RU2786586C2 - New substituted biaryl compounds as indolamine-2,3-dioxygenase (ido) inhibitors - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to a compound of the formula (I) or its pharmaceutically acceptable salt, which have inhibitory activity relatively to indolamine-2,3-dioxygenase (hereinafter – IDO). In the specified formula, n is 1; p is 1; in each case, A is -CH=; M is -O-; R¹ is pyridinyl, where pyridinyl is optionally substituted with 1-3 substitutes independently selected from: (a) halogen, (b) -C_3-8-cycloalkyl optionally substituted with -OH, (e) -O-C_1-8-alkyl optionally substituted with 1-5 halogen atoms, (f) -O-C_3-8-cycloalkyl, (g) -C_1-8-alkyl optionally substituted with 1-4 substitutes independently selected from halogen, -OH, -NH₂, (i) -C(O)-R^f, where R^f is selected from -OH, -NH₂, and -NH-C_1-8-alkyl; R² is phenyl, where phenyl is optionally substituted with 1-3 substitutes independently selected from: (a) halogen, (c) -CN, (d) -O-C_1-8-alkyl optionally substituted with 1-3 halogen atoms, and (e) -C_1-8-alkyl optionally substituted with 1-3 substitutes independently selected from halogen; and R³ is selected from H and halogen. The invention also relates to a pharmaceutical composition inhibiting IDO and containing a pharmaceutically acceptable carrier and effective amount of the compound of the formula (I) or its pharmaceutically acceptable salt and to a separate compound of N-(4-fluorphenyl)-3-(4-(4-(2-hydroxypropane-2-yl)-6-(trifluoromethyl)pyridine-3-yl)phenyl)oxetane-3-carboxamide or its pharmaceutically acceptable salt.

EFFECT: obtainment of compounds for inhibition of indolamine-2,3-dioxygenase.

(I)

16 cl, 16 tbl, 152 ex

Description

BACKGROUND OF THE INVENTION

Tryptophan (Trp) is an essential amino acid required for the biosynthesis of proteins, niacin and the neurotransmitter 5-hydroxytryptamine (serotonin). The enzyme indolamine 2,3-dioxygenase (IDO) catalyzes the first and rate-limiting step in the degradation of L-tryptophan to N-formylkynurenine. In human cells, Trp depletion resulting from IDO activity is an important interferon-gamma (IFNγ) inducible antimicrobial effector mechanism. Stimulation of IFNγ induces IDO activation, which results in Trp depletion, thus resulting in growth arrest 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 has been observed in vivo during rejection of allogeneic tumors, suggesting a possible role for this enzyme in tumor rejection (Daubener, et 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 shown to acquire an immunoinhibitory phenotype through upregulation of IDO activity. It is believed that the decrease in PBL proliferation after treatment with interleukin-2 (IL-2) is due to IDO released by tumor cells in response to PBL IFNγ secretion. This effect is reversed by treatment with 1-methyltryptophan (IMT), a specific inhibitor of IDO. It has been suggested that IDO activity in tumor cells may impair antitumor responses (Logan, et al, 2002, Immunology, 105: 478-87).

Several lines of evidence suggest that IDO is involved in the induction of immunological tolerance. Studies of mammalian pregnancy, tumor resistance, chronic infections, and autoimmune diseases have shown that IDO-expressing cells can suppress T-cell responses and promote tolerance. Accelerated catabolism of Trp is observed in diseases and disorders associated with cellular activation of immunity, such as infections, malignancies, autoimmune diseases and AIDS, as well as during pregnancy. For example, in autoimmune diseases, elevated levels of IFN and elevated levels of Trp metabolites in the urine are determined; suggest that systemic or local depletion of Trp that occurs in autoimmune diseases may be associated with degradation and depletion symptoms in these diseases. In support of this hypothesis, high levels of IDO were detected in cells isolated from the synovial fluid of arthritis joints. IFN is also elevated in patients with human immunodeficiency virus (HIV), and elevated levels of IFN are associated with worse prognosis. Thus, it is suggested that IDO is chronically induced in HIV infection and further elevated in opportunistic infections, and that chronic loss of Trp triggers mechanisms responsible for cachexia, dementia and diarrhea and possibly immunosuppression in AIDS patients (Brown, et al., 1991, Adv. Exp. Med. Biol, 294: 425-35). In this regard, it has recently been shown that inhibition of IDO can increase levels of virus-specific T cells and simultaneously reduce the number of virus-infected macrophages in a mouse model of HIV (Portula et al., 2005, Blood, 106: 2382-90).

It is believed that IDO plays a role in immunosuppressive processes that prevent fetal rejection in utero . Over 40 years ago it was shown that during pregnancy a genetically different mammalian concept survived despite what would be suggested from tissue transplantation immunology (Medawar, 1953, Symp. Soc. Exp. Biol. 7: 320-38 ).

The anatomical separation of mother and fetus and antigenic immaturity of the fetus cannot fully explain the survival of the fetal allograft. Recently, attention has been focused on maternal immunological tolerance. Because IDO is expressed by human syncytiotrophoblastic cells and systemic tryptophan concentrations fall during normal pregnancy, it has been suggested that IDO expression at the transplacental barrier is necessary to prevent immunological rejection of fetal allografts. To test this hypothesis, pregnant mice (bearing syngeneic or allogeneic fetuses) were subjected to IMT and a rapid, T-cell-induced rejection of all allogeneic concepts was observed. Thus, by catabolizing tryptophan, the mammalian conceptus appears to suppress T cell activity and protect itself from rejection, and blocking tryptophan catabolism during mouse pregnancy allows maternal T cells to induce fetal allograft rejection (Moan, et al., 1998, Science, 281: 1191-3).

Further evidence that the mechanism of tumor immunological resistance is based on IDO tryptophan degradation comes from the observation that most human tumors constitutively express IDO, and that immunogenic mouse tumor cell expression of IDO prevents their rejection by pre-immunized mice. This effect is accompanied by a lack of accumulation of specific T cells in the tumor site, and it can be partially reversed by systemic administration of an IDO inhibitor to mice in the absence of significant toxicity. Thus, it is suggested that the effectiveness of therapeutic vaccination of patients with malignant neoplasms can be improved by the simultaneous administration of an IDO inhibitor (Uyttenhove et al., 2003, Nature Med., 9: 1269-74). It has also been shown that an IDO 1-MT inhibitor can act synergistically with chemotherapeutic agents to reduce tumor growth in mice, suggesting that IDO inhibition may also increase the antitumor activity of conventional cytotoxic therapies (Muller et al, 2005, Nature Med., 11: 312-9).

One of the mechanisms contributing to the immunological non-response in relation to tumors may be the presentation of tumor antigens by tolerogenic APCs of the host organism. A subpopulation of human IDO-expressing antigen presenting cells (APCs) co-expressing CD123 (IL3RA) and CCR6 and inhibiting T cell proliferation has been described. Mature and immature CD123 positive dendritic cells suppressed T cell activity and this IDO suppressor activity was blocked by 1MT (Munn, et al, 2002, Science, 297: 1867-70). Mouse tumor-draining lymph nodes (TDLNs) have also been shown to contain a subpopulation of plasmacytoid dendritic cells (pDCs) constitutively expressing immunosuppressive levels of IDO. Although they represent only 0.5% of lymph node cells, in vitro these pDCs potently suppress T-cell responses to antigens presented by the pDCs themselves, and also dominantly suppress T-cell responses to third-party antigens presented by non-suppressor APCs. In the pDC population, the bulk of functional IDO-mediated suppressor activity is shared with a new subset of pDCs co-expressing the B-lymphocyte marker CD19. Thus, IDO-mediated suppression by pDCs in TDLN is proposed to create a local microenvironment that potently suppresses host antitumor T-cell responses (Munn, et al., 2004, J. Clin. Invest, 114(2): 280 -90).

IDO causes degradation of the indole residue of tryptophan, serotonin and melatonin and initiates the production of neuroactive and immunoregulatory metabolites collectively known as kynurenins. Through local tryptophan depletion and an increase in pro-apoptotic kynurenins, IDO expressed by dendritic cells (DCs) can significantly influence T cell proliferation and survival. The induction of IDO in DC may be a common mechanism for deletion tolerance regulated by regulatory T cells. Because While such tolerogenic responses can be expected to occur under various pathophysiological conditions, tryptophan metabolism and kynurenine production may represent a key area of contact between the immune and nervous systems (Grohmann, et al, 2003, Trends Immunol, 24: 242-8). In a state of continuous immune activation, the availability of free Trp in serum is reduced, and due to reduced production of serotonin, serotonergic functions may also be affected (Wirleitner, et al., 2003, Curr. Med. Chem., 10: 1581-91).

In light of the potential role of IDO in immunosuppression, tumor resistance and/or rejection, chronic infections, HIV infection, AIDS (including its manifestations such as cachexia, dementia, and diarrhea), autoimmune diseases or disorders (such as rheumatoid arthritis), immunological tolerance, and prevention of fetal rejection in utero, therapeutic agents aimed at suppressing tryptophan degradation by inhibiting IDO activity are desirable. IDO inhibitors can be used to activate T cells and thus increase T cell activation when T cells are suppressed by pregnancy, cancer, or a virus such as HIV. Inhibition of IDO may also be an important treatment strategy in patients with neurological or neuropsychiatric diseases or disorders such as depression. The compounds provided herein can be used in the possible treatment or prevention of IDO-related diseases.

SUMMARY OF THE INVENTION

The present invention relates to new compounds of formula (I), which are inhibitors of IDO enzymes. The present invention also relates to the use of these compounds in the possible treatment or prevention of an IDO-associated disease or disorder. The present invention also relates to compositions containing one or more of the compounds. The present invention further relates to the use of these compositions in the possible prevention or treatment of an IDO-associated disease or disorder.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I),

(I)

where:

n is selected from 1, 2 and 3;

p is selected from 0, 1 and 2;

in each case, A is independently selected from -CH= and -N=, provided that at least one A is -CH=;

M is selected from -O-, -S- and -CR ^a R ^b -, each of R ^a and R ^b is independently selected from H, halogen, -OH and -C _1-8 -alkyl; or alternatively R ^a and R ^b together with the carbon atom to which they are attached form a C _3-4 carbocyclic ring optionally substituted with 1-2 substituents independently selected from halogen and C _1-4 alkyl;

R ¹ is selected from:

(1) arila and

(2) heterocyclyl;

where aryl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-8 -cycloalkyl, optionally substituted with -OH,

(c) -CN,

(d) oxo groups,

(e) -OC _1-8 -alkyl, optionally substituted with 1-5 halogen atoms,

(f) -OC _3-8 -cycloalkyl,

(g) -C _1-8 -alkyl, optionally substituted with 1-4 substituents independently selected from halogen, -OH, -NH ₂ , NHC(O)R ^c and -S(O) ₂ -C _1-8 - alkyl, where R ^c is selected from -C _1-8 -alkyl and -C _3-8 -cycloalkyl,

(h) -NH-S(O) ₂ -R ^c , where R ^c is selected from -C _1-8 -alkyl and -C _3-8 -cycloalkyl,

(i) -C(O)-R ^e , where R ^e is selected from -OH and -C _1-8 -alkyl,

(j) aryl optionally substituted with 1-3 halogen atoms, and

(k) heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen and —C _1-8 alkyl; and

where heterocyclyl (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-8 -cycloalkyl, optionally substituted with -OH,

(c) -CN,

(d) oxo groups,

(e) -OC _1-8 -alkyl, optionally substituted with 1-5 halogen atoms,

(f) -OC _3-8 -cycloalkyl,

(g) -C _1-8 -alkyl, optionally substituted with 1-4 substituents independently selected from halogen, -OH, -NH ₂ , NHC(O)R ^c and -S(O) ₂ -C _1-8 - alkyl, where R ^c is selected from -C _1-8 -alkyl and -C _3-8 -cycloalkyl,

(h) -NH-S(O) ₂ -R ^c , where R ^c is selected from -C _1-8 -alkyl and -C _3-8 -cycloalkyl,

(i) -C(O)-R ^f , where R ^{f is} selected from -OH, -NH ₂ and -NH-C _1-8 -alkyl,

(j) aryl optionally substituted with 1-3 halogen atoms, and

(k) heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen and —C _1-8 alkyl;

R ² is selected from:

(1) C _1-8 -alkyl,

(2) C _3-8 -carbocyclyl,

(3) arila and

(4) heterocyclyl;

where C _1-8 -alkyl (1), optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-8 -cycloalkyl,

(c) -OC _1-8 -alkyl and

(d) heterocyclyl; and

where each of C _3-8 -carbocyclyl (2), aryl (3) and heterocyclyl (4), optionally, is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-8 -cycloalkyl,

(c) -CN,

(d) -OC _1-8 -alkyl, optionally substituted with 1-3 halogen atoms, and

(e) -C _1-8 -alkyl, optionally substituted with 1-3 substituents independently selected from halogen, -OH and -NH ₂ ; and

R ³ is selected from H, halogen and -C _1-8 -alkyl, optionally substituted with -OH.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

n is selected from 1 and 2;

p is chosen from 0 and 1;

M is selected from -O- and -CR ^a R ^b - each of R ^a and R ^b is independently selected from H and halogen; or alternatively R ^a and R ^b together with the carbon atom to which they are attached form a C _3-4 cycloalkyl ring;

R ¹ is selected from:

(1) arila and

(2) heterocyclyl;

where aryl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-6 -cycloalkyl, optionally substituted with -OH,

(c) -CN,

(d) -OC _1-6 -alkyl, optionally substituted with 1-3 halogen atoms,

(e) -OC _3-6 -cycloalkyl,

(f) -C _1-6 -alkyl, optionally substituted with 1-4 substituents independently selected from halo and -OH, and

(g) -C(O)-R ^e , where R ^e is selected from -OH and -C _1-6 -alkyl;

where heterocyclyl (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-6 -cycloalkyl, optionally substituted with -OH,

(c) -CN,

(d) oxo groups,

(e) -OC _1-6 -alkyl, optionally substituted with 1-3 halogen atoms,

(f) -OC _3-6 -cycloalkyl,

(g) -C _1-6 -alkyl, optionally substituted with 1-4 substituents independently selected from halogen, -OH and -NH ₂ ,

(h) -C(O)-R ^f , where R ^{f is} selected from -OH, -NH ₂ and -NH-C _1-6 -alkyl,

(i) phenyl optionally substituted with 1-3 halogen atoms;

R ² is selected from:

(1) C _1-6 -alkyl, optionally substituted with 1-3 halogen atoms,

(2) C _3-6 -cycloalkyl,

(3) arila and

(4) 4-7 membered monocyclic heterocyclyl;

where each of C _3-6 -cycloalkyl (2), aryl (3) and heterocyclyl (4), optionally, is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-6 -cycloalkyl,

(c) -CN,

(d) -OC _1-6 -alkyl, optionally substituted with 1-3 halogen atoms, and

(e) -C _1-6 -alkyl, optionally substituted with 1-3 substituents independently selected from halo and -OH; and

R ³ is selected from H, halogen and -C _1-6 -alkyl, optionally substituted with -OH.

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 A group is -N= and each of the other A groups is -CH=;

or alternatively each of the two A groups is -N= and each of the other two A groups is -CH=; and

.M is selected from -O-, -CH ₂ -, -CHF, -CF ₂ - and

.

In one embodiment of a compound of formula (I) or a pharmaceutically acceptable salt thereof, R ³ is selected from H, halo and -CH ₂ -OH.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

R ¹ is selected from:

(1) phenyl,

(2) a 4-7 membered monocyclic heterocyclyl selected from a saturated, partially unsaturated, and aromatic ring containing 1-4 heteroatoms independently selected from N, O, and S, and

(3) a 7-10 membered fused bicyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S in any of the rings;

where phenyl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-6 -cycloalkyl, optionally substituted with -OH,

(c) -CN,

(d) -OC _1-6 -alkyl, optionally substituted with 1-3 halogen atoms,

(e) -OC _3-6 -cycloalkyl,

(f) -C _1-6 -alkyl, optionally substituted with 1-4 substituents independently selected from halo and -OH, and

(g) -C(O)-R ^e , where R ^e is selected from -OH and -C _1-6 -alkyl; and

where each of the monocyclic heterocyclyl (2) and the fused bicyclic heterocyclyl (3) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-6 -cycloalkyl, optionally substituted with -OH,

(c) -CN,

(d) oxo groups,

(e) -OC _1-6 -alkyl, optionally substituted with 1-3 halogen atoms,

(f) -OC _3-6 -cycloalkyl,

(g) -C _1-6 -alkyl, optionally substituted with 1-4 substituents independently selected from halogen, -OH and -NH ₂ ,

(h) -C(O)-R ^f , where R ^{f is} selected from -OH, -NH ₂ and -NH-C _1-6 -alkyl,

(i) phenyl optionally substituted with 1-3 halogen atoms.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

R ¹ is selected from:

(1) phenyl;

(2) a monocyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl and 1,2,4-oxadiazolyl; and

(3) a fused bicyclic heterocyclyl selected from 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, imidazol[4,5-b]pyridinyl, imidazol[4,5-c]pyridinyl , indolyl, isoindolinyl;

where phenyl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) cyclobutyl, optionally substituted with -OH,

(d) -OC _1-4 -alkyl, optionally substituted with 1-3 halogen atoms,

(e) -O-cyclopropyl,

(f) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halo and -OH, and

(g) -C(O)-C _1-4 -alkyl; and

where each of the monocyclic heterocyclyl (2) and the fused bicyclic heterocyclyl (3) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) cyclobutyl, optionally substituted with -OH,

(d)-CN,

(e) oxo groups,

(f) -OC _1-4 -alkyl, optionally substituted with 1-3 halogen atoms,

(g) -O-cyclopropyl,

(h) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halo and -OH, and

(i) phenyl optionally substituted with 1-3 halogen atoms.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

R ² is selected from:

(1) C _1-6 -alkyl, optionally substituted with 1-3 halogen atoms,

(2) C _3-6 -cycloalkyl,

(3) phenyl, and

(4) 5-6 membered monocyclic heterocyclyl;

where each of C _3-6 -cycloalkyl (2), phenyl (3) and heterocyclyl (4), optionally, is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-6 -cycloalkyl,

(c) -CN,

(d) -OC _1-6 -alkyl, optionally substituted with 1-3 halogen atoms, and

(e) -C _1-6 -alkyl, optionally substituted with 1-3 substituents independently selected from halo and -OH.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

R ² is selected from:

(1) C _1-4 -alkyl,

(2) C _3-6 -cycloalkyl,

(3) phenyl, and

(4) 5-6 membered monocyclic heterocyclyl selected from oxazolyl, pyridinyl and thiazolyl;

where each of C _3-6 -cycloalkyl (2), phenyl (3) and heterocyclyl (4), optionally, is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -OC _1-4 -alkyl, optionally substituted with 1-3 halogen atoms, and

(e) -C _1-4 -alkyl, optionally substituted with 1-3 halogen atoms.

In one embodiment, 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 A group is -N= and each of the other A groups is -CH=;

or alternatively, the two A groups are -N= and each of the other two A groups is -CH=;

;M is selected from -O-, -CH ₂ -, -CHF, -CF ₂ - and

;

R ¹ is selected from:

(1) phenyl;

(2) a monocyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl and 1,2,4-oxadiazolyl; and

(3) a fused bicyclic heterocyclyl selected from 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, imidazol[4,5-b]pyridinyl, imidazol[4,5-c]pyridinyl , indolyl, isoindolinyl;

where phenyl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) cyclobutyl, optionally substituted with -OH,

(d) -OC _1-4 -alkyl, optionally substituted with 1-3 halogen atoms,

(e) -O-cyclopropyl,

(f) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halo and -OH, and

(g) -C(O)-C _1-4 -alkyl; and

where each of the monocyclic heterocyclyl (2) and the fused bicyclic heterocyclyl (3) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) cyclobutyl, optionally substituted with -OH,

(d)-CN,

(e) oxo groups,

(f) -OC _1-4 -alkyl, optionally substituted with 1-3 halogen atoms,

(g) -O-cyclopropyl,

(h) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halo and -OH, and

(i) phenyl optionally substituted with 1-3 halogen atoms;

R ² is selected from:

(1) C _1-4 -alkyl,

(2) C _3-6 -cycloalkyl,

(3) phenyl, and

(4) 5-6 membered monocyclic heterocyclyl selected from oxazolyl, pyridinyl and thiazolyl;

where each of C _3-6 -cycloalkyl (2), phenyl (3) and heterocyclyl (4), optionally, is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -OC _1-4 -alkyl, optionally substituted with 1-3 halogen atoms, and

(e) -C _1-4 -alkyl, optionally substituted with 1-3 halogen atoms; and

R ³ is selected from H, halogen and -CH ₂ -OH.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

each group A is -CH=;

M is -O-;

R ¹ is selected from:

(1) phenyl; and

(2) a monocyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl and 1,2,4-oxadiazolyl;

where phenyl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) -OC _1-4 -alkyl, optionally substituted with 1-3 halogen atoms,

(d) -O-cyclopropyl, and

(e) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halo and -OH, and

where the monocyclic heterocyclyl (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -OC _1-4 -alkyl, optionally substituted with 1-3 halogen atoms,

(d) -O-cyclopropyl,

(e) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halo and -OH;

R ² is selected from:

(1) phenyl, and

(2) pyridinyl;

where each of phenyl (1) and pyridinyl (2), optionally, is substituted by 1-3 halogen atoms; and

R ³ is H.

In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound has formula (Ia):

(Ia),

(Ia)

where:

R ¹ is selected from:

(1) phenyl; and

(2) a monocyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl and 1,2,4-oxadiazolyl;

where phenyl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) cyclobutyl, optionally substituted with -OH,

(d) -OC _1-4 -alkyl, optionally substituted with 1-3 halogen atoms,

(e) -O-cyclopropyl, and

(f) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halo and -OH, and

(g) -C(O)-C _1-4 -alkyl; and

where the monocyclic heterocyclyl (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -OC _1-4 -alkyl, optionally substituted with 1-3 halogen atoms,

(c) -O-cyclopropyl and

(d) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halo and -OH; and

R ² is selected from:

(1) phenyl and

(2) pyridinyl;

where each of phenyl (1) and pyridinyl (2), optionally, is substituted with 1-3 halogen atoms.

In one embodiment, a compound of formula (Ia), or a pharmaceutically acceptable salt thereof:

R ¹ is pyridinyl optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -CH ₃ ,

(c) -CHF ₂ ,

(d) -CF ₃ and

(e) -C(CH ₃ ) ₂ OH; and

R ² is phenyl, optionally substituted with 1-3 halogen atoms.

In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound has the formula selected from (Ii), (Ij) and (Ik):

(Ii),

(Ij) и

(Ik);

(ii),

(Ij) and

(Ik);

where:

R ¹ is selected from:

(1) phenyl and

(2) a monocyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl and 1,2,4-oxadiazolyl;

where phenyl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) -OC _1-4 -alkyl, optionally substituted with 1-3 halogen atoms,

(d) -O-cyclopropyl and

(e) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halo and -OH, and

where the monocyclic heterocyclyl (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -OC _1-4 -alkyl, optionally substituted with 1-3 halogen atoms,

(d) -O-cyclopropyl,

(e) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halo and -OH; and

^Rd is selected from:

(a) halogen,

(b)-CN,

(c) -OC _1-3 -alkyl, optionally substituted with 1-3 halogen atoms, and

(d) C _1-3 alkyl, optionally substituted with 1-3 halogen atoms.

In one embodiment, a compound of formula (Ii), (Ij) or (Ik) or a pharmaceutically acceptable salt thereof:

R ¹ is pyridinyl optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -CH ₃ ,

(c) -CHF ₂ ,

(d) -CF ₃ and

(e) -C(CH ₃ ) ₂ OH; and

^Rd is selected from:

(a) halogen,

(b)-CN,

(c) -CH ₃ and

(d) -CF ₃ .

In one embodiment, 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 -CR ^a R ^b -, each of R ^a and R ^b is independently selected from H, halogen, -OH and -C _1-6 -alkyl; or alternatively R ^a and R ^b together with the carbon atom to which they are attached form a C _3-4 cycloalkyl ring, optionally substituted with 1-2 substituents independently selected from halogen and C _1-4 alkyl;

R ¹ is selected from:

(1) arila and

(2) heterocyclyl;

where aryl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-8 -cycloalkyl, optionally substituted with -OH,

(c) -CN,

(d) oxo groups,

(e) -OC _1-8 -alkyl, optionally substituted with 1-5 halogen atoms,

(f) -OC _3-8 -cycloalkyl,

(g) -C _1-8 -alkyl, optionally substituted with 1-4 substituents independently selected from halogen, -OH, -NH ₂ , NHC(O)R ^c and -S(O) ₂ -C _1-8 - alkyl, where R ^c is selected from -C _1-8 -alkyl and -C _3-8 -cycloalkyl,

(h) -NH-S(O) ₂ -R ^c , where R ^c is selected from -C _1-8 -alkyl and -C _3-8 -cycloalkyl,

(i) -C(O)-OH,

(j) aryl optionally substituted with 1-3 halogen atoms, and

(k) heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen and —C _1-8 alkyl;

where heterocyclyl (2) is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-8 -cycloalkyl, optionally substituted with -OH,

(c) -CN,

(d) oxo groups,

(e) -OC _1-8 -alkyl substituted with 1-5 halogen atoms,

(f) -OC _3-8 -cycloalkyl,

(g) -C _1-8 -alkyl substituted with 1-4 substituents independently selected from halogen, -NH ₂ , NHC(O)R ^c and -S(O) ₂ -C _1-8 -alkyl, where R ^c selected from -C _1-8 -alkyl and -C _3-8 -cycloalkyl,

(h) -NH-S(O) ₂ -R ^c , where R ^c is selected from -C _1-8 -alkyl and -C _3-8 -cycloalkyl,

(i) -C(O)-OH,

(j) aryl optionally substituted with 1-3 halogen atoms, and

(k) heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen and —C _1-8 alkyl;

R ² is selected from:

(1) C _1-8 -alkyl,

(2) C _3-8 -carbocyclyl,

(3) arila and

(4) heterocyclyl;

where C _1-8 -alkyl (1), optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-8 -cycloalkyl,

(c) -OC _1-8 -alkyl and

(d) heterocyclyl; and

where each of C _3-8 -carbocyclyl (2), aryl (3) and heterocyclyl (4), optionally, is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-8 -cycloalkyl,

(c) -CN,

(d) -OC _1-8 -alkyl, optionally substituted with 1-3 halogen atoms, and

(e) -C _1-8 -alkyl, optionally substituted with 1-3 substituents independently selected from halogen, -OH and -NH ₂ ; and

R ³ is selected from H, halogen and -C _1-8 -alkyl.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

R ¹ is selected from:

(1) phenyl,

(2) a monocyclic heterocyclyl selected from isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl and 1,2,3-thiadiazolyl, and

(3) a bicyclic heterocyclyl selected from 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, indolyl, 1,2,3-thiadiazolyl, 1H-benzo[d]imidazolyl, 3H- imidazo[4,5-c]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyridinyl and imidazo[1,2-b]pyridazinyl;

where phenyl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) C _3-4 -cycloalkyl, optionally substituted with -OH,

(c) -CN,

(d) oxo groups,

(e) -OC _1-4 -alkyl, optionally substituted with 1-5 halogen atoms,

(f) -O-cyclopropyl,

(g) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halogen, -OH, -NH ₂ , NHC(O)C _1-3 -alkyl and -S(O) ₂ -C _1-4 -alkyl,

(h) -NH-S(O) ₂ -R ^c , where R ^c is selected from methyl, ethyl, propyl and cyclopropyl,

(i) -C(O)-OH,

(j) phenyl optionally substituted with 1-3 halogen atoms, and

(k) oxadiazolyl optionally substituted with methyl or ethyl; and

where monocyclic heterocyclyl (2) and bicyclic heterocyclyl (3) are substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) C _3-4 -cycloalkyl, optionally substituted with -OH,

(c) -CN,

(d) oxo groups,

(e) -OC _1-4 -alkyl substituted with 1-5 halogen atoms,

(f) -O-cyclopropyl,

(g) -C _1-4 -alkyl substituted with 1-4 substituents independently selected from halogen, -NH ₂ , NHC(O)C _1-3 -alkyl and -S(O) ₂ -C _1-4 -alkyl ,

(h) -NH-S(O) ₂ -R ^c , where R ^c is selected from methyl, ethyl, propyl and cyclopropyl,

(i) -C(O)-OH,

(j) phenyl optionally substituted with 1-3 halogen atoms, and

(k) oxadiazolyl optionally substituted with methyl or ethyl.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

R ¹ is selected from:

(1) phenyl and

(2) a monocyclic heterocyclyl selected from isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl and 1,2,3-thiadiazolyl;

where phenyl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) cyclobutyl, optionally substituted with -OH,

(d) -OC _1-3 -alkyl, optionally substituted with 1-5 halogen atoms,

(e) -O-cyclopropyl and

(f) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halo, -OH and -NH ₂ ; and

where the monocyclic heterocyclyl (2) is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) cyclobutyl, optionally substituted with -OH,

(d) -OC _1-3 -alkyl substituted with 1-5 halogen atoms,

(e) -O-cyclopropyl and

(f) -C _1-4 -alkyl substituted with 1-4 substituents independently selected from halo and -NH ₂ .

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

R ² is selected from:

(1) phenyl,

(2) pyridinyl and

(3) pyrimidinyl;

where each of phenyl (1), pyridinyl (2) and pyrimidinyl (3), optionally, is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -OC _1-4 -alkyl, optionally substituted with 1-3 halogen atoms, and

(d) C _1-4 -alkyl, optionally substituted with 1-3 halogen atoms.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

R ² is selected from:

(1) phenyl,

(2) pyridinyl, and

where each of phenyl (1) and pyridinyl (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -O-CHF ₂ ,

(d) -O-CF ₃ ,

(e) -CH ₃ ,

(f) -CH ₂ F,

(g) -CHF ₂ and

(h) -CF ₃ .

In one embodiment, 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 A group is -N= and each of the other three A groups is -CH=;

;M is selected from -O-, -CH ₂ -, -CF ₂ - and

;

R ¹ is selected from:

(1) phenyl,

(2) pyridinyl and

(3) pyrimidinyl;

where phenyl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) cyclobutyl, optionally substituted with -OH,

(d) -O-CH ₃ ,

(e) -O-CH ₂ CH ₃ ,

(f) -O-CF ₃ ,

(g) -O-CHF ₂ ,

(h) -O-CF ₂ CF ₃ ,

(i) -CH ₃ ,

(j) -CH ₂ F,

(k)-CHF ₂ ,

(l)-CF ₃ ,

(m) -CH ₂ CF ₃ ,

(n)-CH ₂ OH,

(o) -CH ₂ CH ₃ ,

(p) -CH(CH ₃ )OH,

(q) -CH ₂ CH ₂ OH,

(r)-CH(CHF ₂ )OH,

(s) -C(CH ₃ ) ₂ OH,

(t) -C (CF ₃ ) ₂ OH,

(u)-O-cyclopropyl and

(v) -O-cyclobutyl;

where each of pyridinyl (2) and pyrimidinyl (3) is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) cyclobutyl, optionally substituted with -OH,

(d) -O-CF ₃ ,

(e) -O-CHF ₂ ,

(f) -O-CF ₂ CF ₃ ,

(g) -CH ₂ F,

(h) -CHF ₂ ,

(i) -CF ₃ ,

(j) -CH ₂ CF ₃ ,

(k) -CH(CHF ₂ )OH,

(l) -C (CF ₃ ) ₂ OH,

(m) -O-cyclopropyl and

(n) -O-cyclobutyl;

R ² is selected from:

(1) phenyl and

(2) pyridinyl;

where each of phenyl (1) and pyridinyl (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -O-CHF ₂ ,

(d) -O-CF ₃ ,

(e) -CH ₃ ,

(f) -CH ₂ F,

(g) -CHF ₂ and

(h) -CF ₃ ; and

R ³ is H.

In one embodiment, 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 A group is -N= and each of the other three A groups is -CH=;

;M is selected from -O-, -CH ₂ -, -CF ₂ - and

;

R ¹ is selected from:

(1) phenyl and

(2) pyridinyl;

where phenyl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) -O-CH ₃ ,

(d) -O-CF ₃ ,

(e) -O-CHF ₂ ,

(f) -CHF ₂ ,

(g)-CF ₃ ,

(h) -CH ₂ CF ₃ ,

(i) -CH ₂ OH,

(j) -CH ₂ CH ₃ ,

(k) -CH(CH ₃ )OH,

(l) -CH ₂ CH ₂ OH,

(m) -CH(CHF ₂ )OH,

(n) -C (CH ₃ ) ₂ OH,

(o) -C(CF ₃ ) ₂ OH and

(p) -O-cyclopropyl;

where pyridinyl (2) is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) -O-CF ₃ ,

(d) -O-CHF ₂ ,

(e) -CHF ₂ ,

(f) -CF ₃ ,

(g) -CH ₂ CF ₃ ,

(h) -CH(CHF ₂ )OH,

(i) -C(CF ₃ ) ₂ OH and

(j) -O-cyclopropyl;

R ² is selected from:

(1) phenyl and

(2) pyridinyl;

where each of phenyl (1) and pyridinyl (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -O-CHF ₂ ,

(d) -O-CF ₃ ,

(e) -CHF ₂ and

(f) -CF ₃ ; and

R ³ is H.

In one embodiment, 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 A group is -N= and each of the other three A groups is -CH=;

;M is selected from -O-, -CH ₂ -, -CF ₂ - and

;

R ¹ is selected from:

(1) phenyl and

(2) pyridinyl;

where each of phenyl (1) and pyridinyl (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) -O-CH ₃ ,

(d) -O-CF ₃ ,

(e) -O-CHF ₂ ,

(f) -CHF ₂ ,

(g)-CF ₃ ,

(h) -CH ₂ CF ₃ ,

(i) -CH ₂ OH,

(j) -CH ₂ CH ₃ ,

(k) -CH(CH ₃ )OH,

(l) -CH ₂ CH ₂ OH,

(m) -CH(CHF ₂ )OH,

(n) -C (CH ₃ ) ₂ OH,

(o) -C(CF ₃ ) ₂ OH and

(p) -O-cyclopropyl; and

R ² is phenyl optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -O-CHF ₂ ,

(d) -O-CF ₃ ,

(e) -CH ₃ ,

(f) -CH ₂ F,

(g) -CHF ₂ and

(h) -CF ₃ ; and

R ³ is H.

In one embodiment, 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 A group is -N= and each of the other three A groups is -CH=;

;M is selected from -O-, -CH ₂ -, -CF ₂ - and

;

R ¹ is selected from:

(1) phenyl and

(2) pyridinyl;

where each of phenyl (1) and pyridinyl (2) is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) -O-CH ₃ ,

(d) -O-CF ₃ ,

(e) -O-CHF ₂ ,

(f) -CHF ₂ ,

(g)-CF ₃ ,

(h) -CH ₂ CF ₃ ,

(i) -CH ₂ OH,

(j) -CH(CH ₃ )OH,

(k) -CH ₂ CH ₂ OH,

(l) -CH(CHF ₂ )OH,

(m) -C(CH ₃ ) ₂ OH and

(n) -C(CF ₃ ) ₂ OH; and

R ² is phenyl optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -O-CHF ₂ ,

(d) -O-CF ₃ ,

(e) -CHF ₂ and

(f) -CF ₃ and

R ³ is H.

In one embodiment, a compound of formula (I) described above, or a pharmaceutically acceptable salt thereof, n is 1; p is 1; and M is -O-.

In one embodiment, a compound of formula (I) described above, or a pharmaceutically acceptable salt thereof:

each group A is -CH=;

R ¹ is selected from:

(1) phenyl and

(2) pyridinyl;

where each of phenyl (1) and pyridinyl (2) is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) -O-CH ₃ ,

(d) -O-CF ₃ ,

(e) -O-CHF ₂ ,

(f) -CHF ₂ ,

(g)-CF ₃ ,

(h) -CH ₂ CF ₃ ,

(i) -CH ₂ OH,

(j) -CH(CH ₃ )OH,

(k) -CH ₂ CH ₂ OH,

(l) -CH(CHF ₂ )OH,

(m) -C(CH ₃ ) ₂ OH and

(n) -C(CF ₃ ) ₂ OH; and

R ² is phenyl optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -O-CHF ₂ ,

(d) -O-CF ₃ ,

(e) -CHF ₂ and

(f) -CF ₃ ; and

R ³ is H.

In one embodiment, a compound of formula (I) described above, or a pharmaceutically acceptable salt thereof:

one A group is -N= and each of the other three A groups is -CH=;

R ¹ is selected from:

(1) phenyl and

(2) pyridinyl;

where each of phenyl (1) and pyridinyl (2) is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) -O-CH ₃ ,

(d) -O-CF ₃ ,

(e) -O-CHF ₂ ,

(f) -CHF ₂ ,

(g)-CF ₃ ,

(h) -CH ₂ CF ₃ ,

(i) -CH ₂ OH,

(j) -CH(CH ₃ )OH,

(k) -CH ₂ CH ₂ OH,

(l) -CH(CHF ₂ )OH,

(m) -C(CH ₃ ) ₂ OH and

(n) -C(CF ₃ ) ₂ OH; and

R ² is phenyl optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -O-CHF ₂ ,

(d) -O-CF ₃ ,

(e) -CHF ₂ and

(f) -CF ₃ ; and

R ³ is H.

In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound has formula (Ia) or (Ib):

(Ia)

(Ib).

(Ia)

(Ib).

In one embodiment of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound has formula (Ic) or (Id):

(Ic),

(Id).

(Ic),

(ID).

In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound has formula (Ie) or (If):

(Ie),

(If).

(Ie)

(If).

In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound has formula (Ig) or (Ih):

(Ig) или

(Ih);

(Ig) or

(Ih);

where q is 1 or 2; each A is independently -CH= or -N=; and R ^c is H, halo, or C _1-3 alkyl.

In one embodiment of a compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound has formula (Ii), (Ij), or (Ik):

(Ii),

(Ij) или

(Ik);

(ii),

(Ij) or

(Ik);

where:

R ¹ is selected from:

(1) phenyl and

(2) a monocyclic heterocyclyl selected from isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl and 1,2,3-thiadiazolyl;

(3) a 6-12-membered fused bicyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S in any of the rings;

where each of phenyl (1), monocyclic heterocyclyl (2) and fused bicyclic heterocyclyl (3) is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) cyclobutyl, optionally substituted with -OH,

(d) -OC _1-3 -alkyl, optionally substituted with 1-5 halogen atoms,

(e) -O-cyclopropyl and

(f) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halo, -OH and -NH ₂ ; and

^Rd is selected from:

(a) halogen,

(b)-CN,

(c) -OC _1-3 -alkyl, optionally substituted with 1-3 halogen atoms, and

(d) C _1-3 alkyl, optionally substituted with 1-3 halogen atoms.

In one embodiment, a compound of formula (Ii), (Ij) or (Ik) or a pharmaceutically acceptable salt thereof:

R ¹ is selected from:

(1) phenyl and

(2) pyridinyl;

where each of phenyl (1) and pyridinyl (2) is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) -O-CH ₃ ,

(d) -O-CF ₃ ,

(e) -O-CHF ₂ ,

(f) -CHF ₂ ,

(g)-CF ₃ ,

(h) -CH ₂ CF ₃ ,

(i) -CH ₂ OH,

(j) -CH ₂ CH ₃ ,

(k) -CH(CH ₃ )OH,

(l) -CH ₂ CH ₂ OH,

(m) -CH(CHF ₂ )OH,

(n) -C (CH ₃ ) ₂ OH,

(o) -C(CF ₃ ) ₂ OH and

(p) -O-cyclopropyl; and

^Rd is selected from:

(a) halogen,

(b)-CN,

(c) -O-CHF ₂ ,

(d) -O-CF ₃ ,

(e) -CH ₃ ,

(f) -CH ₂ F,

(g) -CHF ₂ and

(h) -CF ₃ .

In one embodiment, a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik) or its pharmaceutically acceptable salt:

R ¹ is selected from:

(1) phenyl;

(2) a monocyclic heterocyclyl selected from a saturated, partially unsaturated and aromatic 4-7 membered ring containing 1-4 heteroatoms independently selected from N, O and S; and

(3) a 6-12-membered fused bicyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S in any of the rings;

where phenyl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-6 -cycloalkyl,

(c) -CN,

(d) oxo groups,

(e) -OC _1-6 -alkyl, optionally substituted with 1-3 halogen atoms,

(f) -OC _3-6 -cycloalkyl,

(g) -C _1-6 -alkyl, optionally substituted with 1-4 substituents independently selected from halogen, -OH, -NH ₂ and -S(O) ₂ -C _1-6 -alkyl,

(h) -NH-S(O) ₂ -R ^c , where R ^c is selected from -C _1-6 -alkyl and -C _3-6 -cycloalkyl,

(i) -C(O)-OH,

(j) phenyl optionally substituted with 1-3 halogen atoms, and

(k) aromatic 4-7-membered monocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, optionally substituted-C _1-6 -alkyl;

where monocyclic heterocyclyl (2) and fused bicyclic heterocyclyl (3) are substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) -C _3-6 -cycloalkyl,

(c) -CN,

(d) oxo groups,

(e) -OC _1-6 -alkyl substituted with 1-3 halogen atoms,

(f) -OC _3-6 -cycloalkyl,

(g) -C _1-6 -alkyl substituted with 1-4 substituents independently selected from halogen, -NH ₂ and -S(O) ₂ -C _1-6 -alkyl,

(h) -NH-S(O) ₂ -R ^c , where R ^c is selected from -C _1-6 -alkyl and -C _3-6 -cycloalkyl,

(i) -C(O)-OH,

(j) phenyl optionally substituted with 1-3 halogen atoms, and

(k) aromatic 4-7-membered monocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, optionally substituted-C _1-6 -alkyl; and

R ² , if present, is selected from:

(1) C _1-6 -alkyl, optionally substituted with 1-3 halogen atoms,

(2) C _3-6 -cycloalkyl,

(3) C _4-6 bridged bicyclic saturated carbocyclyl,

(4) phenyl and

(5) a monocyclic heterocyclyl selected from a saturated, partially unsaturated and aromatic 4-7 membered ring containing 1-4 heteroatoms independently selected from N, O and S;

where each of C_3-6-cycloalkyl (2), C_4-6-bridge bicyclic saturated carbocyclyl (3), phenyl (4) and heterocyclyl (5), optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -OC _1-6 -alkyl, optionally substituted with 1-3 halogen atoms, and

(d) -C _1-6 -alkyl, optionally substituted with 1-3 halogen atoms.

In one embodiment, a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik) or its pharmaceutically acceptable salt:

R ¹ is selected from:

(1) phenyl; and

(2) a monocyclic heterocyclyl selected from isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl and 1,2,3-thiadiazolyl;

where phenyl (1) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) cyclobutyl, optionally substituted with -OH,

(d) -OC _1-3 -alkyl, optionally substituted with 1-5 halogen atoms,

(e) -O-cyclopropyl and

(f) -C _1-4 -alkyl, optionally substituted with 1-4 substituents independently selected from halo, -OH and -NH ₂ ;

where the monocyclic heterocyclyl (2) is substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) cyclobutyl, optionally substituted with -OH,

(d) -OC _1-3 -alkyl substituted with 1-5 halogen atoms,

(e) -O-cyclopropyl and

(f) -C _1-4 -alkyl substituted with 1-4 substituents independently selected from halo and -NH ₂ ; and

R ² , if present, is selected from:

(1) phenyl and

(2) pyridinyl;

where each of phenyl (1) and pyridinyl (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -OC _1-3 -alkyl, optionally substituted with 1-3 halogen atoms, and

(d) C _1-3 alkyl, optionally substituted with 1-3 halogen atoms.

In one embodiment, a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik) or its pharmaceutically acceptable salt:

R ¹ is selected from:

(1) phenyl and

(2) pyridinyl;

where each of phenyl (1) and pyridinyl (2) is optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b) cyclopropyl, optionally substituted with -OH,

(c) -O-CH ₃ ,

(d) -O-CF ₃ ,

(e) -O-CHF ₂ ,

(f) -O-CF ₂ CF ₃ ,

(g) -CH ₃ ,

(h)-CH ₂ F,

(i) -CHF ₂ ,

(j) -CF ₃ ,

(k) -CH ₂ CF ₃ ,

(l) -CH ₂ OH,

(m) -CH(CH ₃ )OH,

(n) -CH ₂ CH ₂ OH,

(o) -CH(CHF ₂ )OH,

(p) -C (CH ₃ ) ₂ OH,

(q) -C(CF ₃ ) ₂ OH, and

R ² , if present, is phenyl optionally substituted with 1-3 substituents independently selected from:

(a) halogen,

(b)-CN,

(c) -O-CHF ₂ ,

(d) -O-CF ₃ ,

(e) -CH ₃ ,

(f) -CH ₂ F,

(g) -CHF ₂ and

(h) -CF ₃ .

In one embodiment, the implementation of the connection presented in the present description, selected from the group consisting of compounds, examples of which are given in examples 1-131; or their pharmaceutically acceptable salts, solvates or hydrates.

The present invention also relates to a pharmaceutical composition containing the compound presented in the present description, and at least one pharmaceutically acceptable carrier.

The present invention also relates to a method for inhibiting the activity of indoleamine-2,3-dioxygenase (IDO), comprising contacting IDO with a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also provides a method for inhibiting immunosuppression in a patient, comprising administering to said patient an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also relates to a method of treating cancer, viral infection, depression, neurodegenerative disorder, trauma, age-related cataract, organ transplant rejection, or autoimmune disease in a patient, comprising administering to said patient an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. , solvate or hydrate.

The present invention also provides a method for treating melanoma in a patient, comprising administering to said patient an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention further relates to a compound provided herein, or a pharmaceutically acceptable salt thereof, for use in therapy. In one embodiment, the present invention relates to the use of a compound provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for the preparation of a therapeutic medicament.

The term "alkyl" refers to branched and straight chain saturated aliphatic hydrocarbon groups of 1-18 carbon atoms, or more particularly 1-12 carbon atoms. Non-limiting examples of such groups include methyl (Me), ethyl (Et), n-propyl (Pr), n-butyl (Bu), n-pentyl, n-hexyl and their isomers such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentyl and isohexyl. Alkyl groups may optionally be substituted with one or more substituents as described herein. The term "C _1-6 -alkyl" refers to an alkyl group, as described in the present description, containing 1-6 carbon atoms.

The term "aryl" refers to an aromatic monocyclic or polycyclic ring containing 6-14 ring carbon atoms, or more specifically 6-10 ring carbon atoms. Monocyclic aryl rings include, but are not limited to, phenyl. Polycyclic rings include, but are not limited to, naphthyl and bicyclic rings where phenyl is fused to a C _4-7 cycloalkyl or C _4-7 cycloalkenyl ring. Aryl groups may optionally be substituted with one or more substituents as described herein. The bonding can be through any of the carbon atoms of any ring. In one embodiment, the aryl is phenyl.

The term "carbocyclyl" refers to a non-aromatic (ie, saturated or partially unsaturated) monocyclic carbocyclic radical or a fused bicyclic, bridged bicyclic or spirocyclic carbocyclic radical containing certain ring carbon atoms. For example, the term "C _3-8 -carbocyclyl" refers to a non-aromatic 3-8 membered monocyclic carbocyclic radical or a non-aromatic 6-8 membered fused bicyclic, bridged bicyclic or spirocyclic carbocyclic radical. The carbocycle can be attached at any atom of the cycle, resulting in a stable structure. Non-limiting examples of 3-8 membered monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, and cycloheptenyl. Non-limiting examples of 6-8 membered fused bicyclic carbocyclic radicals include bicyclo[3.3.0]octane. Non-limiting examples of 5-8 membered bridged bicyclic carbocyclic radicals include bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]heptanyl, bicyclo[2.2.2]octanyl, and bicyclo[3.2.1]octanyl. Non-limiting examples of 6-8 membered spirocyclic carbocyclic radicals include spiro[3.3]heptanyl and spiro[3.4]octanyl.

The term "cycloalkyl" refers to a monocyclic saturated carbocyclic ring containing a certain number of ring carbon atoms. For example, the term "C _3-8 -cycloalkyl" refers to a cycloalkyl group, as described herein, containing 3-8 carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptanyl. Cycloalkyl groups may optionally be substituted with one or more substituents as described herein.

The term "halogen", unless otherwise indicated, refers to fluorine, chlorine, bromine or iodine.

The term "heterocycle" or "heterocyclyl" refers to a saturated, partially unsaturated or aromatic ring moiety containing 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 multiple heteroatoms may contain different heteroatoms. Heterocyclyl residues include monocyclic and polycyclic (eg, bicyclic) ring residues. Bicyclic ring residues include fused, spirocyclic and bridged bicyclic rings and may contain 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 in a bicyclic heterocycle may be saturated, partially unsaturated, or aromatic. The heterocycle can 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, heterocyclyl is a 4-7 membered monocyclic heterocyclyl selected from a saturated, partially unsaturated, and aromatic ring containing 1-4 heteroatoms independently selected from N, O, and S.

In one embodiment, heterocyclyl is a 6-12 membered fused bicyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S in any of the rings

In one embodiment, heterocyclyl is a monocyclic heterocyclyl selected from imidazolyl, oxazolyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, tetrazolyl, and 1,2,4-oxadiazolyl.

In one embodiment, heterocyclyl is a monocyclic heterocyclyl selected from oxazolyl, pyridinyl, and thiazolyl.

In one embodiment, the heterocyclyl is pyridinyl.

In one embodiment, 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.

Heterocyclic groups may optionally be substituted with one or more substituents as described herein.

The term "optionally substituted" refers to "unsubstituted or substituted", and thus, the general structural formulas presented in the present description include compounds containing certain optional substituents, as well as compounds not containing optional substituents. Each substituent is independently defined each time it occurs in the definitions of the general structural formulas.

Polymorphism

The compound presented in the present description, including its salt, solvate or hydrate, may exist in crystalline form, non-crystalline form, or mixtures thereof. A compound or a salt or solvate thereof may also exhibit polymorphism, ie. the ability to exist in different crystalline forms. These different crystalline forms are generally known as "polymorphs". The polymorphs have the same chemical composition but differ in packaging, geometric arrangement, and other descriptive properties of the solid crystalline state. Thus, polymorphs can have different physical properties such as shape, density, hardness, deformability, stability, and dissolution. The polymorphs typically show different melting points, IR spectra, and powder X-ray diffraction profiles, all of which can be used for identification. One skilled in the art will appreciate that different polymorphs can be obtained, for example by changing or adjusting the conditions used in crystallization/recrystallization of the compound described herein.

Optical isomers - Diastereomers - Geometric isomers - Tautomers

The present description includes various isomers of the compounds presented in the present description. The term "isomers" refers to compounds having the same composition and molecular weight but different physical and/or chemical properties. The structural difference may be in the structure (geometric isomers) or the ability to rotate the plane of polarized light (stereoisomers).

With respect to stereoisomers, a compound provided herein may contain one or more asymmetric carbon atoms and may occur as mixtures (such as a racemic mixture) or as single enantiomers or diastereomers. All such isomeric forms are included herein, including mixtures thereof. If the connection presented in the present description, contains a double bond, the substituent may be in the E - or Z-configuration. When a compound provided herein contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in the cis or trans configuration. All tautomeric forms are also intended to be included in the present description.

Any asymmetric atom (eg, carbon atom) in the compound provided in the present description, may be in the racemic mixture or be enantiomerically enriched, for example, in the (R)-, (S)-or (R, S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least at least 95% ee or at least 99% ee in the (R)- or (S)-configuration. Substituents on atoms with unsaturated double bonds, if possible, may be in cis-(Z)- or trans-(E)-form.

The compound provided herein may be in the form of one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, e.g., essentially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated, taking into account the physico-chemical differences of the constituent parts, into pure or essentially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

Any resulting racemates of the final compounds of examples or intermediate compounds can be resolved to optical antipodes by known methods, for example, by separating their diastereomeric salts obtained using an optically active acid or base and isolating the optically active acidic or basic compound. In particular, the basic residue can thus be used to resolve the compounds of the present invention to their optical antipodes, for example by fractional crystallization of a salt formed with an optically active acid, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O, O ' -p -toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic compounds can also be resolved by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.

Some of the compounds described herein may exist with different hydrogen attachment points and are referred to as tautomers. For example, compounds containing carbonyl -CH ₂ C(O)- groups (keto forms) may undergo tautomerism to form hydroxyl -CH=C(OH)- groups (enol forms). The keto forms and the enol forms alone, as well as in mixtures thereof, are included within the scope of the present invention.

Isotopic options

The compounds provided herein include unlabeled forms as well as isotopically labeled forms. Isotopically labeled compounds have the structures represented by the formulas given herein, except that one or more atoms are substituted for atoms having a selected atomic mass or mass number. Examples of isotopes that may be included in the compounds provided herein include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H (i.e., deuterium or "D"), ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl. the present invention includes various isotopically labeled compounds provided herein, for example, compounds in which radioactive isotopes such as ³ H and ¹⁴ C are present, or compounds in which non-radioactive isotopes such as ² H and ¹³ C are present. Such labeled isotopic compounds can be used in metabolic studies ( ¹⁴ C), reaction kinetics studies (e.g. ² H or ³ H), detection or imaging methods such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including assays distribution of drugs or substrates in tissue, or in radiation therapy patients. In particular, substitution with positron active isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N may be particularly desirable for PET or SPECT studies.

Labeled with isotopes of the compounds presented in the present description, as a rule, can be obtained by conventional methods known to specialists in this field. In addition, substitution with heavier isotopes, in particular deuterium (i.e. ² H or D), may lead to some therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life, or reduced doses required, or improving the therapeutic index.

Pharmaceutically acceptable salts

The term "pharmaceutically acceptable salt" refers to a salt derived from a pharmaceutically acceptable non-toxic base or acid, including an inorganic or organic base and an inorganic or organic acid. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron(III), iron(II), lithium, magnesium, manganese(VI), manganese(II), potassium, sodium, zinc, and the like. . Specific embodiments include ammonium, calcium, magnesium, potassium and sodium salts. Salts in solid form may exist in several crystal structures, and may also be 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 naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine , diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

If the compound presented in the present description is basic, the salt can be obtained from a pharmaceutically acceptable non-toxic acid, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethic, lactic, maleic, malic, mandelic, methanesulfonic, mucinic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric , tartaric, p-toluenesulfonic acid, trifluoroacetic acid (TFA), and the like. Specific embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, tartaric, and trifluoroacetic acids.

Application methods

The compounds provided herein can inhibit the activity of the enzyme indolamine-2,3-dioxygenase (IDO). For example, the compounds provided herein can potentially be used to inhibit IDO activity in a cell or individual in need of enzyme modulation by administering an effective amount of the compound. The present invention further relates to methods for inhibiting tryptophan degradation in a system containing cells expressing IDO, such as a tissue, living organism, or cell culture. In some embodiments, the present invention provides methods for altering (eg, 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 degradation are well known in the art.

The present invention also provides methods for inhibiting immunosuppression, such as IDO-mediated immunosuppression, in a patient by administering to the patient an effective amount of a compound or composition provided herein. IDO-mediated immunosuppression is associated with, for example, malignancy, tumor growth, metastasis, viral infection, viral replication, and so on.

The present invention also provides methods for treating diseases associated with activity or expression, including abnormal activity and/or overexpression, of IDO in an individual (e.g., patient) by administering to an individual in need of such treatment an effective amount or dose of a compound provided herein. , or its pharmaceutical composition. An example of a disease may include any disease, disorder, or condition that may be directly or indirectly associated with IDO enzyme expression or activity, such as overexpression or abnormal activity. An IDO-associated disease may also include any disease, disorder, or condition that can be prevented, ameliorated, or cured by modulating enzyme activity. Examples of IDO-associated diseases include cancer, viral infection such as HIV and HCV, depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (eg, organ transplant rejection), and autoimmune diseases, including asthma, rheumatoid arthritis, multiple sclerosis, allergic inflammation, inflammatory bowel disease, psoriasis and systemic lupus erythematosus. Examples of cancers potentially treatable by the methods provided herein include colon, pancreas, breast, prostate, lung, brain, ovarian, cervical, testicular, kidney, head and neck, lymphoma, leukemia, melanoma, etc. The compounds of the invention can also be used in the treatment of obesity and ischemia. Within the scope of the invention, the term "cell" is intended to mean a cell in vitro , ex vivo or in vivo . In some embodiments, the ex vivo cell may be part of a tissue sample removed from an organism, such as a mammal. In some embodiments, the in vitro cell may be a cell in cell culture. In some embodiments, the in vivo cell is a living cell in an organism, such as a mammal.

Within the scope of the invention, the term "bringing into contact" refers to the bringing together of said residues in an in vitro system or an in vivo system. For example, "contacting" an IDO enzyme with a compound provided herein includes administering a compound of the present invention to an individual or patient, such as a human, as well as, for example, administering a compound of the invention to a sample containing a cell or purified preparation containing IDO enzyme.

The subject administered with a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, is typically a mammal, such as a human, male or female. The term "individual" also refers to cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish and birds. In one embodiment, the individual is a human.

Within the scope of the invention, the term "treatment" refers to all processes, including slowing, preventing, stopping, controlling or stopping the progression of a disease or disorder that may be associated with IDO enzyme activity. The term does not necessarily mean the complete elimination of all symptoms of a disease or disorder. The terms also include the possible prophylactic treatment of said conditions, in particular in an individual predisposed to such a disease or disorder.

The term "administration" of a compound should be understood to include providing an individual with a compound as described herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and compositions of the above compounds.

The amount of compound administered to an individual is an amount sufficient to inhibit the activity of the IDO enzyme in the individual. In an embodiment, the amount of a compound may be an "effective amount", where the compound of the invention is administered in an amount that will elicit the biological or medical response of the tissue, system, animal, or human that is being sought by the researcher, veterinarian, physician, or other clinician. An effective amount does not necessarily include the toxicity and safety factors associated with the administration of the compound. It is known that a person skilled in the art can influence physiological disorders associated with IDO enzyme activity by treating an individual currently suffering from a disorder, or by prophylactically treating an individual who is likely to suffer from a disorder, using an effective amount of a compound represented by herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The effective amount of a compound will vary depending on the particular compound chosen (eg, in terms of potency, potency, and/or half-life of the compound); the chosen route of administration; the condition being treated; the severity of the condition being treated; age, size, weight and physical condition of the individual being treated; the medical history of the individual being treated; nature of concomitant therapy; the desired therapeutic effect and the like, and those skilled in the art can determine it by conventional means.

The compounds provided herein may be administered by any suitable route, including oral and parenteral administration. Parenteral administration is generally by injection or infusion and includes intravenous, intramuscular and subcutaneous injection or infusion.

The compounds provided herein can be administered as a single dose or in an administration schedule where a series of doses are administered at different time intervals over a period of time. 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 schemes for the introduction of the compounds presented in the present description, depend on the pharmacokinetic properties of this connection, such as absorption, distribution and half-life, which can be determined by experts in this field. In addition, suitable administration regimens, including the duration of use of such administration regimens, of the compound provided herein depend on the disease or condition being treated, the severity of the disease or condition, the age and physical condition of the individual being treated, the medical history of the individual being treated , the nature of the concomitant therapy, the desired therapeutic effect and similar factors, the determination of which is within the knowledge and competence of specialists in this field. Those skilled in the art will also appreciate that appropriate administration schedules may need to be adjusted based on the individual's response to the administration regimen or over time as changes may be required for the individual. Typical daily doses may vary depending on the particular route of administration chosen. Typical daily doses for oral administration to a human weighing about 70 kg will be in the range from about 0.1 mg to about 2 g, or more specifically from 0.1 mg to 500 mg, or even more specifically from 0.2 mg to 100 mg of the compound presented in the present description.

One embodiment of the present invention relates to a method of treating a disease or disorder associated with IDO enzyme activity, comprising administering an effective amount of a compound provided herein to an individual in need of treatment. In one embodiment, the IDO enzyme-associated disease or disorder is a cell proliferation disorder.

In one of the embodiments, the implementation of the present invention relates to the use of the compounds presented in the present description, in therapy. The compound can be used in a method of inhibiting IDO enzyme activity in a subject, such as a mammal, in need of such inhibition, comprising administering to the subject an effective amount of the compound.

In one embodiment, the present invention provides a pharmaceutical composition comprising a compound provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for use in the possible treatment of a disorder or disease associated with IDO enzyme activity.

Compositions

Within the scope of the invention, the term "composition" is intended to include a dosage form containing a specific compound in a specific amount, as well as any dosage form obtained directly or indirectly by combining a specific compound in a specific amount. Such a term is intended to include a dosage form containing a compound described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and one or more pharmaceutically acceptable carriers or excipients. Thus, the compositions of the present invention include any composition obtained by admixing 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 described herein and with the other ingredients of the composition.

In one embodiment, the present invention relates to a composition comprising a compound provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and one or more pharmaceutically acceptable carriers or excipients. The composition can be prepared and packaged in bulk form, where an effective amount of the compound of the invention can be separated and then administered to the individual, for example, as in the case of powders or syrups. Alternatively, the composition can be prepared and packaged in a unit dosage form, where each physically discrete unit contains an effective amount of the compound presented in the present description. When prepared in unit dosage form, a composition of the invention typically contains from about 0.1 mg to 2 g, or more specifically from 0.1 mg to 500 mg, or even more specifically from 0.2 mg to 100 mg a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The compound presented in the present description, and pharmaceutically acceptable carriers or excipients, as a rule, will be in dosage form adapted for administration to the individual by the desired route. For example, dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; and (2) parenteral administration, such as sterile solutions, suspensions and powders for reconstitution. Suitable pharmaceutically acceptable carriers or excipients will vary depending on the particular dosage form chosen. In addition, suitable pharmaceutically acceptable carriers or excipients can be selected for the specific function they can perform in the composition. For example, certain pharmaceutically acceptable carriers or excipients may be selected for their ability to facilitate uniform dosage forms. Certain pharmaceutically acceptable carriers or excipients may be selected for their ability to facilitate the preparation of stable dosage forms. Certain pharmaceutically acceptable carriers or excipients may be selected for their ability to facilitate transport of a compound provided herein after administration to an individual from one organ or body part to another organ or body part. Certain pharmaceutically acceptable carriers or excipients may be selected for their ability to increase patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, lubricants, binders, disintegrants, fillers, glidants, granulating agents, coating agents, humectants, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents , anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants and buffering agents.

Those skilled in the art have the knowledge and skill to select suitable pharmaceutically acceptable carriers and excipients in suitable amounts for use in the present invention. In addition, there are a number of resources available to those skilled in the art that describe pharmaceutically acceptable carriers and excipients and which can be used in the selection of suitable 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 Pharmaceutical Press).

Compositions of the invention are prepared by methods known to those skilled in the art. Some methods commonly used in this area 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, containing an effective amount of a compound of the invention and a diluent or excipient. Suitable diluents and excipients include lactose, sucrose, dextrose, mannitol, sorbitol, starch (eg, corn starch, potato starch, and pregelatinized starch), cellulose and its derivatives (eg, microcrystalline cellulose), calcium sulfate, and calcium hydrogen orthophosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (eg, corn starch, potato starch, and pregelatinized starch), gelatin, gum arabic, sodium alginate, alginic acid, gum tragacanth, guar gum, povidone, and cellulose and its derivatives (eg, microcrystalline cellulose). The oral solid dosage form may further contain a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid, and sodium carboxymethylcellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.

If desired, oral dosage units may be microencapsulated. The composition can also be formulated to prolong or sustain release, for example by coating or encapsulating the particulate material in polymers, wax or the like.

The compounds provided herein can also be combined with soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspartamide phenol or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compounds of the invention can be coupled with a class of biodegradable polymers that can be used to achieve controlled drug release, such as polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic hydrogel block copolymers. .

In one embodiment, the invention relates to a liquid oral dosage form. Oral liquids such as solution, syrups and elixirs can be prepared in unit dosage form such that the amount indicated includes a predetermined amount of a compound described herein. Syrups can be prepared by dissolving a compound of the invention in an appropriately flavored aqueous solution; while elixirs are produced using a non-toxic alcohol carrier. Suspensions can be formulated by dispersing a compound provided herein in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring agents such as peppermint oil or other natural sweeteners or saccharin or other artificial sweeteners and the like can also be added.

In one embodiment, the invention relates to compositions for parenteral administration. Compositions adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostatics, and salts to make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. The compositions may be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a lyophilized state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions can be obtained from sterile powders, granules and tablets.

Combinations

The compound provided herein may be used in combination with one or more other active agents, including, but not limited to, other anticancer agents used in the prevention, treatment, control, amelioration, or reduction of the risk of a particular disease or condition (e.g., disorders cell proliferation). In one embodiment, a compound of the present invention is combined with one or more other anticancer agents for use in the prevention, treatment, control, amelioration, or reduction of the risk of a particular disease or condition for which the compounds of the present disclosure are useful. Such other active agents can be administered in the manner and in the amount commonly used for them, simultaneously or sequentially with the compound of the present invention.

When a compound provided herein is used concurrently with one or more other active agents, a composition is provided that contains other such active agents in addition to the compound provided herein. Thus, the compositions of the present invention include compositions also containing one or more other active ingredients in addition to the compound presented in the present description. The compound presented in the present description, you can enter simultaneously, or before or after one or more other therapeutic agents. The compound presented in the present description, you can enter separately by one or different routes of administration or together in the same pharmaceutical composition as other means.

Products provided as a combination preparation include a composition containing a compound described herein and one or more other active agents together in a single pharmaceutical composition, or a compound provided herein and one or more other therapeutic agents in separate forms. , for example, in the form of a set.

The weight ratio of the compound provided herein to the second active agent may vary and will depend on the effective dose of each agent. Generally, an effective dose of each agent will be used. Thus, for example, if a compound provided herein is combined with another agent, the weight ratio of the compound provided herein to the other agent will typically be in the range of from about 1000:1 to about 1:1000, for example , from about 200:1 to about 1:200. Combinations of a compound provided herein and other active agents will generally also fall within the above range, but in each case an effective dose of each active agent should be used. In such combinations, the compound provided herein and other active agents may be administered separately or together. In addition, the introduction of one element can be carried out before, simultaneously with or after the introduction of other agents.

In one of the embodiments, the invention relates to a composition containing the compound presented in the present description, and at least one other therapeutic agent in the form of a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or disorder associated with IDO enzyme activity.

In one of the embodiments, the invention relates to a kit containing two or more separate pharmaceutical compositions, at least one of which contains the compound presented in the present description. In one embodiment, the kit contains means for holding said compositions separately, such as a container, a split bottle, or a split foil pouch. An example of such a kit is a blister pack, typically used for packaging tablets, capsules, and the like.

The kit provided herein can be used to administer different dosage forms, for example, oral and parenteral, to administer separate compositions at different intervals between injections, or to titrate individual compositions against each other. To facilitate patient compliance with a treatment regimen, the kit of the invention typically contains instructions for administration.

The present invention relates to the use of a compound provided herein for the treatment of a disease or disorder associated with IDO enzyme activity, wherein the drug is formulated to be administered with another active agent. The invention also relates to the use of another active agent for the treatment of a disease or disorder associated with the IDO enzyme, where the drug is administered with the compound presented in the present description.

The invention also relates to the use of a compound provided herein for the treatment of a disease or disorder associated with IDO enzyme activity, where the patient has previously (eg, within 24 hours) been treated with another active agent. The invention also relates to the use of another therapeutic agent for the treatment of a disease or disorder associated with the activity of the IDO enzyme, where the patient was previously (for example, within 24 hours) treated with a compound presented in the present description. The second agent can be used a week, a few weeks, a month or a few months after the administration of the compound presented in the present description.

In one embodiment, the other active agent is selected from the group consisting of vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, Smoothened inhibitors, alkylating agents, anticancer antibiotics, antimetabolites, retinoids, immunomodulatory agents, including but not limited to , antitumor vaccines, antagonists of CTLA-4, LAG-3 and PD-1.

Non-limiting examples of vascular endothelial growth factor (VEGF) receptor inhibitors include bevacizumab (sold by Genentech/Roche under the tradename AVASTIN), axitinib, (N-methyl-2-[[3-[([E])-2-pyridine-2- ylethenyl]-1H-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-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide 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 (sold under the tradename NEXAVAR).

Non-limiting examples of topoisomerase II inhibitors include etoposide (also known as VP-16 and etoposide phosphate sold under the trade names TOPOSAR, VEPESID and ETOPOPHOS) and teniposide (also known as VM-26 sold under the trade name VUMON).

Non-limiting examples of alkylating agents include 5-azacytidine (sold under the trade name VIDAZA), decitabine (sold under the trade name DECOGEN), temozolomide (sold by Schering-Plough/Merck under the trade names TEMODAR and TEMODAL), dactinomycin (also known as actinomycin-D and sold under the trade name COSMEGEN), melphalan (also known as L-PAM, L-sarcolysin and phenylalanine mustard sold under the trade name ALKERAN), altretamine (also known as hexamethylmelamine (HMM) sold under the trade name HEXALEN), carmustine ( sold under the trade name BCNU), bendamustine (sold under the trade name TREANDA), busulfan (sold under the trade names BUSULFEX and MYLERAN), carboplatin (sold under the trade name PARAPLATIN), lomustine (also known as CCNU, sold under the trade name CeeNU), cisplatin (also known as CDDP, sold under the trade names Platinol and Platinol-AQ), chloram bucyl (sold under the trade name Leukeran), cyclophosphamide (sold under the trade names Cytoxan and Neosar), dacarbazine (also known as DTIC, DIC and imidazole-carboxamide, sold under the trade name DTIC-Dome), altretamine (also known as hexamethylmelamine (HMM ), sold under the trade name Hexalen), ifosfamide (sold under the trade name Ifex), procarbazine (sold under the trade name Matulane), mechlorethamine (also known as nitrogen mustard, mustine and mechlorethamine hydrochloride, sold under the trade name Mustargen), streptozocin (sold under the trade name Mustargen), streptozocin (sold under the trade name Matulane), under the trade name Zanosar), thiotepa (also known as thiophosfamide, TESPA and TSPA and sold under the trade name Thioplex).

Non-limiting examples of anticancer antibiotics include doxorubicin (sold under the trade names ADRIAMYCIN and Rubex), bleomycin (sold under the trade name lenoxane), daunorubicin (also known as daunorubicin hydrochloride, daunomycin and rubidomycin hydrochloride, sold under the trade name Cerubidine), liposomal daunorubicin (liposomal daunorubicin citrate, sold under the trade name DaunoXome), mitoxantrone (also known as DHAD, sold under the trade name Novantrone), epirubicin (sold under the trade name Ellence), idarubicin (sold under the trade names Idamycin, Idamycin PFS), and mitomycin C (sold under the trade name the name Mutamycin).

Non-limiting examples of antimetabolites include cladribine (2-chlorodeoxyadenosine, sold under the trade name LEUSTATIN), 5-fluorouracil (sold under the trade name ADRUCIL), 6-thioguanine (sold under the trade name PURINTHOL), pemetrexed (sold under the trade name ALIMTA), cytarabine ( also known as arabinosylcytosine (Ara-C), sold under the trade name CYTOSAR-U), liposomal cytarabine (also known as liposomal Ara-C, sold under the trade name DepoCyt), decitabine (sold under the trade name Dacogen), hydroxyurea (sold under the trade name under the trade names Hydrea, Droxia and Mylocel), fludarabine (sold under the trade name FLUDARA), floxuridine (sold under the trade name FUDR), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA), sold under the trade name Leustatin), methotrexate ( also known as amethopterin sodium methotrexate (MTX), sold under the trade names Rheumatrex and Tr exall) and pentostatin (sold under the trade name Nipent).

Non-limiting examples of retinoids include alitretinoin (sold under the trade name Panretin), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the trade name Vesanoid), isotretinoin (13-cis-retinoic acid, sold under the trade names Accutane, Amnesteem, Claravis, Clarus, Decutan, Isotane, Izotech, Oratane, Isotret and Sotret) and bexarotene (sold under the trade name Targretin).

The term "PD-1 antagonist" means any chemical compound or biological molecule that blocks the binding of PD-L1 expressed on a malignant cell to PD-1 expressed on an immune cell (T cell, B cell, or NKT cell), and preferably also blocking the binding of PD-L2 expressed on the malignant cell to PD-1 expressed on the immune cell. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 in the case of PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H in case of PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 in the case of PD-L2. In any of the treatments, drugs and uses 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 human PD-L1 and PD-L2 to Human PD-1. Amino acid sequences of human PD-1 can be found at NCBI under accession number NP_005009. The amino acid sequences of human PD-L1 and PD-L2 can be found at NCBI under accession numbers NP_054862 and NP_079515, respectively.

PD-1 antagonists that can be used in any of the treatments, drugs and uses of the present invention include a monoclonal antibody (mAb), or an antigen-binding fragment thereof, that specifically binds to PD-1 or PD-L1 and preferably binds specifically to with 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, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 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. Non-limiting examples of PD-1 antagonists include pembrolizumab (sold under the trade name Keytruda) and nivolumab (sold under the trade name Opdivo).

Examples of mAbs that bind to human PD-1 and which can be used in the treatments, medicaments and uses of the present invention are described in US7488802, US7521051, US8008449, US8354509, US8168757, WO2004/004771, WO2004/072286, WO2004/056875 and US2011/0271358.

Examples of mAbs that bind to human PD-L1 and which can be used in the treatments, medicaments and uses of the present invention are described in WO2013/019906, WO2010/077634 A1 and US8383796. Specific anti-human PD-L1 mAbs that can be used as a PD-1 antagonist in the treatments, medicaments and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C, and an antibody containing heavy chain and light chain variable regions. SEQ ID NO: 24 and SEQ ID NO: 21, respectively, from WO2013/019906.

Other PD-1 antagonists that can be used in any of the treatments, drugs and uses of the present invention include an immunoadhesin that specifically binds to PD-1 or PD-L1 and preferably specifically binds to human PD-1 or PD- Human L1, for example, a fusion protein comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region, such as the Fc region of an immunoglobulin molecule. Examples of immunoadhesion molecules that specifically bind to PD-1 are described in WO2010/027827 and WO2011/066342. Specific fusion proteins that can be used as a PD-1 antagonist in the treatments, drugs and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein that binds to PD -1 person.

Non-limiting examples of other cytotoxic agents include arsenic trioxide (sold under the trade name Trisenox), asparaginase (also known as L-asparaginase, and Erwinia L-asparaginase, sold under the trade names Elspar and Kidrolase).

EXPERIMENTAL PART

The following synthesis schemes and examples are presented for illustrative purposes only and not for any limitation. The abbreviations used are those generally accepted in the art or as follows.

ACN Acetonitrile aq. Water Boc tert-butyloxycarbonyl Boc _2O Di-tert-butyl dicarbonate Comput. Calculated Celite Diatomaceous earth used as a filtration medium Cu(I)I Copper(I) iodide CV Column volume °C Degrees Celsius DAST Trifluoride (dimethylamino)sulfur DCM dichloromethane DIEA N,N-diisopropylethylamine DIPEA N,N-diisopropylethylamine DMA Dimethylamine DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide dppf or dppf 1,1'-bis(diphenylphosphino)ferrocene dtbpf 1,1'-bis(di-tert-butylphosphino)ferrocene EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EI Electron ionization EMEM Minimum culture medium Needle Et Ethyl _Et2O Diethyl ether Et ₃ N Triethylamine EtOAc ethyl acetate EtOH ethanol G Gram h. Watch HATU 1-[bis(dimethylamino)-methylene]-1 H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxide-hexafluorophosphate HCl Hydrochloric acid HPLC High Performance Liquid Chromatography _{K3PO4 _} Potassium orthophosphate kg Kilogram KHMDS Potassium bis(trimethylsilyl)amide KO ^t Bu Potassium tert-butoxide l Liter LC Liquid chromatography LCMS Liquid chromatography and mass spectrometry LDA Lithium diisopropylamide LiHMDS Lithium bis(trimethylsilyl)amide LiOH lithium hydroxide M mole Me Methyl MeOH methanol MeMgBr Methylmagnesium bromide mg Milligram _MgSO4 Magnesium sulfate mmol Millimole MS Mass spectrometry MTBE Methyl tert-butyl ether min minutes ml Milliliter m/z Mass-to-charge ratio nm nanometer nM nanomol N Normal N ₂ Nitrogen _{Na2SO4 _} Sodium sulfate NaH sodium hydride _NaHCO3 Bicarbonate of soda NaHMDS Bis(trimethylsilyl)amide sodium NaN ₃ sodium azide NaOH Sodium hydroxide _NH4Cl ammonium chloride OTBDPS tert-butyldiphenylsilyl OTf Trifluoromethanesulfonate Pd ₂ (dba) ₃ Tris(dibenzylideneacetone)dipalladium (0) PdCl ₂ (dppf) 1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride Pd(dppf) ₂ Cl ₂ 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) PdCl ₂ (dtbpf) 1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) PE Petroleum ether PG Protecting group PMP P -methoxyphenyl POCl ₃ Phosphorus oxychloride PS Polystyrene RPMI Roswell Park Memorial Institute rt or rt Room temperature sat. Saturated T ₃ P propylphosphonic anhydride solution TBAF Tetrabutylammonium fluoride TBAT Difluorotriphenyl tetrabutylammonium silicate TBS tert-Butyldimethylsilyl ether TBSCl tert-butyldimethylsilyl chloride t -BuOH tert-butanol t-BuONO tert-butyl nitrite TEA Triethylamine TEMPO 2,2,6,6-tetramethylpiperidin-1-yl)oxyl TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TMPMgCl 2,2,6,6-tetramethylpiperidinyl magnesium chloride TMSCF ₃ Trifluoromethyltrimethylsilane TBSCl tert-butyldimethylsilyl chloride TMSCHN ₂ or TMSCH ₂ N ₂ Trimethylsilyldiazomethane TMSCN Trimethylsilyl cyanide TosCl Toluenesulfonyl chloride µl microliter XPhos Pd G2 Chlorine(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (II) XPhos Pd G3 Palladium (II) 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate

GENERAL SYNTHESIS SCHEMES

Compounds of formula (I) can be prepared by organic synthetic methods known in the art, set forth in part in the following synthesis schemes and synthetic methods and conditions for illustrative intermediates and examples.

From the schemes described below, it is clear that protecting groups for sensitive or reactive groups are used, if necessary, in accordance with the general principles of chemistry. Protective groups are attacked by standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage in the synthesis of the compound by methods obvious to those skilled in the art.

Scheme 1

Compounds of formula I can be prepared according to scheme 1. An appropriate carboxylic acid of general formula 1 is coupled with an appropriate amine R ² -NH ₂ under standard amide coupling conditions to obtain an amide compound intermediate of general formula 2. A compound of general formula 2 is reacted with an appropriate boronic acid, pinacol boronic acid ester, silicone containing agent, zincate, stannan or a suitable metal agent under Suzuki coupling, Negishi reaction, Still reaction or other conditions to form compounds of formula I. Alternatively, compounds of general formula 2 are converted to the corresponding pinacol ester boronic acid of general formula 3 by reaction with bis(pinacolato)diborone (B2pin2) under the conditions of a Pd-catalyzed cross-coupling reaction. By reacting a compound of general formula 3 with an appropriate halide, triflate, etc. Suzuki coupling conditions afford compounds of formula I.

The compounds described herein may be prepared from commercially available starting materials or synthesized by known organic, inorganic and/or enzymatic methods.

¹ H NMR spectra were obtained using a Bruker Ultra Shield spectrometer at 600 MHz or a Varian 500 spectrometer at 499 MHz using tetramethylsilane as internal reference. LC/MS spectra were obtained using Agilent 6120 quadrupole mass spectrometers using electrospray ionization.

EXAMPLES

Example 1 : 3-(4-(6-cyclopropylpyridin-3-yl)phenyl ) -N- (4-fluorophenyl)oxetane-3-carboxamide

Step 1: 3-(4-bromophenyl)- N -(4-fluorophenyl)oxetane-3-carboxamide

To a stirred solution of commercially available 3-(4-bromophenyl)oxetane-3-carboxylic acid (4000.0 mg, 15.56 mmol) in DCM (20.0 mL) was added HATU (7099 mg, 18.67 mmol) and stirred suspension for 15 min at RT. 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 hours at RT. The reaction mixture was diluted with ethyl acetate and washed with 1N aqueous HCl (3 times), water (2 times), brine and saturated aqueous NaHCO ₃ . The organic phase was then dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography (ISCO®; 120 g SepaFlash® silica gel flash column, 10-100% ethyl acetate/DCM) to give the title compound (I-2). MS (ESI) m/z 350 [M+H] ⁺ .

Hereinafter, the reaction conditions in step 1 are referred to as standard amide coupling conditions.

Stage 2: 3-(4-(6-cyclopropylpyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide

To a stirred suspension of 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (47.6 mg, 0.194 mmol), 3-(4-bromophenyl) - N - (4-fluorophenyl) oxetane-3-carboxamide (68.0 mg, 0.194 mmol) and dichloro[1,1'-bis (di-tert-butylphosphino) ferrocene] palladium (II) (15.92 mg, 0.017 mmol) in 1,4-dioxane (1.5 ml) was added sodium carbonate (0.194 ml, 0.388 mmol). The reaction mixture was pumped out and placed back under nitrogen three times and heated to 80° C. for 4 hours when complete conversion was detected by LC-MS. The reaction mixture was cooled to RT and filtered through a Celite pad. The filtrate was concentrated under vacuum. The residue was taken up in CH ₂ Cl ₂ and washed with brine. The organic layer was dried over MgSO ₄ , filtered and the solvent was removed under vacuum. The crude material was purified by mass directed reverse phase chromatography (ACN/water modifier with 0.1% TFA) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 389. ¹ H 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 Step 2 are referred to as standard Suzuki cross-coupling reaction conditions.

Example 2 : 3-(4-(6-cyclopropyl-4-fluoropyridin-3-yl)phenyl ) -N- (4-fluorophenyl)oxetane-3-carboxamide

The title compound was obtained analogously to the synthesis of example 1, except that 2-cyclopropyl-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used. MS (ESI) [M+H] ⁺ : m/z 407, ¹ H NMR (499 MHz, DMSO-d6) δ 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-cyclopropyl-4-methylpyridin-3-yl)phenyl ) -N- (4-fluorophenyl)oxetane-3-carboxamide

The title compound was obtained analogously to the synthesis of example 1, except that 2-cyclopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used. MS (ESI) [M+H] ⁺ : m/z 403. ¹ H NMR (499 MHz, DMSO-d6) 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 : N- (4-fluorophenyl)-3-(4-(7-methylimidazo[1,2-a]pyridin-6-yl)phenyl)oxetan-3-carboxamide

The title compound was prepared analogously to the synthesis of Example 1, except that (7-methylimidazo[1,2-a]pyridin-6-yl)boronic acid was used. MS (ESI) [M+H] ⁺ : m/z 402, ¹ H 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)- N -(4-fluorophenyl)oxetane-3-carboxamide

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, ¹ H 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: N -(4-fluorophenyl)-3-(4-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide

The title compound was obtained analogously to the synthesis of example 1, except that 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- was used as a coupling partner. 2-(trifluoromethyl)pyridine. MS (ESI) [M+H] ⁺ : m/z 431; found, 431, ¹ H 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).

Example 7: N -(4-fluorophenyl)-3-(4-(6-methoxy-2,4-dimethylpyridin-3-yl)phenyl)oxetan-3-carboxamide

Stage 1: N -(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide

In a dry round bottom flask were placed 3-(4-bromophenyl) -N- (4-fluorophenyl)oxetane-3-carboxamide (I-2) (200.0 mg, 0.571 mmol), bis(pinacolato)diborone (377 mg, 1.485 mmol), potassium acetate (166 mg, 1.691 mmol) and PdCl ₂ (dppf)-CH ₂ Cl ₂ (46.6 mg, 0.057 mmol) in dioxane (5.0 ml). The resulting mixture was then pumped out and placed back under nitrogen (3 times). The mixture was heated to 80° C. for 4 hours, then cooled to RT and filtered through a Celite pad. The filtrate was concentrated in vacuo to give a residue which was dissolved in dichloromethane. After washing with water (3 times) and brine, the dichloromethane layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product, which was purified by column chromatography (silica gel, EtOAc/hexane, 12-100%) to give the title compound (I-9). MS (ESI) [M+H] ⁺ : m/z 398.

Stage 2: N -(4-Fluorophenyl)-3-(4-(6-methoxy-2,4-dimethylpyridin-3-yl)phenyl)oxetan-3-carboxamide

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-1, 3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (30.0 mg, 0.076 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (4.92 mg, 7, 55 µmol) and sodium carbonate (0.076 ml, 0.151 mmol) in 1,4-dioxane (2.0 ml) were pumped out and placed back with nitrogen three times and the mixture was heated under nitrogen at 80° C. for 4 h. Then the solvents was removed under vacuum 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 give the title compound. MS (ESI) [M+H] ⁺ : m/z 407, ¹ H 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 8-33 in the table below were prepared analogously to example 7. Methods for the synthesis of selected starting materials are presented in the present description.

Examples of general Suzuki coupling reaction conditions using X-Phos (X-phosG2 or G3) at temperatures in the range of 45-70° C. are given for the formulations in Example 11 and Compound I-14 below.

N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (I-9) (70 mg, 0.141 mmol), (5-bromo-2-methoxypyridin-4-yl)methanol (30.7 mg, 0.141 mmol) and X-PhosPdG2 (11.09 mg, 0.014 mmol) were added to a 4 ml reaction tube, pumped out and placed back with nitrogen 3 times. THF (564 µl) and potassium orthophosphate (1 M aqueous solution) (282 µl, 0.282 mmol) were added. The reaction mixture was heated to 70°C for 1 hour and cooled to RT. The reaction mixture was diluted with 4 ml DCM, passed through a phase separator, the organic phase was collected and concentrated under vacuum. The residue was dissolved in 1 ml DMSO and subjected to reverse phase purification (ACN/water gradient with 0.1% TFA modifier). Pure fractions were frozen and lyophilized to give N-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-methoxypyridin-3-yl)phenyl)oxetan-3-carboxamide (Example 11) as TFA salt in the form of a solid.

Preparation of 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethan-1-ol (I-11): Coupling Partner for Example 15

(I-11)

(I-11)

Methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)acetate (480 mg, 1.893 mmol) was dissolved in THF (9464 μl) and the mixture was cooled to -78°C. DIBAL-H (4732 μl, 4.73 mmol) was then added and the mixture was allowed to warm to RT over 1 h. The reaction was quenched with saturated aqueous sodium potassium tartrate and stirred overnight at RT. The organic layer was separated and the aqueous layer was extracted with 50 ml EtOAc 1 time. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethanol as an orange oil which was used to prepare Example 15 without subsequent cleaning. MS (ESI) [M+H] ⁺ : m/z 226.

Preparation of 2-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)propan-2-ol (I-12): Coupling Partner for Example 12

(I-12)

(I-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 methyl magnesium bromide (3 M in Et ₂ O) ( 3.52 ml, 10.56 mmol) and allowed the mixture to warm to RT over 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and stirred overnight at RT. Separated organic compounds, washed with brine, dried over sodium sulfate and removed solvents under vacuum to obtain 2-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)propan-2-ol (I-12) as a solid substance that was used to obtain examples 12 and 20 without further purification. MS (ESI) [M+H] ⁺ : m/z 284/286.

Alternatively, I-12 can be prepared as follows: LDA (2 M, 33.2 mL) was placed in a round bottom flask under nitrogen. 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. for 3 hours, and the mixture was stirred at ≤-65° C for another 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 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, 2 times). 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 give I-12. ¹ H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.19 (s, 1H), 5.82 (s, 1H), 1.62 (s, 6H).

Preparation of 1-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)ethan-1-ol (I-13): Coupling Partner for Examples 16-17

(I-13)

(I-13)

5-bromo-2-(trifluoromethyl)isonicotinaldehyde (333 mg, 1.311 mmol) was dissolved in THF (6555 μl) in a 40 ml vial and the solution was degassed under nitrogen and cooled to -78°C. Methyl magnesium bromide (3 M in Et ₂ O) (524 μl, 1.573 mmol) was added and the resulting mixture was slowly heated to RT over 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and stirred for 1 h. The organic layer was separated, the aqueous was extracted layer with 50 ml EtOAc and the combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to obtain 1-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)ethanol, which was used to obtain examples 16-17 without further purification. MS (ESI) [M+H] ⁺ : m/z 270/272.

The racemic mixture obtained by the Suzuki coupling reaction was separated by SFC using a 21×250 mm Lux-2 column and 20% MeOH/0.25% DMEA as a modifier at a flow rate of 70 ml/min. The first eluting peak was collected and concentrated to give compound 16. The second eluting peak was collected and concentrated to give compound 17.

Preparation of 2-(5-bromo-2-(difluoromethoxy)pyridin-4-yl)propan-2-ol (I-14): Coupling Partner for Example 18

Step 1: Methyl 5-bromo-2-(difluoromethoxy)isonicotinate

Sodium chlorodifluoroacetate (0.891 g, 5.84 mmol) and ACN (30 mL) were added to methyl 5-bromo-2-hydroxyisonicotinate (1.13 g, 4.87 mmol) and the mixture heated to condensation overnight. Additional sodium chlorodifluoroacetate (0.891 g, 5.84 mmol) was added and the reaction heated to condensation overnight. The reaction was quenched with saturated ammonium chloride solution, extracted 2 times with help. 50 ml EtOAc, the combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica gel, 0-10% Et ₂ O/hexanes to give 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 (I-14)

The connection was obtained 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 (I-15): Coupling Partner for Example 32

(I-15)

(I-15)

The compound was prepared from methyl 3-bromo-6-(trifluoromethyl)nicotinate in the same 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 (I-16): Coupling Partner for Example 13

(I-16)

(I-16)

I-16 was prepared from methyl 5-bromo-2-(trifluoromethyl)isonicotinate and DIBAL-H in a similar manner to compound I-11. MS (ESI) [M+H] ⁺ : m/z 254/256.

Synthesis of (3-bromo-6-cyclopropylpyridin-2-yl)methanol (I-17) is shown in the following scheme:

Stage 1: Synthesis of 5-bromo-2-cyclopropylpyridine

Into a 4-necked 5 L round-bottom flask, purged with nitrogen and maintained under an inert atmosphere of nitrogen, was placed a solution of Mg (200 g, 8.33 mol, 10.00 eq.) in tetrahydrofuran (1500 ml), I ₂ (1 g ) and bromocyclopropane (400 g, 3.33 mol, 4.00 eq.). The reaction mixture was stirred for 3 hours at 65°C and then added to a solution of ZnCl ₂ (560 g, 4.12 mol, 5.00 eq.) in tetrahydrofuran (2000 ml) at 10°C. The resulting solution was stirred for 2 hours at RT and then Pd(dppf)Cl ₂ (20 g), 2,5-dibromopyridine (200 g, 843.88 mmol, 1.00 eq.) was added. The reaction mixture was stirred overnight at RT and quenched by adding 500 ml of water. The resulting mixture was concentrated under vacuum and then extracted 3 times with 5 l of ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using a silica gel column with EtOAc/petroleum ether (1/2) to give 5-bromo-2-cyclopropylpyridine as a solid.

Step 2: Synthesis of 5-bromo-2-cyclopropylpyridine 1-oxide

A solution of 5-bromo-2-cyclopropylpyridine (184 g, 924.62 mmol, 1.00 eq.) in dichloromethane (1500 ml) was placed in a 4-necked 3 L round bottom flask. 3-Chlorobenzoperoxoic acid (209 g, 1.22 mol, 1.00 eq.) was added to the solution in portions at 0° C. over 5 minutes. The resulting solution was stirred overnight at RT. The pH of the solution was adjusted to 11 using sodium hydroxide (20%). The resulting solution was extracted 4 times with 400 ml of ethyl acetate, the combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified using a silica gel column with ethyl acetate to give 5-bromo-2-cyclopropylpyridine 1-oxide as a solid.

Stage 3: Synthesis of 3-bromo-6-cyclopropylpicolinonitrile

A solution of 5-bromo-2-cyclopropylpyridine 1-oxide (100 g, 467.29 mmol, 1.00 eq.) in ACN (1200 ml), TMSCN (190 g, 1.00 eq.) 92 mol, 4.00 eq.) and TEA (192 ml, 3.00 eq.). The resulting solution was stirred overnight at reflux and then diluted with water and extracted 4 times with 500 ml of ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using a silica gel column with ethyl acetate/petroleum ether (1/50) to give 3-bromo-6-cyclopropylpicolinonitrile as a solid.

Stage 4: Synthesis of 3-bromo-6-cyclopropylpicolinic acid

In a 4-necked 3 liter round bottom flask were placed 3-bromo-6-cyclopropylpicolinonitrile (74 g, 331.84 mmol, 1.00 eq.) and sodium hydroxide (20%, 1500 ml). The resulting solution was stirred overnight at reflux, cooled to RT and then extracted 3 times with 200 ml of ether. The pH of the combined aqueous layer was adjusted to 4 with hydrochloric acid (3 N) and the resulting solution was extracted 4 times with 300 ml of ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using a silica gel column with ethyl acetate/petroleum ether (1/5) to give 3-bromo-6-cyclopropylpicolinic acid as a solid.

Stage 5: Synthesis of (3-bromo-6-cyclopropylpyridin-2-yl)methanol (I-17)

Into a 3 liter 4-necked round bottom flask was placed a solution of 3-bromo-6-cyclopropylpicolinic acid (80 g, 330.58 mmol, 1.00 eq.) in tetrahydrofuran (20 ml). Triethylamine (72 ml, 1.50 eq.) was added dropwise to the reaction mixture with stirring at -5-0°C for 5 min, and then ethyl chloroformate (41 g, 379.63 mmol, 1.30 eq. .) with stirring at -20°C. The resulting solution was stirred for 60 min at -20°C. The solid was filtered off and a solution of NaBH ₄ (28 g, 2.00 eq.) in water (84 g) was added dropwise to the filtrate with stirring at -10°C. The resulting solution was stirred for another 20 min at -10°C. The reaction was then quenched by adding NH ₄ Cl (saturated). The resulting solution was extracted 3 times with 1000 ml of ethyl acetate, the combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified using a silica gel column with petroleum ether/ethyl acetate (50/1). Thus, compound I-17 was obtained 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=5.7Hz), 4.52(2H, d，J=5.7Hz). This material was used to prepare Example 26.

Example No. Structure chemical name Mass [M+H]+ eight

3-(4-(6-(difluoromethoxy)-2,4-dimethylpyridin-3-yl)phenyl)- N- (4-fluorophenyl)oxetane-3-carboxamide 443 nine

3-(4-(6-(difluoromethoxy)-4-methylpyridin-3-yl)phenyl)- N- (4-fluorophenyl)oxetane-3-carboxamide 429 10

N- (4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide 447 eleven

N-(4-fluorophenyl)-3-[4-[4-(hydroxymethyl)-6-methoxy-pyridin-1-y-3-yl]phenyl]oxetan-3-carboxamide 431 [M + Na] ⁺ 12

N-(4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide 475 13

3-[4-[6-(difluoromethoxy)-4-(hydroxymethyl)-3-pyridyl]phenyl]-N-(4-fluorophenyl)oxetane-3-carboxamide 445 fourteen

N-(4-fluorophenyl)-3-[4-[3-(hydroxymethyl)-1-methyl-pyrazol-4-yl]phenyl]oxetan-3-carboxamide 382 fifteen

N-(4-fluorophenyl)-3-[4-[3-(2-hydroxyethyl)-5-(trifluoromethyl)-2-pyridyl]phenyl]oxetane-3-carboxamide 461 16

(Isomer 1 obtained by SFC) (R or S)-N-(4-fluorophenyl)-3-(4-(4-(1-hydroxyethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane -3-carboxamide 461 17

(Isomer 2 obtained by SFC) (S or R)-N-(4-fluorophenyl)-3-(4-(4-(1-hydroxyethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane -3-carboxamide 461 eighteen

3-[4-[6-(difluoromethoxy)-4-(1-hydroxy-1-methyl-ethyl)pyridin-1-y-3-yl]phenyl]-N-(4-fluorophenyl)oxetane-3-carboxamide ; 2,2,2-trifluoroacetate 473 nineteen

3-[4-[6-(difluoromethoxy)-4-(1-hydroxy-1-methyl-ethyl)pyridin-1-y-3-yl]phenyl]-N-(4-fluorophenyl)oxetane-3-carboxamide ; 2,2,2-trifluoroacetate 446 twenty

N-(4-chlorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide 491 21

N-(4-chlorophenyl)-3-[4-[4-(hydroxymethyl)-6-methoxy-pyridin-1-yl-3-yl]phenyl]oxetan-3-carboxamide; 2,2,2-trifluoroacetate 425 22

N-(4-chlorophenyl)-3-[4-[4-(hydroxymethyl)-6-(trifluoromethyl)-3-pyridyl]phenyl]oxetane-3-carboxamide 463 23

N-(4-chlorophenyl)-3-[4-[6-(difluoromethoxy)-4-(hydroxymethyl)-3-pyridyl]phenyl]oxetane-3-carboxamide 461 24

N-(4-fluorophenyl)-3-[4-[2-(hydroxymethyl)phenyl]phenyl]oxetane-3-carboxamide 378 25

N-(4-fluorophenyl)-3-[4-[2-(hydroxymethyl)pyridin-1-yl-3-yl]phenyl]oxetan-3-carboxamide; 2,2,2-trifluoroacetate 379 26

3-[4-[6-cyclopropyl-2-(hydroxymethyl)pyridin-1-yl-3-yl]phenyl]-N-(4-fluorophenyl)oxetane-3-carboxamide; 2,2,2-trifluoroacetate 419 27

3-[4-[2-cyclopropyl-4-(hydroxymethyl)thiazol-3-ium-5-yl]phenyl]-N-(4-fluorophenyl)oxetane-3-carboxamide; 2,2,2-trifluoroacetate 425 28

N-(4-fluorophenyl)-3-[4-[4-(hydroxymethyl)pyridin-1-yl-3-yl]phenyl]oxetan-3-carboxamide; 2,2,2-trifluoroacetate 379 29

N-(4-fluorophenyl)-3-[4-[6-(trifluoromethyl)pyridin-1-yl-3-yl]phenyl]oxetan-3-carboxamide; 2,2,2-trifluoroacetate 417 thirty

N-(4-fluorophenyl)-3-[4-[4-(hydroxymethyl)-6-methyl-pyridin-1-yl-3-yl]phenyl]oxetan-3-carboxamide; 2,2,2-trifluoroacetate 393 31

N-(4-fluorophenyl)-3-[4-[2-(hydroxymethyl)-6-(trifluoromethyl)-3-pyridyl]phenyl]oxetane-3-carboxamide 447 32

N-(4-fluorophenyl)-3-(4-(2-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide 475 33

N-(6-chloropyridin-3-yl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide 464

Example 10 can also be obtained in the following way:

Stage 1: Synthesis of 5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(trifluoromethyl)pyridine (I-44)

(5-bromo-2-(trifluoromethyl)pyridin-4-yl)methanol (600.0 mg, 2.344 mmol) was dissolved in DCM/DMF (v/v 4:1, 12 ml) with stirring and thus obtained thus the solution was cooled to 0°C. DIEA (0.573 mL, 3.28 mmol) and t-butyldimethylsilyl chloride (495 mg, 3.28 mmol) were added and the mixture was stirred at RT for 20 h. The reaction mixture was then concentrated in vacuo and partitioned with 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 silica gel column with 40 g RediSep gold, 2-20% MeOH/DCM as eluents) to give compound I-44. MS (ESI) [M+H] ⁺ : m/z 370.

Stage 2: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (I-45)

A mixture of compound I-44 (720.0 mg, 1.944 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (593 mg, 2.333 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (127 mg, 0.194 mmol) and potassium acetate (573 mg, 5.83 mmol) in 1,4-dioxane (5.0 ml) was pumped out and placed back with nitrogen 3 times. The mixture was heated to 80° C. in a sealed tube for 2 hours. After cooling to RT, the reaction mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to give a residue which was dissolved in dichloromethane. After washing with water (3 times) and brine, the dichloromethane layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a 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-3-yl)phenyl)- N -(4-fluorophenyl)oxetane-3-carboxamide (I-46)

A solution of (4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-3-yl)boronic acid (96 mg, 0.286 mmol), 3-(4-bromophenyl)- N -(4- fluorophenyl)oxetane-3-carboxamide (I-2) (100 mg, 0.286 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (18.61 mg, 0.029 mmol) and sodium carbonate (0.286 ml , 0.571 mmol) in 1,4-dioxane (2.0 ml) was subjected to a Suzuki cross-coupling reaction under standard conditions and the crude product was purified by silica gel column chromatography (ethyl acetate/DCM, 10-70%) to give compound I-46 . MS (ESI) [M+H] ⁺ : m/z 561.

Stage 4: N -(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide

To a solution of compound I-46, (143.0 mg, 0.255 mmol) in THF (5.0 ml) was added ammonium tetra-N-butyl chloride in 1 M THF (0.255 ml, 0.255 mmol) at 0°C and the reaction mixture was stirred within 2 hours at RT. The solvent was evaporated under vacuum and the residue was redissolved in dichloromethane. After successively washing with water, saturated aqueous sodium bicarbonate and brine, the organic phase was dried over sodium sulfate, filtered and the filtrate was evaporated under vacuum. The crude material was purified by mass directed reverse phase chromatography (ACN/water modifier with 0.1% TFA) to give the title compound.

Example 12 : N- (4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide

N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan- 3-carboxamide (I-9) (5 g, 12.5 mmol), 2-(5-bromo-2-(trifluoromethyl) pyridin-4-yl) propan-2-ol (I-12) (4 g, 14 mmol) and PdCl ₂ (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 solution (40 ml, 1 M). The mixture was again subjected to a vacuum/nitrogen cycle three times and then heated to 60° C. under nitrogen for 4 hours. The mixture was allowed to cool to RT, transferred to a separating funnel and diluted with water (50 ml) and dichloromethane (100 ml). The organic phase was collected and the aqueous phase was re-extracted with dichloromethane (100 ml). The combined organic extracts were washed with brine and stirred 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 product was purified by silica gel chromatography using an ethyl acetate in hexane gradient to give the crude material. This crude material was taken up in diethyl ether (25 ml) and stirred for 15 minutes. The solids were filtered and washed with diethyl ether to give the title compound. MS (ESI+) m/z [M+H] ⁺ : 475. ¹ H 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) -N- (4-fluorophenyl)oxetane-3-carboxamide

To a solution of N- (4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide (I-20) (70.0 mg , 0.157 mmol) in DCM (3 ml) at 0°C was added 1,1,1-trifluoro- N,N -bis(2-methoxyethyl)-1,4-sulfonamine. After stirring at 0° C. for 1 hour, the reaction was carefully quenched with aqueous NaHCO ₃ 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 give the title compound. MS (ESI) [M+H] ⁺ : m/z 449. ¹ H 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=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-(4-(trifluoromethoxy)phenyl)oxetane-3-carboxamide

Step 1: Methyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetane-3-carboxylate (I-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(1,3,2-dioxaborolane) (2.065 g, 8.13 mmol) in dioxane (30 ml) were added AcOK (2.281 g, 23.24 mmol) and Pd(dppf)Cl ₂ (0.567 g, 0.775 mmol) with stirring at RT under nitrogen. After completion of the addition, the reaction mixture was stirred at 80°C for 14 hours, cooled to RT 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®; silica gel-CS Agela® flash chromatography column (12 g), eluting with a 0~7% ethyl acetate/petroleum ether gradient at 30 ml/min) to give the compound I-48 as a solid. MS (ESI) m/z 360 [M+ACN+H ⁺ ].

Step 2: Preparation of 3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxylic acid (I-49)

To a solution of compound I-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) K ₃ PO ₄ (1.001 g, 4.71 mmol) and Pd(dtbpf)Cl ₂ (102 mg, 0.157 mmol) were added. The reaction mixture was sealed, stirred at 100°C in a nitrogen atmosphere, and transferred to a microwave oven. After stirring at 100°C for 0.5 h, the reaction mixture was cooled to RT and diluted with water (10 ml). The mixture was extracted with EtOAc (30 ml, 3 times). The combined organic layers were washed with brine (20 ml) and dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography (ISCO®; Agela® silica gel-CS flash column (12 g), eluting with a 0~27% ethyl acetate/petroleum ether gradient at 30 ml/min) to give 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)pyridin-3-yl)phenyl)oxetan-3-carboxylate prepared as above (520 mg, 1.416 mmol) in THF (4 ml), MeOH (4 ml) and water (2 ml) were added LiOH (102 mg, 4.25 mmol) at RT and stirring, and the reaction mixture was stirred at RT for 14 h. 3 N HCl was added to the mixture with stirring until pH ~4 is reached. Then the reaction mixture was diluted with water (5 ml) and was extracted with EtOAc (10 ml, 5 times). The combined organic layer was washed with brine (10 ml) and dried over Na ₂ SO ₄ , filtered and concentrated to give compound I-49 as a solid, which was used in the next step without further purification. MS (ESI) m/z 354 [M+H ⁺ ].

Step 3: 3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-(trifluoromethoxy)phenyl)oxetane-3-carboxamide

To a solution of compound I-49 (30 mg, 0.085 mmol) and 4-(trifluoromethoxy)aniline (30 mg, 0.169 mmol) in pyridine (1.0 ml) was added EDCI (50 mg, 0.261 mmol) with stirring and RT. After the addition was complete, the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC using a GILSON 281 equipped with an aYMC-Actus Pro C18 150×30×5 µm column using water (0. 1% TFA) and ACN as eluents. The desired fractions were concentrated and then lyophilized to give the title compound as a solid. MS (ESI) m/z 513.2 [M+H ⁺ ]. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.54 (s, 1H), 8.07 (s, 1H), 7.61-7.74 (m, 4H), 7.50 (d, J= 8.3 Hz, 2H), 7.24 (d, J= 8.3 Hz, 2H), 5.37 (d, J= 6.6 Hz, 2H), 5.04 (d, J= 6.6 Hz, 2H), 4.65 (s, 2H).

Examples 36-42 in the following table were prepared analogously to example 35.

Example No. Structure chemical name Mass [M+H]+ 36

N-(4-bromophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide 507 37

3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-(trifluoromethyl)phenyl)oxetan-3-carboxamide 497 38

N- (3,4-difluorophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide 465 39

N-(4-cyanophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide 454 40

N-(6-fluoropyridin-3-yl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide 448 41

N-(4-(difluoromethoxy)phenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide 495 42

3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(6-(trifluoromethyl)pyridin-3-yl)oxetan-3-carboxamide 498

Example 43 : 3-(4-( 1H -tetrazol-5-yl)phenyl ) -N- (4-fluorophenyl)oxetane-3-carboxamide

Stage 1: Synthesis N -(4-fluorophenyl)-3-(4-isocyanophenyl)oxetane-3-carboxamide

In a dry flask was placed 3-(4-bromophenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide (I-2) (1000.0 mg, 2.86 mmol) in anhydrous DMF (10.0 ml). To this was added zinc cyanide (671 mg, 5.71 mmol), Pd ₂ (dba) ₃ (105 mg, 0.114 mmol) and dppf (79 mg, 0.143 mmol), followed by zinc dust (18.67 mg, 0.286 mmol ). The reaction mixture was then purged with nitrogen for 5 minutes. The reaction mixture was heated at 120° C. for 4 hours and cooled to RT, filtered through a Celite pad, which was then washed with DCM. The filtrate was concentrated in vacuo and the crude product was purified on a Biotage silica gel column (EtOAc/hexane 5-40%) to give N- (4-fluorophenyl)-3-(4-isocyanophenyl)oxetane-3-carboxamide. MS (ESI) [M+H] ⁺ : m/z 297.

Stage 2: 3-(4-( 1H -tetrazol-5-yl)phenyl)- N -(4-fluorophenyl)oxetane-3-carboxamide (compound 43)

N-(4-fluorophenyl)-3-(4-isocyanophenyl)oxetane-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) was added to a mixture of water (923 µl) and 2-propanol (461 µl). The resulting suspension was then heated to condensation and stirred overnight. The mixture was cooled to RT, filtered through a Celite pad and concentrated. The crude material was purified by mass directed reverse phase chromatography (ACN/water modifier with 0.1% TFA) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 340, ¹ H 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).

Example 44 : N- (4-fluorophenyl)-3-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)oxetane-3-carboxamide

Stage 1: Synthesis (Z)- N -(4-fluorophenyl)-3-(4-(N'-hydroxycarbamimidoyl)phenyl)oxetane-3-carboxamide (I-59)

Nitrile- N- (4-fluorophenyl)-3-(4-isocyanophenyl)oxetane-3-carboxamide (60.0 mg, 0.203 mmol) was dissolved in MeOH (1.0 ml) and then hydroxylamine (50% wt.) was added. in water) (0.137 ml, 2.228 mmol). The mixture was heated to 60° C. for 2 hours. The reaction mixture was diluted with brine and extracted with EtOAc (3 times). The combined organic layers were dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure to give compound I-59. MS (ESI) [M+H] ⁺ : m/z 330. The crude product was used directly in the next step without purification.

Stage 2: N -(4-fluorophenyl)-3-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)oxetane-3-carboxamide

TFAA (0.064 ml, 0.455 mmol) was added to a mixture of compound I-59 (50.0 mg, 0.152 mmol) and pyridine (0.037 ml, 0.455 mmol) in toluene (2.0 ml) at 10°C. After the addition was complete, the mixture was stirred at 110° C. for 3 hours. After cooling to RT, the mixture was concentrated under reduced pressure and the residue was separated with EtOAc and water. The aqueous layer was extracted with EtOAc (2 times) and the collected organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ . The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by mass directed reverse phase chromatography (ACN/water modifier with 0.1% TFA) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 408, ¹ H 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).

Example 45 : 3-(4-(1H-benzo[d]imidazol-2-yl)phenyl ) -N- (4-fluorophenyl)oxetane-3-carboxamide

Step 1: Synthesis of ethyl 4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)benzoate (I-61)

1,1'-Bis(diphenylphosphino)ferrocene(II) dichloride complex in dichloromethane (152 mg, 0.186 mmol) was added to a stirred solution containing Compound I-2 (325.0 mg, 0.928 mmol), TEA (517 µl, 3 .71 mmol) in EtOH (1084 µl, 18.56 mmol) and DMF (4640 µl). The mixture was stirred under a carbon dioxide atmosphere at 90° C. overnight. The reaction mixture was cooled to RT and then filtered through a Celite pad. The filtrate was concentrated, diluted with ethyl acetate, washed with water (2 times) and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified on a Biotage (silica gel) column using EtOAc/hexanes (5-40%) as eluents to give compound I-61. MS (ESI) [M+H] ⁺ : m/z 344.

Step 2: Synthesis of 4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)benzoic acid (I-62)

1 M LiOH (3.0 ml, 3.00 mmol) was added to a solution of compound I-61 (300.0 mg, 0.874 mmol) in MeOH (5.0 ml). This mixture was stirred at RT for 4 hours and evaporated under reduced pressure. The residue was diluted with water and acidified with aqueous hydrochloric acid (2 N). This aqueous mixture was extracted with ethyl acetate (2 times, 50 ml) and the combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure to obtain compound I-62. MS (ESI) [M+H] ⁺ : m/z 316.

Step 3: 3-(4-(1H-benzo[d]imidazol-2-yl)phenyl)- N -(4-fluorophenyl)oxetane-3-carboxamide

Into a 20 ml vial was placed a magnetic stir bar, Compound I-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 several minutes. Then, benzene-1,2-diamine (17.15 mg, 0.159 mmol), DIEA (83 μl, 0.476 mmol) was added to the mixture and the reaction mixture was stirred for 4 hours at RT. The reaction mixture was diluted with 50 ml of ethyl acetate and washed with 1 N aqueous HCl, water, brine and saturated aqueous NaHCO ₃ . The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated. The residue was dissolved in DCM and purified by silica gel chromatography (flash column 12 g, EtOAc in hexane 0-50%, 15 CV) to give compound I-63. MS (ESI) [M+H] ⁺ : m/z 406.

Compound I-63 was dissolved in MeOH (1910 μl) and acetic acid (200.0 μl, 3.49 mmol) and then heated at 100°C for 1 h. The mixture was diluted with MeOH, filtered and purified by reverse mass -phase HPLC (ACN/water, TFA) to obtain the title compound. MS (ESI) [M+H] ⁺ : m/z 388, ¹ H 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 46-50 were prepared in the same way as example 45 using acid I-62 and 4-chlorophenylenediamine, pyridine-3,4-diamine, 4-fluorobenzene-1,2-diamine, 4,5-difluorobenzene-1, 2-diamine, pyridine-2,3-diamine and 5-bromopyridine-2,3-diamine, respectively.

Example No. Structure chemical name Mass [M+H]+ 46

3-(4-(5-chloro-1H-benzo[d]imidazol-2-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide 422 47

3-(4-(3H-imidazo[4,5-c]pyridin-2-yl)phenyl)- N- (4-fluorophenyl)-oxetane-3-carboxamide 389 48

3-(4-(6-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)- N- (4-fluorophenyl)oxetane-3-carboxamide 389 49

3-(4-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)phenyl)- N- (4-fluorophenyl)oxetane-3-carboxamide 424 fifty

3-(4-(3H-imidazo[4,5-b]pyridin-2-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide 389

Example 51: 3-(4-(6-cyano-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)- N -(4-fluorophenyl)oxetane-3-carboxamide

3-(4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide (obtained by the method described for Example 45) (70.0 mg, 0.150 mmol), zinc cyanide (42.2 mg, 0.360 mmol), zinc dust (7.05 mg, 0.108 mmol), Pd ₂ (dba) ₃ (21.95 mg, 0.024 mmol) and DPPF (26.6 mg, 0.048 mmol) in N,N -dimethylacetamide (2.0 mL) was added to a microwave reaction vessel. The mixture was then irradiated at 130°C for 60 min. The reaction mixture was cooled and then filtered through a Celite pad and concentrated. The crude material was purified by mass directed reverse phase chromatography (ACN/water modifier with 0.1% TFA) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 414, ¹ H 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).

Example 52: 3-(4-(6-cyclopropylpyridin-3-yl)phenyl)- N -(5-fluoropyridin-2-yl)oxetan-3-carboxamide

Step 1: 3-(4-bromophenyl)-N-(5-fluoropyridin-2-yl)oxetan-3-carboxamide

In a 100 ml vessel was placed a magnetic stir bar, 3-(4-bromophenyl)oxetane-3-carboxylic acid (1000.0 mg, 3.89 mmol) and DMF (10.0 ml). To this was added HATU (1775 mg, 4.67 mmol) at RT and stirring, and the reaction mixture was stirred for several minutes. 5-Fluoropyridine-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 hours at RT. The reaction mixture was diluted with ethyl acetate and washed with 1N aqueous HCl (3 times), water, brine and saturated aqueous NaHCO ₃ . The organic solution was then dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated. The crude product was purified on a Biotage column with DCM/EtOAc (10-100%) to give compound I-72. MS (ESI) [M+H] ⁺ : m/z 351.

Step 2: 3-(4-(6-cyclopropylpyridin-3-yl)phenyl)- N -(5-fluoropyridin-2-yl)oxetan-3-carboxamide

To a stirred suspension of compound I-72, (50.0 mg, 0.142 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium 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 placed back under nitrogen three times and then heated to 80° C. for 4 hours. The reaction mixture was cooled to RT, filtered through a Celite pad and concentrated. The product was purified by mass directed reverse phase chromatography (ACN/water gradient with 0.1% TFA modifier) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 390, ¹ H 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).

Example 53: 3-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)- N -(4-fluorophenyl)oxetane-3-carboxamide

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 (I-62) (112.0 mg, 0.355 mmol) in DCM (2.0 ml) and the mixture was stirred at RT for 2 h. Then N'-hydroxycyclopropanecarboximidamide (89 mg, 0.888 mmol) was added and the mixture was stirred at RT for another 2 h, concentrated, evaporated with toluene, redissolved in toluene (2 ml) and heated at 110° C. for 2 h. The mixture was cooled, quenched with water and extracted with ethyl acetate (3 times). The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and the solvents were evaporated under reduced pressure. The crude material was purified by mass directed reverse phase chromatography (ACN/water modifier with 0.1% TFA) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 380. ¹ H 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-oxopyrimidine-1( 6H )-yl)phenyl)- N -(4-fluorophenyl)oxetane-3-carboxamide

6-cyclopropylpyrimidin-4( 1H )-one (43.0 mg, 0.316 mmol), copper iodide (6.01 mg, 0.032 mmol), 3-(4-bromophenyl)-N-(4-fluorophenyl )oxetane-3-carboxamide (I-2) (111 mg, 0.316 mmol) and trans- N,N' -dimethylcyclohexane-1,2-diamine (8.98 mg, 0.063 mmol). This mixture was then pumped out and placed back with nitrogen (3 times). Dry, degassed 1,4-dioxane (1263 μl) was then added and then the mixture was heated at 110°C for 24 h. The crude material was purified by mass directed reverse phase chromatography (ACN/water gradient with 0.1% modifier). TFA) to obtain the title compound. MS (ESI) [M+H] ⁺ : m/z 406, ¹ H NMR (499 MHz, DMSO-d6) δ 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 (n, J=6.9 Hz, 1H), 1.05-0.71 (m, 2H).

Example 55: 3-(4-(4-cyclopropyl-6-methyl-2-oxopyrimidine-1( 2H )-yl)phenyl)- N -(4-fluorophenyl)oxetane-3-carboxamide

Example 55 was prepared analogously to Example 54. MS (ESI) [M+H] ⁺ : m/z 420. ¹ H NMR (499 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.79 (d, J=8.3Hz, 2H), 7.60(dd, J=8.8, 5.0Hz, 2H), 7.29(d, J=8.3Hz, 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: N -(4-fluorophenyl)-1-(6-(2-phenyloxazol-4-yl)pyridin-3-yl)cyclobutan-1-carboxamide

Step 1: Synthesis of 1-(6-chloropyridin-3-yl)- N -(4-fluorophenyl)cyclobutane-1-carboxamide (I-77)

In a 100 ml vessel was placed a magnetic stir bar, 1-(6-chloropyridin-3-yl)cyclobutanecarboxylic acid (715.0 mg, 3.38 mmol) in DCM (20.0 ml). HATU (1541 mg, 4.05 mmol) was added with stirring and the reaction mixture was stirred for several 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 hours at RT. The reaction mixture was diluted with ethyl acetate and washed with 1N HCl. HCl (2 times), water, brine and saturated aqueous NaHCO ₃ . The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified with a Biotage silica gel column using DCM/EtOAc (10 to 100%) as eluents to give compound I-77. MS (ESI) [M+H] ⁺ : m/z 305.

Stage 2: N -(4-fluorophenyl)-1-(6-(2-phenyloxazol-4-yl)pyridin-3-yl)cyclobutan-1-carboxamide

Compound I-77 (50 mg, 0.164 mmol), a mixture of palladium(II) acetate, 1,1'-bis(di-tert-butylphosphino)ferrocene and 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, the reaction mixture was siphoned off, placed back under nitrogen 3 times and heated at 80° C. for 12 h. The reaction mixture was then cooled and filtered through a Celite pad. The crude material was purified by mass directed reverse phase chromatography (ACN/water modifier with 0.1% TFA) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 414.

Example 57-63 in the following table was prepared analogously to example 56 using the appropriate boronates.

Example No. Structure chemical name Mass [M+H]+ 57

1-(6'-cyclopropyl-[2,3'-bipyridin]-5-yl)- N- (4-fluorophenyl)cyclobutane-1-carboxamide 388 58

1-(6-(5-cyano-1H-indol-2-yl)pyridin-3-yl)-N-(4-fluorophenyl)cyclobutane-1-carboxamide 411 59

1-(6-(3-cyclopropyl-1H-pyrazol-5-yl)pyridin-3-yl)-N-(4-fluorophenyl)cyclobutane-1-carboxamide 377 60

N-(4-fluorophenyl)-1-(6-(3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-3-yl)cyclobutan-1-carboxamide 405 61

N-(4-fluorophenyl)-1-(6-(3-methyl-1H-pyrazol-5-yl)pyridin-3-yl)cyclobutan-1-carboxamide 351 62

1-(6-(1H-pyrazol-5-yl)pyridin-3-yl)-N-(4-fluorophenyl)cyclobutane-1-carboxamide 337 63

N-(4-fluorophenyl)-1-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl) cyclobutan-1-carboxamide 446

Example 64: 1-(4-(4-cyclopropyl-1H-pyrazol-1-yl)phenyl)-N-propylcyclobutane-1-carboxamide

Stage 1: Synthesis of 1-(4-bromophenyl)-N-propylcyclobutane-1-carboxamide (I-135)

A magnetic stir bar was placed in a 20 ml flask, and 1-(4-bromophenyl)cyclobutanecarboxylic acid (800.0 mg, 3.14 mmol) in DMF (4.0 ml) and HATU (1431 mg, 3.76 mmol) and stirred the reaction mixture for several minutes. Propan-1-amine (185 mg, 3.14 mmol) and DIEA (1.643 mL, 9.41 mmol) were then added and the mixture was stirred for 4 hours at RT. The reaction mixture was diluted with ethyl acetate and washed with 1N aqueous HCl (3 times), water, brine and saturated aqueous NaHCO ₃ . The solution was then dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography (Isco CombiFlash system, using silica gel column with 48 g RediSep gold, 10-100% EtOAc/hexanes as eluents) to give compound I-135. MS (ESI) [M+H] ⁺ : m/z 296.

Stage 2: Synthesis of 1-(4-(4-cyclopropyl-1H-pyrazol-1-yl)phenyl)-N-propylcyclobutane-1-carboxamide

Compound I-135 (25.0 mg, 0.084 mmol) and copper iodide (1.607 mg, 8.44 µmol) were added to a 20 ml vial followed by 4-cyclopropyl-1H-pyrazole (9.13 mg, 0.084 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (2.401 mg, 0.017 mmol). This mixture was then pumped out and placed back with nitrogen (3 times). Dry, degassed 1,2-dioxane (338 µl) was then added. The mixture was heated at 110°C for 24 hours and cooled to RT. The crude material was purified by mass directed reverse phase chromatography (ACN/water modifier with 0.1% TFA) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 324. ¹ H 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 (n, J=7.0 Hz, 2H), 2.77-2.62 (m, 2H), 2.33 (dc, J=19.2, 10.1, 9.3 Hz, 2H), 1.86-1.68 (m, 3H), 1.32 (n, 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: 1-(4-(2-(4-Fluorophenyl)oxazol-4-yl)phenyl)-N-propylcyclobutane-1-carboxamide

The title compound was prepared from intermediate bromo compound I-98 and (2-(4-fluorophenyl)oxazol-4-yl)boronic acid by a Suzuki coupling reaction under standard conditions. MS (ESI) [M+H] ⁺ : m/z 279.

Example 66: 1-(4-(6-cyclopropylpyridin-3-yl)phenyl)-N-propylcyclobutane-1-carboxamide

This compound was prepared analogously to the synthesis of example 64, except that (6-cyclopropylpyridin-3-yl)boronic acid was used. MS (ESI) [M+H] ⁺ : m/z 335.

Example 67: 1-(4-(6-(4-fluorophenyl)pyridin-3-yl)phenyl)-N-propylcyclobutane-1-carboxamide

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

Stage 1: 1-(4-bromophenyl)-N-(5-fluoropyridin-2-yl)cyclobutan-1-carboxamide (I-140)

A magnetic stir bar was placed in a 100 ml vessel, and 1-(4-bromophenyl)cyclobutanecarboxylic acid (1000.0 mg, 3.92 mmol) in DMF (10.0 ml) and HATU (1789 mg, 4.70 mmol) and stirred the mixture for several minutes. 5-Fluoropyridine-2-amine (439 mg, 3.92 mmol), DIEA (2.054 ml, 11.76 mmol) was added and the reaction mixture was stirred for 4 hours at RT. The reaction was carried out as described above and the crude product was purified by chromatography (Isco CombiFlash system, using silica gel column with 48 g RediSep gold, 10-100% EtOAc/hexanes as eluents) to give compound I-140. MS (ESI) [M+H] ⁺ : m/z 349.

Stage 2: 1-(4-(6-cyclopropylpyridin-3-yl)phenyl)-N-(5-fluoropyridin-2-yl)cyclobutan-1-carboxamide

Mixture of 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (42.1 mg, 0.172 mmol), Compound I-140 (60.0 mg , 0.172 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (14.09 mg, 0.015 mmol) and sodium carbonate (0.172 ml, 0.344 mmol) in 1,4-dioxane (1.5 ml ) were subjected to a Suzuki coupling reaction under standard conditions. The crude material was purified by mass directed reverse phase chromatography (ACN/water modifier with 0.1% TFA) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 388, ¹ H 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: 1-(4-(6-cyclopropyl-4-fluoropyridin-3-yl)phenyl)-N-(5-fluoropyridin-2-yl)cyclobutan-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-1,3,2-dioxaborolan-2-yl)pyridine was used. MS (ESI) [M+H] ⁺ : m/z 406, ¹ H NMR (499 MHz, DMSO-d6) 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, 1H), 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-2-yl)cyclobutan-1-carboxamide

This compound was prepared analogously to the synthesis of example 68, except that 2-cyclopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used. MS (ESI) [M+H] ⁺ : m/z 402. ¹ H NMR (499 MHz, DMSO-d6) 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 : 1-(4-(6,7-difluoro-1H-benzo[d]imidazol-2-yl)phenyl)-N-(5-fluoropyridin-2-yl)cyclobutan-1-carboxamide

Step 1: Methyl 4-(1-((5-fluoropyridin-2-yl)carbamoyl)cyclobutyl)benzoate (I-144)

1-(4-(methoxycarbonyl)phenyl)cyclobutanecarboxylic acid (2000.0 mg, 8.54 mmol) and oxalyl chloride (0.747 ml, 8.54 mmol) were stirred in DCM (10.0 ml), DMF (0 .2 ml). The reaction mixture was stirred at RT for 4 h, concentrated under vacuum and left overnight in a lyophilizer. Then a mixture of 2-amino-5-fluoropyridine (957 mg, 8.54 mmol) in pyridine (10.0 ml) was added to the crude product and the mixture was cooled to 0°C. The mixture was slowly warmed to RT, stirred overnight, concentrated under vacuum and the crude product was purified using Biotage (SiO ₂ , CH ₂ Cl ₂ /MeOH; 0-10%) to obtain compound I-144. MS (ESI) [M+H] ⁺ : m/z 329.

Step 2: 4-(1-((5-Fluoropyridin-2-yl)carbamoyl)cyclobutyl)benzoic acid (I-145)

To a vessel containing compound I-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 RT for 24 h. The organic solvents were evaporated and the aqueous layer was acidified to pH~3 by adding HCl (1 N) and then extracted with DCM 3 times. The organic phases were combined, washed with brine, dried and concentrated to give compound I-145. MS (ESI) [M+H] ⁺ : m/z 315.

Step 3: Synthesis of N-(6-amino-2,3-difluorophenyl)-4-(1-((5-fluoropyridin-2-yl)carbamoyl)cyclobutyl)benzamide (I-146)

Compound I-145 (30.0 mg, 0.095 mmol) in DMF (1.0 mL) was placed in a 20 mL vessel, followed by HATU (43.6 mg, 0.115 mmol) with stirring. After a few minutes, 1,2-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 hours at RT. The reaction mixture was diluted with ethyl acetate and washed with 1N HCl. HCl (3 times). The organic layer was concentrated and the residue was purified by chromatography (Isco CombiFlash system, using silica gel column with 12 g RediSep gold and 0-20% MeOH/DCM as eluents) to give compound I-146. MS (ESI) [M+H] ⁺ : m/z 441.

Step 4: 1-(4-(6,7-difluoro-1H-benzo[d]imidazol-2-yl)phenyl)-N-(5-fluoropyridin-2-yl)cyclobutan-1-carboxamide

A solution of compound I-146 (17.0 mg, 0.039 mmol) in AcOH (1.5 ml) was heated at 150° C. in a microwave oven for 30 minutes. The mixture was evaporated under reduced pressure. The crude material was purified by mass directed reverse phase chromatography (ACN/water modifier with 0.1% TFA) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 423. ¹ H 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, 7.4 Hz, 2H).

Example 72: 1-(4-(7-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-N-(5-fluoropyridin-2-yl)cyclobutan-1-carboxamide

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, ¹ H 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: 1-(4-(5-cyano-1H-benzo[d]imidazol-2-yl)phenyl)-N-(5-fluoropyridin-2-yl)cyclobutan-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, ¹ H 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: 1-(4-(4,7-difluoro-1H-benzo[d]imidazol-2-yl)phenyl)-N-(5-fluoropyridin-2-yl)cyclobutan-1-carboxamide

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. ¹ H NMR (499 MHz, DMSO-d6) δ 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-1H-benzo[d]imidazol-2-yl)phenyl)-N-(5-fluoropyridine-2- yl)cyclobutane-1-carboxamide

The title compound was prepared analogously to the synthesis of Example 71, except that ( 1R,2R )-3,3-difluorocyclohexane-1,2-diamine was used. MS (ESI) [M+H] ⁺ : m/z 429, ¹ H 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: N -(4-fluorophenyl)-3-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3-carboxamide

Stage 1: 3-(5-bromopyridin-2-yl)oxetan-3-carbonitrile (I-152)

5-bromo-2-fluoropyridine (58.5 µl, 0.568 mmol), oxetane-3-carbonitrile (47.2 µl, 0.625 mmol) and toluene (2840 µl) were added to the vial with the magnetic stir bar. The reaction mixture was cooled to 0°C with stirring under nitrogen atmosphere. 1.0 M KHMDS in THF (682 µl, 0.682 mmol) was slowly added to the stirred reaction mixture. After 5 min the reaction was quenched with MeOH (~5 ml). The crude reaction mixture was filtered through a Celite pad, which was washed 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, fractions were collected and concentrated under reduced pressure to give compound I-152. MS (ESI) [M+H] ⁺ : m/z 239.

Stage 2: Obtaining 3-(5-bromopyridin-2-yl)oxetane-3-carboxylic acid (I-153)

Compound I-152 (190 mg, 0.795 mmol), NaOH (127 mg, 3.18 mmol), ethanol (2660 µl) and water (1310 µl) were added to a vial with a magnetic stir bar. The vessel was sealed and heated to 80° C. for 20 hours. After 20 hours, the crude reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and the pH was adjusted to ~2 by adding 1N HCl. HCl drops. The mixture was washed with water. The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give compound I-153. MS (ESI) [M+H] ⁺ : m/z 258.

Step 3: Preparation of 3-(5-bromopyridin-2-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide (I-154)

Compound I-153 (127 mg, 0.493 mmol), HATU (281 mg, 0.739 mmol) and DMF (4930 µl) were added to a vial with a magnetic stir bar. 4-fluoroaniline (56.0 μl, 0.591 mmol) was added followed by DIEA (258 μl, 1.48 mmol). The reaction mixture was stirred at RT for 21 hours. After 21 hours, the crude reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO ₃ solution and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc/hexanes) to give compound I-154. MS (ESI) [M+H] ⁺ : m/z 351.

Step 4: Preparation of N-(4-fluorophenyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxetan-3- carboxamide (I-155)

Compound I-154 (113 mg, 0.320 mmol), bis(pinacolato)diborone (203 mg, 0.801 mmol), potassium acetate (94 mg, 0.961 mmol) and PdCl ₂ adduct (dppf)-CH ₂ Cl ₂ (26.2 mg, 0.032 mmol) in dioxane (1600 μl). 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 through a Celite pad which was washed with ethyl acetate. The combined organic compounds 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 MgSO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in ACN/water and dried in a lyophilizer overnight to give compound I-155. MS (ESI) [M+H] ⁺ : m/z calculated: 399; found 317 (mass of boronic acid).

Stage 5: N -(4-fluorophenyl)-3-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3-carboxamide

Compound I-155 (17 mg, 0.043 mmol), (5-bromo-2-(trifluoromethyl)pyridin-4-yl)methanol (10.9 mg, 0.043 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-tri-I-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (3.36 mg , 4.27 µmol), potassium orthophosphate (1 M aqueous solution) (85 µl, 0.085 mmol) and THF (427 µl). The vessel was purged with nitrogen, sealed and heated to 40° C. for 1 hour. After 1 hour, the crude reaction mixture was filtered through a Celite pad, which was washed with ethyl acetate. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with saturated NaCl solution. Organic compounds were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc/hexanes) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 448. ¹ H 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).

Example 77: 3-(6'-(difluoromethoxy)-4'-(hydroxymethyl)-[3,3'-bipyridin]-6-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide

The title compound was prepared from intermediate I-155 and (5-bromo-2-(difluoromethoxy)pyridin-4-yl)methanol analogously to the synthesis of Example 76. MS (ESI)) [M+H] ⁺ : m/z 446. ¹ H NMR (600 MHz, DMSO- d 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)-4'-(2-hydroxypropan-2-yl)-[3,3'-bipyridin]-6-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide

The title compound was prepared analogously to Example 76. MS (ESI) [M+H] ⁺ : m/z 474. ¹ H NMR (600 MHz, DMSO- d ₆ ) 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, 1H), 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-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3-carboxamide

The title compound was prepared analogously to Example 76. MS (ESI) [M+H] ⁺ : m/z 476.

Example 80: 3,3-difluoro-N-(4-fluorophenyl)-1-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutan-1-carboxamide

Stage 1. 2-(4-bromophenyl)-N-(4-fluorophenyl)-5,8-dioxaspiro[3,4]octane-2-carboxamide (I-163)

4-Fluoroaniline ( 0.30 ml, 3.2 mmol) and Hunig's base (1.12 ml, 6.4 mmol) and then HATU (1.58 g, 4.2 mmol) was added in portions. The mixture was stirred at RT for 14 hours. The reaction mixture was diluted with aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was separated, washed with water, brine, dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give compound I-163. MS (ESI) [M+H] ⁺ : m/z 406.

Stage 2: 1-(4-bromophenyl)-N-(4-fluorophenyl)-3-oxocyclobutane-1-carboxamide (I-164)

To a flask containing compound I-163 (380 mg, 0.94 mmol) was added HCl (4 N in dioxane, 2 ml) and H ₂ O (2 ml). The mixture was heated at 80°C for 2 hours the Mixture was cooled, neutralized with saturated NaHCO ₃ solution and was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ and concentrated to give compound I-164 as a solid. This material was used directly in the next step. MS (ESI) [M+H] ⁺ : m/z 362.

Stage 3: 1-(4-bromophenyl)-3,3-difluoro-N-(4-fluorophenyl)cyclobutane-1-carboxamide (I-165)

To a solution of compound I-164 (127 mg, 0.35 mmol) in CH ₂ Cl ₂ (2.3 ml) at -30°C was added DAST (185 μl, 1.4 mmol). After the addition, the reaction mixture was slowly warmed to RT and stirring was continued for 3 h. At this point, the mixture was quenched by adding an aqueous solution of NaHCO ₃ and was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give compound I-165. MS (ESI) [M+H] ⁺ : m/z 384.

Step 4: 3,3-difluoro-N-(4-fluorophenyl)-1-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutan-1-carboxamide

4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine mixture (98 mg , 0.23 mmol), compound I-165 (60 mg, 0.15 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (15 mg, 0.023 mmol) and sodium carbonate (195 μl, 0.39 mmol) in 1,4-dioxane (1.0 ml) was siphoned off and placed back under nitrogen 3 times and the mixture was heated under 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 MgSO ₄ and concentrated. The residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give 1-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl) -3,3-difluoro-N-(4-fluorophenyl)cyclobutane-1-carboxamide as an oil. MS (ESI) [M+H] ⁺ : m/z 595.

To a flask containing 1-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-3,3-difluoro-N-(4-fluorophenyl )cyclobutanecarboxamide (83 mg, 0.14 mmol), TBAF (1.0 M in THF, 42 μl, 0.42 mmol) and THF (0.3 ml) were added at RT. The mixture continued to stir at RT for 1 h. The mixture was diluted with sat. NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 480. ¹ H NMR (500 MHz, DMSO-d ₆ ): 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), 3.55 (k, J = 13.2 Hz, 2H), 3.21 (k, J = 13.2 Hz, 2H).

Example 81: N-(4-fluorophenyl)-1-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutan-1-carboxamide

Step 1. 1-(4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)cyclobutane-1-carboxamide

4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine mixture (180 mg , 0.43 mmol), 1-(4-bromophenyl)-N-(4-fluorophenyl)cyclobutanecarboxamide (100 mg, 0.29 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (28 mg, 0.043 mmol) and sodium carbonate (287 μl, 0.57 mmol) in 1,4-dioxane (1.9 ml) were pumped out and placed back with nitrogen 3 times and the mixture was heated under nitrogen at 90°C for 3 hours The reaction mixture was cooled, diluted with water and was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give the title compound as a solid. MS (ESI) [M+H] ⁺ : m/z 559.

Stage 2. N-(4-fluorophenyl)-1-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutan-1-carboxamide

To a flask containing 1-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)cyclobutanecarboxamide (107 mg, 0.19 mmol), TBAF (1.0 M in THF, 575 μl, 0.575 mmol) and THF (0.3 ml) were added at RT. The mixture continued to stir at RT for 1 h. The mixture was diluted with sat. NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 445, ¹ H NMR (500 MHz, DMSO-d ₆ ) 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 (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-3-yl)phenyl)spiro[2,3]hexane-5-carboxamide

Stage 1: 5-(4-chlorophenyl)spiro[2,3]hexane-5-carbonitrile (I-168)

1-Chloro-4-fluorobenzene (193 µl, 1.8 mmol) and spiro[2,3]hexane-5-carbonitrile (179 µl, 1.5 mmol) were added to the flask under nitrogen atmosphere and then 1.5 ml THF. To this was added KHMDS (1 M in THF, 1.58 ml, 1.58 mmol) dropwise. The mixture was stirred for 15 hours at RT, evaporated in vacuo and then checked for conversion by NMR. The residue was purified by chromatography (Isco CombiFlash system using hexanes and ethyl acetate as eluents) to give compound I-168, ¹ H NMR (600 MHz, CDCl ₃ ) 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)spiro[2,3]hexane-5-carboxylic acid (I-169)

Lithium hydroxide (99 mg, 4.1 mmol) was added to the flask containing compound I-168 (150 mg, 0.69 mmol). To this was added 1 ml of water and 1 ml of ethanol. The mixture was then heated in a sealed flask under argon atmosphere at 65° C. for 72 hours. Upon completion, the product was acidified with 1 M HCl (aqueous solution) until pH~3 was reached. The product was then extracted with ethyl acetate, dried over MgSO ₄ , filtered through a Celite pad and then evaporated in vacuo to give I-169, which was used directly in the next step. MS (ESI) [M+H] ⁺ : m/z 237.

Stage 3: 5-(4-chlorophenyl)-N-(4-fluorophenyl)spiro[2,3]hexane-5-carboxamide (I-170)

5-(4-Chlorophenyl)spiro[2,3]hexane-5-carboxylic acid (125 mg, 0.53 mmol) and HATU (221 mg, 0.58 mmol) were added to a 1.5 ml DMF vial. To this was added 4-fluoroaniline (55 μl, 0.58 mmol) followed by DIPEA (231 μl, 1.3 mmol). This mixture was stirred for 2 hours, after which it was evaporated under vacuum. The crude residue was purified by chromatography (Isco CombiFlash system using hexanes and ethyl acetate as eluents) to give compound I-170. MS (ESI) [M+H] ⁺ : m/z 330.

Step 4: N-(4-fluorophenyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)spiro[2,3]-hexane- 5-carboxamide (I-171)

Compound I-170 (118 mg, 0.36 mmol), bis(pinacolato)diborone (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 RT and filtered through a Celite pad. The filtrate was concentrated in vacuo to give a residue which was purified by chromatography (Isco CombiFlash system using hexanes and ethyl acetate as eluents) to give compound I-171. MS (ESI) [M+H] ⁺ : m/z 422.

Step 5: N-(4-fluorophenyl)-5-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)spiro[2,3]hexane-5-carboxamide

Xphos G3 (8.46 mg, 10.00 µmol), (5-bromo-2-(trifluoromethyl)pyridin-4-yl)methanol (28.2 mg, 0.11 mmol) was placed in a dry vessel with a magnetic stir bar. and Compound I-171 (42.1 mg, 0.1 mmol) and kept under nitrogen. To this was added THF 0.50 ml and potassium orthophosphate (1 M in H ₂ O, 0.200 ml, 0.200 mmol). The reaction mixture was then purged with argon and heated at 70° C. overnight. She was allowed to cool to RT and then filtered through a Celite pad. This crude material was purified by mass directed reversed phase chromatography (ACN/water modifier with 0.1% TFA) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 471, ¹ H NMR (600 MHz, DMSO- d ₆ ) 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), 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) -N- (4-fluorophenyl)cyclobutane-1-carboxamide

Step 1: Ethyl 1-(4-(4,7-difluoro-1,3-dioxoisoindolin-2-yl)phenyl)cyclobutane-1-carboxylate (I-173)

4,7-difluoroisobenzofuran-1,3-dione (184 mg, 1 mmol) and ethyl 1-(4-aminophenyl)cyclobutanecarboxylate (329 mg, 1.500 mmol) were placed in a vessel. To this vessel was added 4 ml of glacial acetic acid, and then the vessel was purged with argon and heated at 80° C. for 15 hours. The reaction mixture was then concentrated in vacuo. This crude material was dissolved in DCM (10 ml) and transferred to a separating funnel. It was washed with saturated sodium bicarbonate solution and the organic compounds were separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (Isco CombiFlash system using hexanes and ethyl acetate as eluents) to give compound I-173. MS (ESI) [M+H] ⁺ : m/z 386.

Stage 2: 1-(4-(4,7-difluoro-1,3-dioxoisoindolin-2-yl)phenyl)cyclobutane-1-carboxylic acid (I-174)

Compound I-173 (200 mg, 0.519 mmol) was placed in a vessel and 2 ml of dioxane was added thereto. Lithium hydroxide (37.3 mg, 1.557 mmol) was then added followed by 2 ml of water. This mixture was stirred at RT for 2 h. The organic compounds were then evaporated in vacuo and the aqueous layer was acidified with 1 M HCl to pH ~2. Then they were extracted 3 times with DCM (5 ml), dried over magnesium sulfate, filtered and evaporated under vacuum. Under these conditions, the lactam ring was opened, so 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. The reaction mixture was then concentrated in vacuo. This crude material was dissolved in DCM (10 ml) and transferred to a separating funnel. It was washed with saturated sodium carbonate solution and the organic compounds were separated, dried over sodium sulfate, filtered and concentrated to give compound I-174, which was used immediately. MS (ESI) [M+H] ⁺ : m/z 358.

Stage 3: 1-(4-(4,7-difluoro-1-oxoisoindolin-2-yl)phenyl)cyclobutane-1-carboxylic acid (I-175)

Compound I-174 (90 mg, 0.252 mmol) and NaBH ₄ (10.48 mg, 0.277 mmol) were added to the vessel under nitrogen and kept under nitrogen. To this was added 1 ml THF and 1 ml MeOH. This mixture was stirred for 5 min at 0° C. and then stirred at RT for 2 h. When complete, 2 drops of acetic acid were added and evaporated in vacuo. Then 5 ml of DCM and 5 ml of saturated sodium bicarbonate solution were added and the organic compounds were separated. They were extracted two more times with 5 ml of DCM and the organic compounds were combined, dried over magnesium sulfate, filtered and evaporated under vacuum. This crude material was then dissolved in TFA (1 ml) and triethylsilane (0.161 ml, 1.008 mmol) was added. This mixture was stirred at RT for 30 minutes and evaporated in vacuo. The crude residue was purified by chromatography (Isco CombiFlash system using hexanes and ethyl acetate as eluents) to give compound I-175. MS (ESI) [M+H] ⁺ : m/z 344.

Step 4: 1-(4-(4,7-difluoro-1-oxoisoindolin-2-yl)phenyl)- N -(4-fluorophenyl)cyclobutane-1-carboxamide

Compound I-175 (17 mg, 0.050 mmol) and HATU (19.77 mg, 0.052 mmol) were added to a vial with 1.5 ml DMF. To this was added 4-fluoroaniline (5.17 µl, 0.054 mmol) followed by DIPEA (12.97 µl, 0.074 mmol). The mixture was stirred for 24 hours. When complete, the mixture was evaporated in vacuo . The crude material was purified by mass directed reverse phase chromatography (ACN/water modifier with 0.1% TFA) to give the title compound. MS (ESI) [M+H] ⁺ : m/z 437, ¹ H NMR (600 MHz, DMSO- d 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, J =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).

Example 84 : N-(4-fluorophenyl)-3-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)oxetan-3-carboxamide

Step 1: Methyl 2-(6-chloropyridin-3-yl)acetate

((trimethylsilyl)methyl)diazene (8.3 ml , 175 mmol) at 0°C. The reaction mixture was stirred at RT for 16 hours and then the solvent was concentrated under reduced pressure. The residue was diluted with water (100 ml), extracted with EtOAc (100 ml, 3 times) and the organic layers were collected, washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography to give 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 RT and the reaction mixture 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 give the title compound as an oil. MS (ESI) m/z 245.9 [M+H ⁺ ].

Step 3: 2-(6-chloropyridin-3-yl)-2-(hydroxymethyl)propan-1,3-diol

Lithium tetrahydroborate (1.224 g , 56.2 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 5 hours. The mixture was quenched with MeOH (50 ml) and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to give the title compound as a solid. MS (ESI) m/z 217.8 [M+H ⁺ ].

Stage 4: (3-(6-chloropyridin-3-yl)oxetan-3-yl)methanol

n -BuLi (4 ml, 10.0 mmol) (2.5 M) at 0°C and the mixture was stirred at 0°C for 30 min. A solution of TsCl (1.340 g, 7.03 mmol) in 5 ml THF at 0°C was then added and stirring continued at 0°C for 1 h. To the above mixture was added n -BuLi (3.12 ml, 7.80 mmol) (2.5 M) at 0°C and the mixture was stirred at 0°C for another 0.5 h and then heated to 60°C for 0.5 h. After cooling to RT, the reaction was quenched with aqueous NH ₄ Cl (30 ml), was extracted with EtOAc (30 ml, 3 times) and the organic layers were collected, washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered, the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography to give the title compound. MS (ESI) m/z 199.9 [M+H ⁺ ].

Stage 5: 3-(6-chloropyridin-3-yl)oxetane-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) was added successively TEMPO (42 mg, 0.269 mmol), sodium chlorite (489 mg, 5.41 mmol) in 1 ml water and sodium hypochlorite (1007 mg, 1.352 mmol) (10% in water) at RT. The mixture was stirred at RT for 16 h. The reaction mixture was treated with 2 M NaOH until pH 10 was reached, then 10% sodium thiosulfate (30 ml) was added. The mixture was separated with ethyl acetate (30 ml) and water (15 ml), the aqueous phase was acidified with HCl (2 M in water) to pH 4 and was extracted with ethyl acetate (30 ml, 3 times). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as an oil which was used in the next step without further purification. MS (ESI) m/z 214.0 [M+H ⁺ ].

Stage 6: 3-(6-chloropyridin-3-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide

To a stirred solution of 3-(6-chloropyridin-3-yl)oxetan-3-carboxylic acid (250 mg, 1.170 mmol) in DMF (10 ml) was added HATU (667 mg, 1.755 mmol), Et ₃ N (0.5 ml, 3.59 mmol) and 4-fluoroaniline (195 mg, 1.755 mmol) at RT and continued stirring for 16 h. The reaction mixture was worked up and the crude product was purified by preparative TLC (petroleum ether/EtOAc=1:1) to the title compound as an oil. MS (ESI) m/z 307.1 [M+H ⁺ ].

Step 7: 3-(4'-(((tert-butyldimethylsilyl)oxy)methyl)-6'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)-N-(4-fluorophenyl)oxetane -3-carboxamide

To a stirred solution of 3-(6-chloropyridin-3-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide (30 mg, 0.098 mmol) and 4-(((tert-butyldimethylsilyl)oxy)methyl)-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (49 mg, 0.117 mmol) in dioxane (2 ml) and water (0.4 ml) K ₃ PO ₄ (62 mg, 0.292 mmol) and Pd(dtbpf)Cl ₂ (7 mg, 10.74 µmol) were added at RT. The mixture was heated to 100°C with stirring for 15 hours and cooled to RT. The reaction mixture was diluted with ethyl acetate (5 ml) and filtered. The filtrate was washed with water (2 ml) and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/EtOAc=1:1 as eluents) to give 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'-bipyridin]-5-yl)oxetan-3-carboxamide

To a stirred solution of 3-(4'-(((tert-butyldimethylsilyl)oxy)methyl)-6'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)-N-(4-fluorophenyl)oxetane -3-carboxamide (21 mg, 0.037 mmol) in THF (2 ml) was added TBAF (0.05 ml, 0.050 mmol) at RT and the mixture was stirred at RT for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse -phase HPLC using a GILSON 281 equipped with a Phenomenex Synergi column (C18 150*30 mm*4 µm) using water (0.225% FA) and ACN as eluents and then lyophilized to give the title compound as a solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.85 (d, 1H), 8.79 (s, 1H), 8.12 (t, 2H), 7.82 (d, 1H), 7, 60-7.56 (m, 2H), 7.07 (t, 2H), 5.38 (d, 2H), 5.06 (d, 2H), 4.82 (s, 2H); MS (ESI) m/z 448.0 [M+H ⁺ ].

Example 85: N-(4-fluorophenyl)-3-(6-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxetan-3-carboxamide

Step 1: 3-(6-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(trifluoromethyl)phenyl)pyridin-3-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide

To a stirred solution of 3-(6-chloropyridin-3-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide (42 mg, 0.137 mmol) and tert-butyldiphenyl ((2-(4.4.5.5 -tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl)oxy)silane (89 mg, 0.164 mmol) in dioxane (1.0 ml) and water (0.2 ml) was added K ₃ PO ₄ (87 mg, 0.411 mmol) and Pd(dtbpf)Cl ₂ (9 mg, 0.014 mmol) at RT. The mixture was heated to 100° C. with stirring for 15 hours. The reaction mixture was cooled to RT, diluted with EtOAc (5 ml) and filtered. The filtrate was washed with water (2 ml) and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/EtOAc=1:1 as eluents) to give 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-3-yl)oxetan-3-carboxamide

To a stirred solution of 3-(6-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(trifluoromethyl)phenyl)pyridin-3-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide ( 40 mg, 0.058 mmol) in THF (2 ml) was added TBAF (0.1 ml, 0.100 mmol) at RT. The mixture was stirred at RT for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to give the title compound as a solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.80 (d, 1H), 8.12 (dd, 8.3 Hz, 1H), 7.92 (s, 1H), 7.78 (d, 1H), 7.71 (s, 2H), 7.59 (dd, 9.2 Hz, 2H), 7.10-7.04 (m, 2H), 5.38 (d, 2H), 5, 06 (d, 2H), 4.66 (s, 2H); 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-1,3,2-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(1,3,2-dioxaborolane) (686 mg, 2.70 mmol) in dioxane (2 ml) was added potassium acetate (531 mg, 5.41 mmol) and Pd(dppf)Cl ₂ (132 mg, 0.180 mmol ) at RT. The mixture was heated to 100°C with stirring for 16 hours and the solvent was concentrated under reduced pressure. Saturated NaHCO ₃ solution was added to the residue to adjust pH to >8 and the mixture was extracted with EtOAc (20 ml, 3 times). The organic layers were collected, washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/EtOAc=5:1) to give 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-(4-fluorophenyl)oxetane-3-carboxamide (30 mg, 0.098 mmol) and (2-(2-(methoxycarbonyl)-4-(trifluoromethyl) phenyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-4-yl)methylium (62 mg, 0.188 mmol) in dioxane (2 ml) and water (0.4 ml) was added K ₃ PO ₄ (62 mg, 0.292 mmol) and Pd(dtbpf)Cl ₂ (7 mg, 10.74 µmol) at RT. The mixture was heated to 100° C. for 15 hours. The reaction mixture was diluted with EtOAc (5 ml) and filtered. The filtrate was washed with water (2 ml) and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC (SiO ₂ , petroleum ether/EtOAc=1:1 as eluents) to give the title compound as an oil. MS (ESI) m/z 475.2 [M+H ⁺ ].

Stage 3: N-(4-fluorophenyl)-3-(6-(2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)phenyl)-pyridin-3-yl)oxetan-3-carboxamide

To a stirred solution of methyl 2-(5-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)pyridin-2-yl)-5-(trifluoromethyl)benzoate (30 mg, 0.063 mmol) in THF ( 2 ml) was added 3 M MeMgBr (0.1 ml, 0.300 mmol) at 0°C. The reaction mixture was stirred at RT under nitrogen atmosphere for 15 h. The reaction mixture was slowly quenched with saturated NH ₄ Cl solution (10 ml, aqueous solution) and was extracted with EtOAc (20 ml, 3 times). The combined organic layer was washed with brine (5 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by reverse phase HPLC using a GILSON 281 device with a Phenomenex Synergi C18 150×30 mm×4 µm column to give the title compound as a solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.74 (d, 1H), 8.16 (dd, 8.2 Hz, 1H), 7.96 (s, 1H), 7.70 (d, 1H), 7.66 (brd, 1H), 7.57 (tdd, 6.9 Hz, 2H), 7.47 (d, 1H), 7.07 (t, 2H), 5.38 (d, 2H), 5.05 (d, 2H), 1.43 (s, 6H); MS (ESI) m/z 475.2 [M+H ⁺ ].

Example 87: N-(4-fluorophenyl)-3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)oxetan-3-carboxamide

Step 1: Methyl 5-(4,4,5,5-tetramethyl-1,3,2-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(1,3,2-dioxaborolane) (697 mg, 2.75 mmol) in dioxane (2 ml) was added potassium acetate (539 mg, 5.49 mmol) and Pd(dppf)Cl ₂ (134 mg, 0.183 mmol ) at RT. The mixture was heated to 100° C. with stirring for 16 h. The mixture was concentrated under reduced pressure and a saturated solution of NaHCO ₃ was added to bring the pH to >8. The mixture was then extracted with EtOAc (20 ml, 3 times) and the organic layers were collected, washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/EtOAc=5:1) to give the title compound as an oil. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.86 (s, 1H), 8.44 (s, 1H), 3.86 (s, 3H), 1.37-1.32 (m, 8H ), 1.30 (s, 1H).

Step 2: Methyl 5-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)-6'-(trifluoromethyl)-[2,3'-bipyridine]-4'-carboxylate

To a stirred solution of 3-(6-chloropyridin-3-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide (30 mg, 0.098 mmol) and methyl-5-(4,4,5,5-tetramethyl- K ₃ PO ₄ (62 mg, 0.292 mmol) and Pd(dtbpf)Cl ₂ (15 mg, 0.023 mmol) at RT. The reaction mixture was reacted under the same conditions as in Step 1 and the crude product was purified by reverse phase HPLC using a GILSON 281 equipped with a Phenomenex Synergi C18 150×30 mm×4 µm column to give the title compound as an oil. . MS (ESI) m/z 475.9 [M+H ⁺ ].

Step 3: N-(4-fluorophenyl)-3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[2,3'-bipyridin]-5-yl)oxetan-3 -carboxamide

To a stirred solution of methyl 5-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)-6'-(trifluoromethyl)-[2,3'-bipyridine]-4'-carboxylate (10 mg, 0.021 mmol) in THF (2 ml) was added dropwise methylmagnesium bromide (0.1 ml, 0.300 mmol) (3 M in ether) at RT. The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (5 mL) and then filtered under reduced pressure to give a residue which was purified by reverse phase HPLC using a GILSON 281 equipped with a Phenomenex Synergi C18 150×30 column. mm×4 μm, to obtain the title compound as a solid. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.83 (d, 1H), 8.57 (s, 1H), 8.19-8.16 (m, 1H), 8.14 (s, 1H ), 7.73 (d, 1H), 7.63-7.60 (m, 2H), 7.60-7.59 (m, 1H), 7.10 (t, 2H), 5.42 ( d, 2H), 5.09 (d, 2H), 2.71 (br.s., 1H), 2.55 (br.s., 1H), 2.07-2.03 (m, 1H) , 1.47 (s, 6H). MS (ESI) m/z 476.2[M+H ⁺ ]

Example 88 : 3-(6'-cyclopropoxy-4'-(hydroxymethyl)-[2,3'-bipyridin]-5-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide

Stage 1: 5-bromo-4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-cyclopropoxypyridine

To a stirred solution of (5-bromo-2-cyclopropoxypyridin-4-yl)methanol (500 mg, 2.048 mmol) in DCM (10 mL) was added tert-butylchlorodiphenylsilane (619 mg, 2.253 mmol) and 1H-imidazole (307 mg, 4 .51 mmol) at RT. The reaction mixture was stirred at RT for 16 h. The mixture was diluted with water (50 ml), extracted with EtOAc (50 ml, 3 times) and the organic layers were collected, washed with brine (20 ml) and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated in vacuo and the residue was purified by silica gel flash chromatography to give the title compound. ¹ H NMR (400 MHz, CD ₃ OD) 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, 1H), 1.11 (s, 9H), 0.82-0.72 (m, 4H)

Stage 2: 4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-cyclopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a stirred solution of 5-bromo-4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-cyclopropoxypyridine (940 mg, 1.948 mmol), 4,4,4',4',5,5,5',5 '-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (742 mg, 2.92 mmol) in dioxane (20 ml) was added potassium acetate (574 mg, 5.84 mmol) and Pd(dppf )Cl ₂ (143 mg, 0.195 mmol) at RT. The reaction mixture was stirred at 100°C for 16 h. After cooling to RT, the mixture was extracted with EtOAc (50 ml, 3 times), the organic layers were collected, washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated the filtrate in vacuo. The residue was purified by silica gel flash chromatography to give 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'-bipyridin]-5-yl)-N-(4-fluorophenyl)oxetan-3 -carboxamide

To a stirred solution of 3-(6-chloropyridin-3-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide (30 mg, 0.098 mmol) and 4-(((tert-butyldiphenylsilyl)oxy)methyl)-2 -cyclopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (62 mg, 0.117 mmol in dioxane (2 ml) and water (0.4 ml) was added K ₃ PO ₄ (62 mg, 0.292 mmol) and Pd(dtbpf)Cl ₂ (7 mg, 10.74 μmol) at RT The mixture was subjected to a Suzuki coupling reaction under standard conditions as above The crude product was purified by preparative TLC (SiO ₂ , petroleum ether/EtOAc=1:1 as eluents) to give the title compound as an oil MS (ESI) m/z 674.2 [M+H ⁺ ].

Step 4: 3-(6'-cyclopropoxy-4'-(hydroxymethyl)-[2,3'-bipyridin]-5-yl)-N-(4-fluorophenyl)oxetane-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 α-carboxamide (25 mg, 0.037 mmol) in THF (2 mL) was added tetrabutylammonium fluoride (0.1 mL, 0.100 mmol) at RT. The mixture was stirred at RT for 16 h. The solvent was concentrated under reduced pressure and the residue was purified by reverse phase HPLC using a GILSON 281 equipped with a Phenomenex Synergi C18 column (150 x 30 mm x 4 µm) to give the title compound as a solid. . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.77 (d, 1H), 8.27 (s, 1H), 8.08 (dd, 1H), 7.73 (d, 1H), 7, 58 (dd, 2H), 7.22 (s, 1H), 7.07 (t, 2H), 5.37 (d, 2H), 5.04 (d, 2H), 4.68 (s, 2H ), 4.23-4.17 (m, 1H), 0.88-0.83 (m, 2H), 0.77 (br.s., 2H). MS (ESI) m/z 436.1 [M+H ⁺ ].

Example 89: N-(5-fluorothiazol-2-yl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide

Step 1: Methyl 3-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxylate

To a solution of methyl 3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxylate (220 mg, 0.599 mmol) and imidazole (82 mg, 1.198 mmol) in DMF (2.0 ml) was added TBS-Cl (108 mg, 0.719 mmol) with stirring at RT. The reaction mixture was stirred at RT for 14 hours. The reaction mixture was diluted with water (15 ml) and extracted with EtOAc (15 ml, 3 times). The combined organic layer was washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography to give the title compound as a solid. MS (ESI) m/z 482.3 [M+H ⁺ ].

Stage 2: 3-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-potassium carboxylate

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) was added TMSOK (50 mg, 0.390 mmol) with stirring at RT under nitrogen atmosphere. The reaction mixture was stirred at RT for 14 hours. The solvent was concentrated to give 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-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-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 potassium (15 mg, 0.030 mmol) and 5 -fluorothiazol-2-amine (8 mg, 0.068 mmol) in pyridine (0.5 ml) was added POCl ₃ (0.03 ml, 0.326 mmol) with stirring at 0°C and the resulting mixture was stirred at 0°C for 1 h. The reaction was quenched by adding a saturated solution of Na ₂ CO ₃ (1.0 ml), and then diluted with water (5 ml), and was extracted with EtOAc (5 ml, 3 times). The combined organic layer was washed with brine (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated to obtain the 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-3-yl)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) was added LiOH (5 mg, 0.209 mmol) with stirring at RT. The mixture was stirred at RT for 1 h. HCl until reaching pH~7 and concentrated. The residue was purified by reverse phase HPLC using a GILSON 281 equipped with an Xtimate C18 column (150 x 25 mm x 5 µm) using water and ACN as eluents and then lyophilized to give the title compound as a solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.53 (s, 1H), 8.07 (s, 1H), 7.56-7.65 (m, 2H), 7.50 (d, 2H ), 7.09 (d, 1H), 5.34 (d, 2H), 5.06 (d, 2H), 4.64 (s, 2H). MS (ESI) m/z 453.9 [M+H ⁺ ].

Examples 90-93 in the following table were prepared analogously to example 89.

Example No. Structure chemical name Mass [M+H]+ 90

3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(5-(trifluoromethyl)oxazol-2-yl)oxetan-3-carboxamide 488.1 91

N-cyclohexyl-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide 435.2 92

3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(5-(trifluoromethyl)thiazol-2-yl)oxetan-3-carboxamide 503.9 93

3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-(trifluoromethyl)oxazol-2-yl)oxetan-3-carboxamide 488.0

Example 94: N-(4-fluorophenyl)-1-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)cyclobutanecarboxamide

Stage 1: 1-(5-bromopyridin-2-yl)cyclobutanecarboxylic acid

To a solution of 1-(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 RT under nitrogen atmosphere and stirred the reaction mixture at 85°C for 18 hours, the Reaction mixture was cooled to RT and concentrated. The residue was diluted with DCM (20 ml) and filtered. The filter cake was suspended in EtOAc (20 ml) and water (20 ml) with stirring, then 3 N HCl was added until pH~3 was reached and all solids were dissolved. The mixture was extracted with EtOAc (20 ml, 2 times), the organic layers were combined, washed with brine (60 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as an oil, which was used directly in the next step without subsequent cleaning. MS (ESI) m/z 257.9 [M+H ⁺ ].

Step 2: 1-(5-bromopyridin-2-yl)-N-(4-fluorophenyl)cyclobutanecarboxamide

HATU (4 .11 g, 10.80 mmol) and 4-fluoroaniline (1.0 g, 9.00 mmol) at RT. The reaction mixture was stirred at RT for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with EtOAc (15 ml, 3 times). 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 give the title compound as a solid. MS (ESI) m/z 350.8 [M+H ⁺ ].

Step 3: N-(4-fluorophenyl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutanecarboxamide

To a solution of 1-(5-bromopyridin-2-yl)-N-(4-fluorophenyl)cyclobutanecarboxamide (500 mg, 1.432 mmol) and 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (545 mg, 2.148 mmol) in dioxane (20 ml) was added KOAc (281 mg, 2.86 mmol) and Pd(dtbpf)Cl ₂ (47 mg, 0.072 mmol) with stirring at RT under nitrogen. The reaction mixture was stirred at 90° C. for 14 h. After cooling to RT and dilution with water (30 ml), the mixture was extracted with EtOAc (30 ml, 3 times). The combined organic layer was washed with brine (20 ml) and dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography to give the title compound as a solid. MS (ESI) m/z 315.0 (weight of corresponding boronic acid).

Step 4: N-(4-fluorophenyl)-1-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)cyclobutanecarboxamide

To a solution of N-(4-fluorophenyl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutanecarboxamide (50 mg, 0.126 mmol) in 1,4-dioxane (1 ml) and water (0.2 ml) was added Pd(dtbpf)Cl ₂ (8 mg, 0.012 mmol), (5-bromo-2-(trifluoromethyl)pyridin-4-yl ) methanol (33 mg, 0.129 mmol) and potassium phosphate (80 mg, 0.379 mmol) at RT. The reaction mixture was stirred at 100° C. in a microwave oven for 0.5 h. The solvent was removed, the residue was diluted with water (5 ml) and extracted with EtOAc (5 ml, 3 times). The organic layers were collected, washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The reaction mixture was purified by reverse phase HPLC using a GILSON 281 equipped with a Waters XSELECT C18 column (150 x 30 mm x 5 µm) using water (0.1% TFA) and ACN as eluents and then lyophilized to obtain the title compounds in the form of a solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.71 (d, 1H), 8.61 (s, 1H), 8.09 (s, 1H), 8.02 (brd, 1H) , 7.74 (d, 1H), 7.51-7.58 (m, 2H), 7.03 (t, 2H), 4.66 (s, 2H), 2.91-3.09 (m , 2H), 2.71-2.88 (m, 2H), 1.93-2.16 (m, 2H). MS (ESI) m/z 446.0 [M+H ⁺ ].

Example 95: N-(4-fluorophenyl)-1-(4'-(1-hydroxycyclobutyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)cyclobutanecarboxamide

Step 1: 1-(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 under nitrogen atmosphere . After 3 hours, cyclobutanone (0.372 g, 5.31 mmol) was added dropwise at -60°C, the mixture was stirred at this temperature for 1 hour and allowed to warm to RT. The reaction was quenched with saturated aqueous NH ₄ Cl (10 ml) and was extracted with EtOAc (15 ml, 2 times). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography to give the title compound as a solid. MS (ESI) m/z 295.9, 297.9 [M+H ⁺ ].

Step 2: N-(4-fluorophenyl)-1-(4'-(1-hydroxycyclobutyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)cyclobutanecarboxamide

To a solution of N-(4-fluorophenyl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutanecarboxamide (50 mg, 0.126 mmol) and 1-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)cyclobutanol (45 mg, 0.152 mmol) in THF (2.0 ml) and water (0.2 ml) was added K ₃ PO ₄ (80 mg, 0.379 mmol) and Pd(dtbpf)Cl ₂ (8 mg, 0.012 mmol) with stirring at RT under nitrogen. The reaction mixture was stirred at 90° C. for 14 hours. The reaction mixture was cooled to RT, diluted with water (5 ml) and the mixture was extracted with EtOAc (5 ml, 3 times). The combined organic layer was washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase HPLC using a GILSON 281 equipped with a YMC-Actus Pro C18 (150 x 30 x 5 µm) column using water (0.1% TFA) and ACN as eluents and then lyophilized to obtain the title compounds in the form of a solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.79 (s, 1H), 8.59 (s, 1H), 8.14 (dd, 1H), 7.80 (s, 1H), 7, 73 (d, 1H), 7.53 (dd, 2H), 7.03 (t, J = 8.8 Hz, 2H), 2.93-3.04 (m, 2H), 2.74-2 .84 (m, 2H), 2.27-2.39 (m, 2H), 1.91-2.13 (m, 5H), 1.62 (b.d., 1H). MS (ESI) m/z 486.3 [M+H ⁺ ].

Examples 96-97 in the following table were prepared analogously to example 95.

Example No. Structure chemical name Mass [M+H]+ 96

N-(4-fluorophenyl)-1-(5-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)pyridin-2-yl)cyclobutanecarboxamide 444.9 97

N-(4-fluorophenyl)-1-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-yl)cyclobutanecarboxamide 474.0

Example 98: N-(4-fluorophenyl)-3-(4-(3-(hydroxymethyl)-5-(trifluoromethyl)pyridin-2-yl)phenyl)oxetan-3-carboxamide

Stage 1: 2-chloro-5-(trifluoromethyl)nicotinaldehyde

n -BuLi (6 ml, 15.00 mmol) (2.5 M hexane) at -78°C and the reaction mixture 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 HCl (1 M) (60 ml), then was extracted with EtOAc (50 ml, 2 times). The organic layers were collected, washed with brine, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to give the title compound as an oil. ¹ H NMR (500 MHz, CDCl ₃ ) δ 10.44-10.51 (m, 1H) 8.87 (d, 1H) 8.47 (d, 1H).

Step 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 NaBH ₄ (141 mg, 3.72 mmol) at 0°C and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with a saturated solution of NH ₄ Cl (5 ml), then was extracted with EtOAc (5 ml, 2 times). The organic layers were collected, washed with brine, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to give 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-2-yl)phenyl)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- K ₃ PO ₄ (120 mg, 0.567 mmol) and Pd(dtbpf)Cl ₂ (13 mg, 0.020 mmol) at RT. The reaction mixture was stirred at 80°C for 16 hours After cooling to RT, the reaction mixture was diluted with water (2 ml) and was extracted with EtOAc (2 ml, 2 times). The organic layers were collected, washed with brine, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC using a GILSON 281 equipped with a Boston Green ODS (150×30×5 μm) column using water (0.1% TFA) and CH ₃ CN as eluents and then concentrated (at below 50°C) to obtain the title compound as an oil. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.85 (br.s., 1H) 8.38 (s, 1H) 7.63-7.70 (m, 4H) 7.52-7.61 (m, 2H) 7.00-7.10 (m, 2H) 5.36 (d, 2H), 5.04 (d, 2H) 4.67 (s, 2H). MS (ESI) m/z 447.0 [M+H ⁺ ].

Example 99: N-(4-fluorophenyl)-3-(4-(4-(1-hydroxycyclobutyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide

To a solution of N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (35 mg, 0.088 mmol) and 1-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)cyclobutanol (30 mg, 0.101 mmol) in THF (2.0 ml) and water (0.2 ml) was added K ₃ PO ₄ (56 mg, 0.264 mmol) and Pd(dtbpf)Cl ₂ (6 mg, 9.21 µmol). The reaction mixture was sealed and stirred at 100° C. in a microwave oven for 0.5 h. The reaction mixture was cooled to RT and diluted with water (5 ml). The mixture was extracted with EtOAc (5 ml, 3 times), the combined organic layer was washed with brine (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase HPLC using a GILSON 281 equipped with a YMC-Actus Pro C18 column (150 x 30 x 5 µm) using water (0.1% TFA) and ACN as eluents and then lyophilized to obtain the title compound as a solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.52 (s, 1H), 7.75 (s, 1H), 7.52-7.64 (m, 6H), 6.98-7, 13 (m, 2H), 5.36 (d, 2H), 5.03 (d, 2H), 2.22-2.32 (m, 2H), 2.02-2.12 (m, 1H) , 1.93-2.01 (m, 2H), 1.52-1.62 (m, 1H). MS (ESI) m/z 487.0 [M+H ⁺ ].

Example 100: N-(4-fluorophenyl)-3-(4-(4-(1-hydroxycyclopropyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide

Stage 1:1-ethoxycyclopropanol

To a solution of (1-ethoxycyclopropoxy)trimethylsilane (5.0 g, 28.7 mmol) in MeOH (35 ml) was added 4.0 M HCl (0.07 ml, 0.274 mmol, in MeOH) with stirring at RT. The reaction mixture was stirred at RT for 14 h. The solvent was removed and the residue was purified by distillation under reduced pressure (65° C., 10-12 mbar) to give the title compound as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.76 (q, 2H), 3.14 (b.s., 1H), 1.22 (t, 3H), 0.91-0.99 ( m, 4H).

Step 2: 1-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)cyclopropan-1-ol

To a solution of 5-chloro-2-(trifluoromethyl)pyridine (2.0 g, 11.02 mmol) in THF (8 mL) was added TMPMgCl LiCl (12.12 mL, 12.12 mmol) dropwise at 0°C in a nitrogen atmosphere. The mixture was stirred at RT for 0.5 h. At the same time, methylmagnesium bromide (4.04 ml, 12.12 mmol) at 0°C and the resulting white suspension was stirred at 0°C for 10 min. Then the specified solution of organolithium compound was added to this suspension and the resulting reaction mixture was stirred at ambient temperature for 30 min, and then stirred at 40°C for 14 h. The reaction mixture was cooled to 0°C and quenched by slowly adding a saturated solution of NH ₄ Cl (25 ml). The mixture was diluted with EtOAc (20 ml) and filtered. The filtrate was extracted with EtOAc (15 ml, 3 times). The combined organic layer was washed with brine (15 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc (20:1-10:1) as eluents to give a crude product which was then purified by preparative TLC (petroleum ether/ethyl acetate 4:1 as eluents) to obtaining 1-(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-(1-hydroxycyclopropyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane-3-carboxamide

To a solution of 1-(5-chloro-2-(trifluoromethyl)pyridin-4-yl)cyclopropanol (10 mg, 0.042 mmol) and N-(4-fluorophenyl)-3-(4-(4.4.5.5 -tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (17 mg, 0.043 mmol) in dioxane (1.0 ml) and water (0.1 ml) was added sodium carbonate (18 mg, 0.170 mmol) and Pd(dtbpf)Cl ₂ (3 mg, 4.60 µmol) with stirring at RT under nitrogen atmosphere. The mixture was sealed and heated to 100° C. in a microwave oven for 40 minutes and then cooled to RT. The cooled mixture was diluted with water (2 ml) and extracted with EtOAc (5 ml, 3 times). The combined organic layer was concentrated and the residue was purified by reverse phase HPLC using a GILSON 281 equipped with an Xtimate C18 column (150×25 mm×5 μm) using water (10 mM NH ₄ HCO ₃ ) and ACN as eluents, and then lyophilized to obtain the title compound as a solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.62-8.74 (m, 1H), 7.78 (s, 1H), 7.67-7.72 (m, 1H), 7.71 ( d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.41 (t, J = 6.4 Hz, 2H), 6.97-7, 07 (m, 3H), 5.43 (d, J =6.0 Hz, 2H), 5.12 (d, J =6.0 Hz, 2H), 2.48 (s, 1H), 1 .05-1.16 (m, 2H), 0.79-0.89 (m, 2H). MS (ESI) m/z 473.1 [M+H ⁺ ].

Examples 101-102 in the following table were prepared analogously to example 100.

Example No. Structure chemical name Mass [M+H]+ 101

3-(4-(6-cyclopropoxy-4-(hydroxymethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide 435.2 102

3-(4-(6-cyclopropoxy-4-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide 463.2

Example 103: 5-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-N-methyl-2-(trifluoromethyl)isonicotinamide

Step 1: Methyl 5-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-2-(trifluoromethyl)isonicotinate

To a solution of N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (200 mg, 0.503 mmol) in dioxane (2.5 ml) and water (0.5 ml) was added Pd(dtbpf)Cl ₂ (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 RT. The mixture was subjected to a Suzuki coupling reaction under standard conditions and a process was carried out to give a crude product, which was purified by silica gel flash chromatography to give the title compound as an oil. MS (ESI) m/z 475.2 [M+H ⁺ ].

Step 2: 5-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-2-(trifluoromethyl)isonicotinic acid

To a solution of methyl 5-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)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 RT. The reaction mixture was stirred at RT for 3 h. The solvent was removed and the residue was acidified to pH 3 with 6 M HCl. The aqueous mixture was extracted with EtOAc (20 ml, 3 times), during extraction, brine was added to the aqueous layer. The combined organics were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give 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)isonicotinamide

TEA ( 0.2 ml, 1.435 mmol), HATU (99 mg, 0.261 mmol) and methylamine hydrochloride (18 mg, 0.267 mmol) at RT. The reaction mixture was stirred for 16 hours at RT. The reaction mixture was diluted with water (40 ml) and extracted with EtOAc (30 ml, 3 times). The combined organic layer was washed with brine (20 ml) and dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase HPLC using a Phenomenex Synergi C18 150×30 mm×4 µm column and water (0.1% TFA) and ACN as eluents to give the title compound as a solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.80 (s, 1H) 7.86 (s, 1H) 7.60-7.64 (m, 2H) 7.52-7.58 (m, 4H) 7.04 (t, 2H) 5.34 (d, 2H) 5.01 (d, 2H) 2.70-2.74 (m, 3H). MS (ESI) m/z 474.2 [M+H ⁺ ].

Example 104 in the following table was prepared analogously to example 103.

Example No. Structure chemical name Mass [M+H]+ 104

5-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide 460.1

Example 105: (R)-3-(4-(4-(1-amino-2,2,2-trifluoroethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetan-3 -carboxamide

Step 1: -5-bromo-2-(trifluoromethyl)isonicotinaldehyde

To a solution of diisopropylamine (1.343 g, 13.27 mmol) in THF (20 ml) was added dropwise butyllithium (4.60 ml, 11.50 mmol) at -60°C under nitrogen atmosphere. After 1 hour, 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 hour. The reaction was quenched with saturated aqueous NH ₄ Cl (100 ml) and extracted with EtOAc (20 ml×2). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography to give the title compound as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.4 (s, 1H), 9.0 (s, 1H), 8.1 (s, 1H).

Step 2: (R, E)-N-((5-bromo-2-(trifluoromethyl)pyridin-4-yl)methylene)-2-methylpropan-2-sulfinamide

To a stirred solution of 5-bromo-2-(trifluoromethyl)isonicotinaldehyde (721 mg, 2.84 mmol) in CH ₂ Cl ₂ (20 ml) was added (R)-2-methylpropane-2-sulfinamide (344 mg, 2.84 mmol) and Cs ₂ CO ₃ (1110 mg, 3.41 mmol) at RT. The reaction mixture was stirred at RT for 15 h. The reaction mixture was concentrated to remove CH ₂ Cl ₂ and then diluted with water (30 ml) and was extracted with EtOAc (30 ml, 2 times). The organic layers were collected, washed with brine (20 ml), dried over Na ₂ SO ₄ and after filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography to give the title compound as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.9-9.0 (m, 2H), 8.2 (s, 1H), 1.3 (s, 9H).

Step 3: (R)-N-(1-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)-2,2,2-trifluoroethyl)-2-methylpropan-2-sulfinamide

To a stirred solution of (R, Z)-N-((5-bromo-2-(trifluoromethyl)pyridin-4-yl)methylene)-2-methylpropan-2-sulfinamide (659 mg, 1.845 mmol) in THF (10 mL ) TBAT (1195 mg, 2.214 mmol) was added at RT. The reaction mixture was stirred at RT for 0.5 h. Then the mixture was cooled to -60°C, trimethyl(trifluoromethyl)silane (1312 mg, 9.22 mmol) was added thereto and stirring continued at -60°C for 2 h The mixture was quenched with aqueous NH ₄ Cl (15 ml), extracted with EtOAc (30 ml, 2 times) and the organic layers were collected, washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and the filtrate concentrated in vacuo . The residue was purified by silica gel chromatography to give the title compound as a solid. MS (ESI) m/z 467.8 [M+ACN+H ⁺ ].

Step 4: (R)-1-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)-2,2,2-trifluoroethanamine hydrochloride

To a stirred solution of (R)-N-(1-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)-2,2,2-trifluoroethyl)-2-methylpropan-2-sulfinamide (90 mg, 0.211 mmol) in 1,4-dioxane (5 ml) was added 4 M HCl (5 ml, 20.00 mmol, in dioxane) at RT. The reaction mixture was stirred at RT 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 further purification. MS (ESI)m/z 363.8 [M+ACN+H⁺].

Step 5: (R)-3-(4-(4-(1-amino-2,2,2-trifluoroethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl) oxetane-3-carboxamide

To a stirred solution of (R)-1-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)-2,2,2-trifluoroethanamine hydrochloride (76 mg, 0.211 mmol) in 1,4-dioxane (2, 5 ml) and water (0.5 ml) was added N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) oxetane-3-carboxamide (101 mg, 0.254 mmol), K ₃ PO ₄ (135 mg, 0.634 mmol) and Pd(dtbpf)Cl ₂ (16 mg, 0.025 mmol) at RT. The mixture was subjected to a Suzuki coupling reaction under standard conditions and worked up to give the crude title compound, which was purified by HPLC using a GILSON 281 equipped with a Waters XSELECT C18 150×30 mm×5 µm column using water (0.1% TFA) and CH ₃ CN as mobile phases to obtain the title compound as a solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.7 (s, 1H), 8.0 (s, 1H), 7.4-7.5 (m, 6H), 7.1 (br.s ., 1H), 7.0 (t, 2H), 5.4 (t, 2H), 5.1 (dd, 2H), 4.6 (q, 1H). MS (ESI) m/z 514.2 [M+H ⁺ ].

Example 106: (S)-3-(4-(4-(1-amino-2,2,2-trifluoroethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetan-3 -carboxamide

Step 1: (c,E)-N-((5-bromo-2-(trifluoromethyl)pyridin-4-yl)methylene)-2-methylpropan-2-sulfinamide

This compound was prepared analogously to example 105, except that (S)-2-methylpropane-2-sulfinamide was used. MS (ESI) m/z 400.1 [M+ACN+H ⁺ ].

Step 2: N-((S)-1-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)-2,2,2-trifluoroethyl)-2-methylpropan-2-sulfinamide

This compound was prepared analogously to example 105. MS (ESI) m/z 470.1 [M+ACN+H ⁺ ].

Step 3: (S)-1-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)-2,2,2-trifluoroethanamine hydrochloride

The hydrolysis was carried out analogously to step 3 of example 105. MS (ESI) m/z : 364.0 [M+ACN+H ⁺ ].

Step 5: (S)-3-(4-(4-(1-amino-2,2,2-trifluoroethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl) oxetane-3-carboxamide

The title compound was obtained analogously to example 105, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.7 (s, 1H), 8.0 (s, 1H), 7.4-7.5 (m, 6H), 7 .1 (br.s., 1H), 7.0 (br.s., 2H), 5.4 (t, 2H), 5.1-5.2 (m, 2H), 4.6 (c , 1H). MS (ESI) m/z 514.1 [M+H ⁺ ].

Example 107: N-(4-fluorophenyl)-3-(4-(3-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-2-yl)phenyl)oxetan-3-carboxamide

Step 1: Methyl 2-chloro-5-(trifluoromethyl)nicotinate

To a stirred solution of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (2 g, 8.87 mmol) in THF (5 ml) and MeOH (5 ml), ml, 17.73 mmol) (2 M in hexane) at -20°C and the reaction mixture was stirred at -20°C for 2 h. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel to obtain the title compound in the form of oil. MS (ESI) m/z 242.2 [M+H ⁺ ]

Step 2: Methyl 2-(4-(3-((4-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-1,3 ,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (166 mg, 0.417 mmol) in THF (2 ml) was added Pd(dtbpf)Cl ₂ (28 mg, 0.043 mmol) and potassium phosphate (266 mg, 1.252 mmol) at RT. The mixture was stirred at 80°C for 2 h. After cooling to RT, the reaction mixture was diluted with water (2 ml), extracted with EtOAc (1 ml, 2 times) and the organic layers were collected, washed with brine, dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography to give 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-2-yl)phenyl)oxetan-3-carboxamide

To a stirred solution of methyl magnesium bromide (0.1 mL, 0.300 mmol) (3 M in hexane) in THF (0.5 mL) was added methyl 2-(4-(3-((4-fluorophenyl)carbamoyl)oxetane-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 hours. The reaction was quenched with NH ₄ Cl (3 ml), the mixture was diluted with water (2 ml) and extracted with EtOAc (5 ml, 2 times). The organic layers were collected, washed with brine, dried over Na ₂ SO ₄ and after filtration the filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC using a GILSON 281 equipped with a YMC-Actus Pro C18 150×30×5 µm column using water (0.1% TFA) and CH ₃ CN as eluents to give the title compound as solids after lyophilization. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.75-8.80 (m, 1H) 8.68 (d, 1H) 7.60-7.65 (m, 2H) 7.52-7, 58 (m, 2H) 7.45-7.51 (m, 2H) 7.01-7.12 (m, 2H) 5.37 (d, 2H) 5.05 (d, 2H) 1.33- 1.43 (m, 6H). MS (ESI) m/z 475.2 [M+H ⁺ ]

Example 108: 3-(4-(5-cyclopropoxy-3-(hydroxymethyl)pyridin-2-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide

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 ) was added cesium carbonate (1300 mg, 3.99 mmol) at RT. The reaction vessel was sealed and heated in a microwave oven at 150° C. under nitrogen for 1 h. The reaction mixture was cooled to RT, poured into water (20.0 ml) and extracted with ethyl acetate (10.0 ml, 3 times). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel flash chromatography to give the title compound as an oil. MS (ESI) m/z 229.9 [M+H ⁺ ].

Stage 2: 2-bromo-5-cyclopropoxynicotinic 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 RT. The reaction mixture was stirred at 100° C. for 3 hours. The resulting hot mixture was then filtered through a Celite pad, the filtrate was cooled and washed with EtOAc (5 ml, 3 times). The aqueous layer was acidified with 6 N HCl to pH=4, concentrated to a small volume (5 ml) and extracted with EtOAc (10 ml, 3 times). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give 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 BH ₃ ·THF (0.50 ml, 0.500 mmol) dropwise at 0°C and the reaction mixture was stirred at RT for 15 h. The mixture was carefully quenched with MeOH (5 ml), then concentrated in vacuo. The residue was purified by preparative TLC to give the title compound as an oil. MS (ESI) m/z 243.9 [M+H ⁺ ].

Stage 4: 3-(4-(5-cyclopropoxy-3-(hydroxymethyl)pyridin-2-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide

To a stirred solution of N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (41 mg, 0.103 mmol) in dioxane (2.0 ml) and water (0.4 ml) were added K ₃ PO ₄ (65 mg, 0.306 mmol) and Pd(dtbpf)Cl ₂ (7 mg, 10.74 μmol) at RT. The reaction mixture was subjected to a Suzuki coupling reaction under standard conditions and worked up to give a crude product which was purified by reverse phase HPLC using a GILSON 281 equipped with a Phenomenex Synergi C18 column (250×21.2 mm×4 µm) using water ( 0.2% formic acid) and ACN as eluents and then lyophilized to give the title compound as a solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.34 (d, 1H), 8.01 (d, 1H), 7.52-7.68 (m, 6H), 7.06 (t, 2H), 5.36 (d, 2H), 5.04 (d, 2H), 4.59 (s, 2H), 4.02 (dt, 1H), 0.79-0.96 (m, 4H ).MS (ESI) m/z 435.1 [M+H ⁺ ].

Example 109 : 3-(4-(5-cyclopropoxy-3-(2-hydroxypropan-2-yl)pyridin-2-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide

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 stirred the mixture at RT for 15 h. The solvent was concentrated under reduced pressure and the residue was purified by preparative TLC (petroleum ether/EtOAc=2:1) to give the title compound as an oil. MS (ESI) m/z 271.8 and 273.8 [M+H ⁺ ].

Step 2: Methyl 5-cyclopropoxy-2-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)nicotinate

To a stirred solution of N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (52 mg, 0.131 mmol) and methyl 2-bromo-5-cyclopropoxynicotinate (30 mg, 0.110 mmol) in dioxane (2 ml) and water (0.4 ml) were added K ₃ PO ₄ (70 mg, 0.330 mmol) and Pd(dtbpf )Cl ₂ (7 mg, 10.74 µmol) at RT. The mixture was heated to 100° C. with stirring for 16 h. After cooling to RT, the mixture was extracted with EtOAc (30 ml, 2 times), the organic layers were collected, washed with brine, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether/EtOAc=1:1) to give 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-(4-fluorophenyl)oxetane-3-carboxamide

3 M MeMgBr (0.08 ml, 0.240 mmol) at RT. The mixture was stirred at RT for 15 h. The mixture was diluted with water (20 ml), extracted with EtOAc (20 ml, 3 times), the organic layers were collected, washed with brine (10 ml), dried over Na ₂ SO ₄ and after filtration concentrated the filtrate in vacuo. The residue was purified by reverse phase HPLC using a GILSON 281 equipped with a Phenomenex Synergi C18 column (150×30 mm×4 µm) using water (0.225% FA) and ACN as eluents to give the title compound as a solid after lyophilization of the desired fractions. ¹ H NMR (400 MHz, CD ₃ OD) 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 (b.d., 2H), 0.85 (br.s., 2H). MS (ESI) m/z 463.2 [M+H ⁺ ].

Example 110: 3-(4'-cyclopropoxy-2'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-N-(4-fluorophenyl)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) was added 2-methylpropan-2-olate dropwise potassium (7.5 ml, 7.50 mmol) (1 M in THF) at 0°C. The reaction mixture was stirred at 0°C for 30 min. The mixture was warmed to RT and stirred at RT for 3 hours. The reaction mixture was partitioned with 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 give the title compound as an oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.07 (d, 1H), 7.32 (dd, 2.8 Hz, 1H), 7.26-7.30 (m, 1H), 3, 96 (tt, 3.0 Hz, 1H), 3.89 (s, 3H), 0.85-0.91 (m, 2H), 0.76-0.80 (m, 2H).

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 RT. The mixture was stirred at 80° C. for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with water (30 ml), extracted with EtOAc (15 ml, 2 times) and the combined organic layer was washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the title compound as oil, which was used in the next step without further purification. MS (ESI) m/z 208.1 [M+H ⁺ ].

Stage 3: Methyl 2-bromo-5-cyclopropoxybenzoate

To a solution of methyl 2-amino-5-cyclopropoxybenzoate (50 mg, 0.241 mmol) in CH ₃ CN (5 ml) was added copper (I) bromide (70 mg, 0.483 mmol) and tert-butyl nitrite (50 mg, 0.483 mmol) at 0°C. After stirring at RT for 16 hours, the reaction mixture was diluted with water (30 ml) and extracted with DCM (30 ml, 3 times). The combined organic layer was washed with brine (20 ml) and dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC (petroleum ether/EtOAc=2:1) to give the title compound as an oil. ¹ H NMR (400 MHz, CDCl 3 ) δ 7.52 (d, 1H), 7.46 (d, 1H), 7.00 (dd, 1H), 3.92 (s, 3H), 3, 71-3.76 (m, 1H), 0.75-0.81 (m, 4H).

Stage 4: 2-(2-bromo-5-cyclopropoxyphenyl)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. After the addition was complete, the reaction mixture was stirred at RT for 16 hours, slowly quenched with saturated NH ₄ Cl solution (20 ml, aqueous solution) and extracted with EtOAc (10 ml, 3 times). The combined organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound as an oil, which was used in the next step without further purification. ¹ H NMR (400 MHz, CD3OD) δ 7.51 (d, J 1 H), 7.44 (d, 1H), 6.83 (dd, 1H), 3.75 (td, 1H), 1, 68 (s, 6H), 0.78 (b.d., 2H), 0.67 (br.s., 2H).

Step 5: 3-(4'-cyclopropoxy-2'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide

N-(4-fluorophenyl)-3-(4 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) oxetan-3-carboxamide (117 mg, 0.295 mmol), Pd (dtbpf) Cl ₂ (19.23 mg , 0.030 mmol) and K ₃ PO ₄ (188 mg, 0.885 mmol) at RT. The mixture was subjected to a Suzuki coupling reaction under standard conditions and worked up to give a crude product which was purified by reverse phase HPLC using a GILSON 281 equipped with an Xtimate C18 150×25 mm×5 µm column and the desired fractions were collected and concentrated to give the title compound in the form of a solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.56 (t, 2H), 7.43-7.48 (m, 3H), 7.32 (d, 2H), 7.06 (t, 2H ), 6.89-6.94 (m, 2H), 5.34 (d, 2H), 5.02 (d, 2H), 3.80 (tt, 1H), 1.32 (s, 6H ), 0.76-0.83 (m, 2H), 0.67-0.73 (m, 2H). MS (ESI) m/z 484.3 [M+Na ⁺ ].

Example 111: 3-(4'-cyclopropoxy-2'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide

Step 1: (2-bromo-5-cyclopropoxyphenyl)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 hours The reaction mixture was cooled, filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water (30 ml), extracted with EtOAc (15 ml, 2 times) and the combined organic layer was washed with brine (10 ml) and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the title compound as oil, which was used in the next step without further purification.

Stage 2: 3-(4'-cyclopropoxy-2'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide

N-(4-fluorophenyl)-3-(4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (82 mg, 0.206 mmol), Pd(dppf)Cl ₂ (15.05 mg, 0.021 mmol) and potassium phosphate (131 mg, 0.617 mmol) at RT. The mixture was subjected to a Suzuki coupling reaction under standard conditions and worked up to give the crude product, which was purified by reverse phase HPLC using a GILSON 281 equipped with a Phenomenex Synergi C18 column (150×30 mm×4 µm) to give the title compound as a solid substances. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.46-7.61 (m, 4H), 7.40 (d, 2H), 7.26 (d, 1H), 7.16 (d, 1H ), 6.96-7.11 (m, 3H), 5.33 (d, 2H), 5.01 (d, 2H), 4.48 (s, 2H), 3.81 (dt, 1H) , 0.75-0.84 (m, 2H), 0.66-0.75 (m, 2H). MS (ESI) m/z 456.1 [M+Na ⁺ ].

Example 112: N-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-isopropoxypyridin-3-yl)phenyl)oxetane-3-carboxamide

Stage 1:5-bromo-2-isopropoxypyridine

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) under nitrogen at 0°C and stirred the reaction mixture at RT for 15 h. Then 5-bromo-2-fluoropyridine (2.7 g, 15.34 mmol) in DMF (5 ml) was added and the reaction mixture was heated to 130°C for 4 h. After cooling to RT the solvent was concentrated and the residue was quenched with water (20 ml) and was extracted with EtOAc (30 ml, 2 times). The organic layers were combined, washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to give the title compound as an oil. MS (ESI) m/z 215.9 [M+H ⁺ ].

Stage 2: 5-bromo-2-isopropoxyisonicotinaldehyde

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 was stirred at this temperature over 1 h. Then N,N-dimethylformamide (0.913 g, 12.50 mmol) was added and the mixture was stirred at RT for 1 h. The solvent was concentrated, the residue was quenched with water (20 ml) and extracted with EtOAc (30 ml, 2 times). The organic layers were collected, washed with brine (20 ml), dried over Na ₂ SO ₄ and after filtration the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound as an oil. MS (ESI) m/z 243.9 [M+H ⁺ ].

Stage 3: (5-bromo-2-isopropoxypyridin-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 NaBH ₄ (0.299 g, 7.90 mmol) at 0°C and stirred the reaction mixture at RT for 1 h. The reaction was quenched with NH ₄ Cl (20 ml) and the mixture was extracted with EtOAc (30 ml, 2 times). The organic layers were collected, washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 6.89 (s, 1H), 5.23 (csp, 1H), 4.67 (d, 2H), 4.12 (q, 1H), 1.34 (d, 6H).

Step 4: N-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-isopropoxypyridin-3-yl)phenyl)oxetane-3-carboxamide

To a stirred solution of N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (300 mg, 0.755 mmol) in 1,4-dioxane (2.5 ml) and water (0.5 ml) were added PdCl ₂ (dppf) (45 mg, 0.062 mmol) and K ₃ PO ₄ (388 mg, 1.829 mmol) at RT . The mixture was subjected to a Suzuki coupling reaction under standard conditions and worked up to give the crude title compound, which was purified by HPLC using a GILSON 281 equipped with a Waters Xbridge Prep OBD C18 column (100×19 mm×5 µm) using water (0.225% formic acid )/CH ₃ CN as eluents to obtain the title compound as a solid after concentrating the desired fractions. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.48 (m, 6H), 6.94-7.06 (m, 4H), 5.41 (d, 1H), 5.29 -5.38 (m, 1H), 5.09 (d, 2H), 4.63 (s, 2H), 1.40 (d, 6H). MS (ESI) m/z 437.2 [M+H ⁺ ].

Example 113: N-(4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridazin-3-yl)phenyl)oxetan-3-carboxamide

Step 1: 2-(3-chloro-6-(trifluoromethyl)pyridazin-4-yl)propan-2-ol

To a solution of 2.5 M BuLi in hexanes (1.3 ml, 3.3 mmol) was added dropwise THF (5 ml) with stirring at -78°C under nitrogen atmosphere. 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 dropwise to the mixture. The reaction mixture was stirred at -70°C for 1.5 h. Acetone (3 mL, 40.9 mmol) was added dropwise to the mixture. The reaction mixture was stirred at -70°C for 1 h, extinguished with saturated aqueous ammonium chloride (5 ml) and was extracted with EtOAc (20 ml, 2 times). The combined organic layers were washed with brine, dried over MgSO ₄ , concentrated in vacuo and the residue was purified by silica gel flash chromatography followed by preparative TLC (SiO ₂ , petroleum ether/EtOAc=3/1) to give the title compound as a solid substances. MS (ESI) m/z 240.9 [M+H ⁺ ].

Step 2: N-(4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridazin-3-yl)phenyl)oxetan-3-carboxamide

N-( 4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (I-9) (59 mg, 0.149 mmol), potassium orthophosphate (79 mg, 0.374 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) (8 mg, 0.012 mmol). The reaction mixture was stirred at 100° C. for 16 hours under nitrogen. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (Phenomenex Synergi C18 column (150×30 mm×4 µm)) using water (0.1% TFA) and ACN as mobile phases to give the title compound in the form of a solid. ¹ H NMR (400 MHz, MeOD) δ 8.47 (s, 1H), 7.68-7.66 (m, 2H), 7.58-7.55 (m, 4H), 5.38-5 .37 (m, 2H), 5.06-5.05 (m, 2H), 3.3 (m, 4H), 1.38 (m, 6H). MS (ESI) m/z 476 [M+H ⁺ ].

Example 114: N-(4-chlorophenyl)-1-(5-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)pyrazin-2-yl)cyclobutan-1-carboxamide

Stage 1: 1-(5-bromopyrazin-2-yl)cyclobutan-1-carbonitrile

To a solution of 2,5-dibromopyrazine (200 mg, 0.841 mmol) in THF (10.0 ml) was added NiXantphos (46 mg, 0.083 mmol), Pd ₂ (dba) ₃ (40 mg, 0.044 mmol) and cyclobutanecarbonitrile (75 mg , 0.925 mmol) then LiHMDS (1.6 ml, 1.600 mmol) (1 M in THF) was added at 0°C. The resulting mixture was heated to 80°C for 15 hours and cooled to RT, extinguished NH ₄ Cl (10.0 ml) and was extracted with EtOAc (20 ml, 2 times). The combined organic layer was washed with brine and concentrated in vacuo. The residue was purified by reverse phase HPLC using a GILSON 281 equipped with a Phenomenex Synergi C18 column (250×21.2 mm×4 µm) using water (0.2% formic acid) and ACN as eluents. The desired fractions were collected and concentrated by lyophilization to give the title compound as a solid. MS (ESI) m/z 237.9 [M+H ⁺ ].

Stage 2: 1-(5-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(trifluoromethyl)phenyl)pyrazin-2-yl)cyclobutan-1-carbonitrile

To a stirred solution of 1-(5-bromopyrazin-2-yl)cyclobutanecarbonitrile (50 mg, 0.210 mmol) and tert-butyldiphenyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-5-(trifluoromethyl)-benzyl)oxy)silane (125 mg, 0.231 mmol) in dioxane (1.0 ml) and water (0.2 ml) was added K ₃ PO ₄ (134 mg, 0.630 mmol) and Pd(dtbpf)Cl ₂ (10 mg, 0.015 mmol) at RT. The reaction mixture was subjected to a Suzuki coupling reaction under standard conditions and worked up to give the crude title compound, which was purified by preparative TLC (petroleum ether/ethyl acetate=5:1 as eluents) to give the title compound as an oil. MS (ESI) m/z 572.2 [M+H ⁺ ].

Step 3: 1-(5-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)pyrazin-2-yl)cyclobutane-1-carboxylic 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) was added KOH (45 mg, 0.802 mmol) at RT 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 HCl to pH=5 and was extracted with EtOAc (3 ml, 3 times). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give 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)-1-(5-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)pyrazin-2-yl)cyclobutan-1-carboxamide

To a stirred solution of 4-chloroaniline (20 mg, 0.16 mmol), TEA (40 mg, 0.395 mmol) and 1-(5-(3-(hydroxymethyl)-4-(trifluoromethyl)phenyl)pyrazin-2-yl) cyclobutanecarboxylic acid (27 mg, 0.077 mmol) in DMF (1.0 ml) was added HATU (50 mg, 0.131 mmol) at RT and the reaction mixture was stirred at RT for 1 h. The residue was purified by reverse phase HPLC using a GILSON instrument 281 equipped with a Phenomenex Synergi C18 (250×21.2 mm×4 µm) column using water (0.2% formic acid) and ACN as eluents. The title compound was obtained as a solid after lyophilization of the desired fractions. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.95 (d, 1H), 8.78 (d, 1H), 8.17 (s, 1H), 7.84 (s, 1H), 7.71 -7.78 (m, 2H), 7.49 (d, 2H), 7.29 (s, 2H), 4.57 (s, 2H), 3.08 (ddd, 2H), 2.73- 2.83 (m, 2H), 2.13-2.29 (m, 1H), 1.94-2.11 (m, 1H). MS (ESI) m/z 461.9 [M+H ⁺ ].

Example 115: N-(6-fluoropyridin-3-yl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide

Step 1: 3-(4-bromophenyl)-N-(6-fluoropyridin-3-yl)oxetane-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-fluoropyridine-3-amine (0.654 g, 5.83 mmol) and EDC (2.237 g, 11.67 mmol) at RT. The reaction mixture was stirred at RT for 15 hours. The solvent was concentrated and the residue was diluted with water (20 ml) and extracted with ethyl acetate (30 ml, 2 times). The organic layers were collected, washed with brine (20 ml), dried over Na ₂ SO ₄ and after filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography to give 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-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide

4 ,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.128 g, 4.44 mmol), potassium acetate (1.090 g, 11.11 mmol) and Pd(dppf)Cl ₂ (0.271 g, 0.370 mmol) at RT. The reaction mixture was heated to 100° C. with stirring for 15 hours. After cooling to RT, the reaction was quenched with water (30 ml) and the mixture was extracted with EtOAc (30 ml, 2 times). The organic layers were collected, washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to give the title compound as a solid. MS (ESI) m/z 399.1 [M+H ⁺ ].

Step 3: N-(6-fluoropyridin-3-yl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3- carboxamide

To a stirred solution of N-(6-fluoropyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (220 mg, 0.552 mmol) in 1,4-dioxane (2.5 ml) and water (0.5 ml) was added 2-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)propan-2- ol (189 mg, 0.665 mmol), K ₃ PO ₄ (352 mg, 1.657 mmol) and Pd(dtbpf)Cl ₂ (36 mg, 0.055 mmol) at RT. The mixture was subjected to a Suzuki coupling reaction under standard conditions and worked up to give the crude title compound, which was purified by reverse phase HPLC using a GILSON 281 equipped with a Waters Xbridge Prep OBD C18 column (100×19 mm×5 µm) using water ( 0.225% formic acid) and CH ₃ CN as eluents to give the title compound as a solid. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.4 (br.s., 1H), 8.3 (s, 1H), 8.2-8.3 (m, 2H), 7.6 ( brd, 2H), 7.4 (b.d., 2H), 7.1 (dd, 1H), 5.4 (b.d., 2H), 5.1 (b.d., 2H), 1.4 (s, 6H). MS (ESI) m/z 476.1 [M+H ⁺ ].

Examples 116 and 117 in the following table were prepared analogously to example 115.

Example No. Structure chemical name Mass [M+H]+ 116

3-(4-(6-cyclopropoxy-4-(hydroxymethyl)pyridin-3-yl)phenyl)-N-(6-fluoropyridin-3-yl)oxetan-3-carboxamide 436.2 117

3-(4-(6-cyclopropoxy-4-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)-N-(6-fluoropyridin-3-yl)oxetan-3-carboxamide 464.2

Example 118 : 3-fluoro-N-(4-fluorophenyl)-1-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)cyclobutanecarboxamide

Stage 1: 1-(5-bromopyridin-2-yl)-3-methylenecyclobutanecarbonitrile

LiHMDS (31.3 ml, 62.5 mmol) at 0°C and the mixture was stirred at 0°C for 3 h. The reaction mixture was diluted with an aqueous solution of NH ₄ Cl (200 ml), extracted with EtOAc (100 ml, 2 times), organic compounds were collected and washed with brine , dried over anhydrous Na ₂ SO ₄ and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to give the title compound as an oil.

Stage 2: 1-(5-bromopyridin-2-yl)-3-oxocyclobutanecarbonitrile

Ruthenium(III) chloride hydrate (III ) (46 mg, 0.204 mmol) and NaIO ₄ (2147 mg, 10.04 mmol) at RT. The reaction mixture was stirred at RT for 16 h. Then the reaction was quenched by adding a saturated solution of Na ₂ S ₂ O ₃ (50 ml) and the resulting mixture was extracted with EtOAc (100 ml, 2 times). The organic layers were collected, washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to give the title compound as a solid. MS (ESI) m/z 292.0; 294.0 [M+ACN+H ⁺ ].

Stage 3: 1-(5-bromopyridin-2-yl)-3-hydroxycyclobutanecarbonitrile

To a solution of 1-(5-bromopyridin-2-yl)-3-oxocyclobutanecarbonitrile (430 mg, 1.713 mmol) in MeOH (10 ml) was added NaBH ₄ (130 mg, 3.43 mmol) at 0°C and the mixture was stirred at 0°C for 1 h. The reaction mixture was carefully diluted with water (50 ml) and was extracted with EtOAc (20 ml, 2 times). The organics were collected and washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to give the corresponding alcohol as a solid.

Stage 4: 1-(5-bromopyridin-2-yl)-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarbonitrile

To a solution of 1-(5-bromopyridin-2-yl)-3-hydroxycyclobutanecarbonitrile (300 mg, 1.185 mmol) in THF (10 ml) was added imidazole (161 mg, 2.371 mmol) and tert-butylchlorodimethylsilane (214 mg, 1.422 mmol) at RT. The mixture was stirred at RT for 2 hours. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (50 ml, 2 times). The organics were collected and washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound as an oil.

Stage 5: 1-(5-bromopyridin-2-yl)-3-hydroxycyclobutanecarboxylic acid

NaOH ( 87 mg, 2.178 mmol) at RT. 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. An aqueous solution of 3 N HCl was added dropwise to bring the pH to ~2 and the mixture was extracted with EtOAc (20 ml, 3 times). The organic layers were collected, washed with brine, dried over Na ₂ SO ₄ and after filtration the filtrate was concentrated to give the title compound as a solid. MS (ESI) m/z 272.0, 274.0 [M+H ⁺ ].

Step 6: 1-(5-bromopyridin-2-yl)-N-(4-fluorophenyl)-3-hydroxycyclobutanecarboxamide

TEA (0.2 ml, 1.435 mmol) and 4-fluoroaniline (35 mg, 0.315 mmol) at RT. The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (50 ml), extracted with EtOAc (20 ml, 3 times), the organic layers were collected, washed with brine (10 ml), dried over Na ₂ SO ₄ . filtered and concentrated the filtrate in vacuo. The residue was purified by preparative TLC to give the title compound as an oil. MS (ESI) m/z 365.1, 367.1 [M+H ⁺ ].

Stage 7: 1-(5-bromopyridin-2-yl)-3-fluoro-N-(4-fluorophenyl)cyclobutanecarboxamide

To a stirred solution of 1-(5-bromopyridin-2-yl)-N-(4-fluorophenyl)-3-hydroxycyclobutanecarboxamide (800 mg, 2.191 mmol) in DCM (20 ml) was added DAST (0.29 ml, 2.195 mmol) at 0°C and the reaction mixture was stirred at RT for 1.5 h. The reaction was quenched by adding a saturated solution of NaHCO ₃ (20 ml) and was extracted with DCM (10 ml, 2 times). The organic layers were collected, washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound as a solid. MS (ESI) m/z 366.9 [M+H ⁺ ].

Stage 8: 1-(4'-(((tert-butyldimethylsilyl)oxy)methyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)-3-fluoro-N-(4 -fluorophenyl)cyclobutanecarboxamide

To a stirred solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine ( 273 mg, 0.654 mmol) in 1,4-dioxane (5 ml) and water (1 ml) were added K ₃ PO ₄ (347 mg, 1.634 mmol), Pd(dtbpf)Cl ₂ (36 mg, 0.055 mmol) and 1 -(5-bromopyridin-2-yl)-3-fluoro-N-(4-fluorophenyl)cyclobutanecarboxamide (200 mg, 0.545 mmol) at RT. The mixture was subjected to a Suzuki coupling reaction under standard conditions and worked up to give 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)-1-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)cyclobutanecarboxamide

To a solution of 1-(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) was added TBAF (0.17 mL, 0.170 mmol) (1 M in THF) at RT. The mixture was stirred at RT for 2 h. The solvent was removed and the residue was purified by reverse phase HPLC using a GILSON 281 equipped with a Phenomenex Synergi C18 column (150×30 mm×4 µm) using water (0.1% TFA) /ACN as eluents. The title compound was obtained as a solid after lyophilization of the desired fractions. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.71 (d, 1H), 8.63 (s, 1H), 8.11 (s, 1H), 7.97 (dd, 1H), 7, 62 (d, 1H), 7.53-7.58 (m, 2H), 7.04-7.09 (m, 2H), 5.09-5.30 (m, 1H), 4.68 ( s, 2H), 3.36-3.43 (m, 2H), 2.89-3.01 (m, 2H). MS (ESI) m/z 464.1 [M+H ⁺ ]

Example 119: 4-fluoro-N-(1-(7-hydroxy-5-(2-methylpyrimidin-4-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)cyclopropyl)benzamide

Stage 1: 1-tert-butyl-3-ethyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate

To a stirred solution of 1-tert-butyl-3-ethyl-4-oxopiperidine-1,3-dicarboxylate (4.0 g, 14.74 mmol) and DIPEA (4.76 g, 36.9 mmol) in DCM (60 ml) Tf ₂ O (3.2 ml, 18.94 mmol) was added dropwise at -70°C and the reaction mixture was stirred at -70°C under nitrogen atmosphere for 3 h. The mixture was diluted with water (40 ml) and extracted with DCM (20 ml, 3 times). The organic layers were collected, washed with brine, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to give the title compound as an oil.

Stage 2: 1-tert-butyl 3-ethyl 4-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate

To a stirred solution of 1-tert-butyl-3-ethyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (1.218 g, 3.02 mmol) and N -(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (1.0 g, 2, 52 mmol) in THF (18 ml) was added potassium phosphate (1.603 g, 7.55 mmol) and Pd(dtbpf)Cl ₂ (9 mg, 0.014 mmol) at RT. The reaction mixture was stirred at 80° C. under nitrogen for 16 hours. After cooling to RT, the reaction mixture was diluted with water (80 ml) and extracted with EtOAc (100 ml, 2 times). The organic layers were collected, washed with brine, dried over Na ₂ SO ₄ and after filtration the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography to give the title compound as a solid.

Stage 3: 1-tert-butyl-3-ethyl-4-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)piperidine-1,3-dicarboxylate

To a stirred solution of 1-tert-butyl-3-ethyl 4-(4-(3-((4-fluorophenyl)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 RT. The mixture was stirred at RT for 16 hours. The reaction mixture was filtered and the precipitate was washed with MeOH (10 ml, 2 times). The filtrates were combined and concentrated in vacuo. The residue was diluted with EtOAc (30 ml), washed with HCl (20 ml, 2 M) and brine, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under vacuum to obtain the title compound as an oil, which was used in the next step without further purification . MS (ESI) m/z 549.0 [M+Na ⁺ ].

Step 4: tert-Butyl-4-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-3-(2-hydroxypropan-2-yl)piperidine-1-carboxylate

To a stirred solution of methyl magnesium bromide (2.215 mL, 6.65 mmol, 3 M in Et ₂ O) in THF (5 mL) was added 1-tert-butyl-3-ethyl-4-(4-(3-(( 4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)piperidine-1,3-dicarboxylate (1.0 g, 1.899 mmol) in THF (20 mL) at RT. The reaction mixture was stirred at RT for 4 hours. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (10 ml, 2 times). The organic layers were collected, washed with brine, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound as an oil. MS (ESI) m/z 513.1 [M+H ⁺ ].

Step 5: N-(4-fluorophenyl)-3-(4-(3-(2-hydroxypropan-2-yl)piperidin-4-yl)phenyl)oxetane-3-carboxamide

To a stirred solution of tert-butyl 4-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-3-(2-hydroxypropan-2-yl)piperidine-1-carboxylate (310 mg, 0.605 mmol) in DCM (5 mL) TFA (3 mL, 38.9 mmol) was added at RT. The reaction mixture was stirred at RT for 2 hours. The reaction mixture was diluted with saturated NaHCO ₃ solution (40 ml) and extracted with DCM (15 ml, 2 times). The organic layers were collected, washed with brine, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo to give 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 6: N-(4-fluorophenyl)-3-(4-(3-(2-hydroxypropan-2-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)oxetan- 3-carboxamide

To a stirred solution of N-(4-fluorophenyl)-3-(4-(3-(2-hydroxypropan-2-yl)piperidin-4-yl)phenyl)oxetan-3-carboxamide (210 mg, 0.509 mmol) in CH ₃ CN (10 ml) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (236 mg, 1.018 mmol) and Cs ₂ CO ₃ (332 mg, 1.018 mmol) at RT. The reaction mixture was stirred at RT for 2 h. After filtration, the reaction mixture was purified by reverse phase HPLC using a GILSON 281 equipped with a Phenomenex Synergi C18 column (150×30 mm×4 µm) using water (0.1% TFA ) and CH ₃ CN as eluents to obtain peak 1, isomer 1 as a solid. Subsequent elution gave peak 2, isomer 2 as a solid. MS (ESI) m/z 495.0 [M+H ⁺ ].

Isomer 1 was further resolved by separation with SFC using a Phenomenex-Amylose-1 column (250 mm×30 mm×5 μm) to give example 119a (enantiomer 1, peak 1) and example 119b (enantiomer 2, peak 2).

Example 119a: ¹ H NMR (400 MHz, CD ₃ OD) 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), 3.34-3, 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 ⁺ ].

Example 119b: ¹ H NMR (400 MHz, CD ₃ OD) 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), 3.34-3, 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×30 mm×5 μm) to obtain enantiomer 2-1 and enantiomer 2-2.

Example 119c: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.42-7.56 (m, 6H), 7.04 (t, 2H), 5.30 (dd, 2H), 4.94 ( b.w., 2H), 3.71-4.04 (m, 3H), 3.41-3.61 (m, 2H), 3.35 (b.s., 1H), 3.17- 3.25 (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: ¹ H NMR (400 MHz, CD ₃ OD) 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: N -(4-fluorophenyl)-3-(4-(hydroxymethyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3-carboxamide

Stage 1: 5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoropyridine (B)

(5-Bromo-2-fluoropyridin-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 RT for 63 hours. The reaction mixture was then diluted with saturated NaHCO ₃ solution and extracted with EtOAc. Then the organic layer was separated, washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound. MS (ESI) m/z 320, 322 [M+H] ⁺ .

Stage 2: 3-(5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)oxetane-3-carbonitrile (C)

In a 50 ml round-bottom flask with a magnetic stir bar under nitrogen atmosphere was added 5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoropyridine (B) (712 mg, 2.22 mmol), oxetane- 3-carbonitrile (185 μl, 2.45 mmol) and toluene (18 ml). The flask was cooled to 0°C and KHMDS (2668 μl, 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, the aqueous layer was extracted with EtOAc and the combined organics were washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was then purified by flash chromatography to give the title compound. MS (ESI): 383, 385 [M+H] ⁺ .

Stage 3: 3-(5-bromo-4-(hydroxymethyl)pyridin-2-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide (D)

3-(5-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)oxetan-3-carbonitrile (D) (410 mg, 1.07 mmol) was added to a vessel with a magnetic stir bar. , NaOH (1.07 ml, 1.07 mmol, 1 N in water) and ethanol (2.7 ml). The vessel was sealed and heated to 75° C. for 16 h. The reaction mixture was then cooled and EtOAc (4 ml) was added, then HCl (1 N in water) was added dropwise to bring the pH to ~2. The reaction mixture was then further 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 give 3-(5-bromo-4-(hydroxymethyl)pyridin-2-yl)oxetan-3-carboxylic acid (loss observed under reaction conditions). TBS groups).

3-(5-Bromo-4-(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 µl). Then 4-fluoroaniline (304 μl, 3.21 mmol) was added followed by DIEA (560 μl, 3.21 mmol). The reaction mixture was stirred at RT for 48 hours. Water and EtOAc were then added and the mixture was extracted with EtOAc. The combined organics were washed with brine, 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 give 3-(5-bromo-4-(hydroxymethyl)pyridin-2-yl)-N-(4-fluorophenyl)oxetane -3-carboxamide. MS (ESI): 381, 383 [M+H] ⁺ .

Step 4: N-(4-fluorophenyl)-3-(4-(hydroxymethyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3-carboxamide

3-(5-Bromo-4-(hydroxymethyl)pyridin-2-yl)-N-(4-fluorophenyl)oxetane-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 vessel was then sealed and deflated and placed back with argon (3 times). Then THF (3.4 ml) and potassium orthophosphate (512 μl, 0.512 mmol, 1 M aqueous solution) were added and the reaction mixture was heated to 50°C for 1 h, and then to 80°C for 1 h. Then the reaction mixture was cooled to RT 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 preparative reverse phase HPLC (5:95 to 95:5 acetonitrile:water: 0.1% v/v TFA modifier) to give the title compound as the TFA salt. ¹ H 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-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide

N-(4-fluorophenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-carboxamide (50 mg, 0.12 mmol), (5-bromo-2-(2,2-difluoroethoxy)pyridin-4-yl)methanol (38.5 mg, 0.143 mmol), XPhos Pd G3 (10 mg, 0.012 mmol), THF ( 600 µl) and K₃PO₄ (1M) (250 µl, 0.250 mmol). The mixture was pumped out and placed back under nitrogen 4 times and heated at 45° C. for 2 hours. The mixture was filtered through a Celite pad. The filtrate was diluted with water and EtOAc, transferred to a separating funnel. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo to give a residue which was purified by silica gel column chromatography to give the title compound.^oneH NMR (600 MHz, DMSO-d ₆) 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), 4.91 (d, 2H), 4.70- 4.50 (m, 2H), 4.44 (s, 2H). MS (EI)m/z 459 [M+H]⁺.

Examples 122-124 in the following table were prepared analogously to example 121.

Example No. Structure chemical name Mass [M+H]+ 122

N-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)oxetan-3-carboxamide 477 123

N-(4-fluorophenyl)-3-(2'-(1-hydroxycyclopropyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxetan-3-carboxamide 472 124

N-(4-fluorophenyl)-1-(2'-propionyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)cyclobutan-1-carboxamide 472

Example 125: N-(4-fluorophenyl)-3-(2'-(hydroxymethyl)-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxetan-3-carboxamide

Stage 1: (2-bromo-5-(trifluoromethoxy)phenyl)methanol

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 RT for 1 h, then quenched with NH₄Cl (saturated solution), diluted with EtOAc and water. The organic phase was separated from the aqueous phase and the aqueous phase was re-extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated in vacuo to give the title compound, which was used directly in the next step.^oneH NMR (600 MHz, DMSO-d 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-(2'-(hydroxymethyl)-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxetan-3-carboxamide

The title compound was prepared analogously to Example 121. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 10.04 (s, 1H), 7.66 (ddt, 2H), 7.57 (d, 2H), 7.52 (s, 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 (EI) m/z 462 [M+H] ⁺ .

Example 126: 3-(3-fluoro-4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide

Step 1: Ethyl 2-(4-bromo-3-fluorophenyl)-3-hydroxy-2-(hydroxymethyl)propanoate

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 placed in the flask. To this suspension was added KOtBu (0.34 g, 3.07 mmol) at a time. The mixture was stirred at RT for 30 min, quenched with 1 M HCl (aq) 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 MgSO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography to give the title compound. MS (EI) m/z 321 [M+H] ⁺ .

Step 2: 2-(4-bromo-3-fluorophenyl)-2-(hydroxymethyl)propane-1,3-diol

Ethyl 2-(4-bromo-3-fluorophenyl)-3-hydroxy-2-(hydroxymethyl)-propanoate (456.6 mg, 1.422 mmol), MeOH (2000 µl) and THF (6000 µl) were added to the flask. NaBH was added to this mixture.₄ (300 mg, 7.93 mmol) at a time at 0°C. The mixture was heated at 60°C for 2 hours, another part of NaBH was added₄(172 mg, 4.55 mmol) and continued heating at 60°C for another 1 hour. The reaction was quenched with 5 ml of NH₄Cl (saturated solution) and 5 ml HCl (1 M) to reach pH~2, then extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO₄, filtered, concentrated under vacuum to obtain the crude product, which was dissolved in 2 ml of DMSO and 1 ml of water. The mixture was stirred at RT overnight, then concentrated in vacuo, dissolve the residue in DCM and wash with NaHCO₃, brine, dried over MgSO₄, filtered and concentrated to give the title compound.^oneH NMR (600 MHz, DMSO-d 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-4-methylbenzenesulfonate

To a vial containing 2-(4-bromo-3-fluorophenyl)-2-(hydroxymethyl)propane-1,3-diol (118 mg, 0.423 mmol) was added DCM (3500 µl) and TEA (200 µl, 1. 43 mmol). To this solution was added a solution of tosyl-Cl (81 mg, 0.42 mmol) in DCM (1000 μl) at 0°C. The mixture was then stirred at RT for 24 hours. Low conversion was determined by LCMS. To this mixture was added pyridine (150 μl, 1.86 mmol) and another batch of tosyl-Cl (20 mg, 0.11 mmol). The mixture was stirred at RT for an additional 4 hours, diluted with DCM, washed with NaHCO ₃ (saturated solution), brine, dried over MgSO ₄ , filtered, concentrated in vacuo to give the title compound, which was used directly in the next step. MS (EI) 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 µl) and Cs ₂ CO ₃ ( 108 mg, 0.331 mmol). The mixture was heated at 65°C for 18 hours, then at 70°C for 3 hours. 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 Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound, which was used directly in the next step. MS (EI) m/z 261 [M+H] ⁺ .

Stage 5: 3-(4-bromo-3-fluorophenyl)oxetane-3-carboxylic acid

To a vial containing (3-(4-bromo-3-fluorophenyl)oxetan-3-yl)methanol (26.2 mg, 0.100 mmol) was added acetone (500 µl) and Jones reagent (110 µl, 0.72 mmol ). The mixture was stirred at RT for 5 h, then diluted with EtOAc and water. The organic phase was washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound, which was used directly in the next step. MS (EI) m/z 275 [M+H] ⁺ .

Step 6: 3-(4-bromo-3-fluorophenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide

3-(4-Bromo-3-fluorophenyl)oxetane-3-carboxylic acid (19.6 mg, 0.0710 mmol), HATU (54.2 mg, 0.143 mmol), DMF (800 µl), 4 -fluoroaniline (30 mg, 0.27 mmol) and DIEA (100 μl, 0.573 mmol). The mixture was stirred at RT for 18 h, diluted with EtOAc and washed with 1 M HCl, NaHCO ₃ (saturated solution), brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the title compound, which was used directly in the next step. . MS (EI) m/z 368 [M+H] ⁺ .

Step 7: 3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide

3-(4-Bromo-3-fluorophenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide (26.2 mg, 0.0710 mmol), bis(pinacolato)diborone (45.2 mg, 0.178 mmol), potassium acetate (20.9 mg, 0.213 mmol), PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (5.81 mg, 7.12 µmol) and dioxane (700 µl). The mixture was then pumped out and placed back with N ₂ 3 times. The mixture was heated to 80° C. for 20 hours, cooled to RT and filtered through a Celite pad. The filtrate was concentrated in vacuo to give a residue which was dissolved in DCM, washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound, which was used directly in the next step. MS (EI) m/z 416 [M+H] ⁺ .

Step 8: 3-(3-fluoro-4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide

3-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide was added to the vessel (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 µmol), THF (700 µl) and K ₃ PO ₄ (1 M, 200 µl, 0.200 mmol). The mixture was pumped out and placed back under 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 separating funnel. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue which was purified by silica gel column chromatography to give the title compound. ¹ H NMR (600 MHz, DMSO- d 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 (EI) m/z 465 [M+H] ⁺ .

Example 127: N-(6-chloropyridin-3-yl)-3-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3-carboxamide

Step 1: 3-(5-bromopyridin-2-yl)-N-(6-chloropyridin-3-yl)oxetan-3-carboxamide

3-(5-Bromopyridin-2-yl)-oxetan-3-carboxylic acid (1023 mg, 3.96 mmol), HATU (2261 mg, 5.95 mmol) and DMF (9910 µl) were added to a vessel with a magnetic stir bar. . To this was added 6-chloropyridine-3-amine (612 mg, 4.76 mmol) followed by DIEA (2077 μl, 11.89 mmol). The mixture was stirred at 45°C for 2 hours, diluted with EtOAc, and washed with saturated NaHCO ₃ solution. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography to give the title compound. MS (ESI) [M+H] ⁺ m/z 368.

Step 2: Preparation of N-(6-chloropyridin-3-yl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl) oxetane-3-carboxamide

3-(5-Bromopyridin-2-yl)-N-(6-chloropyridin-3-yl)oxetan-3-carboxamide (952 mg, 2.58 mmol), bis(pinacolato)diborone was added to a vessel with a magnetic stir bar. (1640 mg, 6.46 mmol), potassium acetate (761 mg, 7.75 mmol) and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (211 mg, 0.26 mmol) in dioxane (8612 μl). The vessel was purged with nitrogen for 5 min, sealed and heated to 80° C. for 23 h. After cooling to RT, the mixture was diluted with EtOAc and washed with saturated NaHCO ₃ solution. The organic compounds were dried over MgSO ₄ , filtered and loaded dry onto 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, fractions were collected and concentrated under reduced pressure to give the title compound. MS (ESI): calculated for C ₂₀ H ₂₃ BClN ₃ O ₄ [M+H] ⁺ , 334; found, 334 (the mass of boronic acid was determined).

Step 3: Preparation of N-(6-chloropyridin-3-yl)-3-(4'-(hydroxymethyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3- carboxamide

N-(6-chloropyridin-3-yl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2 -yl)oxetan-3-carboxamide (212mg, 0.51mmol), (5-bromo-2-(trifluoromethyl)pyridin-4-yl)methanol (131mg, 0.51mmol), potassium orthophosphate (aqueous solution , 1 M) (1020 µl, 1.02 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1 '-biphenyl)]palladium (II) (43.2 mg, 0.05 mmol) and THF (2550 µl). The vessel was purged with nitrogen, sealed and heated to 40° C. for 1 hour. After 1 hour, the crude product was filtered through a Celite pad and washed with methanol. The combined organic compounds were concentrated under reduced pressure. The material was dissolved in EtOAc and dry loaded onto silica gel. The material was injected into a 40 g gold column; ran from 100% DCM to 100% EtOAc. The desired product was eluted; fractions were collected and concentrated under reduced pressure. Preparative resolution of the resulting material was performed using supercritical liquid chromatography using a Sepiatec Prep 100. An ES Industries GreenSep column with ethyl pyridine (5 μm, 20 mm×250 mm, ES Industries, West Berlin, NJ) was used as the stationary phase. The mixture of compounds was dissolved in a 1:1:1 mixture of N,N-dimethylformamide, methanol and ACN. Injection and collection was performed 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 40°C, total flow rate 70 ml/min. The retention time for peak collection was 2.7 minutes. MS (ESI): calculated for C ₂₁ H ₁₆ ClF ₃ N ₄ O ₃ [M+H] ⁺ , 465; found, 465, ¹ H 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=2.4Hz, 1H), 7.79-7.73(m, 1H), 7.53(d, J=8.7Hz, 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-(trifluoromethyl)phenyl)pyridin-2-yl)oxetan-3-carboxamide

N-(4-fluorophenyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxetane was added to a vessel with a magnetic stirrer armature. -3-carboxamide (I-155; see preparation in Example 76) (500 mg, 1.26 mmol), (2-bromo-5-(trifluoromethyl)phenyl)methanol (320 mg, 1.26 mmol), orthophosphate potassium (aqueous solution, 1 M) (2511 μl, 2.51 mmol), methanesulfonate (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino -1,1'-biphenyl)]palladium(II) and THF (1.26E+04 µl). The vessel was purged with nitrogen, sealed and heated to 40° C. for 1.5 hours. After 1.5 hours, the crude product was washed with EtOAc and saturated NaHCO ₃ solution. The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The material was loaded dry into a 120 g column and run from 100% DCM to 100% EtOAc. The desired product was eluted, the fractions were collected and concentrated under reduced pressure. The material was added to the vessel and ACN was slowly added dropwise. Almost immediately, the solid disintegrated and a liquid was obtained. More ACN was added dropwise, stirred by rotation, and no solid entered the solution. The mixture was heated with a hair dryer to obtain a homogeneous solution. The mixture was left for 3.5 hours. After 3.5 hours, the sample was transferred to a refrigerator for 12 hours. After 12 hours, the mixture was washed with cold (ice-bath cooled) ACN to give the title compound as a solid. MS (ESI) calculated for C ₂₃ H ₁₈ F ₄ N ₂ O ₃ [M+H] ⁺ , 447; found, 447. ¹ H NMR (600 MHz, DMSO-d6) δ 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)-[3,3'-bipyridin]-6-yl )oxetane-3-carboxamide

Step 1: 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxetan-3-carbonitrile

To a flask with a magnetic stir bar was added 3-(5-bromopyridin-2-yl)oxetan-3-carbonitrile (2 g, 8.37 mmol), bis(pinacolato)diborone (4.25 g, 16.73 mmol), potassium acetate (2.46 g, 25.10 mmol); and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.68 g, 0.84 mmol). The mixture was purged with nitrogen for 5 minutes. Dioxane (41.8 ml) was added and the mixture stirred. The resulting mixture was heated to 80° C. with stirring under nitrogen atmosphere for 24 hours. After 24 hours, the crude reaction mixture was filtered through a Celite pad and washed with EtOAc. The combined organic compounds were concentrated under reduced pressure. The residue was washed with EtOAc and water. The combined organics were dried over MgSO ₄ , 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, fractions were collected and concentrated under reduced pressure to give the title compound. MS (ESI): calculated for C ₁₅ H ₁₉ BN ₂ O ₃ [M+H] ⁺ , 205; found, 205 (the mass of boronic acid was determined).

Step 2: Preparation of 3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3-carbonitrile

3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxetan-3 -carbonitrile (1.72 g, 6.01 mmol), 2-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)propan-2-ol (1.88 g, 6.61 mmol), orthophosphate potassium (aqueous solution, 1 M) (12.02 ml, 12.02 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (0.39 g, 0.60 mmol) and dioxane (10.02 ml). The vial was sealed with a septum and purged with nitrogen while heating to 65° C. for 4 hours. After 4 hours, the reaction mixture was cooled to RT. The reaction mixture was filtered through a Celite pad and washed with EtOAc. The combined organics were concentrated under reduced pressure and washed with EtOAc and water; the combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting mixture was injected into an 80 g gold column; the column was run from 100% DCM to 100% EtOAc. The desired product was eluted, fractions were collected and concentrated under reduced pressure to give the title compound. MS (ESI): calculated for C ₁₈ H ₁₆ F ₃ N ₃ O ₂ [M+H] ⁺ , 364; discovered, 364.

Step 3: Preparation of 3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3-carboxylic acid

3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[3,3'-bipyridine]-6-yl)oxetan-3-carbonitrile ( 932 mg, 2.57 mmol), NaOH (410 mg, 10.26 mmol), ethanol (8550 µl) and water (4275 µl). The flask was sealed and heated to 65° C. for 2 hours. After 2 hours, the reaction mixture was cooled to RT and concentrated under reduced pressure. The reaction mixture was dissolved in EtOAc and 1 N sodium hydroxide was added dropwise. HCl to reach pH ~2. The mixture was washed with water and EtOAc. The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound. MS (ESI): calculated for C ₁₈ H ₁₇ F ₃ N ₂ O ₄ [M+H] ⁺ , 383; discovered, 383.

Step 4: Preparation of N-(6-chloropyridin-3-yl)-3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[3,3'-bipyridine]-6- yl)oxetane-3-carboxamide

3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3-carboxylic acid ( 34.5 mg, 0.09 mmol), HATU (51.5 mg, 0.14 mmol) and DMF (902 µl). The mixture was stirred for 5 minutes. 6-chloropyridine-3-amine (58.0 mg, 0.45 mmol) was added followed by DIEA (47.3 μl, 0.27 mmol). The mixture was stirred at 45° C. for 48 hours. After 48 hours, the dry mixture was injected into a 24 g gold column; the column was run from 100% DCM to 100% EtOAc. The desired product was eluted, the fractions were collected and concentrated under reduced pressure. The mixture was dissolved in ACN/water then lyophilized overnight. The resulting mixture was dissolved in 1.5 ml of DMSO and immediately subjected to purification by HPLC (purification by HPLC, elution gradient ACN/water with TFA modifier, linear gradient) to obtain the title compound. MS (ESI): calculated for C ₂₃ H ₂₀ ClF ₃ N ₄ O ₃ [M+H] ⁺ , 493; found, 493. ¹ H NMR (600 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.71 (d, J=2.7 Hz, 1H), 8.66 (d, J=1 .8 Hz, 1H), 8.46 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 8.20 (d, J=2.7 Hz, 2H), 7, 94 (dd, J=8.1, 2.3Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 7.55 (d, J=8.7Hz, 1H), 5.16 (dd, J=94.6, 6.4 Hz, 4H), 1.35 (s, 6H).

Examples 130-131 in the following table were prepared analogously to example 129.

Example No. Structure chemical name Mass [M+H] ⁺ 130

N-(6-fluoropyridin-3-yl)-3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan- 3-carboxamide 477 131

N-(2,4-difluorophenyl)-3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3- carboxamide 494

Example 132 : N-(4-chlorophenyl)-3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3 -carboxamide

Step 1: 3-(5-bromopyridin-2-yl)-N-(4-chlorophenyl)oxetane-3-carboxamide

3-(5-Bromopyridin-2-yl)-oxetan-3-carboxylic acid (500 mg, 1.94 mmol), HATU (1105 mg, 2.91 mmol) and DMF (4844 µl) were added to a vessel with a magnetic stir bar. . 4-Chloroaniline (297 mg, 2.33 mmol) was added followed by DIEA (1015 μl, 5.81 mmol). The mixture was stirred at 45° C. for 4 hours. After 4 hours, the crude product was washed with EtOAc and saturated NaHCO ₃ solution. The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The material was loaded dry into a 120 g gold column and the column was run from 100% hexanes to 100% EtOAc. The desired product was eluted, fractions were collected and concentrated under reduced pressure to give the title compound. MS (ESI): calculated for C ₁₅ H ₁₂ BrClN ₂ O ₂ [M+H] ⁺ , 367; discovered, 367.

Step 2: N-(4-chlorophenyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxetan-3-carboxamide

3-(5-Bromopyridin-2-yl)-N-(4-chlorophenyl)oxetane-3-carboxamide (200 mg, 0.54 mmol), bis(pinacolato)diborone (207 mg, 0.82 mmol), potassium acetate (160 mg, 1.63 mmol) and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (44.4 mg, 0.054 mmol). The mixture was purged with nitrogen for 5 minutes. Dioxane (2720 μl) was added and the mixture was stirred. The vessel was heated to 80°C for 12 hours After 12 hours the crude product was washed with EtOAc and saturated NaHCO ₃ solution. The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The material was loaded dry into a 40 g gold column and the column was run from 100% DCM to 100% EtOAc. The desired product was eluted, fractions were collected and concentrated under reduced pressure to give the title compound. MS (ESI): calculated for C ₂₁ H ₂₄ BClN ₂ O ₄ [M+H] ⁺ , 333; found, 333 (the mass of boronic acid was determined).

Step 3: N-(4-chlorophenyl)-3-(4'-(2-hydroxypropan-2-yl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-6-yl)oxetan-3 -carboxamide

N-(4-chlorophenyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxetane was added to a vessel with a magnetic stirrer armature. -3-carboxamide (93.7mg, 0.23mmol), 2-(5-bromo-2-(trifluoromethyl)pyridin-4-yl)propan-2-ol (70.6mg, 0.25mmol) , potassium orthophosphate (aqueous solution, 1 M) (452 μl, 0.45 mmol), PdCl ₂ (dtbpf) (29.5 mg, 0.045 mmol) and dioxane (1130 μl). The vessel was purged with nitrogen, sealed and heated to 65° C. for 22 hours. After 22 hours, 1 small spoonful of MgSO ₄ was added, followed by EtOAc, and the solids were filtered off. Organic compounds were concentrated under reduced pressure, dissolved in 1.5 ml DMSO and immediately purified by HPLC (purification by HPLC, elution gradient ACN/water with TFA modifier, linear gradient). Fractions were returned and lyophilized in a lyophilizer overnight to obtain the title compound. MS (ESI): calculated for C ₂₄ H ₂₁ ClF ₃ N ₃ O ₃ [M+H] ⁺ , 492; found, 492, ¹ H 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 133-139 in the following table were prepared analogously to example 112 using intermediate I-9 (see preparation in example 7) and the corresponding alcohols.

Example No. Structure chemical name Mass [M+H]+ 133

3-(4-(6-ethoxy-4-(hydroxymethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide 423 134

3-(4'-(difluoromethoxy)-2'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide 444 135

N-(4-fluorophenyl)-3-(4-(3-(hydroxymethyl)-5-(trifluoromethyl)pyridin-2-yl)phenyl)oxetan-3-carboxamide 447 136

N-(4-fluorophenyl)-3-(2'-(hydroxymethyl)-4'-methoxy-[1,1'-biphenyl]-4-yl)oxetan-3-carboxamide 408 137

3-(4'-(difluoromethoxy)-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-4-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide 458 138

3-(4-(2-cyclopropyl-4-(hydroxymethyl)pyrimidin-5-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide 420 139

N-(4-fluorophenyl)-3-(2'-(2-hydroxypropan-2-yl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxetan-3-carboxamide 474

Examples 140-148 in the following table were prepared analogously to example 76 using intermediate I-155 (see preparation in example 76) and the appropriate alcohols-coupling partners.

Example No. Structure chemical name Mass [M+H]+ 140

3-(5-(4-(difluoromethoxy)-2-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide 473 141

N-(4-fluorophenyl)-3-(3-(hydroxymethyl)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)oxetan-3-carboxamide 448 142

3-(6'-ethoxy-4'-(hydroxymethyl)-[3,3'-bipyridin]-6-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide 424 143

3-(6'-cyclopropoxy-4'-(hydroxymethyl)-[3,3'-bipyridin]-6-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide 436 144

3-(6'-cyclopropoxy-4'-(2-hydroxypropan-2-yl)-[3,3'-bipyridin]-6-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide 464 145

N-(4-fluorophenyl)-3-(4'-(hydroxymethyl)-6'-isopropoxy-[3,3'-bipyridin]-6-yl)oxetan-3-carboxamide 438 146

N-(4-fluorophenyl)-3-(3-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)oxetan-3-carboxamide 476 147

(S)-N-(4-fluorophenyl)-3-(3-(1-hydroxyethyl)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)oxetan-3-carboxamide 462 148

3-(6'-(2,2-difluoroethoxy)-4'-(hydroxymethyl)-[3,3'-bipyridin]-6-yl)-N-(4-fluorophenyl)oxetane-3-carboxamide 460

Examples 149-151 in the following table were prepared analogously to example 81.

Example No. Structure chemical name Mass [M+H] ⁺ 149

1-(4-(6-ethoxy-4-(hydroxymethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)cyclobutane-1-carboxamide 421 150

N-(4-fluorophenyl)-1-(4-(4-(hydroxymethyl)-6-isopropoxypyridin-3-yl)phenyl)cyclobutan-1-carboxamide 435 151

N-(4-fluorophenyl)-1-(4-(3-(hydroxymethyl)-5-(trifluoromethyl)pyridin-2-yl)phenyl)cyclobutan-1-carboxamide 445

Example 152: 3-fluoro-N-(4-fluorophenyl)-1-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutan-1-carboxamide

Step 1: Methyl 1-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-3-hydroxycyclobutane-1-carboxylate

Methyl 1-(4-bromophenyl)-3-hydroxycyclobutanecarboxylate (113 mg, 0.396 mmol), 4-(((tert-butyldimethylsilyl)oxy)-methyl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (248 mg, 0.594 mmol), XPhos Pd G3 (33 mg, 0.04 mmol), THF (2000 μl) and K ₃ PO ₄ (1000 µl, 1 mmol). The mixture was pumped out and placed back with nitrogen 4 times and heated at 60°C for 1 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 Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue which was purified by silica gel column chromatography to give the title compound. MS (EI) m/z 496 [M+H ⁺ ].

Step 2: Methyl 1-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-3-fluorocyclobutane-1-carboxylate

A solution of methyl 1-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-3-hydroxycyclobutanecarboxylate (147 mg, 0.297 mmol) in DCM ( 2500 μl) were treated with DAST (96 mg, 0.59 mmol) at 0°C. The mixture was stirred at RT for 3 h, then quenched with NaHCO ₃ (saturated solution) and diluted with DCM. The organic phase was concentrated in vacuo and purified by silica gel column chromatography to give the title compound. MS (EI) m/z 498 [M+H ⁺ ].

Step 3: 3-fluoro-1-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutane-1-carboxylic acid

To a vial containing methyl 1-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-3-fluorocyclobutanecarboxylate (21 mg, 0.043 mmol) , MeOH (100 µl), THF (300 µl) and NaOH (1 M) (50 µl, 0.050 mmol) were added. The mixture was stirred at RT for 18 hours. The solvent was concentrated in vacuo to give a residue which was dissolved in 0.1 ml of water. The solution was adjusted to pH~3 with HCl (1 M), then concentrated in vacuo. The residue was dried by azeotropic drying twice with ACN and once with toluene to give the title compound, which was used directly in the next step. MS (EI) m/z 370 [M+H ⁺ ].

Step 4: 3-fluoro-N-(4-fluorophenyl)-1-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutan-1-carboxamide

To a vial containing 3-fluoro-1-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)cyclobutanecarboxylic acid (16 mg, 0.043 mmol) was added DMF 4-fluoroaniline (21 mg, 0.19 mmol), HATU (33 mg, 0.087 mmol) and DIEA (30 µl, 0.17 mmol). The mixture was stirred at RT for 15 minutes. The mixture was filtered and purified by reverse phase HPLC eluting with water (0.1% TFA) and ACN to give the title compound. ¹ H NMR (600 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.61 (s, 1H), 8.02 (s, 1H), 7.69-7.60 (m, 2H ), 7.56 (d, 2H), 7.50 (d, 2H), 7.19-7.08 (m, 2H), 5.65 (t, 1H), 5.17 (dp, 1H) , 4.56 (d, 2H), 3.50-3.36 (m, 2H), 2.75-2.58 (m, 2H). MS (EI) m/z 463 [M+H ⁺ ].

Biological analyzes

Cellular analysis of IDO1 using HeLa cells stimulated with IFNγ

HeLa cells were cultured in complete HeLa culture medium (90% EMEM, 10% thermally inactivated fetal bovine serum) and grown to approximately 1×10 ⁹ cells. The cells were then harvested and frozen at 1×10 ⁷ cells/vial in 1 ml freezing medium (90% complete HeLa culture medium, 10% DMSO).

Test compounds were serially diluted at ten 3-fold dilutions in DMSO, starting with a stock of 10 mM DMSO, in low volume Echo plates. Compound dilutions or DMSO alone were then transferred from the dilution plates to Greiner black 384-well assay plates (p/n 781086, 50 nl/well) using an Echo 550 sonic fluid arm (Labcyte).

Frozen HeLa cells were thawed and transferred to HeLa assay medium (99% complete HeLa culture medium, 1% penicillin/streptomycin) using 20 ml medium/cell vial. Cells were centrifuged at 250×g with a tabletop centrifuge for 5 min and suspended in the same volume of HeLa assay medium. Cells were then counted and adjusted to a density of 2×10 ⁵ cells/ml in HeLa assay medium. Sterile L-tryptophan was added to the cells at a final concentration of 300 μM L-tryptophan. A small aliquot (2 ml/plate) of HeLa cells was set aside and not treated with IFNγ, using it as a Max-E control. Sterile IFNγ (Cat. No. 285-IF, R&D systems) was added to the remaining HeLa cells at a final concentration of 100 ng/mL.

HeLa cells with and without IFNγ were transferred to the appropriate wells of 384-well assay plates containing compounds. The plates were incubated for approximately 48 hours at 37° C. in a 5% CO ₂ incubator. Then 12 μl of 0.5 M methylisonipecotate in dimethylsulfoxide was added to each well, the plates were sealed and incubated at 37° C. without CO ₂ overnight. The plates were centrifuged for 1 min at 200×g. Final fluorescence was measured with a Spectramax plate reader (Molecular Devices) using a 400 nm excitation filter and a 510 nm emission filter.

Fluorescence intensity in each well was corrected for background fluorescence detected in wells with IFNγ-untreated cells and expressed as a fraction of the intensity detected in wells with IFNγ-treated cells and DMSO alone. Activities were calculated by non-linear least squares in relation to the four-parameter logistic equation for IC ₅₀ .

Biological activity data obtained using the IDO1 cellular assay described above are shown in the table below. The compounds provided herein typically have an IC ₅₀ of about 0.1 nM to about 20,000 nM, or more specifically, about 1 nM to about 10,000 nM, or more specifically, about 5 nM to about 5,000 nM, or more specifically, from about 10 nM to about 1000 nM, or even more specifically, from about 10 nM to about 500 nM. Data on the IC ₅₀ specific activity for the examples of compounds presented in the present description, are shown in the following table.

Analysis of human IDO1 in whole blood

Test compounds were serially diluted in ten 3-fold dilutions of DMSO starting at 10 mM. Then, 3 μl of compound dilutions or DMSO alone were transferred from the dilution plate to a polypropylene 96-well assay plate containing 97 μl of RPMI using an Echo 555 sonic fluidic arm (Labcyte). LPS and IFNγ were prepared in RPMI at 10-fold final concentration (1000 ng/ml), the final concentration being 100 ng/ml.

Whole human blood obtained from healthy donors was collected in test tubes with sodium heparin. 240 μl of blood was transferred to each of the wells of a 96-well V-bottom plate. 30 µl of the compound was transferred from the intermediate dilution plate and incubated for 15 minutes. Then 30 μl of stimulants were transferred into the blood and mixed thoroughly. The plate was covered with a breathable membrane and incubated at 37° C. overnight (18 hours).

On day 2, an isotope-labeled standard of kynurenine and tryptophan was prepared in water at a 10-fold concentration and 30 μl was added to the blood at a final concentration of 3 μM. The assay plates were centrifuged at 300×g for 10 min without a stopper to separate plasma from erythrocytes. 60 μl of plasma samples were removed without touching the erythrocytes. Plasma was diluted 1:1 with RPMI and proteins were precipitated with two volumes of acetonitrile. The plates were centrifuged at 4000×g for 60 min. 20 μl of the supernatant was carefully transferred to a 384-well plate containing 40 μl of 0.1% formic acid in water and analyzed by LC/MS/MS.

LC/MS/MS analyzes were performed using a Thermo Fisher's LX4-TSQ Quantum Ultra system. This system consists of four Agilent binary high performance liquid chromatography (HPLC) pumps and a TSQ Quantum Ultra triple quadrupole mass spectrometer. For each sample, 5 μl was injected into an Atlantis T3 column (2.1 mm×150 mm, particle size 3 μm) from Waters. A mobile phase gradient pumped at a rate of 0.8 ml/min was used to elute the analytes from the column at 25°C. Elution was started at 0% B, increasing linearly to 25% B over 6.5 min, holding at 25% for 1 min, re-equilibrating to 10 min. Mobile phase A consisted of 0.1% formic acid in water. Mobile phase B consisted of 0.1% formic acid in acetonitrile. Data were acquired in positive ion detection mode using the HESI interface. TSQ Quantum Ultra operating parameters were 4000V electrostatic spray voltage, 380°C capillary temperature, 400°C evaporator temperature, 60 CU shield gas, 20 CU exit gas, 85 cylindrical lens, and 1.2 mTorr collision gas . SRM chromatograms of kynurenine (Q1: 209.2>Q3:94.0) and internal standard (Q1: 215.3>Q3:98.2) were recorded over 90 sec. The peak area was integrated using Xcalibur Quan software. The ratios between the kynurenine formed during the reaction and the internal standard supplemented with 2D6-kynurenine were used to obtain percent inhibition and IC ₅₀ values. Compounds were titrated and IC ₅₀ was calculated using the 4-parameter sigmoid curve fitting formula.

Data on the biological activity of selective compounds using the analysis of human IDO1 in whole blood, described above, are shown in the table below.

Example No. Activity in HeLa cell assay, IC ₅₀ (nM) Activity in human whole blood assay, IC ₅₀ (nM) one 6.3 2 16.1 1,850 3 2.3 128 4 50.1 five 35.1 6 2.2 7 1.1 39 eight 1.0 76 nine 0.85 10 1.4 82 eleven 2.7 12 2.3 twenty 13 2.0 438 fourteen 580 fifteen 495 16 0.8 37 17 1.4 191 eighteen 0.6 44 nineteen 0.88 161 twenty 0.7 21 21 0.93 70 22 0.56 151 23 1.1 95 24 9.4 25 38.3 26 1.2 42 27 4.2 80 28 40.1 29 5.8 thirty 4.2 31 0.72 117 32 2.4 33 1.0 156 34 1.3 125 35 4.2 36 0.94 238 37 1.0 38 3.1 39 0.85 40 4.5 41 4.1 42 17.3 43 10000 44 106.6 45 3.2 46 2.6 47 808.8 48 4.2 49 5.4 fifty 35.1 979 51 59.7 52 59.7 53 86.2 54 217.0 55 93.2 56 11.7 57 13.3 2.058 58 29.7 59 163.3 60 54.4 61 1.469 62 873.5 63 3.7 95 64 2.837 65 109.4 66 165.8 67 107.6 68 185.4 69 152.6 70 5.4 71 4.8 72 5.5 3.024 73 51.3 74 2.6 3.014 75 3.277 76 5.3 110 77 2.9 17 78 3.6 22 79 0.56 80 2.7 80 81 3.3 65 82 2.3 918 83 8.8 84 7.8 88 85 6.0 343 86 2.9 273 87 7.4 88 8.6 389 89 5.8 90 49.1 91 42.8 92 96.3 93 113.5 94 5.0 95 26.8 96 4.8 434 97 2.1 98 2.6 65 99 5.1 100 5.0 619 101 2.6 118 102 1.6 27 103 583.8 104 56.8 105 100.0 106 42.3 107 1.8 23 108 3.5 109 4.5 28 110 1.6 51 111 1.9 40 112 1.4 113 2.2 five 114 2.5 726 115 1.9 38 116 4.8 117 117 1.7 24 118 5.7 600 119a 367.8 119b 1.3 76 119c 69.2 119d 3.5 69 120 30.3 121 1.6 fourteen 122 2.0 248 123 2.2 414 124 3.4 639 125 1.5 126 2.1 132 127 2.4 115 118 1.6 148 129 3.4 32 130 9.9 131 2.8 22 132 2.0 16 133 1.5 28 134 1.5 87 135 2.6 65 136 1.7 129 137 1.6 147 138 15.3 261 139 2.0 128 140 3.0 7 141 9.4 177 142 2.5 67 143 2.4 126 144 2.2 28 145 1.7 55 146 4.2 60 147 6.0 148 6.1 77 149 1.52 eighteen 150 2.0 12 151 1.45 54 152 1.8 175

While the present invention has been described and illustrated with reference to certain specific embodiments, those skilled in the art will appreciate that various adaptations, alterations, modifications, substitutions, omissions, or inclusions can be made to the methods without departing from the spirit and scope of the invention.

Claims (163)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I) where: n is 1; p is 1; in each case A is -CH=; M is -O-; R ¹ is pyridinyl; where pyridinyl is optionally substituted with 1-3 substituents independently selected from: (a) halogen, (b) -C _3-8 -cycloalkyl, optionally substituted with -OH, (e) -OC _1-8 -alkyl optionally substituted with 1-5 halogen atoms, (f) -OC _3-8 -cycloalkyl, (g) -C _1-8 -alkyl optionally substituted with 1-4 substituents independently selected from halo, -OH, -NH ₂ , (i) -C(O)-R ^f , where R ^{f is} selected from -OH, -NH ₂ and -NH-C _1-8 -alkyl; R ² is phenyl; where phenyl is optionally substituted with 1-3 substituents independently selected from: (a) halogen, (c) -CN, (d) -OC _1-8 -alkyl optionally substituted with 1-3 halogen atoms, and (e) -C _1-8 -alkyl optionally substituted with 1-3 substituents independently selected from halogen; and R ³ is selected from H and halogen. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where: M is -O-; and R ³ is H. 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where: R ¹ is pyridinyl; where pyridinyl is optionally substituted with 1-3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c) cyclobutyl optionally substituted with -OH, (f) -OC _1-4 -alkyl optionally substituted with 1-3 halogen atoms, (g) -O-cyclopropyl and (h) -C _1-4 -alkyl optionally substituted with 1-4 substituents independently selected from halo and -OH. 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where: R ² is phenyl; where phenyl is optionally substituted with 1-3 substituents independently selected from: (a) halogen, (c) -CN, (d) -OC _1-6 -alkyl optionally substituted with 1-3 halogen atoms, and (e) -C _1-6 -alkyl optionally substituted with 1-3 substituents independently selected from halo. 5. The compound according to claim 1 or its pharmaceutically acceptable salt, where: R ² is phenyl; where phenyl is optionally substituted with 1-3 substituents independently selected from: (a) halogen, (b)-CN, (c) -OC _1-4 -alkyl optionally substituted with 1-3 halogen atoms, and (d) -C _1-4 -alkyl optionally substituted with 1-3 halogen atoms. 6. The compound according to claim 1 or its pharmaceutically acceptable salt, where: M is -O-; R ¹ is pyridinyl; where pyridinyl is optionally substituted with 1-3 substituents independently selected from: (a) halogen, (b) cyclopropyl optionally substituted with -OH, (c) -OC _1-4 -alkyl optionally substituted with 1-3 halogen atoms, and (d) -C _1-4 -alkyl optionally substituted with 1-4 substituents independently selected from halo and -OH; and R ² is phenyl; where phenyl is optionally substituted with 1-3 substituents independently selected from: (a) halogen, (b)-CN, (c) -OC _1-4 -alkyl optionally substituted with 1-3 halogen atoms, and (d) -C _1-4 -alkyl optionally substituted with 1-3 halogen atoms. 7. The compound according to claim 6 or its pharmaceutically acceptable salt, where: R ¹ is pyridinyl; where pyridinyl is optionally substituted with 1-3 substituents independently selected from: (a) halogen and (b) -C _1-4 -alkyl optionally substituted with 1-4 substituents independently selected from halo and -OH; R ² is phenyl; where phenyl is optionally substituted with 1-3 halogen atoms; and R ³ is H. 8. The compound according to claim 1 of formula (Ia) or a pharmaceutically acceptable salt thereof:

(Ia) where: R ¹ is pyridinyl; where pyridinyl is optionally substituted with 1-3 substituents independently selected from: (a) halogen, (b) -OC _1-4 -alkyl optionally substituted with 1-3 halogen atoms, (c) -O-cyclopropyl and (d) -C _1-4 -alkyl optionally substituted with 1-4 substituents independently selected from halo and -OH; and R ² is phenyl optionally substituted with 1-3 halogen atoms. 9. The compound according to claim 8 or its pharmaceutically acceptable salt, where: R ¹ is pyridinyl optionally substituted with 1-3 substituents independently selected from: (a) halogen, (b) -CH ₃ , (c) -CHF ₂ , (d) -CF ₃ and (e) -C(CH ₃ ) ₂ OH; and R ² is phenyl optionally substituted with 1-2 halogen atoms. 10. The compound according to claim 1 of formula (Ii) or a pharmaceutically acceptable salt thereof:

(ii); where: R ¹ is pyridinyl; where pyridinyl is optionally substituted with 1-3 substituents independently selected from: (a) halogen, (c) -OC _1-4 -alkyl optionally substituted with 1-3 halogen atoms, (d) -O-cyclopropyl and (e) -C _1-4 -alkyl optionally substituted with 1-4 substituents independently selected from halo and -OH; and ^Rd is selected from: (a) halogen, (b)-CN, (c) -OC _1-3 -alkyl optionally substituted with 1-3 halogen atoms, and (d) C _1-3 alkyl optionally substituted with 1-3 halogen atoms. 11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, where: R ¹ is pyridinyl optionally substituted with 1-3 substituents independently selected from: (a) halogen, (b) -CH ₃ , (c) -CHF ₂ , (d) -CF ₃ , (e) -CH ₂ OH and (f) -C(CH ₃ ) ₂ OH; and ^Rd is selected from: (a) a halogen selected from F, Cl and Br, (b) -CH ₃ and (c) -CF ₃ . 12. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 3-(4-(6-cyclopropylpyridin-3-yl)phenyl) -N- (4-fluorophenyl)oxetane-3-carboxamide, 3-(4-(6-cyclopropyl-4-fluoropyridin-3-yl)phenyl) -N- (4-fluorophenyl)oxetane-3-carboxamide, 3-(4-(6-cyclopropyl-4-methylpyridin-3-yl)phenyl) -N- (4-fluorophenyl)oxetane-3-carboxamide, N- (4-fluorophenyl)-3-(4-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide, 3-(4-(6-(difluoromethoxy)-2,4-dimethylpyridin-3-yl)phenyl) -N- (4-fluorophenyl)oxetane-3-carboxamide, 3-(4-(6-(difluoromethoxy)-4-methylpyridin-3-yl)phenyl) -N- (4-fluorophenyl)oxetane-3-carboxamide, N- (4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide, N-(4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide, 3-[4-[6-(difluoromethoxy)-4-(hydroxymethyl)-3-pyridyl]phenyl]-N-(4-fluorophenyl)oxetane-3-carboxamide, N-(4-fluorophenyl)-3-[4-[3-(2-hydroxyethyl)-5-(trifluoromethyl)-2-pyridyl]phenyl]oxetane-3-carboxamide, (R or S)-N-(4-fluorophenyl)-3-(4-(4-(1-hydroxyethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide, 3-[4-[6-(difluoromethoxy)-4-(1-hydroxy-1-methyl-ethyl)pyridin-1-y-3-yl]phenyl]-N-(4-fluorophenyl)oxetane-3-carboxamide , N-(4-chlorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide, N-(4-chlorophenyl)-3-[4-[4-(hydroxymethyl)-6-(trifluoromethyl)-3-pyridyl]phenyl]oxetane-3-carboxamide, N-(4-chlorophenyl)-3-[4-[6-(difluoromethoxy)-4-(hydroxymethyl)-3-pyridyl]phenyl]oxetane-3-carboxamide, 3-[4-[6-cyclopropyl-2-(hydroxymethyl)pyridin-1-y-3-yl]phenyl]-N-(4-fluorophenyl)oxetane-3-carboxamide, N-(4-fluorophenyl)-3-[4-[6-(trifluoromethyl)pyridin-1-y-3-yl]phenyl]oxetan-3-carboxamide, N-(4-fluorophenyl)-3-[4-[2-(hydroxymethyl)-6-(trifluoromethyl)-3-pyridyl]phenyl]oxetane-3-carboxamide, N-(4-fluorophenyl)-3-(4-(2-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide, 3-(4-(4-(fluoromethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl) -N- (4-fluorophenyl)oxetane-3-carboxamide, 3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-(trifluoromethoxy)phenyl)oxetane-3-carboxamide, N-(4-bromophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide, 3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-(trifluoromethyl)phenyl)oxetan-3-carboxamide, N- (3,4-difluorophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide, N-(4-cyanophenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide, N-(4-(difluoromethoxy)phenyl)-3-(4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide, N-(4-fluorophenyl)-3-(4-(3-(hydroxymethyl)-5-(trifluoromethyl)pyridin-2-yl)phenyl)oxetan-3-carboxamide, N-(4-fluorophenyl)-3-(4-(4-(1-hydroxycyclobutyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide, N-(4-fluorophenyl)-3-(4-(4-(1-hydroxycyclopropyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide, 3-(4-(6-cyclopropoxy-4-(hydroxymethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide, 3-(4-(6-cyclopropoxy-4-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide, 5-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-N-methyl-2-(trifluoromethyl)isonicotinamide, 5-(4-(3-((4-fluorophenyl)carbamoyl)oxetan-3-yl)phenyl)-2-(trifluoromethyl)isonicotinamide, (R)-3-(4-(4-(1-amino-2,2,2-trifluoroethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetan-3 -carboxamide, (S)-3-(4-(4-(1-amino-2,2,2-trifluoroethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetan-3 -carboxamide, N-(4-fluorophenyl)-3-(4-(3-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-2-yl)phenyl)oxetan-3-carboxamide, 3-(4-(5-cyclopropoxy-3-(hydroxymethyl)pyridin-2-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide, 3-(4-(5-cyclopropoxy-3-(2-hydroxypropan-2-yl)pyridin-2-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide, N-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-isopropoxypyridin-3-yl)phenyl)oxetane-3-carboxamide, 3-(4-(6-(2,2-difluoroethoxy)-4-(hydroxymethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide, N-(4-fluorophenyl)-3-(4-(4-(hydroxymethyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)oxetan-3-carboxamide, 3-(3-fluoro-4-(4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide, 3-(4-(6-ethoxy-4-(hydroxymethyl)pyridin-3-yl)phenyl)-N-(4-fluorophenyl)oxetane-3-carboxamide and N-(4-fluorophenyl)-3-(4-(3-(hydroxymethyl)-5-(trifluoromethyl)pyridin-2-yl)phenyl)oxetane-3-carboxamide. 13. An indolamine-2,3-dioxygenase (IDO) inhibitory pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 14. A compound that is N-(4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetan-3-carboxamide or a pharmaceutically acceptable salt thereof. 15. The compound according to claim 14, which is N-(4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)phenyl)oxetane -3-carboxamide. 16. The compound according to claim 14, which is a pharmaceutically acceptable salt of N-(4-fluorophenyl)-3-(4-(4-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl) phenyl)oxetane-3-carboxamide.