EA041318B1 - ARYLIMIDAZOLYLISOXAZOLES AND THEIR APPLICATIONS - Google Patents

Description

Technical field

The invention relates to a number of new arylimidazolylisoxazoles and their use as modulators of p300 and/or CBP activity.

State of the art

Genetic and epigenetic modifications are critical for all stages of cancer progression, and epigenetic expression silencing has been shown to be important in the dysregulation of genes involved in all important aspects of cancer (Jones, P. A., Baylin, S. B. (2007) The epigenomics of cancer, Cell, Vol. 128, pp. 683-692). Primary epigenetic modifications mediating regulation include DNA methylation and post-translational histone modification. The latter includes methylation, acetylation, and ubiquitinylation. DNA demethylating agents and histone deacetylase inhibitors have been shown to have antitumor activity, and a number of agents have been approved for use in the treatment of hematological malignancies. Enzymes that mediate histone modification, including histone acetyltransferases (HATs), which acetylate histones and non-histone proteins, represent a wave of second generation targets for small molecule drug intervention.

Prostate cancer is one of the most common malignant diseases and is the second leading cause of cancer death in men. Surgery or radiation therapy is usually used to treat clinically localized disease. For patients who regularly relapse after radical treatment, or in patients with locoregional or metastatic disease, long-term control of the disease is a major challenge. It usually includes a range of hormonal therapies that suppress androgen receptor signaling (AR, AR) since the survival and progression of prostate cancers are highly dependent on AR. Although AR-targeted therapeutics suppress tumor growth, they rarely eliminate the disease and resistance to therapy occurs due to restored AR function. Progression to such castration-resistant prostate cancer (CRPC) represents a lethal phenotype of the disease. An estimated 50-60% of patients who develop metastatic disease have CRPC. Recently, several new therapeutic agents have been approved for the treatment of CRPC. However, they have only limited clinical efficacy and serve only to increase the progression period. Accordingly, new and tolerable agents are needed for further progress in the treatment of CRPC.

The progression of CRPC is mediated by many cellular mechanisms. In all cases, acquisition of the CRPC phenotype is mediated by reactivation of the AR (androgen receptor) cascade. p300 acetyltransferase directly regulates AR levels and AR signaling activity in prostate cancer cells (Zhong et al., p300 acetyltransferase regulates androgen-receptor degradation and PTEN-deficient prostate tumorigenesis, Cancer Res., Vol. 74, pp. 1870-1880, 2014 ). Accordingly, therapeutic modulation of p300 activity would affect all known adaptive mechanisms that lead to the development of CRPC. Approved therapeutics and therapeutics and agents in clinical trials primarily target one or the other of these cellular mechanisms. Modulation of p300 activity directly allows for a wider modulation of AR activity in CRPC than is provided by current and other experimental strategies. Additionally, mechanisms of resistance to newly approved agents have been shown to be AR-dependent (Cai, C. et al. (2011) Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is up-regulated by treatment with Cyp17A1 inhibitors, Cancer Res., Vol. 71, pp. 6503-6513).

Accordingly, modulation of p300 should inhibit resistance to current therapies and possibly provide increased and consistent efficacy and greater clinical applicability.

Like p300, CREB (cyclic AMP sensitive element-containing binding protein) binding protein (CBP) is an acetyltransferase that acts on a transcriptional coactivator in human cells. Both CBP and p300 have a single bromo domain (BRD) and a lysine acetyltransferase (KAT) domain that are involved in post-translational modification and recruitment of histones and non-histone proteins. There is high sequence similarity between CBP and p300 in conserved functional domains (see Duncan A. Hay et al., JACS 2014, 135, 9308-9319). Accordingly, modulation of CBP activity is a promising avenue for the treatment of certain cancers. Accordingly, compounds that can modulate, eg, inhibit, p300 and/or CBP activity are of interest in cancer therapy.

Tumors that carry loss-of-function mutations in CVR become p300 dependent and exceptionally sensitive to p300 inhibition (see Ogiwara et al., 2016 Cancer Discovery. 6; 430-445). Conversely, tumors with mutations in p300 are exceptionally sensitive to CVR inhibition. Genetic analysis shows that such loss-of-function mutations

- 1 041318 carry up to 15% of both non-small cell and small cell lung tumors. Similar mutations are also found in up to 25% of bladder cancers. Accordingly, compounds that can modulate, eg, inhibit, p300 and/or CBP activity are of interest in cancer therapy for tumors with such molecular alterations.

In addition, CBP/p300 regulates the expression of key immune checkpoint proteins such as CTLA4/PD-L1 (see Casey et al., Science. 352; p227-231, 2016) and plays an important role in the differentiation and functioning of regulatory T- cells that are involved in avoiding the immune response by tumors. Accordingly, compounds that can modulate, eg, inhibit, p300 and/or CBP activity are of interest for cancer therapy in combination with agents that target the onco-immune system.

Brief description of the invention

In the present work, it was found that a number of new compounds have activity that modulates the activity of p300 and/or CBP. Accordingly, these compounds may be useful in the treatment of cancer, in particular prostate cancer.

Accordingly, the present invention provides a compound which is an arylimidazolylisoxazole of formula (I)

^R1

R ² where each of R ⁰ and R, which are the same or different, is H or C1C ₆ -alkyl, which is unsubstituted or has OH as a substituent;

W is N or CH;

R ¹ is a group selected from C-linked 4-6 membered heterocyclyl; C3-C6 cycloalkyl; C ₁ -C ₆ alkyl which is unsubstituted or substituted by C ₆ -C ₁₀ aryl, 5-6 membered N-containing heteroaryl, C ₃ -C ₆ cycloalkyl, OH, -OC(O)R' or OR ', where R' represents unsubstituted C ₁ -C ₆ -alkyl; and spiro groups of the following formula:

JWV ⁴ wherein R ¹ is unsubstituted or substituted with -S(O) ₂ Me, -OH, -S(O) ₂ cyclopropyl, -C(=O)Me, -C(=O)CH2CF3, F, oxo, Me, OMe, -OEt, -OC(=O)Me, -CH2OH, NH2, -C(=O)OH, -C(O)NHPr or -C(=O)N(Me)Pr;

Y is -CH ₂ - or -CH2CH2-;

n is 0 or 1;

R ² is a group selected from C ₆ -C ₁₀ -aryl, 5-6 membered N-containing heteroaryl, C ₃ -C ₆ -cycloalkyl and C ₅ -C ₆ -cycloalkenyl, and this group is unsubstituted or substituted by F , Cl, -OMe, OPr, -OCF ₃ , OEt, Me and CN, while C ₆ -C ₁₀ -aryl is optionally fused to a tetrahydrofuran ring;

4-6 membered heterocyclyl is selected from pyrrolidinyl, piperidinyl, tetrahydropyranide and tetrahydrothiopyranyl; And

The 5-6 membered N-containing heteroaryl is selected from pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl;

or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention, there is provided a pharmaceutical composition comprising an arylimidazolylisoxazole of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition may further contain one or more additional chemotherapeutic agents, such as those listed below.

In another aspect, the present invention provides an arylimidazolylisoxazole of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as a modulator of p300 and/or CBP activity.

- 2 041318

Detailed description of the invention

The term substituted includes the implication that the substitution must correspond to the allowable valency of the atom being replaced and the substituent, and that the substitution results in a stable compound (i.e., a compound that does not undergo spontaneous transformations such as rearrangement with cyclization or elimination). In some embodiments, one atom may be replaced by one or more substituents, provided that such a substitution corresponds to the allowable valency of that atom. In some embodiments, the group may be substituted with one substituent group, or it may contain multiple (more than one) substituents on multiple carbon atoms. If any group defined herein is substituted, it will typically be substituted with R ¹⁰ as defined below. The group may, for example, be substituted with one, two or three R ¹⁰ as defined below.

In some arylimidazolylisoxazoles of formula (I), depending on the nature of the substituent, chiral carbon atoms may be present and, accordingly, these compounds may exist as stereoisomers. The present invention embraces all optical isomers such as stereoisomeric forms of the compounds of formula (I), including enantiomers, diastereomers and mixtures thereof such as racemates. The various stereoisomeric forms may be resolved or separated from one another by conventional means, or any individual isomer may be obtained by conventional stereoselective or stereospecific synthesis.

The compounds of the present invention may exist in various tautomeric forms, and it is to be understood that the present invention encompasses all such tautomeric forms.

It should be understood that some of the compounds of the present invention contain both acidic and basic groups, and thus, at certain pH values, may exist in the form of zwitterions.

It should also be understood that any atom present in a compound of the present invention may be present in the form of any available natural isotope. For example, the carbon atom may be ¹² C or ¹³ C. The hydrogen atom may be 1 H or ² H (deuterium).

In the present text, the terms treat and treatment refer to both therapeutic treatment and prophylactic or preventive measures, the purpose of which is to prevent or slow down (reduce) unwanted physiological changes, such as the spread or development of cancer. Treatment may also mean an increase in the duration of survival compared to expected survival in the absence of treatment. Those in need of treatment include those who already have the condition or disorder, as well as those who are prone to acquiring the condition or disorder, or those in whom the condition or disorder is to be prevented.

The phrase pharmaceutically acceptable indicates that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients contained in the formulation and/or with the patient being treated with them.

_C1 . _{The 6} αalkyl group or moiety is linear or branched. _C1 . _{The 6} alkylα group is usually C ₁ . ₄ alkyl group or C ₁ . ₂ alkyl group. Examples C ₁ . _{The 6} alkyl groups and moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl (i.e. 3-methylbut-1-yl), t-pentyl (t i.e. 2-methylbut-2-yl), neopentyl (i.e. 2,2-dimethylpropan-1yl), n-hexyl, isohexyl (i.e. 4-methylpentan-1-yl), t-hexyl ( i.e. 3-methylpentan-3-yl) and neopentyl (i.e. 3,3-dimethylbuten-1-yl). Usually C ₁ . _{The 6} alkyl group is methyl (Me). For the avoidance of doubt, if two alkyl moieties are present in a group, these alkyl moieties may be the same or different. _C1 . _{The 6} alkyl group is unsubstituted or substituted, typically with one or more R ¹⁰ groups as defined below. For example, _C1 . _{The 6} alkyl group is unsubstituted or substituted with 1, 2 or 3 R ¹⁰ groups as defined below.

_C1 . _{The 6} alkylene group or moiety is substituted or unsubstituted, linear or branched, saturated, divalent aliphatic group or moiety containing from 1 to 6 carbon atoms. Usually it is C ₁ . ₃ alkylene group or fragment. Examples include methylene, ethylene, n-propylene and isopropylene groups and moieties. More typically, it is methylene or ethylene. If the alkylene group is substituted, it is usually substituted with an R ¹⁰ group, as defined below.

_C3 . ₆ cycloalkyl group or fragment is a saturated monovalent hydrocarbon ring containing from 3 to 6 carbon atoms. Accordingly, it is a 3-, 4-, 5- or 6-membered carbocyclic ring containing only saturated bonds. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In one embodiment, the cycloalkyl group is cyclopropyl.

A 5-12 membered N-containing heteroaryl group or fragment is a monovalent 5-12 membered aromatic heterocyclic group that contains 1, 2, 3, or 4 nitrogen atoms, typically 1 or 2 N atoms, and 0, 1, or 2 others heteroatoms selected from O and S. It is attached through one of the N or C atoms in its ring and is monocyclic or bicyclic. In one

- 3 041318 embodiment, it is N-linked. In another implementation, it is

C-related. It may be, for example, a 5-7 membered N-containing monocyclic heteroaryl group, for example a 5- or 6-membered N-containing heteroaryl group such as pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl.

Examples of the 5-12 membered, N-containing heteroaryl group include the following groups: pyrrolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, indolyl, isoindolyl, indazolyl, pyrrolopyridinyl and pyrrolopyrimidinyl. When it is substituted, a 5-12 membered, N-containing heteroaryl group is usually substituted with one or more, for example 1, 2 or 3, groups selected from unsubstituted C _1-4 alkyl and an R ¹⁰ group defined below. In one embodiment, the 5-12 membered, N-containing heteroaryl group is unsubstituted.

A 4-6 membered C-linked heterocyclic is a saturated monovalent 4-, 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from O, N and S. It is attached through one of the C atoms of its ring. Examples include oxetane, thietane, azetidine, pyrrolidine, piperidine, tetrahydropyran, tetrahydrothiopyran and tetrahydrofuran. The 4-6 membered C-linked, heterocyclic group is unsubstituted or substituted, typically with R ¹⁰ as defined below. It may be substituted at the carbon atom in the ring or the N or S atom of the ring, as the valence of the atom permits.

The halogen or halo group is F, Cl, Br, or I. Typically, it is F, Cl, or Br, more typically, F.

C _1-6 alkoxy group is linear or branched. It is usually a C _1-4 alkoxy group, for example a methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, n-butoxy, secbutoxy or tert-butoxy group. The C _1-6 alkoxy group is unsubstituted or substituted, typically with one or more R ¹⁰ groups as defined below.

When in formula (I) R ¹ is substituted, the substituents are usually 1, 2 or 3 groups, more typically 1 or 2 groups which are the same or different and are selected from -SO ₂ Me, -SO ₂ -cyclopropyl , oxo (=O), C ₁ -C ₆ -alkoxy, OH, hydroxy (C1-C ₆ ) alkyl, halo, -NH ₂ , OH, CN, -OC(O)R, -C(O)NHR, -NHC(O)R and -COOR, where R is H or C ₁ -C ₆ alkyl optionally substituted with halogen. In this context, a typical halogen is F or Cl.

The 4-6 membered heterocyclyl is usually pyrrolidinyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl. More typically, it is pyrrolidin-3-yl, piperidin-4-yl, tetrahydropyran-4-yl or tetrahydrothiopyran-4-yl. Pyrrolidinyl and piperidinyl are usually substituted at the N atom in the ring with —SO ₂ Me or C ₁ -C ₆ alkyl (eg methyl) groups. Tetrahydropyranyl is usually substituted at the C atom in the ring with C ₁ -C ₆ alkyl (eg methyl). Tetrahydrothiopyranyl is usually disubstituted at the S atom in the ring with an oxo group.

The C ₃ -C ₆ cycloalkyl group is usually cyclobutyl, cyclopropyl or cyclohexyl. Cycloalkyl is usually substituted with 1 or 2 groups selected from halo, OH and C ₁ -C ₆ -alkoxy.

In the definition of R ¹ C ₁ -C ₆ -alkyl substituted with 5-12 membered N-containing heteroaryl is usually C ₁ -C ₆ -alkyl, for example, methyl or ethyl, substituted with 5-12-membered N-containing heteroaryl, defined above. Representative examples of R ¹ in formula (I) defined above include the following groupings:

Each of R ⁰ and R in formula (I) is independently H or C 1-6 alkyl which is unsubstituted or substituted as defined above. Accordingly, for example, R ⁰ is H and R is C 1-6 alkyl which is unsubstituted or substituted as defined above; R is H and R ⁰ is C _1-6 alkyl which is unsubstituted or substituted as defined above; each of R ⁰ and R is H; or each of R ⁰ and R represents

- 4 041318 is C ₁ _ ₆ alkyl which is unsubstituted or substituted as defined above. In each of these options C _1-6 alkyl is usually methyl or ethyl, preferably methyl.

The integer n in formula (I) defined above is 0 or 1, usually 0.

Typically Y is -CH2- or -CH2CH2- such that the ring containing it is a 5- or 6-membered ring. When Y is -CH2-, the ring is pyrrolidin-2-one. When Y is -CH2CH2-, the ring is piperidin-2-one. More typically Y is -CH2CH2- and the ring containing it is a 6-membered piperidin-2-one ring.

R ² is typically aromatic. Accordingly, it is typically soda C ₆ -C ₁₀ -aryl or C ₅ -C ₆ -heteroaryl group, where C ₆ -C ₁₀ -aryl is optionally fused to a 5 - or 6-membered heterocyclic ring. The C ₆ -C ₁₀ aryl group is usually phenyl or naphthyl. A C ₆ -C ₁₀ aryl group fused to a 5- or 6-membered heterocyclic ring is usually a tetrahydrobenzofuranyl group.

When R ² is a C ₆ -C ₁₀ aryl group, eg phenyl, it will typically be mono-, di-, or tri-substituted. The substituents are 1, 2 or 3 groups which are the same or different and are usually selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, OH, cyano and halo, the alkyl and alkoxy groups being each usually substituted with halogen (halo). The halo in this context is typically F or Cl.

When the C ₆ -C ₁₀ aryl group is phenyl, it is usually substituted with 1, 2 or 3 groups, more typically 1 or 2 groups. These 1 or 2 groups typically have a meta and/or para arrangement on the phenyl ring. These groups are typically selected from halo, OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and CN.

R ¹⁰ is selected from unsubstituted C1_6 alkyl, C3_6 cycloalkyl, halo, OH, C1_6 alkoxy, -C(O)R', -C(O)2R', -C(O)NR'2, oxo (=O), dioxo, -CH2OR , -S(O)mR, -NR'C(O) R, -S(O)mNR'2 and CF3, where m is 1 or 2 and each R is independently selected from H and unsubstituted C1_6 alkyl. Typically, R ¹⁰ is selected from unsubstituted C1_ ₆ alkyl, halo, OH, C ₁ _ ₆ alkoxy, -C(O)R, -C(O)NR' ₂ , oxo (=O) and dioxo.

In one preferred embodiment, the arylimidazolylisoxazole according to the present invention has the following formula (Ia) where R ¹ corresponds to the definition above for formula (I);

Y' is -CH2- or -CH2CH2-; And

R ² is a group selected from C ₆ -C ₁₀ aryl optionally fused to a 5 or 6 heterocyclic ring and C ₅ -C ₆ heteroaryl, this group being unsubstituted or mono-, di- or tri-substituted.

Compounds of the present invention may contain asymmetric or chiral centers and exist in various stereomeasurable forms. Structural formulas (I) and (Ia) above encompass all stereoisomeric forms of the compounds of the present invention, including diastereomers, enantiomers and racemic mixtures. Diastereomers and enantiomers can be obtained by stereoselective synthetic strategies, for example by enantiomeric synthesis.

In the compounds of the present invention, stereoisomerism may occur due to the presence of an asymmetric carbon atom in the piperidin-2-one or pyrrolidin-2-one ring. Accordingly, as shown in the structural formula below:

the carbon center C ^x is chiral and each of R, R ⁰ , W, R ¹ , Y, R ² and n corresponds to the above definition for formula (I). Chirality at the Cv position means that the compound

- 5 041318 according to the present invention may be racemic or optically pure. In the case of an optically pure compound, it may be the R enantiomer or the S enantiomer, usually the S enantiomer.

Specific examples of compounds according to the present invention include the compounds shown in the table.

No. Structure Name 1 O Ά-- ⁰ S \ _{_} f /---\ o 5-(5-(3,5-dimethylisoxazol-4-yl)1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1//-benzo|X]imidazol-2-yl)-1 phenylpyrrolidin-2-one 2 O __® S \ _k F /—y A ⁰ o 5-(5-(3,5-d imethylisoxazol-4-yl)1 -(tetrahydro-2H-pyran-4-yl)- 1Hbenzo|//]imidazol-2-yl)-1 phenylpyrrolidin-2-one 3 O W <0 P Me [TWA? \ J JL /)—\ J. a ^Me pp 5-(5-(3,5-dimethylisoxazol-4-yl)1-(1,1-dioxytetrahydro-2Nathiopyran-4-yl)-1Hbenzo|//]imidazol-2-yl)-1 phenylpyrrolidin-2-one 4 o φ // Ξ _Ζ Ο ΓΛ ,__ AL \--/ φ \ Ξ φ—Α .Ο S Ζ (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|//]imidazol-2-yl)-1 phenylpyrrolidin-2-one 5 °\ 'Me Me ^''.A \ Η J //~\ 1 D ⁰ ° ^Μ θ 0 (R)-5 -(5 -(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|//]imidazol-2-yl)-1 phenylpyrrolidin-2-one

- 6 041318

6 o f // S _x o G\ ___ ° 1 (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)-N-benzo|X]imidazol-2-yl)-1 (3-fluorophenyl)pyrrole ide in-2-one 7 O ^f S \__ _{_} f /---\ W XXl x° -n^ \J ° S ' f O (S) -1 - (3,4-difluorophenyl) -5- (5- (3,5 dimethylisoxazol-4-yl) -1 - ((R) -1 (methylsulfonyl) pyrrolidin-3 yl) - 1R-benzo |/7] imide azol-2yl)pyrrolidin-2-one 8 °\ ^{Leo Lo} Ύ XX'>.....Cl ^ν /Χ^ ^ν D ^{0 0 me} 0 Cl ^F (5) -1 - (4-chloro-3 -fluorophenyl) -5 - (5 (3,5 -d imethylisoxazol-4-yl) -1 - (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|X] imide azol-2- yl) pyrrolidin-2-one

- 7 041318

9 °\ Me sa ° Ύ XX'>.....Cl ^Ν υΓ^ ^Ν D ⁰ ° J" (5)-1-(3-chloro-4-fluorophenyl)-5 -(5 (3,5-d imethylisoxazol-4-yl)-1 ((^)-i- (methylsulfonyl)pyrrolidin-3 yl)-III-benzo|X]imide azol-2yl)pyrrolidin-2-one 10 °* L ^e s O '° Ύ iX>..... O ^N s T j ⁰ b-\ Ax ^Me Cl-O Cl (S) -1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1 (methylsulfonyl)pyrrolidin-3 yl)- 1R-benzo| X]imide azol-2yl)pyrrolidin-2-one eleven °\ z ^Me s cr° Ύ XX'>.....Cl \ T ⁰ bA Λ ⁼ \ Me / // ^Cl Nt-Λ F (5)-1-(3-chloro-5-fluorophenyl)-5-(5(3,5-d-imethylisoxazol-4-yl)-1 - (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|X]imide azol-2yl)pyrrolidin-2-one

- 8 041318

12 o f ___ > _X O G\ ,__ ° ^Ζ Λ i K/ LQ^'z^z \___/ ° O ^E \--/ f k S f—.O Ξ Z (5)-1-(3-chloro-5-methoxyphenyl)-5 (5-(3,5-d-imethylisoxazol-4-yl)-1 ((^)-ι- (methylsulfonyl) pyrrolidin-3 yl) - N-benzo [b /] imidazol-2yl) pyrrolidin-2-one 13 ° \ _x Me o ^s ° Ύ LS>.....Cl <T ^{0 me} 0 MeO ^F (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)-1 //-benzoIimidazol-2-yl)-1 (3-fluoro-4- methoxyphenyl)pyrrolidin-2-one 14 % Me s db ύ CX ^N/ >.....Cl c MeO (5)-1-(3-chloro-4-methoxyphenyl)-5 (5-(3,5-d-imethylisoxazol-4-yl)-1 ((R)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo[b(]imide azol-2yl)pyrrolidin-2-one

- 9 041318

15 °\ _x Me θΆ Ύ ΧΧ'>..... Cl Ν Ν^ _η <L X ^Me Ο MeO (5)-5-(5-(3,5-dimethylisoxazole-4- silt)-1-((D)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo[D]imidazol-2-yl)-1 (4-methoxyphenyl)pyrrolidin-2-one 16 °\ _z Me _ό α Ύ ΧΧ'>.....Cl D ^{0 0 Me} y) Me (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1//-benzo|X]imidazol-2-yl)-1 (4-propoxyphenyl)pyrrolidin-2one 17 °\ _x Me S O° Ύ XY>.....Cl ^N 0( A ^Me y# Cl (5)-1-(4-chlorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)-1-((А)-1(methylsulfonyl)pyrrolidin-3yl)-1//-benzo |X]imide azol-2yl)pyrrolidin-2-one

- 10 041318

18 O S \___ _to F /---K W CXa \J ° S β ^t o (E-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)-1 R-benzoI imidazol-2-yl)-1 (pyridin-3-yl)pyrrolidin-2-one 19 o f A /O G\ __ ^ζ ll \--/ f \ Ξ f—X' .O Ξ Ζ (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|X]imidazol-2-yl)-1 (6-fluoropyridin-3-yl)pyrrolidin2-one 20 °* L ^e Ύ /Υ'>.....Cl \ Τ J ° oA A^v-'x ^Me L— 7 (6)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|/7]imidazol-2-yl)-1 (naphthalene-1-yl)pyrrolidin-2-one 22 °\ L ^e S a ^h ° T XX'>..... Cl SS^ a ^{0 me} m F (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|/7]imidazol-2-yl)-1 (5-fluoropyridin-3-yl)pyrrolidin2-one

- 11 041318

(5)-1 - (3,5-difluorophenyl) -5- (5- (3,5 dimethylisoxazol-4-yl) -1 - ((R) -1 (methylsulfonyl) pyrrolidin-3 yl) - N-benzo [<7]imidazol-2yl)pyrrolidin-2-one (5)-1 -(5-chloro-6-methoxypyride in-3yl)-5 -(5-(3,5-dimethylisoxazol-4yl)-1 -((7?)-1(methylsulfonyl)pyrrolidin-3 yl)- 1//-benzoIimide azol-2 yl)pyrrolidin-2-one (5)-5-(5-(3,5-dimethylisoxazol-4yl) -1-((7?)-1(methylsulfonyl)pyrrolidin-3 yl)-I //-benzo[<7] imidazol-2-yl)-1 (3-fluoro-5methoxyphenyl)pyrrolidin-2-one

- 12 041318

(5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((N)-1(methylsulfonyl)pyrrolidin-3 yl)- I //-benzo[<7]imidazol-2-yl )-1 (3(trifluoromethoxy)phenyl)pyrrolide in-2-one (5)-1-(2,3-dihydrobenzofuran-5yl)-5 -(5-(3,5-dimethylisoxazol-4yl)-1-( (7?)-1(methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|X] imide azol-2 yl)pyrrolidin-2-one (5)-1-(3,4-dichlorophenyl)-5 -(5 -(3,5dimethylisoxazol-4-yl)-1 -((A)-1 (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|X]azol-2-yl)pyrrolidin-2-one imide

- 13 041318

29 z o ^x Χ—Ξ I / ^ro s \__ _{_} Φ /---\ w ο _Υχ χΏ _l \J ° S i ^f o (E-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)-17/-benzo[b/]imidazol-2-yl)-1 (6-methoxypyridin-3 yl)pyrrolidin-2-one thirty Z ^E O Sx—- ^f S \__ _{_} φ /---\ w . to ^ζ ν ^ζ Ό xVA x° ' \ J °' s o ($)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)-1 N-benzoIimidazol-2-yl)-1 (3,4,5-trifluorophenyl)pyrrolidin2-one 31 Ф /° Ξ _X O Г\ ___ O-.A _Z o \--/ φ K Ξ φ-χ. -Ο S Ζ (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((L)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|X]imidazol-2-yl)-1 (4- (trifluoromethyl)phenyl)pyrrolidine-2-one

- 14 041318

32 o f // S /O G\ w XX \/ °' ^A LA \—/ f \ Ξ f—.O SZ (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)-1 ZZ-benzoI imidazol-2-yl)-1 (4- (trifluoromethoxy)phenyl)pyrrolide in-2-one 33 °\ L ^e S O Ύ ..... O y y j ^{0 0 Me} °Chl ( F Me (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)-17/-benzo[</] imidazol-2-yl)-1 - (3-ethoxy-5- fluorophenyl)pyrrolidin-2-one 34 ° \ Me S a ^h ° t xx ^ ..... A N ⁷ Y / ⁰ θΑ /> - ^me Me Z jj (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|//]imidazol-2-yl)-1 (o-tolyl)pyrrolidin-2-one

- 15 041318

35 Chu _z Me “to sss.....Cl N ⁷ T / ⁰ O\ (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)-1 R-benzo[b/]imidazol-2-yl)-1 (5-fluoro-2- methylphenyl)pyrrolidin-2-one 36 °\ Me sc ° Ύ ICC.....Cl N ⁷ T / ^{0 0 Me F} Xc( 4 3 -((5)-2-(5-(3,5-dimethylisoxazol4-yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)-III-benzo[b/]imidazol-2-yl)-5oxopyrrolidin-1-yl)-5 fluorobenzonitrile 37 Chu _x Me _σ % Ύ ICC.....Cl D ^{0 0 me} 0 (5) -1 - (cyclohex-1 -en-1 -yl) -5 - (5 (3,5 -d imethylisoxazol-4-yl) -1 ((7?) -1- (methylsulfonyl) pyrrolidin-3 yl) - N-benzo [b /] imidazol-2yl) pyrrolidin-2-one

- 16 041318

38 °\ _x Me s c° \ XX ".....Ci Ν'/G / ⁰ O-X Λλ— Me fAj F (5)-1-(4,5-difluoro-2-methylphenyl)5-(5-(3,5-dimethylisoxazol-4-yl)1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)-III-benzo|/7]imide azol-2yl)pyrrolidin-2-one 39 ° \ _x Me s O "k XX'>..... Cl 7 ⁰ G l - Me Η (5)-1-(3,4-dichloro-2-methylphenyl)-5(5-(3,5-d-imethylisoxazol-4-yl)-1 ((R)-1- (methylsulfonyl) pyrrolidin-3 yl) - 1H-benzoIimide azol-2yl) pyrrolidin-2-one 40 Z ³ o A__ ^f S \__ _{_} f /---k o (R)-5 -(5 -(3,5-dimethylisoxazol-4yl)-1-((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|X]imidazol-2-yl)-1 (3-fluorophenyl)pyrrole ide in-2-one

- 17 041318

41 °\ Me sg*° Ύ χχ ^Ν/ ^ο, ⁿ 0A A ^Me fAJ F (7?)-1-(3,4-difluorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)-1 -((R)-1 (methylsulfonyl)pyrrolidin-3 yl)- 1R-benzo |X] imide azol-2 yl) pyrrolidin-2-one 42 °\ L ^e Ύ χχ ^N/ Αί <VA ^me gj Cl (7?)-1-(4-chloro-3-fluorophenyl)-5-(5(3,5-dimethylisoxazol-4-yl)-1 ((^)-1- (methylsulfonyl)pyrrolidin-3 yl)-1H-benzo[y0imidazol-2yl)pyrrolidin-2-one 43 °\ L ^e sg° \ χχ ^ν άα g II __/ ° oA Ax ^Me “BP Cl (R)-1-(3,5-d ichlorophenyl)-5 -(5-(3,5 dimethylisoxazol-4-yl)-1 -((K)-1 (methylsulfonyl)pyrrolidin-3 yl)-17/ -benzo|X]imide azol-2yl)pyrrolidin-2-one

- 18 041318

44 Ξ \ φ -%¾ ^a o (R) -1 - (3 -chloro-4-fluorophenyl) -5 - (5 (3,5 -d imethylisoxazol-4-yl) -1 ((^) -1- (methylsulfonyl)pyrrolidin-3 yl)-17/-benzo|X]imide azol-2yl)pyrrolidin-2-one 45 o f Z' NN \___/ O ΖΆ \—/ f to Ξ f—Xch .O S Z (R) -1 - (3 -chloro-5 -fluorophenyl) -5 - (5 (3,5 -d imethylisoxazol-4-yl) -1 ((^) -1- (methylsulfonyl)pyrrolidin-3 yl)-17/-benzo|X]imide azol-2yl)pyrrolidin-2-one 46 Λ X ^z \—/ f K Ξ f—.O S Z (5)-1-(3,4-difluorophenyl)-5-(5-(3,5 dimethylisoxazol-4-yl)-1-(1,1dioxidotetrahydro-2H-thiopyran4-yl)-1//-benzo| X]imidazol-2yl)pyrrolidin-2-one

- 19 041318

47 0w<0 P \ P5> ..... O ° c (5)-1-(3-chloro-4-fluorophenyl)-5-(5(3,5-d-imethylisoxazol-4-yl)-1(1,1-dioxidotetrahydro-2//thiopyran-4-yl) - 1HbenzoIimidazol-2yl)pyrrolidin-2-one 48 0 W <0 P “i ir>.....a x ^{0 0 me} QF (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-(1,1-dioxidotetrahydro-2Nathiopyran-4-yl)- 1Hbenzo[b/]imidazol-2-yl)-1 -( 3 fluorophenyl)pyrrolidin-2-one 49 o- ⁰ ' A o \—/ Φ K s φ— ., O S z (5)-1-(4-chloro-3-fluorophenyl)-5-(5(3,5-d-imethylisoxazol-4-yl)-1(1,1-dioxidotetrahydro-2//thiopyran-4-yl) - 1HbenzoIimidazol-2yl)pyrrolidin-2-one

- 20 041318

50 θ^Ο P ύ jTX ^N/ >.....a \ Y J b-Ά Λχ. me Z // ^C| -h-d ome (5)-1-(3-chloro-5-methoxyphenyl)-5 (5-(3,5-d-imethylisoxazol-4-yl)-1 (1,1-otetrahydro-2-thiopyran-4-yl dioxide)-\ Nbenzo[b/]imidazol-2yl)pyrrolidin-2-one 51 O \ TsO R ^m to jOO ..... Cl A MeO ^F (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-(1,1 - otetrahydro-27/thiopyran-4-yl dioxide)-\H- benzo[b/]imidazol-2-yl)-1 -(3-fluoro4-methoxyphenyl)pyrrolidin-2-one 52 O \\ <0 for γύ>.....a th, Meo (5)-1-(3-chloro-4-methoxyphenyl)-5 (5-(3,5-d imethylisoxazol-4-yl)-1 (1,1-dioxidotetrahydro-2Nathiopyran-4-yl)-\Hbenzo [b/]imidazol-2yl)pyrrolidin-2-one

- 21 041318

53 / F 1 Ad ζ ^ζ \ \___/ο ΖΆ \—/ φ \ S φ—χ" .ο Ξ Ζ (5)-1-(3,5-dichlorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(1,1dioxytetrahydro-2H-thiopyran4-yl)-1H-benzo|X]imidazole -2yl)pyrrolidin-2-one 54 θ ^0 Ρ ν ΓΧ/>.....Ο Ν / ^Ν ° ο-\ Λν, ^{Me f} AJ Cl (5)-1-(3-chloro-5-fluorophenyl)-5-(5(3,5-d imethylisoxazol-4-yl)-1 (1,1-dioxidotetrahydro-2Nathiopyran-4-yl)-\Hbenzo |X]imidazol-2yl)pyrrolidin-2-one 55 Λ X V^/^Z ^z \ \—/ φ \ Ξ o > χ. .O Ξ Ζ (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-(1,1-dioxidotetrahydro-2Nathiopyran-4-yl)- (Н- benzo|X]imidazol-2-yl)-1-(3,4,5trifluorophenyl)pyrrolidin-2-one

- 22 041318

(5)-1 -(3,5-difluorophenyl)-5-(5-(3,5 dimethylisoxazol-4-yl)-1-(1,1dioxidotetrahydro-2H-thiopyran4-yl)-1//-benzoate] imidazol-2yl)pyrrolidin-2-one (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-(1,1-d ioxytetrahydro-2nthiopyran-4-yl)-\HbenzoIimidazol-2 -yl)-1 -(5-fluoro6-methoxypyr idin-3 yl)pyrrolidin-2-one (5)-1-(2,3-dihydrobenzofuran-5yl)-5 -(5-(3,5-dimethylisoxazol- 4yl)-1-(1,1-dioxidotetrahydro-2Nathiopyran-4-yl)-\Hbenzo[g/]imidazol-2yl)pyrrolidin-2-one

- 23 041318

59 z s O® f 2=\w Wed = (5)-1-(3,4-dichlorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(1,1dioxytetrahydro-2H-thiopyran4-yl)-1H-benzoIimidazol-2yl)pyrrolidine -2-he 61 He at AC.....Cl 0. (5)-1-(3,4-difluorophenyl)-5 -(5-(3,5 dimethylisoxazol-4-yl)-1-((1 g,45)4-hydroxycyclohexyl)- 1H-benzo[</]imidazole -2yl)pyrrolidin-2-one 62 pH ύ jCC.....Cl ⁿ CC^' ⁿ С ⁰ ° “ 0, Cl (5)-1-(4-Chloro-3-fluorophenyl)-5-(5(3,5-d-ymethylisoxazol-4-yl)-1 ((1 g,45)-4-hydroxycyclohexyl)1H-benzo[ b/]imidazol-2yl)pyrrolidin-2-one

- 24 041318

63 he L GO ..... O DS ^ D ⁰ ° ^me 0 MeO ^F (5)-5-(5-(3,5-dimethylisoxazole-4- silt)-1-((lr,45)-4- hydroxycyclohexyl)-1/7- benzoIimidazol-2-yl)-1-(3-fluoro4-methoxyphenyl)pyrrolidin-2-one 64 He ύ SD>.....Cl s Meo (5)-1-(3-chloro-4-methoxyphenyl)-5 (5-(3,5-d-imethylisoxazol-4-yl)-1 ((1 g, 45)-4-hydroxycyclohexyl)III-benzo[ 0/]imidazol-2yl)pyrrolidin-2-one 65 He with CD.....Cl with (5)-1-(3-chloro-4-fluorophenyl)-5-(5(3,5-d-ymethylisoxazol-4-yl)-1 ((1 g,45)-4-hydroxycyclohexyl)1H-benzo[ <7]imidazol-2yl)pyrrolidin-2-one

- 25 041318

(5)-1-(2,3-dihydrobenzofuran-5yl)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((Ir, 45)-4hydroxycyclohexyl)-\Hbenzo[</]imidazole -2yl)pyrrolidin-2-one (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((Ir,45)-4hydroxycyclohexyl)-\Hbenzo[</]imidazol-2-yl )-1 (naphthalen-1-yl)pyrrolidin-2-one (5)-1-(3,4-dichlorophenyl)-5 -(5-(3,5dimethylisoxazol-4-yl)-1-(4hydroxycyclohexyl)- 1Нbenzo[</]imidazol-2yl)pyrrolidin-2-one

- 26 041318

73 zs O Hu-- ^f Ξ \ _{_} ° O z \ ^z *^cc Zhr L o (5)-1-(3,4-difluorophenyl)-5-(5-(3,5 dimethylisoxazol-4-yl)-1-((5)-1 (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo |X]imide azol-2yl)pyrrolidin-2-one 74 Ζ o Ά-- ^φ Ξ \ _{_} ° O ^m Y4 Λ '<° -^ P o (5)-5-(1-((7?)-1- (cyclopropylsulfonyl) pyrrolidin-3 -yl) -5 - (3,5 dimethylisoxazol-4-yl) - 1Hbenzo[</]imidazol-2-yl) -1 - (3,4 difluorophenyl) pyrrolidin-2-one 75 0 \ Lk>.....O N^X _n 'A (5)-5-(1-((7?)-1-acetylpyrrolidin3-yl)-5-(3,5-dimethylisoxazol-4yl)- 1H-benzo|//]imidazol-2-yl)-1 ( 3,4-difluorophenyl)pyrrolidin-2one

- 27 041318

76 3An Z—y £''z^^z O f \ s f—v Ξ z (5)-1-(3,4-difluorophenyl)-5 -(5 -(3,5 dimethylisoxazol-4-yl)-1 -((R)-1 (3,3,3- trifluoropropanoyl)pyrrolide in-3 yl)-1H-benzo|X] imide azol-2 yl)pyrrolidin-2-one 77 Z 3 O Ns—— ^ro S ^ro O o (55)-1 -(3,4-difluorophenyl)-5 -(5 -(3,5 dimethylisoxazol-4-yl)-1 -(1 methylpyrrolidin-3 -yl)- 1Hbenzo|/7]imidazol-2yl) pyrrolidin-2-one 78 Me 9 Ύ Xji>.....Cl D ⁰ ° “ V Cl ^F (55) -1 - (4-chloro-3 -fluorophenyl) -5 - (5 (3,5 -d ymethylisoxazol-4-yl) -1 - (1 methylpyrrolidin-3 -yl) - 1Hbenzo[b /]imidazole -2yl)pyrrolidin-2-one

- 28 041318

(55)-1-(3,4-dichlorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(1methylpyrrolidin-3-yl)-\Hbenzo|X]imidazol-2yl)pyrrolidin- 2-one (5)-1-(3,4-dichlorophenyl)-5 -(5-(3,5dimethylisoxazol-4-yl)-1-((1 g,45)4-methoxycycle ohexyl)- 1Hbenzo|D ]imidazol-2yl)pyrrolidin-2-one (5)-1-(3,4-difluorophenyl)-5 -(5 -(3,5 dimethylisoxazol-4-yl)-1-((1 r,4S)4 -methoxycycle ohexyl)- 1Hbenzo|X]imidazol-2yl)pyrrolidin-2-one

- 29 041318

82 OME \LU.....O Meo (5)-1-(3-Chloro-4-methoxyphenyl)-5(5-(3,5-dimethylisoxazol-4-yl)-1((1 g,45)-4-methoxycyclohexyl)III-benzo[ <7]imidazol-2yl)pyrrolidin-2-one 83 OME Ύ XX ".....Cl b (5)-1-(2,3-dihydrobenzofuran-5yl)-5 -(5-(3,5-dimethylisoxazol-4yl)-1-((1g,45)-4methoxycyclohexyl)- 1Hbenzo[</]imidazole- 2yl) pyrrolidin-2-one 84 OME 1 £T/>.....Cl Λ (5)-1-(3-chloro-4-fluorophenyl)-5-(5(3,5-d-imethylisoxazol-4-yl)-1((1 g,45)-4-methoxycyclohexyl)III-benzo[ 0/]imidazol-2yl)pyrrolidin-2-one

- 30 041318

85 Ο 'Ν_- ^φ Ξ \__, * Ο ζ. ζ _Ζ( „ Ο Ζ^ - \ V Ν' A : Αρ ' (5)-1-(4-chloro-3-fluorophenyl)-5-(5(3,5-dimethylisoxazol-4-yl)-1((1 g,45)-4-methoxycyclohexyl)III-benzo[ <7]imidazol-2yl)pyrrolidin-2-one 86 Ύ ΧΙ>.....Cl MeO ^F (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((1g,45)-4- methoxycyclohexyl)-\HbenzoIimidazol-2-yl)-1-(3-fluoro4-methoxyphenyl)pyrrolidin-2-one 87 OH y HG>.....Ci 0 _F (5)-1-(3,4-difluorophenyl)-5 -(5-(3,5 dimethylisoxazol-4-yl)-1-((15.47?)4-hydroxycyclohexyl)-\Hbenzo|X]imidazole -2yl)pyrrolidin-2-one

- 31 041318

88 Ύ XjO.....Cl (5)-1-(3,4-difluorophenyl)-5 -(5 -(3,5 dimethylisoxazol-4-yl)-1-((15.47?)4-Methoxycycle ohexyl)- 1Hbenzo[<7] imidazol-2yl)pyrrolidin-2-one 89 ? Me Ύ HOY.....Cl M/ (5)-1-(3,4-difluorophenyl)-5 -(5 -(3,5 dimethylisoxazol-4-yl)-1 -((17?,45)4-ethoxycyclohexyl)-Nibenzo[</]imidazole -2yl)pyrrolidin-2-one 90 pc Ύ A5>.....Cl Ζ^χ^^χ^^Ν N^> _n ^< - y (55)-1-(3,4-dichlorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(1,1dioxidotetrahydro-2//-thiopyran- 3-yl)-1 R-benzo[b/]imidazol-2yl)pyrrolidin-2-one 91 .--\ _Z O __ ., N /-A 1 №.....Cl Cl ^F (55)-1-(4-chloro-3-fluorophenyl)-5-(5(3,5-d imethylisoxazol-4-yl)-1 (1,1-d ioxytetrahydro-2/7thiopyran-3-yl) - 1Нbenzo|/7]imidazol-2yl)pyrrolidin-2-one 92 ,--\ / ⁰ __^0 ^Me k jOO.....Cl ^v “ ά MeO (55)-1 -(3-chloro-4-methoxyphenyl)-5(5-(3,5-d imethylisoxazol-4-yl)-1 (1,1-dioxytetrahydro-2Nathiopyran-3 -yl)- 1Hbenzo[ c7]imidazol-2yl)pyrrolidin-2-one 93 .--- _z o (/^° 1 kk>.....Q “ 6 (55)-1-(2,3-dihydrobenzofuran-5yl)-5-(5-(3,5-dimethylisoxazol-4yl)-1-(1,1-dioxidotetrahydro-277thiopyran-3-yl)- 1Hbenzo|/ /]imidazol-2yl)pyrrolidin-2-one

- 32 041318

94 0 °-s /Me p Ύ .....Cl (5)-1-(3,4-dichlorophenyl)-5 -(5-(3,5dimethylisoxazol-4-yl)-1-(1(methylsulfonyl)piperidin-4yl)-III-benzo[b/]imidazol- 2yl) pyrrolidin-2-one 95 0 °-s /Me P L kU.....O Cl ^F (5)-1-(4-chloro-3-fluorophenyl)-5-(5(3,5-d-imethylisoxazol-4-yl)-1-(1(methylsulfonyl)piperidin-4yl)-III-benzo[b /]imidazol-2yl)pyrrolidin-2-one 96 0 °^s /Me P i sh.....Cl \ Y "λ ° s MeO (5)-1-(3-chloro-4-methoxyphenyl)-5 (5-(3,5-d-imethylisoxazol-4-yl)-1 (1-(methylsulfonyl)piperidin-4yl)-III-benzo [b/]imidazol-2yl)pyrrolidin-2-one

- 33 041318

97 Me ^5H Me (5)-1-(2,3-dihydrobenzofuran-5yl)-5 -(5-(3,5-d imethylisoxazol-4yl)-1-(1- (methylsulfonyl)piperidin-4yl)- 1H-benzo|X]imide azol-2yl)pyrrolidin-2-one KG o- i 43 98 0M..0 Me (5)-1-(3,4-difluorophenyl)-5-(5-(3,5 dimethylisoxazol-4-yl)-1-(1 (methylsulfonyl)piperidin-4yl)-N-benzo[b/]imidazole -2- Me || s...../ yl) pyrrolidin-2-one KT o- ⁴ Me 11'/ ^4N ) F 99 0 0 Me (5)-1-(3-chloro-4-fluorophenyl)-5-(5(3,5-d-imethylisoxazol-4-yl)-1-(1(methylsulfonyl)piperidin-4yl)-III-benzo[b /] imidazole-2- Me Il s...../ yl) pyrrolidin-2-one KF o- 2 ⁴ Me IL'/'N N ^ ) F ^4ci

- 34 041318

100 0 °-s/Mep Ύ £1/.....Cl P, MeO (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1-(1- (methylsulfonyl)piperidin-4yl)-1 N-benzo[<7]imidazol-2-yl)-1 (3-fluoro-4- methoxyphenyl)pyrrolidin-2-one 101 Ύ jOC.....Cl p” Cl ^F (5)-1-(4-chloro-3-fluorophenyl)-5-(5(3,5-dimethylisoxazol-4-yl)-1((17?, 37?)-3-hydroxycyclopentyl)1H-benzo |I]imidazol-2yl)pyrrolidin-2-one 102 Ύ jOC>.....Cl ⁿ ul^ ⁿ D ⁰ ° c MeO (5)-1-(3-chloro-4-methoxyphenyl)-5 (5-(3,5-d-imethylisoxazol-4-yl)-1 ((17?, 37?)-3-hydroxycyclopentyl)1H-benzo |I]imidazol-2yl)pyrrolidin-2-one

- 35 041318

(5)-1-(3,4-dichlorophenyl)-5 -(5-(3,5dimethylisoxazol-4-yl)-1 ((17?, 35)-3-hydroxycyclopentyl)1H-benzo|X] imide azole -2 yl)pyrrolidin-2-one (17?,37?)-3-(2-((5)-1-(3,4difluorophenyl)-5-oxopyrrolidin2-yl)-5 -(3,5-dimethylisoxazole -4yl)- 1H-benzo|X] imidazol-1 yl)cyclopentyl acetate (17?,37?)-3 -(2-((5)-1 -(3-chloro-4methoxyphenyl)-5-oxopyrrolidin2-yl) -5-(3,5-dimethylisoxazol-4yl)- 1H-benzo|X]imidazol-1yl)cyclopentyl acetate (5)-1-(3-chloro-4-methoxyphenyl)-5 (5-(3.5 - d-imethylisoxazol-4-yl)-1(trans-(\r,Zry3methoxycyclopentyl)-\Hbenzo|X]imidazol-2yl)pyrrolidin-2-one

- 36 041318

107 ^^OMe “to .....Ci I (5)-1-(3,4-dichlorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(trans(1r,3r)-3-methoxycyclopentyl)-1H-benzoIimidazol-2yl)pyrrolidine -2-he 108 ^^OMe ι jCO.....Cl Cl ^F (5)-1-(4-chloro-3-fluorophenyl)-5-(5(3,5-d-imethylisoxazol-4-yl)-1(trans-(1g,3g)-3methoxycyclopentyl)-1HbenzoIimidazol-2yl) pyrrolidin-2-one 109 ^^OEt Ύ A5>.....Cl Ζ^χ ⁴ ^^ NN^'n (5)-1-(3,4-difluorophenyl)-5 -(5 -(3,5 dimethylisoxazol-4-yl)-1 -(trans(1 g, 3g)-3-ethoxycyclopentyl)- 1Hbenzo|X] imidazol-2yl)pyrrolidin-2-one 110 Z S About X--® 'r\w \ \-n W (5)-5-(1-(4,4-Difluorocyclohexyl)5-(3,5-dimethylisoxazol-4-yl)- 1Hbenzo|X]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidin- 2nd

- 37 041318

(5)-1-(3-Chloro-4-methoxyphenyl)-5 (1-(4,4-d ifluorocycle ohexyl)-5-(3,5 dimethylisoxazol-4-yl)-\Hbenzo[</]imidazole -2yl)pyrrolidin-2-one (5)-1 -(3-fluoro-4-methoxyphenyl)-5(1 -(4,4-d ifluorocycle ohexyl)-5 -(3,5 dimethylisoxazol-4-yl) - 1Hbenzo[</]imidazol-2yl)pyrrolidin-2-one (55)-1-(3,4-difluorophenyl)-5 -(5 -(3,5 dimethylisoxazol-4-yl)-1-(2methyltetrahydro- 2//-pyran-4-yl)1H-benzo[c1]imide azol-2 yl)pyrrolidin-2-one

- 38 041318

114 rG y-Me “k ..... Sk ^v th. Meo (55)-1-(3-chloro-4-methoxyphenyl)-5(5-(3,5-d-imethylisoxazol-4-yl)-1(2-methyltetrahydro-2//-pyran-4yl)-III- benzo[b/]imidazol-2yl)pyrrolidin-2-one 115 tdx; Ο ^Ζ \ Ξ = ΖΑ \--/ φ Y Ξ φ—unit .Ο S Ζ (55)-5-(5-(3,5-dimethylisoxazol-4yl)-1-(2-methyltetrahydro-2Hyran-4-yl)-1H-benzo|//]imidazole- 2-yl)-1-(3-fluoro-4- methoxyphenyl)pyrrolidin-2-one 116 ζ S Ο ''Χ-— φ * /=\ W 5-(2-((5)-1-(3,4-difluorophenyl)-5oxopyrrolide in-2-yl)-5 -(3,5 dimethylisoxazol-4-yl)- 1Hbenzo[</]imidazol-1 - yl)piperidine2-one 117 _χ Z 3 Ο Χ_-Φ f 2=\ W Ή' (5)-1-(3,4-difluorophenyl)-5 -(5-(3,5 dimethylisoxazol-4-yl)- 1Hbenzo[</]imidazol-2yl)pyrrolidin-2-one

- 39 041318

(5)-1-(3,4-difluorophenyl)-5 -(5-(3,5 dimethylisoxazol-4-yl)-1-((15.47?)4-hydroxy-4-methylcyclohexyl)1H-benzo |X] imide azol-2 yl)pyrrolidin-2-one (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1 -((15.47?)-4-hydroxy-4methylcyclohexyl)- 1Nenzo[<7]imidazol-2-yl)-1 -(3-fluoro4-methoxyphenyl)pyrrolidin-2-one (5)-1-(3,4-dichlorophenyl)-5 -(5 -(3,5dimethylisoxazol- 4-yl)-1-((15.47?)4-hydroxy-4-methylcyclohexyl)17/-benzo[d(] imide azol-2 yl)pyrrolidin-2-one

- 40 041318

121 ^Μ θ he 0 Ύ NS.....Cl AA Cl ^F (5)-1 - (4-chloro-3-fluorophenyl) -5 - (5 (3,5 -d imethylisoxazol-4-yl) -1 ((15.47?) -4-hydroxy-4-methylcyclohexyl) -\ Nbenzo|E]imidazol-2yl)pyrrolidin-2-one 122 0 y j3C.....Cl X/X/X _N N^X _n (5)-1-(3-Chloro-4-methoxyphenyl)-5 (5-(3,5-d-imethylisoxazol-4-yl)-1 (2-oxaspiro[3.3]heptan-6-yl)-1HbenzoIimidazol- 2yl) pyrrolidin-2-one 123 0 Ύ ICC.....Cl '^I MeO (5)-5-(5-(3,5-dimethylisoxazol-4yl)-1 -(2-oxaspiro[3.3]heptan-6yl)- 1H-benzo|X]imidazol-2-yl)-1 (3- fluoro-4- methoxyphenyl)pyrrolidin-2-one

- 41 041318

124 He Ύ.....Cl (5)-1-(3,4-difluorophenyl)-5 -(5 -(3,5 dimethylisoxazol-4-yl)-1-((1g,35)- 3-hydroxycyclobutyl)- 1R-benzo|X]imidazol-2yl)pyrrolidin-2-one 125 0 oL ? Me “to χχ^.....A SS Y (15,3r)-3-(2-((5)-l-(3,4difluorophenyl)-5-oxopyrrolidin2-yl)-5-(3,5-dimethylisoxazol-4yl)-1R-benzo[d(] imidazol-1 yl) cyclobutyl acetate 126 z 3 O ^y—-® ^φ ΛΛ W Ο γ>. _p (5)-5-(1-benzyl-5-(3,5- dimethylisoxazol-4-yl)-1Hbenzo|X]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidin-2-one 127 Me S τ XXY.....Cl <d^ ^m D ⁰ ” 0, (5)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-propyl1H-benzo|X]imidazol-2yl)pyrrolidin-2-one 128 Me MeA^ Ύ XI>.....Cl N N-^ _n tY a ° ° ' c (5)-1-(3,4-difluorophenyl)-5 -(5 -(3,5 dimethylisoxazol-4-yl)-1 - isobutyl-1H-benzo|X]imidazol-2yl)pyrrolidin-2-one 129 zs O Su— ® ¹ ΛΑ \ / s \—/ "o / \ ° z _x XV (5)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(3-methoxypropyl)-1H-benzoIimidazol-2yl)pyrrolidin-2-one

- 42 041318

131 ύ OS.....α MeO ^F (5)-5-(1-benzyl-5-(3,5- dimethylisoxazol-4-yl)-1HbenzoIimidazol-2-yl)-1-(3-fluoro4-methoxyphenyl)pyrrolidin-2-one 132 8 Ύ LS.....Cl 0. (5)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1(pyridin-3-ylmethyl)-Nibenzo|H]imidazol-2yl)pyrrolidin-2 -He 133 oAU ¹ ΛΑ ^Η< ^ ^Η ^Ά o 'I (5)-1-(3,4-difluorophenyl)-5-(5-(3,5 dimethylisoxazol-4-yl)-1-((1s,3R)~3-(hydroxymethyl)cyclobutyl)1H-benzo |I]imidazol-2yl)pyrrolidin-2-one

- 43 041318

134 Ο Ο . Φ—χ. .Ο 5 ζ (5)-1-(3,4-difluorophenyl)-5 -(5-(3,5 dimethylisoxazol-4-yl)-1-((1g,35)3-(hydroxymethyl)cyclobutyl)- III-benzo[0/]imidazole-2- yl) pyrrolidin-2-one 135 Λ Ύ ΧΧ^.....Cl (5)-5-(1 -(cyclopropylmethyl)-5(3,5-d imethylisoxazol-4-yl)- 1Hbenzo[d(]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidin-2- He 136 sluL ¹ ΛΑ \ / > \--/ ο / \ Ο Ζ _χ 'Ο (5)-3-(2-(1-(3,4-difluorophenyl)-5oxopyrrolidin-2-yl)-5-(3,5 dimethylisoxazol-4-yl)- 1HbenzoIimidazol-1 yl)propyl acetate

- 44 041318

137 nh _2nd “to OC>.....Cl 0. (5)-5-(1-(3-aminocycle butyl)-5(3,5-d-imethylisoxazol-4-yl)- 1HbenzoIimidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidin-2-one 138 Z Ξ O __® S \__ _t ^f Kl 'V (5)-1-(3,4-difluorophenyl)-5 -(5 -(3,5 dimethylisoxazol-4-yl)-1 -(thiazol4-ylmethyl)- 1//-benzo|//]imidazol2-yl )pyrrolidin-2-one 139 HO 1.....Cl “ c (5)-5-(1-(3-carboxycyclobutyl)-5(3,5-d-imethylisoxazol-4-yl)- 1Hbenzo[</]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidin- 2nd

- 45 041318

140 Mp--X Η ^me Ν (5)-3 -(2-( 1 -(3,4-difluorophenyl)-5- ζ° oxopyrrolidin-2-yl)-5 -(3.5 - l dimethylisoxazol-4-yl)- IH- Υ benzoimidazole-1 -ιιπ)-Ν- ^Μ ι ΥΥΥ.....ο propylcyclobutanecarboxamide <Υ u 141 F (5)-5-(1-((7?)-3,3- difluorocyclopentyl)- 5-(3,5- dimethylisoxazol-4-yl)- 1H- ”1 Λα.....ο benzo[</]imidazol-2-yl)-1 -(3,4- ^N A ⁰ difluorophenyl)pyrrolidin-2-one οΆ Λν “θ ο Λ 142 F (5)-5-(1-0)-3.3- F difluorocyclopentyl)- 5-(3,5- dimethylisoxazol-4-yl)- 1H- l ΥΊΥ.....Cl benzo[</]imidazol-2-yl)-1 -(3 -fluoro- ^Ν Λ ⁰ 4-methoxyphenyl)pyrrolidin-2-one οΆ - ο Γ F MeO

- 46 041318

(5)-5-(l-((7?)-3,3d ifluorocycle opentyl)- 5-(3,5dimethylisoxazol-4-yl)-\Hbenzo|X]imidazol-2-yl)-1 -(3 -chloro4-methoxyphenyl)pyrrolidin-2-one (55)-1-(3,4-difluorophenyl)-5 -(5 -(3,5 dimethylisoxazol-4-yl)-1-(2hydroxypropyl)-\HbenzoIimidazol-2yl )pyrrolidin-2-one (diastereoisomer 1) (55)-1-(3,4-difluorophenyl)-5 -(5 -(3,5 dimethylisoxazol-4-yl)-1-(2hydroxypropyl)-\Hbenzo|X ]imidazol-2yl)pyrrolidin-2-one (diastereoisomer 2) (7?)-1 -(3,4-d ichlorophenyl)-6-(5 -(3,5 dimethylisoxazol-4-yl)-1 -(( 5)-1(methylsulfonyl)pyrrolidin-3 yl)-1H-benzo|X]imide azol-2yl)piperidin-2-one

- 47 041318

147 ° ₄ \ Me .....Q ^{0 Μ} θ Cl Cl (5)-1-(3,4-dichlorophenyl)-6-(5-(3,5dimethylisoxazol-4-yl)-1-((R)-1 (methylsulfonyl)pyrrolidin-3 yl)-17/-benzo |X] imide azol-2 yl) piperidin-2-one 148 ° ₄ \ _x Me _σ % \ ίΧ>.....Q ^{0 me} (5)-1 -(4-chloro-3-fluorophenyl)-6-(5 (3,5-dimethylisoxazol-4-yl)-1 ((^)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|X]imide azol-2 yl)piperidin-2-one 149 °\ / ^Me ..... O N ^Z / ___/ \i ^{0 Me} FF (5)-1-(3,4-difluorophenyl)-6-(5-(3,5 dimethylisoxazol-4-yl)-1-((R)-1 (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo |X] imide azol-2 yl) piperidin-2-one 150 ° ₄ \ _x Me 4105 ..... O%^ ⁿ j4 ^{0 Μ} θ MeO Cl (5)-1-(3-chloro-4-methoxyphenyl)-6(5-(3,5-d-imethylisoxazol-4-yl)-1 ((^)-1- (methylsulfonyl)pyrrolidin-3 yl)- 1H-benzo|X]imide azol-2 yl)piperidin-2-one 151 ° ₄ \ _x Me _a ^s _o 4 χχ>.....o ^{0 Me} MeO F (5)-1-(3-fluoro-4-methoxyphenyl)-6(5-(3,5-d-imethylisoxazol-4-yl)-1 ((7?)-1- (methylsulfonyl)pyrrolidin-3 yl)-17/-benzo|X]imide azol-2yl)piperidin-2-one 152 OMe 4 Ώύ.....Q ^{0 Μ} θ FF (5)-6-(5-(3,5-dimethylisoxazol-4yl)-1-((Ir,45)-4methoxycyclohexyl)-\HbenzoIimidazol-2-yl)-1-(3,4-difluorophenyl)piperidine- 2nd

- 48 041318

153 Me hr o- ome (5)-1-(4-chloro-3-fluorophenyl)-6-(5(3,5-d-ymethylisoxazol-4-yl)-1((1 g,45)-4-methoxycyclohexyl)1H-benzo[ </]imidazol-2yl)piperidin-2-one ⁴ Me T ^N />.....c 'N 5 N- F 154 ome (5)-1-(3-chloro-4-methoxyphenyl)-6- (5-(3,5-d-imethylisoxazol-4-yl)-1 ((1 g,45)-4-methoxycyclohexyl)- Me N ^Z o- Jl ⁴ Me X'> N / < III-benzo[<7]imidazol-2yl)piperidin-2-one MeO Cl 155 ome (5)-6-(5-(3,5-dimethylisoxazole-4- silt) -1 -((1g, 45) -4- methoxycyclohexyl)-\H- Me o- /— Λ benzo[</]imidazol-2-yl)-1 -(3 -fluoro- 2 ⁴ Me YU { V 4-methoxyphenyl)piperidin-2-one /MeO F

- 49 041318

156 "Υλ d ΤΎ S IJ^zY \—/ f to Ξ ®—V .o S Z (5)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((Is, 4R)4-hydroxy-4-methylcyclohexyl)III-benzo[ <7]imidazol-2yl)piperidin-2-one 157 ^m ^one 0 Ύ 1U>.....O ^{0 Me} MeO Cl (5)-1-(3-chloro-4-methoxyphenyl)-6(5-(3,5-d-imethylisoxazol-4-yl)-1 ((Is, 45)-4-hydroxy-4-methylcyclohexyl)-\Hbenzo [b/]imidazol-2-yl)piperidin2-one 158 ^Μ θ OH 0 0 000>.....Q ^N 'd^ ^m D ^{0 me} Cl Cl (5)-1-(3,4-dichlorophenyl)-6-(5-(3,5dimethylisoxazol-4-yl)-1-((15.45)4-hydroxy-4-methylcyclohexyl)1 d(]imide azol-2yl)piperidin-2-one

- 50 041318

159 OH 0 tjOX.....Q ° ^Me 66 MeO F (5)-6-(5-(3,5-dimethylisoxazol-4yl)-1 -((15.47?)-4-hydroxy-4methylcyclohexyl)-1H- benzo|A]imidazol-2-yl)-1-(3-fluoro4-methoxyphenyl)piperidin-2-one 160 ^m - he 0 ^M i O0> ..... Q nA NT / A ^{0 Me} 6 ^ Cl F (5)-1 -(4-chloro-3-fluorophenyl)-6-(5(3,5-d-imethylisoxazol-4-yl)-1 ((1x.47?)-4-hydroxy-4methylcyclohexyl)-1Нbenzo [b/]imidazol-2-yl)piperidin2-one 161 he Ύ xx^.....o ° ^Me 66 FF (5)-1-(3,4-difluorophenyl)-6-(5 -(3,5 dimethylisoxazol-4-yl)-1-((1g,35)- 3-hydroxycyclobutyl)-1Hbenzo|A]imidazol-2-yl)piperidine- 2nd 162 he Ύ χχ ^Ν/ >.....o ^{0 Me} 66 MeO Cl (5)-1-(3-chloro-4-methoxyphenyl)-6(5-(3,5-d-imethylisoxazol-4-yl)-1 ((1 g, 35)-3-hydroxycyclobutyl)1H-benzo| A] imide azol-2 yl) piperidin-2-one 163 he “to χχ ^{Ν /} >..... about ^{0 Me} 66 Cl Cl (5)-1-(3,4-dichlorophenyl)-6-(5-(3,5dimethylisoxazol-4-yl)-1-((1g,35)3-hydroxycyclobutyl)-1H- benzo|A]imidazol-2-yl)piperidin2-one 164 ^M Ya chon 0 ^m aOX ..... o A / A ^ N nA N T __ / A A 0' FF (5)-1-(3,4-difluorophenyl)-6-(5 -(3,5 dimethylisoxazol-4-yl)-1 4S)- 4-hydroxy-4-methylcyclohexyl)III-benzo|A]imidazole-2- yl)piperidine-2-one

- 51 041318

(5)-1-(3-Chloro-4-methoxyphenyl)-6(5-(3,5-d-ymethylisoxazol-4-yl)-1 {{1d, 45)-4-hydroxy-4methylcyclohexyl)-\HbenzoIimidazole -2-yl)piperidin2-one (5)-6-(5-(3,5-dimethylisoxazol-4yl)-1 -{{1g, 45)-4-hydroxy-4methylcyclohexyl)-1HbenzoIimidazol-2-yl)- 1-(3-fluoro4-methoxyphenyl)piperidin-2-one (5)-1-(3,4-dichlorophenyl)-6-(5-(3,5dimethylisoxazol-4-yl)-1isobutyl-1p-benzo [<7]imide azol-2-yl)piperidin-2-one (5)-1-(3-chloro-4-methoxyphenyl)-6(5-(3,5-d-imethylisoxazol-4-yl)-1isobutyl - W-benzoI imide azol-2 yl) piperidin-2-one

- 52 041318

169 Me Me-^^ .....Q ^{0 me} MeO F (5)-6-(5-(3,5-dimethylisoxazole-4- yl)-1 -isobutyl- 1//- benzo[b/]imidazol-2-yl)-1 -(3-fluoro4-methoxyphenyl)piperidin-2-one 170 1 W.....Q ^{0 Μ} θ MeO F (5)-6-(1-(4,4-Difluorocyclohexyl)5-(3,5-dimethylisoxazol-4-yl)- 1H-benzoIimidazol-2-yl)-1-(3-fluoro4-methoxyphenyl)piperidine-2- He 171 Ύ .....ο Ν Τ __/ \χ ^{0 Μ} θ FF (5)-6-(1-(4,4-Difluorocyclohexyl)5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[b/]imidazol-2-yl)-1-(3,4difluorophenyl)piperidine -2-he 172 $ ym.....ο ^{0 me} MeO Cl (5)-1-(3-chloro-4-methoxyphenyl)-6- (1 - (4,4-d ifluorocycle ohexyl) -5 - (3.5 - dimethylisoxazol-4-yl)- 1R-benzo[b/]imidazol-2-yl)piperidine- 2nd 173 pH Ύ jO4>..... About ^{0 Me} Cl Cl (5)-1-(3,4-dichlorophenyl)-6-(5-(3,5dimethylisoxazol-4-yl)-1 4S)- 4-hydroxycyclohexyl)- 1Нbenzo[b/]imidazol-2-yl)piperidin2-one 174 OH Ύ ϊϊ>..... О ^{Ν Ν} , / ο ^{0 Μβ} <0* FF (5)-1-(3,4-difluorophenyl)-6-(5 -(3,5 dimethylisoxazol-4-yl)-1 -{{lr, 4S)4-hydroxycyclohexyl)- 1Нbenzo[b/]imidazol- 2-yl)piperidine2-one

- 53 041318

175 he V XX>.....Q ^{0 Μ} θ MeO Cl (5)-1-(3-Chloro-4-methoxyphenyl)-6(5-(3,5-d-imethylisoxazol-4-yl)-1 ((1g, 45)-4-hydroxycyclohexyl)1R-benzo|D ]imidazol-2yl)piperidin-2-one 176 Ύ JPX ^N/ >.....Cl \X a ⁰ ρ ρ, (5)-1-(3,4-difluorophenyl)-5-(1((7g,45)-4-hydroxycyclohexyl)-5(5-(hydroxymethyl)-3 methylisoxazol-4-yl)-1//benzo [<7]imidazol-2yl)pyrrolidin-2-one 177 I ο ζ / ο <y— ^J S ^φ ο Lr = (5)-1-(3,4-difluorophenyl)-5 -(1 ((7g,45)-4-hydroxycyclohexyl)-5(3 -(hydroxymethyl)-5 - methylisoxazol-4-yl)-1/7- benzo[<7]imidazole-2- yl) pyrrolidin-2-one

- 54 041318

178 Z ³ ο Ά— ^go s \__ _{_} f )---\ w (5)-6-(1-(4,4-Difluorocyclohexyl)5-(3,5-dimethylisoxazol-4-yl)-1H-benzo|X]imidazol-2-yl)-1-phenylpiperidin-2-one 179 to ^M k XX ^m "..... O £^/=4° ^{0 Μ} θ MeO Cl (5)-1-(3-chloro-4-methoxyphenyl)-6(1-(3,3-d butyl fluorocycle)-5-(3,5 dimethylisoxazol-4-yl)-\Hbenzo[b/]imidazole -2-yl)piperidine- 2nd 180 to ^m kXX> ..... O NT __ / A ^{0 Me} FF (8)-6-(1-(3,3-difluorocyclobutyl)-5(3,5-d-imethylisoxazol-4-yl)-1Hbenzo[c!]imidazol-2-yl)-1-(3,4difluorophenyl) piperidine-2-one 181 to ^M kXX>.....o Pl^a/Ch ^{0 Μ} θ MeO F (5)-6-(1-(3,3-difluorocyclobutyl)-5(3,5-d-imethylisoxazol-4-yl)-\HbenzoIimidazol-2-yl)-1-(3-fluoro4-methoxyphenyl)piperidine- 2nd

- 55 041318

(15.4 g)-methyl 4-(2-((5)-1-(3,4difluorophenyl)-6-oxopiperidin-2yl)-5-(3,5-dimethylisoxazol-4-yl)1H-benzoIimidazol-1yl )cyclohexanecarboxylate (15.4g)-4-(2-((5)-1-(3,4difluorophenyl)-6-oxopiperidin-2yl)-5-(3,5-dimethylisoxazol-4-yl)N-benzo[ 0/]imidazol-1yl)cyclohexanecarboxylic acid (15.4g)-4-(2-((5)-1-(3,4difluorophenyl)-6-oxopiperidin-2yl)-5-(3,5-dimethylisoxazol-4 -yl)1H-benzo[<7]imidazol-1 -yl)-Hpropylcyclohexanecarboxamide

- 56 041318

(15.4g)-4-(2-((5)-1-(3,4difluorophenyl)-6-oxopiperidin-2yl)-5-(3,5-dimethylisoxazol-4-yl)N-benzoIimidazol-1 -yl)-#methyl-TV propylcyclohexanecarboxamide

(5)-6-(1-(4,4-difluorocyclohexyl)5-(3,5-dimethylisoxazol-4-yl)-\Hbenzo|X]imidazol-2-yl)-1-(6fluoropyridine-3- yl)piperidine-2-one

(5)-6-(1-(4,4-difluorocyclohexyl)5-(3,5-dimethylisoxazol-4-yl)- 1Hbenzo[d?]imidazol-2-yl)-1-(5fluoropyridine-3- yl)piperidine-2-one

- 57 041318

(5)-6-(1-(4,4-difluorocyclohexyl)5-(3,5-dimethylisoxazol-4-yl)- 1Hbenzo[</]imidazol-2-yl)-1(pyridin-3-yl) piperidin-2-one (5)-1-(3-chloro-4-methoxyphenyl)-6(6-(3,5-d-imethylisoxazol-4-yl)-3 ((1 g,45)-4-hydroxycyclohexyl )3H-imidazo[4,5-5]pyridin-2yl)piperidin-2-one (5)-1-(3,4-difluorophenyl)-6-(6-(3,5 dimethylisoxazol-4-yl)- 3-((1 g, 45)4-hydroxycyclohexyl)-3Rimidazo[4,5-b}pyride in-2yl)piperidin-2-one

- 58 041318

(5)-6-(6-(3,5-dimethylisoxazol-4yl)-3-((1g, 45)-4hydroxycyclohexyl)-3Rimidazo[4,5-b} pyride in-2-yl)-1 - (3-fluoro-4-methoxyphenyl)piperidin2-one (5)-1-(3-chloro-4-methoxyphenyl)-5 (3-(4,4-d iflorcycle ohexyl)-6-(3,5 dimethylisoxazole-4 -yl)-3Rimidazo[4,5-b\ pyrid in-2yl)pyrrolidin-2-one (5)-5-(3-(4,4-difluorocyclohexyl)6-(3,5-dimethylisoxazol-4 -yl)-3Rimidazo[4,5-b} pyrid in-2-yl)-1(3,4-difluorophenyl)pyrrolidin-2one

- 59 041318

(5)-6-(6-(3,5-dimethylisoκcasol-4yl)-3-isobutyl-3^-imidazo[4,5b} pyridin-2-yl)-1-(3-fluoro-4methoxyphenyl)piperidine- 2-one (5)-5-(3-(4,4-difluorocyclohexyl)6-(3,5-dimethylisoxazol-4-yl)-3//imidazo[4,5-ό]pyridin-2-yl) -1 -(3 fluoro-4methoxyphenyl)pyrrolidin-2-one (5)-1-(3,4-difluorophenyl)-6-(6-(3,5 dimethylisoxazol-4-yl)-3 isobutyl-37/- imidazo[4,5/>]pyridin-2-yl)piperidin-2-one (5)-1-benzyl-5-(5-(3,5dimethylisoxazol-4-yl)-1-((1g,45) 4-Methoxycyclohexyl)-1Nabenzo|X]imidazol-2yl)pyrrolidin-2-one (5)-6-(1 -(4,4-difluorocyclohexyl)5-(3,5 - dimethyl lysoxazol-4-u l)- 1Hbenzo|X]imidazol-2-yl)-1(pyrimidin-5-yl)piperidin-2-one and their pharmaceutically acceptable salts.

The compound according to the present invention, in which the integer n=0, can be obtained by a method that includes processing a compound of formula (II)

where each of R, R ⁰ , R ¹ , W and Y corresponds to the above definition for formula (I),

- 60 041318 boronic acid of the formula R ² -B(OH) 2 , where R ² corresponds to the definition given above for formula (I), in the presence of Pd(PPh3) ₄ and Na ₂ CO ₃ in an aqueous solution of ethanol. An aqueous solution of ethanol usually contains 20-60% EtOH in water.

The compound according to the present invention, in which the integer n=0, can also be obtained by a method that includes processing a compound of formula (III)

where each of R, R ⁰ , R ¹ , R ² , W and Y corresponds to the above definition for formula (I), acetic acid at 60-100°C or a solution of HCl/1,4-dioxane 20-90%.

The compound according to the present invention, in which the integer n is 1, can be obtained by a method comprising treating a compound of formula (II) as defined above with a compound of formula R ² -CH ₂ Br, in which R ² corresponds to the above for formula (I) definition. Typically, the reaction is carried out by adding sodium hexamethyldisilazane (NaHMDS) in THF to a solution of the compound of formula (II) in DMF, followed by adding a solution of the compound of formula R ² -CH2Br in DMF.

The following schemes illustrate the synthetic strategies, including the steps of the methods described above, which allow you to get the compounds according to the present invention.

Pathway A. Non-convergent approach to the preparation of γ-lactam analogs

a. Dimethylisoxazoleboronic acid, Na ₂ CO ₃ , Pd(PPh ₃ ) ₄ , EtOH/water - 50-70%.

b. R1-NH2, TEA, THF, rt or R _r NH _r HCl, TEA, DMF, 70-90°C - 60-90%.

c. Na2S2O4, THF/H2O, NH4OH or Fe, AcOH or Fe, NH4Q, EtOH/HO, 80°C - 30-80%.

d. HATU, pyroglutamic acid, TEA, DXM or DMF - 50-90% (purified or used without purification).

e. AcOH, 60-100°C - 20-60%.

f. Arylboronic acid, Na ₂ CO ₃ , Pd(PPh ₃ ) ₄ , EtOH/water - 20-60%.

Pathway B. Convergent approach to the preparation of γ-lactam analogues from N-arylpyroglutamic acid

a. Arylboronic acid, Na ₂ CO ₃ , Pd(PPh ₃ ) ₄ , EtOH/water - 20-60%.

b. HATU, hydrocinnamic acid, TEA, DXM or DMF - 50-90% (purified or used without purification).

- 61 041318

c. AcOH, 60-100°C or HCl/1,4-dioxane - 20-90%.

Pathway C. Reductive amination approach to the synthesis of γ-lactam analogs

a. Dimethylisoxazolboronic acid, Na ₂ CO ₃ , Pd(PPh ₃ ) ₄ , EtOH/water.

b. HATU, pyroglutamic acid, TEA, DXM or DMF.

c. Pt, H2, EtOH.

d. Ketone or aldehyde, STAB, DXM.

e. AcOH, 60-100°C.

f. Arylboronic acid, Na ₂ CO ₃ , Pd(PPh ₃ ) ₄ , EtOH/water.

Pathway D. Non-convergent approach to the preparation of verolactam analogs

A. Dimethylisoxazolboronic acid, Na2CO ₃ , Pd(PPh ₃ ) ₄ , EtOH/Boga - 50-70%.

b. R1-NH2, TEA, THF, rt or R _r NH _r HCl, TEA, DMF, 70-90°C - 60-90%.

c. Na ₂ S ₂ O ₄ , THF/H2O, NH4OH or Fe, AcOH or Fe, NH4Cl, EtOH/H ₂ O, 80°C - 30-80%.

d. HATU, pyroglutamic acid, TEA, DXM or DMF - 50-90% (purified or used without purification).

e. AcOH, 60-100°C - 20-60%.

f. Arylboronic acid, Na ₂ CO ₃ , Pd(PPh ₃ ) ₄ , EtOH/water or pyridine.

- 62 041318

Pathway E. Non-convergent approach to the preparation of azabenzimidazole analogs

Pathway F: Convergent Approach to the Preparation of N-Alkyl Lactam Analogs

a. R2-Br, NaHMDS, DMF.

Explanation of abbreviations, section Examples.

used in all the above schemes is given below in

The arylimidazolylisoxazole of formula (I) may be converted to a pharmaceutically acceptable salt and the salts may be converted to the free compound by conventional means. Pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and salts of organic acids such as acetic acid, oxalic acid, malic acid, methanesulfonic acid, trifluoroacetic acid, benzoic acid, citric acid and tartaric acid. . In the case of compounds containing a free carboxy substituent, the salts include the acid addition salts mentioned above, and the sodium, potassium, calcium and ammonium salts. The latter are obtained by treating the free benzarylimidazolylisoxazoal of formula (I) or its acid addition salt with an appropriate metal base or ammonia.

The arylimidazolylisoxazole of formula (I), or a pharmaceutically acceptable salt thereof, is hereinafter referred to as a compound of the present invention. In biological tests, the compounds of the present invention were found to bind to histone acetyltransferase (HAT), p300, and to CBP as described in Example 199 below.

The CREB binding protein (CBP) and its paralogue, p300, are two closely related histone acetyltransferase cofactor proteins that are involved in a wide variety of cancer processes, including cell proliferation, apoptosis, cell cycle regulation, and DNA damage response. CBP/p300 primarily act as transcription cofactors for a number of oncoproteins including Jun, Fos and E2F. Additionally, it acts as a histone acetyltransferase and can also acetylate some non-histone proteins such as p53, p73 and Rb. There is evidence that CBP/p300 acts as a tumor suppressor or as an oncoprotein, depending on the nature of the particular cancer. Several studies have shown that p300 expression correlates with disease progression and worse survival.

CBP and p300 are upregulated during the progression of human prostate cancer and have been shown to be co-activators of the androgen receptor (AR) (Debes, J.D., et al. (2003) p300 in prostate cancer proliferation and progression, ' Cancer Res., Vol. 63, pp. 7638-7640 and Linja, MJ. et al. (2004) Expression of androgen receptor coregulators in prostate cancer, Clin. Cancer Res., Vol. 10, pp. 1032-1040 ).

It has recently been shown that p300 directly regulates the degradation of the AR protein (Zhong et al., 2014). p300-mediated AR acetylation has been shown to inhibit AR ubiquitination and subsequent AR degradation by proteasomes (Zhong et al., 2014, cited above). Accordingly, direct inhibition of p300 activity will result in destruction of the AR.

Given the heterogeneity of prostate cancer, the identification of suitable biomarkers is critical for effective positioning and evaluation of targeted small molecule therapeutics. It is assumed that markers of the development of the CRPC phenotype due to

- 63 041318 AR recovery is used to stratify patients to evaluate p300 modulators. These include PSA (PSA) and circulating tumor cell count (CTC), as well as the presence of AR and AR splicing variants in circulating tumor cells.

In terms of biomarkers, direct measurable parameters that allow monitoring of the modulation of p300 activity include: determination of AR levels and AR splice variants; modulating AR activity by assessing levels of AR-responsive genes, including TMPRSS2 and KLK3. Other surrogate markers of AR functional activity include p21, c-Myc, and p53. With therapeutic agents that modulate AR activity approved for use in CRPC, biomarkers to assess the effects of p300 targeting and subsequent AR modulation are already widely available and used in the clinical setting.

AR has been shown to be expressed by various types of cancers. In addition to prostate cancer, they include breast and bladder cancer. Modulating p300 activity would be expected to have therapeutic utility in the treatment of these cancers, as well as other conditions in which AR is expressed. In addition, it is likely that p300 regulates the levels of other nuclear hormone receptors, which also expands the scope for clinical applications of p300-targeting agents.

A recent publication (Ogiwara et al. (2016) Cancer Discovery. 6; 430-445) showed that tumors that carry loss-of-function mutations in CVR are exceptionally sensitive to p300 inhibition. Conversely, tumors with p300 mutations are exceptionally sensitive to CVR inhibition. In the case of lung cancer, genetic analysis indicates that such loss-of-function mutations carry up to 15% of both non-small cell and small cell tumors. Similar mutations are also found in up to 25% of bladder cancers, as well as in a number of hematological malignancies, including lymphoma and leukemia. Modulation of p300 and/or CVR is expected to be useful in the treatment of tumors carrying these mutations.

Other recent publications (Casey et al. (2016) Science. 352; 227-231; Ghosh et al. (2016) JBC online) have shown that CBP/p300 regulates the expression of key immune checkpoint proteins such as CTLA4/PDL1, and also differentiation and function of t-regulatory cells. It can be expected that the regulation of p300 and/or CBP will provide additional therapeutic effects in combination with agents that target the immune-oncological system.

The compound of the present invention has the activity of modulators of p300 and/or CBP activity. Accordingly, it can be used to treat cancer or other medical condition in which AR is expressed, or in cancers in which CBP and/or p300 function is activated. Cancers that can be treated include cancers that express AR or are otherwise associated with AR, those that carry loss-of-function mutations in CBP or p300, and those that have CBP and/or p300 activated.

Cancers that can be treated include, but are not limited to, prostate cancer, breast cancer, bladder cancer, lung cancer, lymphoma, and leukemia. The prostate cancer may be, for example, castration-resistant prostate cancer (CRPC). The lung cancer can be, for example, non-small cell lung cancer or small cell lung cancer. Thus, a patient or animal suffering from cancer can be treated by a method comprising administering to him the compounds of the present invention. This will improve the condition of the specified patient.

Thus, the compound of the present invention may be administered to a patient, human or animal, in combination with radiation therapy or other therapeutic agent for the treatment of cancer. Accordingly, the present invention, inter alia, provides a combination therapy in which the compound of the present invention or a pharmaceutical composition containing the compound of the present invention is administered simultaneously or sequentially with radiation therapy; or administered simultaneously, sequentially or in combination with another therapeutic agent or agents for the treatment of cancer.

Such a therapeutic agent, or any other therapeutic agent, would be an agent conventionally used to treat cancer of the type indicated. Classes of therapeutic agents with which a compound of the present invention is typically combined for the treatment of prostate cancer include androgen receptor antagonists, eg enzalutamide, and CYP17A1 (17a-hydroxylase/C17,20-lyase) inhibitors, eg abiraterone; cytotoxic chemotherapy agents, eg docetaxel; for the treatment of lung cancer include agents of cytotoxic chemotherapy, such as cisplatin, carboplatin, docetaxel; for the treatment of bladder cancer, cytotoxic chemotherapy agents such as gemcitabine, cisplatin, or immune therapy agents such as Bacillus Calmette-Guerin (BCG) are included. Other classes of agents with which a compound of the present invention may be combined include immune checkpoint inhibitors, eg pembrolizumab, nivolumab, atezolizumab, ipilumumab; PARP (poly-(ADFribose) polymerase) inhibitors such as olaparib; and inhibitors of CDK4/6 (cyclin-dependent kinase 4 and 6).

The term combination as used herein refers to simultaneous, separate or sequential administration. If the introduction is sequential or separate, the delay in the introduction of the second component should not lead to loss of the beneficial effect of the combination.

The present invention also relates to a product containing:

(a) a compound according to the present invention as described above; and (b) one or more other therapeutic agents;

for separate, simultaneous or sequential administration in the prophylactic or therapeutic treatment of cancer, for example, the specific cancers mentioned above. The other therapeutic agent may be, for example, an androgen receptor antagonist, a CYP17A1 inhibitor, a PARP inhibitor, or a CDK4/6 inhibitor. More specifically, it may be enzalutamide, abiraterone, or olaparib.

The compound of the present invention can be administered in various dosage forms, for example, orally, in forms such as tablets, capsules, sugar or film-coated tablets, liquid solutions or suspensions, or parenterally, for example, intramuscularly, intravenously or subcutaneously. Therefore, said compound can be administered by injection or infusion.

The dosage depends on a variety of factors including the age, weight and condition of the patient and the route of administration. Daily doses can vary widely and will be adjusted to individual requirements in each case. However, in general, the dosage adopted for each route of administration when said compound is administered alone to adult humans is 0.0001 to 50 mg/kg, most commonly in the range of 0.001 to 10 mg/kg body weight, for example 0.01 to 1 mg/kg. Such a dosage may be administered, for example, 1 to 5 times a day. For intravenous injection, a suitable daily dose is 0.0001 to 1 mg/kg body weight, preferably 0.0001 to 0.1 mg/kg body weight. The daily dose can be administered as a single dose or according to a divided dose regimen.

The compound of the present invention is designed for use as a pharmaceutical or veterinary composition also containing a pharmaceutically or veterinarily acceptable carrier or diluent. Said compositions are generally prepared according to conventional methods and administered in a pharmaceutically or veterinarily acceptable form. Said compound may be administered in any conventional form, for example as follows.

A) Orally, for example, in the form of tablets, coated tablets, dragees, lozenges, aqueous or oily suspensions, liquid solutions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral administration may be prepared in accordance with any method known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more agents selected from the groups consisting of sweeteners, flavorings, coloring agents and preservatives, to provide pharmaceutically elegant and palatable preparations.

The tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, dextrose, sucrose, cellulose, corn starch, potato starch, calcium phosphate or sodium phosphate; granulating agents and disintegrators, for example corn starch, alginic acid, alginates or sodium starch glycolate; binding agents, for example starch, gelatin or acacia; lubricants, for example silica, magnesium or calcium stearate, stearic acid or talc; effervescent mixtures; colorants, sweeteners, wetting agents such as lecithin, polysorbates or lauryl sulfate. Said tablets may be uncoated or may be coated by known methods in order to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained effect over a longer period of time. For example, a sustained release material such as glyceryl monostearate or glyceryl distearate may be used. Such preparations can be prepared in a known manner, for example by mixing, granulating, tableting, sugar coating or film coating.

Compositions for oral administration may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is present as such, or mixed with an aqueous or oily medium such as peanut butter, liquid paraffin or olive oil.

Aqueous suspensions contain the active substances in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents can be natural phosphatides, for example, lecithin or pro

- 65 041318 condensation products of alkylene oxides with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol or condensation products of ethylene oxide with partial esters derived from fatty acids and mannitol, such as polyoxyethylene sorbitol monooleate , or condensation products of ethylene oxide with partial esters derived from fatty acids and mannitol anhydrides, for example, polyoxyethylene sorbitan monooleate.

Said aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants such as sucrose or saccharin.

An oil suspension can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Said oil suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol.

Sweeteners such as those mentioned above and flavoring agents may be added to provide a palatable oral preparation. The shelf life of these compositions can be extended by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those mentioned above. Additional excipients may also be present, such as sweeteners, flavors and colors.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or mixtures thereof. Suitable emulsifiers may be naturally occurring gums such as gum arabic or tragacanth, naturally occurring phosphatides such as soy bean lecithin and esters or partial esters derived from fatty acids, mannitol anhydrides such as sorbitan monooleate and the condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Said emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be mixed with sweeteners such as glycerin, sorbitol or sucrose. In particular, a syrup for patients with diabetes may only contain carriers, for example sorbitol, which are not metabolized to glucose or which metabolize to glucose to a very small extent.

Such compositions may also contain an emollient, preservative, fragrance and coloring agent.

B) Parenterally, either subcutaneously, or intravenously, or intramuscularly, or intragastrically, or by infusion methods, in the form of sterile injectable aqueous or oily suspensions. Such a suspension may be prepared in accordance with the prior art using those suitable dispersions of wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic initial acceptable diluent or solvent, for example in the form of a solution in 1,3-butanediol.

Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. Additionally, sterile, fixed oils are typically used as the solvent or suspending medium. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

C) By inhalation, in the form of aerosols or solutions for nebulizers.

D) Rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

E) Topically (topically), in the form of creams, ointments, jellies, eye drops, solutions or suspensions.

The present invention is described below by way of examples and reference examples:

- 66 041318

Table 1 AcOH Abbreviations crystalline acetic acid Aq (water) AC water acetyl Vos prss-butoxycarbonyl br wide CatCart® catalytic cartridge CDI 1,1-carbonyldiimidazole d doublet DXM dichloromethane DIPEA A,A-diisopropylethylamine DMF A, A- e have lf ormamide DMSO dimethyl sulfoxide (electrospray ⁺ ) Et electrospray ionization, positive mode Ethyl EtOAc ethyl acetate FBS HOBt Fetal bovine serum 1-hydroxybenzotriazole 4 watch) (M+H) ⁺ Protonated molecular ion Me methyl MeCN acetonitrile MeOH methanol MHz megahertz min minute(s) m/z: Mass/charge ratio NMP 1-methylpyrrolidin-2-one (A-methyl-2-pyrrolidone) NMR Nuclear magnetic resonance (spectroscopy) PdC12dppf Ph (1,1'-bis(diphenylphosphino)ferrocene)palladium(II)phenyl dichloride

FSB Phosphate buffered saline PPh ₃ triphenylphosphine q kt quartet Room temperature RP-HPLC Reverse Phase High Performance Liquid Chromatography S singlet SCX Solid state cation exchanger (resin) snat Nucleophilic aromatic substitution t triplet TBAF Tetrabutylammonium fluoride TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TIPS-C1 chlorotriisopropylsilane tmv Xantphos 3,3,5,5-tetramethylbenzidine 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

- 67 041318

General procedures.

All starting materials and solvents were either obtained from commercial sources or obtained as described in the literature. Unless otherwise indicated, all reactions were carried out with stirring. The organic solutions were dried in a routine manner using anhydrous magnesium sulfate. Hydrogenation was carried out in a Thales H-cube flow reactor under the indicated conditions.

Column chromatography was performed on pre-packaged silica cartridges (230400 mesh, 40-63 μM) using the indicated amount. A solid supported cation exchanger (solid phase) was purchased from Supelco and treated with 1M hydrochloric acid prior to use. Unless otherwise indicated, the reaction mixture to be purified was first washed with methanol (MeOH) and acidified with a few drops of AcOH. This solution was loaded directly onto the cation exchanger (SCX) and washed with methanol (MeOH). The target material was then eluted using 1% NH ₃ in MeOH for washing.

Analytical methods.

Reversed phase high performance chromatography.

Analytical HPLC was performed using a Waters Xselect CSH C18, 2.5 µm, 4.6x30 mm column, eluting with a gradient of 0.1% formic acid in MeCN in 0.1% aqueous formic acid; Waters Xbridge BEN C18, 2.5 µm, 4.6x30 mm columns, eluting with a MeCN gradient in 10 mM ammonium bicarbonate. The UV spectra of the eluted peaks were measured using either a diode array or a variable wavelength detector on an Agilent 1100 system.

Analytical LCMS was performed using a Waters Xselect CSH C18, 2.5 µm, 4.6x30 mm column, eluting with a gradient of 0.1% formic acid in MeCN in 0.1% aqueous formic acid (method 1); column Waters Xbridge BEN C18, 2.5 μm, 4.6x30 mm, eluting with a gradient of MeCN in 10 mM aqueous ammonium bicarbonate (method 2). UV and mass spectra of the eluted peaks were measured using a variable wavelength detector on an Agilent 1200 or Agilent Infinity 1260 LCMS instrument with a 6120 single quadrupole mass spectrometer with positive and negative electrospray ionization modes.

Preparative HPLC was performed using a Waters Xselect CSH C18, 5 µm, 19x50 mm column using either a 0.1% formic acid gradient in MeCN in 0.1% formic acid aqueous solution or a MeCN gradient in 10 mM aqueous ammonium bicarbonate solution; or Waters Xbridge BEN C18, 5 µm, 19x50 mm columns using MeCN gradient in 10 mM ammonium bicarbonate aqueous solution. Fractions were collected after single wavelength UV detection, measured with a variable wavelength detector on a Gilson 215 reparative HPLC or Varian PrepStar HPLC; mass and UV were recorded at the same wavelength, the measurement was carried out using a ZQ single quadrupole mass spectrometer, with electrospray ionization in positive and negative mode, and a two-wave detector on a Waters FractionLynx LCMS device.

Chiral preparative HPLC was performed using Gilson Diacel Chiralpak IA or IB, 5 μm, 20x250 mm, 60 min cycles, 1.0 ml/min, using the following solvent systems.

Method A - 10% EtOH in 4:1 isohexane (0.1% DEA):DCM (Diacel Chiralpak IA).

Method B - 10% EtOH in 4:1 isohexane (0.1% DEA):DCM (Diacel Chiralpak IA).

Method C - 20% EtOH in 4:1 isohexane (0.2% DEA):DCM (Diacel Chiralpak IA).

Method D - 35% EtOH in 4:1 isohexane (0.2% DEA):DCM (Diacel Chiralpak IC).

Method E - 35% EtOH in 4:1 isohexane (0.2% DEA):DCM (Diacel Chiralpak IC).

Method F - 20% EtOH in 4:1 isohexane (0.2% DEA): DCM (Diacel Chiralpak IA).

¹ H-NMR Spectroscopy: ¹ H-NMR spectra were obtained on a Bruker Avance III spectrometer at 400 MHz. The central peaks of chloroform-d, dimethyl sulfoxide-d ₆ or the internal standard of tetramethylsilane were used as references.

1H-NMR spectroscopy:

1 H-NMR spectra were obtained on a Bruker Avance III spectrometer at 400 MHz using residual non-deuterated solvent as reference.

Reference examples.

General Pathway A: A non-convergent approach to γ-lactam analogs.

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (intermediate A)

Me

PdCl ₂ (dppf) (60 g, 82 mmol) was added to a stirred mixture of potassium carbonate (407 g, 2947 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (180 g, 1277 mmol) and 4-bromo -1-fluoro-2-nitrobenzene (216 g, 982 mmol) in 4:1 dioxane/water (3 L). The reaction mixture was stirred at 90° C. for 18 hours. After cooling to rt. the mixture was diluted with water (1 L) and extracted with ethyl acetate (1x2 L and 1x1 L). The combined organics were eluted through a pad of Celite and evaporated under reduced pressure. DCM (1 L) was added to the crude product and the resulting solution was purified in three batches; each batch (400 ml) was loaded onto a 1 kg silica gel filter and eluted with DCM. Fractions from all three filter layers were analyzed by HPLC; Product containing fractions were combined and concentrated in vacuo to give 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (177.6 g, 76%) as a light yellow solid; temp. beats 2.08 min (method 1), m/z 237 (M+H)+ (electrospray ⁺ ).

(R)-N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1-(methylsulfonyl)pyrrolidin-3-amine (B1)

(R)-3-methyl-1-(methylsulfonyl)pyrrolidine hydrochloride (4.9 g, 24.54 mmol) and TEA (11.40 ml, 82 mmol) were dissolved in DMF (30 ml, 387 mmol), 4-(4-fluoro- 3-nitrophenyl)-3,5dimethylisoxazole (3.86 g, 16.36 mmol) and stirred at 45°C for 30 h. The mixture was evaporated under vacuum and the residue was dissolved in EtOAc (200 ml), washed with water (2x100 ml) and brine (50 ml), dried (MgSO ₄ ), filtered and evaporated under vacuum. The resulting orange solid was purified by silica gel chromatography (220 g column, 0-100% EtOAc in (50% DCM/isohexane) to give (R)-N-(4-(3,5-dimethylisoxazole-4 -yl)-2-nitrophenyl)-1(methylsulfonyl)pyrrolidine-3-amine (5.3 g, 85%), temp 1.99 min (method 2), m/z 381 (M+H)+ (electrospray ⁺ ).

(R)-4-(3,5-dimethylisoxazol-4-yl)-N ¹ -(1-(methylsulfonyl)pyrrolidin-3-yl)benzene-1,2-diamine (intermediate C1)

(R)-N-(4-(3,5-dimethylisoksazol-4-yl)-2-nitrophenyl)-1-(methylsulfonyl)pyrrolidin-3-amine (5.2 g, 13.67 mmol) was dissolved in THF/water ( 1:1, 400 ml), then concentrated aqueous ammonia solution (10.65 ml, 273 mmol) and sodium dithionite (23.80 g, 137 mmol) were added and the reaction mixture was stirred at rt. within 1 h. The layers were separated and the aqueous extracts were extracted with ethyl acetate (20 ml). The combined organics were washed with brine (20 ml), dried (MgSO ₄ ), filtered and evaporated in vacuo to give (R)-4-(3,5-dimethylisoxazol-4yl)-N ¹ -(1-( methylsulfonyl)pyrrolidin-3-yl)benzene-1,2-diamine (3.89 g, 72%) as a pink foam; temp. beats 1.68 min (method 2); m/z 351 (M+H)+ (electrospray ⁺ ).

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)tetrahydro-2H-pyran-4-amine (B2)

Tetrahydro-2H-pyran-4-amine (2.63 ml, 25.4 mmol) was dissolved in dry THF (10 ml, 122 mmol) and TEA (8.85 ml, 63.5 mmol) and cooled to 0°C. 4-(4-Fluoro-3-nitrophenyl)-3,5dimethylisoxazole intermediate A (5 g, 21.17 mmol) was added and the reaction mixture was stirred at 60°C for 16 h.

Additional amine/base mixture (1/2 molar equivalent) was added and heated at 60° C. overnight. The reaction mixture was poured into water (100 ml), the resulting solid was filtered under vacuum, washed with water (50 ml), isohexane (100 ml) and dried under vacuum to give N-(4-(3,5-dimethylisoxazole- 4-yl)-2-nitrophenyl)tetrahydro-2H- 69 041318 pyran-4-amine (6.5 g, 96%) bright orange solid; temp. beats 2.13 min (method 2); m/z 318 (M+H)+ (electrospray ⁺ ).

4-(3,5-dimethylisoxazol-4-yl)-N ¹ -(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine (С2)

Sodium dithionite (75 g, 431 mmol) was added to a solution of N-(4-(3,5-dimethylisoxazol-4-yl)-2nitrophenyl)tetrahydro-2H-pyran-4-amine (13.1 g, 40.9 mmol) and concentrated ammonia (32 ml, 822 mmol) in THF/water (1:1, 200 ml) and the reaction mixture was stirred at rt. for 2 h. The reaction mixture was partitioned between EtOAc (200 ml) and brine (100 ml), the phases were separated, the organics were dried with MgSO ₄ , filtered and concentrated under vacuum, resulting in a sticky pink foam. This foam was diluted in diethyl ether (150 ml) overnight then collected by filtration to give 4-(3,5-dimethylisoxazol-4-yl)N ¹ -(tetrahydro-2H-pyran-4-yl)benzene -1,2-diamine (8.57 g, 70%) as a pink solid; temp. beats 0.83 min (method 1); m/z 288 (M+H) ⁺ (electrospray ⁺ ).

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)tetrahydro-2H-pyran-4-amine (B3)

To a mixture of 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (6.60 g, 27.9 mmol) and 4-aminotetrahydro2H-thiopyran-1,1-dioxide (5 g, 33.5 mmol) in DMF (40 ml ) was added TEA (8.56 ml, 61.4 mmol). The mixture was stirred at 60°C for 18 h, then quenched in ice water (200 ml). The solid was collected by filtration and washed with water to give 4-((4-(3,5-dimethylisoxazol-4yl)-2-nitrophenyl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (10.2 g, 92% ) as a bright orange solid; temp. beats 1.91 min (method 1); m/z 366 (M+H) ⁺ (electrospray ⁺ ).

4-((2-Amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (С3)

4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (10.2 g, 27.9 mmol) was added to a solution of sodium dithionite (48.6 g, 279 mmol) and ammonium hydroxide (78 ml, 558 mmol) in THF (150 ml) and water (100 ml). The reaction mixture was stirred at rt. for 18 hours, then concentrated in vacuo to remove organics. The remaining aqueous layer (containing the solid) was filtered under vacuum, washed with water (2x100 ml) and vacuumed to dryness. The solid was transferred to a flask and triturated with ether. Filtration and drying under vacuum gave 4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)tetrahydro-2Hthiopyran 1,1-dioxide (4.94 g, 48%) as light -beige solid; temp. beats 1.24 min (method 1); m/z 336 (M+H) ⁺ (electrospray ⁺ ).

(1 r,4r)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclohexan-1-ol (B4)

- 70 041318

G,

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (32.6

138 mmol), trans-4-aminocyclohexanol (18.5 g, 160.6 mmol) and potassium carbonate (40 g, 289 mmol) were refluxed in acetonitrile (500 ml) for 3 h. The mixture was diluted dropwise with water (2 L) with vigorous stirring. The resulting precipitate was collected by filtration to give (1r,4r)-4-((4-(3,5dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclohexanol (56.5 g, 99%) as a bright orange a solid; temp. beats 2.00 min (method 1); m/z 332 (M+H)+ (electrospray ⁺ ).

(1r,4r)-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclohexan-1-ol (С4)

Sodium dithionite (300 g, 1465 mmol) was slowly added in three portions (approximately 100 g) to the mixture of (1r,4r)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino) cyclohexanol (56 g, 135 mmol), concentrated ammonia (110 ml, 2825 mmol), THF/water (1:1, 1 L, then stirred at room temperature for 40 min. (total) The mixture was diluted with water (2 L), then the precipitate was collected by filtration to give a pink solid The solid was evaporated in acetonitrile (500 ml) to give (1r,4r)-4-((2-amino-4-(3.5 -dimethylisoxazol-4yl)phenyl)amino)cyclohexan-1-ol (33 g, 80%) as a pink solid, time sp 1.05 min (method 1), m/z 302 (M+H)+ (electrospray ⁺ ).

(S)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydrothiophene 1,1-dioxide (B5)

A mixture of 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (2.92 g, 12.35 mmol) and (S)-3aminotetrahydrothiophene-1,1-dioxide (1.67 g, 12.35 mmol) was stirred in dry THF (20 ml) and TEA (6.89 ml, 49.4 mmol) was added. The reaction mixture was stirred at rt. for 72 h, then poured into ice water (100 ml). The solid residue was collected by filtration. The solid was washed with water to give (S)-3-((4-(3,5-dimethylisoxazol-4-yl)-2nitrophenyl)amino)tetrahydrothiophene 1,1-dioxide (B5) (4.47 g, 100%) as a bright orange solid; temp. beats 1.88 min (method 1); m/z 352 (M+H)+ (electrospray ⁺ ).

(S)-3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)tetrahydrothiophene 1,1-dioxide (C5)

(S)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydrothiophene-1,1-dioxide (3.42 g, 9.73 mmol) was dissolved in water (150 ml) and THF (150 ml). Ammonium hydroxide solution (7.58 ml, 195 mmol) and sodium dithionite (16.95 g, 97 mmol) were added and the reaction mixture was stirred at rt. over 2 h. EtOAc (200 ml) was added, the mixture was transferred to a separating funnel and washed successively with 1M NaOH solution (2x200 ml) and brine (100 ml). The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo to give an off-white solid,

- 71 041318 which was triturated with ether and collected by filtration to give (S)-3-((2-amino-4-(3,5dimethylisoxazol-4-yl)phenyl)amino)tetrahydrothiophene 1,1-dioxide (1.4 g, 42%) as a flowing light pink solid; temp. beats 1.26 min (method 1); m/z 322 (M+H)+ (electrospray ⁺ ).

tert-Butyl (S)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate (B6)

A mixture of 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (6.34 g, 26.8 mmol) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (5 g, 26.8 mmol) was stirred in dry THF ( 100 ml) and TEA (11.23 ml, 81 mmol) was added. The reaction mixture was stirred at 40°C for 72 h, then heated to 50°C and stirred for 18 h. the reaction mixture was poured into ice water (300 mL). The mixture was extracted with ethyl acetate (2x500 ml). The combined organics were dried (MgSO ₄ ) and concentrated in vacuo to give (S)-tert-butyl 3-((4(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidin-1 -carboxylate (11.57 g, 99%) as a thick orange oil; temp. beats 1.26 min (method 1); m/z 322 (M+H)+ (electrospray ⁺ ).

tert-Butyl (S)-3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)pyrrolidine-1-carboxylate (С6)

(S)-tert-butyl 3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate (10.8 g, 26.8 mmol) was dissolved in water (500 ml) and THF (500 ml). Concentrated ammonia (20.90 ml, 537 mmol) and sodium dithionite (46.7 g, 268 mmol) were added and the reaction mixture was stirred at rt. over 18 h. EtOAc (500 ml) was added, the mixture was transferred to a separating funnel and washed successively with 1M NaOH solution (400 ml) and brine (200 ml). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give an off-white solid. This material was triturated with ether and collected by filtration. The filtrate was concentrated in vacuo to give a light, fluffy off-white solid. After analysis by LCMS and NMR, the triturated material and the material obtained from the filtrate were combined to give (S)-tert-butyl 3-((2-amino-4-(3,5-dimethylisoxazol-4yl)phenyl)amino )pyrrolidine-1-carboxylate (7.64 g, 76%) as an off-white friable solid; temp. beats 1.98 min (method 1); m/z 273 (M-Boc+H)+ (electrospray ⁺ ).

tert-Butyl (R)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate (B6)

Sun /—N

A mixture of 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (10 g, 42.3 mmol) and (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (7.89 g, 42.3 mmol) was stirred in dry THF ( 100 ml) and TEA (17.70 ml, 127 mmol) was added. The reaction mixture was stirred at rt. for 18 h, then heated to 40°C and stirred for 72 h, then heated to 50°C and stirred for 18 h. the reaction mixture was poured into ice water (300 ml). The mixture was extracted with ethyl acetate (2x500 ml). The combined organics were dried (MgSO ₄ ) and concentrated in vacuo to give (R)-tert-butyl 3-((4-(3,5-dimethylisoxazol-4-yl)-2nitrophenyl)amino)pyrrolidin-1- carboxylate (17.85 g, 96%) as a thick orange oil; temp. beats

- 72 041318

2.55 min (method 1); m/z 403 (M+H)+ (electrospray ⁺ ).

tert-Butyl (K)-3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)pyrrolidine-1-carboxylate (С6)

(R)-T-butyl 3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate (17.04 g, 42.3 mmol) was dissolved in THF/water ( 1:1, 1 l). Ammonia (33.0 ml, 847 mmol) and sodium dithionite (73.7 g, 423 mmol) were added and the reaction mixture was stirred at RT. over 18 h. EtOAc (500 ml) was added, the mixture was transferred to a separating funnel and washed successively with 1M NaOH solution (400 ml) and brine (200 ml). The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo to give a light peach crumbly solid. This material was triturated with ether and collected by filtration. The filtrate was concentrated in vacuo to give a clear foam. The ground material and the material obtained from the filtrate were combined, resulting in (R)-tert-butyl 3-((2-amino-4-(3,5-dimethylisoxazol4-yl)phenyl)amino)pyrrolidine-1-carboxylate (13.58 g, 85%) as light peach crumbly solid; temp. beats 1.98 min (method 1); m/z 273 (M-Boc+H)+ (electrospray ⁺ ).

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1-methylpyrrolidin-3-amine (B7)

1-methylpyrrolidin-3-amine (1.060 g, 10.58 mmol) was added to a suspension of 1-methylpyrrolidin-3amine, bis-hydrochloride (2.75 g, 15.88 mmol) in DIPEA (8.32 ml, 47.6 mmol) and THF (30 ml, 366 mmol ), stirred and sonicated for 15 min. A solution of 4-(4fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (2.5 g, 10.58 mmol) in DMF (5 ml, 64.6 mmol) was added to the suspension and the reaction mixture was stirred at 50°C for 20 h, then for another 20 hours at 70°C. Additional 1-methylpyrrolidin-3-amine (1.060 g, 10.58 mmol) was added and stirred for 5 h.

Additional DMF (10 mL, 129 mmol) was added and stirred for another 20 h. Solvents were evaporated in vacuo, the residue was partitioned between EtOAc (100 mL) and saturated aqueous sodium hydrogen carbonate (100 mL) and the layers were separated. The aqueous phase was extracted with additional EtOAc (2x50 ml), the combined organic extracts were washed with water (50 ml) and brine (50 ml). The solution was dried (MgSO ₄ ), filtered and evaporated under vacuum. The resulting resin was purified by Companion chromatography (180 g column, 0100% EtOAc in DCM, then 0-50% (DCM/MeOH/NH3 (80:20:1) in DCM, loading in DCM) to give N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1-methylpyrrolidin-3-amine Intermediate B7 (2.5 g, 75%) sp temp 1.10 min (method 1 m/z 317 (M+H)+ (electrospray ⁺ ).

4-(3,5-dimethylisoxazol-4-yl)-N ¹ -(1-methylpyrrolidin-3 -yl)benzene-1,2-diamine (С7)

Intermediate B7 (2.5 g, 7.90 mmol) and concentrated ammonia (5 ml, 128 mmol) were dissolved in THF/water (1:1, 150 ml). Sodium dithionite (13.76 g, 79 mmol) was added and the reaction mixture was stirred at rt. for 3 h. The layers were separated, the aqueous layer was extracted with ethyl acetate (100 ml), the combined organic layers were washed with brine (50 ml), dried (MgSO ₄ ), filtered and evaporated under vacuum, resulting in 4-(3.5 -dimethylisooxazol-4-yl)-N ¹ (1-methylpyrrolidin-3-yl)benzene-1,2-diamine Intermediate C7 (1.8 g, 77%) as orange-yellow solid; temp. beats 0.31 min (method 1); m/z 287 (M+H)+ (electrospray ⁺ ).

- 73 041318

4-(3,5-dimethylisoxazol-4-yl)-N-((1g,4g)-4-methoxycyclohexyl)-2-nitroaniline (B8)

4-(4-Fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (0.609 g, 2.58 mmol) was dissolved in dry THF (20 mL) and TEA (1.079 mL, 7.74 mmol). (1r,4r)-4-Methoxycyclohexanamine (0.4 g, 3.10 mmol) was added and the reaction mixture was heated to 60°С and allowed to stir at rt. within 84 hours. After cooling to rt. The reaction mixture was poured into ice water (100 ml) then extracted with ethyl acetate (2x100 ml). The combined organics were concentrated in vacuo (azeotroping with acetonitrile) to give crude 4-(3,5-dimethylisoxazol-4-yl)-N-((1g,4g)-4methoxycyclohexyl)-2-nitroaniline (1.1 g, 3.12 mmol, >100%), which was used without purification in the next step; temp. beats 2.40 min (method 1); m/z 346 (M+H)+ (electrospray ⁺ ).

4-(3,5-dimethylisoxazol-4-yl)-N ¹ -(( 1 g, 4 g)-4-methoxycyclohexyl)benzene-1,2-diamine (С8)

4-(3,5-dimethylisoxazol-4-yl)-N-((1g,4g)-4-methoxycyclohexyl)-2-nitroaniline (0.89 g, 2.58 mmol) was dissolved in water (50 ml) and THF (50 ml ). Concentrated ammonia (2.0 ml, 51.5 mmol) and sodium dithionite (4.49 g, 25.8 mmol) were added and the reaction mixture was stirred at rt. over 2 hours EtOAc (250 ml) was added, the mixture was transferred to a separating funnel and washed successively with 1M NaOH solution (150 ml) and brine (100 ml). The organic phase was passed through a phase separation cartridge and concentrated in vacuo to give 4-(3,5dimethylisoxazol-4-yl)-N ¹ -((1g,4g)-4-methoxycyclohexyl)benzene-1,2-diamine (680 mg, 81%) as an orange solid; temp. beats 1.24 min (method 1); m/z 316 (M+H) ⁺ (electrospray ⁺ ).

3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (B9)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (2 g, 8.47 mmol) was dissolved in dry THF (50 ml) and TEA (4.72 ml, 33.9 mmol). 3-Aminotetrahydro-2N-thiopyran 1,1-dioxide hydrochloride (1.89 g, 10.16 mmol) was added and the reaction mixture was heated to 60° C. and allowed to stir at rt. over 84 h. DMF (20 ml) was added and the reaction mixture was heated at 70° C. for 18 h. After cooling to rt. The reaction mixture was poured into ice water (200 ml) then extracted with ethyl acetate (2x200 ml). The combined organics were concentrated in vacuo (azeotroping with acetonitrile) to give 3-((4-(3,5-dimethylisoxazol-4-yl)-2nitrophenyl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (3.6 g, 8.37 mmol, 99%) as an orange solid; temp. beats 1.93 min (method 1); m/z 366 (M+H) ⁺ (electrospray ⁺ ).

3-((2-Amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (C9)

3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (3.09 g, 8.46 mmol) was dissolved in a THF/water mixture (1: 1, 400 ml). Add concentrated ammonia (6.59

- 74 041318 ml, 169 mmol) and sodium dithionite (14.72 g, 85 mmol) and the reaction mixture was stirred at room temperature. over 2 hours. EtOAc (500 ml) was added, the mixture was transferred to a separating funnel and washed successively with 1M NaOH solution (400 ml) and brine (200 ml). The organic phase was passed through a PhaseSep© cartridge and concentrated in vacuo to give 3-((2-amino-4(3,5-dimethylisoxazol-4-yl)phenyl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (1.80 g, 62%) as a whitish film; temp. beats 1.31 min (method 1); m/z 336 (M+H)+ (electrospray ⁺ ).

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1-(methylsulfonyl)piperidine-4-amine (B10)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (2 g, 8.47 mmol) was dissolved in dry THF (50 ml) and TEA (4.72 ml, 33.9 mmol). 1-(methylsulfonyl)piperidine-4-amine hydrochloride (2.182 g, 10.16 mmol) was added, the reaction mixture was heated to 60°C and allowed to stir at RT. over 84 h. DMF (20 ml) was added and the reaction mixture was heated at 70° C. for 18 h. the reaction mixture was poured into ice water (200 ml) then extracted with ethyl acetate (2x200 ml). The combined organics were concentrated in vacuo (azeotroping with acetonitrile) to give N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1(methylsulfonyl)piperidine-4-amine (4.67 g, 11.72 mmol, 138% yield) as an orange solid, which was used without further purification in the next step; temp. beats 2.11 min (method 1); m/z 395 (M+H) ⁺ (electrospray ⁺ ).

4-(3,5-dimethylisoxazol-4-yl)-N ¹ -(1 -(methylsulfonyl)piperidin-4-yl)benzene-1,2-diamine (С10)

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-1-(methylsulfonyl)piperidine-4-amine (3.34 g, 8.47 mmol) was dissolved in water (200 ml) and THF (200 ml). Concentrated ammonia (6.59 ml, 169 mmol) and sodium dithionite (14.74 g, 85 mmol) were added and the reaction mixture was stirred at rt. over 2 hours. EtOAc (500 ml) was added, the mixture was transferred to a separating funnel and washed successively with 1M NaOH solution (400 ml) and brine (200 ml). The organic phase was passed through a phase separator cartridge and concentrated in vacuo to give 4-(3,5dimethylisoxazol-4-yl)-N ¹ -(1-(methylsulfonyl)piperidin-4-yl)benzene-1,2- diamine (1.97 g, 4.97 mmol, 58.7% yield) as a whitish film; temp. beats 1.35 min (method 1); m/z 365 (M+H) ⁺ (electrospray ⁺ ).

(1R,3R)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentan-1-ol (B 11)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (1.14 g, 4.84 mmol), (1r,3r)-3-aminocyclopentanol hydrochloride (1.0 g, 7.27 mmol) and TEA (2.4 ml, 16.96 mmol ) was refluxed in THF (17.47 mL, 213 mmol) for 18 h. The mixture was cooled to RT and concentrated in vacuo/pre-adsorbed on silica. Purification by flash chromatography on a Companion (40 g column, 50-100% EtOAc/isohexane) gave (1r,3r)-3-((4-(3,5-dimethylisoxazol-4-yl)-2nitrophenyl)amino)cyclopentanol (0.66 g, 40%) as an orange solid; temp. beats 1.94 min (method 1); m/z 318 (M+H) ⁺ (electrospray ⁺ ).

- 75 041318 (1 R, 3R) -3 - ((2-amino-4- (3,5-dimethylisoxazol-4-yl) phenyl) amino) cyclopentan-1 -ol (C11)

(1R,3R)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentanol (0.66 g, 2.080 mmol) and concentrated ammonia (1.296 ml, 33.3 mmol) were dissolved in mixtures of THF/water (40 ml). Sodium dithionite (3.62 g, 20.80 mmol) was added and the reaction mixture was stirred at rt. over 1.5 h. EtOAc (200 ml) was added, the mixture was transferred to a separating funnel and washed successively with 1M NaOH solution (50 ml) and brine (100 ml). The organic phase was passed through a PhaseSep® cartridge and concentrated in vacuo to give (1R,3R)-3-((2-amino-4(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclopentanol (0.45 g , 1.535 mmol, 73.8% yield) as a violet solid; temp. beats 1.06 min (method 1); m/z 288 (M+H)+ (electrospray ⁺ ).

X-(4,4-difluorocyclohexyl)-4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline (B12)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (4.0 g, 16.77 mmol), 4,4-difluorocyclohexanamine hydrochloride (3.0 g, 17.48 mmol) and potassium carbonate (7.0 g, 50.6 mmol) were heated with reflux in acetonitrile (60 ml) for 2 h. Add 4,4-difluorocyclohexanamine hydrochloride (3.0 g, 17.48 mmol) and potassium carbonate (7.0 g, 50.6 mmol) and heat the mixture for another 4 h. diluted with water (200 mL) and filtered to give N-(4,4-difluorocyclohexyl)4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline (5.85 g, 98%) as an orange crystalline a solid; temp. beats 1.67 min (method 1); m/z 352 (M+H)+ (electrospray ⁺ ).

N ¹ - (4,4-difluorocyclohexyl) -4- (3,5-dimethylisoxazol-4-yl) benzene-1,2-diamine (C12)

188 g

Sodium dithionite (38.5 mmol) was added to a mixture of N-(4,4-difluorocyclohexyl)-4-(3,5 dimethylisoxazol-4-yl)-2-nitroaniline (5.85 g, 16.48 mmol), concentrated ammonia (15 ml, 385 mmol), THF/water (1:1, 120 mL), then stirred at room temperature for 2.5 h. The mixture was diluted with water (250 mL), then filtered to give N1-(4,4difluorocyclohexyl)-4 -(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine (4.1 g, 70% yield); temp. beats 1.27 min (method 1); m/z 322 (M+H)+ (electrospray ⁺ ).

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-2-methyltetrahydro-2H-pyran-4-amine (B13)

A solution of 2-methyltetrahydro-2H-pyran-4-amine (1.024 g, 8.89 mmol), DIPEA (2.59 ml, 14.82 mmol) and 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (1.75 g, 7.41 mmol) in THF (40 ml) was heated under reflux for 24 h. The reaction mixture was concentrated under vacuum/preadsorbed on silica. The crude product was purified by silica gel chromatography (40 g column, 0-50% EtOAc/isohexane) to give N-(4-(3.5-76041318 dimethylisoxazol-4-yl)-2-nitrophenyl)-2- methyltetrahydro-2H-pyran-4-amine (1.76 g, 71%) as a yellow solid; temp. beats 2.27 min (method 1); m/z 332 (M+H)+ (electrospray ⁺ ).

The product was analyzed by LCMS (Agilent, X-Select, Waters X-Select C18, 2.5 µm, 4.6x30 mm, acidic conditions (0.1% formic acid) 4 minute method, 5-95% MeCN/water): 1576-41-P , m/z 332.2 (M+H)+ (electrospray ⁺ ); at 2.27 min, 99% pure at 254 nm. ¹ H-NMR (d ₆ -DMSO) was consistent with the structure of the product, as a mixture of 9:1 diastereomers.

4-(3,5-dimethylisoxazol-4-yl)-N ¹ -(2-methyltetrahydro-2H-pyran-4-yl)benzene-1,2-diamine (С13)

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-2-methyltetrahydro-2H-pyran-4-amine (1.66 g, 5.01 mmol) was dissolved in THF (71.0 ml, 867 mmol) , water (68.2 ml, 3787 mmol), ammonia (3.90 ml, 100 mmol) and sodium dithionite (8.72 g, 50.1 mmol) were added and the reaction mixture was stirred at rt. for 2 h. The layers were separated, the aqueous layer was extracted with ethyl acetate (2x20 ml), the combined organic layers were washed with brine (20 ml), dried (MgSO ₄ ), filtered and evaporated under vacuum, resulting in 4-(3.5 -dimethylisoxazol-4-yl)-N ¹ -(2-methyltetrahydro-2H-pyran-4-yl)benzene1,2-diamine (1.45 g, 85% yield) as a yellow oil; temp. beats 1.55 min (method 1); m/z 302 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO), which is consistent with the structure of the product, as a mixture of diastereomers 9:1.

4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)piperidin-2-one (B14)

To a solution of 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (1.3 g, 5.50 mmol) in tetrahydrofuran (26.6 ml) and DIPEA (1.923 ml, 11.01 mmol) was added 4-aminopiperidin-2-one ( 0.942 g, 8.26 mmol). The reaction mixture was stirred at 70° C. for 48 hours. The reaction mixture was cooled to rt. Solvents were evaporated in vacuo and the orange residue was partitioned between EtOAc (100 ml), DCM (100 ml) and saturated aqueous NaHCO ₃ (100 ml) and the layers were separated. The aqueous phase was extracted with additional DCM (2x100 ml), the combined organic extracts were washed with water (100 ml) and brine (100 ml). The solution was dried (MgSO ₄ ), filtered and evaporated under vacuum. The resulting orange solid was purified by Companion chromatography (24 g column, 0-100% EtOAc in DCM followed by 0-10% MeOH in DCM, loaded on silica gel) to give 4-((4-(3 ,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)piperidin-2-one (1.0 g, 54%) as an orange foam; temp. beats 1.66 min (method 1); m/z 331 (M+H)+ (electrospray ⁺ ).

4-((2-Amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)piperidin-2-one (С14)

4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)piperidin-2-one (1.0 g, 3.03 mmol) and concentrated ammonia (1.886 ml, 48.4 mmol) were dissolved in a mixture of THF /water (1:1, 58 ml). Sodium dithioate (6.24 g, 30.3 mmol) was added and the reaction mixture was stirred at rt. After 1 h stirring, the layers were separated, the aqueous layer was extracted with ethyl acetate (100 ml), and the combined organic layers were washed with brine (50 ml), dried (MgSO ₄ ), filtered and evaporated under vacuum, resulting in 4-((2- amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)piperidin-2-one (0.67 g, 71%) as a white solid; temp. beats 1.41 min (method 1); m/z 301 (M+H)+ (electrospray ⁺ ).

- 77 041318 (1s,4s)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)-1-methylcyclohexan-1-ol (B15)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (750 mg, 3.18 mmol), (^^)-4-amino-1-methylcyclohexanol (500 mg, 3.87 mmol) and potassium carbonate (600 mg, 4.34 mmol) was heated under reflux in acetonitrile (10 ml) for 1 h. The mixture was diluted with water (50 ml), then the precipitate was collected by filtration. The crude product was purified by Companion chromatography (40 g column, 0-50% EtOAc/isohexane) to give (1s,4s)-4-((4-(3,5-dimethylisoxazol-4-yl)2- nitrophenyl)amino)-1-methylcyclohexanol (855 mg, 74%) as an orange solid; temp. beats 2.15 min (method 1); m/z 346 (M+H)+ (electrospray ⁺ ).

(1s,4s)-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-methylcyclohexan-1-ol (С15)

Sodium dithionite (5 g, 24.41 mmol) was added to a mixture of (1s,4s)-4-((4-(3,5-dimethylisoxazol-4-yl)-2nitrophenyl)amino)-1-methylcyclohexanol (844 mg, 2.444 mmol ), concentrated ammonia (2 ml, 51.4 mmol), THF/water (1:1 12 ml), then stirred at room temperature for 3 h. The mixture was diluted with brine (100 ml), then extracted with ethyl acetate (3x 150 ml) , then dichloromethane (2x50 ml). The combined organic phases were concentrated under reduced pressure. The residue was stirred in ethanol (15 ml) and water (35 ml) with sodium bicarbonate (205 mg, 2.444 mmol) for 15 min. The solid was collected by filtration to give (1s,4s)-4-((2-amino4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-methylcyclohexanol (574 mg, 73%) in as a pink solid; temp. beats 1.28 min (method 1); m/z 316 (M+H)+ (electrospray ⁺ ).

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-2-oxaspiro[3.3]heptan-6-amine (B16)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (1.435 g, 6.08 mmol) and 2-oxaspiro[3.3]heptan-6amine hydrochloride (1 g, 6.68 mmol) were dissolved in dry dimethylformamide (20 ml) . TEA (2.54 mL, 18.23 mmol) was added and the reaction mixture was heated to 60°C and allowed to stir at rt. within 3 hours. After cooling to rt. the reaction mixture was poured into ice water (100 ml) then extracted with ethyl acetate (2 x 100 ml). The combined organics were dried (MgSO ₄ ) and concentrated in vacuo, then azeotroped with acetonitrile to give N-(4-(3,5dimethylisoxazol-4-yl)-2-nitrophenyl)-2-oxaspiro[3.3]heptan- 6-amine (2.58 g, >100% yield) as an orange solid, which was used in the next step without further purification; temp. beats 2.14 min (method 1); m/z 330 (M+H)+ (electrospray ⁺ ).

4-(3,5-dimethylisoxazol-4-yl)-N ¹ -(2-oxaspiro[3.3]heptan-6-yl)benzene-1,2-diamine (C16)

- 78 041318

N-(4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-2-oxaspiro[3.3]heptan-6-amine (2.00 g, 6.07 mmol) was dissolved in a mixture of THF/water (1:1 , 300 ml). Sodium dithionite (10.57 g, 60.7 mmol) was added followed by concentrated ammonia (4.73 ml, 121 mmol) and the reaction mixture was stirred at rt. within 10 min.

EtOAc (200 ml) was added, the mixture was transferred to a separating funnel and washed successively with 1M NaOH solution (100 ml) and brine (100 ml). The organic phase was passed through a PhaseSep© cartridge and concentrated in vacuo to give 4-(3,5dimethylisoxazol-4-yl)-N ¹ -(2-oxaspiro[3.3]heptan-6-yl)benzene-1,2- diamine (1.47 g, 4.76 mmol, 78% yield) as a light pink solid; temp. beats 1.35 min (method 1); m/z 300 (M+H)+ (electrospray ⁺ ).

(1g,3d)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclobuten-1-ol (B17)

4-(4-Fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (8.69 g, 36.8 mmol) was dissolved in dry dimethylformamide (50 ml) and TEA (20.51 ml, 147 mmol). (1g,3g)-3-aminocyclobutanol hydrochloride (5 g, 40.5 mmol) was added and the reaction mixture was heated to 60°C and allowed to stir at rt. within 18 hours. After cooling to rt. the reaction mixture was poured into ice water (300 ml) The precipitate was collected to give (1g,3g)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclobutanol (11.16 g, 98%) as an orange solid; temp. beats 1.89 min (method 1); m/z 304 (M+H)+ (electrospray ⁺ ).

(1g,3d)-3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclobuten-1-ol (С17)

(1g,3g)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclobutanol (11.16 g, 36.8 mmol) was dissolved in THF/water (1:1, 800 ml). Sodium dithionate (64.1 g, 368 mmol) was added followed by concentrated ammonia, 28% sol. (28.7 ml, 736 mmol) and stirred the reaction mixture at rt. within 18 hours was Added EtOAc (1 l)and then 1M NaOH (500 ml). After stirring for 5 minutes, the layers were allowed to separate and the aqueous phase was removed. The organic phase was stirred with brine (500 ml), allowed to separate, then collected and dried (MgSO ₄ ). The solvent was removed in vacuo and the residue was triturated with ether (200 ml) to give (1g,3g)-3-((2-amino-4(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclobutanol ( 7.07 g, 70%) as a beige solid; temp. beats 1.09 min (method 1); m/z 274 (M+H)+ (electrospray ⁺ ).

(1 g, 4 g)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)-1-methylcyclohexan-1-ol (B 18)

- 79 041318

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (1.618 g, 6.85 mmol), (1g,4g)-4-amino-1methylcyclohexanol (1.0 g, 7.74 mmol) and potassium carbonate (1.638 g, 11.85 mmol) was heated under reflux in acetonitrile (20.75 ml) for 1 h. The reaction mixture was cooled to RT and stirred overnight. The mixture was diluted with water (200 ml), then the orange precipitate was collected by filtration. The crude product (about 4 g as a wet solid) was purified by Companion chromatography (24 g column, 0-50% EtOAc/DCM) to give (1 g.4 g)4-((4-(3.5 -dimethylisoxazol-4-yl)-2-nitrophenyl)amino)-1-methylcyclohexanol (2.0 g, 79%) as an orange solid; temp. beats 2.10 min (method 1); m/z 346 (M+H)+ (electrospray ⁺ ).

(1 g, 4 g)-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-methylcyclohexan-1-ol (C 18)

Me OH Me OH ff me ίι ίίι ^ν Α/^ ^ν ° ² '

BAHA

meme

Sodium dithionite (11.10 g, 53.9 mmol) was added to a mixture of (1 g, 4 g)-4-((4-(3,5-dimethylisoxazol-4-yl)2-nitrophenyl)amino)-1-methylcyclohexanol (2.0 g, 5.39 mmol), concentrated ammonia (4.09 mL, 105 mmol), THF/water (1:1, 32.6 mL), then stirred at room temperature. Due to the low solubility, the solvent volume was doubled. After 2 h the layers were separated, the aqueous layer was extracted with ethyl acetate (2x100 ml), the combined organic layers were washed with water (50 ml) and brine (50 ml), dried (MgSO ₄ ), filtered and evaporated under vacuum, resulting in (1 g .4d)-4-((2-amino-4(3,5-dimethylisoxazol-4-yl)phenyl)amino)-1-methylcyclohexanol (1.45 g, 82%) as a violet solid; temp. beats 1.10 min (method 1); m/z 316 (M+H)+ (electrospray ⁺ ).

1-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)propan-2-ol (B19)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (4 g, 16.93 mmol) was dissolved in dry THF (69.4 ml, 847 mmol) and TEA (7.08 ml, 50.8 mmol). 1-Aminopropan-2-ol (1.438 ml, 18.63 mmol) was added and the reaction mixture was heated to 60°C and allowed to stir at rt. within 18 hours. After cooling to rt. The reaction mixture was poured into ice water (300 ml) and extracted with ethyl acetate (2x75 ml). The organic extracts were combined and then dried with MgSO ₄ , filtered and concentrated in vacuo to give 1-((4-(3,5-dimethylisoxazol-4-yl)-2nitrophenyl)amino)propan-2-ol ( 4.90 g, 98%) as a yellow solid; temp. beats 1.85 min (method 1); m/z 292 (M+H)+ (electrospray ⁺ ).

-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)propan-2-ol (C 19) he he

me ^me

Me i| ^N A/^ ^N ° ² oAoA

meme

1-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)propan-2-ol (4.9 g, 16.82 mmol) was dissolved in THF/water (1:1, 132 ml). Sodium dithionite (34.5 g, 168 mmol) was added followed by concentrated ammonia (13.10 mL, 336 mmol) and the reaction mixture was stirred at rt. over 1 h. EtOAc (200 ml) was added, the mixture was transferred to a separating funnel and washed successively with 1M NaOH (100 ml) and brine (100 ml). The organic phase was passed through a Phase Sep© cartridge and concentrated in vacuo to give 1-((2-amino-4-(3,5-dimethylisoxazol-4yl)phenyl)amino)propan-2-ol (3.7 g, 78 %) as a red solid; temp. beats 2.10 min (method 1); m/z 262 (M+H)+ (electrospray ⁺ ).

4-(3,5-dimethylisoxazol-4-yl)-N-isobutyl-2-nitroaniline (B20)

- 80 041318

A mixture of 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (10 g, 42.3 mmol) and 2-methylpropan-1-amine (21.04 ml, 212 mmol) was stirred in dry THF (100 ml) and stirred reaction mixture at room temperature for 18 h, then poured into ice water (300 ml). The mixture was extracted with ethyl acetate (2x500 ml). The combined organics were dried (MgSO ₄ ) and concentrated in vacuo to give 4-(3,5-dimethylisoxazol-4-yl)-N-isobutyl-2-nitroaniline (12.25 g, 100%) as an orange solid ; temp. beats 2.64 min (method 1); m/z 290 (M+H)+ (electrospray ⁺ ).

4-(3,5-dimethylisoxazol-4-yl)-N ¹ -isobutylbenzene-1,2-diamine (С20)

4-(3,5-dimethylisoxazol-4-yl)-N-isobutyl-2-nitroaniline (12.25 g, 42.3 mmol) was dissolved in THF/water (1:1, 800 ml). Sodium dithionite (73.7 g, 423 mmol) was added followed by concentrated ammonia (33.0 ml, 847 mmol) and the reaction mixture was stirred at rt. over 18 hours. EtOAc (1 L) was added followed by 1M NaOH (500 ml). After stirring for 5 minutes, the layers were allowed to separate and the aqueous phase was removed. The organic phase was stirred with brine (500 ml), allowed to separate, then collected and dried (MgSO ₄ ). The solvent was removed in vacuo and the residue triturated with ether (200 ml) to give 4-(3,5-dimethylisoxazol-4-yl)-N ¹ isobutylbenzene-1,2-diamine as a beige solid; temp. beats 1.09 min (method 1); m/z 274 (M+H)+ (electrospray ⁺ ).

N-(3,3-difluorocyclobutyl)-4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline (B21)

4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (1.870 g, 7.92 mmol) and 3,3-difluorocyclobutanamine hydrochloride (1.25 g, 8.71 mmol) were dissolved in dry dimethylformamide (20 ml). TEA (3.31 mL, 23.75 mmol) was added and the reaction mixture was heated to 60°C and allowed to stir at rt. within 3 hours. After cooling to rt. the reaction mixture was poured into ice water (100 ml) then extracted with ethyl acetate (2x100 ml). The combined organics were dried (MgSO ₄ ) and concentrated in vacuo (azeotroping with acetonitrile) to give N-(3,3-difluorocyclobutyl)-4(3,5-dimethylisoxazol-4-yl)-2-nitroaniline (2.11 g, 5.94 mmol, 75% yield) as an orange solid; temp. beats 2.42 min (method 1); m/z 324 (M+H)+ (electrospray ⁺ ).

N ¹ -(3,3-difluorocyclobutyl)-4-(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine (C21)

N-(3,3-difluorocyclobutyl)-4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline (2.10 g, 6.50 mmol) was dissolved in THF/water (1.1, 200 ml). Sodium dithionate (11.31 g, 65.0 mmol) was added followed by concentrated ammonia (5.06 mL, 130 mmol) and the reaction mixture was stirred at RT. within 1 h. Added EtOAc (200 ml) and then 1M NaOH (150 ml). The mixture was vigorously shaken and the aqueous phase was discarded. The organic phase was washed with brine (100 ml), then collected and dried

- 81 041318 (MgSO ₄ ). The solvent was removed in vacuo to give N ¹ -(3,3-difluorocyclobutyl)-4(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine (1.12 g, 58%) as an off-white solid substances; temp. beats

1.84 min (method 1); m/z 294 (M+H) ⁺ (electrospray ⁺ ).

Methyl (1g,4g)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclohexane-1-carboxylate (B22)

To a suspension of (1g,4g)-methyl 4-aminocyclohexanecarboxylate hydrochloride (3.4 g, 17.56 mmol) and DIPEA (7.67 ml, 43.9 mmol) in acetonitrile (68.8 ml) was added 4-(4-fluoro-3-nitrophenyl)-3, 5dimethylisoxazole (4.56 g, 19.31 mmol). The heterogeneous reaction mixture was stirred at 75° C. for 39 hours. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo to give a mixture of oil and orange solid (11 g). The solid was triturated twice with Et ₂ O (50 ml) then isohexanes (50 ml). The solid was dried under vacuum to give 7.5 g of a solid which was dried, loaded and purified by column chromatography (120 g, DCM/MeOH: 100/0 to 95/5) to give (1 g, 4d)-methyl 4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclohexanecarboxylate (4.29 g, 63%), which was isolated as an orange solid; temp. beats 2.49 min (method 1); m/z 374 (M+H) ⁺ (electrospray ⁺ ).

Methyl (1g,4g)-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclohexane-1-carboxylate (C22)

Sodium dithionite (23.68 g, 115 mmol) was added to a mixture of (1 g, 4 g)-methyl-4-((4-(3,5-dimethylisoxazol4-yl)-2-nitrophenyl)amino)cyclohexanecarboxylate (4.29 g, 11.49 mmol) , concentrated ammonia (8.72 ml, 224 mmol), water (34.8 ml) and THF (43.3 ml), then stirred at room temperature for 15 h. The layers were separated, the aqueous layer was extracted with ethyl acetate (2x100 ml), the combined organic layers were washed with water (2x100 ml) and brine (100 ml), dried (MgSO ₄ ), filtered and evaporated in vacuo to give (1g,4g)-methyl-4-((4-(3,5-dimethylisoxazol4-yl )-2-nitrophenyl)amino)cyclohexanecarboxylate (3.52 g, 87%) as a crude pink-red substance; temp. beats 1.49 min (method 1); m/z 344 (M+H)+ (electrospray ⁺ ).

(R)-N ¹ -(3,3-difluorocyclopentyl)-4-(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine (B23)

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Examples

Example 1: 5-(5-(3,5-dimethylisoksazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl)- 1-phenylpyrrolidin-2-one.

N-(5-(3,5-dimethylisoksazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-5oxo-1-phenylpyrrolidin-2-carboxamide

HATU (110 mg, 0.289 mmol) was added to a solution of intermediate C1 (100 mg, 0.254 mmol), 5-oxo-1-phenylpyrrolidine-2-carboxylic acid (55 mg, 0.268 mmol) and N,N-diisopropylethylamine (55 µl, 0.315 mmol) in N,N-dimethylformamide (2 ml), then stirred at room temperature overnight. The mixture was diluted with water (20 ml) then extracted with ethyl acetate (2x20 ml). The combined organic phases were washed with 20% brine (2x20 ml), brine (20 ml), then dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (12 g column, 50-100% EtOAc/DCM) to give N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)- 1(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-5-oxo-1-phenylpyrrolidine-2-carboxamide (87 mg, 63%) as a colorless foam; temp. beats 1.78 min (method 1); m/z 538 (M+H) + (electrospray ⁺ ).

5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Нbenzo[d]imidazol-2-yl)-1-phenylpyrrolidine -2-he

N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-5oxo-1-phenylpyrrolidin-2-carboxamide (135 mg, 0.251 mmol) was heated to 80°C in acetic acid (3 ml) for 2.5 days. Volatiles were removed under reduced pressure, then the residue was purified by preparative HPLC (Gilson, acid conditions (0.1% formic acid), acid conditions, Waters X-Select Prep-C18 column, 5 µm, 19x50 mm, 15-40% MeCN in water) , resulting in 5-(5(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3 -yl)-1 H-benzo[d]imidazol-2 -yl)-1 phenylpyrrolidin-2-one (15 mg, 11%) as a colorless glassy substance; temp. beats 1.77 min 2 (method 1); m/z 520 (M+H)+ (electrospray ⁺ );

¹ H-NMR in DMSO-b6 7.75 (dt, J=8.4, 0.9 Hz, 1H), 7.65 (dd, J=1.6, 0.6 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.31 (ddd, J =8.8, 7.3, 1.8Hz, 2H), 7.25 (dd, J=8.5, 1.8Hz, 1H), 7.09 (tq, J=7.6, 1.0Hz, 1H), 6.06 (dd, J=8.2, 2.3Hz, 1H), 5.59 - 5.46 (m, 1H), 3.83 - 3.58 (m, 3H), 3.47 - 3.36 (m, 1H), 3.09 (s, 3H), 2.82 - 2.47 (m, 4H), 2.42 - 2.30 ( m, 1H), 2.38 (s, 3H), 2.28 - 2.14 (m, 1H), 2.21 (s, 3H).

Example 2: 5-(5-(3,5-dimethylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2yl)-1-phenylpyrrolidin-2 -He.

N-(5-(3,5-dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-5-oxo-1-phenyl pyrrolidine-2-carboxamide

HATU (125 mg, 0.329 mmol) was added to a solution of intermediate C2 (99 mg, 0.331 mmol), 5-oxo-1-phenylpyrrolidine-2-carboxylic acid (70 mg, 0.341 mmol) and N,N

- 83 041318 diisopropylethylamine (70 μl, 0.401 mmol) in Ν,Ν-dimethylformamide (2 ml), then stirred at room temperature over the weekend. The mixture was added dropwise to a rapidly stirred flask of water (20 ml), then the precipitate was collected by filtration, washing with water (2x3 ml) to give N-(5-(3,5-dimethylisoκcasol-4-yl)-2-( (tetrahydro-2H-pyran-4-yl)amino)φenyl)-5-oκco-lphenylpyrrolidine-2-carboxamide (121 mg, 69%) as a red-orange gum; temp. beats 1.17 min 2 (method 1); m/z 475 (M+H) ⁺ (electrospray ⁺ );

5-(5-(3,5-dimethylisoxazol-4-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1 H-benzo[c1]imidazol-2-yl)-1 phenylpyrrolidin-2- He

^(5-(3,5-dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-5-oxo-1-phenyl pyrrolidine-2-carboxamide (121 mg , 0.227 mmol) was heated to 80°С in pivalic acid (3 ml) for 2 h. 1,4-dioxane (3 ml) was added to improve solubility, then the mixture was heated at 80°С for another 3 h. to 100° C. and stirred for 18 hours. The mixture was diluted with water (20 ml), then extracted with dichloromethane (3x10 ml). The combined organic phases were concentrated under reduced pressure then purified by Companion chromatography (RP Flash C18) (12 g column, 15-75% MeCN/water 0.1% formic acid) to give 5(5-(3.5- dimethylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[c1]imidazol-2-yl)-1phenylpyrrolidin-2-one (18 mg, 16%) as an off-white solid substances; temp. beats 1.77 min (method 1); m/z 457 (M+H) ⁴ (electrospray ⁴ );

^-NMR (b ₆ -DMSO) δ: 7.74 (d, J=8.5 Hz, IH), 7.61 (d, J=1.6 Hz, IH), 7.51 - 7.45 (m, 2H), 7.29 (dd, J= 8.6, 7.4 Hz, 2H), 7.17 (dd, J=8.5, 1.7 Hz, IH), 7.11 - 7.04 (m, IH), 6.10 (dd, J=8.3, 2.2 Hz, IH), 4.87 - 4.74 (m , IH), 4.04 (td, J=14.2, 12.9, 4.3 Hz, 2H), 3.57 (ddd, J=12.3, 9.6, 3.3 Hz, 2H), 2.85 - 2.72 (m, IH), 2.65 (dq, J =12.0, 8.8 Hz, IH), 2.59 - 2.51 (m, IH), 2.43 (td, J=12.3, 4.6 Hz, 2H), 2.36 (s, 3H), 2.19 (s, 3H), 2.18 - 2.09 ( m, IH), 1.81 (d, J=12.6 Hz, IH), 1.58 (d, J=12.5 Hz, IH).

Example 3: 5-(5-(3,5-dim ethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1 Hbenzo[d]imidazol-2-yl) -l-φenylpyrpolidin-2-one.

^(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)phenyl)-5oxo-1-phenylpyrrolidin-2-carboxamide

HATU (125 mg, 0.329 mmol) was added to a solution of intermediate C3 (99 mg, 0.269 mmol), 5-oxo-1-phenylpyrrolidine-2-carboxylic acid (70 mg, 0.341 mmol) and Ν,Νdiisopropylethylamine (70 µl, 0.401 mmol) in Ν,N-dimethylformamide (2 ml), then stirred at room temperature over the weekend. The mixture was added dropwise to a flask of water (20 ml) with rapid stirring, then the precipitate was collected by filtration, washing with water (2x3 ml) to give Na(5-(3,5-dimethylisoxazol-4-yl)-2- ((1,1-dioxidotetrahydro-2H-thiopyran-4yl)amino)phenyl)-5-oxo-1-phenylpyrrolidine-2-carboxamide (135 mg, 92%) as an off-white solid; temp. beats 1.07 min (method 1), m/z 523 (M+H) ⁺ (electrospray ⁴ ).

5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1Hbenzo[b]imidazol-2-yl)-1-phenylpyrrolidin- 2nd

-84041318

N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)phenyl)-5oxo-1-phenylpyrrolidin-2-carboxamide ( 135 mg, 0.248 mmol) was heated to 80°C in pivalic acid (3 ml) for 2 h. 1,4-dioxane (3 ml) was added to improve solubility, then the mixture was heated at 80°C for another 3 h The temperature was raised to 100°C and stirred for 18 hours, heated further for 3 hours at 160°C with microwave heating, and then for another 4 hours at 180°C with microwave heating. Solvents were removed under reduced pressure, then the crude product was purified by Companion chromatography (RP Flash C18) (12 g column, 15-75% MeCN/water 0.1% formic acid) to give 5-(5-(3,5dimethylisoxazole -4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1 H-benzo[d]imidazol-2-yl)-1 phenylpyrrolidin-2-one (37 mg, 28% ) as a pale cream solid; temp. beats 1.69 min (method 1), m/z 505 (M+H)+ (electrospray ⁺ );

¹ H-NMR (06-DMSO) δ: 7.65 (d, J=1.6 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.34 - 7.25 (m, 3H), 7.10 (dt, 1H), 5.97 (d, J=7.1 Hz, 1H), 5.12-4.95 (m, 1H), 3.63-3.51 (m, 2H), 3.31-3.21 (m, 2H), 2.96 -2.53 (m, 5H), 2.38 (s, 3H), 2.29-2.14 (m, 2H), 2.21 (s, 3H), 1.97 (brd, J=13.5 Hz, 1H).

Example 4: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-phenylpyrrolidin-2-one.

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-5oxopyrrolidine-2-carboxamide (intermediate connection D1)

HATU (350 mg, 0.920 mmol) was added to a solution of intermediate C1 (300 mg, 0.822 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (120 mg, 0.929 mmol) and N,N-diisopropylethylamine (175 µl, 1.002 mmol) in N,N-dimethylformamide (5 ml), then stirred at room temperature for 2 h. The mixture was diluted with water (40 ml), then extracted with ethyl acetate (3x20 ml). The combined organic phases were washed with 20% brine (2x20 ml), brine (20 ml), then dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give (S)-N-(5-(3 ,5-dimethylisoxazol-4-yl)-2-(((R)-1(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (293 mg, 66%) as red - brown resin; temp. beats 1.45 min (method 1), m/z 462 (M+H) ⁺ (electrospray ⁺ ).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) pyrrolidin-2-one (intermediate E1)

Intermediate D1 (293 mg, 0.546 mmol) was heated to 80°C in acetic acid (5 ml) for 6 h. The mixture was concentrated under reduced pressure, then diluted with water (40 ml) and extracted with ethyl acetate (3x20 ml). The combined organic phases were washed with 20% brine (2x20 ml), brine (20 ml), then dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (12 g column, 15-75% MeAs/DCM) to give (S)-5-(5-(3,5dimethylisoxazol-4-yl)-1-((R) -1-(methylsulfonyl)pyrrolidin-3-yl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2-one (99 mg, 41%) as a dark brown solid; temp. beats 0.84 min (method 1), m/z 444 (M+H) ⁺ (electrospray ⁺ ).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-phenylpyrrolidin-2-one

- 85 041318

to solution

DBU (11 µl, 0.073 mmol) intermediate E1 (30 mg, 0.068 mmol) in acetonitrile (5 ml) was added, then stirred for 5 min. CuTMEDA (5 mg, 10.77 µmol) was added and the suspension was stirred for another 2 min, after which phenylboronic acid (10 mg, 0.082 mmol) was added and stirred for 18 h. The mixture was concentrated under reduced pressure, then purified by chromatography on a Companion ( 12 g column, 15-75% acetone/DCM) to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl) pyrrolidin-3yl)-1H-benzo[d]imidazol-2-yl)-1-phenylp-pyrrolidin-2-one (12 mg, 33%) as a pale yellow solid; temp. beats 1.75 min (method 1), m/z 520 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.79 - 7.70 (m, 1H), 7.70 - 7.60 (m, 1H), 7.50 (dd, J=8.7, 1.2 Hz, 2H), 7.31 (dd, J= 8.6, 7.4 Hz, 2H), 7.25 (dd, J=8.4, 1.7 Hz, 1H), 7.13 - 7.05 (m, 1H), 6.06 (dd, J=8.2, 2.3 Hz, 1H), 5.59 - 5.44 (m , 1H), 3.83 - 3.55 (m, 3H), 3.43 - 3.36 (m, 1H), 3.09 (s, 3H), 2.83 - 2.54 (m, 3H), 2.49 - 2.43 (m, 1H), 2.41 2.30 ( m, 1H), 2.38 (s, 3H), 2.26 - 2.16 (m, 1H), 2.21 (s, 3H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=9.36 min, 96%, 92% diastereomeric excess at 254 nm.

Example 5: (R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-phenylpyrrolidin-2-one.

(R)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)5-oxopyrrolidin-2- carboxamide

HATU (225 mg, 0.592 mmol) was added to a solution of intermediate C1 (200 mg, 0.548 mmol), (R)-5-oxopyrrolidine-2-carboxylic acid (75 mg, 0.581 mmol) and N,N-diisopropylethylamine (110 µl , 0.630 mmol) in N,N-dimethylformamide (3 ml), then stirred at room temperature for 18 h. The mixture was diluted with water (15 ml), then extracted with ethyl acetate (3x15 ml). The combined organic phases were washed with 20% brine (2x20 ml), brine (20 ml), then dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give (R)-N-(5- (3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (253 mg, 0.548 mmol, 100% exit) in the form of a red-brown resin; temp. beats 1.45 min (method 1), m/z 462 (M+H) + (electrospray ⁺ ).

(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) pyrrolidin-2-one (intermediate E23)

(R)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)5-oxopyrrolidin-2- carboxamide (253 mg, 0.548 mmol) was heated to 80°C in acetic acid (3 ml) for 5 h. The solvent was removed under reduced pressure, then diluted with water (40 ml) and extracted with ethyl acetate (3x20 ml). The combined organic phases were washed with 20% brine (2x20 ml), brine (20 ml), then dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on a Companion (12 g column, 15-75% MeAs/DCM) to give (R)-5-(5-(3.5-86041318 dimethylisoxazol-4-yl)- 1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (71 mg, 0.158 mmol, 28.9% yield) as an off-white solid , time beats 1.33 min (method 1), m/z 444 (M+H) + (electrospray ⁺ ).

(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-phenylpyrrolidin-2-one

DBU (25 µl, 0.166 mmol) was added to a solution of (R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (70 mg, 0.156 mmol) in acetonitrile (5 mL), then stirred for 5 min. CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred for another 2 min, after which phenylboronic acid (20 mg, 0.164 mmol) was added and stirred for 18 h. The mixture was concentrated under reduced pressure, then purified by chromatography on a Companion ( 4 g column, 0-50% MeAs/DCM) to give (R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl) pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one (18 mg, 22%) as an off-white solid; temp. beats 1.78 min (method 1), m/z 520 (M+H)+ (electrospray ⁺ );

¹ H-NMR (H6-DMSO) δ: 7.78 - 7.72 (m, 1H), 7.69 - 7.62 (m, 1H), 7.56 - 7.45 (m, 2H), 7.30 (dd, J=8.6, 7.3 Hz, 2H ), 7.25 (dd, J=8.4, 1.7 Hz, 1H), 7.13 - 7.05 (m, 1H), 6.11 - 5.99 (m, 1H), 5.60 - 5.44 (m, 1H), 3.72 (ddd, J=11.1 , 8.6, 2.9 Hz, 2H), 3.63 (dd, J=10.5, 6.8 Hz, 1H), 3.47 - 3.36 (m, 1H), 3.10 (s, 3H), 2.79 - 2.59 (m, 2H), 2.59 - 2.40 (m, 3H), 2.38 (s, 3H), 2.21 (s, 3H), 2.20 - 2.10 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=10.49 min, 99.8%, 99.6% diastereomeric excess at 254 nm.

Example 6: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(3-fluorophenyl)pyrrolidin-2-one

A solution of DBU (25 μl, 0.166 mmol) and intermediate E1 (70 mg, 0.156 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3fluorophenyl)boronic acid (25 mg, 0.179 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give (S)-5-(5-(3,5-dimethylisoxazol-4 yl)- 1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1 -(3fluorophenyl)pyrrolidin-2-one (30 mg, 34% yield) as an off-white solid; temp. beats 1.85 min (method 1), m/z 538 (M+H)+ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.77 (d, J=8.4 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.61 (dt, J=11.9, 2.3 Hz, 1H), 7.34 (td, J=8.3, 6.9Hz, 1H), 7.26 (dd, J=8.5, 1.7Hz, 1H), 7.22 (ddd, J=8.4, 2.1, 0.9Hz, 1H), 6.93 (tdd, J=8.4 , 2.5, 0.9 Hz, 1H), 6.12 (dd, J=8.1, 1.9 Hz, 1H), 5.62 - 5.46 (m, 1H), 3.95 - 3.61 (m, 3H), 3.47 - 3.36 (m, 1H), 3.10 (s, 3H), 2.81 - 2.52 (m, 5H), 2.37 (s, 3H), 2.21 (s, 3H), 2.19 - 2.13 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=8.38 min, 93%, 86% diastereomeric excess at 254 nm.

Example 7: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one

- 87 041318

A solution of DBU (25 μl, 0.166 mmol) and intermediate E1 (70 mg, 0.156 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3,4difluorophenyl)boronic acid (25 mg , 0.158 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give (S)-1-(3,4-difluorophenyl)-5-(5-( 3,5dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (43 mg, 0.074 mmol, 47.1% yield) as an off-white solid; temp. beats 1.92 min (method 1), m/z 556 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.83 (ddd, J=13.3, 7.4, 2.7 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H ), 7.39 (dt, J=10.6, 9.2 Hz, 1H), 7.26 (dd, J=8.4, 1.7 Hz, 1H), 7.24 - 7.16 (m, 1H), 6.16 - 6.02 (m, 1H), 5.58 - 5.44 (m, 1H), 3.88 - 3.61 (m, 3H), 3.45 - 3.35 (m, 1H), 3.10 (s, 3H), 2.78 - 2.52 (m, 5H), 2.38 (s, 3H), 2.21 ( s, 3H), 2.20 - 2.13 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=6.78 min, 93%, 86% diastereomeric excess at 254 nm.

Example 8: (S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3 -yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (25 μl, 0.166 mmol) was added to a solution of intermediate E1 (70 mg, 0.156 mmol) in acetonitrile (5 ml), then stirred for 5 min. CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred for another 2 min, after which (4-chloro-3fluorophenyl)boronic acid (30 mg, 0.172 mmol) was added and stirred for 18 h at 40°С. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give (8)-1-(4-chloro-3-fluorophenyl)-5-(5 -(3,5dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (39 mg, 41 %) as an off-white solid; temp. beats 2.05 min (method 1), m/z 572 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.85 (dd, J=12.1, 2.5 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.64 (dd, J=1.6, 0.6 Hz, 1H), 7.52 (t, J=8.8 Hz, 1H), 7.30 - 7.23 (m, 2H), 6.18 - 6.08 (m, 1H), 5.58 - 5.46 (m, 1H), 3.87 - 3.63 (m, 3H), 3.46 3.36 ( m, 1H), 3.10 (s, 3H), 2.77 - 2.52 (m, 5H), 2.37 (s, 3H), 2.20 (s, 3H), 2.19 - 2.12 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 mm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=7.75 min, 86%, 73% diastereomeric excess at 254 nm.

Example 9: (S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3 -yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

- 88 041318

DBU (25 μl, 0.166 mmol) was added to a solution of intermediate E1 (70 mg, 0.156 mmol) in acetonitrile (5 ml), then stirred for 5 min. CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred for another 2 min, after which (3-chloro-4fluorophenyl)boronic acid (30 mg, 0.172 mmol) was added and stirred for 18 h at 40°С. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give (S)-1-(3-chloro-4-fluorophenyl)-5-(5 -(3,5dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2-one (44 mg, 0.073 mmol, 46.8% yield) as an off-white solid; temp. beats 2.07 min (method 1), m/z 572 (M+H)+ (electrospray ⁺ );

¹ H-NMR (b ₆ -DMSO) δ: 7.95 (dd, J=6.9, 2.3 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.44 7.33 (m, 2H), 7.26 (dd, J=8.5, 1.7 Hz, 1H), 6.17 - 6.06 (m, 1H), 5.56 - 5.49 (m, 1H), 3.86 - 3.62 (m, 3H), 3.44 3.36 (m, 1H), 3.10 (s, 3H), 2.79 - 2.52 (m, 5H), 2.38 (s, 3H), 2.21 (s, 3H), 2.20 - 2.12 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=6.89 min, 93%, 86% diastereomeric excess at 254 nm.

Example 10: (S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin3-yl)-1 H -benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (25 μl, 0.166 mmol) was added to a solution of intermediate E1 (70 mg, 0.156 mmol) in acetonitrile (5 ml), then stirred for 5 min. CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred for another 2 min, after which (3,5dichlorophenyl)boronic acid (35 mg, 0.183 mmol) was added and stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give (S)-1-(3,5-dichlorophenyl)-5-(5-( 3,5dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2-one (40 mg, 0.065 mmol , 41.3% yield) as an off-white solid; temp. beats 2.18 min (method 1), m/z 588 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.83 - 7.75 (m, 1H), 7.69 (d, J=1.9 Hz, 2H), 7.66 (dd, J=1.6, 0.5 Hz, 1H), 7.34 (t, J=1.8 Hz, 1H), 7.27 (dd, J=8.5, 1.7 Hz, 1H), 6.29 - 6.17 (m, 1H), 5.60 - 5.49 (m, 1H), 3.88 - 3.65 (m, 3H), 3.40 (q, J=9.4, 9.0 Hz, 1H), 3.10 (s, 3H), 2.82 - 2.53 (m, 5H), 2.38 (s, 3H), 2.21 (s, 3H), 2.17 (d, J=9.9 Hz, 1H).

Chiral HPLC (Lab. 1 Div. 4, Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=7.02 min, 90%, 80% diastereomeric excess at 254 nm.

Example 11: (S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3 -yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

- 89 041318

A solution of DBU (25 μl, 0.166 mmol) and intermediate E1 (70 mg, 0.156 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3-chloro-5fluorophenyl)boronic acid ( 30 mg, 0.172 mmol) and then stirred for 18 h at 40°С. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give (S)-1-(3-chloro-5-fluorophenyl)-5-(5 (3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (40 mg, 42%) as an off-white solid; temp. beats 2.08 min (method 1), m/z 572 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.79 (d, J=8.5 Hz, 1H), 7.66 (dd, J=1.7, 0.6 Hz, 1H), 7.57 (dt, J=2.4, 1.2 Hz, 1H) , 7.49 (dt, J=11.4, 2.2 Hz, 1H), 7.27 (dd, J=8.4, 1.7 Hz, 1H), 7.18 (dt, J=8.5, 2.1 Hz, 1H), 6.23 - 6.15 (m, 1H ), 5.59 - 5.47 (m, 1H), 3.88 - 3.66 (m, 3H), 3.40 (q, J=9.0 Hz, 1H), 3.10 (s, 3H), 2.79 -2.52 (m, 5H), 2.38 ( s, 3H), 2.21 (s, 3H), 2.19–2.12 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=7.10 min, 89%, 78% diastereomeric excess at 254 nm.

Example 12: (S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3 -yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (25 μl, 0.166 mmol) was added to a solution of intermediate E1 (70 mg, 0.156 mmol) in acetonitrile (5 ml), then stirred for 5 min. CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred for another 2 min, after which (3-chloro-5methoxyphenyl)boronic acid (33 mg, 0.177 mmol) was added and stirred for 2 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give (S)-1-(3-chloro-5-methoxyphenyl)-5-(5 -(3,5dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2-one (39 mg, 40%) as an off-white solid; temp. beats 2.02 min (method 1), m/z 584 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.77 (dd, J=8.5, 0.6 Hz, 1H), 7.65 (dd, J=1.7, 0.6 Hz, 1H), 7.33 (t, J=1.9 Hz, 1H ), 7.26 (dd, J=8.4, 1.7 Hz, 1H), 7.06 (t, J=2.1 Hz, 1H), 6.78 (t, J=2.0 Hz, 1H), 6.19 - 6.08 (m, 1H), 5.61 -5.51 (m, 1H), 3.86 - 3.64 (m, 3H), 3.69 (s, 3H), 3.40 (td, J=9.6, 7.3 Hz, 1H), 3.09 (s, 3H), 2.82 - 2.52 (m , 5H), 2.38 (s, 3Н), 2.21 (s, 3Н), 2.19–2.11 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=8.44 min, 94%, 88% diastereomeric excess at 254 nm.

Example 13: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

- 90 041318

DBU (25 μl, 0.166 mmol) was added to a solution of intermediate E1 (70 mg, 0.156 mmol) in acetonitrile (5 ml), then stirred for 5 min. CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred for another 2 min, after which (3-fluoro-4methoxyphenyl)boronic acid (30 mg, 0.177 mmol) was added and stirred for 2 h at 40°С. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl) -1((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1 H-benzo[d]imidazol-2-yl)-1 -(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one (52 mg, 56%) as an off-white solid; temp. beats 1.83 min (method 1), m/z 568 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.76 (dd, J=8.5, 0.7 Hz, 1H), 7.65 (dd, J=1.7, 0.6 Hz, 1H), 7.64 -7.55 (m, 1H), 7.25 (dd, J=8.4, 1.7 Hz, 1H), 7.14 - 7.03 (m, 2H), 6.02 (dd, J=8.2, 2.3 Hz, 1H), 5.56 - 5.46 (m, 1H), 3.86 - 3.62 (m , 3Н), 3.76 (s, 3Н), 3.44 - 3.33 (m, 1H), 3.09 (s, 3Н), 2.79 - 2.53 (m, 4H), 2.45 - 2.38 (m, 1H), 2.38 (s, 3Н ), 2.21 (s, 3H), 2.20 -2.12 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=9.72 min, 94%, 88% diastereomeric excess at 254 nm.

Example 14: (S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)n-pyrrolidine-3 -yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1 -(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 (methylsulfonyl)n-pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (25 μl, 0.166 mmol) was added to a solution of intermediate E1 (70 mg, 0.156 mmol) in acetonitrile (5 ml), then stirred for 5 min. CuTMEDA (10 mg, 0.022 mmol) was added and the suspension was stirred for another 2 min, after which (3-chloro-4methoxyphenyl)boronic acid (33 mg, 0.177 mmol) was added and stirred for 2 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/CH ₂ Cl ₂ ) to give (8)-1-(3-chloro-4-methoxyphenyl)-5 -(5-(3,5dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2-one ( 42 mg, 44%) as an off-white solid; temp. beats 1.91 min (method 1), m/z 584 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.77 (d, J=2.6 Hz, 1H), 7.76 - 7.73 (m, 1H), 7.66 (dd, J=1.7, 0.6 Hz, 1H), 7.30 (dd , J=9.0, 2.6Hz, 1H), 7.25 (dd, J=8.4, 1.7Hz, 1H), 7.08 (d, J=9.1Hz, 1H), 6.05 (dd, J=8.2, 2.4Hz, 1H) , 5.57 - 5.47 (m, 1H), 3.84 - 3.60 (m, 3H), 3.78 (s 3H), 3.38 (td, J=9.6, 7.2 Hz, 1H), 3.09 (s, 3H), 2.80 - 2.52 ( m, 4H), 2.42 2.32 (m, 1H), 2.38 (s, 3H), 2.24 - 2.16 (m, 1H), 2.21 (s, 3H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=9.55 min, 94%, 88% diastereomeric excess at 254 nm.

Example 15: (8)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(4-methoxyphenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(4-methoxyphenyl)πirrolidin-2-one

- 91 041318

A solution of DBU (25 μl, 0.166 mmol) and intermediate E1 (70 mg, 0.156 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (4methoxyphenyl)boronic acid (28 mg, 0.184 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give (S)-5-(5-(3,5-dimethylisoxazol-4yl)-1 - ((R) -1 - (methylsulfonyl) pyrrolidin-3 -yl) -1 H-benzo [d] imidazol-2-yl) -1 - (4 methoxyphenyl) pyrrolidin-2-one (54 mg, 60%) in as an off-white solid; temp. beats 1.75 min (method 1), m/z 550 (M+H) + (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.73 (d, J=8.5 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.24 (dd, J= 8.4, 1.7 Hz, 1H), 6.91 - 6.81 (m, 2H), 5.97 (dd, J=8.2, 2.7 Hz, 1H), 5.52 -4.42 (m, 1H), 3.82 - 3.49 (m, 3H), 3.68 (s, 3H), 3.39 - 3.28 (m, 1H), 3.08 (s, 3H), 2.82 - 2.52 (m, 3H), 2.50 - 2.40 (m, 1H), 2.38 (s, 3H), 2.27 - 2.17 (m, 2H), 2.22 (s, 3H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=10.41 min, 95.7%, 91.4% diastereomeric excess at 254 nm.

Example 16 (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2- yl)-1-(4-propoxyphenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(4-propoxyphenyl)pyrrolidin-2-one

A solution of DBU (25 μl, 0.166 mmol) and intermediate E1 (70 mg, 0.156 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (4propoxyphenyl)boronic acid (32 mg, 0.178 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give (S)-5-(5-(3,5-dimethylisoxazol-4yl)-1 - ((R) -1 - (methylsulfonyl) pyrrolidin-3 -yl) -1 H-benzo [d] imidazol-2-yl) -1 - (4 propoxyphenyl) pyrrolidin-2-one (56 mg, 59%) in as an off-white solid; temp. beats 2.00 min (method 1), m/z 578 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (de-DMSO) δ: 7.73 (d, J=8.5 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.24 (dd, J= 8.5, 1.7 Hz, 1H), 6.90 - 6.82 (m, 2H), 5.96 (dd, J=8.2, 2.7 Hz, 1H), 5.52 - 5.42 (m, 1H), 3.84 (t, J=6.6 Hz, 2H ), 3.75 (dd, J=10.6, 8.9 Hz, 1H), 3.68 (td, J=9.5, 8.5, 2.5 Hz, 1H), 3.60 (dd, J=10.6, 6.8 Hz, 1H), 3.40 - 3.29 ( m, 1H), 3.08 (s, 3H), 2.83 - 2.52 (m, 3H), 2.47 - 2.40 (m, 1H), 2.38 (s, 3H), 2.28 - 2.16 (m, 2H), 2.22 (s, 3Н), 1.71 1.62 (m, 2H), 0.92 (t, J=7.4 Hz, 3Н).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=8.07 min, 94.9%, 89.8% diastereomeric excess at 254 nm.

Example 17: (S)-1 -(4-chlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 (methylsulfonyl)pyrrolidin-3-yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(4-chlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one

- 92 041318

A solution of DBU (25 μl, 0.166 mmol) and intermediate E1 (70 mg, 0.156 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (4-chlorophenyl)boronic acid (28 mg, 0.179 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/CH ₂ Cl ₂ ) to give (S)-1-(4-chlorophenyl)-5-(5- (3,5dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (43 mg, 47% ) as an off-white solid; temp. beats 1.96 min (method 1), m/z 554 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.81 - 7.72 (m, 1H), 7.64 (dd, J=1.7, 0.6 Hz, 1H), 7.61 - 7.51 (m, 2H), 7.42 - 7.31 (m, 2H), 7.25 (dd, J=8.5, 1.7 Hz, 1H), 6.08 (dd, J=8.1, 2.3 Hz, 1H), 5.57 - 5.47 (m, 1H), 3.79 (t, J=9.8 Hz, 1H ), 3.72 (td, J=9.3, 8.1, 2.8 Hz, 1H), 3.66 (dd, J=10.6, 6.7 Hz, 1H), 3.44 - 3.35 (m, 1H), 3.10 (s, 3H), 2.78 - 2.52 (m, 4H), 2.49 - 2.43 (m, 1H), 2.37 (s, 3H), 2.21 (s, 3H), 2.20 - 2.14 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH in isohexane (0.2% TFA)): 148476, temp. sp=9.53 min, 94.8%, 89.6% diastereomeric excess at 254 nm.

Example 18: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(pyridin-3-yl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(pyridin-3-yl)pyrrolidin-2-one

A solution of DBU (20 μL, 0.133 mmol) and intermediate E1 (50 mg, 0.113 mmol) in acetonitrile (4 mL) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and pyridin-3ylboronic acid (15.24 mg, 0.124 mmol ) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-80% MeAs/CH ₂ Cl ₂ ) to give (S)-5-(5-(3,5-dimethylisoxazole-4 -yl)-1((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1-(pyridin-3-yl)pyrrolidin-2one (23 mg , 39%) as an off-white solid; temp. beats 1.40 min (method 1), m/z 521 (M+H) + (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 8.69 (1H, d, J=2.6 Hz), 8.28 (1H, dd, J=4.7, 1.4 Hz), 7.98 (1H, ddd, J=8.4, 2.6, 1.4 Hz), 7.76 (1H, d, J=8.4 Hz), 7.64 (1H, d, J=1.8 Hz), 7.36 (1H, ddd, J=8.4, 4.7, 0.7 Hz), 7.25 (1H, dd, J =8.5, 1.7 Hz), 6.13 (1H, d, J=6.4 Hz), 5.58 - 5.41 (1H, m), 3.86 - 3.75 (1H, m), 3.75 - 3.59 (2H, m), 3.45 - 3.35 ( 1H, m), 3.09 (3H, s), 2.76 - 2.61 (2H, m), 2.61 - 2.51 (2H, m), 2.36 (3H, s), 2.23 (1H, d, J=8.2 Hz), 2.20 (3H, s), 1.14 (1H, s).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=11.85 min, >99% diastereomeric excess at 254 nm.

Example 19: (S)-5-(5-(3,5-dimethylisooxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(6-fluoropyridin-3-yl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxαzol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1 -(6-fluoropyridin-3 -yl)pyrrolidin-2-one

- 93 041318

F

A solution of DBU (20 µL, 0.133 mmol) and intermediate E1 (50 mg, 0.113 mmol) in acetonitrile (4 mL) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (6-fluoropyridin-3yl)boronic acid ( 17.47 mg, 0.124 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-50% MeAs/DCM) to give (S)-5-(5-(3,5-dimethylisoxazol-4-ul) -1((R)-1 -(methylsulfonyl)pyrrolidin-3 -yl)-1 H-benzo[d]imidazol-2-yl)-1 -(6-fluoropyridin-3 yl)pyrrolidin-2-one (18 mg, 0.033 mmol, 29.3% yield) as an off-white solid; temp. beats 1.70 min (method 1), m/z 539 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 8.33 (1H, dd, J=3.0, 1.3 Hz), 8.18 (1H, ddd, J=8.9, 7.2, 2.8 Hz), 7.76 (1H, d, J= 8.4 Hz), 7.64 (1H, d, J=1.6 Hz), 7.25 (1H, dd, J=8.4, 1.7 Hz), 7.18 (1H, dd, J=9.0, 3.3 Hz), 6.15 - 6.04 (1H, m), 5.51 - 5.39 (1H, m), 3.85 - 3.76 (1H, m), 3.76 - 3.61 (2H, m), 3.42 - 3.34 (1H, m), 3.08 (3H, s), 2.79 - 2.62 ( 2H, m), 2.51 (3H, s), 2.37 (3H, s), 2.26 - 2.21 (1H, m), 2.20 (3H, s).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=9.00 min, >99% diastereomeric excess at 254 nm.

Example 20: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(naphthalene-1-yl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(naphthalene-1-yl)pyrrolidin-2-one

A solution of DBU (20 µL, 0.133 mmol) and intermediate E1 (50 mg, 0.113 mmol) in acetonitrile (4 mL) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and naphthalene-1ylboronic acid (21.33 mg, 0.124 mmol ) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-50% MeAc/CH ₂ Cl ₂ ) to give (S)-5-(5-(3,5-dimethylisoxazole-4 -yl)-1((R)-1 -(methylsulfonyl)pyrrolidin-3 -yl)-1 H-benzo[d]imidazol-2-yl)-1 -(naphthalen-1 -yl)pyrrolidin-2one (7 mg, 11%) as an off-white solid; temp. beats 1.86 min (method 1), m/z 570 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.96 (2H, br. s), 7.90 (1H, d, J=8.4 Hz), 7.74 (1H, s), 7.64 - 7.35 (5H, m), 7.18 (1H, d, J=8.4 Hz), 5.99 - 5.82 (1H, m), 4.93 (1H, br. s), 3.68 - 3.56 (1H, m), 3.45 - 3.36 (2H, m), 3.05 - 2.81 (6H, m), 2.78 - 2.63 (2H, m), 2.56-2.51 (2H, m), 2.40 (3H, s), 2.23 (3H, s).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. beats = 9.23 min, 97% diastereomeric excess at 254 nm.

Example 22: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(5-fluoropyridin-3-yl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(5-fluoropyridin-3-yl)pyrrolidin-2-one

- 94 041318

A solution of DBU (20 μl, 0.133 mmol) and intermediate E1 (50 mg, 0.113 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (5-fluoropyridin-3yl)boronic acid ( 17.47 mg, 0.124 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-50% MeAs/DCM) to give a solid. This solid was dissolved in EtOAc (~3 ml) and then hexane (20 ml) was added. The resulting solid was collected by filtration, washing with hexane (5 mL) and dried in vacuo to give (S)-5-(5(3,5-dimethylisoxazol-4-yl)-1-((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1 H-benzo[d]imidazol-2-yl)-1(5-fluoropyridin-3-yl)pyrrolidin-2-one (12 mg, 20%) as whitish a solid; temp. beats 1.68 min (method 1), m/z 539 (M+H)+ (electrospray ⁺ );

¹ H-NMR (dg-DMSO) δ: 8.51 (1H, s), 8.32 (1H, d, J=2.6 Hz), 8.14 (1H, dt, J=11.4, 2.3 Hz), 7.78 (1H, d, J=8.5 Hz), 7.64 (1H, d, J=1.6 Hz), 7.26 (1H, dd, J=8.5, 1.7 Hz), 6.24 - 6.17 (1H, m), 5.55 - 5.43 (1H, m), 3.88 3.78 (1H, m), 3.77 -3.64 (2H, m), 3.39 (1H, q, J=8.7 Hz), 3.09 (3H, s), 2.76 - 2.65 (2H, m), 2.65 - 2.53 (3H , m), 2.36 (3H, s), 2.26 - 2.20 (1H, m), 2.19 (3H, s).

Chiral HPLC (Lab. 1, Div. 4, Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. beats=9.22 min, >99% diastereomeric excess at 254 nm.

Example 23 (S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-ul)-1-((R)-1-(methylsulfonyl)pyrrolidin3-ul)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one

F

A solution of DBU (20 μl, 0.133 mmol) and intermediate E1 (50 mg, 0.113 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3,5difluorophenyl)boronic acid (19.58 mg , 0.124 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-50% MeAs/DCM) to give a solid. The solid was dissolved in EtOAc (~3 ml) and then hexane (20 ml) was added. The resulting solid was collected by filtration, washing with hexane (5 mL) and dried in vacuo to give (S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethyluzoxazole-4- yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (18 mg, 28%) as an off-white solid ; temp. beats 1.92 min (method 1), m/z 556 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.78 (d, J=8.5 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.27 (dd, J =8.4, 1.7 Hz, 1H), 7.05 - 6.93 (m, 1H), 6.16 (d, J=7.4 Hz, 1H), 5.60 - 5.45 (m, 1H), 3.83 (t, J=9.8 Hz, 1H) , 3.79 -3.64 (m, 2H), 3.40 (q, J=9.0 Hz, 1H), 3.10 (s, 3H), 2.78 - 2.53 (m, 5H), 2.38 (s, 3H), 2.21 (s, 3H ), 2.16 (d, J=10.1 Hz, 1Н).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=10.83 min, >99% diastereomeric excess at 254 nm.

Example 24 (S)-1-(5-Chloro-6-methoxypyridin-3-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl) pyrroludin-3-yl)-1H-benzo[d]imidazol-2-ul)pyrrolidin-2-one.

(S)-1 - (5-chloro-6-methoxypyridin-3-yl) -5- (5- (3,5-dimethylisoxazol-4-yl) -1 - ((R) -1 (methylsulfonyl) pyrroludin- 3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

- 95 041318

A solution of DBU (20 μl, 0.133 mmol) and intermediate E1 (50 mg,

0.113 mmol) in acetonitrile (4 mL) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (5-chloro-6-methoxypyridin-3-yl)boronic acid (23.24 mg, 0.124 mmol) and then stirred in for 18 hours at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-50% MeAs/CH ₂ Cl ₂ ) to give a solid. The solid was dissolved in EtOAc (~3 ml) and then hexane (20 ml) was added. The resulting solid was collected by filtration, washing with hexane (5 ml) and dried in vacuo to give (S)-1-(5-chloro-6-methoxypyridin-3-yl)-5-(5-(3, 5-dimethylisoxazol-4-yl)-1 -((R)-1 (methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidαzol-2-yl)pyrrolidin-2-one (15 mg, 22% ) as a yellow solid; temp. beats 1.91 min (method 1), m/z 585 (M+H)+ (electrospray ⁺ );

¹ H-NMR (H6-DMSO) δ: 8.31 (1H, d, J=2.4 Hz), 8.11 (1H, d, J=2.4 Hz), 7.76 (1H, d, J=8.4 Hz), 7.67 (1H , d, J=1.6 Hz), 7.26 (1H, dd, J=8.4, 1.7 Hz), 6.13 - 6.03 (1H, m), 5.53 - 5.39 (1H, m), 3.86 (3H, s), 3.85 - 3.78 (1H, m), 3.77 - 3.61 (2H, m), 3.44 - 3.36 (1H, m), 3.09 (3H, s), 2.78 - 2.61 (2H, m), 2.59 - 2.53 (1H, m), 2.48 - 2.42 (2H, m), 2.38 (3H, s), 2.27 - 2.23 (1H, m), 2.21 (3H, s).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=8.32 min, >99% diastereomeric excess at 254 nm.

Example 25 (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2- yl)-1-(3-fluoro-5-methoxyphenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3-fluoro-5-methoxyphenyl)pyrrolidin-2-one

F

A solution of DBU (20 μl, 0.133 mmol) and intermediate E1 (50 mg, 0.113 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3-fluoro-5methoxyphenyl)boronic acid ( 21.07 mg, 0.124 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-50% MeAs/DCM) to give (S)-5-(5-(3,5dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3 -yl)-1 H-benzo[d]imidazol-2-yl)-1 -(3 fluoro-5-methoxyphenyl)pyrrolidin-2-one (19 mg , 29%) as an off-white solid; temp. beats 1.91 min (method 1), m/z 568 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.77 (d, J=8.5 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.26 (dd, J=8.5, 1.7 Hz, 1H), 7.12 (dt, J=11.5, 2.1Hz, 1H), 6.95 - 6.89 (m, 1H), 6.60 (dt, J=10.8,2.3Hz, 1H), 6.12 (d, J=8.3Hz, 1H), 5.63 - 5.49 (m, 1H), 3.87 - 3.69 (m, 3H), 3.68 (s, 3H), 3.44 - 3.35 (m, 1H), 3.10 (s, 3H), 2.81 - 2.65 (m, 1H), 2.66 - 2.52 (m, 4H), 2.38 (s, 3H), 2.21 (s, 3H), 2.16 (d, J=9.9 Hz, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=8.56 min, >99% diastereomeric excess at 254 nm.

Example 26: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(3-(trifluoromethoxy)phenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxαzol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3-(trifluoromethoxy)phenyl)pyrrolidin-2-one

- 96 041318

A solution of DBU (20 µL, 0.133 mmol) of intermediate E1 (50 mg, 0.113 mmol) in acetonitrile (4 mL) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and 3(trifluoromethoxy)phenyl)boronic acid (25.5 mg , 0.124 mmol) and then stirred for 18 h at 40°С. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-50% MeAs/DCM) to give (S)-5-(5-(3,5dimethylisoxazol-4-yl)-1 - ((R) -1 - (methylsulfonyl) pyrrolidin-3 -yl) -1 H-benzo[d] imidazol-2-yl) -1- (3 (trifluoromethoxy) phenyl) pyrrolidin-2-one (20 mg, 29%) as an off-white solid; temp. beats 2.09 min (method 1), m/z 604 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.90 - 7.85 (m, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.43 (t, J =8.3 Hz, 1H), 7.32 - 7.22 (m, 2H), 7.13 -7.06 (m, 1H), 6.13 (d, J=7.5 Hz, 1H), 5.59 - 5.48 (m, 1H), 3.85 - 3.77 ( m, 1H), 3.77 - 3.61 (m, 2H), 3.44 - 3.35 (m, 2H), 3.09 (s, 3H), 2.79 - 2.63 (m, 2H), 2.63 - 2.52 (m, 2H), 2.37 ( s, 3H), 2.20 (s, 3H), 2.20–2.16 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=6.30 min, >99% diastereomeric excess at 254 nm.

Example 27: (S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidine -3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethyluzoxαzol-4-ul)-1-((R)-1(methylsulfonyl)pyrrolidine-3- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (20 μL, 0.133 mmol) and intermediate E1 (50 mg, 0.113 mmol) in acetonitrile (4 mL) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (2,3dihydrobenzofuran-5-yl)boronic acid (20.33 mg, 0.124 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-50% MeAs/DCM) to give (S)-1-(2,3dihydrobenzofuran-5-ul)-5-(5 -(3,5-dimethyluzoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3yl)-1H-benzo[d]umidazol-2-yl)pyrrolidin-2-one (24 mg , 37%) as an off-white solid; temp. beats 1.72 min (method 1), m/z 562 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.72 (d, J=8.5 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.38 (dd, J=2.3, 1.2 Hz, 1H), 7.24 (dd, J=8.5, 1.6Hz, 1H), 7.05 (dd, J=8.5, 2.3Hz, 1H), 6.67 (d, J=8.6Hz, 1H), 5.93 (dd, J=8.3, 2.8Hz, 1H), 5.52 5.40 (m, 1H), 4.47 (t, J=8.7 Hz, 2H), 3.80 - 3.71 (m, 1H), 3.71 - 3.64 (m, 1H), 3.63 - 3.55 (m, 1H), 3.33 - 3.29 (m, 1H), 3.14 - 3.09 (m, 2H), 3.08 (s, 3H), 2.84 - 2.70 (m, 1H), 2.68 - 2.57 (m, 1H), 2.49 - 2.41 (m, 2H ), 2.39 (s, 3H), 2.26 (s, 1H), 2.22 (s, 3H), 2.21–2.09 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=11.67 min, >99% diastereomeric excess at 254 nm.

Example 28: (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylusoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethyluzoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidine-

-yl)-1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

- 97 041318

A solution of DBU (20 μl, 0.133 mmol) and intermediate E1 (60 mg, 0.129 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3,4dichlorophenyl)boronic acid (25 mg , 0.131 mmol) and then stirred for 18 h at 40°C.

The mixture was diluted with water, then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazole -4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3 -yl)1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (48 mg, 62%) as pale yellow glassy substances; temp. beats 2.13 min (method 1), m/z 588 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 8.03 (d, J=2.6 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.68 - 7.62 (m, 1H), 7.57 (d, J=8.9 Hz , 1H), 7.43 (dd, J=8.9, 2.6 Hz, 1H), 7.26 (dd, J=8.4, 1.7 Hz, 1H), 6.19 - 6.12 (m, 1H), 5.61 - 5.47 (m, 1H), 3.87 3.64 (m, 3H), 3.45 - 3.35 (m, 1H), 3.10 (s, 3H), 2.78 - 2.53 (m, 5H), 2.37 (s, 3H), 2.21 (s, 3H), 2.19 - 2.12 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH in isohexane (0.2% TFA), temp=8.80 min, >99%, > 98% diastereomeric excess at 254 nm.

Example 29: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pirrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(6-methoxypyridin-3-yl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(6-methoxypyridin-3-yl)pyrrolidin-2-one

Meo

A solution of DBU (20 μl, 0.133 mmol) and intermediate E1 (60 mg, 0.129 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (6-methoxypyridin-3yl)boronic acid ( 25 mg, 0.163 mmol) and then stirred for 18 h at 40°C. The mixture was diluted with water, then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give (S)-5-(5(3,5-dimethylisoxazol-4-yl)-1-((R )-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)-1(6-methoxypyridin-3-yl)pyrrolidin-2-one (38 mg, 52%) in the form of pale yellow glassy substances; temp. beats 1.69 min (method 1), m/z 551 (M+H) ⁺ (electrospray ⁺ );

1H-NMR (de-DMSO) δ: 8.19 - 8.13 (m, 1H), 7.92 (dd, J=8.9, 2.8 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.67 (d, J =1.5 Hz, 1H), 7.26 (dd, J=8.5, 1.7 Hz, 1H), 6.81 (dd, J=8.9, 0.6 Hz, 1H), 6.05 - 5.95 (m, 1H), 5.52 - 5.39 (m, 1H), 3.84 - 3.78 (m, 1H), 3.77 (s, 3H), 3.74 - 3.59 (m, 2H), 3.40 - 3.35 (m, 1H), 3.09 (s, 3H), 2.77 - 2.61 (m, 2H), 2.58 - 2.52 (m, 1h), 2.49 - 2.43 (m, 1H), 2.38 (s, 3H), 2.37 - 2.29 (m, 1H), 2.26 - 2.22 (m, 1H), 2.22 (s, 3H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=11.55 min, >99%, >98% diastereomeric excess at 254 nm.

Example 30: (8)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(3,4,5-trifluorophenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pirrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3,4,5-trifluorophenyl)pyrrolidin-2-one

- 98 041318

A solution of DBU (20 μl, 0.133 mmol), intermediate E1 (60 mg, 0.129 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3,4,5trifluorophenyl)boronic acid ( 25 mg, 0.142 mmol) and then stirred for 18 h at 40°C. The mixture was diluted with water, then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(( R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol2-yl)-1-(3,4,5-trifluorophenyl)pyrrolidin-2-one (47 mg, 61%) in the form of pale yellow glassy substances; temp. beats 2.05 min (method 1), m/z 574 (M+H) ⁺ (electrospray ⁺ );

1H-NMR (d6-DMSO) δ: 7.82 - 7.74 (m, 1H), 7.67 - 7.63 (m, 1H), 7.59 (dd, J=10.5, 6.4 Hz, 2H), 7.27 (dd, J=8.5, 1.7 Hz, 1H), 6.13 (d, J=7.3 Hz, 1H), 5.55 - 5.43 (m, 1H), 3.83 (s, 1H), 3.79 - 3.64 (m, 2H), 3.45 - 3.35 (m, 1H ), 3.10 (s, 3Н), 2.77 - 2.53 (m, 5H), 2.37 (s, 3Н), 2.21 (s, 3Н), 2.19 - 2.12 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH in isohexane (0.2% TFA)): 148497, temp. sp=6.32 min, 98.5%, 97% diastereomeric excess at 254 nm.

Example 31: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1 Hbenzo[d]imidazol-2-yl )-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol) and intermediate E1 (60 mg, 0.129 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (4(trifluoromethyl)phenyl)boronic acid ( 28 mg, 0.147 mmol) and then stirred for 18 h at 40°C. The mixture was diluted with water, then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(( R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H benzo^]imidazol-2-yl)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one (42 mg, 54%) as pale yellow glassy substances; temp. beats 2.09 min (method 1), m/z 588 (M+H)+ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.83 - 7.73 (m, 3H), 7.73 - 7.65 (m, 2H), 7.63 (d, J=1.6 Hz, 1H), 7.26 (dd, J=8.4, 1.7 Hz, 1H), 6.21 -6.12 (m, 1H), 5.63 -5.48 (m, 1H), 3.88 - 3.78 (m, 1H), 3.78 - 3.64 (m, 2H), 3.46 - 3.36 (m, 1H), 3.10 (s, 3H), 2.79 - 2.54 (m, 5H), 2.37 (s, 3H), 2.25 - 2.14 (m, 1H), 2.20 (s, 3H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=7.19 min, >99%, >98% diastereomeric excess at 254 nm.

Example 32: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(4-(trifluoromethyloxy)phenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1 Hbenzo[d]imidazol-2-yl )-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one

- 99 041318

A solution of DBU (20 μl, 0.133 mmol) and intermediate E1 (60 mg, 0.129 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (4(trifluoromethoxy)phenyl)boronic acid ( 30 mg, 0.146 mmol) and then stirred for 18 h at 40°C. The mixture was diluted with water, then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(( R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo^]imidazol-2-yl)-1-(4-(trifluoromethoxy)phenyl)pyrrolidin-2-one (40 mg, 50%) as pale yellow glassy substances; temp. beats 2.14 min (method 1), m/z 604 (M+H) + (electrospray ⁺ );

¹ H-NMR (dg-DMSO) δ: 7.77 (d, J=8.5 Hz, 1H), 7.69 - 7.59 (m, 3H), 7.39 - 7.29 (m, 2H), 7.26 (dd, J=8.4, 1.7 Hz, 1H), 6.13 - 6.02 (m, 1H), 5.57 - 5.44 (m, 1H), 3.87 - 3.76 (m, 1H), 3.76 - 3.63 (m, 2H), 3.44 - 3.35 (m, 1H), 3.10 (s, 3H), 2.80 - 2.53 (m, 4H), 2.49 - 2.40 (m, 1H), 2.38 (s, 3H), 2.27 - 2.15 (m, 1H), 2.21 (s, 3H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=6.26 min, >99%, >98% diastereomeric excess at 254 nm.

Example 33: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(3-ethoxy-5-fluorophenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethyluzoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrroludin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3-ethoxy-5-fluorophenyl)pyrrolidin-2-one

Me

A solution of DBU (20 μl, 0.133 mmol) and intermediate E1 (60 mg, 0.129 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3-ethoxy-5fluorophenyl)boronic acid ( 25 mg, 0.136 mmol) and then stirred for 18 h at 40°C. The mixture was diluted with water, then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(( R)-1 -(methylsulfonyl)pyrrolidin-3 -yl)-1 H-benzo[d]imidazol2-yl)-1-(3-ethoxy-5-fluorophenyl)pyrrolidin-2-one (39 mg, 51%) in the form of pale yellow glassy substances; temp. beats 2.02 min (method 1), m/z 582 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (dg-DMSO) δ: 7.77 (d, J=8.5 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.26 (dd, J=8.5, 1.7 Hz, 1H), 7.08 (dt, J=11.4, 2.1Hz, 1H), 6.94 (t, J=1.8Hz, 1H), 6.57 (dt, J=10.9, 2.3Hz, 1H), 6.17 - 6.07 (m, 1H), 5.61 - 5.49 (m, 1H), 3.94 (dq, J=6.9, 2.2 Hz, 2H), 3.80 (t, J=9.8 Hz, 1H), 3.77 - 3.70 (m, 1H), 3.67 (dd, J=10.6, 6.9 Hz, 1H), 3.43 - 3.35 (m, 1H), 3.10 (s, 3H), 2.81 - 2.45 (m, 5H), 2.38 (s, 3H), 2.21 (s, 3H), 2.19 - 2.13 (m , 1H), 1.25 (t, J=7.0 Hz, 3Н).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=8.70 min, >99%, >98% diastereomeric excess at 254 nm.

Example 34: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1 -(o-tolyl)pyrrolidin-2 -one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1 -(o-tolyl)pyrrolidine-2 -one

- 100 041318

A solution of DBU (20 μl, 0.133 mmol) and intermediate E1 (60 mg, 0.129 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and o-tolylboronic acid (20 mg, 0.147 mmol ) and then stirred for 18 h at 40°C. The mixture was diluted with water, then was extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give (S)-5-(5-(3,5dimethylisoxazol-4-yl)-1-((R) -1-(methylsulfonyl)pyrrolidin-3-yl)-1 H-benzo[d]imidazol-2-yl)-1-(otolyl)pyrrolidin-2-one (22 mg, 30%) as a pale yellow glassy substances; temp. beats 1.78 min (method 1), m/z 534 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.73 (d, J=1.6 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.30 - 7.06 (m, 5H), 5.84 - 5.69 (m , 1H), 5.21 - 5.06 (m, 1H), 3.75 - 3.66 (m, 1H), 3.58 - 3.44 (m, 2H), 3.19 - 3.09 (m, 1H), 3.03 (s, 3H), 2.94 - 2.82 (m, 1H), 2.78 - 2.65 (m, 1H), 2.64 - 2.52 (m, 3H), 2.42 (s, 3H), 2.25 (s, 3H), 2.17 - 2.00 (m, 1H), 2.05 (s , 3H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=6.68 min, >96.8%, >93.6% diastereomeric excess at 254 nm.

Example 35: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(5-fluoro-2-methylphenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(5-fluoro-2-methylphenyl)pyrrolidin-2-one

A solution of DBU (20 μl, 0.133 mmol) and intermediate E1 (60 mg, 0.129 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (5-fluoro-2methylphenyl)boronic acid ( 22 mg, 0.143 mmol) and then stirred for 18 h at 40°С. The mixture was diluted with water, then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(( R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol2-yl)-1-(5-fluoro-2-methylphenyl)pyrrolidin-2-one (16 mg, 21%) in the form of pale yellow glassy substances; temp. beats 1.84 min (method 1), m/z 552 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.72 (d, J=1.6 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.31 - 7.21 (m, 2H), 7.21 - 7.12 (m, 1H), 7.06 (td, J=8.5, 2.8 Hz, 1H), 5.84 - 5.75 (m, 1H), 5.34 - 5.21 (m, 1H), 3.73 (dd, J=10.6, 8.8 Hz, 1H), 3.60 (td, J=9.2, 2.6 Hz, 1H), 3.53 (dd, J=10.6, 6.8 Hz, 1H), 3.28 - 3.17 (m, 1H), 3.05 (s, 3H), 2.90 - 2.65 (m, 2H ), 2.61 - 2.52 (m, 1H), 2.49 - 2.45 (m, 1H), 2.41 (s, 3H), 2.27 - 2.15 (m, 1H), 2.24 (s, 3H), 2.07 (s, 3H).

Chiral HPLC (Lab. 1, Div. 4, Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=6.53 min, >99%, >98% diastereomeric excess at 254 nm.

Example 36 3-((S)-2-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)1H-benzo[d ]imidazol-2-yl)-5-oxopyrrolidin-1-yl)-5-fluorobenzonitrile.

3-((S)-2-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3 -yl)- 1Hbenzo[d]imidazol-2 -yl)-5-oxopyrrolidin-1 -yl)-5-fluorobenzonitrile

- 101 041318

A solution of DBU (20 µL, 0.133 mmol) and intermediate E1 (60 mg, 0.129 mmol) in acetonitrile (4 mL) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3-cyano-5fluorophenyl)boronic acid ( 25 mg, 0.152 mmol) and then stirred for 18 h at 40°C. The mixture was diluted with water, then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give 3-((S)-2-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl)-5-oxopyrrolidin-1-yl)-5-fluorobenzonitrile (35 mg, 47%) as pale yellow glassy substances; temp. beats 1.92 min (method 1), m/z 563 (M+H)+ (electrospray ⁺ );

1H-NMR (d6-DMSO) δ: 7.94 - 7.86 (m, 2H), 7.78 (d, J=8.5 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.60 (ddd, 1H), 7.27 (dd, J=8.5, 1.7 Hz, 1H), 6.22 (d, J=7.1 Hz, 1H), 5.56 - 5.43 (m, 1H), 3.89 - 3.80 (m, 1H), 3.80 - 3.73 (m, 1H), 3.69 (dd, J=10.6, 6.8 Hz, 1H), 3.46 - 3.36 (m, 1H), 3.10 (s, 3H), 2.78 - 2.53 (m, 5H), 2.37 (s, 3H), 2.28 2.12 (m, 1H), 2.20 (s, 3H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=8.95 min, >99%, >98% diastereomeric excess at 254 nm.

Example 37: (S)-1-(cyclohex-1-en-1-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidine -3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

3-((S)-2-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3 -yl)-1Hbenzo[d]imidazol-2 -yl)-5-oxopyrrolidin-1-yl)-5-fluorobenzonitrile

A solution of DBU (50 µL, 0.332 mmol) and intermediate E1 (150 mg, 0.321 mmol) in acetonitrile (4 mL) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and cyclohex-1-en-1-ylboronic acid (50 mg, 0.397 mmol) and then stirred for 18 h at 70°C. The mixture was diluted with water, then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give (S)-1(cyclohex-1-en-1-yl)-5-(5-(3, 5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (58 mg, 0.105 mmol , 32.7% yield) as pale yellow glassy substances; temp. beats 1.78 min (method 1), m/z 524 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (de-DMSO) δ: 7.78 (d, J=8.5 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.27 (dd, J=8.4, 1.6 Hz, 1H), 5.58 (dd, J=8.2, 2.6 Hz, 1H), 5.55 - 5.44 (m, 1H), 5.43 - 5.36 (m, 1H), 3.82 - 3.62 (m, 3H), 3.44 - 3.34 (m, 2H), 2.70 2.52 (m, 2H), 2.50 - 2.42 (m, 3H), 2.41 (s, 3H), 2.40 - 2.03 (m, 5H), 2.25 (s, 3H), 1.98 -1.89 (m, 2H), 1.56 - 1.35 (m, 4H). Contains 1.9 wt./wt.%, isohexane; chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic mode 30% EtOH in isohexane (0.2% TFA)): temp. sp=7.95 min, 97.5%, 95% diastereomeric excess at 254 nm.

Example 38: (S)-1-(4,5-difluoro-2-methylphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidine -3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

3-((S)-2-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3 -yl)-1Hbenzo[d]imidazol-2 -yl)-5-oxopyrrolidin-1-yl)-5-fluorobenzonitrile

- 102 041318

A solution of DBU (20 μl, 0.133 mmol) and intermediate E1 (60 mg, 0.129 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (4,5-difluoro-2methylphenyl)boronic acid (25 mg, 0.145 mmol) and then stirred for 18 h at 70°C.

The mixture was diluted with water, then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give a pale brown gum. This resin was purified by Companion chromatography (RP Flash C18) (12 g column, 15-75% MeCN/water 0.1% formic acid) to give (S)-1-(4.5 difluoro-2-methylphenyl) -5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)1H-benzo[d]imidazol-2-yl)πirrolidin- 2-one (22 mg, 28%) as a pale yellow glassy substance; temp. beats 1.99 min (method 1), m/z 570 (M+H)+ (electrospray ⁺ );

¹ H-NMR (R6-DMSO) δ: 7.75 - 7.67 (m, 2H), 7.47 (dd, J=11.5, 7.9 Hz, 1H), 7.34 (dd, J=11.7, 8.9 Hz, 1H), 7.26 ( dd, J=8.4, 1.7 Hz, 1H), 5.77 (dd, J=7.9, 3.5 Hz, 1H), 5.37 -5.26 (m, 1H), 3.79 - 3.69 (m, 1H), 3.68 - 3.59 (m, 1H), 3.55 (dd, J=10.6, 6.7 Hz, 1H), 3.33 - 3.21 (m, 2H), 3.06 (s, 3H), 2.86 - 2.64 (m, 2H), 2.59 - 2.53 (m, 1H) , 2.46 - 2.42 (m, 1H), 2.41 (s, 3H), 2.35 - 2.24 (m, 1H), 2.24 (s, 3H), 2.11 (s, 3H).

The product was analyzed by chiral HPLC (Lab. 1, Zone 4, Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic mode 30% EtOH in isohexane (0.2% TFA)): 1561183, temp. sp=6.17 min, >99%, >98% diastereomeric excess at 254 nm.

Example 39: (S)-1-(3,4-dichloro-2-methylphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidine -3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1 -(3,4-dichloro-2-methylphenyl)-5 -(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 (methylsulfonyl)pyrrolidin-3- yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (21 μl, 0.139 mmol) and intermediate E1 (60 mg, 0.129 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3,4-dichloro-2methylphenyl)boronic acid (30 mg, 0.146 mmol) and then stirred for 18 h at 70°C. The mixture was diluted with water, then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give a pale brown gum. This resin was purified by Companion chromatography (RP Flash C18) (12 g column, 15-75% MeCN/water 0.1% formic acid) to give (S)-1-(3,4dichloro-2-methylphenyl)- 5-(5-(3,5-dimethylisoxazol-4-yl)-1-(N)-1-(methylsulfonyl)pyrrolidin-3-yl)1H-benzo[d]imidazol-2-yl)pyrrolidin-2- it (14 mg, 17%) as a pale yellow glassy substance; temp. beats 2.10 min (method 1), m/z 602 (M+H)+ (electrospray ⁺ );

1H-NMR (d6-DMSO) δ: 7.77 - 7.60 (m, 2H), 7.58 - 7.45 (m, 1H), 7.47 - 7.01 (m, 2H), 6.06 - 5.54 (m, 1H), 5.40 - 5.20 ( m, 1H), 3.81 - 3.68 (m, 1H), 3.67 - 3.58 (m, 1H), 3.58 - 3.47 (m, 1H), 3.32 - 3.20 (m, 2H), 3.06 (s, 3H), 2.89 - 2.69 (m, 2Н), 2.65 - 2.54 (m, 1H), 2.47 - 2.37 (m, 1H), 2.41 (s, 3Н), 2.35 - 2.12 (m, 4Н), 2.24 (s, 3Н).

Example 40: (R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-1-(3-fluorophenyl)pyrrolidin-2-one.

(R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3-fluorophenyl)pyrrolidin-2-one

- 103 041318

A solution of DBU (25 μl, 0.166 mmol) and intermediate E23 (70 mg, 0.158 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3fluorophenyl)boronic acid (25 mg, 0.179 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-50% MeAs/DCM) to give (R)-5-(5-(3,5-dimethylisoxazol-4yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1 H-benzo[d]imidazol-2-yl)-1-(3fluorophenyl)pyrrolidin-2-one (41 mg, 48%) in as an off-white solid; temp. beats 1.85 min (method 1), m/z 538 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.76 (1H, d, J=8.5 Hz), 7.69 - 7.57 (2H, m), 7.39 - 7.18 (3H, m), 6.92 (1H, tdd, J=8.4 , 2.6, 0.9 Hz), 6.10 (1H, d, J=6.9 Hz), 5.59 - 5.42 (1H, m), 3.85 (1H, dd, J=10.5, 8.9 Hz), 3.78 - 3.62 (2Н, m) , 3.49 - 3.37 (1H, m), 3.11 (3H, s), 2.79 - 2.60 (2H, m), 2.60 - 2.52 (2H, m), 2.49 - 2.43 (1H, m), 2.37 (3H, s) , 2.20 (3H, s), 2.17–2.08 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=10.83 min, >99% diastereomeric excess at 254 nm.

Example 41: (R)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(R)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-

-yl)-1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (25 μl, 0.166 mmol) and intermediate E23 (70 mg, 0.158 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and boronic acid (3,4-difluorophenyl)boronic acid (27.4 mg, 0.174 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-50% MeAs/DCM) to give (R)-1-(3,4-difluorophenyl)-5-(5(3 ,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2-one (31 mg, 35 %) as an off-white solid; temp. beats 1.91 min (method 1), m/z 556 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.85 (1H, ddd, J=13.3, 7.4, 2.7 Hz), 7.76 (1H, d, J=8.4 Hz), 7.64 (1H, d, J=1.6 Hz ), 7.41 - 7.31 (1H, m), 7.28 - 7.19 (2H, m), 6.11 - 6.04 (1H, m), 5.54 - 5.40 (1H, m), 3.83 (1H, dd, J=10.5, 8.8 Hz ), 3.77 - 3.64 (2H, m), 3.48 - 3.36 (1H, m), 3.10 (3H, s), 2.75 - 2.60 (2H, m), 2.60 - 2.51 (3H, m), 2.37 (3H, s ), 2.20 (3H, s), 2.14–2.09 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=9.57 min, >99% diastereomeric excess at 254 nm.

Example 42: (R)-1 -(4-chloro-3-fluorophenyl)-5 -(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 (methylsulfonyl)pyrrolidin-3 -yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(R)-1 -(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 (methylsulfonyl)n-pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

- 104 041318

A solution of DBU (25 µL, 0.166 mmol) and intermediate E23 (70 mg, 0.158 mmol) in acetonitrile (4 mL) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (4-chloro-3fluorophenyl)boronic acid ( 30.3 mg, 0.174 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-50% MeAs/DCM) to give (R)-1-(4-chloro-3-fluorophenyl)-5-(5 (3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)nurroludin-3-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (30 mg, 33%) as an off-white solid; temp. beats 2.03 min (method 1), m/z 572 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.86 (1H, dd, J=12.2, 2.5 Hz), 7.77 (1H, d, J=8.5 Hz), 7.63 (1H, d, J=1.5 Hz), 7.50 (1H, t, J=8.8Hz), 7.30 (1H, ddd, J=9.0, 2.6, 1.0Hz), 7.26 (1H, dd, J=8.5, 1.7Hz), 6.11 (1H, d, J= 6.7 Hz), 5.55 5.41 (1H, m), 3.89 (1H, dd, J=10.5, 8.8 Hz), 3.73 (2Н, dd, J=10.4, 7.1 Hz), 3.49 - 3.35 (1H, m), 3.11 (3H, s), 2.76 - 2.61 (2H, m), 2.61 - 2.51 (3H, m), 2.36 (3H, s), 2.20 (3H, s), 2.14 - 2.08 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=11.66 min, >99% diastereomeric excess at 254 nm.

Example 43: (R)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-ul )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(R)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrroludin3-yl)-1 H -benzo[d]imidazol-2-yl)pyrrolidin-2-one

C: (3-chloro-5-fluorophenyl) boronic acid (30.3 mg, 0.174 mmol)

A solution of DBU (25 μl, 0.166 mmol) and intermediate E23 (70 mg, 0.158 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3,5dichlorophenyl)boronic acid (33.1 mg , 0.174 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-40% MeAs/DCM) to give (K)-1-(3,5-dichlorophenyl)-5-(5-( 3,5dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1 H-benzo[d]umidazol-2yl)pyrrolidin-2-one (40 mg, 43% ) as an off-white solid; temp. beats 2.15 min (method 1), m/z 588 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (de-DMSO) δ: 7.77 (1H, d, J=8.5 Hz), 7.70 (2H, d, J=1.8 Hz), 7.65 (1H, d, J=1.7 Hz), 7.34 (1H , t, J=1.8 Hz), 7.26 (1H, dd, J=8.4, 1.7 Hz), 6.21 (1H, d, J=7.0 Hz), 5.55 - 5.43 (1H, m), 3.92 - 3.84 (1H, m), 3.78 3.66 (2Н, m), 3.49 - 3.39 (1H, m), 3.12 (3H, s), 2.75 - 2.62 (2Н, m), 2.61 - 2.52 (3H, m), 2.37 (3H, s ), 2.20 (3H, s), 2.11 (1H, s).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=9.00 min, >99% diastereomeric excess at 254 nm.

Example 44: (R)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3 -ul)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(R)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-ul) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

- 105 041318

A solution of DBU (25 μl, 0.166 mmol) and intermediate E23 (70 mg, 0.158 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3-chloro-4fluorophenyl)boronic acid ( 30.3 mg, 0.174 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-40% MeAs/DCM) to give (R)-1-(3-chloro-4-fluorophenyl)-5-(5 (3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1 H-benzo[i]imidazol-2yl)pyrrolidin-2-one (27 mg , 30%) as an off-white solid; temp. beats 1.97 min (method 1), m/z 572 (M+H)+ (electrospray ⁺ );

¹ H-NMR (dg-DMSO) δ: 8.02 - 7.96 (1H, m), 7.76 (1H, d, J=8.4 Hz), 7.65 (1H, d, J=1.6 Hz), 7.42 - 7.31 (2H, m), 7.25 (1H, dd, J=8.5, 1.7 Hz), 6.13 - 6.07 (1H, m), 5.53 - 5.42 (1H, m), 3.82 (1H, dd, J=10.5, 8.8 Hz), 3.77 -3.64 (2H, m), 3.48 - 3.36 (IH, m), 3.10 (3H, s), 2.77 - 2.60 (2H, m), 2.61 - 2.51 (3H, m), 2.37 (3H, s), 2.20 (3H, s), 2.15 - 2.10 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=10.55 min, >99% diastereomeric excess at 254 nm.

45:

Example (R)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl )-1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one. (R)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (25 μl, 0.166 mmol) and intermediate E23 (70 mg, 0.158 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3,5dichlorophenyl)boronic acid (33.1 mg , 0.174 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-40% MeAs/DCM) to give (K)-1-(3-chloro-5-fluorophenyl)-5-(5 (3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2-one (31 mg , 34%) as an off-white solid; temp. beats 2.05 min (method 1), m/z 572 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.78 (1H, d, J=8.4 Hz), 7.68 - 7.59 (2H, m), 7.46 (1H, dt, J=11.4, 2.1 Hz), 7.26 (1H , dd, J=8.5, 1.7 Hz), 7.16 (1H, dt, J=8.5, 2.1 Hz), 6.16 (1H, d, J=6.9 Hz), 5.54 - 5.41 (1H, m), 3.90 (1H, dd, J=10.4, 8.8 Hz), 3.78 - 3.67 (2H, m), 3.50 - 3.38 (1H, m), 3.12 (3H, s), 2.78 - 2.61 (2H, m), 2.61 - 2.51 (3H, m), 2.37 (3H, s), 2.20 (3H, s), 2.15–2.09 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=8.76 min, >99% diastereomeric excess at 254 nm.

Example 46: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro2H-thiopyran-4-yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)phenyl)5-oxo-1-phenylpyrrolidine -2-carboxamide (intermediate D3)

- 106 041318

HATU (550 mg, 1.446 mmol) was added to a solution of intermediate C3 (194 mg, 0.526 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (200 mg, 1.549 mmol) and N,N-diisopropylethylamine (0.27 ml, 1.546 mmol) in N,N-dimethylformamide (5 ml), then stirred at room temperature for 18 hours. The mixture was diluted with 30% brine (100 ml), then extracted with ethyl acetate (3x75 ml). The combined organic phases were dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give a red-brown oil. This oil was dissolved in acetone (25 ml) then diluted with diethyl ether (75 ml). The resulting precipitate was collected by filtration to give (S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1dioxytetrahydro-2H-thiopyran-4-yl)amino)phenyl) -5-oxopyrrolidine-2-carboxamide intermediate D3 (438 mg, 68%) as a pale brown solid; temp. beats 1.36 min (method 1), m/z 447 (M+H) + (electrospray ⁺ ).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1 Hbenzo[d]imidazol-2-yl) -1-phenylpyrrolidin-2-one (intermediate E3)

Intermediate D3 (438 mg, 0.961 mmol) was heated to 80°C in acetic acid (10 mL) for 4 h. ml). The combined organic phases were dried (Na ₂ SO ₄ ), then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (24 g column, 50100% MeAs/CH ₂ Cl ₂ ) to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-( 1,1dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one - intermediate E3 (139 mg, 33%) as a colorless glassy substance; temp. beats 1.32 min (method 1), m/z 429 (M+H) + (electrospray ⁺ ).

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran4-yl)-1H-benzo [d]imidazol-2-yl)-pyrrolidin-2-one

A solution of DBU (22 μl, 0.146 mmol) and intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3,4difluorophenyl)boronic acid (25 mg , 0.158 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give (S)-1-(3,4-difluorophenyl)-5-(5-( 3,5dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2-one (31 mg, 39%) as an off-white solid; temp. beats 1.88 min (method 1), m/z 541 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.85 (ddd, J=13.3, 7.4, 2.7 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.37 (dt, J=10.7, 9.2 Hz, 1H) , 7.29 (dd, J=8.5, 1.7Hz, 1H), 7.19 (d, J=9.0Hz, 1H), 5.99 (d, J=7.3Hz, 1H), 5.02 (t, J=12.3Hz, 1H) , 3.58 (q, J=12.7 Hz, 2H), 3.32 - 3.23 (m, 2H), 2.90 (q, J=13.1 Hz, 2H), 2.78 - 2.51 (m, 3H), 2.38 (s, 3H), 2.35 - 2.22 (m, 2H), 2.21 (s, 3H), 2.19 - 2.10 (m, 1H).

- 107 041318

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH in isohexane (0.2% TFA)): 148480, temp. sp=8.82 min, 96.9%, 93.8% diastereomeric excess at 254 nm.

Example 47: (S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1dioxytetrahydro-2H-thiopyran-4-yl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2Hthiopyran-4-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μl, 0.146 mmol) and intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3-chloro-4fluorophenyl)boronic acid ( 25 mg, 0.143 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give ^)-1-(3-chloro-4-fluorophenyl)-5-(5( 3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2-one (34 mg, 42 %) as an off-white solid; temp. beats 1.94 min (method 1), m/z 557 (M+H)+ (electrospray ⁺ );

¹ H-NMR (06-DMSO) δ: 7.98 (dt, J=6.9, 1.4 Hz, 1H), 7.70 -7.58 (m, 2H), 7.39 - 7.33 (m, 2H), 7.29 (dd, J=8.5 , 1.7 Hz, 1H), 6.01 (d, J=7.1 Hz, 1H), 5.11 - 4.95 (m, 1H), 3.68 - 3.48 (m, 2H), 3.32 - 3.23 (m, 2H), 2.90 (q, J=13.0 Hz, 2H), 2.80 - 2.52 (m, 3H), 2.38 (s, 3H), 2.32 - 2.11 (m, 3H), 2.21 (s, 3H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=8.90 min, 96.1%, 92.2% diastereomeric excess at 254 nm.

Example 48: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1Hbenzo[d]imidazol-2- yl)-1-(3-fluorophenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1Hbenzo[d]imidazol-2-yl)- 1-(3-fluorophenyl)pyrrolidin-2-one

F

A solution of DBU (22 μl, 0.146 mmol) and intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3fluorophenyl)boronic acid (20 mg, 0.143 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give a colorless gum. This resin was dissolved in methyl ethyl ketone (0.5 ml), then diluted with diethyl ether (2 ml). The supernatant was removed, then the solids were dried overnight in a desiccator at 50°C, resulting in (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1 - dioxidotetrahydro-2H-thiopyran-4-yl)-1Hbenzo[d]imidazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one (23 mg, 30%) as a white solid; temp. beats 1.80 min (method 1), m/z 523 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (dg-DMSO) δ: 7.70 - 7.56 (m, 3H), 7.39 - 7.24 (m, 2H), 7.24 - 7.14 (m, 1H), 6.93 (tdd, J=8.4, 2.5, 0.9 Hz , 1H), 6.01 (d, J=7.4 Hz, 1H), 5.12 - 4.98 (m, 1H), 3.58 (t, J=13.6 Hz, 2H), 3.33 - 3.25 (m, 2H), 2.91 (q, J=12.9 Hz, 2H), 2.80 - 2.62 (m, 2H), 2.60 - 2.52 (m, 1H), 2.38 (s, 3H), 2.34 - 2.10 (m, 3H), 2.21 (s, 3H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH in isohexane (0.2% TFA)): 148483, temp. sp=11.76 min, >99%, >98% diastereomeric excess at 254 nm.

Example 49: (S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1dioxytetrahydro-2H-thiopyran-4-yl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H- 108 041318 thiopyran-4- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μl, 0.146 mmol) and intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (4-chloro-3fluorophenyl)boronic acid ( 25 mg, 0.143 mmol) and then stirred for 18 h at 40°С. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/CH ₂ Cl ₂ ) to give a gum. This resin was triturated in diethyl ether to give (S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4yl)-1-(1,1-dioxidotetrahydro -2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (41 mg, 50%) as an off-white solid; temp. beats 2.00 min (method 1), m/z 557 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.87 (dd, J=12.1, 2.5 Hz, 1H), 7.71 -7.57 (m, 2H), 7.51 (t, J=8.8 Hz, 1H), 7.30 (dd, J=8.5, 1.6Hz, 1H), 7.25(ddd, J=8.9, 2.6, 1.0Hz, 1H), 6.03(d, J=7.2Hz, 1H), 5.13 - 4.93(m, 1H), 3.58(dd , J=16.1,7.0 Hz, 2H), 3.33 - 3.23 (m, 2H), 2.92 (q, J=12.9 Hz, 2H), 2.79 - 2.62 (m, 2H), 2.62 - 2.52 (m, 1H), 2.40 2.26 (m, 2H), 2.37 (s, 3H), 2.20 (s, 3H), 2.18 - 2.10 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=10.81 min, 98.3%, 96.6% diastereomeric excess at 254 nm.

Example 50: (S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1dioxytetrahydro-2H-thiopyran-4-yl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1 -(3-chloro-5-methoxyphenyl)-5 -(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro-2Hthiopyran-4-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one

OME

A solution of DBU (22 μl, 0.146 mmol) and intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3-chloro-5methoxyphenyl)boronic acid ( 28 mg, 0.150 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give a colorless gum. This resin was dissolved in methyl ethyl ketone (0.5 ml), then diluted with diethyl ether. The supernatant was removed, then the solids were dried overnight in a desiccator at 50°C, resulting in (S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazole- 4-yl)-1-(1,1-Dioxytetrahydro-2Hthiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (47 mg, 57%) as a white solid ; temp. beats 1.94 min (method 1), m/z 569 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (de-DMSO) δ: 7.66 (d, J=1.6 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.33 (t, J=1.9 Hz, 1H), 7.30 (dd , J=8.5, 1.7 Hz, 1H), 7.06 (t, J=2.1 Hz, 1H), 6.79 (t, J=2.0 Hz, 1H), 6.05 (d, J=7.5 Hz, 1H), 5.16 - 4.99 (m, 1H), 3.69 (s, 3H), 3.64 - 3.51 (m, 2H), 3.33 - 3.26 (m, 2H), 3.02 - 2.83 (m, 2H), 2.83 - 2.52 (m, 3H), 2.38 (s, 3Н), 2.35-2.23 (m, 1H), 2.21 (s, 3Н), 2.19-2.08 (m, 2H); chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH in isohexane (0.2% TFA)): 148485, temp. sp=10.72 min, >99%, >98% diastereomeric excess at 254 nm.

Example 51: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1Hbenzo[d]imidazol-2- yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-ul)-1Hbenzo[d]imidazol-2-yl)- 1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

- 109 041318

A solution of DBU (22 μl, 0.146 mmol) and intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3-fluoro-4methoxyphenyl)boronic acid ( 25 mg, 0.147 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give a gum. This resin was dissolved in methyl ethyl ketone (0.5 ml), then diluted with diethyl ether (2 ml). The supernatant was removed, then the solids were dried overnight in a desiccator at 50°C to give (S)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran -4-yl)-1 H-benzo[d]imidazol-2-yl)-1-(3fluoro-4-methoxyphenyl)pyrrolidin-2-one (28 mg, 35%) as an off-white solid; temp. beats 1.76 min (method 1), m/z 553 (M+H)+ (electrospray ⁺ );

¹ H-NMR (H6-DMSO) δ: 7.70 - 7.56 (m, 3H), 7.29 (dd, J=8.4, 1.6 Hz, 1H), 7.15-7.02 (m, 2H), 5.93 (d, J=7.7 Hz, 1H), 5.11 - 4.93 (m, 1H), 3.75 (s, 3H), 3.65 - 3.48 (m, 2H), 3.32 - 3.23 (m, 2H), 2.88 (d, J=13.4 Hz, 2H) , 2.81 - 2.53 (m, 3H), 2.38 (s, 3H), 2.35 - 1.98 (m, 6H), 2.21 (s, 3H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH in isohexane (0.2% TFA)): 148486, temp. sp=12.91 min, >99%, >98% diastereomeric excess at 254 nm.

Example 52: (S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxαzol-4-yl)-1-(1,1dioxytetrahydro-2H-thiopyran-4-yl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxαzol-4-yl)-1-(1,1-dioxytetrahydro-2Hthiopyran-4-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μl, 0.146 mmol) and intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3-chloro-4methoxyphenyl)boronic acid ( 28 mg, 0.150 mmol) and then stirred for 18 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give a gum.

This resin was dissolved in methyl ethyl ketone (0.5 ml), then diluted with diethyl ether (3 ml). The supernatant was removed and the solid was dried at 50° C. in a desiccator overnight to give (S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazole- 4-yl)-1-(1,1dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (39 mg, 48%) as an off-white solid ; temp. beats 1.83 min (method 1), m/z 569 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.80 (d, J=2.6 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.27 ( td, J=8.7, 2.1 Hz, 2H), 7.07 (d, J=9.1 Hz, 1H), 5.96 (d, J=7.8 Hz, 1H), 5.11 - 4.98 (m, 1H), 3.77 (s, 3H ), 3.64 - 3.49 (m, 2H), 3.33 - 3.23 (m, 2H), 2.95 - 2.52 (m, 5H), 2.38 (s, 3H), 2.34 - 2.14 (m, 2H), 2.20 (s, 3H ), 2.05 - 1.92 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=12.12 min, >99%, >98% diastereomeric excess at 254 nm.

Example 53: (S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro2H-thiopyran-4-yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran4-yl)- 1H-benzo [d] imidazol-2-yl)pyrrolidin-2-one

- 110 041318

A solution of DBU (22 μl, 0.146 mmol) and intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3,5dichlorophenyl)boronic acid (28 mg , 0.147 mmol) and then stirred for 18 h at 40°С. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM), then triturated in diethyl ether to give (S)-1-(3,5-dichlorophenyl)- 5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro-2H-thiopyran-4yl)-1H-benzo[d]imidazol-2-yl)πirrolidin-2-one (49 mg, 60%) as an off-white solid; temp. beats 2.12 min (method 1), m/z 573 (M+H)+ (electrospray ⁺ );

Ή-NMR (d ₆ -DMSO) δ: 7.70 (d, J=1.9 Hz, 2H), 7.67 - 7.61 (m, 2H), 7.34 (t, J=1.8 Hz, 1H), 7.31 (dd, J= 8.4, 1.7 Hz, 1H), 6.13 (d, J=7.6 Hz, 1H), 5.14 - 4.98 (m, 1H), 3.69 - 3.50 (m, 2H), 3.33 - 3.25 (m, 2H), 3.04 - 2.84 (m, 2H), 2.83 - 2.53 (m, 3H), 2.38 (s, 3H), 2.35 - 2.22 (m, 2H), 2.21 (s, 3H), 2.18 - 2.11 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=10.02 min, >99%, >98% diastereomeric excess at 254 nm.

Example 54: (S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1dioxytetrahydro-2H-thiopyran-4-yl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2Hthioniran-4-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one

CI

A solution of DBU (22 µL, 0.146 mmol) and intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 mL) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3-chloro-5fluorophenyl)boronic acid ( 25 mg, 0.143 mmol) and then stirred for 18 h at 40°С. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give a gum which was triturated in diethyl ether to give (S)-1-(3 -chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1(1,1-dioxido tetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazole -2-yl)pyrrolidin-2-one (28 mg, 34%) as an off-white solid; temp. beats 2.02 min (method 1), m/z 557 (M+H)+ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.67 - 7.62 (m, 2H), 7.62 - 7.57 (m, 1H), 7.47 (dt, J=11.4, 2.1 Hz, 1H), 7.31 (dd, J=8.5 , 1.6 Hz, 1H), 7.17 (dt, J=8.5, 2.1 Hz, 1H), 6.09 (d, J=7.4 Hz, 1H), 5.12 - 4.96 (m, 1H), 3.71 - 3.48 (m, 2H) , 3.29 (d, J=4.0 Hz, 2H), 3.05 - 2.84 (m, 2H), 2.83 - 2.53 (m, 3H), 2.38 (s, 3H), 2.36 - 2.23 (m, 2H), 2.21 (s , 3Н), 2.18 - 2.10 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=10.55 min, >99%, >98% diastereomeric excess at 254 nm.

Example 55: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1Hbenzo[d]imidazol-2- yl)-1-(3,4,5-trifluorophenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1Hbenzo[d]imidazol-2-yl)- 1-(3,4,5-trifluorophenyl)pyrrolidin-2-one

- 111 041318

A solution of DBU (22 μl, 0.146 mmol) and intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3,4,5trifluorophenyl)boronic acid ( 25 mg, 0.142 mmol) and then stirred for 18 h at 40°С. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give (8)-5-(5-(3,5-dimethylisoxazol-4yl)-1 -(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1 H-benzo[d]imidazol-2-yl)-1-(3,4,5trifluorophenyl)pyrrolidin-2-one (49 mg, 61 %) as an off-white solid; temp. beats 2.00 min (method 1), m/z 559 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.69 - 7.52 (m, 4H), 7.30 (dd, J=8.5, 1.6 Hz, 1H), 6.03 (d, J=6.9 Hz, 1H), 5.06 4.88 ( m, 1H), 3.64 (td, J=13.6, 3.5 Hz, 1H), 3.55 (td, J=13.7, 3.5 Hz, 1H), 3.33 - 3.24 (m, 2H), 2.92 (q, J=13.1 Hz , 2Н), 2.77 - 2.63 (m, 2H), 2.63 - 2.53 (m, 1H), 2.41 - 2.27 (m, 2H), 2.38 (s, 3H), 2.21 (s, 3H), 2.17 - 2.10 (m , 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 mm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=9.04 min, >99%, >98% diastereomeric excess at 254 nm.

Example 56: (8)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro2H-thiopyran-4-yl)- 1H-benzo[d]umidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran4-yl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one

of intermediate E3 (60 mg, 0.139 mmol) in acetic CuTMEDA (10 mg, 0.022 mmol) and (3.5 DBU solution (22 µl, 0.146 mmol) and nitrile (4 ml) was added to the vial, difluorophenyl)boronic acid (23 mg , 0.146 mmol) and then stirred for 18 h at 40°С. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM) to give (S)-1-(3,5-difluorophenyl)-5-(5-( 3,5dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2-one (36 mg, 43%) as an off-white solid; temp. beats 1.92 min (method 1), m/z 541 (M+H)+ (electrospray ⁺ );

1H-NMR ^-DMSO) δ: 7.69 - 7.60 (m, 2H), 7.41 - 7.33 (m, 2H), 7.30 (dd, J=8.6, 1.6 Hz, 1H), 6.98 (tt, J=9.2, 2.3 Hz, 1H), 6.05 (d, J=7.3 Hz, 1H), 5.02 (t, J=12.4 Hz, 1H), 3.70 - 3.48 (m, 2H), 3.33 - 3.24 (m, 2H), 3.04 - 2.85 (m, 2H), 2.80 - 2.53 (m, 3H), 2.38 (s, 3H), 2.36 - 2.28 (m, 2H), 2.21 (s, 3H), 2.13 (q, J=7.9, 7.3 Hz, 1H ).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=11.07 min, >99%, >98% diastereomeric excess at 254 nm.

Example 57: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1Hbenzo[d]imidazol-2- yl)-1-(5-fluoro-6-methoxypyridin-3-yl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1Hbenzo[d]imidazol-2-yl)- 1 - (5-fluoro-6-methoxypyridin-3 -yl) pyrrolidin-2-one

- 112 041318

Meo

A solution of DBU (22 μl, 0.146 mmol) and intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (5-fluoro-6methoxypyridin-3-yl )boronic acid (25 mg, 0.146 mmol) and then stirred for 18 h at 40°С. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% MeAs/DCM), then triturated in diethyl ether to give (S)-5-(5-(3.5- dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro-2H-thiopyran-4-yl)-1Hbenzo[d]imidazol-2-yl)-1-(5-fluoro-6-methoxypyridin-3-yl )pyrrolidin-2-one (20 mg, 26%) as an off-white solid; temp. beats 1.78 min (method 1), m/z 554 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 8.13 (dd, J=12.2, 2.3 Hz, 1H), 7.97 (d, J=2.2 Hz, 1H), 7.71 - 7.58 (m, 2H), 7.30 (dd , J=8.4, 1.7 Hz, 1H), 5.96 (d, J=7.2 Hz, 1H), 5.04 - 4.88 (m, 1H), 3.86 (s, 3H), 3.70 - 3.57 (m, 1H), 3.57 - 3.46 (m, 1H), 3.33 - 3.24 (m, 2H), 3.00 - 2.79 (m, 2H), 2.79 - 2.63 (m, 2H), 2.60 - 2.52 (m, 1H), 2.38 (s, 3H), 2.36 2.25 (m, 1H), 2.25 - 2.15 (m, 2H), 2.21 (s, 3H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=12.97 min, >99%, >98% diastereomeric excess at 254 nm.

Example 58: (S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1dioxidotetrahydro-2H-thiopyran-4 -yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro2H-thiopyran-4-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μl, 0.146 mmol) and intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (2,3dihydrobenzofuran-5-yl)boronic acid (25 mg, 0.152 mmol) and then stirred for 18 h at 70°С. The mixture was diluted with water, then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give (S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3 ,5-dimethylisoxazol-4-yl)-1-(1,1dioxidotetrahydro-2H-thiopyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (35 mg, 44%) in the form of pale yellow glassy substances; temp. beats 1.68 min (method 1), m/z 547 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.68 (d, J=1.6 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 7.27 ( dd, J=8.5, 1.7Hz, 1H), 7.01 (dd, J=8.6, 2.3Hz, 1H), 6.66 (d, J=8.5Hz, 1H), 5.84 (d, J=7.8Hz, 1H), 5.04 - 4.91 (m, 1H), 4.47 (t, J=8.7 Hz, 2H), 3.61 - 3.42 (m, 2H), 3.31 - 3.20 (m, 2H), 3.10 (t, J=8.7 Hz, 2H) , 2.93 - 2.72 (m, 3H), 2.71 - 2.58 (m, 1H), 2.44 - 2.33 (m, 1H), 2.39 (s, 3H), 2.32 - 2.10 (m, 2H), 2.22 (s, 3H) , 1.75 - 1.61 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=16.8 min, 97.4%, 94.8% diastereomeric excess at 254 nm.

Example 59: (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro2H-thiopyran-4-yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran4-yl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one

- 113 041318

A solution of DBU (22 μl, 0.146 mmol) and intermediate E3 (60 mg, 0.139 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3,4dichlorophenyl)boronic acid (28 mg , 0.147 mmol) and then stirred for 18 h at 70°С. The mixture was diluted with water, then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazole -4-yl)-1 -(1,1-dioxidotetrahydro-2H-thiopyran-4yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (41 mg, 49%) as pale yellow glassy substances; temp. beats 2.08 min (method 1), m/z 573 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 8.07 (d, J=2.5 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.56 (d, J=8.9 Hz, 1H), 7.39 (dd, J =8.9, 2.6 Hz, 1H), 7.30 (dd, J=8.5, 1.6 Hz, 1H), 6.06 (d, J=7.2 Hz, 1H), 5.14-4.97 (m, 1H), 3.66 - 3.51 (m, 2H), 3.33 - 3.23 (m, 2H), 3.00 - 2.84 (m, 2H), 2.80 - 2.52 (m, 3H), 2.37 (s, 3H), 2.35 - 2.25 (m, 2H), 2.21 (s, 3H), 2.18 - 2.10 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=10.91 min, 83.6%, 67.2% diastereomeric excess at 254 nm.

Example 61: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4hydroxycyclohexyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one.

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,4S)-4-hydroxycyclohexyl)amino)phenyl)-5oxopyrrolidine-2-carboxamide (Intermediate D4) he he

O

HATU (1.5 g, 3.94 mmol) was added to a stirred solution of TEA (0.6 ml, 4.30 mmol), (S)-5oxopyrrolidine-2-carboxylic acid (0.5 g, 3.87 mmol) and (1r,4r)-4-((2 -amino-4-(3,5-dimethylisoxazol4-yl)phenyl)amino)cyclohexanol (1.15 g, 3.78 mmol) in N,N-dimethylformamide (10 ml), then the mixture was stirred at room temperature for 18 h. The solvents were removed under reduced pressure (evaporating together with xylenes), then adsorbed on loose silica gel. The silicate was purified by flash chromatography on a Companion (80 g column, 0-10% MeOH/DCM) to give (S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-( ((1r,4S)-4-hydroxycyclohexyl)amino)phenyl)-5oxopyrrolidine-2-carboxamide Intermediate D4 (1.5 g, 89%) as a pale pink solid; temp. beats 1.31 min (method 1), m/z 413 (M+H) ⁺ (electrospray ⁺ ).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (intermediate connection E4)

Intermediate D4 (500 mg, 1.115 mmol) was heated to 80° C. in acetic acid (10 ml) for 4 h. The mixture was concentrated under reduced pressure, then redissolved in methanol (20 ml). Was added solid potassium carbonate (2 g) and stirred the mixture for 1 h, and then concentrated on loose silica gel. The crude product was purified by Companion chromatography (40 g column, 5-15% MeOH/DCM) to give a colorless gum. This resin was stirred overnight in diethyl ether (25 ml) then collected by filtration to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-( (1r,4S)-4-Hydroxycyclohexyl)-1H-benzo[d]imidazol2-yl)pyrrolidin-2-one (Intermediate E4) (232 mg, 52%) as a white solid;

temp. beats 1.13 min (method 1), m/z 395 (M+H) + (electrospray ⁺ ).

(S)-1 -(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-hydroxycyclohexyl)-1Hbenzo[d] umidazol-2-yl)pyrrolidin-2-one

A solution of DBU (22 μl, 0.146 mmol) and intermediate E4 (55 mg, 0.137 mmol) in acetonitrile (4 ml) was added to a vessel containing CuTMEDA (10 mg, 0.022 mmol) and (3,4difluorophenyl)boronic acid (25 mg , 0.158 mmol) and then stirred for 2 h at 70°С. The mixture was diluted with water (8 ml), then extracted with dichloromethane (3x8 ml). The organic phases were combined, then filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (4 g column, 2-5% MeOH/DCM) to give a pale brown gum. This resin was purified by Companion chromatography (12 g column, 0-10% MeOH/DCM) to give (S)-1-(3,4-difluorophenyl)-5-(5-(3,5dimethylisoxazole-4 -yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-ul)pyrrolidin-2-one (40 mg, 56%) as an off-white solid; temp. beats 1.78 min; m/z 507 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.89 - 7.76 (m, 2H), 7.59 (d, J=1.6 Hz, 1H), 7.44 - 7.33 (m, 1H), 7.22 - 7.11 (m, 2H), 6.17 -6.05 (m, 1H), 4.75 (d, J=4.2 Hz, 1H), 4.57 - 4.43 (m, 1H), 3.82 - 3.66 (m, 1H), 2.81 -2.52 (m, 3H), 2.43 - 2.26 (m, 2H), 2.37 (s, 3H), 2.20 (s, 3H), 2.14 - 2.05 (m, 1H), 2.04 - 1.93 (m, 2H), 1.87 - 1.79 (m, 1H), 1.78 - 1.68 (m, 1H), 1.61 - 1.39 (m, 2H).

Example 62: (S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 r,4S)-4hydroxycyclohexyl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1 -(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-hydroxycyclohexyl)-

H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL, 0.133 mmol), intermediate E4 (50 mg, 0.127 mmol), and (4-chloro-3-fluorophenyl)boronic acid (24.31 mg, 0.139 mmol) in acetonitrile (4 ml) with stirring for 108 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(4-chloro-3-fluorophenyl)-5 -(5(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (15 mg, 22%) as whitish solid; temp. beats 1.56 min; m/z 523 (M+H) ⁺ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.87 - 7.79 (m, 2H), 7.58 (d, J=1.6 Hz, 1H), 7.52 (t, J=8.8 Hz, 1H), 7.23 (ddd, J= 8.9, 2.6, 1.0 Hz, 1H), 7.16 (dd, J=8.5, 1.7 Hz, 1H), 6.22 - 6.08 (m, 1H), 4.76 (d, J=4.2 Hz, 1H), 4.59 - 4.45 (m , 1H), 3.81 -3.67 (m, 1H), 2.80 - 2.53 (m, 3H), 2.41 - 2.29 (m, 2H), 2.36 (s, 3H), 2.20 (s, 3H), 2.11 -1.95 (m , 3Н), 1.89 - 1.78 (m, 2H), 1.63 - 1.39 (m, 2H).

Example 63: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 r,4S)-4-hydroxycyclohexyl)-1Hbenzo[d]umidazol-2-yl)- 1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-hydroxycyclohexyl)-1 H-benzo[d]imudazol-2yl)-1 - (3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

- 115 041318

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL, 0.133 mmol), intermediate E4 (50 mg, 0.127 mmol), and (3-fluoro-4-methoxyphenyl)boronic acid (23.70 mg, 0.139 mmol) in acetonitrile (4 ml) with stirring for 108 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 010% MeOH in DCM, gradient elution) to give (S)-5-(5-(3,5dimethylisoxazol-4-yl)- 1-(4-hydroxycyclohexyl)-1 H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4methoxyphenyl)pyrrolidin-2-one (9 mg, 13%) as an off-white solid; temp. beats 1.69 min; m/z 519 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.81 (d, J=8.5 Hz, 1H), 7.59 (td, J=7.2, 6.5, 1.9 Hz, 2H), 7.14 (dd, J=8.5, 1.7 Hz, 1H), 7.12 - 7.03 (m, 2H), 6.04 (dd, J=8.4, 2.2 Hz, 1H), 4.75 (d, J=4.1 Hz, 1H), 4.56 - 4.43 (m, 1H), 3.82 - 3.65 (m, 1H), 3.75 (s, 3H), 2.82 - 2.52 (m, 3H), 2.37 (s, 3H), 2.35 - 2.25 (m, 2H), 2.20 (s, 3H), 2.15 - 2.06 (m , 1H), 2.03 - 1.91 (m, 2H), 1.84 - 1.75 (m, 1H), 1.65 - 1.39 (m, 3H).

Example 64:

(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4 hydroxycyclohexyl)-1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4hydroxycyclohexyl)-1H-benzo[d ]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μl, 0.133 mmol), intermediate E4, and (3-chloro-4-methoxyphenyl)boronic acid (26.0 mg, 0.139 mmol) in acetonitrile (4 ml) with stirring for 108 hours at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(3-chloro-4-methoxyphenyl)-5 -(5-(3,5dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (15 mg, 22%) as whitish a solid; temp. beats 1.76 min; m/z 535 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.80 (d, J=8.5 Hz, 1H), 7.75 (d, J=2.6 Hz, 1H), 7.59 (d, J=1.7 Hz, 1H), 7.27 (dd , J=9.0, 2.6 Hz, 1H), 7.13 (dd, J=8.5, 1.7 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.11 - 6.03 (m, 1H), 4.74 (d, J=4.2 Hz, 1H), 4.50 (s, 1H), 3.76 (s, 3H), 3.71 (s, 2H), 2.83 - 2.69 (m, 1H), 2.67 - 2.53 (m, 1H), 2.37 (s , 3Н), 2.28 (d, J=12.3 Hz, 1H), 2.20 (s, 3Н), 2.15-2.05 (m, 1H), 1.96 (t, J=13.6 Hz, 3Н), 1.77 (m, 1H) , 1.52 (m, 3H).

65:

Example (S)-1 -(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4 hydroxycyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one]

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL, 0.133 mmol), intermediate E4 (50 mg, 0.127 mmol), and (3-chloro-4-fluorophenyl)boronic acid (24.31 mg, 0.139

- 116 041318 mmol) in acetonitrile (4 ml) with stirring for 108 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-10%

MeOH in DCM, gradient elution) to give (S)-1-(3-chloro-4-fluorophenyl)-5-(5(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl )-1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (16 mg, 24%) as an off-white solid; temp. beats 1.90 min; m/z 523 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.92 (dt, J=6.8, 1.4 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.40 7.33 (m, 2H), 7.14 (dd, J=8.4, 1.7 Hz, 1H), 6.17 - 6.10 (m, 1H), 4.75 (d, J=4.2 Hz, 1H), 4.50 (s, 1H), 3.72 (m, 1H), 2.75 (dt, J=15.4, 9.1 Hz, 1H), 2.66 - 2.54 (m, 1H), 2.36 - 2.31 (m, 6H), 2.19 (s, 3H), 2.14 - 2.03 ( m, 1H), 1.97 (s, 2Н), 1.82 (s, 1H), 1.71 (s, 1H), 1.50 (dd, J=29.4, 13.8 Hz, 2Н).

Example 66: (S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4hydroxycyclohexyl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1 -(2,3-dihydrobenzofuran-5-yl)-5 -(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4hydroxycyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one he he

Me

0^/

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL, 0.133 mmol), [d]imidazol-2-ul)pyrrolidin-2-one (50 mg, 0.127 mmol) and (2,3-dihydrobenzofuran-5-yl)boronic acid (22.86 mg, 0.139 mmol) in acetonitrile (4 ml) with stirring for 108 hours at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(2,3-dihydrobenzofuran-5-yl) -5-(5-(3,5dimethylisoxazol-4-yl)-1 -(4-hydroxycyclohexyl)-1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (13 mg, 19%) in as an off-white solid; temp. beats 1.59 min; m/z 513 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.77 (d, J=8.5 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.38 (dd, J=2.2, 1.2 Hz, 1H), 7.12 (dd, J=8.4, 1.7Hz, 1H), 7.01 (dd, J=8.6, 2.3Hz, 1H), 6.65 (d, J=8.5Hz, 1H), 5.94 (dd, J=8.3, 2.7Hz , 1H), 4.72 (d, J=4.2 Hz, 1H), 4.45 (m, 4H), 3.67 (m, 1H), 3.43 - 3.28 (m, 1H), 3.20 - 3.05 (m, 2H), 2.78 ( dt, J=16.0, 9.0 Hz, 1H), 2.66 - 2.51 (m, 1H), 2.38 (s, 3H), 2.31 - 2.15 (m, 5H), 2.01 - 1.91 (m, 1H), 1.88 (m, 1H), 1.75 (m, 1H), 1.48 - 1.30 (m, 3H).

Example 67: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-hydroxycyclohexyl)-1Hbenzo[d]umidazol-2-yl)- 1-(naphthalene-1-yl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2yl)-1-(naphthalene -1 -yl)pyrrolidine-2-he he he

Me

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL, 0.133 mmol), intermediate E4 (50 mg, 0.127 mmol), and naphthalene-1-ylboronic acid (23.98 mg, 0.139 mmol) in acetonitrile (4 mL) with stirring for 108 h at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-5-(5-(3,5-dimethylisoxazole-4 -yl)-1(4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(naphthalen-1-yl)pyrroludin-2-one (4 mg, 6%) as an off-white solid ; temp. beats 1.75 min; m/z 521 (M+H) ⁺ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.96 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.68 (s, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.40 (bs, 6H), 7.07 (d, J=8.4 Hz, 1H), 5.89 (s, 1H), 4.54 (s, 1H), 3.81 (bs, 1H), 3.38 (bm, 2H), 2.96 (bs, 1H), 2.84 (bs, 1H), 2.73 (bm, 4H), 2.40 (s, 3H), 2.22 (s, 3H), 1.99 (bm, 1H), 1.75 (m, 2H), 1.63 (m, 1H ) - Wide spectrum, rotamers.

Example 68: (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)1H-benzo[d]imidazol-2 -yl)pyrrolidin-2-one.

- 117 041318 (S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL, 0.133 mmol), intermediate E4 (50 mg, 0.127 mmol), and (3,4-dichlorophenyl)boronic acid (26.6 mg, 0.139 mmol) in acetonitrile ( 4 ml) with stirring for 18 hours at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(3,4-dichlorophenyl)-5-( 5-(3,5dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-N-benzo[d]imidazol-2-yl)pyrrolidin-2-one (25 mg, 36%) as an off-white solid; temp. beats 2.03 min; m/z 539 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.99 (d, J=2.5 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.63 - 7.50 (m, 2H), 7.42 (dd, J =8.9, 2.5 Hz, 1H), 7.16 (dd, J=8.5, 1.7 Hz, 1H), 6.24 - 6.13 (m, 1H), 4.76 (d, J=4.3 Hz, 1H), 4.60 - 4.46 (m, 1H), 3.84 - 3.63 (m, 1H), 2.82 - 2.53 (m, 3H), 2.42 - 2.28 (m, 2H), 2.37 (s, 3H), 2.20 (s, 3H), 2.13 - 1.93 (m, 3Н), 1.89 - 1.74 (m, 2H), 1.65 - 1.39 (m, 2H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH in isohexane (0.2% TFA)): 156120, temp. bp=5.88 min, 98%, 96% ee at 254 nm.

Example 69: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3-yl)-1Hbenzo[d]imidazol-2- yl) pyrrolidin-2-one.

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((S)-1,1-dioxidotetrahydrothiophen-3-yl)amino)phenyl)-5oxopyrrolidine-2-carboxamide ( intermediate connection D5)

A solution of intermediate C5 (500 mg, 1.556 mmol), 2-(3H-[1,2,3]triazolo[4,5b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (651 mg, 1.711 mmol), (S)-5oxopyrrolidine-2-carboxylic acid (221 mg, 1.711 mmol) and triethylamine (651 μl, 4.67 mmol) in DMF (5 ml) was stirred at room temperature for 18 h. partitioned between DCM (20 ml) and saturated sodium bicarbonate (10 ml). The organic phase was collected and washed successively with saturated sodium bicarbonate (10 ml) and water (2x10 ml), after which the layers were separated using a PhaseSep© cartridge. The organic phase was evaporated in vacuo to give crude Intermediate D5 (theoretically quantitative yield), which was used without further purification; temp. beats 1.38 min; m/z 433 (M+H)+ (electrospray ⁺ ).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3-yl)-1Hbenzo[d]imidazol-2-yl)pyrrolidine -2-one (intermediate E5)

A solution of intermediate D5 (336 mg, 0.777 mmol) in acetic acid (1 mL) was heated to 80°C for 18 h. The solvent was removed in vacuo and the residue was purified by chromatography (12 g silica gel, 0-10% methanol in DCM, gradient elution), resulting in (S)-5-(5-(3,5dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3 -yl)-1 H-benzo[d ] imidazol-2-118 041318 yl)pyrrolidin-2-one - intermediate compound E5 (80 mg, 24%) as a glassy white solid;

Example 70: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1,1dioxidotetrahydrothiophen-3-yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3yl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one o o

CuTMEDA (13.11 mg, 0.028 mmol) was added to a solution of DBU (29.8 μL, 0.198 mmol), intermediate E5 (78 mg, 0.188 mmol), and (3,4-difluorophenyl)boronic acid (32.7 mg, 0.207 mmol) in acetonitrile ( 4 ml) with stirring for 18 hours at 40°C. The mixture was concentrated under reduced pressure, then purified by flash chromatography on a Companion (12 g column, 010% MeOH in DCM, gradient elution) to give (S)-1-(3,4-difluorophenyl)-5-( 5(3,5-dimethylisoxazol-4-yl)-1-((S)-1,1-dioxidotetrahydrothiophen-3-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (12 mg, 12%) as an off-white solid; temp. beats 1.96 min; m/z 527 (M+H)+ (electrospray ⁺ );

Example 71 tert-Butyl (S)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5dimethylisoxazol-4-yl) -1 H-benzo[d]imidazol-1-yl)pyrrolidine-1-acarboxylate tert-Butyl (S)-3-((2-((S)-1-(3,4-difluorophenyl)-5-oxonirrolidine -2-carboxamido)-4-(3,5dimethylisoxazol-4-yl)phenyl)amino)pyrrolidine-1-carboxylate (intermediate D6)

F

Solution of intermediate C6 (600 mg, 1.611 mmol), 2-(3H-[1,2,3]triazolo[4,5b]-pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (674 mg, 1.772 mmol), (S)-5oxopyrrolidine-2-carboxylic acid (229 mg, 1.772 mmol) and triethylamine (674 μl, 4.83 mmol) in DMF (5 ml) was stirred at room temperature for 18 h. partitioned between DCM (20 ml) and saturated sodium bicarbonate (10 ml). The organic phase was collected and washed successively with saturated sodium bicarbonate (10 ml) and water (2x10 ml), after which the layers were separated using a PhaseSep© cartridge. The organic phase was evaporated in vacuo and DCM (2 ml) was added to the free residue. 1 ml of the solution was taken with a pipette and used (after removal of the solvent) in 1493-51. The remaining solution was concentrated in vacuo to give crude intermediate D6 (expected quantitative yield) which was used without further purification; temp. beats 1.93 min; m/z 384 (M+H)+ (electrospray ⁺ ).

(S)-tert-butyl 3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-1Hbenzo[d]imudazol-1-yl) pyrrolidine-1-carboxylate (intermediate E6)

F

A solution of intermediate D6 (389 mg, 0.804 mmol) in acetic acid (1 mL) was heated to 80°C for 18 h. The solvent was removed in vacuo and the residue was purified by chromatography (12 g

- 119 041318 silica gel, 0-10% methanol in DCM, gradient elution) to give (S)-tert-butyl 3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)- 5-Oxopyppolidin-2-yl)-1 H-benzo[d]imidazol-1 yl)pyrrolidine-1-carboxylate Intermediate E6 (54 mg, 14%) as a glassy substance which stretched to a white solid; temp. beats 1.77 min; m/z 466 (M+H)+ (electrospray ⁺ ).

tert-Butyl (S)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyppolidin-2-yl)-5-(3,5-dimethylisoxazol-4yl)-1 H -benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate

CuTMEDA (7.78 mg, 0.017 mmol) was added to a solution of DBU (17.68 μL, 0.117 mmol), intermediate E6 (52 mg, 0.112 mmol), and (3,4-difluorophenyl)boronic acid (19.40 mg, 0.123 mmol) in acetonitrile ( 4 ml) with stirring for 18 hours at 40°C. The mixture was concentrated under reduced pressure, then purified by flash chromatography on a Companion (12 g column, 010% MeOH in DCM, gradient elution) to give (S)-tert-butyl 3-(2-((S)- 1(3,4-difluorophenyl)-5-oxopyppolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1yl)pyrrolidin-1-carboxylate (28 mg , 43%) as an off-white solid; temp. beats 2.36 min; m/z 578 (M+H)+ (electrospray ⁺ ); 7.82 (s, 1H), 7.71 - 7.60 (m, 2H), 7.43 - 7.31 (m, 1H), 7.27 - 7.15 (m, 2H), 6.08 (s, 1H), 5.40 (m, 1H), 3.87 ( m, 1H), 3.75 - 3.65 (m, 2H), 3.39 (m, 1H), 2.67 - 2.53 (m, 2H), 2.36 (s, 3H), 2.33 (m, 1H), 2.19 (s, 3H) , 2.13 (m, 1H), 1.45 (d, J=9.6 Hz, 9H). 2H, short.

Example 72 tert-Butyl (R)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyppolidin-2-yl)-5-(3,5dimethylisoxazol-4-yl) -1 H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate.

(R)-tert-butyl 3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate

A mixture of intermediate A (10 g, 42.3 mmol) and (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (7.89 g, 42.3 mmol) was stirred in dry THF (100 ml) and TEA (17.70 ml, 127 mmol) was added. The reaction mixture was stirred at rt. for 18 h, then heated to 40°C and stirred for 72 h, then heated to 50°C and stirred for 18 h. the reaction mixture was poured into a mixture of water and ice (300 ml). The mixture was extracted with ethyl acetate (2x500 ml). The combined organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to give (R)-tert-butyl-3-((4-(3,5-dimethylisoxazol-4-yl)-2nitrophenyl)amino)pyrrolidine-1 -carboxylate (17.85 g, 96%) as a thick orange oil; temp. beats 2.48 min; m/z 403 (M+H)+ (electrospray ⁺ ).

(R)-tert-butyl 3-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)pyrrolidine-1-carboxylate

(R)-tert-butyl 3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)pyrrolidine-1-carboxylate (17.04 g, 42.3 mmol) was dissolved in THF/water (1 :1, 1,000 ml). Concentrated ammonia (33.0 ml, 847 mmol) and sodium dithionite (73.7 g, 423 mmol) were added and the reaction mixture was stirred at rt. over 18 h. EtOAc (500 ml) was added, the mixture was transferred to a separating funnel and washed successively with 1M NaOH solution (400 ml) and brine (200 ml). The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo to give a light friable solid. This material was triturated with diethyl ether and collected by filtration. The filtrate was concentrated in vacuo to give a light peach colored crumbly solid. After analysis by LCMS and NMR, the triturated material obtained from the filtrate was combined to give (R)-tert-butyl-3-((2-amino-4-(3,5-dimethylisoxazol-4yl)phenyl)amino) pyrrolidine-1-carboxylate (13.58 g, 85%) as a light peach crumbly solid; temp. beats 2.24 min; m/z 372 (M+H)+ (electrospray ⁺ ).

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((4-hydroxycyclohexyl)amino)phenyl)-5-oxopyrrolidine2-carboxamide

(R)-tert-butyl carboxylate solution (600 mg,

3-((2-Amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)pyrrolidine-11.611 mmol), 2-(3H-[1.2.3]triazolo[4.5-b ]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (674 mg, 1.772 mmol), (B)-5-oxopyrrolidine-2-carboxylic acid (229 mg, 1.772 mmol) and triethylamine (674 μl, 4.83 mmol) in DMF (5 ml) was stirred at room temperature for 18 h. The mixture was partitioned between DCM (20 ml) and saturated sodium bicarbonate (10 ml). The organic phase was collected and washed successively with saturated sodium bicarbonate (10 ml) and water (2x10 ml), after which the layers were separated using a PhaseSep© cartridge. The organic phase was evaporated in vacuo to give crude (S)-N-(5-(3,5dimethylisoxazol-4-yl)-2-((4-hydroxycyclohexyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (assumed quantitative yield), which was used without further purification; temp. beats 1.94 min; m/z 384 (M+H) ⁺ (electrospray ⁺ ).

(R)-tert-butyl

3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-1Hbenzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((4-hydroxycyclohexyl)amino)phenyl)-5 Oxopyrrolidine-2-carboxamide solution (342 mg, 0.829 mmol) in acetic acid heated to 80° C. for 3 hours. The solvent was removed in vacuo and the residue was purified by chromatography (12 g silica gel, 0-10% methanol in DCM, gradient elution) to give (R)-tert-butyl 3-(5 -(3,5dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-1 H-benzo[d]imidazol-1-yl)pyrrolidine-1 carboxylate (54 mg, 14% ) as a glassy substance that stretched into a white solid; temp. beats 1.77 min; m/z 466 (M+H) ⁺ (electrospray ⁺ ).

tert-Butyl (R)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4yl)-1 H -benzo[i]imidazol-1-yl)pyrrolidine-1-carboxylate

CuTMEDA (7.78 mg, 0.017 mmol) was added to a solution of DBU (17.68 μL, 0.117 mmol), (R)-tert-butyl 3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5 -oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1yl)pyrrolidine-1-carboxylate (52 mg, 0.112 mmol) and (3,4-difluorophenyl)boronic acid (19.40 mg, 0.123 mmol) in acetonitrile ( 4 ml) with stirring for 18 hours at 40°C. The mixture was concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 010% MeOH in DCM, gradient elution) to give (R)-tert-butyl 3-(2-((S )-1(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-1 yl)pyrrolidin-1- carboxylate (28 mg, 43% yield) as an off-white solid; temp. beats 2.38 min; m/z 578 (M+H)+ (electrospray ⁺ ); 7.82 (ddd, J=13.1, 7.3, 2.7 Hz, 1H), 7.71 - 7.60 (m, 2H), 7.38 (dt, J=10.6, 9.2 Hz, 1H), 7.19 (dd, J=8.4, 1.8 Hz, 1H), 6.07 (d, J=8.1 Hz, 1H), 5.46-5.37 (m, 1H), 3.72 (m, 3H), 3.42 (m, 1H), 2.79 - 2.53 (m, 2H), 2.36 (s , 3Н), 2.32 (m, 1H), 2.19 (s, 3H), 2.15 (d, J=10.5 Hz, 1H), 1.44 (d, J=13.6 Hz, 9Н).

73:

Example (S)-1 -(3,4-difluorophenyl)-5 -(5 -(3,5-dimethylisoxazol-4-yl)-1 -((S)-1 (methylsulfonyl)pyrrolidin-3-yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1 -(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((S)-pyrrolidin-3 -yl)-1Hbenzo[d]imidazole -2-yl)pyrrolidin-2-one

(S)-tert-butyl

-(2-((S)-1 -(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5 -(3.5 Dimethylisoxazol-4-yl solution)-1H-benzo[d]imidazol-1 -yl)pyrrolidine-1-carboxylate (26 mg, 0.045 mmol) in DCM (5 mL) and TFA (1 mL) was stirred at room temperature. for 1 h. Solvents were removed in vacuo to give (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S )-pyrrolidin3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (22 mg, 0.046 mmol, 102% yield) as a spot inside a scintillation vial; temp. beats 1.31 min; m/z 478 (M+H)+ (electrospray ⁺ );

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-1-(methylsulfonyl)n-irrolidin-3yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one

To a solution of (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S)-pyrrolidin-3-yl)-1Hbenzo[d ]imidazol-2-yl)pyrrolidin-2-one (21 mg, 0.044 mmol) and methanesulfonyl chloride (3.74 μl, 0.048 mmol) in DCM (2 ml) were added with DIPEA (15.36 μl, 0.088 mmol). The reaction mixture was stirred at rt. for 18 h, then DIPEA (38.4 µl, 0.220 mmol) and methanesulfonyl chloride (6.81 µl, 0.088 mmol) were added. After stirring for 1 h, the reaction mixture was diluted with dichloromethane (10 ml) and washed with 0.2M aqueous hydrochloric acid (5 ml). The organic phase was collected using a PhaseSep© cartridge and concentrated in vacuo. The residue was purified by chromatography (4 g silica gel, 0-10% methanol in DCM, gradient elution). Product containing fractions were concentrated in vacuo and triturated with ether to give (S)-1-(3,4difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((S )-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl)n-pyrrolidin-2-one (13 mg, 53%) as a white solid; temp. beats 1.96 min; m/z 556 (M+H)+ (electrospray ⁺ );

¹ H-NMR (400 MHz, DMSO-d6) δ 7.90 - 7.73 (m, 2H), 7.64 (d, J=1.6 Hz, 1H), 7.44 - 7.30 (m, 1H), 7.24 (ddd, J=11.3 ,8.1, 1.5 Hz, 2Н), 6.11-6.04 (m, 1H), 5.47 (р, J=8.6 Hz, 1H), 3.83 (dd, J=10.5, 8.8 Hz, 1H), 3.70 (dd, J= 10.4, 7.0 Hz, 2H), 3.47 - 3.28 (m, 2H), 3.10 (d, J=6.1 Hz, 3H), 2.75 - 2.51 (m, 2H), 2.46 (m, 2H), 2.37 (s, 3H ), 2.20 (s, 3Н), 2.11 (m, 1H).

Example 74: (S)-5-(1-((R)-1-(cyclopropylsulfonyl)πpyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4yl)-1 H-benzo[d]imidazole- 2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one.

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-pyrrolidin-3-yl)-1Hbenzo[d]imidazole -2-yl)pyrrolidin-2-one

- 122 041318

Solution

(R)-tert-butyl

3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5dimethylisoxazol-4-yl)-III-benzo^]imidazol-1- yl)pyrrolidine-1-carboxylate (29 mg, 0.050 mmol) in DCM (5 mL) and TFA (1 mL) was stirred at room temperature. for 1 h. Solvents were removed in vacuo to give (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R )-pyrrolidin3-ul)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (24 mg, 100% yield) as a spot inside a scintillation vial; temp. beats 1.35 min; m/z 478 (M+H)+ (electrospray ⁺ ).

(S)-5-(1-((R)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3,4-difluorophenyl)pyrrolidin-2-one

To a solution of (S)-1 -(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-pyrrolidin-3-yl)-1Hbenzo[d ]imidazol-2-yl)pyrrolidin-2-one (24 mg, 0.050 mmol) and cyclopropanesulfonyl chloride (5.63 μl, 0.055 mmol) in DCM (2 ml) were added with DIPEA (17.56 μl, 0.101 mmol). The reaction mixture was stirred at rt. for 18 hours. The reaction mixture was stirred at room temperature. for 18 h, then DIPEA (43.9 μl, 0.251 mmol) and cyclopropanesulfonyl chloride (10.24 μl, 0.101 mmol) were added. After stirring for 1 h, the reaction mixture was diluted with dichloromethane (10 ml) and washed with 0.2M aqueous HCl (5 ml). The organic phase was collected using a phase separator cartridge and concentrated in vacuo. The residue was purified by chromatography (4 g silica gel, 0-10% methanol in DCM, gradient elution). Product-containing fractions were concentrated in vacuo and triturated with ether to give (S)-5-(1-((R)-1(cyclopropylsulfonyl)nirrolidin-3-yl)-5-(3,5-dimetuluzoxazol- 4-yl)-1H-benzo[d]umidazol-2-yl)-1(3,4-difluorophenyl)pyrrolidin-2-one (8 mg, 27%) as a white solid; temp. beats 2.10 min; m/z 582 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (400 MHz, DMSOL) δ 7.82 (ddd, J=13.2, 7.4, 2.7 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H) , 7.44 - 7.30 (m, 1H), 7.30 - 7.17 (m, 2H), 6.07 (dd, J=10.5, 8.1 Hz, 1H), 5.52 (t, J=8.0 Hz, 1H), 3.93 - 3.65 (m , 3Н), 3.46 (q, J=8.8 Hz, 1H), 2.96 - 2.83 (m, 1H), 2.77 - 2.44 (m, 4H), 2.37 (s, 3Н), 2.20 (m, 4H), 2.20- 2.06 (m, 1H), 1.09 (s, 1H), 1.10-0.97 (m, 3H).

Example 75: (S)-5-(1-((R)-1-acetylpyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3,4-difluorophenyl)pyrrolidin-2-one.

(S)-5-(1-((R)-1-acetylpyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)1 -(3,4-difluorophenyl)pyrrolidin-2-one

Acetyl chloride (8.11 μl, 0.114 mmol) was added to a solution of (S)-1-(3,4-difluorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)-1-((R)-pyrrolidine-3 -yl)-1H-benzo[d]imidazol-2-ul)n-rrrolidin-2-one (66 mg, 0.104 mmol) and DIPEA (0.036 ml, 0.207 mmol) in DCM (3 ml). The reaction mixture was stirred for 16 h, water (3 ml) was added and the phases were separated. The organic layer was dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by Companion chromatography (40 g column, 0-10% MeOH/DCM) and then purified by preparative HPLC (Waters, acid

- 123 041318 conditions (0.1% formic acid) column Waters X-Select Prep-C18, 5 µm, 19x50 mm, 15-35% MeCN in water), resulting in (S)-5-(1-((R )-1-acetylpyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one (10 mg, 18%) as a light white solid; temp. beats 1.80 min (method 1), m/z 520 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.73 - 7.55 (m, 3H), 7.36 - 7.14 (m, 3H), 6.02 - 5.94 (m, 1H), 5.48 - 5.38 (m, 1H), 3.90 ( m, 3Н), 3.56 (m, 1H), 2.86 - 2.63 (m, 2H), 2.61 - 2.50 (m, 1H), 2.37 (s, 3Н), 2.23 - 2.17 (1H, m) 2.19 (s, 3Н ), 2.04 (s, 3H).

Example 76: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(3,3,3trifluoropropanoyl) pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(3,3,3trifluoropropanoyl)pyrrolidin-3 -yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

DIPEA (0.057 ml, 0.328 mmol) was added to a solution of 3,3,3-trifluoropropanoic acid (0.016 ml, 0.180 mmol), HATU (81 mg, 0.213 mmol) and (S)-1-(3,4-difluorophenyl)- 5-(5-(3,5-dimethylisoxazol-4-yl)-1((R)-pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (89 mg , 0.164 mmol) in DMF (2 mL, 25.8 mmol), stirred at room temperature. for 3 hours. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (5 ml). The organic layer was separated and then dried with MgSO ₄ , filtered and concentrated under vacuum. The crude product was purified by flash chromatography on a Companion (40 g column, 0-10% MeOH/DCM) and then purified by preparative HPLC (Varian, acidic conditions (0.1% formic acid), acidic conditions, Waters X-Select Prep- C18, 5 µm, 19x50 mm, 5-50% MeCN in water) to give (S)-1-(3,4-difluorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)- 1-((R)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (5 mg, 5%) as white a solid; temp. beats 2.09 min (method 1), m/z 588 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.75-7.55 (m, 3H), 7.35-7.15 (m, 3H), 5.98 (d, J=7.8 Hz, 1H), 5.45 (m, 1H), 3.96 ( m, 3Н), 3.54 (m, 3Н), 2.85-2.5 (m, 6H), 2.36 (s, 3Н), 2.19 (s, 3Н).

Example 77: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)1H-benzo[d ]imidazol-2-yl)pyrrolidin-2-one.

(2S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1-methylpyrrolidin-3-yl)amino)phenyl)-5oxopyrrolidine-2-carboxamide

O

HATU (1.111 g, 2.92 mmol) was added to a solution of 4-(3,5-dimethylisoxazol-4-yl)-N ¹ -(1methylpyrrolidin-3-yl)benzene-1,2-diamine (0.82 g, 2.86 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (0.373 g, 2.89 mmol) and DIPEA (0.545 ml, 3.12 mmol) in N,N-dimethylformamide (5 ml), then stirred at room temperature for 18 h. diluted with 30% brine (100 ml), then extracted with ethyl acetate (3x75 ml). The aqueous layer was concentrated in vacuo to give a yellow solid. The solid was sonicated in DCM (100 ml)/MeOH (100 ml). The suspension was filtered and the liquid concentrated in vacuo to give a yellow sticky oil (2.7 g) which was retained on silica gel. The crude product was purified by column chromatography (12 g, DCM/10% NH3/MeOH in DCM: 100/0 to 0/100) to give (2S)-N-(5-(3,5-dimethylisoxazole- 4-yl)-2-((1methylpyrrolidin-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (0.68 g, 59%) was isolated as a sticky resin, sp time 0.81 min (method 1) , m/z 398 (M+H)+ (electrospray ⁺ ).

(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one

- 124 041318

(2S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1-methylpyrrolidin-3-yl)amino)phenyl)-5oxopyrrolidine-2-carboxamide (0.68 g, 1.711 mmol) was dissolved in acetic acid (6.86 ml, 120 mmol) and stirred at 70°C for 15 h. The reaction mixture was cooled to rt. and concentrated in vacuo to give a brown oil. This oil was dissolved in DCM (20 ml) and washed with aqueous sodium bicarbonate (20 ml). The aqueous layer was extracted with dichloromethane (20 ml). The organic extracts were combined and concentrated in vacuo to give a brown oil (0.73 g) which was purified by flash chromatography (4 g, 0-10% MeOH in DCM) to give (5S)-5-(5-(3, 5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1 H-benzo[d]imidazol2-yl)pyrrolidin-2-one (0.38 g, 53%) as a beige foam; temp. beats 0.83 min (method 1), m/z 380 (M+H) ⁺ (electrospray ⁺ ).

(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)pyrrolidin-2-one

CuTMEDA (9.18 mg, 0.020 mmol) was added to a solution of DBU (0.021 mL, 0.138 mmol), (5S)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl) -1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one of intermediate E7 (50 mg, 0.132 mmol) and (3,4-difluorophenyl)boronic acid (22.89 mg, 0.145 mmol) in acetonitrile (3.99 ml, 76 mmol) with stirring for 15 h at 40°C.

The reaction mixture was cooled to rt, then concentrated under reduced pressure and purified by flash chromatography on a Companion (12 g column, 0-10% MeOH in DCM, gradient elution) to give (5S)-1-( 3,4-difluorophenyl)-5-(5-(3,5-dimethylisooxazol-4-yl)-1(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2 -on (20.8 mg, 31%) as a whitish film; temp. beats 1.25 min (method 1), m/z 492 (M+H)+ (electrospray ⁺ );

¹ H-NMR (dg-DMSO) δ: 8.13 (d, 1H), 7.86 - 7.72 (m, 1H), 7.59 (s, 1H), 7.44 - 7.31 (m, 1H), 7.25 - 7.16 (m, 2H ), 6.16 - 6.07 (m, 1H), 5.43 - 5.30 (m, 1H), 3.21 - 3.05 (m, 2H), 2.81 - 2.53 (m, 4H), 2.47 - 2.26 (s+m, 8H), 2.20 (s, 3H), 2.17-2.01 (m, 2H).

Example 78: (5S)-1-(4-Chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin3-yl)-1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one.

(5S)-1 -(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -(1-methylpyrrolidin-3-yl)- 1Hbenzo[d]imidazole -2-yl)pyrrolidin-2-one

CuTMEDA (9.18 mg, 0.020 mmol) was added to a solution of DBU (0.021 mL, 0.138 mmol), (5S)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl) -1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (50 mg, 0.132 mmol) and (4-chloro-3-fluorophenyl)boronic acid (25.3 mg, 0.145 mmol) in acetonitrile (3.99 ml, 76 mmol) with stirring for 15 h at 40°C. The reaction mixture was cooled to RT and concentrated under reduced pressure, then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (5S)-1-(4-chloro-3fluorophenyl )-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)- 1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (33.8 mg, 49%) as a whitish foam; temp. beats 1.36 min (method 1), m/z 508 (M+H) ⁺

- 125 041318 (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 8.13 (dd, J=25.6, 8.5 Hz, 1H), 7.81 (ddd, J=12.4, 10.1, 2.5 Hz, 1H), 7.61 -7.56 (m, 1H), 7.56 - 7.46 (m, 1H), 7.32 - 7.25 (m, 1H), 7.21 (dd, J=8.4, 1.7 Hz, 1H), 6.19-6.11 (m, 1H), 5.43 -5.33 (m, 1H), 3.24 - 3.06 (m, 2H), 2.80 - 2.52 (m, 4H), 2.45 - 2.28 (m, 7H), 2.19 (s, 3H), 2.16 - 2.01 (m, 2H).

Example 79: (5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3yl)-1H-benzo[d ]imidazol-2-yl)pyrrolidin-2-one.

(5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)pyrrolidin-2-one

CuTMEDA (9.18 mg, 0.020 mmol) was added to a solution of DBU (0.021 mL, 0.138 mmol), (5S)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl) -1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (50 mg, 0.132 mmol) and (3,4-dichlorophenyl)boronic acid (27.7 mg, 0.145 mmol) in acetonitrile (3.99 ml, 76 mmol) with stirring for 15 h at 40°C. The reaction mixture was cooled to rt, concentrated under reduced pressure, then purified by flash chromatography on a Companion (12 g column, 0-10% MeOH in DCM, gradient elution) to give (5S)-1-( 3,4dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one ( 31 mg, 43%) as a yellowish solid; temp. beats 1.42 min (method 1), m/z 524 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 8.13 (dd, J=16.9, 8.4 Hz, 1H), 8.00 (dd, J=2.6 Hz, 1H), 7.60 - 7.53 (d+dd, 2H), 7.43 (ddd, J=18.4, 8.9, 2.6 Hz, 1H), 7.21 (dd, J=8.5, 1.7 Hz, 1H), 6.21 - 6.16 (m, 1H), 5.43 - 5.36 (m, 1H), 3.24 3.07 ( m, 2H), 2.79 - 2.52 (m, 4H), 2.45 - 2.27 (m, 8H), 2.20 (s, 3H), 2.17 - 2.01 (m, 2H).

80:

Example (S)-1 -(3,4-difluorophenyl)-5 -(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4 methoxycyclohexyl)-1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one.

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,4S)-4-methoxycyclohexyl)amino)phenyl)-5oxopyrrolidine-2-carboxamide (Intermediate D8)

compounds C8 (680 mg,

Intermediate solution

2.156 mmol), 2-(3H-[1,2,3]triazolo[4,5

b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (902 mg, 2.372 mmol), (S)-5oxopyrrolidine-2-carboxylic acid (306 mg, 2.372 mmol) and triethylamine ( 901 μl, 6.47 mmol) in DMF (20 ml) was stirred at room temperature for 3 h. The mixture was partitioned between ethyl acetate (200 ml) and water (100 ml), after which the layers were separated. The organic phase was washed with water (100 ml), passed through a PhaseSep© cartridge and evaporated in vacuo to give (S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r ,4S)-4-Methoxycyclohexyl)amino)phenyl)-5oxopyrrolidine-2-carboxamide - Intermediate D8 (0.96 g, quantitative yield) as crude residue, which was used without further purification; temp. beats 1.65 min (method 1), m/z 427 (M+H) + (electrospray ⁺ ).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (intermediate connection E8)

A solution of intermediate D8 (0.92 g, 2.157 mmol) in acetic acid (1 ml) was heated

- 126 041318 to 80°C for 18 hours. The solvent was removed under vacuum and the residue was purified by chromatography (12 g silica gel, 0-10% methanol in DCM, gradient elution), resulting in (S)-5-(5- (3,5dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1 H-benzo^]imidazol-2-yl)pyrrolidin-2-one Intermediate E8 (480 mg, 52 %) as a glassy substance which stretched into an orange solid; temp. beats 1.41 min (method 1), m/z 409 (M+H) + (electrospray ⁺ ).

(S)-1 -(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-methoxycyclohexyl)-1Hbenzo[0] imidazol-2-yl)pyrrolidin-2-one

ome ome

CuTMEDA (8.53 mg, 0.018 mmol)) was added to a solution of DBU (19.37 μL, 0.129 mmol), intermediate E8 (50 mg, 0.122 mmol), and (3,4-difluorophenyl)boronic acid (21.26 mg, 0.135 mmol) in acetonitrile (4 ml) with stirring for 18 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and purified by Companion chromatography (4 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(3.4 -difluorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-methoxycyclohexyl)-1 H-benzo[d]imidazol-2-yl)pyrrolidin-2 -one (33 mg, 51%) as an off-white solid; temp. beats 2.16 min (method 1), m/z 521 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (dg-DMSO) δ: 7.77 (d, J=8.7 Hz, 1H), 7.67 (m, 1H), 7.54 (s, 1H), 7.29 (d, J=9.7 Hz, 1H), 7.15 (m, 2Н), 5.98 (s, 1H), 4.51 (s, 1H), 3.45 (s, 1H), 2.92 (s, 4H), 2.37 (s, 5H), 2.20 (s, 7H), 1.79 ( s, 2H), 1.48 (m, 3H).

Example 81: (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4methoxycyclohexyl)-1H-benzo[ d]imidazol-2-yl)n-pyrrolidin-2-one.

(S)-1 -(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-methoxycyclohexyl)-1Hbenzo[d] imidazol-2-yl)pyrrolidin-2-one

ome ome

CuTMEDA (8.53 mg, 0.018 mmol) was added to a solution of DBU (19.37 μL, 0.129 mmol), intermediate E8 (50 mg, 0.122 mmol), and (3,4-dichlorophenyl)boronic acid (25.7 mg, 0.135 mmol) in acetonitrile ( 4 ml) with stirring for 18 hours at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(3.4 -dichlorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-methoxycyclohexyl)-1 H-benzo[d]imidazol-2-yl)pyrrolidin-2 -one (35 mg, 51%) as an off-white solid; temp. beats 2.39 min (method 1), m/z 553 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (dg-DMSO) δ: 7.99 (d, J=2.5 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.61 - 7.53 (m, 2H), 7.41 (dd, J= 8.9, 2.5 Hz, 1H), 7.15 (dd, J=8.5, 1.7 Hz, 1H), 6.20 - 6.13 (m, 1H), 4.58 (t, J=12.7 Hz, 1H), 3.44 (m, 1H), 3.31 (s, 4H), 2.75 (dt, J=15.4, 9.0 Hz, 1H), 2.66 - 2.51 (m, 1H), 2.36 (m, 5H), 2.19 (m, 4H), 2.07 (t, J= 10.5 Hz, 1H), 1.94 - 1.81 (m, 3H), 1.45 (dt, J=37.1, 12.1 Hz, 2H).

Example 82: (S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4methoxycyclohexyl)-1H- benzo[d]imidazol-2-yl)n-pyrrolidin-2-one.

(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one

- 127 041318

CuTMEDA (8.53 mg, 0.018 mmol) was added to a solution of DBU (19.37 μL, 0.129 mmol), intermediate E8 (50 mg, 0.122 mmol), and (3-chloro-4-methoxyphenyl)boronic acid (25.10 mg, 0.135 mmol) in acetonitrile (4 ml) with stirring for 18 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(3 -chloro-4methoxyphenyl)-5 -(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-methoxycyclohexyl)-1Hbenzo[d]imidazol-2-yl)pyrrolidin- 2-one (49 mg, 0.088 mmol, 72.2% yield) as an off-white solid; temp. beats 2.11 min (method 1), m/z 549 (M+H)+ (electrospray ⁺ );

¹ H-NMR (06-DMSO) δ: 7.82 (d, J=8.5 Hz, 1H), 7.75 (d, J=2.6 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.27 (dd , J=9.0, 2.6 Hz, 1H), 7.18 - 7.03 (m, 2H), 6.06 (dd, J=8.2, 2.3 Hz, 1H), 4.55 (t, J=11.9 Hz, 1H), 3.76 (s, 3Н), 3.44 (m, 1H), 3.30 (s, 3Н), 2.77 (dt, J=16.0, 9.1 Hz, 1H), 2.67 - 2.52 (m, 1H), 2.45 (m, 1H), 2.37 (s , 3Н), 2.29 (m, 2H), 2.20 (s, 3Н), 2.12 (m, 3Н), 1.85 (d, J=12.3 Hz, 1H), 1.62 (d, J=12.1 Hz, 1H), 1.44 (dd, J=21.1, 11.4 Hz, 2H).

Example 83: (S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4methoxycyclohexyl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4methoxycyclohexyl)-1 H- benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.53 mg, 0.018 mmol) was added to a solution of DBU (19.37 μL, 0.129 mmol), intermediate E8 (50 mg, 0.122 mmol) and (2,3-dihydrobenzofuran-5-yl)boronic acid (22.08 mg, 0.135 mmol ) in acetonitrile (4 ml) with stirring for 18 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(2 ,3dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-7Нbenzo[d]imidazol-2-yl)pyrrolidine -2-one (46 mg, 71%) as an off-white solid; temp. beats 1.88 min (method 1), m/z 527 (M+H)+ (electrospray ⁺ );

¹ H-NMR (R6-DMSO) δ: 7.79 (d, J=8.5 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.13 (dd , J=8.5, 1.7 Hz, 1H), 7.01 (dd, J=8.5, 2.4 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H), 5.97 - 5.89 (m, 1H), 4.45 (m, 2H), 3.29 (d, J=8.7 Hz, 1H), 3.29 (s, 3H), 3.20 - 3.04 (m, 2H), 2.77 (dd, J=16.3, 8.9 Hz, 1H), 2.60 (m, 1H ), 2.38 (s, 3Н), 2.28 (m, 1H), 2.21 (s, 3Н), 2.16 (m, 1H), 2.12 (m, 4H), 1.81 (d, J=12.4 Hz, 1H), 1.38 (m,4H).

Example 84: (S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4methoxycyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1Hbenzo[d ]imidazol-2-yl)pyrrolidin-2-one

- 128 041318

CuTMEDA (8.53 mg, 0.018 mmol) was added to a solution of DBU (19.37 μL, 0.129 mmol), intermediate E8 (50 mg, 0.122 mmol), and (3-chloro-4-fluorophenyl)boronic acid (23.48 mg, 0.135 mmol) in acetonitrile (4 ml) with stirring for 18 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 010% MeOH in DCM, gradient elution) to give (S)-1-(3-chloro -4-fluorophenyl)5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 r,4S)-4-methoxycyclohexyl)-1 H-benzo[d]imidazol-2yl)pyrrolidin- 2-one (34 mg, 51%) as an off-white solid; temp. beats 2.24 min (method 1), m/z 537 (M+H)+ (electrospray ⁺ );

Ή-NMR (66-DMSO) δ: 7.91 (dt, J=6.8, 1.2 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.40 7.33 (m, 2H), 7.15 (dd, J=8.5, 1.7 Hz, 1H), 6.13 (d, J=7.1 Hz, 1H), 4.56 (t, J=12.2 Hz, 1H), 3.41 (m, 1H) , 3.31 (s, 3H), 2.76 (dt, J=15.7, 9.0 Hz, 1H), 2.67 - 2.51 (m, 1H), 2.36 - 2.29 (m, 5H), 2.20 - 2.16 (m, 6H), 2.09 (t, J=10.8 Hz, 1H), 1.88 (d, J=12.7 Hz, 1H), 1.75 (d, J=12.2 Hz, 1H), 1.45 (dq, J=24.3, 10.9 Hz, 2H).

Example 85: (S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 r,4S)-4methoxycyclohexyl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1 -(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-methoxycyclohexyl)-1Hbenzo[ d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.53 mg, 0.018 mmol) was added to a solution of DBU (19.37 μL, 0.129 mmol), intermediate E8 (50 mg, 0.122 mmol), and (4-chloro-3-fluorophenyl)boronic acid (23.48 mg, 0.135 mmol) in acetonitrile (4 ml) with stirring for 18 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with a minimum of DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 010% MeOH in DCM, gradient elution) to give (S)-1-(4-chloro -3-fluorophenyl)5-(5-(3,5-dimethylisooxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2- it (36 mg, 54%) as an off-white solid; temp. beats 2.28 min (method 1), m/z 537 (M+H) ⁺ (electrospray ⁺ );

Ή-NMR (d ₆ -DMSO) δ: 7.89 - 7.79 (m, 2H), 7.58 (d, J=1.6 Hz, 1H), 7.52 (t, J=8.8 Hz, 1H), 7.22 (ddd, J= 9.0, 2.5, 1.0 Hz, 1H), 7.15 (dd, J=8.5, 1.7 Hz, 1H), 6.14 (d, J=7.1 Hz, 1H), 4.62-4.51 (m, 1H), 3.52 - 3.42 (m , 1H), 3.31 (s, 3Н), 2.80-2.50 (m, 3Н), 2.36 (m, 5H), 2.19 (m, 5H), 2.06 (t, J=10.4 Hz, 1H), 1.89 (s, 2Н), 1.46 (dq, J=35.4, 11.8 Hz, 2Н).

Example 86: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1Hbenzo[d]imidazol-2-yl)-1 -(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)1-( 3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

- 129 041318

CuTMEDA (8.53 mg, 0.018 mmol) was added to a solution of DBU (19.37 μL, 0.129 mmol), intermediate E8 (50 mg, 0.122 mmol), and (3-fluoro-4-methoxyphenyl)boronic acid (22.88 mg, 0.135 mmol) in acetonitrile (4 ml) with stirring for 18 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-5-(5 -(3,5dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4methoxyphenyl)pyrrolidin-2 -one (16 mg, 24%) as an off-white solid; temp. beats 2.01 min (method 1), m/z 533 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.82 (d, J=8.5 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.18 - 7.02 (m, 3H), 6.04 (d, J=7.2 Hz , 1H), 4.54 (s, 1H), 3.74 (s, 3H), 3.50 -3.35 (m, 1H), 3.30 (s, 3H), 2.74 (dd, J=15.9, 9.3 Hz, 1H), 2.67 - 2.52 (m, 1H), 2.37 (s, 3H), 2.34 - 2.23 (m, 1H), 2.20 (m, 4H), 2.14 - 2.08 (m, 4H), 1.87 (s, 1H), 1.64 (d, J=11.5 Hz, 1H), 1.43 (t, J=13.3 Hz, 2H).

Example 87: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4hydroxycyclohexyl)-1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one.

(1R,4s)-4-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Нbenzo [d] imidazol-1 -yl) cyclohexyl acetate

DIAD (diisopropylazodicarboxylate, 110 µl, 0.566 mmol) was added to a solution of (S)-1-(3,4difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 r,4S )-4-hydroxycyclohexyl)-1Hbenzo[d]umidazol-2-yl)pyrrolidin-2-one (150 mg, 0.290 mmol), acetic acid (50 µl, 0.873 mmol) and triphenylphosphine (200 mg, 0.763 mmol) in tetrahydrofuran (2 ml), then stirred at room temperature for 1 h. DIAD (110 μl, 0.566 mmol) was added and the mixture was stirred for another 18 h. The mixture was concentrated on loose silica gel, then the silicate was purified by chromatography on a Companion device (12 g column , 5-25% THF/CH ₂ C1 ₂ ), resulting in (1R,4s)-4-(2-((S)-1(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl) -5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1yl)cyclohexyl acetate (109 mg, 66%) as a white solid; temp. beats 2.20 min (method 1), m/z 549 (M+H)+ (electrospray ⁺ );

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxycyclohexyl)-1Hbenzo[d]imidazole -2-yl)pyrrolidin-2-one

OAc OH

Potassium carbonate (50 mg, 0.362 mmol) was added to a solution of (1R,4s)-4-(2-((S)-1-(3,4-difluorophenyl)-5oxopyrrolidin-2-yl)-5-(3, 5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexyl acetate (108 mg, 0.191 mmol) in methanol (3 ml) and tetrahydrofuran (3 ml), then stirred at room temperature for 1 h. Methanol (8 ml) was added, followed by 1.0 M aqueous hydrogen chloride solution (1.0 ml, 1.000 mmol). The solution was loaded onto a solid phase cation exchanger (1 g), washed with methanol (3x10 ml). The product was eluted with 0.7 M ammonia in methanol (3x5 ml) to give (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1- ((1 s,4R)-4-hydroxycyclohexyl)-1Hbenzo[d]umidazol-2-yl)pyrrolidin-2-one (97 mg, 0.182 mmol, 95% yield) as a white solid; temp. beats 1.81 min (method 1), m/z 507 (M+H)+ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.83 (ddd, J=13.3, 7.4, 2.6 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H) , 7.39 (dd, J=10.7, 9.2 Hz, 1H), 7.23 (dd, J=8.5, 1.7 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.10 (dd, J=8.1, 1.9 Hz, 1H ), 4.73 (d, J=2.9 Hz, 1H), 4.64 - 4.49 (m, 1H), 4.05 - 3.91 (m, 1H), 2.81 -2.52 (m, 5H), 2.38 (s, 3H), 2.21 ( s, 3H), 2.14 - 2.04 (m, 1H), 1.93 - 1.81 (m, 2H), 1.79 - 1.50 (m, 4H).

- 130 041318

Example 88: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4methoxycyclohexyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-methoxycyclohexyl)-1Hbenzo[d]imidazole -2-yl)pyrrolidine-2-he OMe

Sodium hydride, 60% dispersion in mineral oil (5 mg, 0.125 mmol) was added to a solution of (S)1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 s,4R)-4-hydroxycyclohexyl)-1 Hbenzo[d]imidazol-2-yl)pyrrolidin-2-one (51 mg, 0.096 mmol) in N,N-dimethylformamide (2 ml), then stirred for 2 min at room temperature. Iodomethane (7 μl, 0.112 mmol) was added, then the mixture was stirred at room temperature overnight. Ammonium chloride (15 mg, 0.280 mmol) was added, then the mixture was purified by Companion chromatography (RP Flash C18) (12 g column, 15-75% MeCN/water 0.1% formic acid) followed by Companion chromatography (4 g column , 5-15% THF/DCM), then triturated in diethyl ether to give (S)1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)- 1 -((1 s,4R)-4-methoxycyclohexyl)-1 Hbenzo[d]imidazol-2-yl)pyrrolidin-2-one (6 mg, 11%) as a white solid; temp. beats 2.22 min (method 1), m/z 521 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.83 (ddd, J=13.3, 7.4, 2.6 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H) , 7.39 (dd, J=10.6, 9.2 Hz, 1H), 7.24 (dd, J=8.4, 1.7 Hz, 1H), 7.20 - 7.14 (m, 1H), 6.10 (d, J=7.6 Hz, 1H), 4.68 4.52 (m, 1H), 3.60 - 3.52 (m, 1H), 3.36 (s, 3H), 2.82 - 2.52 (m, 4H), 2.49 - 2.40 (m, 1H), 2.38 (s, 3H), 2.21 (s, 3Н), 2.16 - 2.03 (m, 3Н), 1.75 - 1.52 (m, 4Н).

Example 89: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 R,4s)-4ethoxycyclohexyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-ethoxycyclohexyl)-1Hbenzo[d]imidazole -2-yl)pyrrolidin-2-one

OH O—\ ? Me

NaHMDS (148 µl, 0.148 mmol) was added to a suspension of (S)-1-(3,4-difluorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)-1 -((1 r,4S)- 4-hydroxycyclohexyl)-1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (75 mg, 0.148 mmol) in dry THF (849 μL, 10.36 mmol) at 0°С. The suspension was stirred for 5 minutes. DMF (894 μl, 11.55 mmol) was added to dissolve the solid. Then ethyl iodide (14.36 μl, 0.178 mmol) was added dropwise. After 4.5 h stirring, the reaction mixture was diluted in DCM (5 ml) and saturated aqueous ammonium chloride (10 ml). The layers were separated, the organic layer was washed with water (5 ml). The organic phases were combined and concentrated in vacuo to give a brown oil which was purified by column chromatography (4 g, DCM/MeOH: 100/0 to 90/10) then (4 g, DCM/MeOH: 100/ 90 to 90/10), resulting in (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S) -4-ethoxycyclohexyl)-1Hbenzo[d]imidazol-2-yl)pyrrolidin-2-one (10.6 mg, 13%) as a white solid; temp. beats 2.25 min (method 1), m/z 535 (M+H)+ (electrospray ⁺ );

1Н-NMR (d ₆ -DMSO) δ: 7.88 - 7.77 (m, 2H), 7.59 (d, J=1.7 Hz, 1H), 7.44 - 7.32 (m, 1H), 7.19 - 7.11 (m, 2H), 6.10 (dd, 1H), 4.59 - 4.47 (m, 1H), 3.61 - 3.47 (m + q, 3H), 2.81 - 2.50 (m, 3H), 2.41 - 2.26 (m + s, 5H), 2.19 (s , 3H), 2.16-2.03 (m, 3H), 1.91-1.83 (m, 1H), 1.81-1.73 (m, 1H), 1.54-1.39 (m, 2H), 1.14 (t, J=7.0 Hz, 3H ).

Example 90: (5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro2H-thiopyran-3-yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(2S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-3yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide ( intermediate connection D9)

- 131 041318

A solution of intermediate C9 (1.8 g, 5.37 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (2.245 g, 5.90 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (0.762 g, 5.90 mmol) and triethylamine (2.24 ml, 16.10 mmol) in DMF (20 ml) was stirred at room temperature for 3 h. was divided between ethyl acetate (200 ml) and water (100 ml), after which the layers were separated.

The organic phase was washed with water (100 mL), passed through PhaseSep© and evaporated in vacuo to give (2S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1.1 -dioxidotetrahydro2H-thiopyran-3-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide - intermediate D9 (1.05 g, 35%) as crude residue; temp. beats 1.42 min (method 1), m/z 447 (M+H) + (electrospray ⁺ ).

(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1Hbenzo[d]imidazol-2-yl)pyrrolidine -2-one (intermediate E9)

(2S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1,1-dioxidotetrahydro-2H-thiopyran-3yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide solution (1.05 g, 2.352 mmol) in acetic acid (5 ml) was heated to 80°C for 48 h, then allowed to cool to rt. The reaction mixture was cooled to RT and concentrated in vacuo to give a brown oil which was dissolved in MeOH then loaded onto a solid phase cation exchanger (SCX) column. The column was washed with methanol (MeOH) and then the product was eluted with 7 M ammonia in MeOH (30 ml). The resulting mixture was concentrated in vacuo, then sonicated with diethyl ether (15 ml) and concentrated again to give a brown solid (520 mg). Purification by flash chromatography (4 g, DCM/AcOEt: 100/0 to 60/40, then DCM/10% MeOH in DCM: 60/40 to 0/100) gave (5S)-5 -(5-(3, 5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1 Hbenzo[d]imidazol-2-yl)pyrrolidin-2-one (0.295 g, 27%) as an off-white solid; temp. beats 1.33 min (method 1), m/z 429 (M+H) + (electrospray ⁺ ).

(5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2Hthiopyran-3-yl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.13 mg, 0.018 mmol) was added to a solution of DBU (0.018 mL, 0.123 mmol), (5S)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro-2Н- thiopyran-3-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (50 mg, 0.117 mmol) and (3,4-dichlorophenyl)boronic acid (24.49 mg, 0.128 mmol) in acetonitrile (3.535 ml, 67.7 mmol) with stirring for 15 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (5S)-1(3, 4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1Hbenzo[d]imidazol-2-yl) pyrrolidin-2-one (30.6 mg, 43%) as a yellow solid; temp. beats 2.10 min (method 1), m/z 573 (M+H)+ (electrospray ⁺ );

- 132 041318

Ή-NMR (d6-DMSO) δ: 8.17 - 8.12 (m, 1H), 8.12 - 8.04 (m, 1H), 7.62 (dd, J=9.2, 1.6 Hz, 1H), 7.54 (dd,

J=8.9, 6.1 Hz, 1H), 7.46 (d, J=9.3 Hz, 0.5H), 7.33 (dd, 0.5H), 7.21 (ddd, J=8.4, 6.5, 1.7 Hz, 1H), 6.39 - 6.24 (m,

0.5H), 6.02 - 5.90 (m, 0.5H), 4.99 - 4.89 (m, 0.5H), 4.88 - 4.75 (m, 0.5H), 4.23 - 4.08 (m, 1H), 3.81 - 3.61 (m,

1H), 3.61 - 3.49 (m, 1H), 3.27 - 3.14 (m, 1H), 2.80 - 2.55 (m, 2H), 2.54 -2.42 (m, 3H), 2.36 (d, J=3.7 Hz, 3H) ,

2.27 - 2.06 (m+d, 5H), 2.07 - 1.92 (m, 1H).

Example 91: (5S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1dioxidotetrahydro-2H-thiopyran-3-yl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(5S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro-2Hthiopyran-3-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.13 mg, 0.018 mmol) was added to a solution of DBU (0.018 mL, 0.123 mmol), intermediate E9 (50 mg, 0.117 mmol), and (4-chloro-3-fluorophenyl)boronic acid (22.38 mg, 0.128 mmol) in acetonitrile (3.535 ml, 67.7 mmol) with stirring for 15 h at 40°C. After 15 hours of stirring, the mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (5S)-1 -(4 -chloro-3-fluorophenyl)-5 -(5 -(3,5-dimethylisoxazol-4-yl)-1-(1,1dioxytetrahydro-2H-thiopyran-3-yl)-1H-benzo[d]imidazol-2 -yl)pyrrolidin-2-one (34 mg, 50%) as a yellow solid; temp. beats 2.03 min (method 1), m/z 557 (M+H) ⁺ (electrospray+);

¹ H-NMR (d ₆ -DMSO) δ: 8.19 - 8.08 (m, 1H), 7.87 (ddd, J=12.9, 10.5, 2.5 Hz, 1H), 7.61 (dd, J=9.8, 1.7 Hz, 1H) , 7.53 - 7.43 (m, 1H), 7.38 - 7.24 (m, 1H), 7.24 - 7.18 (m, 1H), 6.33 - 6.26 (m, 0.5H), 5.99 - 5.86 (m, 0.5H), 4.99 - 4.87 (m, 0.5H), 4.86 - 4.75 (m, 0.5H), 4.21 - 4.07 (m, 1H), 3.86 - 3.63 (m, 1H), 3.61 - 3.48 (m, 1H), 3.26 3.15 (m, 1H), 2.77 - 2.65 (m, 1H), 2.65 - 2.54 (m, 1H), 2.50 (m, J=1.8 Hz, 2H), 2.36 (d, J=4.1 Hz, 3H), 2.27 2.01 (m+ d, 6H), 1.99 (m, 1H).

Example 92: (5S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1dioxytetrahydro-2H-thiopyran-3-yl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(5S)-1 -(3-chloro-4-methoxyphenyl)-5 -(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro-2Hthiopyran-3-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.13 mg, 0.018 mmol) was added to a solution of DBU (0.018 mL, 0.123 mmol), (5S)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro-2Н- thiopyran-3-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (50 mg, 0.117 mmol) and (3-chloro-4-methoxyphenyl)boronic acid (23.93 mg, 0.128 mmol) in acetonitrile (3.53 ml, 67.7 mmol) with stirring for 15 h at 40°С. The mixture was concentrated under reduced pressure. The residue was diluted with a minimum of DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (5S)-1-(3 chloro -4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro-2H-thiopyran-3-yl)1H-benzo[d]imidazol-2- yl) pyrrolidin-2-one (27 mg, 39%) as a yellow solid; temp. beats 1.84 min (method 1), m/z 569 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 8.16 - 8.03 (m, 1H), 7.80 (dd, J=39.1, 2.6 Hz, 1H), 7.64 (dd, J=9.8, 1.6 Hz, 1H), 7.33 (d, 0.5H), 7.25 - 7.15 (m, 1.5H), 7.06 (dd, J=9.1, 1.7 Hz, 1H), 6.19 - 6.12 (m, 0.5H), 5.94 - 5.87 (m, 0.5H) , 4.96 - 4.79 (m, 1H), 4.17 - 4.07 (m, 1H), 3.77 (s, 3H), 3.68 - 3.43 (m, 2H), 3.24 - 3.13 (m, 1H), 2.80 - 2.52 (m, 2H), 2.51 - 2.38 (m, 2H), 2.37 (d, J=3.8 Hz, 3H), 2.35 - 2.24 (m, 1H), 2.20 (d, 3H), 2.20 - 2.00 (m, 2H), 1.97 1.70(m, 1H).

Example 93: (5S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1dioxytetrahydro-2H-thiopyran-3 -yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

- 133 041318 (5S) -1 - (2,3-dihydrobenzofuran-5 -yl) -5- (5 - (3,5-dimethylisoxazol-4-yl) -1- (1,1 -dioxidotetrahydro2H-thiopyran-3 -yl) -1 H-benzo[d]imidazol-2 -yl)pyrrolidin-2 -one

CuTMEDA (8.13 mg, 0.018 mmol) was added to a solution of DBU (0.018 mL, 0.123 mmol), intermediate E9 (50 mg, 0.117 mmol), and (2,3-dihydrobenzofuran-5-yl)boronic acid (21.05 mg, 0.128 mmol ) in acetonitrile (3.53 mL, 67.7 mmol) with stirring for 15 h at 40°С. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (5S)1-(2, 3-dihydrobenzofurαn-5-yl)-5-(5-(3,5-dimethyluzoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2Hthiopyran-3-yl)-1H-benzo[d]imidazol- 2-yl)pyrrolidin-2-one (28 mg, 42%) as a yellow solid; temp. beats 1.72 min (method 1), m/z 547 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 8.13 - 8.02 (m, 1H), 7.65 (dd, J=8.2, 1.7 Hz, 1H), 7.38 (dd, J=44.0, 2.2 Hz, 1H), 7.21 - 7.16 (m, 1H), 7.06 (dd, J=8.6, 2.3 Hz, 0.5H), 6.86 (d, J=8.7 Hz, 0.5H), 6.63 (dd, J=14.3, 8.5 Hz, 1H), 5.94 (dd, J=8.2, 2.4 Hz, 0.5H), 5.87 - 5.79 (m, 0.5H), 4.90 - 4.72 (m, 1H), 4.49 - 4.42 (m, 2H), 4.11 - 3.97 (m, 1H ), 3.65 - 3.45 (m, 1H), 3.23 - 3.05 (m, 3H), 2.86 - 2.54 (m, 2H), 2.50 (p, J=1.8 Hz, 2 H), 2.39 (m+d, J= 4.1 Hz, 4H), 2.34 - 2.25 (m, 1H), 2.21 (d, J=3.8 Hz, 3H), 2.11 (d, J=18.1 Hz, 1H), 1.99 (m, 1H).

Example 94: (5)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1(methylsulfonyl)piperidin-4-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)phenyl)-5oxopyrrolidine-2-carboxamide (Intermediate D10 )

A solution of intermediate C10 (1.97 g, 5.41 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (2.26 g, 5.95 mmol), (S)-5-oxopyrrolidine-2carboxylic acid (0.768 g, 5.95 mmol) and TEA (2.26 ml, 16.22 mmol) in DMF (20 ml) was stirred at room temperature for 3 h. was divided between ethyl acetate (200 ml) and water (100 ml), after which the layers were separated. The organic phase was washed with water (100 ml), passed through a PhaseSep© cartridge and evaporated in vacuo to give (S)-N-(5-(3,5dimethylisoxazol-4-yl)-2-((1-(methylsulfonyl )piperidin-4-yl)amino)phenyl)-5-oxopyrrolidine-2carboxamide - intermediate D10 (1.92 g, 68%), which was used without further purification; temp. beats 1.55 min (method 1), m/z 476 (M+H) ⁺ (electrospray ⁺ ).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol2-yl)pyrrolidin-2- he (intermediate E10)

O=S-Me

Ν ' ^Μθ f o ^me , GT I ____ 1 GT?..... L \ hi; \ Y ^{n 0}

BA ^hn A oA

Me W Me

ABOUT

A solution of intermediate D10 (1.92 g, 4.04 mmol) in acetic acid (5 mL) was heated to 80°C for 48 h, then allowed to cool to rt.

The reaction mixture was passed on to the Fluids Laboratory (FL) for processing and purification. The reaction mixture was concentrated in vacuo to give a beige solid.

- 134 041318

MeOH (5 ml) was added followed by DCM (5 ml). The beige suspension was filtered through a PhaseSep© cartridge. The solid was washed with methanol (MeOH, 4 ml) and then with diethyl ether (10 ml). The solid was dissolved in DCM (100 ml), washed with saturated aqueous sodium bicarbonate (2x50 ml). The organics were washed with water (100 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1 (methylsulfonyl) piperidin-4-yl)-1H-benzo[d]imidazol-2-yl) pyrrolidin-2-one - intermediate E10 (0.798 g, 41%) in the form of a white solid; temp. beats 1.34 min (method 1), m/z 458 (M+H) + (electrospray ⁺ ).

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)π and πeridin-4-yl)1H-benzo[d ]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (0.017 mL, 0.115 mmol), intermediate E10 (0.050 g, 0.109 mmol), and (3,4-dichlorophenyl)boronic acid (0.023 g, 0.120 mmol) in acetonitrile ( 3.31 ml, 63.4 mmol) with stirring for 15 h at 40°C. The reaction mixture is a gray suspension. DCM (1.5 ml) was added to the reaction mixture. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1(3, 4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1Нbenzo[d]imidazol-2-yl)pyrrolidin-2 -one (33 mg, 48%) as a yellow solid; temp. beats 2.19 min (method 1), m/z 602 (M+H)+ (electrospray ⁺ );

¹ H-NMR (R6-DMSO) δ: 8.03 (d, J=2.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.57 (d , J=8.9 Hz, 1H), 7.40 (dd, J=8.9, 2.6 Hz, 1H), 7.19 (dd, J=8.5, 1.7 Hz, 1H), 6.17 (d, 1H), 4.82 - 4.69 (m, 1H), 3.87 -3.79 (m, 2H), 3.13 - 2.99 (m+s, 5H), 2.81 - 2.51 (m, 4H), 2.36 (s, 3H), 2.19 (s, 3H), 2.15 - 2.07 ( m, 2H), 2.06 1.96 (m, 2H).

95:

Example (S)-1 -(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1 (methylsulfonyl)π and πeridin-4-yl)-1H- benzo[d]imidazol-2-yl)-pyrrolidin-2-one.

(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4yl)-1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μL, 0.115 mmol), intermediate E10 (50 mg, 0.109 mmol), and (4-chloro-3-fluorophenyl)boronic acid (20.96 mg, 0.120 mmol) in acetonitrile (3310 μl, 63.4 mmol) and DCM (1.5 ml) with stirring for 15 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(4 -chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl) pinerudin-4-yl)-1H-benzo[d]imidazol-2- yl) pyrrolidin-2-one (36 mg, 55%) as a white solid; temp. beats 2.08 min (method 1), m/z 587 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.85 (dd, J=12.1, 2.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.51 (t, J=8.8Hz, 1H), 7.24 (dd, J=9.0, 2.5, 1.1Hz, 1H), 7.19 (dd, J=8.5, 1.7Hz, 1H), 6.14 (d, J=7.9Hz, 1H), 4.77 4.72 (m, 1H), 3.83 (d, J=12.1 Hz, 2H), 3.13 - 2.98 (m+s, 5H), 2.79 - 2.59 (m, 2H), 2.58 - 2.43 (m, 2H ), 2.36 (s, 3H), 2.19 (s, 3H), 2.15–2.00 (m, 3H).

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Example 96:

(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1(methylsulfonyl)piperidin-4-yl)-1H-benzo [d]imidazol-2-yl)pyrroludin-2-one.

(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin4-yl)-III-benzo^ ]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μL, 0.115 mmol), intermediate E10 (50 mg, 0.109 mmol), and (3-chloro-4-methoxyphenyl)boronic acid (22.41 mg, 0.120 mmol) in acetonitrile (3310 μl, 63.4 mmol) and DCM (1.5 ml) with stirring for 15 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1 -(3 -chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1 -(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2- yl) pyrroludin-2-one (33.8 mg, 51%) as a white solid; temp. beats 1.90 min (method 1), m/z 598 (M+H) + (electrospray ⁺ );

1I-NMR (d ₆ -DMSO) δ: 7.79 (d, J=2.6 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.28 (dd , J=9.0, 2.6Hz, 1H), 7.19 (dd, J=8.5, 1.7Hz, 1H), 7.08 (d, J=9.1Hz, 1H), 6.07 (dd, J=8.1, 2.2Hz, 1H) , 4.82 -4.70 (m, 1H), 3.81 (m, 2H), 3.77 (s, 3H), 3.10 - 2.96 (m+s, 5H), 2.77 (dt, 1H), 2.69 -2.53 (m, 2H) , 2.50 - 2.39 (m,

2H), 2.37 (s, 3H), 2.24 - 2.11 (m+s, 4H), 2.03 - 1.95 (m, 1H), 1.80 - 1.70 (m, 1H).

Example 97: (S)-1-(2,3-dihydrobenzofuran-5-ul)-5-(5-(3,5-dimethylisooxazol-4-ul)-1-(1(methylsulfonyl)piperidin-4-yl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-ul)-1-(1(methylsulfonyl)piperidin-4-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μL, 0.115 mmol), intermediate E10 (50 mg, 0.109 mmol) and (2,3-dihydrobenzofuran-5-yl)boronic acid (19.71 mg, 0.120 mmol ) in acetonitrile (3310 µL, 63.4 mmol) and DCM (1.5 mL) with stirring for 15 h at 40°С. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by flash chromatography on a Companion (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(2 ,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2 -yl)pyrrolidin-2-one (32 mg, 50%) as a white solid; temp. beats 1.75 min (method 1), m/z 576 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (dg-DMSO) δ: 7.70 (d, J=8.5 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.39 - 7.36 (m, 1H), 7.18 (dd, J= 8.4, 1.7Hz, 1H), 7.05 (dd, J=8.5, 2.4Hz, 1H), 6.68 (d, J=8.5Hz, 1H), 5.94 (dd, J=8.2, 2.7Hz, 1H), 4.73 - 4.63 (m, 1H), 4.47 (t, J=8.7 Hz, 2H), 3.77 (t, J=14.9 Hz, 2H), 3.10 (t, J=8.7 Hz, 2H), 3.02 (s, 3H), 3.00 - 2.90 (m, 2H), 2.78 (dt, 1H), 2.70 - 2.56 (m, 1H), 2.46 - 2.31 (m+s, 5H), 2.26 - 2.16 (m+s, 4H), 1.99 - 1.90 (m, 1H), 1.52-1.44 (m, 1H).

Example 98: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1(methylsulfonyl)piperidin-4-yl)-1H- benzo[d]umidazol-2-yl)pyrroludin-2-one.

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)1H-benzo[d ]imidazol-2-yl)pyrrolidin-2-one

- 136 041318

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μL, 0.115 mmol), intermediate E10 (50 mg, 0.109 mmol), and (3,4-difluorophenyl)boronic acid (18.98 mg, 0.120 mmol) in acetonitrile ( 3310 µl, 63.4 mmol) and DCM (1.5 ml) with stirring for 15 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (4 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1 -(3 ,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin- 2-one (41.9 mg, 66%) as a beige solid; temp. beats 2.00 min (method 1), m/z 570 (M+H) + (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.83 (ddd, J=13.3, 7.4, 2.7 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H ), 7.38 (dt, J=10.6, 9.2 Hz, 1H), 7.22 - 7.14 (m, 2H), 6.10 (dd, J=8.2, 1.9 Hz, 1H), 4.80 - 4.65 (m, 1H), 3.82 ( d, J=11.7 Hz, 2H), 3.11 - 2.93 (m+s, 5H), 2.78 - 2.59 (m, 2H), 2.58 - 2.43 (m, 3H), 2.36 (s, 3H), 2.19 (s, 3Н), 2.14 2.06 (m, 1H), 2.05 - 1.90 (m, 2H).

99:

Example (S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1(methylsulfonyl)piperidin-4-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(8)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4yl)-1 H-benzo [d] imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μL, 0.115 mmol), intermediate E10 (50 mg, 0.109 mmol), and (3-chloro-4-fluorophenyl)boronic acid (20.96 mg, 0.120 mmol) in acetonitrile (3310 μl, 63.4 mmol) and DCM (1.5 ml) with stirring for 15 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (4 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(3 -chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin4-yl)-1H-benzo[d]imidazol-2-yl) pyrrolidin-2-one (35.5 mg, 54%) as a beige solid; temp. beats 2.03 min (method 1), m/z 586 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.99 - 7.90 (m, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.42 - 7.32 (m , 2H), 7.19 (dd, J=8.5, 1.7 Hz, 1H), 6.12 (dd, J=8.1, 1.9 Hz, 1H), 4.81 - 4.68 (m, 1H), 3.82 (d, J=11.8 Hz, 2H), 3.11 -2.96 (m+s, 5H), 2.81 - 2.59 (m, 2H), 2.58 - 2.41 (m, 3H), 2.36 (s, 3H), 2.19 (s, 3H), 2.16 -2.07 ( m, 1H), 2.06 - 1.97 (m, 1H), 1.95 - 1.85 (m, 1H).

Example 100: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)- 1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one.

(8)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1 -(methylsulfonyl)piperidin-4-yl)-1 H-benzo[d]imidazol2-yl)-1- (3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

- 137 041318

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μL, 0.115 mmol of intermediate E10 (50 mg, 0.109 mmol) and (3-fluoro-4-methoxyphenyl)boronic acid (20.43 mg, 0.120 mmol) in acetonitrile ( 3310 µl, 63.4 mmol) and DCM (1.5 ml) with stirring for 15 h at 40° C. The mixture was concentrated under reduced pressure. (4 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl) piperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one (36.4 mg, 55%) as a beige solid; 1.85 min (method 1), m/z 582 (M+H)+ (electrospray ⁺ );

¹ H-NMR (p-DMSO) δ: 7.73 (d, J=8.5 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.18 (dd, J=8.5, 1.7 Hz, 1H), 7.12 7.04 (m , 2H), 6.03 (dd, J=8.3, 2.1 Hz, 1H), 4.79 - 4.67 (m, 1H), 3.86 - 3.76 (m, 2H), 3.75 (s, 3H), 3.09 - 2.97 (m+s , 5H), 2.81 - 2.69 (m, 1H), 2.69 - 2.56 (m, 1H), 2.57 - 2.40 (m, 3H), 2.36 (s, 3H), 2.20 (s, 3H), 2.16 - 2.08 (m , 1H), 2.00–1.97 (m, 1H), 1.84–1.74 (m, 1H).

Example 101: (S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3hydroxycyclopentyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1R,3R)-3-hydroxycyclopentyl)amino)phenyl)-5oxopyrrolidine-2-carboxamide (Intermediate D11) he he b

A solution of intermediate C11 (450 mg, 1.566 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (222 mg, 1.723 mmol), HATU (655 mg, 1.723 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid ( 222 mg, 1.723 mmol) and TEA (655 µl, 4.70 mmol) in DMF (121 µl, 1.566 mmol) were stirred at room temperature for 15 h. The mixture was partitioned between ethyl acetate (200 ml) and water (100 ml), after which separated the layers. The organic phase was washed with brine (100 ml), concentrated in vacuo to give a crude violet mixture. The crude product was purified by Companion chromatography (12 g column, 0-10% MeOH/DCM) to give (S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(( (1R,3R)-3hydroxycyclopentyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide Intermediate D11 (57 mg, 9%) as white sticky solid; temp. beats 1.31 min (method 1), m/z 399 (M+H) ⁺ (electrospray ⁺ ); Some more product was obtained from the aqueous layer by concentration under vacuum. The resulting solid was washed with dichloromethane (2x50 ml) and MeOH (50 ml). The organics were combined and concentrated in vacuo. The yellow residue was loaded onto a cation exchange resin (SCX) (capture and release) to give 659 mg of a yellow-green sticky solid which was purified by flash chromatography (12 g, Companion, DCM/10% MeOH in DCM 100/0 to 0 /100), resulting in the main portion of (S)-N-(5-(3,5dimethylisoxazol-4-yl)-2-(((1R,3R)-3-hydroxycyclopentyl)amino)phenyl)-5- oxonyrrolidine-2carboxamide-intermediate D11 (334 mg, 0.830 mmol, 53.0% yield) was isolated as a white colorless glassy substance; temp. beats 1.31 min (method 1), m/z 399 (M+H) ⁺ (electrospray ⁺ ).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)- 1-((1R,3R)-3 - hydroxycyclopentyl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2- he (intermediate E11)

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(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1R,3R)-3-hydroxycyclopentyl)amino)phenyl)-5oxopyrrolidine-2-carboxamide - intermediate D11 ( 391 mg, 0.981 mmol) was dissolved in acetic acid (3932 μl, 68.7 mmol) and stirred at 80°C for 15 h. The mixture was concentrated under reduced pressure, then redissolved in methanol (20 ml). Solid potassium carbonate (1.5 g) was added and the mixture was stirred for 1 hour. The slurry was difficult to filter so it was concentrated in vacuo/pre-adsorbed onto silica gel. The crude product was purified by Companion chromatography (4 g column, 5-15% MeOH/DCM) to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(( 1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (140 mg, 36%) was isolated as a white solid; temp. beats 1.13 min (method 1), m/z 381 (M+H) + (electrospray ⁺ ).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol2-yl)-1-( 3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

CuTMEDA (8.39 mg, 0.018 mmol) was added to a solution of DBU (19.14 μL, 0.127 mmol), intermediate E11 (46 mg, 0.121 mmol), and (4-chloro-3-fluorophenyl)boronic acid (23.19 mg, 0.133 mmol) in acetonitrile (4 ml) with stirring for 18 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 05% MeOH in DCM, gradient elution) to give (8)-1-(4-chloro -3-fluorophenyl)-5(5-(3,5-dimethylisoxazol-4-yl)- 1-((1R,3R)-3-hydroxycyclopentyl)-1 H-benzo[d]imidazol-2 yl)pyrrolidin- 2-one (46 mg, 42%) as an off-white solid; temp. beats 1.97 min (method 1), m/z 508 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.81 (td, J=12.1, 2.5 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.51 (td, J=8.7, 2.2 Hz, 1H), 7.35 - 7.23 (m, 1H), 7.17 (dt, J=8.5, 2.1 Hz, 1H), 6.14 (dd, J=37.6, 7.5 Hz, 1H), 5.34 - 5.25 (m, 1H), 4.89 (dd, J =3.6, 1.5 Hz, 1H), 4.50 (s, 1H), 2.69 (m, 1H), 2.56 (m, 1H), 2.36 (d, J=1.1 Hz, 3H), 2.31-2.27 (m, 4H) , 2.19 (d, J=1.0 Hz, 3H), 2.15 - 2.04 (m, 3H), 1.76 (d, J=9.5 Hz, 1H).

Example 102: (S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3hydroxycyclopentyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3hydroxycyclopentyl)-1H-benzo[d ]imidazol-2-yl)nirrolidin-2-one

CuTMEDA (8.39 mg, 0.018 mmol) was added to a solution of DBU (19.14 μL, 0.127 mmol), intermediate E11 (46 mg, 0.121 mmol), and (3-chloro-4-methoxyphenyl)boronic acid (24.79 mg, 0.133 mmol) in acetonitrile (4 ml) with stirring for 18 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 0-5% MeOH in DCM, gradient elution) to give (S)-1-(3 -chloro-4methoxyphenyl)-5 -(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 R,3R)-3-hydroxycyclopentyl)-1Hbenzo[d]imidazol-2-yl)pyrrolidin- 2-one (26 mg, 41%) as a light yellow solid; temp. beats

- 139 041318

1.77 min (method 1), m/z 521 (M+H)+ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.74 (dd, J=20.7, 2.6 Hz, 1H), 7.65 - 7.52 (m, 2H), 7.32 (ddd, J=11.8, 9.0, 2.6 Hz, 1H), 7.16 (ddd, J=8.5, 3.0, 1.6Hz, 1H), 7.07 (dd, J=9.1, 2.8Hz, 1H), 6.04 (dd, J=7.4, 7.7Hz, 1H), 5.29 (m, 1H) , 4.88 (t, J=3.2 Hz, 1H), 4.48 (s, 1H), 3.76 (d, J=0.7 Hz, 3H), 2.76 -2.55 (m, 1H), 2.37 (d, J=0.9 Hz, 3H), 2.30 2.25 (m, 5H), 2.20 (d, J=0.9 Hz, 3H), 2.12 - 2.05 (m, 2H), 1.97 (dd, J=14.6, 7.2 Hz, 1H), 1.74 (d, J=6.2Hz, 1H).

Example 103: (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3hydroxycyclopentyl)-1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1H-benzo[d]imidazole -2-yl)pyrrolidin-2one

CuTMEDA (7.61 mg, 0.016 mmol) was added to a solution of DBU (17.30 μL, 0.115 mmol), intermediate E11 (50 mg, 0.109 mmol), and (3,4-difluorophenyl)boronic acid (18.98 mg, 0.120 mmol) in acetonitrile ( 3310 µl, 63.4 mmol) and DCM (1.5 ml) with stirring for 15 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (4 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(3 ,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)1H-benzo[d]imidazol-2-yl)pyrrolidin- 2-one (69.3 mg, 38%) as a beige solid; temp. beats 2.04 min (method 1), m/z 525 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.97 (dd, J=19.0, 2.5 Hz, 1H), 7.65 -7.53 (m, 3H), 7.46 (ddd, J=14.9, 9.0, 2.6 Hz, 1H) , 7.17 (ddd, J=8.3, 2.8, 1.6Hz, 1H), 6.17 (dd, J=38.2, 7.2Hz, 1H), 5.31 (h, J=8.7Hz, 1H), 4.90 (dd, J=3.4 , 1.0 Hz, 1H), 4.56 - 4.45 (m, 1H), 2.78 - 2.61 (m, 2H), 2.61 - 2.46 (m, 1H), 2.43 - 2.21 (m+s, 5H), 2.19 (d, J =1.0 Hz, 3H), 2.17 - 1.95 (m, 2H), 1.81 - 1.70 (m, 1H).

104:

Example (1R,3R)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5 dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-1-yl)cyclopentyl acetate.

(1R,3R)-3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2-yl)-III-benzo[d]imidazol-1yl)cyclopentyl acetate

Intermediate D11 (1.35 g, 3.39 mmol) was dissolved in acetic acid (5 ml) and stirred at 80°C for 18 h. The reaction mixture was cooled to RT and the solvent was removed under vacuum. The residue was purified by chromatography (24 g silica gel, 0-10% methanol in DCM, gradient elution). Fraction containing (1R,3R)-3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2yl)-1H-benzo[d]imidazole-1- yl)cyclopentyl acetate, combined and concentrated in vacuo to give (1R,3R)-3-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-5-oxopyrrolidin-2- yl)-1Hbenzo[d]imidazol-1-yl)cyclopentyl acetate (354 mg, 26%) as a white solid; temp. beats 1.37 mn (method 1), m/z 423 (M+H)+ (electrospray ⁺ ).

(1 R,3R)-3 -(2-((S)-1 -(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)- 1Hbenzo[d]imidazol-1-yl)cyclopentyl acetate

- 140 041318

CuTMEDA (8.24 mg, 0.018 mmol) was added to a solution of DBU (0.019 mL, 0.124 mmol), (1R,3R)-3-(5(3,5-dimethylisoxazol-4-yl)-2-((S)-5 -oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1yl)cyclopentyl acetate (50 mg, 0.118 mmol) and (3,4-difluorophenyl)boronic acid (20.56 mg, 0.130 mmol) in acetonitrile (3.585 ml, 68.6 mmol) with stirring for 15 h at 40°C. The reaction mixture was cooled to rt, the mixture was filtered and then purified by flash chromatography on a Companion (4 g column, 0-10% MeOH in DCM, gradient elution) to give (1R,3R)-3- (2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-1-yl )cyclopentyl acetate (40 mg, 60%) as a colorless glassy substance; temp. beats 2.12 min (method 1), m/z 535 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.86 - 7.76 (m, 1H), 7.68 (dd, J=8.5, 4.1 Hz, 1H), 7.62 (t, J=2.0 Hz, 1H), 7.44 7.32 ( m, 1H), 7.29 - 7.13 (m, 2H), 6.17 - 6.07 (m, 1H), 5.46 - 5.35 (m, 1H), 5.31 - 5.15 (m, 1H), 2.78 - 2.44 (m, 5H), 2.37 (d, 3H), 2.30-2.20 (m, 2H), 2.20 (d, J=1.5 Hz, 3H), 2.18-2.05 (m+d, 5H), 1.92-1.80 (m, 1H).

Example 105: (1R,3R)-3-(2-((S)-1-(3-chloro-4-methoxyphenyl)-5-oxopyrrolidin-2-yl)-5-(3,5dimethylisoxazol-4-yl )-1H-benzo[d]imidazol-1-yl)cyclopentyl acetate.

(1R,3R)-3-(2-((S)-1-(3-chloro-4-methoxyphenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4ul)-1H -benzo[d]imidazol-1-yl)cyclopentyl acetate

CuTMEDA (8.24 mg, 0.018 mmol) was added to a solution of DBU (0.019 mL, 0.124 mmol), (1R,3R)-3-(5(3,5-dimethylisoxazol-4-yl)-2-((S)-5 -oxopyrrolidin-2-yl)-1H-benzo[d]imidazol-1yl)cyclopentyl acetate (50 mg, 0.118 mmol) and (3-chloro-4-methoxyphenyl)boronic acid (24.27 mg, 0.130 mmol) in acetonitrile (3.58 ml , 68.6 mmol) with stirring for 15 h at 40°C. The reaction mixture was cooled to rt, the mixture was filtered, and then purified by chromatography on a Companion device (12 g column, 0-10% MeOH in DCM, gradient elution) to give (1R,3R)-3-(2 -((S)-1-(3-chloro-4-methoxyphenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-1-yl )cyclopentyl acetate (19.1 mg, 27% yield) as a beige solid; temp. beats 2.06 min (method 1), m/z 563 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (de-DMSO) δ: 7.74 (dd, J=22.2, 2.6 Hz, 1H), 7.66 (dd, J=8.5, 3.6 Hz, 1H), 7.63 (dd, J=3.2, 1.6 Hz, 1H), 7.29 (ddd, J=26.2, 9.0, 2.6 Hz, 1H), 7.20 - 7.15 (m, 1H), 7.06 (dd, J=9.1, 4.7 Hz, 1H), 6.08 (dd, 1H), 5.42 - 5.34 (m, 1H), 5.24 (h, J=9.3 Hz, 1H), 3.76 (d, 3H), 2.80 - 2.57 (m, 2H), 2.56 - 2.41 (m, 3H), 2.37 (d, J =1.9 Hz, 3H), 2.26 - 2.09 (m+d, 6H), 2.08 (s, 3H), 2.04 - 1.94 (m, 1H), 1.89 -1.75 (m, 1H).

Example 106: (S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3methoxycyclopentyl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

4-(3,5-dimethylisoxazol-4-yl)-N-(trans-(1r,3r)-3-methoxycyclopentyl)-2-nitroaniline

trans-(1r,3r)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentanol (815 mg, 2.57 mmol) was dissolved in THF (1.62E + 04 µl, 198 mmol). The solution is cooled to 0°C, then 18 crown-6 (45.8 mg, 0.173 mmol) in dry THF (0.1 ml) is added, followed by NaH (60% in oil) (113 mg, 2.83 mmol). After 15 min stirring, methyl iodide (177 μl, 2.83 mmol) is added. The reaction mixture was allowed to warm up to rt. during the night. After 15 h, NaH (40 mg) 0°C was added, then the reaction mixture was stirred for 1 h, and then methyl iodide (18 μl) was added. 18-crown-6 (75 mg). In 20 minutes. additional methyl iodide (18 μl) was added. The reaction mixture was stirred overnight and then saturated aqueous ammonium chloride (10 ml) was added followed by DCM (2x5 ml) via separatory funnel, the organic layer was dried (MgSO ₄ ), filtered, evaporated and concentrated to give an orange sticky gum which was purified by flash chromatography (24 g, DCM/MeOH: 100/90 to 90/10) to give 4-(3,5dimethylisoxazol-4-yl)-N-(trans-(1r,3r) -3-methoxycyclopentyl)-2-nitroaniline (481 mg, 55%) as a red-orange glassy substance; temp. beats 2.36 min (method 1), m/z 332 (M+H) ⁺ (electrorast

- 141 041318 dusting ⁺ ).

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((trans-(1r,3r)-3-methoxycyclopentyl)amino)phenyl)-5oxopyrrolidine-2-carboxamide

OMe OMe bC ^{NH NH} me l II ^Me I II ?

_m νη ₂ ν ⁿ Ά\

Ν ² Ν ΗI / οΑ οΑ ^ΗΝ -Ζ

Me Mem

Ο

HATU (550 mg, 1.445 mmol) was added to a solution of 4-(3,5-dimethylisoxazol-4-yl)-N ¹ -(trans-(1r,3r)3-methoxycyclopentyl)benzene-1,2-diamine (363 mg , 1.108 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (171 mg, 1.325 mmol) and DIPEA (0.316 ml, 1.806 mmol) in DMF (3.357 ml, 43.4 mmol), then stirred at room temperature for 18 hours The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml), after which the layers were separated. The organic phase was washed with brine (100 ml), concentrated in vacuo to give a crude pink oil (693 mg). The crude product was purified by Companion chromatography (12 g column, 0-10% MeOH/DCM) to give (S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(( trans-(1r,3r)-3methoxycyclopentyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (0.42 g, 82%) as a colorless foam; temp. beats 1.58 min (method 1), m/z 413 (M+H) ⁺ (electrospray ⁺ ).

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((trans-(1r,3r)-3-methoxycyclopentyl)amino)phenyl)-5oxopyrrolidine-2-carboxamide

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((trans-(1r,3r)-3-methoxycyclopentyl)amino)phenyl)-5oxopyrrolidine-2-carboxamide (0.42 g , 0.988 mmol) was dissolved in acetic acid (3.96 ml, 69.1 mmol) and stirred at 70°C for 15 h. The mixture was concentrated under vacuum. The crude brown oil was purified by flash chromatography (4 g, DCM/MeOH: 100/0 to 90/10) to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl)- 1-(trans-(1r,3r)-3-methoxycyclopentyl)-1Hbenzo[d]imidazol-2-yl)pyrrolidin-2-one (202 mg, 48%) as a pink foam; temp. beats 1.38 min (method 1), m/z 395 (M+H) ⁺ (electrospray ⁺ ).

(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3methoxycyclopentyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL, 0.133 mmol), (S)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(trans-(1r,3r)- 3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin2-one (50 mg, 0.127 mmol) and (3-chloro-4-methoxyphenyl)boronic acid (26.0 mg, 0.139 mmol) in acetonitrile (3840 µL, 73.5 mmol) with stirring for 22 h at 40°С. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (4 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(3 -chloro-4methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -(trans-(1r,3r)-3-methoxycyclopentyl)-1Hbenzo[d]imidazol-2-yl)pyrrolidine -2-one (41 mg, 57%) as a greenish solid; temp. beats 2.10 min (method 1), m/z 535 (M+H) ⁺ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.74 (dd, J=25.9, 2.6 Hz, 1H), 7.65 -7.57 (m, 2H), 7.31 (ddd, J=15.8, 8.9, 2.6 Hz, 1H), 7.16 (ddd, J=8.4, 2.8, 1.7 Hz, 1H), 7.07 (dd, J=9.1, 3.3 Hz, 1H), 6.07 (ddd, 1H), 5.24 - 5.11 (m, 1H), 4.19 4.08 (m , 1H), 3.76 (d, J=1.5 Hz, 3H), 3.27 (s, 3H), 2.78 - 2.56 (m, 2H), 2.37 (d, J=1.6 Hz, 3H), 2.36 - 2.25 (m, 2H), 2.20 (d, J=1.6 Hz, 3H), 2.18 - 2.03 (m, 5H), 1.90 - 1.78 (m, 1H).

- 142 041318

Example 107: (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-( 1 r,3r)-3 methoxycyclopentyl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL, 0.133 mmol), (S)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(trans-(1r,3r)- 3-methoxycyclopentyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin2-one (50 mg, 0.127 mmol) and (3,4-dichlorophenyl)boronic acid (26.6 mg, 0.139 mmol) in acetonitrile (3840 µl, 73.5 mmol) with stirring for 22 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (4 g column, 010% MeOH in DCM, gradient elution) to give (S)-1-(3.4 -dichlorophenyl)-5-(5(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2- it (44 mg, 62%) as a beige foam; temp. beats 2.37 min (method 1), m/z 539 (M+H) ⁺ (electrospray ⁺ );

1Н-NMR (d ₆ -DMSO) δ: 7.98 (dd, J=16.4, 2.6 Hz, 1H), 7.67 - 7.59 (m, 2H), 7.56 (dd, J=8.9, 3.5 Hz, 1H), 7.45 ( ddd, J=11.7, 8.9, 2.6 Hz, 1H), 7.22 - 7.14 (m, 1H), 6.19 (dd, J=25.2, 7.6 Hz, 1H), 5.25 - 5.16 (m, 1H), 4.24 - 4.07 ( m, 1H), 3.29 (d, 3H), 2.79 - 2.59 (m, 2H), 2.58 - 2.45 (m, 1H), 2.44 - 2.28 (m + d, 6H), 2.27 - 2.11 (m + d, 5H ), 2.10–2.00 (m, 1H), 1.94–1.79 (m, 1H).

Example 108: (S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3methoxycyclopentyl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3methoxycyclopentyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (8.83 mg, 0.019 mmol) was added to a solution of DBU (20.06 μL, 0.133 mmol), (S)-5-(5-(3,5dimethylisoxazol-4-yl)-1 -(trans-( 1 r,3r) -3-methoxycyclopentyl)-1 H-benzo Iimidazol-2-yl)pyrrolidin2-one (50 mg, 0.127 mmol) and (4-chloro-3-fluorophenyl)boronic acid (24.31 mg, 0.139 mmol) in acetonitrile (3840 µl , 73.5 mmol) with stirring for 15 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with a minimum of DCM, passed through a syringe filter, and then purified by flash chromatography on a Companion (4 g column, 0-10% MeOH in DCM, gradient elution) to give (8)-1- (4-chloro-3fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1 r,3r)-3-methoxycyclopentyl)-1Hbenzo[0]imidazol-2- yl) pyrrolidin-2-one (47.8 mg, 68%) as a beige solid; temp. beats 2.25 min (method 1), m/z 523 (M+H)+ (electrospray ⁺ );

¹ H-NMR (R6-DMSO) δ: 7.81 (ddd, J=12.1, 7.6, 2.5 Hz, 1H), 7.63 (dd, J=8.5, 4.0 Hz, 1H), 7.60 (t, J=2.0 Hz, 1H), 7.51 (td, J=8.8, 3.4 Hz, 1H), 7.33 - 7.24 (m, 1H), 7.18 (dt, J=8.4, 2.0 Hz, 1H), 6.17 (dd, J=26.0, 7.8 Hz , 1H), 5.25 - 5.14 (m, 1H), 4.21 - 4.10 (m, 1H), 3.29 (d, 3H), 2.78 - 2.59 (m, 2H), 2.59 - 2.50 (m, 1H), 2.47 - 2.25 (m+d, 6H), 2.26-2.11 (m+d, 5H), 2.11-2.01 (m, 1H), 1.92-1.80 (m, 1H).

110:

Example (S)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H benzo^]imidazol-2-yl)-1-(3,4- difluorophenyl)pyrrolidin-2-one.

(S)-N-(2-((4,4-difluorocyclohexyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine2-carboxamide (Intermediate D12)

- 143 041318

HATU (600 mg, 1.578 mmol) was added to a stirred solution of TEA (0.25 ml, 1.794 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (250 mg, 1.936 mmol) and intermediate C12 (500 mg, 1.400 mmol ) in N,N-dimethylformamide (5 ml), then the mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (40 ml), then extracted with ethyl acetate (2x40 ml). The combined organic phases were washed with 20% brine (2x40 ml) then brine (40 ml). The organic phase was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (40 g column, 0-50% THF/DCM), then triturated in diethyl ether to give (S)-N-(2((4,4-difluorocyclohexyl)amino)- 5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide (605 mg, 99%) as a white solid; temp. beats 1.86 min (method 1), m/z 433 (M+H) + (electrospray ⁺ ).

(S)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2-one (intermediate E12)

Intermediate D12 (605 mg, 1.385 mmol) was heated to 80°C in acetic acid (15 mL) for 2 h. sodium carbonate (50 ml). The resulting solid was collected by filtration, then purified by Companion chromatography (40 g column, 15-75% THF/DCM), then triturated in diethyl ether to give (S)-5-(1-(4,4- difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-ul)-1H-benzo[d]umidazol-2yl)pyrrolidin-2-one - intermediate E12 (420 mg, 72%) as a white solid; temp. beats 1.70 min (method 1), m/z 415 (M+H) ⁺ (electrospray ⁺ ).

4-(2-(1 -(3 -fluoro-4-(trifluoromethoxy)phenyl)propan-2-yl)-1 -(3-(methylsulfonyl)propyl)-1 Hbenzo[d]imidazol-5-yl)- 3,5-dimethylisoxazole

CuTMEDA (55 mg, 0.118 mmol) was added to a stirred solution of Intermediate E12 (100 mg, 0.239 mmol) in pyridine (3 ml), then the mixture was stirred for 15 min at 40°C. (3,4-Difluorophenyl)boronic acid (100 mg, 0.633 mmol) was added, then the mixture was heated to 40°C for 2 h. The mixture was diluted with ethyl acetate (25 ml), then washed with water (3x25 ml) and brine ( 25 ml). The organic phase was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on a Companion (12 g column, 0-25% THF), then triturated in diethyl ether to give (S)-5-(1-(4,4difluorocyclohexyl)-5-(3,5- dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidin-2-one (106 mg, 83%) as a white solid; temp. beats 2.32 min; m/z 527 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.84 (1H, ddd, J=13.2, 7.4, 2.7 Hz), 7.62 (1H, d, J=1.6 Hz), 7.59 (1H, d, J=8.5 Hz ), 7.38 (1H, dt, J=10.5, 9.2 Hz), 7.22 (1H, dd, J=8.5, 1.7 Hz), 7.20 - 7.12 (1H, m), 6.06 (1H, d, J=8.1 Hz) , 4.81 (1H,

- 144 041318

s), 2.80 - 2.58 (2H, m), 2.60 - 2.52 (1H, m), 2.43 (2H, s), 2.36 (3H, s), 2.30 - 2.21 (4H, m), 2.19 (3H, s) , 2.17 2.08 (1H, m), 2.07 - 1.98 (1H, m), 1.98 - 1.89 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=4.13 min (5.65 min minor fraction), ~90% e.e. excess at 254 nm.

111:

Example (S)-1-(3-Chloro-4-methoxyphenyl)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole -2-yl)pyrrolidin-2-one.

(S)-1-(3-chloro-4-methoxyphenyl)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2 -yl)pyrrolidin-2-one

DBU (0.027 mL, 0.181 mmol) was added to a solution of intermediate E12 (50 mg, 0.121 mmol) in MeCN (2 mL, 38.3 mmol) and stirred for 10 min. CuTMEDA (11.21 mg, 0.024 mmol) was added, sonicated and stirred for 10 min, (3-chloro-4methoxyphenyl)boronic acid (33.7 mg, 0.181 mmol) was added, and the reaction mixture was stirred at room temperature over 18 hours. The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (12 g column, 0-10% MeOH/DCM) to give (S)-1-(3chloro-4-methoxyphenyl)- 5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)pyrrolidin-2-one (36 mg, 53%) in as a dark brown solid; temp. beats 2.26 min; m/z 555 (M+H)+ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.78 (1H, d, J=2.6 Hz), 7.63 (1H, d, J=1.6 Hz), 7.57 (1H, d, J=8.5 Hz), 7.26 (1H , dd, J=9.0, 2.7 Hz), 7.21 (1H, dd, J=8.5, 1.7 Hz), 7.07 (1H, d, J=9.1 Hz), 6.08 - 5.98 (2H, m), 4.89 - 4.77 ( 1H, m), 3.76 (3H, s), 2.84 - 2.70 (1H, m), 2.70 - 2.58 (1H, m), 2.48 - 2.39 (2H, m), 2.37 (3H, s), 2.29 - 2.21 ( 4Н, m), 2.20 (3H, s), 2.18 - 2.12 (1H, m), 2.04 - 1.93 (1H, m), 1.75 - 1.66 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp.=5.37 min (7.89 minor fraction), ~90% enantiomeric excess at 254 nm.

112: (S)-1-(3-fluoro-4-methoxyphenyl)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-

1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3-chloro-4-methoxyphenyl)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2 -yl)pyrrolidin-2-one

DBU (0.027 mL, 0.181 mmol) was added to a solution of intermediate E12 (50 mg, 0.121 mmol) in MeCN (2 mL, 38.3 mmol) and stirred for 10 min. CuTMEDA (11.21 mg, 0.024 mmol) was added, sonicated and stirred for 10 min, (3-fluoro-4methoxyphenyl)boronic acid (30.8 mg, 0.181 mmol) was added and the reaction mixture was stirred at rt. over 18 hours. The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (12 g column, 0-10% MeOH/DCM) to give (S)-5-(1(4,4-difluorocyclohexyl )-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4methoxyphenyl)pyrrolidin-2-one (44 mg, 67%) as a pink solid; temp. beats 2.20 min; m/z 539 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.65 - 7.54 (3H, m), 7.22 (1H, dd, J=8.5, 1.7 Hz), 7.14 - 7.05 (2H, m), 6.00 (1H, dd, J=8.6, 1.7 Hz), 4.81 (1H, s), 3.75 (3H, s), 2.82 - 2.69 (1H, m), 2.70 - 2.57 (1H, m), 2.46 - 2.38 (2H, m), 2.37 (3H, s), 2.30 - 2.21 (4H, m), 2.20 (3H, s), 2.18 - 2.10 (2H, m), 2.05 - 1.92 (1H, m), 1.82 - 1.70 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=5.54 min (7.90 min minor fraction), ~90% ee at 254 nm.

Example 113: (5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2Hpyran-4-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(2S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((2-methyltetrahydro-2H-pyran-4-yl)amino)phenyl)-5oxopyrrolidine-2-carboxamide (intermediate D13)

HATU (1.791 g, 4.71 mmol) was added to a solution of intermediate C13 (1.45 g, 4.28 mmol), (S)-5-oxon-pyrrolidine-2-carboxylic acid (0.608 g, 4.71 mmol) and N,N-diisopropylethylamine (0.897 ml , 5.14 mmol) in DMF (8 ml, 103 mmol), then stirred at room temperature overnight.

The mixture was diluted with water (20 ml) then extracted with ethyl acetate (3x40 ml). The combined organic phases were washed with 1M aqueous HCl (10 ml), saturated aqueous NaHCO ₃ (10 ml) and brine (3x10 ml), then dried (MgSO ₄ ), filtered and concentrated to give a brown oil which purified by flash chromatography (40 g column, 0-10% MeOH/DCM) to give Intermediate D13 (1.63 g, 3.91 mmol, 91%) as a white foam; temp. beats 1.61 min; m/z 413 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO), which is consistent with the structure of the product, as a mixture of diastereomers (ratio ~ 9: 1) at >95% purity (5S)-5-(5-(3,5-dimethylisoxazole-4 -yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol2-yl)pyrrolidin-2-one (intermediate E13)

Intermediate D13 (1.60 g, 3.88 mmol) was heated to 80° C. in acetic acid (8.88 ml, 155 mmol) for 20 h. After cooling to rt, the mixture was concentrated under reduced pressure. The reaction mixture was diluted with MeOH methanol (30 ml) and solid potassium carbonate (1 g) was added. The mixture was stirred for 1 hour and then concentrated on loose silica gel. The crude product was purified by silica gel flash chromatography (40 g column, 0-10% (0.7 M Ammonia/MeOH)/DCM) to give (5S)-5-(5-(3,5-dimethylisoxazole-4- yl)-1-(2-methyl tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one - intermediate E13 (970 mg, 63%) as dark brown solid; temp. beats 1.36 min; m/z 395 (M+H)+ (electrospray ⁺ ).

(5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one

DBU (0.042 mL, 0.279 mmol) was added to a solution of intermediate E13 (50 mg, 0.127 mmol) in MeCN (2 mL, 38.3 mmol) and stirred for 10 min. CuTMEDA (11.77 mg, 0.025 mmol) was added, sonicated and stirred for 10 min, then (3,4difluorophenyl)boronic acid (40.0 mg, 0.254 mmol) was added and the reaction mixture was stirred at rt. over 18 hours. The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (12 g column, 0-10% MeOH/DCM) to give (5S)-1-146 041318 (3,4-difluorophenyl )-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1Hbenzo[b]imidazol-2-yl)pyrrolidin-2-one (54 mg, 83%) as light pink solid; temp. beats

2.03 min; m/z 507 (M+H)+ (electrospray ⁺ );

¹ H-NMR (66-DMSO) δ: NMR corresponds to a mixture of 4 diastereomers.

Example 114: (5S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2methyltetrahydro-2H-pyran-4-yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(5 S)-1 -(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -(2-methyltetrahydro-2H-pyran4-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one

DBU (0.042 mL, 0.279 mmol) was added to a solution of intermediate E13 (50 mg, 0.127 mmol) in MeCN (2 mL, 38.3 mmol) and stirred for 10 min. CuTMEDA (11.77 mg, 0.025 mmol) was added, sonicated and stirred for 10 min, then boronic acid was added and the reaction mixture was stirred at rt. over 18 hours. The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (24 g column, 0-10% MeOH/DCM) to give (58)-1-(3-chloro-4-methoxyphenyl )-5-(5-(3,5dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyrαn-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2one (48 mg, 0.089 mmol, 70%) as a dark brown solid; temp. beats 1.98 min; m/z 535 (M+H)+ (electrospray ⁺ );

¹ H-NMR (66-DMSO) δ: NMR corresponds to a mixture of 4 diastereoisomers.

Example 115: (5S)-5-(5-(3,5-dimethylisooxazol-4-yl)-1-(2-methyltetrahydro-2H-piran-4-yl)-1Hbenzo[b]imidazol-2-yl) -1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one.

(5S)-5-(5-(3,5-dimethylisoκazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol2-yl)-1 - (3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

DBU (0.042 mL, 0.279 mmol) was added to a solution of intermediate E13 (50 mg, 0.127 mmol) in MeCN (2 mL, 38.3 mmol) and stirred for 10 min. CuTMEDA (11.77 mg, 0.025 mmol) was added, sonicated and stirred for 10 min, then (3-fluoro-4methoxyphenyl)boronic acid (43.1 mg, 0.254 mmol) was added and the reaction mixture was stirred at rt. over 18 hours. The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (24 g column, 0-10% MeOH/DCM) to give (5S)-5-(5(3,5-dimethylisoxazole -4-yl)-1 -(2-methyltetrahydro-2H-pyran-4-yl)-1 H-benzo[d]imidazol-2-yl)-1 -(3-fluoro-4-methoxyphenyl)pyrrolidin-2- it (39 mg, 59%) as a pink solid; temp. beats 1.91 min; m/z 519 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: NMR corresponds to a mixture of 4 diastereoisomers.

Example 118: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4methylcyclohexyl)- 1H-benzo[d]imidazol-2-yl)π-pyrrolidin-2-one.

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1s,4R)-4-hydroxy-4-methylcyclohexyl)amino)phenyl)-5oxopyrrolidine-2-carboxamide ( intermediate connection D15)

HATU (750 mg, 1.972 mmol) was added to a stirred solution of TEA (0.3 ml, 2.152 mmol),

- 147 041318 (S)-5-oxopyrrolidine-2-carboxylic acid (0.25 g, 1.936 mmol) and intermediate C15 (574 mg, 1.820 mmol) in N,N-dimethylformamide (10 ml), then the mixture was stirred at room temperature for 2 hours. The mixture was diluted with brine (100 ml), then extracted with ethyl acetate (3x100 ml). The combined organic phases were concentrated under reduced pressure. The crude product was purified by Companion chromatography (40 g column, 50-100% THF/DCM), then triturated in diethyl ether to give (S)-N-(5-(3,5-dimethylisoxazol-4-yl )-2(((1s,4R)-4-hydroxy-4-methylcyclohexyl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (773 mg, 95% yield) as a pale pink solid; temp. beats 1.58 min; m/z 427 (M+H)+ (electrospray ⁺ ).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 s,4R)-4-hydroxy-4-methylcyclohexyl)-1Hbenzo[d]imidazol-2-yl) pyrrolidin-2-one (intermediate E15)

Intermediate D15 (750 mg, 1.758 mmol) was heated to 80°C in acetic acid (15 ml) for 1.5 h. The solvents were removed under reduced pressure, then the mixture was dissolved in dichloromethane (50 ml) and diethylamine (6 ml) and concentrated on loose silica gel. The silicate was purified by Companion chromatography (40 g column, 50-75% THF/DCM), then triturated in diethyl ether (15 mL) to give (S)-5-(5-(3,5-dimethylisoxazole- 4-yl)-1-((1s,4R)-4hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one Intermediate E15 (550 mg, 76%) in the form white solid; temp. beats 1.19 min; m/z 409 (M+H) ⁺ (electrospray ⁺ ).

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4methylcyclohexyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (10 mg, 0.022 mmol) was added to a stirred suspension of intermediate E15 (70 mg, 0.171 mmol) and DBU (28 μL, 0.186 mmol) in acetonitrile (6 mL). (3,4difluorophenyl)boronic acid (30 mg, 0.190 mmol) was added and the mixture was heated to 70°C for 3 h. Volatiles were removed under reduced pressure, then the residue was dissolved in THF, filtered, and adsorbed on loose silica gel. Purified by Companion chromatography (12 g column, 050% THF/DCM), then triturated in diethyl ether to give (S)-1-(3,4difluorophenyl)-5-(5-(3,5-dimethylisoxazole -4-yl)-1-((1 s,4R)-4-hydroxy-4-methylcyclohexyl)- 1Hbenzo[d]imidazol-2-yl)pyrrolidin-2-one (47 mg, 52.2% yield) as beige solid; temp. beats 1.92 min; m/z 521 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (de-DMSO) δ: 7.83 (ddd, J=13.2, 7.4, 2.6 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H) , 7.39 (dd, J=10.7, 9.2 Hz, 1H), 7.23 (dd, J=8.4, 1.7 Hz, 1H), 7.19-7.13 (m, 1H), 6.08 (dd, J=8.1, 2.0 Hz, 1H ), 4.52 (tt, 1H), 4.47 (s, 1H), 2.82 - 2.52 (m, 5H), 2.38 (s, 3H), 2.21 (s, 3H), 2.13 - 2.03 (m, 1H), 1.79 - 1.50 (m, 6H), 1.23 (s, 3H).

Example 119: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1Hbenzo[d]imidazol-2 -yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-Hbenzo[d]imidazol-2-yl)- 1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

- 148 041318

Intermediate E15 (70 mg, 0.170 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (30 mg, 0.177 mmol), CuTMEDA (10 mg, 0.022 mmol) and DBU (26 µl, 0.172 mmol) in acetonitrile ( 3 ml) was heated to 70°C for 2 hours the Mixture was concentrated on loose silica gel. The silicate was purified by Companion chromatography (4 g column, 5-50% THF/DCM), then triturated in diethyl ether to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl) -1-((1s,4R)-4-hydroxy-4methylcyclohexyl)-1 H-benzo[d]imidazol-2 -yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one (43 mg , 47%) as a white solid; temp. beats 1.78 min; m/z 533 (M+H)+ (electrospray ⁺ );

¹ H-NMR (66-DMSO) δ: 7.74 (d, J=8.5 Hz, 1H), 7.66 - 7.54 (m, 2H), 7.22 (dd, J=8.5, 1.3 Hz, 1H), 7.14 7.01 (m , 2H), 6.01 (d, J=7.9 Hz, 1H), 4.62 - 4.32 (m, 2H), 3.75 (s, 3H), 2.84 - 2.70 (m, 1H), 2.70 - 2.52 (m, 4H), 2.38 (s, 3H), 2.21 (s, 3H), 2.15 - 2.06 (m, 1H), 1.80 - 1.66 (m, 2H), 1.66-1.51 (m, 3H), 1.48 - 1.37 (m, 1H), 1.22 (s, 3H).

Example 120: (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4methylcyclohexyl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4methylcyclohexyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one

Mixture of intermediate E15 (70 mg, 0.170 mmol), (3,4-dichlorophenyl)boronic acid (35 mg, 0.183 mmol), CuTMEDA (10 mg, 0.022 mmol) and DBU (26 µl, 0.172 mmol) in acetonitrile (3 ml) was heated to 70°C for 2 hours the Mixture was concentrated on loose silica gel. The silicate was purified by Companion chromatography (4 g column, 5-50% THF/DCM), then triturated in diethyl ether to give (S)-1-(3,4-dichlorophenyl)-5-(5-( 3,5-dimethylisoxazol-4-yl)-1-((1s,4R)4-hydroxy-4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (49 mg, 50 %) in the form of a white solid; temp. beats 2.14 min; m/z 553 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.99 (d, J=2.5 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.58 (d , J=8.9 Hz, 1H), 7.41 (dd, J=8.9, 2.6 Hz, 1H), 7.23 (dd, J=8.4, 1.7 Hz, 1H), 6.14 (d, J=8.3 Hz, 1H), 4.63 - 4.51 (m, 1H), 4.48 (s, 1H), 2.84 - 2.53 (m, 5H), 2.38 (s, 3H), 2.21 (s, 3H), 2.13 - 2.02 (m, 1H), 1.81-1.51 (m, 6H), 1.24 (s, 3H).

Example 121: (S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4methylcyclohexyl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4methylcyclohexyl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one

Mixture of intermediate E15 (70 mg, 0.170 mmol), (4-chloro-3-fluorophenyl)boronic acid (32 mg, 0.184 mmol), CuTMEDA (10 mg, 0.022 mmol) and DBU (26 µl, 0.172 mmol) in acetonitrile (3 ml) was heated to 70°C for 2 hours the Mixture was concentrated on loose silica gel. The silicate was purified by Companion chromatography (4 g column, 5-50% THF/DCM), then triturated in diethyl ether to give ((S)-1-(4-chloro-3-fluorophenyl) -5-(5-(3,5-dimethylisoxazol-4yl)-1 -((1 s,4R)-4-hydroxy-4-methylcyclohexyl)-1 H-benzo[d]imidazol-2-yl)pyrrolidin- 2-one (38 mg, 40%) as a white solid, temp 2.06 min, m/z 537 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.84 (dd, J=12.1, 2.4 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.52 (t, J=8.8 Hz, 1H), 7.28 - 7.19 (m, 2H), 6.13 (d, J=7.8 Hz, 1H), 4.61 - 4.48 (m, 1H), 4.44 (br s, 1H), 2.82 - 2.52 (m, 5H), 2.37 (s, 3H), 2.21 (s, 3H), 2.12 - 2.03 (m, 1H), 1.81 - 1.52 (m, 6H), 1.24 (s, 3H).

Example 122: (S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2oxaspiro[3.3]heptan-6-yl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-N-(2-(2-oxaspiro[3.3]heptan-6-ylamino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5oxopyrrolidine-2-carboxamide (intermediate D16) O

O

A solution of intermediate C16 (1.47 g, 4.91 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (S)-5-oxopyrrolidine2-carboxylic acid (0.697 g, 5.40 mmol) and TEA (2.053 ml, 14.73 mmol) in DMF (20 ml) were stirred at room temperature for 2 h. was divided between ethyl acetate (200 ml) and water (100 ml), after which the layers were separated. The organic phase was washed with brine (100 ml), dried (MgSO ₄ ) and concentrated in vacuo to give a purple oil. Intermediate D16 (1.6 g, 3.04 mmol) was used in the next step without further purification; temp. beats 1.53 min; m/z 411(M+H) ⁺ (electrospray ⁺ ).

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2 -one (intermediate E16)

O

Intermediate D16 was dissolved in acetic acid (6 ml) and stirred at 80° C. for 18 hours. The reaction mixture was cooled to RT and the solvent was removed in vacuo. The residue was purified by chromatography (24 g silica gel, 0-10% methanol in DCM, gradient elution). Fractions containing product were combined and concentrated in vacuo to give crude (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6- yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one Intermediate E16 (ca. 206 mg, 13%); temp. beats 1.53 min; m/z 411(M+H) ⁺ (electrospray ⁺ ).

(S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one

CuTMEDA (17.75 mg, 0.038 mmol) was added to a solution of DBU (40.3 μL, 0.268 mmol), intermediate E16 (100 mg, 0.255 mmol), and (3-chloro-4-methoxyphenyl)boronic acid (52.2 mg, 0.280 mmol) in acetonitrile (4 ml) with stirring for 18 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(4 -chloro-3- 150 041318 fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1Hbenzo[d]imidazole -2-yl)pyrrolidin-2-one (53 mg, 38%) as an off-white solid; temp. beats 1.91 min; m/z 533 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.78 - 7.67 (m, 2H), 7.62 (dd, J=1.7, 0.6 Hz, 1H), 7.28 - 7.15 (m, 2H), 7.07 (d, J= 9.1 Hz, 1H), 5.91 (dd, J=8.2, 2.3 Hz, 1H), 5.76 (s, 1H), 5.09 (p, J=8.9 Hz, 1H), 4.83 - 4.73 (m, 2H), 4.70 ( s, 2H), 3.78 (s, 3H), 3.03 (t, J=10.1 Hz, 2H), 2.91 - 2.51 (m, 3H), 2.51 -2.45 (m, 1H), 2.37 (s, 3H), 2.20 (s, 3H), 2.15–2.05 (m, 1H).

Example 123: (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-benzo[d]imidazol-2-yl)- 1(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

CuTMEDA (17.75 mg, 0.038 mmol) was added to a solution of DBU (40.3 μL, 0.268 mmol), intermediate E16 (100 mg, 0.255 mmol), and (3-fluoro-4-methoxyphenyl)boronic acid (47.6 mg, 0.280 mmol) in acetonitrile (4 ml) with stirring for 18 h at 40°C. The mixture was concentrated under reduced pressure. The residue was diluted with minimal DCM, passed through a syringe filter, and then purified by Companion chromatography (12 g column, 0-10% MeOH in DCM, gradient elution) to give (S)-5-(5 -(3,5dimethylisoxazol-4-yl)-1 -(2-oxaspiro[3.3]heptan-6-yl)-1 H-benzo[d]imidazol-2 -yl)-1 -(3-fluoro-4methoxyphenyl) pyrrolidin-2-one (43 mg, 32%) as an off-white solid; temp. beats 1.84 min; m/z 517 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.70 (dd, J=8.5, 0.7 Hz, 1H), 7.63 - 7.52 (m, 2H), 7.18 (dd, J=8.4, 1.7 Hz, 1H), 7.07 (dd, J=4.6, 2.0 Hz, 2H), 5.87 (dd, J=8.2, 2.2 Hz, 1H), 5.08 (p, J=8.9 Hz, 1H), 4.82 - 4.73 (m, 2H), 4.69 ( s, 2H), 3.75 (s, 3H), 3.03 (q, J=9.8 Hz, 2H), 2.92-2.51 (m, 4H), 2.36 (s, 3H), 2.19 (s, 3H), 2.12-2.00 (m, 1H), 1.701.58 (m, 1H).

Example 141: (S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)-1 -(3,4-difluorophenyl)pyrrolidin-2-one.

(R)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentanone

A stirred solution of DMSO (101 μl, 1.418 mmol) in DCM (1703 μl, 26.5 mmol) at -78°C was treated dropwise with oxalyl chloride (124 μl, 1.418 mmol). After 15 min at -78°C, a solution of (1R,3R)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentanol (300 mg, 0.945 mmol) was slowly added in DCM (1 ml). After 45 min at -78°C, DIPEA (826 µl, 4.73 mmol) was added slowly. The reaction mixture was stirred at -70°C for 20 h, then neutralized with NaHCO ₃ (20 ml) and diluted in DCM (10 ml), then separated by passage through PhaseSep©, washing with additional DCM. The solution was concentrated in vacuo to give an orange-red crude solid (0.378 g) which was purified by flash chromatography on a Companion (12 g, DCM/AcOEt: 100/90 to 90/10) to give (R )-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentanone (0.264 g, 86%) as a sticky orange oil; temp. beats 2.00 min; m/z 316 (M+H) ⁺ (electrospray ⁺ ).

(R)-N-(3,3-difluorocyclopentyl)-4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline

- 151 041318

DAST (3.51 ml, 9.51 mmol) was added dropwise to a stirred, cooled (0°C) solution of (R)-3-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclopentanone (1.0 g, 3.17 mmol) in DCE (9.99 ml, 127 mmol). The reaction mixture was stirred at rt. and over the weekend, and then for another 20 hours. The reaction was quenched in saturated aqueous NaHCO ₃ (100 ml) (gas evolved), the phases were separated, the aqueous phase was extracted with dichloromethane (3x150 ml), the combined organic layers were dried with MgSO ₄ , filtered through PhaseSep© and concentrated in vacuo to give a dark brown crude oil which was purified by column chromatography (24 g, DCM 100%) to give (R)-N-(3,3-difluorocyclopentyl )-4-(3,5dimethylisoxazol-4-yl)-2-nitroaniline (0.87 g, 80%) was isolated as a red oil; temp. beats 2.44 min; m/z 338 (M+H)+ (electrospray ⁺ ).

(R)-N ¹ -(3,3-difluorocyclopentyl)-4-(3,5-dimethylisoxazol-4-yl)benzene-1,2-diamine

Sodium dithionite (5.52 g, 26.8 mmol) was added to a mixture of (R)-N-(3,3-difluorocyclopentyl)-4-(3,5dimethylisoxazol-4-yl)-2-nitroaniline (0.903 g, 2.68 mmol) concentrated ammonia (2.085 ml, 53.5 mmol), water (8.10 ml, 450 mmol) and THF (10.09 ml, 123 mmol), then stirred at room temperature overnight. After 15 hours of stirring, the reaction mixture was filtered to remove a white solid. The solid was washed with ethyl acetate (AcOEt, 100 ml). The layers were separated, then the aqueous layer was extracted with ethyl acetate (2x100 ml), the combined organic layers were washed with water (50 ml) and brine (50 ml), dried (MgSO ₄ ), filtered and evaporated under vacuum, resulting in a crude material in the form brown solid, which was dissolved in AcOEt (50 ml), washed with aqueous NaOH solution (1M; 10 ml) and brine (20 ml). The organic layer was dried (MgSO ₄ ), filtered and concentrated to give a beige foam which was dissolved in DCM and loaded onto a solid phase cation exchanger. Capture (washing with methanol - MeOH) and release using 1% NH ₃ in MeOH gave (R)-N ¹ -(3,3difluorocyclopentyl)-4-(3,5-dimethylisoxazol-4-yl)benzene-1,2- diamine (0.685 g, 79%) was isolated as a brown glassy substance; temp. beats 1.88 min; m/z 308 (M+H)+ (electrospray ⁺ ).

(S)-N-(2-(((R)-3,3-difluorocyclonentyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5oxopyrrolidine-2-carboxamide

DIPEA (0.973 ml, 5.57 mmol) was added to a solution of (R)-N ¹ -(3,3-difluorocyclopentyl)-4-(3,5dimethylisoxazol-4-yl)benzene-1,2-diamine (0.685 g, 2.229 mmol ), (S)-5-oxopyrrolidine-2-carboxylic acid (0.317 g, 2.452 mmol) and HATU (1.102 g, 2.90 mmol) in DMF (7.42 ml, 96 mmol). The brown solution was stirred at rt. for 15 h, then diluted with dichloromethane (100 ml) and washed with saturated aqueous sodium bicarbonate (100 ml). The aqueous extracts were extracted with dichloromethane (2x100 ml), the organics were combined and washed with brine (100 ml), dried (MgSO ₄ ), filtered and concentrated under vacuum, resulting in a crude mixture. The crude material was dried on silica gel and purified by column chromatography (24 g, DCM/AcOEt: 100/0 to 100/100) to give (S)-N-(2-(((R)-3, 3difluorocyclopentyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide (0.7 g, 72%) was isolated as an off-white solid; temp. beats 1.78 min; m/z 419 (M+H)+ (electrospray

- 152 041318 ⁺ ).

(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2- He

(S)-N-(2-(((R)-3,3-difluorocyclonentyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5oxopyrrolidine-2-carboxamide (0.7 g, 1.673 mmol) was dissolved in acetic acid (6.70 ml, 117 mmol) and stirred at 70°C for 15 h. The reaction mixture was cooled to rt, stored in a cold room over the weekend and the reaction mixture was concentrated under vacuum. The crude brown oil was purified by flash chromatography (12 g, DCM/MeOH: 100/0 to 90/10) then fixed onto a solid cation exchange resin and released to give a brown oil (530 mg) which was purified by chromatography. column (12 g, AcOEt/MeOH: 100/0 to 95/5) to give (S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3.5 -dimethylusoxazol-4-yl)1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (0.267 g, 38%) was isolated as a white solid; temp. beats 1.65 min; m/z 401 (M+H) ⁺ (electrospray ⁺ ).

(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1( 3,4-difluorophenyl)pyrrolidin-2-one

CuTMEDA (29.0 mg, 0.062 mmol) was added to a stirred solution of (S)-5-(1-((R)-3,3difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d ]imidazol-2-yl)pyrrolidin-2-one (50 mg, 0.125 mmol) in pyridine (1.50 ml, 18.61 mmol), then the mixture was stirred for 15 min at 40°C. (3,4-Difluorophenyl)boronic acid (52.3 mg, 0.331 mmol) was added, then the mixture was heated to 40°C for 2 h. The reaction mixture was cooled to RT and stirred overnight at the same temperature. The mixture was diluted with ethyl acetate (20 ml), then washed with water (3x10 ml). The organic phase was then filtered using a phase separation cartridge and concentrated under reduced pressure. The residue was diluted in DCM, purified by Companion chromatography (4 g column, 0-10% (10% MeOH in DCM) in DCM, gradient elution). After concentrating the combined fractions, diethyl ether (10 mL) was added and the suspension was concentrated in vacuo to give ((S)-5-(1-((R)-3,3-dufluorocyclonentyl)-5-(3,5- dimethyluzoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one (51 mg, 78%) as white foam, SP 2.33 min, m/z 513 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.89 - 7.79 (m, 1H), 7.67 - 7.59 (m, 2H), 7.42 - 7.32 (m, 1H), 7.28 - 7.17 (m, 2H), 6.09 ( td, J=8.2 Hz, 1H), 5.39 (p, J=9.1 Hz, 1H), 2.88 - 2.44 (m, 7H), 2.36 (s, 3H), 2.34 - 2.22 (m, 2H), 2.20 (s , 3Н), 2.16-2.01 (m, 1H).

Example

142:

(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-ul)-1-(3 -fluoro-4-methoxyphenyl)pyrrolidin-2-one.

(S)-5-(1 -((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2-yl)-1 (3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

CuTMEDA (29.0 mg, 0.062 mmol) was added to a stirred solution of (S)-5-(1-((R)-3,3-153 041318 difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-III -benzo^]imidazol-2-yl)pyrrolidin-2-one (50 mg, 0.125 mmol) in pyridine (1.505 ml, 18.61 mmol), then the mixture was stirred for 15 min at 40°C. (3-Fluoro-4-methoxyphenyl)boronic acid (56.2 mg, 0.331 mmol) was added, then the mixture was heated to 40°C for 2 h. The mixture was diluted with ethyl acetate (20 ml), then washed with water (3x10 ml). The organic was then filtered using a phase separation cartridge and concentrated under reduced pressure. The residue was diluted in DCM, purified by Companion chromatography (4 g column, 0-10% (10% MeOH in DCM) in DCM, gradient elution). After concentrating the combined fractions, ethyl ether (10 ml) was added and the suspension was concentrated in vacuo to give (S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazole -4yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one (53 mg, 79%) as a yellowish foam; temp. beats 2.21 min; m/z 525 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.66 - 7.64 (m, 1H), 7.64 - 7.58 (m, 2H), 7.24 (dt, J=8.5, 1.9 Hz, 1H), 7.14 - 7.02 (m, 2H), 6.03 (td, J=7.6 Hz, 1H), 5.46 - 5.32 (m, 1H), 3.75 (s, 3H), 2.82 - 2.42 (m, 7H), 2.37 (s, 3H), 2.34 - 2.22 (m, 2H), 2.20 (s, 3H), 2.15 - 2.07 (m, 1H).

Example 143: (S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)-1 -(3-chloro-4-methoxyphenyl)pyrrolidin-2-one.

(S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1( 3-chloro-4-methoxyphenyl)pyrrolidin-2-one

CuTMEDA (29.0 mg, 0.062 mmol) was added to a stirred solution of (S)-5-(1-((R)-3,3difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d ]imidazol-2-yl)pyrrolidin-2-one (50 mg, 0.125 mmol) in pyridine (1.50 ml, 18.61 mmol), then the mixture was stirred for 15 min at 40°С. (3-Chloro-4-methoxyphenyl)boronic acid (61.7 mg, 0.331 mmol) was added, then the mixture was heated to 40°C for 2 h. The reaction mixture was cooled to RT and diluted with ethyl acetate (20 mL), then washed with water ( 3x10 ml). The organic phase was then filtered through a PhaseSep cartridge and concentrated under reduced pressure. The residue was diluted in DCM and purified by Companion chromatography (4 g column, 0-10% (10% MeOH in DCM) in DCM, gradient elution). After concentrating the combined fractions, diethyl ether (10 mL) was added and the suspension was concentrated in vacuo to give (S)-1-(3-chloro-4-methoxyphenyl)-5-(1-((R)-3, 3difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (52 mg, 75%) as a white foam; temp. beats 2.28 min; m/z 541 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.79 (dd, J=3.9, 2.6 Hz, 1H), 7.65 (d, 1H), 7.61 (t, J=8.4 Hz, 1H), 7.33 - 7.21 (m , 2H), 7.07 (dd, J=9.1, 2.9 Hz, 1H), 6.06 (td, J=8.6 Hz, 1H), 5.42 (q, J=9.2 Hz, 1H), 3.77 (s, 3H), 2.82 - 2.40 (m, 7H), 2.37 (s, 3H), 2.34 - 2.22 (m, 2H), 2.20 (s, 3H), 2.18 - 2.07 (m, 1H).

Example 144: (5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1 Hbenzo[d]imidazol- 2-yl)pyrrolidin-2-one and Example 145: (58)-1-(3,4-difluorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (2S)-N-(5(3,5-dimethylisoxazol-4-yl)-2-((2-hydroxypropyl)amino)phenyl)- 5-oxopyrrolidine-2-carboxamide he he

O

TEA (2.88 ml, 20.66 mmol) was added to a solution of intermediate C19 (1.8 g, 6.89 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (0.978 g, 7.58 mmol) and HATU (2.88 g, 7.58 mmol) in DMF (15 ml, 194 mmol), then stirred at rt. within 6 hours Most of the DMF was removed under vacuum. The residue was diluted with water (10 ml) then extracted with dichloromethane (50 ml). The organic phase was washed with water (10 ml), then passed through a phase separation cartridge and concentrated in vacuo. The residue was purified by chromatography (24 g silica gel, 0-10% methanol in DCM, gradient elution) to give (2S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((2hydroxypropyl )amino)phenyl)-5-oxopyrrolidine-2-carboxamide (1.94 g, 68%) as dark

- 154 041318 brown solid; temp. beats 0.79 min; m/z 373 (M+H)+ (electrospray ⁺ ).

(5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (2 separate diastereoisomers, stereochemistry alcohol unknown)

(2S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((2-hydroxypropyl)amino)phenyl)-5-oxopyrrolidine-2carboxamide (1.94 g, 5.21 mmol) was heated to 80° C in acetic acid (11.93 ml, 208 mmol) for 3 h. The reaction mixture was concentrated. The crude product was purified by flash chromatography (40 g column, 0-10% (0.7 M Ammonia/MeOH)/DCM) to give (5S)-5-(5-(3,5dimethylisoxazol-4-yl)-1 -(2-hydroxypropyl)-1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one - Diastereoisomer 1 (666 mg, 36%) and (5S)-5-(5-(3.5- dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1Hbenzo[d]umidazol-2-yl)pyrroludin-2-one - diastereoisomer 2 (671 mg, 34% yield) as brown solids (absolute alcohol stereochemistry unknown). Diastereoisomer 1: temp. beats 0.74 min; m/z 355 (M+H) ⁺ (electrospray ⁺ ); diastereoisomer 2 b. beats 0.68 min; m/z 355 (M+H) ⁺ (electrospray ⁺ ).

(5S)-1 -(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -(2-hydroxypropyl)-1Нbenzo[d]umidazol-2-yl)pyrroludin -2-one (diastereoisomer 1)

mmol) was added to a solution of (5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2DBU (0.085 ml, 0.564 hydroxypropyl)-1H-benzo[d]imidazol-2-yl) pyrrolidin-2-one - diastereoisomer 1 (100 mg, 0.282 mmol) in MeCN (2.5 ml, 47.9 mmol), DCM (0.25 ml, 3.89 mmol) and the mixture was stirred for 10 min CuTMEDA (13.10 mg, 0.028 mmol) was added , stirred for 10 min, (3,4-difluorophenyl)boronic acid (49.0 mg, 0.310 mmol) was added, and the reaction mixture was stirred at 35°С for 20 h. An additional amount of (3,4-difluorophenyl)boronic acid (49.0 mg , 0.310 mmol) and (3,4-difluorophenyl)boronic acid (49.0 mg, 0.310 mmol) and the mixture was stirred for another 5 h. % MeOH/DCM), resulting in (5S)-1-(3,4difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1H-benzo [d]imidazol-2yl)pyrrolidin-2-one (diastereoisomer 1) (40 mg, 30%) as protein oval solid; temp. beats 1.82 min; m/z 467 (M+H) ⁺ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.86 (1H, ddd, J=13.6, 7.4, 2.7 Hz), 7.68 (1H, d, J=8.3 Hz), 7.57 (1H, d, J=1.5 Hz) , 7.49 (1Н, d, J=8.9 Hz), 7.37 - 7.23 (1Н, m), 7.20 (1Н, dd, J=8.4, 1.6 Hz), 5.95 (1Н, d, J=7.0 Hz), 5.28 ( 1Н, d, J=4.1 Hz), 4.46 - 4.27 (1Н, m), 4.17 - 3.98 (2Н, m), 2.75 - 2.56 (3Н, m), 2.57 - 2.53 (1Н, m), 2.36 (3Н, s), 2.19 (3Н, s), 1.29 (3Н, d, J=5.5 Hz).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=6.95 min, >99% diastereomeric excess at 254 nm.

(5S)-1 -(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -(2-hydroxypropyl)-1Нbenzo[d]umidazol-2-yl)pyrroludin -2-one (diastereoisomer 2)

mmol) was added to a solution of (5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2DBU (0.085 ml, 0.564 hydroxypropyl)-1H-benzo[d]imidazol-2-yl) pyrrolidin-2-one - diastereoisomer 2 (100 mg, 0.282

- 155 041318 mmol) in MeCN (2.5 ml, 47.9 mmol), DCM (0.25 ml, 3.89 mmol) and the mixture was stirred for 10 min. CuTMEDA (13.10 mg, 0.028 mmol) was added, the mixture was stirred for 10 min, (3,4difluorophenyl)boronic acid (49.0 mg, 0.310 mmol) was added, and the reaction mixture was stirred at 35°C for 20 h. Additional CuTMEDA ( 13.10 mg, 0.028 mmol) and (3,4difluorophenyl)boronic acid (49.0 mg, 0.310 mmol) and the mixture was stirred for another 5 h. The mixture was concentrated on loose silica gel. The silicate was purified by flash chromatography on a Companion (12 g column, 0-4% MeOH/DCM followed by 4 g column, 100% EtOAc) to give (5S)-1-(3,4-difluorophenyl) -5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-hydroxypropyl)-1 Hbenzo[d]imidazol-2-yl)pyrrolidin-2-one (diastereoisomer 2) (22 mg, 16%) as a colorless solid; temp. beats 1.81 min; m/z 467 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.78 (1H, ddd, J=13.2, 7.4, 2.5 Hz), 7.66 (1H, dd, J=8.4, 0.7 Hz), 7.59 (1H, dd, J= 1.6, 0.6 Hz), 7.41 - 7.22 (2H, m), 7.19 (1H, dd, J=8.3, 1.6 Hz), 5.96 (1H, dd, J=8.2, 2.2 Hz), 5.20 (1H, d, J =4.5 Hz), 4.35 - 4.21 (2H, m), 4.13 - 3.97 (1H, m), 2.83 - 2.72 (1H, m), 2.63 - 2.51 (2H, m), 2.36 (3H, s), 2.28 - 2.20 (1H, m), 2.19 (3H, s), 1.22 (3H, d, J=6.3 Hz).

Chiral HPLC (Lab. 1 Zone 4, Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=6.39 min, >99% diastereomeric excess at 254 nm.

General Pathway B: A convergent approach to the preparation of γ-lactam analogs from N-arylpyroglutamic acid.

Example 109 (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3ethoxycyclopentyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one.

4-(3,5-Dimethylisoxazol-4-yl)-N-(trans-(1r,3r)-3-ethoxycyclopentyl)-2-nitroaniline

OH OEt

0 me \ Χ^ ^Me \ Χ^

BA BA

me me

4-(3,5-dimethylisoxazol-4-yl)-N-trans-((1r,3r)-3-ethoxycyclopentyl)-2-nitroaniline (0.417 g, 1.159 mmol, 73.6% yield) is dissolved in dry THF (9.94 ml, 121 mmol). The solution was cooled to 0°C, then 18-crown-6 (0.458 g, 1.733 mmol) in dry THF (9.94 ml, 121 mmol) was added, followed by NaH (0.069 g, 1.733 mmol). After 15 min stirring, ethyl iodide (0.140 ml, 1.733 mmol) is added. The reaction mixture was stirred overnight at rt, then saturated ammonium chloride (10 ml) was added followed by DCM (2x5 ml), the mixture was shaken in a separating funnel. The organic layer was then filtered through a PhaseSep© cartridge then concentrated to give an orange oil which was purified by flash chromatography (24 g, DCM/MeOH: 100/0 to 95/5) to give 4(3. 5-Dimethylisoxazol-4-yl)-N-trans-((1r,3r)-3-ethoxycyclopentyl)-2-nitroaniline (0.417 g, 74% yield) was isolated as an orange oil; temp. beats 2.58 min (method 1), m/z 346 (M+H) ⁺ (electrospray ⁺ ).

4-(3,5-dimethylisoxazol-4-yl)-N ¹ -(trans-(1r,3r)-3-ethoxycyclopentyl)benzene-1,2-diamine

4-(3,5-dimethylisoxazol-4-yl)-N-(trans-(1r,3r)-3-ethoxycyclopentyl)-2-nitroaniline (0.417 g, 1.207 mmol) and concentrated ammonia (0.752 ml, 19.32 mmol) was dissolved in THF/water (1:1, 23 ml), then sodium dithionite (2.488 g, 12.07 mmol) was added and the reaction mixture was stirred at rt. within 18 hours the Layers were separated, the aqueous layer was extracted with ethyl acetate (2x100 ml). The combined organics were washed with water (50 ml) and brine (50 ml), dried (MgSO ₄ ), filtered and evaporated in vacuo to give 4-(3,5-dimethylisoxazol-4-yl)-X1-( trans(1r,3r)-3-ethoxycyclopentyl)benzene-1,2-diamine (0.31 g, 80%) as a pink solid; temp. beats 1.64 min (method 1), m/z 316 (M+H) ⁺ (electrospray ⁺ ).

(S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxylic acid

- 156 041318

DBU (2.4 ml, 15.92 mmol) was added to a suspension of (S)-5-oxopyrrolidine-2-carboxylic acid (1.0 g, 7.75 mmol) in acetonitrile (15 ml), then stirred for 10 min at room temperature. CuTMEDA (100 mg, 0.215 mmol) was added, then the mixture was stirred for another 10 min. (3,4-difluorophenyl)boronic acid (1.25 g, 7.92 mmol) was added, then the mixture was heated to 50°C for 18 h. CuTMEDA (100 mg, 0.215 mmol) was added, then the mixture was stirred for another 18 h (reaction A). DBU (20 ml, 133 mmol) was then added to a suspension of (S)-5-oxopyrrolidine-2-carboxylic acid (8.0 g, 62.0 mmol) in acetonitrile (15 ml), then stirred for 10 min at room temperature. CuTMEDA (1.5 g, 3.23 mmol) was added, then the mixture was stirred for another 10 min.

(3,4-Difluorophenyl)boronic acid (10.0 g, 63.3 mmol) was added, then the mixture was heated to 50°C for 18 h (reaction B). The mixture of reaction A was combined with reaction B, then concentrated under reduced pressure. The residue was diluted with water (200 ml) then extracted with diethyl ether (2x200 ml). The aqueous layer was treated with 1 M aqueous hydrochloride solution (200 ml, 200 mmol), then extracted with ethyl acetate (3x200 ml). The combined organic phases were concentrated on loose silica gel. The silicate was purified on a silica gel filter plug eluting with EtOAc/dichloromethane (0-100%) to give, after long rotary evaporation, (S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine- 2-carboxylic acid (2.8 g, 16%) as a pale yellow glass; temp. beats 1.41 min (method 1), m/z 242 (M+H) + (electrospray ⁺ ).

(S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((trans-(1r,3r)-3ethoxycyclopentyl)amino)phenyl)- 5-oxopyrrolidine-2-carboxamide

DIPEA (0.208 ml, 1.189 mmol) was added to a solution of 4-(3,5-dimethylisoxazol-4-yl)-1H-(trans(1r,3r)-3-ethoxycyclopentyl)benzene-1,2-diamine (0.15 g, 0.476 mmol), (S)-1-(3,4-difluorophenyl)-5oxopyrrolidine-2-carboxylic acid (0.126 g, 0.523 mmol) and HATU (0.235 g, 0.618 mmol) in DMF (1.583 ml, 20.45 mmol). The brown solution was stirred at rt. for 3 h, then the mixture was partitioned between ethyl acetate (100 ml) and water (100 ml), after which the layers were separated. The organic phase was washed with water (3x100 ml) and brine (100 ml), then concentrated in vacuo to give a crude brown oil (340 mg) which was purified by flash chromatography on a Companion (4 g, 0-10% MeOH /DCM), resulting in (S)-1-(3,4-difluorophenyl)-N-(5(3,5-dimethylisooxazol-4-yl)-2-(((1R,3R)-3- ethoxycyclopentyl)amino)phenyl)-5-oxopyrroludin-2carboxamide (0.238 g, 91%) was obtained as a colorless foam; temp. beats 2.24 min (method 1), m/z 539 (M+H) + (electrospray ⁺ ).

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-ethoxycyclopentyl)1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one

(S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisooxazol-4-yl)-2-((trans-(1r,3r)-3ethoxycyclopentyl)amino)phenyl)- 5-oxopyrrolidine-2-carboxamide (0.238 g, 0.442 mmol) was dissolved in acetic acid (1.771 ml, 30.9 mmol) and stirred at 70°С for 15 h. After 15 h, the reaction mixture was cooled to RT and concentrated under vacuum, in resulting in brown

- 157 041318 oil which was purified by flash chromatography on a Companion (4 g, DCM/MeOH: 100/0 to 90/10). Fractions containing the desired product with impurities were pooled (150 mg) and purified again on a 12 g column using the same conditions as used with another solvent system (12 g, DCM/AcOEt: 100/0 to 0/100), as a result which gave a brown solid (69 mg). Final purification by flash chromatography on Companion (4 g, DCM/AcOEt: 100/0 to 0/100) gave (S)-1-(3,4-difluorophenyl)-5-(5-(3,5- dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-ethoxycyclopentyl)1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (14 mg, 6%) as a beige solid substances; temp. beats 2.25 min (method 1), m/z 521 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.80 (tdd, J=13.7, 7.4, 2.6 Hz, 1H), 7.66 - 7.57 (m, 2H), 7.42 -7.33 (m, 1H), 7.28 7.19 (m , 1H), 7.19 - 7.15 (m, 1H), 6.20 - 6.04 (dd, 1H), 5.25 - 5.10 (m, 1H), 4.33 - 4.19 (m, 1H), 3.54 - 3.44 (m, 2H), 2.79 - 2.52 (m, 3H), 2.43 - 2.27 (m, 5H), 2.26 - 2.02 (m, 7H), 1.89 - 1.75 (m, 1H), 1.17 (t, J=7.0 Hz, 3H).

Example 116 5-(2-((5)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)1 H-benzo[ d]imidazol-1 -yl)piperidin-2-one (2S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)2-((2-oxo-piperidine -4-yl)amino)phenyl)-5-oxopyrrolidine-2-carboxamide (intermediate D14)

DIPEA (288 µl, 1.649 mmol) was added to the solution

4-((2-amino-4-(3,5-dimethylisoxazol-4 yl)phenyl)amino)piperidin-2-one (198 mg, 0.660 mmol), (S)-1-(3,4-difluorophenyl) -5-oxopyrrolidine-2-carboxylic acid (175 mg, 0.726 mmol) and HATU (326 mg, 0.857 mmol) in DMF (2196 µl, 28.4 mmol). The green solution was stirred at rt. for 15 h, then divided between ethyl acetate (100 ml) and water (100 ml), after which the layers were separated. The organic phase was then washed with brine (100 ml) and concentrated in vacuo to give a crude oil. Purification by flash chromatography on a Companion device (12 g, 0-10% MeOH/DCM) gave (2S)-1-(3,4difluorophenyl)-N-(5-(3,5-dimethylusoxazol-4-yl)-2 -((2-oxopuperidin-4-yl)amino)phenyl)-5oxopyrrolidine-2-carboxamide - intermediate D14 (0.356 g, 93%) as a colorless oil; temp. beats 1.68 min (method 1), m/z 524 (M+H) ⁺ (electrospray ⁺ ).

5-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-1 -yl)piperidine-2-one

Intermediate D14 (0.191 g, 0.317 mmol) was dissolved in acetic acid (1.27 ml,

22.22 mmol) and heated at 90°С. The reaction mixture was concentrated in vacuo and TFA (1.71 ml, 22.22 mmol) was added. The mixture was heated at 70°C for 15 h, the mixture was cooled to RT and concentrated under vacuum/pre-adsorbed on silica gel. Flash chromatography on Companion (4 g, DCM/MeOH: 100/0 to 90/10) gave 5-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin2-yl) -5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)piperidin-2-one (31 mg, 19%) as a pink solid; temp. beats 1.64 min (method 1), m/z 506 (M+H) ⁺ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.92 (d, J=8.5 Hz, 1H), 7.83 (ddd, 1H), 7.80 - 7.75 (m, 1H), 7.64 -7.58 (m, 1H), 7.36 ( dt, J=10.5, 9.1 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.17 (dd, J=8.5, 1.7 Hz, 1H), 6.15 (d, J=7.4 Hz, 1H), 5.06-4.95 (m, 1H), 3.91 (t, J=11.1 Hz, 1H), 3.44-3.35 (m, 1H), 2.90 - 2.73 (m, 1H), 2.73 - 2.62 (m, 1H), 2.62 - 2.49 (m , 1H), 2.48 - 2.38 (m, 1H), 2.36 (s, 3H), 2.19 (s, 3H), 2.13 - 1.98 (m, 2H).

Example 117: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]umidazol-2yl)pyrrolidin-2-one.

- 158 041318 (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]umidazol-2-yl)pyrrolidin2-one

Intermediate D14 (356 mg, 0.612 mmol) was dissolved in acetic acid (2.725 mL, 47.6 mmol) and heated at 90°C for 4 h. The reaction mixture was concentrated in vacuo and TFA (3.67 mL, 47.6 mmol) was added. The mixture was heated at 70° C. for 15 h, then cooled to RT and concentrated in vacuo. The resulting black oil was purified by flash chromatography on a Companion (4 g, DCM/MeOH: 100/0 to 90/10) to give (S)-1-(3,4difluorophenyl)-5-(5-( 3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (112 mg, 39%) was isolated as a beige solid; temp. beats 1.70 min (method 1), m/z 409 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.79 (ddd, J=13.1, 7.4, 2.6 Hz, 1H), 7.62 (dd, J=8.3, 0.7 Hz, 1H), 7.53 (d, J=1.7 Hz , 1H), 7.44 - 7.32 (m, 1H), 7.29 - 7.25 (m, 1H), 7.19 (dd, J=8.3, 1.6 Hz, 1H), 5.74 (d, 1H), 2.85 - 2.75 (m, 1H ), 2.73 - 2.62 (m, 1H), 2.61 - 2.48 (m, 1H), 2.37 (s, 3H), 2.23 - 2.14 (m + s, 4H).

Example 124: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 r,3 S)-3 hydroxycyclobutyl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one and Example 125: (1S,3r)-3-(2-((S)-1-(3,4difluorophenyl)-5-oxopyrrolidin-2- yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1yl)cyclobutyl acetate.

(S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethyluzoxazol-4-yl)-2-(((1r,3S)-3hydroxycyclobutyl)amino)phenyl)-5- oxopyrrolidine-2-carboxamide

TEA (765 μl, 5.49 mmol) was added to a solution of intermediate C17 (500 mg, 1.829 mmol), (S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxylic acid (485 mg, 2.012 mmol ) and HATU (765 mg, 2.012 mmol) in DMF (5 ml), then stirred at rt. within 48 hours. Most of the DMF was removed under vacuum. The fluffy residue was diluted with water (10 ml) then extracted with dichloromethane (30 ml). The organic phase was washed with water (10 ml), then passed through a phase separation cartridge and concentrated in vacuo. The residue was purified by chromatography (24 g silica gel, 010% methanol in DCM, gradient elution) to give (S)-1-(3,4-difluorophenyl)-N(5-(3,5-dimethylisoxazol-4-yl )-2-((( 1 r,3S))-3-hydroxycyclobutyl)amino)phenyl)-5-oxopyrrolidine-2carboxamide (500 mg, 55%) as a pale brown solid; temp. beats 1.79 min; m/z 497 (M+H) ⁺ (electrospray ⁺ ).

(S)-1 -(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1r,3S)-3-hydroxycyclobutyl)-1Hbenzo[d] imidazol-2-yl)pyrrolidin-2-one

- 159 041318 (S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,3S)-3hydroxycyclobutyl)amino)phenyl) -5-oxopyrrolidine-2-carboxamide (100 mg, 0.201 mmol) was dissolved in acetic acid (1 ml) and stirred at 80°С for 18 h. The reaction mixture was cooled to RT and the solvent was removed under vacuum. The residue was purified by chromatography (12 g silica gel, 0-10% methanol in DCM, gradient elution). Product containing fractions were combined and concentrated in vacuo to give ((S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4yl)-1-((1r,3S )-3-Hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (41 mg, 41%) as a light beige solid, sp temp 1.79 min (method 1), m/z 479 (M+H)+ (electrospray ⁺ );

Ή-NMR (d ₆ -DMSO) δ: 7.86 - 7.74 (m, 2H), 7.60 (d, J=1.6 Hz, 1H), 7.43 - 7.30 (m, 1H), 7.20 (dt, J=9.1, 2.0 Hz, 2H), 6.04 - 5.96 (m, 1H), 5.49 (p, J=8.6 Hz, 1H), 5.37 (d, J=3.9 Hz, 1H), 4.61 (s, 1H), 3.08 (dtd, J =36.6, 15.0, 14.1, 6.5 Hz, 2H), 2.74 - 2.52 (m, 3H), 2.46 (m, 1H), 2.36 (s, 3H), 2.19 (s, 3H), 2.11 -1.96 (m, 2H ).

Fractions containing acetate were combined and concentrated in vacuo to give (1S,3r)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)- 5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-1-yl)cyclobutyl acetate (27 mg, 24%) as; temp. beats 2.11 min (method 1), m/z 521 (M+H) ⁺ (electrospray ⁺ );

Ή-NMR (d ₆ -DMSO) δ: 7.92 (d, J=8.4 Hz, 1H), 7.83 (ddd, J=13.2, 7.5, 2.7 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H) , 7.37 (dt, J=10.6, 9.1 Hz, 1H), 7.22 (dd, J=8.5, 1.7 Hz, 2H), 6.03 (d, J=7.1 Hz, 1H), 5.51 (p, J=8.7 Hz, 1H), 5.34 (t, J=7.3 Hz, 1H), 3.44 - 3.14 (m, 3H), 2.76 - 2.51 (m, 4H), 2.37 (s, 3H), 2.20 (s, 3H), 2.13 (s , 3Н), 2.07 (m, 1H).

General Pathway C: An Approach to the Preparation of γ-Lactam Analogues by Reductive Amination

Example 126: (S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidine -2-he.

5-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline

From a vessel with a mixture of potassium carbonate (14.33 g, 104 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (7.31 g, 51.8 mmol) and 5-bromo-2-nitroaniline (7.5 g, 34.6 mmol) in mixtures of 1,4-dioxane:water (4:1, 150 ml) were evacuated to atmosphere and then filled with nitrogen three times. PdCl ₂ (dppf) (1.770 g, 2.419 mmol) was added, then the mixture was heated to 90° C. under nitrogen for 16 h. The reaction mixture was cooled to RT, then diluted with water (50 ml) and extracted with ethyl acetate (2x45 ml). The combined organics were dried (MgSO ₄ ), filtered and evaporated under reduced pressure. The crude product was dissolved in DCM and passed through a pad of silica gel (~2 cm thick) to give a yellow solid which was triturated with Et ₂ O (2x100 mL). The resulting solid was filtered, rinsing with diethyl ether-Et ₂ O (50 mL) and dried under vacuum to give 5-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline (6.64 g, 79%) in as a yellow solid; temp. beats 1.88 min (method 1), m/z 234 (M+H) ⁺ (electrospray ⁺ ).

(S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carbonyl chloride

To a suspension of (S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxylic acid (1.45 g, 6 mmol) in anhydrous THF (5 ml, 61.0 mmol) cooled to 0°C was added drops of thionyl chloride (0.482 ml, 6.60 mmol). The resulting solution was stirred for 6 h at room temperature and the solvent was evaporated in vacuo to give crude (S)-1-(3,4-difluorophenyl)-5oxopyrrolidine-2-carbonyl chloride (1.6 g, 51%), which was used without further purification.

(S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-5-oxopyrrolidine-2carboxamide

(S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carbonyl chloride (779 mg, 3 mmol) in DCM (7 ml, 109

- 160 041318 mmol) was added to a solution of 5-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline (636 mg, 2.73 mmol) in DCM (7 ml, 109 mmol) at 0°C, then stirred at room temperature temperature for 18 h. The mixture was diluted with water (20 ml), then was extracted with ethyl acetate (3x30 ml). The combined organic phases were washed with 1M HCl (10 ml), saturated aqueous NaHCO ₃ (10 ml) and brine (10 ml), then dried (MgSO ₄ ), filtered and concentrated to give a brown oil. The crude product was purified by flash chromatography (40 g column, 0100% EtOAc/isohexane) to give (S)-1-(3,4-difluorophenyl)-N-(5-(3,5dimethylisoxazol-4-yl) -2-nitrophenyl)-5-oxopyrrolidine-2-carboxamide (425 mg, 32%) as a yellow solid; temp. beats 1.13 min (method 1), m/z 427 (M+H) + (electrospray ⁺ ).

(S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2carboxamide

Suspension of (S)-1-(3,4-difluorophenyl)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-5oxopyrrolidine-2-carboxamide (420 mg, 0.920 mmol) and 5% Pt/Al ₂ O ₃ - 5R94 (42 mg, 10.76 µmol) in ethanol (25 ml, 428 mmol) was stirred in a hydrogen atmosphere at a pressure of 2 bar at room temperature for 24 h. The white suspension was diluted with tetrahydrofuran (10 ml) and then filtered through celite©, washing with ethanol (50 ml) and THF (20 ml) and the solvent was removed under reduced pressure. The resulting yellow solid was dissolved in ethanol (25 ml, 428 mmol) and THF (5 ml) and 5% Pt/Al ₂ O ₃ -5R94 (42 mg, 10.76 μmol) was added at a hydrogen pressure of 2 bar at room temperature for another 3 hours. The reaction mixture was filtered through celite©, washing with ethanol (50 ml) and THF (20 ml) and the solvent was removed under reduced pressure, resulting in (S)-N-(2amino-5-(3,5-dimethylisoxazole -4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2-carboxamide (386 mg, 89%) as a yellow solid; temp. beats 1.13 min (method 1), m/z 427 (M+H) + (electrospray ⁺ ).

(S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidin-2- He

To a mixture of (S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5oxopyrrolidine-2-carboxamide (30 mg, 0.070 mmol ) and DCM (1 mL, 15.54 mmol), benzaldehyde (9.30 μL, 0.091 mmol) and acetic acid (0.5 mL, 8.73 mmol) were added. The mixture was stirred at room temperature for 20 min, then pyridine-borane (0.015 mL, 0.141 mmol) was added. The mixture was stirred at room temperature for 1 h, then a few drops of concentrated HCl were added and the mixture was stirred at 80°C for 1 h. Additional acetic acid (0.5 ml, 8.73 mmol) was added and stirred at rt. during the night. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12 g column, 0-5% MeOH/DCM) to give ((S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)- 1Hbenzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one (15 mg, 41%) as dark brown solid, sp temp 2.26 min (method 1) , m/z 499 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.69 - 7.57 (m, 3H), 7.41 - 7.30 (m, 3H), 7.31 - 7.16 (m, 4H), 7.10 - 6.97 (m, 1H), 5.95 - 5.83 (m, 1H), 5.73 (d, J=16.6 Hz, 1H), 5.63 (d, J=16.6 Hz, 1H), 2.80 - 2.66 (m, 2H), 2.49 - 2.42 (m, 1H), 2.38 (s, 3H), 2.21 (s, 3H), 1.90–1.79 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH in isohexane (0.2% TFA)): 156281, temp. beats=5.65 min, >99% ee at 254 nm.

Example 127: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-propyl-1Hbenzo[d]imidazol-2-yl)pyrrolidin- 2nd.

- 161 041318 (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-propyl-1H-benzo[d]imidazol-2yl)pyrrolidin- 2nd

Me

To a solution of (S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5oxopyrrolidine-2-carboxamide (50 mg, 0.117 mmol ) in THF (2 mL, 24.41 mmol) was added propionaldehyde (11.00 μL, 0.152 mmol) and stirred at room temperature. for 1 h. Then sodium triacetoxyborohydride (39.8 mg, 0.188 mmol) was added and stirred at rt. over 4 h. Additional propionaldehyde (3 μl) was added and the mixture was stirred for another 3 h. The reaction mixture was diluted with methanol (MeOH) and loaded onto a solid phase cation exchanger column (2 g) in MeOH. The column was washed with methanol (MeOH) and then the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to give product IV as a yellow residue (82 mg). The yellow residue was heated to 80° C. in acetic acid (2 mL, 34.9 mmol) for 18 h. C18, 5 µm, 19x50 mm, 35-65% MeCN in water), resulting in (8)-1-(3,4-difluorophenyl)-5-(5-(3,5dimethylisoxazol-4-yl)- 1-propyl-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (10 mg, 18%) as dark brown solid; temp. beats 2.10 min (method 1), m/z 451 (M+H)+ (electrospray ⁺ );

¹ H-NMR (06-DMSO) δ: 7.76 (1H, ddd, J=13.0, 7.4, 2.6 Hz), 7.71 - 7.64 (1H, m), 7.59 (1H, dd, J=1.6, 0.6 Hz), 7.37 (1H, dt, J=10.6, 9.1 Hz), 7.24 - 7.14 (2H, m), 6.03 - 5.95 (1H, m), 4.35 (1H, dt, J=14.8, 7.4 Hz), 4.25 (1H, dt, J=14.8, 7.6 Hz), 2.88 - 2.73 (1H, m), 2.70 - 2.52 (2H, m), 2.36 (3H, s), 2.19 (3H, s), 2.08 (1H, t, J= 10.6 Hz), 1.78 (2Н, q, J=7.4 Hz), 0.95 (3H, t, J=7.4 Hz).

Example 128: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1Hbenzo[d]imidazol-2-yl)pyrrolidin- 2nd.

(S)-1 -(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1 H-benzo[d]imidazol-2yl)pyrrolidin-2- He

Me

(S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5-oxon-pyrrolidine-2carboxamide (100 mg, 0.235 mmol) and isobutyraldehyde (0.025 ml, 0.469 mmol) in THF (2 ml, 24.41 mmol) at RT acetic acid (0.013 ml, 0.235 mmol) was added and stirred at room temperature. for 1 h. Then sodium triacetoxyborohydride (80 mg, 0.375 mmol) was added and stirred at room temperature. for 4 hours. The reaction mixture was diluted with methanol (MeOH) and loaded onto a column of solid phase cation exchanger (2 g) in MeOH. The column was washed with methanol (MeOH) and then the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to give a yellow residue which was heated to 80°C in acetic acid (2 ml, 34.9 mmol) for 18 h. The reaction mixture was concentrated, the crude product was purified by preparative HPLC (Acquity, acid conditions (0.1 % formic acid), Waters X-Select Prep-C18 column, 5 µm, 19x50 mm, 3565% MeCN in water), resulting in (8)-1-(3,4-difluorophenyl)-5-(5- (3,5-dimethylisoxazol-4yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)-pyrrolidin-2-one (10 mg, 9%) as a dark brown solid; temp. beats 2.21 min (method 1), m/z 465 (M+H) + (electrospray ⁺ );

1H-NMR (d6-DMSO) δ: 7.76 - 7.65 (m, 2H), 7.61 (d, J=1.6 Hz, 1H), 7.44 - 7.30 (m, 1H), 7.24 - 7.14 (m, 2H), 5.99 - 5.92 (m, 1H), 4.24 (dd, J=14.6, 7.2 Hz, 1H), 4.08 (dd, J=14.5, 8.2 Hz, 1H), 2.80 (dd, J=16.5, 9.0 Hz, 1H), 2.70 - 2.53 (m, 2H), 2.38 (s, 3H), 2.33 (p, J=1.9 Hz, 1H), 2.21 (s, 3H), 2.13 - 2.05 (m, 1H), 0.96 (d, J= 6.6 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. beats=13.2 min, >99% ee

- 162 041318 at 254 nm.

Example 129: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(3-methoxypropyl)-1Hbenzo[d]imidazol-2- yl) pyrrolidin-2-one.

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(3-methoxypropyl)-1Hbenzo[d]imidazol-2-yl)pyrrolidine -2-he

Meo

To a solution of (S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5oxopyrrolidine-2-carboxamide (100 mg, 0.235 mmol ) in THF (2 mL, 24.41 mmol) was added 3-methoxypropanal (31.0 mg, 0.352 mmol) and stirred at room temperature. for 1 h. Then sodium triacetoxyborohydride (80 mg, 0.375 mmol) was added and stirred at room temperature. for 4 hours. The reaction mixture was diluted with methanol (MeOH) and loaded onto a column of solid phase cation exchanger (2 g) in MeOH. The column was washed with methanol (MeOH) and then the product was eluted with 0.7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to give a yellow residue (82 mg) which was heated to 80° C. in acetic acid (2 ml, 34.9 mmol) for 18 h. The reaction mixture was concentrated, the crude product was purified by preparative HPLC (Acquity, acidic conditions (0.1% formic acid), Waters X-Select Prep-C18 column, 5 µm, 19x50 mm, 35-65% MeCN in water), resulting in (8)-1-(3,4-difluorophenyl) -5-(5-(3,5-dimethylisoxazol-4-yl)-1-(3methoxypropyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (8 mg, 7%) as dark brown solid; temp. beats 2.00 min (method 1), m/z 481 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.76 (ddd, J=13.2, 7.4, 2.6 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.42 - 7.31 (m, 1H), 7.27 - 7.14 ( m, 1H), 5.93 (dd, J=8.4, 2.0 Hz, 1H), 4.44 (dt, J=14.5, 7.2 Hz, 1H), 4.33 (dt, J=14.9, 7.4 Hz, 1H), 3.39 (t , J=6.0 Hz, 2H), 3.26 (s, 3H), 2.82 - 2.53 (m, 3H), 2.37 (s, 3H), 2.35 - 2.31 (m, 1H), 2.20 (s, 3H), 2.16 - 2.08 (m, 1H), 2.02 (t, J=6.6 Hz, 2H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. beats=7.65 min, >99% ee at 254 nm.

Example 130: (S)-5-(1-((4,4-difluorocyclohexyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)-1- (3,4-difluorophenyl)pyrrolidin-2-one.

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-5-oxopyrrolidine-2-carboxamide

o (S)-5-oxopyrrolidine-2-carbonyl chloride (0.940 g, 6.37 mmol) in DCM (7 ml, 109 mmol) was added to a solution of 5-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline (1.35 g, 5.79 mmol) in DCM (7 ml, 109 mmol) at 0°C, then stirred at room temperature overnight. The mixture was diluted with water (20 ml) then extracted with ethyl acetate (3x30 ml). The combined organic phases were washed with aqueous 1M HCl (10 ml), saturated aqueous NaHCO ₃ (10 ml) and brine (10 ml), then dried (MgSO ₄ ), filtered and concentrated to give a brown oil which purified by silica gel chromatography (40 g column, 0-100% EtOAc/isohexane) to give (S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-5oxopyrrolidine- 2-carboxamide (1.25 g, 62%) as a yellow solid; temp. beats 1.53 min (method 1), m/z 345 (M+H) + (electrospray ⁺ ).

(S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide

Suspension of (S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)-5-oxopyrrolidine-2carboxamide (550 mg, 1.597 mmol) and 5% Pt/Al ₂ O ₃ - 5R94 (55 mg, 0.014 mmol) in ethanol (30 ml, 514

- 163 041318 mmol) was stirred under a hydrogen pressure of 2 bar at room temperature for 20 hours.

The reaction mixture was filtered through Celite©, washing with ethanol (50 ml) and the solvent was removed under reduced pressure to give (S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl )5-oxopyrrolidine-2-carboxamide (540 mg, 100% yield) as a yellow solid; temp. beats 1.14 min (method 1), m/z 315 (M+H) + (electrospray ⁺ ).

(S)-5-(1-((4,4-difluorocyclohexyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one

F

4,4-Difluorocyclohexanecarbaldehyde (70.5 mg, 0.476 mmol) was added to a solution of (S)-N-(2-amino-5(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide (125 mg, 0.366 mmol) in DCM (4 ml, 62.2 mmol) at rt. and stirred for 20 min. Then acetic acid (2 ml, 34.9 mmol) was added and stirred at rt. for another 20 min, then pyridine-borane (0.078 ml, 0.732 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then a few drops of concentrated HCl were added and the mixture was stirred at 80° C. for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12 g column, 0-5% (0.7 M Ammonia/MeOH)/DCM) to give (S)-5-(1((4,4-difluorocyclohexyl)methyl)-5 -(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin2-one (45 mg, 27%) as a yellow solid; temp. beats 1.70 min (method 1), m/z 429 (M+H) ⁺ (electrospray ⁺ ).

(S)-5-(1-((4,4-difluorocyclohexyl)methyl)-5-(3,5-dimethyluzoxazol-4-ul)-1H-benzo[d]imidazol-2yl)-1 -(3, 4-difluorophenyl)pyrrolidin-2-one

DBU (0.024 ml, 0.158 mmol) was added to a solution of (8)-5-(1-((4,4-difluorocyclohexyl)methyl)-5-(3,5dimethylisoxazol-4-yl)-1H-benzo[d]imudazole -2-yl)pyrrolidin-2-one (45 mg, 0.105 mmol) in MeCN (1.5 ml, 28.7 mmol) and stirred at room temperature. within 10 min. CuTMEDA (9.76 mg, 0.021 mmol) was added, sonicated and stirred for another 10 min. Then (3,4difluorophenyl)boronic acid (24.88 mg, 0.158 mmol) was added and the reaction mixture was stirred at 35°C for 24 h. The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (12 g column, 0- 10% MeOH/DCM) to give (S)-5-(1-((4,4-difluorocyclohexyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d ]imidazol2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one (28 mg, 49%) as a dark brown solid; temp. beats 2.30 min (method 1), m/z 541 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.76 - 7.64 (2H, m), 7.61 (1H, d, J=1.5 Hz), 7.38 (1H, dt, J=10.7, 9.1 Hz), 7.28 7.08 ( 2Н, m), 5.96 (1H, dd, J=8.3, 2.0 Hz), 4.33 (1H, dd, J=14.6, 7.2 Hz), 4.19 (1H, dd, J=14.7, 8.0 Hz), 2.88 2.75 ( 1H, m), 2.71 - 2.51 (2H, m), 2.37 (3H, s), 2.20 (3H, s), 2.06 - 1.91 (4H, m), 1.85 - 1.61 (3H, m), 1.56 - 1.33 ( 3H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH in isohexane (0.2% TFA)): 156287, temp. beats=6.65 min, >99% ee at 254 nm.

Example 131: (S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro4-methoxyphenyl) pyrrolidin-2-one; (S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol2-yl)pyrrolidin-2-one

- 164 041318

To a mixture of (S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide (50 mg, 0.146 mmol) in DCM (2 ml, 31.1 mmol), benzaldehyde (0.019 mL, 0.190 mmol) and acetic acid (1 mL, 17.47 mmol) were added. The mixture was stirred at room temperature for 20 min, then pyridine-borane (0.031 mL, 0.293 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with methanol (MeOH) (2 ml) and loaded onto a solid phase cation exchanger column (1.5 g). The column was washed with methanol (MeOH) and then the product was eluted with 7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to give a yellow oil which was dissolved in acetic acid (1 mL, 17.47 mmol) and heated to 80° C. for 1 h. The crude product was loaded onto a solid phase cation exchanger column (1 g) in MeOH. The column was washed with methanol (MeOH) and then the product was eluted with 7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to give the crude product as a pink solid. The crude product was purified by silica gel flash chromatography (4 g column, 0-8% (0.7 M Ammonia/MeOH)/DCM) to give (S)-5-(1-benzyl-5-(3,5dimethylisoxazol- 4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (22 mg, 35%) as a colorless solid, 90% pure.

(S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4methoxyphenyl)pyrrolidin-2 -He

DBU (0.012 mL, 0.077 mmol) was added to a solution of (S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)1H-benzo[d]imidazol-2-yl)pyrrolidin-2 -one (22 mg, 0.051 mmol) in MeCN (1.5 mL, 28.7 mmol) and stirred for 10 min at room temperature. CuTMEDA (4.76 mg, 10.25 µmol) was added, sonicated and stirred for another 10 min. Then (3-fluoro-4-methoxyphenyl)boronic acid (13.06 mg, 0.077 mmol) was added and the reaction mixture was stirred at 35°C for 24 h. The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (12 g column , 0-10% MeOH/DCM), resulting in (S)-5-(1-benzyl-5-(3,5dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)- 1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one (10 mg, 37%) as a colorless solid; temp. beats 2.14 min (method 1), m/z 511 (M+H)+ (electrospray ⁺ );

¹ H-NMR (de-DMSO) δ: 7.64 (1H, dd, J=1.7, 0.7 Hz), 7.62 (1H, dd, J=8.4, 0.7 Hz), 7.46 -7.39 (1H, m), 7.38 - 7.28 (3H, m), 7.20 (1H, dd, J=8.3, 1.6 Hz), 7.18 - 7.13 (2H, m), 6.99 - 6.89 (2H, m), 5.88 - 5.81 (1H, m), 5.68 ( 1H, d, J=16.5 Hz), 5.61 (1H, d, J=16.5 Hz), 3.74 (3H, s), 2.77 - 2.65 (1H, m), 2.45 (2H, dd, J=12.3, 8.1 Hz ), 2.37 (3H, s), 2.20 (3H, s), 1.90–1.81 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. beats=14.1 min, 97% ee at 254 nm.

Example 132: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(pyridin-3-ylmethyl)-1Hbenzo[d]imidazol- 2-yl)pyrrolidin-2-one.

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(pyridin-3-ylmethyl)-1Hbenzo[d]imidazol-2-yl )pyrrolidin-2-one

- 165 041318

To a mixture of (S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5oxopyrrolidine-2-carboxamide (40 mg, 0.094 mmol ) and DCM (1 ml, 15.54 mmol) were added nicotinaldehyde (0.011 ml, 0.122 mmol) and acetic acid (0.5 ml, 8.73 mmol). The mixture was stirred at room temperature for 20 min, then pyridine-borane (0.020 mL, 0.188 mmol) was added. The mixture was stirred at room temperature for 1 h, then a few drops of concentrated HCl were added and stirring was continued at rt. within 5 min. Then acetic acid (1 ml, 17.47 mmol) was added and the mixture was stirred at 80° C. for 18 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12 g column, 0-5% (0.7 M Ammonia/MeOH)/DCM) to give (S)-1-(3,4-difluorophenyl)-5(5-(3 ,5-dimethylisoxazol-4-yl)-1-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (21 mg, 43%) as a colorless solid; temp. beats 1.66 min (method 1), m/z 500 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 8.58 - 8.47 (2H, m), 7.69 - 7.64 (2H, m), 7.59 (1H, ddd, J=13.0, 7.4, 2.6 Hz), 7.48 (1H, dt , J=8.0, 1.9 Hz), 7.36 (1H, ddd, J=7.9, 4.8, 0.9 Hz), 7.31 - 7.20 (2H, m), 7.12 - 7.03 (1H, m), 5.99 - 5.93 (1H, m ), 5.81 - 5.65 (2H, m), 2.80 - 2.68 (1H, m), 2.55 - 2.52 (1H, m), 2.48 - 2.43 (1H, m), 2.37 (3H, s), 2.20 (3H, s ), 1.91 - 1.81 (1H, m).

Example 133: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)- 1-((1s,3R)-3(hydroxymethyl)cyclobutyl)- 1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one and Example 134: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4- yl)-1-((1r,3S)-3(hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -(3-(hydroxymethyl)cyclobutyl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2-one no

To a mixture of (S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-5-oxopyrrolidine-2-carboxamide (125 mg, 0.366 mmol) in DCM (4 ml, 62.2 mmol), 3-(hydroxymethyl)cyclobutanone (47.6 mg, 0.476 mmol) and acetic acid (2 ml, 34.9 mmol) were added. The mixture was stirred at rt. for 20 min, then pyridine-borane (0.078 mL, 0.732 mmol) was added and stirred at room temperature. for 1 hour Added a few drops of concentrated HCl and stirred the mixture at 80°C for 16 hours the Mixture was concentrated under reduced pressure. The yellow residue was dissolved in MeOH (3 ml), K ₂ CO ₃ (76 mg, 0.549 mmol) was added and stirred at rt. for 48 h, then the mixture was concentrated under vacuum, then diluted between water (10 ml) and EtOAc (3x20 ml). The combined organics were washed with brine (15 ml), dried (MgSO ₄ ) and concentrated in vacuo to give (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(3 -(hydroxymethyl)cyclobutyl)-1Hbenzo[d]imidazol-2-yl)pyrrolidin-2-one (150 mg, 81%) as a 1:1 mixture of diastereoisomers; temp. beats 1.08 min (method 1), m/z 381 (M+H) + (electrospray ⁺ ).

(S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,3R)-3(hydroxylmethyl)cyclobutyl)-1 H- benzo[d]imidazol-2-yl)pyrrolidin-2-one and (S)-1-(3,4-difluorophenyl)-5 (5-(3,5-dimethylisoxazol-4-yl)-1 -(( 1 r,3 S)-3 -(hydroxymethyl)cyclobutyl)-1 H-benzo[d]imidazol-2yl)pyrrolidin-2-one

- 166 041318

DBU (0.083 ml, 0.549 mmol) was added to a solution of (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(3(hydroxymethyl)cyclobutyl)-III-benzo^]imidazol-2 -yl)pyrrolidin-2-one (139 mg, 0.366 mmol) in MeCN (8 mL, 153 mmol) and stirred for 10 min. CuTMEDA (34.0 mg, 0.073 mmol) was added, sonicated and stirred for 10 min, (3,4-difluorophenyl)boronic acid (87 mg, 0.549 mmol) was added and the reaction mixture was stirred at 35°C for 24 h. an additional amount of DBU (0.083 ml, 0.549 mmol), CuTMEDA (34.0 mg, 0.073 mmol) and (3,4difluorophenyl)boronic acid (87 mg, 0.549 mmol) and the reaction mixture was stirred for another 18 h at 35°С. The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (24 g column, 0-5% (0.7 M Ammonia/MeOH)/DCM) to give (S)-1-(3,4-difluorophenyl) -5-(5-(3,5-dimethylisoxazol-4-ul)-1-((1s,3R)-3(hydroxymethyl)cyclobutyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2 -one (20 mg, 11%) as a yellow solid; temp. beats 1.78 min (method 1), m/z 493 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 8.09 (1H, d, J=8.4 Hz), 7.79 (1H, ddd, J=13.2, 7.4, 2.6 Hz), 7.59 (1H, d, J=1.6 Hz ), 7.37 (1H, dt, J=10.5, 9.1 Hz), 7.23 - 7.15 (2Н, m), 6.01 (1H, dd, J=8.2, 2.1 Hz), 5.17 - 5.03 (1H, m), 4.97 ( 1H, t, J=5.1 Hz), 3.55 (2Н, t, J=4.5 Hz), 2.88 - 2.57 (5Н, m), 2.58 - 2.52 (1H, m), 2.49 - 2.39 (2Н, m), 2.37 (3H, s), 2.20 (3H, s), 2.14 - 2.01 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=4.56 min, >99% diastereomeric excess at 254 nm.

The second fraction then gave (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)3-(hydroxymethyl)cyclobutyl) -1H-benzo[d]imidazol-2-ul)pyrrolidin-2-one (15 mg, 8%) as a yellow solid; temp. beats 1.79 min (method 1), m/z 493 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.92 (1H, d, J=8.4 Hz), 7.77 (1H, ddd, J=13.2, 7.4, 2.6 Hz), 7.61 (1H, d, J=1.7 Hz ), 7.36 (1H, dt, J=10.6, 9.2 Hz), 7.26 - 7.15 (2H, m), 6.03 - 5.95 (1H, m), 5.37 - 5.24 (1H, m), 4.79 (1H, t, J =5.2 Hz), 3.65 (2Н, dd, J=6.8, 5.1 Hz), 3.02 - 2.83 (2Н, m), 2.77 - 2.51 (1H, m), 2.65 - 2.60 (3H, m), 2.37 (2Н, s), 2.36 - 2.30 (3H, m), 2.20 (3H, s), 2.08 - 1.96 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=4.72 min, >99% diastereomeric excess at 254 nm.

Example 135: (S)-5-(1-(cyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2yl)-1-(3,4-difluorophenyl) pyrrolidin-2-one.

(S)-5-(1-(cyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidin-2 -He

To a mixture of (S)-N(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5oxopyrrolidine-2-carboxamide (50 mg, 0.117 mmol) and DCM (1 ml, 15.54 mmol), cyclopropanecarbaldehyde (0.011 ml, 0.152 mmol) and acetic acid (0.5 ml, 8.73 mmol) were added. The mixture was stirred at room temperature for 20 min, then pyridine-borane (0.025 mL, 0.235 mmol) was added. The mixture was stirred at room temperature for 1 h, then a few drops of concentrated HCl were added and stirring was continued at rt. within 5 min. Acetic acid (0.5 ml, 8.73 mmol) was added and the mixture was stirred at 80° C. for 18 h. The mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on a Companion (12 g column, 0-5% MeOH/DCM) to give ((S)-5-(1-(cyclopropylmethyl)-5-(3,5dimethylisoxazole-4- yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one (16 mg, 29%) as dark brown solid, SP 2.11 min (method 1), m/z 463 (M+H)+ (electrospray + 167 041318 ⁾ ;

1H-NMR (d6-DMSO) δ: 7.76 (1H, ddd, J=13.1, 7.4, 2.6 Hz), 7.72 (1H, dd, J=8.4, 0.6 Hz), 7.60 (1H, dd, J=1.6, 0.6 Hz), 7.36 (1H, dt, J=10.7, 9.1 Hz), 7.24 - 7.15 (2H, m), 5.97 (1H, dd, J=8.3, 1.9 Hz), 4.33 (1H, dd, J=15.2 , 7.0 Hz), 4.23 (1H, dd, J=15.1, 7.0 Hz), 2.80 (1H, dt, J=16.0, 9.3 Hz), 2.72 - 2.52 (2H, m), 2.37 (3H, s), 2.20 (3H, s), 2.09 (1H, dd, J=12.9, 8.4 Hz), 1.34-1.19 (1H, m), 0.65 - 0.47 (4H, m).

Example 136: (S)-3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxαzol-4-yl)1 H-benzo[ d] imidazol-1-yl)propyl acetate.

(S)-3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-1 -yl) propyl acetate

To a mixture of (S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5oxopyrrolidine-2-carboxamide (40 mg, 0.094 mmol ) and DCM (1 mL, 15.54 mmol), 3-((tert-butyldimethylsilyl)oxy)propanal (0.026 mL, 0.122 mmol) and acetic acid (0.5 mL, 8.73 mmol) were added. The mixture was stirred at room temperature for 20 min, then pyridine-borane (0.020 mL, 0.188 mmol) was added. The mixture was stirred at room temperature for 1 h, then a few drops of concentrated HCl were added and stirring was continued at rt. within 5 min. Then acetic acid (1 ml, 17.47 mmol) was added and the mixture was stirred at 80° C. for 18 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters, acid conditions (0.1% formic acid), Waters X-Select Prep-C18 column, 5 µm, 19x50 mm, 35-65% MeCN in water) to give ((S)- 3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)propyl acetate (4 mg, 8%) as a colorless solid, temp 1.96 min (method 1), m/z 509 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.69 - 7.58 (2H, m), 7.57 (1H, dd, J=1.6, 0.7 Hz), 7.28 (1H, dd, J=8.4, 1.6 Hz), 7.21 (1H, dt, J=10.2, 8.8 Hz), 7.12 (1H, dddd, J=9.0, 3.9, 2.6, 1.5 Hz), 5.91 (1H, dd, J=8.4, 3.7 Hz), 4.57 - 4.42 (2Н , m), 4.20 - 4.06 (2Н, m), 2.98 (1H, ddd, J=16.8, 9.5, 7.6 Hz), 2.89 - 2.78 (1H, m), 2.78 - 2.67 (1H, m), 2.41 (3H , s), 2.37 - 2.27 (1H, m), 2.25 (3H, s), 2.22 - 2.12 (2H, m), 1.90 (3H, s).

Example 137: (S)-5-(1-(3-aminocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2yl)-1-(3.4 -difluorophenyl)pyrrolidin-2-one.

(S)-5-(1-(3-aminocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2-yl)-1-(3,4difluorophenyl) pyrrolidin-2-one nh ₂

To a mixture of (S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5oxopyrrolidine-2-carboxamide (50 mg, 0.117 mmol ) and DCM (1 mL, 15.54 mmol), tert-butyl(3-oxocyclobutyl)carbamate (21.72 mg, 0.117 mmol) and acetic acid (0.5 mL, 8.73 mmol) were added. The mixture was stirred at room temperature for 20 min, then pyridine-borane (0.025 mL, 0.235 mmol) was added. The mixture was stirred at room temperature for 1 hour. A few drops of concentrated HCl were added and stirred at rt. within 5 min. Acetic acid (1 ml, 17.47 mmol) was then added and the mixture was stirred at 80° C. for 18 h. The mixture was concentrated under reduced pressure and the crude product was purified by silica gel chromatography (12 g column, 0-5% MeOH/DCM), to resulting in (S)-5-(1-(3-α-minocyclobutyl)-5-(3,5dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4- difluorophenyl)pyrrolidin-2-one (29 mg, 50%) as a dark brown solid; temp. beats 1.22 min (method 1), m/z 478 (M+H) ⁺ (electrospray ⁺ );

1H-NMR (de-DMSO) δ: two stereoisomers in a 3:1 ratio, 8.04 (d, J=8.5 Hz, 1H, basic), 7.89 7.76 (m, 2H, mixture), 7.59-7.63 (m, 2H, mixture), 7.42-7.34 (m, 2H, mixture), 7.26 - 7.12 (m, 3H, mixture), 5.99 - 168 041318

5.91 (m, 2H, mixture), 4.82-4.69 (m, 1H, major), 4.55-4.43 (m, 1H, minor fraction), 3.31 - 3.19 (m, 1H, mixture), 2.89 - 2.76 (m, 2H , mixture), 2.77 - 2.60 (m, 3H, mixture), 2.59 -2.52 (m, 1H, mixture), 2.37 (s, 3H, mixture),

2.33 - 2.24 (m, 1H, mixture), 2.20 (s, 3H, mixture), 2.11 - 2.01 (m, 1H, mixture).

Example 138: (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(thiazol-4-ylmethyl)-1Hbenzo[d]imidazol- 2-yl)pyrrolidin-2-one

To a solution of (S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5oxopyrrolidine-2-carboxamide (75 mg, 0.176 mmol ) in DCM (1.5 mL, 23.31 mmol) were added thiazole-4carbaldehyde (0.032 mL, 0.229 mmol) and acetic acid (0.75 mL, 13.10 mmol). The mixture was stirred at room temperature for 20 min, then pyridine-borane (0.037 mL, 0.352 mmol) was added. The mixture was stirred at room temperature for 1 hour.

A few drops of concentrated HCl were added and stirring was continued at rt. within 5 min. Then acetic acid (0.75 ml, 13.10 mmol) was added and the mixture was stirred at 80° C. for 18 h. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12 g column, 0-5% MeOH/DCM) to give (S)-1-(3,4difluorophenyl)-5-(5-(3,5-dimethylisoxazole-4- yl)-1-(thiazol-4-ylmethyl)-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one (65 mg, 72%) as a dark brown solid; temp. beats 2.01 min (method 1), m/z 506 (M+H)+ (electrospray ⁺ );

¹ H-NMR (de-DMSO) δ: 9.14 (d, J=1.9 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.88 (ddd, J=13.6, 7.4, 2.6 Hz, 1H) , 7.79 - 7.70 (m, 1H), 7.62 - 7.53 (m, 1H), 7.49 - 7.39 (m, 1H), 7.34 (dt, J=10.5, 9.2 Hz, 1H), 7.20 (dd, J=8.4, 1.6 Hz, 1H), 6.18 - 6.10 (m, 1H), 5.80 (d, J=16.1 Hz, 1H), 5.71 (d, J=16.1 Hz, 1H), 2.80 - 2.57 (m, 3H), 2.35 ( s, 3H), 2.18 (s, 3H), 2.15–2.09 (m, 1H).

Example 139: (S)-5-(1-(3-Aminocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2yl)-1-(3,4- difluorophenyl)pyrrolidin-2-one.

(S)-5-(1-(3-Carboxycyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidine -2-he but

F

To a mixture of (S)-N-(2-amino-5-(3,5-dimethylisoxazol-4-yl)phenyl)-1-(3,4-difluorophenyl)-5oxopyrrolidine-2-carboxamide (0.094 ml, 0.176 mmol ) and DCM (1.5 ml, 23.31 mmol), 3oxocyclobutanecarboxylic acid (26.1 mg, 0.229 mmol) and acetic acid (0.75 ml, 13.10 mmol) were added. The mixture was stirred at room temperature for 20 min, then pyridine-borane (0.037 mL, 0.352 mmol) was added. The mixture was stirred at room temperature for 1 hour. A few drops of concentrated HCl were added and stirring was continued at RT. within 5 min. Then acetic acid (0.75 ml, 13.10 mmol) was added and the mixture was stirred at 80° C. for 18 h. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12 g column, 0-5% MeOH/DCM) to give (S)-3-(2-(1-(3,4-difluorophenyl)5-oxopyrrolidin-2-yl )-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1yl)cyclobutanecarboxylic acid (40 mg, 43%) as a dark brown solid; temp. beats 1.91 min (method 1), m/z 507 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 8.45 (d, J=8.5 Hz, 0.5H), 8.12 (t, J=5.7 Hz, 0.5H), 7.96 (t, J=5.7 Hz, 0.5H) , 7.91 (d, J=8.4 Hz, 0.5H), 7.87 - 7.74 (m, 1H), 7.64-7.60 (m, 1H), 7.47 - 7.31 (m, 1H), 7.30 - 7.11 (m, 1H), 6.05 (d, J=7.8 Hz, 0.5H), 5.97 (d, J=7.0 Hz, 0.5H), 5.44-5.32 (m, 0.5H), 5.30 - 5.20 (m, 0.5H), 3.16 - 3.07 ( m, 5H), 3.06 - 2.91 (m, 1H), 2.77 - 2.58 (m, 4H), 2.38 (2xs, 3H), 2.22 (2xs, 3H), 2.12 - 2.00 (m, 2H), 1.53 - 1.39 ( m, 2H), 0.93 -

- 169 041318

0.84 (m, 3H).

Example 140: (S)-3-(2-(1-(3,4-difluorophenyl)-5-oxon-pyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)1 H-benzo [ d]imidazol-1-yl)-N-propylcyclobutanecarboxyamide.

(S)-5-(1-(3-Aminocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidine -2-he

Me

Oh me

TEA (24.77 µl, 0.178 mmol) was added to a solution of N-propylamine (5.42 µl, 0.065 mmol), (S)-3(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)- 5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1yl)cyclobutanecarboxylic acid (30 mg, 0.059 mmol) and HATU (24.77 mg, 0.065 mmol) in DCM (3.81 µl, 0.059 mmol ), then stirred at room temperature. within 24 hours the Residue was diluted with water (10 ml), then was extracted with dichloromethane (50 ml). The organic phase was washed with water (10 ml), then passed through a phase separation cartridge and concentrated in vacuo. The residue was purified by chromatography (24 g silica gel, 0-10% methanol in DCM, gradient elution) to give a 40:60 mixture of (S)-3-(2-(1-(3,4-difluorophenyl)-5- oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-1-yl)-N-propylcyclobutanecarboxyamide (15 mg, 46%) as a colorless solid; temp. beats 2.00 min (method 1), m/z 548 (M+H) + (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 8.45 (d, J=8.5 Hz, 0.5H), 8.12 (t, J=5.7 Hz, 0.5H), 7.96 (t, J=5.7 Hz, 0.5H) , 7.91 (d, J=8.4 Hz, 0.5H), 7.87 - 7.74 (m, 1H), 7.64-7.60 (m, 1H), 7.47 -7.31 (m, 1H), 7.30 -7.11 (m, 1H), 6.05 (d, J=7.8 Hz, 0.5H), 5.97 (d, J=7.0 Hz, 0.5H), 5.44-5.32 (m, 0.5H), 5.30-5.20 (m, 0.5H), 3.16 - 3.07 ( m, 5H), 3.06 - 2.91 (m, 1H), 2.77 - 2.58 (m, 4H), 2.38 (2xs, 3H), 2.22 (2xs, 3H), 2.12 - 2.00 (m, 2H), 1.53 - 1.39 ( m, 2H), 0.93 0.84 (m, 3H).

Common pathway D. Non-convergent approach to valerolactam analogues.

Example 146: (R)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)n-pyrrolidin-3-yl )-1H-benzo[d]imidazol-2-yl)niperidin-2-one.

(R)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)πpyrrolidin-3-yl)amino)phenyl)6-oxo-piperidin-2- carboxamide

O

DIPEA (0.623 ml, 3.57 mmol) was added to a solution of (R)-4-(3,5-dimethylisooxazol-4-yl)-N ¹ -(1(methylsulfonyl)pyrrolidin-3-yl)benzene-1,2-diamine (0.5 g, 1.427 mmol), HATU (0.705 g, 1.855 mmol) and (R)-6-oxo-piperidine-2-carboxylic acid (0.225 g, 1.569 mmol) in DMF (5 ml, 1.427 mmol) and stirred for 20 h. The mixture was evaporated under vacuum, EtOAc (20 ml), washed the residue was dissolved in saturated aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (10 ml), dried (MgSO ₄ ), filtered and evaporated under vacuum. The resulting brown gum was purified by silica gel chromatography (40 g column, 0-10% MeOH in (50% DCM/EtOAc)) to give (R)-N-(5-(3,5-dimethylisoxazole-4 -yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3yl)amino)phenyl)-6-oxo-piperidine-2-carboxamide (0.63 g, 93%) as a white solid; temp. beats 1.52 min (method 1), m/z 476 (M+H) ⁺ (electrospray ⁺ ).

(R)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) piperidine-2-one

- 170 041318

(R)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)6-oxo-piperidin-2- carboxamide (0.61 g, 1.283 mmol) was dissolved in TFA (20 ml, 1.283 mmol) and stirred at 70°C for 3 days. The mixture was evaporated in vacuo and the resulting brown gum was purified by flash chromatography (40 g column, 0-20% MeOH in (50% DCM/EtOAc)) to give (R)-6-(5-(3 ,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (0.53 g, 90% ) as a colorless foam; temp. beats 2.00 min (method 1), m/z 602 (M+H) + (electrospray ⁺ ).

(R)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-

-yl)-1 H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (0.036 ml, 0.240 mmol) was added to a solution of (R)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl)- 1H-benzo[d]imidazol-2-yl)piperidin-2-one (50 mg, 0.109 mmol) in dichloroethane (1 mL, 0.109 mmol) and stirred for 10 min. CuTMEDA (18.78 mg, 0.040 mmol) was added, stirred for 10 min, (3,4-dichlorophenyl)boronic acid (20.85 mg, 0.109 mmol) was added and the reaction mixture was stirred for 20 h. The reaction mixture was diluted with ethyl acetate (20 ml) , washed with saturated aqueous NaHCO3 (10 ml), water (10 ml) and brine (5 ml), dried (MgSO ₄ ), filtered and evaporated in vacuo. The resulting resin was purified by flash chromatography (24 g column, 0-20% MeOH in (50% EtOAc/DCM)) to give (R)-1-(3,4-dichlorophenyl)-6-(5 -(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (6 mg, 8%) as an off-white solid; temp. beats 2.00 min (method 1), m/z 602 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.76 (d, J=1.6 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.55 ( d, J=8.7Hz, 1H), 7.26 (dd, J=8.4, 1.7Hz, 1H), 7.21 (dd, J=8.7, 2.4Hz, 1H), 5.82 (t, J=4.5Hz, 1H), 5.38 (p, J=8.6 Hz, 1H), 3.70 (ddd, J=9.7, 6.9, 4.4 Hz, 1H), 3.56 - 3.30 (m, 4H), 3.06 (s, 3H), 2.65 - 2.52 (m, 2Н), 2.46 (d, J=8.2 Hz, 1H), 2.42 (s, 3Н), 2.25 (s, 3Н), 2.15 - 2.06 (m, 2H), 1.89 (s, 1H), 1.80 (s, 1H ).

(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin3-yl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one; (S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-6-oxo-piperidin-2- carboxamide

DIPEA (0.623 ml, 3.57 mmol) was added to a solution of (R)-4-(3,5-dimethylisoxazol-4-yl)-N ¹ -(1(methylsulfonyl)pyrrolidin-3-yl)benzene-1,2-diamine (0.5 g, 1.427 mmol), HATU (0.705 g, 1.855 mmol) and (S)-6-oxo-piperidine-2-carboxylic acid (0.225 g, 1.569 mmol) in DMF (5 ml, 1.427 mmol) and stirred for 20 h. DMF was evaporated under vacuum, and the residue was dissolved in EtOAc (20 ml), washed with an aqueous solution of NaHCO ₃ (20 ml), water (20 ml) and brine (10 ml), dried (MgSO ₄ ), filtered and evaporated under vacuum. The resulting brown gum was purified by flash chromatography (40 g column, 0-10% MeOH in (50% DCM/EtOAc)) to give (S)N-(5-(3,5-dimethylisoxazole-4- yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-6- 171 041318 oxopiperidine-2-carboxamide (0.62 g, 90%) as a white foam; temp. beats 1.54 min (method 1), m/z 476 (M+H) ⁺ (electrospray ⁺ ).

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) piperidine-2-one

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)phenyl)-6oxo-piperidine-2-carboxamide (0.6 g, 1.262 mmol) was dissolved in TFA (20 ml, 1.262 mmol) and stirred at 70°C for 3 days. The mixture was concentrated in vacuo and the resulting brown gum was purified by flash chromatography (40 g column, 0-20% MeOH in (50% DCM/EtOAc)) to give (S)-6-(5-(3 ,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (0.53 g, 92% ) in the form of a white solid; temp. beats 1.52 min (method 2), m/z 458 (M+H) + (electrospray ⁺ ).

(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin3-yl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one

DBU (0.036 ml, 0.240 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl)- 1H-benzo[d]imidazol-2-yl)piperidin-2-one (50 mg, 0.109 mmol) in DCM (2 ml, 0.109 mmol) and stirred for 10 min. CuTMEDA (10.15 mg, 0.022 mmol) was added, sonicated and stirred for 10 min, (3,4dichlorophenyl)boronic acid (41.7 mg, 0.219 mmol) was added and the reaction mixture was stirred for 48 h. The reaction mixture was diluted with ethyl acetate (20 ml ), washed with aqueous NaHCO ₃ (10 ml), water (10 ml) and brine (5 ml), dried (MgSO ₄ ), filtered and evaporated in vacuo. The resulting resin was purified by silica gel chromatography (24 g column, 0-20% MeOH in (50% EtOAc/DCM)) to give (S)-1-(3,4-dichlorophenyl)-6-(5 -(3,5-dimethylisoxazol-4-yl)-1((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (18 mg, 27% yield) as an off-white solid; temp. beats 2.00 min (method 1), m/z 602 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.75 (d, J=1.6 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.55 ( d, J=8.7 Hz, 1H), 7.29 - 7.19 (m, 2H), 5.83 (t, J=4.7 Hz, 1H), 5.45 - 5.32 (m, 1H), 3.79 (dd, J=10.6, 8.9 Hz , 1H), 3.70 - 3.57 (m, 2H), 3.33 (m, 2H), 3.08 (s, 3H), 2.67 - 2.52 (m, 2H), 2.41 (s, 3H), 2.46 - 2.27 (m, 1H ), 2.25 (s, 3H), 2.20 - 2.03 (m, 2H), 1.91 (d, J=7.6 Hz, 1H), 1.79 (d, J=9.5 Hz, 1H).

Example

148:

(S)-1 -(4-chloro-3-fluorophenyl)-6-(5 -(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 (methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)piperidin-2-one. (S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1 H-benzo[d]imidazol-2-yl)piperidin-2-one

DBU (0.054 ml, 0.361 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-172 041318 (methylsulfonyl)pyrrolidine-3- yl)-1H-benzo[d]imidαzol-2-yl)piperudin-2-one (75 mg, 0.164 mmol) in DCM (2 ml, 0.164 mmol) and stirred for 10 min. CuTMEDA (15.23 mg, 0.033 mmol) was added, sonicated, and stirred for 10 min. (4-Chloro-3fluorophenyl)boronic acid (57.2 mg, 0.328 mmol) was added and the reaction mixture was stirred at rt. for 18 h. DBU (20 μl), CuTMEDA (10 mg) and boronic acid (20 mg) were added and the reaction mixture was stirred at rt. for an additional 7 hours. The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (24 g column, 0-10% MeOH/DCM) to give (S)-1-(4-chloro-3- fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidαzol-2-yl) piperidin-2-one (40 mg, 41%) as a light pink solid; temp. beats 1.95 min (method 1), m/z 586 (M+H) ⁺ (electrospray ⁺ );

1H-NMR (dg-DMSO) δ: 7.75 - 7.72 (1H, m), 7.70 (1H, d, J=8.5 Hz), 7.50 (1H, t, J=8.6 Hz), 7.37 (1H, dd, J =10.9, 2.3 Hz), 7.25 (1H, dd, J=8.5, 1.7 Hz), 7.11 (1H, ddd, J=8.6, 2.3, 1.0 Hz), 5.81 (1H, t, J=4.6 Hz), 5.45 5.30 (1H, m), 3.79 (1H, dd, J=10.6, 8.9 Hz), 3.68 - 3.57 (2H, m), 3.32 - 3.25 (1H, m), 3.07 (3H, s), 2.65 - 2.51 ( 2H, m), 2.40 (3H, s), 2.39 - 2.26 (2H, m), 2.24 (3H, s), 2.19 - 2.09 (2H, m), 1.98 - 1.85 (1H, m), 1.83 - 1.72 ( 1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=8.96 min, >99% diastereomeric excess at 254 nm.

149:

Example (8)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((K)-1(methylsulfonyl)pyrrolidin-3-yl)- 1H-benzo[d]imidazol-2-yl)piperidin-2-one.

(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin3-yl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one

DBU (0.054 ml, 0.361 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl)- 1H-benzo[d]imidazol-2-yl)piperidin-2-one (75 mg, 0.164 mmol) in DCM (2 ml, 0.164 mmol) and stirred for 10 min. CuTMEDA (15.23 mg, 0.033 mmol) was added, sonicated, and stirred for 10 min. (3,4dfluorophenyl)boronic acid (51.8 mg, 0.328 mmol) was added and the reaction mixture was stirred at rt. over 18 hours. The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (24 g column, 0-10% MeOH/DCM) to give (S)-1-(3,4difluorophenyl)-6- (5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)- 1Hbenzo[d]imidαzol-2-yl)piperidin-2-one ( 39 mg, 40%) as a dark brown solid; temp. beats 1.86 min (method 1), m/z 570 (M+H)+ (electrospray ⁺ );

¹ H-NMR (0 ₆ -DMSO) δ: 7.75 (1H, d, J=1.6 Hz), 7.69 (1H, d, J=8.4 Hz), 7.42 - 7.29 (2H, m), 7.25 (1H, dd , J=8.5, 1.7 Hz), 7.11 - 7.02 (1H, m), 5.76 (1H, t, J=4.7 Hz), 5.40 - 5.29 (1H, m), 3.81 - 3.73 (1H, m), 3.65 - 3.57 (2H, m), 3.31 - 3.25 (1H, m), 3.06 (3H, s), 2.63 - 2.52 (2H, m), 2.41 (3H, s), 2.38 - 2.35 (1H, m), 2.35 - 2.26 (1H, m), 2.24 (3H, s), 2.16 - 2.08 (2H, m), 2.02 - 1.87 (1H, m), 1.84 - 1.72 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=7.86 min, >99% diastereomeric excess at 254 nm.

Example

150:

(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1 (methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)piperidin-2-one. (S)-1-(3-Chloro-4-methoxyphenyl)-6-(5-(3,5-dimethyluzoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrroludin-3-yl) -1H-benzo[d]imidαzol-2-yl)piperudin-2-one

DBU (0.054 ml, 0.361 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-173 041318 (methylsulfonyl)pyrrolidine-3- yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (75 mg, 0.164 mmol) in DCM (2 ml, 0.164 mmol) and stirred for 10 min. CuTMEDA (15.23 mg, 0.033 mmol) was added, sonicated, and stirred for 10 min. (3-Chloro-4methoxyphenyl)boronic acid (61.1 mg, 0.328 mmol) was added and the reaction mixture was stirred at rt. over 18 hours. The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (24 g column, 0-10% MeOH/DCM) to give (S)-1-(3chloro-4-methoxyphenyl)- 6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)1H-benzo[d]imidazol-2-yl)piperidin-2 -one (23 mg, 22%) as a pink solid; temp. beats 1.83 min (method 1), m/z 598 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.75 (1H, d, J=1.6 Hz), 7.68 (1H, d, J=8.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.24 ( 1H, dd, J=8.5, 1.7Hz), 7.12 (1H, dd, J=8.8, 2.5Hz), 7.01 (1H, d, J=8.9Hz), 5.73 (1H, t, J=4.8Hz), 5.42 - 5.31 (1H, m), 3.81 - 3.72 (4H, m), 3.66 - 3.54 (2H, m), 3.31 - 3.22 (1H, m), 3.06 (3H, s), 2.61 - 2.52 (1H, m ), 2.41 (3H, s), 2.39 - 2.29 (1H, m), 2.24 (3H, s), 2.17 - 2.08 (2H, m), 2.06 - 1.89 (3H, m), 1.84 - 1.72 (1H, m ).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=11.53 min, >99% diastereomeric excess at 254 nm.

Example 151: (S)-1-(3-fluoro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3 -yl)-1 H-benzo[d]imidazol-2-yl)piperidin-2-one.

(S)-1-(3-fluoro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1 H-benzo[d]imidazol-2-yl)piperidin-2-one

MeO F

DBU (0.054 ml, 0.361 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl)- 1H-benzo[d]imidαzol-2-yl)piperidin-2-one (75 mg, 0.164 mmol) in DCM (2 ml, 0.164 mmol) and stirred for 10 min. CuTMEDA (15.23 mg, 0.033 mmol) was added, sonicated, and stirred for 10 min. (3-Fluoro-4methoxyphenyl)boronic acid (55.7 mg, 0.328 mmol) was added and the reaction mixture was stirred at rt. over 18 hours. The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (24 g column, 0-10% MeOH/DCM) to give (S)-1-(3fluoro-4-methokCyphenyl)- 6-(5-(3,5-dimethylisooxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)1H-benzo[d]imidazol-2-yl)piperidin-2 -one (26 mg, 27%) as a dark brown solid; temp. beats 1.77 min (method 1), m/z 582 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.75 (1H, d, J=1.7 Hz), 7.68 (1H, d, J=8.6 Hz), 7.24 (1H, dd, J=8.5, 1.7 Hz), 7.12 (1H, dd, J=12.7, 2.4 Hz), 7.08 - 7.00 (1H, m), 6.99 - 6.91 (1H, m), 5.70 (1H, d, J=5.0 Hz), 5.42 - 5.30 (1H, m), 3.80 - 3.70 (4H, m), 3.66 - 3.53 (2H, m), 3.30 - 3.24 (1H, m), 3.06 (3H, s), 2.63 - 2.53 (1H, m), 2.41 (3H, s), 2.39 - 2.32 (2H, m), 2.24 (3H, s), 2.16 - 2.08 (1H, m), 2.01 (3H, s), 1.84 - 1.70 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 ml/min, isocratic 30% EtOH in isohexane (0.2% TFA)): 156251D, temp. sp=11.82 min, >99% diastereomeric excess at 254 nm.

Example 152: (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 r,4S)-4-methoxycyclohexyl)-1Hbenzo[d]imidαzol-2-yl)- 1-(3,4-difluorophenyl)piperidin-2-one.

(S)-N-(5-(3,5-dimethylisoksazol-4-yl)-2-(((1r,4S)-4-methoxycyclohekCyl)amino)phenyl)-6oxo-piperidine-2-carboxamide

ome ome

ABOUT

HATU (1061 mg, 2.79 mmol) was added to a solution of (S)-6-oxopiperidin-2-κcarboxylic acid (399 mg, 2.79 mmol), intermediate C8 (800 mg, 2.54 mmol) N,N-diisopropylethylamineα (0.532 ml, 3.04 mmol) in DMF (6 ml, 77 mmol), then stirred at room temperature for

- 174 041318 nights. The mixture was diluted with water (20 ml) then extracted with ethyl acetate (3x50 ml). The combined organic phases were washed with 1M HCl (10 ml), saturated NaHCO ₃ (10 ml) and brine (3x10 ml), then dried (MgSO ₄ ), filtered and concentrated to give a brown oil. The crude product was purified by silica gel chromatography (40 g column, 0-10% MeOH/DCM) to give (S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-((( 1r,4S)4-methoxycyclohexyl)amino)phenyl)-6-oxopiperidine-2-carboxamide (693 mg, 53%) as a pink solid; temp. beats 1.64 min (method 1), m/z 441 (M+H)+ (electrospray ⁺ ).

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2yl)piperidin-2-one

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,4S)-4-methoxycyclohexyl)amino)phenyl)-6oxo-piperidine-2-carboxamide (200 mg, 0.454 mmol) was heated to 80°C in acetic acid (1040 μl, 18.16 mmol) for 24 h. The crude product was loaded onto a column with a solid phase cation exchanger (2 g) in MeOH. The column was washed with methanol (MeOH) and then the product was eluted with 7 M ammonia in MeOH. The resulting mixture was concentrated in vacuo to give (S)-6(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d] imidazol-2-yl)piperidin2-one (120 mg, 62%) as a pink solid; temp. beats 1.71 min (method 1), m/z 423 (M+H) ⁺ (electrospray ⁺ ).

(S)-6-(5-(3,5-dimethyluzoxazol-4-yl)-1 -((1 r,4S)-4-methoxycyclohexyl)-1 H-benzo[d]imidazol-2-yl)1 -(3,4-difluorophenyl)piperidin-2-one

DBU (0.080 mL, 0.531 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)4-methoxycyclohexyl)-1H-benzo[d ]imidazol-2-yl)piperidin-2-one (120 mg, 0.241 mmol) in DCM (2 mL, 0.241 mmol) and stirred at room temperature. within 10 min. CuTMEDA (22.42 mg, 0.048 mmol) was added, sonicated and stirred at RT. for another 10 min. Then (3,4difluorophenyl)boronic acid (76 mg, 0.483 mmol) was added and the reaction mixture was stirred at rt. over 18 hours. The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (24 g column, 0-10% MeOH/DCM) to give (S)-6-(5(3,5-dimethylisoxazole -4-yl)-1 -((1 r,4S)-4-methoxycyclohexyl)-1 H-benzo[d]imidazol-2-yl)-1 -(3,4difluorophenyl)piperidin-2-one (37 mg , 28%) as a light pink solid; enantiomers were separated by chiral preparative HPLC (general method E); temp. beats 2.07 min; m/z 535 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.78 (1H, d, J=8.5 Hz), 7.69 (1H, d, J=1.6 Hz), 7.42 - 7.28 (2H, m), 7.14 (1H, dd , J=8.5, 1.7 Hz), 7.08 - 7.01 (1H, m), 5.77 (1H, t, J=4.6 Hz), 4.45 - 4.29 (1H, m), 3.45 - 3.34 (1H, m), 3.28 ( 3H, s), 2.63 - 2.52 (2H, m), 2.40 (3H, s), 2.37 - 2.28 (2H, m), 2.23 (3H, s), 2.21-2.11 (2H, m), 2.07 (3H, s), 1.87 - 1.71 (2H, m), 1.46 - 1.29 (2H, m), 1.29 - 1.17 (1H, m).

Example 153: (S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 r,4S)-4methoxycyclohexyl)-1H -benzo[d]imidazol-2-yl)niperidin-2-one.

(S)-1 -(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-methoxycyclohexyl)-1Hbenzo[ d]umidazol-2-yl)piperidin-2-one

- 175 041318

ome ome

DBU (0.039 mL, 0.260 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)4-methoxycyclohexyl)-1H-benzo[d ]imidazol-2-yl)piperidin-2-one (50 mg, 0.118 mmol) in DCM (0.2 ml, 0.118 mmol) and MeCN (2 ml, 38.3 mmol) and stirred for 10 min. CuTMEDA (10.99 mg, 0.024 mmol) was added, sonicated and stirred for 10 min, (4-chloro-3fluorophenyl)boronic acid (41.3 mg, 0.237 mmol) was added and the reaction mixture was stirred at 35°C for 24 h. concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (24 g column, 0-10% MeOH/DCM) to give (S)-1-(4chloro-3-fluorophenyl)-6-(5-( 3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-methoxycyclohexyl)-1Hbenzo[d]imidazol-2-yl)piperidin-2-one (23 mg, 34%) as light pink solid; temp. beats 2.17 min; m/z 551 (M+H)+ (electrospray ⁺ );

¹ H-NMR (06-DMSO) δ: 7.79 (d, J=8.5 Hz, 1H), 7.69 (d, J=1.7 Hz, 1H), 7.50 (t, J=8.6 Hz, 1H), 7.38 (dd , J=10.9, 2.3 Hz, 1H), 7.15 (dd, J=8.5, 1.7 Hz, 1H), 7.09 (ddd, J=8.7, 2.3, 1.0 Hz, 1H), 5.85 - 5.79 (m, 1H), 4.45 4.33 (m, 1H), 3.46 - 3.36 (m, 1H), 3.29 (s, 3H), 2.65 - 2.54 (m, 2H), 2.41 (s, 3H), 2.39 -2.27 (m, 2H), 2.24 (s, 3Н), 2.20 - 2.10 (m, 2H), 2.10 - 1.91 (m, 3Н), 1.88 - 1.73 (m, 2Н), 1.46 - 1.32 (m, 2H), 1.32 - 1.22 (m, 1H) .

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=5.69 min, >99% diastereomeric excess at 254 nm.

Example 154: (S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4methoxycyclohexyl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one.

(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)1H-benzo[ d]imidazol-2-yl)piperidin-2-one

ome ome

MeO CI

DBU (0.039 mL, 0.260 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)4-methoxycyclohexyl)-1H-benzo[d ]imidazol-2-yl)piperidin-2-one (50 mg, 0.118 mmol) in DCM (0.2 ml, 0.118 mmol) and MeCN (2 ml, 38.3 mmol) and stirred for 10 min. CuTMEDA (10.99 mg, 0.024 mmol) was added, sonicated and stirred for 10 min, (3-chloro-4methoxyphenyl)boronic acid (44.1 mg, 0.237 mmol) was added and the reaction mixture was stirred at 35°С for 24 h. concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (24 g column, 0-10% MeOH/DCM) to give (S)-1(3-chloro-4-methoxyphenyl)-6-(5- (3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1Hbenzo[d]imidazol-2-yl)piperidin-2-one (20 mg, 29%) as pink solid; temp. beats 2.02 min; m/z 563 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.76 (d, J=8.5 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.13 (dd , J=8.5, 1.7 Hz, 1H), 7.09 (dd, J=8.8, 2.5 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 5.79 - 5.70 (m, 1H), 4.45 -4.31 ( m, 1H), 3.76 (s, 3H), 3.45 - 3.35 (m, 1H), 3.28 (s, 3H), 2.64-2.53 (m, 1H), 2.41 (s, 3H), 2.38 - 2.27 (m, 2H), 2.24 (s, 3H), 2.18 - 1.97 (m, 6H), 1.87 - 1.74 (m, 2H), 1.49 - 1.28 (m, 2H), 1.18 - 1.09 (m, 1H).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. sp=7.00 min, >99% diastereomeric excess at 254 nm.

Example 155: (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1Hbenzo[d]imidazol-2-yl)-1 -(3-fluoro-4-methoxyphenyl)piperidin-2-one.

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)1-( 3-fluoro-4-methoxyphenyl)piperidin-2-one

- 176 041318

solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)c

DBU (0.039 ml, 0.260 mmol) was added

4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (50 mg, 0.118 mmol) in DCM (0.2 ml, 0.118 mmol) and MeCN (2 ml, 38.3 mmol) and stirred in within 10 min. CuTMEDA (10.99 mg, 0.024 mmol) was added, sonicated and stirred for 10 min; concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (24 g column, 0-10% MeOH/DCM) to give (S)-6(5-(3,5-dimethylisoxazol-4-yl)- 1-((1 r,4S)-4-methoxycyclohexyl)-1 H-benzo[d]imidazol-2-yl)-1-(3-fluoro4-methoxyphenyl)piperidin-2-one (25 mg, 37%) as a dark brown solid; temp. beats 1.94 min; m/z 547 (M+H)+ (electrospray ⁺ );

Ή-NMR (d ₆ -DMSO) δ: 7.76 (1H, d, J=8.5 Hz), 7.69 (1H, d, J=1.6 Hz), 7.16 - 7.07 (2H, m), 7.07 -6.98 (1H, m), 6.98 - 6.92 (1H, m), 5.75 - 5.68 (1H, m), 4.42 - 4.28 (1H, m), 3.74 (3H, s), 3.46 - 3.36 (1H, m), 3.28 (3H, s), 2.64 - 2.52 (2H, m), 2.40 (3H, s), 2.37 - 2.27 (2H, m), 2.24 (3H, s), 2.20 - 1.95 (5H, m), 1.77 (2H, d, J=11.6 Hz), 1.49 - 1.26 (2H, m), 1.20 - 1.07 (1H, m).

Chiral HPLC (Diacel Chiralpak IA, 5 µm, 4.6x250 mm, 30 min method, 1.0 mL/min, isocratic 30% EtOH in isohexane (0.2% TFA)): temp. beats = 7.58 min, >99% diastereomeric excess at 254 nm.

Example 156: (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4methylcyclohexyl) -1H-benzo[d]imidazol-2-yl)piperidin-2-one.

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1s,4R)-4-hydroxy-4-methylcyclohexyl)amino)phenyl)-6oxo-piperidine-2-carboxamide

HATU (900 mg, 2.367 mmol) was added to a stirred solution of TEA (0.35 ml, 2.51 mmol), (S)-6-oxo-piperidine-2-carboxylic acid (350 mg, 2.445 mmol) and intermediate C24 (710 mg, 2.206 mmol ) in N,N-dimethylformamide (10 ml), then the mixture was stirred at room temperature for 2 hours. The mixture was diluted with brine (100 ml), then extracted with ethyl acetate (3x100 ml). The combined organic phases were concentrated under reduced pressure. The crude product was purified by Companion chromatography (40 g column, 50-100% THF/DCM), then triturated in diethyl ether to give (S)-N-(5-(3,5-dimethyl-uzoxazol-4-yl )-2(((1s,4R)-4-hydroxy-4-methylcyclohexyl)amino)phenyl)-6-oxo-piperidine-2-carboxamide (822 mg, 80%) as a white solid; temp. beats 1.62 min; m/z 441 (M+H)+ (electrospray ⁺ ).

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxu-4-methylcyclohexyl)-1Hbenzo[d]imidazol-2-yl)piperidine -2-he

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1s,4R)-4-hydroxy-4-methylcyclohexyl)amino)phenyl)-6oxo-piperidine-2-carboxamide ( 800 mg, 1.780 mmol) was heated to 80°C in acetic acid (20 ml) for 4 hours. The acetic acid was removed under reduced pressure, then the residue was dissolved in DCM:MeOH:diethylamine (25 ml, 8:1:1) and concentrated on loose silica gel. silicate purified

- 177 041318 Companion chromatography (40 g column, 15-75% DCM/THF) then triturated in diethyl ether to give (S)-6-(5-(3,5-dimethylisoxazol-4-yl )-1-((1s,4R)-4-hydroxy-4methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (480 mg, 61%) as a white solid; temp. beats 1.26 min; m/z 423 (M+H)+ (electrospray ⁺ );

¹ H-NMR (66-DMSO) δ: 7.75 (d, J=8.5 Hz, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.23 (dd , J=8.4, 1.7 Hz, 1H), 5.12 - 5.00 (m, 1H), 4.50 - 4.36 (m, 1H), 4.43 (s, 1H), 2.71 - 2.54 (m, 2H), 2.41 (s, 3H ), 2.31 - 2.24 (m, 2H), 2.24 (s, 3H), 2.17 - 2.03 (m, 1H), 1.92 - 1.49 (m, 9H), 1.21 (s, 3H).

(S)-1 -(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 s,4R)-4-hydroxy-4methylcyclohexyl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one

0.022 mmol), (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4CuTMEDA (10 mg, methylcyclohexyl)-1H-benzo[ d]imidazol-2-yl)piperidin-2-one (70 mg, 0.166 mmol), (3,4difluorophenyl)boronic acid (30 mg, 0.190 mmol) and DBU (27 µl, 0.179 mmol) were heated to 70°C in acetonitrile (2 ml) for 18 hours The mixture was concentrated on loose silica gel The silicate was purified by chromatography on a Companion device (12 g column, 0-50% THF/DCM), then further purified on a Companion device (4 g column, 1-4 % MeOH/DCM), resulting in (S)-1-(3,4difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4- hydroxy-4-methylcyclohexyl)-1Hbenzo[d]imidazol-2-yl)piperidin-2-one (35 mg, 37%) as an off-white solid, enantiomers were separated by chiral preparative HPLC (General Method A); 1.82 min, m/z 535 (M+H)+ (electrospray ⁺ );

1H-NMR (d6-DMSO) δ: 7.71 (d, J=1.6 Hz, IH), 7.68 (d, J=8.6 Hz, IH), 7.41 - 7.29 (m, 2H), 7.22 (dd, J=8.4 , 1.7 Hz, 1H), 7.08 - 6.99 (m, 1H), 5.75 - 5.70 (m, 1H), 4.42 (s, 1H), 4.41 - 4.28 (m, 1H), 2.64 - 2.52 (m, 2H), 2.48 - 2.31 (m, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 2.10 -1.90 (m, 2H), 1.84 - 1.43 (m, 6H), 1.18 (s, 3H), 1.07 0.91 (m, 1H).

Example 157: (S)-1-(3-Chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4hydroxy-4- methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one.

(S)-1 -(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 s,4R)-4-hydroxy-4methylcyclohexyl)- 1H-benzo[d]imidazol-2-yl)piperidin-2-one

0.022 mmol), (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4CuTMEDA (10 mg, methylcyclohexyl)-1H-benzo[ d]imidazol-2-yl)piperidin-2-one (70 mg, 0.166 mmol), (3-chloro-4methoxyphenyl)boronic acid (35 mg, 0.188 mmol) and DBU (27 µl, 0.179 mmol) were heated to 70°C C in acetonitrile (2 ml) for 18 hours The mixture was concentrated on loose silica gel The silicate was purified by chromatography on a Companion device (12 g column, 0-50% THF/DCM), then further purified on a Companion device (4 g column, 1 -4% MeOH/DCM) to give (S)-1-(3chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 s, 4R)-4-Hydroxy-4-methylcyclohexyl)-1Hbenzo[d]imidazol-2-yl)piperidin-2-one (25 mg, 0.042 mmol, 25.5% yield) as an off-white solid, sp temp 1.79 min m/z 563 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.71 (d, J=1.6 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.20 (dd , J=8.5, 1.7 Hz, 1H), 7.09 (dd, J=8.8, 2.5 Hz, 1H), 7.00 (d, J=8.9 Hz, 1H), 5.74 - 5.65 (m, 1H), 4.41 (s, 1H), 4.40 4.27 (m, 1H), 3.75 (s, 3H), 2.62 - 2.52 (m, 2H), 2.48 - 2.29 (m, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 2.11-1.93 (m, 2H), 1.84 - 1.72 (m, 1H), 1.72 - 1.64 (m, 1H), 1.63 - 1.44 (m, 4H), 1.18 (s, 3H), 0.97 - 0.84 (m, 1H ).

Example 158: (S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4methylcyclohexyl) -1H-benzo[d]imidazol-2-yl)piperidin-2-one.

(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethyluzoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4- 178 041318 methylcyclohexyl) -1H-benzo^]imidazol-2-yl)piperidin-2-one

CuTMEDA (10 mg, 0.022 mmol) ]imidazol-2-yl)piperidin-2-one (70 mg, 0.166 mmol), (3,4dichlorophenyl)boronic acid (35 mg, 0.183 mmol) and DBU (27 µl, 0.179 mmol) were heated to 70°C in acetonitrile (2 ml) for 18 h. The mixture was concentrated on loose silica gel. The silicate was purified by chromatography on a Companion (12 g column, 0-50% THF/DCM), then further purified on a Companion (4 g column, 1.5-4% MeOH/DCM) to give (S)-1- (3,4dichlorophenyl)-6-(5-(3,5-dimethyluzoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1Hbenzo^]imidazol-2-yl) piperidin-2-one (19 mg, 19%) as a white solid; temp. beats 2.01 min; m/z 567 (M+H)+ (electrospray ⁺ );

¹ H-NMR (06-DMSO) δ: 7.72 - 7.66 (m, 2H), 7.62 (d, J=2.4 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.22 (dd, J= 8.4, 1.7 Hz, 1H), 7.18 (dd, J=8.7, 2.4 Hz, 1H), 5.81 (t, J=4.7 Hz, 1H), 4.44 (s, 1H), 4.42 - 4.31 (m, 1H), 2.66 2.53 (m, 3H), 2.49 - 2.42 (m, 1H), 2.41 (s, 3H), 2.39 -2.32 (m, 1H), 2.25 (s, 3H), 2.10 - 1.89 (m, 2H), 1.84 - 1.74 (m, 1H), 1.74 - 1.66 (m, 1H), 1.66 - 1.46 (m, 4H), 1.19 (s, 3H), 1.07 - 0.95 (m, 1H).

Example 159: (S)-6-(5-(3,5-dimethylisoxαzol-4-yl)-1-((1 s,4R)-4-hydroxy-4-methylcyclohexyl)-1Hbenzo[d]imidazol-2 -yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one.

(S)-6-(5-(3,5-dimethyluzoxαzol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1Hbenzo[d]umidazol-2-yl)- 1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

0.022 mmol), (S)-6-(5-(3,5-dimethyluzozazol-4-yl)-1-((1s,4R)-4-hydroxy-4CuTMEDA (10 mg, methylcyclohexyl)-1H-benzo[ d]imidazol-2-yl)piperidin-2-one (70 mg, 0.166 mmol), (3-fluoro-4methoxyphenyl)boronic acid (32 mg, 0.188 mmol) and DBU (27 µl, 0.179 mmol) were heated to 70°C C in acetonitrile (2 ml) for 18 hours The mixture was concentrated on loose silica gel The silicate was purified by chromatography on a Companion device (12 g column, 0-50% THF/DCM), then further purified on a Companion device (4 g column, 1.5 -4% MeOH/DCM) to give (S)-6-(5(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl) -1 H-benzo[d]imidazol-2-yl)-1(3-fluoro-4-methoxyphenyl)piperidin-2-one (18 mg, 19%) as a white solid, sp temp 1.72 min; m/z 547 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.71 (d, J=1.6 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.21 (dd, J=8.4, 1.7 Hz, 1H), 7.13 (dd, J=12.8, 2.4Hz, 1H), 7.03 (dd, J=9.2Hz, 1H), 6.95 (ddd, J=8.8, 2.4, 1.2Hz, 1H), 5.69 (t, J=4.5Hz , 1H), 4.42 (s, 1H), 4.40 - 4.27 (m, 1H), 3.74 (s, 3H), 2.62 - 2.53 (m, 2H), 2.49 - 2.43 (m, 1H), 2.42 (s, 3H ), 2.41 - 2.28 (m, 2Н), 2.25 (s, 3Н), 2.10 - 1.96 (m, 2Н), 1.84 - 1.42 (m, 6Н), 1.18 (s, 3Н), 1.00 - 0.79 (m, 1H ).

Example 160: (S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethyluzoxazol-4-yl)-1-((1s,4R)-4-hydroxyu-4methylcyclohexyl )-1H-benzo[d]imidazol-2-yl)piperidin-2-one.

(S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-ul)-1-((1s,4R)-4-hydroxyu-4methylcyclohexyl)-1H -benzo[d]imidazol-2-yl)piperidin-2-one

- 179 041318

CuTMEDA (10 mg, 0.022 mmol) 2-yl)piperidin-2-one (70 mg, 0.166 mmol), (4-chloro-3fluorophenyl)boronic acid (32 mg, 0.184 mmol), and DBU (27 μL, 0.179 mmol) were heated to 70°С in acetonitrile ( 2 ml) over 18 hours. The mixture was concentrated on loose silica gel. The silicate was purified by chromatography on a Companion (12 g column, 0-50% THF/DCM), then further purified on a Companion (4 g column, 1.5-4% MeOH/DCM) to give ((S)-1 -(4chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 s,4R)-4-hydroxy-4-methylcyclohexyl)-1Hbenzo[d]umidazole -2-yl)piperudin-2-one (20 mg, 21%) as a white solid, temp 1.93 min, m/z 551 (M+H)+ (electrospray ⁺ );

Ή-NMR (d ₆ -DMSO) δ: 7.74 - 7.66 (m, 2H), 7.50 (dd, J=8.6 Hz, 1H), 7.38 (dd, J=10.9, 2.3 Hz, 1H), 7.23 (dd, J=8.5, 1.6Hz, 1H), 7.08(ddd, J=8.7, 2.3, 1.0Hz, 1H), 5.79(t, J=4.6Hz, 1H), 4.44(s, 1H), 4.37(t, J =12.3 Hz, 1H), 2.65 - 2.52 (m, 3H), 2.49 - 2.43 (m, 1H), 2.41 (s, 3H), 2.40 - 2.32 (m, 1H), 2.25 (s, 3H), 2.10 - 1.89 (m, 2H), 1.84-1.44 (m, 6H), 1.19 (s, 3H), 1.08-0.98 (m, 1H).

Example 161: (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3hydroxycyclobutyl)-1H-benzo [d]imidazol-2-yl)piperidin-2-one.

(S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,3S)-3-hydroxycyclobutyl)amino)phenyl)-6oxo-piperidine-2-carboxamide

TEA (3.06 ml, 21.95 mmol) was added to a solution of (1r,3r)-3-((2-amino-4-(3,5-dimethylisoxazol-4yl)phenyl)amino)cyclobutanol (2 g, 7.32 mmol), ( S)-6-oxo-piperidine-2-carboxylic acid (1.152 g, 8.05 mmol) and HATU (3.06 g, 8.05 mmol) in DMF (20 ml), then stirred at room temperature for 18 h. The mixture was concentrated on a rotary evaporator to removal of the main part

DMF. The friable residue was diluted with dichloromethane (200 ml) and washed with water (2x50 ml). The organic phase was collected using a phase separation cartridge and concentrated in vacuo to give a viscous orange oil. The crude material was purified by chromatography (80 g silica gel, 0-10% MeOH in DCM, gradient elution). Product containing fractions were concentrated in vacuo to give (S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(((1r,3S)-3hydroxycyclobutyl)amino)phenyl)-6 -oxpiperidine-2-carboxamide (587 mg, 20%) as a brown/yellow sticky solid/foam; temp. beats 1.38 min; m/z 399 (M+H) ⁺ (electrospray ⁺ ).

(S)-6-(5-(3,5-dimethyluzoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imudazol-2yl)piperidin-2-one

(S)-N-(5-(3,5-dimethyluzoxazol-4-yl)-2-(((1r,3S)-3-hydroxycyclobutyl)amino)phenyl)-6oxopiperidine-2-carboxamide (585 mg, 1.468 mmol) was dissolved in acetic acid (2 ml) and stirred at 80°C for 18 hours. The reaction mixture was cooled to RT and the solvent was removed under vacuum. The residue was purified by chromatography (12 g silica gel, 0-10% methanol in DCM, gradient elution). Product containing fractions were combined and concentrated in vacuo to give crude (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)- 1 H- 180 041318 benzo[d]imidazol-2-yl)piperidin-2-one (950 mg) as light brown solid; temp. beats

1.18 min; m/z 381 (M+H)+ (electrospray ⁺ ).

(S)-1 -(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,3S)-3-hydroxycyclobutyl)-1Hbenzo[d] imidazol-2-yl)piperidin-2-one pH

F F

DBU (83 µl, 0.552 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3hydroxycyclobutyl)-1H-benzo[d] imidazol-2-yl)piperidin-2-one (200 mg, 0.526 mmol), CuTMEDA (36.6 mg, 0.079 mmol) and (3,4-difluorophenyl)boronic acid (91 mg, 0.578 mmol) in acetonitrile (2 ml) . The reaction mixture was stirred for 18 hours at 40° C., then concentrated under reduced pressure. DCM and silica were added and the solvent was removed in vacuo. The crude product (adsorbed on silica) was purified by chromatography (12 g silica gel, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(3,4-difluorophenyl)-6-(5- (3,5dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (97mg, 36%) in the form of light yellow glassy substances in the form of light yellow glassy substances, which scraped into a crystalline solid; temp. beats 1.70 min; m/z 493 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (66-DMSO) δ: 7.81 - 7.69 (m, 2H), 7.40 (ddd, J=12.0, 7.4, 2.5 Hz, 1H), 7.33 (dt, J=10.7, 9.0 Hz, 1H), 7.19 (dd, J=8.5, 1.7 Hz, 1H), 7.14 - 7.05 (m, 1H), 6.55 (s, 1H), 5.68 (dd, J=5.4, 4.0 Hz, 1H), 5.37 - 5.24 (m, 2H), 4.54 (s, 1H), 2.98 (dt, J=12.8, 7.8 Hz, 1H), 2.86 (dt, J=15.0, 7.7 Hz, 1H), 2.60 -2.46 (m, 2H), 2.40 (m , 4H), 2.23 (s, 3Н), 2.19 (m, 1H), 2.03 (m, 1H), 1.91–1.71 (m, 2H).

Example 162: (S)-1-(3-Chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3hydroxucyclobutyl)-1H -benzo[d]imidazol-2-yl)piperidin-2-one.

(S)-1 -(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,3S)-3-hydroxycyclobutyl)1H-benzo [d]imidazol-2-yl)piperidin-2-one pH

MeOCl

DBU (83 μl, 0.552 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3hydroxucyclobutyl)-1H-benzo[d] imidazol-2-yl)-n-piperidin-2-one (200 mg, 0.526 mmol), CuTMEDA (36.6 mg, 0.079 mmol) and (3-chloro-4-methoxyphenyl)boronic acid (108 mg, 0.578 mmol) in acetonitrile (2 ml). The reaction mixture was stirred for 18 hours at 40° C., then concentrated under reduced pressure. DCM and silica were added and the solvent was removed in vacuo. The crude product (adsorbed on silica) was purified by chromatography (12 g silica gel, 010% MeOH in DCM, gradient elution) and sonicated with ether (removing the solvent in vacuo) to give (S)-1-(3-chloro -4-methoxyphenyl)-6-(5-(3,5dimethylisoxazol-4-yl)-1 -((1r,3 S)-3-hydroxycyclobutyl)-1 H-benzo[d]imidazol-2-yl)nineridine -2-one (52 mg, 17%) as a light yellow solid; temp. beats 1.69 min; m/z 521 (M+H) ⁺ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.80 - 7.69 (m, 2H), 7.38 (d, J=2.5 Hz, 1H), 7.22 - 7.12 (m, 2H), 7.00 (d, J=8.9 Hz, 1H), 5.64 (t, J=4.8 Hz, 1H), 5.36 -5.27 (m, 2H), 4.53 (s, 1H), 3.75 (s, 3H), 2.98 (dt, J=12.7, 7.7 Hz, 1H ), 2.84 (dt, J=14.9, 7.7 Hz, 1H), 2.60 - 2.35 (m, 4H), 2.40 (s, 3H), 2.24 (s, 3H), 2.27 - 2.15 (m, 1H), 2.01 ( s, 1H), 1.88 (s, 1H), 1.77 (s, 1H).

Example 163: (S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1-r,3S)-3hydroxycyclobutyl)-1H-benzo [d]imidazol-2-yl)piperidin-2-one.

(S)-1 -(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1r,3 S)-3-hydroxycyclobutyl)-1 Hbenzo[d ]imidazol-2-yl)piperidin-2-one

- 181 041318

DBU (83 μl, 0.552 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisooxazol-4-yl)-1-((1g,3S)-3hydroxycyclobutyl)-1H-benzo[d] imidazol-2-yl)piperidin-2-one (200 mg, 0.526 mmol), CuTMEDA (36.6 mg, 0.079 mmol) and (3,4-dichlorophenyl)boronic acid (110 mg, 0.578 mmol) in acetonitrile (2 ml) . The reaction mixture was stirred for 18 hours at 40° C., then concentrated under reduced pressure. DCM and silica were added and the solvent was removed in vacuo. The crude product (adsorbed on silica) was purified by chromatography (12 g silica gel, 0-10% MeOH in DCM, gradient elution) and sonicated with ether (removing the solvent in vacuo) to give (S)-1-(3 ,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1((1r,3S)-3-hydroxycyclobutyl)-1H-benzo[d]imudazol-2-yl)piperidine- 2-one (71 mg, 25%) as a light yellow solid; temp. beats 1.90 min; m/z 525 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.78 (d, J=8.5 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.53 ( d, J=8.7 Hz, 1H), 7.22 (ddd, J=21.6, 8.6, 2.0 Hz, 2H), 5.74 (t, J=4.7 Hz, 1H), 5.32 (q, J=8.7 Hz, 2H), 4.55 (t, J=7.1Hz, 1H), 2.99 (dt, J=12.6, 7.7Hz, 1H), 2.87 (dt, J=12.5, 7.6Hz, 1H), 2.63 - 2.45 (m, 2H), 2.44 - 2.35 (m, 5H), 2.27 -2.21 (m, 5H), 2.07 - 1.99 (m, 1H), 1.85 - 1.75 (m, 1H).

Example 164: (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1g,4S)-4-hydroxu-4methylcyclohexyl)- 1H-benzo[d]imidazol-2-yl)piperidin-2-one.

(S)-1 -(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 g,48)-4-hydroxy-4methylcyclohexyl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one

0.030 mmol) was added to a solution of ^)-6-(5-(3,5-dimethylisoxazol-4-yl)-1CuTMEDA (13.79 mg, (trans-(1r,4S)-4-hydroxy-4-methylcyclohexyl)-1H -benzo[d]imidazol-2-yl)piperidin-2-one (96.5 0.228 mmol), (3,4-difluorophenyl)boronic acid (54.1 mg, 0.343 mmol) and DBU (0.038 ml, mmol) in acetonitrile (3.0 ml, 57.4 mmol) was heated to 70°C for 6 h. Difluorophenyl)boronic acid (20 mg) was added and stirring was continued at the same temperature in mg, 0.251 (3.4 for another 16 h. The mixture was concentrated on loose silica gel. Silicate purified by Companion chromatography (12 g column, 1-3%; 3% isocratic then 10% MeOH/DCM) to give (S)-1-(3,4-difluorophenyl)-6-( 5-(3,5-dimethylisoxazol-4-yl)-1-((1 g,4S)-4-hydrokCi4-methylcyclohexyl)-1H-benzo[d]imidazol-2-yl)piperudin-2-one (56 mg, 44%) as a brown-yellow solid, temp 1.84 min, m/z 535 (M+H) ⁺ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.71 (d, J=1.6 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.39 (ddd, 1H), 7.36 - 7.29 (m, 1H) , 7.21 - 7.17 (m, 1H), 7.08 - 7.02 (m, 1H), 5.80 - 5.76 (m, 1H), 4.58 (s, 1H), 4.41 - 4.28 (m, 1H), 2.64 - 2.52 (m, 2H), 2.40 (s, 3H), 2.39 - 2.30 (m, 1H), 2.24 (s, 3H), 2.21 - 2.07 (m, 2H), 2.06 - 1.92 (m, 2H), 1.83 - 1.72 (m, 2H), 1.70 - 1.56 (m, 4Н), 1.32 (s, 3Н), 1.15 (dd, J=12.8, 8.8 Hz, 1H).

Example 165: (S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1g,4S)-4hydroxy-4-methylcyclohexyl )-1 H-benzo[d]imidazol-2-yl)piperidin-2-one.

(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1g,4S)-4-hydroxy-4methylcyclohexyl)-1H -benzo[d]umidazol-2-yl)niperidin-2-one

- 182 041318

CuTMEDA (13.79 mg, 0.030 mmol) was added to a solution of (3-chloro-4-methoxyphenyl)boronic acid (63.9 mg, 0.343 mmol), (S)-6-(5-(3,5-dimethylisoxαzol-4-ul) -1-(trans-(1r,4S)-4-hydroxu-4methylcyclohexyl)-1H-benzo^]imidazol-2-yl)piperidin-2-one (96.5 mg, 0.228 mmol) and DBU (0.038 ml, 0.251 mmol ) in acetonitrile (3.0 mL, 57.4 mmol) was heated to 70°С for 6 h, then more (3-chloro-4-methoxyphenyl)boronic acid (20 mg) was added and stirring continued for 22 h. CuTMEDA (14 mg) and the reaction mixture was heated for another 3 hours. The mixture was concentrated on loose silica gel. The silicate was purified by Companion chromatography (12 g column, 13%; isocratic then 10% MeOH/DCM) to give (S)-1-(3-chloro-4methoxyphenyl)-6-(5-(3 ,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-hydroxy-4-methylcyclohexyl)-1Hbenzo[d]imidαzol-2-yl)punerudin-2-one (52.7 mg, 39% ) as a brown-yellow solid; temp. beats 1.81 min; m/z 564 (M+H)+ (electrospray ⁺ );

¹ H-NMR (0 ₆ -DMSO) δ: 7.71 (d, J=1.7 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.18 ( dd, J=8.4, 1.7 Hz, 1H), 7.09 (dd, J=8.8, 2.5 Hz, 1H), 6.99 (d, J=8.9 Hz, 1H), 5.74 (t, 1H), 4.57 (s, 1H ), 4.40 - 4.29 (m, 1H), 3.75 (s, 3H), 2.61 - 2.52 (m, 2H), 2.41 (s, 3H), 2.38 -2.30 (m, 1H), 2.26-2.13 (m+s , 1H), 2.11-1.96 (m, 3H), 1.85-1.75 (m, 1H), 1.74-1.64 (m, 4H), 1.63-1.54 (m, 1H), 1.31 (s, 3H), 1.09-1.01 (m, 1H).

Example 166: (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1Hbenzo[d]imidazol-2- yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one.

(S)-6-(5-(3,5-dimethyluzoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1Нbenzo[d]imidazol-2-yl)- 1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

MeO F

CuTMEDA (13.79 mg, 0.030 mmol) was added to a solution of (3-fluoro-4-methoxyphenyl)boronic acid (58.2 mg, 0.343 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (58.2 mg, 0.343 mmol) and DCM (0.30 ml, 4.66 mmol) in acetonitrile (3.0 ml, 57.4 mmol) was heated to 70°C for 6 h. 3Fluoro-4-methoxyphenyl)boronic acid (20 mg) was added, then heated for 6 h, then the mixture was stirred for 22 h at the same temperature, after which more CuTMEDA (14 mg) was added and the reaction mixture was heated for another 3 h. The mixture was concentrated on loose silica gel. The silicate was purified by Companion chromatography (12 g column, 1-3% MeOH/DCM, then isocratic and elevated to 10% MeOH) to give (S)-6-(5-(3,5-dimethylisoxazol- 4-yl)-1((1 r,4S)-4-hydroxy-4-methylcyclohexyl)-1 H-benzo[d]umidazol-2-yl)-1-(3-fluoro-4methoxyphenyl)piperidin-2- it (52 mg, 40%) as a beige solid; enantiomers were separated by chiral preparative HPLC (general method C); temp. beats 1.71 min; m/z 507 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (dg-DMSO) δ: 7.71 (d, J=1.6 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.18 (dd, J=8.5, 1.7 Hz, 1H), 7.13 (dd, J=12.7, 2.4 Hz, 1H), 7.02 (t, J=9.1 Hz, 1H), 6.96 (ddd, J=2.4, 1.1 Hz, 1H), 5.72 (t, 1H), 4.57 (s, 1H), 4.39 4.27 (m, 1H), 3.73 (s, 3H), 2.57 - 2.52 (m, 1H), 2.47 - 2.29 (m + s, 5H), 2.28 - 2.16 (m + s, 4H), 2.14 - 1.96 (m, 3H), 1.84 - 1.67 (m, 4H), 1.62 - 1.56 (m, 2H), 1.34 - 1.29 (s, 3H), 1.02 (m, 1H).

Example 167: (S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1Hbenzo[d]imidazol-2-yl)piperidine- 2nd.

(S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2yl)piperidin-2-one

me me

Cl Cl

DBU (86 μl, 0.573 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl1H-benzo[d]imidazol-2-yl)-nineridin-2- heα (200 mg, 0.546 mmol), CuTMEDA (38.0 mg, 0.082 mmol), and (3,4-dichlorophenyl)boronic acid (115 mg, 0.600 mmol) in acetonitrile (3 mL). The reaction mixture was stirred for 18 hours at 40° C. and then concentrated under reduced pressure. DCM and silica were added and the solvent was removed in vacuo. The crude product (adsorbed on silica) was purified by chromatography (12 g silica gel, 0-10% MeOH in DCM, gradient

- 183 041318 elution). Product-containing fractions were combined and concentrated in vacuo. The residue was sonicated with ether and the solid was collected by filtration to give (S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl -1H-benzo[d]imidazol-2yl)piperidin-2-one (49 mg, 17%) as a light beige solid; temp. beats 2.37 min; m/z 511 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.71 (d, J=1.6 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.18 (dd, J=8.5, 1.7 Hz, 1H), 7.13 (dd, J=12.7, 2.4 Hz, 1H), 7.02 (t, J=9.1 Hz, 1H), 6.96 (ddd, J=2.4, 1.1 Hz, 1H), 5.72 (t, 1H), 4.57 (s , 1H), 4.39 4.27 (m, 1H), 3.73 (s, 3H), 2.57 - 2.52 (m, 1H), 2.47 - 2.29 (m + s, 5H), 2.28 - 2.16 (m + s, 4H), 2.14 - 1.96 (m, 3H), 1.84 - 1.67 (m, 4H), 1.62 - 1.56 (m, 2H), 1.34 - 1.29 (s, 3H), 1.02 (m, 1H).

Example 168: (S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1Hbenzo[d]imidazol-2-yl) piperidine-2-one.

(S)-1 -(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1 H-benzo[d]imidazol2-yl)piperidin- 2nd

me me

MeO Cl

DBU (86 μl, 0.573 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl1H-benzo[d]imidazol-2-yl)piperidin-2- she (200 mg, 0.546 mmol), CuTMEDA (38.0 mg, 0.082 mmol) and (3-chloro-4-methoxyphenyl)boronic acid (112 mg, 0.600 mmol) in acetonitrile (3 ml). The reaction mixture was stirred for 18 hours at 40° C. and then concentrated under reduced pressure. DCM and silica were added and the solvent was removed in vacuo. The crude product was pre-adsorbed on silica and purified by chromatography (12 g silica gel, 0-10% MeOH in DCM, gradient elution) and finally sonicated with diethyl ether (removing the solvent in vacuo) to give (S)-1- (3-chloro-4-methoxyphenyl)-6-(5-(3,5dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)piperidin-2-one (55 mg, 19%) as a light pink/purple solid; temp. beats 2.14 min; m/z 507 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d _6- DMSO) δ: temp. beats 2.14 min; m/z 547 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.73 (dd, J=1.6, 0.6 Hz, IH), 7.57 (dd, J=8.4, 0.7 Hz, IH), 7.31 (d, J=2.5 Hz, IH ), 7.18 (dd, J=8.4, 1.6Hz, IH), 7.11 (dd, J=8.8, 2.5Hz, 1H), 6.99 (d, J=8.9Hz, 1H), 5.51 (dd, J=5.6, 3.1 Hz, 1H), 3.95 (dd, J=14.6, 6.8 Hz, 1H), 3.89 - 3.73 (m, 1H), 3.74 (s, 3H), 3.17 (d, J=4.0 Hz, 1H), 2.62 - 2.52 (m, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 2.10 (d, J=9.9 Hz, IH), 2.06 - 1.97 (m, 1H), 1.95 - 1.79 (m, 1H) , 1.77 - 1.70 (m, 1H), 1.62 (s, 1H), 0.75 (d, J=6.6 Hz, 3H), 0.48 (d, J=6.6 Hz, 3H).

Example 169: (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)-1-(3fluoro-4-methoxyphenyl) piperidine-2-one.

(S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4methoxyphenyl)piperidin-2 -He

me me

MeO F

DBU (86 μl, 0.573 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl1H-benzo[d]imidazol-2-yl)piperidin-2- she (200 mg, 0.546 mmol), CuTMEDA (38.0 mg, 0.082 mmol) and (3-fluoro-4-methoxyphenyl)boronic acid (102 mg, 0.600 mmol) in acetonitrile (3 ml). The reaction mixture was stirred for 18 hours at 40° C. and then concentrated under reduced pressure. DCM and silica were added and the solvent was removed in vacuo. The crude product (adsorbed on silica) was purified by chromatography (12 g silica gel, 0-10% MeOH in DCM, gradient elution) and sonicated with ether (removing the solvent in vacuo) to give (S)-6-(5 -(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1 H-benzo[d]imidazol-2-yl)-1 (3-fluoro-4-methoxyphenyl)piperidin-2-one (27 mg, 10%) as a light pink/purple solid; enantiomers were separated by chiral preparative HPLC (general method F); temp. beats 2.06 min; m/z 491 (M+H) ⁺ (electrospray ⁺ );

1Н-NMR (d ₆ -DMSO) δ: 5 7.73 (dd, J=1.6, 0.6 Hz, 1H), 7.57 (dd, J=8.4, 0.6 Hz, 1H), 7.18 (dd, J=8.3, 1.6 Hz , IH), 7.11 - 6.90 (m, 3H), 5.49 (dd, J=5.5, 3.1 Hz, 1H), 3.94 (dd, J=14.5, 6.7 Hz, 1H), 3.83 (dd, J=14.5, 8.7

- 184 041318

Hz, 1H), 3.73 (s, 3H), 2.56 (dd, J=13.4, 5.2 Hz, 1H), 2.41 (s, 3H), 2.35 (m, 1H), 2.25 (s, 3H), 2.15 - 1.97 (m,

2H), 1.95 - 1.79 (m, 1H), 1.74 (m, 1H), 0.76 (d, J=6.6 Hz, 3H), 0.48 (d, J=6.6 Hz, 3H).

Example 170: (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)-1-(3- fluoro-4-methoxyphenyl)piperidin-2-one.

(S)-N-(2-((4,4-difluorocyclohekCyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-6-OkCOpiperidine

2-carboxamide

HATU (1.4 g, 3.68 mmol) was added to a stirred solution of TEA (0.6 ml, 4.30 mmol), (S)-6oxo-piperidine-2-carboxylic acid (500 mg, 3.49 mmol) and intermediate C12 (1.0 g,

3.11 mmol) in N,N-dimethylformamide (10 ml), then the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, then purified by chromatography on a Companion device (40 g column, 0-25% THF/DCM) and triturated in diethyl ether to give (S)-N-(2-((4,4-difluorocyclohexyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-6-oxopiperidine- 2-carboxamide (1.5 g, 97%) as a white solid; temp. beats 1.94 min; m/z 447 (M+H)+ (electrospray ⁺ ).

(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2yl)piperidin-2-one

(S)-N-(2-((4,4-difluorocyclohexyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-6-oxopineridine2-carboxamide (1.5 g, 3.02 mmol) was heated to 80° C. in acetic acid (25 ml) for 18 h. The solvents were removed under reduced pressure, then the residue was dissolved in DCM:MeOH:DEA (20:2.5:2.5, 25 ml) and concentrated on loose silica gel. The silicate was purified by Companion chromatography (40 g column, 15-75% THF/DCM), then triturated in diethyl ether to give (S)-6-(1-(4,4-difluorocyclohexyl)-5-( 3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2yl)piperidin-2-one (878 mg, 67%) as a white solid; temp. beats 1.78 min; m/z 429 (M+H) ⁺ (electrospray ⁺ ).

(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisooxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3fluoro-4 -methoxyphenyl)piperidin-2-one

CuTMEDA (55 mg, 0.118 mmol) was added to a suspension of (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2- yl)piperidin-2-one (100 mg, 0.233 mmol) in pyridine (5 ml), then stirred at 40°C for 15 min. (3-Fluoro-4-methoxyphenyl)boronic acid (100 mg, 0.588 mmol) was added, then the mixture was stirred at 40°C for 2 h. The mixture was diluted with ethyl acetate (25 ml), then washed with water (3x25 ml) and saturated saline solution (25 ml). The organic phase was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by Companion chromatography (12 g column, 0-25% THF), then triturated in diethyl ether to give (S)-6-(1-(4,4-difluorocyclohexyl)-5(3, 5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one (106 mg, 81%) as a white solid substances; enantiomers were separated by chiral preparative HPLC (general method B); temp. beats 2.18 min; m/z 597 (M+H) ⁺ (electrospray ⁺ );

- 185 041318

1H-NMR ^-DMSO) δ: 7.74 (d, J=1.6 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.22 (dd, J=8.5, 1.7 Hz, 1H), 7.10 (dd , J=12.7, 2.4 Hz, 1H), 7.05 (dd, J=9.2 Hz, 1H), 6.95 (ddd, J=8.8, 2.4, 1.2 Hz, 1H), 5.76 - 5.60 (m, 1H), 4.74 4.56 (m, 1H), 3.75 (s, 3H), 2.63 - 2.52 (m, 2H), 2.41 (s, 3H), 2.39 - 2.26 (m, 2H), 2.25 (s, 3H), 2.24 - 1.85 (m ,

8H), 1.83 - 1.73 (m, 1H), 1.30 - 1.18 (m, 1H).

Example 171: (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)-1-(3, 4-difluorophenyl)piperidin-2-one.

(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2-yl)-1-(3, 4difluorophenyl)piperidin-2-one

CuTMEDA (28 mg, 0.060 mmol) was added to a stirred solution of (S)-6-(1-(4,4difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2 -yl)piperidin-2-oneα (50 mg, 0.116 mmol) and DBU (35 μl, 0.232 mmol) in acetonitrile (2 ml), then the mixture was stirred for 30 min. (3,4-Difluorophenyl)boronic acid (35 mg, 0.222 mmol) was added, then the mixture was heated to 50° C. overnight. The mixture was concentrated on loose silica under reduced pressure. The crude product was purified by Companion chromatography (12 g column, 5-25% THF/DCM) to give (8)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazole -4-yl)1H-benzo[d]imidazol-2-yl)-1-(3,4-difluorophenyl)piperidin-2-one (35 mg, 53%) as a white solid; temp. beats 2.27 min; m/z 541 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.74 (d, J=1.6 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.43 - 7.29 (m, 2H), 7.23 (dd, J= 8.5, 1.7 Hz, 1H), 7.11 - 6.97 (m, OH), 5.79 - 5.67 (m, 1H), 4.75 - 4.56 (m, 1H), 2.67 - 2.52 (m, 2H), 2.48 2.42 (m, 1H ), 2.41 (s, 3Н), 2.40 - 2.26 (m, 3Н), 2.24 (s, 3Н), 2.23 - 2.03 (m, 5Н), 2.03 - 1.90 (m, 2H), 1.85 - 1.73 (m, 1H ), 1.44 - 1.30 (m, 1H).

Example 172: ^)-1-(3-chloro-4-methoxyphenyl)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5dimethylisoksazol-4-yl)-1H-benzo[d]imidazole -2-yl)piperidine-2-one.

(S)-1 -(3-chloro-4-methoxyphenyl)-6-( 1-(4,4-difluorocyclohexyl)-5 -(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2 -yl)piperidine-2-one

MeO Cl

CuTMEDA (50 mg, 0.108 mmol) was added to a suspension of (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2- yl)piperidin-2-oneα (75 mg, 0.175 mmol) in pyridine (5 mL), then stirred at 40°C for 15 min. (3-Chloro-4-methoxyphenyl)boronic acid (100 mg, 0.536 mmol) was added, then the mixture was stirred at 40°C for 2 h. The mixture was diluted with ethyl acetate (25 ml), then washed with water (3x25 ml) and brine solution (25 ml). The organic phase was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on a Companion (12 g column, 0-25% THF), then triturated in diethyl ether to give (S)-1-(3-chloro-4-methoxyphenyl)-6-( 1(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2-yl)piperidin-2-one (3 5 mg, 0.060 mmol, 34.4 % yield) as a white solid; temp. beats 2.26 min; m/z 569 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.74 (d, J=1.6 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.21 ( dd, J=8.4, 1.7 Hz, 1H), 7.08 (dd, J=8.8, 2.5 Hz, 1H), 7.01 (d, J=8.9 Hz, 1H), 5.74 - 5.67 (m, 1H), 4.74 - 4.58 (m, 1H), 3.76 (s, 3H), 2.65 - 2.53 (m, 2H), 2.45 - 2.25 (m, 6H), 2.24 (s, 3H), 2.23 - 1.98 (m, 6H), 1.98 - 1.88 (m, 1H), 1.85 - 1.74 (m, 1H), 1.30-1.13 (m, 1H).

Example 173: (S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4hydroxycyclohexyl)-1 H-benzo [d]imidazol-2-yl)piperidin-2-one.

(S)-1 -(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-hydroxycyclohexyl)-1Hbenzo[d] imidazol-2-yl) piperidin-2-one

- 186 041318 he he

Into a scintillation vial containing (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1((1g,48)-4-hydroxycyclohexyl)-III-benzo[0]imidazol-2 -yl)piperidin-2-one (157 mg, 0.384 mmol) in pyridine (3 mL), CuTMEDA (89 mg, 0.192 mmol) was added. The reaction mixture was stirred at 40°C for 15 min, then (3,4-dichlorophenyl)boronic acid (183 mg, 0.961 mmol) was added and the reaction mixture was allowed to stir at 80°C for 48 h. beats 1.86 min; m/z 521 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.76 (d, J=8.5 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.43 - 7.27 (m, 2H), 7.13 (dd, J =8.5, 1.7 Hz, 1H), 7.04 (ddd, J=9.1, 4.0, 1.9 Hz, 1H), 5.80 - 5.73 (m, 1H), 4.71 (d, J=4.1 Hz, 1H), 4.31 (t, J=12.4 Hz, 1H), 3.74 - 3.53 (m, 1H), 2.63 - 2.50 (m, 2H), 2.40 (m, 5H), 2.23 (m, 6H), 2.03 (d, J=13.4 Hz, 2H ), 2.01 1.91 (m, 2H), 1.86 (d, J=12.3 Hz, 1H), 1.81 - 1.65 (m, 1H), 1.35 (m, 4H).

Example 174: (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4hydroxycyclohexyl)-1H-benzo [d]imidazol-2-yl)piperidin-2-one.

(S)-1 -(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 r,4S)-4-hydroxycyclohexyl)-1Hbenzo[d] imidazol-2-yl) piperidin-2-one

Into a scintillation vial containing (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazole-2 -yl)piperidin-2-one (157 mg, 0.384 mmol) in pyridine (3 mL), CuTMEDA (89 mg, 0.192 mmol) was added. The reaction mixture was stirred at 40°C for 15 min, then (3,4-difluorophenyl)boronic acid (152 mg, 0.961 mmol) was added and the reaction mixture was left to stir at 80°C for 48 h. The reaction mixture was cooled to RT and partitioned between ethyl acetate (20 ml) and water (10 ml). The organic phase was washed with additional portions of water (2x10 ml), dried (MgSO ₄ ) and concentrated under vacuum. The crude residue was purified by chromatography (4 g silica gel, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazole -4-yl)-1-((1 r,4S)-4hydroxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (54 mg, 27%) as an off-white solid; enantiomers were separated by chiral preparative HPLC (general method D); temp. beats 1.86 min; m/z 521 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.76 (d, J=8.5 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.43 - 7.27 (m, 2H), 7.13 (dd, J =8.5, 1.7 Hz, 1H), 7.04 (ddd, J=9.1,4.0, 1.9 Hz, 1H), 5.80-5.73 (m, 1H), 4.71 (d, J=4.1 Hz, 1H), 4.31 (t, J=12.4 Hz, 1H), 3.74 - 3.53 (m, 1H), 2.63 - 2.50 (m, 2H), 2.40 (m, 5H), 2.23 (m, 6H), 2.03 (d, J=13.4 Hz, 2H ), 2.01 1.91 (m, 2H), 1.86 (d, J=12.3 Hz, 1H), 1.81 - 1.65 (m, 1H), 1.35 (m, 4H).

Example 175: (S)-1-(3-Chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 r,4S)-4hydroxycyclohexyl)-1H -benzo[d]imidazol-2-yl)piperidin-2-one.

(S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4hydroxycyclohexyl)-1H-benzo[d ]imidazol-2-yl)piperidin-2-one

Into a scintillation vial containing (S)-6-(5-(3,5-dimethyluzoxazol-4-yl)-1((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazole-2 -ul)piperudin-2-one (157 mg, 0.384 mmol) in pyridine (3 mL), CuTMEDA (89 mg, 0.192 mmol) was added. The reaction mixture was stirred at 40°C for 15 min, then (3,4-dichlorophenyl)boronic acid (183 mg, 0.961 mmol) was added and the reaction mixture was allowed to stir at 80°C for 48 h.

Example 176: (S)-1-(3,4-difluorophenyl)-5-(1-((1 g,4S)-4-hydroxycyclohexyl)-5-(5-(hydroxymethyl)-3methylisoxazol-4-ul) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

Trans-(1 g,4 g)-4-((4-bromo-2-nitrophenyl)amino)cyclohexanol

4-bromo-1-fluoro-2-nitrobenzene (2.85 ml, 23.14 mmol), trans-(1 g, 4 g)-4-aminocyclohexanol (4.00 g, 34.7 mmol) and TEA (6.45 ml, 46.3 mmol) were heated under reflux in THF (83 ml, 1018 mmol) for 48 h. The reaction mixture was cooled to rt, then the solvents were evaporated under vacuum and the orange residue was divided between EtOAc (100 ml) and DCM (100 ml) and saturated aqueous NaHCO ₃ ( 100 ml) and the layers were separated. The aqueous phase was extracted with additional DCM (2x100 ml), the combined organic extracts were washed with water (100 ml) and brine (100 ml). The solution was concentrated on loose silica gel. The silicate was purified by Companion chromatography (80 g column, 0-100% EtOAc/isohexane) to give trans-(1g,4g)-4-((4bromo-2-nitrophenyl)amino)cyclohexanol (5.79, 78%) was isolated as an orange solid, temp 2.22 min, m/z 316 (M+H)+ (electrospray ⁺ ).

trans-(1 g,4 g)-4-((2-amino-4-bromophenyl)amino)cyclohexanol

Trans-(1g,4g)-4-((4-bromo-2-nitrophenyl)amino)cyclohexanol (5.79 g, 18.37 mmol) and ammonium hydroxide (11.45 ml, 294 mmol) were dissolved in THF (175 ml, 2131 mmol) and water (174 ml, 9682 mmol), sodium dithionate (37.9 g, 184 mmol) was added and the reaction mixture was stirred at rt. during the night. The layers were separated, the aqueous layer was extracted with ethyl acetate (100 ml), the combined organic layers were washed with brine (50 ml), dried (MgSO ₄ ), filtered and evaporated under vacuum, resulting in trans-(1 g, 4 g)-4-( (2-amino-4-bromophenyl)amino)cyclohexanol (3.87 g, 72%) as a pink solid; temp. beats 1.16 min; m/z 285 (M+H)+ (electrospray ⁺ ).

(S)-N-(5-bromo-2-((trans-(1g,4g)-4-hydroxycyclohexyl)amino)phenyl)-1-(3,4-difluorophenyl)-5oxopyrrolidine-2-carboxamide

DIPEA (1.646 ml, 9.42 mmol) was added to a solution of trans-(1g,4g)-4-((2-amino-4bromophenyl)amino)cyclohexanol (1.8 g, 6.31 mmol), (S)-1-(3.4 -difluorophenyl)-5-oxopyrrolidine-2carboxylic acid (1.0 g, 4.15 mmol) and HATU (1.863 g, 4.90 mmol) in DMF (12.55 ml, 162 mmol). The brown solution was stirred at rt. for 15 hours. The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml), after which the layers were separated. The organic phase was washed with water (3x100 ml) and brine (100 ml), concentrated in vacuo to give a crude dark oil (3.3 g) which was purified by flash chromatography on a Companion (40 g column, 010% MeOH/DCM ), resulting in (S)-N-(5-6poM-2-((trans-(1g,4g)-4hydroxycyclohexyl)amino)phenyl)-1-(3,4-difluorophenyl)-5-oxopyrrolidine- 2-carboxamide (1.36 g, 68%) as a gray-violet film; temp. beats 1.98 min; m/z 508 (M+H)+ (electrospray ⁺ ).

Trans-( 1 g, 4 g)-4-(5-bromo-2-((S)-1 -(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-1 H-benzo[d]imidazole1 -yl)cyclohexyl acetate

- 188 041318

(S)-N-(5-bromo-2-((trans-(1r,4r)-4-hydroxycyclohexyl)amino)phenyl)-1-(3,4-difluorophenyl)-5oxopyrrolidine-2-carboxamide (1.36 g , 2.68 mmol) was dissolved in acetic acid (10.72 ml, 187 mmol) and stirred at 70°С for 72 h.

The reaction mixture was cooled to RT and concentrated in vacuo. The crude brown oil was purified by flash chromatography on a Companion (4 g, DCM/MeOH: 100/90 to 90/10). The desired fractions were concentrated, the residue was dissolved in DCM (50 ml) and washed with saturated NaHCO ₃ solution (2x50 ml). The organic phase was dried with a phase separator and concentrated in vacuo to give (S)-5-(5-bromo-1-((1r,4S)-4-hydroxycyclohexyl)-1Hbenzo[d]imidazol-2-yl )-1-(3,4-difluorophenyl)pyrrolidin-2-one (365 mg, 26%) was isolated as a beige solid; temp. beats 2.36 min; m/z 534 (M+H)+ (electrospray ⁺ ).

Trans-(1r,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-ul)-5-(4,4,5,5-tetramethyl- 1,3,2dioxaborolan-2-yl)-1 H-benzo[d]imidazol-1-yl)cyclohexyl acetate 1555-88

To a solution of trans-(1r,4r)-4-(5-bromo-2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-1Hbenzo[d]imidazole-1 -yl)cyclohexylacetate (0.345 g, 0.648 mmol) and bis-(pinacolato)diboron (0.247 g, 0.972 mmol) in 1,4-dioxane (5.40 ml, 0.648 mmol) were added potassium bicarbonate (0.204 g, 2.074 mmol) and PdCl ₂ (dppf) (0.045 g, 0.062 mmol). The mixture was degassed with nitrogen and heated at 85° C. for 2 h and then cooled to RT and concentrated in vacuo. The crude product was purified by Companion chromatography (12 g column, 0-100% AcOEt/DCM) to give trans(1 r,4r)-4-(2-((S)-1-(3,4- difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)cyclohexyl acetate ( 0.244 g, 60%) as a brown solid; temp. beats 2.45 min; m/z 580 (M+H) ⁺ (electrospray ⁺ ).

(4-( 1 -(trans-( 1 r,4s)-4-acetoxycyclohexyl)-2-((S)-1 -(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)1H-benzo[ d] imidazol-5 -yl)-3-methylisoxazol-5 -yl)methyl acetate

A mixture of water (0.293 ml, 16.26 mmol) and trans-(1r,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-5oxopyrroludin-2-yl)-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolαn-2-yl)-1H-benzo[d]imidazol-1yl)cyclohexyl acetate (0.244 g, 0.421 mmol) and (4-bromo-3-methylisoxazol-5 -yl)methyl acetate (0.068 g, 0.292 mmol) in PdCl ₂ (dppf) (0.021 g, 0.029 mmol) and potassium carbonate (0.121 g, 0.877 mmol) was purged with nitrogen (N2) for 10 min. Then 1,4-dioxane (1.626 ml, 19.01 mmol) was added. The reaction mixture was heated at 90°C for 4.5 h. The reaction mixture was cooled to RT and concentrated under vacuum. The organic layer was concentrated in vacuo, then purified by flash chromatography (12 g, DCM/MeOH: 100/90 to 90/10), then by flash column (12 g, DCM/MeOH: 100/90 to 90/10), resulting in (4-(1-(trans-(1r,4r)-4-acetoxycyclohexyl)2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidine-2 -yl)-1H-benzo[d]imidazol-5-yl)-3-methylisoxazol-5yl)methyl acetate (100 mg, 39%) was isolated as a brown solid; temp. beats 2.17 min; m/z 607

- 189 041318 (M+H)+ (electrospray ⁺ ).

(S)-1-(3,4-difluorophenyl)-5-(1-((1g,4S)-4-hydroxycyclohexyl)-5-(5-(hydroxymethyl)-3methylisoxazol-4-yl)-1 H- benzo[d]imidazol-2-yl)pyrrolidin-2-one

(4-(1-(trans-(1g,4S)-4-acetoxycyclohexyl)-2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)1H-benzo[d ]imidazol-5-yl)-3-methylisoxazol-5-yl)methyl acetate (107 mg, 0.123 mmol) was diluted in MeOH (4.995 ml, 123 mmol). Potassium carbonate (171 mg, 1.235 mmol) was added and the suspension stirred at rt. for 24 h. The reaction mixture was concentrated in vacuo, then the solids were dissolved in DCM (5 ml), sonicated and loaded dry on silica gel. The compound was purified by flash chromatography (DCM/MeOH: 100/90 to 90/10) to give (S)1-(3,4-d iflorphenyl)-5-( 1 -((1 g, 4S) -4-hydroxycyclohexyl)-5-(5-(hydroxymethyl)-3-methylisoxazol-4yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (30 mg, 46%) was isolated as white a solid; temp. beats 1.55 min; m/z 523 (M+H)+ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 7.88 - 7.78 (m, 2H), 7.69 (d, J=1.6 Hz, 1H), 7.38 (dt, J=10.7, 9.2 Hz, 1H), 7.28 (dd, J=8.5, 1.7 Hz, 1H), 7.20 - 7.10 (m, 1H), 6.11 (dd, J=8.2, 2.0 Hz, 1H), 5.42 (t, J=5.5 Hz, 1H), 4.75 (d, J =4.2 Hz, 1H), 4.56 - 4.39 (m+d, 3H), 3.78 - 3.66 (m, 1H), 2.82 - 2.53 (m, 3H), 2.41 (s, 3H), 2.39 - 2.22 (m, 2H ), 2.14 2.04 (m, 1H), 2.04 - 1.92 (m, 2H), 1.88 - 1.76 (m, 1H), 1.76 - 1.68 (m, 1H), 1.59 - 1.36 (m, 2H).

Example 177: (S)-1-(3,4-difluorophenyl)-5-( 1 -((1 g,4S)-4-hydroxycyclohexyl)-5-(3-(hydroxymethyl)-5 methylisoxazol-4-yl )-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one.

(4-(1-((1 g,4S)-4-acetoxycyclohexyl)-2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-1Hbenzo[d]imidazole -5 -yl)-5 -methylisoxazol-3 -yl)methyl acetate

(S)-1 -(3,4-difluorophenyl)-5-(1 -((1 g,4S)-4-hydroxycyclohexyl)-5 -(3-(hydroxymethyl)-5 methylisoxazol-4-yl)-1 H-benzo[d]imidazol-2-yl)pyrrolidin-2-one

(4-( 1 -((1 r,4s)-acetoxycyclohexyl)-2-((S)-1 -(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-1Hbenzo[d]imidazol-5 -yl)-5-methylisoxazol-3-yl)methyl acetate (36.9 mg, 0.054 mmol) was diluted in MeOH (2166 µl, 53.5 mmol). Potassium carbonate (22.19 mg, 0.161 mmol) was added and the suspension was stirred at rt. for 2 h. The reaction mixture was concentrated in vacuo and then the solid was dissolved in DCM (5 ml), sonicated and loaded onto silica gel dry. This compound was purified by column chromatography (DCM/MeOH: 100/90 to 90/10) to give (8)-1-(3,4-difluorophenyl)-5-(1-((1g,48 )-4-hydroxycyclohexyl)-5-(3(hydroxymethyl)-5-methylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (8 mg, 28%) in the form white solid; temp. beats 1.61 min; m/z 523 (M+H)+ (electrospray ⁺ );

1I-NMR (d6-DMSO) δ: 7.88 - 7.77 (m, 2H), 7.69 (d, J=1.6 Hz, 1H), 7.38 (q, J=10.6, 9.2 Hz, 1H), 7.28 (dd, J =8.5, 1.7 Hz, 1H), 7.20 - 7.10 (m, 1H), 6.11 (dd, J=8.2, 2.0 Hz, 1H), 5.42 (t, J=5.5 Hz, 1H), 4.75 (d, J= 4.2 Hz, 1H), 4.54 - 4.40 (m+d, 3H), 3.77 - 3.67 (m, 1H), 2.81 - 2.67 (m, 1H), 2.67 - 2.53 (m, 1H), 2.41 (s, 3H) , 2.38-2.26 (m, 2H), 2.11 -2.03 (m, 1H), 2.03 - 1.91 (m, 3H), 1.85 - 1.77 (m, 1H), 1.76 - 1.68 (m, 1H), 1.59 - 1.39 ( m, 2H).

- 190 041318

Example 178: (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)-1-phenylpiperidin-2 -He.

(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2-yl)-1 phenylpiperidin-2- He

CuTMEDA (60 mg,

0.129 mmol) was added to a stirred suspension of (S)-6-(1-(4,4difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2-yl)piperidine -2-one (70 mg, 0.163 mmol) in pyridine (3 ml), at 40°C, then stirred for 15 min. Phenylboronic acid (100 mg, 0.820 mmol) was added, then the mixture was stirred at 40° C. overnight. The mixture was diluted with dichloromethane (10 ml), then washed with water (2x15 ml) and then with brine (15 ml). The organic phase was concentrated under reduced pressure, then purified by flash chromatography on a Companion device (4 g column, 0-50% THF/DCM). The product was triturated in diethyl ether to give ((S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4yl)-1H-benzo[d]imidazole-2- yl)-1-phenylpiperidin-2-one (64 mg, 74%) as a white solid, temp 2.12 min, m/z 505 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.73 (dd, J=1.7, 0.6 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.31 - 7.09 (m, 6H), 5.76 5.64 (m , 1H), 4.62 (t, J=12.4 Hz, 1H), 2.67 - 2.52 (m, 2H), 2.45 - 2.31 (m, 2H), 2.41 (s, 3H), 2.25 (s, 3H), 2.23 1.79 (m, 9H), 1.10-1.01 (m, 1H).

Example 179: (S)-1-(3-Chloro-4-methoxyphenyl)-6-( 1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol4-yl)-1H-benzo[d] imidazol-2-yl)piperidin-2-one.

(S)-N-(2-((3,3-difluorocyclobutyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-6-oxopineridine-2carboxamide

dimethylisoxazol-4-yl)benzene-1,2-diamine (1.11 g, 3.78 mmol), (S)-6-oxopuperidin-2-carboxylic acid (0.596 g, 4.16 mmol) and HATU (1.583 g, 4.16 mmol) in DMF (10 ml), then stirred at rt. within 18 hours the Mixture was diluted with water (30 ml), then was extracted with dichloromethane (100 ml). The organic phase was washed with water (30 ml), passed through a PhaseSep phase separator and concentrated in vacuo. The residue was purified by flash chromatography to give (S)-N(2-((3,3-difluorocyclobutyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-6-oxopiperidine-2carboxamide (751 mg, 46%) as a viscous red-brown oil; temp. beats 1.78 min; m/z 419 (M+H) ⁺ (electrospray ⁺ ).

(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2yl)piperidin-2-one

A solution of (S)-N-(2-((3,3-difluorocyclobutyl)amino)-5-(3,5-dimethylisoksazol-4-yl)phenyl)-6oxo-piperidine-2-carboxamide (1.58 g, 3.78 mmol) in acetic acid (5 ml) was heated at 80°C for 18 hours. The solvent was removed under vacuum, the crude product was diluted in a minimum amount of DCM and purified by chromatography (40 g silica gel, 0-10% MeOH in DCM, gradient elution). Product containing fractions were combined and concentrated in vacuo to give (S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d] imidazol-2-191 041318 yl)piperidin-2-one (497 mg, 32%) as a beige solid; temp. beats 1.70 min; m/z 401 (M+H) ⁺ (electrospray ⁺ ).

(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]umidazol-2-yl)-1phenylpiperidin-2-one

Into a scintillation vial containing (S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidine- 2-one (100 mg, 0.250 mmol) in pyridine (3 mL), CuTMEDA (58.0 mg, 0.125 mmol) was added. The reaction mixture was stirred at 40°C for 15 min, then (3-chloro-4-methoxyphenyl)boronic acid (116 mg, 0.624 mmol) was added and the reaction mixture was left to stir at 40°C for 18 h. The reaction mixture was cooled to RT and partitioned between ethyl acetate (20 ml) and water (10 ml). The organic phase was washed with an additional portion of water (2x10 ml), dried (MgSO ₄ ) and concentrated under vacuum. The crude residue was purified by chromatography (4 g silica gel, 0-4% MeOH in DCM, gradient elution) to give (S)-1-(3-chloro-4-methoxyphenyl)-6-(1-(3.3 -difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4yl)-1H-benzo[d]imidazol-2-ul)piperidin-2-one (74 mg, 55%) as a beige solid; temp. beats 2.17 min; m/z 541 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.77 (dd, J=1.7, 0.6 Hz, 1H), 7.59 (dd, J=8.5, 0.6 Hz, 1H), 7.36 (d, J=2.5 Hz, 1H ), 7.28 (dd, J=8.5, 1.7Hz, 1H), 7.14 (dd, J=8.8, 2.5Hz, 1H), 7.01 (d, J=8.9Hz, 1H), 5.69 (t, J=4.8Hz , 1H), 5.14 (dq, J=8.8, 3.7 Hz, 1H), 3.76 (s, 3H), 3.57-3.33 (m, 2H), 3.03 (m, 1H), 2.60 - 2.53 (m, 2H), 2.50 - 2.31 (m, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.08 (d, J=5.6 Hz, 1H), 1.87 (s, 1H), 1.77 (s, 1H).

Example 180: (S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol2-yl)-1-(3, 4-difluorophenyl)piperidin-2-one.

(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1phenylpiperidin-2-one

Into a scintillation vial containing (S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidine- 2-one (100 mg, 0.250 mmol) in pyridine (3 mL), CuTMEDA (58.0 mg, 0.125 mmol) was added. The reaction mixture was stirred at 40°C for 15 min, then (3,4-difluorophenyl)boronic acid (99 mg, 0.624 mmol) was added and the reaction mixture was left to stir at 40°C for 18 h. The reaction mixture was cooled to RT and partitioned between ethyl acetate (20 ml) and water (10 ml). The organic phase was washed with an additional portion of water (2x10 ml), dried (MgSO ₄ ) and concentrated under vacuum. The crude residue was purified by flash chromatography (4 g silica gel, 0-4% MeOH in DCM, gradient elution) to give (S)-6-(1-(3,3-difluorocyclobutyl)-5-(3.5 -dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1(3,4-difluorophenyl)piperidin-2-one (78 mg, 60%) as an off-white solid; temp. beats 2.18 min; m/z 513 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.77 (d, J=1.6 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.43 - 7.24 (m, 3H), 7.14 -7.05 (m , 1H), 5.78-5.69 (m, 1H), 5.14 (td, J=8.5, 3.7 Hz, 1H), 3.58 - 3.33 (m, 2H), 3.10 (m, 1H), 2.61 - 2.46 (m, 2H ), 2.40 (m, 5H), 2.24 (s, 3H), 2.07 (d, J=4.8 Hz, 1H), 1.83 (m, 1H), 1.77 (m, 1H).

Example 181: (S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol2-yl)-1-(3- fluoro-4-methoxyphenyl)piperidin-2-one.

(S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3fluoro-4 -methoxyphenyl)piperidin-2-one

- 192 041318

Into a scintillation vial containing (S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidine- 2-one (100 mg, 0.250 mmol) in pyridine (3 mL), CuTMEDA (58.0 mg, 0.125 mmol) was added. The reaction mixture was stirred at 40°C for 15 min, then (3-fluoro-4-methoxyphenyl)boronic acid (106 mg, 0.624 mmol) was added and the reaction mixture was left to stir at 40°C for 18 h. The reaction mixture was cooled to RT and partitioned between ethyl acetate (20 ml) and water (10 ml). The organic phase was washed with an additional portion of water (2x10 ml), dried (MgSO ₄ ) and concentrated under vacuum. The crude residue was purified by chromatography (4 g silica gel, 0-4% MeOH in DCM, gradient elution) to give (S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazole -4-yl)-1H-benzo[d]imidazol-2yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one (85 mg, 64%) as a beige solid; temp. beats 2.09 min; m/z 525 (M+H)+ (electrospray ⁺ );

Ή-NMR (de-DMSO) δ: 7.77 (dd, J=1.7, 0.6 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.4, 1.7 Hz, 1H), 7.13 (dd, J=12.7, 2.3Hz, 1H), 7.08 - 6.95 (m, 2H), 5.68 (t, J=4.7Hz, 1H), 5.14 (td, J=8.4, 3.7Hz, 1H), 3.75 (s, 3Н), 3.47 (dt, J=16.8, 8.5 Hz, 1H), 3.36 - 3.26 (m, 2H), 3.09 - 2.97 (m, 1H), 2.59 - 2.41 (m, 2H), 2.41 (s , 3H), 2.36 (m, 1H), 2.24 (s, 3H), 2.07 (d, J=13.0 Hz, 1H), 1.87 (m, 1H), 1.76 (m, 1H).

Example 182: (1S,4r)-methyl 4-(2-((S)-1-(3,4-difluorophenyl)-6-oxo-piperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl) -1 H-benzo[d]imidazol-1 -yl)cyclohexanecarboxylate (1S,4r)-methyl 4-(2-((S)-1-(3,4-difluorophenyl)-6-oxo-piperidin-2-yl) -5-(3,5-dimethylisoxazol-4-yl)1 H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate

O. O \-OMe V-OH

CuTMEDA (0.722 g, 1.554 mmol) was added to a stirred solution of (1S,4r)-methyl-4-(5-(3,5dimethylisoxazol-4-yl)-2-((S)-6-oxo-piperidin-2-yl) -1H-benzo[d]imidazol-1yl)cyclohexanecarboxylate (1.4 g, 3.11 mmol) in pyridine (37.4 ml, 463 mmol), then the mixture was stirred for 15 min at 40°C. (3,4-difluorophenyl)boronic acid (1.300 g, 8.23 mmol) was added, then the mixture was heated to 40°C for 2.5 h, then stirred at rt. during the night. The mixture was concentrated in vacuo to give a green residue which was diluted with ethyl acetate (100 ml) and filtered through a pad of celite to remove the copper salts. The organic phase was washed with water (3x100 ml) and brine (100 ml), dried (MgSO ₄ ), filtered and concentrated under reduced pressure, and the crude product was purified by flash chromatography on a Companion device (24 g column, DCM/MeOH: from 100 /90 to 90/10), then purified by flash chromatography (12 g, DCM/AcOEt: 100/90 to 0/100) to give (1S,4r)-methyl 4-(2((S)-1 -(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-1 yl)cyclohexanecarboxylate (1.0 g, 55 %) was isolated as a pinkish foam; temp. beats 2.15 min; m/z 563 (M+H) ⁺ (electrospray ⁺ );

Ή-NMR (d ₆ -DMSO) δ: 7.85 (d, J=8.4 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.42 - 7.28 (m, 2H), 7.14 (dd, J= 8.4, 1.7 Hz, 1H), 7.09 - 7.00 (m, 1H), 5.78 (t, J=4.6 Hz, 1H), 4.44 - 4.32 (m, 1H), 3.63 (s, 3H), 2.71 - 2.59 (m , 1H), 2.59 - 2.43 (m, 2H), 2.40 (s, 3H), 2.39 - 2.25 (m, 2H), 2.23 (s, 3H), 2.22 - 2.13 (m, 1H), 2.08 - 1.99 (m , 2H), 1.99 - 1.91 (m, 2H), 1.87 - 1.72 (m, 2H), 1.71 - 1.56 (m, 2H), 1.28 - 1.18 (m, 1H).

Example 183: (1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxo-piperidin-2-yl)-5-(3,5-dimethylisoxazol4-yl)- 1 H-benzo[d]imidazol-1 -yl)cyclohexanecarboxylic acid (1 S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxo-piperidin-2-yl) -5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-1-yl)cyclohexanecarboxylic acid

- 193 041318

O. O ν°Μθ won

A solution of LiOH (0.054 g, 2.240 mmol) in water (15.85 mL, 880 mmol) was added to a solution of (1S,4r)methyl 4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidine -2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-1-yl)cyclohexanecarboxylate (0.900 g, 1.600 mmol) in THF (15.86 ml, 194 mmol). The solution was stirred at 50° C. for 2 hours at RT, an aqueous 1M HCl solution (3 ml) (pH 2) was added. The resulting white solid was filtered, washed with water (3x10 ml), washed with diethyl ether (3x5 ml). The solid was dried in vacuo at 40° C. for 15 h to give (1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidine-2- yl)-5-(3,5-dimethylisoxazol-4ul)-1H-benzo[d]umidazol-1-yl)cyclohexanecarboxylic acid (698 mg, 77%) as a white solid; temp. beats 1.86 min; m/z 549 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 12.17 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.43 - 7.28 (m, 2H ), 7.15 (d, J=8.0 Hz, 1H), 7.09 - 7.00 (m, OH), 5.80 (t, 1H), 4.44 - 4.30 (m, 1H), 2.64 - 2.45 (m, 2H), 2.41 ( s, 3H), 2.39 - 2.25 (m, 2H), 2.24 (s, 3H), 2.21 - 2.10 (m, 1H), 2.08 - 2.00 (m, 2H), 2.00 - 1.92 (m, 2H), 1.87 - 1.73 (m, 2H), 1.68 - 1.53 (m, 2H), 1.28 - 1.18 (m, 1H).

Example 184: (1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxonunerudin-2-yl)-5-(3,5-dimethylisoxazol4-yl)- 1H-benzo[d]imidazol-1-yl)-N-propylcyclohexane carboxamide.

(1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-ul)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo [d]imidazol-1-yl)-N-propylcyclohexane carboxamide

Me λ o G

V- ^0H V-- ^NH

DIPEA (0.040 ml, 0.228 mmol) was added to a solution of propane-1-amine (8.23 µl, 0.100 mmol), (1 S,4r)-4-(2-((S)-1-(3,4-difluorophenyl) -6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imudazol-1-yl)cyclohexanecarboxylic acid (50 mg, 0.091 mmol) and HATU (45.0 mg, 0.118 mmol) in DMF (0.303 ml, 3.91 mmol). The brown solution was stirred at rt. for 15 h, then the reaction mixture was diluted in AcOEt (30 ml) and washed with water (3x20 ml) and brine (20 ml). The organics were dried with MgSO ₄ , filtered and concentrated in vacuo to give a beige foam as crude material. This crude material was purified by flash chromatography on a Companion (4 g, DCM/AcOEt: 100/90 to 0/100) to give (1S,4r)-4-(2-((S)-1- (3,4-difluorophenyl)-6-oxopineridin-2-yl)-5-(3,5dimethylisoxazol-4-ul)-1H-benzo[d]imidazol-1-yl)-N-propylcyclohexane carboxamide (36 mg, 66% yield) was isolated as a white solid; temp. beats 1.99 min; m/z 590 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 7.77 - 7.69 (m, 3H), 7.43 - 7.28 (m, 2H), 7.16 (dd, J=8.5, 1.6 Hz, 1H), 7.09 - 7.01 (m, 1H), 5.79 (t, J=4.9 Hz, 1H), 4.46 -4.31 (m, 1H), 3.02 (q, J=6.5 Hz, 2H), 2.63 - 2.52 (m, 2H), 2.43 - 2.39 (m , 3H), 2.39 - 2.26 (m, 2H), 2.24 (s, 3H), 2.22 - 1.94 (m, 4H), 1.93 - 1.74 (m, 4H), 1.74 - 1.59 (m, 2H), 1.41 (h , J=7.3 Hz, 2Н), 1.29 - 1.20 (m, 1H), 0.84 (t, J=7.4 Hz, 3Н).

Example 185: (1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxonunerudin-2-yl)-5-(3,5-dimethylisoxazol4-yl)- 1 H-benzo[d]imidazole-1-ul)-N-methyl-N-propylcyclohexanecarboxamide.

(1 S,4r)-4-(2-((S)-1 -(3,4-difluorophenyl)-6-oxo-piperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)- 1Hbenzo[d]imidazol-1-yl)-N-methyl-N-p-propylcyclohexanecarboxamide

- 194 041318

DIPEA (0.040 ml, 0.228 mmol) was added to a solution of N-methylpropan-1-amine (10.27 μl, 0.100 mmol), (1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl )-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (50 mg, 0.091 mmol) and HATU (45.0 mg, 0.118 mmol) in DMF (0.303 ml, 3.91 mmol). The yellow solution was stirred at rt. for 2 hours. The reaction mixture was diluted in AcOEt (30 ml) and washed with water (3x20 ml) and brine (20 ml). The organics were dried with MgSO ₄ , filtered and a beige foam as crude material was purified by flash chromatography on a Companion (4 g, DCM/AcOEt: 100/90 to 0/100) to give ((1S ,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d ]imidazol-1-yl)-N-methyl-N-propylcyclohexanecarboxamide (35.1 mg, 62%) as yellow glass, temp 2.12 min, m/z 604 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.97 - 7.86 (m, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.44-7.27 (m, 2H), 7.15 (ddd, J=8.5, 4.9 , 1.7 Hz, 1H), 7.10 - 7.00 (m, 1H), 5.88-5.78 (m, 1H), 4.47-4.31 (m, 1H), 3.37 (t, J=7.3 Hz, 1H), 3.30 - 3.21 ( m, 1H), 3.06 (s, 1.6H), 2.96 - 2.89 (m, 1H), 2.80 (s, 11.4H), 2.60 - 2.52 (m, 1H), 2.44 - 2.29 (m+d, 6H), 2.292.13 (m+d, 4H), 2.09 - 1.91 (m, 2H), 1.86 - 1.61 (m, 6H), 1.61 - 1.52 (m, 1H), 1.46 (h, J=7.3 Hz, 1H), 1.22-1.13 (m, 1H), 0.91 (t, J=7.3 Hz, 1.4H), 0.81 (t, J=7.4 Hz, 1.6H).

Example 186: (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)-1-(6- fluoropyridin-3-yl)piperidin-2-one.

(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(6fluoropyridin-3 -yl)piperidine-2-one

CuTMEDA (60 mg, 0.129 mmol) was added to a stirred suspension of (S)-6-(1-(4,4difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2 -yl)piperidin-2-one (70 mg, 0.163 mmol) in pyridine (3 ml) at 40°C, then stirred for 15 min. (6fluoropyridin-3-yl)boronic acid (100 mg, 0.710 mmol) was added, then the mixture was stirred at 40° C. overnight. The mixture was diluted with dichloromethane (10 ml), then washed with water (2x15 ml) and then with brine (15 ml). The organic phase was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% THF/DCM). The product was triturated in diethyl ether to give (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl )-1-(6-fluoropyridin-3-yl)piperidin-2-one (11 mg, 12%) as a white solid; temp. beats 2.10 min; m/z 524 (M+H) ⁺ (electrospray ⁺ );

1P-NMR (d ₆ -DMSO) δ: 8.16 - 8.04 (m, 1H), 7.85 (ddd, J=8.7, 7.3, 2.7 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.54 ( d, J=8.5Hz, 1H), 7.23 (dd, J=8.4, 1.7Hz, 1H), 7.14 (dd, J=8.7, 3.0Hz, 1H), 5.77 (t, J=4.6Hz, 1H), 4.63 (t, J=12.4 Hz, 1H), 2.60 (dt, J=9.2, 5.3 Hz, 2H), 2.50 - 2.42 (m, 1H), 2.41 (s, 3H), 2.40 - 2.25 (m, 2H) , 2.24 (s, 3Н), 2.15 (dd, J=34.4, 15.8 Hz, 5Н), 1.96 (d, J=12.1 Hz, 2Н), 1.87 - 1.77 (m, 1H), 1.44 - 1.36 (m, 1H ).

Example 187: (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)-1-(5- fluoropyridin-3-yl)piperidin-2-one.

(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(5fluoropyridin-3 -yl)piperidine-2-one

- 195 041318

CuTMEDA (60 mg, 0.129 mmol) was added to a stirred suspension of (S)-6-(1-(4,4difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-III-benzo^]imidazol-2- yl)piperidin-2-one (70 mg, 0.163 mmol) in pyridine (3 ml) at 40°C, then stirred for 15 min. (5fluoropyridin-3-yl)boronic acid (100 mg, 0.710 mmol) was added, then the mixture was stirred at 40°С overnight. The mixture was diluted with dichloromethane (10 ml), then washed with water (2x15 ml) and then with brine (15 ml). The organic phase was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% THF/DCM). The product was triturated in diethyl ether to give (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl )-1-(5-fluoro-pyridin-3-yl)-piperidin-2-one (5 mg, 6%) as a white solid; temp. beats 2.06 min; m/z 524 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 8.38 (d, J=2.6 Hz, 1H), 8.34 (t, J=1.7 Hz, 1H), 7.75 - 7.72 (m, 1H), 7.69 (ddd, J= 10.3, 2.7, 1.9Hz, 1H), 7.54 (d, J=8.5Hz, 1H), 7.23 (dd, J=8.5, 1.7Hz, 1H), 5.85 (t, J=4.6Hz, 1H), 4.73 - 4.55 (m, 1H), 2.66 - 2.53 (m, 2H), 2.47 - 2.26 (m, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 2.13 (t, J=23.0 Hz, 5H) , 1.98 (d, J=12.8 Hz, 2H), 1.82 (s, 1H), 1.42 (d, J=12.5 Hz, 1H).

Example 188: (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)-1-(pyridin- 3-yl)piperidine-2-one.

(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1(pyridin-3- yl)piperidine-2-one

CuTMEDA (60 mg, 0.129 mmol) was added to a stirred suspension of (S)-6-(1-(4,4difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol- 2-yl)piperidin-2-one (100 mg, 0.233 mmol) in pyridine (3 ml) at 40°C, then stirred for 15 min. Pyridine-3ylboronic acid (100 mg, 0.814 mmol) was added, then the mixture was stirred at 40° C. overnight. The mixture was diluted with dichloromethane (10 ml), then washed with water (2x15 ml) and then with brine (15 ml). The organic phase was concentrated under reduced pressure, then purified by Companion chromatography (4 g column, 0-50% THF/DCM), then purified by preparative HPLC (Waters, acidic conditions (0.1% formic acid), acidic conditions, Waters X-column). Select Prep-C18, 5 µm, 19x50 mm, 25-70% MeCN in water) to give (S)-6-(1-(4,4difluorocyclohexyl)-5-(3,5-dimethylisoxazole-4- yl)-1 H-benzo[d]imidazol-2-yl)-1-(pyridin-3 yl)piperidin-2-one (26 mg, 21%) as a white solid; temp. beats 1.87 min; m/z 506 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 8.43 (dd, J=2.5, 0.7 Hz, 1H), 8.32 (dd, J=4.7, 1.5 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H ), 7.65 (ddd, J=8.2, 2.5, 1.5 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.33 (ddd, J=8.1, 4.7, 0.8 Hz, 1H), 7.22 (dd, J=8.5, 1.7 Hz, 1H), 5.79 (t, J=4.6 Hz, 1H), 4.72 - 4.56 (m, 1H), 2.66 - 2.52 (m, 2H), 2.49 -2.42 (m, 1H), 2.41 (s, 3H), 2.40 2.25 (m, 2H), 2.24 (s, 3H), 2.22 - 1.90 (m, 7H), 1.83 (s, 1H), 1.33 - 1.17 (m, 1H).

Example 195: (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisooxazol-4-yl)-1Hbenzo[d]imidazol-2-yl)-1-(pyrimidin- 5-yl)piperidine-2-one.

(S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1(pyrimidin-5- yl)piperidine-2-one

- 196 041318

CuTMEDA (27.1 mg, 0.058 mmol) was added to a stirred solution of (S)-6-(1-(4,4difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2 -yl)piperidin-2-one (50 mg, 0.117 mmol) in pyridine (2 ml, 24.73 mmol), then the mixture was stirred for 15 min at 40°C. Pyrimidin-5-ylboronic acid (38.3 mg, 0.309 mmol) was added, then the mixture was heated to 40°C for 2 h. The mixture was diluted with ethyl acetate (25 ml), then washed with water (3x25 ml) and brine (25 ml) . The mixture was concentrated under reduced pressure, then the crude product was purified by silica gel chromatography (24 g column, 0-10% MeOH/DCM) to give ((S)-6-(1-(4,4-difluorocyclohexyl)-5 -(3,5-dimethylisooxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1(pyrimidin-5-yl)piperidin-2-one (8 mg, 13%) as a colorless solid substances, sp time 1.96 min, m/z 507 (M+H)+ (electrospray ⁺ );

Ή-NMR (d6-DMSO) δ: 8.94 (s, 1H), 8.74 (s, 2H), 7.77 - 7.67 (m, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.23 (dd, J =8.5, 1.7 Hz, 1H), 5.89 (t, J=4.5 Hz, 1H), 4.77 - 4.54 (m, 1H), 2.66 - 2.58 (m, 2H), 2.48 - 2.44 (m, 2H), 2.40 ( s, 3H), 2.37 - 2.26 (m, 2H), 2.24 (s, 3H), 2.21 - 2.05 (m, 4H), 2.05 - 1.80 (m, 3H), 1.56 - 1.43 (m, 1H).

Generic E: A non-convergent approach to the preparation of azabenzimidazole analogues.

Example 189: (S)-1-(3-chloro-4-methoxyphenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4hydroxycyclohexyl)-3H- imidazo[4,5-b]pyridin-2-yl)piperidin-2-one.

(S)-1-(3-chloro-4-methoxyphenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4hydroxycyclohexyl)-3H-imidazo[4 ,5-b]pyridin-2-yl)piperidine-2-he he he

MeO CI

Into a scintillation vial containing (S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b ]pyridin-2-yl)piperidin-2-one (100 mg, 0.244 mmol) in pyridine (3 mL), CuTMEDA (56.7 mg, 0.122 mmol) was added. The reaction mixture was stirred at 40°C for 15 min, then (3-chloro-4-methoxyphenyl)boronic acid (114 mg, 0.611 mmol) was added and the reaction mixture was left to stir at 40°C for 18 h. The reaction mixture was cooled to RT and partitioned between ethyl acetate (20 ml) and water (10 ml). The organic phase was washed with an additional portion of water (2x10 ml), dried (MgSO ₄ ) and concentrated under vacuum. The crude residue was purified by chromatography (4 g silica gel, 0-10% MeOH in DCM, gradient elution). Product-containing fractions were combined and concentrated in vacuo. The residue was triturated with ether to give (8)-1-(3-chloro-4-methoxyphenyl)-6-(6-(3,5-dimethylisoxazol-4yl)-3-((1r,4S)-4 -hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one (66 mg, 49%) as a beige solid; temp. beats 1.76 min; m/z 550 (M+H)+ (electrospray ⁺ );

Ή-NMR (d6-DMSO) δ: 8.30 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.10 (dd, J=8.8, 2.5 Hz, 1H), 7.01 (d, J=8.9 Hz, 1H), 5.79 (t, J=4.8 Hz, 1H), 4.70 (d, J=4.1 Hz, 1H), 4.35 (m, 1H), 3.76 (s, 3H), 3.52 (m, 1H), 2.69 - 2.46 (m, 3H), 2.42 (s, 3H), 2.38 (m, 1H), 2.25 (s, 3H), 2.06 (m , 2H), 1.95 (d, J=12.5 Hz, 1H), 1.83 (m, 3H), 1.72 (d, J=12.5 Hz, 1H), 1.39 (m, 2H), 1.16 -1.06 (m, 1H) .

Example 190: (S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4hydroxycyclohexyl)-3H-imidazo [4,5-b]pyridin-2-yl)piperidin-2-one.

(S)-1-(3-chloro-4-methoxyphenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4hydroxycyclohexyl)-3H-imidazo[4 ,5-b]pyridin-2-yl)piperidin-2-one

- 197 041318

Into a scintillation vial containing (S)-6-(6-(3,5-dimethyl-isoxazol-4-yl)-3((1r,4S)-4-hydroxycyclohexyl)-3H-umidazo[4,5-b ]pyrudin-2-yl)pineridin-2-one (100 mg, 0.244 mmol) in pyridine (3 mL), CuTMEDA (56.7 mg, 0.122 mmol) was added. The reaction mixture was stirred at 40°C for 15 min, then (3,4-difluorophenyl)boronic acid (96 mg, 0.611 mmol) was added and the reaction mixture was left to stir at 40°C for 18 h. The reaction mixture was cooled to RT and partitioned between ethyl acetate (20 ml) and water (10 ml). The organic phase was washed with an additional portion of water (2x10 ml), dried (MgSO ₄ ) and concentrated under vacuum. The crude residue was purified by chromatography (4 g silica gel, 0-10% MeOH in DCM, gradient elution). Product-containing fractions were combined and concentrated in vacuo. The residue was triturated with ether to give (S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4hydroxycyclohexyl )-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one (61 mg, 47%) as a creamy solid; temp. beats 1.77 min; m/z 522 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 8.31 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.45 - 7.29 (m, 2H), 7.10 - 7.01 (m , 1H), 5.82 (t, J=4.5 Hz, 1H), 4.71 (d, J=4.2 Hz, 1H), 4.35 (m, 1H), 3.53 (m, 1H), 2.67 -2.48 (m, 2H) , 2.48 - 2.36 (m, 4H), 2.25 (s, 3H), 2.07 (m, 1H), 1.96 (d, J=12.2 Hz, 2H), 1.87 (d, J=12.0 Hz, 1H), 1.76 ( t, J=15.8 Hz, 3H), 1.38 (m, 3H), 1.20 (d, J=12.5 Hz, 1H).

Example 191: (S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3Himidazo[4,5-b]pyridine-2- yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one.

(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5b]pyridin-2-yl)- 1-(3-fluoro-4-methoxyphenyl)piperidin-2-one

Into a scintillation vial containing (S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b ]pyridin-2-yl)piperidin-2-one (100 mg, 0.244 mmol) in pyridine (3 mL), CuTMEDA (56.7 mg, 0.122 mmol) was added. The reaction mixture was stirred at 40°C for 15 min, then (3-fluoro-4-methoxyphenyl)boronic acid (104 mg, 0.611 mmol) was added and the reaction mixture was left to stir at 40°C for 18 h. The reaction mixture was cooled to RT and partitioned between ethyl acetate (20 ml) and water (10 ml). The organic phase was washed with an additional portion of water (2x10 ml), dried (MgSO ₄ ) and concentrated under vacuum. The crude residue was purified by chromatography (4 g silica gel, 0-10% MeOH in DCM, gradient elution). Product-containing fractions were combined and concentrated in vacuo. The residue was triturated with ether to give (S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4hydroxycyclohexyl)-3H-imidaαzo[4,5- b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one (59 mg, 45%) as a beige solid; temp. beats 1.70 min; m/z 534 (M+H) ⁺ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 8.31 (d, J=2.0 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.15 (dd, J=12.7, 2.4 Hz, 1H), 7.09 - 6.93 (m, 2H), 5.77 (t, J=4.6 Hz, 1H), 4.71 (d, J=4.1 Hz, 1H), 4.34 (s, 1H), 3.75 (s, 3H), 3.52 (m, 1H), 2.67 2.37 (m, 4H), 2.43 (s, 3H), 2.26 (s, 3H), 2.05 (m, 2H), 1.96 (d, J=12.9 Hz, 1H), 1.90 - 1.78 (m, 2Н), 1.74 (d, J=13.2 Hz, 1H), 1.38 (t, J=13.6 Hz, 2Н), 1.11 (m, 2H).

Example 192: (S)-1-(3-Chloro-4-methoxyphenyl)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4 ,5-b]pyridin-2-yl)pyrrolidin-2-one.

(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5b]n-iridin-2-yl)- 1-(3-fluoro-4-methoxyphenyl)n-pyrrolidin-2-one

- 198 041318

Into a scintillation vial containing (S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridine-2- yl)n-pyrrolidin-2-one (100 mg, 0.241 mmol) in pyridine (3 mL), CuTMEDA (55.9 mg, 0.120 mmol) was added. The reaction mixture was stirred at 40°C for 15 min, then (3-chloro-4-methoxyphenyl)boronic acid (112 mg, 0.602 mmol) was added and the reaction mixture was left to stir at 40°C for 18 h. The reaction mixture was cooled to RT and partitioned between ethyl acetate (20 ml) and water (10 ml). The organic phase was washed with an additional portion of water (2x10 ml), dried (MgSO ₄ ) and concentrated under vacuum. The crude residue was purified by chromatography (4 g silica gel, 0-10% MeOH in DCM, gradient elution). Product-containing fractions were combined and concentrated in vacuo. The residue was triturated with ether to give (S)-1-(3-chloro-4-methoxyphenyl)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5dimethylisoxazol-4-yl)- 3H-imidazo[4,5-b]pyridin-2-yl)pyrrolidin-2-one (33 mg, 24%) as a brown solid; temp. beats 2.35 min; m/z 556 (M+H)+ (electrospray ⁺ );

1H-NMR (H6-DMSO) δ: ^1H -NMR (400 MHz, DMSO-06) δ 8.34 (d, J=2.0 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.81 (d , J=2.6Hz, 1H), 7.28 (dd, J=9.0, 2.6Hz, 1H), 7.08 (d, J=9.1Hz, 1H), 6.09 (dd, J=8.3, 2.2Hz, 1H), 4.78 (s, 1H), 3.77 (s, 3H), 2.93 (dt, J=23.5, 11.8 Hz, 2H), 2.83 - 2.50 (m, 3H), 2.39 (s, 3H), 2.23-2.08 (m, 8H ), 1.95 (d, J=12.7 Hz, 1H), 1.68 (d, J=12.4 Hz, 1H).

Example 193: (S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5b]pyridin-2-yl)-1 -(3,4-difluorophenyl)pyrrolidin-2-one.

(S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5b]pyridin-2-yl)- 1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one

Into a scintillation vial containing (S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridine-2- yl)pyrrolidin-2-one (100 mg, 0.241 mmol) in pyridine (3 mL), CuTMEDA (55.9 mg, 0.120 mmol) was added. The reaction mixture was stirred at 40°C for 15 min, then (3,4-difluorophenyl)boronic acid (95 mg, 0.602 mmol) was added and the reaction mixture was left to stir at 40°C for 18 h. The reaction mixture was cooled to RT and partitioned between ethyl acetate (20 ml) and water (10 ml). The organic phase was washed with an additional portion of water (2x10 ml), dried (MgSO ₄ ) and concentrated under vacuum. The crude residue was purified by chromatography (4 g silica gel, 0-10% MeOH in DCM, gradient elution). Product-containing fractions were combined and concentrated in vacuo. The residue was triturated with ether to give (S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5b]pyridine- 2-yl)-1-(3,4-difluorophenyl)pyrrolidin-2-one (70 mg, 55%) as a light pink solid; temp. beats 2.39 min; m/z 528 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: ¹ H-NMR (400 MHz, DMSO^) δ 8.35 (d, J=2.0 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.87 (ddd , J=13.2, 7.4, 2.7 Hz, 1H), 7.39 (dt, J=10.6, 9.2 Hz, 1H), 7.19 (dddd, J=9.0, 3.9, 2.6, 1.5 Hz, 1H), 6.16 6.08 (m, 1H), 4.76 (s, 1H), 3.04 - 2.88 (m, 2H), 2.78 - 2.63 (m, 2H), 2.61 - 2.50 (m, 1H), 2.39 (s, 3H), 2.21 (s, 3H) , 2.21 - 2.03 (m, 5H), 1.98 (d, J=12.9 Hz, 1H), 1.89 (d, J=12.4 Hz, 1H).

Example 194: (S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5b]pyridin-2-yl)-1 -(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one; (S)-6-(6-(3,5-dimethylisoxαzol-4-yl)-3((1r,4 S)-4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridin-2-yl )- 1 -(3-fluoro-4methoxyphenyl)pyrrolidin-2-one

- 199 041318

Into a scintillation vial containing (S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5dimethylisoxazol-4-yl)-3H-umidazo[4,5-b]pyrudin-2- yl)pyrrolidin-2-one (100 mg, 0.241 mmol) in pyridine (3 mL), CuTMEDA (55.9 mg, 0.120 mmol) was added. The reaction mixture was stirred at 40°C for 15 min, then (3-fluoro-4-methoxyphenyl)boronic acid (102 mg, 0.602 mmol) was added and the reaction mixture was left to stir at 40°C for 18 h. The reaction mixture was cooled to RT and partitioned between ethyl acetate (20 ml) and water (10 ml). The organic phase was washed with additional water (2x10 ml), dried (MgSO ₄ ) and concentrated in vacuo. The crude residue was purified by chromatography (4 g silica gel, 0-10% MeOH in DCM, gradient elution). Product-containing fractions were combined and concentrated in vacuo. The residue was triturated with ether to give (S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3Himidazo[4,5-b]pyridine- 2-yl)-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one (38 mg, 29%) as a brown solid; temp. beats 2.28 min; m/z 540 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d ₆ -DMSO) δ: 8.34 (d, J=2.0 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.69 - 7.60 (m, 1H), 7.13 -7.06 (m , 2H), 6.10 - 6.02 (m, 1H), 4.77 (s, 1H), 3.75 (s, 3H), 3.02 - 2.84 (m, 2H), 2.82 - 2.51 (m, 3H), 2.39 (s, 3H ), 2.22 (s, 3Н), 2.22 - 2.08 (m, 5H), 1.96 (d, J=12.7 Hz, 1H), 1.72 (d, J=12.5 Hz, 1H).

Example 196: (S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5b]pyridine-2- u) piperidin-2-one; (S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl3H-imidazo[4,5-b]nuridin-2-yl)piperidine -2-he

me me

CuTMEDA (0.063 g, 0.136 mmol) was added to a stirred solution of (S)-6-(6-(3,5dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl )piperidin-2-one (0.1 g, 0.272 mmol) in pyridine (3.28 ml, 40.6 mmol), then the mixture was stirred for 15 min at 40°C. (3,4-Difluorophenyl)boronic acid (0.107 g, 0.680 mmol) was added, then the mixture was heated to 40°C for 15 h. The reaction mixture was cooled to rt. The reaction mixture was cooled to rt. The mixture was concentrated in vacuo to give a green residue which was diluted with dichloromethane (10 ml) then washed with water (3x10 ml) and brine (10 ml). The organic phase was filtered through a phase separator and concentrated under reduced pressure. The crude residue was purified by flash chromatography (4 g silica gel, 0-10% MeOH in DCM, gradient elution) to give (S)-1-(3,4-difluorophenyl)-6-(6-(3.5 -dimethylisoxazol-4-yl)-3-isobutyl 3H-imidazo[4,5-b]pyridin-2-yl)piperidin-2-one (45 mg, 33%), which was isolated as a brownish-pink solid; temp. beats 2.17 min; m/z 480 (M+H) ⁺ (electrospray ⁺ );

¹ H-NMR (dg-DMSO) δ: 8.31 (d, J=1.9 Hz, 1H), 8.23 (d, J=1.9 Hz, 1H), 7.41 - 7.28 (m, 2H), 7.13 - 7.04 (m, 1H), 5.64 (dd, J=5.7, 2.9 Hz, 1H), 4.08 (dd, J=14.1, 6.7 Hz, 1H), 3.85 (dd, J=14.1, 8.8 Hz, 1H), 2.64 - 2.51 (m , 2H), 2.46 - 2.35 (m+s, 4H), 2.25 (s, 3H), 2.12 - 2.00 (m, 3H), 1.80 - 1.70 (m, 1H), 0.75 (d, J=6.7 Hz, 3H ), 0.50 (d, J=6.6 Hz, 3Н).

Example 197: (S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl)-1(3-fluoro -4-methoxyphenyl)piperidin-2-one.

(S)-6-(6-(3,5-dimethyluzoxazol-4-yl)-3-usobutyl-3H-imidazo[4,5-b]nuridin-2-yl)-1-(3-fluoro-4methoxyphenyl) )piperidine-2-one

- 200 041318

me me

MeO F

CuTMEDA (0.063 g, 0.136 mmol) was added to a stirred solution of (S)-6-(6-(3,5dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl )piperidin-2-one (0.1 g, 0.272 mmol) in pyridine (3.28 ml, 40.6 mmol), then the mixture was stirred for 15 min at 40°C. (3-Fluoro-4-methoxyphenyl)boronic acid (0.116 g, 0.680 mmol) was added, then the mixture was heated to 40° C. for 15 h. The reaction mixture was cooled to rt. The reaction mixture was cooled to rt. The mixture was concentrated in vacuo to give a green residue which was diluted with dichloromethane (10 ml) then washed with water (3x10 ml) and brine (10 ml). The organic phase was filtered with a phase separator and concentrated under reduced pressure. The crude residue was purified by chromatography (4 g silica gel, 0-10% MeOH in DCM, gradient elution) to give (S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl- 3Himidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4-methoxyphenyl)piperidin-2-one (48 mg, 35%) was isolated as a brown glass; temp. beats 2.02 min; m/z 492 (M+H)+ (electrospray ⁺ );

1H-NMR (d ₆ -DMSO) δ: 8.31 (d, J=2.0 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.09 (dd, J=12.6, 2.3 Hz, 1H), 7.05 - 6.95 (m, 2H), 5.58 (dd, J=5.6, 2.8 Hz, 1H), 4.05 (dd, J=14.1, 6.7 Hz, 1H), 3.85 (dd, J=14.1, 8.7 Hz, 1H), 3.73 (s, 3H), 2.56 - 2.51 (m, 2H), 2.46 - 2.34 (m, 4H), 2.26 (s, 3H), 2.10 -2.00 (m, 3H), 1.79 - 1.70 (m, 1H), 0.73 (d, J=6.7 Hz, 3H), 0.50 (d, J=6.6 Hz, 3H).

General synthetic route F. Convergent approach to the preparation of N-alkyl-lactam analogues.

Example 198: (S)-1-benzyl-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 g, 4S)-4-methoxycyclohexyl)-1Hbenzo[d]imidazol-2 -yl)pyrrolidin-2-one.

(S)-1-benzyl-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 g,4S)-4-methoxycyclohexyl)-1Hbenzo[d]imidazol-2-yl) pyrrolidin-2-one

(S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 g,4S)-4-methoxycyclohexyl)-1Hbenzo[d]imidazol-2-yl)pyrrolidin-2 solution -one (50 mg, 0.121 mmol) in N,N-dimethylformamide (1 ml) was treated with 1.0 M NaHMDS solution in tetrahydrofuran (125 µl, 0.125 mmol), then stirred at room temperature for 5 min. A solution of benzyl bromide (21 mg, 0.123 mmol) in N,N-dimethylformamide (1 ml) was added, then the mixtures were stirred at room temperature for 18 h. The mixture was diluted with water (6 ml), then extracted with dichloromethane (2x6 ml). The combined organic phases were washed with brine (6 ml), then concentrated under reduced pressure. The crude products were purified by Companion chromatography (4 g column, 0-50% THF/DCM), then triturated in diethyl ether:isohexane (1:1, 8 mL) to give (S)-1-benzyl- 5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1Hbenzo[d]imidazol-2-yl)pyrrolidin-2-one (42 mg, 66%) as a white solid; temp. beats 1.97 min; m/z 499 (M+H)+ (electrospray ⁺ );

¹ H-NMR (d6-DMSO) δ: 7.84 (d, J=8.5 Hz, 1H), 7.69 (dd, J=1.7, 0.6 Hz, 1H), 7.38 - 7.24 (m, 3H), 7.21 7.13 (m , 3Н), 5.10 (dd, J=7.9, 3.0 Hz, 1H), 4.99 (d, J=15.5 Hz, 1H), 4.26 (t, J=12.3 Hz, 1H), 3.79 (d, J=15.5 Hz , 1H), 3.37 - 3.30 (m, 1H), 3.26 (s, 3H), 2.60 - 2.53 (m, 1H), 2.50 - 2.42 (m, 2H), 2.42 (s, 3H), 2.31 - 2.12 (m , 2H), 2.25 (s, 3Н), 2.10 - 2.01 (m, 2H), 2.01 - 1.91 (m, 1H), 1.84 - 1.75 (m, 1H), 1.74 - 1.64 (m, 1H), 1.39 - 1.13 (m, 2H).

Example 199 Biological test

Study of binding to EP300, CBP and BRD4 BD1 using surface plasmon resonance (BIAcore).

BIAcore data on compound binding to EP300 and BRD4 was obtained using a T200 BIAcore instrument at 4°C. Histidine labeled EP300 bromodomain (1046-1163), histidine labeled CBP bromodomain (1081-1197), and histidine labeled BRD4 bromodomain 1 (49-170) were fixed on the NTA chip using a combined capture and amine attachment method. The NTA groups were first chelated with 30 mM nickel chloride and then activated with 0.2 M N-ethyl-N'-201 041318 (diethylaminopropyl)carbodiimide (EDC) and 0.05 μM N-hydroxysuccimide (NHS).

Bromodomain proteins diluted to 9.6 M in sodium phosphate buffer (PBS) with 0.05% Tween-20 were injected at 10 L/min and covalently bound. Ethanolamine injections were made to bind unreacted fragments on the surface and remove unbound protein. Typical immobilization resulted in the binding of ~2-4 cfu of the protein immobilized on the surface.

Test compounds were serially diluted to 1, 10, 100, 1000, and 10,000 nM concentration solutions in running buffer (sodium phosphate buffer with 0.005% Tween-20, 0.1% DMSO). Increasing concentration runs of injected compounds interleaved with test samples consisting of 5 replicate injections of running buffer were performed using a flow rate of 90 μl/min.

Sensorgrams were analyzed by BIAevaluation (GE Healthcare) using a 1:1 interaction model to obtain _ka and kd values to describe the binding kinetics. The K _D values were obtained from the ratio of kd and k _a . Compounds were analyzed twice on the surfaces of EP300, CBP and/or BRD4 bromodomains, resulting in geometric averages of kinetic and affinity parameters. All tested compounds had KD values in the range of 0.5-10000 nM. For example, for EP300 and CBP, compounds 70-140 had K _D values in the range of 1-200 nM.

Cell viability analysis.

The 22Rv1 cell line was obtained from ATCC (UK) and cultured according to the supplier's recommendations. Cell growth inhibitory activity of the studied compounds was determined using the CellTiter-Glo® cell viability assay kit (Promega, USA).

22Rv1 cells were maintained in RPMI 1640 medium containing 10% fetal bovine serum, 2 mM glutamine, 1 mM sodium pyruvate and 100 units of penicillin - 100 μg of streptomycin. Cells were incubated at 37°C in a humid atmosphere with 95% O ₂ and 5% CO 2 . 2000 cells/well were plated in 96-well poly-D-lysine (PDL) coated clear bottom black plates in 50 µl of growth medium. After 48 hours, the medium was removed and replaced with growth medium containing diluted test compounds. Compound dilutions were performed by serial half-log dilution of stock solutions with DMSO to a maximum concentration of 10 mM, 7 dilutions in total. An aliquot of 1 μl of each dilution was added to 99 μl of growth medium and 50 μl was added to each well containing cells, providing a compound concentration of 100 μM at the point of maximum concentration (1% DMSO). Cells treated with 1% DMSO were used as controls.

Cells were incubated for 72 hours at 37° C. and cell viability was determined using the CellTiter-Glo® fluorescent cell viability assay according to the manufacturer's instructions. Briefly, a volume of CellTiter-Glo® reagent equal to the volume of growth medium was added to each well. The plates were shaken for approximately 2 minutes and incubated at room temperature (22° C.) for 10 minutes. The luminescence signal was measured using an Envision plate reader with a signal accumulation time of 1 s per well.

All data were normalized to the mean of 6 controls. Half maximum inhibitory concentration (IC ₅₀ ) was calculated from a 4-parameter logistic data fit curve using Dotmatics software (UK). All compounds tested had IC ₅₀ values in the range of 100 nM to 100 μM, typically 100 nM to 30 μM.

Cell-based assays are likely to show some variability due to the complexity of the system, and it should be understood that the results of these assays may vary depending on assay conditions. Some level of cell growth inhibition indicates that the compound has some inhibitory activity in said cells, while the absence of inhibition below the highest concentration tested does not necessarily indicate that the compound does not have inhibitory activity in said cells.

Example 200: tablet formulation.

Tablets, each weighing 0.15 g and containing 25 mg of the compound of the present invention, are made as follows:

Composition per 10,000 tablets

Compound according to the present invention (250 g)

Lactose (800 g)

Corn starch (415 g)

Talc powder (30 g)

Magnesium stearate (5 g)

Mix the compound according to the present invention, lactose and half of the corn starch. This mixture is then passed through a 0.5 mm sieve. Corn starch (10 g) is suspended in warm water (90 ml). The resulting paste is used for powder granulation. The granulate is dried and crushed into small fragments on a sieve with a mesh size of 1.4 mm. Add the remaining amount

- 202 041318 starch, talc and magnesium stearate, mix thoroughly and form tablets.

Example 201 Composition for injection Compound according to the present invention 200 mg 0.1 M hydrochloric acid solution or

0.1 M sodium hydroxide solution until pH 4.0 - 7.0 is reached

Sterile water up to 10 ml

The compound of the present invention is dissolved in most water (35-40° C.) and the pH is adjusted to 4.0-7.0 with hydrochloric acid or sodium hydroxide, as appropriate. The batch is then made up to volume with water and filtered through a sterile microporous filter into a sterile 10 ml amber vial (type 1) and sealed with sterile stoppers and caps.

Example 202 Intramuscular Injection

Compound according to the present invention 200 mg

Benzyl alcohol 0.10 g

Glycofurol 75 1.45 g

Water for injection up to 3.00 ml

The compound according to the present invention is dissolved in glycofurol. Then add benzyl alcohol and dissolve, add water to 3 ml. This mixture is then filtered through a sterile microporous filter and sealed into sterile 3 ml glass vials (type 1).

Example 203 Syrup Composition

Compound according to the present invention 250 mg Sorbitol solution 1.50 g Glycerol 2.00 g sodium benzoate 0.005 g Flavoring substance 0.0125 ml Purified water up to 5.00 ml

The compound according to the present invention is dissolved in a mixture of glycerol and most of the purified water. An aqueous solution of sodium benzoate is then added to the solution, followed by the addition of the sorbitol solution and finally the flavoring agent. Dilute to volume with purified water and mix well.

Claims (14)

CLAIM 1. A compound which is an arylimidazolylisoxazole of formula (I) ^R1 where each of R ⁰ and R, which are the same or different, represent H or C1C ₆ -alkyl, which is unsubstituted or contains as a substituent OH; W is N or CH; R ¹ is a group selected from C-linked 4-6 membered heterocyclyl; C ₃ C ₆ cycloalkyl; C ₁ -C ₆ alkyl which is unsubstituted or substituted by C ₆ -C ₁₀ aryl, 5-6 membered N-containing heteroaryl, C ₃ -C ₆ cycloalkyl, OH, -OC(O)R' or OR', where R' represents unsubstituted C ₁ -C ₆ -alkyl; and spiro groups of the following formula: wherein R ¹ is unsubstituted or substituted with -S(O) ₂ Me, -OH, -S(O) ₂ cyclopropyl, -C(=O)Me, -C(=O)CH2CF3, F, oxo, Me, OMe, -OEt, -OC(=O)Me, -CH2OH, NH2, -C(=O)OH, -C(O)NHPr or -C(=O)N(Me)Pr; - 203 041318 Y represents -CH ₂ - or -CH2CH2-; n is 0 or 1; R ² is a group selected from C ₆ -C ₁₀ -aryl, 5-6 membered N-containing heteroaryl, C ₃ -C ₆ -cycloalkyl and C ₅ -C ₆ -cycloalkenyl, and this group is unsubstituted or substituted by F , Cl, -OMe, OPr, -OCF ₃ , OEt, Me and CN, while C ₆ -C ₁₀ -aryl is optionally fused to a tetrahydrofuran ring; 4-6 membered heterocyclyl is selected from pyrrolidinyl, piperidinyl, tetrahydropyranide and tetrahydrothiopyranyl; And The 5-6 membered N-containing heteroaryl is selected from pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that the arylimidazolylisoxazole has the following formula (Ia): ^R1 where R ¹ corresponds to the definition given in paragraph 1; Y' represents -CH ₂ - or -CH2CH2-; And R ² ' is a group selected from C ₆ -C ₁₀ aryl optionally fused to a tetrahydrofuran ring and 5-6 membered heteroaryl as defined in claim 1, said group being unsubstituted or mono-, di- or trisubstituted as defined in claim 1 for R ² . 3. The compound according to claim 1 or 2, where R ¹ is selected from the following structures: 4. A compound according to any one of the preceding claims which is the S-enantiomer (at the chiral C atom in the pyrrolidin-2-one or piperidin-2-one ring). 5. The compound according to claim 1, which is selected from: 5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[b]imidazol-2-yl)-1-phenylpyrrolidine -2-she; 5-(5-(3,5-dimethylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-2-yl)-1-phenylpyrrolidin-2-one; 5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1 Hbenzo[b]imidazol-2-yl)-1-phenylpyrrolidine -2-she; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)πpyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-phenylpyrrolidin-2-one; (R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[b]imidazol-2-yl) -1-phenylpyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)πpyrrolidin-3-yl)-1Hbenzo[b]imidazol-2-yl) -1-(3-fluorophenyl)pyrrolidin-2-one; - 204 041318 (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(4-methoxyphenyl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(4-propoxyphenyl)pyrrolidin-2-one; (S)-1 -(4-chlorophenyl)-5 -(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(pyridin-3-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(6-fluoropyridin-3-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1 -(naphthalene-1-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(5-fluoropyridin-3-yl)pyrrolidin-2-one; (S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(5-chloro-6-methoxypyridin-3-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin- 3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3-fluoro-5-methoxyphenyl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3-(trifluoromethoxy)phenyl)pyrrolidin-2-one; (S)-1 -(2,3-dihydrobenzofuran-5-yl)-5 -(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 (methylsulfonyl)pyrrolidin-3- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(6-methoxypyridin-3-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3,4,5-trifluorophenyl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(4-(trifluoromethoxy)phenyl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3-ethoxy-5-fluorophenyl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1 -(o-tolyl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2-yl) -1-(5-fluoro-2-methylphenyl)pyrrolidin-2-one; 3 -((S)-2-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl)-5-oxopyrrolidin-1-yl)-5-fluorobenzonitrile; (S)-1 -(cyclohex-1 -en-1 -yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 (methylsulfonyl)pyrrolidin-3- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1 -(4,5-difluoro-2-methylphenyl)-5 -(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 (methylsulfonyl)pyrrolidin-3- yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; - 205 041318 (S)-1-(3,4-dichloro-2-methylphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidine -3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (R)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin-3-yl)-1 Hbenzo[d]imidazol-2-yl )-1-(3-fluorophenyl)pyrrolidin-2-one; (R)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one; (R)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (R)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin3-yl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one; (R)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (R)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran4-yl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2Hthiopyran-4-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1Hbenzo[d]imidazol-2-yl)- 1-(3-fluorophenyl)pyrrolidin-2-one; (S)-1 -(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2Hthiopyran-4-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3-chloro-5-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro-2Hthiopyran-4-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1Hbenzo[d]imidazol-2-yl)- 1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro-2Hthiopyran-4-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3,5-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran4-yl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3-chloro-5-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2Hthiopyran-4-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1Hbenzo[d]imidazol-2-yl)- 1-(3,4,5-trifluorophenyl)pyrrolidin-2-one; (S)-1-(3,5-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran4-yl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1Hbenzo[d]imidazol-2-yl)- 1-(5-fluoro-6-methoxypyridin-3-yl)pyrrolidin-2-one; (S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro2H-thiopyran-4-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran4-yl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclorexyl)-Nibenzo[d]imidazole -2-yl)pyrrolidin-2-one; (S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2yl)-1-(3 -fluoro-4-methoxyphenyl)pyrrolidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4hydroxycyclohexyl)-1H-benzo[d ]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4hydroxycyclohexyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1H-benzo[d]imidazol-2yl)-1-(naphthalene -1 -yl)pyrrolidin-2-one; (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxycyclohexyl)-1Hbenzo[d]imidazol-2-yl)pyrrolidine -2-she; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)- 1-((S)-1-(methylsulfonyl)pyrrolidin-3yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(1-((R)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2-yl) -1-(3,4-difluorophenyl)pyrrolidin-2-one; - 206 041318 (8)-5-(1-((R)-1-acetylpyrrolidin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2- yl) 1 -(3,4-difluorophenyl)pyrrolidin-2-one; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(3,3,3trifluoropropanoyl)pyrrolidin-3 -yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1Нbenzo[d]imidazol-2 -yl) pyrrolidin-2-one; (5S)-1 -(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -(1-methylpyrrolidin-3-yl)-1Нbenzo[d]imidazole -2-yl)pyrrolidin-2-one; (5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-methylpyrrolidin-3-yl)-1Hbenzo[d]imidazol-2 -yl) pyrrolidin-2-one; (8)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,48)-4-methoxycyclohexyl)-1Hbenzo[d]imidazole -2-yl)pyrrolidin-2-one; (8)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,48)-4-methoxycyclohexyl)-1Hbenzo[d]imidazole -2-yl)pyrrolidin-2-one; (8)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,48)-4-methoxycyclohexyl)1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one; (8)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,48)-4methoxycyclohexyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (8)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,48)-4-methoxycyclohexyl)-1Hbenzo[d ]imidazol-2-yl)pyrrolidin-2-one; (8)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,48)-4-methoxycyclohexyl)-1Hbenzo[d ]imidazol-2-yl)pyrrolidin-2-one; (8)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,48)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)1-( 3-fluoro-4-methoxyphenyl)pyrrolidin-2-one; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 s,4R)-4-hydroxycyclohexyl)-1Hbenzo[d] imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 s,4R)-4-methoxycyclohexyl)-1Hbenzo[d] imidazol-2-yl)pyrrolidin-2-one; (8)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,4s)-4-ethoxycyclohexyl)-1Hbenzo[d]imidazole -2-yl)pyrrolidin-2-one; (5S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro-2Hthiopyran-3-yl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (5S)-1 -(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -(1,1-dioxidotetrahydro-2Hthiopyran-3-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one; (5S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxytetrahydro-2Hthiopyran-3-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one; (5S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1,1-dioxidotetrahydro2H-thiopyran-3-yl) -1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (8)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)1H-benzo[d ]imidazol-2-yl)pyrrolidin-2-one; (8)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4yl)-1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one; (8)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin4-yl)-1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(2,3-dihydrobenzofuran-5-yl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1(methylsulfonyl)piperidin-4-yl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one; (8)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)1H-benzo[d ]imidazol-2-yl)pyrrolidin-2-one; (8)-1-(3-chloro-4-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4yl)-1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one; (8)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol2-yl)-1-( 3-fluoro-4-methoxyphenyl)pyrrolidin-2-one; (8)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one; (8)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(((1R,3R)-3hydroxycyclopentyl)-1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one; (8)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1R,3R)-3-hydroxycyclopentyl)-1Hbenzo[d]imidazole -2-yl)pyrrolidin-2-one; (1R,3R)-3-(2-((8)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo [d]imidazol-1-yl)cyclopentyl acetate; (1R,3R)-3-(2-((8)-1-(3-chloro-4-methoxyphenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4yl)-1H -benzo[d]imidazol-1-yl)cyclopentyl acetate; - 207 041318 (S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3methoxycyclopentyl)- 1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-methoxycyclopentyl)1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3methoxycyclopentyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(trans-(1r,3r)-3-ethoxycyclopentyl)1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4difluorophenyl) )pyrrolidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2 -yl) pyrrolidin-2-one; (S)-1-(3-fluoro-4-methoxyphenyl)-5-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2 -yl)pyrrolidin-2-one; (5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)1H-benzo[ d]imidazol-2-yl)pyrrolidin-2-one; (5S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran4-yl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (5S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol2-yl)-1- (3-fluoro-4-methoxyphenyl)pyrrolidin-2-one; 5-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-1 -yl)piperidin-2-one; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin2-one; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1 s,4R)-4-hydroxy-4methylcyclohexyl)-1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1Hbenzo[d]imidazol-2-yl)- 1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one; (S)-1-(3,4-dichlorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4methylcyclohexyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(4-chloro-3-fluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4methylcyclohexyl)-1H -benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)1H- benzo[d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-benzo[d]imidazol-2-yl)- 1(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)- 1-((1r,3 S)-3-hydroxycyclobutyl)-1Hbenzo[d] imidazol-2-yl)pyrrolidin-2-one; (1S,3r)-3-(2-((S)-1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo [d] imidazol-1-yl)cyclobutyl acetate; (S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidin-2-one ; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-propyl-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one ; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2yl)pyrrolidin-2-one ; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -(3-methoxypropyl)-1 Hbenzo[d]imidazol-2-yl) pyrrolidin-2-one; (S)-5-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4methoxyphenyl)pyrrolidin-2 -she; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(pyridin-3-ylmethyl)-1Hbenzo[d]imidazol-2-yl )pyrrolidin-2-one; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,3R)-3(hydroxymethyl)cyclobutyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3(hydroxymethyl)cyclobutyl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (S)-5-(1-(cyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidin-2 -she; (S)-3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-1 -yl) propyl acetate; (S)-5-(1-(3-Aminocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidine -2-she; - 208 041318 (S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1-(thiazol-4-ylmethyl)-1Hbenzo[d]imidazol- 2-yl)pyrrolidin-2-one; (S)-5-(1-(3-carboxycyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4difluorophenyl)pyrrolidine -2-she; (8)-3-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-Nibenzo[d]imidazol-1 -yl)-N-propylcyclobutanecarboxamide; (S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1( 3,4-difluorophenyl)pyrrolidin-2-one; (S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1( 3-fluoro-4-methoxyphenyl)pyrrolidin-2-one; (S)-5-(1-((R)-3,3-difluorocyclopentyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1( 3-chloro-4-methoxyphenyl)pyrrolidin-2-one; (5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -(2-hydroxypropyl)-1 Hbenzo[d]imidazol-2-yl) pyrrolidin-2-one (diastereoisomer 1); (5S)-1-(3,4-difluorophenyl)-5-(5-(3,5-dimethylisoxazol-4-yl)-1 -(2-hydroxypropyl)-1 Hbenzo[d]imidazol-2-yl) pyrrolidin-2-one (diastereoisomer 2); (R)-1 -(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin3-yl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one; (S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin3-yl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one; (S)-1 -(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 (methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)piperidin-2-one; (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((R)-1 -(methylsulfonyl)pyrrolidin3-yl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)piperidin-2-one; (S)-1-(3-fluoro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((R)-1(methylsulfonyl)pyrrolidin-3-yl) -1H-benzo[d]imidazol-2-yl)piperidin-2-one; (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)1 -( 3,4-difluorophenyl)piperidin-2-one; (S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1Hbenzo[d ]imidazol-2-yl)piperidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)1H-benzo[ d]imidazol-2-yl)piperidin-2-one; (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)1-( 3-fluoro-4-methoxyphenyl)piperidin-2-one; (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4methylcyclohexyl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4methylcyclohexyl)-1H -benzo[d]imidazol-2-yl)piperidin-2-one; (S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1 -((1 s,4R)-4-hydroxy-4methylcyclohexyl)-1H- benzo[d]imidazol-2-yl)piperidin-2-one; (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4-methylcyclohexyl)-1Hbenzo[d]imidazol-2-yl)- 1-(3-fluoro-4-methoxyphenyl)piperidin-2-one; (S)-1-(4-chloro-3-fluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1s,4R)-4-hydroxy-4methylcyclohexyl)-1H -benzo[d]imidazol-2-yl)piperidin-2-one; (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)- 1-((1r,3 B)-3-hydroxycyclobutyl)-1Hbenzo[d] imidazol-2-yl)piperidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)1H-benzo[ d]imidazol-2-yl)piperidin-2-one; (S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,3S)-3-hydroxycyclobutyl)-1Hbenzo[d]imidazole -2-yl)piperidin-2-one; (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4methylcyclohexyl)-1H-benzo [d]imidazol-2-yl)piperidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4methylcyclohexyl)-1H -benzo[d]imidazol-2-yl)piperidin-2-one; (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-1Hbenzo[d]imidazol-2-yl)- 1-(3-fluoro-4-methoxyphenyl)piperidin-2-one; (S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2yl)piperidin-2-one ; (S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol2-yl)piperidin-2 -she; - 209 041318 (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-isobutyl-1H-benzo[d]imidazol-2-yl)-1-(3-fluoro-4methoxyphenyl) piperidin-2-one; (S)-6-(1 -(4,4-difluorocyclohexyl)-5 -(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2-yl)-1-(3fluoro- 4-methoxyphenyl)piperidin-2-one; (S)-6-(1 -(4,4-difluorocyclohexyl)-5 -(3,5-dimethylisoxazol-4-yl)-1 H-benzo[d]imidazol-2-yl)-1-(3, 4difluorophenyl)piperidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2 -yl)piperidin-2-one; (S)-1-(3,4-dichlorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1Hbenzo[d]imidazole -2-yl)piperidin-2-one; (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-hydroxycyclohexyl)-1Hbenzo[d]imidazole -2-yl)piperidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4hydroxycyclohexyl)-1H-benzo[d ]imidazol-2-yl)piperidin-2-one; (S)-1-(3,4-difluorophenyl)-5-(1-((1r,4S)-4-hydroxycyclohexyl)-5-(5-(hydroxymethyl)-3methylisoxazol-4-yl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (S)-1-(3,4-difluorophenyl)-5-(1-((1r,4S)-4-hydroxycyclohexyl)-5-(3-(hydroxymethyl)-5methylisoxazol-4-yl)-1H-benzo [d]imidazol-2-yl)pyrrolidin-2-one; (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1phenylpiperidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1Hbenzo[d]imidazol-2 -yl)piperidin-2-one; (S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3,4difluorophenyl) )piperidine-2-one; (S)-6-(1-(3,3-difluorocyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(3fluoro-4 -methoxyphenyl)piperidin-2-one; (1S,4r)-methyl 4-(2-((S)-1-(3,4-difluorophenyl)-6-oxo-piperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)1H -benzo[d]imidazol-1-yl)cyclohexanecarboxylate; (1 S,4r)-4-(2-((S)-1 -(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5 -(3,5-dimethylisoxazol-4-yl)- 1Hbenzo[d]imidazol-1-yl)cyclohexanecarboxylic acid; (1 S,4r)-4-(2-((S)-1 -(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5 -(3,5-dimethylisoxazol-4-yl)- 1Hbenzo[d]imidazol-1-yl)-N-propylcyclohexane carboxamide; (1 S,4r)-4-(2-((S)-1 -(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5 -(3,5-dimethylisoxazol-4-yl)- 1Hbenzo[d]imidazol-1-yl)-N-methyl-N-propylcyclohexanecarboxamide; (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(6fluoropyridin-3 -yl)piperidin-2-one; (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1-(5fluoropyridin-3 -yl)piperidin-2-one; (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1(pyridin-3 - yl) piperidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4hydroxycyclohexyl)-3Н-imidazo[4 ,5-b]pyridin-2-yl)piperidin-2-one; (S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3Himidazo[4,5 -b]pyridin-2-yl)piperidin-2-one; (S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-((1r,4S)-4-hydroxycyclohexyl)-3H-imidazo[4,5b]pyridin-2-yl)- 1-(3-fluoro-4-methoxyphenyl)piperidin-2-one; (S)-1-(3-chloro-4-methoxyphenyl)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3Himidazo[4,5-b ]pyridin-2-yl)pyrrolidin-2-one; (S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)1 -( 3,4-difluorophenyl)pyrrolidin-2-one; (S)-5-(3-(4,4-difluorocyclohexyl)-6-(3,5-dimethylisoxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)1-( 3-fluoro-4-methoxyphenyl)pyrrolidin-2-one; (S)-6-(1-(4,4-difluorocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)-1(pyrimidin-5- yl) piperidin-2-one; (S)-1-(3,4-difluorophenyl)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin2-yl)piperidine -2-she; (S)-6-(6-(3,5-dimethylisoxazol-4-yl)-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl)-1-(3-fluoro-4methoxyphenyl) )piperidine-2-one; and (S)-1-benzyl-5-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1Hbenzo[d]imidazol-2-yl) pyrrolidin-2-one and their pharmaceutically acceptable salts. 6. A process for preparing a compound according to claim 1, comprising treating a compound of formula (II) - 210 041318 where each of R, R°, R ¹ , W and Y corresponds to the definition in paragraph 1, boronic acid of the formula R ² -B(OH) 2, where R ² corresponds to the definition in paragraph 1, in the presence of Pd(PPh3) ₄ and Na ₂ CO ₃ in an aqueous solution of ethanol. 7. A process for preparing a compound according to claim 1, comprising treating a compound of formula (III) where each of R, R°, R ¹ , R ² , W and Y corresponds to the definition in paragraph 1, acetic acid at 60-100°C or a mixture of HC1/1,4-dioxane 20-90%. 8. A process for the preparation of a compound according to claim 1, comprising treating a compound of formula (II) as defined in claim 6 with a compound of formula R ² -CH ₂ Br, wherein R ² is as defined in claim 1. 9. The method according to claim 6, 7 or 8, which further comprises converting the resulting arylimidazolylisoxazole of formula (I) into a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition which contains a pharmaceutically acceptable carrier or diluent and, as an active ingredient, a compound according to any one of claims 1 to 5. 11. Use of a compound according to any one of claims 1 to 5 as a modulator of p300 and/or CBP activity (CREB (cyclic AMP sensitive element-containing binding protein)-binding protein). 12. The use of a compound according to any one of claims 1 to 5 for the treatment of a cancer selected from a cancer that expresses the androgen receptor (AR), a cancer that expresses c-Myc, a tumor that carries loss-of-function mutations in the CVR, or p300, or cancer, in which there is an activation of the SVR and/or p300 function. 13. A method of treating a cancer selected from a cancer that expresses the androgen receptor (AR), a cancer that expresses c-Myc, a tumor that carries loss-of-function mutations in CVR or p300, or a cancer that has activation CVR and/or p300 functions, comprising administering to a patient in need of this compound according to any one of claims 1-5. 14. The method according to item 13, in which the specified connection is administered simultaneously or sequentially with radiation therapy; or administered simultaneously, sequentially, or in the form of a combined preparation with one or more other therapeutic agents, said or each of said therapeutic agents being selected from androgen receptor antagonists; inhibitors of CYP17A1 (17a-hydroxylase/C17,20-lyase); cytotoxic chemotherapeutic agents; immune checkpoint inhibitors; PARP (poly(ADP-ribose) polymerase) inhibitors; and inhibitors of CDK4/6 (cyclin-dependent kinase 4 and 6).