NOVEL SUBSTITUTED BIARYL COMPOUNDS AS INDOLAMINE 2,3-DIOXYGENASE (IDO) INHIBITORS

Abstract

This document discloses a compound of formula [1], or a pharmaceutically acceptable salt thereof. It also discloses uses of a compound disclosed herein for the possible treatment or prevention of a disorder or disease associated with IDO. It also discloses compositions comprising a compound disclosed herein. Furthermore, it discloses uses of a composition for the possible treatment or prevention of a disorder or disease associated with IDO.

Description

NOVEL SUBSTITUTED BIARYL COMPOUNDS AS INHIBITORS OF INDOLAMINE 2,3-DIOXYGENASE (IDO) BACKGROUND OF THE INVENTION Tryptophan (Trp) is an essential amino acid necessary for the biosynthesis of proteins, niacin, and the neurotransmitter 5-hydroxytryptamine (serotonin). The enzyme indolamine 2,3-dioxygenase (IDO) catalyzes the first rate-limiting step of the degradation of L-tryptophan with respect to N-formyl-kynurenine. In human cells, a decrease in Trp resulting from IDO activity is an important interferon gamma (EFN-γ)-inducible antimicrobial effector mechanism. Stimulation of IFN-γ induces IDO activation, leading to a decrease in Trp, and thereby arrests the growth of Trp-dependent intracellular pathogens such as Toxoplasma gondii and Chlamydia trachomatis. IDO activity also has an antiproliferative effect on many tumor cells, and IDO induction was observed in vivo during allogeneic tumor rejections, indicating a possible role for this enzyme in the tumor rejection process (Daubener, et al. al, 1999, Adv. Exp. Med. Biol, 467: 517-24; Taylor, et al, 1991, FASEB J„ 5: 2516-22). HeLa cells co-cultured with peripheral blood lymphocytes (PBL) have been observed to acquire an immunoinhibitory phenotype by upregulating IDO activity. A reduction in PBL proliferation following interleukin-2 (IL2) treatment was believed to be a result of IDO released by tumor cells in response to IFN-γ secretion by PBLs. This effect was reversed by treatment with 1-methyl-tryptophan (IMT), a specific IDO inhibitor. It was proposed that IDO activity in tumor cells could serve to alter antitumor responses (Logan, et al, 2002, Immunology, 105: 478-87). Several lines of evidence suggest that DDO participates in the induction of immune tolerance. Studies of pregnancy, tumor resistance, chronic infections, and autoimmune diseases in mammals showed that IDO-expressing cells can suppress T cell responses and promote tolerance. Accelerated Trp catabolism has been observed in diseases and disorders that are 233,166 IF-2018-68202357-APN-ANPAINPI Page 1 of 185 associated with cellular immune activation, such as infection, neoplasia, autoimmune diseases and AIDS, as well as during pregnancy. For example, elevated levels of IFN and elevated levels of urinary Trp metabolites were observed in autoimmune diseases; It was proposed that the systemic or local decrease in Trp that occurs in autoimmune diseases may be related to the symptoms of degeneration and wasting of these diseases. Supporting this hypothesis is the fact that elevated levels of IDO were observed in cells isolated from the synovial fluid of arthritic joints. IFNs are also elevated in patients with human immunodeficiency virus (HIV), and increasing levels of IFN are associated with a worse prognosis. Therefore, it was proposed that IDO is chronically induced by HIV infection, and also increased by opportunistic infections, and that chronic loss of Trp initiates mechanisms responsible for cachexia, dementia and diarrhea and possibly immunosuppression of patients who have AIDS (Brown, et al., 1991, Adv. Exp. Med. Biol, 294: 425-35). For this purpose, it has recently been shown that IDO inhibition can enhance the levels of virus-specific T lymphocytes and, concomitantly, reduce the number of macrophages infected by a virus in a mouse model of HIV (Portula et al. , 2005, Blood, 106: 2382-90). IDO is believed to play a role in immunosuppressive processes that prevent fetal rejection in utero. More than 40 years ago, it was observed that, during pregnancy, the genetically disparate mammalian conceptus survives, despite what would have been predicted, by tissue transplant immunology (Medawar, 1953, Symp. Soc. Exp. Biol. 7 : 320-38). Anatomical separation of mother and fetus and antigenic immaturity of the fetus cannot fully explain fetal allograft survival. Recently, attention has focused on the mother's immune tolerance. Since IDO is expressed by human syncytiotrophoblastic cells and the systemic concentration of tryptophan decreases during normal pregnancy, we hypothesized that IDO expression at the maternofetal interface is necessary to prevent immune rejection of fetal allografts. To test this hypothesis, pregnant mice (with syngeneic or allogeneic fetuses) were exposed to IMT, and rapid T cell-induced rejection of any allogeneic conception was observed. Therefore, by catabolizing tryptophan, the mammalian conceptus appears to suppress the activity of IF-2018-68202357-APN-ANP#INPI Page 2 of 185 T cells and defends against rejection, and blocking tryptophan catabolism during kitten pregnancy allows T cells to cause rejection of the fetal allograft (Moan, et al., 1998, Science, 281: 1191 -3). Additional evidence for the mechanism of tumor immune resistance based on tryptophan degradation by IDO arises from the observation that most human tumors express IDO constitutively, and that expression of IDO by mouse tumor cells immunogen prevents its rejection by previously immunized mice. This effect is accompanied by a lack of accumulation of specific T cells at the tumor site and can be partially reversed by systemic treatment of mice with an IDO inhibitor, in the absence of detectable toxicity. Therefore, it was suggested that the efficacy of therapeutic vaccination of cancer patients could be improved by concomitant administration of an IDO inhibitor (Uyttenhove et al., 2003, Nature Med., 9: 1269-74). It was also shown that the IDO inhibitor, 1-Mt, can synergize with chemotherapeutic agents to reduce tumor growth in mice, suggesting that IDO inhibition may also promote the antitumor activity of conventional cytotoxic treatments (Muller et al. , 2005, Nature Med., 11: 312-9). One mechanism contributing to the lack of immune response toward tumors may be the presentation of tumor antigens by APCs of tolerogenic hosts. A subset of human IDO-expressing antigen-presenting cells (APCs) that coexpressed CD 123 (IL3RA) and CCR6 and inhibited T cell proliferation was also described. Mature and immature CD123-expressing dendritic cells suppressed the activity of T lymphocytes. T lymphocytes, and this IDO suppressive activity was blocked by 1MT (Munn, et al, 2002, Science, 297: 1867-70). Mouse tumor-draining lymph nodes (TDLN) were also shown to contain a subset of plasmacytoid dendritic cells (pDCs) that constitutively express immunosuppressive levels of IDO. Despite comprising only 0.5% of lymph node cells, in vitro, these pDCs potently suppressed T cell responses to antigens presented by pDCs and also dominantly suppressed T cell responses. T lymphocytes to third-party antigens presented by non-suppressive APCs. In the pDC population, most of the functional IDO-mediated suppressive activity IF-2018-68202357-APN-ANP#INPI Page 3 of 185 segregated with a novel subset of pDCs that co-express the B lineage marker CD19. Therefore, we hypothesized that IDO-mediated suppression by pDCs in TDLN creates a local microentome that is potently suppressive of the host antitumor T cell responses (Munn, et al., 2004, J. Clin. Invest, 114(2): 280-90). IDO degrades the indole portion of tryptophan, serotonin, and melatonin, and initiates the production of neuroactive and immunoregulatory metabolites, collectively known as kynurenines. By locally decreasing tryptophan and increasing proapoptotic kynurenines, IDO expressed in dendritic cells (DCs) can greatly affect the proliferation and survival of T lymphocytes. Induction of IDO in DCs may be a common mechanism elimination tolerance driven by regulatory T cells. Since such tolerogenic responses can be expected to function in a variety of pathophysiological conditions, tryptophan metabolism and kynurenine production may represent a fundamental interface between the immune system and the nervous system (Grohmann, et al, 2003, Trends Immunol, 24 : 242-8). In states of persistent immune activation, the availability of free Trp in serum is decreased and, as a consequence of reduced serotonin production, serotonergic functions may also be affected (Wirleitner, et al., 2003, Curr. Med. Chem. , 10: 158191). Given the possible role of IDO in immunosuppression, tumor rejection and / or resistance, chronic infections, HIV infection, AIDS (including its manifestations such as cachexia, dementia and diarrhea), disorders or autoimmune diseases (such as rheumatoid arthritis), and immune tolerance and prevention of fetal rejection in utero, therapeutic agents that aim to suppress tryptophan degradation by inhibiting IDO activity are desirable. IDO inhibitors can be used to activate T cells and thus promote T cell activation when T cells are suppressed by pregnancy, neoplasia, or a virus, such as HIV. Inhibition of IDO may be an important treatment strategy for patients with neurological or neuropsychiatric disorders or diseases, such as depression. The compounds disclosed herein are useful for the possible treatment or prevention of IDO-related diseases. IF-2018-68202357-APN-ANP#INPI Page 4 of 185 SUMMARY OF THE INVENTION Disclosed herein are compounds of Formula (I), which are inhibitors of IDO enzymes. Also disclosed herein are uses of these compounds in the possible treatment or prevention of a disorder or disease that is associated with IDO. Also disclosed herein are compositions comprising one or more of the compounds. Also disclosed herein are uses of these compositions in the possible prevention or treatment of a disorder or disease that is associated with IDO. DETAILED DESCRIPTION OF THE INVENTION Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof: where: n is selected from 1, 2 and 3; p is selected from 0, 1 and 2; each instance of A is selected independently of -CH - and -N=, provided that at least one A is -CH=; M is selected from -O-, -S- and -CRaRb-, each of Ray Rbse independently selected from H, halogen, -OH and -Ci-8 alkyl; or alternatively, Ray Rb, together with the carbon to which they are attached, form a C3.4 carbocyclic ring, optionally substituted with 1 to 2 substituents independently selected from halogen and Cu alkyl; R1 is selected from: (1) aryl and (2) heterocyclyl; wherein the aryl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, IF-2018-68202357-APN-ANP#INPI Page 5 of 185 (b) -C3.8 cycloalkyl, optionally substituted with -OH, (c) -CN, (d) oxo, (e) -O-C1-8 alkyl, optionally substituted with 1 to 5 halogens, 5 (f) - O-C3.8 cycloalkyl, (g) -C1-8 alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen, -OH, -NH2, NHC(O)R° and -S(O)2-Ci- 8 alkyl, where Rc is selected from -C1-8 alkyl and -C3.8 cycloalkyl, 10 (h) -NH-S(O)2-Rc, where Rc is selected from -C1-8 alkyl and -C3 .8 cycloalkyl, (i) -C(O)-Re, Re is selected from -OH and -C1-8 alkyl, (j) aryl, optionally substituted with 1 to 3 halogens and (k) heterocyclyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-8 alkyl; and wherein the heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3-8 cycloalkyl, optionally substituted with -OH, (c) -CN, (d ) oxo, (e) -O-C1-8 alkyl, optionally substituted with 1 to 5 halogens, (f) -O-C3-8 cycloalkyl, (g) -C1-8 alkyl, optionally substituted with 1 to 4 substituents 25 independently selected from halogen, -OH, -NH2, NHC(O)RC and -S(O)2-Cj-8 alkyl, where R° is selected from -Ci-8 alkyl and -C3.8 cycloalkyl, (h ) -NH-S(O)2-Rc, where Rc is selected from -C1-8 alkyl and -C3.8 cycloalkyl, 30 (i) -C(O)-Rf, Rf is selected from -OH, - NH2 and -NH-Ci-s alkyl, (j) aryl, optionally substituted with 1 to 3 halogens and (k) heterocyclyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-8 alkyl; IF-2018-68202357-APN-ANP#INPI Page 6 of 185 R2 is selected from: (1) Ci-8 alkyl, (2) C3-8 carbocyclyl, (3) aryl and (4) heterocyclyl; wherein the C1-8 alkyl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3-8 cycloalkyl, (c) -O-C1-8 alkyl and (d) heterocyclyl; and wherein each of the C3-8 carbocyclyl of (2), the aryl of (3) and the heterocyclyl of (4) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3.8 cycloalkyl, (c) -CN, (d) -O-C1-8 alkyl, optionally substituted with 1 to 3 halogens and (e) -C1-8 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -OH and -NH2; and R3 is selected from H, halogen and -C1-8 alkyl, optionally substituted with -OH. In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt thereof: n is selected from 1 and 2; p is selected from 0 and 1; M is selected from -O- and -CRaRb-, each of Raand Rbse independently selected from H and halogen; or alternatively, Ray Rb together with the carbon to which they are attached form a C3.4 cycloalkyl ring; R1 is selected from: (1) aryl and (2) heterocyclyl; wherein the aryl of (1) is optionally substituted with 1 to 3 substituents independently selected from: IF-2018-68202357-APN-ANP#INPI Page 7 of 185 (a) halogen, (b) -C3.6 cycloalkyl optionally substituted with -OH, (c) -CN, (d) -O-Ci-6 alkyl optionally substituted with 1 to 3 halogens, (e) -O-C3-6 cycloalkyl, (f) -Ci-6 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen and -OH, and (g) -C(O)-Re, Rese selected from -OH and - Cm alkyl; wherein the heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3-6 cycloalkyl, optionally substituted with -OH, (c) -CN, (d) oxo, (e) -O-Ci-6 alkyl, optionally substituted with 1 to 3 halogens, (f) -O-C3.6 cycloalkyl, (g) -Ci-6 alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen, -OH and -NH2, (h) -C(O)-Rf, Rfse select from -OH, -NH2 and -NH-Cm alkyl, (i) phenyl, optionally substituted with 1 to 3 halogens; R2 is selected from: (1) Ci-6 alkyl, optionally substituted with 1 to 3 halogens, (2) C3.6 cycloalkyl, (3) aryl and (4) a 4 to 7 membered monocyclic heterocyclyl; wherein each of C3.6cycloalkyl of (2), the aryl of (3) and the heterocyclyl of (4) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3.6 cycloalkyl, (c) -CN, (d) -O-Ci-6 alkyl, optionally substituted with 1 to 3 halogens and (e) -Cm alkyl, optionally substituted with 1 to 3 substituents IF-2018-68202357-APN-ANP#INPI Page 8 of 185 independently selected from halogen and -OH; and R3 is selected from H, halogen and -Ci-6 alkyl, optionally substituted with -OH. In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt: nes 1; P is 1; each group A is -CH=; or alternatively, one A group is -N= and the other three A groups are each -CH=; or alternatively, two A groups are each -N= and the other two A groups are each -CH=; and M is selected from -O-, -CH2-, -CHF, -CF2- and . In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R3 is selected from H, halogen and -CH2-OH. In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) phenyl, (2) a 4- to 7-membered monocyclic heterocyclyl selected from one saturated, one partially unsaturated, and one aromatic ring containing 1 to 4 heteroatoms independently selected from N, O, and S; and (3) a 7- to 10-membered fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S in any of the rings; wherein the phenyl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3-6 cycloalkyl, optionally substituted with -OH, (c) -CN, (d) -O-Ci-6 alkyl, optionally substituted with 1 to 3 halogens, (e) -O -C3-6 cycloalkyl, (f) -Ci-6 alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and -OH, and (g) -C(O)-Re, Rese selected from -OH and -Ci -6alkyl; and IF-2018-68202357-APN-ANP#INPI Page 9 of 185 wherein each of the monocyclic heterocyclyl of (2) and the fused bicyclic heterocyclyl of (3) are optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3-6 cycloalkyl, optionally substituted with -OH, (c) -CN, (d) oxo, (e) O-Ci-6 alkyl, optionally substituted with 1 to 3 halogens, ( f) -O-C3-6 cycloalkyl, (g) -Ci-6 alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen, -OH and -NH2, (h) -C(O)-Rf, Rf is selected -OH, -NH2y -NH-Cm alkyl, (i) phenyl, optionally substituted with 1 to 3 halogens. In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) phenyl; (2) a monocyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl and 1,2,4oxadiazolyl; and (3) a fused bicyclic heterocyclyl selected from 3a,4,5,6,7,7a-hexahydrolH-benzo[d]imidazolyl, imidazole[4,5-b]pyridinyl, imidazole[4,5-c]pyridinyl, indolyl, isoindolinyl; wherein the phenyl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl, optionally substituted with -OH, (c) cyclobutyl, optionally substituted with -OH, (d) -Ο-Cm alkyl, optionally substituted with 1 to 3 halogens, (e) -O- cyclopropyl, (f) -Ci-4 alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and -OH, and (g) -C(O)-C|.4 alkyl; and IF-2018-68202357-APN-ANP#INPI Page 10 of 185 wherein each of the monocyclic heterocyclyl of (2) and the fused bicyclic heterocyclyl of (3) are optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl, optionally substituted with -OH, (c) cyclobutyl, optionally substituted with -OH, (d) -CN, (e) oxo, (f) -O-Ci-4 alkyl, optionally substituted with 1 to 3 halogens, (g) -O-cyclopropyl, (h) -Ci-4 alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and -OH, and (i) phenyl, optionally substituted with 1 to 3 halogens. In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt thereof: R2 is selected from: (1) Ci-6 alkyl, optionally substituted with 1 to 3 halogens, (2) C3-6 cycloalkyl, (3) phenyl and (4) a 5- to 6-membered monocyclic heterocyclyl; wherein each of C3.6 cycloalkyl of (2), the phenyl of (3) and the heterocyclyl of (4) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3.6 cycloalkyl, (c) -CN, (d) -O-Ci-6 alkyl, optionally substituted with 1 to 3 halogens and (e) -Ci-6 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen and -OH. In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt thereof: R2 is selected from: (1) Cj.4 alkyl, IF-2018-68202357-APN-ANP#INPI Page 11 of 185 (2) C3.6 cycloalkyl, (3) phenyl and (4) a 5- to 6-membered monocyclic heterocyclyl selected from oxazolyl, pyridinyl and thiazolyl; wherein each of C3-6 cycloalkyl of (2), the phenyl of (3) and the heterocyclyl of (4) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -CN, (c) -O-Ci-4 alkyl, optionally substituted with 1 to 3 halogens and (e) -Ci-4 alkyl, optionally substituted with 1 to 3 halogens, In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt thereof: n is 1; Pesi; each group A is -CH=; or alternatively, one A group is -N= and the other three A groups are each -CH=; or alternatively, two A groups are -N= and the other two A groups are each -CH=; M is selected from -O-, -CH2-, -CHF, -CF2- and ; R1 is selected from: (1) phenyl; (2) a monocyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl and 1,2,4oxadiazolyl; and (3) a fused bicyclic heterocyclyl selected from 3a,4,5,6,7,7a-hexahydrolH-benzo[d]imidazolyl, imidazole[4,5-b]pyridinyl, imidazole[4,5-c]pyridinyl, indolyl, isoindolinyl; wherein the phenyl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl, optionally substituted with -OH, (c) cyclobutyl, optionally substituted with -OH, (d) -O-C14 alkyl, optionally substituted with 1 to 3 halogens, IF-2018-68202357-APN-ANP#INPI Page 12 of 185 (e) -O-cyclopropyl, (f) -Ci-4 alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and -OH, and (g) -C(O)-Ci-4 alkyl ; and wherein each of the monocyclic heterocyclyl of (2) and the fused bicyclic heterocyclyl of (3) are optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl, optionally substituted with -OH, (c) cyclobutyl, optionally substituted with -OH, (d) -CN, (e) oxo, (f) -O-Ci-4 alkyl, optionally substituted with 1 to 3 halogens, (g) -O-cyclopropyl, (h) -Cui alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and -OH, and (i) phenyl optionally substituted with 1 to 3 halogens; R2 is selected from: (1) Ci-4 alkyl, (2) C3-6 cycloalkyl, (3) phenyl and (4) a 5- to 6-membered monocyclic heterocyclyl selected from oxazolyl, pyridinyl and thiazolyl; wherein each of C3.6cycloalkyl of (2), the phenyl of (3) and the heterocyclyl of (4) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -CN, (c) -O-Ci-4 alkyl, optionally substituted with 1 to 3 halogens and (e) -Ci-4 alkyl, optionally substituted with 1 to 3 halogens; and R3 is selected from H, halogen and -CH2-OH. In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt thereof: IF-2018-68202357-APN-ANP#INPI Page 13 of 185 each group A is -CH=; M is -O-; R1 is selected from: (1) phenyl; and (2) a monocyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl and 1,2,4oxadiazolyl; wherein the phenyl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl, optionally substituted with -OH, (c) -O-Ci-4 alkyl, optionally substituted with 1 to 3 halogens, (d) -O-cyclopropyl and (e) -Ci-4 alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and -OH, and wherein the monocyclic heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -CN, (c) -O-Ci-4 alkyl, optionally substituted with 1 to 3 halogens, (d) -O-cyclopropyl, (e) -Cm alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and -OH; R2 is selected from: (1) phenyl and (2) pyridinyl; wherein each of phenyl of (1) and pyridinyl of (2) is optionally substituted with 1 to 3 halogens; and R3is H. In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound is of Formula (la): IF-2018-68202357-APN-ANP#INPI Page 14 of 185 where: R1 is selected from: (1) phenyl; and (2) a monocyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl and 1,2,4oxadiazolyl; wherein the phenyl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl, optionally substituted with -OH, (c) cyclobutyl, optionally substituted with -OH, (d) -O-Ci-4 alkyl, optionally substituted with 1 to 3 halogens, (e) - O-cyclopropyl and (f) -Cs4 alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and -OH, and (g) -C(O)-Cj.4alkyl; and wherein the monocyclic heterocyclyl of (2) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -O-Ci-4 alkyl, optionally substituted with 1 to 3 halogens, (c) -O-cyclopropyl and (d) -Ci-4 alkyl, optionally substituted with 1 to 4 independently selected substituents halogen and -OH; and R is selected from: (1) phenyl and (2) pyridinyl; wherein each of phenyl of (1) and pyridinyl of (2) is optionally substituted with 1 to 3 halogens. In one embodiment of the compound of Formula (la), or a pharmaceutically acceptable salt thereof: IF-2018-68202357-APN-ANP#INPI Page 15 of 185 R1 is pyridinyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b)-CH3, (c) -CHF2, (d)-CF3, and (e) -C(CH3)2OH; and R2 is phenyl, optionally substituted with 1 to 3 halogens. In one embodiment of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound is of a Formula selected from (li), (Ij) and (Ik): where: R1 is selected from: (1) phenyl; and (2) a monocyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidyl, thiazolyl, tetrazolyl and 1,2,4oxadiazolyl; wherein the phenyl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl, optionally substituted with -OH, (c) -O-Ci-4 alkyl, optionally substituted with 1 to 3 halogens, (d) -O-cyclopropyl and (e) -Cm alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and -OH, and wherein the monocyclic heterocyclyl of (2) is optionally substituted with 1 to substituents independently selected from: (a) halogen, IF-2018-68202357-APN-ANP#INPI Page 16 of 185 (b) -CN, (c) -O-Ci-4 alkyl, optionally substituted with 1 to 3 halogens, (d) -O-cyclopropyl, (e) -Ci-4 alkyl, optionally substituted with 1 to 4 substituents independently selected from halogen and -OH; and Rd is selected from: (a) halogen, (b)-CN, (c)-O-Ci-3 alkyl, optionally substituted with 1 to 3 halogens and (d) Ci-3 alkyl, optionally substituted with 1 to 3 halogens, In one embodiment of the compound of Formulas (li), (Ij) or (Ik), or a pharmaceutically acceptable salt thereof: R1 is pyridinyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b)-CH3, (c) -CHF2, (d)-CF3, and (e) -C(CH3)2OH; and Rd is selected from: (a) halogen, (b)-CN, (c)-CH3, and (d)-CF3. In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof: n is selected from 1,2 and 3; p is selected from 0.1 and 2; M is selected from -O-, -S- and -CRaRb-, each of Ray Rbse independently selected from H, halogen, -OH and -Ci^ alkyl; or alternatively, Ray Rb, together with the carbon to which they are attached, form a C3.4 cycloalkyl ring, optionally substituted with 1 to 2 substituents independently selected from halogen and alkyl; IF-2018-68202357-APN-ANP#INPI Page 17 of 185 R1 is selected from: (1) aryl and (2) heterocyclyl; wherein the aryl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3-8 cycloalkyl optionally substituted with -OH, (c) -CN, (d) oxo, (e) -O-C1-8 alkyl optionally substituted with 1 to 5 halogens, (f ) -O-C3-8 cycloalkyl, (g) -C1-8 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen, -OH, -NH2, NHC(O)RCy -S(O)2-Ci-8 alkyl, wherein Rcse selected from -C1-8 alkyl and -C3.8 cycloalkyl, (h) -NH-S(O)2-Rc, wherein Rcse selected from -C1-8 alkyl and -C3.8 cycloalkyl, (i) -C(O)-OH, (j) aryl optionally substituted with 1 to 3 halogens and (k) heterocyclyl optionally substituted with 1 to 3 substituents independently selected from halogen and -C1-8 alkyl; wherein the heterocyclyl of (2) is substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3.8 cycloalkyl optionally substituted with -OH, (c) -CN, (d) oxo, (e) -O-C1-8 alkyl substituted with 1 to 5 halogens, (f) -O-C3.8 cycloalkyl, (g) -C1-8 alkyl substituted with 1 to 4 substituents independently selected from halogen, -NH2, NHC(O)Rcy-S(O)2-Ci-8 alkyl, where R ° is selected from -C1-8 alkyl and -C3.8 cycloalkyl, (h) -NH-S(O)2-RC, where R° is selected from -C1-8 alkyl and -C3.8 IF-2018-68202357-APN-ANP#INPI Page 18 of 185 cycloalkyl, (i)-C(O)-OH, (j) aryl optionally substituted with 1 to 3 halogens and (k) heterocyclyl optionally substituted with 1 to 3 substituents independently selected from halogen and -Ci-s alkyl ; R2 is selected from: (1) Ci-8 alkyl, (2) C3-8 carbocyclyl, (3) aryl and (4) heterocyclyl; wherein the C1-8 alkyl of (1) is optionally substituted with 1 to 3 substituents independently selected from; (a) halogen, (b) -C3-8 cycloalkyl, (c) -O-C1-8 alkyl and (d) heterocyclyl; and wherein each of C3-8 carbocyclyl of (2), aryl of (3) and heterocyclyl of (4) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3-8 cycloalkyl, (c) -CN, (d) O-C1-8 alkyl optionally substituted with 1 to 3 halogens and (e) -C]-8alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -OH and -NH2; and R3 is selected from H, halogen and -Ci-8alkyl. In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) phenyl, (2) monocyclic heterocyclyl selected from isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl and 1,2,3- IF-2018-68202357-APN-ANP#INPI Page 19 of 185 thiadiazolyl, and (3) bicyclic heterocyclyl selected from 3a,4,5,6,7,7a-hexahydro-lHbenzo[d]imidazolyl, indolyl, 1,2,3-thiadizolyl, lH-benzo[d] imidazolyl, 3Himidazo[4,5-c]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo-[l,2- a]pyridinyl and imidazole-[l,2-b]pyridazinyl; wherein the phenyl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) C3-4 cycloalkyl, optionally substituted with -OH, (c) -CN, (d) oxo, (e) -O-C1-4 alkyl optionally substituted with 1 to 5 halogens, (f ) -O-cyclopropyl, (g) -Ci-4 alkyl optionally substituted with 1 to 4 substituents selected from halogen, -OH, -NH2, NHC(O)Ci-3 alkyl and -S(0)2-Cj^ alkyl , (h) -NH-S(O)2-R°, wherein Rcse selected from methyl, ethyl, propyl and cyclopropyl, (i) -C(O)-OH, (j) phenyl optionally substituted with 1 to 3 halogens and (k) oxadiazolyl optionally substituted with methyl or ethyl; and wherein the monocyclic heterocyclyl of (2) and the bicyclic heterocyclyl of (3) are substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) C3.4 cycloalkyl, optionally substituted with -OH, (c ) -CN, (d) oxo, (e) -O-C1-4 alkyl substituted with 1 to 5 halogens, (f) -O-cyclopropyl, (g) -Ci-4 alkyl substituted with 1 to 4 independently selected substituents of halogen, -NH2, NHC(O)Ci.3alkyl and -S(O)2-Cm alkyl, (h) -NH-S(O)2-Rc, where Rcse selected from methyl, ethyl, propyl and IF-2018-68202357-APN-ANP#INPI Page 20 of 185 cyclopropyl, (i)-C(O)-OH, (j) phenyl optionally substituted with 1 to 3 halogens and (k) oxadiazolyl optionally substituted with methyl or ethyl. In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) phenyl; and (2) monocyclic heterocyclyl selected from isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl and 1,2,3thiadiazolyl; wherein the phenyl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c) cyclobutyl optionally substituted with -OH, (d) -O-Ci-3 alkyl optionally substituted with 1 to 5 halogens, (e) -O-cyclopropyl and (f) -Ci-4 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen, -OH and -NH2; and wherein the monocyclic heterocyclyl of (2) is substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c) cyclobutyl optionally substituted with -OH, (d) -O-C1-3 alkyl substituted with 1 to 5 halogens, (e) -O-cyclopropyl and (f) -C1-4 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen and -NH2. In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof: R2 is selected from: IF-2018-68202357-APN-ANP#INPI Page 21 of 185 (1) phenyl, (2) pyridinyl and (3) pyrimidinyl; wherein each of phenyl of (1), pyridinyl of (2) and pyrimidinyl of (3) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -CN, (c) -O-Ci-4 alkyl optionally substituted with 1 to 3 halogens and (d) Ci-4 alkyl optionally substituted with 1 to 3 halogens, In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof: R2 is selected from: (1) phenyl, (2) pyridinyl and wherein each of phenyl of (1) and pyridinyl of (2) is optionally substituted with 3 substituents independently selected from: (a) halogen, (b)-CN, (c)-O-CHF2, (d) -o-cf3, (e)-CH3, (f)-CH2F, (g)-CHF2, and (h)-CF3. In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof: n is 1; pes 1; each group A is -CH=; or alternatively, one group A is -N=, and three other groups A are each -CH=; M is selected from -O-, -CH2-, -CF2- and ; R1 is selected from: IF-2018-68202357-APN-ANP#INPI Page 22 of 185 (1) phenyl, (2) pyridinyl and (3) pyrimidinyl; wherein the phenyl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c) cyclobutyl optionally substituted with -OH, (d)-O-CH3, (e)-O-CH2CH3, (f)-O-CF3, ( g)-O-CHF2, (h)-O-CF2CF3, (i)-CH3, (j)-CH2F, (k)-CHF2, (1)-cf3, (m)-CH2CF3, (n)-CH2OH , (o) -CH2CH3, (p)-CH(CH3)OH, (q) -CH2CH2OH, (r) -CH(CHF2)OH, (s)-C(CH3)2OH, (t)-C(CF3 )2OH, (u) -O-cyclopropyl and (v) -O-cyclobutyl; wherein each of pyridinyl of (2) and pyrimidinyl of (3) is substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c) cyclobutyl optionally substituted with -OH, (d)-O-CF3, IF-2018-68202357-APN-ANPAINPI Page 23 of 185 (e) -O-CHF2, (f)-O-CF2CF3, (g)-CH2F, (h)-CHF2, (O-CF3, (j)-CH2CF3, (k) -CH(CHF2 )OH, (1)-C(CF3)2OH, (m) -O-cyclopropyl and (n) -O-cyclobutyl; R2 is selected from: (1) phenyl and (2) pyridinyl; wherein each of phenyl of (1) and pyridinyl of (2) is optionally substituted with 3 substituents independently selected from: (a) halogen, (b)-CN, (c)-O-CHF2, (d) -O-CF3, (e)-CH3, (f)-CH2F, (g)-CHF2, and (h) -CF3; and R3is H. In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof: n is 1; p is 1; each group A is -CH=; or alternatively, one group A is -N=, and three other groups A are each -CH=; M is selected from -O-, -CH2-, -CF2- and ; R1 is selected from: (1) phenyl and IF-2018-68202357-APN-ANP#INPI Page 24 of 185 (2) pyridinyl; wherein the phenyl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c)-O-CH3, (d)-O-CF3, (e)-O-CHF2, (f)-CHF2, (g)-CF3 , (h)-CH2CF3, (i)-CH2OH, 0) -ch2ch3, (k) -CH(CH3)OH, (1)-CH2CH2OH, (m) -CH(CHF2)OH, (n)-C( CH3)2OH, (o)-C(CF3)2OH and (p) -O-cyclopropyl; wherein the pyridinyl of (2) is substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c)-O-CF3, (d)-O-CHF2, (e)-CHF2, (f)-CF3, (g)-CH2CF3, ( h) -CH(CHF2)OH, (i)-C(CF3)2OH and G) -O-cyclopropyl; R2 is selected from: (1) phenyl and IF-2018-68202357-APN-ANP#INPI Page 25 of 185 (2) pyridinyl; wherein each of phenyl of (1) and pyridinyl of (2) is optionally substituted with 3 substituents independently selected from: (a) halogen, (b)-CN, (c)-O-CHF2, (d) -O-CF3, (e)-CHF2, and (f) -CF3; and R3es H. In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof: n is 1; pes 1; each group A is -CH=; or alternatively, one group A is -N=, and three other groups A are each -CH=; M is selected from -O-, -CH2-, -CF2- and R1 is selected from: (1) phenyl and (2) pyridinyl; wherein each of phenyl of (1) and pyridinyl of (2) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c)-O-CH3, (d)-O-CF3, (e)-O-CHF2, (f)-CHF2, (g)-CF3 , (h)-CH2CF3, (i)-CH2OH, 0) -ch2ch3, (k) -CH(CH3)OH, IF-2018-68202357-APN-ANP#INPI Page 26 of 185 (1)-CH2CH2OH, (m) -CH(CHF2)OH, (n) -C(CH3)2OH, (o)-C(CF3)2OH and (p) -O-cyclopropyl; and R2 is phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b)-CN, (c)-O-CHF2, (d) -O-CF3, (e)-CH3, (f)-CH2F, (g)-CHF2, and (h)-CF3; and R3is H. In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof: n is 1; Pes1; each group A is -CH=; or alternatively, one group A is -N= and three other groups A are each -CH=; M is selected from -O-, -CH2-, -CF2- and ; R1 is selected from: (1) phenyl and (2) pyridinyl; wherein each of phenyl of (1) and pyridinyl of (2) is substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c)-O-CH3, (d)-O-CF3, (e)-O-CHF2, IF-2018-68202357-APN-ANP#INPI Page 27 of 185 (f)-CHF2, (g)-CF3, (h)-CH2CF3, (i)-CH2OH, 0) -CH(CH3)OH, (k)-CH2CH2OH, (1) -CH(CHF2)OH, (m)-C(CH3)2OH and (n)-C(CF3)2OH; and R2 is phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b)-CN, (c) -O-CHF2, (d) -O-CF3, (e) -CHF2y (f)-CF3y R3is H. In one embodiment of a compound of Formula (I) described above, or a pharmaceutically acceptable salt thereof, n is 1; p is 1; and M is In one embodiment of a compound of Formula (I) described above, or a pharmaceutically acceptable salt thereof: each group A is -CH=; R1 is selected from: (1) phenyl and (2) pyridinyl; wherein each of phenyl of (1) and pyridinyl of (2) is substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c)-O-CH3, (d)-O-CF3, IF-2018-68202357-APN-ANP#INPI Page 28 of 185 (e) -O-CHF2, (f)-CHF2, (g)-CF3j(h)-CH2CF3, (i)-CH2OH, (j) -CH(CH3)OH, (k) -CH2CH2OH , (1)-CH(CHF2)OH, (m)-C(CH3)2OH and (n)-C(CF3)2OH; and R2 is phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b)-CN, (c) -O-CHF2, (d) -O-CF3, (e)-CHF2, and (f) -CF3; and R3es H. In one embodiment of a compound of Formula (I) described above, or a pharmaceutically acceptable salt thereof: one group A is -N= and three other groups A are each -CH=; R1 is selected from: (1) phenyl and (2) pyridinyl; wherein each of phenyl of (1) and pyridinyl of (2) is substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c)O-CH3, (d)-O-CF3, (e) -O-CHF2, (í)-CHF2, IF-2018-68202357-APN-ANP#INPI Page 29 of 185 (g)-CF3, (h)-CH2CF3, (i)-CH2OH, (j) -CH(CH3)OH, (k)-CH2CH2OH, (1) -CH(CHF2)OH, (m )-C(CH3)2OH and (n)-C(CF3)2OH; and R2 is phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b)-CN, (c)-O-CHF2, (d) -O-CF3, (e) -CHF2y (f)-CF3;y R3es H. In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound is of Formulas (la) or (Ib): In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound is of Formulas (Ic) or (Id): In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound is of Formulas (le) or (If): IF-2018-68202357-APN-ANP#INPI Page 30 of 185 In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound is of Formulas (Ig) or (Ih): where q is 1 or 2; each A is independently -CH= or -N=; and Rces H, halogen or Ci-3 alkyl. In one embodiment of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound is of Formulas (li), (Ij) or (Ik): where: R1 is selected from: (1) phenyl; and (2) monocyclic heterocyclyl selected from isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl and 1,2,3thiadiazolyl; (3) a 6- to 12-membered fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S in any of the rings; wherein each of phenyl of (1), monocyclic heterocyclyl of (2) and the fused bicyclic heterocyclyl of (3) is substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c) cyclobutyl optionally substituted with -OH, (d) -O-Ci-3 alkyl optionally substituted with 1 to 5 halogens, IF-2018-68202357-APN-ANP#INPI Page 31 of 185 (e) -O-cyclopropyl and (f) -Ci-4 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen, -OH and -NH2; and Rd is selected from: (a) halogen, (b)-CN, (c) -O-C1-3 alkyl optionally substituted with 1 to 3 halogens and (d) Ci-3 alkyl optionally substituted with 1 to 3 halogens. In one embodiment of a compound of Formulas (li), (Ij) or (Ik), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) phenyl and (2) pyridinyl; wherein each of phenyl of (1) and pyridinyl of (2) is substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c)-O-CH3, (d)-O-CF3, (e) -O-CHF2, (í)-CHF2, (g)-CF3 , (h)-CH2CF3, (i)-CH2OH, (j) -ch2ch3, (k) -CH(CH3)OH, (1) -CH2CH2OH, (m) -CH(CHF2)OH, (n)-C (CH3)2OH, (o) -C(CF3)2OH and (p) -O-cyclopropyl; and Rd is selected from: (a) halogen, IF-2018-68202357-APN-ANP#INPI Page 32 of 185 (b)-CN, (c) -O-CHF2, (d) -O-CF3, (e)-CH3, (f)-CH2F, (g)-CHF2and (h)-CF3. In one embodiment of a compound of the Formulas (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (li), (Ij) 0 (Ik), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) phenyl; (2) monocyclic heterocyclyl selected from one saturated, one partially unsaturated, and one 4- to 7-membered aromatic ring containing 1 to heteroatoms independently selected from N, O, and S; and (3) a 6- to 12-membered fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S in any of the rings; wherein the phenyl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3.6cycloalkyl, (c) -CN, (d) oxo, (e) -O-Ci-6 alkyl optionally substituted with 1 to 3 halogens, (f) -O-C3_6cycloalkyl, (g) -C1-6 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen, -OH, -NH2y-S(O)2-Ci-6 alkyl, (h) -NH-S(O)2-Rc , wherein R° is selected from -Ci^ alkyl and -C3.6cycloalkyl, (i)-C(O)-OH, (j) phenyl optionally substituted with 1 to 3 halogens and (k) a monocyclic aromatic ring of 4 to 7 members containing 1 to 3 IF-2018-68202357-APN-ANP#INPI Page 33 of 185 heteroatoms independently selected from N, O and S, optionally substituted with -Ci-6 alkyl; wherein the monocyclic heterocyclyl of (2) and the fused bicyclic heterocyclyl of (3) are substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3.6 cycloalkyl, (c) -CN, (d) oxo, (e) -O-Ci-6 alkyl substituted with 1 to 3 halogens, (f) -O-C3- 6 cycloalkyl, (g) -Ci-6 alkyl substituted with 1 to 4 substituents independently selected from halogen, -NH2y -S(O)2-Ci^ alkyl, (h) -NH-S(O)2-Rc, in where Rcse selected from -C1-6 alkyl and -C3.6 cycloalkyl, (i) -C(O)-OH, (j) phenyl optionally substituted with 1 to 3 halogens and (k) a 4 to 7 monocyclic aromatic ring members containing 1 to 3 heteroatoms independently selected from N, O and S, optionally substituted with -Ci-e alkyl; and R2, when present, is selected from: (1) Ci-6 alkyl, optionally substituted with 1 to 3 halogens, (2) C3.6 cycloalkyl, (3) C4.6 bridged bicyclic saturated carbocyclyl, (4) phenyl and (5) monocyclic heterocyclyl selected from a ring saturated, one partially unsaturated and one 4- to 7-membered aromatic containing 1 to 4 heteroatoms independently selected from N, O and S; wherein each of C3.6 cycloalkyl of (2), bridged bicyclic C445saturated carbocyclyl of (3), phenyl of (4) and heterocyclyl of (5) is optionally substituted with 3 substituents independently selected from: (a) halogen, (b) -CN, (c) -O-Ci-6 alkyl optionally substituted with 1 to 3 halogens and IF-2018-68202357-APN-ANP#INPI Page 34 of 185 (d) -Ci-6 alkyl optionally substituted with 1 to 3 halogens. In one embodiment of a compound of the Formulas (la), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (E), (Ij) or (Ik), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) phenyl; and (2) monocyclic heterocyclyl selected from isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl and 1,2,3thiadiazolyl; wherein the phenyl of (1) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c) cyclobutyl optionally substituted with -OH, (d) -O-Ci-3 alkyl optionally substituted with 1 to 5 halogens, (e) -O-cyclopropyl and (f) -Ci-4 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen, -OH and -NH2; wherein the monocyclic heterocyclyl of (2) is substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c) cyclobutyl optionally substituted with -OH, (d) -O-Ci-3 alkyl substituted with 1 to 5 halogens, (e) -O-cyclopropyl and (f) -Ci-4 alkyl optionally substituted with 1 to 4 substituents independently selected from halogen and -NH2; and R2, when present, is selected from: (1) phenyl and (2) pyridinyl; wherein each of phenyl of (1) and pyridinyl of (2) is optionally substituted with 3 substituents independently selected from: IF-2018-68202357-APN-ANP#INPI Page 35 of 185 (a) halogen, (b)-CN, (c) -O-Ci-3 alkyl optionally substituted with 1 to 3 halogens and (d) Ci-3 alkyl optionally substituted with 1 to 3 halogens. In one embodiment of a compound of the Formulas (la), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (li), (Ij) or (Ik), or a pharmaceutically acceptable salt thereof: R1 is selected from: (1) phenyl and (2) pyridinyl; wherein each of phenyl of (1) and pyridinyl of (2) is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -ΌΗ, (c)-O-CH3, (d)-O-CF3, (e)-O-CHF2, (f)-O-CF2CF3, (g) -CH3, (h) -CH2F, (í)-CHF2, Ü)-CF3, (k)-CH2CF3, (1)-CH2OH, (m) -CH(CH3)OH, (n) -CH2CH2OH, (o)-CH(CHF2)OH, (p)-C(CH3 )2OH, (q)-C(CF3)2OH and R2, when present, is phenyl, optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b)-CN, IF-2018-68202357-APN-ANP#INPI Page 36 of 185 (c)-O-CHF2, (d) -O-CF3, (e)-CH3, (f)-CH2F, (g)-CHF2and (h) -CF3. In one embodiment, a compound disclosed herein is selected from the group consisting of the compounds exemplified in Examples 1 to 131; or a pharmaceutically acceptable salt, solvate or hydrate thereof. Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein and at least one pharmaceutically acceptable carrier. Also disclosed herein is a method for inhibiting indoleamine 2,3-dioxygenase (EDO) activity, comprising contacting IDO with a compound disclosed herein, or a salt, solvate or hydrate thereof pharmaceutically. acceptable. Also disclosed herein is a method of inhibiting immunosuppression in a patient, comprising administering to said patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof. Also disclosed herein is a method of treating cancer, viral infection, depression, a neurodegenerative disorder, trauma, age-related cataracts, organ transplant rejection, or an autoimmune disease in a patient, comprising administering to said patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof. Also disclosed herein is a method of treating melanoma in a patient, comprising administering to said patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof. Also disclosed herein is a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in treatment. In one embodiment, the use of a IF-2018-68202357-APN-ANP#INPI Page 37 of 185 compound disclosed herein or a pharmaceutically acceptable salt, solvate or hydrate thereof, for the preparation of a medicament for use in treatment. The term alkyl refers to straight or branched chain saturated aliphatic hydrocarbon groups with 1 to 18 carbon atoms, or more specifically, 1 to 12 carbon atoms. Examples of these groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl (Pr), n-butyl (Bu), n-pentyl, n-hexyl and isomers of these, such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), / er-butyl (t-Bu), isopentyl and isohexyl. The alkyl groups may optionally be substituted with one or more substituents as defined herein. The term "Cy.6alkyl" refers to an alkyl group as defined herein, having 1 to 6 carbon atoms. The term aryl refers to a portion of the monocyclic or multicyclic aromatic ring comprising 6 to 14 ring carbon atoms, or more specifically, 6 to 10 ring carbon atoms. Monocyclic aryl rings include, but are not limited to, phenyl. Multicyclic rings include, but are not limited to, naphthyl and bicyclic rings where the phenyl is fused to a C4 ring. 7cycloalkyl or C4-7CÍcloalkenyl. The aryl groups may optionally be substituted with one or more substituents as defined herein. The union can be made through any of the carbon atoms of any ring. In one embodiment, the aryl is phenyl. The term carbocyclyl refers to a non-aromatic (i.e., saturated or partially unsaturated) monocyclic carbocyclic radical or to a fused bicyclic, bridged bicyclic or spirocyclic carbocyclic radical having the specified ring carbon atoms. For example, "C3.8carbocyclyl" refers to a 3- to 8-membered non-aromatic monocyclic carbocyclic radical or to a 6- to 8-membered fused bicyclic, bridged bicyclic or non-aromatic spirocyclic carbocyclic radical. The carbocycle can be bonded by any atom in the cycle resulting in the creation of a stable structure. Non-limiting examples of 3- to 8-membered monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl and cycloheptenyl. Non-limiting examples of 6- to 8-membered fused bicyclic carbocyclic radicals include, but are not limited to, bicyclo[3.3.0]octane. Non-limiting examples of 5- to 8-membered bridged bicyclic carbocyclic radicals include, but are not limited to, IF-2018-68202357-APN-ANP#INPI Page 38 of 185 bicycle[ 1.1. IJpentanyl, bicyclo[2.2.2]heptanyl, bicyclo[2.2.2]octanyl and bicyclo[3.2.1]octanyl. Non-limiting examples of 6- to 8-membered spirocyclic carbocyclic radicals include, but are not limited to, spiro[3,3]heptanyl and spiro[3,4]octanyl. The term "cycloalkyl" refers to a saturated monocyclic carbocyclic ring having the specified number of ring carbon atoms. For example, C3.8 cycloalkyl refers to a cycloalkyl group as defined herein, having 3 to 8 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptanyl. The cycloalkyl groups may optionally be substituted with one or more substituents as defined herein. The terms “halo” or “halogen” refer to fluoro, chlorine, bromine or iodine, unless otherwise indicated. The terms heterocycle or heterocyclyl refer to a saturated, partially unsaturated or aromatic ring portion having at least one ring heteroatom and at least one ring carbon atom. In one embodiment, the heteroatom is oxygen, sulfur or nitrogen. A heterocycle containing more than one heteroatom may contain different heteroatoms. Heterocyclyl moieties include monocyclic and multicyclic (e.g., bicyclic) ring moieties. Bicyclic ring portions include fused, spirocyclic, and bridged rings and may comprise one or more heteroatoms in any of the rings. The ring attached to the rest of the molecule may or may not contain a heteroatom. Any ring of a bicyclic heterocycle can be saturated, partially unsaturated or aromatic. The heterocycle may be attached to the rest of the molecule via a ring carbon atom, a ring oxygen atom, or a ring nitrogen atom. Non-limiting examples of heterocycles are described below. In one embodiment, the heterocyclyl is a 4- to 7-membered monocyclic heterocyclyl selected from one saturated, one partially unsaturated, and one aromatic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. In one embodiment, the heterocyclyl is a 6- to 12-membered fused bicyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S in any of the rings. IF-2018-68202357-APN-ANP#INPI Page 39 of 185 In one embodiment, the heterocyclyl is a monocyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl and 1,2,4-oxadiazolyl. In one embodiment, the heterocyclyl is a monocyclic heterocyclyl selected from oxazolyl, pyridinyl and thiazolyl. In one embodiment, the heterocyclyl is pyridinyl. In one embodiment, the heterocyclyl is a fused bicyclic heterocyclyl selected from 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, imidazole[4,5-b]pyridinyl, imidazole[4 ,5-c]pyridinyl, indolyl, isoindolinyl. The heterocyclic groups may optionally be substituted with one or more substituents as defined herein. The term "optionally substituted" refers to "unsubstituted or substituted" and, therefore, the generic structural formulas described herein encompass both compounds containing the specified optional substituents, as well as compounds that do not contain the specified optional substituents. optional substituents. Each substituent is defined independently each time it occurs in the definitions of the generic structural formula. Polymorphism A compound disclosed herein, including a salt, a solvate, or a hydrate thereof, may exist in a crystalline form, a non-crystalline form, or a mixture thereof. A compound, or a salt or a solvate thereof, can also present polymorphism, that is, the ability to occur in different crystalline forms. These different crystalline forms are commonly known as polymorphs. The polymorphs have the same chemical composition, but differ in packing, geometric distribution, and other properties descriptive of the crystalline solid state. Therefore, polymorphs can have different physical properties, such as shape, density, hardness, deformability, stability and dissolution properties. Polymorphs generally exhibit different melting points, IR spectra, and powder X-ray diffraction patterns, and all of these can be used for identification. A person skilled in the art will understand that different polymorphs can be produced, for example, by changing or adjusting the conditions that are used when crystallizing or recrystallizing a compound disclosed herein. ' IF-2018-68202357-APN-ANP#INPI Page 40 of 185 Optical isomers - Diastereomers - Geometric isomers - Tautomers Included herein are various isomers of the compounds disclosed herein. The term isomers refers to compounds that have the same composition and molecular weight, but that differ in their physical and / or chemical properties. The structural difference may be in terms of constitution (geometric isomers) or the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, a compound disclosed herein may have one or more asymmetric carbon atoms and may exist as mixtures (such as racemic mixtures) or as individual enantiomers or diastereomers. All such isomeric forms are included herein, including mixtures thereof. If a compound disclosed herein contains a double bond, the substituent may be in the E or Z configuration. If a compound disclosed herein contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also included. Any asymmetric atom (e.g., carbon) of a compound disclosed herein may be present in a racemic or enantiomerically enriched mixture, e.g., the (R)-, (S)- or (R,S)- configuration. In some embodiments, each asymmetric atom has an enantiomeric excess of at least 50%, an enantiomeric excess of at least 60%, an enantiomeric excess of at least 70%, an enantiomeric excess of at least 80%, an enantiomeric excess of at least 90%, an enantiomeric excess of at least 95% or an enantiomeric excess of at least 99% in the (R)- or (S)- configuration. Substituents on atoms with unsaturated double bonds can, if possible, occur in the cis (Z) or trans (E) form. A compound disclosed herein may be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric isomers (cis or trans), diastereomers, optical isomers (antipodes), racemates or mixtures of these. Any resulting mixture of isomers can be separated based on the physicochemical differences of the constituents, into pure or substantially pure optical or geometric isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization. IF-2018-68202357-APN-ANP#INPI Page 41 of 185 Any racemate resulting from the final compounds of the examples or the intermediates can be resolved at the optical antipodes by known methods, for example, by separating the diastereomeric salts thereof, obtained with an optically active acid or base, and releasing of the optically active acidic or basic compound. In particular, a basic moiety may, therefore, be employed to resolve the compounds of the present invention at their optical antipodes, for example, by fractional crystallization of a salt formed with an optically active acid, for example, tartaric acid, dibenzoyl acid. tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic compounds can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC), by means of a chiral adsorbent. Some of the compounds described herein may exist with different hydrogen bonding sites, called tautomers. For example, compounds that include carbonyl groups -CH2C(O)- (keto forms) can undergo tautomerism to form hydroxyl groups -CH=C(OH)- (enol forms). The keto and enol forms, both individually and mixtures thereof, are included within the scope of the present invention. Isotopic variations The compounds disclosed herein include unlabeled forms as well as isotopically labeled forms. Isotopically labeled compounds possess structures that are represented by the formulas provided herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2H (i.e., deuterium or "D"), 3H ,nC,13C,14C,13N,1SN,15O,17O,18O,32P,35S,18F,123I,125I and36C1. The invention includes various isotopically labeled compounds as defined herein, for example, those in which radioactive isotopes occur, such as 3H and 14C, or those in which non-radioactive isotopes occur, such as 2H and 13C. Such isotopically labeled compounds are useful in metabolic studies (withI4C), studies IF-2018-68202357-APN-ANP#INPI Page 42 of 185 reaction kinetics (with, for example, 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission tomography (SPECT), including distribution assays of drug or substrate in tissues, or in radioactive treatments of patients. In particular, substitution with positron-emitting isotopes, such as nC,18F,15O and i3N, may be particularly desirable for PET or SPECT studies. Generally, the isotopically labeled compounds disclosed herein can be prepared by conventional techniques known to those of ordinary skill in the art. Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), may provide some therapeutic advantages that are a result of greater metabolic stability, for example, longer half-life in vivo, or fewer dosage requirements or an improvement in the therapeutic index. Pharmaceutically acceptable salts The term "pharmaceutically acceptable salt" refers to a salt prepared from a non-toxic pharmaceutically acceptable base or acid, including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric salt, ferrous salt, lithium, magnesium, manganic salts, potassium, sodium, zinc and the like. In particular embodiments, ammonium, calcium, magnesium, potassium and sodium salts are included. Salts in solid form can exist in more than one crystal structure and can also exist in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, Ν, Ν'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, resins of polyamine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When a compound disclosed herein is basic, a salt can be prepared from a non-toxic pharmaceutically acceptable acid, including IF-2018-68202357-APN-ANP#INPI Page 43 of 185 an inorganic acid and an organic acid. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, trifluoroacetic (TFA) and the like. Particular embodiments may include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, tartaric and trifluoroacetic acids. Methods of use The compounds disclosed herein can inhibit the activity of the enzyme indoleamine-2,3-dioxygenase (IDO). For example, the compounds disclosed herein can potentially be used to inhibit IDO activity in the cell or in a person in need of modulation of the enzyme by administering an effective amount of a compound. Also disclosed herein are methods for inhibiting the degradation of tryptophan in a system containing IDO-expressing cells, such as a tissue, a living organism, or a cell culture. In some embodiments, the present invention provides methods of altering (e.g., increasing) extracellular tryptophan levels in a mammal by administering an effective amount of a compound or composition provided herein. Methods for measuring tryptophan levels and tryptophan degradation are common in the state of the art. Furthermore, disclosed herein are methods of inhibiting immunosuppression, such as IDO-mediated immunosuppression in a patient by administering to the patient an effective amount of a compound or composition mentioned herein. IDO-mediated immunosuppression has been associated with, for example, different types of cancer, tumor growth, metastasis, viral infection, viral replication, etc. Additionally, methods are disclosed herein for treating diseases associated with the activity or expression, including abnormal activity and / or overexpression, of IDO in a person (e.g., a patient) by administering to the person in need of such treatment an effective amount. or dose of a compound disclosed herein or a pharmaceutical composition thereof. Examples of diseases may include any disease, disorder or condition that may be directly or IF-2018-68202357-APN-ANP#INPI Page 44 of 185 indirectly related to the expression or activity of the IDO enzyme, such as overexpression or abnormal activity. A gone-associated disease may also include any disease, disorder or condition that can be prevented, ameliorated or cured by modulating enzyme activity. Examples of diseases associated with IDO include cancer, viral infection, such as HIV and HCV infection, depression, neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (e.g. example, organ transplant rejection), and autoimmune diseases, including asthma, rheumatoid arthritis, multiple sclerosis, allergic inflammation, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus. Examples of types of cancer that can potentially be treated by the methods herein include colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head and neck, lymphoma, leukemia, melanoma and the like. The compounds of the invention may also be useful for the treatment of obesity and ischemia. As used herein, the term “cell” refers to a cell in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell may be part of a tissue sample obtained from an organism, such as a mammal. In some embodiments, an in vitro cell may be a cell in a cell culture. In some embodiments, an in vivo cell is a cell that lives in an organism, such as a mammal. As used herein, the term "contacting" refers to joining the indicated portions in an in vitro system or an in vivo system. For example, "contacting" the IDO enzyme with a compound disclosed herein includes administering a compound of the present invention to a person or patient, such as a human, in addition to, for example, introducing a compound of the invention in a sample containing a cellular or purified preparation containing the IDO enzyme. Generally, a subject administered a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, is a mammal, such as a human, male or female. A subject also refers to cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, and birds. In one embodiment, the subject is a human being. IF-2018-68202357-APN-ANP#INPI Page 45 of 185 As used herein, the terms treatment and treat refer to all processes where there may be a slowing, interruption, arrest, control or pause in the progression of a disease or disorder that may be associated with the activity of the IDO enzyme. . The terms do not necessarily indicate the total elimination of all symptoms of the disease or disorder. The terms also include potential prophylactic treatment of the aforementioned conditions, particularly in a subject predisposed to such disease or disorder. It should be noted that the terms administration of and / or administering a compound include providing to a subject a compound described herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and compositions of the above. The amount of compound administered to a subject is an amount sufficient to inhibit the activity of the IDO enzyme in the subject. In one embodiment, the amount of a compound may be an “effective amount,” wherein the desired compound is administered in an amount that elicits a biological or medical response from a tissue, system, animal, or human, sought by a researcher, veterinarian, physician, or other clinical professional. An effective amount does not necessarily include toxicity and safety considerations related to the administration of a compound. It is recognized that a person skilled in the art at a mid-level level can influence the physiological disorders associated with the activity of an IDO enzyme by treating a subject who currently has the disorders, or by prophylactically treating a subject who is prone to suffer from the disorders, with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof. An effective amount of a compound will vary depending on the particular compound selected (for example, based on the potency, efficacy and / or half-life of the compound); the chosen route of administration; the condition being treated; the severity of the condition being treated; the age, size, weight and physical condition of the subject being treated; the medical history of the subject being treated; the duration of treatment; the nature of my concurrent treatment; the desired therapeutic effect; and similar factors that a mid-level subject matter expert can routinely determine. The compounds disclosed herein can be administered IF-2018-68202357-APN-ANP#INPI Page 46 of 185 by any suitable route, including oral and parenteral administration. Generally, parenteral administration is carried out by injection or infusion, and includes subcutaneous, intramuscular and intravenous infusion or injection. The compounds disclosed herein may be administered once or according to a dosage regimen wherein a number of doses are administered at various time intervals over a given period. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosage regimens for a compound disclosed herein depend on the pharmacokinetic properties of that compound, such as absorption, distribution and half-life, which can be determined by a person of ordinary skill in the art. Furthermore, appropriate dosage regimens, including the duration over which such regimens are administered, for a compound disclosed herein depend on the disease or condition being treated, the severity of the disease or condition, age, and physical status. of the subject being treated, the medical history of the subject being treated, the nature of a concurrent treatment, the desired therapeutic effect and similar factors that are within the knowledge and experience of the person skilled in the middle level subject. Those skilled in the art will also understand that suitable dosage regimens may need adjustment based on a subject's response to the dosage regimen or over time if the subject requires a change. The usual daily doses may vary depending on the particular route of administration selected. The usual daily dose for oral administration to a human weighing about 70 kg may vary from about 0.1 mg to about 2 grams, or more specifically, 0.1 mg to 500 mg or, even more specifically, 0.2 mg to 100 mg, of a compound disclosed herein. One embodiment of the present invention provides a method of treating a disease or disorder that is associated with the activity of the IDO enzyme, comprising administering an effective amount of a compound disclosed herein to a subject in need of said treatment. In one embodiment, the disease or disorder associated with the IDO enzyme is a cell proliferation disorder. In one embodiment, the use of a IF-2018-68202357-APN-ANP#INPI Page 47 of 185 compound disclosed herein in a treatment. The compound may be useful in a method of inhibiting the activity of the IDO enzyme in a subject, such as a mammal in need of such inhibition, and comprises administering to the subject an effective amount of the compound. In one embodiment, a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in the potential treatment of a related disorder or disease is disclosed herein. with the activity of the IDO enzyme. Compositions As used herein, the term composition encompasses a dosage form comprising a specified compound in a specified amount, as well as any dosage form that results, directly or indirectly, from the combination of a specified compound in a specified amount. specified. Said term encompasses a dosage form comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and one or more pharmaceutically acceptable carriers or excipients. Accordingly, the compositions of the present invention encompass any composition that was obtained by mixing a compound of the present invention and one or more pharmaceutically acceptable carriers or excipients. The term "pharmaceutically acceptable" means that the carriers or excipients are compatible with the compound disclosed herein and with other ingredients of the composition. In one embodiment, disclosed herein is a composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or hydrate of that salt, and one or more pharmaceutically acceptable carriers or excipients. The composition may be prepared and packaged in bulk, wherein an effective amount of a compound of the invention may be extracted and then administered to a subject, for example, with powders or syrups. Alternatively, the composition may be prepared and packaged in unit dosage form, wherein each physically separate unit contains an effective amount of a compound disclosed herein. When prepared in imitation dosage form, the composition of the invention generally contains about 0.1 mg to 2 grams, or more IF-2018-68202357-APN-ANP#INPI Page 48 of 185 specifically, 0.1 mg to 500 mg or, even more specifically, 0.2 mg to 100 mg, of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof. A compound disclosed herein and a pharmaceutically acceptable carrier or excipient will generally be formulated in a dosage form adapted for administration to a subject via the desired route of administration. For example, dosage forms include those adapted for (1) oral administration, for example, tablets, capsules, caplets, pills, tablets, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and wafers; and (2) parenteral administration, for example, sterile solutions, suspensions, and powders for reconstitution. Suitable pharmaceutically acceptable carriers or excipients vary depending on the particular dosage form selected. Furthermore, suitable pharmaceutically acceptable carriers or excipients may be selected to fulfill a particular function in the composition. For example, some pharmaceutically acceptable carriers or excipients may be selected for their ability to facilitate the production of uniform dosage forms. Some pharmaceutically acceptable carriers or excipients may be selected for their ability to facilitate the production of stable dosage forms. Some pharmaceutically acceptable carriers or excipients may be selected for their ability to facilitate the transfer or transport of a compound disclosed herein, once administered to the subject, from one organ or body part to another organ or body part. Some pharmaceutically acceptable carriers or excipients may be selected for their ability to improve patient compliance. Suitable pharmaceutically acceptable carriers or excipients include the following types of excipients: diluents, lubricants, binders, disintegrants, filling agents, slip agents, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffering agents. The mid-level person skilled in the art has the knowledge and ability to select pharmaceutically acceptable carriers or excipients. IF-2018-68202357-APN-ANP#INPI Page 49 of 185 suitable in amounts suitable for use in the invention. Additionally, there are several resources available to the mid-level skilled person that describe pharmaceutically acceptable carriers or excipients and may be helpful in selecting appropriate pharmaceutically acceptable carriers and excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press). The compositions of the invention are prepared by techniques and methods known to those skilled in the art at an intermediate level. Some methods commonly used in the prior art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company). In one embodiment, the invention relates to a solid oral dosage form, such as a tablet or capsule comprising an effective amount of a compound of the invention and a diluent or a filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g., corn starch, potato starch, and pregelatinized starch), cellulose and its derivatives (e.g., microcrystalline cellulose), sulfate. calcium and dibasic calcium phosphate. The solid oral dosage form may also comprise a binder. Suitable binders include starch (for example, corn starch, potato starch and pregelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone and cellulose and its derivatives (for example, microcrystalline cellulose). . The solid oral dosage form may also comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid and sodium carboxymethylcellulose. The solid oral dosage form may also comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc. Where appropriate, unit dose formulations for oral administration may be microencapsulated. The composition may also be prepared to prolong or sustain release, for example, by coating or embedding particulate material in polymers, wax or the like. The compounds disclosed herein can also be coupled to soluble polymers, as addressable drug carriers. Those IF-2018-68202357-APN-ANP#INPI Page 50 of 185 polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the invention can be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked block copolymers. or amphipathic hydrogels. In one embodiment, the invention relates to a liquid oral dosage form. Oral liquids, such as solutions, syrups and elixirs can be prepared in dosage units, so that a certain quantity contains a predetermined amount of a compound disclosed herein. Syrups can be prepared by dissolving the compound of the invention in a suitably flavored aqueous solution, while elixirs are prepared with a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing a compound disclosed herein in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives, such as peppermint oil or other natural sweeteners, or saccharin or other artificial sweeteners, and the like, may also be used. In one embodiment, the invention relates to compositions for parenteral administration. Compositions adapted for parenteral administration include sterile aqueous and non-aqueous injectable solutions, which may contain antioxidants, buffers, bacteriostatics and solutes that cause the formulation to become isotonic with the blood of the intended recipient; and sterile aqueous and non-aqueous suspensions which may include thickening or suspending agents. The compositions may be presented in unit dosage or multiple dose containers, e.g., sealed ampoules and vials, and may be stored under lyophilized conditions requiring only the addition of the sterile liquid carrier, e.g., water for injections, immediately prior to use. . Solutions and suspensions for extemporaneous injections can be prepared from sterile powders, granules and tablets. Combinations A compound disclosed herein can be used in combination with IF-2018-68202357-APN-ANP#INPI Page 51 of 185 one or more active agents, including, for example, other antineoplastic agents, that are used to prevent, treat, control, improve or reduce the risk of a particular disease or condition (for example, cell proliferation disorders) . In one embodiment, a compound disclosed herein is combined with one or more other antineoplastic agents, for use in preventing, treating, controlling, ameliorating or reducing the risk of a particular disease or condition for the that the compounds disclosed herein are useful. These different active agents can be administered by a route and in an amount usually used for this purpose, simultaneously or sequentially with a compound of the present invention. When a compound disclosed herein is used simultaneously with one or more other active agents, a composition containing those different active agents in addition to the compound disclosed herein is contemplated. Accordingly, compositions of the present invention include those that also contain one or more other active ingredients in addition to a compound disclosed herein. A compound disclosed herein may be administered simultaneously, before or after one or more other therapeutic agents. A compound disclosed herein may be administered separately, by the same route of administration or a different route of administration, or in the same pharmaceutical composition as the other agents. Products provided as a combination preparation include a composition comprising a compound disclosed herein and one or more different active agents together in the same pharmaceutical composition, or a compound disclosed herein, and one or more different therapeutic agents in separately, for example, in kit form. The weight ratio between a compound disclosed herein and a second active agent may vary and will depend on the effective dose of each agent. Typically, an effective dose of each will be used. Therefore, for example, when a compound disclosed herein is combined with another agent, the weight ratio of the compound disclosed herein to the other agent will generally vary from about 1000:1 to about 1 :1000, for example, from about 200:1 to about 1:200. Combinations of a compound disclosed herein and other active agents will generally also be within the ranges IF-2018-68202357-APN-ANP#INPI Page 52 of 185 mentioned, but in each case an effective dose of each active agent must be used. In such combinations, the compound disclosed herein and other active agents may be administered together or separately. Furthermore, the administration of an element can be carried out before, during or after the administration of the other agents. In one embodiment, the invention provides a composition comprising a compound disclosed herein and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in treatment. In one embodiment, the treatment is the treatment of a disease or disorder associated with the activity of the IDO enzyme. In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, and at least one of these contains a compound disclosed herein. In one embodiment, the kit comprises means for storing those compositions separately, for example, a container, a bottle with divisions, or an aluminum container with divisions. An example of this type of kit is a blister-type packaging, which is commonly used in the packaging of tablets, capsules and the like. A kit disclosed herein can be used to administer various dosage forms, for example, oral and parenteral, to administer the separate compositions at different dosage ranges, or to titrate the compositions to each other. In order to aid compliance, a kit of the invention generally includes directions for its administration. Disclosed herein is the use of a compound disclosed herein to treat a disease or disorder associated with the activity of the IDO enzyme, wherein the medicament is prepared for administration with another active agent. Furthermore, the invention provides the use of another active agent to treat a disease or disorder associated with an IDO enzyme, wherein the medicament is administered with a compound disclosed herein. Furthermore, the invention also provides the use of a compound disclosed herein to treat a disease or disorder associated with IDO enzyme activity, wherein the patient was previously treated with another active agent (e.g., within 24 hours). hours). Furthermore, the invention provides the use of another therapeutic agent to treat a disease or disorder associated with IDO enzyme activity, wherein the patient was previously treated (e.g. IF-2018-68202357-APN-ANP#INPI Page 53 of 185 within 24 hours) with a compound disclosed herein. The second agent may be administered one week, several weeks, one month, or several months after administration of a compound disclosed herein. In one embodiment, the other active agent is selected from the group consisting of vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen [SIC] inhibitors, alkylating agents, antineoplastic antibiotics, antimetabolites. , retinoids, immunomodulatory agents including, but not limited to, cancer vaccines, PD-1, LAG-3 and CTLA-4 antagonists. Examples of vascular endothelial growth factor (VEGF) receptor inhibitors include, but are not limited to, bevacizumab (marketed under the brand name AV ASTIN from Genentech / Roche), axitinib, (N-methyl-2-[[3-[( [E])-2-pyridin-2ylethenyl]-! H-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and described in PCT Publication No. WO 01 / 002369), Brivanib alaninate (( S)-((R)-1(4-(4-fluoro-2-methyl-1 H-indol-5-yloxy)-5-methylpyrrolo[2,1 -f] [ 1,2,4]triazin- 6yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-l H-indoi-6-yl)-2-[ (4-pyridinylmethyl)amino]-3pyridinecarboxamide, and described in PCT Publication No. WO 02 / 068470), pasireotide (also known as SO 230, and described in PCT Publication No. WO 02 / 010192) and sorafenib ( marketed under the brand NEXAVAR). Examples of topoisomerase II inhibitors include, but are not limited to, etoposide (also known as VP-16 and etoposide phosphate, marketed under the brand names TOPOSAR, VEPESID and ETOPOPHOS) and teniposide (also known as VM-26, marketed under the brand name VUMON). Examples of alkylating agents include, but are not limited to, 5-azacytidine (marketed under the brand name VIDAZA), decitabine (marketed under the brand name DECOGEN), temozolomide (marketed under the brand names TEMODAR and TEMODAL, from Schering-Plough / Merck), dactinomycin ( also known as actinomycin D, and marketed under the brand name COSMEGEN), melphalan, also known as L-PAM, L sarcolysin, and phenylalanine mustard, marketed under the brand name ALKERAN), altretamine (also known as hexamethylmelamine (HMM), marketed under the brand name HEXALEN), carmustine (marketed under the brand name BCNU), bendamustine (marketed under the brand name TREANDA), busulfan (marketed under the brand names IF-2018-68202357-APN-ANPAINPI Page 54 of 185 BUSULFEX and MYLERAN), carboplatin (marketed under the brand name PARAPLAT1N), lomustine (also known as CCNU, marketed under the brand name CeeNU), cisplatin (also known as CDDP, marketed under the brand names PLATINOL and PLATINOL-AQ), chlorambucil (marketed brand LEUKERAN), cyclophosphamide (marketed under the brand names CYTOXAN and NEOSAR), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, marketed under the brand name DTIC-Dome), altretamine (also known as hexamethylmelamine (HMM), marketed brand name HEXALEN), ifosfamide (marketed under the brand name IFEX), procarbazine (marketed under the brand name MATULANE), mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, marketed under the brand name MUSTARGEN), streptozocin (marketed under the brand name ZANOSAR), thiotepa (also known as thiophosphoamide, TESPA and TSPA, and marketed under the brand name THIOPLEX). Examples of antineoplastic antibiotics include, but are not limited to, doxorubicin (marketed under the brand names ADRIAMYCIN and RUBEX), bleomycin (marketed under the brand name LENOXANE), daunorubicin (also known as carubicin hydrochloride, daunomycin and amrubicin hydrochloride, marketed under the brand name CERUBIDINE), liposomal daunorubicin (liposomal daunorubicin citrate, marketed under the brand name DAUNOXOME), mitoxantrone (also known as DHAD, marketed under the brand name NOV ANTRONE), epirubicin (marketed under the brand name ELLENCE), idarubicin (marketed under the brand names IDAMYCIN, IDAMYCIN PFS) and mitomycin C (marketed under the brand name MUTAMYCIN). Examples of antimetabolites include, but are not limited to, cladribine (2-chlorodeoxyadenosine, marketed under the brand name LEUSTATIN), 5-fluorouracil (marketed under the brand name ADRUCIL), 6-thioguanine (marketed under the brand name PURINETHOL), pemetrexed (marketed under the brand name ALIMTA) , cytarabine (also known as arabinosylcytosine (Ara-C), marketed under the brand name CYTOSAR-U), liposomal cytarabine (also known as Ara-C liposomal, marketed under the brand name DEPOCYT), decitabine (marketed under the brand name DACOGEN), hydroxyurea (marketed under the brand names HYDREA, DROXIA and MYLOCEL), fludarabine (marketed under the brand name FLUDARA), floxuridine (marketed under the brand name FUDR), cladribine (also known as 255 IF-2018-68202357-APN-ANP#INPI Page 55 of 185 chlorodeoxyadenosine (2-CdA), marketed under the brand name LEUSTATIN), methotrexate (also known as amethopterin, methotrexate sodium (MTX), marketed under the brand names RHEUMATREX and TREXALL), and pentostatin (marketed under the brand name NIPENT). Examples of retinoids include, but are not limited to, alitretinoin (marketed under the brand name PANRETIN), tretinoin (total trans retinoic acid, also known as ATRA, marketed under the brand name VESANOID), Isotretinoin (13-cis retinoic acid, marketed under the brand names ACCUTANE, AMNESTEEM, CLARAVIS, CLARUS, DECUTAN, ISOTANE, IZOTECH, ORATANE, ISOTRET and SOTRET) and bexarotene (marketed under the brand name TARGRETIN). The term “PD-1 antagonist” refers to any chemical compound or biological molecule that blocks the binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell, or NKT cell) and preferably also blocks the binding of PD-L2 that is expressed on a cancer cell to the immune cell that expresses PD-1. Alternative or synonymous names for PD-1 and its ligands include: PDCD1, PD1, CD279, and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc, and CD273 for PD-L2. In any treatment, medication and use method of the present invention in which a human is treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and preferably blocks the binding of PD-1. Human L1 and PD-L2 to human PD-1. The amino acid sequences of human PD-1 can be found in NCBI Locus No.: NP 005009. The amino acid sequences of human PD-L1 and PD-L2 can be found in NCBI Locus No.: NP 054862 and NP 079515, respectively. PD-1 antagonists useful in any method of treatment, medication and use of the present invention include a monoclonal antibody (mAb), or an antigen-binding fragment thereof, that specifically binds PD-1 or PD -L1, and preferably specifically binds to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody, and may include a human constant region. In some embodiments, a human constant region is selected from the group consisting of the IgGl, IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments, IF-2018-68202357-APN-ANP#INPI Page 56 of 185 the human constant region is an IgGl or IgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments. Examples of PD-1 antagonists include, but are not limited to, pembrolizumab (marketed under the brand name Keytruda) and nivolumab (marketed under the brand name OPDIVO). Examples of mAbs that bind to human PD-1 and are useful in the treatment method, medicaments and uses of the present invention are described in US7488802, US7521051, US8008449, US8354509, US8168757, W02004 / 004771, W02004 / 072286, W02004 / 056875 and US2011 / 0271358. Examples of mAbs that bind to human PD-L1 and are useful in the treatment method, medications and uses of the present invention are described in WO2013 / 019906, W02010 / 077634 Al and US8383796. Specific anti-human PD-L1 mAbs useful as PD-1 antagonists in the treatment method, medicaments and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C and an antibody comprising the variable regions of the heavy and light chains of SEQ ID NO:24 and SEQ ID NO:21, respectively, of WO2013 / 019906. Other PD-1 antagonists useful in any of the treatment methods, medications and uses of the present invention include an immunoadhesin that specifically binds to PD-1 or PD-L1, and that preferably binds specifically to human PD-1. or human PD-L1, for example, a fusion protein containing the PD-1 binding or extracellular portion of PD-L1 or PD-L2 fused to a constant region, such as an Fe region of an immunoglobulin molecule. Examples of immunoadhesion molecules that specifically bind PD-1 are described in W02010 / 027827 and WO2011 / 066342. Specific fusion proteins useful as PD-1 antagonists in the treatment method, medications and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-fusion protein. FC and binds to human PD-1. Examples of other cytotoxic agents include, but are not limited to, arsenic trioxide (marketed under the brand name TRISENOX), asparaginase (also known as L-asparaginase, and Erwinia L-asparaginase, marketed under the brand names ELSPAR and KIDROLASE). IF-2018-68202357-APN-ANP#INPI Page 57 of 185 EXPERIMENTAL The following synthesis schemes and examples are provided for illustrative purposes only, and should not be construed as limiting. The abbreviations used are those conventional in the state of the art or the following. ACN acetonitrile ac. aqueous Boc íer-butyloxycarbonyl BoczO di-tert-butyl dicarbonate Cale. calculated Celite diatomaceous earth used as filtration medium Cu(I)I CV copper(I) iodide column volume °C degrees Celsius DAST (dimethylamino)sulfur trifluoride DCM dichloromethane DIEA N,N-diisopropylethylamine DIPEA N,N-diisopropylethylamine DMA dimethylamine DMF N,N-dimethylformamide DMSO dimethylsulfoxide dppf 0 DPPF dtbpf EDC 1,1 '-bis(diphenylphosphino)ferrocene 1,1 '-bis(di-t-butylphosphino)ferrocene hydrochloride N-(3-dimethylaminopropyl)-N' -ethylcarbodiimide EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide Electron ionization EMEM minimal essential medium Eagle Et ethyl Et2O diethyl ether Et3N triethylamine EtOAc ethyl acetate EtOH ethanol g gram IF-2018-68202357-APN-ANP#INPI Page 58 of 185 • h hour(s) HATU 1 -(bis(dimethylamino)methylene]-\H-1,2,3-triazolo[4,5-&]pyridinium 3-hexafluorophosphate oxide HC1 hydrochloric acid 5 HPLC high pressure liquid chromatography K3PO4 potassium tribasic phosphate kg kilogram LiOH lithium hydroxide M molar Me methyl MeOH methane] MeMgBr methylmagnesium bromide 20 mg milligram MgSO4 magnesium sulfate mmol millimole MS mass spectrometry MTBE methyl / er-butyl ether 25 min minutes ml milliliter(s) m / z mass-charge ratio nm nanometer nM nanomolar 30 N normal n2 nitrogen Na2SO4 sodium sulfate NaH sodium hydride IF-2018-68202357-APN-ANP#INPI Page 59 of 185 NaHCO3 NaHMDS sodium bicarbonate sodium bis(trimethylsilyl)amide NaN3 sodium azide NaOH sodium hydroxide 5 NH4C1 ammonium chloride OTBDPS tert-butyldiphenylsilyl OTf trifluoromethanesulfonate Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) PdCl2(dppf) dichloride l,r-bis(diphenylphosphino)ferrocene-palladium(II) 10 Pd(dppf)2Cl2 1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(dtbpf) 1,1 '-bis(di-ter- butylphosphino)ferrocene]dichloropalladium(II) PE petroleum ether PG protecting group PMP P-methoxyphenyl 15 POC13 phosphorus oxychloride PS polystyrene RPMI Roswell Park Memorial Institute RT 0 rt room temperature sat. saturated 20 T3P propylphosphonic anhydride solution TBAF tetrabutylammonium fluoride TBAT tetrabutylammonium difluorotriphenylsilicate TBS tert-butyldimethylsilyl ether TBSC1 tert-butyldimethylsilyl chloride 25 / -BuOH / er-butanol t-BuONO tert-butyl nitrite TEA triethylamine TEMPO (2,2 2,2,6,6-tetramethylpiperidinylmagnesium chloride tmscf3 trifluoromethyltrimethylsilane IF-2018-68202357-APN-ANP#INPI Page 60 of 185 TBSC1 tert-butyldimethylsilyl chloride TMSCHN20 TMSCH2N2 trimethylsilyldiazomethane TMSCN trimethylsilyl cyanide TosCl toluenesulfonyl chloride ul microliter(s) XPhos Pd G2 chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1 '-biphenyl)[2-(2'amino-1,1 '-biphenyl)]palladium(II) XPhos PdG3 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,rbiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate GENERAL SYNTHESIS SCHEMES The compounds of Formula I can be prepared by methods known in the state of the art of organic synthesis, as set forth, in part, by the following synthesis schemes and the synthesis procedures and conditions of the illustrative intermediates and examples. In the schemes described below, it is understood that protecting groups for sensitive or reactive groups are used when necessary in accordance with general principles of chemistry. Protective groups are manipulated according to standard organic synthesis methods (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley, New York 1999). These groups are removed at a convenient step in the compound synthesis by methods known to those skilled in the art. Scheme 1 The compounds of Formula I can be prepared by means of Scheme 1. A suitable carboxylic acid of the general structure Gen-1 couples with IF-2018-68202357-APN-ANP#INPI Page 61 of 185 a suitable R2-NH2 amine under standard amide coupling conditions to obtain a Gen-2 amide intermediate. Gen-2 reacts with a suitable boronic acid, pinacolester of boronic acid, silicon-containing agent, zincate or stannane or suitable metallic agents under Suzuki, Negishi, Stille or other coupling conditions to obtain the compounds of Formula I. Alternatively, Gen-2 is converted to the corresponding boronic acid pinacolester of Gen-3 by reaction with bis(pinacolato)diboron (B2pin2) under Pd-catalyzed cross-coupling conditions. The reaction of Gen-3 with a halide, triflate, etc. suitable under the coupling conditions of Suzuki provides the compounds of Formula I. The compounds described herein can be produced from commercially available starting materials or synthesized by known organic, inorganic and / or enzymatic processes. 1H NMR spectra were obtained on a Broker Ultra Shield spectrometer at 600 MHz or a Varian 500 spectrometer at 499 MHz with tetramethylsilane used as an internal reference. LC / MS spectra were obtained using Agilent 6120 Quadrupole LC / MS spectrometers via electrospray ionization. EXAMPLES Example 1: 3-(4-(6-cyclopropylniridin-3-yl)phenyl)-A-(4-fluorophenyl)oxetan-3-carboxamide Step 1: 3-(4-bromophenyl)-7V-(4-fluorophenyl)oxetan-3-carboxamide To a stirring solution of commercially available 3-(4-bromophenyl)oxetane-3carboxylic acid (4000.0 mg, 15.56 mmol) in DCM (20.0 ml), HATU (7099 mg, 18.0 ml) was added. 67 mmol), and the suspension was stirred for 15 min at room temperature. Then 4-fluoroaniline (1729 mg, 15.56 mmol) and DIEA (8.15 ml, 46.7 mmol) were added sequentially, and the reaction mixture was stirred for 4 IF-2018-68202357-APN-ANP#INPI Page 62 of 185 h at room temperature. The reaction was diluted with ethyl acetate and washed with 1N aqueous HC1 (3x), water (2x), brine and NaHCO3. The organic phase was then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (ISCO® silica flash column; 120 g SepaFlash®, 10 to 100% ethyl acetate / DCM) to obtain the title compound (1-2). MS (ESI) m / z 350 [M+HJ+. Hereinafter, the reaction conditions in step 1 are referred to as standard amide coupling conditions. Step 2: 3-4-(6-cyclonroylpyridin-3-yl)phenyl-N-(4-fluorophenyl)oxetan-3-carboxamide To a stirred suspension of 2-cyclopropyl-5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)pyridine (47.6 mg, 0.194 mmol), 3-(4-bromophenyl) -7V-(4fluorophenyl)oxetan-3-carboxamide (68.0 mg, 0.194 mmol) and palladium(II) dichloro[l,l'bis(di-t-butylphosphino)ferrocene]palladium(II) (15.92 mg , 0.017 mmol) in 1,4-dioxane (1.5 ml), sodium carbonate (0.194 ml, 0.388 mmol) was added. The reaction mixture was evacuated and refilled with nitrogen three times and heated to 80 °C for 4 h when LCMS showed complete conversion. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residue was taken up in CH2C12, and washed with brine. The organic layer was dried over MgSC>4, filtered, and the solvent was removed in vacuo. The crude material was purified by mass-directed reversed-phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 389. 1H NMR (600 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.82 (s, 1H), 8.21 (s, 1H), 7.79 ( d, J = 8.1 Hz, 2H), 7.70 - 7.58 (m, 4H), 7.50 (d, J = 8.2 Hz, 1H), 7.15 (t, J = 8.7 Hz, 2H), 5.23 (d, J = 6.5 Hz, 2H), 4.91 (d, J = 6.5 Hz, 2H), 2.29 - 2.16 (m, 1H), 1.14-1.09 (m, 2H), 1.05 (s, 2H). Hereinafter, the reaction conditions in stage 2 are referred to as standard Suzuki cross-coupling conditions. IF-2018-68202357-APN-ANP#INPI Page 63 of 185 Example 2: 3-(4-(6-cyclonropyl-4-fluoropyridin-3-yl)phenyl)-Ar-(4-fluorophenyl)oxetan-3carboxamide The title compound was prepared analogously to the synthesis of Example 1, except that 2-cyclopropyl-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyridine was used. MS (ESI) [M+H]+: m / z 407. 1H NMR (499 MHz, DMSOd6) 5 10.03 (s, 1H), 8.58 (d, J = 10.7 Hz, 1H), 7.72 - 7.51 (m, 4H), 7.39 (d, J = 11.7 Hz, 1H), 7.15 (t, J = 8.8 Hz, 2H), 5.22 (d, J = 6.5 Hz, 2H), 4.91 (d, J = 6.5 Hz, 2H) , 2.26 2.12 (m, 1H), 1.05 (t, J = 7.7 Hz, 2H), 1.01 (s, 2H). Example 3: 3-(4-(6-cyclonropyl-4-methiIniridin-3-iDphenyl)-7V-(4-fluorophenyl)oxetane-3carboxamide The title compound was prepared analogously to the synthesis of Example 1, except that 2-cyclopropyl-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl) was used. )pyridine. MS (ESI) [M+H]+: m / z 403. 1H NMR (499 MHz, DMSOd6) δ 10.11 (s, 1H), 8.48 (s, 1H), 7.70 - 7.60 (m, 4H), 7.58 - 7.49 (m, 3H), 7.15 (t, J = 8.8 Hz, 2H), 5.25 (d, J = 6.5 Hz, 2H), 4.92 (d, J = 6.5 Hz, 2H), 2.38 (s, 3H), 2.28 (tt, J = 8.5, 5.0 Hz, 1H), 1.32 - 1.22 (m, 2H), 1.20 - 1.07 (m, 2H). Example 4: 7V-(4-fluorophenyl)-3-(4-(7-methylimidazo[1.2-a1pyridin-6-yl)phenyl)oxetane-3carboxamide The title compound was prepared analogously to the synthesis of IF-2018-68202357-APN-ANP#INPI Page 64 of 185 Example 1 except that (7-methylimidazo[l,2-a]pyridin-6-yl)boronic acid was used. MS (ESI) [M+H]+: m / z 402. 1H NMR (499 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.83 (s, 1H), 8.19 (s, 1H), 8.15 ( s, 1H), 7.92 (s, 1H), 7.66 (t, J = 7.5 Hz, 4H), 7.56 (d, J = 8.1 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H), 5.26 ( d, J = 6.5 Hz, 2H), 4.93 (d, J = 6.5 Hz, 2H), 2.42 (s, 3H). Example 5: 3-(4-(4,6-dimethylpyrimidin-5-yl)phenyl)-A-(4-fluorophenyl)oxetane-3carboxamide or The title compound was prepared analogously to the synthesis of Example 1, except that (4,6-dimethylpyrimidin-5-yl)boronic acid was used. MS (ESI) [M+H]+: m / z 378. 1H NMR (499 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.90 (s, 1H), 7.77 7.56 (m, 4H), 7.38 (d, J = 8.1 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H), 5.24 (d, J = 6.5 Hz, 2H), 4.92 (d, J = 6.5 Hz, 2H), 2.20 (s , 6H). Example 6: 7V-(4-fluorophenyl)-3-í4-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3carboxamide The title compound was prepared analogously to the synthesis of Example 1, except that 4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- was used. 2(trifluoromethyl)pyridine as coupling component. MS (ESI) [M+H]+: m / z 431; found, 431. 1H NMR (499 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.57 (s, 1H), 7.92 (s, 1H), 7.72 - 7.61 (m, 4H), 7.55 (d, J = 8.0 Hz, 2H), 7.17 (t, J = 8.7 Hz, 2H), 5.24 (d, J = 6.5 Hz, 2H), 4.93 (d, J = 6.5 Hz, 2H), 2.39 (s, 3H). IF-2018-68202357-APN-ANP#INPI Page 65 of 185 Example 7: 7V-(4-fluorophenyl)-3-(4-(6-methoxy-2,4-dimethylpyridin-3-yl)phenyl)oxetane-3carboxamide Step 1: A-í4-fluorophenyl)-3-(4-(4.4,5.5-tetramethyl-L3.2-dioxaborolan-2-yl)phenyl)oxetan3-carboxamide A dried round bottom flask was charged with 3-(4-bromophenyl)-7V-(4phiorophenyl)oxetan-3-carboxamide (1-2) (200.0 mg, 0.571 mmol), bis(pinacolato)diboron (377 mg , 1.485 mmol), potassium acetate (166 mg, 1.691 mmol) and PdC12(dppf)-CH2Cl2 (46.6 mg, 0.057 mmol) in dioxane (5.0 ml). Then, the resulting mixture was evacuated and refilled with nitrogen (3 times). The mixture was heated to 80 °C for 4 h, then cooled to room temperature and filtered through a celite pad. The filtrate was concentrated in vacuo to obtain a residue that was dissolved in dichloromethane. After washing with water (3x) and brine, the dichloromethane layer was dried over anhydrous Na2SC>4 and concentrated in vacuo to obtain a crude product, which was purified by column chromatography (silica gel, EtOAc / hexane, 12 to 100%) to obtain the title compound (1-9). MS (ESI) [M+H]+: m / z 398. Step 2: 7V-(4-fluorophenyl)-3-(4-(6-methoxy-2.4-dimethylpyridin-3-yl)phenyl')oxetane-3carboxamide A solution of 3-bromo-6-methoxy-2,4-dimethylpyridine (16.32 mg, 0.076 mmol), N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)oxetan3-carboxamide, (30.0 mg, 0.076 mmol), 1,l*-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (4.92 mg, 7.55 pmol) and sodium carbonate (0.076 ml, 0.151 mmol) in 1,4-dioxane (2.0 ml) was evacuated and refilled with nitrogen three times, and the mixture was heated to 80 °C in nitrogen for 4 h. The solvents were then removed in vacuo, and the resulting residue was suspended in EtOAc / DCM, filtered through a Celite pad, which was washed with EtOAc / DCM. The combined filtrates were concentrated, and the crude material was purified by mass-directed reverse-phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the IF-2018-68202357-APN-ANP#INPI Page 66 of 185 composed of the title. MS (ESI) [M+H]+: m / z 407. 1H NMR (499 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.66 (dd, J = 8.7, 5.0 Hz, 2H), 7.59 ( d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H), 6.68 (s, 1H), 5.23 (d, J = 6.5 Hz, 2H), 4.90 (d, J = 6.5 Hz, 2H), 3.86 (s, 3H), 2.11 (s, 3H), 1.97 (s, 3H). Examples 8 to 33 in the following table were prepared in a similar manner to Example 7. Procedures for the synthesis of selected starting materials are described herein. General Suzuki coupling conditions using N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (1-9) were added (70 mg, 0.141 mmol), (5-bromo-2methoxypyridin-4-yl)methanol (30.7 mg, 0.141 mmol) and X-PhosPdG2 (11.09 mg, 0.014 mmol) to a 4 ml reaction tube, which It was evacuated and refilled with nitrogen 3 times. THF (564 μΐ) and tribasic potassium phosphate (1 M aqueous solution) (282 μΐ, 0.282 mmol) were added. The reaction mixture was heated to 70 °C for 1 h and cooled to room temperature. The reaction was diluted with 4 ml of DCM, poured through a phase separator, and the organic phase was collected and concentrated in vacuo. The residue was dissolved in 1 ml of DMSO and subjected to reverse phase purifications (ACN / water gradient with 0.1% TFA modifier). The pure fractions were frozen and lyophilized to obtain N-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6methoxypyridin-3-yl)phenyl)oxetan-3-carboxamide (Example 11) as the salt. of TFA as a solid. Preparation of 2-(3-chloro-5-(trifluoromethyl)DÍridin-2-yl)ethan-l-ol (1-11): coupling component for Example 15 Methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)acetate (480 mg, 1.893 mmol) was dissolved in THF (9464 μΐ), and the mixture was cooled to −78 °C. Then, DIBAL-H (4732 μΐ, 4.73 mmol) was added, and the mixture was warmed to room temperature for 1 h. The reaction was quenched with saturated aqueous sodium potassium tartrate solution and stirred overnight at room temperature. The organic layer IF-2018-68202357-APN-ANP#INPI Page 67 of 185 was separated, and the aqueous layer was extracted with 1 x 50 ml of EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethanol as an orange oil which was used for the preparation of Example 15 without further purification. MS (ESI) [M+H]+: m / z 226. Preparation of 2-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)pronan-2-ol (1-12): coupling component for Example 12 To a solution of methyl 5-bromo-2-(trifluoromethyl)isonicotinate (1.5 g, 5.28 mmol) in THF (21.12 mL) at -78 °C was added methylmagnesium bromide (3 M in Et2O) (3.52 ml, 10.56 mmol) and the mixture was warmed to room temperature for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and stirred overnight at room temperature. The organics were separated, washed with brine, dried over sodium sulfate, and the solvents were removed in vacuo to obtain 2-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)propan-2-ol ( 1-12) as a solid that was used for the preparation of Examples 12 and 20 without further purification. MS (ESI) [M+H]+: m / z 284 / 286. Alternatively, 1-12 can be prepared according to the following procedure: a round bottom flask under nitrogen was charged with LDA (2 M, 33.2 ml). A solution of 5-bromo-2-(trifluoromethyl)pyridine (15 g, 66.4 mmol) in THF (15 mL) was added dropwise to the mixture at <-65 °C over 3 h and the mixture was stirred at < 65 °C for an additional 1 h. Acetone (3.8 g, 66.4 mmol) was added dropwise over 0.5 h at <-65°C, and the mixture was stirred at <-65°C for 1 h. The mixture was then diluted with ethyl acetate (270 ml) and quenched with water (170 ml). The phases were separated, and the aqueous phase was extracted with ethyl acetate (70 ml x2). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography to obtain 1-12. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1 H), 8.19 (s, 1 H), 5.82 (s, 1 H), 1.62 (s, 6 H). IF-2018-68202357-APN-ANP#INPI Page 68 of 185 Preparation of l-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)ethan-l-ol (1-13): coupling component for Examples 16 to 17 5-Bromo-2-(trifluoromethyl)isonicotinaldehyde (333 mg, 1.311 mmol) was dissolved in THF (6555 μΐ) in a 40 mL vial, and the solution was degassed with nitrogen and cooled to −78 °C. Methylmagnesium bromide (3M in Et2O) (524 μΐ, 1.573 mmol) was added, and the resulting mixture was slowly warmed to room temperature for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and stirred for 1 h. The organic layer was separated, and the aqueous was extracted with 50 ml of EtOAc, and the combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain l-(5-bromo-2 (trifluoromethyl)pyridin-4-yl)ethanol which was used for the preparation of Examples 16 to 17 without further purification. MS (ESI) [M+H]+: m / z 270 / 272. The racemic mixture from the Suzuki coupling reaction was separated by SFC using a 21 x 250 mm Lux-2 column and 20% MeOH / 0.25% DMEA as the modifier at a flow rate of 70 ml / min . The peak that eluted first was collected and concentrated to obtain Compound 16. The peak that eluted second was collected and concentrated to obtain Compound 17. Preparation of 2-(5-bromo-2-(difluoromethoxy)pyridin-4-yl)propan-2-ol (1-14): coupling component for Example 18 Stage 1: Methyl 5-bromo-2-(difluoromethoxy)isonicotinate Methyl 5-bromo-2-hydroxyisonicotinate (1.13 g, 4.87 mmol) was charged with sodium chlorodifluoroacetate (0.891 g, 5.84 mmol) and ACN (30 ml), and the mixture was heated to reflux for the duration. evening. An additional portion of sodium chlorodifluoroacetate (0.891 g, 5.84 mmol) was added, and the reaction was heated to reflux overnight. The reaction was quenched with saturated ammonium chloride, extracted 2x 69 IF-2018-68202357-APN-ANP#INPI Page 69 of 185 with 50 ml of EtOAc, and the combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on 0-10% EtjO / hexanes silica gel to obtain methyl 5-bromo-2-(difluoromethoxy)isonicotinate as a solid. MS (ESI) [M+H]+: m / z 282 / 284. Step 2: 2-(5-bromo-2-(difluoromethoxy)pyridin-4-yl)propan-2-ol (1-14) It was prepared in a similar manner as illustrated above for Example 16. MS (ESI) [M+H]+: m / z 282 / 284. Preparation of 2-(5-bromo-2-(difluoromethoxy)pyridin-4-yl)propan-2-ol (1-15): coupling component for Example 32 f3c 5=n oh Br (1-15) This was prepared from methyl 3-bromo-6-(trifluoromethyl) nicotinate in a similar manner as illustrated above for Example 16. MS (ESI) [M+H]+: m / z 284 / 286. Preparation of (5-bromo-2-(difluoromethoxy)pyridin-4-yl)methanol (1-16): coupling component for Example 13 Br / =K0Hr° F (1-16) 1-16 was prepared from methyl 5-bromo-2-(trifluoromethyl)isonicotinate and DIBAL-H in a similar manner to the preparation of Compound 1-11. MS (ESI) [M+H]+: m / z 254 / 256. The synthesis of (3-bromo-6-cyclopropylpyridin-2-yl)methanol (1-17) is described in the following scheme: IF-2018-68202357-APN-ANP#INPI Page 70 of 185 ci either 1-17 Stage 1: Synthesis of 5-bromo-2-cyclopropylpyridine A solution of Mg (200 g, 8.33 mol, 10.00 eq.) in tetrahydrofuran (1500 ml) was charged to a 4-neck 5 1 round-bottom flask purged and maintained in an inert nitrogen atmosphere. (1 g) and bromocyclopropane (400 g, 3.33 mol, 4.00 eq.). The reaction mixture was stirred for 3 h at 65 °C and then added to a solution of ZnC12 (560 g, 4.12 mol, 5.00 equiv) in tetrahydrofuran (2000 mL) at 10 °C. The resulting solution was stirred for 2 h at room temperature and then Pd(dppf)C12 (20 g), 2,5-dibromopyridine (200 g, 843.88 mmol, 1.00 equiv.) were added. The reaction mixture was stirred for overnight at room temperature and inactivated by adding 500 ml of water. The resulting mixture was concentrated in vacuo and then extracted with 3x5 1 ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column with EtOAc / petroleum ether (1 / 2) to obtain 5-bromo-2-cyclopropylpyridine as a solid. Stage 2: Synthesis of 5-bromo-2-cyclopropylpyridine 1-oxide A solution of 5-bromo-2-cyclopropylpyridine (184 g, 924.62 mmol, 1.00 equiv) in dichloromethane (1500 ml) was charged to a 3 1 4-neck round bottom flask. 3-Chlorobenzoperoxoic acid (209 g, 1.22 mol, 1.00 equiv) was added to the solution in portions at 0 °C in 5 min. The resulting solution was stirred overnight at room temperature. The pH of the solution was adjusted with sodium hydroxide (20%). The resulting solution was extracted with 4x400 ml of ethyl acetate, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column with ethyl acetate to obtain 5-bromo-2-cyclopropylpyridine 1-oxide as a solid. IF-2018-68202357-APN-ANP#INPI Page 71 of 185 Stage 3: Synthesis of 3-bromo-6-cyclopropylpicolmonitrile A solution of 5-bromo-2-cyclopropylpyridine 1-oxide (100 g, 467.29 mmol, 1.00 equiv.) in ACN (1200 mL), TMSCN was charged to a 3 1 4-neck round bottom flask. (190 g, 1.92 mol, 4.00 equiv.) and TEA (192 ml, 3.00 equiv.) The resulting solution was stirred at reflux overnight, and then diluted with water and extracted with 4 x 500 ml of ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column with ethyl acetate / petroleum ether (1 / 50) to obtain 3bromo-6-cyclopropylpicolinonitrile as a solid. Stage 4: Synthesis of 3-bromo-6-cyclopropylpicolinic acid To a 3 1 4-neck round bottom flask was charged 3-bromo-6cyclopropylpicolinonitrile (74 g, 331.84 mmol, 1.00 equiv) and sodium hydroxide (20%, 1500 ml). The resulting solution was stirred at reflux overnight, cooled to room temperature and then extracted with 3 x 200 ml of ether. The pH of the combined aqueous layer was adjusted to 4 with hydrogen chloride (3N), and the resulting solution was extracted with 4x300 ml of ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column with ethyl acetate / petroleum ether (1 / 5) to obtain 3-bromo-6cyclopropylpicolinic acid as a solid. Step 5: Synthesis of (3-bromo-6-cyclopropylpyridin-2-yl)methanol (1-17) A solution of 3-bromo-6-cyclopropylpicolinic acid (80 g, 330.58 mmol, 1.00 equiv) in tetrahydrofuran (20 ml) was charged to a 3 1 4-neck round bottom flask. Triethylamine (72 ml, 1.50 equiv) was added to the reaction dropwise with stirring at -5-0 °C in 5 min and then ethyl carbonchloridate (41 g, 379.63 mmol, 1.30 equiv) was added. .) dropwise with stirring at -20 °C. The resulting solution was stirred for 60 min at −20 °C. The solid was filtered, and a solution of NaBH4 (28 g, 2.00 equiv.) in water (84 g) was added to the filtrate dropwise with stirring at -10 °C. The resulting solution was stirred for an additional 20 min at −10 °C. The reaction was then quenched by the addition of NH4CI (saturated). The resulting solution was extracted with 3x1000 ml of ethyl acetate, and the combined organic phase was dried over anhydrous sodium sulfate and dried. IF-2018-68202357-APN-ANP#INPI Page 72 of 185 concentrated in vacuo. The residue was purified by a silica gel column with petroleum ether / ethyl acetate (50 / 1). This resulted in Compound 1-17 as a solid. MS (ESI) [M+H]+: m / z 229. 1H NMR (300 MHz, DMSO-d6) δ 7.85 (1H, d, J = 8.1 Hz), 7.16 (1H, t), 4.98 (1H, t, J = 5.7 Hz), 4.52 (2H, d, J = 5.7 Hz). This material was used for the preparation of Example 26. Ex. No. Structure Chemical name Mass [M+H]+ 8 F W ¿O 3-(4-(6-(difluoromethoxy)-2,4dimethylpyridin-3-yl)phenyl)-A-(4fluorophenyl)oxetan-3carboxamide 443 9 w3 L II y— NH 3 -(4-(6-(difluoromethoxy)-4methylpyridin-3-yl)phenyl)- / V-(4fluorophenyl)oxetan-3carboxamide 429 10 F T ?H VILO i π y-NH / V-(4-fluorophenyl)-3-(4-(4(hydroxymethyl)-6(trifluoromethyl)pyridin-3yl)phenyl)oxetan-3-carboxamide 447 11 i «=% / z 1Λο o y-V —o N- (4-fluorophenyl)-3-[4-[4(hydroxymethyl)-6-methoxy-pyridin1 -io-3-yl]phenyl]oxetan-3carboxamide 431 [M+Na]+ 12 O-1 lAo O yV sYjP y} or lí? N-(4-fluorophenyl)-3-(4-(4-(2hydroxypropan-2-yl)-6(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide 475 13 F^F ΠΗ F 1 Un / vV 0 i fl y-NH 3-[4-[6-(difluoromethoxy)-4(hydroxymethyl)-3-pyridyl]phenyl]-N(4-fluorophenyl)oxetane-3carboxamide 445 IF-2018-68202357-APN-ANP#INPI Page 73 of 185 14 HO F —N J I fl n-nh N-(4-fluorophenyl)-3-[4-[3(hydroxymethyl)-1 -methyl-pyrazol-4yl]phenyl]oxetan-3-carboxamide 382 15 -n oAj C ) cCx χ O N-(4-fluorophenyl)-3 - [4- [3-(2hydroxyethyl)-5-(trifluoromethyl)-2pyridyl] phenyl] oxetan-3 carboxamide 461 16 F Ax, v τ'ΐύΝ UN I | l J HO^ Ό (Isomer 1 of SFC (R or S)-N-(4fluorophenyl)-3-(4-(4-( 1 hydroxyethyl)-6(trifluoromethyl)pyridin-3yl)phenyl)oxetan-3- carboxamide 461 17 Τχ a i / X)° or zXv / U--X O A i U- L (Isomer 2 of SFC) (S or R) N(4-fluorophenyl)-3-(4-(4-( 1 hydroxyethyl) -6(trifluoromethyl)pyridin-3yl)phenyl)oxetan-3-carboxamide 461 18 FyF / °v% y) Αχ HN --N XaA° HO ^ / X Ό 3-[4-[6-(difluoromethoxy)-4 -(lhydroxy-1 -methyl-ethyl)pyridin-1 -io3-yl]phenyl]-N-(4fluorophenyl)oxetan-3carboxamide;2,2,2trifluoroacetate 473 19 F :in 0 I T i / =° OH^y / ri 3-[4-[6-(difluoromethoxy)-4-(1-hydroxy-1-methyl-ethyl)pyridin-l-io3-yl]phenyl]-N-(4fluorophenyl)oxetan-3carboxamide;2,2,2trifluoroacetate 446 IF-2018-68202357-APN-ANP#INPI Page 74 of 185 20 F Cl HN Λ Ο HO Ό N-(4-chlorophenyl)-3-(4-(4-(2hydroxypropan-2-yl)-6(trifluoromethyl)pyridin-3yl)phenyl)oxetan-3-carboxamide 491 21 Yu o O—< / 1 y=\ P o \ N-(4-chlorophenyl)-3-[4-[4(hydroxymethyl)-6-methoxy-pyridin1 -io-3-yl]phenyl]oxetan-3carboxamide;2 ,2,2trifluoroacetate 425 22 ϋ / κ U-Z'z o O~~\ [ *P o <0 u. N-(4-chlorophenyl)-3-[4-[4(hydroxymethyl)-6-(trifluoromethyl)3 -pin di 1 ] phenyl] oxetan-3 carboxamide 463 23 A o z—< / / z \ 1 J X-O o od / x ___ 1 VAq N-(4-chlorophenyl)-3-[4-[6(difluoromethoxy)-4(hydroxymethyl)-3pyridyl]phenyl]oxetan-3carboxamide 461 24 OH F oj 0 L JI ^-NH OZ N -(4-fluorophenyl)-3-(4-(2(hydroxymethyl)phenyl] phenyl] oxetan3-carboxamide 378 25 deft- N-(4-fluorophenyl)-3-[4-(2(hydroxymethyl)pyridin-1 - io-3yl]phenyl]oxetan-3carboxamide;2,2,2trifluoroacetate 379 26 .. b 'X \= / \= / Lo 3-[4-(6-cyclopropyl-2(hydroxmethyl)pyridin-1 -io-3yl ] phenyl] -N-(4-fluorophenyl)oxetan3-carboxamide;2,2,2trifluoroacetate 419 IF-2018-68202357-APN-ANP#INPI Page 75 of 185 27 .. b ) O^NH \= / L¿ 3 - [4-[2-cyclopropyl-4(hydroxymethyl)thiazol-3-io-5yl] phenyl] -N-(4-fluorophenyl)oxetan3-carboxamide;2 ,2,2trifluoroacetate 425 28 _ δ ) ovnh x= / l—o N-(4-fluorophenyl)-3 -[4- [4(hydroxymethyl)pyridin-1 -io-3yl]phenyl]oxetan-3carboxamide;2, 2,2trifluoroacetate 379 29 6 O^NH Ρ3Ο- / ~Α-Α”Λ-4-η N= / ^=7 Lo N-(4-fluorophenyl)-3 -[4- [6(trifluoromethyl)pyridin- 1 -io-3yl]phenyl]oxetan-3carboxamide;2,2,2trifluoroacetate 417 30 _ b χ-^γΝΗ N=7 \= / L-o N-(4-fluorophenyl)-3 -[4- [4(hydroxymethyl) -6-methyl-pyridin-1 io-3-yl]phenyl]oxetan-3carboxamide;2,2,2trifluoroacetate 393 31 .. b ) O^zNHF c_r mXL γ3^> — / \ / 1 1 \= / \= 7 L-o N-(4-fluorophenyl)-3-[4-[2(hydroxymethyl)-6-(trifluoromethyl)3 -pyridyl] phenyl]oxetan-3 carboxamide 447 32 b At>+ \=Z \= / Lo N -(4-fluorophenyl)-3-(4-(2-(2hydroxypropan-2-yl)-6(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide 475 33 Cl .. ü > °^NHF3CX / —X / X N^7 464 IF-2018-68202357-APN-ANP#INPI Page 76 of 185 Example 10 can also be prepared according to the following procedure: Step k Synthesis of 5-bromo-4-(((tert-butyldjmethylsilyl)oxy)methyl)-2(trifluoromethyl)pyridine (1-44) (5-bromo-2-(trifluoromethyl)pyridin-4-yl)methanol (600.0 mg, 2.344 mmol) was dissolved in a mixture of DCM / DMF (v / v 4:1, 12 ml) with stirring, and The solution thus obtained was cooled to 0 °C. DIEA (0.573 ml, 3.28 mmol) and tert-butyldimethylsilyl chloride (495 mg, 3.28 mmol) were added, and the mixture was stirred at room temperature for 20 h. The reaction mixture was then concentrated in vacuo and partitioned into EtOAc (30 mL) and water (30 mL). The organic layer was washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (Isco CombiFlash system, using a Gold silica gel column of 40 g RediSep, 2-20% MeOH / DCM as eluent) to obtain Compound 1-44. MS (ESI) [M+H]+: m / z 370. Step 2: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-L3,2dioxaborolan-2-ylj-2-(trifluoromethyl)oiridine (1-45 ) A mixture of Compound 1-44 (720.0 mg, 1.944 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3, 2-dioxaborolane) (593 mg, 2.333 mmol), l,r-bis(di-tert-butylphosphine)ferrocene-palladium dichloride (127 mg, 0.194 mmol) and potassium acetate (573 mg, 5.83 mmol) in 1,4-Dioxane (5.0 ml) was evacuated and refilled with nitrogen (3 times). The mixture was heated to 80 °C in a sealed tube for 2 h. After cooling to room temperature, the reaction mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to IF-2018-68202357-APN-ANP#INPI Page 77 of 185 obtain a residue that was dissolved in dichloromethane. After washing with water (3x) and brine, the dichloromethane layer was dried over anhydrous Na2SO4 and concentrated in vacuo to obtain the crude product, which was used directly in the next step without purification. MS (ESI) [M+H]+: m / z 418. Step 3: Synthesis of 3-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-3yl')phenyl)-jV-(4-fluorophenylIoxetan-3-carboxamide (1 -46) A solution of (4-(((tert-butyldimethylsilyl)oxy)methyl)-6(trifluoromethyl)pyridin-3-yl)boronic acid, (96 mg, 0.286 mmol), 3-(4-bromofeni 1)-^- (4fluorophenyl)oxetan-3-carboxamide (1-2), (100 mg, 0.286 mmol), l,l'-bis(diter-butylphosphino)ferrocene-palladium dichloride (18.61 mg, 0.029 mmol) and carbonate Sodium (0.286 ml, 0.571 mmol) in 1,4-dioxane (2.0 ml) was subjected to standard Suzuki cross-coupling conditions, and the crude product was purified by silica gel column chromatography (ethyl acetate / DCM, 10-70%) to obtain Compound 1-46. MS (ESI) [M+H]+: m / z 561. Step 4:7V-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3yl)phenyl)oxetan-3-carboxamide To a solution of Compound 1-46, (143.0 mg, 0.255 mmol) in THF (5.0 ml) was added tetra-N-butylammonium chloride in 1 M THF (0.255 ml, 0.255 mmol) at 0°C , and the reaction mixture was stirred for 2 h at room temperature. The solvent was evaporated in vacuo, and the residue was redissolved in dichloromethane. After washing successively with water, saturated aqueous sodium bicarbonate and brine, the organic phase was dried over sodium sulfate, filtered, and the filtrate was evaporated in vacuo. The crude material was purified by mass-directed reversed-phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. Example 12: N-4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin3-yl)phenyl)oxetan-3-carboxamide A 3-neck round bottom flask under nitrogen was charged with N-(4fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)oxetan. -3-carboxamide (1-9) (5 g, 12.5 mmol), 2-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)propan-2-ol (1-12) (4 g , IF-2018-68202357-APN-ANP#INPI Page 78 of 185 mmol), and PdCl2(dtbpf) (0.53 g, 8.15 mmol) and the flask was subjected to a vacuum / nitrogen cycle three times. Ethanol (100 ml) was then added, followed by aqueous potassium phosphate (40 ml, 1 M). The mixture was again subjected to a vacuum / nitrogen cycle three times and then heated to 60 °C in nitrogen for 4 h. The mixture was then allowed to cool to room temperature, transferred to a separatory funnel, and diluted with water (50 ml) and dichloromethane (100 ml). The organic phase was collected and the aqueous phase was extracted once more with dichloromethane (100 ml). The combined organic extracts were washed with brine and shaken with SiliaMetS Thiol (6.5 g). The resulting suspension was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting crude oil was purified by silica gel chromatography using a gradient of ethyl acetate in hexane to obtain a crude material. This crude material was resuspended in diethyl ether (25 ml) and stirred for 15 min. The solids were filtered and washed with diethyl ether to obtain the title compound. MS (ESI+) m / z [M+H]+: 475. 1H NMR (600 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.35 (s, 1H), 8.22 (s, 1H), 7.67 - 7.62 (m, 2H), 7.58 (d, 2H), 7.41 (d, 2H), 7.20 - 7.14 (m, 2H), 5.49 (s, 1H), 5.24 (d, 2H), 4.91 (d, 2H) , 1.25 (s,6H). Example 34: 3-(4-(4-(fluoromethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-7V-(4fluorophenyl)oxetan-3-carboxamide To a solution of A-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide (1-20) (70.0 mg, 0.157 mmol) in DCM (3 ml) at 0 °C, l,l,l-trifluoro-A,7V-bis(2-methoxyethyl)-l,4-sulfanamine was added. After stirring at 0 °C for 1 h, the reaction was carefully quenched with aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was concentrated, and the crude material was purified by mass-directed reverse phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 449. 1H NMR (499 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.76 (s, 1H), 8.03 (s, 1H), 7.65 ( t, J = 6.9 Hz, 4H), 7.57 (d, J = 8.1 Hz, 2H), 7.17 (t, J = IF-2018-68202357-APN-ANP#INPI Page 79 of 185 8.8 Hz, 2H), 5.60 (d, J = 46.4 Hz, 2H), 5.25 (d, J = 6.5 Hz, 2H), 4.93 (d, J = 6.5 Hz, 2H). Example 35: 3-(4-(4-(Hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4itrifluoromethoxy)phenyl)oxetane-3-carboxamide OH Step 1: methyl 3-(4-(4,4,5.5-tetramethyl-L3,2-dioxaborolan-2-yl)phenyl)oxetan-3carboxylate (1-48) To a solution of methyl 3-(4-bromophenyl)oxetane-3-carboxylate (2.1 g, 7.75 mmol) and 4,4,4',4',5,5,5',5'-octamethyl -2,2'-bi(l,3,2-dioxaborolane) (2.065 g, 8.13 mmol) in dioxane (30 ml) were added AcOK (2.281 g, 23.24 mmol) and Pd(dppf)Cl2( 0.567 g, 0.775 mmol) with stirring at room temperature in a nitrogen atmosphere. Once the addition was complete, the reaction mixture was stirred at 80 °C for 14 h, cooled to room temperature, and diluted with EtOAc (30 mL). The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (ISCO®; Agela® CS Silica Flash Column (12 g), gradient eluent of 0-7% ethyl acetate / petroleum ether at 30 ml / min) to obtain Compound I48 as a solid. MS (ESI) m / z: 360 [M+ACN+H+], Step 2: Preparation of 3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3yl)phenyl)oxetan-3-carboxylic acid (1-49) To a solution of Compound 1-48 (500 mg, 1.571 mmol) and (5-bromo-2(trifluoromethyl)pyridin-4-yl)methanol (402 mg, 1.571 mmol) in THF (6 ml) and water (1 ml ), K3PO4 (1.001 g, 4.71 mmol) and Pd(dtbpf)Cl2 (102 mg, 0.157 mmol) were added. The reaction mixture was sealed and stirred at 100 °C in nitrogen, promoted in microwave. After stirring at 100 °C for 0.5 h, the reaction was cooled to temperature 80 IF-2018-68202357-APN-ANP#INPI Page 80 of 185 room and diluted with water (10 ml). The mixture was extracted with EtOAc (30 ml x3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (ISCO®; Agela® Flash Column Silica-CS (12 g), gradient eluent of 0~27% ethyl acetate / petroleum ether at 30 ml / min) to obtain methyl 3-(4-(4(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxylate as a solid. MS (ESI) m / z: 368.0 [M+H+]. To a solution of methyl 3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin3-yl)phenyl)oxetan-3-carboxylate above (520 mg, 1.416 mmol) in THF (4 ml), MeOH ( 4 ml) and water (2 ml), LiOH (102 mg, 4.25 mmol) was added at room temperature with stirring, and the reaction mixture was stirred at room temperature for 14 h. 3 N HC1 was added to the mixture with stirring until pH~4. The reaction was then diluted with water (5 ml) and extracted with EtOAc (10 ml x5). The combined organic phase was washed with brine (10 ml) and dried over Na2SO4, filtered and concentrated in vacuo to obtain Compound 1-49 as a solid, which was used in the next step without further MS (ESI) purification. m / z: 354 [M+H+], Step 3j 3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4(trifluoromethoxy)phenyl)oxetan-3-carboxamide To a solution of Compound 1-49 (30 mg, 0.085 mmol) and 4(trifluoromethoxy)aniline (30 mg, 0.169 mmol) in pyridine (1.0 ml), EDCI (50 mg, 0.261 mmol) was added with stirring at room temperature. Once the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, and the residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with a YMC-Actus Pro C18 150*30 5u column using water (0.1% TFA) and ACN as eluents. The desired fractions were concentrated and then lyophilized to obtain the title compound as a solid. MS (ESI) m / z: 513.2 [M+H+], 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1 H), 8.07 (s, 1 H), 7.61 - 7.74 (m, 4 H), 7.50 (d, J = 8.3 Hz, 2 H), 7.24 (d, J = 8.3 Hz, 2 H), 5.37 (d, J= 6.6 Hz, 2 H), 5.04 (d, J= 6.6 Hz, 2 H ), 4.65 (s, 2 H). Examples 36 to 42 in the following table were prepared in a similar manner to Example 35. IF-2018-68202357-APN-ANPAINPI Page 81 of 185 Ex.No. Structure Chemical name Mass [M+H]+ 36 Br HO / A V-yA (A l| y-nH N-(4-bromophenyl)-3-(4-(4(hydroxymethyl)-6 (trifluoromethyl)pyridin-3yl)phenyl)oxetan-3-carboxamide 507 37 <0 k Λ° <AA^ O O~X / 1 >=( yj o u? 3-(4-(4-(hydroxymethyl)-6( trifluoromethyl)pyridin-3-yl)phenyl)N-(4(trifluoromethyl)phenyl)oxetan-3carboxamide 497 38 “γΛχ 1—£Q O / '1 o o—< / 1 z=\ V % LL N-(3,4 -diphiorophenyl)-3 -(4-(4(hydroxymethyl)-6(trifluoromethyl)pyridin-3yl)phenyl)oxetan-3-carboxamide 465 39 CN H? Ak f'cW p % N-(4-cyanophenyl)- 3-(4-(4(hydroxymethyl)-6(trifluoromethyl)pyridin-3 yl)phenyl)oxetan-3 -carboxamide 454 40 OH F FaC^^ 1 J j· C· k JI J—NH ό N-(6 -fluoropyridin-3-yl)-3-(4-(4(hydroxymethyl)-6(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide 448 41 OH OCF,H A-n-f L JI V-NH Ό N- (4-(difluoromethoxy)phenyl)-3 (4-(4-(hydroxymethyl)-6(trifluoromethyl)pyridin-3yl)phenyl)oxetan-3-carboxamide 495 42 °H CF3F3C\^ J r-1 L J J| -NH Ό 3-(4-(4-(hydroxymethyl)-6(trifluoromethyl)pyridin-3-yl)phenyl)N-(6-(trifluoromethyl)pyridin-3-yl)oxetan-3-carboxamide 498 IF-2018-68202357-APN-ANP#INPI Page 82 of 185 Example 43: 3-(4-(77f-tetrazol-5-yl)phenyl)- / V-(4-fluorophenyl)oxetan-3-carboxamide 1-2 Stage 1: Synthesis of 7V-(4-fluorophenyl)-3-(4-isocyanophenyl)oxetan-3-carboxamide A dried flask was charged with 3-(4-bromophenyl)-N-(4fluorophenyl)oxetan-3-carboxamide (1-2) (1000.0 mg, 2.86 mmol) in anhydrous DMF (10.0 ml). To this were added zinc cyanide (671 mg, 5.71 mmol), Pd2(dba)s (105 mg, 0.114 mmol) and dppf (79 mg, 0.143 mmol) followed by zinc powder (18.67 mg, 0.286 mmol). The reaction mixture was then purged with nitrogen for 5 min. The reaction mixture was heated to 120 °C for 4 h and cooled to room temperature, filtered through a Celite pad, which was further washed with DCM. The filtrate was concentrated in vacuo, and the crude oil was purified by my Biotage silica column (EtOAc / Hex 5 to 40) to obtain 7V-(4-fluorophenyl)-3-(4-isocyanophenyl)oxetan-3carboxamide. MS (ESI) [M+H]+: m / z 297. Step______21______3-(4-(777-tetrazol-5-yl)phenyl)-7V-(4-fluorophenyl)oxetan-3-carboxamide (Compound 43) N-(4-fluorophenyl)-3-(4-isocyanophenyl)oxetan-3-carboxamide, (41.0 mg, 0.138 mmol), sodium azide (17.99 mg, 0.277 mmol) and zinc bromide ( 31.2 mg, 0.138 mmol) to a mixture of water (923 μΐ) and 2-propanol (461 μΐ). The resulting suspension was then heated to reflux and stirred overnight. The mixture was cooled to room temperature, filtered through a pad of Celite and concentrated. The crude material was purified by mass-directed reversed-phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 340. 1H NMR (600 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.09 (d, J = 8.1 Hz, 2H), 7.71 (d, J - 8.1 Hz, 2H), 7.61 (dd, J = 8.6, 5.0 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H), 5.23 (d, J = 6.5 Hz, 2H), 4.92 (d, J = 6.5 Hz, 2H). IF-2018-68202357-APN-ANP#INPI Page 83 of 185 Example 44: A-(4-fluorophenyl)-3-(4-(5-(trifluoromethyl)-L2.4-oxadiazol-3iDphenyl)oxetan-3-carboxamide 1-59 Step 1: Synthesis of (Z)-V-(4-fluorophenyl)-3-(4-(N'-hydroxycarbamimidoyl)phenyl)oxetan3-carboxamide (1-59) The nitrile 7V-(4-fluorophenyl)-3-(4-isocyanophenyl)oxetan-3-carboxamide (60.0 mg, 0.203 mmol) was dissolved in MeOH (1.0 ml), and then hydroxylamine (50%) was added. by weight in water) (0.137 mi, 2.228 mmol). The reaction was heated at 60 °C for 2 h. The reaction mixture was diluted with brine and extracted with EtOAc (3x). The combined organic phases were dried over MgSCL, filtered, and the filtrate was concentrated under reduced pressure to obtain Compound 1-59. MS (ESI) [M+H]+: m / z 330. The crude oil was used directly in the next step without purification. Step 2: A-(4-fluorophenyl)-3-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)oxetan-3carboxamide TFAA (0.064 ml, 0.455 mmol) was added to a mixture of Compound I59 (50.0 mg, 0.152 mmol) and pyridine (0.037 ml, 0.455 mmol) in toluene (2.0 ml) at 10 °C. Once the addition was complete, the mixture was stirred at 110 °C for 3 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was partitioned into EtOAc and water. The aqueous layer was extracted with EtOAc (2x), and the collected organic layers were washed with brine and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by mass-directed reversed-phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 408. 1H NMR (600 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.13 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.61 (dd, J = 8.5, 5.0 Hz, 2H), 7.16 (t, J = 8.7 Hz, 2H), 5.24 (d, J = 6.6 Hz, 2H), 4.91 (d, J = 6.6 Hz, 2H). IF-2018-68202357-APN-ANP#INPI Page 84 of 185 3-(4-(lH-benzordlimidazole-2-yl)phenyl)-A-(4-fluorophenyl)oxetan-3Examples 45: carboxamide Step 1: Synthesis of ethyl 4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)benzoate (1-61) l,l'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride complex and dichloromethane (152 mg, 0.186 mmol) were added to a stirring solution containing Compound 1-2 (325.0 mg, 0.928 mmol), TEA (517 μΐ, 3.71 mmol) in EtOH (1084 μΐ, 18.56 mmol) and DMF (4640 μΐ). The mixture was stirred in carbon monoxide at 90 °C overnight. The reaction mixture was cooled to room temperature and then filtered through a Celite pad. The filtrate was concentrated, diluted with ethyl acetate, washed with water (2x) and brine. The organic layer was dried over Na2SÜ4, filtered and concentrated. The crude oil was purified by a Biotage (silica) column using EtOAc / Hex (5 to 40%) as eluents to obtain Compound 1-61. MS (ESI) [M+H]+: m / z 344. Step 2: Synthesis of 4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)benzoic acid (1-62) 1 M LiOH (3.0 ml, 3.00 mmol) was added to a solution of Compound 1-61 (300.0 mg, 0.874 mmol) in MeOH (5.0 ml). This mixture was stirred at room temperature for 4 h and evaporated under reduced pressure. The residue was diluted with water and acidified with an aqueous solution of hydrochloric acid (2N). This aqueous mixture was extracted with ethyl acetate (2 x 50 ml), and the combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure to obtain Compound 1-62. MS (ESI) [M+H]+: m / z 316. IF-2018-68202357-APN-ANP#INPI Page 85 of 185 Step 3: 3-(4-(lH-benzord1imidazol-2-yl)phenyl)-7V-(4-fluorophenyl)oxetan-3-carboxamide A 20 ml vial was charged with a magnetic stir bar, Compound 1-62 (50.0 mg, 0.159 mmol) and DMF (1.91 ml). HATU (60.3 mg, 0.159 mmol) was added with stirring, and the mixture was stirred for a few minutes. Then, benzene-l,2-diamine (17.15 mg, 0.159 nmiol) and DIEA (83 μΐ, 0.476 mmol) were added to the mixture, and the reaction was stirred for 4 h at room temperature. The reaction was diluted with 50 ml of ethyl acetate which was washed with 1 N aqueous HC1, water, brine and saturated aqueous NaHCCU. The organic layer was dried over NajSCL, filtered, and the filtrate was concentrated. The residue was dissolved in DCM and purified by silica gel chromatography (12 g 10 flash column, 0-50% EtOAc in hexane, 15 CV) to obtain Compound 1-63. MS (ESI) [M+H]+: m / z 406. Compound 1-63 was dissolved in MeOH (1910 μΐ) and acetic acid (200.0 μΐ, 3.49 mmol), and then heated at 100 °C for 1 h. The mixture was diluted with MeOH, filtered and purified by directed reverse phase HPLC to mass 15 (ACN / water, TFA) to obtain the title compound. MS (ESI) [M+H]+: m / z 388. 1H NMR (600 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.25 (s, 1H), 8.23 ​​(s, 1H), 7.79 ( s, 1H), 7.76 (dd, J = 7.4, 4.6 Hz, 3H), 7.62 (dd, J = 8.6, 5.0 Hz, 2H), 7.51 - 7.38 (m, 2H), 7.16 (t, J = 8.8 Hz , 2H), 5.25 (d, J = 6.6 Hz, 2H), 4.96 (d, J = 6.6 Hz, 2H). Examples 46 to 50 were prepared similarly to Example 45 using acid 1-62 and 4-chlorophenylenediamine, pyridin-3,4-diamine, 4-fluorobenzene-l,2-diamine, 4,5-difluorobenzene-l,2-diamine , pyridm-2,3-diamine and 5-bromopyridine-2,3diamine, respectively. Ex. No. Structure Chemical name Mass [M+H]+ 46 O zCr zz^j^ \=z / A z_ / ^ XX 3-(4-(5-chloro-lHbenzo[d]imidazol-2-yl )phenyl)-N(4-fluorophenyl)oxetan-3carboxamide 422 47 3-carboxamide 389 IF-2018-68202357-APN-ANP#INPI Page 86 of 185 48 F O H L, 1 / N or 3-(4-(6-fluoro-lHbenzo[d]imidazol-2-yl)phenyl)-7V(4-fluorophenyl)oxetan-3 carboxamide 389 49 F\ FF O H L JL / N 3 -(4-(5,6-difluoro-1Hbenzo[d]imidazol-2-yl)phenyl)-7V(4-fluorophenyl)oxetan-3 carboxamide 424 50 F N-4 if H L JL / N ^0 3-( 4-(3H-imidazo[4,5-b]pyridin2-yl)phenyl)-N-(4fluorophenyl)oxetane-3carboxamide 389 Example 51: 3-(4-(6-cyano-3H-imidazor4,5-b]pyridin-2-yl)phenyl)-7V-(4fluorophenyl)oxetan-3-carboxamide 3-(4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)-N-(4fluorophenyl)oxetan-3-carboxamide (prepared according to the procedures described for Example 45) (70.0 mg, 0.150 mmol), zinc cyanide (42.2 mg, 0.360 mmol), zinc powder (7.05 mg, 0.108 mmol), Pd2(dba)3 (21.95 mg , 0.024 mmol) and DPPF (26.6 mg, 0.048 mmol) in ΛζΑ-dimethylacetamide (2.0 ml) to a microwave reaction vessel. Then, the mixture was irradiated at 130 °C for 60 min. The reaction mixture was cooled, then filtered through a pad of Celite and concentrated. The crude material was purified by mass-directed reversed-phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 414. 1H NMR (499 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.77 (s, 1H), 8.61 (s, 1H), 8.32 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.63 (dd, J = 8.7, 5.0 Hz, 2H), 7.16 (t, J = 8.8 Hz, 2H), 5.24 (d, J = 6.5 Hz, 2H), 4.94 (d, J = 6.5 Hz, 2H). IF-2018-68202357-APN-ANP#INPI Page 87 of 185 Example 52: 3-(4-(6-cyclopropylpyridin-3-yl)phenyl)-JV-(5-fluoropyridin-2-yl)oxetan-3carboxamide 1-72 Step 1:3-(4-bromophenyl)-N-(5-fluoropyridin-2-yl)oxetan-3-carboxamide A magnetic stir bar, 3-(4bromophenyl)oxetan-3-carboxylic acid (1000.0 mg, 3.89 mmol) and DMF (10.0 ml) were charged to a 100 ml vial. HATU (1775 mg, 4.67 mmol) was added at room temperature with stirring, and the reaction mixture was stirred for a few minutes. 5-fluoropyridin-2-amine (436 mg, 3.89 mmol) and DIEA (2.038 ml, 11.67 mmol) were added, and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1N aqueous HC1 (3x), water, brine and saturated aqueous NaHCCl. The organic solution was then dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was purified by a Biotage DCM / EtOAc column (10 to 100%) to obtain Compound 1-72. MS (ESI) [M+H]+: m / z 351. Step 2: 3-(4-(6-cyclopronylniridin-3-yl)phenyl)-7V-(5-fluoropyridin-2-yl)oxetan-3carboxamide To a stirred suspension of Compound 1-72, (50.0 mg, 0.142 mmol) and l,l'-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (11.68 mg, 0.013 mmol) in 1, 4-dioxane (1.5 ml) sodium carbonate (0.142 ml, 0.285 mmol) was added. The reaction mixture was evacuated and refilled with nitrogen three times and then heated to 80 °C for 4 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite and concentrated. The product was purified by mass-directed reverse phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 390. 1H NMR (499 MHz, DMSO-d6) δ 12.86 (s, 1H), 9.25 (s, 1H), 8.74 (s, 1H), 8.45 ( t, J = 7.3 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.42 (dd, J = 15.3, 6.3 Hz, 2H), 5.57 (d, J = 15.0 Hz, 2H), 5.22 (d, J = 15.0 Hz, 2H), 2.24 - 2.11 (m, 1H), 1.10 - 1.02 (m, 2H ), 0.99 (s, 2H). IF-2018-68202357-APN-ANP#INPI Page 88 of 185 Example 53: 3-(4-í3-cyclopropyl-L2.4-oxadiazol-5-iDphenyl)-Ar-(4-fluorophenyl)oxetan-3carboxamide F N, N -carbonyldiimidazole (94 mg, 0.579 mmol)) was added to a stirred mixture of 4-(3-(4-fluorophenyl)carbamoyl)oxetan-3-yl)benzoic acid (1-62) (112.0 mg , 0.355 mmol) in DCM (2.0 ml), and the mixture was stirred at room temperature for 2 h. Then, N'-hydroxycyclopropanecarboximidamide (89 mg, 0.888 mmol) was added, and the mixture was stirred at room temperature for an additional 2 h, concentrated, coevaporated with toluene, redissolved in toluene (2 mL), and heated. at 110 °C for 2 h. The mixture was cooled and quenched with water, and extracted with ethyl acetate (3x). The combined organic fractions were washed with brine, dried over Na2SO4, filtered, and the solvents were evaporated under reduced pressure. The crude material was purified by mass-directed reversed-phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 380. 1H NMR (600 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.10 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.60 (dd, J = 8.6, 5.0 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 5.23 (d, J = 6.6 Hz, 2H), 4.90 (d, J = 6.6 Hz, 2H), 2.19 (tt, J = 8.4, 4.8 Hz, 1H), 1.20 - 1.06 (m, 2H), 1.06-0.91 (m,2H). Example 54: 3-(4-(4-cyclopropyl-6-oxopyrimidin-l(ó7 / )-yl)phenyl)-JV-(4fluorophenyl)oxetan-3-carboxamide To a reaction vessel was charged 6-cyclopropylpyrimidin-4(7 / 7)-one (43.0 mg, 0.316 mmol), copper iodide (6.01 mg, 0.032 mmol), 3-(4-bromophenyl)- N(4-fluorophenyl)oxetan-3-carboxamide (1-2) (111 mg, 0.316 mmol) and trans-ΛζΝdimethylcyclohexan-l,2-diamine (8.98 mg, 0.063 mmol). This mixture was then evacuated and IF-2018-68202357-APN-ANP#INPI Page 89 of 185 was refilled with nitrogen (3 times). Then, dry degassed 1,4-dioxane (1263 μΐ) was added and then the mixture was heated at 110 °C for 24 h. The crude material was purified by mass-directed reversed-phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 406. 1H NMR (499 MHz, DMSO-d6) d 10.05 (s, 1H), 8.33 (s, 1H), 7.63 (t, J = 8.4 Hz, 4H), 7.49 (d, J = 8.4 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 6.44 (s, 1H), 5.23 (d, J = 6.5 Hz, 2H), 4.91 (d, J = 6.6 Hz, 2H), 3.36 (s, 2H), 1.95 (p, J = 6.9 Hz, 1H), 1.05-0.71 (m, 2H). Example 55: 3-(4-(4-cycloDropyl-6-methyl-2-oxopyrimidin-l(2 / f)-yl)pheniI)-Ar-(4fluorophenyl)oxetan-3-carboxamide Example 55 was prepared analogously to Example 54. MS (ESI) [M+H]+: m / z 420. 1H NMR (499 MHz, DMSO-d6) d 9.96 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.60 (dd, J = 8.8, 5.0 Hz, 2H), 7.29 (d, J = 8.3 Hz, 3H), 7.15 (t, J - 8.8 Hz, 2H), 5.17 (d, J = 6.5 Hz, 2H), 4.82 (d, J = 6.5 Hz, 2H), 3.37 (s, 4H), 2.50 (s, 3H), 2.08 (s, 1H). Example 56: 7V-(4-fluorophenyl)-1 -(6-(2-phenyloxazol-4-yl)pyridin-3-yl)cyclobutan-1 carboxamide Step 1: Synthesis of l-(6-chloroniridin-3-yl)-A-(4-fluorophenyl)cyclobutan-l-carboxamide (Ε77). A magnetic stir bar was charged to a 100 ml vial, l-(6chloropyridin-3-yl)cyclobutanecarboxylic acid (715.0 mg, 3.38 mmol) in DCM (20.0 ml). HE IF-2018-68202357-APN-ANP#INPI Page 90 of 185 I added HATU (1541 mg, 4.05 mmol) with stirring, and the reaction mixture was stirred for a few minutes. 4-Fluoroaniline (375 mg, 3.38 mmol) and DIEA (1.770 ml, 10.13 mmol) were added, and the reaction mixture was stirred for 4 h at room temperature. The reaction was diluted with ethyl acetate and washed with 1N HC1 (2x), water, brine and saturated aqueous NaHCCl. The organic layer was then dried over Na.?SO4, filtered and concentrated. The crude product was purified by a Biotage silica column using DCM / EtOAc (10 to 100%) as eluents to obtain Compound 1-77. MS (ESI) [M+H]+: m / z 305. Step 2:jV-(4-fluorophenyl)-1 -(6-(2-phenyloxazol-4-yl)pyridin-3-yl)cyclobutan-1 10 carboxamide Compound 1-77 (50 mg, 0.164 mmol), a mixture of palladium(II) acetate / l,l'-bis(di-tert-butylphospho)ferrocene / potassium phosphate (13.46 mg, 0.015 mmol) was dissolved in 1,4-dioxane (1.5 ml) in a 20 ml round bottom flask. Sodium carbonate (0.164 ml, 0.328 mmol) was added, and the reaction mixture was evacuated and refilled with nitrogen 3 times and heated at 80 °C for 12 h. The reaction mixture was cooled and then filtered through a Celite pad. The crude material was purified by mass-directed reversed-phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 414. Examples 57 to 63 in the following table were prepared similarly to Example 56 using the respective boronates. Ex.No. Structure Chemical name Mass [M+H]+ 57 F 1 V-NH l-(6'-cyclopropyl-[2,3'bipyridin]-5-yl)-N-(4fluorophenyl)cyclobutan-1 carboxamide 388 58 Τΐχ ctaV 0 iQf 1 -(6-(5 -cyano-1 H-indol-2yl)pyridin-3-yl)-N-(4fluorophenyl)cyclobutan-1 carboxamide 411 59 <0 F A 0 «I give» 1 -(6-(3-cyclopropyl-1 H-pyrazol5-yl)pyridin-3-yl)-N-(4fluorophenyl)cyclobutan-1 - 377 IF-2018-68202357-APN-ANP#INPI Page 91 of 185 carboxamide 60 Ί.Ζ -n N-(4-fluorophenyl)-1-(6-(3(trifluoromethyl)-1 H-pyrazol-5yl)pyridin-3-yl)cyclobutan-1 carboxamide 405 61 h 0 ÍJQ-NH N-(4-fluorophenyl)-1 -(6-(3 methyl- lH-pyrazol-5-yl)pyridin3-yl)cyclobutan-1 -carboxamide 351 62 N.X z- / F V 0 N / / \\ NH 1 - (6-( 1 H-pyrazol-5-yl)pyridin-3yl)-N-(4-fluorophenyl)cyclobutan1-carboxamide 337 63 OH F njx o x / S H N-(4-fluorophenyl)-1 -(4'( hydroxymethyl)-6'(trifluoromethyl)-[2,3'-bipyridin]5-yl)cyclobutan-1-carboxamide 446 Example 64: 1 -(4-(4-cyclopropyl-IH-pyrazol-l-yl)phenyl)-N-propylcyclobutan-1 carboxamide Stage 1: Synthesis of l-(4-bromophenyl)-N-propylcyclobutan-l-carboxamide (1-135) To a 20 ml vial a magnetic stir bar was charged, l-(4bromophenyl)cyclobutanecarboxylic acid (800.0 mg, 3.14 mmol) in DMF (4.0 ml) was added with stirring HATU (1431 mg, 3, 76 mmol), and the reaction mixture was stirred for a few minutes. Then, propan-1-amine (185 mg, 3.14 mmol) and DIEA (1.643 ml, 9.41 mmol) were added, and the mixture was stirred for 4 h at room temperature. The reaction was diluted with ethyl acetate and washed with 1N aqueous HC1 (3x), water, brine and saturated aqueous NaHCCL. The solution was then dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (Isco CombiFlash system, IF-2018-68202357-APN-ANP#INPI Page 92 of 185 using a Gold column of 48 g of RediSep silica gel, 10-100% EtOAc / Hex as eluent) to obtain Compound 1-135. MS (ESI) [M+H]+: m / z 296. Step 2: Synthesis of l-(4-(4-cyclonropyl-lH-pyrazol-l-yl)phenyl)-N-propylcyclobutane-lcarboxamide To a 20 ml vial, Compound 1-135 (25.0 mg, 0.084 mmol) and copper iodide (1.607 mg, 8.44 pmol) were added followed by 4-cyclopropyl-1H-pyrazole (9.13 mg , 0.084 mmol) and trans-N,N'-dimethylcyclohexan-l,2-diamine (2.401 mg, 0.017 mmol). This mixture was then evacuated and refilled with nitrogen (3 times). Dry degassed 1,2-dioxane (338 μΐ) was then added. The mixture was heated at 110 °C for 24 h and cooled to room temperature. The crude material was purified by mass-directed reversed-phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 324. 1H NMR (600 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.59 (q, J = 6.1, 5.5 Hz, 1H), 7.51 (d, J = 18.9 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 2.96 (p, J = 7.0 Hz, 2H), 2.77 - 2.62 ( m, 2H), 2.33 (dq, J = 19.2, 10.1, 9.3 Hz, 2H), 1.86 - 1.68 (m, 3H), 1.32 (p, J = 7.1 Hz, 2H), 0.86 (t, J = 6.2 Hz , 2H), 0.70 (t, J = 7.3 Hz, 3H), 0.58 (d, J = 4.0 Hz, 2H). Example 65: l-(4-(2-(4-fluorophenyl)oxazol-4-yl)phenyl)-N-propylcyclobutane-1 carboxamide The title compound was prepared from bromine intermediate 1-98 and (2-(4-fluorophenyl)oxazol-4-yl)boronic acid under standard Suzuki coupling conditions. MS (ESI) [M+H]+: m / z 279. Example 66: 1 -(4-(6-cyclopropylpyridin-3-yl)phenyl)-N-propylcyclobutan-1-carboxamide This compound was prepared in an analogous manner to the synthesis of Example IF-2018-68202357-APN-ANP#INPI Page 93 of 185 64, except that (6-cyclopropylpyridin-3-yl)boronic acid was used. MS (ESI) [M+H]+: m / z 335. Example 67: carboxamide l-(4-(6-(4-fluorophenyl)pyridin-3-yl)phenyl)-N-propylcyclobutan-l- This compound was prepared analogously to the synthesis of Example 64, except that (6-(4-fluorophenyl)pyridin-3-yl)boronic acid was used. MS (ESI) [M+H]+: m / z 389. Example 68: 1 -(4-(6-cyclopropylpyridin-3-yl)phenyl)-N-(5-fluoropyridin-2-yl)cyclobutan-1 carboxamide Step 1: l-(4-bromophenyl)-N-(5-fluoropyridin-2-yl)cyclobutan-l-carboxamide(1-140) A 100 ml vial was charged with a magnetic stir bar, 1(4-bromophenyl)cyclobutanecarboxylic acid (1000.0 mg, 3.92 mmol) in DMF (10.0 ml), HATU (1789 mg, 4.0 ml) was added. 70 mmol) with stirring, and the mixture was stirred for a few minutes. 5-fluoropyridin-2-amine (439 mg, 3.92 mmol), DIEA (2.054 ml, 11.76 mmol) were added, and the reaction mixture was stirred for 4 h at room temperature. The reaction was prepared in the usual way, and the crude oil was purified by chromatography (Isco CombiFlash system, using a Gold column of 48 g of RediSep silica gel, 10-100% EtOAc / Hex as eluent) to obtain Compound 1- 140. MS (ESI) [M+H]+: m / z 349. Step 2: l-(4-(6-cyclopropylpyridin-3-yl)phenyl)-N-(5-fluoropyridin-2-yl)cyclobutan-lcarboxamide A mixture of 2-cyclopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-294 IF-2018-68202357-APN-ANP#INPI Page 94 of 185 il)pyridine (42.1 mg, 0.172 mmol), Compound 1-140 (60.0 mg, 0.172 mmol) and l,r-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (14 0.09 mg, 0.015 mmol) and sodium carbonate (0.172 mL, 0.344 mmol) in 1,4-dioxane (1.5 mL) was subjected to standard Suzuki coupling conditions. The crude material was purified by mass-directed reversed-phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 388. 1H NMR (499 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.82 (s, 2H), 8.29 (d, J = 2.7 Hz, 1H), 8.08 (dd, J = 9.2, 4.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 2.89 (q, J = 8.6 Hz, 2H), 2.25 (s, 2H), 1.83 (dt, J = 22.2, 8.5 Hz, 3H), 1.24-1.10 (m, 2H), 1.07 (s, 2H ). Example 69: l-(4-(6-cyclopropyl-4-fluoropyridin-3-iPfeniP-N-(5-fluoropyridin-2 iDcyclobutan-1-carboxamide This compound was prepared analogously to the synthesis of Example 68, except that 2-cyclopropyl-4-fluoro-5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)pyridine was used. . MS (ESI) [M+H]+: m / z 406. 1H NMR (499 MHz, DMSOd6) δ 10.20 (s, 1H), 8.59 (d, J = 10.5 Hz, 1H), 8.29 (d, J = 2.7 Hz, 1H), 8.09 (dd, J = 9.2, 4.0 Hz, IH), 7.76 - 7.68 (m, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 11.7 Hz, 1H), 2.88 (q, J = 8.6 Hz, 2H), 2.20 (d, J = 4.8 Hz, 2H), 1.84 (dt, J = 16.3, 8.4 Hz, 3H), 1.05 (d, J = 7.9 Hz, 2H), 1.02 (s, 2H). Example 70: 1 -(4-(6-cyclopropyl-4-methylpyridin-3-yl)phenyl)-N-(5-fluoropyridin-2iDcyclobutan-1-carboxamide N= / v== / I—I This compound was prepared in an analogous manner to the synthesis of Example 68, except that 2-cyclopropyl-4-methyl-5-(4,4,5,5-tetramethii-l,3.295 IF-2018-68202357-APN-ANP#INPI Page 95 of 185 dioxaborolan-2-yl)pyridine. MS (ESI) [M+H]+: m / z 402. 1H NMR (499 MHz, DMSOd6) δ 10.25 (s, 1H), 8.45 (s, 1H), 8.30 (d, J = 2.8 Hz, 1H) , 8.10 (dd, J = 9.2, 4.1 Hz, 1H), 7.73 (td, J = 8.8, 2.9 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.50 (s, 1H), 7.45 ( d, J = 8.0 Hz, 2H), 2.99 - 2.72 (m, 3H), 2.37 (s, 3H), 2.28 - 2.19 (m, 1H), 1.84 (dt, J = 18.4, 8.5 Hz, 3H), 1.31 - 1.18 (m, 2H), 1.11 (s, 2H). Example 71: l-(4-(6.7-difluoro-lH-benzordlimidazole-2-yl)phenyl)-N-(5-fluoroniridin-2 iDcyclobutan-1-carboxamide Step 1: methyl 4-yl-((5-fluoroniridin-2-yl)carbamoyl)cyclobutyl)benzoate (1-144) l-(4-(methoxycarbonyl)phenyl)cyclobutanecarboxylic acid (2000.0 mg, 8.54 mmol) and oxalyl chloride (0.747 mL, 8.54 mmol) in DCM (10.0 mL) were stirred to this. added DMF (0.2 ml). The reaction mixture was stirred at room temperature for 4 h and concentrated in vacuo and left in a lyophilizer overnight. Then, a mixture of 2-amino-5-fluoropyridine (957 mg, 8.54 mmol) in pyridine (10.0 ml) was added to the crude oil, and the mixture was cooled to 0 °C. The mixture was slowly warmed to room temperature and stirred overnight, concentrated in vacuo, and the crude oil was purified by biotage (SiO2, CH2Cl2 / MeOH; 0-10%) to obtain Compound I144. MS (ESI) [M+H]+: m / z 329. Step 2: 4-(l-((5-fluoroniridin-2-yl)carbamoyl)cyclobutyl)benzoic acid (1-145) To a vial containing Compound 1-144 (1000.0 mg, 3.05 mmol) in tetrahydrofuran (4.0 ml) and MeOH (1.333 ml) was added LiOH in water (6.09 ml, 12.18 mmol). ), and the mixture was stirred at room temperature for 24 h. The solvents IF-2018-68202357-APN-ANPAINPI Page 96 of 185 organics were evaporated, and the aqueous layer was acidified to pH~3 by adding HC1 (1N), then extracted with DCM 3 times. The organic phases were combined, washed with brine, dried and concentrated to obtain Compound 1-145. MS (ESI) [M+H]+: m / z 315. Step 3: Synthesis of N-í6-amino-2,3-difluorophenyl)-4-(l-((5-fluoropyridin-2yl)carbamoyl)cyclobutyl)-benzamide (1-146) Compound 1-145 (30.0 mg, 0.095 mmol) in DMF (1.0 ml) was charged to a 20 ml vial, then HATU (43.6 mg, 0.115 mmol) was added with stirring. After a few minutes, l,2-diamino-3,4-difluorobenzene (13.76 mg, 0.095 mmol) and DIEA (0.100 ml, 0.573 mmol) were added, and the reaction mixture was stirred for 4 h at room temperature. The reaction was diluted with ethyl acetate and washed with 1N (3x). The organic layer was concentrated, and the residue was purified by chromatography (Isco CombiFlash system, using a Gold column of 12 g RediSep silica gel, 0-20% MeOH / DCM as eluent) to obtain Compound 1-146. MS (ESI) [M+H]+: m / z 441. Step 4: l-(4-(6,7-difluoro-lH-benzordlimidazole-2-yl)phenyl)-N-(5-fluoropyridin-2ylcyclobutan-1-carboxamide A solution of Compound 1-146 (17.0 mg, 0.039 mmol) in AcOH (1.5 ml) was heated to 150 °C in a microwave oven for 30 min. The mixture was evaporated under reduced pressure. The crude material was purified by mass-directed reversed-phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 423. 1H NMR (499 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.29 (d, J = 2.7 Hz, 1H), 8.18 (d, J = 8.2 Hz, 3H), 8.09 (dd, J = 9.2, 4.0 Hz, 1H), 7.73 (dd, J = 8.6, 2.6 Hz, 1H), 7.69 (d, J = 8.3 Hz, 3H), 7.37 ( dd, J = 8.6, 3.1 Hz, 1H), 7.31 - 7.17 (m, 1H), 2.90 (dt, J = 14.6, 8.6 Hz, 2H), 2.59 - 2.53 (m, 2H), 1.86 (dt, J = 14.8, 7.4Hz, 2H). IF-2018-68202357-APN-ANP#INPI Page 97 of 185 Example 72: l-(4-(7-fluoro-lH-benzoid]imidazol-2-yl)phenyl)-N-(5-fluoropyridin-2iDcyclobutan-1-carboxamide FΟΦ QN0¾ F The title compound was prepared analogously to the synthesis of Example 71, except that 3-fluorobenzene-1,2-diamine was used. MS (ESI) [M+H]+: m / z 405. 1H NMR (499 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.29 (d, J = 2.7 Hz, 1H), 8.16 (d, J = 8.3 Hz, 2H), 8.09 (dd, J - 9.2, 4.0 Hz, 1H), 7.78 - 7.66 (m, 4H), 7.54 (d, J = 8.9 Hz, 1H), 7.23 (t, J = 9.2 Hz, 1H), 2.92 (dt, J = 14.6, 8.6 Hz, 2H), 2.60 - 2.53 (m, 2H), 1.98 1.78 (m,2H). Example 73: l-(4-(5-cyano-lH-benzord1imidazol-2-yl)phenin-N-(5-fluoropyridin-2iDcyclobutan-1-carboxamide The title compound was prepared analogously to the synthesis of Example 71, except that 3,4-diaminobenzonitrile was used. MS (ESI) [M+H]+: m / z 412. 1H NMR (499 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.29 (d, J = 2.7 Hz, 1H), 8.20 (d, J = 8.2 Hz, 2H), 8.16 (s, 1H), 8.09 (dd, J = 9.2, 4.0 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.3 Hz, 3H), 7.62 (d, J = 8.3 Hz, 1H), 2.91 (dt, J - 14.6, 8.6 Hz, 2H), 2.59 2.52 (m, 2H), 1.86 (dt, J = 17.4, 8.6 Hz, 2H) . Example 74: I-(4-(4.7-difluoro-1H-benzoid1imidazol-2-yl)phenir)-N-(5-fluoroDIridin-2 i Ijcyclobutan-1-carboxamide IF-2018-68202357-APN-ANP#INPI Page 98 of 185 The title compound was prepared analogously to the synthesis of Example 71, except that 3,6-difluorobenzene-1,2-diamine was used. MS (ESI) [M+H]+: m / z 423. 1H NMR (499 MHz, DMSO-d6) δα 10.25 (s, 1H), 8.29 (d, J = 2.7 Hz, 1H), 8.24 (d, J = 8.2 Hz, 2H), 8.09 (dd, J = 9.2, 4.0 Hz, 1H), 7.73 (dd, J = 8.6, 2.7 Hz, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.08 - 7.00 (m, 2H), 2.91 (dt, J = 14.7, 8.6 Hz, 2H), 2.59 2.52 (m, 2H), 1.86 (dt, J = 17.2, 8.6 Hz, 2H). Example 75: 1-(4-(4,4-difluoro-3a,4,5.6.7.7a-hexahydro-lH-benzord1imidazol-2yl)phenyl)-N-(5-fluoropyridin-2-yl)cyclobutan-l -carboxamide The title compound was prepared analogously to the synthesis of Example 71, except that (7J?,2J?)-3,3-difluorocyclohexan-1,2-diamine was used. MS (ESI) [M+H]+: m / z 429. 1H NMR (499 MHz, DMSO-d6) δ 11.12 (s, 1H), 11.01 (s, 1H), 10.32 (s, 1H), 8.30 ( d, J = 2.8 Hz, 1H), 8.11 - 7.97 (m, 3H), 7.80 (d, J = 8.3 Hz, 1H), 7.73 (td, J = 8.8, 2.9 Hz, 1H), 4.71 (s, 2H ), 3.19 - 2.72 (m, 2H), 2.55 (d, J = 8.6 Hz, 2H), 2.24 - 2.07 (m, 1H), 1.97 - 1.85 (m, 3H), 1.85 - 1.58 (m, 4H). Example 76: 7V-(4-fluoropheml)-3-(4,-(hydroxymethyl)-6'-(trifluoromethyl)-r3.3,-bipyridin1-6yl)oxetan-3-carboxamide Step 1: 3-(5-bromopyridin-2-yl)oxetan-3-carbonitrile (1-152) To a vial equipped with a stir bar, 5-bromo-2fluoropyridine (58.5 μΐ, 0.568 mmol), oxetan-3-carbonitrile (47.2 μΐ, 0.625 mmol), and 99 IF-2018-68202357-APN-ANP#INPI Page 99 of 185 toluene (2840 μΐ). The reaction mixture was cooled to 0 °C while stirring under nitrogen. 1.0 M KHMDS in THF (682 μ1, 0.682 mmol) was slowly added to the stirring reaction mixture. After 5 min, the reaction was quenched with MeOH (~5 ml). The crude reaction mixture was filtered onto a Celite pad, which was rinsed with ethyl acetate. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc / hexanes). The desired product was eluted and the fractions were collected and concentrated under reduced pressure to obtain Compound 1-152. MS (ESI) [M+H]+: m / z 239. Step 2: Preparation of 3-(5-bromopyridin-2-yl)oxetan-3-carboxylic acid (1-153) Compound I152 (190 mg, 0.795 mmol), NaOH (127 mg, 3.18 mmol), ethanol (2660 μΐ), and water (1310 μΐ) were added to a vial equipped with a stir bar. The vial was sealed and heated to 80 °C for 20 h. After 20 h the crude reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, and the pH was adjusted to ~2 by adding 1 N HC1 dropwise. The mixture was washed with water. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure to obtain Compound 1-153. MS (ESI) [M+H]+: m / z 258. Step 3: Preparation of 3-(5-bromopyridin-2-yl)-N-(4-fluorophenyl)oxetan-3-carboxamide d-154) Compound I153 (127 mg, 0.493 mmol), HATU (281 mg, 0.739 mmol), and DMF (4930 μΐ) were added to a vial equipped with a stir bar. 4-Fluoroaniline (56.0 μΐ, 0.591 mmol) was added, followed by DIEA (258 μΐ, 1.48 mmol). The reaction mixture was stirred at room temperature for 21 h. After 21 h, the crude reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3, and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc / hexanes) to obtain Compound I-154. MS (ESI) [M+H]+: m / z 351. 100 IF-2018-68202357-APN-ANP#INPI Page 100 of 185 Step 4: Preparation of N-(4-fluorophenyl)-3-(5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2yl)pyridin-2-yl)oxetan-3-carboxamide (I -155) Compound I154 (113 mg, 0.320 mmol), bis(pinacolato)diboron (203 mg, 0.801 mmol), potassium acetate (94 mg, 0.961 mmol), and PdC12(dppf) adduct were added to a vial equipped with a stir bar. )-CH2C12 (26.2 mg, 0.032 mmol) in dioxane (1600 μΐ). The vial was purged with nitrogen for 5 min, and then sealed and heated to 80 °C for 23 h. The crude reaction mixture was filtered onto a Celite pad, which was rinsed with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and extracted with ethyl acetate. The combined organics were dried over MgSC>4, filtered and concentrated under reduced pressure. The residue was dissolved in ACN / water and dried in the lyophilizer overnight to obtain Compound I155. MS (ESI) [M+H]+: calculated m / z: 399; found 317 (mass of boronic acid). Step 5: 7V-í4-Fluorophenyl)-3-(4'-(hydroxymethyl)-6,-(trifluoromethyl)-r3.3'-bipyridin]-6yl)oxetan-3-carboxamide To a vial equipped with a stir bar was added Compound 1-155 (17 mg, 0.043 mmol), (5-bromo-2-(trifluoromethyl)pyridin-4-yl)methanol (10.9 mg, 0.043 mmol), chlorine (2-dicyclohexylphosphino-2',4',6'-tri-I-propyl-1,1 '-biphenyl)(2'-amino-1,1 '-biphenyl2-yl)palladium(II) (3.36 mg, 4.27 pmol), tribasic potassium phosphate (1 M aqueous solution) (85 μΐ, 0.085 mmol), and THF (427 μΐ). The vial was purged with nitrogen, sealed, and heated to 40 °C for 1 h. After 1 h the crude reaction mixture was filtered onto a Celite pad, which was rinsed with ethyl acetate. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, and washed with saturated NaCl. The organics were dried over MgSCL, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc / hexanes) to obtain the title compound. MS (ESI) [M+H]+: m / z 448. 1H NMR (600 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.80 (s, 1H), 8.72 (s, 1H), 8.12 - 8.03 (m, 2H), 7.75 - 7.69 (m, 3H), 7.21 (t, J = 8.6 Hz, 2H), 5.76 (t, J = 5.2 Hz, 1H), 5.22 (d, J = 6.3 Hz, 2H ), 5.08 (d, J - 6.2 Hz, 2H), 4.62 (d, J = 5.2 Hz, 2H). 101 IF-2018-68202357-APN-ANP#INPI Page 101 of 185 Example 77: 3-(6-(difluoromethOxy)-4'-(hydroxymethyl)-r3,3'-binyridin]-6-yl)-N-(4fluorophenyl)oxetan-3-carboxamide The title compound was prepared from intermediate 1-155 and (5-bromo-2(difluoromethoxy)pyridin-4-yl)methanol in a manner analogous to the synthesis of Example 76. MS (ESI)) [M+H]+: m / z 446. 1H NMR (600 MHz, DMSO-t / 6) δ 10.14 (s, 1H), 8.72 (s, 1H), 8.20 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H) , 7.74 - 7.69 (m, 2H), 7.67 (d, J= 8.4 Hz, 1H), 7.26 (s, 1H), 7.20 (t, J= 8.6 Hz, 2H), 5.14 (dd, J= 80.5, 6.2 Hz, 4H), 4.52 (s, 2H). Example 78: 3-(6,-(difluoromethoxy)-4l-(2-hydroxypropan-2-yl)-r3.3'-bipyridin1-6-yl)-N-(4fluorophenyl)oxetan-3-carboxamide EITHER The title compound was prepared similarly to Example 76. MS (ESI) [M+H]+: m / z 474. 1H NMR (600 MHz, DMSO-J6) δ 10.18 (s, 1H), 8.60 (s , 1H), 7.94 (s, 1H), 7.86 (d, J= 8.0 Hz, 1H), 7.78 (t, J= 72 Hz, 1 H), 7.74 - 7.70 (m, 2H), 7.60 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 7.21 (t, J = 8.7 Hz, 2H), 5.13 (dd, J= 83.1, 6.2 Hz, 4H), 1.32 (s, 6H). Example 79: N-(4-fluorophenyl)-3-(4l-(2-hydroxypropan-2-yl)-6,-(trifluoromethyl)-r3,3'bipyridinyl -6-yl)oxetan-3-carboxamide NO EITHER The title compound was prepared similarly to Example 76. MS (ESI) [M+H]+: m / z 476. 102 IF-2018-68202357-APN-ANP#INPI Page 102 of 185 Example 80: 3,3-difluoro-N-(4-fluorophenyl)-l-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutan-1-carboxamide Step 1. 2-(4-bromophenyl)-N-(4-fluorophenyl)-5.8-dioxasniror3.41octan-2-carboxamide (I163) To a solution of 2-(4-bromophenyl)-5,8-dioxaspiro[3.4]octane-2carboxylic acid (1.0 g, 3.2 mmol) in DMF (6.4 ml) was added 4-fluoroaniline (0 .30 ml, 3.2 mmol) and Hunig base (1.12 ml, 6.4 mmol), and then HATU (1.58 g, 4.2 mmol) was added in portions. The reaction was stirred at room temperature for 14 h. The reaction mixture was diluted with aqueous NaOH and extracted with EtOAc. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (0-100% EtOAc / hexanes) to obtain Compound 1-163. MS (ESI) [M+H]+: »i / z406. Step 2: l-(4-bromophenyl)-N-(4-fluorophenyl)-3-oxocyclobutane-I-carboxamide (1-164) To a flask containing Compound 1-163 (380 mg, 0.94 mmol) was added HC1 (4N in dioxane, 2 ml) and H2O (2 ml). The mixture was heated at 80 °C for 2 h. The mixture was cooled, neutralized with NalICO;; saturated and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to obtain Compound 1-164 as a solid. This material was used directly for the next stage. MS (ESI) [M+H]+: m / z 362. 103 IF-2018-68202357-APN-ANP#INPI Page 103 of 185 Step 3: l-(4-bromophenyl)-3,3-difluoro-N-(4-fluorophenyl)cyclobutan-l-carboxamide (I165) To a solution of Compound 1-164 (127 mg, 0.35 mmol) in CH2Q2 (2.3 ml) at -30 °C was added DAST (185 μΐ, 1.4 mmol). After addition, the reaction mixture was slowly warmed to room temperature and stirred for 3 h. The mixture was quenched at this point by the addition of aqueous NaHCO3, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (0100% EtOAc / hexanes) to obtain Compound 1-165. MS (ESI) [M+H]+: m / z 384. Step 4: 3,3-difluoro-N-(4-fluorophenyl)-l-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutan-1-carboxamide A mixture of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (98 mg , 0.23 mmol), Compound I165 (60 mg, 0.15 mmol), 1,l'-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (15 mg, 0.023 mmol) and sodium carbonate (195 μΐ, 0.39 mmol) in 1,4-dioxane (1.0 ml) was evacuated and refilled with nitrogen 3 times, and the mixture was heated in nitrogen at 90 °C for 2 h. The reaction mixture was cooled, diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (0-100% EtOAc / hexanes) to obtain 1 -(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6(trifluoromethyl)pyridin-3-yl)phenyl) -3,3-difluoro-N-(4-fluorophenyl)cyclobutane-lcarboxamide as an oil. MS (ESI) [M+H]+: m / z 595. To a flask containing l-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6(trifluoromethyl)pyridin-3-yl)feml)-3,3-difluoro-N-(4-fluorophenyl )cyclobutanecarboxamide (83 mg, 0.14 mmol) TBAF (1.0 M in THF, 42 μΐ, 0.42 mmol) and THF (0.3 ml) were added at room temperature. The reaction was kept stirring at room temperature for 1 h. The mixture was diluted with saturated NaHCOj, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (0-100% EtOAc / hexanes) to obtain the title compound. MS (ESI) [M+H]+: m / z 480. 1HRMN (500 MHz, DMSO-d6): δ 9.92 (s, 1H), 8.61 (s, 1H), 8.02 (s, 1H), 7.75 - 7.59 (m, 4H), 7.53 (d, J= 8.0 Hz, 2H), 7.14 (t, J= 8.8 Hz, 2H), 5.66 (t, J= 5.3 Hz, 1H), 4.55 (d, J= 5.2 Hz, 2H), 104 IF-2Ó18-68202357-APN-ANP#INPI Page 104 of 185 3.55 (q, J= 13.2 Hz, 2H), 3.21 (q, J= 13.2 Hz, 2H). Example 81: N-(4-fluorophenyl)-l-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)pheny Dcyclobutan-1-carboxamide Step 1. l-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)niridin-3-yl)feml)-N(4-fluorophenyl)cyclobutan-1-carboxamide A mixture of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (98 mg , 0.23 mmol), Compound I165 (60 mg, 0.15 mmol), l,l'-bis(di-tert-butylphosphinojferrocene-palladium dichloride (15 mg, 0.023 mmol) and sodium carbonate (195 μΐ, 0.39 mmol) in 1,4-dioxane (1.0 ml) was evacuated and refilled with nitrogen 3 times, and the mixture was heated in nitrogen at 90 ° C for 2 h. diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried in MgSO4, and concentrated. The residue was purified by flash chromatography (0-100% EtOAc / hexanes) to obtain the compound. of the title as a solid MS (ESI) [M+H]+: m / z 559. Step 2. N-(4-fluorophenyl)-l-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutan-1-carboxamide To a flask containing l-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)cyclobutanecarboxamide (107 mg, 0.19 mmol) at room temperature, TBAF (1.0 M in THF, 575 μΐ, 0.575 mmol) and THF (0.3 ml) were added. The reaction was kept stirring at room temperature for 1 h. The mixture was diluted with saturated NaHCO3, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (0-100% EtOAc / hexanes) to obtain the title compound. MS (ESI) [M+H]+: m / z 445. 1HRMN (500 MHz, DMSO-do. δ 9.62 (s, 1H), 8.62 (s, 1H), 8.03 (s, 1H), 7.75-7.55 (m, 4H), 7.50 (d, J= 7.5 Hz, 2H), 7.14 105 IF-2018-68202357-APN-ANP#INPI Page 105 of 185 (t, J= 8.2 Hz, 2H), 5.68 (s, 1H), 4.57 (d, J = 4.3 Hz, 2H), 2.95-2.75 (m, 2H), 2.40-2.60 (m, 2H ), 1.98 - 1.77 (m, 2H). Example 82: N-(4-fluorophenyl)-5-(4-(4-(hydroxymethyl)-6-(trifluoromethyl')pyridin-3yl)phenyljspiro[2.31hexan-5-carboxamide Step 1: 5-(4-chlorophenyl)spiror2.31hexan-5-carbonitrile (1-168) l-chloro-4-fluorobenzene (193 μΐ, 1.8 mmol) and spiro[2.3]hexan-5-carbonitrile (179 μΐ, 1.5 mmol) were added to a flask under nitrogen, and then 1.5 ml of THF. KHMDS (1 Men THF, 1.58 ml, 1.58 mmol) was added dropwise. It was stirred for 15 h at room temperature, evaporated in vacuo, and then verified by NMR for the conversion. The residue was purified by chromatography (Isco CombiFlash system, using hexanes and ethyl acetate as eluent) to obtain Compound 1-168. 1H NMR (600 MHz, CDC13) δ 7.46 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 2.96 (d, J= 12.3 Hz, 2H), 2.68 (d, J = 12.4 Hz, 2H), 0.77 - 0.69 (m, 2H), 0.60 - 0.53 (m, 2H). Stage 2: 5-(4-chlorophenyl)spiror2.3]hexan-5-carboxylic acid (I-169) Lithium hydroxide (99 mg, 4.1 mmol) was added to a flask containing Compound 1-168 (150 mg, 0.69 mmol). 1 ml of water and 1 ml of ethanol were added. This was then heated in a sealed flask in argon at 65 °C for 72 h. It was then acidified with 1 M HC1 (aqueous) to pH~3. It was then extracted with ethyl acetate, dried with MgSO4, filtered through a Celite pad, and then evaporated in vacuo to obtain Compound 1-169, which was used in the next step directly. MS (ESI) [M+H]+: m / z 237. 106 IF-2018-68202357-APN-ANP#INPI Page 106 of 185 Step 3: 5-(4-chlorophenyl)-N-(4-fluorophenyl)spiror2.31hexan-5-carboxamide (1-170) 5-(4-chlorophenyl)spiro[2.3]hexan-5-carboxylic acid (125 mg, 0.53 mmol) and HATU (221 mg, 0.58 mmol) were added to a vial with 1.5 mL of DMF. . To this was added 4-fluoroaniline (55 μΐ, 0.58 mmol) and then DIPEA (231 μΐ, 1.3 mmol). This mixture was stirred for 2 h, at which time it was evaporated in vacuo. The crude residue was purified by chromatography (Isco CombiFlash system, using hexanes and ethyl acetate as eluent) to obtain Compound 1-170. MS (ESI) [M+H]+: m / z 330. Step 4:N-í4-fluorophenyl)-5-(4-(4.4,5.5-tetramethyl-1,3,2-dioxaborolan-2ylIphenyl)spiror2.3]-hexan-5-carboxamide (1-171) A dried round bottom flask was charged with Compound 1-170 (118 mg, 0.36 mmol), bis(pinacolato)diboron (236 mg, 0.93 mmol), potassium acetate (105 mg, 1.1 mmol). and XPhos G3 (5%, 15 mg). Dioxane (2.4 ml) was then added, purged with argon, and heated to 80 °C for 15 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated in vacuo to obtain a residue that was purified by chromatography (Isco CombiFlash system, using hexanes and ethyl acetate as eluent) to obtain Compound 1-171. MS (ESI) [M+H]+: zm / z422. Step 5j N-(4-fluorophenyl)-5-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3yl)phenyl)spiror2.3]hexan-5-carboxamide To a dry vial equipped with a stir bar was charged Xphos G3 (8.46 mg, 10.00 pmol), (5-bromo-2-(trifluoromethyl)pyridin-4-yl)methanol (28.2 mg, 0. 11 mmol) and Compound 1-171 (42.1 mg, 0.1 mmol), and placed under nitrogen. 0.50 ml THF and tribasic potassium phosphate (1 M in H2O, 0.200 ml, 0.200 mmol) were added. The reaction mixture was then purged with argon and heated to 70 °C overnight. It was cooled to room temperature and then filtered through a Celite pad. This crude material was purified by mass directed reverse phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 471. 1H NMR (600 MHz, DMSO-J6) δ 9.71 (s, 1H), 8.61 (s, 1H), 8.02 (s, 1H), 7.71 - 7.66 (m, 2H), 7.63 (d, J= 7.6 Hz, 2H), 107 IF-2018-68202357-APN-ANP#INPI Page 107 of 185 7.49 (d, J= 7.5 Hz, 2H), 7.13 (t, J = 8.3 Hz, 2H), 4.57 (s, 2H), 3.04 (d, J = 11.9 Hz, 2H), 2.63 (d, J= 11.9 Hz, 2H), 0.49 (s, 4H). Example 83: 1 -(4-(4.7-difluoro-1 -oxoisoindolin-2-yl)phenyl)-? / -(4-fluorophenyl)cyclobutan1-carboxamide Step 1: ethyl l-(4-(4,7-difluoro-L3-dioxoisoindolin-2-yl)phenyl)cyclobutan-l-carboxylate (1-173) 4,7-Difluoroisobenzofuran-l,3-dione (184 mg, 1 mmol) and ethyl l-(4-aminophenyl)cyclobutanecarboxylate (329 mg, 1,500 mmol) were charged to a vial. To this vial, 4 ml of glacial acetic acid was added, and then the vial was purged with argon and heated at 80 °C for 15 h. The reaction mixture was then concentrated in vacuo. This crude material was dissolved in DCM (10 ml) and added to a separatory funnel. It was washed with saturated sodium bicarbonate, and the organics were separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (Isco CombiFlash system, using hexanes and ethyl acetate as eluent) to obtain Compound 1-173. MS (ESI) [M+H]+: m / z 386. Step 2: l-(4-(4,7-difluoro-l,3-dioxoisoindolin-2-yl)phenyl)cyclobutane-lcarboxylic acid (1-174) Compound 1-173 (200 mg, 0.519 mmol) was charged to a vial, and to this was added 2 ml of dioxane. Lithium hydroxide (37.3 mg, 1.557 mmol) was then added and then 2 ml of water was added. It was stirred at room temperature for 2 h. Then, the organics were evaporated in vacuo, and the water layer was acidified with 11 M HC to pH ~2. This was then extracted 3x with DCM (5 ml), dried with magnesium sulfate, filtered and evaporated in vacuo. The lactam ring opened under these conditions, and 108 IF-2018-68202357-APN-ANP#INPI Page 108 of 185 This crude material was then dissolved in 2 ml of acetic acid in a vial, the vial was purged with argon and heated to 100 °C for 15 h. Then, the reaction mixture was concentrated in vacuo. This crude material was dissolved in DCM (10 ml) and added to a separatory funnel. It was washed with saturated sodium carbonate, and the organics were separated, dried over sodium sulfate, filtered and concentrated to obtain Compound 1-174, which was used directly. MS (ESI) [M+H]+: m / z 358. Step 3: l-(4-(4.7-difluoro-l-oxoisoindolin-2-yl)phenyl)cyclobutane-I-carboxylic acid (I175) Compound 1-174 (90 mg, 0.252 mmol) and NaBH4 (10.48 mg, 0.277 mmol) were added to a vial in nitrogen and placed in nitrogen. To this was added 1 ml of THF and 1 ml of MeOH. It was stirred for 5 min at 0 °C, and then stirred at room temperature for 2 h. At the end, 2 drops of acetic acid were added and evaporated in vacuo. Then, 5 ml of DCM and 5 ml of saturated sodium bicarbonate were added, and the organics were separated. It was extracted two more times with 5 ml of DCM, and the organics were combined, dried with magnesium sulfate, filtered, and evaporated in vacuo. This crude material was then dissolved in TFA (1 ml) and triethylsilane (0.161 ml, 1.008 mmol) was added. This was stirred at room temperature for 30 min and evaporated in vacuo. The crude residue was purified by chromatography (Isco CombiFlash system, using hexanes and ethyl acetate as eluent) to obtain Compound 1-175. MS (ESI) [M+H]+: m / z 344. Step 4: 1 -(4-(4,7-difluoro-l-oxoisoindolin-2-yl)phenyl)-Ar-(4-fluorophenyl)cyclobutan-1 carboxamide Compound 1-175 (17 mg, 0.050 mmol) and HATU (19.77 mg, 0.052 mmol) were added to a vial with 1.5 ml of DMF. To this was added 4-fluoroaniline (5.17 μΐ, 0.054 mmol) and then DIPEA (12.97 μΐ, 0.074 mmol). It was stirred for 24 h. When finished, it was evaporated in a vacuum. The crude material was purified by mass-directed reversed-phase chromatography (ACN / water gradient with 0.1% TFA modifier) ​​to obtain the title compound. MS (ESI) [M+H]+: m / z 437. 1H NMR (600 MHz, DMSO-í / 6) δ 9.49 (s, 1H), 7.85 (d, J= 8.1 Hz, 2H), 7.65 - 7.59 (m, 2H), 7.59 - 7.55 (m, 1H), 7.53 (d, 8.1 Hz, 2H), 7.45 - 7.39 (m, 1H), 7.10 (t, J = 8.3 Hz, 2H), 5.10 (s , 2H), 2.88 - 2.80 (m, 2H), 2.50 - 2.44 (m, 2H), 1.89 - 1.77 (m, 2H). 109 IF-2018-68202357-APN-ANP#INPI Page 109 of 185 Example 84: N-(4-fluorophenyl)-3-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-r2.3'-biniridin]-5yl)oxetan-3-carboxamide. Stage 1: methyl 2-(6-chloropyridin-3-iDacetate To a stirred solution of 2-(6-chloropyridin-3-yl)acetic acid (10 g, 58.3 mmol) in DCM (100 ml) and MeOH (50 ml) was added ((trimethylsilyl)methyl)diazene (8 .3 mi, 175 mmol) at 0 °C. The reaction was stirred at room temperature for 16 h and then the solvent was concentrated under reduced pressure. The residue was diluted with water (100 ml), extracted with EtOAc (100 ml x 3), and the organic layers were collected, washed with brine (50 ml), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to obtain the title compound as an oil. MS (ESI) m / z: 185.8 [M+H+]. Step 2: 4-methyl 2-(6-chloropyridin-3-yl)-3-hydroxy-2-(hydroxymethyl)propanoate To a stirred solution of methyl 2-(6-chloropyridin-3-yl)acetate (7.5 g, 40.4 mmol) in THF (50 ml) was added potassium hydroxide (0.227 g, 4.04 mmol), paraformaldehyde (4.85 g, 162 mmol) at room temperature, and the reaction was stirred at 60 °C for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to obtain the title compound as an oil. MS (ESI) m / z: 245.9 [M+H+], 110 IF-2018-68202357-APN-ANP#INPI Page 110 of 185 Step 3: 2-(6-chloropyridin-3-yl)-2-(hydroxymethyl)pronan-1,3-diol To a stirred solution of methyl 2-(6-chloropyridin-3-yl)-3-hydroxy-2(hydroxymethyl)propanoate (4.6 g, 18.73 mmol) in THF (50 ml) was added lithium tetrahydroborate (1.224 g, 56.2 mmol) at 0 °C, and the reaction was stirred at 0 °C for 5 h. The mixture was quenched with MeOH (50 ml) and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to obtain the title compound as a solid. MS (ES I) m / z: 217.8 [M+H+]. Stage 4: (3-(6-chloropyridin-3-yl)oxetan-3-yl)methanol To a stirred solution of 2-(6-chloropyridin-3-yl)-2-(hydroxymethyl)propan1,3-diol (1.7 g, 7.81 mmol) in THF (70 ml) was added n-BuLi (4 ml, 10.0 mmol) (2.5M) dropwise at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then a solution of TsCl (1.340 g, 7.03 mmol) in 5 ml of THF was added at 0 °C and stirring continued at 0 °C for 1 h. n-BuLi (3.12 ml, 7.80 mmol) (2.5 M) was added to the above mixture at 0 °C and the mixture was stirred at 0 °C for an additional 0.5 h, and then heated up to 60 °C for 0.5 h. After cooling to room temperature, the reaction was quenched with aqueous NH4Cl (30 mL), extracted with EtOAc (30 mL x 3), and the organic layers were collected, washed with brine (20 mL), dried in Na2SO4 , were filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to obtain the title compound. MS (ESI) m / z: 199.9 [M+H+], Step 5: 3-(6-chloropyridin-3-yl)oxetan-3-carboxylic acid To a stirred solution of (3-(6-chloropyridin-3-yl)oxetan-3-yl)methanol (270 mg, 1.352 mmol) in ACN (10 ml) TEMPO (42 mg, 0.269 mmol) was successively added. , sodium chlorite (489 mg, 5.41 mmol) in 1 ml of water and sodium hypochlorite (1007 mg, 1.352 mmol) (10% in water) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction was treated with 2 M NaOH at pH 10, and then 10% sodium thiosulfate (30 ml) was added. The mixture was partitioned between ethyl acetate (30 ml) and water (15 ml), and the aqueous phase was acidified with HC1 (2 M in water) to pH 4 and extracted with ethyl acetate (30 mlx3). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound as an oil, which was used in the next step without further purification. MS (ESI) m / z: 214.0 [M+H+]. 111 IF-2018-68202357-APN-ANP#INPI Page 111 of 185 Step 6: 3-(6-chloropyridin-3-yl)-N-(4-fluorophenyl)oxetan-3-carboxamide To a stirred solution of 3-(6-chloropyridin-3-yl)oxetane-3carboxylic acid (250 mg, 1.170 mmol) in DMF (10 ml) were added HATU (667 mg, 1.755 mmol), Et3N (0.5 ml , 3.59 mmol) and 4-fluoroaniline (195 mg, 1.755 mmol) at room temperature and stirring continued for 16 h. The reaction mixture was prepared and the crude oil was purified by preparative TLC (petroleum ether / EtOAc =1:1) to obtain the title compound as an oil. MS (ESI) m / z: 307.1 [M+H+], Step 7: 3-(4'-(((tert-butyldimethylsilyl)oxy)methyl)-6l-(trifluoromethyl)-[2,3l-bipyridin1-5-yl)N-(4-fluorophenyl)oxetan-3-carboxamide To a stirred solution of 3-(6-chloropyridin-3-yl)-N-(4fluorophenyl)oxetan-3-carboxamide (30 mg, 0.098 mmol) and 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-( 4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-iI)-2(trifluoromethyl)pyridine (49 mg, 0.117 mmol) in dioxane (2 ml) and water (0.4 ml) was added K3PO4(62 mg, 0.292 mmol) and Pd(dtbpf)C12 (7 mg, 10.74 pinol) at room temperature. The mixture was heated to 100 °C with stirring for 15 h, and cooled to room temperature. The reaction mixture was diluted with ethyl acetate (5 mL) and filtered. The filtrate was washed with water (2 ml) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=1:1 as eluent) to obtain the title compound as an oil. MS (ESI) m / z: 562.3[M+H+], Step 8: N-(4-fluorophenyl)-3-(4,-(hydroxymethyl)-6'-(trifluoromethyl)-[2,3'-bipyridin1-5yl)oxetan-3-carboxamide, To a stirred solution of 3-(4'-(((tert-butyldimethylsilyl)oxy)methyl)-6'(trifluoromethyl)-[2,3'-bipyridin]-5-yl)-N-(4-fluorophenyl) oxetan-3-carboxamide (21 mg, 0.037 mmol) in THF (2 ml) TBAF (0.05 ml, 0.050 mmol) was added at room temperature and the mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with a Phenomenex Synergi Column (C18 150 * 30 mm * 4 um) using water (0.225% FA) and ACN as eluent. , and then 112 IF-2018-68202357-APN-ANP#INPI Page 112 of 185 lyophilized to obtain the title compound as a solid. 1H NMR (400MHz, CD3OD) δ 8.85 (d, 1 H), 8.79 (s, 1 H), 8.12 (t, 2 H), 7.82 (d, 1 H), 7.60 - 7.56 (m, 2 H), 7.07 (t, 2 H), 5.38 (d, 2 H), 5.06 (d, 2 H), 4.82 (s, 2 H); MS (ESI) m / z: 448.0 [M+H+]. Example 85: N-(4-fluorophenyl)-3-(6-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)pyridin-3iDoxetan-3-carboxamide Pd(dtbdf)CI2K3PO4 Dioxane, H2O, 100 °C, 15 h Step 1: 3-(6-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(trifluoromethyl)phenyl)pyridin-3-yl)-N(4-fluoropheniDoxetan-3-carboxamide To a stirred solution of 3-(6-chloropyridin-3-yl)-N-(4fluorophenyl)oxetan-3-carboxamide (42 mg, 0.137 mmol) and tert-butyldiphenyl((2-(4,4,5,5tetramethyl -l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl)oxy)silane (89 mg, 0.164 mmol) in dioxane (1.0 ml) and water (0.2 ml) K3PO4 were added (87 mg, 0.411 mmol) and Pd(dtbpf)C12 (9 mg, 0.014 mmol) at room temperature. The mixture was heated to 100 °C with stirring for 15 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (5 mL) and filtered. The filtrate was washed with water (2 ml) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=1:1 as eluent) to obtain the title compound as an oil. MS (ESI) m / z: 685.4[M+H+], Step 2: N-(4-fluorophenyl)-3-(6-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)pyridin-3iDoxetan-3-carboxamide To a stirred solution of 3-(6-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-4(trifluoromethyl)phenyl)pyridin-3-yl)-N-(4-fluorophenyl)oxetan-3-carboxamide (40 mg, 0.058 mmol) in THF (2 ml) TBAF (0.1 ml, 0.100 mmol) was added at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to obtain 113 IF-2018-68202357-APN-ANP#INPI Page 113 of 185 composed of the title as a solid. 1H NMR (400MHz, CD3OD) δ 8.80 (d, 1 H), 8.12 (dd, 8.3 Hz, 1 H), 7.92 (s, 1 H), 7.78 (d, 1 H), 7.71 (s, 2 H) , 7.59 (dd, 9.2 Hz, 2 H), 7.10 - 7.04 (m, 2 H), 5.38 (d, 2 H), 5.06 (d, 2 H), 4.66 (s, 2 H); MS (ESI) m / z: 447.0 [M+H+]. Example 86: N-(4-fluorophenyl)-3-(6-(2-(2-hydroxypropan-2-yl)-4(trifluoromethyl)phenyl)pyridin-3-yl)oxetan-3-carboxamide Step 1: methyl 2-(4.4,5.5-tetramethyl-L3.2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoate To a stirred solution of methyl 2-bromo-5-(trifluoromethyl)benzoate (510 mg, 1.802 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2' -bi(l,3,2-dioxaborolane) (686 mg, 2.70 mmol) in dioxane (2 ml) potassium acetate (531 mg, 5.41 mmol) and Pd(dppf)C12 (132 mg, 0.180 mmol) at room temperature. The mixture was heated to 100 °C with stirring for 16 h and the solvent was concentrated under reduced pressure. Saturated NaHCO3 was added to the residue to adjust the pH > 8 and the mixture was extracted with EtOAc (20 ml3). The organic layers were collected, washed with brine (10 mL), dried in NazSCU, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc =5:1) to obtain the title compound as an oil. MS (ESI) m / z: 331.1 [M+H+], Step 2: methyl 2-(5-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)pyridin-2-yl)-5(trifluoromethyl)benzoate To a stirred solution of 3-(6-chloropyridin-3-yl)-N-(4fluorophenyl)oxetan-3-carboxamide (30 mg, 0.098 mmol) and (2-(2-(methoxycarbonyl)-4(trifluoromethyl)phenyl )-4,5,5-trimethyl-l,3,2-dioxaborolan-4-yl)methylium (62 mg, 0.188 mmol) in dioxane (2 ml) and water (0.4 ml) K3PÜ4 (62 mg) was added , 0.292 mmol) and Pd(dtbpf)C12 (7 mg, 10.74 pmol) at room temperature. The mixture was heated until 114 IF-2018-68202357-APN-ANPAINPI Page 114 of 185 100 °C for 15 h. The reaction mixture was diluted with EtOAc (5 mL) and filtered. The filtrate was washed with water (2 ml) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (SiO2, petroleum ether / EtOAc=1:1 as eluent) to obtain the title compound as an oil. MS (ESI) m / z: 475.2[M+H+], Step 3: N-(4-fluorophenyl)-3-(6-(2-(2-hydroxynronan-2-yl)-4-(trifluoromethyl)pheniI)pyridin-3-yl)oxetan-3-carboxamide To a stirred solution of methyl 2-(5-(3-((4fluorophenyl)carbamoyl)oxetan-3-yl)pyridin-2-yl)-5-(trifluoromethyl)benzoate (30 mg, 0.063 mmol) in THF (2 mi) 3 M MeMgBr (0.1 mL, 0.300 mmol) was added at 0 °C. The reaction was stirred at room temperature under nitrogen for 15 h. The reaction mixture was slowly quenched with saturated NH4CI (10 mL, aqueous) and extracted with EtOAc (20 mL x3). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by reverse phase HPLC on a GILSON 281 instrument equipped with a Phenomenex C 18 Synergi 150 x 30 mm x 4 um column to obtain the title compound as a solid. 1H NMR (400MHz, CD3OD) δ 8.74 (d, 1H), 8.16 (dd, 8.2 Hz, 1H), 7.96 (s, 1H), 7.70 (d, 1H), 7.66 (br d, 1H) ) , 7.57 ( tdd , 6.9 Hz , 2 H ) , 7.47 ( d , 1 H ) , 7.07 ( t , 2 H ) , 5.38 ( d , 2 H ) , 5.05 ( d , 2 H ) , 1.43 ( s , 6 H); MS (ESI) m / z: 475.2 [M+H+]. Example 87: N-(4-fluorophenyl)-3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-r2,3'bipyridinyl-5-yl)oxetan-3-carboxamide 115 IF-2018-68202357-APN-ANP#INPI Page 115 of 185 Step k Methyl 5-(4.4.5.5-tetramethyl-k3.2-dioxaborolan-2-yl)-2(trifluoromethyl)isonicotinate To a stirred solution of methyl 5-bromo-2-(trifluoromethyl)isonicotinate (520 mg, 1.831 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2' -bi(l,3,2-dioxaborolane) (697 mg, 2.75 mmol) in dioxane (2 ml) potassium acetate (539 mg, 5.49 mmol) and Pd(dppf)C12 (134 mg, 0.183 mmol) at room temperature. The mixture was heated to 100 °C with stirring for 16. The mixture was concentrated under reduced pressure and saturated NaHCCh solution was added to adjust pH to > 8. It was then extracted with EtOAc (20 ml x 3) and the organic layers were collected, washed with brine (10 ml), dried in Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=5:1) to obtain the title compound as an oil. 1H NMR (500MHz, CD3OD) δ 8.86 (s, 1 H), 8.44 (s, 1 H), 3.86 (s, 3 H), 1.37 - 1.32 (m, 8 H), 1.30 (s, 1 H). Step 2: methyl 5-(3-((4-fluorophenyl)carbamoyl)oxetan-3-iD-6'-(trifluoromethyl)-r2,3'bipyridin]-4,-carboxylate To a stirred solution of 3-(6-chloropyridin-3-yl)-N-(4fluorophenyl)oxetan-3-carboxamide (30 mg, 0.098 mmol) and methyl 5-(4,4,5,5-tetramethyll,3 ,2-dioxaborolan-2-yl)-2-(trifluoromethyl)isonicotinate (48 mg, 0.145 mmol) in dioxane (2 ml) and water (0.4 ml), K3PO4 (62 mg, 0.292 mmol) and Pd( dtbpf)C12 (15 mg, 0.023 mmol) at room temperature. The reaction mixture was subjected to the same conditions as in Step 1 and the crude product was purified by reverse phase HPLC on a GILSON 281 instrument equipped with a Phenomenex 150 x 30 mm x 4 um C 18 Synergi column to obtain the title compound as an oil. MS (ESI) m / z: 475.9 [M+H+], Step 3: N-M-fluorophenylj-S-M'-Q-hydroxypropan^-ylj-ó'-itrifluoromethylj-iyj'bipyridin1-5-yl)oxetan-3-carboxamide To a stirred solution of methyl 5-(3-((4-fluorophenyl)carbamoyl)oxetan-3yl)-6'-(trifluoromethyl)-[2,3'-bipyridine]-4'-carboxylate (10 mg, 0.021 mmol ) in THF (2 ml) methylmagnesium bromide (0.1 ml, 0.300 mmol) (3 M in ether) was added dropwise at room temperature. The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with water (5 ml) and then filtered under reduced pressure to 116 IF-2018-68202357-APN-ANP#INPI Page 116 of 185 obtain a residue, which was purified by reverse phase HPLC on a GILSON 281 instrument equipped with a Phenomenex C 18 Synergi column 150 x 30 mm x 4 um to obtain the title compound as a solid. 1H NMR (500MHz, CD3OD) δ 8.83 (d, 1 H),8.57 (s, 1 H),8.19 -8.16(m, 1 H),8.14 (s, 1 H),7.73 (d, 1 H), 7.63 - 7.60 (m, 2 H), 7.60 - 7.59 (m, 1 H), 7.10 (t, 2 H), 5.42 (d, 2 H), 5.09 (d, 2 H), 2.71 (br s, 1 H), 2.55 (br s, 1 H), 2.07 - 2.03 (m, 1 H), 1.47 (s, 6 H). MS (ESI) m / z: 476.2[M+H+] Example 88: 3-(6'-cyclopropoxy-4'-(hydroxymethyl)-r2.3'-bÍDÍridÍDl-5-yl)-N-(4fluorophenyl)oxetan-3-carboxamide TBDPS-CI, imidazole DCM, r.t., 4 p.m. Pd(dppf)CI2KOAc Dioxane, 100 °C, 16h Step 1: 5-bromo-4-(í(tert-butyldiphenylsilyl)oxy)methyl)-2-cyclopropoxypyridine To a stirred solution of (5-bromo-2-cyclopropoxypyridm-4-yl)methanol (500 mg, 2.048 mmol) in DCM (10 ml) was added tert-butylchlorodiphenylsilane (619 mg, 2.253 mmol) and IH-imidazole (307 mg, 4.51 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. The mixture was diluted with water (50 ml), extracted with EtOAc (50 ml x3), and the organic layers were collected, washed with brine (20 ml), and dried in Na2SO4. After filtration, the filtrate was concentrated in vacuo and the residue was purified by silica gel flash chromatography to obtain the title compound. 1H NMR (400MHz, CD3OD) δ 8.12 (s, 1H), 7.70 - 7.63 (m, 4H), 7.48 - 7.36 (m, 6H), 7.29 (s, 1H), 4.71 (s, 2H) ), 4.09 (tt, 1 H), 1.11 (s, 9 H),0.82 -0.72(m,4H) 117 IF-2018-68202357-APN-ANP#INPI Page 117 of 185 Step 2: 4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-cyclopronoxy-5-(4,4,5.5-tetramethyl-1.3.2dioxaborolan-2-yl)pyridine To a stirred solution of 5-bromo-4-(((tert-butyldiphenylsilyl)oxy)methyl)-2cyclopropoxypyridine (940 mg, 1.948 mmol), 4,4,4',4',5,5,5',5 '-octamethyl-2,2'-bi(l,3,2dioxaborolane) (742 mg, 2.92 mmol) in dioxane (20 ml) potassium acetate (574 mg, 5.84 mmol) and Pd(dppf) were added )CI2 (143 mg, 0.195 mmol) at room temperature. The reaction was stirred at 100 °C for 16 h. After cooling to room temperature, the mixture was extracted with EtOAc (50 ml x 3), the organic layers were collected, washed with brine (30 ml), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. . The residue was purified by silica gel flash chromatography to obtain the title compound as a solid. MS (ESI) m / z: 530.2 [M+H+], Step 3: 3-(4'-(((tert-butyldiphenylsilyl)oxy)methyl)-6'-cyclopropoxy-[2.3'-bipyridin1-5-iD-N(4-fluorophenyl)oxetan-3-carboxamide To a stirred solution of 3-(6-chloropyridin-3-yl)-N-(4fluorophenyl)oxetane-3-carboxamide (30 mg, 0.098 mmol) and 4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-cyclopropoxy -5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pyridine (62 mg, 0.117 mmol in dioxane (2 ml) and water (0.4 ml) K3PO4 (62 mg, 0.292 mmol) and Pd(dtbpf)C12 (7 mg, 10.74 pmol) at room temperature. The mixture was subjected to the usual Suzuki coupling conditions as mentioned above. The crude product was purified by preparative TLC. (SiO2, petroleum ether / EtOAcM:1 as eluent) to obtain the title compound as an oil MS (ESI) m / z: 674.2[M+H+], Step 4:3-(6l-cyclopropoxy-4'-(hydroxymethyl)-r2.3'-bipyridin1-5-yl)-N-(4fluorophenyl)oxetan-3-carboxamide To a stirred solution of 3-(4'-(((tert-butyldiphenylsilyl)oxy)methyl)-6'cyclopropoxy-[2,3'-bipyridin]-5-yl)-N-(4-fluorophenyl)oxetan- 3-carboxamide (25 mg, 0.037 mmol) in THF (2 mL) was added to tetrabutylammonium fluoride (0.1 mL, 0.100 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The solvent was concentrated under reduced pressure and the residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with a C 18 Synergi column. 118 IF-2018-68202357-APN-ANP#INPI Page 118 of 185 Phenomenex (150 x 30 mm x 4 um) to obtain the title compound as a solid. 1H NMR (400 MHz, CD3OD) 5 8.77 (d, 1 H), 8.27 (s, 1 H), 8.08 (dd, 1 H), 7.73 (d, 1 H), 7.58 (dd, 2 H), 7.22 (s, 1 H), 7.07 (t, 2 H), 5.37 (d, 2 H), 5.04 (d, 2 H), 4.68 (s, 2 H), 4.23 - 4.17 (m, 1 H), 0.88 - 0.83 (m , 2 H), 0.77 (br s , 2 H). MS (ESI) m / z: 436.1 [M+H+]. Example 89: N-5-fluorothiazol-2-yl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-ylphenyl)oxetan-3-carboxamide Step 1: methyl 3-í4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-3yl)phenyl)oxetan-3-carboxylate To a solution of methyl 3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin3-yl)phenyl)oxetan-3-carboxylate (220 mg, 0.599 mmol) and imidazole (82 mg, 1.198 mmol) in DMF (2.0 ml) was added to TBS-C1 (108 mg, 0.719 mmol) with stirring at room temperature. The reaction mixture was stirred at room temperature for 14 h. The reaction was diluted with water (15 ml) and extracted with EtOAc (15 mlx3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography to obtain the title compound as a solid. MS (ESI) m / z: 482.3 [M+H+], Stage_______2:_______3-(4-(4-(((tert-butyldimethylsiliI)oxy)methyl)-6-(trifluoromethyl)pyridin-3yl)phenyl)oxetan-3-carboxylate potassium To a solution of methyl 3-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxylate (168 mg, 0.349 mmol) in THF (5.0 ml) TMSOK (50 mg, 0.390 mmol) was added with stirring at room temperature 119 IF-2018-68202357-APN-ANP#INPI Page 119 of 185 in nitrogen. The reaction mixture was stirred at room temperature for 14 h. The solvent was concentrated to obtain the title compound as a solid, which was used in the next step without further purification. MS (ESI) m / z: 468.3 [M+H+], Step 3: 3-(4-í4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)niridin-3-yl)phenyl)-N(5-fluorothiazol-2-yl)oxetan-3- carboxamide To a solution of potassium 3-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxylate (15 mg, 0.030 mmol) and 5-fluorothiazol-2-amine (8 mg, 0.068 mmol) in pyridine (0.5 ml) POCI3 (0.03 ml, 0.326 mmol) was added with stirring at 0 °C and the resulting mixture was stirred at 0 ° C for 1 h. The reaction was quenched by the addition of saturated Na2CÜ3 (1.0 ml) and then diluted with water (5 ml), and extracted with EtOAc (5 mlx3). The combined organic phase was washed with brine (5 ml), dried over Na2SÜ4, filtered and concentrated in vacuo to obtain a crude product, which was used in the next step without further purification MS (ESI) m / z: 568.1 [M+H+], Step 4: N-(5-fluorothiazol-2-yl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3yl)phenyl)oxetan-3-carboxamide To a solution of 3-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6(trifluoromethyl)pyridin-3-yl)phenyl)-N-(5-fluorothiazol-2-yl)oxetan- 3-Carboxamide (16 mg, 0.028 mmol) in THF (2.0 ml), water (1.0 ml) and MeOH (2.0 ml) LiOH (5 mg, 0.209 mmol) was added with stirring at room temperature. The mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of 1N HO to pH~7, and concentrated. The residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with Xtimate C18 column (150 x 25 mm x 5 um) using water and ACN as eluents, followed by lyophilization to obtain the title compound as a solid. 1H NMR (400 MHz, CD3OD) δ 8.53 (s, 1 H), 8.07 (s, 1 H), 7.56 - 7.65 (m, 2 H), 7.50 (d, 2 H), 7.09 (d, 1 H) , 5.34 (d, 2 H), 5.06 (d, 2 H), 4.64 (s, 2 H). MS (ESI) m / z: 453.9 [M+H+], Examples 90 to 93 in the following table were prepared in a similar manner to Example 89. 120 IF-2018-68202357-APN-ANP#INPI Page 120 of 185 Ex.No. Structure Chemical name Mass [M+H]+ 90 co LL yX xz y=O ofx 0¾2 1 Q CO u. 3-(4-(4-(hydroxymethyl)-6(trifluoromethyl)pyridin-3yl)phenyl)-N-(5(trifluoromethyl)oxazol-2yl)oxetan-3-carboxamide 488.1 91 Π ω °\ 1 / \ z° Ο=Λ V ZT Ü N-cyclohexyl-3-(4-(4(hydroxymethyl)-6(trifluoromethyl)pyridin-3yl)phenyl)oxetan-3-carboxamide 435.2 92 co CO xz CQX <oZ<2 x 0 co U_ 3-(4-(4-(hydroxymethyl)-6(trifluoromethyl)pyridin-3yl)phenyl)-N-(5(trifluoromethyl)thiazol-2yl)oxetan-3-carboxamide 503.9 93 co UL O 5b xz. )=° 1 0 co U_ 3-(4-(4-(hydroxymethyl)-6(trifluoromethyl)pyridin-3yl)phenyl)-N-(4(trifluoromethyl)oxazol-2yl)oxetan-3-carboxamide 488.0 121 IF-2018-68202357-APN-ANP#INPI Page 121 of 185 Example 94: N-(4-fluorophenyl)-l-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-r3.3'-bipyridinl-6iQcyclobutanecarboxamide Stage 1: l-(5-bromopyridin-2-yl)cyclobutanecarboxylic acid To a solution of l-(5-bromopyridin-2-yl)cyclobutanecarbonitrile (2.0 g, 8.44 mmol) in water (2 ml) and EtOH (15 ml) was added NaOH (1.687 g, 42.2 mmol ) with stirring at room temperature under nitrogen and the reaction mixture was stirred at 85 °C for 18 h. The reaction was cooled to room temperature and concentrated. The residue was diluted with DCM (20 ml) and filtered. The filtered cake was suspended in EtOAc (20 ml) and water (20 ml) with stirring, then 3 N HC1 was added until pH~3 and all the solid was dissolved. The mixture was extracted with EtOAc (20 mlx2), the organic layers were combined, washed with brine (60 ml), dried over Na2SO4, filtered and concentrated to obtain the title compound as an oil, which was used directly in the next stage without further purification. MS (ESI) m / z: 257.9 [M+H+], Step 2: 1 -(5-bromopyridin-2-yl)-N-(4-fluorophenyl)cyclobutanecarboxamide To a stirred solution of l-(5-bromopyridin-2yl)cyclobutanecarboxylic acid (2.16 g, 8.43 mmol) and DIEA (4.72 ml, 27.0 mmol) in DCM (20 ml) were added HATU ( 4.11 g, 10.80 mmol) and 4-fluoroaniline (1.0 g, 9.00 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. The reaction mixture was poured into water (100 ml) and extracted with EtOAc (15 ml x3). The combined organic layer was washed with brine (20 mL) and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to obtain the title compound as a solid. MS (ESI) m / z: 350.8 [M+H+], 122 IF-2018-68202357-APN-ANP#INPI Page 122 of 185 Step 3: N-(4-fluorophenyl)-l-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl')pyridin-2ylcyclobutanecarboxamide To a solution of l-(5-bromopyridin-2-yl)-N-(4fluorophenyl)cyclobutanecarboxamide (500 mg, 1,432 mmol) and 4,4,4',4',5,5,5',5'- octamethyl2,2'-bi(l,3,2-dioxaborolane) (545 mg, 2.148 mmol) in dioxane (20 ml) KOAc (281 mg, 2.86 mmol) and Pd(dtbpf)Cl2 (47 mg, 0.072 mmol) with stirring at room temperature in nitrogen. The reaction mixture was stirred at 90 °C for 14 h. After cooling to room temperature and diluting with water (30 ml), the mixture was extracted with EtOAc (30 ml <3). The combined organic layer was washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography to obtain the title compound as a solid. MS (ESI) m / z: 315.0 (the mass of the corresponding boronic acid). Step 4: N-(4-fluorophenyl)-l-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-13.3l-bipyridinl-6iDcyclobutanecarboxamide To a solution of N-(4-fluorophenyl)-l-(5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)pyridin-2-yl)cyclobutanecarboxamide (50 mg, 0.126 mmol) in 1,4dioxane (1 ml) and water (0.2 ml) Pd(dtbpf)Cl2 (8 mg, 0.012 mmol), (5bromo-2-(trifluoromethyl)pyridin-4-yl)methanol (33) were added mg, 0.129 mmol) and potassium phosphate (80 mg, 0.379 mmol) at room temperature. The reaction was stirred at 100 °C in my microwave for 0.5 h. The solvent was removed, and the residue was diluted with water (5 ml), and extracted with EtOAc (5 ml x3). The organic layers were collected, washed with brine (10 ml), dried in Na2SO4, filtered, and the filtrate was concentrated in vacuo. The reaction mixture was purified by reverse phase HPLC on a GILSON 281 instrument equipped with Waters C18 obtain the title compound as a solid. 1H NMR (400 MHz, CD3OD) δ 8.71 (d, 1 H), 8.61 (s, 1 H), 8.09 (s, 1 H), 8.02 (br d, 1 H), 7.74 (d, 1 H), 7.51 - 7.58 (m, 2 H), 7.03 (t, 2 H), 4.66 (s, 2 H), 2.91 - 3.09 (m, 2 H), 2.71 - 2.88 (m, 2 H), 1.93 - 2.16 ( m, 2H). MS (ESI) m / z: 446.0 [M+H+], 123 IF-2018-68202357-APN-ANP#INPI Page 123 of 185 Example 95: N-(4-fluorophenyl)-1 -Í4'-Í 1 -hydroxycyclobutyl)-6'-(trifluoromethyl)-r 3,3'bipyridin1-6-yl)cyclobutanecarboxamide Pd(dtbpf)CI2K3PO4-----► thf-h2o, 90 °C. 4 p.m. Step 1: l-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)cyclobutanol To a solution of 5-bromo-2-(trifluoromethyl)pyridine (1 g, 4.42 mmol) in THF (20 ml) was added LDA (2.4 ml, 4.87 mmol) dropwise at -60 °C in nitrogen. After 3 h, cyclobutanone (0.372 g, 5.31 mmol) was added dropwise at -60 °C, the mixture was stirred at this temperature for 1 h, and warmed to room temperature. The reaction was quenched with saturated aqueous NH4Cl (10 ml) and extracted with EtOAc (15 mlx2). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography to obtain the title compound as a solid. MS (ESI) m / z: 295.9, 297.9 [M+H+]. Step 2: N-(4-fluorophenyl)-l-(4'-(l-hydroxycyclobutyl)-6l-(trifluoromethyl)-r3,3'-bipyridin16-yl)cyclobutanecarboxamide To a solution of N-(4-fluorophenyl)-l-(5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)pyridin-2-yl)cyclobutanecarboxamide (50 mg, 0.126 mmol) and l-(5bromo-2-(trifluoromethyl)pyridin-4-yl)cyclobutanol (45 mg, 0.152 mmol) in THF (2.0 ml) and water (0.2 ml) K3PO4 (80 mg, 0.379 mmol) and Pd(dtbpf)Cl2(8 mg, 0.012 mmol) with stirring at room temperature in nitrogen. The reaction mixture was stirred at 90 °C for 14 h. The reaction was cooled to room temperature, diluted with water (5 ml), and the mixture was extracted with EtOAc (5 ml <3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with YMC-Actus Pro C18 column (150x 30x5 um) using water (0.1% TFA) and ACN as eluents, followed by lyophilization to obtain the compound. title as a solid. 1H NMR (400 MHz,CD3OD) δ 8.79 (s, 1 H), 8.59 (s, 1 H), 8.14 (dd, 1 H), 7.80 (s, 1 H), 7.73 (d, 1 H), 7.53 (dd, 2 H), 7.03 (t, .7=8.8 Hz, 2 H), 2.93 - 3.04 (m, 2 124 IF-2018-68202357-APN-ANP#INPI Page 124 of 185 Η), 2.74 - 2.84 (m, 2 Η), 2.27 - 2.39 (m, 2 Η), 1.91 - 2.13 (m, 5 Η), 1.62 (br d, 1 H). MS (ESI) m / z: 486.3 [M+H+], Examples 96 to 97 in the following table were prepared in a similar manner to Example 95. Ex.No. Structure Chemical name Mass [M+H]+ 96 1Ί U> °\ 1 O zx fi N-(4-fluorophenyl)-1 -(5-(2(hydroxymethyl)-4(trifluoromethyl)phenyl) pyridin-2-yl) cyclobutanecarboxamide 444.9 97 LL 0 IZ \=o o 0¾2 x b <*) u. N-(4-fluorophenyl)-1 -(4'-(2hydroxypropan-2-yl)-6'(trifluoromethyl)-[3,3-bipyridin] 6-yl)cyclobutanecarboxamide 474.0 Example 98: N-(4-fluorophenyl)-3-(4-(3-(hydroxymethyl)-5-(trifluoromethyl)pyridin-2iDfeniDoxetan-3-carboxanide Stage 1: 2-chloro-5-(trifluoromethyl)nicotinaldehyde To a stirred solution of 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (3 g, 11.52 mmol) in toluene (60 ml) was added n-BuLi (6 ml, 15.00 mmol) (hexane 2.5 M) at -78 °C, and the reaction was stirred at -78 °C for 1.5 h. Then, DMF (1.2 ml, 15.5 mmol) was added at −78 °C, and the resulting mixture was stirred at −78 °C for 0.5 h. The reaction was quenched with HC1 (1 M) (60 ml), then extracted with EtOAc (50 ml <2). The organic layers were collected, washed with brine, dried in Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to obtain the title compound as an oil. 1H NMR (500 MHz, CDC13) δ 10.44 - 10.51 (m, 1 H) 8.87 (d, 1 H) 8.47 (d, 1 H) 125 IF-2018-68202357-APN-ANP#INPI Page 125 of 185 Stage 2: (2-chloro-5-(trifluoromethyl)pyridin-3-yl)methanol To a stirred solution of 2-chloro-5-(trifluoromethyl)nicotinaldehyde (780 mg, 3.72 mmol) in MeOH (5 ml) was added NaBH4 (141 mg, 3.72 mmol) at 0 °C and the reaction was stirred at 0 °C for 1 h. The reaction mixture was quenched with saturated NH4C1 (5 ml), then extracted with EtOAc (5 ml <2). The organic layers were collected, washed with brine, dried in Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to obtain the title compound as an oil. MS (ESI) m / z: 212.0 [M+H+]. Step 3:N-(4-fluorophenyl)-3-(4-(3-(hydroxymethyl)-5-(trifluoromethyl)pyridin-2iDphenyl)oxetan-3-carboxamide To a stirred solution of (2-chloro-5-(trifluoromethyl)pyridin-3-yl)methanol (40 mg, 0.189 mmol) and N-(4-fluorophenyl)-3-(4-(4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2yl)phenyl-)oxetan-3-carboxamide (75 mg, 0.189 mmol) in THF (2 ml) and water (0.4 ml) K3PO4 (120 mg, 0.567 mmol) and Pd(dtbpf)C12 (13 mg, 0.020 mmol) at room temperature. The reaction was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (2 mL), and extracted with EtOAc (2 mL x 2). The organic layers were collected, washed with brine, dried in Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with Boston Green ODS column (150 x 30 x 5 um) using water (0.1% TFA)-CH3CN as eluents, and then concentration (below 50 °C) to obtain the title compound as an oil. 1H NMR (500 MHz, CD3OD) δ 8.85 (br s, 1 H) 8.38 (s, 1 H) 7.63 - 7.70 (m, 4 H) 7.52 - 7.61 (m, 2 H) 7.00 - 7.10 (m, 2 H) ) 5.36 (d, 2 H) 5.04 (d, 2 H) 4.67 (s, 2 H). MS (ESI) m / z: 447.0 [M+H+]. Example 99: N-(4-fluorophenyl)-3 -(4-(4-(1-hydroxycyclobutyl)-6-(trifluoromethyl)pyridin-3 - To a solution of N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (35 mg, 0.088 mmol) and l-(5-bromo-2126 IF-2018-68202357-APN-ANP#INPI Page 126 of 185 (trifluorometu)pyridm-4-yl)cyclobutanol (30 mg, 0.101 mmol) in THF (2.0 ml) and water (0.2 ml) K3PO4 (56 mg, 0.264 mmol) and Pd( dtbpf)C12 (6 mg, 9.21 pmol). The reaction mixture was sealed and stirred at 100 °C in a microwave for 0.5 h. The reaction was cooled to room temperature and diluted with water (5 ml). The mixture was extracted with EtOAc (5 mlx3), the combined organic layer was washed with brine (5 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with YMC-Actus Pro C18 column (150 x 30 x5 um) using water (0.1% TFA) and ACN as eluents, and then lyophilization to obtain the title compound as a solid. 1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1 H), 7.75 (s, 1 H), 7.52 - 7.64 (m, 6 H), 6.98 - 7.13 (m, 2 H), 5.36 (d, 2 H), 5.03 (d, 2 H), 2.22 - 2.32 (m, 2 H), 2.02 - 2.12 (m, 1 H), 1.93 - 2.01 (m, 2 H), 1.52 - 1.62 (m, 1 H) . MS (ESI) m / z: 487.0[M+H+], Example 100: N-(4-fluorophenyl)-3-(4-(4-(l-hydroxycyclonropyl)-6-(trifluoromethyl)pyridin3-yl)phenyl)oxetan-3-carboxamide Stage 1: 1-ethoxycyclopropanol To a solution of (l-ethoxycyclopropoxy)trimethylsilane (5.0 g, 28.7 mmol) in MeOH (35 ml) was added 14.0 M HC (0.07 ml, 0.274 mmol, in MeOH) with stirring at room temperature. . The reaction mixture was stirred at room temperature for 14 h. The solvent was removed and the residue was purified by distillation under reduced pressure (65 °C, 10-12 mbar) to obtain the title compound as an oil. 1H NMR (400 MHz, CDC13) δ 3.76 (q, 2 H), 3.14 (br s, 1 H), 1.22 (t, 3 H), 0.91 - 0.99 (m, 4H). Step 2: l-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)cyclopropan-l-ol To a solution of 5-chloro-2-(trifluoromethyl)pyridine (2.0 g, 11.02 mmol) in THF (8 ml) was added TMPMgCFLiCl (12.12 ml, 12.12 mmol) dropwise at 0° C in 127 IF-2018-68202357-APN-ANP#INPI Page 127 of 185 nitrogen. The mixture was stirred at room temperature for 0.5 h. Concurrently, to a separate flask containing a solution of 1-ethoxycyclopropanol (1.238 g, 12.12 mmol) in THF (12.0 ml) was added methylmagnesium bromide (4.04 ml, 12.12 mmol) by drip at 0 °C, and the resulting white suspension was stirred at 0 °C for 10 min. The above organolithium solution was then added into this suspension and the resulting reaction mixture was stirred at room temperature for 30 min, and then stirred at 40 °C for 14 h. The reaction was cooled to 0 °C and quenched by the slow addition of saturated NH4C1 (25 ml). The mixture was diluted with EtOAc (20 ml), and filtered. The filtrate was extracted with EtOAc (15 ml <3). The combined organic layer was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / EtOAc (20:1-10:1) as eluent to obtain the crude product which was further purified by preparative TLC (petroleum ether / ethyl acetate 4 :1 as eluent) to obtain l-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)cyclopropanol as an oil. MS (ESI) m / z: 238 [M+H+], Step 3: N-(4-fluorophenyl)-3-(4-(4-(l-hydroxycyclopropyl)-6-(trifluoromethyl)pyridin-3ylphenyl)oxetan-3-carboxamide To a solution of l-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)cyclopropanol (10 mg, 0.042 mmol) and N-(4-fluorophenyl)-3-(4-(4,4,5 ,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenyl)oxetan-3-carboxamide (17 mg, 0.043 mmol) in dioxane (1.0 ml) and water (0.1 ml) sodium carbonate was added (18 mg, 0.170 mmol) and Pd(dtbpf)Cl2(3 mg, 4.60 pmol) with stirring at room temperature in nitrogen. The mixture was sealed and heated to 100 °C in a microwave for 40 min and then cooled to room temperature. The cooled mixture was diluted with water (2 ml) and extracted with EtOAc (5 ml <3). The combined organic layer was concentrated and the residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with Xtimate C18 column (150 * 25 mm * 5 um) using water (10 mM NH4HCO3) and ACN as eluents, and then freeze-drying to obtain the title compound as a solid. 1H NMR (500 MHz, CDC13) δ 8.62 - 8.74 (m, 1 H), 7.78 (s, 1 H), 7.67 - 7.72 (m, 1 H), 7.71 (d, J=8.2 Hz, 1 H), 7.49 (d, J=8.2 Hz, 2 H), 7.41 (t, J=6.4 Hz, 2 H), 6.97 - 7.07 (m, 3 H), 5.43 (d, J-6.0 Hz, 2 H), 5.12 (d, J=6.0 Hz, 2 H), 2.48 (s, 1 H), 1.05 - 1.16 (m, 2 H), 0.79 - 0.89 (m, 2 H). MS (ESI) m / z: 473.1[M+H+], 128 IF-2018-68202357-APN-ANP#INPI Page 128 of 185 Examples 101 and 102 in the following table were prepared in a similar manner to Example 100. Ex. No. Structure Chemical name Mass [M+H]+ 101 u_ 0 IZ °\Z\ <aQ 1 3-(4-(6-cyclopropoxy-4(hydroxymethyl)pyridin-3yl)phenyl)-N-( 4fluorophenyl)oxetan-3carboxamide 435.2 102 u_ 0 TZ . )=o 1 3-(4-(6-cyclopropoxy-4-(2hydroxypropan-2-yl)pyridin-3yl)phenyl)-N-(4fluorophenyl)oxetane-3carboxamide 463.2 Example 103: 5-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-N-methyl-25 (trifluoromethyl)isonicotinamide To a solution of N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (200 mg, 0.503 mmol) in dioxane (2.5 ml) and water (0.5 ml) were added Pd(dtbpf)Cl2 (32.8 mg, 0.050 mmol), methyl 5-bromo-2(trifluoromethyl)isonicotinate (143 mg, 0.503 mmol) and potassium phosphate (321 mg, 1,510 mmol) at room temperature. The mixture was subjected to the usual Suzuki coupling conditions and preparation procedures to obtain a crude product which was purified by silica gel flash chromatography to obtain the 129 IF-2018-68202357-APN-ANP#INPI Page 129 of 185 title compound like an oil. MS (ESI) m / z: 475.2 [M+H+], Stage______21_______Acid_______5-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-2(trifluoromethyl)isonicotinic To a solution give methyl 5-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3yl)phenyl)-2-(trifluoromethyl)isonicotinate (150 mg, 0.316 mmol) in THF (5 ml) and water ( 2.5 ml) LiOH (15 mg, 0.626 mmol) was added at room temperature. The reaction was stirred at room temperature for 3 h. The solvent was removed and the residue was acidified to pH=3 with 6 M HC1. The aqueous mixture was extracted with EtOAc (20 ml x3) with the addition of brine to the aqueous layer during extraction. The combined organics were washed with brine, dried over Na3SO4 and concentrated in vacuo to obtain the title compound as an oil. MS (ESI) m / z: 461.2[M+H+], Step 3:5-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-N-methyl-2(trifluoromethyl)isomcotinamide To a solution of 5-(4-(3-((4-fluoropheml)carbamoyl)oxetan-3yl)phenyl)-2-(trifluoromethyl)isonicotinic acid (120 mg, 0.261 mmol) in DMF (5 ml) TEA was added (0.2 ml, 1.435 mmol), HATU (99 mg, 0.261 mmol) and methylamine hydrochloride (18 mg, 0.267 mmol) at room temperature. The reaction was stirred for 16 h at room temperature. The reaction was diluted with water (40 ml), and extracted with EtOAc (30 ml <3). The combined organic layer was washed with brine (20 mL) and dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC with a 150 x 30 mm x 4 um Phenomenex C18 Synergi, and eluted with water (0.1% TFA)-ACN to obtain the title compound as a solid. 1H NMR (400 MHz, CD3OD) δ 8.80 (s, 1 H) 7.86 (s, 1 H) 7.60 - 7.64 (m, 2 H) 7.52 - 7.58 (m, 4 H) 7.04 (t, 2 H) 5.34 ( d, 2 H) 5.01 (d, 2 H) 2.70 - 2.74 (m, 3 H). MS (ESI) m / z: 474.2[M+H+], Example 104 in the table below was prepared similarly to Example 103. 130 IF-2018-68202357-APN-ANP#INPI Page 130 of 185 Ex.No. Structure Chemical name Mass [M+H]+ 104 0 ZZ OQX O \=y cm \ I IX 5-(4-(3-((4fluorophenyl)carbamoyl)oxet an-3-yl)phenyl) -2(trifluoromethyl)i sonicotine measure 460.1 Example 105: (R)-3-(4-(4-(l-amino-2,2,2-trifluoroethyl)-6-(trifluoromethyl)pyridin-3yl)phenyl)-N-(4-fluorophenyl)oxetan- 3-carboxamide nh2 CS2CO3 TMSCF3 TBAT» THF, -60 °C, 2.5 h cf3 CH2CI2r.t., 15h Step 1: -5-bromo-2-(trifluoromethyl)isonicotinaldehyde To a solution of diisopropylamine (1.343 g, 13.27 mmol) in THF (20 ml) was added butyllithium (4.60 ml, 11.50 mmol) dropwise at -60 °C in nitrogen. After 1 h, 5-bromo-2-(trifluoromethyl)pyridine (2.0 g, 8.85 mmol) in THF (5 mL) was added dropwise at -60 °C and the mixture was stirred at this temperature for 1 hour. DMF (3.43 ml, 44.2 mmol) was added to the above mixture and the solution was stirred at −60 °C for an additional 1 h. The reaction was quenched with saturated aqueous NH4Cl (100 ml) and extracted with EtOAc (20 ml <2). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography to obtain the title compound as an oil. 1H NMR (400 MHz, CDC13) δ 10.4 (s, 1H), 9.0 (s, 1H), 8.1 (s, 1H). 131 IF-2018-68202357-APN-ANP#INPI Page 131 of 185 Step 2: (R,E)-N-((5-bromo-2-(trifluoromethyl)pindin-4-yl)methylene)-2-methylpropan-2sulfinamide To a stirred solution of 5-bromo-2-(trifluoromethyl)isonicotinaldehyde (721 mg, 2.84 mmol) in CH2CI2 (20 ml) was added (R)-2-methylpropan-2-sulfinamide (344 mg, 2.84 mmol). mmol) and Cs2CO3 (1110 mg, 3.41 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 h. The reaction was concentrated to remove CH2CI2 and then diluted with water (30 ml) and extracted with EtOAc (30 ml x2). The organic layers were collected, washed with brine (20 ml), dried in Na2SO4, and after filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to obtain the title compound as a solid. 1H NMR (400 MHz, CDC13) δ 8.9 - 9.0 (m, 2 H), 8.2 (s, 1 H), 1.3 (s, 9 H). Step 3: (R)-N-(l-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)-2,2.2-trifluoroethyl)-2methylpropan-2-sulfinamide To a stirred solution of (R,Z)-N-((5-bromo-2-(trifluoromethyl)pyridin-4yl)methylene)-2-methylpropan-2-sulfmamide (659 mg, 1.845 mmol) in THF (10 ml ) TBAT (1195 mg, 2.214 mmol) was added at room temperature. The reaction was stirred at room temperature for 0.5 h. Then the mixture was cooled to −60 °C and trimethyl(trifluoromethyl)silane (1312 mg, 9.22 mmol) was added, and stirring was continued at 60 °C for 2 h. The mixture was quenched with aqueous NH4Cl (100 mL), extracted with EtOAc (30 mL x 2), and the organic layers were collected, washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to obtain the title compound as a solid. MS (ESI) m / z: 467.8 [M+ACN+H+]. Step 4: (Rj-l-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)-2,2,2trifluoroethanamine hydrochloride To a stirred solution of (R)-N-(l-(5-bromo-2-(trifluoromethyl)pyridin-4yl)-2,2,2-trifluoroethyl)-2-methylpropan-2-sulfinamide (90 mg, 0.211 mmol) in 1,4-dioxane (5 ml) 4 M HC1 (5 ml, 20.00 mmol, in dioxane) was added at room temperature. The reaction was stirred at room temperature for 15 h. The solvent was concentrated in vacuo to obtain the title compound as a solid, which was used in the next step without 132 IF-2018-68202357-APN-ANP#INPI Page 132 of 185 additional purification. MS (ESI) m / z: 363.8 [M +ACN+H+J. Step 5: (R)-3-(4-(4-(l-amino-2.2.2-trifluoroethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N(4-fluorophenyl)oxetan-3 -carboxamide To a stirred solution of (R)-l-(5-bromo-2(trifluoromethyl)pyridin-4-yl)-2,2,2-trifluoroethanamine hydrochloride (76 mg, 0.211 mmol) in 1,4dioxane (2, 5 ml) and water (0.5 ml) N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)phenyl)oxetan were added -3-carboxamide (101 mg, 0.254 mmol), K3PO4 (135 mg, 0.634 mmol) and Pd(dtbpf)Cl2 (16 mg, 0.025 mmol) at room temperature. The mixture was subjected to standard preparation and Suzuki coupling conditions to obtain a crude title compound which was purified by HPLC on a GILSON 281 instrument equipped with a Waters C18 XSELECT 150 x 30mm x 5um column using water ( 0.1% TFA)-CH3CN as mobile phases to obtain the title compound as a solid. 1H NMR (500 MHz, CDC13) δ 8.7 (s, 1 H), 8.0 (s, 1 H), 7.4 - 7.5 (m, 6 H), 7.1 (br s, 1 H), 7.0 (t, 2 H ), 5.4 (t, 2 H), 5.1 (dd, 2 H), 4.6 (q, 1 H). MS (ESI) m / z: 514.2 [M+H+], Example 106: (S)-3-(4-(4-(l-amino-2.2.2-trifluoroethyl)-6-(trifluoromethyl)pyridin-3yl)phenyl)-N-(4-phiorophenyl)oxetan-3- carboxamide nh2 Stage 1: (S.E)-N-((5-bromo-2-(trifluoromethyl)pyridin-4-yl)methylene)-2-methylpropan-2sulfinamide This compound was prepared similarly to Example 105 except that (S)-2-methylpropan-2-sulfmamide was used. MS (ESI) m / z: 400.1 [M+ACN+H+], Step 2: N-((S)-l-(5-bromo-2-itrifluoromethyl)pyridin-4-yl)-2.2.2-trifluoroethyl)-2methylpropan-2-sulfinamide This compound was prepared similarly to Example 105. MS (ESI) m / z: 470.1[M+ACN+H+], 133 IF-2018-68202357-APN-ANP#INPI Page 133 of 185 Step 3: (S)-l-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)-2,2,2trifluoroethanamine hydrochloride Hydrolysis was carried out similarly to Step 3 of Example 105. MS (ESI) m / z: 364.0 [M+ACN+H+], Step 5: (S)-3-(4-(4-(l-amino-2,2,2-trifluoroethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N(4-fluorophenyl)oxetan -3-carboxamide The title compound was prepared similarly to Example 105. 1H NMR (400 MHz, CDC13) δ 8.7 (s, 1 H), 8.0 (s, 1 H), 7.4 - 7.5 (m, 6 H), 7.1 ( br s, 1 H), 7.0 (br t, 2 H), 5.4 (t, 2 H), 5.1 - 5.2 (m, 2 H), 4.6 (q, 1 H). MS (ESI) m / z: 514.1 [M+H+]. Example 107: N-(4-fluorophenyl)-3-(4-(3-(2-hydroxypronan-2-yl)-5-(trifluoromethyl)pyridine -2-yl)phenyl)oxetan-3-carboxamide Stage 1: methyl 2-chloro-5-itrifluoromethyl)nicotinate To a stirred solution of 2-chloro-5-(trifluoromethyl)pyridine-3carboxylic acid (2 g, 8.87 mmol) in THF (5 mL) and MeOH (5 mL) was added (trimethylsilyl)diazomethane (8.87 mL). , 17.73 mmol) (2 M in hexane) dropwise at -20 °C and the reaction was stirred at -20 °C for 2 h. The solvent was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography to obtain the title compound as an oil. MS (ESI) m / z: 242.2 [M+H+] Stage 2: methyl 2-(4-(3-(í4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-5-(trifluoromethyl) nicotinate To a stirred solution of methyl 2-chloro-5-(trifluoromethyl)nicotinate (100 mg, 0.417 mmol) and N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2134 IF-2018-68202357-APN-ANP#INPI Page 134 of 185 yl)phenyl)oxetan-3-carboxamide (166 mg, 0.417 mmol) in THF (2 ml) Pd(dtbpf)C12 (28 mg, 0.043 mmol) and potassium phosphate (266 mg, 1.252 mmol) were added ) at room temperature. The mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with water (2 ml), extracted with EtOAc (1 mlx2), and the organic layers were collected, washed with brine, dried in Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to obtain the title compound as an oil. MS (ESI) m / z: 474.9 [M+H+], Step 3: N-(4-fluorophenyl)-3-(4-(3-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-2iDphenyl)oxetan-3-carboxamide To a stirred solution of methylmagnesium bromide (0.1 ml, 0.300 mmol) (3 M in hexane) in THF (0.5 ml) was added methyl 2-(4-(3-((4fluorophenyl)carbamoyl)oxetan- 3-yl)phenyl)-5-(trifluoromethyl)nicotinate (50 mg, 0.105 mmol) in THF (0.5 ml) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with NH4Cl (3 ml), diluted with water (2 ml), and extracted with EtOAc (5 ml <2). The organic layers were collected, washed with brine, dried in Na3SO4, and after filtration, the filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with a 150 x 30 x 5u YMC-Actus Pro C18 column using water (0.1% TFA)-CH3CN as eluents to obtain the title compound as a solid after freeze-drying. 1H NMR (500 MHz, CD3OD) δ 8.75 - 8.80 (m, 1 H) 8.68 (d, 1 H) 7.60 7.65 (m, 2 H) 7.52 - 7.58 (m, 2 H) 7.45 - 7.51 (m, 2 H) ) 7.01 - 7.12 (m, 2 H) 5.37 (d, 2 H) 5.05 (d, 2 H) 1.33 - 1.43 (m, 6 H). MS (ESI) m / z: 475.2 [M+H+] Example 108: 3-(4-(5-cyclonropoxy-3-(hydroxymethyl)pyridin-2-yl)phenyl)-N-(4fluorophenyl)oxetan-3-carboxamide 135 IF-2018-68202357-APN-ANPAINPI Page 135 of 185 Stage 1: 2-bromo-5-cyclopropoxy-3-methylpyridine To a solution of 6-bromo-5-methylpyridin-3-ol (500 mg, 2.66 mmol), bromocyclopropane (1287 mg, 10.64 mmol) and potassium iodide (50 mg, 0.301 mmol) in DMF (4 .0 ml) cesium carbonate (1300 mg, 3.99 mmol) was added at room temperature. The reaction vessel was sealed and microwave sealed at 150 °C in nitrogen for 1 h. The reaction mixture was cooled to room temperature and poured into water (20.0 ml) and extracted with ethyl acetate (10.0 ml x3). The combined organic layer was washed with brine, dried over Na2SÜ4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography to obtain the title compound as an oil. MS (ESI) m / z: 229.9[M+H+], Stage 2: 2-bromo-5-cyclopropoxynicotomic acid To a stirred mixture of 2-bromo-5-cyclopropoxy-3-methylpyridine (160 mg, 0.701 mmol) in water (10.0 ml) was added KMnO4 (443 mg, 2.81 mmol) in portions at room temperature. The reaction mixture was stirred at 100 °C for 3 h. The resulting mixture was then hot filtered through a Celite pad, the filtrate was cooled and washed with EtOAc (5 ml x3). The aqueous layer was acidified with 6N HC1 to pH=4, concentrated to a small volume (5 ml) and extracted with EtOAc (10 ml x 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to obtain the crude title compound as a solid. MS (ESI) m / z: 259.9 [M+H+], Stage 3: (2-bromo-5-cyclopropoxypyridin-3-yl)methanol To a stirred solution of 2-bromo-5-cyclopropoxynicotinic acid (30 mg, 0.116 mmol) in THF (2.0 ml) was added BH3 THF (0.50 ml, 0.500 mmol) dropwise at 0 °C and the mixture reaction was stirred at room temperature for 15 h. The mixture was carefully quenched with MeOH (5 mL), then concentrated in vacuo. The residue was purified by preparative TLC to obtain the title compound as an oil. MS (ESI) m / z: 243.9 [M+H+], 136 IF-2018-68202357-APN-ANP#INPI Page 136 of 185 Step 4:3-(4-(5-cycloproDoxy-3-(hydroxymethyf)pyridin-2-yl)phenyl)-N-(4fluorophenyl)oxetan-3-carboxamide To a stirred solution of N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (41 mg, 0.103 mmol) in dioxane (2.0 ml) and water (0.4 ml) K3PO4 (65 mg, 0.306 mmol) and Pd(dtbpf)C12 (7 mg, 10.74 pinol) were added at room temperature. The reaction was subjected to Suzuki preparation and coupling procedures to obtain the crude product which was purified by reverse phase HPLC on a GILSON 281 instrument equipped with Phenomenex C 18 Synergi column (250 x 21.2 mm x 4 pm ) using water (0.2% formic acid) and ACN as eluents, and then lyophilization to obtain the title compound as a solid. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, 1 H), 8.01 (d, 1 H), 7.52 - 7.68 (m, 6 H), 7.06 (t, 2 H), 5.36 (d, 2 H) , 5.04 (d, 2 H), 4.59 (s, 2 H), 4.02 (dt, 1 H), 0.79 - 0.96 (m, 4 H). MS (ESI) m / z: 435.1 [M+H+]. Example 109: 3-(4-(5-cyciopropoxy-3-(2-hydroxypropan-2-iDpyridin-2-yl)pheniD-N-(4fluorophenyl)oxetan-3-carboxamide tms-chn2 Pd(dtbpf)CI2 K3PO4 u Dioxane, H¡>0, 100 °C, 15 h Toluene, MeOH, rt, 15 h Stage 1: methyl 2-bromo-5-cyclopropoxynicotinate To a stirred solution of 2-bromo-5-cyclopropoxynicotinic acid (0.11 g, 0.426 mmol) in DCM (5 mL) and MeOH (2.5 mL) was added ((trimethylsilyl)methyl)diazene (0.64 mL). , 1,280 mmol) at 0 °C and the mixture was stirred at room temperature for 15 h. The solvent was concentrated under reduced pressure and the residue was purified by preparative TLC (petroleum ether / EtOAc -2:1) to obtain the title compound as an oil. MS (ESI) m / z: 271.8&273.8 [M+H+], 137 IF-2018-68202357-APN-ANP#INPI Page 137 of 185 Step 2: methyl 5-cyclopropoxy-2-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3yl jfem Dnicotinate To a stirred solution of N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (52 mg, 0.131 mmol) and methyl 2bromo-5-cyclopropoxynicotinate (30 mg, 0.110 mmol in dioxane (2 ml) and water (0.4 ml) were added K3PO4 (70 mg, 0.330 mmol) and Pd(dtbpf)C12 (7 mg, 10.74 pinol) at room temperature. The mixture was heated to 100°C with stirring for 16 h. After cooling to room temperature, the mixture was extracted with EtOAc (30 ml x2), the organic layers were collected, washed. with brine, dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=l:l) to obtain the title compound as an oil MS (ESI). m / z: 463.0 [M+H+], Step 3:3-(4-(5-cyclopropoxy-3-(2-hydroxypropan-2-yl)pyridin-2-yl)phenyl)-N-(4fluorophenyl)oxetan-3-carboxamide To a stirred solution of methyl 5-cycIopropoxy-2-(4-(3-((4fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)nicotinate (13 mg, 0.028 mmol) in THF (1 ml) was added MeMgBr 3 M (0.08 ml, 0.240 mmol) at room temperature. The mixture was stirred at room temperature for 15 h. The mixture was diluted with water (20 ml), extracted with EtOAc (20 ml x3), the organic layers were collected, washed with brine (10 ml), dried over Na2SÜ4, and after filtration, the filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with a Phenomenex C 18 Synergi column (150 x 30 mm x 4 um) which was eluted with water (0.225% FA)-ACN to obtain the compound. titer as a solid after lyophilization of the desired fractions. 1H NMR (400MHz, CD3OD) δ 8.41 (d, 1H), 8.36 (d, 1H), 7.65 (d, 2H), 7.57 7.52 (m, 4H), 7.06 (t, 2H), 5.37 (d, 2H), 5.04 (d, 2H), 4.08 (br s, 1H), 1.38 (s, 6H), 0.94 (br d, 2H), 0.85 (br s, 2H). MS (ESI) m / z: 463.2 M+H+], 138 IF-2018-68202357-APN-ANP#INPI Page 138 of 185 Example 110: 3-(4'-cyclopropoxy-2'-(2-hydroxypropan-2-iD-r 1.1l-biphenyl]-4-yl)-N-(4fluorophenyl)oxetan-3-carboxamide Stage 1: methyl 5-cyclopropoxy-2-nitrobenzoate To a stirred solution of methyl 5-fluoro-2-nitrobenzoate (1 g, 5.02 mmol) and cyclopropanol (0.3 g, 5.17 mmol) in NMP (20 ml) 2-methylpropan-2-olate was added dropwise. of potassium (7.5 ml, 7.50 mmol) (1 M in THF) at 0 °C. The reaction was stirred at 0 °C for 30 min. The mixture was warmed to room temperature and stirred at room temperature for 3 h. The reaction mixture was partitioned between EtOAc / petroleum ether (100 ml, 1 / 1 v / v) and water (80 ml). The organic layer was separated, washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography to obtain the title compound as an oil. 1H NMR (400 MHz, CD3OD) δ 8.07 (d, 1 H) 7.32 (dd, 2.8 Hz, 1 H) 7.26 - 7.30 (m, 1 H) 3.96 (tt, 3.0 Hz, 1 H) 3.89 (s, 3 H) 0.85 - 0.91 (m, 2 H) 0.76 - 0.80 (m, 2 H). Stage 2: methyl 2-amino-5-cyclopropoxybenzoate To a solution of methyl 5-cyclopropoxy-2-nitrobenzoate (300 mg, 1.265 mmol) in EtOH (10 ml) and water (2 ml) were added iron (353 mg, 6.32 mmol) and ammonium chloride (338 mg , 6.32 mmol) at room temperature. The mixture was stirred at 80 °C for 3 h. The reaction was filtered and concentrated under reduced pressure. The residue was diluted with water (30 ml), extracted with EtOAc (15 mix2), and the combined organic layer was washed with brine (10 ml), dried over Na2SÜ4, filtered and concentrated under reduced pressure to obtain the title compound as an oil, which was used in the next step without further purification. MS (ESI) m / z: 208.1 [M+H+], 139 IF-2018-68202357-APN-ANP#INPI Page 139 of 185 Stage 3: methyl 2-bromo-5-cyclonopoxybenzoate To a solution of methyl 2-amino-5-cyclopropoxybenzoate (50 mg, 0.241 mmol) in CH3CN (5 ml) were added copper(I) bromide (70 mg, 0.483 mmol) and tert-butyl nitrite (50 mg, 0.483 mmol) at 0 °C. After stirring at room temperature for 16 h, the reaction was diluted with water (30 ml) and extracted with DCM (30 ml <3). The combined organic layer was washed with brine (20 mL) and dried over Na2SÜ4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc=2:1) ​​to obtain the title compound as an oil. 1H NMR (400 MHz, CDC13) δ 7.52 (d, 1 H) 7.46 (d, 1 H) 7.00 (dd, 1 H) 3.92 (s, 3 H) 3.71 - 3.76 (m, 1 H) 0.75 - 0.81 ( m, 4H). Step 4: 2-(2-bromo-5-cyclonronoxyphenyl')propan-2-ol To a solution of methyl 2-bromo-5-cyclopropoxybenzoate (70 mg, 0.258 mmol) in THF (5 ml) was added methylmagnesium bromide (0.3 ml, 0.900 mmol) (3 M in ethoxyethane) at 0 °C. Once the addition was complete, the reaction was stirred at room temperature for 16 h, quenched with saturated NH4C1 (20 mL, aqueous) slowly, and extracted with EtOAc (10 mL x3). The combined organic layer was washed with brine, dried over anhydrous Na2SÜ4, filtered and concentrated under reduced pressure to obtain the title compound as an oil, which was used in the next step without further purification. 1H NMR (400 MHz, CD3OD) δ 7.51 (d, Jl H), 7.44 (d, 1 H), 6.83 (dd, 1 H), 3.75 (td, 1 H), 1.68 (s, 6 H), 0.78 (br d, 2 H), 0.67 (br s, 2 H). Step 5:3 -(4'-cyclopropoxy-2'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl -4-yl)-N-(4fluorophenyl)oxetan-3-carboxamide To a solution of 2-(2-bromo-5-cyclopropoxyphenyl)propan-2-ol (80 mg, 0.295 mmol) in dioxane (5 ml) and water (1 ml) was added N-(4-fluorophenyl)-3 -(4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (117 mg, 0.295 mmol), Pd(dtbpf)C12 (19.23 mg, 0.030 mmol) and K3PO4 (188 mg, 0.885 mmol) at room temperature. The mixture was subjected to the usual preparation and Suzuki coupling conditions to obtain the crude product which was purified by reverse phase HPLC on a GILSON 281 instrument equipped with an Xtimate C18 150 x 25mm x 5 um column and the desired fractions were collected and concentrated to obtain the title compound as a solid. 1H NMR (400 140 IF-2018-68202357-APN-ANP#INPI Page 140 of 185 MHz, CD3OD) δ 7.56 (t, 2 Η) 7.43 - 7.48 (m, 3 Η) 7.32 (d, 2 Η) 7.06 (t, 2 Η) 6.89 - 6.94 (m, 2 Η) 5.34 (d, 2 Η) ) 5.02 (d, 2 Η) 3.80 (tt, 1 Η) 1.32 (s, 6 Η) 0.76 - 0.83 (m, 2 Η) 0.67 - 0.73 (m, 2 H). MS (ESI) m / z: 484.3 [M+Na+], Example 111: 3-(4'-cyclopronoxy-2'-(hydroxymethyl)-r 1,1'-biphenyl1-4-yl)-N-(4-fluorophenyl)oxetap-3-carboxamide Stage 1: (2-bromo-5-cycloorooxyphenyl)methanol To a stirred solution of methyl 2-bromo-5-cyclopropoxybenzoate (70 mg, 0.258 mmol) in THF (5 mL) was added lithium tetrahydroborate (16.87 mg, 0.775 mmol) at 0 °C and the mixture was heated to 70 °C for 16 h. The reaction was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (30 ml), extracted with EtOAc (15 mU2), and the combined organic layer was washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound as an oil, which was used in the next step without further purification. Step 2: 3-(4'-cyclonropoxy-2'-(hydroxymethyl)-r 1,1'-biphenyl]-4-yl)-N-(4-fluorophenyl)oxetan3-carboxamide N-(4-fluorophenyl)-3-( 4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (82 mg, 0.206 mmol), Pd(dppf)Cl2(15.05 mg, 0.021 mmol) and potassium phosphate (131 mg, 0.617 mmol) at room temperature. The mixture was subjected to the usual preparation and Suzuki coupling conditions to obtain a crude product that was purified by reverse phase HPLC on a GILSON 281 instrument equipped with a Phenomenex C 18 Synergi column (150 x 30 mm x 4 um ) to obtain the title compound as a solid. 1H NMR (400 MHz, CD3OD) δ 7.46 - 7.61 (m, 4 141 IF-2018-68202357-APN-ANP#INPI Page 141 of 185 Η) 7.40 (d, 2 Η) 7.26 (d, 1 Η) 7.16 (d, 1 Η) 6.96 - 7.11 (m, 3 Η) 5.33 (d, 2 Η) 5.01 (d, 2 Η) 4.48 (s, 2 Η) 3.81 (dt, 1 Η) 0.75 - 0.84 (m, 2 Η) 0.66 - 0.75 (m, 2 Η). MS (ESI) m / z: 456.1 [M+Na+], Example 112: N-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-isopronoxyioiridin-3yl)phenyl)oxetati-3-carboxamide Stage 1: 5-bromo-2-isoDropoxypyridine To a stirred solution of propan-2-ol (2.77 g, 46.0 mmol) in DMF (30 mL) was added sodium hydride (0.920 g, 23.01 mmol, 60% in oil) in nitrogen at 0 °C and the reaction mixture was stirred at room temperature for 15 h. 5-Bromo-2-fluoropyridine (2.7 g, 15.34 mmol) in DMF (5 mL) was then added and the reaction was heated to 130 °C for 4 h. After cooling to room temperature, the solvent was concentrated, and the residue was quenched with water (20 ml) and extracted with EtOAc (30x2 ml). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to obtain the title compound as an oil. MS (ESI) m / z: 215.9[M+H+], Stage 2: 5-bromo-2-isonropoxyisonicotinaldehyde To a solution of 5-bromo-2-isopropoxypyridine (1.8 g, 8.33 mmol) in THF (20 ml) was added LDA (5.00 ml, 10.00 mmol) at -60 °C and the mixture stirred at temperature for Ih. N,N-dimethylformamide (0.913 g, 12.50 mmol) was then added and the mixture was stirred at room temperature for 1 h. The solvent was concentrated, and the residue was quenched with water (20 ml) and extracted with EtOAc (30 ml x2). The organic layers were collected, washed with brine (20 ml), dried in Na2SO4, and after filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to obtain the title compound as an oil. M.S. 142 IF-2018-68202357-APN-ANP#INPI Page 142 of 185 (ESI) m / z: 243.9 [M+H+], Step 3: (5-bromo-2-isonropoxypyridin-4-yl)methanol To a stirred solution of 5-bromo-2-isopropoxyisonicotinaldehyde (1.286 g, 5.27 mmol) in THF (20 mL) and MeOH (20 mL) was added NaBFL» (0.299 g, 7.90 mmol) at 0 °C and the reaction was stirred at room temperature for 1 h. The reaction was quenched with NH4C1 (20 ml) and extracted with EtOAc (30 ml x2). The organic layers were collected, washed with brine (20 ml), dried over Na2SÜ4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to obtain the title compound as an oil. 1H NMR (400 MHz, CDC13) δ 8.14 (s, 1 H), 6.89 (s, 1 H), 5.23 (spt, 1 H), 4.67 (d, 2 H), 4.12 (q, 1 H), 1.34 (d, 6H). Step 4: N-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-isopronoxyridin-3-yl)phenyl)oxetan3-carboxamide To a stirred solution of N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (300 mg, 0.755 mmol) in 1,4dioxane (2.5 ml) and water (0.5 ml) PdCl2(dppf) (45 mg, 0.062 mmol) and K3PO4 (388 mg, 1.829 mmol) were added at room temperature. The mixture was subjected to standard Suzuki preparation and coupling conditions to obtain a crude title compound which was purified by HPLC on a GILSON 281 instrument equipped with a Waters C18 Xbridge Prep OBD column (100 x 19 mm x 5 um ) which was eluted with water (0.225% formic acid) / CH3CN to obtain the title compound as a solid after concentration of the desired fractions. 1H NMR (400 MHz, CDC13) δ 7.36 - 7.48 (m, 6 H), 6.94 - 7.06 (m, 4 H), 5.41 (d, 1 H), 5.29 - 5.38 (m, 1 H), 5.09 (d , 2 H), 4.63 (s, 2 H), 1.40 (d, 6 H). MS (ESI) m / z: 437.2 [M+H+], 143 IF-2018-68202357-APN-ANP#INPI Page 143 of 185 Example 113: N-(4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6(trifluoromethyl)pyridazin-3-iF)phenyl)oxetan-3-carboxainide Step 1: 2-(3-chloro-6-(trifluoromethyl~)pyridazin-4-yl)nronan-2-ol To a solution of 2.5 M BuLi in hexanes (1.3 ml, 3.3 mmol) was added THF (5 ml) dropwise with stirring -78 °C in nitrogen. 2,2,6,6-tetramethylpiperidine (503 mg, 3.56 mmol) was added at 0 °C. After stirring at 0 °C for 0.5 h, the mixture was cooled to −70 °C. 3-Chloro-6-(trifluoromethyl)pyridazine (500 mg, 2.74 mmol) was added to the mixture dropwise. The reaction mixture was stirred at −70 °C for 1.5 h. Acetone (3 ml, 40.9 mmol) was added to the mixture dropwise. The reaction mixture was stirred at -70 °C for 1 h, quenched with saturated aqueous ammonium chloride (5 mL), and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo, and the residue was purified by silica gel flash chromatography and then by preparative TLC (SiO2, petroleum ether / EtOAc = 3 / 1) to obtain the title compound as a solid. MS (ESI) m / z: 240.9 [M+H+]. Step 2: N-(4-fluorophenyl~)-3-('4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridazin-3iDphenyl)oxetan-3-carboxamide To a solution of 2-(3-chloro-6-(trifluoromethyl)pyridazin-4-yl)propan-2-ol (30 mg, 0.125 mmol) in dioxane (1 ml) and water (0.2 ml) were added N-(4-fluorophenyl)3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (1-9) (59 mg , 0.149 mmol), tribasic potassium phosphate (79 mg, 0.374 mmol) and l,l'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (8 mg, 0.012 mmol). The reaction was stirred at 100 °C for 16 h in nitrogen. The mixture was concentrated under reduced pressure to obtain a residue that was purified by preparative HPLC (Phenomenex C 18 Synergi column (150 x 30 mm x 4 um) using water (0.1% TFA)-ACN as mobile phases to obtain the title compound as a solid 1H NMR (400 MHz, 144 IF-2018-68202357-APN-ANP#INPI Page 144 of 185 MeOD) δ 8.47 (s, 1 Η), 7.68 - 7.66 (m, 2 Η), 7.58 - 7.55 (m, 4 Η), 5.38-5.37 (m, 2 Η), 5.06-5.05 (m, 2 Η), 3.3 (m, 4 Η), 1.38 (m, 6 H). MS (ESI) m / z: 476 [M+H+], Example 114: N-(4-chloropheml)-l-(5-(2-(hydroxymethyl)-4-(trifluoromethiPfeniP pyrazin-2iPcyclobutan-1-carboxamide Stage I: l-('5-bromopyrazin-2-iPcyclobutan-l-carbonitrile To a solution of 2,5-dibromopyrazine (200 mg, 0.841 mmol) in THF (10.0 mL) were added Nixantphos (46 mg, 0.083 mmol), Pd2(dba)3 (40 mg, 0.044 mmol) and cyclobutancarbonitrile ( 75 mg, 0.925 mmol), and then LiHMDS (1.6 mL, 1.600 mmol) (I M in THF) was added at 0 °C. The resulting mixture was heated to 80 °C for 15 h and cooled to room temperature, quenched with NH4C1 (10.0 ml) and extracted with EtOAc (20 ml x2). The combined organic layer was washed with brine and concentrated in vacuo. The residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with a Phenomenex C 18 Synergi column (250 x 21.2 mm x 4 pm) using water (0.2% formic acid) and ACN as eluents. The desired fractions were collected and concentrated by lyophilization to obtain the title compound as a solid. MS (ESI) m / z: 237.9 [M+H+], Step 2: 1 -(5-(2-((yther-butyldiphenylsiliPoxy)methiP-4-(trifluoromethiPfeniPpyrazin-2iDcyclobutan-1 -carbonitrile To a stirred solution of l-(5-bromopyrazin-2-yl)cyclobutanecarbonitrile (50 mg, 0.210 mmol) and tert-butyldiphenyl((2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2-yl)-5(trifluoromethyl)-benzyl)oxy)silane (125 mg, 0.231 mmol) in dioxane (1.0 ml) and water (0.2 145 IF-2018-68202357-APN-ANP#INPI Page 145 of 185 ml) K3PO4 (134 mg, 0.630 mmol) and Pd(dtbpf)C12 (10 mg, 0.015 mmol) were added at room temperature. The reaction was subjected to the usual preparation and Suzuki coupling procedures to obtain a crude title compound which was purified by preparative TLC (petroleum ether / ethyl acetate =5:1 as eluent) to obtain the title compound as an oil. MS (ESI) m / z: 572.2[M+H+]. Step 3: l-(5-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)pyrazin-2-yl)cyclobutane-Icarboxylic acid To a stirred solution of 1-(5-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4(trifluoromethyl)phenyl)pyrazin-2-yl)cyclobutanecarbonitrile (45 mg, 0.079 mmol) in ethanol (6, 0 ml) and water (2.0 ml), KOH (45 mg, 0.802 mmol) was added at room temperature and the reaction mixture was heated to 80 °C for 16 h. The solvent was removed by concentration in vacuo and the residue was diluted with water (2.0 ml) and extracted with EtOAc (3.0 ml). The aqueous layer was acidified with 3 N HC1 to pH=5 and extracted with EtOAc (3 ml x3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to obtain the title compound as an oil, which was used directly in the next step without further purification. MS (ESI) m / z: 353.0 [M+H+], Step 4: N-(4-chlorophenyl)-l -(5-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)pyrazin-2iDcyclobutan-1-carboxamide To a stirred solution of 4-chloroaniline (20 mg, 0.16 mmol), TEA (40 mg, 0.395 mmol) and l-(5-(3-(hydroxymethyl)-4-(trifluoromethyl)phenyl)pyrazin-2yljcyclobutan acid carboxylic acid (27 mg, 0.077 mmol) in DMF (1.0 ml), HATU (50 mg, 0.131 mmol) was added at room temperature and the reaction mixture was stirred at room temperature for 1 h. The residue was purified by HPLC. reverse phase on a GILSON 281 instrument equipped with a Phenomenex C 18 Synergi column (250 x 21.2 mm x 4 pm) using water (0.2% formic acid) and ACN as eluents. The title compound was obtained as eluents. a solid after lyophilizing the desired fractions 1H NMR (400 MHz, CDC13) δ 8.95 (d, 1 H), 8.78 (d, 1 H), 8.17 (s, 1 H), 7.84 (s, 1 H), 7.71 - 7.78 (m, 2 H), 7.49 (d, 2 H), 7.29 (s, 2 H), 4.57 (s, 2 H), 3.08 (ddd, 2 H), 2.73 - 2.83 (m, 2 H ), 2.13 - 2.29 (m, 1 H), 1.94 - 2.11 (m, 1 H). 146 IF-2018-68202357-APN-ANP#INPI Page 146 of 185 [M+H+], Example 115: N-(6-fluoropyridin-3-yl)-3-(4-(4-(2-hydroxypronan-2-yl)-6(trifluoromethyl)pyridin-3-yl)pheniI)oxetan-3-carboxamide To a stirred solution of 3-(4-bromophenyl)oxetane-3-carboxylic acid (1 g, 3.89 mmol) in pyridine (20 ml) was added 6-fluoropyridin-3-amine (0.654 g, 5.83 mmol ) and EDC (2.237 g, 11.67 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 h. The solvent was concentrated and the residue was diluted with water (20 ml) and extracted with ethyl acetate (30 ml x2). The organic layers were collected, washed with brine (20 ml), dried in Na2SO4, and after filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to obtain the title compound as a solid. MS (ESI) m / z: 351.0[M+H+]. Step 2: N-(6-fluoropyridin-3-yl')-3-(4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2yl)phenyl)oxetan-3-carboxamide To a stirred solution of 3-(4-bromophenyl)-N-(6-fluoropyridin-3yl)oxetane-3-carboxamide (1.3 g, 3.70 mmol) in 1,4-dioxane (10 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.128 g, 4.44 mmol), potassium acetate (1.090 g, 11.11 mmol) and Pd(dppf)Cl2(0.271 g, 0.370 mmol) at room temperature. The reaction mixture was heated to 100 °C with stirring for 15 h. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL x2). The organic layers were collected, washed with brine (30 ml), dried in Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to obtain 147 IF-2018-68202357-APN-ANP#INPI Page 147 of 185 the title compound as a solid. MS (ESI) m / z: 399.1[M+H+], Step 3;N-(6-fluoropyridin-3-yl)-3-('4-(4-C2-hydroxypropan-2-yl')-6(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3- carboxamide To a stirred solution of N-(6-phioropyridin-3-yl)-3-(4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (220 mg, 0.552 mmol) in 1,4-dioxane (2.5 ml) and water (0.5 ml) 2-(5-bromo-2(trifluoromethyl)pyridin-4-yl)propan-2- was added ol (189 mg, 0.665 mmol), K3PO4 (352 mg, 1.657 mmol), and Pd(dtbpf)C12 (36 mg, 0.055 mmol) at room temperature. The mixture was subjected to standard Suzuki preparation and coupling conditions to obtain a crude title compound which was purified by reverse phase HPLC on a GILSON 281 instrument equipped with a Waters C18 Xbridge Prep OBD column (100 x 19 mm x 5 um) using water (0.225% formic acid) and CH3CN as eluents to obtain the title compound as a solid. 1H NMR (500 MHz, CD3OD) δ 8.4 (br s, 1 H), 8.3 (s, 1 H), 8.2 - 8.3 (m, 2 H), 7.6 (br d, 2 H), 7.4 (br d, 2 H), 7.1 ( dd, 1 H), 5.4 (br d, 2 H), 5.1 (br d, 2 H), 1.4 (s, 6 H). MS (ESI) m / z: 476.1 [M+H+], Examples 116 and 117 in the following table were prepared in a similar manner to Example 115. Ex.No. Structure Chemical name Mass [M+H]+ 116 O h IXj S XI Λ. Xi n f O N 3 -(4-(6-cyclopropoxy-4(hydroxymethyl)pyridin-3yl)phenyl)-N-(6-fluoropyridin3-yl)oxetan-3 -carboxamide 436.2 117 O < > H XXj s XI A O ) 3-(4-(6-cyclopropoxy-4-(2hydroxypropan-2-yl)pyridin3-yl)phenyl)-N-(6fluoropyridin-3 -yl)oxetan-3 carboxamide 464.2 148 IF-2018-68202357-APN-ANP#INPI Page 148 of 185 Example 118: 3-fluoro-N-(4-fluorophenyl)-l-(4,-(hydroxymethyl)-6,-(trifluoromethyl)-F3.3'bipyridinl-6-yl)cyclobutanecarboxamide Step 1: l-(5-bromopyridin-2-yl)-3-methylenecyclobutanecarbonitrile To a solution of 5-bromo-2-fluoropyridine (10 g, 56.8 mmol) and 3-methylenecyclobutanecarbonitrile (5.29 g, 56.8 mmol) in toluene (50 ml) was added LiHMDS (31.3 ml, 62. 5 mmol) at 0 °C, and the mixture was stirred at 0 °C for 3 h. The reaction was diluted with aqueous NH4Cl (200 ml), extracted with EtOAc (100 ml x 2), the organic was collected and washed with brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to obtain the title compound as an oil. Step 2: l-(5-bromopyridin-2-yl)-3-oxocyclobutanecarbonitrile To a stirred solution of l-(5-bromopyridin-2-yl)-315 methylenecyclobutanecarbonitrile (500 mg, 2.007 mmol) in ACN (4 ml), DCM (4 ml) and water (6 ml) was added ruthenium chloride ( III) hydrate (46 mg, 0.204 mmol) and NaIO4 (2147 mg, 10.04 mmol) in portions at room temperature. The reaction was stirred to 149 IF-2018-68202357-APN-ANP#INPI Page 149 of 185 room temperature for 16 hours. The reaction was then quenched by the addition of saturated Na2S2O3 solution (50 ml) and the resulting mixture was extracted with EtOAc (100 ml*2). The organic layers were collected, washed with brine (30 ml), dried in Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to obtain the title compound as a solid. MS (ESI) m / z: 292.0; 294.0 [M+ACN+H+], Step 3: l-(5-bromopyridin-2-yl)-3-hydroxycyclobutanecarbonitrile To a solution of l-(5-bromopyridin-2-yl)-3-oxocyclobutanecarbonitrile (430 mg, 1.713 mmol) in MeOH (10 ml) was added NaBH4 (130 mg, 3.43 mmol) at 0 °C and the The mixture was stirred at 0 °C for 1 h. The reaction was carefully diluted with water (50 ml), and extracted with EtOAc (20 ml x 2). The organic was collected and washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to obtain the corresponding alcohol as a solid. Step 4: l-(5-bromopyridin-2-yl)-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarbonitrile To a solution of l-(5-bromopyridin-2-yl)-3hydroxycyclobutanecarbonitrile (300 mg, 1.185 mmol) in THF (10 ml) were added imidazole (161 mg, 2.371 mmol) and tert-butylchlorodimethylsilane (214 mg, 1.422 mmol ) at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was diluted with water (100 ml) and extracted with EtOAc (50 ml*2). The organic product was collected and washed with brine (10 ml), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to obtain the title compound as an oil. Stage 5: l-(5-bromopyridin-2-yl)-3-hydroxycyclobutanecarboxylic acid To a stirred solution of l-(5-bromopyridin-2-yl)-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarbonitrile (200 mg, 0.544 mmol) in EtOH (5 mL) and water (2.5 mL) was added NaOH (87 mg, 2.178 mmol) at room temperature. The reaction mixture was heated to 80 °C with stirring for 16 h. The solvent was removed by concentration in vacuo and the residue was dissolved in EtOAc. Aqueous 3N HC1 was added dropwise to adjust the pH ~2 and the mixture was extracted with EtOAc (20 ml3). 150 IF-2018-68202357-APN-ANPAINPI Page 150 of 185 The organic layers were collected, washed with brine, dried over Na2SO4, and after filtration, the filtrate was concentrated to obtain the title compound as a solid. MS (ESI) m / z: 272.0,274.0 [M+H+], Step 6: l-(5-bromopyridin-2-yl)-N-(4-fluorophenyl)-3-hydroxycyclobutanecarboxamide To a stirred solution of l-(5-bromopyridin-2-yl)-3hydroxycyclobutanecarboxylic acid (70 mg, 0.257 mmol) and HATU (293 mg, 0.772 mmol) in DCM (2 ml) was added TEA (0.2 ml, 1.435 mmol) and 4-fluoroaniline (35 mg, 0.315 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with water (50 ml), extracted with EtOAc (20 ml x3), and the organic layers were collected, washed with brine (10 ml), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC to obtain the title compound as an oil. MS (ESI) m / z: 365.1, 367.1 [M+H+]. Step 7: 1 -(5-bromopyridin-2-yl)-3-fluoro-N-(4-fluorophenyl)cyclobutanecarboxamide To a stirred solution of l-(5-bromopyridin-2-yl)-N-(4-fluorophenyl)-3hydroxycyclobutanecarboxamide (800 mg, 2.191 mmol) in DCM (20 ml) was added DAST (0.29 ml, 2.195 mmol ) at 0 °C and the reaction was stirred at room temperature for 1.5 h. The reaction was quenched by adding a saturated NaHCO3 solution (20 ml) and extracted with DCM (10 ml x2). The organic layers were collected, washed with brine (10 ml), dried in Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to obtain the title compound as a solid. MS (ESI) m / z: 366.9[M+H+]. Step 8: l-(4'-(((tert-butyldimethylsilyl~)oxy)methyl)-6'-(trifluoromethyl)-í3,3'-bipyridin1-6-yl)3-fluoro-N-(4-fluorophenyl )cyclobutanecarboxamide To a stirred solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine ( 273 mg, 0.654 mmol) in 1,4-dioxane (5 ml) and water (1 ml) were added K3PO4 (347 mg, 1.634 mmol), Pd(dtbpf)C12 (36 mg, 0.055 mmol) and l-(5 -bromopyridin-2-yl)-3-fluoro-N-(4fluorophenyl)cyclobutanecarboxamide (200 mg, 0.545 mmol) at room temperature. The mixture was subjected to Suzuki preparation and coupling conditions. 151 IF-2018-68202357-APN-ANP#INPI Page 151 of 185 I usually obtained the title compound as an oil, which was used in the next step without further purification. MS (ESI) m / z: 578.2[M+H+], Step 9: 3-fluoro-N-(4-fluorophenyl)-I-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-r3,3'5bipyridin1-6-yl)cyclobutanecarboxamide To a solution of l-(4'-(((tert-butyldimethylsilyl)oxy)methyl)-6'(trifluoromethyl)-[3,3'-bipyridin]-6-yl)-3-fluoro-N-(4 -fluorophenyl)cyclobutanecarboxamide (50 mg, 0.087 mmol) in THF (2 ml) TBAF (0.17 ml, 0.170 mmol) (1M in THF) was added at room temperature. The mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with Phenomenex C 18 Synergi column (150 x 30 mm x 4 um) using water (0.1% TFA) / ACN as eluents. . The title compound was obtained as a solid after lyophilization of the desired fractions. 1H NMR (500 MHz, CD3OD) δ 8.71 (d, 1 H), 8.63 (s, 1 H), 8.11 (s, 1 H), 7.97 (dd, 1 H), 7.62 (d, 1 H), 7.53 - 7.58 (m, 2 H), 7.04 - 7.09 (m, 2 H), 5.09 - 5.30 (m, 1 H), 4.68 (s, 2 H), 3.36 - 3.43 (m, 2 H), 2.89 - 3.01 (m, 2 H). MS (ESI) m / z: 464.1[M+H+] 152 IF-2018-68202357-APN-ANP#INPI Page 152 of 185 Example 119: 4-fluoro-N-(1-7-hydroxy-5-(2-methylpyrimidin-4-yl j-5.6.7.8-tetrahydro-1.5naphthyridin-2-yl)cyclopropyl)benzamide Step 1: 1-tert-butyl 3-ethyl 4-í(itrifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridin-L3(2H)5 dicarboxylate To a stirred solution of 1-tert-butyl 3-ethyl 4-oxopiperidin-l,3dicarboxylate (4.0 g, 14.74 mmol) and DIPEA (4.76 g, 36.9 mmol) in DCM (60 ml) Tf20 (3.2 ml, 18.94 mmol) was added dropwise at -70 °C and the reaction was stirred at -70 °C in nitrogen for 3 h. The mixture was diluted with water (40 ml) and extracted with 10 DCM (20 miχ3). The organic layers were collected, washed with brine, dried in Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to obtain the title compound as an oil. Step 2: 1-tert-butyl 3-ethyl 4-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-5,6dihydropyridine-1,3(2H)-dicarboxylate To a stirred solution of 1-tert-butyl 3-ethyl 4(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l,3(2H)-dicarboxylate (1.218 g, 3.02 mmol) and N- (4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)oxetan153 IF-2018-68202357-APN-ANP#INPI Page 153 of 185 3-carboxamide (1.0 g, 2.52 mmol) in THF (18 mL) potassium phosphate (1.603 g, 7.55 mmol) and Pd(dtbpf)Cl2 (9 mg, 0.014 mmol) were added at room temperature . The reaction mixture was stirred at 80 °C in nitrogen for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (80 ml) and extracted with EtOAc (100 mlx2). The organic layers were collected, washed with brine, dried in Na2SC>4, and after filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to obtain the title compound as a solid. Step 3: 1-tert-butyl 3-ethyl 4-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)pheniI)piperidinL3-dicarboxylate To a stirred solution of 1-tert-butyl 3-ethyl 4-(4-(3-((4fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-5,6-dihydropyridine-1,3 (2H)-dicarboxylate (1.1 g, 2.097 mmol) in MeOH (20 ml) magnesium (0.153 g, 6.29 mmol) was added at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and the cake was washed with MeOH (10 ml x2). The filtrates were combined and concentrated in vacuo. The residue was diluted with EtOAc (30 mL), washed with HC1 (20 mL, 2M) and brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to obtain the title compound as an oil, which It was used in the next step without further purification. MS (ESI) m / z: 549.0 [M+Na+], Step 4: tert-butyl 4-(4-í3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-3-(2hydroxypropan-2-yl)piperidine-1-carboxylate To a stirred solution of methylmagnesium bromide (2.215 ml, 6.65 mmol, 3 M in Et2O) in THF (5 ml) was added 1-tert-butyl 3-ethyl 4-(4-(3-((4fluorophenyl) carbamoyl)oxetan-3-yl)phenyl)piperidine-l,3-dicarboxylate (1.0 g, 1.899 mmol) in THF (20 ml) dropwise at room temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (10 ml x2). The organic layers were collected, washed with brine, dried in Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to obtain the title compound as an oil. MS (ESI) m / z: 513.1 [M+H+], 154 IF-2018-68202357-APN-ANP#INPI Page 154 of 185 Step 5: N-(4-fluorofeml)-3-(4-(3-(2-hydroxynropan-2-yl)piperidin-4-yl)phenyl)oxetan-3carboxamide To a stirred solution of tert-butyl 4-(4-(3-((4fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-3-(2-hydroxypropan-2-yl)piperidine-l-carboxylate (310 mg , 0.605 mmol) in DCM (5 ml) TFA (3 ml, 38.9 mmol) was added at room temperature. The reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated NaHCCL (40 ml) and extracted with DCM (15 ml x2). The organic layers were collected, washed with brine, dried over Na2SC>4, filtered, and the filtrate was concentrated in vacuo to obtain the title compound as an oil, which was used in the next step without further purification. MS (ESI) m / z: 413.1 [M+H+]. Step&.N-(4-fluorophenyl)-3-(4-(3-(2-hydroxypropan-2-yl)-l-(2.2.2trifluoroethyl)piperidin-4-iDphenyl)oxetan-3-carboxamide To a stirred solution of N-(4-fluorophenyl)-3-(4-(3-(2-hydroxypropan-2yl)piperidin-4-yl)phenyl)oxetan-3-carboxamide (210 mg, 0.509 mmol) in CH3CN (10 ml) 2,2,2-trifluoroethyl trifluoromethanesulfonate (236 mg, 1.018 mmol) and Cs2CO3 (332 mg, 1.018 mmol) were added at room temperature. The reaction was stirred at room temperature for 2 h. After filtration, the reaction was purified by reverse phase HPLC on a GILSON 281 instrument equipped with a Phenomenex Synergi C18 Column (150 x 30 mm x 4 um) eluting with water (0.1% TFA) and CH3CN to obtain peak 1, isomer 1 as a solid. Further elution yielded peak 2, isomer 2 as a solid. MS (ESI) m / z: 495.0 [M+H+]. Isomer 1 was resolved by SFC separation using a Phenomenex-Amylose-1 column (250 mm x 30 mm x 5 um) to obtain Example 119a (enantiomer 1, peak 1) and Example 119b (enantiomer 2, peak 2). Example 119a: 1H NMR (400 MHz, CD3OD) δ 7.50 (dd, 2H), 7.44 (d, 2H), 7.34 (d, 2H), 7.03 (t, 2H), 5.29 (d, 2H), 4.94 (d , 2H), 3.75 (br s, 3H), 3.61-3.62 (m, 1H), 3.343.40 (m, 1H), 2.62-2.96 (m, 3H), 2.23-2.34 (m, 1H), 1.81- 2.04 (m, 2H), 1.06 (s, 3H), 0.70 (s, 3H). MS (ESI) m / z: 495.1 [M+H+]. Example 119b: 1H NMR (400 MHz, CD3OD) δ 7.50 (dd, Hz, 2H), 7.44 (d, 2H), 7.34 (d, 2H), 7.03 (t, 2H), 5.29 (d, 2H), 4.94 (d, 2H), 3.75 (br s, 3H), 3.61-3.62 (m, 1H), 155 IF-2018-68202357-APN-ANP#INPI Page 155 of 185 3.34-3.40 (m, 1H), 2.62-2.96 (m, 3H), 2.23-2.34 (m, 1H), 1.81-2.04 (m, 2H), 1.06 (s, 3H), 0.70 (s, 3H). MS (ESI) m / z: 495.1 [M+H+], Isomer 2 was similarly resolved by SFC separation using a Phenomenex-Amylose-1 column (250 mm x 30 mm x 5 um) to obtain enantiomer 2-1 and enantiomer 2-2. Example 119c: 1H NMR (400 MHz, CD3OD) δ 7.42-7.56 (m, 6H), 7.04 (t, 2H), 5.30 (dd, 2H), 4.94 (br t, 2H), 3.71-4.04 (m, 3H ), 3.41-3.61 (m, 2H), 3.35 (br s, 1H), 3.173.25 (m, 1H), 2.16-2.58 (m, 3H), 1.21 (s, 3H), 0.71 (s, 3H) . MS (ESI) m / z: 495.1 [M+H+], Example 119d: 1H NMR (400 MHz, CD3OD) δ 7.42-7.58 (m, 6H), 7.04 (t, 2H), 5.30 (dd, 2H), 4.94 (t, 2H), 3.75-4.10 (m, 3H) , 3.53 (br s, 2H), 3.34 (br s, 1H), 3.20-3.28 (m, 1H), 2.17-2.58 (m, 3H), 1.22 (s, 3H), 0.71 (s, 3H). MS (ESI) m / z: 495.1 [M+H+], Example 120:7V-(4-fluorophenyl)-3-(4-(hydroxymethyl)-6'-(trifluoromethyl)-r3.3,-biniridinyl-6yl)oxetan-3-carboxamide TBSCI midazole stage 1 stage 3 Step 1: 5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoropyridine (B) To a vial equipped with a stir bar was added (5-bromo-2fluoropyridin-4-yl)methanol (A) (500 mg, 2.43 mmol), DMF (4.9 ml), imidazole (363 mg, 5, 34 mmol) and tert-butyldimethylsilyl chloride (402 mg, 2.67 mmol). The mixture was stirred at room temperature for 63 h. The reaction mixture was then diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer was then separated, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain the title compound. MS (ESI) 156 IF-2018-68202357-APN-ANP#INPI Page 156 of 185 m / z: 320, 322 [M+H]+. Step 2: 3-(5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)oxetan-3-carbonitrile (C) To a 50 ml round bottom flask with a stir bar under nitrogen was added 5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoropyridine (B) (712 mg, 2.22 mmol) , oxetan-3-carbonitrile (185 μΐ, 2.45 mmol) and toluene (18 ml). The flask was cooled to 0 °C and KHMDS (2668 μΐ, 2.67 mmol, 1.0 M in THF) was added dropwise with stirring. The solution was stirred for 10 min at 0 °C, after which the reaction was quenched by slow addition of MeOH with stirring. The resulting mixture was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc, and the combined organics were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was then purified by flash chromatography to obtain the title compound. MS (ESI): 383, 385 [M+H]+. Step 3:3-(5-bromo-4-(hydroxymethiI)pyridin-2-yl)-N-(4-fluorophenyl)oxetane-3carboxamide (D) To a vial equipped with a stir bar was added 3-(5-bromo-4(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)oxetan-3-carbonitrile (D) (410 mg, 1.07 mmol), NaOH (1.07 ml, 1.07 mmol, 1 N in water) and ethanol (2.7 ml). The vial was sealed and heated to 75 °C for 16 h. The reaction was then cooled and EtOAc (4 mL) was added, followed by HC1 (1 N in water) added dropwise to adjust the pH to ~2. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 3-(5-bromo-4(hydroxymethyl)pyridin-2-yl)oxetan-3-carboxylic acid ( loss of the TBS group was observed in the reaction conditions). 3-(5-bromo4-(hydroxymethyl)pyridin-2-yl)oxetan-3-carboxylic acid (308 mg, 1.069 mmol, crude material from the previous step), HATU (610 mg, 1.604 mmol) and DMF (5345 μΐ). 4-fluoroaniline (304 μΐ, 3.21 mmol) was then added, followed by DIEA (560 μΐ, 3.21 mmol). The reaction was stirred at room temperature for 48 h. Water and EtOAc were then added and the mixture was extracted with EtOAc. The combined organics were washed with brine, 157 IF-2018-68202357-APN-ANP#INPI Page 157 of 185 dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by flash chromatography (silica gel, eluted with a gradient of 0 - 100% EtOAc in hexanes) to obtain 3-(5-bromo-4(hydroxymethyl)pyridin-2-yl)-N -(4-fluorophenyl)oxetan-3-carboxamide. MS (ESI): 381, 383 [M+H]+. Step 4: N-f4-fluoropheniB-3-(4-(hydroxymethyl)-6'-(trifluoromethyl)-r3.3l-bipyridinl-6iI)oxetan-3-carboxamide A vial equipped with a stir bar was charged with 3-(5-bromo-4(hydroxymethyl)pyridin-2-yl)-N-(4-fluorophenyl)oxetan-3-carboxamide (65 mg, 0.17 mmol). , (6-(trifluoromethyl)pyridin-3-yl)boronic acid (48.8 mg, 0.256 mmol) and Xphos Pd G3 (14.4 mg, 0.017 mmol). The vial was then sealed and evacuated and refilled with argon (x3). Then, THF (3.4 ml) and tribasic potassium phosphate (512 μΐ, 0.512 mmol, 1 M aqueous solution) were added, and the reaction was heated to 50 °C for 1 h, and then to 80 °C for 1 h. The reaction was then cooled to room temperature and diluted with EtOAc and water. The reaction mixture was extracted with EtOAc and the combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMSO and purified by reverse phase preparative HPLC (5:95 to 95:5 acetonitrile:water:0.1% v / v TFA modifier) ​​to obtain the title compound as a TFA salt. 1H NMR (600 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.87 (d, J = 1.9 Hz, 1H), 8.58 (s, 1H), 8.22 (dd, J = 8.1, 2.0 Hz, 1H) , 8.04 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.67 - 7.71 (m, 2H), 7.24 - 7.08 (m, 2H), 5.20 (d, J = 6.4 Hz, 2H), 5.05 (d, J = 6.4 Hz, 2H), 4.51 (s, 2H). MS (ESI): 448 [M+H]+. Example 121: 3-(4-(6-(2,2-difluoroethoxy)-4-(hydroxymethyl)pyridin-3-ylphenyl)-N-(4fluorophenyl)oxetan-3-carboxamide N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (50 mg, 0.12 mmol), (5-bromo-2-(2.2158 IF-2018-68202357-APN-ANP#INPI Page 158 of 185 ) difluoroethoxy)pyridin-4-yl)methanol (38.5 mg, 0.143 mmol), XPhos Pd G3 (10 mg, 0.012 mmol), THF (600 pL) and K3PO4 (IM) (250 μΐ, 0.250 mmol). The mixture was evacuated and refilled with nitrogen 4 times and heated at 45 °C for 2 h. The mixture was filtered through a Celite pad. The filtrate was diluted with water and EtOAc, transferred to a separatory funnel. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to obtain a residue, which was purified by silica gel column chromatography to obtain the title compound. 1H NMR (600 MHz, DMSO-J6) δ 10.05 (s, 1H), 8.00 (s, 1H), 7.72 - 7.61 (m, 2H), 7.57 (d, 2H), 7.43 (d, 2H), 7.16 ( t, 2H), 7.06 (s, 1H), 6.41 (t, 1H), 5.23 (d, 2H), 10 4.91 (d, 2H), 4.70 - 4.50 (m, 2H), 4.44 (s, 2H). MS (El) m / z 459 [M+H]+. Examples 122 to 124 in the following table were prepared in a similar manner to Example 121. Ex.No. Structure Chemical name Mass [M+H]+ 122 f o 0 0-NH f3c—Z N= / \-__ / ~70 ^0 N-(4-fluorophenyl)-3-(4-(4( hydroxymethyl)-6-(2,2,2trifluoroethoxy)pyridin-3yl)phenyl)oxetan-3-carboxamide 477 123 LL ZI o<Sc° 0 vA 1 V 0 LL N-(4-fluorophenyl)-3 -(2 '-(1-hydroxycyclopropyl)-4'(trifluoromethyl)-[1,1-biphenyl]4-yl)oxetan-3-carboxamide 472 124 LL 0*070° 0*00. or LL N-(4-fluorophenyl)-1 -(2propionyl-4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl)cyclobutan1-carboxamide 472 Example 125: N-(4-fluorophenyl)-3-(2'-(hydroxymethyl)-4'-(trifluoromethoxy)-[1,1'-biphenyl- 159 IF-2018-68202357-APN-ANP#INPI Page 159 of 185 Stage 1: (2-bromo-5-(trifluoromethoxy)phenyl)methanol H.O. To a stirred solution of methyl 2-bromo-5-(trifluoromethoxy)benzoate (2.0 g, 6.7 mmol) in THF (21 mL) and MeOH (7 mL) was added NaBH4 (1.26 g, 33. 4 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h, then quenched with NH4C1 (saturated), diluted with EtOAc and water. The organic phase was separated from the aqueous phase, and the aqueous phase was extracted again with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to obtain the title compound, which was used directly in the next step 1H NMR (600 MHz, DMSO-í / 6) δ 7.72 (d, 1H), 7.46 (s, 1H), 7.30 7.16 (m, 1H), 5.68 (t, 1H), 4.52 (d, 2H). Step 2: N-(4-fluorophenyl)-3-(2l-(hydroxymethyl)-4'-(trifluoromethoxy)-n.r-biphenyl-4yl)oxetan-3-carboxamide The title compound was prepared analogously to Example 121. , 1H), 7.44 (d, 2H), 7.36 (d, 1H), 7.34 - 7.29 (m, 1H), 7.21 - 7.13 (m, 2H), 5.23 (d, 2H), 4.91 (d, 2H), 4.43 (s, 2H). MS (El) m / z 462 [M+H]+. 160 IF-2018-68202357-APN-ANP#INPI Page 160 of 185 Example 126: 3-(3-fluoro-4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4fluorophenyl)oxetan-3-carboxamide NaBH4 MeOH, THF stage 2 Tosil-CI .¿P KOtBu DMSO stage 1 i-O ._I ΌΗ Jones reagent TEA, pyridine, DCM stage 3 CS2CO3 THF stage 4 acetone stages Step 1: ethyl 2-í4-bromo-3-fluorophenyl)-3-hydroxy-2-(hydroxymethyljoropanoate Ethyl 2-(4-bromo-3-fluorophenyl)acetate (4.01 g, 15.4 mmol), DMSO (40 ml), and formaldehyde (1.84 g, 61.4 mmol) were charged to a flask. To this suspension was added KO*Bu (0.34 g, 3.07 mmol) in one portion. The mixture was stirred at room temperature for 30 min, quenched with 1 M HC1 (aqueous) and diluted with water. The mixture was transferred to a separatory funnel and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSÜ4, filtered and concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography to obtain the title compound. MS (El) m / z 321 [M+H]+. Step 2: 2-(4-bromo-3-fluorophenyl)-2-('hydroxymethyl)propan-1,3-diol Ethyl 2-(4-bromo-3-fluorophenyl)-3-hydroxy-2(hydroxymethyl)-propanoate (456.6 mg, 1.422 mmol), MeOH (2000 μΐ), and THF (6000 μΐ) were added to a flask. NaBH4 (300 mg, 7.93 mmol) was added to this mixture in one portion at 0°C. The mix 161 IF-2018-68202357-APN-ANP#INPI Page 161 of 185 was heated at 60 C for 2 h and another portion of NaBH4 (172 mg, 4.55 mmol) was added and further heated at 60 °C for another 1 h. The reaction was quenched with 5 ml of NH4Cl (saturated) and 5 ml of HC1 (1 M) to adjust pH~ 2, then extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered, concentrated in vacuo to obtain a crude product which was dissolved in 2 ml of DMSO and 1 ml of water. The mixture was stirred at room temperature overnight, then concentrated in vacuo and the residue was dissolved in DCM and washed with NalICOs, brine, dried over MgSO4, filtered and concentrated to obtain the title compound. 1H NMR (600 MHz, DMSO-í / 6) δ 7.58 (t, 1H), 7.40 (dd, 1H), 7.22 (d, 1H), 4.51 (t, 3H), 3.67 (d, 6H). Step 3:2-(4-bromo-3-fluorophenyl)-3-hydroxy-2-(hydroxymethyl)propyl 4methylbenzenesulfonate To a vial containing 2-(4-bromo-3-fluorophenyl)-2(hydroxymethyl)propan-l,3-diol (118 mg, 0.423 mmol) were added DCM (3500 pL) and TEA (200 pL, 1. 43 mmol). To this solution was added a solution of tosyl-Cl (81 mg, 0.42 mmol) in DCM (1000 pl) at 0 °C. The mixture was then stirred at room temperature for 24 h. LCMS showed low conversion. To this mixture were added pyridine (150 μl, 1.86 mmol) and another batch of tosyl-Cl (20 mg, 0.11 mmol). The mixture was stirred at room temperature for a further 4 h and diluted with DCM, washed with NaHCO3(satin), brine, dried over MgSCL, filtered, concentrated in vacuo to obtain the title compound, which was used directly in the next stage. MS (El) m / z 455 [M+Na]+. Step 4: (3-(4-bromo-3-fluorophenyl)oxetan-3-yl)methanol 2-(4-bromo-3-fluorophenyl)-3-hydroxy-2(hydroxymethyl)propyl 4-methylbenzenesulfonate (47.8 mg, 0.110 mmol), THF (1000 pl) and Cs2CO3 (108 mg, 0.331 mmol). The mixture was heated to 65 °C for 18 h, then to 70 °C for 3 h. The mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAC 3 times. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound, which was used directly in the next step. MS (El) m / z 261 [M+H]+. 162 IF-2018-68202357-APN-ANP#INPI Page 162 of 185 Step 5: 3-(4-bromo-3-fluorophenyl)oxetan-3-carboxylic acid Acetone (500 μΐ) and Jones reagent (110 μΐ, 0.72 mmol) were added to a vial containing (3-(4-bromo-3-fluorophenyl)oxetan-3-yl)methanol (262 mg, 0.100 mmol). ). The mixture was stirred at room temperature for 5 h, then diluted with EtOAc and water. The organic phase was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo to obtain the title compound, which was used directly in the next step. MS (El) m / z 275 [M+H]+. Step 6: 3-(4-bromo-3-fluorophenyl)-N-(4-fluoropheniDoxetan-3-carboxamide 3-(4-bromo-3-fluorophenyl)oxetane-3carboxylic acid (19.6 mg, 0.0710 mmol), HATU (54.2 mg, 0.143 mmol), DMF (800 μΐ), 4-fluoroaniline were added to a vial. (30 mg, 0.27 mmol) and DIEA (100 μΐ, 0.573 mmol). The mixture was stirred at room temperature for 18 h, diluted with EtOAc and washed with 1 M HC1, NaHCO3 (saturated) and brine, dried over Na2SC>4, filtered and concentrated in vacuo to obtain the title compound , which was used directly in the next stage. MS (El) m / z 368 [M+H]+. Step 7:3-(3-fluoro-4-(4,4,5,5-tetramethyl-L3.2-dioxaborolan-2-yl)phenyl)-N-(4fluorophenyl)oxetan-3-carboxamide 3-(4-bromo-3-fluorophenyl)-N-(4fluorophenyl)oxetan-3-carboxamide (26.2 mg, 0.0710 mmol), bis(pinacolato)diboron (45.2 mg, 0.178 mmol), potassium acetate (20.9 mg, 0.213 mmol), PdCb / dppf)CH2CI2 adduct (5.81 mg, 7.12 pmol), and dioxane (700 μΐ). The mixture was then evacuated and refilled with N2 3 times. The mixture was heated to 80 °C for 20 h, cooled to room temperature, and filtered through a celite pad. The filtrate was concentrated in vacuo to obtain a residue, which was dissolved in DCM, washed with water, brine, dried in Na2SC>4, filtered and concentrated in vacuo to obtain the title compound, which was used directly in the next stage. MS (El) m / z 416 [M+H]+. Step 8: 3-(3-fluoro-4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4fluoropheniDoxetan-3-carboxamide 3-(3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2163) was added to a vial. IF-2018-68202357-APN-ANP#INPI Page 163 of 185 dioxaborolan-2-yl)phenyl)-N-(4-fluorophenyl)oxetan-3-carboxamide (29.5 mg, 0.0710 mmol), (5-bromo-2-(trifluoromethyl)pyridin-4 -yl)methanol (35 mg, 0.14 mmol), DTBPF-Pd G3 (8.8 mg, 10 pmol), THF (700 μΐ), and K3PO4 (IM, 200 μΐ, 0.200 mmol). The mixture was evacuated and refilled with nitrogen 4 times and heated at 50 °C for 1.5 h. The mixture was filtered through a Celite pad, diluted with water and EtOAc, and transferred to a separatory funnel. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to obtain a residue, which was purified by silica gel column chromatography to obtain the title compound. 1H NMR (600 MHz, DMSO-í / 6) δ 10.08 (s, 1H), 9.97 (s, 1H), 8.63 (s, 1H), 8.05 (s, 1H), 7.65 (dd, 1H), 7.61 - 7.51 (m, 2H), 7.43 (d, 1H), 7.26 - 7.04 (m, 2H), 5.68 (t, 1H), 5.24 (d, 2H), 4.95 (d, 2H), 4.46 (d, 2H) . MS (El) m / z 465 [M+H]+. Example 127: N-(6-chloropyridin-3-yl)-3-(4'-(hydroxymethyl)-6l-(trifluoromethyl)-r3.3'bipyridinl-6-yl)oxetan-3-carboxamide Step 1:3-(5-bromopyridin-2-yl)-N-(6-chloropyridin-3-yl)oxetan-3-carboxamide either 3-(5bromopyridin-2-yl)oxetan-3-carboxylic acid (1023 mg, 3.96 mmol), HATU (2261 mg, 5.95 mmol), and DMF (9910 μΐ) were added to a vial equipped with a stir bar. ). To this was added 6-chloropyridin-3-amine (612 mg, 4.76 mmol) and then DIEA (2077 μΐ, 11.89 mmol). The mixture was stirred at 45 °C for 2 h and diluted with EtOAc, and washed with NaHCO3saturated. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography to obtain the title compound. MS (ESI) [M+H]+m / z: 368. 164 IF-2018-68202357-APN-ANP#INPI Page 164 of 185 Step 2: Preparation of N-(6-chloropyridin-3-yl)-3-(5-(4,4.5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyridin-2-yl)oxetan-3 -carboxamide ci To a vial equipped with a stir bar were added 3-(55-bromopyridm-2-yl)-N-(6-chloropyridin-3-yl)oxetan-3-carboxamide (952 mg, 2.58 mmol), bis(pinacolato )diboron (1640 mg, 6.46 mmol), potassium acetate (761 mg, 7.75 mmol) and PdChídppf)-CH2CI2 adduct (211 mg, 0.26 mmol) in dioxane (8612 μΐ). The vial was purged with nitrogen for 5 min and sealed and heated to 80 °C for 23 h. After cooling to room temperature, the mixture was diluted with EtOAc and washed with saturated NaHCO.3. The organics were dried in MgSO4, filtered, and dry loaded onto a silica gel, which was loaded onto an 80 g silica gel column. The column was eluted with 100% DCM to 100% EtOAc. The desired product was eluted and the fractions were collected and concentrated under reduced pressure to obtain the title compound. MS (ESI) calculated for C20H23BC1N3O4 [M+H]+, 334; found, 334 (note mass of boronic acid). Step 3: Preparation of N-(6-chloropyridin-3-yl)-3-(4'-(hydroxymethyl)-6'-(trifluoromethyl)Γ 3.3'-bipyridin-6-yl)oxetan-3-carboxamide To a vial equipped with a stir bar, N-(6-chloropyridin20 3-yl)-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin was added. -2-yl)oxetan-3-carboxamide (212 mg, 0.51 mmol), (5-bromo-2-(trifluoromethyl)pyridin-4-yl)methanol (131 mg, 0.51 mmol), potassium phosphate tribasic (1 M aqueous solution) (1020 μΐ, 1.02 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1, r-biphenyl)[2-(2'-amino-1,1' -biphenyl)]palladium(II) methanesulfonate (43.2 mg, 0.05 mmol) and THF (2550 μΐ). The vial was purged with nitrogen, sealed, and heated to 40°C for 1 h. After 1 h, the crude oil was filtered through Celite and rinsed with methanol. The combined organic layers were concentrated under reduced pressure. The material was dissolved in EtOAc, and loaded dry onto silica gel. The material was loaded onto a 40 g Gold column; was run from 100% DCM to 100% EtOAc. The desired product was eluted; The fractions were collected and concentrated under reduced pressure. The preparative resolution of the resulting material is 165 IF-2018-68202357-APN-ANP#INPI Page 165 of 185 performed using supercritical fluid chromatography on a Sepiatec Prep 100. An ES Industries GreenSep ethyl pyridine column (5 pm, 20 mm X 250 mm, ES Industries, West Berlin, NJ) was used as the stationary phase. The compound mixture was dissolved in a 1:1:1 mixture of Ν,Ν-dimethylformamide, methanol and ACN. Injection and harvesting were carried out using the following isocratic SFC conditions: 80% carbon dioxide and 20% methanol with 0.25% dimethylethylamine as mobile phase, UV wavelength 245 nm, outlet pressure 100 bar , column compartment temperature of 40 °C, total flow rate of 70 ml / min. The retention time for peak collection was 2.7 min. MS (ESI) calculated for C21H16C1F3N4O3 [M+H]+, 465; found, 465. 1H NMR (600 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.79 (d, J = 1.7 Hz, 1H), 8.71 (s, 1H), 8.70 (d, J = 2.7 Hz, 1H), 8.19 (dd, J = 8.7, 2.8 Hz, 1H), 8.09 (s, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.53 (d, J = 8.7 Hz, 1H), 5.75 (t, J - 5.5 Hz, 1H), 5.16 (dd, J = 91.1, 6.4 Hz, 4H), 4.61 (d, J = 5.4 Hz, 2H). Example 128: N-(4-fluorophenyl)-3-(5-(2-hydroxymethyl)-4-itrifluoromethyl)phenyl)DIridin-2yl)oxetan-3-carboxamide N-(4fluorophenyl)-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl) was added to a vial equipped with a stir bar. oxetan-3carboxamide (1-155; see Example 76 for preparation) (500 mg, 1.26 mmol), (2bromo-5-(trifluoromethyl)phenyl)methanol (320 mg, 1.26 mmol), tribasic potassium phosphate (1 M aqueous solution) (2511 pl, 2.51 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl,r-biphenyl)[2-(2'-amino-l,r-biphenyl )]palladium(II) methanesulfonate and THF (1,26E+04 pl). The vial was purged with nitrogen, sealed, and heated to 40 °C for 1.5 h. After 1.5 h, the crude oil was washed with EtOAc and saturated NaHCO3. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The material was dry loaded onto a 120 g Gold column; and the column was run from 100% DCM to 100% EtOAc. The desired product was eluted and the fractions were collected and concentrated under reduced pressure. The material was added to a vial, and ACN was added 166 IF-2018-68202357-APN-ANP#INPI Page 166 of 185 slowly drip. Almost immediately, a solid precipitated and there was a resulting liquid. More ACN was added dropwise, stirred, and the solid did not convert to solution. The mixture was heated with a heat gun to obtain a uniform solution. The mixture was left to stand for 3.5 h. After 3.5 h, the sample was moved into the refrigerator for 12 h. After 12 h, the mixture was rinsed with cold ACN (cooled in ice bath) and the title compound was obtained as a solid. MS (ESI) calculated for C23H18F4N2O3 [M+H]+, 447; found, 447. 1H NMR (600 MHz, DMSO-d6) 8 10.14 (s, 1H), 8.75 (d, J = 1.7 Hz, 1H), 8.01 (dd, J = 8.2, 2.4 Hz, 1H), 7.97 ( s, 1H), 7.78 (d, J = 6.9 Hz, 1H), 7.75 - 7.70 (m, 2H), 7.63 (dd, J = 60.7, 8.0 Hz, 2H), 7.25 - 7.17 (m, 2H), 5.51 (t, J = 5.4 Hz, 1H), 5.15 (dd, J - 76.2, 6.4 Hz, 4H), 4.52 (d, J = 5.4 Hz, 2H). Example 129: N-(6-chloropyridin-3-yl)-3-(4'-(2-hydroxypropan-2-yl)-6,-(trifluoromethyl)r3.3'-bipyridinyl-6-yl)oxetan- 3-carboxamide Step 1: 3-(5-(4.4.5.5-tetramethyl-L3.2-dioxaborolan-2-yl)niridin-2-yl)oxetan-3carbonitrile To a flask equipped with a stirring bar were added 3-(5bromopyridin-2-yl)oxetan-3-carbonitrile (2 g, 8.37 mmol), bis(pinacolato)diboron (4.25 g, 16.73 mmol) , potassium acetate (2.46 g, 25.10 mmol) and PdC12(dppf)-CH2C12 (0.68 g, 0.84 mmol). The mixture was purged with nitrogen for 5 min. Dioxane (41.8 ml) was added and the mixture was stirred. The resulting mixture was heated to 80 °C with stirring under nitrogen for 24 h. After 24 h, the crude reaction mixture was filtered through Celite, and rinsed with EtOAc. The combined organics were concentrated under reduced pressure. The residue was washed with EtOAc and water. The combined organics were dried over MgSÜ4, filtered and concentrated under reduced pressure. The residue was dissolved in DCM and loaded onto a 120 g Gold column. The column was run from 100% DCM to 100% EtOAc. The desired product was eluted and the fractions were collected and 167 IF-2018-68202357-APN-ANP#INPI Page 167 of 185 concentrated under reduced pressure to obtain the title compound. MS (ESI) calculated for C15H19BN2O3 [M+H]+, 205; found, 205 (detect the mass of boronic acid). Step 2: Preparation of 3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-I3.3'-bipyridinyl6-yl)oxetan-3-carbonitrile HO / — / — NC v / HVh N= / 1—0 To a round bottom flask equipped with a stir bar (under nitrogen) was added 3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl )oxetan3-carbonitrile (1.72 g, 6.01 mmol), 2-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)propan-2ol (1.88 g, 6.61 mmol), phosphate tribasic potassium (1M aqueous solution) (12.02 ml, 12.02 mmol), l,r-bis(di-tert-butylphospho)ferrocene-palladium dichloride (0.39 g, 0.60 mmol), and dioxane (10.02 mi). The vial was sealed with a top cap and purged with nitrogen while heated to 65 °C for 4 h. After 4 h, the reaction was cooled to room temperature. The reaction mixture was filtered through Celite, and rinsed with EtOAc. The combined organics were concentrated under reduced pressure and washed with EtOAc and water; The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting mixture was loaded dry onto an 80 g Gold column; the column was run from 100% DCM to 100% EtOAc. The desired product was eluted and the fractions were collected and concentrated under reduced pressure to obtain the title compound. MS (ESI) calculated for C18H16F3N3O2 [M+H]+, 364; found, 364. Stage 3; Preparation of 3-(4'-(2-hydroxynropan-2-yl)-6'-(trifluoromethyl)-r3,3'bipyridin1-6-yl)oxetane-3-carboxylic acid To a round bottom flask equipped with a stirring bar, 3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan was added. -3carbonitrile (932 mg, 2.57 mmol), NaOH (410 mg, 10.26 mmol), ethanol (8550 μΐ) and 168 IF-2018-68202357-APN-ANP#INPI Page 168 of 185 water (4275 μΐ). The flask was sealed and heated to 65 °C for 2 h. After 2 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The reaction mixture was dissolved in EtOAc, and 1 N HC1 was added dropwise to adjust the pH ~2. The mixture was washed with water and EtOAc. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure to obtain the title compound. MS (ESI) calculated for C18H17F3N2O4 [M+H]+, 383; found, 383. Step 4: Preparation of N-(6-chloropyridin-3-yl)-3-(4'-(2-hydroxynropan-2-yl)-6'(trifluoromethiD-13.3'-bipyridin1-6-yl)oxetan-3 -carboxamide 3-(4'-(2hydroxypropan-2-yl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3-carboxylic acid was added to a vial equipped with a stir bar. (34.5 mg, 0.09 mmol), HATU (51.5 mg, 0.14 mmol), and DMF (902 μΐ). The mixture was stirred for 5 min. 6-Chloropyridin-3-amine (58.0 mg, 0.45 mmol) was added, followed by DIEA (47.3 μΐ, 0.27 mmol). The mixture was stirred at 45 °C for 48 h. After 48 h, it was dry loaded onto a 24 g Gold column; the column was run from 100% DCM to 100% EtOAc. The desired product was eluted and the fractions were collected and concentrated under reduced pressure. The mixture was dissolved in ACN / water, then cooled and dried overnight. The resulting mixture was dissolved in 1.5 ml of DMSO, and directly subjected to HPLC purification (purified by HPLC, eluted with ACN / water gradient with TFA modifier, linear gradient) to obtain the title compound. MS (ESI) calculated for C23H2oC1F3N403 [M+H]+, 493; found, 493. IH NMR (600 MHz, DMSO-d6) δ 10.51 (s, IH), 8.71 (d, J = 2.7 Hz, IH), 8.66 (d, J = 1.8 Hz, IH), 8.46 (s, IH), 8.21 (d, J = 2.8 Hz, IH), 8.20 (d, J = 2.7 Hz, 2H), 7.94 (dd, J = 8.1, 2.3 Hz, IH), 7.70 (d, J = 8.0 Hz, IH), 7.55 (d, J = 8.7 Hz, IH), 5.16 (dd, J = 94.6, 6.4 Hz, 4H) l .35 (s, 6H). Examples 130 and 131 in the following table were prepared in a similar manner to Example 129. 169 IF-2018-68202357-APN-ANPAINPI Page 169 of 185 Ex. No. Structure Chemical name Mass [M+H]+ 130 “Π ω O c5 Ó Y oO\ v / =° TZ 9 N-(6-fluoropyridin-3 -yl)-3 -(4'(2 -hydroxypropan-2-yl)-6'(trifluoromethyl)-[3,3'bipyridin]-6-yl)oxetan-3carboxamide 477 131 u_ ZI o= / . 1 il)oxetan-3carboxamide 494 Example 132: N-(4-chlorophenyl)-3-(4'-(2-hydroxypropan-2-yl)-6l-(trifluoromethyl)-r3,3lbipyridinyl-6-yl)oxetan-3-carboxamide Step 1: 3-(5-bromopyridin-2-iB-N-(4-cloiPhenyl)oxetan-3-carboxamide 3-(5bromopyridin-2-yl)oxetan-3-carboxylic acid (500 mg, 1.94 mmol), HATU (1105 mg, 2.91 mmol), and DMF (4844 μΐ) were added to a vial equipped with a stir bar. ). 4-Chloroaniline (297 mg, 2.33 mmol) was added, followed by DIEA (1015 μΐ, 5.81 mmol). The mixture was stirred at 45 °C for 4 h. After 4 h, the crude oil was washed with EtOAc and saturated NaHCOs. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The material was dry loaded onto a 120 g Gold column, and the column was run from 100% hexanes to 100% EtOAc. The desired product was eluted and the fractions were collected and concentrated under reduced pressure to obtain the title compound. MS (ESI) calculated for C15H12BrClN2O2 [M+H]+, 367; found, 367. 170 IF-2018-68202357-APN-ANP#INPI Page 170 of 185 Step 2: N-(4-chlorophenyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl~)pyridm-2iDoxetan-3-carboxamide To a flask equipped with a stirring bar were added 3-(5bromopyridin-2-yl)-N-(4-chlorophenyl)oxetan-3-carboxamide (200 mg, 0.54 mmol), bis(pinacolato)diboron (207 mg , 0.82 mmol), potassium acetate (160 mg, 1.63 mmol) and PdC12(dppf)-CH2C12 adduct (44.4 mg, 0.054 mmol). The mixture was purged with nitrogen for 5 min. Dioxane (2720 μΐ) was added and the mixture was stirred. The vial was heated to 80 °C for 12 h. After 12 h, the crude oil was washed with EtOAc and saturated NaHCOa. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The material was dry loaded onto a 40 g Gold column, and the column was run from 100% DCM to 100% EtOAc. The desired product was eluted and the fractions were collected and concentrated under reduced pressure to obtain the title compound. MS (ESI) calculated for C2iH24BC1N2O4[M+H]+, 333; found, 333 (note mass of boronic acid). Step 3: N-(4-chlorophenyl)-3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-r3.3'-bipyridinl6-yl)oxetan-3-carboxamide N-(4chlorophenyl)-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl) was added to a vial equipped with a stir bar. oxetan-3carboxamide (93.7 mg, 0.23 mmol), 2-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)propan-2ol (70.6 mg, 0.25 mmol), phosphate tribasic potassium (1 M aqueous solution) (452 ​​μΐ, 0.45 mmol), PdC12(dtbpf) (29.5 mg, 0.045 mmol), and dioxane (1130 μΐ). The vial was purged with nitrogen, sealed, and heated to 65 °C for 22 h. After 22 h, 1 tablespoon of MgSO4 and then EtOAc was added, and the solid was filtered. The organics were concentrated under reduced pressure and dissolved in 1.5 ml of DMSO, and directly subjected to HPLC purification (purified by HPLC, eluted with ACN / water gradient with TFA modifier, linear gradient). The fractions were returned and frozen and dried in the freeze dryer overnight to obtain the title compound. MS (ESI) calculated for C24H2iC1F3N3O3 171 IF-2018-68202357-APN-ANP#INPI Page 171 of 185 [M+H]+, 492; found, 492. 1H NMR (600 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.67 (d, J = 1.7 Hz, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 7.93 ( dd, J = 8.1, 2.3 Hz, 1H), 7.79 - 7.70 (m, 2H), 7.66 (d, J - 8.0 Hz, 1H), 7.47 - 7.36 (m, 2H), 5.15 (dd, J = 86.8, 6.4 Hz, 4H), 1.35 (s, 6H). Examples 133 to 139 in the following table were prepared similarly to Example 112 using intermediate 1-9 (see Example 7 for preparation) and the corresponding alcohols. Ex. No. Structure Chemical name Mass [M+H]+ 133 „ i? 3-(4-(6-ethoxy-4(hydroxymethyl)pyridin-3yl)phenyl)-N-(4fluorophenyl)oxetane-3carboxamide 423 134 ) OVNH F—( 5= / 5= / l—o F 3-(4 '-(difluoromethoxy)-2'(hydroxymethyl)- [1,1 '-biphen.yl] -4yl)-N-(4-fluorophenyl)oxetan-3 carboxamide 444 135 „ ) °^NH 5=N 5 = / L_o N-(4-fluorophenyl)-3 -(4-(3 (hydroxymethyl)-5(trifluoromethyl)pyridin-2yl)phenyl)oxetan-3-carboxamide 447 136 „ δ > O^NH / \= / \ = / Lo N-(4-fluorophenyl)-3-(2'(hydroxymethyl)-4'-methoxy-[ 1,1'biphenyl]-4-yl)oxetan-3carboxamide 408 137 F . or O^NHF_( \=z \= / Lo F 3-(4'-(difluoromethoxy)-2'-(l hydroxyethyl)-[ 1,1 '-biphenyl]-4yl)-N-(4-fluorophenyl) oxetan-3carboxamide 458 172 IF-2018-68202357-APN-ANP#INPI Page 172 of 185 138 N==7 \= / Lo 3-(4-(2-cyclopropyl-4(hydroxymethyl)pyrimidin-5yl)phenyl)-N-(4fluorophenyl)oxetan-3carboxamide 420 139 - &g...

Claims

1. A compound of Formula (I), (FORMULA I) characterized in that: n is 1; p is 1; each instance of A is -CH=; M is selected from -O-, and -S-; R 1 is pyridinyl;wherein the pyridinyl group is optionally substituted with 1 to 3 substituents selected independently from: (a) halogen, (b) -C3-8 cycloalkyl, optionally substituted with -OH, (c) -CN, (d) oxo, (e) -O-C1-8 alkyl, optionally substituted with 1 to 5 halogens, (f) -O-C3-8 cycloalkyl, (g) -C1-8 alkyl, optionally substituted with 1 to 4 substituents selected independently from halogen, -OH, -NH2, NHC(O)R cy -S(O)2-C1-8 alkyl, wherein R c is selected from -C1-8 alkyl and -C3-8 cycloalkyl, (h) -NH-S(O)2-R c , wherein R c is selected from -C1-8 alkyl and -C3-8 cycloalkyl, (i) -C(O)-R f , R f is selected from -OH, -NH2 and -NH-C1-8 alkyl, (j) aryl, optionally substituted with 1 to 3 halogens, and (k) heterocyclyl optionally substituted with 1 to 3 substituents selected independently from halogen and -C1-8 alkyl; R 2 is phenyl;wherein the phenyl group is optionally substituted with 1 to 3 substituents independently selected from: (a) halogen, (b) -C3-8 cycloalkyl, (c) -CN, (d) -O-C1-8 alkyl, optionally substituted with 1 to 3 halogens, and (e) -C1-8 alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -OH, and -NH2; and R3 is selected from H, halogen, and -C1-8 alkyl, optionally substituted with -OH; or a pharmaceutically acceptable salt thereof. Twelve claims follow;