UA110701C2 - Macrocyclic compounds as inhibitors of trk kinase - Google Patents

Abstract

The compounds of formula II and their pharmaceutically acceptable salts, wherein ring A, ring B, W, m, D, R, R, R, R and Z such as indicated herein, are Trk kinase inhibitors and are useful for the treatment of pain, cancer, inflammation, neurodegenerative diseases and some infectious diseases.

Description

0001) This invention relates to new compounds, pharmaceutical compositions containing these compounds, methods of obtaining these compounds and to the use of these compounds in therapy. In particular, it refers to certain macrocyclic compounds that exhibit inhibition of protein tyrosine kinase of the TtK family, and which are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases, and certain infectious diseases. 00021 Several classes of compounds are used in current pain regimens. Opioids (such as morphine) have a number of disadvantages, including emetic effects, constipation and adverse effects on the respiratory system, and can also cause dependence. Nonsteroidal anti-inflammatory analgesics (NSAIDs, such as type COX-1 or COX-2) also have disadvantages, including insufficient effectiveness in the treatment of severe pain, the ability to cause internal bleeding of the gastrointestinal tract. In addition, COX-1 inhibitors can cause mucosal ulcers. Accordingly, there remains a need for new and more effective treatments to alleviate pain, especially chronic pain.

І000О3| TICs are high-affinity receptor tyrosine kinases activated by a group of soluble growth factors called neurotrophins (MTs). The TIK receptor family contains three members: TIK, TIK, and TCS. Neurotrophins include (i) nerve growth factor (NGF), which activates TKA, (ii) brain-derived neurotrophic factor (BOME) and MT-4/5, which activate TtKV, and (ii) MTZ, which activates TCS. TICs are widely expressed in neuronal tissue and participate in the maintenance, signaling and survival of nerve cells (Raiarotschiap, A. ei ai., Sitepi

Oriop ip Meigobioiodu, 2001, 11, 272-280).

І0004| Inhibitors of the TgkK/neurotrophin signaling pathway have been shown to be effective in various preclinical animal pain models. For example, antagonistic antibodies against MOG and TKA, such as KM-624, have been shown to be effective in animal models of inflammatory and neuropathic pain (M/ooi,

S.. her a. (1994) Metzgossiepse 62,327-331; 7th anp, R.K. her a). (2004) 9. Raip 5, 157-163; MeMapop, 5.

V. Yei Ai, (1995) Mai. Honey. 1, 774-780; Ma, 0. R. apa M/ooii, b. 9. (1997) Meshygogerop 8, 807-810; zZpeypop, 0. Y. ei ai. (2005) Raip 116, 8-16; Oeiiaisu, I. ei a!. (2003) Raip 105, 489-497; I at, K. ei a). (2003) Mepygodavzygoepiegoi. mine 15, 355-361; dadaag, 5. I. eyi a). (1999) Wu. U. Apaesii. 83, 442-448) and in animal models of neuropathic pain (Kateg, M. 5. apa VizBu, M. A. (1999) Yeig. y). Mashgovsi 11, 837-846; Vo, I. 5. yei a!. (1999); Raip 79, 265-274 Neg2brego, Ts. Yei a. (1997) Mepygogeroti 8, 1613-

Co., Ltd.) 1618; Tneodovoyi, M. ei ai. (1999) Raip 81, 245-255; Yes, oh oh (2003) Mine. SeiI. Mashgovsi 23, 232-250; Suhak, U. 5. ей а. (2003) Meshghozsi. Gene. 336, 117-120). 0005 It has also been shown that MOR, secreted by tumor cells and tumor-infiltrating macrophages, directly stimulates TICA, located on peripheral pain nerve fibers. Using various mouse and rat tumor models, neutralization of MOE with a monoclonal antibody has been shown to suppress associated pain to a degree similar to or superior to that of the highest tolerated dose of morphine. In addition, according to the data of many studies, the activation of the signaling pathway

VOMELTKV is a modulator of various types of pain, including pain during inflammation (Mayauobznpi, 5., ).

РНузиой 2005, 569:685-95), neuropathic pain (Tpotrzop, 5.MU., Ros. Mai!. Asai. 5si. OBA 1999, 96:7714-18) and surgical pain (Gi, S.-O. )., Moiesshtzag Raip, 2008, 4(28), 1-11).

ИО006| Recently published data in the literature also showed that overexpression, activation, amplification of mutations in TIC kinases are associated with many types of oncological diseases, including neuroblastoma (Vgodeig, B. M., Mai. Vem. Sapseg 2003, 3, 203-216 ), ovarian cancer (Oamidzop. V., ei ai., Sip. Sapseg Nez. 2003, 9, 2248-2259), colorectal cancer (Vagaeii,

A., Zsiepse 2003, 300, 949), melanoma (Tgizli, E., ei aiI., Oseptaiyu-Epaostipoiodu 2008, Z (1), pp. 32-36), head and neck cancer (Mita?, T., ei aiY., Sapseg Vioiiosdu apa Tnegaru 2010, 10 (6), pp. 644-653), gastric carcinoma (i, U. ei aiI., UUopa docstai! oi Savigoepiegoiodu 2003, 9 (7), pp. 1431-1434 ), lung carcinoma (Kissi A., ei aI., Ategisap mildayi oi Vezrigayugu SeiYi apa Moyesshiag Vioiodu 25 (4), pp. 439-446), breast cancer (ip, MU., ei ai., Sagsipodepeviz 2010, 31 (11). Yei ai., hilddaii oi Rgoivote Nezeagsy 2008, 7 (5), 1932-1944), secretory breast cancer (Eshyi5, O.M., ei aiI., Sapseg Seyi! 2002, 2 (5), yr. 347-348), cancer of the salivary glands (Ii, U.-S(., eyi aI., Spipese mahtpai oi Sapseg Rgemepiip apa Tgeaitepi 2009, 16 (6), pp. 428-430), papillary thyroid carcinoma (Sgeso, A ., ей аиЙ., MoiIesshag apa Seishag

Epdostipoiodu 2010, 321 (1), pp. 44-49) and myeloid leukemia of adults (Edispi, M., et al., Viosa 1999, 93 (4), pp. 1355-1363). In preclinical models of oncological disease, non-selective low-molecular-weight inhibitors of TgK A, B and C kinases were effective both in inhibiting tumor growth and in stopping the formation of metastases (MaKadamaga, A. (2001) Sapseg I eige 169:107-114; Meuyeg, u) . oh oh (2007) I eiketia, 1-10; Riegozia, M.A. apa Steso A., (2006) Sapseg I eyeg5 232:90-98; Aegis 60 Aagiaepze5epv, E., vi ai. Sapseg Nez (2008) 68:22) 346-351).

00071 In addition, it has been shown that inhibition of the neurotrophin/TtkK signaling pathway is effective in the treatment of preclinical models of inflammatory diseases when using antibodies against

MOR or non-selective low-molecular-weight inhibitors of TIC kinases A, V and S. For example, inhibition of the neurotrophin/Tik signaling pathway has been used in preclinical models of inflammatory lung diseases, including asthma (Egeipa-Mmisneyi, M.; Egozzaga, M., Rpnagtasyodu and Tpegareshiisv (2008), 117(1), 52-76), interstitial cystitis (Ni Mimiap, U., ei. aI. Te hilddaii oi Sgoyudu (2005), 179(3), 1016-21), inflammatory bowel diseases, including non-specific ulcerative colitis and Crohn's disease (Oi Moia, E. E., ей. аи!., ssh (2000), 46(5), 670-678), and inflammatory skin diseases, such as diffuse neurodermatitis (Ooi, MU.-S., her. a). Atspime5 oi Oeptaiyuiodis! Nezeagsp (2006), 298(1), 31-37), eczema and psoriasis (Kauspatczapvygi, 5. R., ei ai., u.

(2004), 122(3), 812-819).

ИО0О8| The connection of the signaling pathway of neutrophils/Ttk was also revealed, in particular,

VOME/tTKV, in the etiology of neurodegenerative diseases, including multiple sclerosis, Parkinson's disease and Alzheimer's disease (BoNgaria, ER., Iemiv, YuOapiveye K., Egopiieg5 ip

Meshygoepaostipoiodu (2006), 27(4), 404-414).

I0009| It is also believed that the TIiKkA receptor plays a critical role in the pathogenesis of the disease in the case of a parasitic infection caused by Tgurapozota sgy7i (Chagas disease) in a person who is the host organism (de Meiyo-ogaye, M., ei a!., Sei! Novi 4 Mistore (2007), 1(4), 251-261). 00101 There are several classes of small molecule TC kinase inhibitors that are believed to be useful in the treatment of pain or cancer (Ehrep Orip. Teg. Raiepiv (2009) 19(3)).

ИО0О11| However, there remains a need for compounds and methods for the treatment of pain, particularly chronic pain, as well as for the treatment of cancer, inflammation, neurodegenerative diseases, and certain infectious diseases.

ESSENCE OF THE INVENTION

00121 Heretofore, macrocyclic compounds have been found to be inhibitors of TtCk kinases, particularly TgKA and/or TgCkV and/or TCS inhibitors, and are useful in the treatment of disorders and diseases such as cancer and pain, including chronic and acute pain . Compounds that are inhibitors of TKA and/or Tt/CkV may be useful in the treatment of various types of pain, including

From inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture. In addition, the compounds of the invention may be useful in the treatment of inflammation, neurodegenerative diseases and certain infectious diseases. 0013) Accordingly, one of the features of the present invention is that it is aimed at creating new compounds having the general Formula I:

M ma s ----

Od 7a in chi

Oh yeah

You

AND

00141) and their stereoisomers and pharmaceutically acceptable salts and solvates, where ring A, ring

В, МУ, т, 0, В, Инга, VU, ИДЗа and 7 have the structure as specified in this document.

И0О015)| Another aspect of the present invention is that it is directed to the creation of new compounds having the general Formula I:

VAV

"KI t Z

IA

0016) or their pharmaceutically acceptable salts or solvates, where the ring A, M/, t, K2, Na, VU, 7, VD» and K5 have the structure as specified in this document.

І0017| Another aspect of the present invention is that it relates to pharmaceutical compositions containing compounds of Formula | and a carrier, solvent, or excipient. 0018) Another aspect of the present invention is that it relates to a method of treating or preventing pain, cancer, inflammation, neurodegenerative diseases, and certain infectious diseases in mammals, which includes administering to said mammal an effective amount of a compound of Formula I.

І0019| Another aspect of the present invention is that it relates to the use of a compound

Formula I in the production of medicine for the treatment or prevention of pain, cancer, inflammation, neurodegenerative diseases and some infectious diseases.

И0020О| Another feature of this invention is that it refers to the use of the compound Formula! in the treatment or prevention of pain, cancer, inflammation, neurodegenerative diseases and some infectious diseases. 0021) Another aspect is that intermediates for the preparation of the compounds are provided

Formula I. In one embodiment, some compounds of Formula I can be used as intermediates for the preparation of other compounds of Formula I. (0022) Another aspect is that the proposed processes for the preparation, methods of separation, and methods of purification of the compounds described herein .

DETAILED DESCRIPTION OF THE INVENTION

ИО023И| One of the variants of the embodiment of the present invention is directed to the creation of general compounds

Formulas I containing a pyrazolo|(1,5-a|pyrimidinyl ring and having the structure: -M o - that

Oh and no "or

Od 3

AND

(00241 or their pharmaceutically acceptable salts, or their solvates, where:

IOO25I ring A is selected from rings A-1, A-2 and A-3, which have the following structures: 1 1 1 to so C.

A. Xx s M si

U uk U li 2 U her ho v! in in! d-1 A- d-3 0026) where the wavy line marked 1 indicates the point of joining ring A to ring B, and the wavy line marked 2 indicates the point of joining ring A to MU;

Co., Ltd.) IOO27| X is M or CH;

IOO28) Y is H or NO;

IOO29I BA" is H, (1-3C) alkoxy group or halogen;

IOOZOI ring B is selected from rings B-1 and B-2, which have the following structures: v o

With i 8) p bo

From Z in c-2

I0OO31) where the wavy line marked 3 indicates the point of attachment to ring A, and the wavy line marked 4 indicates the point of attachment to the pyrazolo|1,5-a|pyrimidine ring of Formula I;

И0ОЗ21 МУ is О, МН or Сн»е", at the same time, ring A is А-2, then UM is СН5;

YOOZZI t is 0, 1 or 2;

00341 O is carbon; 0035) 82 and K22 are independently H, E, (1-3 C)alkyl or OH, provided that KZ and K22 are not present at the same time

He;

IOOZ6) BZ and Ka are independently H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl;

I0037| or O is carbon or nitrogen, B: and EZ are absent, and K22 and Za, together with the atoms to which they are attached, form a 5-membered heteroaryl ring containing 1-2 heteroatoms in the ring;

IOOZ81 2 is -MAlaC(-0)-, "-OMNO(-O)-, "-MASNeg- or 7-OS(-0)-, where the asterisk indicates the point of attachment of 2 to the carbon-containing KZ;

I0OZ39| Va is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-bC)alkyl, hydroxy(1-6C)alkyl or dihydroxy(2-6C)alkyl ; 0040) Bl is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-bC)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C alkyl), (1-6C alkyl)C(0)-, (3-60 cycloalkyl)C(0O)-, ApF(O)-, nOosHnC(O)-, (1-6C alkyl)usulfonyl, (3- 60 cycloalkyl)usulfonyl, Ag"(502)-, HOg26OSH"- or (1-6C alkyl/uMH(CO)-; 0041) Ag is phenyl, optionally substituted by one or more substituents independently selected from halogen, (I -6C)alkyl and (1-6C)alkyl; 00421 Ag is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl and (1-6C)alkyl; and 004.3) A and EAU are independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl. 0044) In one embodiment of Formula I, ring B is ring B-2 having the structure: (9) o o:

With in- , 0045) O is carbon, B? and H are independently (1-3 C)alkyl, and BZ and Ka are independently H, (1-3

C)alkyl or hydroxy(1-3 C)alkyl, or 0046) O is carbon or nitrogen, KZ: and EZ are absent, and Ka and KZa together with the atoms to which they are attached form a 5-6-membered heteroaryl a ring containing 1-2 heteroatoms in the ring.

I0047| In one embodiment of Formula I, ring A is ring A-1, which has the structure: 1 ge:

Have them in

A-1 00481 where X, U and E" have the structure as specified in Formula I. In one of the variants of embodiment

From Formula I, X is CH. In one of the variants of the embodiment of X there is M. In one of the variants of the embodiment of the Formula

There is an ER. In one of the variants of the embodiment of U there is N. In one of the variants of the embodiment of Formula | ВЕ" is H. In one embodiment, K' is a (1-3C) alkoxy group. One example is a methoxy group. In one embodiment, K' is a halogen. In one embodiment, K" is KE. 0049) Specific examples of ring A, when it is represented by the structure A-1, include the structures: 1 1 si M

E E . 0050) In one embodiment, ring A is ring A-2, which has the structure:

ge ku o M

U7Itu, v

A-2 0051 where U is H or P. In one embodiment, U is P. In one embodiment, U is

H. In one embodiment, K' is H. In one embodiment, K' is a (1-3C) alkoxy group. One example is the methoxy group. In one embodiment, K' is a halogen. In one version of the implementation of KE" is E. 0052) Concrete examples of the ring A, when it is represented by the ring A-2, are the structures: A-3, which has the structure: 1 with i, tu 2

IS"

A-3

I0O54| where U and E! have the structure as indicated in Formula I. In one of the variants of embodiment U is E.

In one embodiment, U is H. In one embodiment, K' is H. In one embodiment, K"' is a (1-3C) alkoxy group. One example is a methoxy group. In one embodiment, ЕК! is a halogen. In one embodiment, КЕ" is Е. 0055) Concrete examples of ring A, when it is represented by ring A-3, are the structures: 1 1 а ат

Сх с 5 Е У» У 0056) In one of the versions of the implementation of Formula I MU there is 0.

I0057| In one of the versions of the implementation of the UM there is a MN. 0058) In one of the versions of the embodiment of M/ there is CH".

IOO59) In one version of the implementation of Formula I O is carbon, KZ: and 22 independently are H, P, (1-3

C)alkyl or OH (provided that B: and Ka are not OH at the same time, and KZ and KZa are independently H, (1-3

C) alkyl or hydroxy(1-3 C) alkyl.

ИОО6ОИ In one of the variants of the embodiment of KZ: and Ka are independently H, E, methyl or OH, provided that Kg and K2a are not OH at the same time. 0061) In one of the variants of embodiment KZ and K22 are both N. 00621 In one of the variants of embodiment B? is H, and ge is KE.

ЙОО63) In one of the versions of the implementation of KZ and K72, both are KE. 0064) In one of the versions of the embodiment, the short circuit is H, and 22 is OH. 0065) In one embodiment, KZ is H, and K22 is methyl.

IOO66) In one embodiment, KZ and Ka are both methyl.

Zo 0067) In one of the variants of embodiment EZ and KZa are independently H, (1-3C)alkyl or hydroxy(1-3

C) alkyl.

IOO68) In one of the variants of the embodiment of KZ there is N. In one of the variants of the embodiment of EZ there is N. In one of the variants of the embodiment of both P and cha there is N.

0069 In one embodiment, Za is (1-3C)alkyl. Examples include methyl, ethyl, propyl and isopropyl. In one of the variants of the embodiment, the short circuit is (1-3C)alkyl. Examples include methyl, ethyl, propyl and isopropyl. 0070) In one embodiment, Za is (1-3C)alkyl, and BZ is H. In one embodiment, Za is methyl, and EZ is H. 0071) In one embodiment, both Ka and KZ are ( 1-3C) alkyl. In one embodiment, VZa and VZa are both methyl.

I0072| In one of the variants of the embodiment, the short circuit is hydroxy(1-3C)alkyl. Examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl. In one version of the implementation

BZ is hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl, and Ka is H. 0073) In one embodiment of Formula I, O is carbon or nitrogen, B: and EZ are absent, and

Dga and KZa, together with the atoms to which they are attached, form a 5-6-membered heteroaryl ring containing 1-2 heteroatoms in the ring. In one embodiment, Kg2 and KZa, together with the atoms to which they are attached, form a 5-6-membered heteroaryl ring containing 1-2 nitrogen atoms in the ring. Examples of heteroaryl rings include pyridyl and pyrazolyl rings. Specific examples of heteroaryl rings include the structures:

M- se 00744 In one of the variants of embodiment 2, there is x-MAaS(-0)-. 0075) In one embodiment, IC"2 is H. 0076) In one embodiment, Kg is (1-6C)alkyl. Examples include methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.

І0077| In one embodiment, Ka is a fluoro(1-6C)alkyl. Examples include fluoromethyl and 2-fluoroethyl.

І0078| In one embodiment, Ka is difluoro(1-6C)alkyl. Examples include difluoromethyl and 2,2-difluoroethyl. 0079) In one embodiment, Ba is trifluoro(1-6C)alkyl. Examples include trifluoromethyl and 2,2,2-trifluoroethyl.

ІОО80| In one embodiment, Ka is hydroxy(1-6C)alkyl. Examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl.

From I0O081|| In one embodiment, Ka is a dihydroxy(2-6C)alkyl. An example includes 2,3-dihydroxypropyl.

I0082| In one embodiment, Ka is H or (1-6C)alkyl. In one of the variants of the implementation of KK": is H or Me. 0083) Example 7, represented by the formula 7-MINlab(-0О)-, is "-OMNO(-О)-. 00843 In one of the variants of embodiment 2 there is -MASN»-. 0085) In one of the variants of the embodiment of RE" there is N.

II0086| In one of the versions of BC? selected from (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl and trifluoro(1-6C)alkyl. 0087) In one of the variants of embodiment B: is (1-6C)alkyl. Examples include methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. In one of the options for the implementation of VE? is methyl.

ІОО88| In one embodiment, "B" is fluoro(1-6C)alkyl. Examples include fluoromethyl and 2-fluoroethyl.

І0089| In one of the variants of the implementation of KK? is difluoro(1-6C)alkyl. Examples include difluoromethyl and 2,2-difluoroethyl. 0090) In one embodiment, "B" is trifluoro(1-6C)alkyl. Examples include trifluoromethyl and 2,2,2-trifluoroethyl.

YOO91| In one of the variants of embodiment "B" is selected from (1-6C alkyl)C(0)-, (3-60 cycloalkyl)C(0)-, АГ'С(О)- and HOCH»С(О)-.

ИО092) In one of the variants of embodiment P» is (1-6C. alkyl)uC(0)-. Examples include CH3C(0O)-,

SNaesSnNeS(O)-, SNISNaSneS(O)- and (CH3)2SHO(O)-. In one of the variants of the embodiment of K" is СН3С(О)-.

ИО093| In one embodiment B" is (3-6C cycloalkyl)C(O)-. Examples include cyclopropyl-C(O)-, cyclobutyl-C(O)-, cyclopentyl-C(O)-, and cyclohexyl-C (O)-. 00944 In one of the variants of embodiment KK" eat C(0)-. An example is phenyl-C(O)-. 0095) In one of the variants of embodiment 2"? is NOSN»S(O)-.

ЙО096| In one of the variants of the embodiment, "KK" is selected from (1-6C alkyl)sulfonyl, (3-60 cycloalkyl)sulfonyl and Agg(502)-.

I0097| In one embodiment, K" is (1-6C alkyl)usulfonyl. Examples include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.

ЙО098| In one of the versions of BC? is (3-6C cycloalkyl)usulfonyl. Examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl and cyclohexylsulfonyl. In one embodiment, K" is methylsulfonyl. 0099) In one embodiment, B? is AI7(502)-. An example is phenylsulfonyl. 00100) In one embodiment, 2"? is HO2ССН»-.

ИО0101| In one of the variants of the embodiment of BC" is (1-6C alkyl/uMH(CO)-. Examples include

CHnazaMne(O)-, CHzSnHg.MnNOe(O0)-, CHnaSnH.CHnoMNO(O)- and (CHnaz)CNMNO(O)-. In one embodiment, K" is СНЗМНО(О)-. 001021 In one embodiment, КЕ" is selected from H, methyl, -С(О)СН»3, methylsulfonyl, -ФС(Ф)СнОонН, -СНгСООН and - FS(O)MNONSN:". 00103) In one of the variants of embodiment 2 there is "-0ОС(-0)-. 00104) In one embodiment of Formula I, ring B is ring B-1:

Gee at 4

From what 001051) where P and KU are independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl.

И0О0106)| In one embodiment, KK" and K95 are independently H, E, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl. In one embodiment, EE" is H, and M is H, E, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl.

ЙО0107| In one version of the implementation of K? and KU is independently H, E, OH, (1-3C)alkyl or hydroxy(1-3Alkyl. In one embodiment, E? is hydrogen, and B is H, E, OH, (1-3C)alkyl or hydroxy (1-3C) alkyl.

ИО0108)| In one of the variants of embodiment B? and K9 are independently H, E, OH, methyl, ethyl,

NOSN»- or NOSNoSN-»-. In one of the versions of the implementation of KE? is hydrogen, and K? is H, E, OH, methyl, ethyl, HOCH»2- or HOCHNoCH»»-. 00109) In one of the versions of the implementation of KE? and KU is independently H, E, or methyl. In one embodiment, KZ is H, and Re is H, E or methyl.

IIOO110)| In one of the versions of the implementation Is? is H and Re is E.

ИО0О111| In one of the variants of the implementation of EE? is H and Me is methyl.

Ko) 001121 In one of the variants of the embodiment of EZ and KZ, both are N. 00113) In one of the variants of the embodiment of EE: and Rboboth are E. 00114) In one of the variants of the embodiment of EE: and Robydva is methyl. 00115) In one embodiment, ring B is ring B-1, which is optionally substituted with one or two substituents independently selected from OH and E, provided that the two substituents that are

OH, not attached to the same carbon atom in the ring.

І00116| Specific examples of the B ring, when represented by the B-1 ring, include the structures: but Е Я

And oM- | i- / - c) Z Z

І00117| In one embodiment of Formula I, ring B is ring B-2, having the formula:

(o) o yo:

From c-2 o 00118) In one of the implementation options, t is 0. 00119) In one of the implementation options, t is 1. 00120) In one of the implementation options, t is 2.

I00121| One of the variants of the embodiment of the present invention refers to the compound of the general Formula

Y or their pharmaceutically acceptable salts or solvates, where: 00122 the B ring is the B-1 ring: this is 7

From c-1 00123) ring A is selected from rings A-1, A-2 and A-3 having the structures: 1 1 1 to c

Id xX t M -d u UT, U zhu 2 v v i

A-1 A-2 A-3 00124) where the wavy line marked 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula i, and the wavy line marked 2 indicates the point of attachment of ring A to MU;

IOO1251| X is M or CH;

IOO126) U is H or E;

IOO1271 B" is H, (1-3C) alkoxy group or halogen; 00128) MU is O, MH or CH", while when ring A is A-2, then MU is CH"e;

I00129| t eee 0, 1 or 2; 001301 O is carbon;

ЙО0131| IN? and Ka is independently H, E, (1-3 C)alkyl or OH, provided that K? and Ka are not simultaneously OH; 001321 BZ and KZa are independently H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl; 001331 or B: and KZ are absent, and 22 and Kza, together with the atoms to which they are attached, form a bivalent 5-6-membered heteroaryl ring containing 1-2 nitrogen atoms in the ring. 001341 27 is -MvaС(-0)-, "-OMNO(-0)-, "-MA?СН»e- or 7-0ОС(-0)-, where the asterisk indicates the point of attachment of 7 to the IVF containing carbon ;

ИЙО0135| Va is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-bC)alkyl, hydroxy(1-6C)alkyl or dihydroxy(2-6C)alkyl ;

ИЙО0О136| IN? is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-bC)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-6C alkyl)C(0)-, (3-60 cycloalkyl)C(0O)-, ApF(O)-, nOosHnC(O)-, (1-6C alkyl)usulfonyl, (3-60 cycloalkyl) sulfonyl, Ag"(502)-, HOg5OSH"- or (1-6C alkyl/MH(CO)-; 00137) Ag is phenyl optionally substituted with one or more substituents independently selected from halogen, (I-6C) alkyl and (1-6C) alkoxy; 001381 Ag? is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl and (1-6C) alkoxy; and 001391 B ? and RU are independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl.

00140) One of the variants of the embodiment of the present invention refers to the compounds of the general Formula

IA

OZ sit g de yah ha 2 7 "u t 3

IA

001411 or their pharmaceutically acceptable salts, or their solvates, where: 001421 ring A is selected from rings A-1, A-2 and A-3 having the structures: 1 1 1 , in! in" in!

A-1 A-y A-3 00143) where the wavy line marked 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula i, and the wavy line marked 2 indicates the point of attachment of ring A to MU;

I0O0144)X is M or CH; 00145) M is H or E; 00146) In! is H, (1-3C) alkoxy group or halogen; 001471 MU is О, МН or СН», while when ring A is A-2, then MU is CH»e;

I00148| t eee 0, 1 or 2; 00149) In? and Ka is independently H, E or OH, provided that Pg and 22 are not both OH; 001501 BZ is H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl; 001511 2 is -MAlaC(-0)-, "-OMNO(-O)-, "-MASNeg- or x-OC0(-0)-, where the asterisk indicates the point of attachment 7 to IVF containing carbon;

ИО0152| Va is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-bC)alkyl, hydroxy(1-6C)alkyl or dihydroxy(2-6C)alkyl ;

ИО0153| IN? is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-bC)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-6C alkyl)C(0)-, (3-60 cycloalkyl)C(0O)-, ApF(O)-, nOosHnC(O)-, (1-6C alkyl)usulfonyl, (3-60 cycloalkyl) sulfonyl, Ag"(502)-, HOg5OSH"- or (1-6C alkyl/MH(CO)-; 00154) Ag! is phenyl optionally substituted with one or more substituents independently selected from halogen, (I-6C )alkyl and (1-6C)alkyl; and 00156) B and R are independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl.

I00157| In one embodiment, Formula IA includes compounds where:

From 00158) ring A is ring A-1, represented by the structure 1 du in Che and in'

A-1 00159) where the wavy line marked 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula i, and the wavy line marked 2 indicates the point of attachment of ring A to MU; 00160) the ring B is the ring B-1, represented by the structure ii vm also y"

With c-1 00161) where the wavy line marked 3 indicates the point of attachment to ring A, and the wavy line marked 4 indicates the point of attachment to the pyrazolo|1,5-a|pyrimidine ring of Formula I;

ИООО162) X is M or CH; 00163) M is H or E;

IOO1641 B" is H, (1-3C) alkyl, (1-3C) alkoxy group or halogen; 001651 UM is O or MH;

IOO166) t is 0, 1 or 2; 001671 In? and 222 are independently H, E or OH, provided that KZ and 222 are not both OH;

IOO1681 BZ is H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl; 001691 2 is -MAlaS(-0)-, "-OMNO(-O)- or "-OS(-0)-, where the asterisk indicates the point of attachment to

VU containing carbon;

І00170| Va is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-bC)alkyl, hydroxy(1-6C)alkyl or dihydroxy(1-6C)alkyl ; and 001771) BA'' and K5 are independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl. 00172) In one of the variants of embodiment X is M. In one of the variants of embodiment X is CH. 00173) In one embodiment, Formula IA includes compounds where: 00174 ring A is ring A-2 represented by the structure 1 сх and им

They are 72 years old!

A-2 00175) where the wavy line marked 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula i, and the wavy line marked 2 indicates the point of attachment of ring A to MU; 00176) ring B is ring B-1, represented by the structure 8 in also i"

WITH

B-1

I00177| where the wavy line marked 3 indicates the point of attachment to ring A, and the wavy line marked 4 indicates the point of attachment to the pyrazolo|1,5-a|pyrimidine ring of Formula I; 00178) Y is H or E; 001791 B" is H, (1-3C) alkyl, (1-3C) alkoxy group or halogen;

IOO1801| t is 0, 1 or 2;

I00181| MU is SN";

From I00182| t eee 0, 1 or 2; 001831) In? and 222 are independently H, E or OH, provided that KZ and 222 are not both OH; 001843 BZ is H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl; 001851 27 is "-MAlaS(-O)-, where the asterisk indicates the point of attachment to KU containing carbon;

I00186| Va is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-bC)alkyl, hydroxy(1-6C)alkyl or dihydroxy(1-6C)alkyl ; and

00187) In? and KE is independently H, halogen, OH, (1-6C)alkyl, or hydroxy(1-6C)alkyl. 00188) In one embodiment, Formula IA includes compounds where: 001891) ring A is ring A-3 represented by structure 1

There is Y

UK

77 Ho in!

A-Z 00190) where the wavy line marked 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula i, and the wavy line marked 2 indicates the point of attachment of ring A to MU; 00191) ring B is ring B-1 represented by the structure in 5 ah

C-1 00192) where the wavy line marked 3 indicates the point of attachment to ring A, and the wavy line marked 4 indicates the point of attachment to the pyrazolo|1,5-a|pyrimidine ring of Formula I; 001931 Y is H or E; 001941 V! is H, (1-3C)alkyl, (1-3C)alkyl or halogen;

I00195| MU is 0; 00196) t is 0, 1 or 2; 001971 In? and 222 are independently H, E or OH, provided that KZ and 222 are not both OH;

IO01981 BZ is H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl; 001991 27 is 7-00(-0)- or "-МНлаб(-0)-, where the asterisk indicates the point of attachment to the carbon-containing KZ; (002001 vla is H, (1-6C)alkyl, fluoro(1- 6C) alkyl, difluoro(1-6C) alkyl, trifluoro(1-bC) alkyl, hydroxy(1-6C alkyl) or dihydroxy(1-6C alkyl); and (00201 BA" and B are independently H, halogen, OH , (1-6C)alkyl or hydroxy(1-6C)alkyl.(00202) In one embodiment, Formula IA includes compounds where: 002031 ring A is ring A-1, represented by structure 1 to u z e i v!

A-1 (00204 where the wavy line marked 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula i, and the wavy line marked 2 indicates the point of attachment of ring A to MU; 00205) ring B is ring B-1 represented the structure of it you are still

Kk)

B-1 00206) where the wavy line marked 3 indicates the point of attachment to ring A, and the wavy line marked 4 indicates the point of attachment to the pyrazolo|1,5-a|pyrimidine ring of Formula I;

ИО0207| X is M or CH;

ИОО2О8) Y is H or B; 002091 V! is H, (1-3C)alkyl, (1-3C)alkyl or halogen;

IOO21TO| MU is O; (00211|ie 01 or 2; (002121 B: and Ka is independently H, E or OH, provided that Kg and 22 are not both OH; (00213) BZ is H, (1-3 C)alkyl or hydroxy (1-3 C) alkyl; (0021417 is "-МАСНе-), where the asterisk indicates the point of attachment to РЗ containing carbon;

I00215| IN? is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-bC)alkyl (1-6C alkyl)C(0)-, (3-6C cycloalkyl )C(0)-, AmC(0)-, HOSHeC(O)-, (1-60 alkyl)usulfonyl, (3-6C cycloalkyl)usulfonyl, Ag(502)-, HO»CCNeo- or (1-60 alkyl/MH(CO)-; (00216) Ag is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkyl; (00217) Ag! is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkyl; and (00218) B" and KE are independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl It will be understood that some compounds of the invention may contain one or more centers of asymmetry and, accordingly, may be prepared and isolated as a mixture of isomers, such as a racemic or diastereomeric mixture , or as a pure enantiomeric or diastereomeric form. It is intended that all stereoisomeric forms of the compounds of the invention, including examples of diastereomers, enantiomers and atropisomers, as well as their mixtures, such as racemic mixtures, are part of the present invention. (00220) In one embodiment, the compounds of the general Formula I, where ring B is ring B-1, have an absolute configuration as shown in fig. 1st: x, I pe po

Unit

Ge in: 7 "a od

Ge Y 1-a

From I00221| In one embodiment, the compounds of the general Formula I, where ring B is ring B-1, have an absolute configuration, as shown in Fig. 1st: -M su and more-

Unit

N vl in 7 uchi od v. 1-b

(00222) In the structures shown in this document, where the stereochemistry of each particular chiral atom is not indicated, all stereoisomers are meant and are included as compounds of the invention. When stereochemistry is indicated as a fully colored wedge or dashed line representing a particular configuration, it is assumed that the stereoisomer is thus indicated. (00223) The terms "(1-3C)alkyl" and "(1-6C)alkyl" as used herein mean saturated linear or branched monovalent hydrocarbon radicals containing from one to three carbon atoms and from one to six carbon atoms , respectively. These include, by way of non-limiting examples, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, t-butyl, tert-butyl, 2-methyl-2-propyl, pentyl and hexyl. (00224) The term "fluoro(1-6C)alkyl" as used herein means saturated linear or branched monovalent hydrocarbon radicals containing from one to six carbon atoms, as specified herein, where one of the hydrogen atoms is replaced by a fluorine atom . (00225) The term "difluoro(1-6C)alkyl" as used herein means saturated linear or branched monovalent hydrocarbon radicals containing from one to six carbon atoms, as specified herein, where two hydrogen atoms are replaced by fluorine atoms. (00226) The term "trifluoro(1-6C)alkyl" as used herein refers to saturated linear or branched monovalent hydrocarbon radicals containing from one to six carbon atoms, as specified herein, where three hydrogen atoms are replaced by fluorine atoms. (00227| The term "hydroxy(1-6C alkyl)" as used in this document means saturated linear or branched monovalent hydrocarbon radicals containing from one to six carbon atoms, where one of the hydrogen atoms is replaced by a hydroxyl group (OH). (00228 ) The term "dihydroxy(1-6C alkyl)" as used herein means saturated linear or branched monovalent hydrocarbon radicals containing from one to six carbon atoms, as specified herein, where two hydrogen atoms are replaced by hydroxyl groups (OH) , provided that the hydroxyl groups are not attached to the same carbon atom. (002291 The term "(1-6C alkyl)usulfonyl" as used herein means a (1-60 alkyl)5O group where the radical is attached to an sulfur, and the part corresponding to (1-6C alkyl) has the structure as above. Examples include methylsulfonyl (CH3C2O»2-) and ethylsulfonyl (CHNaCHne5oO2-). (00230) The term "(3-6C cycloalkyl)sulfonyl" when used in this document initiates a (3-6C cycloalkyl)5Og group, where the radical is attached to a sulfur atom. An example is cyclopropylsulfonyl.

I00231| The terms "(1-4C) alkoxy" and "(1-6C) alkoxy" as used herein mean saturated linear or branched monovalent alkoxy radicals containing from one to four carbon atoms or from one to six carbon atoms, respectively , while the radical is attached to an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy groups. (002321 The term "halogen" includes fluoro-, chloro-, bromo- and iodo radicals.

I00233| It is also clear that some compounds of Formula I can be used as intermediates to obtain additional compounds of Formula I.

I00234| Compounds of Formula I also include salts thereof. In some embodiments, the salts are pharmaceutically acceptable salts. In addition, compounds of Formula I include other salts of such compounds which are not necessarily 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 resolution of enantiomers of compounds of Formula Y. ( 00235) The term "Pharmaceutically acceptable" indicates that the substance or composition is compatible by chemical and/or toxicological characteristics with other ingredients that make up the dosage form and/or with the body of a mammal that receives treatment with their use.

I00236| It is also clear that the compounds of Formula I and their salts can be isolated in the form of solvates, and, accordingly, any such solvate is included in the scope of the present invention.

I00237| Compounds according to the invention may also contain isotope ratios of atoms for one or more atoms that are part of such compounds that do not occur in nature.

That is, the atom, in particular, mentioned in connection with the compound of Formula I, contains all isotopes and mixtures of isotopes of this atom, both those found in nature and those obtained synthetically, both in accordance with the prevalence of elements in nature and in a form enriched with certain isotopes.

For example, if a hydrogen atom is mentioned, it is meant that it refers to "H, 2H, ЗН or their mixtures; if a carbon atom is mentioned, it is meant that it refers to "С, 120, 190, 60 146 or their mixtures ; if a nitrogen atom is mentioned, it is understood that it refers to "UM, M,

1»M or their mixtures; if an oxygen atom is mentioned, it is understood that it refers to 770, 150, 160, 170, 180 or their mixtures; and when a fluorine atom is mentioned, it is meant to refer to 18g, 79E or mixtures thereof. Accordingly, the compounds of the invention also include compounds with one or more isotopes of one or more atoms and mixtures thereof, including radioactive compounds where one or more non-radioactive atoms have been replaced by one of its radioactive isotopes.

Radiolabeled compounds are useful as therapeutic agents, such as therapeutic agents for the treatment of cancer, research reagents, such as quantification reagents, and diagnostic agents, such as ip mimo imaging agents. It is intended that all isotopic variants of the compounds of this invention, radioactive or not, are included within the scope of this invention.

I00238| The present invention is further directed to a method of preparing the compound

Formula I or salts thereof, as specified herein, comprising:

IOO2391| (a) in the case of a compound of Formula I, where 2 is "-МНО(-О)-, and ring A, ring B, MU, 0, 2, Idga,

VU, VzZa and t - as indicated for Formula I, cyclization of the corresponding compound having Formula II -M

OM x and po

M o o vza v2 OR! in

Oy t v3 rea p 002401 where P" is H or a carboxy protecting group in the presence of a reagent that promotes the condensation reaction and a base; or (00241 (6) in the case of a compound of Formula I, where MU is O, ring A has formula A-1: 1 zl 2 du ch ich in!

A-1 , 00242 X is M, and ring B, 0, 2, M, EK", Be, Ba, VAZ, VzZa and t - as indicated for Formula Y, cyclization of the corresponding compound having Formula III and -M

Ah g she

M

2 and | what weights And yes memes in! and ).

Sh

I00243| where n is 1, 2, C or 4 and I" is a leaving group or an atom in the presence of a base; or (002441 (c) in the case of a compound of Formula I wherein UM is CH", ring A has the formula A -2:

her and som 7 tro v!

A-2 002451 and ring B, 2, 0, M, EE", Vg, Vga, IVZ, IDcha and t - as indicated for Formula I, cyclization of the corresponding compound having Formula IM -M

Matt! x t sh--

M

77

MN 3

AND? t

IM

002461 where 12 is a leaving group or atom in the presence of a base; or (00247) (d) in the case of a compound of Formula I, where 7 is "-МНО(-О)-, and ring A, ring B, UM, O, K-, Be, BZ,

Vza and t - as indicated for Formula II, cyclization of the corresponding compound having Formula M

My veg ee oda o ha mm KE od t 3 dya

IN

002481 in the presence of a base and a reagent that contributes to the condensation reaction; or 002491 (e) in the case of a compound of Formula I, where 27 is "-MNON"-, and ring A, ring B, UM, 0, B, ha, VU,

Vza and t - as indicated for Formula II, cyclization of the corresponding compound having the Formula MI -M 4 5 chi -

M o o

N ha 7

MU. And Mt

MN" about Go Ka k

E

(002501 in the presence of a reducing agent; or

ИО02511 (is) in the case of a compound of Formula I, where 2 is "-MNON"-, and ring A, ring B, MU, 0, 2, Ba, VU,

Dza and t - as indicated for Formula I, cyclization of the corresponding compound having Formula I

- M

Wh-

M vi on schi

MU. MN"

Od and

WITH

UP

(002521 in the presence of triphenylphosphine; or (00253) in the case of compounds of Formula I, where ring A, ring B, MU, O, t, Kg, ha, BZ and Za - as indicated for Formula I, 7 is "-MASNe-, and CC are (1-60 alkyl)/C(0)-, (3-60 cycloalkyl)C(0)-,

ApF(0)-, HOSHeC(O)-, (1-60 alkyl)usulfonyl, (3-60 cycloalkyl)usulfonyl, (1-60 alkyl)usulfonyl, (3-60 cycloalkyl)usulfonyl or Alg(5052) -, condensation of the corresponding compound having the Formula MP -М я пе п--

Ol ha o

In U Mn (hi ХТ» in

UshSh (002541) with a reagent having the formula (1-60 alkyl)C(0)-I3, (3-60 cycloalkyl)C (0)-I13, AgC(0)-10. IZ, HOSNoC(O)-13 , (1-60 alkyl)x/50O2)-I3, (3-60 cycloalkyl)(502)-IZ or Ag(5052)-IU, respectively, where

IS is a leaving atom in the presence of a base; or (002551 (z) in the case of a compound of Formula I, where ring A, ring B, MU, O, VK, ha, VU, VZai t - as indicated for Formula I, 7 is "-MASN"e-, and B is (1-60 alkyl/mMH(CO)-, carrying out the reaction of the compound having the Formula MP -M

OM x

AK

Mr. Ra v

AL. in MN already, eZ

UP

(00256) with a reagent having the formula (1-60 alkyl)M-C-O, in the presence of a base; or (002571 (i) in the case of a compound of Formula I, where B: is E, 22 is H, and ring A, ring B, 7, MU, 0, BZ, dza and t - as specified for Formula I, carrying out the reaction of the corresponding compounds having Formula IX -M tm X (vi chuk

M n on

We

M. r ody t Z

THEM

(00258) with a fluorinating reagent; 002591 (y) in the case of a compound of Formula I, where MU is O, ring A has the formula A-1:

that

Um X u v u v!

A-1.

I00260| X is CH, and M, EE", 0, ring B, 7, B, ha, BZ and t - as indicated for Formula I, by cyclization of the corresponding compound having the formula X -M ie and more

M

2 E

F on - s vza u tsi v v v! And I, x

I00261|dep 1,2, Zabo 4, and I" is a leaving group or atom in the presence of a base; and

I00262| optionally, removal of any protecting groups and, optionally, obtaining salts of these compounds. 00263) In one of the variants of the implementation of the above-described methods (a)-(k), ring B is ring B-1, which has the structure: ve in - 4 more members

WITH

В' (00264 O is carbon, K? and Hga independently are H, E, (1-3 C)alkyl or OH (provided that KZ? and Kha are not both OH), EZ is H, (1-3 C) alkyl or hydroxy(1-3 C) alkyl, and ring A, MU, t, 27, B" i

Ve - as specified for Formula I. 00265) In the case of method (a), cyclization can be carried out using standard conditions for the formation of an amide bond, for example, by treating a carboxylic acid with an activating agent followed by addition of an amine in the presence of a base. Suitable activating agents include 1-ethyl-33-(dimethylamino)propylcarbodiimide hydrochloride (EOCI), oxalyl chloride, thionyl chloride, NATI, and hydroxybenzotriazole (NOVO. Suitable bases include amino-containing bases, such as triethyl amine, diisopropylethyl amine, pyridine, or excess ammonia. Suitable solvents include dichloromethane (DCM), dichloroethane (DOC), tetrahydrofuran (THE) and dimethylformamide (DME). 00266) In the case of methods (b) and (c), the leaving atoms I" and 12 can be, for example, a halogen atom, such as Bg, Si or I. According to another variant, Y" and 12 can be a leaving group, for example, an arylsulfonyloxy group or an alkylsulfonyloxy group, such as a mesylate or tosylate group. Suitable bases include alkali metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate. Standard solvents include aprotic solvents such as ethers (eg, tetrahydrofuran or p-dioxane), OME, or acetone. The reaction can be carried out as a standard at elevated temperatures, such as 50-150 °C, for example, at 85 °C.

From I00267| In the case of method (d), suitable reagents that promote the condensation reaction include NATIs, NVTIs, TVTIs, dicyclohexylcarbodiimide (OCS), IES, and any other reagents that promote the condensation reaction of amides well known to those skilled in the art. Suitable bases include tertiary amines such as diisopropylethyl amine (O1IEA) and triethyl amine. Standard solvents include dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DHC), and dichloroethane (DHC).

I00268| In the case of method (e), suitable reducing agents include Me«M(OAc)zBN,

Ma(OAs)vVN and MasmMVN:U. Suitable solvents include neutral solvents such as acetonitrile, tetrahydrofuran (THF) and dichloroethane (DHC). The reaction can be carried out as standard at ambient temperature.

IІ00269| In the case of method (e), in some variants of the embodiment, the triphenylphosphine reagent is used in the form of a resin of polystyrene-bound PP (which is sold under the name RBZ-PPZ by Vioiade bZuziet5). The reaction is normally carried out at ambient temperature. Suitable solvents include neutral solvents such as dichloromethane (DCM). 002701 In the case of method (g), the leaving atom, Ж, can be a halogen, for example, Si or

Hg. Suitable bases include tertiary amines such as diisopropylethyl amine and triethyl amine.

The reaction is normally carried out at ambient temperature.

II00271| In the case of method (3), suitable bases include tertiary amines such as diisopropylethyl amine (OIEA) and triethylamine. The reaction is normally carried out at ambient temperature. (00272) In the case of method (i), the fluorinating reagent can be, for example, bis(2-methoxyethyl)aminosulfur trifluoride (Ueocho-Risog"M) or diethyl aminosulfur difluoride (SAZT). Suitable solvents include dichloromethane, chloroform, dichloroethane and toluene. The reaction is typically carried out at ambient temperature. 00273) In the case of method (k), the base may be, for example, an alkali metal carbonate, such as, for example, sodium carbonate, potassium carbonate or cesium carbonate. Standard solvents include aprotic solvents such as ethers (e.g., tetrahydrofuran or p-dioxane) or toluene. The reaction can be carried out in a standard manner at temperatures from ambient to refluxing, e.g., 85°C. (00274) Amino groups in compounds described in any of in the above ways, may be protected by any suitable amino protecting group, for example as described in

Co., Ltd. of publications Sgeepe 5 UUtsi5, eav., "Rgoiesiipd Stoirv ip Ogdapis Zupipeviv", 2'Я4 vd. Meme/ Moik; add

UMieu 5 Zop5, Ips., 1991. Examples of protecting groups for amino groups include acyl and alkoxycarbonyl groups, such as tert-butoxycarbonyl (BOC) and (2-(trimethylsilyl)ethoxy|methyl (ZEM). Similarly, carboxyl groups can be protected by any suitable group protecting the carboxyl group, for example, as described in the publication Sgeepe 5 MUtsiv5, et al., "Rgoiesiipd

Stoyrz ip Ogdapis bZupipeviv", 274 va. Mem/ Mogk; dopp Umieu 5 Bopv, Ips., 1991. Examples of protecting groups for carboxy groups include (1-6C) alkyl groups such as methyl, ethyl and tert-butyl. Alcohol groups can be protected by any suitable group protecting alcohol groups, for example, as described in the publication of Sgeepe 8: Mutsiv5, eiv5., "Rgoiesiipd StoyMrz ip Ogdapis 5upipeviv", 279 va. Mem Mogk; dopp UmMieu 5 Bop5, Ips., 1991 Examples of protecting groups for alcohol groups include benzyl, trityl, silyl ethers, and the like.

I00275| It is also believed that the compounds of Formulas II, PS, IM, M, MI, MII, MIS, IX and X are new and are proposed as additional features of the invention.

I00276| The ability of the compounds of the invention to act as TKA inhibitors can be demonstrated using the quantitative assay methods described in Examples A and B. (00277 Certain compounds that are TKA and/or abotikB inhibitors may be useful in the treatment of various types of pain, including pain in inflammation, neuropathic pain, and pain associated with cancer, surgery, or bone fracture.

I00278| In one of the variants of the embodiment of the compound of the Formula | useful for the treatment of pain, including chronic and acute pain, in a mammal.

I00279| Acute pain, as defined by the International Association for the Study of Pain, is the result of disease, inflammation, or tissue damage. This type of pain usually comes on suddenly, such as after an injury or surgery, and may be accompanied by anxiety or stress. Usually, the cause can be diagnosed and treated, and the pain is limited to a certain period of time and degree of severity. In some rare cases, it can become chronic.

I00280| Chronic pain, as defined by the International Association for the Study of Pain and widely accepted, is itself a disease. It can be enhanced by environmental factors and physiological factors. Chronic pain persists for a longer period of time than acute pain, remaining resistant to most methods of medical treatment, in general - for 3 months. or more It can cause, and often does, serious problems for patients.

I00281| Compounds Formula | also useful for the treatment of oncological disease in a mammal. Specific examples include neuroblastoma, ovarian cancer, pancreatic cancer, colorectal cancer, and prostate cancer.

I00282| The compounds of Formula I are also useful for treating inflammation in a mammal.

I00283| The compounds of Formula I are also useful in the treatment of certain infectious diseases in a mammal, such as Tturaposota sgy?i infection. (00284) Compounds of Formula I can also be used to treat neurodegenerative diseases in a mammal. Examples of neurodegenerative diseases include demyelination and dysmyelination. Additional examples of neurodegenerative diseases include multiple sclerosis, Parkinson's disease, and Alzheimer's disease.

I00285| In addition, compounds of Formula !/ can also be used to treat interstitial cystitis (IS), painful bladder syndrome (PSBS), urinary incontinence, asthma, anorexia, diffuse neurodermatitis and psoriasis in a mammal. (00286) Accordingly, another embodiment of the present invention is directed to the creation of a method of treating or preventing pain in a mammal, which includes the administration of one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective for the treatment or prevention of said pain to said said mammal. In one embodiment, the pain is chronic pain. In one embodiment, the pain is acute pain. In one embodiment, the pain is inflammatory pain. In one embodiment, the pain is neuropathic pain. In one embodiment, the pain is cancer-related pain. In one embodiment, the pain is pain associated with surgery. In one embodiment, the pain is pain associated with a bone fracture. In one embodiment, the method includes a method of treating said type of pain in a mammal. In one embodiment, the method includes a method of preventing said type of pain in a mammal.

I00287| Another version of the embodiment of the present invention is aimed at creating a method of treatment or prevention of inflammation in a mammal, which includes the introduction to the said mammal

Of one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective for the treatment or prevention of said inflammation. In one embodiment, the method includes a method of treating said inflammation in a mammal. In one embodiment, the method includes a method of preventing said inflammation in a mammal.

I00288| Another variant of the embodiment of the present invention is aimed at creating a method of treatment or prevention of a neurodegenerative disease in a mammal, which includes the introduction of one or more compounds of Formula I or their pharmaceutically acceptable salt in an amount effective for the treatment or prevention of the specified neurodegenerative disease to the specified mammal. In one embodiment, the neurodegenerative disease is demyelination. In one embodiment, the neurodegenerative disease is dysmyelination. 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 version of the embodiment of the present invention is aimed at creating a method of treatment or prevention of infectious diseases in a mammal, which includes the introduction of one or more compounds of Formula | or their pharmaceutically acceptable salt in an amount effective for the treatment or prevention of the specified infectious diseases. In one embodiment, the infectious disease is an infection of Tgurapozota sgy;i. In one embodiment, the method includes a method of treating said neurodegenerative disease in a mammal. In one embodiment, the method includes a method of preventing the specified neurodegenerative disease in a mammal.

I00289| Another variant of the embodiment of the present invention is aimed at creating a method of treatment or prevention of cancer in a mammal, which includes the introduction of one or more compounds of Formula I or their pharmaceutically acceptable salt in an amount effective for the treatment or prevention of the cancer. In one embodiment, the oncological disease is neuroblastoma. In one embodiment, the oncological disease is ovarian cancer. In one embodiment, the oncological disease is pancreatic cancer. In one embodiment, the oncological disease is colorectal cancer. In one embodiment, the oncological disease is prostate cancer. In one embodiment, the method includes a method of treating said oncological disease in a mammal. In one embodiment, the method includes a method of preventing the specified oncological disease in a mammal. 00290) Compounds of Formula I can be administered alone, as a single drug therapy, or can be administered in addition to one or more other substances and/or methods of treatment that work by the same or a different mechanism of action. Examples include anti-inflammatory compounds, steroids (such as dexamethasone, cortisone, and fluticasone), analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) (such as aspirin, ibuprofen, indomethacin, and ketoprofen), and opioids (such as morphine), as well as chemotherapeutic agents. These agents can be administered with one or more compounds of Formula I as part of the same dosage form or as a separate dosage form, using the same or different routes of administration and according to the same or different administration schedules, according to standards pharmaceutical practices known to those skilled in the art.

IOO291| In the field of medical oncology, it is normal practice to use a combination of different forms of therapy to treat each individual cancer patient. In medical oncology, another component (or components) of such combination therapy, in addition to the compositions of the present invention, may be, for example, surgery, radiation therapy, chemotherapy, the use of signaling inhibitors and/or monoclonal antibodies. 002921 Accordingly, compounds of Formula I can be administered in combination with one or more agents selected from mitosis inhibitors, alkylating agents, antimetabolites, antisense

DNA or RNA, intercalating antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, cytostatic agents, anti-androgens, antibodies with targeting, HMG-CoA reductase inhibitors and prenyl-protein transferase inhibitors. These agents can be administered with one or more compounds of Formula I as part of the same dosage form or as a separate dosage form, using the same or different routes of administration and according to the same or different schedules of administration, according to standards of pharmaceutical practice known to those skilled in the art.

From 00293) As used herein, the terms "treat" or "treatment" refer to therapeutic, prophylactic, palliative, or preventive measures. Beneficial or desirable clinical outcomes include, by way of non-limiting examples, amelioration of symptoms, reduction in disease severity, stabilized (i.e., not worsening) disease state, delayed onset or slowing of disease progression, amelioration or relief of disease state, and remission ( partial or full), detected or undetected. "Treatment" can also mean an extension of the survival period expected in the absence of treatment. Those in need of treatment include those who already have a condition or disorder, as well as those who have a predisposition to an acquired condition or disorder, or those in whom the condition or disorder needs to be prevented. 00294) In one embodiment, the terms "treatment" or "treatment" as used herein refer to the alleviation, partial or complete, of symptoms associated with a disorder or condition as described herein (eg, many types of pain, including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fractures), or slowing or stopping the further progression or worsening of these symptoms.

I00295| In one embodiment, the term "prophylaxis" as used herein refers to the prevention of the occurrence, recurrence, or spread, in part or in whole, of a disease or condition as described herein (e.g., many types of pain, including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery and bone fractures), or their symptoms. (00296) The terms "effective amount" and "therapeutically effective amount" refer to an amount of a compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat or prevent a particular disease, condition or disorder, (ii) alleviating, reducing the severity of, or relieving one or more symptoms of a particular disease, condition, or disorder, or (ii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein.An amount of a compound of Formula I that will correspond to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the individual parameters (eg, body weight) of the mammal in need of such treatment, but can nevertheless be determined by one skilled in the art this field using standard methods.

I00297| As used herein, the term "mammal" refers to a warm-blooded animal that exhibits or is at risk of developing a disease described herein, including, but not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including a person. 00298) The compounds of the invention can be administered in any standard way, for example, in the gastrointestinal tract (eg, rectally or orally), nasal cavity, lungs, muscles or blood vessels, as well as transdermally or dermally. The compounds can be administered in any standard form for administration, for example, in the form of tablets, powders, capsules, solutions, dispersions, suspensions, syrups, aerosols, suppositories, gels, emulsions, patches, and the like.

Such compositions may contain components that are standardly used in pharmaceutical preparations, for example, solvents, carriers, pH value modifiers, sweeteners, bulking agents and additional active agents. If parenteral administration is required, the compositions will be sterile and in the form of a solution or suspension suitable for injection or infusion. Such compositions form an additional feature of the invention.

I00299| This invention is further directed to the creation of a pharmaceutical composition containing a compound of Formula | or a pharmaceutically acceptable salt thereof, as specified herein. In one embodiment, the pharmaceutical composition includes a compound of Formula

And together with a pharmaceutically acceptable solvent or carrier.

ЯООЗО0| This invention is further directed to the creation of a compound of Formula | or a pharmaceutically acceptable salt thereof for use in therapy. 00301 In one embodiment, the invention is directed to the creation of a compound of Formula or a pharmaceutically acceptable salt thereof for use in the treatment of pain in a mammal. In one embodiment, the pain is chronic pain. In one embodiment, the pain is acute pain. In one embodiment, the pain is inflammatory pain. In one embodiment, the pain is neuropathic pain. In one embodiment, the pain is cancer-related pain. In one embodiment, the pain is pain associated with surgery. In one embodiment, the pain is pain associated with a fracture

From the bones 00302) In one embodiment, the invention is directed to the creation of a compound of the Formula or its pharmaceutically acceptable salt for use in the treatment of inflammation in a mammal. 00303) According to a further aspect, the present invention is directed to the creation of a compound

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 dysmyelination. 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. 00304) In one embodiment, the invention is directed to the creation of a compound of the Formula or its pharmaceutically acceptable salt for use in the treatment of an infectious disease in a mammal. In one embodiment, the infectious disease is an infection

Tturapozota stgygi. 00305) In one embodiment, the invention is directed to the creation of a compound of the Formula or its pharmaceutically acceptable salt for use in the treatment of oncological disease in a mammal. In one embodiment, the oncological disease is neuroblastoma. In one embodiment, the oncological disease is ovarian cancer. In one embodiment, the oncological disease is pancreatic cancer. In one embodiment, the oncological disease is colorectal cancer. In one embodiment, the oncological disease is prostate cancer.

ІОО3О6| Another embodiment of the present invention involves the use of a compound

Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of pain in a mammal.

YOO307| Another embodiment of the present invention involves the use of a compound

Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of inflammation in a mammal. 00308) Another embodiment of the present invention offers the use of a compound of the Formula or its pharmaceutically acceptable salt in the manufacture of a medicinal product for the treatment of neurodegenerative disease in a mammal.

00309) Another embodiment of the present invention offers the use of a compound of the Formula or its pharmaceutically acceptable salt in the manufacture of a medicinal product for the treatment of an infectious disease in a mammal. 00310) Another embodiment of the present invention offers the use of a compound of the Formula or its pharmaceutically acceptable salt in the manufacture of a medicinal product for the treatment of oncological disease in a mammal.

Examples

І00311| The following examples illustrate the invention. In the examples described below, unless otherwise noted, all temperature values are in degrees Celsius. Reagents were purchased from commercial suppliers such as AiYagispy Spetis! Sotrapu, I Apsavieg, AIga,

Aesag, TSI, Maubgidde, Avia Tesi, or other suitable suppliers and were used without further purification unless otherwise noted. Tetrahydrofuran (THE), dichloromethane (DCM), toluene, dimethylformamide (OME) and dioxane were purchased from Ayagis company in Zyge/Zeai "M" bottles and used immediately upon arrival. 00312) The reactions below were generally carried out under excess nitrogen pressure or argon or using a drying tube (unless otherwise specified) in anhydrous solvents, and the reaction flasks were typically equipped with a rubber septa for syringe injection of substrates and reagents.The glassware was dried in a thermostat and/or heat-dried or flow-dried dry nitrogen. 00313) Column chromatography was carried out in a Vioiade system (manufacturer: Ouach Sogrogayop), which includes a reverse-phase column of silica gel or C-18, or with the use of a silica-based zerRak cartridge (Umayeg5), or with the use of standard column flash chromatography on silica gel unless otherwise stated 003141) Abbreviations used in this document have the following meanings: 2,2:-bisidiphenylphos pheno)-1,1"-binaphthyl (benzotriazol-1-yloxy)tris(dimethylamino)phosphorus hexafluorophosphate 1,2-bis(idiphenylphosphino)ethane hexafluorophosphate) tetrakis(triphenylphosphine)palladium (0) tris(dibenzylideneacetone)dipalladium (0)

Biological tests

Example A

EGISA analysis of TIK kinase activity

From I00315| Solid-phase enzyme-linked immunosorbent assay (ELISA) was used to assess the kinase activity of TKA in the presence of inhibitors. In 384-well titration microplates Ittiop 4NVH

(Tpepto, cat. Mo 8755) applied a coating using 0.025 mg/ml solution of polymer Sim,

Ah, Tug in the ratio 6:3:1 (5idta RZ899). Different concentrations of the studied compound, 2.5 nm

TIKA (Ipmigodep Sogr., cytoplasmic domain of human recombinant TITKA with a histidine tag) and 500 μM ATP were incubated for 25 min. at ambient temperature in coated tablets, with shaking. The buffer solution for analysis consisted of 25 mM

MOR, pH 7.5, 0.00595 (vol./06.) Tiop X-100 and 5 mM Mosi2. The reaction mixture was removed from the plate by washing with PB5 buffer containing 0.195 (06./06.) Tmeep 20.

The phosphorylated reaction product was detected with the specific help of 0.2 mg/ml anti-phosphotyrosine monoclonal antibody (clone RU20) conjugated with horseradish peroxidase, together with the system containing the peroxidase substrate - TMV Regohidase Zyrvigaiye bZuviet (KRI).

After adding 1 M of phosphoric acid, the intensity of staining of the chromogenic substrate was quantified by absorption at 450 nm. IC5o values were calculated using point selection of a 4- or 5-parameter logistic curve. 00316) Table 1 presents the average IC values for compounds according to the invention, obtained using this analytical method. In Table 1, the letter "A" indicates the value of ISvo from approximately 1 to 100 nM, and the letter "B" indicates the value of ISvo from 2100 nM to "3000 nM.

Example B

Analysis of TIKKA binding

II00317| The ability of the compound to bind to TIKA was measured using an analytical kit for the study of kinase binding of the company Ipmigodep - I apipabstevep M Eu Kipase Vipaiipa

Awsau In such an analysis, recombinant human TIKA (cytoplasmic domain) carrying the Niz-label from the company Ipmigodep is incubated with the dye AIekha supplied by the company Ipmigodep.

Risoge Tgaseg 236, biotinylated anti-Nyh antibody and europium-labeled streptavidin conjugated (with a final concentration of 2 95 UOM5O) in buffer (25 mM MOR, pH 7.5, 5 mM Massi), 0.00 B95 TiIop X-100 ). After 60 min. incubation at 22 7C, quantitative assessment of the reaction was carried out using the Epmisiop device and detection at two wavelengths according to the principle of fluorescence resonance energy transfer with time resolution (TC-EKET), and the ROS (volatile organic carbon) indicator was calculated from the ratio of the output indicators. The data on the dose-dependent effect of the compound were entered into a 4-parameter logistic model and the IC was determined

Zo as the concentration of the compound for 50 ROS. 00318) Table 1 presents the average IC values for compounds according to the invention, obtained using this analytical method. In Table 1, the letter "A" indicates the value of ISvo from approximately 1 to 100 nM, and the letter "B" indicates the value of ISvo from 2100 nM to "3000 nM.

Таблиця 1 нижиснннннннннннпнпнпнннннн сини шини сини шини сини ла ТА ССС 3 ТА СГ 214 ТА 6 ІВ 1 ДА

IV and FA SG

Table 1 4 IV

TA SG lowlands: now in DA 88 TA SG 88 TA SG 80 STA 11111111

Iv 11111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111

Deuteriumett A

Diastereomer 1

Deeteryumg YES

Diastereomer 2 1 The compound may have been isolated along with the enantiomer and/or one or more diastereomers, with the additional isomer(s) likely to be up to x 1.5 95 of the total amount isolated.

Method of obtaining A

(А)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine 5 ЙОО319| Step A: Preparation of (HB)-tert-butyl 2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-carboxylate: A solution of tert-butyl pyrrolidine-1-carboxylate (4.09 mL, 23.4 mmol) and (-)-sparteine (6.44 ml, 28.0 mmol) in MTBE (50 ml) were cooled to -78 "C and t-butyl lithium (LiLi) (20 ml, 28 .0 mmol, 1.4 M in cyclohexane), maintaining the internal temperature below -78 "C. The resulting solution was stirred for three hours. at -78 "C, then a solution of 2psi2 (21.0 ml, 21.0 mmol, 1 M in

Eg2O) with rapid stirring, maintaining the internal temperature at a level below -65 "С.

The light suspension obtained as a result was stirred at -78 "C for 10 min., and then heated to ambient temperature. 3-bromo-5-fluoro-2-methoxypyridine (5.05 g, 24.5 mmol), RI((OAc)" (0.262 g, 1.17 mmol) and 15. tert-VizR-HBE"; (0.407 g, 1.40 mmol) were combined into one portion. After stirring overnight at at ambient temperature, concentrated MNAOH (1 ml) was added and the mixture was stirred for 1 h. The resulting suspension was filtered through

SeiyetF and washed EBO. The organic fraction was filtered and concentrated, and the crude product was purified by silica gel column chromatography, eluting with EtOAc/hexanes to give the product (H)-tert-butyl 2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine -1-carboxylate in the form of a yellow oily liquid (4.34 g, yield 63 95).

I00320| Step B: Preparation of (H)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine: A solution of TEA (11.3 mL, 146 mmol) in OSM (12 mL) was added to (K)- tert-butyl 2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-carboxylate (4.33 g, 14.6 mmol) and stirred at ambient temperature for 1 h. Then, the reaction mixture was concentrated, transferred to EtOAc, then washed with MnHsSOO and brine. The organic phase was dried (М9505), filtered and concentrated, and the crude product was purified using column chromatography on silica gel, eluting with 1-2 95 7 n МНн--MeonН/ОСсСМ to give (K)-5-fluoro-2-methoxy- 3-(pyrrolidin-2-yl)pyridine as a liquid (1.40 g, yield 49 95).

I00321| The enantiomeric excess (ee 90) of (H)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine was determined as follows: to a solution of a small amount of ((K)-5-fluoro-2-methoxy-3 -(pyrrolidin-2-yl)pyridine in propan-2-ol was added an excess of M-(2,4-dinitro-5-fluorophenyl)-alaninamide (ESAA, Marfa's reagent). The mixture was heated to reflux for about two minutes After cooling to ambient temperature, the reaction mixture was diluted with acetonitrile and analyzed using HPLC (column:

UMS 005-AO 4.6 x 50 mm, Z μm, 120A; mobile phase: 5-95 95 solvent B in A; solvent A:

NgO/1 95 IRA/10 mM ammonium acetate, and solvent B: ACM/1 95 IRA/LO mM ammonium acetate; flow rate: 2 ml/min.) The enantiomeric excess was determined by the peak areas of the two diastereomeric derivatives formed. It was determined that the EE 95 indicator of the product was » 93 Fr.

The method of obtaining B fa; s- she

M M dream / -E "o -

M

(8)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylic acid 00322) Step A: Preparation of ethyl 5 -hydroxypyrazole|1,5-a|pyrimidine-3-carboxylate: In a mixture of ethyl -3-amino-1H-pyrazole-4-carboxylate (25.0 g, 161 mmol) and (E)-ethyl 3-ethoxyacrylate (35, 8 ml,

Cesium carbonate (78.7 g, 242 mmol) was added to OME (537 mL) and the reaction mixture was heated at 110°C for 15 h. After cooling to ambient temperature, the reaction mixture was acidified with acetic acid to pH 4. Obtained in as a result, the precipitate was filtered, washed with water and EtOAc to obtain the product in the form of a white solid. To extract an additional amount of the product, the filtrate was concentrated, diluted

EtOAc (500 mL) and washed with H2H0 (5 x 200 mL). The precipitate obtained as a result in the EWC layer was filtered and washed with water and EWC to obtain the second portion of the product. Two portions of the product were combined and dried under reduced pressure to obtain ethyl -5-hydroxypyrazolo|1,5-a|pyrimidine-3-carboxylate as a white solid (33.3 g, yield 100 95). M5 (arsi) t/2 - 206.2 (M-H).

I0OZ23| Step B: Preparation of ethyl 5-chloropyrazolo|1,5-a|pyrimidine-3-carboxylate: 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 h, the reaction mixture was cooled and concentrated to remove excess ROCIiz. The residue was diluted with OSM (100 mL) and slowly added to a flask containing ice-cooled water. The mixture was separated and the aqueous phase extracted using OSM (2 x 200 ml). The combined organic phases were dried (М950:5), filtered and concentrated to give ethyl -5-chloropyrazolo|1,5-a|pyrimidine-3-carboxylate in the form of a pale yellow of solid matter (24.2 g, yield 97.6 95). M5 (arsenic) t/2 - 225.9 (MN).

I00324| Step C: Preparation of (H)-ethyl -5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate: A mixture of ethyl -5-chloropyrazoloi|1,5-a|Ipyrimidine-3-carboxylate (0.75 g, 3.32 mmol), (K)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine (method A, 0.984 g, 3.66 mmol), OIEA (2.32 mL, 13.3 mmol), and n-butanol (1.11 mL) were packed in a high pressure test tube and heated at 90 C for 48 hours. The reaction mixture was diluted with EOAc and washed with water, saline solution, and saturated Mansoz solution.

The organic phase was dried (Mud5O54), filtered and concentrated to obtain a dark orange oily liquid. The crude material was purified using column chromatography on silica gel, eluting with 50-80 956 EIOAc/hexanes to give (H)-ethyl-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl )-pyrazolo|1,5-a|Ipyrimidine-3-carboxylate (0.72 g, yield 56.2 95) as a yellow foamy solid. M5 (arsi) t/7 - 386.0 (М--Н).

I0OZ25I Step p: Preparation of (H)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)upyrazolo|1,5-a|pyrimidine-3-carboxylic acid: to suspension (K)-ethyl -5-(2-(5-fluoro-2-methoxypyridin-3Z-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate (0.72 g, 1.868 mmol) in Meon (9.34 ml) was added GION (1 N, 3.74 ml, 3.74 mmol) and the reaction mixture was heated at 70 C for 15 h. After cooling, the reaction mixture was concentrated, and the resulting residue was diluted with water. After acidification with citric acid, the aqueous phase was extracted using OSM. The combined organic phases were dried (Ma5O54), filtered and concentrated to obtain (K)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)upyrazolo|1,5-a |Ipyrimidine-3-carboxylic acid (0.67 g, yield 100 95) as a yellow solid. M5 (Arsi) t/2 - 357.9 (MAN).

The method of obtaining S tvo SEZSOZN

MN

Ome

IS

(8)-4-(tert-butyldimethylsilyl)oxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine 2,2,2-trifluoroacetate

I00326| Stages А-ХО correspond to the methodology given in the publication: N. Itatyga ей ай.,

Temganeagop, 2000, 56, 7705.

I00Z327| Step A: Preparation of (H)-4-(tert-butyldimethylsilyloxy)pyrrolidin-2-one: to a suspension of (8)-4-hydroxypyrrolidin-2-one (purchased from Avia Tesp or Aidgisp) (5.030 g, 48.26 mmol) in OME (24 ml) at 0 "C was added TVOM5-SI (7.637 g, 50.67 mmol), and then - imidazole (4.978 g, 72.39 mmol). The resulting mixture was heated to ambient temperature and stirred for 1 hour, then poured into 100 ml of water while stirring.

The resulting suspension was filtered, the solid precipitate was washed with water and dried at

From reduced pressure to obtain (H)-4-(tert-butyldimethylsilyloxy)pyrrolidin-2-one (10.14 g, yield 97.56 95), which was used directly in this form, without additional purification.

I0OZ28) Stage B: Preparation of (H)-tert-butyl-4-(tert-butyldimethylsilyloxy)-2-oxopyrrolidine-1-carboxylate: to a solution of (H)-4-(tert-butyldimethylsilyloxy)pyrrolidin-2-one (10 ,14 g, 47.08 mmol) in Meskm (16 ml) at 0 "С, OMAR (3.221 g, 26.37 mmol), TEA (3.957 ml, 28.25 mmol) and VosgO (11.49 g, 52.65 mmol). The resulting mixture was heated to ambient temperature and stirred for 48 h. The reaction mixture was poured into water and extracted with EtOAc (100 ml). The organic phase was successively washed with a 1 N aqueous solution of NOI (2 x 50 ml), 1 N aqueous Mahon solution (50 ml) and brine. The organic phase was dried over M950", filtered and concentrated in vacuo to give /(H)-tert-butyl-4-(tert-butyldimethylsilyloxy)-2-oxopyrrolidine - 1-carboxylate (13.62 g, yield 91.6995). "H NMR (COsSys) b 4.39 (t, 1H), 3.87 (t, 1H), 3.62 (t, 1H), 2.71 (t, 1H), 2.46 (t, 1H), 1.53 (5, 9H), 0.88 (5, 9H), 0.08 (a, 6H).

I00329| Stage C: Preparation of (HB)-tert-butyl 2-(tert-butyldimethylsilyloxy)-4-(5-fluoro-2-methoxyphenyl)-4-hydroxybutylcarbamate: to a solution of (B)-tert-butyl-4-(tert- butyldimethylsilyloxy)-2-oxopyrrolidine-1-carboxylate (6.00 g, 19.0 mmol) in TNE (36 ml) at 0 "b was added a 0.5 M solution of (5-fluoro-2-methoxyphenyl)magnesium bromide in TNE (50.0 ml, 25.0 mmol).

The resulting mixture was stirred at 0 "С for 30 min., then treated with MeOnH (60 ml) and Movna (0.966 g, 25.2 mmol). After stirring at 0 "С for an additional 30 min. the reaction mixture was poured into a saturated aqueous solution of MNaCl (40 ml) and extracted with EtOAc (2 x 50 ml). The combined organic phases were washed with saline solution, dried over M950»5, filtered and concentrated under reduced pressure to obtain crude material, which was purified using column chromatography on silica gel, eluting with 0-2 95 Meon/OSM to obtain (H)- tert-Butyl 2-(tert-butyldimethylsilyloxy)-4-(5-fluoro-2-methoxyphenyl)-4-hydroxybutylcarbamate (which was predicted to be a mixture of syn and anti isomers) (4.81 g, yield 57, 0 95). "H NMR (SOCIiz) b 7.20 (t, 1H), 6.90 (t, 1H), 6.77 (t, 1H), 5.12 (t, 1H), 4.10 (t, 1H ), 3.82 (t, 3H), 3.29 (t, 2H), 1.71-1.93 (t, 2H), 1.45 (5, 9H), 0.93 (a, 9H) , 0.11-0.14 (t, 6H).

ЯООЗЗО| Step 0: Preparation of (B)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylate: to a solution of (B)-tert-butyl 2-(tert- butyldimethylsilyloxy)-4-(5-fluoro-2-methoxyphenyl)-4-hydroxybutylcarbamate (4.810 g, 10.84 mmol) in SNeaSi" (108 ml) at -60 "C was added TEA (4.534 ml, 32.53 mmol) and then - 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 a saturated aqueous solution of MaHSOOz (50 ml). The organic phase was separated and the aqueous phase was extracted using СНоСи" (2 x 50 ml). The combined organic phases were dried over Md50O", filtered and concentrated under reduced pressure to obtain crude material, which was purified using column chromatography on silica gel, eluting with 2-10 95 Meon/OSM to obtain (HB)-tert-butyl 4- (tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylate (which was predicted to be a mixture of cis and trans isomers; 2.648 g, yield 57.38 95). | S/M5 (Eb--arsi) t/2 - 326.1 (M-A-N-Vos).

I0OZZ1 Step E: Preparation of (A)-4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine 2,2,2--rifluoroacetate: to a solution of (K)-tert-butyl 4-( tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylate (2.648 g, 6.222 mmol) was added to SNeSig (26 ml) at 0 "C with TEA (9.3 ml). The resulting the mixture was heated to ambient temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to obtain the crude material, which was used to prepare an azeotropic mixture with toluene-SNesSig (2x) and dried under reduced pressure to obtain (8)-4-( tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine 2,2,2-trifluoroacetate (which was predicted to be a mixture of cis and trans isomers; 2.92 g, yield 106.8 95) , which was used directly in this form,

Without additional cleaning. And C/M5 (EzZarsi) t/2 - 326.3 (M'-H).

Method of obtaining Yu no no

M nm on sleep

IS

(8!)-5-(2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylic acid

I00332| Step A: Preparation of (HA)-ethyl -5-(4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-Z- carboxylate: to a suspension of ethyl -5-hydroxypyrazolo(|1,5-a|pyrimidine-Z-carboxylate (0.100 g, 0.483 mmol) and BOP reagent (0.320 g, 0.724 mmol) in OME (1 ml) at 0 "C a solution of (H)-4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-2,2,2-trifluoroacetate (production method C; 0.167 g, 0.483 mmol) in СНеСи" ( 1 mL) and M,M-diisopropylethyl amine (0.420 mL, 2.41 mmol). The resulting mixture was warmed to ambient temperature and stirred for 18 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with saturated aqueous MnSO 2 and salt solution. Back extraction of the salt phase was carried out using EIOAc (3). The combined organic phases were dried over Md5O", filtered and concentrated under reduced pressure to obtain crude material, which was purified using column chromatography aphia on silica gel, carrying out elution 0-50 95

EtOAc/hexanes to obtain (H)-ethyl -5-(4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3 -carboxylate (as a mixture of cis- and trans-isomers) (0.0487 g, yield 19.6 95). | S/M5 (EZ-arsi) t/2 - 515.2 (M.N).

I00333| EStep B: Preparation of (NK)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-yl)upyrazolo|1,5-a|Ipyrimidine-3-carboxylate: to the solution (K )-ethyl 5-(4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)-pyrazolo|1,5-a|pyrimidine-3-carboxylate (in the form of a mixture of cis - and trans isomers) (0.0487 g, 0.0946 mmol) in TNE (1 ml) at 0 C was added 1 M TVAE in TNE (0.104 ml, 0.104 mmol). The reaction mixture was heated to ambient temperature and stirred for 2.5 h. The reaction mixture was diluted with EtOAc (10 ml), washed with brine, dried over Ma5O5", filtered and concentrated under reduced pressure to obtain crude (H)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4 -hydroxypyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylate (in the form of a mixture of cis- and trans-isomers; 37.9 mg, yield 100 95). GS/M5 (Eukharsi) t/7 - 401.1 (M--N). 00334) Stage C: Preparation of (H)-ethyl -5-(2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-1-yl)upyrazolo|1,5-a|pyrimidine-3-carboxylate: to solution of (K)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate (in the form of a mixture of cis- and trans - isomers; 0.0379 g, 0.0947 mmol) in SNESSIG (1 ml) at 0 "С, 1 M VViz in SNESSIG (0.473 ml, 0.473 mmol) was added. The resulting mixture was heated to ambient temperature for 25 hours. then it was diluted with SNesSig (10 ml) and poured into a mixture of ice and a saturated aqueous solution of МаНсСОО" (15 ml). The organic phase was separated, and the aqueous phase was acidified with the help of 1 N aqueous solution of HC to pH - 5-6. An aqueous extraction was carried out phase with the help of CNH" (3x), and the combined organic phases were dried over Ma50O", filtered and concentrated under reduced pressure to obtain a mixture of (A)-5-(2-(5-fluoro-2-hydroxyphenyl)-4- hydroxypyrrolidin-1-yl)pyrazolo(1,5-a|pyrimidine-3-carboxylic acid (in the form of a mixture of cis - and trans isomers) and (A)-ethyl -5-(2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo|1,5- a|Ipyrimidine-3-carboxylate ( in the form of a mixture of cis- and trans-isomers). The mixture was dissolved in Meon-

TNE (0.25 ml/0.75 ml) and treated with 1 N aqueous solution of ION (0.474 ml, 0.474 mmol).

The mixture obtained as a result was heated at 50 "C for 1 hour, then cooled to ambient temperature and acidified to pH 3-4 with the help of 1 N aqueous solution of HCl. The mixture was extracted with EOAcC (3 x 15 ml), and The combined organic phases were dried over NaCl, filtered and concentrated under reduced pressure to give crude (8)-5-(2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-1-yl)upyrazolo|1 ,5-a|Ipyrimidine-3-carboxylic acid (in the form of a mixture of cis- and trans-isomers; 33.9 mg, yield 100 Fo). | C/M5 (EzZkarsi) t/2 - 357.1 (M-H ).

Example 1 fa, pesh y o no ,/x is

IS

Ko) (68)-9-fluoro-2,11,15,19,20,23-hexaazapentacyclo|15,5,2,1711,026.02024|Ipentacose- 1(23),7,9,17(24), 18,21-hexaene-16,25-dione

Y00335| Step A: Preparation of (H)-ethyl -5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-1-yl)upyrrolidin-1-yl)upyrazolo|1,5-a| Ipyrimidine-3-carboxylate: to the mixture of (K)-ethyl -5-(2-(5-fluoro-2-methoxypyridin-33-yl)pyrrolidin-1-yl)pyrazolo|1,5-a| pyrimidine-3-carboxylate (method of preparation

B, stage C; 0.92 g, 2.39 mmol) and acetic acid (5.73 g, 95.5 mmol) was added HB»g (4.4 ml, 23.9 mmol, 33 95 in acetic acid). The reaction mixture was heated at 90 "C for 2 hours. After cooling, the reaction mixture was treated with EIOAc, washed with water, a saturated solution of ManHCO3 and brine, then dried (M9505), filtered and concentrated. The crude product was purified using silica gel column chromatography, elution With Meon/OSM to obtain the required product (0.605 g, yield 68 95). M5 (arsi) t/2 - 372.0 (MAN). 00336) Step B: Preparation of (HA)-ethyl -5-(2- (1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo(1,5- a|Ipyrimidine-3-carboxylate: to the suspension (A)-ethyl -5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1, 5-a|pyrimidine-3-carboxylate (0.20 g, 0.54 mmol) in OME (5 ml) was added H IN (6.8 mg, 0.81 mmol) at 0 "C, after which it was first stirred for 20 min., and then a solution of /-2-(3-bromopropyl)isoindoline-1,3-dione (0.29 g, 1.1 mmol) in OME (1 mL) was added. The reaction mixture was warmed to ambient temperature medium and stirred for 17 hours. After cooling to 0 "C, the reaction was stopped with ice water (30 ml), and the aqueous phase was extracted with EOAc (3 x 50 ml). The combined organic phases were washed under reflux with water and brine, dried (Md5O» ), filtered and concentrated.

The crude product was purified using column chromatography on silica gel,

eluting with 2 96 MeOOn/OSM to give the required product (0.2 g, yield 66 95). M5 (arsi) t/2 - 559.0 (M'-H).

И0ОЗ37| Step C: Preparation of (H)-ethyl /-5-(2-(1-(3-aminopropyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo |1,5-a|pyrimidin-3-carboxylate: to a solution of (B)-ethyl -5-(2-(1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-5-fluoro- 2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)upyrazolo|1,5-a|Ipyrimidine-3-carboxylate (0.20 g, 0.36 mmol) in a mixture of 1:11 MeOHn /TNE (12 mL) was added hydrazine-HgO (0.18 g, 3.6 mmol). The reaction mixture was heated at 50 °C for 24 hours.

After cooling, the reaction mixture was poured into water and extracted using OSM (3 x 20 ml). The combined organic phases were dried (Ma5O54), filtered and concentrated to obtain the required product (0.11 g, yield 72 95). M5 (Arsi) t/2 - 429.0 (MAN). 00338) Stage 0: Preparation of (H)-5-(2-(1-(3-aminopropyl)-5-fluoro-2-oxo-1 2-dihydropyridin-3-yl)upyrrolidin-1-yl)pyrazolo|1 ,5-a|pyrimidine-3-carboxylic acid: to a solution of (B)-ethyl -5-(2-(1-(3-aminopropyl)-5-fluoro-2-oxo-1,2-dihydropyridine-3- yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate (0.11 g, 0.26 mmol) in a mixture of 3:1 TNE/MeOn (8 ml) was added GiOH (1 N, 1.5 ml, 1.5 mmol) and heated the reaction mixture at 70 "C for 20 h. After cooling, the reaction mixture was treated with MeOH, acidified with 1 N HCl (1.5 ml) and concentrated to obtain the required product (0, 1 g, output 100 95). M5 (Arsi) t/72 - 401.1 (MA-H).

I0OZZZ9)| Stage E: Preparation of (6K)-9-fluoro-2,11,15,19,20,23- hexaazapentacyclo|15,5,2,1271,026,020,2YIpentacose-1(23),7,9,17(24 ),18,21-hexaene-16,25-dione. To a solution of (8)-5-(2-(1-(3-aminopropyl)-5-fluoro-2-oxo-1 2-dihydropyridin-3-yl)pyrrolidin-1-yl)upyrazolo|1,5-a |Ipyrimidine-3-carboxylic acid (95 mg, 0.24 mmol) in a mixture of 12 OME/USM (9 ml) was added EOSI (0.14 g, 0.71 mmol), and then NOVT (96 mg, 0.71 mmol) at ambient temperature. After stirring for 10 min. was added to the reaction mixture

TEA (0.099 mL, 0.71 mmol) and stirred for 6 h. The reaction mixture was treated with EtOAc, washed with a saturated solution of MNACI, a saturated solution of ManHsoz and a saline solution, then dried (Ma5O»54), filtered, and concentrated. The crude product was purified by column chromatography on silica gel, eluting with 4 96 MEeEOH/OSM to give the indicated product (35 mg, yield 39 95). M5 (Arsi) t/72 - 383.2 (MAN).

Example 2 fa

Mikhail V

Koo)! io (68)-12-oxa-2,16,20,21,24 26-hexaazapentacyclo| 6.5.2.1711,026,02129 Hexacos-1(24),7(26),8,10,18(25), 19,22-heptaen-17-one

Y00340| Step A: Preparation of (H)-2-methoxy-6-(pyrrolidin-2-yl)pyridine: Prepared according to the method described in the section "Preparation method A", substituting 3-bromo-5-fluoro-2-methoxypyridine on 2-bromo-6-methoxypyridine at stage A. M5 (several) t/2 - 179.1 (MAN).

I00341| Step B: Preparation of (HA)-ethyl -5-(2-(6-methoxypyridin-2-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylate: Obtained in the same way as and described in the section "Method of preparation B", step C, replacing (H)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine with (K)-2-methoxy-6-(pyrrolidin- 2-yl)/pyridine. M5 (several) t/7 - 368.0 (M'-H).

I00342| EEEStep C: Preparation of (H)-ethyl -5-(2-(6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-1-yl)upyrazolo|1,5-a|pyrimidine-3-carboxylate: to a mixture of (H)-ethyl -5-(2-(6-methoxypyridin-2-yl)upyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate (0.46 g, 1.25 mmol) and acetic acid (3.0 g, 50 mmol) was added HBg (3.1 g, 12.5 mmol, 33 95 in acetic acid). The reaction mixture was heated at 90 "C for 2 hours. After cooling, the reaction mixture was diluted with E(Ac), washed with water, a saturated solution of ManHsCO3 and brine, then dried (Mo95Ozh), filtered and concentrated. The crude product was purified using column chromatography on silica gel, eluting with 4 95 Meonlosm to obtain the required product (0.3 g, yield 67 95). M5 (arsi) t/2 - 354.1 (M--H). 00343) Step 0: Obtaining (H)-ethyl 5 -(2-(6-(3-(1,3-dioxoisoindolin-2-yl)upropoxy)pyridin-2-yl)upyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylate: to suspension of (K)-ethyl 5-(2-(6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylate (0.091 g, 0 .26 mmol) in OME (2 ml) was added GIN (3.2 mg, 0.39 mmol) at 0 "C. After stirring for 20 min. a solution of 2-(3-bromopropyl)isoindoline-1,3-dione (0.14 g, 0.52 mmol) in OME (1 ml) was added,

the reaction mixture was heated to ambient temperature and stirred for 17 h. After cooling to 0 "C, the reaction was stopped with ice water (30 ml), and extraction was carried out using EtOAc (3 x 50 ml). The combined organic phases were washed with water and brine, dried (Md5O54), filtered and concentrated. The crude product was purified by column chromatography on silica gel, eluting with 1.5 96 MEOH/OSM to give the desired product (0.117 g, yield 84 95).M5 (several) t/7 - 541.1 (MA-N).

I00344| EEEStep E: Preparation of (H)-ethyl -5-(2-(6-(3-aminopropoxy)pyridin-2-yl)pyrrolidin-1-yl)upyrazolo!|1,5-a| pyrimidine-3-carboxylate: to a solution of (B)-ethyl -5-(2-(6-(3-(1,3-dioxoisoindolin-2-yl)upropoxy)pyridin-2-yl)pyrrolidin-1-yl) pyrazolo|1,5-a|Ipyrimidine-3-carboxylate (0.11 g, 0.20 mmol) in a mixture of 1:11 MeOHN/TNE (12 ml) was added hydrazine-H2HO (0.10 g, 2.0 mmol ). The reaction mixture was heated at 50 "C for 24 hours. After cooling, the reaction mixture was poured into water and then extracted using SOHC (3 x 20 ml). The combined organic phases were dried (M9505), filtered and concentrated to obtain the required product ( 70 mg, yield 84

Pho). M5 (Arsi) t/72 - 441.1 (Ma-H).

І00345| Stage b: Preparation // (H)-5-(2-(6-(3-aminopropoxy)pyridin-2-yl)pyrrolidin-1-yl)upyrazolo|1,5-a| pyrimidine-3-carboxylic acid: to a solution of (H)-ethyl /-5-(2-(6-(3-aminopropoxy)pyridin-2-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine -Z-carboxylate (70 mg, 0.17 mmol) in a mixture of 3:11 TNE/Meoion (8 ml) was added GION (1 N, 1.5 ml, 1.5 mmol) and the reaction mixture was heated at 70 C for 20 hours After cooling, the reaction mixture was diluted with Meon, acidified with 1 N NOI (1.5 mL) and concentrated to give the desired product (65 mg, yield 10095). M5 (arsi) pt/: - 383.1 (M'-H).

И0ОоЗ46) Stage о: Obtaining (68)-12-oxa-2,16,20,21,24,26-hexaazapentacyclo-

I16.5.2.1771,026,021,25|)hexacose-1(24),7(26),8,10,18(25),19,22-heptaen-17-one: to a solution of (H)-5- (2-(6-(3-aminopropoxy)pyridin-2-yl)pyrrolidin-1-yl)pyrazolo |1,5-a|pyrimidine-3-carboxylic acid (70 mg, 0.18 mmol) in a mixture of 122 OME /OSM (9 mL) was added EOSI (110 mg, 0.55 mmol), and then

NOVT (74 mg, 0.55 mmol) at ambient temperature. After stirring for 10 min. TEA (0.077 ml, 0.55 mmol) was added to the reaction mixture and stirred for 2 h. The reaction mixture was diluted with EtOAc, washed with saturated solution of MNaCl, saturated solution of Mansoz and saline solution, then dried (Mo5O5), filtered and concentrated. The crude product was purified by column chromatography on silica gel, eluting with 2 96 MEOH/OSM to give the indicated product (30 mg, yield 45 95). M5 (Arsi) t/2 - 365.2 (MAN).

Example Z u shch s ! -e axes I g and M

R

(68)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo| 1 7,5,2,026,0712,02226 Hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one

Y00347| EStep A: Preparation of (H)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-M-(3-hydroxypropyl)pyrazolo|1,5-a|Ipyrimidine- Z-carboxamide: to the suspension of (H)-5-(2-(5-fluoro-2-methoxypyridin-Z-yl)pyrrolidin-1-yl)upyrazolo (P1,5-a|Ipyrimidine-Z-carboxylic acid (method preparation of B, 250 mg, 0.700 mmol) and NATI (319 mg, 0.840 mmol) in OME (2 ml) cooled to 0 "С, 3-aminopropan-1-ol (0.0642 ml, 0.840 mmol) was added dropwise , resulting in a clear yellowish solution. After adding OIEA (0.366 mL, 2.10 mmol) dropwise, the ice bath was removed and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was directly purified using reverse-phase column chromatography (system Vioiade 5P4, C-18 25-M column, 0-54,905 acetonitrile/water mixture) to give the product as a white solid (200 mg, yield 69,965).

M5 (Arsi) t/72 - 415.1 (M--H).

І00348| Stage B: Preparation of /(H)-M-(3-chloropropyl)-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a)pyrimidine -3-carboxamide: Mixture (88)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-M-(3-hydroxypropyl)pyrazolo|1,5-a| pyrimidine-3-carboxamide (20 mg, 0.0483 mmol) in HCl (4 N, dioxane, 1.2 mL, 4.83 mmol) was heated at 85 °C overnight.

The reaction mixture was concentrated, titrated with diethyl ether and

Z was filtered to give the crude product as a beige solid, which was used directly in the next step without further purification (22 mg, yield 106 95). M5 (Arsi) t/2 - 419.1 (MAN). 00349) Stage C. Preparation of (6K)-9-fluoro-13-oxa-2,11,17,21,22,25- hexaazapentacyclo|17,5,2,026,0712 022,26) hexacose-1(25), 7,9,11,19(26),20,23-heptaen-18-one:

Suspension of (8)-M-(3-chloropropyl)-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)upyrazolo|1,5-a|Ipyrimidine-3-carboxamide (5 mg, 0.012 mmol) and C52CO3 (4 mg, 0.06 mmol) in OME (1 mL) were heated at 85 °C overnight. The reaction mixture was filtered through SB/E filter paper and directly purified using a reverse-phase column chromatography (Vioiade 5P4 system, C-18 12-M column, 5-60 95 acetonitrile/water mixture) to obtain the specified product in the form of a white solid (2 mg, yield 44 95). M5 (arsenic) t/72 - 383 ,3 (MAN).

Example 4 dO mm

M but o. Man what? MIND

IS

(628)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25- hexaazapentacyclo| 1 7,5,2,026,0712,02226hexacos-1(25),7,9,11,19(26),20,23-heptayen-18-one

И00ОЗ50| Step A: Preparation of M-(2,3-dihydroxypropyl)-5-(H)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo P,5-a|Ipyrimidine- 3-carboxamide: A mixture of (88)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylic acid (production method B, 250 mg, 0.700 mmol) and NATIi (319 mg, 0.840 mmol) in a 1:11 mixture of OME/OM5O (2 ml) were cooled to 0 °C, after which 3-aminopropane-1,2-diol was first added dropwise (76.5 mg, 0.840 mmol) followed by OIEA (366 μL, 2.10 mmol). The reaction mixture was warmed to ambient temperature, stirred for 20 min, and then directly purified by reverse-phase column chromatography ( Vioiade 5P4 system, C-18 25-M cartridge, 5-50 95 acetonitrile/water mixture) to give the product as a white solid (295 mg, yield 98 95). M5 (arsenic) t/72 - 431.1 ( M--H).

И0ОЗ351| Stage B: Preparation of M-(3-chloro-2-hydroxypropyl)-5-((H)-2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl) Pyrazolo|1,5-a|Ipyrimidine-Z-carboxamide: A mixture of M-(2,3-dihydroxypropyl)-5-(H)-2-(5-fluoro-2-methoxypyridin-3Z-yl)pyrrolidin-1- yl)pyrazolo|1,5-

2 α|Ipyrimidine-3-carboxamide (100 mg, 0.232 mmol) and HCI (4 N, dioxane, 5.8 mL) were packed in a high-pressure test tube and heated at 85 °C overnight. After decanting the clear solution the crude product was obtained as a brownish oily residue, which was dried in vacuo and used directly in the next step without further purification.

I0Ooz52I Stage (o) Preparation of (6K)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25- hexaazapentacyclo|1 7,5,2,026,07y12 02226|hexacose-1(25 ),7,9,11,19(26),20,23-heptayen-18-one:

Suspension M-(3-chloro-2-hydroxypropyl)-5-((H)-2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)upyrrolidin-1-yl)pyrazolo|1 ,5-α|Ipyrimidine-3-carboxamide (100 mg, 0.23 mmol) and Св2СО3 (375 mg, 1.15 mmol) in OME (3 mL) were heated at 85 "C for 2 h. The reaction mixture was filtered through paper OB/E filter and directly purified by reversed-phase column chromatography (Vioiade 5P4 system, C-18 25-M column, 5-50 95 acetonitrile/water) to give the indicated product as a white solid. t/27 - 399.2 (MAN).

Example 5 I, and I and ke oon

Her t - UM

IS

(68,135)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo- (15,5,2,171,026,020,24|)pentacose-1(23),7,9,17(24 ),18,21-hexaene-16,25-dione

И0О353| Stage A: Preparation of M-((5)-3-chloro-2-hydroxypropyl)-5-(A)-2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1 -yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxamide hydrochloride:

Obtained in accordance with the method described in example 3, stages A-B, replacing 3-aminopropan-1-ol in stage A with (5)-3-aminopropan-1 2-diol. M5 (arsi) t/2 - 435.0 (M--H).

I0Oz54 Stage B: Preparation of (68,135)-9-fluoro-13-hydroxy-2,11,15,19,20,23- hexaazapentacyclo|15,5,2,172571,026,02024, pentacose-1(23), 7,9,17(24),18,21-hexaene-16,25-dione:

Suspension M-((5)-Z-chloro-2-hydroxypropyl)-5-((H)-2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)upyrrolidin-1-yl )pyrazolo|1,5-a|Ipyrimidine-3-carboxamide hydrochloride (40 mg, 0.085 mmol) and

C526bOz (138 mg, 0.42 mmol) in OME (0.8 ml) was heated at 85 °C for 2 h. The reaction mixture was filtered through a SB/E paper filter and directly purified by reverse-phase column chromatography (Vioiade 5P4 system , column C-18 12--M, 0-40 Fo mixture of acetonitrile/water) with obtaining the specified product in the form of a white solid (4 mg, yield 12 96). M5 (arsenic) t/72 - 399.2 (M .-N).

Example 6 in English and M

IS

(628)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-17,5,2,025,07y12,02226|hexacose-1(25),7,9 ,11,19(26),20,23-heptaen-18-one

Y00355| It was obtained in accordance with the method described in example 5 and was isolated as a side product in step B. It was found that the enantiomeric integrity of the chiral center to which the HO group was attached was suddenly violated (the K/5 ratio was approximately 10:7 ) in the selected final product - (6НА)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25- hexaazapentacyclo-(17,5,2,026,0712,02226|hexacose-1 (25),7,9,11,19(26),20,23-heptaen-18-one, which was obtained in the form of a white solid (5 mg, yield 15 95) using reversed-phase column chromatography Vioiade 5P4 system , column C-18 12-M, 0-50 95 acetonitrile/water). M5 (Arsi) t/72 - 399.2 (M.--N).

Example 7 to, and nn (F)

M. M. on tires and M

IS

(68,158)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-

И17,5,2,026,07и12 02226|hexacose-1(25),7,9,11,19(26),20,23-heptaen-18-one

І00356| Stage A: Preparation of M-(HA)-3-chloro-2-hydroxypropyl)-5-((H)-2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1 -yl)pyrazolo|1,5-a|Ipyrimidine-Z-carboxamide: Obtained in accordance with the method described in example 3, steps A-B, replacing 3-aminopropan-1-ol in step A with (A)Z- aminopropane-1 2-diol. M5 (arsi) t/2 - 435.0 (M--H).

І00357| Stage B: Preparation of (6H,15H8)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25- hexaazapentacyclo I17,5,2,026,07y12,02226|hexacose-1(25 ),7,9,11,19(26),20,23-heptaen-18-one:

Suspension M-((A)-3-chloro-2-hydroxypropyl)-5-((8)-2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)upyrrolidin-1-yl )pyrazolo|1,5-a|Ipyrimidine-3-carboxamide (30 mg, 0.069 mmol) and Св2СО3 (112 mg, 0.34 mmol) in OME (0.7 ml) were heated at 85 "C for 1 h. The reaction the mixture was filtered through a CE/E paper filter and directly purified using reversed-phase column chromatography (Vioiade 5P4 system, C-18 12-M column, 0-50 95 acetonitrile/water mixture) to obtain the specified product as a white solid ( 10 mg, yield 36 95).Unlike example b, in the final product there was no violation of the enantiomeric integrity of the chiral center to which the HO group is attached. M5 (arsenic) t/72 - 399.2 (М-Н).

Example 8 fa, c po and Ye o en

And Mn and Ii

IS

(6A,138)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo-

I15,5,2,1711,026 02024|pentacose-1(23),7,9,17(24),18,21-hexaene-16,25-dione

Y00O358) was obtained as a by-product in example 7, step B, and isolated as a white solid (1.2 mg, yield 4 95) using reverse-phase column chromatography (Vioiade 5P4 system, column C-18 12-М , 0-44 95 acetonitrile/water mixture) from crude material from example 7, stage B. M5 (arsenic) t/2 - 399.2 (M.N).

Example 9 sh mu y a m' M o o-

BUT

- M

IS

(68)-9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacycloi|16,5,2,026,0712,02125|pentacose-1(24),7,9,11,18 (25),19,22-heptaen-17-one

II00359| EEEStep A: Preparation of (H)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-M-(2-hydroxyethyl)pyrazolo(1,5-a|pyrimidin- 3-carboxamide: to the suspension of /(H)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)upyrazolo (P1,5-a|Ipyrimidine-3-carboxylic acid ( Preparation B, 100 mg, 0.28 mmol) and NATI (128 mg, 0.336 mmol) in OME (1 mL) was added OIEA (0.146 mL, 0.840 mmol) at ambient temperature, and then 2-aminoethanol solution was added dropwise (20.5 mg, 0.336 mmol) in a minimal amount of OME at 0 "C. The reaction mixture was heated to ambient temperature and stirred for 30 min., then directly purified by reverse-phase column chromatography (0-70 Fo mixture of acetonitrile/ water) to obtain the product in the form of a white solid (95 mg, yield 85 FUv). M5 (arsi ROB) t/2 - 401.1 (M.N).

И00З360О| Stage B: Preparation of (H)-M-(2-chloroethyl)-5-(2-(5-fluoro-2-oxo-1 2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo P,5- a|Ipyrimidine-3-carboxamide: to (88)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-M-(2-hydroxyethyl)pyrazolo|1,5 -a|Ipyrimidine-3-carboxamide (77 mg, 0.192 mmol) in a high-pressure test tube was added with hydrochloric acid (4 N, dioxane, 4.8 mL, 19.2 mmol), and the resulting white suspension was heated for 85 "C

From during the night. After heating to ambient temperature, the reaction mixture was decanted to obtain the crude product in the form of a brownish oily residue, which was dried in a vacuum and directly used in the next step, without additional purification. M5 (arsi) pt/2 - 405.0 (M--H). 003611 Stage C. Preparation of (68)-9-fluoro-13-oxa-2,11,16,20,21,24- hexaazapentacycloi16,5,2,026,0712,02125)pentacose-1(24),7,9, 11,18(25),19,22-heptayen-17-one:

Suspension (A)-M-(2-chloroethyl)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)upyrazolo|1,5-a |Ipyrimidine-3-carboxamide (78 mg, 0.19 mmol) and С52СО3 (314 mg, 0.96 mmol) in

OME (5 ml) was heated at 85 "C for 30 min. After filtering through a paper filter

The CP/E reaction mixture was diluted with water (40 ml) and MNACI (saturated, 5 ml), then extraction was carried out with EIOAc (3 x 40 ml). The combined organic extracts were dried (Ma?5Ox), filtered and concentrated. The crude product was purified by reversed-phase column chromatography (Vioiade 5P4 system, C-18 12--M column, 0-73 Fo acetonitrile/water mixture) to obtain the indicated product as a white solid (17 mg, yield 24 96) . M5 (Arsi) t/72 - 369.2 (M.-N).

Example 10

UV chi n-

M. o. M

N

THE SAME

- M

IS

(68)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacycloi|18,5,2,026,0712,02527heptacose-1(26),7,9,11,20(27 ),21,24-heptaen-19-one 00362) Stage A: Preparation of (H)-M-(4-chlorobutyl)-5-(2-(5-fluoro-2-oxo-1 2-dihydropyridin-3- yl)upyrrolidin-1-yl)upyrazolo (1,5-a|Ipyrimidine-3-carboxamide: Obtained in accordance with the method described in example 3, stages A-B, replacing 3-aminopropan-1-ol in stage A with 4-aminobutan-1-ol M5 (arsenic) t/2 - 433.0 (M-А-Н).

I00363| Stage B: Preparation of (6H)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo-

I18,5,2,026,0712, 025,27) heptacose-1(26),7,9,11,20(27),21,24-heptaen-19-one: Obtained in accordance with the method described in example 3 , replacing (H)-M-(Z-chloropropyl)-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-Z- carboxamide on (H)-M-(4-chlorobutyl)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5- a|Ipyrimidine-3-carboxamide in step C. The crude product was purified using reverse-phase column chromatography (Vioiade 5P4 system, C-18 25-M column, 0-80 Fo mixture of acetonitrile/water) to obtain the indicated product in the form of a white solid (32 mg, yield 44 95). M5 (arsi ROB) t/2 -397.2 (M'-H).

Example 11 fa, pe pi

MOm o o 4 AI s-m

IS

(68)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo|16,5,2,1711,026,02125)hexacose-1(24),7,9,18(25), 19,22-hexaene-17,26-dione

І00364| Obtained as a by-product in Example 10, Step B, and isolated as a white solid (4 mg, 6 95) after purification of the crude material obtained in Example 10, Step B, by reversed-phase column chromatography (Vioiade 5P4 system, column C-18 25--M, 0-50 95 mixture of acetonitrile/water). M5 (arsi) t/2 - 397.2 (M.N).

Example 12 me se de i is

N

MA TMN a. p and M

IS

(68)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacycloi|16,5,2,026,0712,02125|)pentacose-1(24),7,9,11,18( 25),19,22-heptaen-17-one

И0ОЗ365| Stage A: Preparation of (HB)-tert-butyl 2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-

From the carboxylate: A solution of tert-butyl pyrrolidine-1-carboxylate (1 mL, 5.70 mmol) and (-)-sparteine (1.31 mL, 5.70 mmol) in anhydrous MTBE (30 mL) was first cooled to -78 " C in a nitrogen atmosphere, and then t-butyl lithium (4.07 ml, 1.4 M, 5.70 mmol) was added dropwise over 15 min using a syringe, maintaining the temperature below -75 °C. The pale yellow solution was stirred at -78 "C for 3 hours before being treated with zinc chloride (3.80 ml, 1.0 M, 3.80 mmol), added dropwise over 15 minutes, while maintaining the temperature below - 73 "S.

The mixture was stirred at -78 "С for 30 min., then placed in a water bath with ambient temperature and stirred for another hour. At the same time, a larger amount of white sediment fell out. The mixture was treated with 3-bromo-2-chloro-5-fluoropyridine (1 .00 g, 4.75 mmol) in MTBE (5 mL), then palladium acetate (53 mg, 0.24 mmol) and tri-tert-butylphosphine tetrafluoroborate (83 mg, 0.28 mmol) were added. The mixture was left to stir at ambient temperature overnight to reach completion The mixture was treated with MNAOH (1 mL), stirred for 30 min, and filtered through SB/E filter paper, washing

MTVE. The filtrate was washed with 10 95 citric acid (30 ml) and the aqueous phase was backwashed with MTBE (2 x 30 ml). The combined organic phases were washed with brine (20 mL), dried (MBO) and concentrated to give the crude product as a dark yellow oily liquid. This crude material was purified with a 50 g silica cartridge

Vioiade 5MAP, eluting with 10 95 E(OAc in hexanes to obtain the required product in the form of a colorless oily liquid (0.5 g, yield: 35 95). M5 (arsenic) t/2 - 201.1 (M--Н- Vos).

I00366| Stage B: Preparation of (H)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochloride: to a solution of (K)-tert-butyl 2-(2-chloro-5-fluoropyridin-Z3- yl)/pyrrolidine-1-carboxylate (500 mg, 1.6 mmol) in dioxane (5 mL) was added NOI (4 N, dioxane, 20 mL) and then stirred at ambient temperature overnight. The mixture was concentrated and processed

Ego, then dried in vacuo to give the product as a white solid (0.36 g, yield: 80 95). M5 (Arsi) t/2 - 201.1 (MAN). It was determined that the enantiomeric excess of the product (ee

Fo) was »92 95, according to the data of the analysis described in the method of obtaining A.

I00367| Step C: Preparation of (HA)-ethyl 5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)upyrazolo|1,5-a|Ipyrimidine-3-carboxylate: to a solution of ethyl -o-hydroxypyrazolo|1,5-a|pyrimidine-

(Benzotriazol-1-yloxy)utris(dimethylamino)phosphonium hexafluorophosphate (BOR) (646 mg, 1.46 mmol). The heterogeneous mixture was stirred for 10 min. before adding OIEA (1.16 mL, 6.6 mmol) and then (H)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochloride (363 mg, 1.33 mmol) was added . The reaction mixture was stirred at ambient temperature overnight to bring the reaction to completion. The mixture was partitioned between 10 95 citric acid (30 mL) and E(OAc (30 mL), and the aqueous phase was extracted with EOAc (2 x 20 mL). The combined organic phases were washed successively with water (20 mL), sat.

Manso:z (20 ml), water (20 ml) and saline solution (3 x 20 ml), then dried (Mag250") and

Z was concentrated to give the crude product as an orange foam. This crude material was purified with a 25 g Vioiade 5MAR silica cartridge, eluting with 1 95 Meon /OSM to give the desired product as a cream-colored foam (0.35 g, yield: 68 95). M5 (arsi) t/2 - 390.0 (М--Н).

ИООЗ368| Stage 0: Preparation of (HB)-ethyl 5-(2-(2-(2-(tert-butoxycarbonylamino)ethyl amino)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a |pyrimidine-3-carboxylate: Mixture of Ragabvaz (7.05 mg, 0.00770 mmol), С82СО3 (125 mg, 0.385 mmol), Gas-Vipar (19.2 mg, 0.0308 mmol), (B)-ethyl -5-(2-(2-chloro-5-fluoropyridin-3Z-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-Z-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 packed and subjected to microwave irradiation (120 "С) for 16 h. After cooling to ambient temperature, the reaction mixture was diluted with EIOAc (10 mL) and washed with water (2 x 5 mL). The organic phase was dried (Mag2505) and concentrated. The crude product was purified by reverse-phase column chromatography (VioFiade 5P4 system, cartridge 0-18 12-M, 5-70 95 mixture of acetonitrile/water) to obtain the required product in the form of a white foamy solid iny (38 mg, yield 58 95). M5 (Arsi) t/2 - 5141 (MAN).

ИООЗ69| Step E: Preparation of (H)-5-(2-(2-(2-(tert-butoxycarbonylamino)ethylamino)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a| of pyrimidine-3-carboxylic acid: to a solution of (B)-ethyl o 5-(2-(2-(2-(tert-butoxycarbonylamino)ethylamino)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)upyrazolo! |1.5-a| pyrimidine-3-carboxylate (38 mg, 0.074 mmol) to a mixture of TNE/MeOH/water (2:21, 0.7 mL) was added HION-H2H2O (9.3 mg, 0.22 mmol), and then stirred for 50 "C within 18 hours.

After removal of the solvent, the remainder of the reaction mixture was transferred to water (0.5 ml) and acidified with 1 N NaOH (0.22 ml) to pH 33. The reaction mixture was extracted with EtOAc (C x 2 ml), dried (Mg5O4), filtered and concentrated to obtain the required product, which was used in the next step directly, without additional purification, assuming that the conversion occurs quantitatively. M5 (arsi) t/7 - 486.0 (М--Н).

I00370| Step E: Preparation of (H)-5-(2-(2-(2-aminoethylamino)-5-fluoropyridin-3-yl)upyrrolidin-1-yl)upyrazolo(1,5-a|pyrimidine-3-carboxylic acid) hydrochloride Acids: Solution of (K)-5-(2-(2-(2-(tert-butoxycarbonylamino)ethyl amino)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine -

of 3-carboxylic acid (31 mg, 0.064 mmol) in HC (4 N, dioxane, 798 μl) and TEA (50 95, OSM, 2 ml) was stirred at ambient temperature for 1 h. before it was concentrated and dried in vacuo to give the desired product as an off-white solid, which was used in the next step directly, without further purification, assuming that the conversion is quantitative. M5 (Arsi) t/7 - 386.1 (M.N).

І00371| Stage b: Preparation of (6H)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo-

И16.5,2,026,07и12,02125| pentacose-1(24),7,9,11,18(25),19,22-heptaen-17-one: to a solution of (H)-5-(2-(2- (2-aminoethyl amino)-5 -fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylic acid (25 mg, 0.065 mmol) in OME (3 mL) was first added NATI (29 mg, 0.077 mmol) , then stirred for 5 min., and then SIEA (56 μl, 0.32 mmol) was added dropwise. After stirring at ambient temperature overnight, the reaction mixture was directly purified by reverse-phase column chromatography (Vioiade system

ЗР4, cartridge 0-18 25-М, 5-45 95 acetonitrile/water mixture) to obtain the product in the form of an off-white solid (7 mg, yield 30 95). M5 (arsi) t/7 - 368.2 (М--Н).

Example 13 dO m is not I MN

N

MA zhk en M

R

(68)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo| 1 7.5.2.026,0712,02226|hexacose-1(25),7,9,11,19(26),20,23-heptaen-18-one 00372) Stage A: Preparation of (H)-ethyl -5- (2-(2-(3-(tert-butoxycarbonylamino)propylamino)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylate: Obtained in accordance with the method , described in example 12, step O, replacing tert-butyl 2-aminoethylcarbamate with tert-butyl C-aminopropylcarbamate. M5 (Arsi) t/2 - 528.1 (MAN).

IІ00373| Stage B: Preparation of (6K)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo-

I17.5.2.026,0712 022,26) hexacose-1(25),7,9,11,19(26),20,23-heptaine-18-one: Obtained in accordance with the method described in example 12, stages E-C, in three stages, with (B)-ethyl 5-(2-(2-(3- (tert-butoxycarbonylamino)propylamino)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo| 1,5-α|Ipyrimidine-3-carboxylate obtained as described above. The crude product was purified by reversed-phase column chromatography (Vioiade 5P4 system, C-18 25-M cartridge, 5-50 95 acetonitrile/water mixture) to give the indicated product as a white solid (6 mg, yield 44 95). M5 (arsi ROB) t/7 -382.2 (M.N).

Example 14

If, pe o

M M

8, 0-79 xx - M

IS

(68)-9-fluoro-13,16-dioxa-2,11,20,21,24-pentaazapentacyclo|16,5,2,026,0712 02125 pentacose-1(24),7,9,11,18(25 ),19,22-heptayen-17-one 00374) Step A: Preparation of (H)-2-chloroethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)upyrazolo| 1.5-a| pyrimidine-Z-carboxylate: to the suspension of (H)-5-(2-(5-fluoro-2-methoxypyridine-

C-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylic acid (preparation method B, 0.1 g, 0.28 mmol) and NATI (0.128 g, 0.336 mmol) in OME (1 mL) was added OIEA (0.146 mL, 0.840 mmol) followed by 2-chloroethanol (0.0270 g, 0.336 mmol) After stirring at ambient temperature for 30 min. the reaction mixture was directly purified using reversed-phase column chromatography (Vioiade 5P4 system, C18,254-M, 5-65 Fo acetonitrile/water mixture) to obtain the intermediate product (H)-ZH-(1,2,3|Itriazoloi| 4,5-5B|pyridin-Z-yl-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylate in as a white solid (94.7 mg, yield: 71 95). This isolated intermediate was dissolved in an excess of chloroethanol (1 mL) and then SIEA was added dropwise at ambient temperature and stirred overnight to bring the reaction to completion. the mixture was directly purified by reversed-phase column chromatography (Vioiade 5P4 system, C-18 25--M, 5-73 95 acetonitrile/water mixture) to obtain the required product in the form of a white foamy solid (56 mg, yield 48 95) .

M5 (arsi) t/2 - 419.9 (M.N).

И0ОЗ375| EEEstep B: Preparation of (H)-2-chloroethyl 5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)upyrrolidin-1-yl)pyrazolo|1,5-a| pyrimidine-3-carboxylate: A mixture of (B)-2-chloroethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate (56 mg, 0.13 mmol) in NOA (4 N, dioxane, 2.5 mL, 10 mmol) was packed in a high-pressure test tube and heated at 100 °C for 45 min. The reaction mixture was cooled and concentrated with obtaining the product in the form of a yellowish oily liquid, which was used in the next step directly, without additional purification, considering that the yield is quantitative. (628)-9-fluoro-13,16-dioxa-2,11,20,21,24- pentaazapentacyclo|16,5,2,026,0712,02125I-pentacose-1(24),7,9,11,18 (25),19,22-heptaen-17-one:

A mixture of (K)-2-chloroethyl 5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-Z- carboxylate (54 mg, 0.133 mmol) and Su2CO3 (217 mg, 0.665 mmol) in OME (6 mL) was heated at 90 °C overnight. The reaction mixture was filtered (through a paper filter

SR/E) and directly purified using reversed-phase column chromatography (system

Vioiade 5P4, 0-18 25-M, 5-60 95 acetonitrile/water mixture) to obtain a mixture of the required product and impurities. The mixture was purified by another stage of column chromatography on a silica column Vioiade ZMAR KR-5II 10 g, eluting with 10 90 hexanes in EtOAc to obtain the purified specified product in the form of a white solid (11 mg, yield: 22

Fe). M5 (arsi ROB) t/2 -370.2 (MAN).

Example 15 g

M M oda give them

IS

(68)-9-fluoro-14-oxa-2,11,18,19,22-pentaazapentacyclo|14,5,2,1711,026015,293|Ihetracose- 1(22),7,9,16(23 ),17,20-hexaene-15,24-dione

І00377| Obtained as a by-product in example 14, step C, and isolated as

From a white solid (5 mg, yield 9 95) using reversed-phase column chromatography (Vioiade 5P4 system, C-18 25-M column, 5-60 95 acetonitrile/water mixture) from crude material from Example 14, step C M5 (arsi) t/72 - 370.2 (M'-H).

Example 16 uva, se so

M M

MN, that's me with M

IS

(62)-9-fluoro-13,16-dioxa-2,11,17,21,22,25- hexaazapentacyclo| 1 7.5.2.026,0712 02226|hexacose-1(25),7,9,11,19(26),20,23-heptaen-18-one

ЙОО378| Step A: Preparation of (H)-M-(2-bromoethoxy)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)upyrrolidin-1-yl)upyrazolo|(1,5-a|Ipyrimidine -Z-carboxamide: to a mixture of //(H)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carbon acid (Preparation B, 100 mg, 0.280 mmol) and NATI (128 mg, 0.336 mmol) in OME (1 mL) was added OIEA (0.146 mL, 0.840 mmol) and then, in one portion, O-(2- bromoethyl) hydroxylamine hydrobromide (74.2 mg, 0.336 mmol). After stirring at ambient temperature overnight, the reaction mixture was directly purified by reverse-phase column chromatography (VioFade 5P4 system, C-18 254-M, 5-67 905 mixture acetonitrile/water) to give the desired product as an off-white solid (91 mg, yield 68 95). M5 (arsi) t/2 - 479.0 (M'-H).

Y00379| Step B: Preparation of (H)-M-(2-chloroethoxy)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)upyrrolidin-1-yl)pyrazolo (1, 5-α|pyrimidine-3-carboxamide: A mixture of (H8)-M-(2-bromoethoxy)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo (| (1,5-α|pyrimidine-Z-carboxamide (70 mg, 0.146 mmol) and NS (4 N, dioxane, 3.65 mL, 14.6 mmol) were packed in a high-pressure test tube and heated at 90 "C for 3 h. Then the reaction mixture was cooled, diluted with Meon, concentrated and dried in a deep vacuum to obtain the required product, which was used in the next step directly, without additional purification, considering that the conversion occurs quantitatively.

I0OZ80) Stage (o Preparation of (628)-9-fluoro-13,16-dioxa-2,11,17,21,22,25- hexaazapentacyclo!|17,5,2,026,0712, 02226) hexacose-1(25 ),7,9,11,19(26),20,23-heptaen-18-one:

A mixture of (8)-M-(2-chloroethoxy)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)upyrazolo|1,5-a |Ipyrimidine-3-carboxamide (60 mg, 0.14 mmol) and С52СО3 (232 mg, 0.71 mmol) in

OME (1.4 ml) was heated at 90 °C for 20 min to complete the reaction. The reaction mixture was filtered (through an OBR/E paper filter) and diluted with water (10 ml), then extracted with EtOAc (3 x 10 ml). The organic phases were combined, washed with saline solution and dried (Mag25054). The crude material was purified by reverse-phase column chromatography (Vioiade ЗР4 system, С18 12-М, 5-55 95 acetonitrile/water mixture) to obtain a mixture of the required product and impurities. The mixture was once again purified using preparative TLC (10,956 MeOOn/OSM) to obtain the purified specified product in the form of a white solid (1 mg, yield: 1 95). M5 (arsenic) t/72 - 385, 1 (MAN).

Example 17 fa, c mon

M o

OB plural and - them

R

(68,138)-9,13-difluoro-2,11,15,19,20,23-hexaazapentacycloi|15,5,2,1711,026,02024|dentacose- 1(23),7,9,17(24 ),18,21-hexaene-16,25-dione

I0OZ811 Solution (68,135)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo- (15,5,2,171,026,020,24| pentacose-1(23),7,9,17( 24),18,21-hexaene-16,25-dione (example 5; 10 mg,

Zo 0.0251 mmol) in a mixture of OSM solvents (0.3 ml) and Z drops of OM5O were treated with bis(2-methoxyethyl)aminosulfur trifluoride (7.87 μl, 0.0427 mmol) at 0 "C, then a solution was added ethanol (0.231 mg, 0.00502 mmol) in OSM (0.1 mL) and the mixture was stirred at ambient temperature overnight.The reaction mixture was poured into a saturated soln.

MansCO3 and extracted with OSM, then dried (Mag250O»4), filtered and concentrated. The crude product was purified by reversed-phase column chromatography (Vioiade 5P4 system, 0-18 12--M cartridge, 5-50 95 acetonitrile/water mixture) to give the indicated product as a beige solid (1.3 mg, yield 12 90). M5 (arsi) t/2 - 401.2 (M.N).

Example 18 /f

M cho t OM

M in (628)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25- hexaazapentacyclo| 1 7,5,2,026,07y12 02226|hexacose-1(25),7,9,11,19(26),20,23-heptaen-18-one

І00382| Step A: Preparation of /(H)-M-(3-chloropropyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)upyrrolidin-1-yl)-M-methylpyrazolo (| 1.5 -a|Ipyrimidine-Z-carboxamide: to the suspension of (K)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo(1,5-a|pyrimidine-Z -carboxylic acid

(preparation method B, 200 mg, 0.56 mmol) and 3-chloro-M-methylpropane-1-amine hydrochloride (177 mg, 1.23 mmol) in OME (4 mL) was added M-methylmorpholine (0.25 mL, 2.30 mmol) and then NATI (234 mg, 0.616 mmol). The reaction mixture was stirred at ambient temperature for 18 h, then diluted with H2O (10 mL) and extracted with

KOS (2 x 20 ml). The combined organic extracts were washed with saline (20 ml), dried (M9505), filtered and concentrated. The crude product was purified by reverse phase column chromatography eluting with 5-60 95 acetonitrile/water to give the desired product as a white foamy solid (129 mg, yield 52,905).

M5 (Arsi) t/2 - 447.0 (MAN). 00383) Stage B: Preparation of (A)-M-(3-chloropropyl)-5-(2-(5-fluoro-2-oxo-1 2-dihydropyridin-3-yl)upyrrolidin-1-yl)-M- methylpyrazolo|1,5-a|pyrimidine-3-carboxamide: A mixture of NOI (4 n, dioxane, 4 ml, 16.0 mmol) and (HA)-M-(3-chloropropyl)-5-(2-(5 -Fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-methylpyrazolo(1,5-a|pyrimidine-3-carboxamide (100 mg, 0.224 mmol) was packed in a test tube for operation under high pressure conditions and heated at 90 "C for 90 min. Then the reaction mixture was diluted with acetonitrile and concentrated to obtain the crude product, which was used in the next step without additional purification (145 mg, yield: 150 95). M5 (arsi) t/2 - 433 ,0 (M.N).

И0ОоЗз84 Stage p. Preparation of (68)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25- hexaazapentacyclo I17,5,2,026,07y12,02226|hexacose-1(25),7,9 ,11,19(26),20,23-heptaen-18-one:

A mixture of (A)-M-(3-chloropropyl)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-M-methylpyrazolo (1, 5-a|Ipyrimidine-Z-carboxamide (50 mg, 0.12 mmol) and C82CO3 (188 mg, 0.58 mmol) in OME (12 mL) were heated at 90 °C for 15 min to complete the reaction. the mixture was filtered, washed with ME, and concentrated. The crude material was purified directly by reverse-phase column chromatography, eluting with 5-60 95 acetonitrile/water to give the title product as a pale yellow powder (17 mg, yield 36 95) M5 (Arsi) t/7 - 397.3 (M-H).

Example 19

UV, and what

M ev

KE and Fr. and AMH you (68)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25- hexaazapentacyclo| 1 7,5,2,026,0712,02226hexacos-1(25),7,9,11,19(26),20,23-heptayen-18-one

І00385| Stage A: Preparation of (5)-1-amino-3-chloropropan-2-ol hydrochloride: an aqueous solution of ammonia (4.01 g , 65.9 mmol) in more parts. After stirring for 10 min. (5)-2-(chloromethyl)oxirane (3.81 g, 41.2 mmol) was added and the reaction mixture was stirred for 2 h. at ambient temperature. Then the reaction mixture was heated at 35-40 "C in a flask heater for two hours, after which it was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated to 5 ml and toluene (5 ml) was added.

The mixture was heated to 36 °C and a solution of concentrated NOSI (6.09 g, 61.8 mmol) and water (5.9 mL) was slowly added over 5 min to maintain the internal temperature of the reaction in the range of 36-41 °C. The biphasic mixture was heated at 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 ), conducting concentrated after each addition. After the last stage of concentration, the suspension was heated to reflux, cooled to ambient temperature, and then kept at -20 "C for 18 h. The product was collected by vacuum filtration, washed with chilled ethanol and dried in vacuo to give the product as a white crystalline solid (3.58 g, yield 60

Fe). "H NMR (45-DMSO) b 8.14 (in, 3H), 5.91 (5, 1H), 3.93 (t, 1H), 3.59 (t, 2H), 2.89 (t , 1H), 2.69 (t, 1H).

I0OoZ86) Step B: Preparation of M-((5)-3-chloro-2-hydroxypropyl)-5-((A)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl) /pyrazolo(1,5-a|pyrimidine-3-carboxamide: Obtained in accordance with the method described in example 18, taking (5)-1-amino-3-chloropropan-2-ol hydrochloride (98.1 mg, 0.672 mmol ) instead of 3-chloro-M-methylpropane-1-amine hydrochloride in step A. M5 (arsenic) t/: - 448.9 (M'-H).

I00387| Step C: Preparation of (H)-M-(3-chloro-2-oxopropyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)upyrrolidin-1-yl)upyrazolo (|(1, 5-a|pyrimidine-3-carboxamide: to a solution of /M-(5)-3-chloro-2-hydroxypropyl)-5-(H)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine -1-yl)pyrazolo|1,5-a|pyrimidine-

To Z-carboxamide (180 mg, 0.401 mmol) in OSM (3 mL) was added Desso-Martin periodinan (204 mg, 0.481 mmol). The reaction mixture was stirred at ambient temperature for three hours. and then purified directly by reverse-phase column chromatography, eluting with 5-60 95 acetonitrile/water to give the desired product as a white foamy solid (114 mg, yield 64 95). M5 (Arsi) t/2 - 447.0 (MAN).

1000388) Step p: Preparation of (8)-M-(3-chloro-2,2-difluoropropyl)-5-(2-(5-fluoro-2-methoxypyridin-33-yl)pyrrolidin-1-yl)pyrazolo| 1,5-a|pyrimidine-3-carboxamide: to a solution of (H)-M-(3-chloro-2-oxopropyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin- To 1-yl)pyrazolo|1,5-a|pyrimidine-33-carboxamide (114 mg, 0.255 mmol) in OSM (3 mL) was added the reagent Yueho-RInog (0.103 mL, 0.561 mmol) and the reaction mixture was stirred at ambient temperature within 23 hours The reaction was quenched with saturated NaHCO 3 (5 mL), diluted with OHM (5 mL) and stirred for 30 min. After the phase separation, the aqueous phase was extracted using OCM (10 ml). The combined organic phases were concentrated and purified by reverse-phase column chromatography eluting with 5-60 95 acetonitrile/water to give the desired product as a white solid (59 mg, yield 49 95). M5 (arsi) t/7 - 469.0 (M--H).

IІ00389| Step E: Preparation of (H)-M-(3-chloro-2,2-difluoropropyl)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1 -yl)/pyrazolo(1,5-a|pyrimidine-3-carboxamide: Obtained in accordance with the method described in example 18, taking (H)-M-(3-chloro-2,2-difluoropropyl)-5- (2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxamide instead of (A)-M-(3-chloropropyl)-5- (2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-M-methylpyrazolo|1,5-a| pyrimidine-3-carboxamide at stage B. M5 (arse) t/2 - 455.0 (M--H).

I0OZ90) Stage E.: Preparation of (68)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25- hexaazapentacyclo!|17,5,2,026,0712 02226) hexacose-1 (25),7,9,11,19(26),20,23-heptaen-18-one:

It was obtained in accordance with the method described in example 18, taking (H)-M-(3-chloro-2,2-difluoropropyl)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridine- 3-yl)pyrrolidin-1-yl)pyrazolo|1,5-

Z a|Ipyrimidine-3-carboxamide instead of (A)-M-(3-chloropropyl)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl )-M-methylpyrazolo|1,5-a|Ipyrimidine-3-carboxamide in step C, and heating at 110 "С for 5 h to obtain the indicated product in the form of a pale pink solid (6 mg, yield 11 95) M5 (Arsi) t/7 - 419.3 (M.--N).

Example 20 - M fe

M cho se 6) it a MN

IS

(68)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo|17,5,2,026,0712,02226I|hexacose-1(25),7,9,11,19(26 ),20,23-heptaene-18-one

ИООЗ391| Stage A: Preparation of (H)-tert-butyl 2-(5-fluoro-2-hydroxyphenyl)pyrrolidine-1-carboxylate. This compound was obtained according to the preparation method A, replacing 3-bromo-5-fluoro-2-methoxypyridine with 2-bromo-4-fluorophenylacetate in step A (3.2 g, yield 4095).

M5 (ARSIarsy) t/2 - 182.1 (M--N-Vos). (00392) Step B: Preparation of (HA)-4-fluoro-2-(pyrrolidin-2-yl)yphenol hydrochloride: to a solution of (B)-tert-butyl-2-(5-fluoro-2-hydroxyphenyl)pyrrolidine -1-carboxylate (3.2 g, 11.4 mmol) in OCM (20 mL) was added NOI (4 N, dioxane, 5.69 mL, 22.7 mmol) and the mixture was stirred at ambient temperature for 15 h. The reaction mixture was concentrated and the resulting precipitate was transferred to OSM (15 ml) and filtered to obtain (HA)-4-fluoro-2-(pyrrolidin-2-yl)uphenol hydrochloride (1.85 g, yield 90 95) as beige solid. M5 (arsi) t/2 - 182.1 (M--H).

Y00393| Step C: Preparation of (H)-ethyl 5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)upyrazolo|1,5-a|pyrimidine-3-carboxylate: It was obtained in the same way as described in the section "Method of preparation B", taking (H)-4-fluoro-2-(pyrrolidin-2-yl)phenol hydrochloride instead of (HA)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)upyridine on step C. The crude material was purified by reverse-phase column chromatography (0-65 95 acetonitrile/H2O) to give pure product (686 mg, yield 80 95).M5 (arsi) pt/2 - 371.0 (MAN) .

Y00394| EEEstep 0: Preparation of (H)-ethyl 5-(2-(2-(3-(1,3-dioxoisoindolin-2-ylpropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo|1,5-a| Pyrimidine-3-carboxylate: Suspension of (B)-ethyl -5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo|1,5-a| pyrimidine-3-carboxylate (280 mg, 0.756 mmol), 2-(3-bromopropyl)isoindoline-1,3-dione (263 mg, 0.983 mmol) and K»2bOz (104 mg, 0.756 mmol) in OME (0.4 mL) were stirred at ambient temperature for 15 h. The reaction mixture was directly purified using reversed-phase column chromatography (5-80 95 mixture of acetonitrile /H2O) to obtain (HB)-ethyl-5-(2-(2-(3-(1,3-dioxoisoindoline) 2-Ilupropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate (202 mg, yield 4895) in the form of a clear oily liquid. M5 (arsenic) t/2 - 558 ,0 (MAN).

IІ00395| Step E: Preparation of (HA)-ethyl -5-(2-(2-(3-aminopropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo|1,5-a)| pyrimidine-3-carboxylate: (A)-ethyl-5-(2-(2-(3-(1,3-dioxoisoindolin-2-ylpropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo|1,5 -α|Ipyrimidine-3-carboxylate (200 mg, 0.359 mmol) and hydrazine monohydrate (115 mg, 3.59 mmol) were combined in MeonH (1 mL) and TNE (1 mL) in a sealed vessel and heated at 60 C for 20 min After cooling to ambient temperature, the reaction mixture was concentrated, and then Mahon (1 N, 2 mL) was added.

Extraction of the mixture was carried out using OSM and the organic phases were dried (Mag5Oy), filtered and concentrated to obtain /(HA)-ethyl-5-(2-(2-(3-aminopropoxy)-5-fluorophenyl)pyrrolidin-1-yl) Pyrazolo|1,5-a|Ipyrimidine-Z-carboxylate (110 mg, yield 7295). M5 (arsi) t/2 - 428.2 (M.N). 00396) Stage E: Preparation of (68)-9-fluoro-13-oxa-2,17,21,22,25- pentaazapentacyclo!y17,5,2,026,0712,02226| hexacose-1(25),7,9,11,19(26),20,23-heptaen-18-one. (B)-ethyl-5-(2-(2-(33-aminopropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate (10 mg, 0.023 mmol) and OIEA (8.1 μL, 0.047 mmol) were combined in anhydrous EOH (0.1 mL) in a sealed vessel and heated at 200 °C overnight. The reaction mixture was concentrated and purified by reverse-phase column chromatography (0- 70 95 of a mixture of acetonitrile/HgO) to obtain the specified compound (4.5 mg, yield 50 95). M5 (arsi) t/2 - 382.2 (M.N).

Example 21

Fe and ---

Mech

We

IS

(68)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo|16,5,2,026,0712,021,25|)pentacose-1(24),7,9,11, 18(25),19,22-heptaene

I00397| Stage A: Preparation of (H)-4-fluoro-2-(1-(pyrazolo|1,5-a|Ipyrimidin-5-yl)pyrrolidin-2-yl)uphenol: Mixture of (HA)-4-fluoro-2 -(pyrrolidin-2-yl)uphenol hydrochloride (Example 20, step B, 1.50 g, 6.89 mmol), OIEA (2.67 g, 20.7 mmol), 5-chloropyrazolo|1,5-a Ipyrimidine (1.11 g, 7.24 mmol) and isopropanol (1 mL) were heated at 120 °C overnight. The reaction mixture was poured into diethyl ether (50 mL) and extracted with Mahon (1 N aqueous solution, C x 25 mL). The combined aqueous extracts were adjusted to pH 4 with concentrated HCl and extracted with OCM. The combined OCM extracts were filtered through phase separation filter paper and concentrated to give (HA)-4-fluoro- 2-(1- (pyrazolo|1,5-a|Ipyrimidin-5-yl)/pyrrolidin-2-iluphenol (1.82 g, yield 89 95) in the form of a beige solid. 299.4 (M.-N).

IІ00398| Step B: Preparation of (H)-5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo|1,5- a|Ipyrimidine-3-carbaldehyde: After adding dropwise POsSys (221 μl , 2.41 mmol) to a solution of (A)-4-fluoro-2-(1-(pyrazolo|1,5-a|pyrimidin-5-yl)pyrrolidin-2-yl phenol (600 mg, 2.01 mmol) in

OME (4 ml) at ambient temperature, the reaction mixture was stirred for 5 min. before adding Mahon (804 mg, 10.1 mmol). The reaction mixture was stirred for another 10 min. before adding NOSI (4 N, dioxane, 3 ml), and then OSM (50 ml). After filtration through Celite, the reaction mixture was concentrated and purified by reverse-phase column chromatography, eluting with 0-70 95 acetonitrile/H2O to give (H)-5-(2-

(5-Fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carbaldehyde (524 mg, yield 80 95) as a beige solid. M5 (arsi) t/2 - 327.2 (М--Н).

ЙОО399| Step C: Preparation of (B)-tert-butyl-2-(4-fluoro-2-(1-(3-formylpyrazolo|1,5-a|pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)ethyl Carbamate: A mixture of (88)-5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)/pyrazolo|(1,5-a|pyrimidine-3-carbaldehyde (159 mg, 0.487 mmol), tert-butyl 2-bromoethyl carbamate (131 mg, 0.585 mmol), potassium carbonate (202 mg, 1.46 mmol) and

OME (1 mL) was combined in a sealed vessel and stirred at ambient temperature overnight and then at 60 °C for 3 h. After dilution with

OSM (20 ml) the reaction mixture was filtered through Seiteb, concentrated and purified by reverse-phase column chromatography eluting with 0-70 905 acetonitrile/H2O to give (B)-tert-butyl-2-(4-fluoro-2- (1-(3-formylpyrazolo|1,5-a|Ipyrimidin-5-yl)upyrrolidin-2-yl)phenoxy)ethyl carbamate (198 mg, yield 86.6 95) as a yellowish solid. M5 (Arsi) pp/2 - 370.4 (MAN - Vos).

І00400| Step 0: Preparation of (/ (H)-5-(2-(2-(2-aminoethoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carbaldehyde: NOSI was added (4n, dioxane, 80 μl, 0.32 mmol) into a solution of (B)-tert-butyl-2-(4-fluoro-2-(1-(3-formylpyrazolo|1,5-a|pyrimidine-5- yl)pyrrolidin-2-yl)phenoxy)ethyl carbamate (198 mg, 0.422 mmol) in OSM (2 mL) and the reaction mixture was purged with Me while stirring at ambient temperature overnight. After removal of the solvent, Mahon (5 mL x 1 n ) and extracted the reaction mixture using several portions of OSM in a phase separation tube. The combined organic extracts were concentrated to give (8)-5-(2-(2-(2-aminoethoxy)-5-fluorophenyl)pyrrolidine-1 - yl)upyrazolo|1,5-a|pyrimidine-Z-carbaldehyde (155 mg, yield 99.5 95), which was directly used in the next step. M5 (arsi) t/2 - 352.3 (Man - NgO) 004011 Stage E: Preparation of (68)-9-fluoro-13-oxa-2,16,20,21,24- pentaazapentacyclo|16,5,2,026,07y12,021.25|pentacose-1(24),7,9 ,11,18(25),19,22-hept aena

Tetramethylammonium triacetoxyborohydride (46.7 mg, 0.629 mmol) was added to a solution of (H)-5-(2-(2-(2-aminoethoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo|1,5-a| Ipyrimidine-33-carbaldehyde (155 mg, 0.420 mmol) in OCM (50 mL) and stirred the reaction mixture at ambient temperature overnight. Then the reaction mixture was diluted with saline solution and carried out

Extracted with several portions of OSM in a phase separation tube, and the combined organic extracts were concentrated and purified by reverse-phase column chromatography, eluting with 0-90 95 acetonitrile/H2O to give the title product (32 mg, yield 21 ,6 95). M5 (Arsi) t/7 - 354.2 (M.-N).

Example 22 fa, se pn and M

Mu

M

R dk 1-K6B8)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo|16,5,2,026,0712,02125|pentacose-1(24),7,9,11, 18(25),19,22-heptaen-16-yl|ethan-1-one

I00402| Acetyl chloride (1.7 mg, 0.021 mmol) was added to a solution of (6K)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo-(16,5,2,026,07y12,021.25|pentacose- 1 (24),7,9,11,18(25),19,22- heptaene (Example 21, 5.0 mg, 0.014 mmol) in OSM (0.5 mL), and then OIEA (7.4 After stirring at ambient temperature overnight, the reaction mixture was concentrated and purified by reverse phase column chromatography eluting with 0-80 95 acetonitrile/H2O to give the indicated product (3.9 mg, 70 95 yield) M5 (arsi) pt/; - 396.2 (M-H).

Example 23 skh pi and M

We

M

Mr. E

1-K6B8)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo|16,5,2,026,0712,02125|pentacose- 1(24),7,9,11,18( 25),19,22-heptaen-16-ylI|-2-hydroxyethan-1-one 00403) in a solution of (6K)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo-

I16,5,2,026,07y12,02125|pentacose-1(24),7,9,11,18(25),19,22-heptaene (example 21, 6 mg, 0.017 mmol) in OSM (0.5 ml ) added 2-chloro-2-oxoethyl acetate (3.5 mg, 0.025 mmol), followed by OIEA (8.P9 μl, 0.051 mmol). The reaction mixture was stirred at ambient temperature overnight, then concentrated and MeonH (0.2 mL) was added, followed by sodium hydroxide (6.8 mg, 0.085 mmol). After stirring at ambient temperature for 5 h, the reaction mixture was diluted with saline solution and extracted using several portions of OSM in a phase separation tube. The combined organic extracts were concentrated and purified by reversed-phase column chromatography, eluting with 0-70 95 acetonitrile/H 2 gO to give the indicated product (3.6 mg, yield 52 Us). M5 (arsi) t/2 - 412.5 (M.N).

Example 24 se p

M is (o) and MH and (68)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo!/|17,5,2,026,0712,02226Hexacosa-1(25),7 ,9,11,19(26),20,23-heptaene

ЙО0404| Step A: Preparation of /(H)-tert-butyl-3-(4-fluoro-2-(1-(3-formylpyrazolo|1,5-a|Ipyrimidin-5-yl)/pyrrolidin-2-yl) phenoxy)propylcarbamate: Obtained according to the method described in example 21, replacing tert-butyl 2-bromoethyl carbamate with tert-butyl-3-bromopropylcarbamate in step C to obtain the required product (119 mg, yield 84.5 95). M5 (Arsi) t/2 - 384.2 (M.N - Vos).

Y00405) Step B: Preparation of (B)-tert-butyl-3-(4-fluoro-2-(1-(3-hydroxymethyl)pyrazolo|1,5-a|pyrimidin-5-yl)pyrrolidin-2 -ylphenoxy)propylcarbamate: Solution of (K)-tert-butyl-3-(4-fluoro-2-(1-(3-formylpyrazolo|1,5-a|pyrimidin-5-yl)ypyrrolidin-2-ylphenoxy) propyl carbamate (85.0 mg, 0.176 mmol) in MeonH (2 ml) was first cooled to 0 "C, then MavBn" (4.04 mg, 0.176 mmol) was added and the reaction mixture was stirred at 0 "C for 1 h. The reaction mixture diluted with a saline solution and extraction was carried out with the help of UOSM in a test tube for phase separation.

The combined organic extracts were concentrated to give (HA)-tert-butyl-3-(4-fluoro-2-(1-(3-

Zo (hydroxy methyl)pyrazolo|1,5-a|Ipyrimidin-5-yl)pyrrolidin-2-ylphenoxy)propylcarbamate (86 mg, yield 101 95) as a beige solid. M5 (ARSiarsi) pt/2 - 468.1 (MAN - NgO).

І00406| Step C: Preparation of (H)-(5-(2-(2-(3-aminopropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo|1,5-a)| Pyrimidin-3-yl)umethanol hydrochloride: (B)-tert-butyl-3-(4-fluoro-2-(1-(3- (hydroxymethyl)pyrazolo|1,5-a|Ipyrimidin-5-yl)pyrrolidin- 2-Iluphenoxy)propylcarbamate (80 mg, 0.16 mmol) was dissolved in 2 mL OSM and treated with NOSI (4 N, in dioxane, 6.0 mg, 0.16 mmol). The reaction mixture was purged with Mo, capped, and stirred at ambient temperature for 18 h, then concentrated to obtain (H)-(5-(2-(2-(3-aminopropoxy)-

B-fluorophenyl)pyrrolidin-1-yl)pyrazol1,5-a| pyrimidine-3-yl methanol hydrochloride (70 mg, yield 101

Fo) in the form of a beige solid. M5 (arsi) pt/2 - 368.5 (MAN-H2gO).

IІ00407| Stage 0: Preparation of (6H)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo-

И17.5,2,026,07и712,02226| hexacose-1(25),7,9,11,19(26),20,23-heptaene. Mixture / (K)-(5-(2-(2-(3-aminopropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidin-3-yl)umethanol (50 mg, 0.130 mmol), RB-RPP (0.259 mmol) and perchloromethane (200 mg, 1.30 mmol) in OSM (5 mL) was shaken at ambient temperature overnight. The reaction mixture was filtered, concentrated and purified by reversed-phase column chromatography, eluting with 0-60 95 acetonitrile/H2O to give the indicated product (27.4 mg, yield 57.5 95). M5 (arsi) pt/: - 368.1 (M'-H).

Example 25

-M fa

M w sh-O-

M

We

M

: /5to o); (68)-9-fluoro-16-methanesulfonyl-13-oxa-2,16,20,21,24- pentaazapentacyclo|16,5,2,026,0712,02125|pentacose-1(24),7,9,11 ,18(25),19,22-heptane 00408) into a solution of (6K)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo-

I16.5.2.026.07y12.02125|pentacose-1(24),7,9,11,18(25),19,22-heptaene (example 21, 5 mg, 0.0141 mmol) in OSM (0, 5 mL) was added OIEA (2.46 μL, 0.0141 mmol), followed by methanesulfonyl chloride (1.10 μL, 0.0141 mmol). The reaction mixture was stirred at ambient temperature for 1 h. before adding MeOH (0.1 mL). The reaction mixture was concentrated and purified by reversed-phase column chromatography, eluting with 0-80 95 acetonitrile/H2O to give the indicated product (3.1 mg, yield 50.8 95). M5 (arsi) t/2 - 432.3 (M.N).

Example 26 fe se p

M

M

M

E --605H 2-K6B8)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacycloi|16,5,2,026,0712,02125|pentacose-1(24),7,9, 11,18(25),19,22-heptaen-16-yl|acetic acid 00409) Solution (628)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo-

И16,5,2,026,07и12,02125|pentacose-1(24),7,9,11,18(25),19,22-heptane (example 21, 5 mg, 0.014 mmol), 2-bromoacetic acid (2 .9 mg, 0.021 mmol) and Mahon (1 N, 42 μl, 0.042 mmol) in IRA (0.1 ml) were heated at 60 °C in a sealed vessel overnight, then at 120 °C for 24 h.

After cooling, the reaction mixture was directly purified by reversed-phase column chromatography eluting with a 0-50 95 mixture of acetonitrile/H2O to give the indicated product (3.1 mg, yield 53,965). M5 (Arsi) t/7 - 412.2 (M.--N).

Example 27 - M pf, tp b m M o mav

WITH

Equation (68)-9-fluoro-17-methanesulfonyl-13-oxa-2,17,21,22,25-pentaazapentacyclo!17,5,2,026,07y12,02226|hexacose-1(25),7, 9,11,19(26),20,23-heptaene

IІ00410| Methanesulfonyl chloride (1.69 μl, 0.0218 mmol) was added to a solution of (6K)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo (17,5,2,026,07 and 12,02226) hexacose-1(25),7,9,11,19(26),20,23-heptaene (Example 24, 4.0 mg, 0.0109 mmol) in OSM (0.5 mL), and then OIEA was added (9.48 μl,

From 0.0544 mmol). The reaction mixture was stirred at ambient temperature overnight, concentrated and purified by reverse phase column chromatography, eluting with 0-80 95 acetonitrile/H2O to give the indicated product (2.9 mg, yield 59.8 95). M5 (ARSiIarsi) t/: - 446.3 (M.--N).

Example 28

-M x Fe a se

M M o zy M o

E.t

Also (68)-M-ethyl-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo 17,5,2,025,07i12 02226I|hexacose-1(25),7,9,11, 19(26),20,23-heptaene-17-carboxamide (004111) To a solution of (6K)-9-fluoro-13-oxa-2,17,21,22,25- pentaazapentacyclo!|17,5,2,026, Isocyanatoethane (1.5 mg, 0.022 mmol), and then -

RIEA (1.9 μL, 0.011 mmol). The reaction mixture was stirred at ambient temperature overnight, then concentrated and purified by reverse phase column chromatography eluting with 0-80 95 acetonitrile/H2O to give the indicated product (3.5 mg, 73 95 yield). M5 (arsi) t/2 - 439.1 (M--H).

Example 29 - M fe se she and M

We

M

E tooth and (68)-M-ethyl-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo- (16.5.2.026,0712,021,25|pentacose-1(24),7 . 5,2,026,07и12,02125|pentacose-1(24),7,9,11,18(25),19,22-heptaene (example 21, 5.5 mg, 0.016 mmol) in OSM (0.5 ml ) isocyanatoethane (1.5 mg, 0.022 mmol) was added, and then -

ORIEA (1.9 μL, 0.011 mmol). After stirring at ambient temperature overnight, the reaction mixture was concentrated and purified by reverse phase column chromatography eluting with 0-80 95 acetonitrile/H2O to give the title compound (3.3 mg, 50 95 yield). M5 (Arsi) t/2 - 425.4 (MAN).

Example 30 o -M

Fa, se o nya

IM M o (c); with Z An

H. M

IS

(65)-9-fluoro-4,13-dioxa-2,11,17,21,22,25-hexaazapentacyclo

И17.5.2.026,07и12,02226|hexacose-1(25),7(12),8,10,19(26),20,23-heptaene-3,18-dione 00413) Stage A: Obtaining (5 ,E)-M-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide: to a solution of (5)-2-methylpropane-2-sulfinimide (3.3 g, 27.2 mmol) in 2-(tert-butyldimethylsilyloxy)acetaldehyde (4.98 g, 28.6 mmol) was added to OSM (50 mL), followed by anhydrous copper sulfate (8.69 g, 54.5 mmol). The heterogeneous mixture was stirred at temperature

From the environment for 3 days and then filtered through SeyjefFf. The filtrate was concentrated and the residue was purified by flash column chromatography, eluting with 10 95 EtOAc in hexanes to give (5,E)-M-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (5.54 g, output 73 95) in the form of a colorless oily liquid. "N

NMR (SOSI") b 7.96 (t, 1H), 444 (0, 1H, U - 2.7 Hu), 1.11 (5, 9H), 0.82 (5, 9H), 0.00 (5, 6H).

ЙО0414| Step B: Preparation of /(5)-M-((5)-2-(tert-butyldimethylsilyloxy)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide: a solution of 3-bromo-5-fluoro-2-methoxypyridine was added dropwise to a solution of n-butyllithium (10.8 ml, 17.3 mmol, 1.6 M in hexanes) in toluene (100 ml) at -78 "С (3.27 g, 15.9 mmol) in toluene (5 mL), maintaining the internal temperature below -70 °C. The mixture was stirred at -78 "C for 1 hour, then treated with a solution of /(5,E)-M-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (4.0 g, 14, 4 mmol) in toluene (10 mL), adding it dropwise, maintaining 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 ambient temperature for 20 min. A saturated solution of MnNsS0Oz (50 ml) was added and the phases were separated. The aqueous phase extracted with EtOAc (2 x 50 mL) and the combined organic phases were washed with brine (50 mL), dried over NaCl5O54, filtered and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 10 95 EtOAc in hexanes to 20 95 EIOAc in hexanes to obtain (5)-M-((5)-2-(tert-butyldimethylsilyloxy)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-2-methylpropan- 2- sulfinamide (1.40 g, yield 24 95) in a mixture with a less polar impurity in the form of a colorless oily liquid. 5)-2-amino-2-(5-fluoro-2-methoxypyridin-3-yl)ethanol dihydrochloride: to a solution of (5)-M-((5)-2-(tert-butyldimethylsilyloxy)-1-(5- fluoro-2-methoxypyridin-3-yl)ethyl)-2-methylprop of an-2-sulfinamide (1.40 g, 3.46 mmol) in methanol (20 mL) was added 4 N HCl/dioxane (8.65 mL, 34.6 mmol). The solution was stirred at ambient temperature for 1 h, then concentrated and dried in vacuo to give /(5)-2-amino-2-(5-fluoro-2-methoxypyridin-3-yl)ethanol dihydrochloride as a yellow oily liquid, which was used without purification, assuming that the yield is 100 Fo. M5 (arsi) t/2 - 186.9 (M--H).

І00416| Step 0: Preparation of (5)-4-(5-fluoro-2-methoxypyridin-3-yl)oxazolidin-2-one: to a solution of (5)-2-amino-2-(5-fluoro-2-methoxypyridin- To 3-yl)ethanol dihydrochloride (897 mg, 3.46 mmol) in KOH (10 mL, 24.2 mmol, 2.42 M in water) was added TNE (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

From the environment with stirring for 16 hours, then separated between

EOAc (50 ml) and water (50 ml) and separated the phases from each other. The aqueous phase was extracted with EtOAc (2 x 30 mL) and the combined organic phases were washed with brine (20 mL), dried over NaCl, filtered and concentrated. The residue was triturated with EBO, filtered and dried under reduced pressure to give /(5)-4-(5-fluoro-2-methoxypyridin-3-yl)uoxazolidin-2-one (254 mg, yield 35 95) as a white powder . "H NMR (SOSI") b 7.98 (t, 1H), 7.44 (t, 1H), 5.61 (Hg 5, 1H), 5.13 (t, 1H), 4.83 (t , 1H), 4.16 (t, 1H), 3.96 (5, ЗН).

I00417| Stage E: Preparation of (5)-ethyl-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxoxazolidin-

Z-il)upyrazolo|1,5-a| pyrimidine-3-carboxylate: sodium hydride was added to a solution of (5)-4-(5-fluoro-2-methoxypyridin-3-yl)uoxazolidin-2-one (254 mg, 1.20 mmol) in OME (10 mL) (58 mg, 1.44 mmol, 6095 in mineral oil). The mixture was stirred at ambient temperature for 20 min, then treated with ethyl 5-chloropyrazolo|1,5-a|pyrimidine-3-carboxylate (270 mg, 1.20 mmol) in one portion. The mixture was stirred for 48 h, then treated with a saturated solution of MNACI (30 ml) and extracted using

EOds (Z x 10 ml). The combined organic phases were washed with water (5 x 10 ml) and brine (10 ml), then dried over Na»5O:, filtered and concentrated. The residue was purified by flash column chromatography, eluting with a gradient from 20 956 ETAcC in hexanes to 66 95 EOAc in hexanes, to give (5)-ethyl-5-(4-(5-fluoro-2-methoxypyridin-3-yl) -2-oxoxazolidin-3-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate (311 mg, yield 65 95) in the form of a white foam. M5 (Arsi) t/7 - 401.9 (M--H).

IO0A18)I Stage E.: Preparation of (5)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo|1,5-a| pyrimidine-3-carboxylic acid: to a solution of (5)-ethyl-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxoxazolidin-3-yl)pyrazolo / P,5-a| Lithium hydroxide monohydrate (97.6 mg, 2.32 mmol) was added to pyrimidine-3-carboxylate (311 mg, 0.77 mmol) in a 1:1:1 mixture of MeOHn:TNE:HgO (15 mL). The mixture was stirred at ambient temperature for 16 h, then at 50 "С for 19 h, after which it was concentrated to 1/3 of the volume, diluted with water (30 ml) and acidified to pH 4-5 with 1 N HCl. The resulting precipitate was collected by filtration, washed with water and Eb2O, then dried under reduced pressure to obtain (5)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo|1, 5-

α|Ipyrimidine-3-carboxylic acid (121 mg, yield 45 95) in the form of a white powder. M5 (arsi) t/2 - 347.9 (M.N).

І00419| Stage b: Preparation of (5)-M-(3-chloropropyl)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethyl amino)pyrazolo (|1,5-a|pyrimidine -3-carboxamide: to the suspension of (5)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo (1,5-a|Ipyrimidine-3-carboxylic acid (50 mg, 0.14 mmol) in OSM (2 ml) was added NOVI (44 mg, 0.29 mmol), and then - EOSI (83 mg, 0.43 mmol).

The heterogeneous mixture was stirred at ambient temperature for 10 min, then treated with triethylamine (100 μl, 0.72 mmol), after which 3-chloropropylamine hydrochloride (56 mg, 0.43 mmol) was added. The mixture was stirred for 2 hours, then added

OME (2 ml) and continued stirring for 48 h. The mixture was separated between a saturated solution of MNACI (20 ml) and EIHUOAc (20 ml) and the phases were separated. The aqueous phase 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 Mag2505, filtered and concentrated to obtain (5)-M -(3-chloropropyl)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethyl amino)pyrazolo|1,5-a|pyrimidine-3-carboxamide (60 mg, yield 99 95) in the form of pale yellow foam, which was used without additional purification. M5 (Arsi) t/2 - 423.0 (MAN).

І00420| Step H: Preparation of (5)-M-(3-chloropropyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxoxazolidin-3-yl)pyrazolo P1,5-a| pyrimidine-3-carboxamide: to a solution of (5)-M-(3-chloropropyl)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethyl amino)pyrazolo|1,5- a|Ipyrimidine-3-carboxamide (60 mg, 0.14 mmol) in ACM (2 ml) was added SOY (35 mg, 0.21 mmol).

The solution was stirred at ambient temperature for 16 h, then separation was carried out between a saturated solution of MNACI (20 ml) and EIOAc (10 ml) and the phases were separated.

The aqueous phase was extracted with EOAc (2 x 10 ml) and the combined organic phases were washed with brine (10 ml), dried over Na»5O», filtered and concentrated. The residue was purified using flash column chromatography, eluting with 1,960 MEOH/USM to obtain (5)-M-(3-chloropropyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2 -oxoxazolidin-3-yl)upyrazolo|1,5-a|Ipyrimidine-3-carboxamide (37 mg, yield 58 95) in the form of a white solid.

M5 (arsi) t/2 - 449.0 (M.N). 004211 Stage I: Preparation of (5)-M-(3-chloropropyl)-5-(4-(5-fluoro-2-oxo-1,2-dihydropyridine-3-

Zoyl)-2-oxoxazolidin-3-yl)pyrazolo|1,5-a|pyrimidine-3-carboxamide: Suspension // (5)-M-(3-chloropropyl)-5-(4-(5-fluoro -2-methoxypyridin-3-yl)-2-oxoxazolidin-3-yl)pyrazoloyl|1,5- a|pyrimidine-3-carboxamide (37 mg, 0.08 mmol) in 4 N HCl/dioxane (4 mL) stirred at 85 "С for 17 h and then at ambient temperature for 48 h.

The resulting solution was concentrated to 1/2 volume, transferred to a sealed test tube, treated with 4 N HCl/dioxane (2 ml) and stirred at 100 "C for 2 h. The heterogeneous mixture was concentrated, dried under reduced pressure and used directly in the next step, assuming that the yield is 100 95. M5 (arsi) t/72 - 435.1 (MAN). (00422 Step C: Preparation of (65)-9-fluoro-4,13-dioxa-2, 11,17,21,22,25- hexaazapentacyclo|1 7,5,2,026,0712 022,26) hexacose-1(25),7(12),8,10,19(26),20,23-heptaene -3,18-dione: to the solution / (5)-M-(3-chloropropyl)-5-(4-(5-fluoro-2-oxo-1, 2-dihydropyridin-3-yl)-2-oxoxazolidine -Z-yl)pyrazolo|1,5-a|pyrimidine-3-carboxamide (35 mg, 0.08 mmol) in OME (3 mL) was added cesium carbonate (79 mg, 0.24 mmol). The mixture was stirred at 65 "C for 30 minutes, then at ambient temperature for 48 hours. The mixture was treated with water (30 mL) and extracted with EOAc (3 x 10 mL). The combined organic phases were washed with water (5 x 10 ml) and brine (10 ml), then dried over Mag5O54, filtered and concentrated. The residue was purified by flash column chromatography, eluting with 2 96 Meon/OSM to give the title compound (13 mg, yield 41 95) as an amorphous white solid. M5 (arsi) t/2 - 399.2 (M.N).

Example 31

Fa a:

OM about that amn

WE

IS

(65)-9-fluoro-4.13-dioxa-2,11,16,20,21,24- hexaazapentacyclo|16,5,2,026,07и12,021,25|)pentacose-1(24),7(12) ,8,10,18(25),19,22-heptaene-3,17-dione

Y00423| Stage A: Preparation of 5-hydroxypyrazolo|1,5-a| pyrimidine-3-carboxylic acid: to a solution of ethyl 5-hydroxypyrazolo|1,5-a|pyrimidine-3-carboxylate (method of preparation B, step A; 2.0 g, 9.65 mmol) in a mixture of 2:11 TNE: MeonH (40 mL) was added lithium hydroxide monohydrate (29 mL, 29.0 mmol, 1.0 M in water). The solution was stirred under heating in a reflux vessel for 16 hours, then cooled and concentrated. The residue was dissolved in water (100 ml) and acidified with b M NH. The resulting precipitate was collected by filtration, washed with water and Eg6O, then dried under reduced pressure to obtain 5-hydroxypyrazole (1,5-a|pyrimidine-3-carboxylic acid (1.18 g, yield 68 95) as a white solid . "H NMR (d6-DMSO) 5 8.50 (y, 2H, y - 7.7 Hz), 8.02 (5.2), 6.07 (a, 2H,7U4-8.2

Gu). 00424) Stage B: Preparation of 5-chloropyrazolo|1,5-a| of pyrimidine-3-carbonyl chloride: to suspension

B-Hydroxypyrazole (1,5-a|pyrimidine-3-carboxylic acid (1.18 g, 6.59 mmol) in OME (10 ml) at 0 "Sb was added dropwise thionyl chloride (10 ml) over 5 min. The reaction the mixture was heated to ambient temperature, then stirred at 60 "C for 16 hours.

The cooled solution was purged with M2 for 20 min., then diluted with 50 95 EtOAc in hexanes (100 mL) and vigorously stirred for 30 min. The organic phase was decanted, treated with MgSO:z and activated carbon, stirred for 5 min., then filtered through Seiyeff and concentrated. The residue was dissolved in toluene (100 ml), treated with activated carbon and filtered through SeShetF again. The filtrate was concentrated and dried under reduced pressure to give 5-chloropyrazolo|1,5-a|pyrimidine-3-carbonyl chloride (800 mg, yield 56 95) as a cream-colored solid. "H NMR (SOCIi") b 8.70 (t, 1H), 8.66 (5, 1H), 7.16 (t, 1H). (00425) Step C. Preparation of 5-chloro-M-(2 -chloroethyl)pyrazolo|1,5-a|pyrimidine-3-carboxamide: to a suspension of 5-chloropyrazolo|1,5-a|pyrimidine-3-carbonyl chloride (284 mg, 1.31 mmol) in OSM (10 ml) was added OIEA (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 during! hours

Z. The mixture was separated between water (30 ml) and SOCM (30 ml) and the phases were separated. Extraction of the aqueous phase was carried out with the help of USM (2 x 20 ml) and the combined organic phases were washed with saline solution (20 ml), dried over Ma»5O:, filtered and concentrated to obtain 5-chloro-M-(2-chloroethyl) Pyrazolo|1,5-a|Ipyrimidine-3-carboxamide (290 mg, yield 85

Fo) in the form of a beige solid. M5 (Arsi) t/7 - 258.9 (M.N).

IІ00426| Stage 0: Preparation of (5)-M-(2-chloroethyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxoxazolidin-3-yl)pyrazolo |1,5-a |pyrimidine-3-carboxamide: to a solution of (5)-4-(5-fluoro-2-methoxypyridin-3-yl oxazolidin-2-one (obtained as described in example 30; 50 mg, 0.236 mmol) in OME (1 ml ) added sodium hydride (11 mg, 0.28 mmol, 60 95 in mineral oil).

The mixture was stirred at ambient temperature for 20 min, then treated with 5-chloro-M-(2-chloroethyl)pyrazolo|1,5-a|pyrimidine-3-carboxamide (61 mg, 0.236 mmol). The mixture was stirred for 16 h, then treated with a saturated solution of MNACI (10 ml) and water (20 ml). The precipitate obtained as a result was collected by filtration, washed with water and

Ego, then dried under reduced pressure to obtain (5)-N-(2-chloroethyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxoxazolidin-3-yl)pyrazolo| 1,5-α|Ipyrimidine-Z-carboxamide (83 mg, yield 81 95) as a beige solid. M5 (Arsi) pt/7 - 434.9 (MAN).

I00427| Step E: Preparation of (5)-M-(2-chloroethyl)-5-(4-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)-2-oxoxazolidin-3-yl)pyrazolo |1,5-a|pyrimidine-3-carboxamide: Suspension // (5)-M-(2-chloroethyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxoxazolidine -3-yl)pyrazolo|1,5-a|pyrimidine-3-carboxamide (80 mg, 0.18 mmol) in 5-6 N HCl (2.5 ml) was heated to 90 "C in a sealed test tube for 1, 5 h. The cooled mixture was filtered and the filtrate was concentrated. The residue was concentrated twice with ETO and dried under reduced pressure to give (5)-M-(2-chloroethyl)-5-(4-(5-fluoro-2-oxo-1 ,2-dihydropyridin-3-yl)-2-oxooxazolidin-3-yl)/pyrazolo|1,5-a| pyrimidine-3-carboxamide (63 mg, yield 82 95) as a beige solid. M5 (ARSIarsi) pt/2 - 421.0 (MAN). (004281 Stage E: Preparation of (65)-9-fluoro-4,13-dioxa-2,11,16,20,21,24- hexaazapentacyclo|16,5,2,026 ,07 and 12,021,25|)pentacose-1(24),7(12),8,10,18(25),19,22-heptaene-3,17-dione: Obtained according to the method described in example 30 , stage in, apply (5)-M-(2-chloroethyl)-5-(4-(5-fluoro-2-oxo-1 2-dihydropyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo

P,5-a-pyrimidine-3-carboxamide instead of (5)-M-(3-chloropropyl)-5-(4-(5-fluoro-2-oxo-1,2-bo dihydropyridin-3-yl)-2- oxoxazolidin-3-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxamide, with obtaining the specified compound (14 mg, yield 2495) in the form of a white solid. M5 (arsi) t/2 - 385.1 (М--Н).

Example 32 - M no se p

M where (in)

IN

And M

E.M H (68)-9-fluoro-2,11,16,20,21,24-hexaazapentacycloi16,5,2,026,07y12,02125|pentacose-1(24),7,9,11,18(25 ),19,22-heptaen-17-one 00429) Step A: Preparation of (H)-ethyl 5-(2-(2-(3-(tert-butoxycarbonyl)amino)prop-1-yn-1-yl) -

B-fluoropyridin-Z-yl)pyrrolidin-1-yl)/pyrazolo|1,5-a|pyrimidine-Z-carboxylate: to a solution of (K)-ethyl 5-(2-(2-chloro-5-fluoropyridin- 3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate (Example 12, step C; 153 mg, 0.392 mmol) in OME (2 ml) was added tert-butylprop-2-ynylcarbamate (122 mg, 0.785 mmol), 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 packed and heated to 95 °C for 8 h, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel, elution 33 90

EOAcS in hexanes to obtain the final product in a mixture with RezR (160 mg, yield 80.2 95). M5 (arsi) t/2 - 508.9 (M.N). 00430) Stage B: Preparation of (H)-ethyl -5-(2-(2-(3-aminopropyl)-5-fluoropyridin-3-yl)pyrrolidin-1-ylpyrazolo|1,5-a|pyrimidin-3- carboxylate: to a solution of (K)-ethyl 5-(2-(2-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-o-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo | 1, 5-a|pyrimidine-

To the Z-carboxylate (160 mg, 0.315 mmol) in MeonH (10 mL) was added dihydroxypalladium (101 mg, 0.144 mmol). The reaction mixture was stirred under hydrogen purging for 2 h, then filtered through a Seishe?tzh insert and washed with Meon (30 mL). The filtrate was concentrated and the resulting residue was treated with 4 M HCl in dioxane (3 mL). After stirring for 30 min. the solution was concentrated to obtain the product in the form of the NCI salt (140 mg, yield 108 95). M5 (arsi) t/: - 413.0 (M'-H).

І00431| Stage C: Preparation of (H)-5-(2-(2-(3-aminopropyl)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)upyrazolo(1,5-a|pyrimidine-3-carbon acids: to a solution of (K)-ethyl5-(2-(2-(33-aminopropyl)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate hydrochloride (160 mg, 0.356 mmol) in TNE/Meon (2 mL/1 mL) was added lithium hydroxide (1.1 mL, 2.20 mmol). The reaction mixture was heated to 70 °C for 5 h, then concentrated under reduced pressure . Water (10 ml) was added and the mixture was washed with EfO (2 x 5 ml), then neutralized using NOI (1 M) to pH - 4. The aqueous solution was extracted with OSM (2 x 10 ml). Organic extract dried over Mag25O», filtered and concentrated under reduced pressure to obtain the crude desired product (16.0 mg, yield 11.7 95). M5 (arsenic) t/2 - 385.0 (MH). (00432 Step p : Preparation of (628)-9-fluoro-2,11,16,20,21,24- hexaazapentacyclo|16,5,2,026,0712,021,25|)pentacose-1(24),7,9,11, 18(25),19,22-heptaen-17-one: to the solution (H)-5-(2-(2-(33-aminopropyl)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidin-

To 3-carboxylic acid (16 mg, 0.042 mmol) in OME (5 mL) was added NATI (63 mg, 0.17 mmol) and M-ethyl-M-isopropylpropan-2-amine (22 mg, 0.17 mmol). The reaction mixture was stirred for 3 hours, then concentrated under reduced pressure. The crude residue was purified (using column chromatography on silica gel, eluting with 100 95 EAs to obtain the indicated compound (6.0 mg, yield 39 95). M5 (arsenic) t/72 - 367.3 (M-H).

Example 33 fa t BUke (6)

Sai! M vm H (68)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacycloi|16,5,2,026,0712,021,25|pentacose-1(24),7, 9,11,18(25),19,22-heptaen-17-one

Y00433| It was obtained according to the method described in example 37, replacing tert-butyl 2-methylbut-3-yn-2-yl-carbamate with tert-butylbut-3-yn-2-yl-carbamate in step B to obtain the specified compound in the form mixtures of diastereomers 1:1. M5 (Arsi) t/2 - 381.2 (MAN).

Example 34 no, x m o (in) : MN

Eky (68,138)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo (15,5,2,171,026,020,24|)pentacose-1(23),7,9,17( 24), 18,21-hexaene-16,25-dione

IІ00434| EEEstep A: Preparation of (H)-methyl 5-(2-(5-fluoro-2-hydroxypyridin-3-yl)/pyrrolidin-1-yl)upyrazolo|1,5-a|pyrimidine-3-carboxylate: to suspension (H)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)upyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylic acid (production method B; 5.01 g, 14.0 mmol) in MeonN (150 ml) was added TM5SNM" (8.41 ml, 16.8 mmol) dropwise. The reaction mixture was stirred for 30 min., and then the reaction was stopped with 1 ml of acetic acid.

The solvent was removed under reduced pressure and the residue was dried under deep vacuum conditions to obtain the crude methyl ester. 4 N HCl in dioxane (100 ml) was added to the crude methyl ester, then the reaction mixture was packed and heated to 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in OSM (100 ml) and washed with a saturated solution of ManNsoz (40 mL). The organic phase was dried over NaCl, filtered and concentrated under reduced pressure to give the crude desired product (4.67 mg, yield 93.2 95). .N).

І00435| Stage B: Preparation of methyl 5-(H)-2-(1-((5)-3-(1,3-dioxoisoindolin-2-yl)-2-methylpropyl)-5-fluoro-2-oxo-1, 2-dihydropyridin-Z-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylate: to a solution of (NK)-methyl 5-(2-(5-fluoro-2-hydroxypyridine-Z) -yl)pyrrolidine-1-yl)upyrazolo|1,5-a|pyrimidine-3-carboxylate (202 mg, 0.565 mmol) in OME (5 mL) was added lithium hydride (22.5 mg, 2.83 mmol) and (H8)-2-(3-bromo-2-methylpropyl)isoindoline-1,3-dione (obtained according to the method described in the publication of Eigo. U. May. Spect. 2000, 147-156) (239 mg, 0.848 mmol). The reaction mixture was stirred for 2 hours. at 70 °C, and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (2 x 10 mL). The organic phase was dried over NaCl,

Zo was filtered and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel eluting with 66 95 EOAcs in hexanes to give the product (110 mg, yield 34.8 95). M5 (arsi) t/7 - 559.0 (M'-H).

І00436| Stage C: Preparation of methyl 5-((H)-2-(1-(B)-3Z-amino-2-methylpropyl)-5-fluoro-2-oxo-1,2-dihydropyridin-Z-yl)pyrrolidin- 1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate: to the solution methyl 5-((8)-2-(1-((5)-3-(1,3-dioxoisoindolin-2-yl) )-2-methylpropyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylate (110 mg, 0.197 mmol ) in Meon/TtNE (3 mL/3 mL) was added hydrazine (31.6 mg, 0.985 mmol). The reaction mixture 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 a saturated aqueous solution of NaHSO:Z (5 ml), water (2 x 5 ml) and brine (5 ml). The organic phase was dried with Ma»5O:, filtered and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel, eluting with a mixture

EOAcS/Meon/MchnAsn in a ratio of 10:1:0.1 to obtain the required product (65 mg, yield 77 uv). M5 (Arsi) t/2 - 429.2 (MNN). (00437 Stage p: Preparation of (68,138)-9-fluoro-13-methyl-2,11,15,19,20,23- hexaazapentacyclo|15,5,2,172571,026,02024, pentacose-1(23) ,7,9,17(24),18,21-hexaene-16,25-dione: to the solution methyl 5-((H)-2-(1-(H)-3-amino-2-methylpropyl)- 5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate (65 mg, 0.15 mmol) in TNE/MeOH (6 mL/2 mL) was added lithium hydroxide (455 μL, 0.91 mmol). The reaction mixture was stirred at 70 C for 3 hours, then the reaction was quenched with hydrochloric acid (910 μl, 0.91 mmol).

The solvent was removed under reduced pressure and the precipitate was dried under high vacuum. OME (10 mL), NATIi (115 mg, 0.30 mmol) and M-ethyl-N-isopropylpropan-2-amine (78 mg, 0.61 mmol) were added to the resulting crude residue. The reaction mixture was stirred continuously

After hours, the solvent was then removed under reduced pressure. The residue was purified using 5O0 column chromatography on silica gel, eluting with 10 95 Meon/EuAc to give the indicated product (6.0 mg, yield 10 95 ). M5 (Arsi) t/72 - 397.3 (M-H).

Example 35 M

With more

M that o (8) and Zh kn sho. and M

IS

(68,135)-9-fluoro-13-methyl-2,11,15,19,20,23- hexaazapentacyclo|15,5,2,1271,026,020,2YIpentacose-1(23),7,9,17(24 ),18,21-hexaene-16,25-dione 00438) Obtained according to the method described in example 34, taking (5)-2-(3-bromo-2-methylpropyl)isoindoline-1,3-dione (obtained in accordance with the method described in the publication

Ego. U. Med. Spent 2000, 147-156) instead of (H)-2-(3-bromo-2-methylpropyl)isoindoline-1,3-dione at stage B. M5 (arsenic) t/2 - 397.3 (MAN).

Example 36 fa, x Kk:

EL M

(68)-9-fluoro-15,15-dimethyl-13-oxa-2,11,17,21,22,25- hexaazapentacyclo| 1 7,5,2,026,0712,02226hexacos-1(25),7,9,11,19(26),20,23-heptayen-18-one

І00439| It was obtained according to the method described in example 3, taking 3-amino-2,2-dimethylpropan-1-ol instead of 3-aminopropan-1-ol in step A. M5 (arsenic) t/2 - 411.2 (M. --N).

Example 37 no, dis, (6) t M

And N

E OM

(628)-9-fluoro-15,15-dimethyl-2,11,16,20,21,24- hexaazapentacyclo|16,5,2,026,0712,021,25|)pentacose-1(24),7, 9,11,18(25),19,22-heptaen-1 7-one (00440) Step A: Preparation of (A)-methyl 5-(2-(5-fluoro-2-(trifluoromethyl-sulfonyloxy)pyridine- 3-yl)pyrrolidin-1-yl)pyrazolo(1,5-a|pyrimidine-3-carboxylate: to a solution of (A)-methyl 5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidine -1-yl)pyrazolo P1,5-a|pyrimidine-3-carboxylate (obtained according to the method described in example 34, step A; 2.31 g, 6.46 mmol) in OME (20 ml) was added 1, 1,1-trifluoro-M-phenyl-M-(trifluoromethylsulfonyl)methanesulfonamide (2.54 g, 7.11 mmol) and triethyl amine (0.785 g, 7.76 mmol).

The reaction mixture was stirred for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with 33 95 EtOAc in hexanes to give the required product (2.36 g, yield 74.6 95). M5 (arsi) it/2 -

Co., Ltd.) 490.0 (M.N).

ЙО0441| Stage B: Preparation of (H)-methyl 5-(2-(2-(3-(tert-butoxycarbonylamino)-3-methylbutyl)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5 -α|Ipyrimidine-Z-carboxylate. To the solution (H)-methyl 5-(2-(5-fluoro-2-trifluoromethyl-sulfonyloxy)pyridin-3-yl)pyrrolidin-1-yl)upyrazolo|1,5-a| pyrimidine-3-carboxylate (503 mg, 1.03 mmol) in OME (2 ml) was added tert-butyl 2-methylbut-3-yn-2-yl-carbamate (377 mg, 2.06 mmol), copper iodide ( I) (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 packed and heated at 65 "C for 8 h. The solvent was removed under reduced pressure. The residue was purified using column chromatography on silica gel, eluting 66 with EIOAc in hexanes to give (H)-methyl 5-(2-(2 -(3-(tert-butoxycarbonylamino)-3-methylbut-1-ynyl)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate in a mixture with RizR , which was immediately hydrogenated with dihydroxypalladium on carbon (200 mg, 0.285 mmol) in Meon (20 mL) under a purge of Neg for 15 h. After filtering through a SeilleF insert and washing with Meon, the filtrate was concentrated under reduced pressure and purified using column chromatography on silica gel, eluting with 66,956 EOAc in hexanes to give the product (166 mg, yield 30.7

Fe). M5 (arsi) t/2 - 527.1 (M--H). (00442 Stage c. Preparation of (68)-9-fluoro-15,15-dimethyl-2,11,16,20,21,24- hexaazapentacycloi|16,5,2,026,0712,02125| pentacose-1(24) ,7,9,11,18(25),19,22-heptaen-17-one: to a solution of (NK)-methyl 5-(2-(2-(3-(tert-butoxycarbonylamino)-3-methylbutyl) -5-fluoropyridin-3-yl)upyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylate (166 mg, 0.315 mmol) in TNE/MeOH (3 mL/1 mL) was added lithium hydroxide ( 946 μl, 1.89 mmol). The reaction vessel was packed and heated at 70 °C for 3 h. The reaction mixture was then dried under reduced pressure and NOI (4 mL, 4 M 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.Then, to the residue was added UOME (8 mL), NOVT-NgO (96.5 mg, 0.630 mmol), EOSI (121 mg, 0.630 mmol), and triethylamine (159 mg , 1.58 mmol). The reaction mixture was stirred at 45 "C for 18 hours, then concentrated in vacuo. The residue was purified using column chromatography on silica gel and eluting with 5 96 mmol to give the title compound (60.0 mg, yield 48.3 95). M5 (ARSiarsi) t/7 - 395.1 (Ma-H).

Example 38

What do you think about MN?

M -

Aye

M--. (628)-9-fluoro-13-oxa-2,11,16,17,21,25,26,29- octaazahexacyclo(|(21,5,2,025,0712 01620 d2639 Itriaconta-1(29),7,9 ,11,17,19,23(30),24,27-nonaen-22-one 00443) Stage A: Preparation of 1-(2-(tert-butyl-diphenylsilyloxy)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 OME (10 ml) tert-butyl-chlorodiphenylsilane (4.96 ml, 19.1 mmol) was added dropwise.

The reaction mixture was stirred for 15 h. The solvent was removed under reduced pressure and the residue was diluted in OSM (40 mL). The organic phase was washed with 1 N HCl (10 mL), water (10 mL), and brine (10 mL), then concentrated to give the crude desired product (5.62 g, yield 96.4 95), which was used in the next stage without

From cleaning. 00444) Stage B: Preparation of (H)-M-(1-(2-(tert-butyldiphenylsilyloxy)ethyl)-1H-pyrazol-5-yl)- 5-(2-(5-fluoro-2-methoxypyridine- 3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxamide: to the suspension of (K)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin- 1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylic acid (220 mg, 0.16 mmol) in HOME (5 mL) was added dropwise 2,4,6-trichlorobenzoyl chloride (106 μL, 0.677 mmol) and triethyl amine (81.0 mg, 0.800 mmol). The reaction mixture was stirred for 2 hours. and 1-(2-(tert-butyl-diphenylsilyloxy)ethyl)-1H-pyrazol-5-amine (338 mg, 0.923 mmol) was added to the reaction mixture. The reaction mixture was heated to 60 °C for 3 h, and then cooled to ambient temperature.

The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give the desired product (201 mg, yield 46.3 95). M5 (arsi) t/2 - 705.1 (М--Н). 00445) Stage C: Preparation of (6K)-9-fluoro-13-oxa-2,11,16,17,21,25,26,29-octaazhexacyclo (21,5,2,026,0712,01620 d26,30Itriacontu-1 (29),7,9,11,17,19,23(30), 24,27-nonaen-22-one: Suspension of (8)-M-(1-(2-(tert-butyldiphenylsilyloxy)ethyl)- 1 H-pyrazol-5-yl)-5-(2-(5-fluoro-2-methoxypyridin-

3-yl)pyrrolidin-1-yl)pyrazolo(1,5-a|pyrimidine-33-carboxamide (201 mg, 0.285 mmol) in 4 M NOSI in dioxane (b mL) was packed and heated to 100 °C for four hours . The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with OCM (20 mL) and washed with sat. by obtaining crude /(H)-5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)-M-(1-(2-hydroxyethyl)-1H-pyrazol-5- il) pyrazolo|1,5-a|pyrimidine-3-carboxamide, to which were added TNE (20 mL), OEAO (53.9 μL, 0.342 mmol) and triphenylphosphine (89.8 mg, 0.342 mmol). The reaction mixture was stirred for 18 g, then concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 10 96 Meon/lOOsCM to give the indicated product (1.8 mg, yield 1.5 90). M5 (arsi) t/72 - 435.3 (MAN).

Example 39 -M

This is the floor

M co

SHU about 9 and MH 7 M p-(68)-9-fluoro-13-oxa-2,11,19,21,25,26,29-heptaazhexacyclo (21,5,2,026,07y12,015.20 d2630Igriakonta-1( 29),7,9,11,15(20),16,18,23(30),24,27-decaen-22-one

І00446| Step A: Preparation of 3-((tert-butyl-diphenylsilyloxy)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, 868.2 mmol) in

Tert-butylchlorodiphenylsilane (5.49 mL, 21.2 mmol) was added dropwise to OME (10 mL). The reaction mixture was stirred for 15 h. The solvent was removed under reduced pressure and the residue was diluted in OSM (4.0 mL). The organic phase was washed with 1N NOSI (10 mL), water (10 mL), and brine (10 mL) and then concentrated to give the crude product (6.03 g, yield 94.3 90). M5 (Arsi) t/2 - 363.1 (MNN).

I00447| Stage B: Preparation of (6H8)-9-fluoro-13-oxa-2,11,19,21,25,26,29-heptaazhexacyclo (21,5,2,026,07y12,015,20 d2630Igriaconta-1(29), 7,9,11,15(20),16,18,23(30),24,27-decaen-22-one: to the suspension of (8)-5-(2-(5-fluoro-2-methoxypyridin- To 3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxylic acid (303 mg, 0.848 mmol) in OME (5 mL) was added triethyl amine (103 mg, 1.02 mmol), after which 2,4,b-trichlorobenzoyl chloride (227 mg, 0.933 mmol) was added dropwise.

The reaction mixture 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 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography. , eluting with 10 96 MeEOH/OSM to obtain (8)-M-(3-«(tert-butyldiphenylsilyloxy)methyl)pyridin-2-yl)-5-(2-(5-fluoro-2-methoxypyridin-3Z- yl)pyrrolidin-1-yl)pyrazolo|1,5-a|pyrimidine-3-carboxamide, to which was added

TNE (5 ml) and TVAE (848 μl, 0.848 mmol). The reaction mixture was stirred for one hour, then the reaction was quenched with a saturated solution of MNaCl (1 ml), after which it was concentrated under reduced pressure to give crude (H)-5-(2-(5-fluoro-2-methoxypyridin-3-yl) )pyrrolidin-1-yl)-M-(3-(hydroxy methyl)pyridin-2-yl)pyrazolo|1,5-a|pyrimidine-3-carboxamide, to which was added NOSI (4 M in dioxane, 5 ml) . The reaction mixture was packed and

The mixture was heated to 100 °C for four hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with USM (20 ml) and the organic phase was washed with a saturated solution of ManNsoz (5 ml), water (5 ml) and brine (5 ml). The organic phase was concentrated under reduced pressure to obtain crude (H)-M-(3-(chloromethyl)pyridin-2-yl)-5-(2-(5-fluoro-2-hydroxypyridine-3 - yl)upyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxamide, to which UOME (10 ml) was added and

C52bOz (276 mg, 0.848 mmol). The reaction mixture was heated to 60 "C for 4 h, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified using column chromatography on silica gel, eluting with 10 96 MEOH/OSM to obtain the indicated product (8.0 mg, output 2.2 95).M5 (arsi) t/7 - 432.3 (M.N).

Example 40 no

M BUYE -- (8) o x Ol LN sh-- M

IS

(628)-9-fluoro-13,13-dimethyl-2,11,15,19,20,23- hexaazapentacyclo|15,5,2,1711,026,020,24|)pentacose-1(23),7, 9,17(24),18,21-hexaene-16,25-dione

І00448| 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 95 aqueous solution of HBr

(10 ml) was heated in a reflux vessel for 18 hours. The reaction mixture was cooled to ambient temperature and the solid precipitate formed was filtered off. The filtrate was concentrated under reduced pressure to obtain crude material, to which toluene (3x) was added to form an azeotropic mixture, and then - acetonitrile to form a solid precipitate. The crude material was triturated with diethyl ether and dried under reduced pressure to give 3-bromo-2,2-dimethylpropane-1-amine hydrobromide (0.816 g, 3.07 mmol, yield 91.0 95) (confirmed by "H-NMR and rosari- M5). The isolated product was used directly, without additional purification. 00449) Step B: Preparation of (8)-M-(3-bromo-2,2-dimethylpropyl)-5-(2-(5-fluoro-2-hydroxypyridine- 3-yl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxamide: to a solution of (H)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin- 1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylic acid (preparation method B; 150 mg, 0.420 mmol), EOSI (88.5 mg, 0.462 mmol) and NOVT-NgO (70.7 mg, 0.462 mmol) in OME (10 mL) was added 3-bromo-2,2-dimethylpropane-1-amine hydrobromide (124 mg, 0.504 mmol), followed by triethyl amine (55.2 mg, 0.546 mmol). The reaction mixture was stirred for 18 h. The solvent was removed under reduced pressure and the residue was purified using column chromatography on silica gel, eluting with 50 95 EOACs in hexanes from (H)-M-(3-bromo-2,2-dimethylpropyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)upyrazolo|1,5-a |pyrimidine-3-carboxamide (180 mg) to which CARRIERS (5 ml, 4 M in dioxane) were added. The reaction mixture was packed and heated to 90 °C for 2 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with 20 95 hexanes/E(OAc) to give the desired product (130 mg, yield 63,965). 00450) Stage c. Preparation of (6K)-9-fluoro-13,13-dimethyl-2,11,15,19,20,23- hexaazapentacyclo(|15,5,2,1711,026.,020,24| )pentacose-1(23),7,9,17(24),18,21-hexaene-16,25-dione: to a solution of (8)-M-(3-bromo-2,2-dimethylpropyl)-5 -(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)upyrazolo|1,5-a|Ipyrimidine-3-carboxamide (30 mg, 0.061 mmol) in TNE (5 ml) by potassium 2-methylpropan-2-olate (153 μl, 0.15 mmol) was added dropwise. The reaction mixture was heated at 50 °C for two hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with 10 96 ppm to give

From the specified product (15 mg, output 60 90). M5 (arsi) t/2 - 411.0 (M.N).

Example 41 no se

M-k- -

M

M 9; и -иВ 9 en (48,68,155)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo|17,5,2,026,07и12,02226|hexacose-1 (25),7(12),8,10,19(26),20,23-heptaen-18-one 00451 Stage A: Preparation of M-((5)-3-chloro-2-hydroxypropyl)-5- ((A)-2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxamide: to the suspension of (8!)-5-(2 -(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo|1,5-a)pyrimidine-3-carboxylic acid (method of preparation 0; 0.0339 g, 0.0946 mmol) and NATI (0.0540 g, 0.142 mmol) in OME (0.5 ml) at 0 "C was added (5)-1-amino-3-chloropropan-2-ol hydrochloride (example 19, step A; 0.0155 g , 0.142 mmol; obtained in accordance with the method described in the publication of Ogud. Rgose55

Transportation Hey 2003, mine. 7, p. 533) and M,M-diisopropylethyl amine (0.0494 ml, 0.284 mmol). The resulting mixture was heated to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with EtOAc (10 ml), washed with brine, dried over Ma50O:5, filtered and concentrated under reduced pressure to obtain crude material, which was purified using column chromatography on silica gel, eluting with 0-20 95 Meon/losm with the preparation of M-((5)-3-chloro-2-hydroxypropyl)-5-((A)-2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo|1,5 - α|Ipyrimidine-Z-carboxamide (in the form of a mixture of cis- and trans-isomers, 0.0407 g, yield 82.2 95, purity 86 95). | S/M5 (EZ-Arsi) t/7 - 448.1 (M-N).

І00452| Stage B: Preparation of (4H,68,155)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacyclo!|17,5,2,026,0712 02226Ihexacose-1(25) ,7(12),8,10,19(26),20,23-heptayen-18-one:

Mixture /M-(5)-3-chloro-2-hydroxypropyl)-5-(H)-2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-1-yl)upyrazolo|1,5-a |Ipyrimidine-3-carboxamide (0.0407 g, 0.0778 mmol) and Sv2bOz (0.127 g, 0.389 mmol) in UOME (3.6 ml) were heated at 85 °C for 30 min. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude material, which was purified by column chromatography on silica gel, eluting with 0-20 96 MeOHN/EOAc to give the crude product. The crude material was purified by chiral column chromatography (Spiga!I Tesp column О0О-Н, 20,906 EN in hexanes).Isolation of the material with a retention time of approximately 21.8 min allowed to obtain the specified compound (0.0052 g, yield 16.2

Pho). The stereochemistry of the compound indicated in the title was confirmed by the experiment "H-NMR MOB. I C/M5 (EzZ-carsi) t/2 - 414.1 (M--H).

Example 41-8 no no o ho id i kak"

In B o - one (48,65,155)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo|17,5,2,026,07y12,02226|hexacose-1 (25),7(12),8,10,19(26),20,23-heptaen-18-one

Y00453| The title compound was isolated by chiral resolution as described in Example 41 from fractions having a retention time of about 30.6 min to give 5.4 mg (yield 16.8 95) of a compound which may have been co-isolated with an enantiomer and/or one or more diastereomers. The stereochemistry of the compound indicated in the title was confirmed by the experiment "H-NMR MOE, I C/M5 (Eb-carsi) m/2 - 414.1 (MAN).

Example 42 but not St

M (6)

Ery o (48,62)-9-fluoro-4-hydroxy-13-oxa-2,17,21,22,25- pentaazapentacyclo|1 7,5,2,026,07712 02226Hexacose-1(25),7( 12),8,10,19(26),20,23-heptayen-18-one

Y00454| The title compound was obtained according to the method described in example 41, taking 3-chloropropane-1-amine hydrochloride instead of (5)-1-amino-3-chloropropan-2-ol hydrochloride in step A: 13.8 mg (yield 16,905; Spiga column! Tesp О0-Н, 20 95 EN in hexanes, retention time approximately 17.2 min.) The stereochemistry of the title compound was confirmed using the experiment "H-NMR MOB. I C/M5 (Ebhjarsi) t /72 - 398.1 (MA-N).

Example 42-8 no NO

Se - Mi mo (c) (48,65)-9-fluoro-4-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo|1 7,5,2,026,07712 02226Hexacose-1( 25),7(12),8,10,19(26),20,23-heptayen-18-one 00455) The title compound was obtained by chiral separation described in example 42, selecting fractions that had a retention time of approx. 26.2 min. (21.1 mg, yield 24.5 95), the compound may have been isolated along with the enantiomer and/or one or more diastereomers. The stereochemistry of the compound indicated in the title was confirmed by the experiment "H-NMR MOB. I C/M5 (Ez-narsi) t/2 - 398.1 (М--Н).

Example 43 but no

M po zm o (o)

MN

IS

(48,62)-9-fluoro-4-hydroxy-13-oxa-2,16,20,21,24-pentaazapentacycloi|16,5,2,026,07и12,021.25|pentacose-1(24),7,9 ,11,18(25),19,22-heptaene-17-one

І00456| The title compound was obtained according to the method described in example 41, taking 2-chloroethylamine hydrochloride instead of (5)-1-amino-3-chloropropan-2-ol hydrochloride in step iA. The title compound was purified on a Spiga column! Tesp 0-H, 20 95 EN in hexanes, selecting fractions with a retention time of approximately 15.7 min. (10.7 mg, yield 14.2 95). The stereochemistry of the compound indicated in the title was confirmed by the experiment "H-NMR MOB. I C/M5 (EzZ-carsi) m/2 - 384.1 (M.H).

Example 43-B no no

MA and OE- and (9)

IS

(48,65)-9-fluoro-4-hydroxy-13-oxa-2,16,20,21,24-pentaazapentacycloi|16,5,2,026,07и12,021.25|pentacose-1(24),7,9 ,11,18(25),19,22-heptaene-17-one

І00457| The title compound was isolated by the chiral separation described in Example 43, selecting fractions having a retention time of approximately 21.3 min. (15.9 mg, yield 21.1

Fo), the compound may have been isolated together with the enantiomer and/or one or more diastereomers. The stereochemistry of the compound indicated in the title was confirmed by the experiment "H-NMR MOE, I C/M5 (EzZ karsi) t/2 - 384.1 (M.N).

Example 44 but no

M to

M c) on (48,6Н,15Н8)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacyclo|1 7,5,2,026,07712 02226Ihexacose-1( 25),7(12),8,10,19(26),20,23-heptayen-18-one

І00458| The title compound was prepared according to the method described in example 41, taking (HA)-1-amino-3-chloropropan-2-ol hydrochloride (obtained according to the method described in example 19, step A, using (H )-2-(chloromethyl)oxirane) instead of (5)-1-amino-3-chloropropan-2-ol hydrochloride in step A. The crude material was purified using column chromatography on silica gel, eluting from СНоСи» to

MNaOH:Meon:sSnNesi" (0.5:5:95) (4 runs). Fractions containing the compound that eluted first were collected to give 12 mg (yield 10.9 95) of the required material. Stereochemistry specified in

From the title of the compound, it was confirmed using the experiment "H-NMR MOB. IS/M5 (Eb--arsy) t/2 - 414.0 (MAN).

Example 44-B but not g to

Io; at

Her M o i on

(48,65,158)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacyclo|17,5,2,026,07и12,02226|hexacose-1(25),7 (12),8,10,19(26),20,23-heptaen-18-one 00459) The title compound was isolated during the purification described in example 44.

Fractions containing the compound eluted at a later stage were collected to give 15 mg (yield 13.6 95) of the title compound, which may have been isolated along with the enantiomer and/or one or more diastereomers. The stereochemistry of the compound indicated in the title was confirmed by the experiment "H-NMR MOE, GS/M5 (Ebzharsi) t/2 - 4141 (M.N).

Example 45

To St. Sn

M. rani Zmy y - V iny 0 shi 7 VN

Diastereomer 1 and diastereomer 2 (155)-4,4,9-trifluoro-15-hydroxy-13-oxa-2,17,21,22, 25- pentaazapentacyclo!|17,5,2,026,0712 02226Ihexacose-1(25 ),7(12),8,10,19(26),20,23-heptaen-18-one 00460) Stage A: Preparation of (K)-5-(5-fluoro-2-methoxyphenyl)pyrrolidin-3Z- ol-hydrochloride: to a solution of (K)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl) pyrrolidine-1-carboxylate (1.01 g, 2.37 mmol) in СНеСС » (10 ml) at 0 "С, 4 M HC in dioxane (5.93 ml, 23.7 mmol) was added. The resulting mixture was heated to ambient temperature and stirred for 8 h. The reaction mixture was concentrated under reduced pressure to give of the crude material, which was triturated with diethyl ether.The resulting solids were filtered and dried under reduced pressure to give (K)-5-(5-fluoro-2-methoxyphenyl)pyrrolidin-3-ol hydrochloride (0.577 g, 2, 33 mmol, yield 98.2 90). M5 (ARSIarsy) t/2 - 212.0 (M--H).

I00461| Step B: Preparation of (K)-ethyl5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-ylupyrazolo|1,5-a|pyrimidine-3-carboxylate: to the suspension of ethyl-5-hydroxypyrazolo |1,5-α|pyrimidine-Z-carboxylate (0.541 g, 2.61 mmol) and BOP reagent (1.57 g, 3.56 mmol) in

(K)-5-(5-fluoro-2-methoxyphenyl)pyrrolidin-3-ol hydrochloride (0.588 g, 2.37 mmol) was added to OME/SNeasCl (3 ml/3 ml) at 0°C, and then - OIEA (1.66 mL, 9.50 mmol).The resulting mixture was heated to ambient temperature and stirred for 18 h.

The reaction mixture was concentrated under reduced pressure to give crude material, which was further diluted with EOAc (30 mL). The organic phase was washed with a saturated aqueous solution of NaHCO3, then with a saline solution, dried over Ma5ox, filtered and concentrated under reduced pressure to obtain the crude material, which was purified by flash column chromatography on silica gel, eluting with a gradient from СНеСиг2 to 5 95 MeON in СНоС» with the preparation of (K)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylate (0.735 g, 1.84 mmol, yield 77.3

Uv). Y S/MY5 (EZ-karsi) t/2 - 401.1 (M.--N).

I00462| Step C: Preparation of ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-oxopyrrolidin-1-yl)upyrazolo|1,5-a|pyrimidine-3-carboxylate: to a suspension of Deso-Martin periodinan (0.233 g, 0.549 mmol) in SNCl (2.2 ml) at 0 "С was added to a solution of (HB)-ethyl 5-(2-(5-fluoro-2-methoxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo| 1,5-α|Ipyrimidine-3-carboxylate (0.200 g, 0.499 mmol) in SiCl (1.5 mL). The resulting mixture was heated to ambient temperature and stirred for 18 h. The reaction mixture was cooled to 0 "C and the reaction was quenched with a saturated aqueous solution of ManHsoz (5 mL) containing Mag52Oz (0.608 g, 3.85 mmol). The resulting mixture was heated to ambient temperature and stirred for 10 min. The organic phase was separated, washed with saturated aqueous Mansoz solution (10 ml), then with saline solution (10 ml), dried over Md50O5", filtered and concentrated under reduced pressure to obtain ethyl-5-(2-(5-fluoro-2- methoxyphenyl)-4-oxopyrrolidin-1-yl)upyrazolo|1,5-a|pyrimidine-3-carboxylate (0.164 g, yield 82.4 95). | S/M5 (EbBnarsi) t/2 - 399.1 (MAN).

I00463| Stage 0: Preparation of ethyl 5-(4,4-difluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)upyrazolo|1,5-a|pyrimidine-3-carboxylate: to a solution of ethyl 5-(2-(5-Fluoro-2-methoxyphenyl)-4-oxopyrrolidin-1-yl)pyrazolo|(1,5-a|pyrimidine-3-carboxylate (0.162 g, 0.407 mmol) in CHClS (3 mL) a solution of bis-(2-methoxyethyl)aminosulfur trifluoride (0.134 ml, 0.691 mmol) was added, and then -

EUN (0.00475 ml, 0.0813 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (b ml) and extracted with СНоСи» (2 x 10 ml). The combined organic phases were dried over M950", filtered and concentrated under reduced pressure to obtain crude material, which was purified using column chromatography on silica gel, eluting with 0-50 906 E(UAc/hexanes to obtain ethyl-5-(4, 4-Difluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylate (0.126 g, yield 65.6 95). M5 (arsi) t /2 - 420.9 (M.N).

IІ00464| EEstep EE: Preparation of 5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)upyrazolo|1,5-a|Ipyrimidine-3-carboxylic acid: to a solution of ethyl-5 -(4,4-difluoro-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-33-carboxylate (0.126 g, 0.267 mmol) in

To SNeosi" (1.3 ml) at 0 "C was added 1 M VVgz in SNgSi" (1.50 ml, 1.50 mmol). The resulting mixture was heated to ambient temperature and stirred for 18 hours.

The reaction mixture was diluted with SNeoSi" (5 ml) and poured into a mixture of ice and a saturated aqueous solution of MaHsSoO: (3 ml). Then the aqueous phase was acidified to approximately pH 3 with the help of 1 N aqueous solution of HC. Extraction of the aqueous phase was carried out with the help of SNeSi" (Z x 10 ml).

The combined organic phases were dried over Mo5O:, filtered and concentrated under reduced pressure to obtain a mixture of ethyl-5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)/pyrazolo| 1,5-a|Ipyrimidine-3-carboxylate and 5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo|1,5-a|Ipyrimidine-3- carboxylic acid. This mixture was dissolved in Meon-TNE (0.25 mL/0.75 mL) at ambient temperature and a 2 N aqueous solution of GION (0.667 mL, 1.33 mmol) was added. The resulting mixture was heated at 50 °C for 24 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to remove organic solvents. The residue was diluted with 5 ml of EOAc and acidified to pH 3-3-4 with 6 N aqueous solution

NOI when stirring. The organic phase was separated and an acidic aqueous phase was extracted with EOAc (2 x 5 ml). The combined organic phases were dried over Md50O»5, filtered and concentrated under reduced pressure to obtain / 5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo (1, 5-a|Ipyrimidine-3-carboxylic acid (0.094 g, yield 93.1

Fe). M5 (arsi) t/2 - 378.9 (М--Н).

І00465| ER stage: Preparation of M-((5)-3-chloro-2-hydroxypropyl)-5-(4,4-difluoro-2-(5-fluoro-2-

From hydroxyphenyl)pyrrolidin-1-yl)/pyrazolo|(1,5-a|pyrimidine-3-carboxamide: to a mixture of 5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidine-1 -yl)pyrazolo|1,5-a|Ipyrimidine-3-carboxylic acid (0.047 g, 0.124 mmol) and NOVT (0.0252 g, 0.186 mmol) in OME (1 mL) at ambient temperature was added EOSI (0, 0357 g, 0.186 mmol). The resulting mixture was stirred for 1 hour. To this mixture was added (5)-1-amino-3-chloropropan-2-ol hydrochloride (Example 19, step A; 0.0218 g, 0.149 mmol ), and then SIEA (0.0656 mL, 0.373 mmol) at ambient temperature. The resulting mixture was stirred for 48 h.

The reaction mixture was diluted with EtOAc (10 mL), and the organic phase was washed with a 1:1 mixture of brine and water. Separated the aqueous phase and extracted it with EAs (2 x 10 ml). The combined organic phases were washed with a 1:1 mixture of brine and water (15 mL) and combined with the organic phase obtained earlier. The organic phase was dried over Ma95O», filtered and concentrated under reduced pressure to obtain M-((5)-3-chloro-2-hydroxypropyl)-5-(4,4-difluoro-2-(5-fluoro-2- Hydroxyphenyl)pyrrolidin-1-yl)/pyrazolo|1,5-a|Ipyrimidine-3-carboxamide (0.061 g, yield 105,905).

Y S/M5 (Eb-narsi) t/2 - 468.1 (M-N). 00466) Stage c: Preparation of diastereomers 1 and 2 (155)-4,4,9-trifluoro-15-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo|17,5,2,026,07y12, 02226|hexacos-1(25),7(12),8,10,19(26),20,23- heptaen-18-one: Mixture of M-((5)-3-chloro-2-hydroxypropyl)- 5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)/pyrazolo|1,5-a|pyrimidine-3-carboxamide (0.060 g, 0.128 mmol) and

C52bOz (0.208 g, 0.639 mmol) in OME (6.4 mL) was heated at 85 °C for 30 min. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to give crude material, which was purified by column flash chromatography on silica gel, eluting with a gradient from (СНоСи» to

MNaOH:Meon:snNesI" - 0.5:5:95) to obtain a mixture of diastereomers. The isolated diastereomers were further purified using chiral column chromatography (Spiga column! Thesp

O0B-H, 20 95 EN in hexanes). Fractions with a retention time of approximately 17.1 min were separated to give the title compound designated as diastereomer 1 (11 mg, yield 20 90; M5 (arsenic) t/2 - 434.2 (Ma-H). Fractions with a retention time of approximately 21.0 min were separated to give the title compound designated as diastereomer 2 (13 mg, yield 24 95); M5 (arsi) t/2 - 434.2 (M.N) (510)

Claims (1)

FORMULA OF THE INVENTION 1. The compound of the general formula I rai ma ih s s Od va v" 7 z MM. ra - t Eva Z Kk or its pharmaceutically acceptable salts, where ring A is selected from rings A-1, A-2 and A-3, having the structures: 2 dО and | у ОО -ШЧО Й M х - ры M " у 2 7 У 2 в" В в' А-1 А-2 А-3 where the wavy line marked 1 indicates the joining point of ring A to ring B, and the wavy line, marked 2, indicates the point of attachment of ring A to MU; X is M or CH; Y is H or E; B' is H, (1-3C)alkyl, (1-3C)alkyl or halogen; ring B is selected from rings B-1 and B-2 having structures: in? c) in? sn ts - 4 / uh - 4 Y yi Z ; From c-1 c-2 where the wavy line marked 3 indicates the point of attachment to ring A, and the wavy line marked 4 indicates the point of attachment to the pyrazolo|1,5-a|pyrimidine ring of formula Y; МУ is О, МН or Сн», while when ring A is A-2, then M is СН»; teo,1 orog2; OR is carbon, B: and 22 are independently H, E, (1-3C)alkyl or OH (provided that KZ: and 822 are not simultaneously OH), and EZ and KZa are independently H, (1-3C) alkyl or hydroxy(1-3C)alkyl, or p is carbon or nitrogen, EZ: and BZ are absent, and 22 and Za together with the atoms to which they are attached form a 5-6-membered heteroaryl ring containing 1- 2 ring heteroatoms; 2 in -Mmnlab(-O)-, "-OMNO(-O)-, "-МАСН»e- or 7-ОС(-0)-, where the asterisk indicates the point of attachment of 7 to the KZ containing carbon; Va is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl or dihydroxy(2-bAlkyl); B is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6Alkyl), dihydroxy(2-bAlkyl), ( 1-6Alkyl)C(0)-, (3-bCcycloalkyl)C(0)-, AgSF(0)-, HnHOCHnF(O)-, (1-6Alkyl)usulfonyl, (3-6Ccycloalkyl)usulfonyl, Ag7(502 )-, Koo) HOzhCH»- or (1-6Alkyl/MH(CO)-; Ag is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkyl; Huh? is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkyl; and Vo and Ke are independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl. 2. The compound according to claim 1, which has the general formula: in A-M OK Kk - n-. M M ra v? 2 SUA t in or its pharmaceutically acceptable salt, where: ring A is selected from rings A-1, A-2 and A-3, having the structures: ' in ' 2 (c) dO | where the wavy line marked 1 indicates the point of attachment of ring A to the pyrrolidine ring in formula I, and the wavy line marked 2, indicates the point of attachment of ring A to MU; X is M or CH; U is H or E; B" is H, (1-3C) alkoxy group or halogen; МУ is О, МН or Сн», while when ring A is A-2, then M is СН»; teo,1 orog2; IN? and 22 are independently H, E or OH, provided that KZ: and Kg are not OH at the same time; BZ is H, (1-3C)alkyl or hydroxy(1-3C)alkyl; 20.7 is -MNlaF(-0)-, "-OMNO(-O)-, "-MA?CH»- or 7-OS(0)-, where the asterisk indicates the point of attachment of 7 to the KZ containing carbon; Va is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl or dihydroxy(2-bAlkyl); A is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6bAlkyl), dihydroxy(2-bAlkyl), ( 1-6Alkyl)C(0)-, (3-bCcycloalkyl)C(0)-, AgF(0)-, HOSNoC(O)-, (1-6Alkyl)usulfonyl, (3-6Ccycloalkyl)usulfonyl, Ag(50O2 )-, HOzhCH»- or (1-6Alkyl/MH(CO)-; Ag is phenyl, optionally substituted by one or more substituents independently selected from halogen, (1-6C)alkyl and (1-6C)alkyl; Ko) Ah? is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkyl; and B? and EX is independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl. 3. A compound according to any of claims 1 or 2, where ring A is ring A-1, having the structure: bo da 2 and x U v' A-1 4. Compound zap. 3, where X is CH. 5. Compounding. Of which there is M. 6. A compound according to any of claims 1 or 2, where ring A is ring A-3 having the structure: 1 edchchuch g y U 2 y' WITH 7. Compound according to any of claims 1-6, where MU is 0. 8. Compound according to any of claims 1-6, where UM is MN. 9. The compound according to any of claims 1-6, where UM is SN". 10. A compound according to any of claims 1 or 2, where ring A is ring A-2, having the structure: 1 da (c) сх M Я, na, y 2 ve log 11. A compound according to any of claims 1-10, where U is KE. 12. The compound according to any of claims 1-10, where M is H. 13. The compound according to any of claims 1-12, where B" is H. 14. The compound according to any one of claims 1-12, where B" is a (1-3C)alkyl or (1-3C)alkyl group. 15. The compound according to claim 14, where B! is methyl or methoxy. 16. The compound according to any of claims 1-12, where B" is a halogen. 17. The compound according to claim 16, where B' is fluorine. 18. The compound according to any of claims 1-17, where 2 is "-MAlab(-0)-. 19. The compound according to claim 18, where IN"a is hydrogen. 20. The compound according to claim 18, where Ba is (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl or dihydroxy( 2-bSalkilom). 21. The compound according to claim 20, where IZ"a is (1-6C)alkyl. 22. The compound according to any of claims 1-17, where 27 is "-ЮОМНО(-О).-. 23. The compound according to any of claims 1-17, where 7 is -MA?SN»-. 24. Compound according to claim 23, where 2 is H. 25. The compound according to claim 23, where B? selected from (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl and trifluoro(1-6C)alkyl. 26. Compound according to claim 25, where B? is (1-6C)alkyl. 27. The compound according to claim 23, where B" is selected from (1-6Alkyl)C(O)-, (3-Ccycloalkyl)C(O)-, Ag C(O).- and Coo) nOosHneC(O)- . 28. The compound according to claim 27, where B" is (1-6Alkyl)C(0)-. 29. The compound according to claim 23, where B" is selected from (1-6Alkyl)usulfonyl, (3-ECcycloalkyl)sulfonyl and AgI(505)-. 30. The compound according to claim 29, where B" is (1-6Alkyl)usulfonyl. 31. The compound according to claim 23, where B? is HOg2ССН»-. 32. The compound according to claim 23, where B? is (1-6Alkyl/MH(CO)-. 33. The compound according to any of claims 1 or 3-32, where Y is carbon, BC? and Ka are independently H, E, (1- C C ) alkyl or OH (provided that KVK: and 22 are not simultaneously OH), and BE and Ka are independently H, (1- C C ) alkyl or hydroxy(1- 3C) alkyl. 34. The compound according to any one of claims 1-33, where is VZ? and K2a are each hydrogen. 35. The compound according to any of claims 1-33, where B? and K72 are each fluorine. 36. A compound according to any one of claims 1-33, wherein B2 is hydrogen and K2a is fluorine. 37. A compound according to any one of claims 1-33, wherein B: is hydrogen and Kha is OH. 38. A compound according to any one of claims 1 or 3-33, where B: is H and Ka is methyl, or KZ: and K2a are both methyl. 39. The compound according to any of claims 1 or 3-33, where: ВЗ and вза is H; or Bza is methyl and EZ is H; or Dzag and EZ are both methyl. 40. A compound according to any one of claims 1 or 3-32, where O is carbon or nitrogen, P: and EZ are absent, and 22 and z together with the atoms to which they are attached form a 5-6-membered heteroaryl ring , containing 1-2 heteroatoms in the ring; 41. The compound according to any of claims 1-40, where ring B is ring B-1: in? in? i-th 4 Masata C in-1 "and Wo i E5 are independently H, E, OH, methyl, ethyl, HOCH"e- or HOSNoCH"e-. 42. The compound according to claim 41, where IV: is hydrogen and Ke is H, E, OH, methyl, ethyl, HOCH»- or HOCHNoCH-»-. 43. The compound according to claim 42, where Ve is H. 44. The compound according to any of claims 1 or 3-40, where ring B is ring B-2: (c) 5-4 x A, C in-2 45. Compound according to any of claims 1-44, child. 46. The compound according to any of claims 1-44, where t is 1. 47. The compound according to any of claims 1-44, where t is 2. 48. A compound according to any one of claims 1-47 having an absolute configuration as in FIG. 1st: M in the rain and their M M ha in? mm and ra shk t vza in 1-a 49. A compound according to any one of claims 1-47 having an absolute configuration as in FIG. 1st: M in? ot and ih M M : la v? I M X/ 2 a ve t for in the 1st year 50. A pharmaceutical composition containing a compound of formula I according to any one of claims 1-49 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable solvent or carrier. 51. A method of treating a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease, or Tturapozota gyti?i infection in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I according to any one of claims 1-49 or its pharmaceutically acceptable salt. 52. The method of claim 51, wherein the disease or disorder is pain. 53. The compound of formula I according to any one of claims 1-49 or its pharmaceutically acceptable salt for use in the treatment of pain, oncological disease, inflammation, neurodegenerative disease or infection of Ttgurapozota sgy?i. 54. The method of obtaining the compound according to claim 1, which is carried out: (a) in the case of the compound of formula I, where 2 is 7-МНО(-О)- and ring A, ring B, МУ, О, Кг, Вга, ВЗ, for Her t - as indicated for formula I, cyclization of the corresponding compound having formula II: o m- ich s pn M (c) ra v? X/ OR! M r One t v EZa I where P" is H or a carboxy protecting group in the presence of a reagent that promotes the condensation reaction and a base; or (6) in the case of a compound of formula I, where MU is O, ring A has the formula A-1: add di 2 and xX U v' A-1 X E M, iii ring B, 0, 27, M, KK", r, IVha, IVZ, Iza and t - as indicated for formula I, cyclization of the corresponding compound having the formula III ho. ma ih Od M y o y 2 ha Her 5 sh M z v Il di, y Sh depeye1,2,Zabo4, and 1" is a group or atom leaving, in the presence of a base; or (c) in the case of a compound of the formula I, where M/ is CH", ring A has the formula A-2: 1 aa a (c) and M re i y; в' A-2 and the ring B, 2, 0, M, EE", IN, IZha, IV, Vza and t - as indicated for the formula Y, cyclization of the corresponding compound having the formula IM: dk -mzh Ox Osh M y where 12 is a leaving group or atom in the presence of a base; or (d) in the case of a compound of formula I, where 2 is "-MHO(- О)-, and ring A, ring B, МУ, О, Бе, га, ВУ, Aza and т - as indicated for formula Y, cyclization of the corresponding compound having formula Y: 7О/ m-і іх чо ни M (vi on (c) va v? m M t v' V Za U in the presence of a base and a reagent that promotes the condensation reaction; or (e) in the case of a compound of formula I, where 2 is "-MNSON"-, and ring A, ring B, MU, Y, 2, Inga, IZ, Vza and t - as indicated for the formula Y, cyclization of the corresponding compound having the formula MI: du m- ich still M ( c) N ra v? MI M (hu Ya gich t v B By MI in the presence of a reducing agent; or (is) in the case of a compound of formula I, where 7 is "-MNSON"-, and ring A, ring B, MU . g) in the case of a compound of formula I, where ring A, ring B, UM, O, t, B, Inga, VZ and yirza - as indicated for formula I, 2 is -MA"СНе-, and B" is (1- 6Alkyl)C(0)-, (3-6Ccycloalkyl)C(0)-, Ag C(O)-, HOHNS(O)-, (1-6Calkyl)sulfonyl, (3-bCcycloalkyl)usulfonyl, (1-6Calkyl)sulfonyl, (3-6Ccycloalkyl)usulfonyl or Ag-(502)-, condensation of the corresponding compound having the formula MI: and m-7 of them still nan M ha in? х/ МН Od t ц E Za MI with a reagent having the formula (1-6Calkyl)/C(0)-IZ, (3-6Ccycloalkyl)/C(0)-15, AgC(O)-I3, HOSHeC( O)-1I3, (1-6Alkyl) (5052)-I3, (3-6Ccycloalkyl) (5052)-IZ or Ag7(505)-Iz3, respectively, where IZ is a leaving atom, in the presence of a base; or (3) in the case of a compound of formula I, where ring A, ring B, MU, O, K2, FZ, VZ, Iza, etc. - as indicated for formula I, 2 is -MA"СНе-, and B" is ( 1-6Salkyl/MH(CO)-, carrying out the reaction of a compound with the formula MI: Dt ykh s M ra v? -C-O, in the presence of a base; or () in the case of a compound of formula I, where KZ is E, Kgae is H, and ring A, ring B, 7, MU, O, KZ, FSHchai t - as indicated for formula Y , carrying out the reaction of the corresponding compound having the formula IX: и m-7 их с ж M НОоН 7 Х/ Арт vza in IX with a fluorinating reagent; (k) in the case of a compound of the formula I, where MU is O, ring A has formula A-1: add di 2 and xX U v' A-1 HeESN,M, i, 0, ring B, 7, NK, IZha, VZ and t - as indicated for formula I, cyclization of the corresponding compound having the formula X 0 mA ih ( 8) M onia 7 ha A za U v shchi v3 Il p x depeye1,2,Zabo4, a" is a leaving group or atom in the presence of a base; and, optionally, removal of any protecting groups and, optionally, obtaining salts of these compounds. 55. The method according to claim 54, which differs in that: ring B is ring B-1 having the structure: in? in? i-th 4 The mass З В О is carbon; IN? and 22 are independently H, E, (1-3C)alkyl or OH, provided that P: and 222 are not both OH; and BZ is independently H, (1-3C)alkyl or hydroxy(1-3C)alkyl. 56. A compound selected from (68)-9-fluoro-2,11,15,19,20,23-hexaazapentacyclo|15.5.2.1711.026.02024|Ipentacose-1(23),7,9,17(24), 18,21-hexaene-16,25-dione; (68)-12-oxa-2,16,20,21,24 26-hexaazapentacyclo|16.5.2.1711.026.02129Ihexacose- 1(24),7(26),8,10,18(25),19,22 -heptayen-17-one; (68)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacycloi|17.5.2.0256.0712.02226Ihexacose-1(25),7,9,11,19(26),20 ,23-heptayen-18-one; (628)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25- hexaazapentacyclo!|17.5.2.026.0712,02226|hexacose-1(25),7,9, 11,19(26),20,23-heptayen-18-one; (68,135)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo- (15.5.2.1711.0256,02024|Ipentacose-1(23),7,9,17(24),18,21-hexaene-16,25-dione; (628)-9-fluoro-15-hydroxy-13 -oxa-2,11,17,21,22,25-hexaazapentacyclo- I17.5.2.026.0712,022,26|hexacose-1(25),7,9,11,19(26),20,23-heptayen-18-one; (6A,158)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- I17.5.2.026.0712,022,26|hexacose-1(25),7,9,11,19(26),20,23-heptayen-18-one; (6A,138)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo- I15.5.2.1711.026.020,24|)pentacose-1(23),7,9,17(24),18,21-hexaene-16,25-dione; (68)-9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacyclo|16.5.2.026,0712.02125|pentacose-1(24),7,9,11,18(25), 19,22-heptayen-17-one; (68)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo|18.5.2.026,0712.0232Lheptacose-1(26),7,9,11,20(27),21 ,24-heptayen-19-one; (68)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo|16.5.2.1711,026,02125)hexacose-1(24),7,9,18(25),19,22- hexaene-17,26-dione; (68)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo|16.5.2.026.0712.02125|pentacose-1(24),7,9,11,18(25),19, 22-heptayen-17-one; (68)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo|1 7.5.2.026.0712.02226|hexacose- 1(25),7,9,11,19(26),20 ,23-heptayen-18-one; (68)-9-fluoro-13,16-dioxa-2,11,20,21,24-pentaazapentacyclo|16.5.2.026.07.12,021.25|-pentacose- 1(24),7,9,11,18( 25),19,22-heptayen-17-one; (68)-9-fluoro-14-oxa-2,11,18,19,22-pentaazapentacyclo hexaene-15,24-dione; (68)-9-fluoro-13,16-dioxa-2,11,17,21,22,25-hexaazapentacyclo!|17.5.2.026.0712.02226|hexacose- 1(25),7,9,11,19( 26),20,23-heptayen-18-one; (68,138)-9,13-difluoro-2,11,15,19,20,23-hexaazapentacyclo|15.5.2.1711,026.02024|dentacose- 1(23),7,9,17(24),18,21- hexaene-16,25-dione; (68)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25- hexaazapentacyclo|1 7.5.2.0256.0712.022,26|hexacose-1(25),7,9, 11,19(26),20,23-heptayen-18-one; (68)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25- hexaazapentacyclo|1 7.5.2.0256.0712.022,26|hexacose-1(25),7,9, 11,19(26),20,23-heptayen-18-one; (68)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo|17.5.2.026.0712.02226|hexacose-1(25),7,9,11,19(26),20, 23-heptayen-18-one; (68)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo|16.5.2.026.07.12,021,25|pentacose-1(24),7,9,11,18(25 ),19,22-heptane; 1-K(68)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo|16.5.2.026,0712.02125|pentacose-Zo 1(24),7,9,11,18(25 ), 19,22-heptayen-16-yl|ethan-1-one; 1-К(68)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo|16.5.2.026,0712.02125|pentacose-1(24),7,9,11,18(25) ,19,22-heptayen-16-yl|-2-hydroxyethan-1-one; (68)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo|17.5.2.026.0712.02226|hexacose-1(25),7,9,11,19(26),20, 23-heptaene; (68)-9-fluoro-16-methanesulfonyl-13-oxa-2,16,20,21,24- pentaazapentacyclo|16.5.2.026.07.12,021.25|pentacose-1(24),7,9,11,18 (25),19 22-heptane; 2-K68)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo|16.5.2.026.0712.02125|)pentacose-1(24),7,9,11,18(25), 19,22-heptayen-16-yl|acetic acid; (628)-9-fluoro-17-methanesulfonyl-13-oxa-2,17,21,22,25- pentaazapentacyclo!|17.5.2.026.0712,02226I|hexacose-1(25),7,9,11, 19(26),20,23-heptaine; (68)-M-ethyl-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo!|17.5.2.026.0712.022,26|hexacose-1(25),7,9,11, 19(26),20,23-heptaene-17-carboxamide; (68)-M-ethyl-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo-(|16.5.2.026.0712.02125|pentacose-1(24),7,9,11,18 (25),19,22-heptaene-16-carboxamide; (65)-9-fluoro-4,13-dioxa-2,11,17,21,22,25-hexaazapentacycloi|17.5.2.0256.0712,02226| hexacose-1(25),7(12),8,10,19(26),20,23-heptaene-3,18-dione; (65)-9-fluoro-4,13-dioxa-2,11 ,16,20,21,24-hexaazapentacyclo(|16.5.2.0256.0712,02125|pentacose-1(24),7(12),8,10,18(25),19,22-heptaene-3,17 -dione; (68)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo|16.5.2.026,0712.02125|pentacose-1(24),7,9,11,18(25),19 ,22-heptaine-17-one; (68)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo|16.5.2.026.0712,021,25|pentacose-1(24 ),7,9,11,18(25),19,22-heptaine-17-one; (68,138)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacycloi|15.5 .2.17711,026.020,24|)dentacose-1(23),7,9,17(24),18,21-hexaene-16,25-dione; (68,135)-9-fluoro-13-methyl-2, 11,15,19,20,23-hexaazapentacyclo|15.5.2.1711.026.020.24|pentacose-1(23),7,9,17(24),18,21-hexaene-16,25-dione; IEN) -9-fluoro-15,15-d Imethyl-13-oxa-2,11,17,21,22,25- hexaazapentacyclo|1 7.5.2.0256.0712.022,26|hexacose-1(25),7,9,11,19(26),20,23 -heptayen-18-one; (68)-9-fluoro-15,15-dimethyl-2,11,16,20,21,24- 60 hexaazapentacyclo|16.5.2.0256.0712.,021,25|)pentacose-1(24),7, 9,11,18(25),19,22-heptayen-17-one; (628)-9-fluoro-13-oxa-2,11,16,17,21,25,26,29- octaazahexacyclo|21.5.2.026.07.12.016,20.026,39)griaconta-1(29),7 ,9,11,17,19,23(30),24,27-nonaen-22-one; (68)-9-fluoro-13-oxa-2,11,19,21,25,26,29- heptaazhexacyclo (20),16,18,23(30),24,27-decayen-22-one; (628)-9-fluoro-13,13-dimethyl-2,11,15,19,20,23- hexaazapentacyclo|1 5.5.2.1711.026,020,2ЯIpdentacose-1(23),7,9,17(24) ,18,21-hexaene-16,25-dione; (48,68,155)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacyclo!y17.5.2.026.07.12,02226|hexacose-1(25),7 (12),8,10,19(26),20,23-heptayen-18-one; (48,65,155)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacyclo!| 1 7.5.2.026.07.12,02226|hexacose-1(25),7(12),8,10,19(26),20,23-heptayen-18-one; (48,62)-9-fluoro-4-hydroxy-13-oxa-2,17,21,22,25- pentaazapentacyclo!y17.5.2.026.07.12,02226|hexacose-1(25),7(12 ),8,10,19(26),20,23-heptayen-18-one; (48,65)-9-fluoro-4-hydroxy-13-oxa-2,17,21,22,25- pentaazapentacyclo!|17.5.2.026.0712,02226I|hexacose-1(25),7(12) ,8,10,19(26),20,23-heptayen-18-one; (48,62)-9-fluoro-4-hydroxy-13-oxa-2,16,20,21,24- pentaazapentacyclo|16.5.2.026.0712.02125|pentacose-1(24),7,9,11,18 (25),19,22-heptayen-17-one; (48,65)-9-fluoro-4-hydroxy-13-oxa-2,16,20,21,24- pentaazapentacyclo|16.5.2.026.0712.02125|pentacose-1(24),7,9,11,18 (25),19,22-heptayen-17-one; (48,68,158)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo!y17.5.2.026.07.12,02226|hexacose-1(25),7 (12),8,10,19(26),20,23-heptayen-18-one; (48,65,158)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25- pentaazapentacyclo!y17.5.2.026.07.12,02226|Hexacose-1(25),7 (12),8,10,19(26),20,23-heptaine-18-one and diastereomers 1 and 2 (155)-4,4,9-trifluoro-15-hydroxy-13-oxa-2,17 ,21,22,25- pentaazapentacyclo!|17.5.2.026.0712,02226I|hexacose-1(25),7(12),8,10,19(26),20,23-heptayen-18-one. 57. The method according to claim 51, which is characterized by the fact that the disease or disorder is an oncological disease. 58. The method of claim 51, wherein the disease or disorder is caused by tropomyosin-related kinases (TK). 59. The method according to claim 58, which differs in that the disease or disorder is an oncological disease caused by TIC. 60. The compound according to claim 53, characterized in that the disease or disorder is an oncological disease. 61. The compound of claim 53, wherein the disease or disorder is pain. 62. The compound of claim 53, wherein the disease or disorder is caused by tropomyosin-related kinases (TCs). 63. The compound according to claim 62, characterized in that the disease or disorder is a TIC-induced oncological disease. 64. The compound according to claim 1, which has the general formula: in A-M OK M M ra v? 7 SUA or its pharmaceutically acceptable salts, where: ring A is selected from rings A-1, A-2 having the structures: 1 pd un 2 o de | 5 M x - У у г. 2 в А 1 Аг ' where the wavy line marked 1 indicates the point of attachment of ring A to the pyrrolidine ring in formula I, and the wavy line marked 2 indicates the point of attachment of ring A to MU; X EM; M is E; AND! is H; MI is SNho or 0; teo or 1; B2 and K2a are independently H, E, (1-3C)alkyl or OH (provided that KZ and 22 are not OH at the same time); BZ is H, (1-3C)alkyl or hydroxy(1-3C)alkyl; 2 is -MAlaC(-0)-, where the asterisk indicates the point of attachment of 2 to the short-circuit containing carbon; Va is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, or dihydroxy(2-6C)alkyl; and B? and EX is independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl. 65. The compound according to claim 1, which has the general formula: in? и MA и их к - ш-. М M вга в? 2 MM. m t v or its pharmaceutically acceptable salts, where: ring A has the structure: 1 ali 2 y x U v' A , where the wavy line marked 1 indicates the point of attachment of ring A to the pyrrolidine ring in formula I, and the wavy line marked 2, indicates the point of attachment of ring A to MU; X EM; M is E; Vie NN; MI is SNho or 0; teo or 1; IN? and 22 are independently H, E, (1-3C)alkyl or OH (provided that KE: and Kg are not simultaneously OH); BZ is H or (1-3C)alkyl; 2 is -MAlaC(-0)-, where the asterisk indicates the point of attachment of 2 to the short-circuit containing carbon; Koo) daeyanH; and Vo and KU are independently H, halogen, OH or (1-6C)alkyl. 66. The compound according to claim 1, which has the general formula: in A-M uva VE - pe M M ra v? ura Ni t v or its pharmaceutically acceptable salts, where: ring A has the structure: class (c) su M U / tu ? A-2, where the wavy line marked 1 indicates the point of attachment of ring A to the pyrrolidine ring in formula I, and the wavy line marked 2 indicates the point of attachment of ring A to MU; M is E; AND! is H; UM is SN"; teo or 1; B2 and K2a are independently H, E, (1-3C)alkyl or OH (provided that KZ and 22 are not OH at the same time); BZ is H or methyl; 2 is -MAlaC(-0)-, where the asterisk indicates the point of attachment of 2 to the short-circuit containing carbon; Does N;i V? and EX is independently H, halogen, OH or (1-6C)alkyl. 67. The compound according to claim 64, selected from: (68)-9-fluoro-2,11,15,19,20,23-hexaazapentacyclo|15.5.2.1711,026.02024|dentacose-1(23),7,9,17 (24),18,21-hexaene-16,25-dione; (68,138)-9,13-difluoro-2,11,15,19,20,23-hexaazapentacyclo|15.5.2.1711.026.020,24|)pentacose-1(23),7,9,17(24),18 ,21-hexaene-16,25-dione; (68,138)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo|15.5.2.1711.02,6.020,24|)pentacose-1(23),7,9,17( 24), 18,21-hexaene-16,25-dione; (68,135)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacycloi|15.5.2.1711,026.02024|dpentacose-1(23),7,9,17(24),18, 21-hexaene-16,25-dione; (68)-9-fluoro-13,13-dimethyl-2,11,15,19,20,23- hexaazapentacyclo|1 5.5.2.1711.026,020,2ЯIpdentacose-1(23),7,9,17(24) ,18,21-hexaene-16,25-dione. 68. The compound according to claim 64, selected from: (68)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacycloi|16.5.2.026.0712.021,25|)pentacose-1(24), 7,9,11,18(25),19 22-heptaine-17-one; (68)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo|16.5.2.026.0712,02125|pentacose-1(24),7,9,11,18(25 ), 19,22-heptayen-17-one; (68)-9-fluoro-15,15-dimethyl-2,11,16,20,21,24- hexaazapentacyclo|16.5.2.0256.0712.,021,25|)pentacose-1(24),7,9 ,11,18(25),19,22-heptayen-17-one; (68)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacycloi|17.5.2.0256.0712.02226Ihexacose-1(25),7,9,11,19(26),20 ,23-heptayen-18-one; (68)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25- hexaazapentacyclo| 1 7.5.2.026.0712,02226|hexacose-1(25),7,9,11,19(26),20,23-heptayen-18-one. 69. A pharmaceutical composition containing a compound according to any one of claims 64-68 or its pharmaceutically acceptable salts and a pharmaceutically acceptable solvent and carrier. 70. A method of treating a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease, or infection with Tturapozota gyti?i in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I according to any of claims 64-68 or its pharmaceutically acceptable salt. 71. The method of claim 70, wherein the disease or disorder is pain. 72. The method according to claim 70, characterized in that the disease or disorder is an oncological disease. 73. The method of claim 70, wherein the disease or disorder is caused by tropomyosin-related kinases (TCs). 74. The method according to claim 73, which differs in that the disease or disorder is an oncological disease caused by TIC. 75. A compound of formula I according to any one of claims 64-68 or a pharmaceutically acceptable salt thereof for use in the treatment of pain, oncological disease, inflammation, neurodegenerative disease or infection of Tturapozota sgy?i. 76. The compound of claim 75, wherein the disease or disorder is cancer. 71. The compound of claim 75, wherein the disease or disorder is pain. 78. The compound of claim 75, wherein the disease or disorder is caused by tropomyosin-linked kinases (TCs). 79. The compound of claim 75, wherein the disease or disorder is a TIC-induced cancer.