16.0 mmol) and 1H-imidazole (5.43 g, 79.8 mmol) in DMF (10 mL) was added dropwise tert-butylchlorodiphenylsilane (4.96 mL, 19.1 mmol) . The reaction was stirred for 15 hours. The solvent was removed under reduced pressure and the residue was diluted with DCM (40 ml). The organic layer was washed with 1N HCl (10 ml), water (10 ml) and brine (10 ml), then concentrated to produce the desired crude product (5.62 g, 96.4% yield), which was used in the next step without purification.
[000435] Step B: Preparation of (R) -N- (1- (2- (tert-butyldiphenylsilyloxy) ethyl) -1H-pyrazol-5-yl) -5- (2- (5-fluor-2-methoxypyridine) -3- yl) pyrrolidin-1-yl) pyrazol [1,5-alpirimidine-3-carboxamide: To a suspension of (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) acid pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylic (220 mg, 0.616 mmol) in DMF (5 mL) was added dropwise 2,4,6-trichlorobenzoyl chloride (106 μL, 0.677 mmol) and triethylamine (81.0 mg, 0.800 mmol). The reaction was stirred for 2 hours, and 1- (2- (tert-butyldiphenylsilyloxy) ethyl) -1H-pyrazol-5-amine (338 mg, 0.923 mmol) was added to the reaction mixture. The reaction was heated to 60 ° C for 3 hours and then cooled to room temperature. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography to produce the desired product (201 mg, 46.3% yield). MS (apci) m / z = 705.1 (M + H).
[000436] Step C: Preparation of (6R) -9-fluor-13-oxa- 2,11,16,17,21,25,26,29- octaazahexacycle [21,5,2,02'6,07 '12,016'20,026'30] triaconta- 1 ('29), 7,9,11,17,19,23 (30), 24,27-nonaen-22-one: A suspension of (R) -N- (1 - (2- (tert-butyldiphenylsilyloxy) ethyl) -1H-pyrazol-5-yl) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazole [1,5 -a] pyrimidine-3-carboxamide (201 mg, 0.285 mmol) in 4M HCl in dioxane (6 mL) was sealed and heated to 100 ° C for four hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (20 ml) and washed with saturated NaHCO3 (5 ml), water (5 ml) and brine (5 ml). The organic layer was concentrated to produce (R) -5- (2- (5-fluor-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) -N- (1- (2-hydroxyethyl) -1H- pyrazol-5-yl) pyrazol [1,5- a] pyrimidine-3-carboxamide, to which was added THF (20 mL), DEAD (53.9 μL, 0.342 mmol) and triphenylphosphine (89.8 mg, 0.342 mmol). The reaction mixture was stirred for 18 hours, then concentrated in vacuo. The residue was purified by silica column chromatography, eluting with 10% MeOH / DCM to yield the title compound (1.8 mg, 1.5% yield). MS (apci) m / z = 435.3 (M + H). Example 39
(6R) -9-fluor-13-oxa-2,11,19,21,25,26,29- heptaazahexacyclo [21,5,2,02'6,07'12,015'20,026'30] triaconta- 1 ( '29), 7,9,11,15 ('20), 16,18,23 (30), 24,27-decaen-22-one
[000437] Step A: Preparation of 3 - ((tert-butyldiphenylsilyloxy) methyl) pyridin-2-amine: To a suspension of (2-aminopyridin-3-yl) methanol (2.19 g, 17.6 mmol) and 1H-imidazole (6.00 g, 88.2 mmol) in DMF (10 mL) was added dropwise with tert-butylchlorodiphenylsilane (5.49 mL, 21.2 mmol). The reaction was stirred for 15 hours. The solvent was removed under reduced pressure and the residue was diluted with DCM (40 ml). The organic layer was washed with 1N HCl (10 ml), water (10 ml) and brine (10 ml) and then concentrated to produce the crude product (6.03 g, 94.3% yield). MS (apci) m / z = 363.1 (M + H).
[000438] Step B: Preparation of (6R) -9-fluor-13-oxa- 2,11,19,21,25,26,29- heptaazahexacycle [21,5,2,02'6,07'12,015 '20,026'30] triaconta- 1 ('29), 7,9,11,15 ('20), 16,18,23 (30), 24,27-decaen-22-one: To an acid suspension (R ) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylic (303 mg, 0.848 mmol) in DMF (5 ml) was added triethylamine (103 mg, 1.02 mmol), followed by the dropwise addition of 2,4,6-trichlorobenzoyl chloride (227 mg, 0.933 mmol). The reaction was stirred for two hours. 3 - ((tert-butyldiphenylsilyloxy) methyl) pyridin-2-amine (369 mg, 1.02 mmol) was added and the reaction mixture was heated to 60 ° C for 5 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 10% MeOH / DCM to produce (R) -N- (3 - ((tert-butyldiphenylsilyloxy) methyl) pyridin-2- il) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5- a] pyrimidine-3-carboxamide, to which THF (5 ml) was added and TBAF (848 μL, 0.848 mmol). The reaction mixture was stirred for one hour, then quenched with saturated NH4Cl (1 mL) and then concentrated under reduced pressure to produce (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) ) pyrrolidin-1-yl) -N- (3- (hydroxymethyl) pyridin-2-yl) pyrazol [1,5- a] pyrimidine-3-carboxamide, to which was added HCl (4M in dioxane, 5 ml) . The reaction mixture was sealed and heated to 100 ° C for four hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (20 ml) and the organic layer was washed with saturated NaHCO3 (5 ml), water (5 ml) and brine (5 ml). The organic layer was concentrated under reduced pressure to produce (R) -N- (3- (chloromethyl) pyridin-2-yl) -5- (2- (5-fluor-2-hydroxypyridin-3-yl) pyrrolidin- 1-yl) pyrazol [1,5-a] crude pyrimidine-3-carboxamide, to which was added DMF (10 mL) and Cs2CO3 (276 mg, 0.848 mmol). The reaction mixture was heated to 60 ° C for 4 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with 10% MeOH / DCM to yield the title compound (8.0 mg, 2.2% yield). MS (apci) m / z = 432.3 (M + H). Example 40
(6R) -9-fluor-13,13-dimethyl-2,11,15,19,20,23-hexaazapentacycle [15,5,2,17,11,02,6,020'24] pentacosa- 1 ('23 ), 7,9,17 ('24), 18,21-hexaene-16,25-dione
[000439] Step A: Preparation of 3-bromo-2,2-dimethylpropan-1-amine hydrobromide: A mixture of 2- (3-bromo-2,2-dimethylpropyl) isoindoline-1,3-dione (1, 00 g, 3.38 mmol) in 48% aqueous HBr (10 mL) was refluxed for 18 hours. The reaction mixture was cooled to room temperature and the solids formed were filtered. The filtrate was concentrated under reduced pressure to produce the crude material which was azeotroped with toluene (3x) followed by acetonitrile until the solids were formed. The crude material was triturated with ether and dried under reduced pressure to yield 3-bromo-2,2-dimethylpropan-1-amine hydrobromide (0.816 g, 3.07 mmol, 91.0% yield) (confirmed by 1H- NMR and posAPCI-MS). The isolated product was used directly without further purification.
[000440] Step B: Preparation of (R) -N- (3-bromo-2,2-dimethylpropyl) -5- (2- (5-fluor-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide: To a solution of (R) -5- (2- (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazole [1 , 5-a] pyrimidine-3-carboxylic (Preparation B; 150 mg, 0.420 mmol), EDCI (88.5 mg, 0.462 mmol), and HOBT-H2O (70.7 mg, 0.462 mmol) in DMF (10 mL ) 3-bromo-2,2-dimethylpropan-1-amine hydrobromide (124 mg, 0.50 mmol) was added followed by triethylamine (55.2 mg, 0.546 mmol). The reaction was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 50% EtOAc / Hexanes to provide (R) -N- (3-bromo-2,2-dimethylpropyl) -5- (2 - (5-fluor-2-methoxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (180 mg), to which was added HCl (5 mL, 4M in dioxane ). The reaction was sealed and heated to 90 ° C for 2 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 20% Hexanes / EtOAc to provide the desired product (130 mg, 63% yield).
[000441] Step C: Preparation of (6R) -9-fluor-13,13-dimethyl- 2,11,15,19,20,23-hexaazapentacycle [15.5.2.17,11.02'6.020'24] pentacosa- 1 ( 23), 7,9,17 (24), 18,21-hexaene-16,25-dione: To a solution of (R) -N- (3-bromo-2,2-dimethylpropyl) -5- (2 - (5-fluor-2-hydroxypyridin-3-yl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (30 mg, 0.061 mmol) in THF (5 mL) was added dropwise drop 2-methylpropan-2-potassium olate (153 μL, 0.15 mmol). The reaction was heated to 50 ° C for two hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography, eluting with 10% MeOH / DCM to provide the title compound (15 mg, 60% yield). MS (apci) m / z = 411.0 (M + H). Example 41
(4R, 6R, 15S) -9-fluor-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacycle [17.5.2.02'6.07'12.022'26] hexacosa- 1 (25) , 7 (12), 8,10,19 (26), 20,23-heptaen-18-one
[000442] Step A: Preparation of N - ((S) -3-chloro-2-hydroxypropyl-5 - ((R) - 2- (5-fluor-2-hydroxyphenyl-4-hydroxypyrrolidin-1-yl) pyrazole [1,5-a] pyrimidine-3-carboxamide: To a suspension of (R) -5- (2- (5-fluor-2-hydroxyphenyl) -4-hydroxypyrrolidin-1-yl) pyrazole acid [1,5 -a] pyrimidine-3-carboxylic (Preparation D; 0.0339 g, 0.0946 mmol) and HATU (0.0540 g, 0.142 mmol) in DMF (0.5 mL) at 0 ° C ( S) -1-amino-3-chloropropan-2-ol (Example 19, Step A; 0.0155 g, 0.142 mmol; prepared according to the method described in Org. Process Res. Dev. 2003, vol. 7, p. 533) and N, N-diisopropylethylamine (0.0494 mL, 0.284 mmol). The resulting mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with brine , dried over MgSO4, filtered and concentrated under reduced pressure to produce the crude material which was purified by silica column chromatography, eluting with 0-20% MeOH / DCM to yield N - ((5) -3-chloro-2- hydroxypropyl) - 5 - ((R) -2- (5-fluor-2-hydroxyphenyl) -4-hydroxypyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (as a mixture of cis and trans isomers, 0.0407 g, 82.2% yield, 86% purity). LC / MS (ES + APCI) m / z = 448.1 (M-H).
[000443] Step B: Preparation of (4R, 6R, 15S) -9-fluor-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacycle [17.5.2.02'6.07'12.022 ' 26] hexacosa- 1 ('25), 7 (12), 8,10,19 ('26), 20,23-heptaen-18-one: A mixture of N - ((S) - 3-chloro-2 -hydroxypropyl) -5 - ((R) -2- (5-fluor-2-hydroxyphenyl) -4-hydroxypyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (0.0407 g, 0.0778 mmol) and Cs2CO3 (0.127 g, 0.389 mmol) in DMF (3.6 mL) was heated to 85 ° C for 30 minutes. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to produce the crude material which was purified by silica column chromatography, eluting with 0-20% MeOH / EtOAc to produce the crude product. The crude material was purified using chiral column chromatography (Chiral Tech OD-H column, 20% EtOH in hexanes). Isolation of the material having a retention time of about 21.8 minutes yielded the title compound (0.0052 g, 16.2% yield). The stoichiometry of the title compound was confirmed by 1H-NMR in the experiment. LC / MS (ES + APCI) m / z = 414.1 (M + H). Example 41-B
(4R, 6S, 15S) -9-fluor-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacycle [17,5,02'6,07'12,022'26] hexacosa- 1 (25), 7 (12), 8,10,19 (26 '), 20,23-heptaen-18-one
[000444] The title compound was isolated during the chiral separation reported in Example 41 from fractions having a retention time of about 30.6 minutes, to provide 5.4 mg (16.8% yield) of the compound which may have been isolated together with the enantiomer and / or one or more diastereomers. The stoichiometry of the title compound was confirmed by 1H-NMR in the experiment), LC / MS (ES + APCI) m / z = 414.1 (M + H). Example 42
(4R, 6R) -9-fluor-4-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo- [17.5.2.02'6.07'12.022'26] hexacosa-1 (25), 7 ( 12), 8,10,19 (26), 20,23- heptaen- 18-one
[000445] The title compound was prepared according to the method of Example 41, replacing 3-chloropropan-1-amine hydrochloride with (S) -1-amino-3-chloropropan-2-ol hydrochloride in Step A: 13.8 mg (16% yield; Chiral Tech OD-H column, 20% EtOH in hexanes, retention time about 17.2 minutes). The stoichiometry of the title compound was confirmed by 1H-NMR in the experiment. LC / MS (ES + APCI) m / z = 398.1 (M + H). Example 42-B
(4R, 6S) -9-fluor-4-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacycle [17.5.2.02,6.07,12.022,26] hexacosa-1 (25), 7 (12 ), 8,10,19 (26), 20,23- heptaen-18-one
[000446] The title compound was prepared during the chiral separation reported in Example 42 by isolating the fractions having a retention time of about 26.2 minutes (21.1 mg, 24.5% yield) which may have been isolated together with the enantiomer and / or one or more diastereomers. The stoichiometry of the title compound was confirmed by 1H-NMR in the experiment. LC / MS (ES + APCI) m / z = 398.1 (M + H). Example 43
(4R, 6R) -9-fluor-4-hydroxy-13-oxa-2,16,20,21,24-pentaazapentacyclo- [16.5.2.02,6.07,12.021,25] pentacosa-1 (24), 7, 9,11,18 (25), 19,22-heptaen- 17-one
[000447] The title compound was prepared according to the method of Example 41, replacing 2-chloroethylamine hydrochloride with (S) -1-amino-3-chloropropan-2-ol hydrochloride in Step A. The title compound was purified using a Chiral Tech OJ-H column, 20% EtOH in hexanes, by isolating the fractions having a retention time of about 15.7 minutes (10.7 mg, 14.2% yield). The stoichiometry of the title compound was confirmed by 1H-NMR in the experiment. LC / MS (ES + APCI) m / z = 384.1 (M + H). Example 43-B
(4R, 6S) -9-fluor-4-hydroxy-13-oxa-2,16,20,21,24-pentaazapentacyclo- [16.5.2.02'6.07'12.021'25] pentacosa-1 (24) 7,9 , 11,18 (25), 19,22-heptaen-17-one
[000448] The title compound was isolated during the chiral separation reported in Example 43 by isolating the fractions having a retention time of about 21.3 minutes (15.9 mg, 21.1% yield) which may have been isolated together with the enantiomer and / or one or more diastereomers. The stoichiometry of the title compound was confirmed by 1H-NMR in the experiment), LC / MS (ES + APCI) m / z = 384.1 (M + H). Example 44
(4R, 6R, 15R) -9-fluor-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacyclo- [17.5.02'6.07'12.022'26] hexacosa- 1 (25 ), 7 (12), 8,10,19 (26 '), 20,23-heptaen-18-one
[000449] The title compound was prepared according to the method of Example 41, replacing (R) -1-amino-3-chloropropan-2-ol hydrochloride (prepared according to the procedure described in Example 19, Step A using (R) -2- (chloromethyl) oxirane) by (S) -1-amino-3-chloropropan-2-ol hydrochloride in Step A. The crude material was purified on a silica gel column, eluting with CH2Cl2 for NH4OH: MeOH: CH2Cl2 (0.5: 5: 95) (4 runs). Fractions containing the compound from the previous elution were collected to provide 12 mg (10.9% yield) of the desired material. The stoichiometry of the title compound was confirmed by 1H-NMR in the experiment. LC / MS (ES + APCI) m / z = 414.0 (M + H). Example 44-B
(4R, 6S, 15R) -9-fluor-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacycle [17.5.02'6 07'12 022'26] hexacosa- 1 ( 25), 7 (12), 8,10,19 (26 '), 20,23-heptaen-18-one
[000450] The title compound was isolated during the purification reported in Example 44. Fractions containing the last eluting compound were collected to provide 15 mg (13.6% yield) of the title compound, which may have been isolated together with the enantiomer and / or one or more diastereomers. The stoichiometry of the title compound was confirmed by 1H-NMR in the experiment); LC / MS (ES + APCI) m / z = 414.1 (M + H). Example 45
Diastereomer 1 and Diastereomer 2 of (15S) -4,4,9-trifluor-15-hydroxy-13-oxa-2,17,21,22,25- pentaazapentacycle [17.5.2.02'6 07'12 022'26] hexacosa- 1 (25), 7 (12), 8,10,19 (26), 20,23-heptaen-18-one
[000451] Step A: Preparation of (R) -5- (5-fluor-2-methoxyphenyl) pyrrolidin-3-ol hydrochloride: (R) -tert-butyl 4- (tert-butyldimethylsilyloxy) -2 solution - (5-fluor-2-methoxyphenyl) pyrrolidine-1-carboxylate (1.01 g, 2.37 mmol) in CH2Cl2 (10 mL) at 0 ° C was added 4 M HCL in dioxane (5.93 mL, 23 , 7 mmol). The resulting mixture was warmed to room temperature and stirred for 8 hours. The reaction mixture was concentrated under reduced pressure to produce the crude material which was triturated with ether. The resulting solids were filtered and dried under reduced pressure to yield (R) -5- (5-fluor-2-methoxyphenyl) pyrrolidin-3-ol hydrochloride (0.577 g, 2.33 mmol, 98.2% yield) . MS (APCI) m / z = 212.0 (M + H).
[000452] Step B: Preparation of (R) -ethyl 5- (2- (5-fluor-2-methoxyphenyl) - 4-hydroxypyrrolidin-1-yl pyrazol [1,5-a] pyrimidine-3-carboxylate: A a suspension of ethyl 5-hydroxypyrazole [1,5-a] pyrimidine-3-carboxylate (0.541 g, 2.61 mmol) and BOP reagent (1.57 g, 3.56 mmol) in DMF / CH2Cl2 (3 mL / 3 mL) at 0 ° C (R) -5- (5-fluor-2-methoxyphenyl) pyrrolidin-3-ol hydrochloride (0.588 g, 2.37 mmol) was added followed by DIEA (1.66 mL, 9.50 mmol). The resulting mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to produce the crude material which was diluted again with EtOAc (30 mL). The organic layer was washed with aqueous saturated NaHC03 followed by brine, dried over MgSO4, filtered and concentrated under reduced pressure to produce the crude material which was purified by silica gel chromatography on a fast column, eluting with CH2Cl2 to 5% MeOH in CH2Cl2 to yield (R) - ethyl 5- (2- (5-fluor-2-methoxyphenyl) -4-hydroxypyrrolidi n-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate (0.735 g, 1.84 mmol, 77.3% yield). LC / MS (ES + APCI) m / z = 401.1 (M + H).
[000453] Step C: Preparation of ethyl 5- (2- (5-fluor-2-methoxyphenyl) -4-oxopyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate: To a suspension of Dess-Martin periodinane (0.233 g, 0.549 mmol) in CH2Cl2 (2.2 mL) at 0 ° C a solution of (R) -ethyl 5- (2- (5-fluor-2-methoxyphenyl) -4 was added -hydroxypyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate (0.200 g, 0.499 mmol) in CH2Cl2 (1.5 mL). The resulting mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was cooled to 0 ° C and quenched with saturated aqueous NaHCO3 (5 mL) containing Na2S2O3 (0.608 g, 3.85 mmol). The resulting mixture was warmed to room temperature and stirred for 10 minutes. The organic layer was separated, washed with saturated aqueous NaHCO3 (10 ml) followed by brine (10 ml), dried over MgSO4, filtered and concentrated under reduced pressure to yield ethyl 5- (2- (5-fluor-2-methoxyphenyl) -4-oxopyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate (0.164 g, 82.4% yield). LC / MS (ES + APCI) m / z = 399.1 (M + H).
[000454] Step D: Preparation of ethyl 5- (4,4-difluor-2- (5-fluor-2-methoxyphenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate: A a solution of ethyl 5- (2- (5-fluor-2-methoxyphenyl) -4-oxopyrrolidin-1-yl) pyrazol [1,5- a] pyrimidine-3-carboxylate (0.162 g, 0.407 mmol) in CH2Cl2 ( 3 ml) a solution of bis (2-methoxyethyl) amino sulfur trifluoride (0.134 ml, 0.691 mmol) followed by EtOH (0.00475 ml, 0.0813 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into saturated aqueous NaHCO3 (6 ml) and extracted with CH2Cl2 (2 x 10 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to produce the crude material which was purified by silica column chromatography, eluting with 0-50% EtOAc / Hexanes to yield ethyl 5- (4,4-difluor -2- (5-fluor-2-methoxyphenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate (0.126 g, 65.6% yield). MS (APCI) m / z = 420.9 (M + H).
[000455] Step E: Preparation of 5- (4,4-difluor-2- (5-fluor-2-hydroxyphenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylic acid: A a solution of ethyl 5- (4,4-difluor-2- (5-fluor-2-methoxyphenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxylate (0.126 g, 0.267 mmol) in CH2Cl2 (1.3 ml) at 0 ° C 1 M BBr3 in CH2Cl2 (1.50 ml, 1.50 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was diluted with CH2Cl2 (5 ml) and poured into a mixture of ice and saturated aqueous NaHCO3 (3 ml). The aqueous layer was then acidified to about pH 3 with 1N aqueous HCl. The aqueous layer was extracted with CH2Cl2 (3 x 10 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to produce a mixture of ethyl 5- (4,4-difluor-2- (5-fluor-2-hydroxyphenyl) pyrrolidin-1-yl) pyrazole [1 , 5-a] pyrimidine-3-carboxylate and 5- (4,4-difluor-2- (5-fluor-2-hydroxyphenyl) pyrrolidin-1-yl) pyrazol [1,5- a] pyrimidine-3- carboxylic. This mixture was taken up in MeOH-THF (0.25 ml / 0.75 ml) at room temperature, and 2 N aqueous LiOH (0.667 ml, 1.33 mmol) was added. The resulting mixture was heated to 50 ° C for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove organic solvents. The residue was diluted with 5 ml of EtOAc and acidified to pH 3 to 4 with 6 N aqueous HCl with stirring. The organic layer was separated and the acidic aqueous layer was extracted with EtOAc (2 x 5 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield 5- (4,4-difluor-2- (5-fluor-2-hydroxyphenyl) pyrrolidin-1-yl) pyrazole [1,5- a] pyrimidine-3-carboxylic (0.094 g, 93.1% yield). MS (APCI) m / z = 378.9 (M + H).
[000456] Step F: Preparation of N - ((S) -3-chloro-2-hydroxypropyl) -5- (4,4-difluor-2- (5-fluor-2-hydroxyphenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide: To a mixture of 5- (4,4-difluor-2- (5-fluor-2-hydroxyphenyl) pyrrolidin-1-yl) pyrazole [1,5 -a] pyrimidine-3-carboxylic (0.047 g, 0.124 mmol) and HOBT (0.0252 g, 0.186 mmol) in DMF (1 mL) at room temperature EDCI (0.0357 g, 0.186 mmol) was added. The resulting mixture was stirred for 1 hour. To this mixture (S) -1-amino-3-chloropropan-2-ol hydrochloride (Example 19, Step A; 0.0218 g, 0.149 mmol) was added followed by DIEA (0.0656 mL, 0.373 mmol) at room temperature. The resulting mixture was stirred for 48 hours. The reaction mixture was diluted with EtOAc (10 ml), and the organic layer was washed with a 1: 1 mixture of brine and water. The aqueous layer was separated and extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with a 1: 1 mixture of brine and water (15 ml) and combined with the previously obtained organic layer. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to yield N - ((S) -3-chloro-2-hydroxypropyl) -5- (4,4-difluor-2- (5-fluor-2- hydroxyphenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (0.061 g, 105% yield). LC / MS (ES + APCI) m / z = 468.1 (M-H).
[000457] Step G: Preparation of Diastereomers 1 and 2 of (15S) - 4,4,9-trifluor-15-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacycle [17,5,2 , 02'6,07'12,022'26] hexacosa- 1 (25), 7 (12), 8,10,19 (26), 20,23-heptaen-18-one: A mixture of N - ((S ) - 3-chloro-2-hydroxypropyl) -5- (4,4-difluor-2- (5-fluor-2-hydroxyphenyl) pyrrolidin-1-yl) pyrazol [1,5-a] pyrimidine-3-carboxamide (0.060 g, 0.128 mmol) and Cs2CO3 (0.208 g, 0.639 mmol) in DMF (6.4 mL) was heated to 85 ° C for 30 minutes. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to produce the crude material which was purified by silica gel flash column chromatography (CH2Cl2 to NH4OH: MeOH: CH2Cl2 = 0.5: 5: 95) to yield a mixture of the diastereomers. The isolated diastereomers were further purified by chiral column chromatography (Chiral Tech OD-H column, 20% EtOH in hexanes). Fractions having a retention time of about 17.1 minutes were isolated to yield the title compound designated as diastereomer 1 (11 mg, 20% yield .; MS (APCI) m / z = 434.2 (M + H) Fractions having a retention time of about 21.0 minutes were isolated to provide the title compound designated as Diastereomer 2 (13 mg; 24% yield); MS (APCI) m / z = 434.2 (M + H).

权利要求:
Claims (36)
[0001]
1. Compound, characterized by the fact that it presents the general Formula I
[0002]
2. Compound according to claim 1, characterized by the fact that ring A is an A-1 ring having the structure
[0003]
3. Compound according to claim 2, characterized by the fact that X is CH.
[0004]
4. Compound according to claim 2, characterized by the fact that X is N.
[0005]
5. Compound according to claim 1, characterized by the fact that ring A is ring A-3 having the structure
[0006]
A compound according to any one of claims 1 to 5, characterized by the fact that W is O.
[0007]
Compound according to any one of claims 1 to 5, characterized by the fact that W is NH.
[0008]
A compound according to any one of claims 1 to 5, characterized by the fact that W is CH.
[0009]
9. Compound according to claim 1, characterized by the fact that ring A is an A-2 ring having the structure
[0010]
10. A compound according to any one of claims 1 to 9, characterized by the fact that Y is F.
[0011]
A compound according to any one of claims 1 to 9, characterized by the fact that Y is H.
[0012]
12. A compound according to any one of claims 1 to 11, characterized in that R1 is H.
[0013]
13. A compound according to any one of claims 1 to 12, characterized in that Z is * -NR4aC (= O) -.
[0014]
14. A compound according to claim 13, characterized by the fact that R4a is hydrogen.
[0015]
Compound according to any one of claims 1 to 12, characterized in that Z is * -ONHC (= O) -.
[0016]
16. A compound according to any one of claims 1 to 12, characterized in that Z is * -NR4bCH2-.
[0017]
17. Compound according to claim 16, characterized by the fact that R4b is H.
[0018]
18. A compound according to any one of claims 1 to 17, characterized by the fact that D is carbon, R2 and R2a are independently H, F, (1-3C) alkyl or OH (provided that R2 and R2a are not both OH), and R3 and R3a are, independently, H, (1-3 C) alkyl or hydroxy (1-3 C) alkyl.
[0019]
19. A compound according to any one of claims 1 to 18, characterized in that R2 and R2a are each hydrogen.
[0020]
20. A compound according to any one of claims 1 to 18, characterized in that: R3 and R3a are H, or R3a is methyl and R3 is H; or R3a and R3a are both methyl.
[0021]
21. A compound according to any one of claims 1 to 20, characterized by the fact that ring B is a ring B-1:
[0022]
22. A compound according to claim 21, characterized by the fact that R5 is hydrogen and R6 is H, F, OH, methyl, ethyl, or HOCH2-HOCH2CH2-.
[0023]
23. Compound according to claim 22, characterized by the fact that R6 is H.
[0024]
24. A compound according to claims 1 to 20, characterized by the fact that ring B is a ring B-2:
[0025]
25. A compound according to any one of claims 1 to 24, characterized in that m is 0.
[0026]
26. A compound according to any one of claims 1 to 24, characterized in that m is 1.
[0027]
27. A compound according to any one of claims 1 to 24, characterized in that m is 2.
[0028]
28. A compound according to any one of claims 1 to 27, characterized by the fact that it has the absolute configuration of Figure 1-a:
[0029]
29. Compound according to any one of claims 1 to 27, characterized by the fact that it has the absolute configuration of Figure 1-b
[0030]
30. Pharmaceutical composition, characterized in that it comprises a compound of Formula I as defined in any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
[0031]
31. Use of a compound of Formula I or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 29, characterized in that it is for the preparation of a pharmaceutical composition to treat a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease or infection by Trypanosoma cruzi, in a mammal.
[0032]
32. Use, according to claim 31, characterized by the fact that the disease or disorder is pain selected from chronic pain, acute pain, inflammatory pain, neuropathic pain, pain associated with cancer, pain associated with surgery and pain associated with fracture of bones.
[0033]
33. Use according to claim 31, characterized by the fact that the disease or disorder is a cancer selected from neuroblastoma, ovarian cancer, pancreatic cancer, colorectal cancer and prostate cancer.
[0034]
34. Process for the preparation of a compound of claim 1, characterized in that it comprises: (a) for a compound of Formula I in which Z is * -NHC (= O) -, and ring A, ring B, W, D, R2, R2a, R3, R3a and are as defined for Formula I, cyclize a corresponding compound having formula II
[0035]
35. Process according to claim 34, characterized by the fact that: ring B is ring B-1 having the structure:
[0036]
36. Compound, characterized by the fact that it is selected from: (6R) -9-fluoro-2,11,15,19,20,23- hexaazapentacycle [15.5.2.17,11.02,6.020,24] pentacosa- 1 (23 ), 7,9,17 (24), 18,21-hexaene-16,25-dione; (6R) -12-oxa-2,16,20,21,24,26- hexaazapentacycle [16.5.2.17,11.02,6.021,25] hexacosa- 1 (24), 7 (26), 8,10,18 ( 25), 19,22-heptaen-17-one; (6R) -9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacycle [17.5.2.02.6.07,12.022.26] hexacosa- 1 (25), 7,9,11,19 (26), 20,23-heptaen-18-one; (6R) -9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacycle [17.5.2.02,6.07,12.022,26] hexacosa- 1 (25), 7,9 , 11.19 (26), 20.23-heptaen-18-one; (6R, 13S) -9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo- [15.5.2.17,11.02,6.020,24] pentacosa- 1 (23), 7,9, 17 (24), 18,21-hexaene-16,25-dione; (6R) -9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17.5.2.02,6.07,12.022,26] hexacosa- 1 (25), 7, 9,11,19 (26), 20,23-heptaen-18-one; (6R, 15R) -9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17.5.2.02,6.07,12.022,26] hexacosa- 1 (25), 7,9,11,19 (26), 20,23-heptaen-18-one; (6R, 13R) -9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo- [15.5.2.17,11.02,6.020,24] pentacosa- 1 (23), 7,9, 17 (24), 18,21-hexaene-16,25-dione; (6R) -9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacycle [16.5.2.02.6.07,12.021.25] pentacosa- 1 (24), 7,9,11,18 (25), 19,22-heptaen-17-one; (6R) -9-fluoro-13-oxa-2,11,18,22,23,26- hexaazapentacycle [18.5.2.02.6.07,12.023.27] heptacous- 1 (26), 7,9,11,20 (27), 21,24-heptaen-19-one; (6R) -9-fluoro-2,11,16,20,21,24- hexaazapentacycle [16.5.2.17,11.02,6.021,25] hexacosa- 1 (24), 7,9,18 (25), 19, 22-hexaene-17,26-dione; (6R) -9-fluoro-2,11,13,16,20,21,24- heptaazapentacycle [16.5.2.02.6.07,12.021.25] pentacosa- 1 (24), 7,9,11,18 (25 ), 19,22-heptaen-17-one; (6R) -9-fluoro-2,11,13,17,21,22,25- heptaazapentacycle [17.5.2.02.6.07,12.022.26] hexacosa- 1 (25), 7,9,11,19 (26 ), 20,23-heptaen-18-one; (6R) -9-fluoro-13,16-dioxa-2,11,20,21,24- pentaazapentacycle [16.5.2.02.6.07,12.021,25] -pentacosa- 1 (24), 7,9,11, 18 (25), 19,22-heptaen-17-one; (6R) -9-fluoro-14-oxa-2,11,18,19,22- pentaazapentacycle [14.5.2.17,11.02,6.019,23] tetracosa- 1 (22), 7,9,16 (23), 17,20-hexaene-15,24-dione; (6R) -9-fluoro-13,16-dioxa-2,11,17,21,22,25-hexaazapentacycle [17.5.2.02.6.07,12.022.26] hexacosa- 1 (25), 7,9,11 , 19 (26), 20,23-heptaen-18-one; (6R, 13R) -9,13-difluoro-2,11,15,19,20,23-hexaazapentacycle [15.5.2.17,11.02,6.020,24] pentacosa- 1 (23), 7,9,17 (24 ), 18,21-hexaene-16,25-dione; (6R) -9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacycle [17.5.2.02,6.07,12.022,26] hexacosa- 1 (25), 7,9 , 11.19 (26), 20.23-heptaen-18-one; (6R) -9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacycle [17.5.2.02,6.07,12.022,26] hexacosa- 1 (25), 7,9 , 11.19 (26), 20.23-heptaen-18-one; (6R) -9-fluoro-13-oxa-2,17,21,22,25- pentaazapentacycle [17.5.2.02.6.07,12.022.26] hexacosa- 1 (25), 7,9,11,19 (26 ), 20,23-heptaen-18-one; (6R) -9-fluoro-13-oxa-2,16,20,21,24- pentaazapentacycle [16.5.2.02.6.07,12.021.25] pentacosa- 1 (24), 7,9,11,18 (25 ), 19,22-heptaene; 1 - [(6R) -9-fluoro-13-oxa-2,16,20,21,24- pentaazapentacyclo [16.5.2.02,6.07,12.021,25] pentacosa- 1 (24), 7,9,11, 18 (25), 19,22-heptaen-16-yl] ethan-1-one; 1 - [(6R) -9-fluoro-13-oxa-2,16,20,21,24- pentaazapentacyclo [16.5.2.02,6.07,12.021,25] pentacosa- 1 (24), 7,9,11, 18 (25), 19,22-heptaen-16-yl] -2-hydroxyethan-1-one; (6R) -9-fluoro-13-oxa-2,17,21,22,25- pentaazapentacycle [17.5.2.02.6.07,12.022.26] hexacosa- 1 (25), 7,9,11,19 (26 ), 20,23-heptaene; (6R) -9-fluoro-16-methanesulfonyl-13-oxa-2,16,20,21,24-pentaazapentacycle [16.5.2.02,6.07,12.021,25] pentacosa- 1 (24), 7,9,11 , 18 (25), 19,22-heptaene; 2 - [(6R) -9-fluoro-13-oxa-2,16,20,21,24- pentaazapentacyclo [16.5.2.02,6.07,12.021,25] pentacosa- 1 (24), 7,9,11, 18 (25), 19,22-heptaen-16-yl] acetic acid; (6R) -9-fluoro-17-methanesulfonyl-13-oxa-2,17,21,22,25-pentaazapentacycle [17.5.2.02,6.07,12.022,26] hexacosa- 1 (25), 7,9,11 , 19 (26), 20,23-heptaene; (6R) -N-ethyl-9-fluoro-13-oxa-2,17,21,22,25- pentaazapentacycle 17.5.2.02,6.07,12.022,26] hexacosa- 1 (25), 7,9,11, 19 (26), 20,23-heptaene-17-carboxamide; (6R) -N-ethyl-9-fluoro-13-oxa-2,16,20,21,24- pentaazapentacyclo- [16.5.2.02,6.07,12.021,25] pentacosa- 1 (24), 7,9, 11.18 (25), 19.22-heptaene-16-carboxamide; (6S) -9-fluoro-4,13-dioxa-2,11,17,21,22,25-hexaazapentacycle [17.5.2.02.6.07,12.022.26] hexacosa- 1 (25), 7 (12), 8,10,19 (26), 20,23-heptaene-3,18-dione; (6S) -9-fluoro-4,13-dioxa-2,11,16,20,21,24-hexaazapentacyclo [16.5.2.02,6.07,12.021,25] pentacosa- 1 (24), 7 (12), 8,10,18 (25), 19,22-heptaene-3,17-dione; (6R) -9-fluoro-2,11,16,20,21,24-hexaazapentacycle [16.5.2.02.6.07,12.021.25] pentacosa- 1 (24), 7,9,11,18 (25), 19,22-heptaen-17-one; (6R) -9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacycle [16.5.2.02.6.07,12.021.25] pentacosa- 1 (24), 7,9,11,18 (25), 19,22-heptaen-17-one; (6R, 13R) -9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo [15.5.2.17,11.02,6.020,24] pentacosa- 1 (23), 7,9,17 (24), 18,21-hexaene-16,25-dione; (6R, 13S) -9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacycle [15.5.2.17,11.02,6.020,24] pentacosa- 1 (23), 7,9,17 (24), 18,21-hexaene-16,25-dione; (6R) -9-fluoro-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacycle [17.5.2.02.6.07,12.022.26] hexacosa- 1 (25), 7 , 9,11,19 (26), 20,23-heptaen-18-one; (6R) -9-fluoro-15,15-dimethyl-2,11,16,20,21,24-hexaazapentacyclo [16.5.2.02,6.07,12.021,25] pentacosa- 1 (24), 7,9,11 , 18 (25), 19,22-heptaen-17-one; (6R) -9-fluoro-13-oxa-2,11,16,17,21,25,26,29- octaazahexacycle [21.5.2.02,6.07,12.016,20.026,30] triaconta- 1 (29), 7 , 9,11,17,19,23 (30), 24,27-nonaen-22-one; (6R) -9-fluoro-13-oxa-2,11,19,21,25,26,29- heptaazahexacyclo [21.5.2.02,6.07,12.015,20.026,30] triaconta- 1 (29), 7,9 , 11.15 (20), 16.18.23 (30), 24.27-decaen-22-one; (6R) -9-fluoro-13,13-dimethyl-2,11,15,19,20,23- hexaazapentacycle [15.5.2.17,11.02,6.020,24] pentacosa- 1 (23), 7,9,17 (24), 18,21-hexaene-16,25-dione; (4R, 6R, 15S) -9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacycle [17.5.2.02,6.07,12.022,26] hexacosa- 1 (25) , 7 (12), 8,10,19 (26), 20,23-heptaen-18-one; (4R, 6S, 15S) -9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacycle [17.5.2.02,6.07,12.022,26] hexacosa- 1 (25) , 7 (12), 8,10,19 (26), 20,23-heptaen-18-one; (4R, 6R) -9-fluoro-4-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacycle [17.5.2.02,6.07,12.022,26] hexacosa- 1 (25), 7 (12 ), 8,10,19 (26), 20,23-heptaen-18-one; (4R, 6S) -9-fluoro-4-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacycle [17.5.2.02,6.07,12.022,26] hexacosa- 1 (25), 7 (12 ), 8,10,19 (26), 20,23-heptaen-18-one; (4R, 6R) -9-fluoro-4-hydroxy-13-oxa-2,16,20,21,24-pentaazapentacycle [16.5.2.02,6.07,12.021,25] pentacosa- 1 (24), 7,9 , 11.18 (25), 19.22-heptaen-17-one; (4R, 6S) -9-fluoro-4-hydroxy-13-oxa-2,16,20,21,24-pentaazapentacycle [16.5.2.02,6.07,12.021,25] pentacosa- 1 (24), 7,9 , 11.18 (25), 19.22-heptaen-17-one; (4R, 6R, 15R) -9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacycle [17.5.2.02,6.07,12.022,26] hexacosa- 1 (25) , 7 (12), 8,10,19 (26), 20,23-heptaen-18-one; and (4R, 6S, 15R) -9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacycle [17.5.2.02,6.07,12.022,26] hexacosa- 1 (25 ), 7 (12), 8,10,19 (26), 20,23-heptaen-18-one.

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-07-02| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-09-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-06-02| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-10-27| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-01-05| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 13/05/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US34676710P| true| 2010-05-20|2010-05-20|

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US61/346,767|2010-05-20|

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US201061426716P| true| 2010-12-23|2010-12-23|

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US61/426,716|2010-12-23|

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PCT/US2011/036452|WO2011146336A1|2010-05-20|2011-05-13|Macrocyclic compounds as trk kinase inhibitors|BR122019024201-1A| BR122019024201B1|2010-05-20|2011-05-13|MACROCYCLIC COMPOUND AS TRK KINASE INHIBITORS, ITS USE, AND PHARMACEUTICAL COMPOSITION|