EA038888B1 - Pyrazole derivatives as bromodomain inhibitors - Google Patents

Abstract

The invention relates to pyrazole derivatives of formula (I)pharmaceutical compositions comprising the compounds and the use of the compounds or the compositions in the treatment of various diseases.

Description

Scope of invention

The invention relates to pyrazole derivatives that are inhibitors of bromodomain, pharmaceutical compositions containing these compounds, and the use of these compounds or compositions in the treatment of various diseases or conditions, for example, acute or chronic autoimmune and / or inflammatory diseases, viral infections and cancer.

Prior art

Eukaryotic genomes are highly organized in the cell nucleus. Long strands of a DNA duplex are twisted around a histone protein octamer (usually containing two copies of histones H2A, H2B, H3, and H4) to form a nucleosome. This basic unit is then further compressed by aggregation and stacking of nucleosomes to form a highly condensed chromatin structure. A number of different condensation states are possible, and the compactness of this structure changes during the cell cycle, being most compact during the process of cell division. Chromatin structure plays an important role in the regulation of gene transcription, which cannot occur efficiently from highly condensed chromatin. Chromatin structure is controlled by a series of post-translational modifications to histone proteins, especially histones H3 and H4, and usually in histone tails that extend beyond the nucleosome nucleus structure. These modifications include acetylation, methylation, phosphorylation, ubiquitination, and sumoylation. These epigenetic marks are recorded and erased by special enzymes that mark specific residues in the histone tail, thereby creating an epigenetic code that is then decoded by the cell, allowing gene-specific regulation of chromatin structure and thus transcription.

Acetylation of histones is usually associated with the activation of gene transcription, since the modification weakens the interaction of DNA and the histone octamer by altering electrostatics. In addition to this physical change, specific proteins recognize and bind to acetylated lysine residues in histones to read the epigenetic code. Bromodomains are small (approximately 110 amino acids) special domains in proteins that bind to acetylated lysine residues, usually, but not exclusively, in the region of histones. There is a family of about 50 known proteins that contain bromodomains, and they perform a number of functions in the cell.

The BET family of proteins containing bromodomains includes 4 proteins (BRD2, BRD3, BRD4, and BRDT) that contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction. When numbered from the N-terminus of each BET protein, tandem bromodomains are usually designated binding domain 1 (BD1) and binding domain 2 (BD2) (Chung et al., J. Med. Chem., 2011, 54, 3827-3838).

Chan et al. report that inhibition of BET bromodomains suppresses transcriptional responses to cytokine mediated Jak-STAT signaling in a gene-specific manner in human monocytes, indicating that inhibition of BET partially reduces inflammation through suppression of cytokine activity (Chan et al., Eur. J. Immunol., 2015, 45: 287-297).

Klein et al. reported that the bromodomain protein inhibitor I-BET151 suppresses the expression of inflammatory genes and enzymes involved in matrix degradation in synovial fibroblasts in rheumatoid arthritis, indicating therapeutic potential in targeting epigenetic reader proteins in rheumatoid arthritis (Annlein et al. Rheum Dis. 2014 0: 1-8).

Park-Min et al. report that 1-BET151, targeting bromo and extraterminal (BET) proteins that read chromatin states by binding to acetylated histones, potently inhibits osteoclastogenesis (Park-Min et al. Nature Communications, 2014, 5, 5418).

In each of the PCT patent applications PCT / EP2016 / 070519, PCT / EP2016 / 072216 and PCT / EP2016 / 073532, a number of pyridone derivatives are described as inhibitors of bromodomain.

Summary of the invention

The invention relates to a compound of formula (I)

or its salt, where

R ¹ is —C _1-3 alkyl or cyclopropyl;

R ² is —C _0-3 alkylcycloalkyl, where the cycloalkyl group is optionally substituted with one, two or three R ⁵ groups, which may be the same or different; or

R ² is —C _0-4 alkylheterocyclyl, wherein said heterocyclyl is optionally substituted with one or two R ⁹ groups, which may be the same or different; or

R ² is H, —CH3, —C _2-6 alkyl optionally substituted with one, two, three, four or

- 1 038888 five substituents fluorine, -C ₂ . ₆ alkylOR ⁶ , -C2-6anKUBNR ^10a R ^11a , - (CH2) _m SO ₂ C ₁ . ₃ alkyl, - (CH ₂ ) mSO ₂ NR ¹⁰ R ⁿ , - (CH2) mC (O) NR ¹⁰ R ¹¹ , - (CH2) mCN, - (CH2) mCO2R ⁶ , - (CH2) mNHCO2C1-4 alkyl, - (CH2) mNHC (O) C1-4 alkyl or - (CH _{2) n} geτeroaril, wherein said heteroaryl is optionally substituted with one or two R ⁷ groups which may be the same or different;

R ³ is —H, —C1.4αalkyl, cyclopropyl, —CH2F, —C1.3αalkylOR ^6, or —C1. ₃ alkylCN;

R ⁴ represents a phenyl or heteroaryl group, where each is optionally substituted with one, two or three R ⁷ groups, which may be the same or different;

each R ^{5 is} independently halogen, —C0.6alkyl — R ⁸ , —O — C2. ₆ alkyl-R ⁸ , —OCH ₂ phenyl, —CN or —SO ₂ Cl. ₃ alcohol;

R ⁶ is H or —C ₁ . ₄ alkyl;

each R ^{7 is} independently oxo, halogen, —C1.4αalkyl optionally substituted with one, two or three fluoro substituents, C3.4cycloalkyl, —C0.3alkylOR ⁶ , —OC2. ₃ alkylOR ⁶ , -C0.3 alkyl NR ¹⁰ R ¹¹ , -C0. ₃ αalkyl-CONR ¹⁰ R ¹¹ , -CN, -SO2-C1.3 alkyl, -SO2NR10R ¹¹ or -SO2phenyl, optionally substituted with -Cl. _{4 with} α-alkyl;

R ⁸ is H, —OR ^6, or —NR ¹⁰ R ¹¹ ;

each R ^{9 is} independently halogen, —C1.4alkyl, cyclopropyl, cyclobutyl, —CH2CF3, —CH2CHF2, —CH2CH2F, —OCH2CH2OR ⁶ , —C0. ₃ αalkylOR ⁶ , -C0.3alkylNR ¹⁰ R ¹¹ , -NHCH2CH2OR ⁶ , -NHCO2C ₁ . ₄ alkyl, oxo, —C (O) R ⁶ , —C (O) OR ^6, or —C (O) NR ¹⁰ R ¹¹ ;

R ¹⁰ and R ^{11 are} each independently selected from H and —C ₁ . ₃ alkyl;

R ^10a and R ^{11a are} each independently selected from H and —C ₁ . ₃ alkyl;

m is an integer selected from 2, 3 or 4; and n is an integer selected from 0, 1, 2, 3 or 4, wherein said cycloalkyl refers to a saturated hydrocarbon mono- or bicyclic ring or a saturated spiro-linked bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8 , 9 or 10 atoms - members of the ring;

said heterocyclyl refers to a non-aromatic heterocyclic monocyclic or bicyclic ring system containing 4, 5, 6, 7, 8, 9 or 10 ring member atoms, including one heteroatom and optionally containing an additional heteroatom selected from nitrogen, oxygen or sulfur; and said heteroaryl refers to a monocyclic or bicyclic group having 5, 6, 8, 9, 10 or 11 ring member atoms including one, two or three heteroatoms independently selected from nitrogen, sulfur and oxygen, wherein at least part of the group is aromatic.

In one embodiment, R ¹ is methyl.

In another embodiment, R ² is —C ₀ . _{3 is an} alkylcycloalkyl group wherein said cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclohexyl or bicyclo [3.1.0] hexanyl, said groups optionally substituted with one, two or three R ⁵ groups which may be the same or different.

In another embodiment, R ² is —C ₀ . ₄ alkylheterocyclyl, wherein said heterocyclyl is selected from oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl, piperidinyl, piperazinyl, (1r, 5s) -3-oxabicyclo [3.1.0] hexanyl, and (1r, 5s) -3 3.1.0] hexanyl, said groups being optionally substituted with one or two R ⁹ groups, which may be the same or different.

In another embodiment, R ² is methyl, ethyl, propyl, isopropyl, butyl, —CH2CH2CH (CH3) 2, —CH2CH2CH (CH3) 2, —CH2CH2OR ⁶ , —CH2CH2CH2OR ⁶ , —CH2CH (CH3) OR ⁶ ,

-CH2CH2CH (CH3) OR ⁶ , -CH2CH2CH (CH3) NR ^10a R ^11a , -CH2CH2CH2NR ^10a R ^11a , - (CH2) mSO2CH3,

- (CH2) mC (O) NHCH3, - (CH2) mCN, - (CH2) mCO2R ⁶ , - (CH2) mCF3 and - (CH2) mNHCO2C (CH3) 3.

In another embodiment, R ² is - (CH ₂ ) _n heteroaryl, wherein said heteroaryl group is selected from furanyl, thienyl, pyrrolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyridinyl, pyridazinyl, and pyrimidinyl, said groups optionally substituted by one or two substituents independently selected from halogen, C ₁ . ₄ αalkyl, C ₃ _ ₄ cycloalkyl and -C ₀ groups. ₃ alkylOR ⁶ .

In a further embodiment, R ³ is H, methyl, ethyl, —CH ₂ F, —CH ₂ OH, —CH (OH) CH ₃ , —CH ₂ OMe, or —CH 2 CN.

In another embodiment, R ⁴ is unsubstituted phenyl or is phenyl substituted with one or two R ⁷ groups, which may be the same or different, selected from halogen, —C ₁ . ₄ α-alkyl, groups -C ₀ . ₃ alkylOR ⁶ and —CN.

In another embodiment, R ⁴ is a heteroaryl group selected from the group consisting of pyridyl, indolyl and pyrrolopyridinyl, said groups optionally substituted with one, two or three R ⁷ groups, which may be the same or different.

In a preferred embodiment, the compound of the invention is selected from

- 2 038888

Μ - ((1 g, 45) -4-hydroxycyclohexyl) -N ³ -methyl-1 - ((5) -1-phenylethyl) - 177-pyrazole-

3,5-dicarboxamide;

No - ((17 ?, 37 ?, 55.6g) -3-hydroxycyclo [3.1. 0] hexan-6-yl) -7U ³ -methyl-1 - ((5) -1 phenylethyl) - 177-pyrazole- 3,5-dicarboxamide;

No - ((17 ?, 55.6g) -3-oxabicyclo [3.1.0] hexan-6-yl) -1 - ((5) -1 - (4-chlorophenyl) ethyl) -No methyl-177-pyrazole -3.5-dicarboxamide;

(5) -No-methyl-1- (1-phenylethyl) -No- (1/7-pyrazol-4-yl) -1 // - pyrazole-3,5-dicarboxamide;

- ((5) -1 - (4-chlorophenyl) ethyl) -No - ((17 ?, 37 ?, 55.6g) -3-hydroxybicyclo [3.1.0] hexane-6yl) -No ³ -methyl-17 / -pyrazole-3,5-dicarboxamide;

- ((5) -1 - (3-chlorophenyl) ethyl) -No - ((17 ?, 37 ?, 55.6g) -3-hydroxycyclo [3.1,0] hexane-6yl) -No ³ -methyl-17 / -pyrazole-3,5-dicarboxamide;

No - ((17 ?, 37 ?, 55.6g) -3-hydroxycyclo [3.1. 0] hexan-6-yl) -7U ³ -methyl-1 - ((5) -1 phenylpropyl) -1N-pyrazole- 3,5-dicarboxamide; and No. - ((1 g, 45) -4-methoxycyclohexyl) -No-methyl-1 - ((5) -1-phenylethyl) - 177-pyrazole-

3,5-dicarboxamide, or their salts.

In a more preferred embodiment, the compound of the invention is N ⁵ ((1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1 - ((S) -1-phenylethyl ) -1H-pyrazole-3,5-dicarboxamide represented by the formula

or its salt.

In a preferred embodiment, the salt of the compound of the invention is a pharmaceutically acceptable salt.

This invention also relates to a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

This invention also relates to a pharmaceutical combination comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, together with one or more other therapeutically active agents.

This invention also relates to the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition in which a bromodomain inhibitor is indicated.

This invention also relates to a method of treating a disease or condition in which a bromodomain inhibitor is indicated in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment of the method of treatment, the disease or condition is an acute or chronic autoimmune and / or inflammatory condition.

In another preferred embodiment of the method, the disease or condition is cancer.

In another preferred embodiment of the method, the disease or condition is rheumatoid arthritis.

The compounds of the invention have been shown to be inhibitors of bromodomain, in particular selective for BD2, and may be useful in the treatment of these diseases or conditions.

Detailed description of the invention

The compounds of formula (I) and their salts are referred to herein as compounds of the invention.

The term BD2 refers to binding domain 2 of any of the BET family of proteins BRD2, BRD3, BRD4, or BRDT.

The term alkyl refers to a saturated hydrocarbon chain having a specific number of carbon atoms. For example, as used herein, the term C ₁ . ₃ alkyl and C ₁ . ₄ alkyl refers to straight or

- 3,038888 branched alkyl group having from 1 to 3 or from 1 to 4 carbon atoms, respectively. Furthermore, the term C ₀ - ₃ alkyl refers to a straight or branched alkyl group having from 0 (i.e., bond) to 3 carbon atoms. Typical branched alkyl groups have one, two or three branches. An alkyl group may form part of a chain, for example —C _0-3 alkyl OR ⁶ refers to a straight or branched alkyl chain having from 0 (ie, a bond) to 3 carbon atoms bonded to the R ⁶ group. Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, and hexyl.

The term cycloalkyl refers to a saturated hydrocarbon mono- or bicyclic ring, or a saturated spiro-linked bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring member atoms. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl and spiro [3.3] heptanyl, bicyclo [2.2.1] heptanyl, adamantyl, bicyclo [3.1.0] hexanyl, and bicyclo [2.2.2] octanyl ... The term "C _3-7 cycloalkyl" refers to a saturated hydrocarbon mono- or bicyclic ring, or a saturated spiro-linked bicyclic hydrocarbon ring having 3, 4, 5, 6, or 7 ring member atoms. Examples of C ₃ _ ₇ cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, and bicyclo [3.1.0] hexanyl.

The term halogen refers to a halogen radical such as fluorine, chlorine, bromine or iodine.

The term heteroaryl refers to a monocyclic or bicyclic group having 5, 6, 8, 9, 10, or 11 ring member atoms including one, two, or three heteroatoms independently selected from nitrogen, sulfur and oxygen, wherein at least a portion of the group is aromatic. The point of attachment to the rest of the molecule can be any suitable carbon or nitrogen atom. Examples of heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, triazinylidinyl, benzofenzyl, iso-thiazolyl, 1,3benzodioxolyl, dihydrobenzodioxinil, benzothienyl, benzazepinyl, 2,3,4,5-tetrahydro-1H-benzo [d] azepinyl, indolizinyl, indolyl, indolinyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzidazylazylazylazole, benzothiazolyl dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, pyrrolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoxoquinolinyl, quinolinyl 1,8-naphthyridinyl and pteridinyl, but are not limited to them.

The term C _5-6 heteroaryl refers to a monocyclic aromatic group having 5 or 6 ring member atoms including 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. The point of attachment to the rest of the molecule can be any suitable carbon or nitrogen atom. Examples of C ₅ - ₆ heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl and triazinyl, but not limited thereto.

The term heteroatom refers to a nitrogen, sulfur, or oxygen atom.

The term heterocyclyl refers to a non-aromatic heterocyclic monocyclic or bicyclic ring system containing 4, 5, 6, 7, 8, 9 or 10 ring member atoms, including one heteroatom and optionally containing an additional heteroatom selected from nitrogen, oxygen or sulfur. Examples of heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolipiranyl 3-dioxanyl, 1,4-dioxanyl, 1,3oxathiolanyl, 1,3-oxathianil, 1,3-dithianil, 1,4-oxathiolanyl, 1,4-oxathianil, 1,4-dithianil, morpholinyl, thiomorpholinyl, hexahydro- 1H-1,4-diazepinyl, azabicyclo [3.2.1] octyl, azabicyclo [3.3.1] nonyl, azabicyclo [4.3.0] nonyl, oxabicyclo [2.2.1] heptyl, 1,1-dioxidotetrahydro-2H-thiopyranyl, 1,5,9-triazacyclododecyl, 3-oxabicyclo [3.1.0] hexanyl, 3-azabicyclo [3.1.0] hexanyl, (1r, 5s) -3-oxabicyclo [3.1.0] hexanyl and (1r, 5s) - 3-azabicyclo [3.1.0] hexanyl, but not limited to them.

The term 4-7 membered heterocyclyl refers to a non-aromatic heterocyclic ring system containing 4, 5, 6 or 7 ring member atoms, including one heteroatom and optionally containing an additional heteroatom selected from nitrogen, oxygen or sulfur. Examples of 4-7 membered heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.

The term atoms - ring members refers to the atom or atoms that form a chain or ring. In cases where more than one ring member is present in a chain and in a ring, each ring member atom is covalently bonded to an adjacent ring member in a chain or ring. The atoms that form a substituent group attached to a chain or ring are not ring-in-chain or ring atoms.

The term substituted with respect to a group indicates that a hydrogen atom attached to a ring member of the group has been replaced. It should be understood that the term substituted includes the position

- 4 038888 meaning that such a substitution corresponds to the permissible valence of the substituted atom and substituent, and that the substitution results in a stable compound (i.e., the compound does not spontaneously undergo transformation, such as rearrangement, cyclization or elimination). In some embodiments, a single atom may be substituted with more than one substituent, provided that such substitution corresponds to the allowable valency of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

The term pharmaceutically acceptable refers to those compounds, substances, compositions and dosage forms that are medically suitable for use in contact with tissues of humans and animals without undue toxicity, irritation or other problem or complication, in accordance with an acceptable risk / benefit ratio.

The term pharmaceutically acceptable excipient refers to a pharmaceutically acceptable substance, composition, or carrier associated with the shaping or consistency of a pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed so as to avoid interactions that would significantly reduce the efficacy of a compound of formula (I) or a pharmaceutically acceptable salt thereof when administered to a patient. In addition, each excipient must, of course, be pharmaceutically acceptable, for example of a reasonably high purity.

The term rac refers to a racemic mixture of compounds of formula (I).

The compounds of the invention can exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or non-crystalline form, or as a mixture thereof. One skilled in the art will appreciate that for compounds of the invention that are in crystalline form, pharmaceutically acceptable solvates can be formed when solvent molecules are incorporated into the crystal lattice during crystallization. Solvates can include non-aqueous solvents such as ethanol, isopropyl alcohol, dimethyl sulfoxide (DMSO), acetic acid, ethanolamine, and ethyl acetate, or they can include water as a solvent that is incorporated into the crystal lattice. Solvates in which water is the solvent included in the crystal lattice are commonly referred to as hydrates. Hydrates include stoichiometric hydrates as well as compositions containing varying amounts of water. The invention includes all such solvates.

It will also be understood that certain compounds of the invention that exist in crystalline form, including their various solvates, may exhibit polymorphism (i.e., the ability to exist in different crystal structures). These various crystalline forms are commonly known as polymorphs. The invention includes such polymorphs. Polymorphs have the same chemical composition, but differ in packing, geometric configuration, and other descriptive properties of the crystalline solid state. Polymorphs can therefore have different physical properties such as shape, density, hardness, deformability, stability, and solubility. Polymorphs typically exhibit different melting points, IR spectra, and powder X-ray diffraction patterns that can be used for identification. It will be understood that various polymorphs can be obtained, for example, by changing or adjusting the reaction conditions or reagents used in the preparation of the compound. For example, changes in temperature, pressure, or solvent change can lead to the formation of polymorphs. In addition, one polymorph can spontaneously transform into another polymorph under certain conditions. Polymorphic forms of compounds of formula (I) can be characterized and differentiated using a number of traditional analytical techniques, including powder X-ray diffraction patterns (XRD), infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) ) and solid state nuclear magnetic resonance (SSNMR), but are not limited to them.

Compounds of formula (I) may contain one or more asymmetric centers (also called chiral centers) and may therefore exist as single enantiomers, diastereoisomers or other stereoisomeric forms, or as mixtures thereof. Chiral centers such as chiral carbon atoms can also be present on a substituent such as an alkyl group. When the stereochemistry of a chiral center present in a compound of formula (I) or in any chemical structure provided herein is not defined, the structure is intended to include any stereoisomer and all mixtures thereof. Thus, compounds of formula (I) containing one or more chiral centers can be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure single stereoisomers. Therefore, the present invention encompasses all isomers of the compounds of formula (I), both as individual isomers, isolated so as to be substantially free of the other isomer (i.e., pure), and as mixtures (i.e. racemic mixtures). A single isomer isolated so as to be substantially free of the other isomer (i.e., pure) can be isolated so that less than 10% is present, in particular less than about 1%, for example less than about 0.1% of the other. isomer.

Racemic compounds with one stereocenter denote either without a stereochemical bond

- 5 038888 (single bond) or marked (+/-) or rac. Racemic compounds with two or more stereocenters where the relative stereochemistry is known are cis or trans as defined in the structure. Separated individual enantiomers with unknown absolute stereochemistry, but known relative stereochemistry, are designated with (R * or S *), and the corresponding relative stereochemistry is displayed.

In cases where diastereoisomers are presented and we are talking only about relative stereochemistry, even bold or dotted bond designations (- /) are used. In cases where the absolute stereochemistry is known and the compound is an individual enantiomer, bold or dotted wedge designations (- /) are used as appropriate.

Individual stereoisomers of a compound of formula (I) that contain one or more asymmetric centers can be separated by methods known to those skilled in the art. For example, such a separation can be carried out (1) through the formation of diastereoisomeric salts, complexes, or other derivatives; (2) by selective interaction with a stereoisomer-specific reagent, for example, by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral medium, for example on a chiral support such as silica with an associated chiral ligand or in the presence of a chiral solvent. It should be understood that in cases where the desired stereoisomer is converted to another chemical using one of the separation methods described above, an additional step is required to isolate the desired form. Alternatively, specific stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, supports, catalysts or solvents, or by converting one enantiomer to another by amimetric transformation.

It should be understood that tautomers may be observed for compounds of formula (I). Any comment on the biological activity of a tautomer should take into account both tautomers.

As used herein, references to compounds of formula (I) and their salts are to be understood to encompass compounds of formula (I) in the form of the free bases or in the form of their salts, for example in the form of their pharmaceutically acceptable salts. Thus, in one embodiment, the invention relates to compounds of formula (I) in free base form. In another embodiment, the invention relates to compounds of formula (I) and salts thereof. In another embodiment, the invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof.

Because of their potential medical use, the salts of the compounds of formula (I) are desirably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts may include acid addition salts and base addition salts. For a review of suitable pharmaceutically acceptable salts see Berge et al. J. Pharm. Sci. 66: 1-19 (1977). In general, a pharmaceutically acceptable salt can be readily prepared using the desired acid or base, as appropriate. The resulting salt can be precipitated from solution and collected by filtration, or can be isolated by evaporation of the solvent.

A pharmaceutically acceptable acid addition salt can be formed by reacting a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, aspartic, para-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, such as 2-naphthalenesulfonic or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to form a salt which is usually isolated, for example filtration or by evaporation followed by trituration into powder. A pharmaceutically acceptable acid addition salt of a compound of formula (I) may contain or be, for example, a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (eg 2-naphthalenesulfonate) or hexanoate.

Other salts that are not pharmaceutically acceptable, for example formates or trifluoroacetates, can be used, for example, in the isolation of compounds of formula (I) and are included within the scope of the present invention.

Included within the scope of the invention are all possible stoichiometric and non-stoichiometric salt forms of the compounds of formula (I).

From the foregoing, it should be understood that the scope of the invention includes solvates, isomers and polymorphic forms of the compounds of formula (I) and their salts.

Statement of the essence of the invention.

In a first aspect, there are provided compounds of formula (I)

- 6 038888

or their salt, where

R ¹ is —C _1-3 alkyl or cyclopropyl;

R ² is —C _0-3 alkylcycloalkyl, where the cycloalkyl group is optionally substituted with one, two or three R ⁵ groups, which may be the same or different; or

R ² is —C _0-4 alkylheterocyclyl, where each heterocyclyl is optionally substituted with one or two R ⁹ groups, which may be the same or different; or

R ² is H, —CH3, —C2-6alkyl, optionally substituted with one, two, three, four or five fluoro substituents, —C2-6alkylOR ⁶ , —C2-6alkylNR ^10a R ^11a , - (CH2) mSO2C1-3alkyl, - (CH2) mSO2NR ¹⁰ R ¹¹ , - (CH2) mC (O) NR ¹⁰ R ¹¹ , - (CH2) _m CN, - (CH2> _m CO2R ⁶ , - (C ^ mNH ^ Q ^^,

- (CH ₂ ) _m NHC (O) C _1-4 alkyl or - (CH ^ heteroaryl, where said heteroaryl is optionally substituted with one or two R ⁷ groups, which may be the same or different;

R ³ is H, —C1-4alkyl, cyclopropyl, —CH2F, —C1-3alkylOR ^6, or —C1-3alkylCN;

R ⁴ represents a phenyl or heteroaryl group, where each is optionally substituted with one, two or three R ⁷ groups, which may be the same or different;

each R ^{5 is} independently halogen, —C0-6 alkyl-R ⁸ , —O — C2-6 alkyl-R ⁸ , —OCH ₂ phenyl, —CN, or —SO ₂ C _1-3 alkyl;

R ⁶ is H or —C _1-4 alkyl;

each R ⁷ independently represents oxo, halogen, -C1-4alkyl optionally substituted with one, two or three fluoro substituents, C3-4cycloalkyl, -C0-3alkylOR ⁶ , -OC2-3alkylOR ⁶ , -C0-3alkylNR ¹⁰ R ¹¹ , - C0-3alkyl-CONR ¹⁰ R ¹¹ , -CN, -SO2-C1-3 alkyl, -SO2NR ¹⁰ R ⁿ or -SO2 phenyl optionally substituted with -C ₁ . _{4 with} α-alkyl;

R ⁸ is H, —OR ^6, or —NR10R ¹¹ ;

each R ^{9 is} independently halogen, -C1-4alkyl, cyclopropyl, cyclobutyl, -CH2CF3, -CH2CHF2, -CH2CH2F, -OCH2CH2OR ⁶ , -C0-3alkylOR ⁶ , -C0-3alkylNR ¹⁰ R ¹¹ , -NHCH2CH2OR ⁶ , -NHCO2C _1-4 alkyl, oxo, —C (O) R ⁶ , —C (O) OR ^6, or —C (O) NR ¹⁰ R ¹¹ ;

R ¹⁰ and R ^{11 are} each independently selected from H and —C _1-3 alkyl;

R ^10a and R ^{11a are} each independently selected from H and —C _1-3 alkyl;

m is an integer selected from 2, 3 or 4; and n is an integer selected from 0, 1, 2, 3, or 4.

In one embodiment, there is provided a compound of formula (I), or a salt thereof, wherein

R ¹ is —C _1-3 alkyl or cyclopropyl;

R ² is —C _0-3 alkyl-cycloalkyl, where the cycloalkyl group is optionally substituted with one, two or three R ⁵ groups, which may be the same or different; or

R ² is —C _0-4 alkylheterocyclyl, where each heterocyclyl is optionally substituted with one or two R ⁹ groups, which may be the same or different; or

R ² is H, -CH3, -C2-6alkyl, optionally substituted with five substituents inclusive, representing fluoro, -C2-6alkylOR ⁶ , -C2-6alkylNR ^10а R ^11а , - (CH2) mSO2C1-3alkyl, - (CH2) mSO2NR ¹⁰ R ¹¹ , - (CH2) mC (O) NR ¹⁰ R ¹¹ , - (CH2) mCN, - (CH2) mCO2R ⁶ , - (CH2) mNHCO2C1-4alkyl, - (CH2) _m NHC (O) C _{1 -4} alkyl or - (CH ₂ ) _n heteroaryl, where heteroaryl is optionally substituted with one or two R ⁷ groups, which may be the same or different;

R ³ is —H, —C1-4alkyl, cyclopropyl, —CH2F, —C1-3alkylOR ^6, or —C1-3alkylCN;

R ⁴ represents a phenyl or heteroaryl group, where each is optionally substituted with one, two or three R ⁷ groups, which may be the same or different;

each R ^{5 is} independently halogen, —C0-6 alkyl-R ⁸ , —O — C2-6 alkyl-R ⁸ , —CN, or —SO ₂ C _1-3 alkyl;

R ⁶ is —H or —C _1-4 alkyl;

each R ⁷ independently represents oxo, halogeno, -C1-4alkil optionally substituted with 1, 2 or 3 fluoro substituents, -S0-3alkilOR ⁶ -OS2-3alkilOR ⁶ -S0-3alkilNR ¹⁰ R ^11, -S0-3alkil- CONR ¹⁰ R ¹¹ , -CN, -SO2-C1-alkyl or -SO2NR10R ¹¹ ;

R ⁸ is —H, —OR ^6, or —NR10R ¹¹ ;

each R ^{9 is} independently halogen, —C1-4alkyl, cyclopropyl, cyclobutyl, —CH2CF3, —CH2CHF2, —CH2CH2F, —OCH2CH2OR ⁶ , —C0-3alkylOR ⁶ , —C0-3alkylNR ¹⁰ R ¹¹ , —NHCH2CH ₂ OR ⁶ , -NHCO2R ⁶ , oxo, -C (O) R ⁶ , -C (O) OR ⁶ or -C (O) NR ¹⁰ R ¹¹ ;

R ¹⁰ and R ^{11 are} each independently selected from H and —C _1-3 alkyl;

R ^10a and R ^{11a are} each independently selected from —H and —C _1-3 alkyl;

- 7 038888

m. is an integer selected from 2, 3 or 4; and n is an integer selected from 0, 1, 2, 3, or 4.

In one embodiment, R ¹ is methyl.

In one embodiment, R ² is —C0_3alkylcycloalkyl, wherein the cycloalkyl group is optionally substituted with one, two or three R ⁵ groups, which may be the same or different. In one embodiment, R ² represents -S0_ ₃ alkyl-C ₃ _7tsikloalkilnuyu group, wherein the C _3-7 cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl or bicyclo [3.1.0] hexane, wherein said groups are optionally substituted by one , two or three groups R ⁵ , which may be the same or different. In another embodiment, R ² is cyclopropyl, cyclobutyl, cyclohexyl or bicyclo [3.1.0] hexanyl, optionally substituted with one, two or three R ⁵ groups, which may be the same or different. In another embodiment, R ² is cyclopropyl, cyclobutyl, cyclohexyl, or bicyclo [3.1.0] hexanyl, optionally substituted with one R ⁵ group selected from methyl, fluoro, and —OH. In a specific embodiment, R ² is cyclohexyl optionally substituted with one methyl group. In another specific embodiment, R ² is a cyclohexyl group optionally substituted with an OH group. In another embodiment, R ² is a cyclohexyl group optionally substituted with a methoxy group.

In one embodiment, R ² is —C0-4alkylheterocyclyl, where each heterocyclyl is optionally substituted with one or two R ⁹ groups, which may be the same or different. In another embodiment, R ² is —C0-4alkylheterocyclyl, wherein the heterocyclyl is optionally substituted with one or two R ⁹ groups, which may be the same or different. In another embodiment, R ² is —C0-4alkylheterocyclyl, which is heterocyclyl, —CH2CH2heterocyclyl, or —CH2CH2CH2-heterocyclyl. In another embodiment, R ² is —C0-4alkylheterocyclyl, wherein the heterocyclyl is selected from oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl, piperidinyl, piperazinyl, (1r, 5s) -3-oxabicyclo [3.1.0] hexanyl , 5s) -3-azabicyclo [3.1.0] hexanyl, said groups being optionally substituted by one or two R ⁹ groups, which may be the same or different. In another embodiment, R ² is —C0-4alkylheterocyclyl, wherein the heterocyclyl is selected from oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl, piperidinyl, piperazinyl, (1r, 5s) -3-oxabicyclo [3.1.0] hexanyl , 5s) -3-azabicyclo [3.1.0] hexanyl, optionally substituted with one or two R ⁹ groups selected from methyl, —C (O) CH3, and fluorine. In another embodiment, R ² is —C _0-4 alkylheterocyclyl, wherein the heterocyclyl optionally substituted with one or two R ⁹ groups is selected from * denotes the point of attachment.

In another embodiment, R ² is H, —CH3, C2-6alkyl optionally substituted with one, two, three, four or five fluoro substituents, —C2_6alkylOR ⁶ , —C2-6alkylNR ¹⁰ R ¹¹ , - (CH2) mSO2C1-zalkyl, - (CH2) mSO2NR ¹⁰ R ¹¹ , - (CH2) mC (O) NR ¹⁰ R ¹¹ , - (CH2) mCN, - (CH2) mCO2R ⁶ , - (CH2) _m NHCO ₂ C _1-4 alkyl, - ( CH ₂ ) _m NHC (O) C _1-4 alkyl or - (CH ₂ ) _p heteroaryl, where heteroaryl is optionally substituted with one or two R ⁷ groups, which may be the same or different.

In another embodiment, R ^{2 is} selected from methyl, ethyl, propyl, isopropyl, butyl, —CH ₂ CH ₂ CH (CH ₃ ) ₂ ,

-CH2CH (CH3) 2, -CH2CH2OR ⁶ , -CH2CH2CH2OR ⁶ , -CH2CH (CH3) OR ⁶ , -CH2CH2CH (CH3) OR ⁶ ,

-CH2CH2CH (CH3) NR ^10a R ^11a , -CH2CH2CH2NR ^10a R ^11a , - (CH2) mSO2CH3, - (CH2) mC (O) NHCH3, - (CH2) mCN, - (CH2) mCO2R ⁶ , - (CH2) mCF3 and - (CH2) mNHCO2C (CH ₃ ) ₃ . ²

In another embodiment, R ² represents -C ₁ _ ₆ alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, -CH ₂ CH ₂ CH (CH _{3) 2} and -CH ₂ CH (CH _{3) 2.} In another embodiment, R ² is

- 8 038888

-C1-6alkylOR ⁶ , selected from -CH2CH2OR ⁶ , -CH2CH2CH2OR ⁶ , -CH2CH (CH3) OR ^6, and -SCHCCCCHCHCHSH ⁶ . In another embodiment, R ² is —C1-6alkylNR ^10a R ^11a selected from —CH2CH ₂ CH (CH ₃ ) NR ^10a R ^11a and —CH2CH2CH2NR ^10a R ^11a . In another embodiment, R ² is - (CH2) mSO ₂ CH ₃ . In another embodiment, R ² is - (CH2) mC (O) NHCH3. In another embodiment, R ² is - (CH2) mCN. In another embodiment, R ² is - (CH2) mCO2R ⁶ . In another embodiment, R ² is - (CH2) _m CF ₃ . In another embodiment, R ² is - (CH2) mNHCO2C (CH3) 3.

In one embodiment, R ² is - (CH 2) n-heteroaryl, wherein the heteroaryl is optionally substituted with one or two R ⁷ groups, which may be the same or different. In another embodiment, R ² is - (CH2) _n C _5-6 heteroaryl, wherein the C _5-6 heteroaryl is selected from furanyl, thienyl, pyrrolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl, said groups optionally substituted with one or two R ⁷ substituents independently selected from halogen, C1-4 alkyl (such as methyl) and —C0-3 alkylOR ⁶ groups. In another embodiment, there are compounds of formula (I) in which R ² is - (CH 2) _n C _5-6 heteroaryl, where C _5-6 heteroaryl is pyrazolyl optionally substituted with C _1-4 αalkyl or -C _{0- 3} alkylOR ⁶ . In a specific embodiment, there are provided compounds of formula (I) in which R ² is - (CH ₂ ) _n C _5-6 heteroaryl, where an optionally substituted C _5-6 heteroaryl group is selected from the group consisting of

where * means attachment point.

In one embodiment, R ³ is H, methyl, ethyl, —CH ₂ F, —CH 2 OH, —CH (OH) CH ₃ , —CH 2 OMe, or —CH 2 CN. In one embodiment, R ³ is H, methyl, ethyl, or —CH 2 OH.

In one embodiment, R ⁴ is phenyl optionally substituted with one, two or three R ⁷ groups, which may be the same or different. In another embodiment, R ⁴ is unsubstituted phenyl. In another embodiment, R ⁴ is phenyl substituted with one or two R ⁷ groups, which may be the same or different, selected from halogen, —C1-4alkyl, optionally substituted with one, two or three fluoro substituents, —C0-3αalkylOR ⁶ groups, groups -OC2-3alkylOR ⁶ and -CN. In another embodiment, R ⁴ is phenyl substituted with one or two R ⁷ groups, which may be the same or different, selected from halogen, —C _1-4 alkyl, —C _0-3 αalkylOR ^6, and —CN. In another embodiment, R ⁴ is phenyl substituted with one R ⁷ group selected from the group consisting of fluoro, chloro, methyl, cyano and methoxy.

In another embodiment, R ⁴ is a heteroaryl group which is pyridyl, optionally substituted with one, two or three R ⁷ groups, which may be the same or different. In another embodiment, R ⁴ is a heteroaryl group which is unsubstituted pyridyl.

In another embodiment, R ⁴ is a heteroaryl group that is indolyl (eg 1H-indol-4-yl or 1H-indol-5-yl) optionally substituted with one, two or three R ⁷ groups, which may be the same or different. In another embodiment, R ⁴ is a heteroaryl group which is 1H-indol-4-yl.

In another embodiment, R ⁴ is a heteroaryl group which is pyrrolopyridinyl (e.g. 1H-pyrrolo [2,3, b] pyridinyl or N-pyrrolo [2,3, c] pyridinyl) optionally substituted with one, two or three R groups ⁷ , which can be the same or different. In another embodiment, R ⁴ is a heteroaryl group which is unsubstituted pyrrolopyridinyl.

In one embodiment, each R ^{5 is} independently halogen or —C _0-6 alkyl — R ⁸ , where R ⁸ is H, OR ⁶ (such as OH), or NR ¹⁰ R11 (such as NH2).

In one embodiment, R ⁶ is H, methyl, ethyl, or tert-butyl.

- 9 038888

In one embodiment, each R ^{7 is} independently oxo, halogen, —C1.4alkyl, optionally substituted with one, two or three substituents such as fluoro, —C0-zalkylOR ⁶ , —C0. ₃ αalkyl NR ¹⁰ R ¹¹ , -C0.3alkyl-CONR ¹⁰ R ¹¹ , -CN, -SO2-C ₁ . ₃ alkyl or -SO2NR ¹⁰ R ¹¹ . In another embodiment, each R ^{7 is} independently halo, —C ₁ . ₄ alkyl optionally substituted with one, two or three substituents such as fluoro, —C ₀ . ₃ αalkylOR ⁶ or CN.

In one embodiment, each R ^{7 is} independently halo, —C ₁ . ₄ alkyl, -C ₀ . ₃ alkylOR ⁶ or —CN.

In one embodiment, R ⁸ is H, —OH, or methoxy.

In one embodiment, each R ^{9 is} independently halogen, C1.4 alkyl (such as methyl), —C0.3alkylOR ⁶ , —C0. ₃ αalkyl NR ¹⁰ R ¹¹ , oxo or —C (O) R ⁶ (such as C (O) CH ₃ ).

In one embodiment, m is 2 or 3.

In one embodiment, n is 0, 1, or 2. In another embodiment, n is 0. In another embodiment, n is 2.

It should be understood that all combinations of substituent groups described above are encompassed by the present invention.

The compounds of the invention include the compounds of Examples 1 to 261 and their salts.

The compounds of the invention include the compounds of Examples 1 to 138 and their salts.

In one embodiment, the compound of formula (I) is selected from No. - ((17 ?, 55.6g) -3-oxabicyclo [3.1.0] hexan-6-yl) -No-methyl-1 - ((S) -1 - phenylethyl) 177-pyrazole-3, 5-dicarboxamide;

No. - ((1 g, 45) -4-hydroxycyclohexyl) -No-methyl-1 - ((5) -1-phenylethyl) - 177-pyrazole-

3,5-dicarboxamide and N - ((17 ?, 37 ?, 55.6 g) -3-hydroxycyclo [3.1.0] hexan-6-yl) -No-methyl-1 - ((5) -1 phenylethyl) - 177-pyrazole-3,5-dicarboxamide, or a salt thereof.

In one embodiment, there is provided or a pharmaceutically acceptable salt thereof. In one embodiment, it is proposed

In one embodiment, there is provided or a pharmaceutically acceptable salt thereof. In one embodiment, it is proposed

HE

In another embodiment, the compound of formula (I) is selected from

- 10 038888 No - ((17 ?, 55.6g) -3-oxabicyclo [3.1.0] hexan-6-yl) -1 - ((5) -1 - (4-chlorophenyl) ethyl) -No methyl- 1 // - pyrazole-3,5-dicarboxamide;

(5) -No-methyl-1- (1-phenylethyl) -No- (1H-pyrazol-4-yl) -1H-pyrazole-3,5 dicarboxamide;

- ((5) -1 - (4-chlorophenyl) ethyl) -No - ((17 ?, 37 ?, 55) 6d) -3-hydroxycyclo [3.1.0] hexane-6yl) -No-methyl-17 / -pyrazole-3,5-dicarboxamide;

- ((5) -1 - (3-chlorophenyl) ethyl) -No - ((17?, 37 ?, 55 ', 6d) -3-hydroxybicyclo [3.1.0] hexane-6yl) -No-methyl-177 -pyrazole-3,5-dicarboxamide and No - ((17 ?, 37 ?, 55) 6 /) - 3-hydroxycyclo [3.1.0] hexan-6-yl) -No-methyl-1 - ((5) -1 phenylpropyl) - 177-pyrazole-3,5-dicarboxamide, or a salt thereof.

In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

In a third aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy, in particular in the treatment of diseases or conditions in which a bromodomain inhibitor is indicated.

In a fourth aspect, the present invention provides a method of treating diseases or conditions in which a bromodomain inhibitor is indicated in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

A fifth aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diseases or conditions in which a bromodomain inhibitor is indicated.

Compounds of the invention may have an improved profile over known BET inhibitors (including properties such as potency, selectivity and / or convertibility). Certain compounds of the invention may have a beneficial combination of these properties.

Description of the application.

The compounds of formula (I) and their salts are inhibitors of bromodomain and are therefore believed to have potential utility in the treatment of diseases or conditions for which a bromodomain inhibitor is indicated.

Bromodomain inhibitors are believed to be useful in the treatment of a variety of diseases or conditions associated with systemic inflammation or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis, and in the prevention and treatment of viral infections.

Bromodomain inhibitors can be useful in the treatment of a wide range of acute or chronic autoimmune and / or inflammatory conditions such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease ( and ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis (including atopic dermatitis), alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, hypercholesterolemia, atherosclerosis Sjogren's syndrome, sialoadenitis, central retinal vein occlusion, central retinal vein branch occlusion, Irwin-Gass syndrome (after cataract and postoperative), retinitis pigmentosa, parsplanitis, shot retinochoroidopathy, epiretinal membrane, cystic macular edema, telfovecolaris ration maculopathies, vitreomacular traction syndromes, retinal detachment, neuroretinitis, idiopathic macular edema, retinitis, dry eye syndrome (keratoconjunctivitis dry), vernal keratoconjunctivitis, atopic keratoconjunctivitis, uveitis (uveitis), anterior macular uveiteitis, posterior macular uveiteitis , scleritis, diabetic retinopathy, diabetic macular edema, age-related macular degeneration, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, acute alcoholic hepatitis, chronic alcoholic hepatitis, alcoholic steatohepatitis, non-alcoholic steatohepatitis, cirrhosis (HA autoimmune hepatitis, fulminant hepatitis, chronic viral hepatitis, alcoholic liver disease, systemic sclerosis, interstitial lung disease associated with systemic sclerosis, sarcoidosis, neurosarcoidosis, Addison's disease, hypophysitis, thyroiditis, type I diabetes, type II diabetes, gigantocell including I lupus nephritis, vasculitis with organ damage such as glomerulonephritis, vasculitis including giant-11 038888 lethal arteritis, Wegener's granulomatosis, polyarteritis nodosa, Behcet's disease, Kawasaki disease, Takayasu arteritis, pyoderma gangrenosum, organ transplant vasculitis and systemic sclerosis.

In one embodiment, the acute or chronic autoimmune and / or inflammatory condition is a disorder of lipid metabolism mediated through the regulation of APO-A1 (apolipoprotein A1), such as hypercholesterolemia, atherosclerosis, or Alzheimer's disease.

In another embodiment, the acute or chronic autoimmune and / or inflammatory condition is a respiratory disorder such as asthma or chronic obstructive airway disease.

In another embodiment, the acute or chronic autoimmune and / or inflammatory condition is a systemic inflammatory disorder such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, or inflammatory bowel disease (Crohn's disease or ulcerative colitis).

In another embodiment, acute or multiple sclerosis.

In another embodiment, it is acute or type I diabetes.

In another embodiment, it is acute or is rheumatoid arthritis.

chronic chronic chronic autoimmune autoimmune autoimmune and / or and / or and / or inflammatory inflammatory inflammatory condition condition

Bromodomain inhibitors can be helpful in treating depression.

Bromodomain inhibitors can be useful in the treatment of diseases or conditions that include inflammatory responses to infections caused by bacteria, viruses, fungi, parasites or their toxins, such as sepsis, acute sepsis, septic syndrome, septic shock, endotoxemia, systemic inflammatory response syndrome ( SSVR), multiple organ failure syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer's reactions, encephalitis, myelitis, meningitis malaria and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex, and coronavirus. In one embodiment, the disease or condition that includes an inflammatory response to an infection caused by bacteria, virus, fungi, parasite, or toxins thereof is acute sepsis.

Bromodomain inhibitors may be useful in the treatment of conditions associated with ischemic reperfusion injury, such as myocardial infarction, cerebrovascular ischemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass surgery, kidney embolism , liver, gastrointestinal tract or peripheral arteries of the extremities.

Bromodomain inhibitors may be useful in the treatment of cardiovascular diseases such as coronary heart disease (eg angina pectoris and myocardial infarction), pulmonary arterial hypertension, cerebrovascular ischemia (stroke), hypertensive cardiopathy, rheumatic heart disease, cardiomyopathy, atrial fibrillation , endocarditis, aortic aneurysm, or peripheral arterial disease.

Bromodomain inhibitors may be useful in the treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, pulmonary fibrosis, cystic fibrosis, progressive massive fibrosis, renal fibrosis, liver fibrosis, cirrhosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease, post-NAFL stricture, formation of keloid scars, scleroderma (including focal scleroderma and systemic sclerosis), cardiac fibrosis, atrial fibrosis, endomyocardial fibrosis, myocardial infarction, arthrofibrosis, Dupuytren's contracture, mediastinal fibrosis disease, myelofibrosis retinal fibrosis and adhesions capsulitis.

Bromodomain inhibitors may be useful in treating viral infections such as herpes simplex virus infections and reactivation, febrile herpes, herpes zoster virus infections and reactivation, chickenpox, shingles, human papillomavirus (HPV), human immunodeficiency virus (HIV), neoplasia cervix, adenoviral infections including acute respiratory disease, poxvirus infections such as vaccinia or smallpox, or African swine fever virus. In one embodiment, the viral infection is an HPV infection of the skin or epithelial tissues of the cervix. In another embodiment, the viral infection is a latent HIV infection.

Bromodomain inhibitors can be useful in the treatment of a wide variety of bone lesions such as osteoporosis, osteopenia, osteoarthritis, and ankylosing spondylitis.

Bromodomain inhibitors can be useful in the treatment of cancers, including hematologic cancers (such as leukemia, lymphoma, and multiple myeloma), epithelial cancers (including lung, breast, and colon carcinomas), midline carcinomas, or mesenchymal, hepatic, hepatic, renal tumors or tumors of the nervous system.

Bromodomain inhibitors may be useful in the treatment of one or more cancers selected from brain cancer (gliomas), glioblastomas, Banayan-Zonan syndrome, Cowden's disease, Lermitte-Duclos disease, breast cancer, inflammatory breast cancer, colorectal cancer and rectum, Wilms tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcomas, osteosarcomas, giant cell bone tumors, thyroid cancer, T-cell lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic plasma leukemia, acute T-leukemia leukemia, mantle cell leukemia, many neural myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, mixed leukemia, erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular cell carcinoma, bladder cancer, bladder cancer vulva, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, stomach cancer, nasopharyngeal cancer, cheek cancer, oral cancer, GST (gastrointestinal stromal tumor), median NUT carcinoma and testicular cancer.

In one embodiment, the cancer is a leukemia, eg, a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed linear leukemia (MLL). In another embodiment, the cancer is a midline NUT carcinoma. In another embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is lung cancer, such as small cell lung cancer (SCLC). In another embodiment, the cancer is neuroblastoma. In another embodiment, the cancer is Burkitt's lymphoma. In another embodiment, the cancer is cervical cancer. In another embodiment, the cancer is esophageal cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is breast cancer. In another embodiment, the cancer is colon and rectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is castration-resistant prostate cancer.

Bromodomain inhibitors may be useful in the treatment of diseases associated with systemic inflammatory response syndrome such as sepsis, burns, pancreatitis, extensive trauma, bleeding, and ischemia. In this embodiment, the bromodomain inhibitor will be administered at diagnosis to reduce the incidence of SSIR, the onset of shock, multiple organ failure syndrome, which includes the onset of acute lung injury, ARDS, acute kidney, liver, myocardial or gastrointestinal tract injury, and death. In another embodiment, the bromodomain inhibitor will be administered prior to surgical or other procedures associated with a high risk of sepsis, bleeding, extensive tissue damage, SSVR, or MUD (Multiple Organ Dysfunction Syndrome). In a specific embodiment, the disease or condition in which the bromodomain inhibitor is indicated is sepsis, septic syndrome, septic shock, or endotoxemia. In another embodiment, a bromodomain inhibitor is indicated for the treatment of acute or chronic pancreatitis. In another embodiment, a bromodomain inhibitor is indicated for treating burns.

Thus, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. One embodiment provides N ⁵ ((1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1 - ((S) -1-phenylethyl) -1H-pyrazole -3,5-dicarboxamide or a pharmaceutically acceptable salt thereof for use in therapy.

The compound of formula (I), or a pharmaceutically acceptable salt thereof, can be used in the treatment of diseases or conditions in which a bromodomain inhibitor is indicated. Thus, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition in which a bromodomain inhibitor is indicated. In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of acute or chronic autoimmune and / or inflammatory conditions. In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis. In another embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases or conditions that include inflammatory responses to infections caused by bacteria, viruses, fungi, parasites, or toxins thereof. In another embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of conditions associated with ischemia-reperfusion injury. In another embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular diseases. In another embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for

- 13 038888 applications in the treatment of fibrotic conditions. In another embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of viral infections. In another embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of bone lesions. In another embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In another embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases associated with systemic inflammatory response syndrome.

Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of diseases or conditions in which a bromodomain inhibitor is indicated. In one embodiment, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of acute or chronic autoimmune and / or inflammatory conditions. In one embodiment, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of rheumatoid arthritis. In another embodiment, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diseases or conditions that include inflammatory responses to infections caused by bacteria, viruses, fungi, parasites or their toxins. In another embodiment, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of conditions associated with ischemia-reperfusion injury. In another embodiment, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cardiovascular diseases. In another embodiment, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of fibrotic conditions. In another embodiment, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of viral infections. In another embodiment, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. In another embodiment, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diseases associated with systemic inflammatory response syndrome.

Also provided is a method of treating diseases or conditions in which a bromodomain inhibitor is indicated in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, there is provided a method of treating acute or chronic autoimmune and / or inflammatory conditions in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, there is provided a method of treating rheumatoid arthritis in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In another embodiment, there is provided a method of treating diseases or conditions that include inflammatory responses to infections caused by bacteria, viruses, fungi, parasites or their toxins in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt. In another embodiment, there is provided a method of treating conditions associated with ischemia-reperfusion injury in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In another embodiment, there is provided a method of treating cardiovascular disease in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In another embodiment, there is provided a method of treating a fibrotic condition in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In another embodiment, there is provided a method of treating viral infections in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In another embodiment, there is provided a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In another embodiment, there is provided a method of treating diseases associated with systemic inflammatory response syndrome in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Accordingly, a subject in need of this is a mammal, in particular a person.

The invention further provides a method for inhibiting a bromodomain-containing protein comprising contacting the bromodomain-containing protein with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

As used herein, reference to the term treating a particular disease or condition includes preventing or preventing such disease or condition.

- 14 038888

Pharmaceutical compositions / routes of administration / dosage.

Compositions.

While it is possible that for use in therapy, the compound of formula (I) as well as its pharmaceutically acceptable salts may be administered in the form of the parent compound, usually the active ingredient is presented in the form of a pharmaceutical composition. Before administration to a patient, the compounds of formula (I) and their pharmaceutically acceptable salts are usually formulated into pharmaceutical compositions, but not necessarily. Therefore, in another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more (eg, two, three, four, five, or six) pharmaceutically acceptable excipients. One embodiment provides N ⁵ - ((1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1 - ((S) -1-phenylethyl) 1H-pyrazole -3,5-dicarboxamide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The compounds of formula (I) and their pharmaceutically acceptable salts are as described above. The excipient (s) must be acceptable in the sense that they must be compatible with the other ingredients of the composition and are harmless to their recipient. Another aspect of the invention also provides a method for preparing a pharmaceutical composition comprising mixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable excipients. A pharmaceutical composition containing a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be prepared by, for example, mixing at ambient temperature and atmospheric pressure. The pharmaceutical composition can be used in the treatment of any of the conditions described herein.

In a further aspect, the invention relates to pharmaceutical compositions for the treatment of a disease or condition in which a bromodomain inhibitor is indicated, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Since the compounds of formulas (I) are intended for use in pharmaceutical compositions, it will be readily understood that they are all preferably presented in substantially pure form, for example, they are at least 85% pure, especially at least 98% pure (% by weight based on total weight).

Pharmaceutical compositions can be presented in unit dosage forms containing a predetermined amount of active ingredient per dosage unit. Preferred standard dosage compositions are compositions containing a daily dose, or a sub-dose, or an appropriate portion thereof, of the active ingredient. Therefore, such dosage units can be administered more than once a day. Preferred standard dosage compositions are compositions containing a daily dose, or a sub-dose (for administration more than once a day), as set forth herein above, or a corresponding portion thereof, of the active ingredient.

The pharmaceutical compositions can be designed to be administered via any suitable route, for example, oral (including buccal or sublingual), rectal, inhalation, intranasal, topical (including buccal, sublingual, or transdermal), ocular (including local, intraocular, subconjunctival, episcleral, subtenon ), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. Such compositions can be prepared by any method known in the pharmaceutical art, for example, by combining the active ingredient with the carrier (s) or excipient (s).

The pharmaceutical compositions of the invention can be prepared and packaged in bulk form from which a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be recovered and then administered to a patient, for example, with powders or syrups. Alternatively, the pharmaceutical compositions of the invention can be prepared and packaged in unit dosage form, where each physically discrete unit contains a compound of formula (I) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the invention, prepared in unit dosage form, can usually contain, for example, from 0.25 mg to 1 g, or from 0.5 to 500 mg, or from 1 to 100 mg of a compound of formula (I) or a pharmaceutically acceptable salt.

A compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or excipients will generally be formulated for administration to a patient via the desired route of administration. For example, dosage forms include those intended for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) administration by inhalation such as aerosols, solutions and dry powders; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically acceptable excipients will vary depending on the end

- 15 038888 of the selected selected dosage form. In addition, suitable pharmaceutically acceptable excipients can be selected based on the particular function they can perform in the composition. For example, certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the manufacture of homogeneous dosage forms. Certain pharmaceutically acceptable excipients can be selected for their ability to facilitate the manufacture of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the transfer or transport of a compound or compounds of formula (I), or pharmaceutically acceptable salts thereof, immediately after administration to a subject from one organ or body part to another organ or body part. Certain pharmaceutically acceptable excipients may be selected for their ability to improve patient compliance and treatment regimen.

Suitable pharmaceutically acceptable excipients include the following types of excipients: carriers, diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosifiers, antioxidants, preservatives, stabilizers, surfactants and buffering agents. One of ordinary skill in the art will understand that some pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much excipient is present in the formulation and what other excipients are present in the formulation.

Those of skill in the art have the necessary knowledge and skill in the art to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of sources available to those skilled in the art that describe pharmaceutically acceptable excipients and which may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

Pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Several methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In one embodiment, the pharmaceutical composition is for parenteral administration, in particular intravenous administration.

In one embodiment, the pharmaceutical composition is for oral administration.

In one embodiment, the pharmaceutical composition is for topical administration.

Pharmaceutical compositions intended for parenteral administration include aqueous and non-aqueous sterile injection solutions (which may contain antioxidants, buffers, bacteriostatic agents and solutes that render the composition isotonic with the blood of the intended recipient) and aqueous and non-aqueous sterile suspensions (which may contain suspending agents and thickeners). The compositions can be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Injectable solutions and suspensions for immediate administration can be prepared from sterile powders, granules and tablets.

Pharmaceutical compositions for oral administration may be presented as discrete units such as capsules or tablets; powders and granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders suitable for inclusion in tablets or capsules can be prepared by grinding the compound to a suitable small particle size (eg, by micronization) and mixing with a similarly prepared pharmaceutical carrier such as an edible carbohydrate, eg starch or mannitol. A flavoring, preservative, dispersing agent and colorant may also be present.

Capsules can be prepared by preparing a powder mixture as described above and filling the formed gelatinous shells. Sliding and lubricating agents such as colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture prior to filling. A disintegrant or solubilizer such as agar agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the drug when the capsule is swallowed.

- 16 038888

In addition, when desired or necessary, suitable binders, glidants, lubricants, sweeteners, flavors, disintegrating agents (disintegrants) and colorants can also be included in the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sugars, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets are prepared, for example, by preparing a powder mixture, granulating or aggregating, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing an appropriately ground compound with a diluent or base as described above and optionally with a binder such as carboxymethyl cellulose, alginate, gelatin or polyvinyl pyrrolidone, a dissolution retardant such as paraffin; a fast absorption agent such as a quaternary salt; and / or an absorbing agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia gluten, or solutions of cellulosic or polymeric materials, and forcing through a sieve. As an alternative to granulation, the powder mixture can be passed through a tabletting machine and the result is imperfectly shaped lumps that break into granules. The granules can be lubricated to prevent sticking to the tablet forming press tool by adding stearic acid, stearate, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of formula (I) and their pharmaceutically acceptable salts can also be combined with a free flowing inert carrier and compressed directly into tablets without the need for granulating or aggregating steps. A transparent or opaque protective coating can be provided consisting of an insulating shellac layer, a sugar or polymer coating, and a glossy wax coating. Colorants can be added to these coatings to differentiate between different dosage units.

Oral fluids such as solution, syrups, and elixirs can be prepared in unit dosage form such that a specified amount contains a specified amount of a compound. Syrups can be prepared by dissolving the compound in an appropriately flavored aqueous solution, while elixirs are prepared using a non-toxic alcoholic carrier. Suspensions can be formulated by dispersing the compound in a non-toxic carrier. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol esters, preservatives, flavoring such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added.

Compositions for oral administration can be designed to provide a modified release profile to facilitate or otherwise control the release of the therapeutically active agent.

When appropriate, dosage unit compositions for oral administration may be microencapsulated. A sustained or sustained release composition can be prepared, for example, by coating or encapsulating the granular material in polymers, wax, or the like.

For compositions suitable and / or intended for oral administration, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be in the form of particulate matter, for example obtained by micronization. The preferred particle size of the milled (eg micronized) compound or salt is defined as a D ₅₀ value of from about 0.5 to about 10 microns (eg, as measured using laser diffraction).

The compounds of formula (I) and their pharmaceutically acceptable salts can also be administered in the form of liposomal delivery systems such as small monolamellar vesicles, large monolamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine, or phosphatidylcholines.

Pharmaceutical compositions for topical administration may be formulated as ointments, creams, suspensions, emulsions, lotions, powders, solutions, pastes, gels, foams, sprays, aerosols or oils. Such pharmaceutical compositions may contain conventional excipients, which include, but are not limited to, preservatives, solvents to promote drug penetration, cosolvents, emollients, propellants, viscosity modifiers (gelling agents), surfactants and carriers. In one embodiment, there is provided a pharmaceutical composition intended for topical administration, containing from 0.01 to 10% or from 0.01 to 1% of a compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the composition.

- 17 038888

For the treatment of the eye or other superficial tissues such as the mouth and skin, the compositions are preferably used as an ointment, cream, gel, spray or foam for topical application. When formulated as an ointment, the active ingredient can be used with either a paraffinic or a water-soluble ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical compositions for topical administration to the eye include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Compositions for administration to the eye will have an ophthalmologically compatible pH and osmolality.

One or more ophthalmologically acceptable pH adjusters and / or buffering agents may be included in the composition of the invention, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate and sodium lactate; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases and buffers can be included in the amount required to maintain the pH of the composition in an ophthalmologically acceptable range. One or more ophthalmologically acceptable salts may be included in the composition in an amount sufficient to bring the osmolality of the composition to the ophthalmologically acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions.

An ocular drug delivery device can be designed for the controlled release of one or more therapeutic agents with multiple defined release rates and sustained dose kinetics and permeability. Controlled release can be achieved through the development of polymer matrices, including various choices and properties of biodegradable / biodegradable polymers (e.g., poly (ethylene vinyl) acetate (EVA), superhydrolyzed polyvinyl acetate (PVA), hydroxyalkyl cellulose (HPC), methyl cellulose (MC), hydroxypropyl methylcellulose ), polycaprolactone, poly (glycolic) acid, poly (lactic) acid, polyanhydride) with molecular weights, crystallinity, copolymer ratios, processing conditions, surface treatment, geometry, addition of excipients and polymer coatings that will accelerate drug diffusion, erosion, dissolution and osmosis.

Pharmaceutical compositions for delivery to the eye also include an in situ gellable aqueous composition. Such a composition contains a gelling agent at a concentration effective to stimulate gelling upon contact with the eye or lacrimal fluid. Suitable gelling agents include, but are not limited to thermosetting polymers. As used herein, the term in situ gellable includes not only low viscosity fluids that form gels upon contact with the eye or tears, but also includes more viscous fluids, such as semi-liquid and thixotropic gels, which exhibit significantly increased viscosity or thickening when administered to the eye. ... See, for example, Ludwig (2005) Adv. Drug Deliv. Rev. 3; 57: 1595-639, incorporated herein by reference, to study examples of polymers for use in drug delivery to the eye.

Dosage forms for nasal or inhalation administration can be readily prepared as aerosols, solutions, suspensions, gels, or dry powders.

For compositions suitable and / or intended for inhalation administration, it is preferred that the compound of formula (I), or a pharmaceutically acceptable salt thereof, be in the form of particulate matter, for example obtained by micronization. The preferred particle size of the milled (eg micronized) compound or salt is defined as a D ₅₀ value of from about 0.5 to about 10 microns (eg, as measured using laser diffraction).

Aerosol compositions, for example for inhalation administration, may contain a solution or a finely dispersed suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol compositions can be presented in single or multiple dose amounts in sterile form in an airtight container that can take the form of a cartridge or refillable cartridge for use with a nebulizer or inhaler. Alternatively, the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser equipped with a metering valve (metered dose inhaler) that is intended to be disposed of as soon as the contents of the container are used up.

When the dosage form contains an aerosol dispenser, it will preferably contain a suitable pressurized propellant such as compressed air, carbon dioxide, or an organic propellant such as hydrofluorocarbon (HFC). Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropane and 1,1,1,2-tetrafluoroethane. Aerosol dosage forms can also be in the form of a pump spray. The pressurized aerosol may contain a solution or suspension of the active compound. This may require the inclusion of additional excipients, for example with

- 18 038888 solvents and / or surfactants to improve dispersion characteristics and homogeneity of suspension preparations. Solution formulations may also require the addition of cosolvents such as ethanol.

For pharmaceutical compositions suitable and / or intended for inhalation administration, the pharmaceutical composition may be a dry powder inhalation composition. Such compositions may contain a powder base such as lactose, glucose, trehalose, mannitol or starch, a compound of formula (I), or a pharmaceutically acceptable salt thereof (preferably in particulate form, e.g. micronized form) and optionally an activity modifier such as L β-leucine or another amino acid and / or a metal salt of stearic acid such as magnesium or calcium stearate. Preferably, the dry powder inhalation composition contains a dry powder mixture of lactose, for example lactose monohydrate, and a compound of formula (I) or a salt thereof. Such compositions can be administered to a patient using a suitable device such as the DISKUS® device available from GlaxoSmithKline, which is described, for example, in GB 2242134 A.

The compounds of formula (I) and their pharmaceutically acceptable salts can be formulated as a liquid preparation for delivery from a liquid dispenser, for example, a liquid dispenser having a dispensing nozzle or a dispensing tip through which a metered dose of a liquid preparation is dispensed upon application of user force to the pumping mechanism of the liquid dispenser ... These liquid dispensers are usually equipped with a multiple dispensing reservoir for liquid preparation, the doses being dispensed as the pump is actuated in succession. The dispensing nozzle or tip may be shaped for insertion into the nostrils of a user to jet dispense a liquid preparation into the nasal cavity. A liquid dispenser of the above type is described and illustrated in International Patent Application No. WO 2005/044354 A1.

A therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, will depend on a number of factors, including, for example, the age and weight of the patient, the exact condition requiring treatment and its severity, the nature of the formulation and the route of administration, and ultimately, will be determined at the discretion of the treating physician or veterinarian. In a pharmaceutical composition, each oral or parenteral dosage unit preferably contains 0.01 mg to 3000 mg, more preferably 0.5 mg to 1000 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. Each dosage unit for nasal or inhalation administration preferably contains 0.001 mg to 50 mg, more preferably 0.01 to 5 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.

The pharmaceutically acceptable compounds of formula (I) and their pharmaceutically acceptable salts may be administered in a daily dose (for an adult patient), for example, an oral or parenteral dose of 0.01 to 3000 mg per day, 0.5 to 1000 mg per day, or 100 to 2500 mg per day, or a nasal or inhalation dose of 0.001 to 50 mg per day, or 0.01 to 5 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. This amount can be given as one dose per day or, more often, as several (eg, two, three, four, five, or six) subdoses per day, so that the total daily dose is the same. The effective amount of its salt can be defined as the proportion of the effective amount of the compound of formula (I) per se.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used alone or in combination with other therapeutic agents. Thus, the combination therapies of the present invention comprise administering at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, and using at least one other therapeutically active agent. The compound (s) of formula (I) and their pharmaceutically acceptable salts and the other therapeutically active (s) agent (s) can be administered together in one pharmaceutical composition or separately, and when administered separately, this can be carried out simultaneously or sequentially in any order. The amounts of the compound (s) of formula (I) and their pharmaceutically acceptable salts and other therapeutically active agent (s) and the relative timing of their administration will be selected so as to achieve the desired therapeutic effect from the combination. Thus, in a further aspect, there is provided a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with one or more other therapeutically active agents.

Thus, in one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, of the invention can be used in combination with one or more other therapeutic agents, or include such an agent, for example, selected from antibiotics, antiviral agents, glucocorticosteroids, muscarinic receptor antagonists, β-2 receptor agonists, and vitamin D3 analogs. In an additional embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be used in combination with an additional therapist

- 19 038888 tic agent that is suitable for the treatment of cancer. Examples of such additional therapeutic agents are described in Cancer Principles and Practice of Oncology V.T. Devita and S. Hellman (editors), 6th Edition (2001), Lippincott Williams & Wilkins Publishers. One skilled in the art will be able to determine which combinations of agents will be beneficial based on the particular properties of the drugs and the type of cancer in question. Additional therapeutic agents used in combination with a compound of formula (I), or a pharmaceutically acceptable salt thereof, include anti-microtubule agents (such as diterpenoids and vinca alkaloids); coordination complexes of platinum; alkylating agents (such as nitrogen mustards, oxazaphosphorines, alkyl sulfonates, nitrosoureas, and triazenes); antibiotic agents (such as anthracyclines, actinomycins, and bleomycins); topoisomerase II inhibitors (such as epipodophyllotoxins); antimetabolites (such as purine and pyrimidine analogs and antifolate compounds); topoisomerase I inhibitors (such as camptothecins; hormones and hormonal analogs); inhibitors of signal transduction pathways (such as inhibitors of thyropsin receptors); inhibitors of angiogenesis of non-receptor tyrosine kinase; immunotherapeutic agents (such as PD-1 (programmed cell death protein1) inhibitors, including nivolumab and pembrolizumab, and CTLA-4 (cytotoxic T lymphocyte type 4 antigen) inhibitors, including ipilimumab); proapoptotic agents; epigenetic or transcriptional modulators (such as histone deacetylase inhibitors) and inhibitors of cell cycle signaling, but are not limited to them.

It should be understood that when a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with other therapeutic agents, usually administered via the inhalation, intravenous, oral, or intranasal route, then the resulting pharmaceutical composition may be administered by the same routes. Alternatively, the individual components of the composition can be administered in a variety of ways.

The person skilled in the art will understand that, where appropriate, the other therapeutic agent (s) can be used in the form of salts, for example in the form of alkali metal or ammonium salts, or in the form of acid addition salts, or prodrugs, or in the form of esters, eg esters of lower alkyls, or in the form of solvates, eg hydrates, to optimize the activity and / or stability and / or physical properties, such as solubility, of the therapeutic agent. It will also be clear that when appropriate, therapeutic agents can be used in optically pure form.

The combinations described above can be readily provided for use in the form of a pharmaceutical composition, and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable excipient constitute a further aspect of the invention.

General synthesis methods.

The compounds of the invention can be prepared in a variety of ways. Any previously defined value retains the previously defined value, unless otherwise noted. Illustrative general synthetic methods are set forth in the following schemes and can be readily adapted to prepare other compounds of the invention. Specific compounds of the invention are prepared as described in the Examples section.

Compounds of formula (I) can be prepared as described in any of the schemes below.

Scheme 1

where R ¹ , R ² , R ³ and R ⁴ are as described above and X is either Br, Cl, or OH.

According to the steps shown in the above scheme 1, can be used

- 20 038888 the following reaction conditions.

Step 1: This is the amidation of the ester and can be carried out using the appropriate amine of formula R1-NH2, optionally in the presence of a suitable solvent such as THF (tetrahydrofuran), at a suitable temperature such as from 0 ° C to room temperature.

Step 2: is a Mitsunobu coupling reaction where X is OH and can be carried out using any suitable alcohol in the presence of a Mitsunobu coupling reagent such as either DEAD (diethyl azodicarboxylate) or DIAD (diisopropyl azodicarboxylate) with a suitable phosphine such as Ph ₃ P; or alternatively, with a suitable phosphorane reagent such as CMBP (cyanomethylene) tributylphosphorane in a suitable solvent such as THF or acetonitrile at a suitable temperature such as room temperature or 120 ° C.

Step 3: This is an alkylation reaction where X is Br or Cl and can be carried out using a suitable base such as potassium carbonate in a suitable solvent such as acetone at a suitable temperature such as room temperature.

Step 4: This is a base-mediated ester hydrolysis and can be carried out using any suitable base such as lithium hydroxide, optionally in a suitable solvent or mixture of solvents such as 1,4-dioxane and water, at a suitable temperature, such as room temperature. temperature.

Step 5: This is an amide coupling reaction and can be carried out using an amine reagent, R ² -NH ₂ , in the presence of a suitable tertiary amine such as triethylamine or DIPEA (diisopropylethylamine), in the presence of a suitable amide coupling reagent such as HATU (hexafluorophosphate O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium) in a suitable solvent such as DCM (dichloromethane) or DMF (dimethylformamide) at a suitable temperature such as room temperature.

Step 6: This is acid-mediated ester cleavage and can be carried out using any suitable acid such as sulfuric acid, optionally in a suitable solvent or mixture of solvents such as 1,4-dioxane and water, at a suitable temperature such as temperature reflux (heating under reflux).

Step 7: This is an amide coupling reaction and can be carried out using an amine reagent, R ¹ -NH ₂ , in the presence of a suitable tertiary amine such as triethylamine or DIPEA, in the presence of a suitable amide coupling reagent such as HATU, in a suitable solvent, such as DCM or DMF at a suitable temperature such as room temperature.

Those of skill in the art will understand that it may be beneficial to protect one or more functional groups of the compounds described above. Examples of protecting groups and methods for removing them can be found in T.W. Greene Protective Groups in Organic Synthesis (4th edition, J. Wiley and Sons, 2006), incorporated herein by reference in relation to such techniques.

Suitable amine protecting groups include acyl (e.g. acetyl, carbamate (e.g. 2 ', 2', 2'-trichloroethoxycarbonyl, benzyloxycarbonyl, or tert-butoxycarbonyl) and arylalkyl (e.g. benzyl), which can be removed by acid cleavage (e.g. when using an acid such as hydrochloric acid in 1,4-dioxane or trifluoroacetic acid in dichloromethane) or reduction (for example, hydrogenolysis of a benzyl or benzyloxycarbonyl group or reductive cleavage of a 2 ', 2', 2'-trichloroethoxycarbonyl group using zinc in acetic acid ) as appropriate Other suitable amine protecting groups include trifluoroacetyl (—COCF3), which can be removed by base catalyzed hydrolysis.

It should be understood that in any of the methods described above, the exact order of the synthetic steps through which the various groups and moieties are introduced into the molecule can be changed. The person skilled in the art will understand that the groups or moieties introduced in one stage of the process should not undergo subsequent transformations and interactions, and he will appropriately choose the order of the synthesis stages.

Certain intermediates described above form a further aspect of the invention.

For any of the above interactions or methods, conventional heating and cooling techniques can be used, for example, temperature controlled oil baths or temperature controlled heating blocks and ice and salt baths or dry ice and acetone baths, respectively. Can be used conventional methods of isolation, for example, extraction from aqueous or non-aqueous solvents or aqueous or non-aqueous solvents. Conventional drying methods for organic solvents, solutions or extracts can be used, such as shaking with anhydrous magnesium sulfate or anhydrous sodium sulfate, or passing through a hydrophobic frit. If required, can be used conventional methods of purification, for example crystallization and chromatography, for example chromatography on silica or reverse phase chromatography. Crystallization can be carried out using conventional solvents such as ethyl acetate, methanol, ethanol or butanol, or their aqueous

- 21 038888 mixtures. It will be understood that specific reaction times and temperatures can generally be determined by monitoring the progress of the reaction, for example, thin layer chromatography and LC-MS (liquid chromatography-mass spectrometry).

Basic methods.

General details of the experiment.

All temperatures mentioned are in ° C.

The symbols and conventions used in this document in the description of the methods, in the diagrams and in the examples correspond to the symbols and conventions that are used in modern scientific literature, for example, in the Journal of the American Chemical Society. Unless otherwise noted, all starting materials were purchased from commercial suppliers and used without further purification. Specifically, the following abbreviations can be used in the examples and throughout the specification.

Abbreviations.

AcOH - acetic acid;

amu - atomic mass units;

aq. - water;

BOC / Boc - tert-butyloxycarbonyl;

Cs ₂ CO ₃ - cesium carbonate;

CHCl ₃ - chloroform;

CMBP - (cyanomethylene) tributylphosphorane;

CPME - cyclopentyl methyl ether;

CV is the column volume;

DCM - dichloromethane;

DIAD, diisopropyl azodicarboxylate;

DIBAL-H - diisobutylaluminum hydride;

DIPEA for diisopropylethylamine;

DMAP - 4-dimethylaminopyridine;

DMF - dimethylformamide;

DMSO - dimethyl sulfoxide;

DMSO-d ₆ - deuterated dimethyl sulfoxide;

DPPA, diphenylphosphorylazide;

Et ₃ N - triethylamine;

EtOAc - ethyl acetate;

EtOH for ethanol;

h - hour (s);

HATU - O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate;

HBr - hydrogen bromide;

HCl - hydrochloric acid;

HPLC - high performance liquid chromatography;

Isolera - flash cleaning system from Biotage;

K2CO ₃ - potassium carbonate;

LiCl - lithium chloride;

LC-MS - liquid chromatography-mass spectrometry;

LiOH - lithium hydroxide;

M - molar (concentration);

MDAP - mass directed autopreparation chromatography;

MeCN - acetonitrile;

MeOH - methanol;

2-MeTHF - 2-methyltetrahydrofuran;

min - minute (s);

MS - mass spectrometry;

Ms-Cl is methanesulfonyl chloride;

N - normal (concentration);

N ₂ is nitrogen;

NaBH ₄ - sodium borohydrite;

Na2CO3 - sodium carbonate;

NaH is sodium hydride;

NaHCO3 - sodium bicarbonate;

NaOH - sodium hydroxide;

Na2SO4 - sodium sulfate;

NH ₃ is ammonia;

NH ₄ Cl - ammonium chloride;

- 22 038888

NUT - nuclear protein in the testicle;

cross. - covered;

PPh ₃ - triphenylphosphine;

RBF - round bottom flask;

Rt is the retention time;

Ph. D. - room temperature;

saturate - saturated;

SCX - Isolute SPE strong cation exchange sorbent;

SFC - supercritical fluid chromatography;

SiO2 - silicon dioxide;

SNAP - flash chromatography cartridge from Biotage® (silicon dioxide);

SP4 - Flash Cleaning System from Biotage®;

SPE - solid phase extraction;

T ₃ P - propylphosphonic anhydride;

TFA, trifluoroacetic acid;

THF - tetrahydrofuran;

TBDMS-Cl = tert-butyldimethylsilyl chloride;

TLC - thin layer chromatography;

Ts - tosil;

pTsCl is tosyl chloride;

UELC - ultra high performance liquid chromatography;

UV - ultraviolet;

Xantphos-1,1 '- (9,9-dimethyl-9H-xαnten-4,5-diyl) bis [1,1-diphenylphosphine].

The following compound names were obtained using the ACD Name Pro 6.02 compound naming program or using the functional group names from Chem Draw Ultra 12.0.

LC-MS method.

Formate method.

LC conditions.

HPLC analysis was performed on an Acquity UPLC CSH C18 column (50x2.1 mm i.d. (inner diameter), filler grain diameter 1.7 μm) at 40 ° C.

Solvents used.

A - 0.1% v / v a solution of formic acid in water;

B - 0.1% v / v a solution of formic acid in acetonitrile.

Gradient used

Time (min) Flow rate (ml / min) % A %V 0 one 97 3 1.5 one 5 95 1.9 one 5 95 2.0 one 97 3

UV detection was a summed signal of wavelengths from 210 to 350 nm.

MC conditions

ms Waters ZQ Ionization mode: electric spray with alternating scanning in positive and negative mode Scan range: from 100 to 1000 amu Scan time: 0.27 s Delay between scans: 0.10 s

Delay between scans: 0.10 s

High pH method.

LC conditions.

HPLC analysis was performed on an Acquity UPLC CSH C18 column (50x2.1 mm i.d., filler grain diameter 1.7 μm) at 40 ° C.

Solvents used.

- 23 038888

A - 10 mM ammonium bicarbonate in water, adjusted to pH 10 with ammonia solution;

B - acetonitrile.

Gradient used

Time (min) Flow rate (ml / min) % A %V 0 one 97 3 0.05 one 97 3 1.5 one 5 95 1.9 one 5 95 2.0 one 97 3

UV detection was a summed signal of wavelengths from 210 to 350 nm.

MC conditions

MC

Ionization mode:

Scan range:

Scan time:

Delay between scans: TFA method.

LC conditions.

Waters ZQ Alternating Scan Positive and Negative Electrospray 100 to 1000 amu 0.27 s 0.10 s

HPLC analysis was performed on an Acquity UPLC CSH C18 column (50x2.1 mm i.d., filler grain diameter 1.7 μm) at 40 ° C.

Solvents used.

A - 0.1% v / v a solution of trifluoroacetic acid in water;

B - 0.1% v / v a solution of trifluoroacetic acid in acetonitrile.

Gradient used

Time (min) Flow rate (ml / min) % A %V 0 one 95 5 1.5 one 5 95 1.9 one 5 95 2.0 one 95 5

UV detection was a summed signal of wavelengths from 210 to 350 nm.

MC conditions

MS Waters ZQ

Ionization mode: electrospray with alternating scanning in positive and negative mode

Scanning range: 100 to 1000 amu

Scan time: 0.27 s

Delay between scans: 0.10 s

Method A.

LC conditions.

HPLC analysis was performed on an Acquity BEN C18 column (50x2.1 mm i.d., filler grain diameter 1.7 μm) at 35 ° C. Solvents used: A - 0.1% v / v a solution of formic acid in water; B - 0.1% v / v a solution of formic acid in acetonitrile.

Gradient used

- 24 038888

Time (min) Flow rate (ml / min) % A %V 0 0.6 97 3 0,4 0.6 97 3 3.2 0.6 2 98 3.8 0.6 2 98 4.2 0.6 97 3 4.5 0.6 97 3

Method B.

LC conditions.

HPLC analysis was performed on an Acquity BEN C18 column (50x2.1 mm i.d., filler grain diameter 1.7 μm) at 35 ° C.

Solvents used.

A - 0.05% v / v a solution of formic acid in water;

B - 0.05% v / v a solution of formic acid in acetonitrile.

Gradient used

Time (min) Flow rate (ml / min) % A %V 0 0.6 97 3 0,4 0.6 97 3 3.2 0.6 2 98 3.8 0.6 2 98 4.2 0.6 97 3 4.5 0.6 97 3

Method C.

LC conditions.

HPLC analysis was performed on an Xbridge C18 column (150x4.6 mm i.d., filler grain diameter 3.5 μm) at 35 ° C.

Solvents used.

A - 0.05% v / v a solution of trifluoroacetic acid in water;

B - acetonitrile.

Gradient used

Time (min) Flow rate (ml / min) % A %V 0 1.0 95 5 0.5 1.0 95 5 7 1.0 5 95 14 1.0 5 95 14.5 1.0 95 5 15 1.0 95 5

Method D.

LC conditions.

HPLC analysis was performed on an Acquity BEN C18 column (100x2.1 mm i.d., filler grain diameter 1.7 μm) at 35 ° C.

Solvents used.

A - 0.05% v / v a solution of formic acid in acetonitrile;

B - 0.05% v / v a solution of formic acid in water.

Gradient used

- 25 038888

Time (min) Flow rate (ml / min) % A %v 0 0.45 3 97 0,4 0.45 3 97 7.5 0.45 98 2 9.5 0.45 98 2 9.6 0.45 3 97 10 0.45 3 97

Method E.

LC conditions.

HPLC analysis was performed on an Acquity BEN C18 column (50x2.1 mm i.d., filler grain diameter 1.7 μm) at 35 ° C.

Solvents used.

A - 0.05% v / v a solution of formic acid in acetonitrile;

B - 0.05% v / v a solution of formic acid in water.

Gradient used

Time (min) Flow rate (ml / min) % A %V 0 0.45 3 97 0,4 0.45 3 97 4.0 0.45 98 2 4.5 0.45 97.5 2.5 5.0 0.45 3 97 5.5 0.45 3 97

Basic cleaning methods with MDAP.

The following are examples of mass directed autopreparation chromatography (MDAP) methods that have been or may be used in the purification of compounds.

MDAP (high pH). HPLC analysis was performed on an Xselect CSH C18 column (150x30 mm id, filler grain diameter 5 μm) at ambient temperature, eluting with 10 mM ammonium bicarbonate in water with pH adjusted to 10 with ammonia solution (solvent A) and acetonitrile (solvent B ), using a gradient elution from 0 to 100% solvent B in 15 or 25 minutes.

UV detection was a summed signal of wavelengths from 210 to 350 nm. Mass spectra were recorded on a Waters ZQ mass spectrometer using alternating positive and negative ionization electrospray scanning. Ionization data were rounded to the nearest whole number.

MDAP (formate). HPLC analysis was performed on an Xselect CSH C18 column (150x30 mm id, filler grain diameter 5 μm) at ambient temperature, eluting with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B) , using a gradient elution from 0 to 100% solvent B in 15 or 25 minutes.

UV detection was a summed signal of wavelengths from 210 to 350 nm. Mass spectra were recorded on a Waters ZQ mass spectrometer using alternating positive and negative ionization electrospray scanning. Ionization data were rounded to the nearest whole number.

MDAP (TFA). HPLC analysis was performed on an Xselect CSH C18 column (150x30 mm i.d., filler grain diameter 5 μm) at ambient temperature, eluting with 0.1% v / v. a solution of trifluoroacetic acid in water (solvent A) and 0.1% v / v. a solution of trifluoroacetic acid in acetonitrile (solvent B), using a gradient elution from 0 to 100% solvent B in 15 or 25 minutes.

UV detection was a summed signal of wavelengths from 210 to 350 nm. Mass spectra were recorded on a Waters ZQ mass spectrometer using alternating positive and negative ionization electrospray scanning. Ionization data were rounded to the nearest whole number.

NMR.

The spectra were recorded on an NMR tomograph with a frequency of either 400 MHz or 600 MHz at 302 K.

Intermediate 1: methyl 3- (methylcarbamoyl) -1H-pyrazole-5-carboxylate

- 26 038888

A solution of dimethyl 1H-pyrazole-3,5-dicarboxylate (10 g; 54.3 mmol; commercially available from, for example, Fluorochem) in methanamine (5% w / w solution in water) (67.5 g; 109 mmol; commercially available from, for example, Spectrochem) was stirred under nitrogen at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min. After 16 h, the reaction mixture was neutralized with 1N. HCl, extracted with EtOAc (500 ml) and washed with brine (100 ml). The organic layer was dried over Na2SO _4, filtered and the filtrate concentrated to afford methyl 5- (methylcarbamoyl) -1Hpirazol-3-carboxylate (4 g; 14.19 mmol; yield 26%) of crude compound. The reaction was repeated again on the same scale to obtain an additional 3.8 g of the crude compound and again using a solution of dimethyl 1H-pyrazole-3,5-dicarboxylate (20 g; 54.3 mmol) in methanamine (5% (wt.) solution in water) (67.5 g; 109 mmol) was stirred under nitrogen atmosphere at 0 ° C using the same work-up methods as described above to obtain an additional 7 g of the crude product. The combined portions of the crude product were purified by column chromatography (silica gel 100-200) eluting with 0-10% MeOH in DCM. Desired fractions were collected and dried under reduced pressure to give the crude compound (10 g). It was diluted with anhydrous methanol (100 ml) and kept at room temperature for 24 hours. After 24 hours, the solid was filtered through a Buchner funnel, washed with chilled anhydrous methanol (20 ml) and the residue was then washed with pentane and dried to give methyl 5- ( methylcarbamoyl) -1H-pyrazole-3-carboxylate (8 g; 43.6 mmol; 20% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 14.27 (br s, 1H), 8.42 (br s, 1H), 7.22 (br s, 1H), 3.83 (s, 3H), 2.76 (d, J = 4.6 Hz, 3H).

LCMS (2 min formate method): retention time 0.44 min, [MH] ⁺ 184.1.

Intermediate 2: methyl (S) -dimethyl-1- (1-phenylethyl) -1H-pyrazole-3,5-dicarboxylate

Diisopropyl (E) -diazen-1,2-dicarboxylate (8.24 g; 40.7 mmol) was added dropwise to a suspension of dimethyl 1H-pyrazole-3,5-dicarboxylate (5 g; 27.2 mmol; available commercially available from, for example, Fluorochem), (R) -1-phenylethan-1-ol (3.98 g; 32.6 mmol; commercially available from, for example, Sigma Aldrich) and polymer-linked triphenylphosphine 3 mmol / g (13.70 g; 40.7 mmol; commercially available from, for example, Sigma Aldrich) in 2-MeTHF (50 ml) at 0 ° C under nitrogen. The mixture was stirred overnight while allowing it to warm to room temperature. In a separate reaction, dimethyl 1H-pyrazole-3,5-dicarboxylate (2 g; 10.86 mmol), (R) -1-phenylethan-1-ol (1.592 g; 13.03 mmol) and polymer-bound triphenylphosphine 3 mmol / g (5.48 g; 16.29 mmol) was combined in a round bottom flask, 2-MeTHF (50 ml) was added and the mixture was stirred under nitrogen atmosphere, cooling in an ice bath for 30 min, then diisopropyl- ( E) -diazen-1,2-dicarboxylate (3.29 g; 16.29 mmol) for 30 min and the resulting mixture was stirred overnight while allowing it to warm to room temperature. The reaction mixtures were combined, the combined suspension was filtered and the solid polymer-bound triphenylphosphine (oxide) was washed with EtOAc (100 ml). The combined organic layers were then washed with water (200 ml), dried and evaporated in vacuo and the residue was purified by chromatography on a 340 g silica column eluting with 0-25% EtOAc / cyclohexane. Product containing fractions were evaporated in vacuo to give dimethyl- (S) -1- (1-phenylethyl) -1H-pyrazole-3,5-dicarboxylate (7.2 g; 24.97 mmol; 66% yield) as a colorless oil ...

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 7.39 (s, 1H), 7.29-7.33 (m, 4H), 7.22-7.28 (m, 1H), 6.63 (q, J = 7.1 Hz, 1H), 3.96 (s, 3H), 3.86 (s, 3H), 1.99 (d, J = 7.1 Hz, 3H).

LCMS (2 min high pH method): retention time 1.13 min, [MH] ⁺ 289.2.

Intermediate 3: (S) -5- (methoxycarbonyl) -1- (1-phenylethyl) -1H-pyrazole-3-carboxylic acid

- 27 038888

Dimethyl- (S) -1- (1-phenylethyl) -1H-pyrazole-3,5-dicarboxylate (15 g; 52.0 mmol) was dissolved in 1,4 dioxane (60 ml), then water (120 ml) was added with followed by the dropwise addition of H ₂ SO ₄ (1.664 ml; 31.2 mmol). The mixture was heated under reflux for 3 days, then cooled to room temperature and extracted with EtOAc (2x100 ml). The combined organic layers were dried and evaporated in vacuo to give a colorless gum, which was dissolved in DCM and loaded onto a 340 g silica column, then eluted with 0-50% (1% AcOH / EtOAc) / cyclohexane and the product fractions evaporated in vacuo to give (S) -5- (methoxycarbonyl) -1- (1phenylethyl) -1H-pyrazole-3-carboxylic acid (6.7 g; 24.43 mmol; 47% yield) as a colorless solid.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 7.46 (s, 1H), 7.24-7.37 (m, 5H), 6.66 (q, J = 7.1 Hz, 1H), 3.88 (s, 3H), 2.00 (d, J = 7.1 Hz, 3H) ... Not a single exchangeable proton has been registered.

LCMS (2 min formate method): retention time 0.96 min, [MH] ⁺ 275.3.

Intermediate 4: (S) -methyl-3- (methylcarbamoyl) -1- (1-phenylethyl) -1H-pyrazole-5-carboxylate

(S) -5- (Methoxycarbonyl) -1- (1-phenylethyl) -1H-pyrαzole-3-carboxylic acid (2 g; 7.29 mmol) was dissolved in DCM (20 ml) and Et ₃ N (1.525 ml ; 10.94 mmol) and HATU (3.33 g; 8.75 mmol) followed by the addition of methanamine (2M in THF) (3.65 ml; 7.29 mmol) and the mixture was stirred for 2 h at room temperature, then washed with water (20 ml) and 0.5M HCl (20 ml). The organic layer was dried and evaporated in vacuo, and the residue was purified by chromatography on a 50 g silica column to give methyl- (S) -3- (methylcarbamoyl) -1- (1-phenylethyl) -1H-pyrazole-5-carboxylate (2 , 1 g; 7.31 mmol; 100% yield) as a colorless gum.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 7.38 (s, 1H), 7.23-7.35 (m, 5H), 6.96 (d, 7 = 3.7 Hz, 1H), 6.63 (q, J = 7.1 Hz, 1H), 3.86 (s, 3H) , 3.03 (s, 3H), 1.92 (d, J = 7.1 Hz, 3H).

LCMS (2 min formate method): retention time 0.99 min, [MH] ⁺ 288.2.

Intermediate 5: (S) -3- (methylcarbamoyl) -1- (1-phenylethyl) -1H-pyrazole-5-carboxylic acid

Methyl- (S) -3- (methylcarbamoyl) -1- (1-phenylethyl) -1H-pyrazole-5-carboxylate (4.2 g; 14.62 mmol) was dissolved in a mixture of methanol (10 ml) and THF (10 ml), then NaOH (2M aqueous solution; 14.62 ml; 29.2 mmol) was added and the mixture was stirred for 3 h at room temperature. The solvent was evaporated in vacuo, the residue was dissolved in water (30 ml) and washed with ether, then the aqueous layer was acidified with 2M HCl to pH 4 and the resulting mixture was stirred for 20 min while cooling in an ice bath. The resulting solid was collected by filtration to give (S) -3- (methylcarbamoyl) -1- (1phenylethyl) -1H-pyrazole-5-carboxylic acid (3.3 g; 12.07 mmol; 83% yield) as a colorless solid matter.

¹ H NMR (400 MHz, DMSO-d6) δ ppm. 13.62 (br s, 1H), 8.26 (d, J = 4.6 Hz, 1H), 7.18-7.37 (m, 5H), 7.14 (s, 1H), 6.61 (q, J = 6.8 Hz, 1H), 2.77 (d, J = 4.6 Hz, 3H), 1.80-1.91 (m, 3H).

LCMS (2 min formate method): retention time 0.86 min, [MH] ⁺ 274.2.

Intermediate 6: dimethyl 1-benzyl-1H-pyrazole-3,5-dicarboxylate

- 28 038888

To a solution of dimethyl 1H-pyrazole-3,5-dicarboxylate (10 g; 54.3 mmol) in acetone (100 ml), stirring under nitrogen atmosphere at 0 ° C, was added K2CO3 (15.01 g; 109 mmol) with followed by the dropwise addition of benzyl bromide (7.10 ml; 59.7 mmol) over 1 min. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product. The crude product was triturated with n-pentane (3x10 ml) then dried in vacuo to give pure dimethyl 1-benzyl-1H-pyrazole-3,5 dicarboxylate (8.5 g; 31.0 mmol; 57% yield) as white solid matter.

LCMS (10 min Method D): Retention time 4.87 min, [MH] ⁺ 275.0.

Intermediate 7: 1-benzyl-5- (methoxycarbonyl) -1H-pyrazole-3-carboxylic acid

To a solution of dimethyl 1-benzyl-1H-pyrazole-3,5-dicarboxylate (30 g; 109 mmol) in 1,4-dioxane (140 ml) and water (280 ml), stirring under nitrogen atmosphere at room temperature, was added conc. H ₂ SO ₄ (2.92 ml; 54.7 mmol; 18.4 M) in one portion. The reaction mixture was stirred under reflux for 72 hours. The reaction mixture was then cooled to room temperature and extracted with EtOAc (3x125 ml). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude product. The crude product was added to a silica gel 60-120 column and eluted with 15% EtOAc in n-hexane and the collected starting material fractions were concentrated under reduced pressure to recover the starting material (15 g) as an off-white solid. The column was then eluted with 60% EtOAc in hexane and the collected pure fractions were concentrated in vacuo to give pure 1-benzyl-5- (methoxycarbonyl) -1H-pyrazole-3-carboxylic acid (6 g) as a white solid. Contaminated fractions were also isolated to give an additional 10 g of the crude mixture, which was added to a silica gel 60-120 column and eluted with 60% EtOAc in hexane to provide additional pure fractions. They were concentrated in vacuo to give a second crop of pure desired product (5.5 g), which was combined with the first crop to give 1-benzyl5- (methoxycarbonyl) -1H-pyrazole-3-carboxylic acid (11.5 g; 44.0 mmol; yield 40%) as an off-white solid. The column was then washed with EtoAc to give an additional portion of impurities (3.4 g).

LCMS (10 min Method D): Retention time 4.89 min, [MH] ⁺ 261.0.

Intermediate 8: methyl 1-benzyl-3- (methylcarbamoyl) -1H-pyrazole-5-carboxylate

To a solution of 1-benzyl-5- (methoxycarbonyl) -1H-pyrazole-3-carboxylic acid (13.6 g; 50.7 mmol) and DIPEA (26.6 ml; 152 mmol) in DMF (100 ml), stirring under nitrogen at room temperature, HATU (28.9 g; 76 mmol) was added followed by the addition of methanamine hydrochloride (4.11 g; 60.8 mmol) in one portion over 1 min. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water, then extracted with EtOAc (3x100 ml). The combined organic layer was washed with water (3x50 ml), brine, then dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude product. The crude product was added to a silica gel 60-120 column and eluted with 65% EtOAc in n-hexane and the collected pure fractions were concentrated under reduced pressure to give methyl 1-benzyl-3- (methylcarbamoyl) -1H-pyrazole-5-carboxylate (12.1 g; 42.7 mmol; 84% yield) as an off-white solid.

LCMS (5.5 min Method E): Retention time 2.32 min, [MH] ⁺ 274.1.

Intermediate 9: 1-benzyl-3- (methylcarbamoyl) -1H-pyrazole-5-carboxylic acid

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Into a solution of methyl 1-benzyl-3- (methylcarbamoyl) -1H-pyrazole-5-carboxylate (12.1 g; 42.7 mmol) in THF (70 ml) and water (70 ml), stirred under nitrogen at room temperature, LiOH (5.11 g; 213 mmol) was added in one portion over 1 min. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with water (20 ml), then the aqueous layer was washed with EtOAc (3x15 ml). Then the pH of the aqueous layer was adjusted using 2N. HCl to pH 1, then extracted with EtoAc (3x100 ml). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude product. The crude product was added to a silica gel 60-120 column and eluted with 85% EtOAc in n-hexane and the collected pure fractions were concentrated under reduced pressure to give the desired product 1-benzyl-3- (methylcarbamoyl) -1H-pyrazole-5-carboxylic acid ( 8.5 g; 32.8 mmol; 77% yield) as an off-white solid.

LCMS (10 min Method D): Retention time 3.25 min, [MH] ⁺ 260.1.

Intermediate 10: N ⁵ -cyclopropyl-N ³ -methyl-1H-pyrazole-3,5-dicarboxamide

To a solution of 1-benzyl-N ⁵ -cyclopropyl-N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (500 mg; 1.525 mmol; for preparation see example 92) in ethanol (1 ml), stirring under nitrogen atmosphere at room temperature, palladium hydroxide-carbon (100 mg; 0.712 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a pad of celite, then washed with ethanol (25 ml) and the filtrate was concentrated in vacuo to give the crude product. The crude product was triturated with diethyl ether (3x1 ml) to give a crystalline solid, filtered and the solid dried in vacuo to give N ⁵ -cyclopropyl-N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (250 mg; 1.045 mmol ; yield 68.5%) as a white solid.

LCMS (5.5 min Method E): Retention time 1.29 min, [MH] ⁺ 209.3.

Intermediate 11: N ⁵ -cyclopropyl-N ³ -methyl-1- (1-phenylethyl) -1H-pyrazole-3,5 dicarboxamide

To a solution of ⁵ N -cyclopropyl-N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (250 mg, 1.045 mmol) in DMF (2 ml), stirred under nitrogen at room temperature was added K ₂ CO ₃ (433 mg; 3.13 mmol) followed by the addition of (1-bromoethyl) benzene (232 mg; 1.253 mmol) in one portion. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water, then extracted with EtOAc (3x20 ml). The combined organic layer was washed with water (3x15 ml), brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude product. It contained two regioisomers.

Regioisomer 1.

LCMS (10 min Method D): Retention time 3.40 min, [MH] ⁺ 313.1.

Regioisomer 2.

LCMS (10 min Method D): Retention time 3.48 min, [MH] ⁺ 313.1.

Intermediate 12: Methyl 1-tosyl-1H-indole-5-carboxylate

NaH (0.548 g; 13.70 mmol; 60% dispersion in mineral

- 30 038888 oil), then the reaction mixture was stirred for 10 min at the same temperature, then at room temperature for 30 min, after which pTsCl (2.61 g; 13.70 mmol) was added in portions over 1 min. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, then extracted with EtOAc (3x25 ml). The combined organic layer was washed with cold water (3x15 ml), brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude product. The crude product was added to a silica gel 60-120 column and eluted with 15% EtOAc in n-hexane, and the collected pure fractions were concentrated under reduced pressure to give methyl 1-tosyl-1H-indole-5-carboxylate (1.9 g; 5.59 mmol; yield 49.0%) as an off-white solid.

LCMS (5.5 min Method E): Retention time 3.27 min, [MH] ⁺ 330.0.

Intermediate 13: (1-tosyl-1H-indole-5-yl) methanol

A solution of DIBAL-H (25 , 2 ml; 25.2 mmol; 1M solution in toluene) for 1 min. The reaction mixture was stirred at -78 ° C for 2.5 h. The reaction mixture was then quenched with methanol (0.226 ml; 5.59 mmol) at -78 ° C and then allowed to warm to ambient temperature. The reaction mixture was diluted with a saturated solution of Rochelle's salt (120 ml) and stirred for 16 h, then the layers were separated and the aqueous phase was extracted with DCM (2x100 ml). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude product. The crude product was triturated with n-pentane (3x2 ml) then dried under vacuum to give (1-tosyl-1H-indol-5-yl) methanol (1.70 g; 5.41 mmol; 97% yield) as an off-white solid.

LCMS (5.5 min Method E): Retention time 2.72 min, [MH] ⁺ 300.0.

Intermediate 14: 5- (bromomethyl) -1-tosyl-1H-indole

A solution of HBr (0.294 ml ; 5.41 mmol) for 1 min. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, then stirred for 10 minutes at room temperature, then filtered and the solid was dried under vacuum to give 5- (bromomethyl) -1-tosyl-1Hindole ( 1.48 g; 3.49 mmol; 65% yield) as an off-white solid.

LCMS (5.5 min Method E): Retention time 3.47 min, [MH] ⁺ 365.9.

Intermediate 15: N ⁵ -cyclopropyl-N ³ -methyl-1 - ((1-tosyl-1H-indol-5-yl) methyl) -1Hpyrazole-3,5-dicarboxamide

To a solution of N ⁵ -tsiklopropil-N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (300 mg, 1.366 mmol) in DMF (2 ml), stirred under nitrogen at room temperature was added K ₂ CO ₃ (566 mg; 4.10 mmol) followed by the dropwise addition of 5- (bromomethyl) -1-tosyl-1H-indole (703 mg; 1.640 mmol) over 1 min. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, then extracted with EtOAc (3x15 ml). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude product (420 mg) as a mixture of regioisomers that was used in the next step without purification.

LCMS (5.5 min Method E): Retention time 2.82 min, [MH] ⁺ 492.0. Regioisomer 1.

LCMS (5.5 min Method E): Retention time 2.85 min, [MH] ⁺ 492.0. Regioisomer 2.

Intermediate 16: N ⁵ -cyclopropyl-N ³ -methyl-1 - ((1-tosyl-1H-indole-4-yl) methyl) -1Hpyrazole-3,5-dicarboxamide

- 31 038888

To a solution of ⁵ N -cyclopropyl-N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (300 mg, 1.366 mmol) in acetone (1 ml), stirred under nitrogen at room temperature was added K ₂ CO ₃ (566 mg; 4.10 mmol) followed by the addition of 4- (bromomethyl) -1-tosyl-1H-indole (597 mg; 1.640 mmol) in one portion. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water, then extracted with EtOAc (3x25 ml). The combined organic layers were washed with water (3x15 ml), brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo to give the crude product as a mixture of regioisomers (550 mg) which was used in the next step without purification.

LCMS (10 min Method D): Retention time 4.39 min, [MH] ⁺ 492.1. Regioisomer 1.

LCMS (10 min Method D): Retention time 4.44 min, [MH] ⁺ 492.1. Regioisomer 2.

Intermediate 17: N ³ , N ⁵ -dimethyl-1H-pyrazole-3,5-dicarboxamide

1H-pyrazole-3,5-dicarboxylic acid (200 mg; 1.281 mmol), methanamine (2M in THF; 0.705 ml; 1.409 mmol) and HATU (536 mg; 1.409 mmol) were combined in DMF (2 ml). DIPEA (0.448 ml; 2.56 mmol) was added and the reaction mixture was stirred at room temperature under N ₂ for 2 hours. The reaction mixture was concentrated to dryness and used crude for the next step.

LCMS (2 min formate method): retention time 0.37 min, [MH] ⁺ 183.1.

Intermediate 18: 4-6rom-1-tosyl-1H-pyrrolo [2,3-c] pyridine

4-Bromo-III-pyrrolo [2,3-c] pyridine (5 g; 25.4 mmol; commercially available from, for example, Fluorochem) was dissolved in DMF (50 ml) and cooled in an ice bath under nitrogen atmosphere, then NaH (60% suspension in mineral oil; 1.319 g; 33.0 mmol) was added in small portions and the mixture was stirred for 20 min before adding tosyl chloride (5.32 g; 27.9 mmol). The mixture was stirred overnight while allowing it to warm to room temperature, then the mixture was diluted with water (100 ml) and stirred for 30 minutes to give a white suspension. It was filtered and the solid was washed with water, then dried to give a colorless solid. The crude product was suspended in ether (20 ml) and stirred for 5 min, then diluted with cyclohexane (20 ml) and filtered to give the desired product (7.9 g; 22.49 mmol; 89% yield) as a colorless solid.

LCMS (2 min high pH method): retention time 1.24 min, [MH] ⁺ 351/353.

Intermediate 19: Methyl 1-tosyl-1H-pyrrolo [2,3-c] pyridine-4-carboxylate

4-Bromo-1-tosyl-1H-pyrrolo [2,3-c] pyridine (7.8 g; 22.21 mmol), palladium (P) acetate (0.499 g; 2.221 mmol) and xantphos (1.285 g; 2.221 mmol) were combined in a round bottom flask, which was sealed with a Suba-seal membrane and purged with nitrogen. DMF (20 ml), Et ₃ N (9.29 ml; 66.6 mmol) and methanol (17.97 ml; 444 mmol) were added, the vessel was flushed with carbon monoxide from a balloon, then heated under CO atmosphere overnight. The mixture was diluted with water (20 ml) and extracted with EtOAc (20 ml), the organic layer was washed with 10% aq. LiCl solution, dried and evaporated in vacuo and the residue was purified by chromatography on a 50 g silica column eluting with 0-100% EtOAc / cyclohexane to give the desired product (4.4 g; 13.32 mmol; 60% yield) ...

- 32 038888

LCMS (2 min high pH method): retention time 1.12 min, [MH] ⁺ 331.1.

Intermediate 20: (1-tosyl-1H-pyrrolo [2,3-c] pyridin-4-yl) methanol

Methyl 1-tosyl-1H-pyrrolo [2,3-c] pyridine-4-carboxylate (510 mg; 1.544 mmol) was placed in DCM (15 ml) under nitrogen atmosphere and cooled to -78 ° C. DIBAL-H (1M in THF; 15.44 ml; 15.44 mmol) was added dropwise to the reaction mixture and left stirring at -78 ° C for 3 h. The reaction mixture was quenched with methanol (15 ml was added dropwise) at - 78 ° C and then left to warm to room temperature. Rochelle's salt (saturated in 25 ml water) was added and the mixture was stirred for 45 minutes. The mixture was separated and the organic layer was washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo to give a yellow solid. This solid was taken up in DCM (15 ml), placed under nitrogen and cooled to -78 ° C. DIBAL-H (1M in THF; 15.44 ml; 15.44 mmol) was added dropwise and then the reaction mixture was allowed to warm to -40 ° C. Leave to stir at this temperature for 5 hours. The reaction mixture was quenched with methanol (15 ml was added dropwise) at -40 ° C and then left to warm to room temperature. Rochelle's salt (saturated in 30 ml of water) was added and the mixture was stirred for 45 minutes. The mixture was separated and the organic layer was washed with brine (2x25 ml), filtered through a hydrophobic frit and concentrated in vacuo to give a yellow oil (486 mg). The crude product was purified by column chromatography on silica gel, eluting with 5-50% mixture (3: 1 EtOAc: EtOH) in cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the desired product (148 mg; 0.416 mmol; 27% yield) as a white solid.

LCMS (2 min formate method): retention time 0.57 min, [MH] ⁺ 303.1.

Intermediate 21: 1- (1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-yl) ethanone

1- (1H-Pyrrolo [2,3-b] pyridin-4-yl) ethan-1-one (500 mg; 3.12 mmol; commercially available from, for example, Activate Scientific) was dissolved in DMF (5 ml ) and cooled to 0 ° C in an ice bath under nitrogen atmosphere. Sodium hydride (60% in mineral oil; 150 mg; 3.75 mmol) was added in portions and the reaction mixture was stirred at 0 ° C for 30 min before warming to room temperature for 30 min. Tosyl chloride (714 mg; 3.75 mmol) was added to give an orange suspension (exothermic addition) and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled to 0 ° C in an ice bath and quenched by adding water dropwise (3 ml). The mixture was then distributed between ethyl acetate (20 ml) and sat. aq. LiCl solution (20 ml). The organic layer was separated and aq. the layer was further extracted with ethyl acetate. The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give about 1.5 g of a crude brown residue. This was purified by column chromatography on silica gel, eluting with 5-50% ethyl acetate / cyclohexane, to afford the desired product (438 mg; 1.254 mmol; 40% yield) as a pale yellow solid.

LCMS (2 min formate method): retention time 1.12 min, [MH] ⁺ 315.

Intermediate 22: 1- (1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-yl) ethanol

To a suspension of 1- (1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-yl) ethan-1-one (438 mg; 1.393 mmol) in ethanol (10 ml) was added THF (4 ml) for increasing the solubility of the reaction mixture, followed by the addition of sodium borohydride (58.0 mg; 1.533 mmol) in an ice bath. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 1 h. 1M HCl solution (20 ml) was added and the aqueous solution was extracted with DCM. The combined organic layers were dried (hydrophobic frit) and concentrated to give the desired product (493 mg; 1.325 mmol; 95% yield) as a pale yellow oil.

LCMS (2 min formate method): retention time 0.98 min, [MH] ⁺ 317.

Intermediate 23: Methyl 1-tosyl-1H-indole-5-carboxylate

- 33 038888

Methyl 1H-indole-5-carboxylate (4.31 g; 24.60 mmol; commercially available from, for example, Sigma Aldrich) was placed in DMF (50 ml) and cooled to 0 ° C. NaH (60% suspension in mineral oil; 1.181 g; 29.5 mmol) was added in small portions and the reaction mixture was left stirring for 1 h. Tosyl chloride (5.63 g; 29.5 mmol) was added and the reaction mixture was allowed to warm to room temperature temperature and stirred overnight. Additional NaH (0.480 g; 60% suspension in mineral oil) was added and the reaction mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was quenched with water (25 ml). Water (175 ml) was added and the reaction mixture was extracted with ethyl acetate (2x250 ml). The combined organic layers were washed with brine (200 ml), dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give a brown solid. A mixture of MeOH: DCM 1: 1 (50 ml) was added to the crude product and free flowing silica (5 g) was added. The solvent was removed in vacuo and the silica loaded onto a 100 g silica gel column chromatography cartridge and eluted with 5-25% ethyl acetate in cyclohexane. Fractions were combined and concentrated in vacuo. The crude product was loaded onto a 340 g silica gel column chromatography cartridge in a minimum amount of DCM and eluted with 0-25% ethyl acetate in cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the desired product (6.463 g; 18.64 mmol; 76% yield) as a white solid.

LCMS (2 min formate method): retention time 1.27 min, [MH] ⁺ 330.4.

Intermediate 24: 1- (1-tosyl-1H-indol-5-yl) ethanone

1- (1H-Indol-5-yl) ethan-1-one (1 g; 6.28 mmol; commercially available from, for example, Fluorochem) was placed in DMF (10 ml) and cooled to 0 ° C. NaH (0.302 g; 7.54 mmol; 60% dispersion in mineral oil) was added in small portions and left stirring for 15 minutes. Tosyl-Cl (1.437 g; 7.54 mmol) was added and the reaction mixture was allowed to warm to room temperature and allowed to stir for 1.5 h. Additional NaH (63 mg; 0.25 equiv .; 60% dispersion in mineral oil) and the reaction mixture was left stirring for 30 min. The reaction mixture was quenched with water (40 ml). The reaction mixture was extracted with ethyl acetate (2x50 ml) and the combined organic layers were washed with brine (75 ml), dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give a brown solid. The crude product was loaded onto a 100 g ULTRA SNAP cartridge in a minimum amount of DCM and eluted with 0-5% ethyl acetate in DCM. The appropriate fractions were combined and concentrated in vacuo to give 1- (1-tosyl-1H-indol-5-yl) ethan-1-one (1.408 g; 4.27 mmol; 68% yield) as a cream solid.

LCMS (2 min high pH method): retention time 1.20 min, [MH] ⁺ 314.3.

Intermediate 25: 1- (1-tosyl-1H-indol-5-yl) ethanol

1- (1-Tosyl-1H-indol-5-yl) ethan-1-one (1.394 g; 4.45 mmol) was placed in THF (40 ml), cooled to 0 ° C in an ice bath and placed under a nitrogen atmosphere ... Sodium borohydride (0.337 g; 8.90 mmol) was added and the reaction mixture was allowed to stir at room temperature overnight. Added additional amount of sodium borohydride (0.169 g) and the reaction mixture was left to stir for 2.5 h. The reaction mixture was cooled to 0 ° C and slowly quenched with 1N. HCl (20 ml). It was then extracted with DCM (2x25 ml) and the combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo to give 1- (1-tosyl-1H-indol-5-yl) ethan-1-ol (1.398 g; 4.21 mmol; yield 95%) as a colorless resin.

LCMS (2 min high pH method): retention time 1.11 min, [M-H] ^-

- 34 038888 is 314.3.

Intermediate 26: (1-tosyl-1H-indol-5-yl) methanol

Methyl 1-tosyl-1H-indole-5-carboxylate (1.027 g; 3.12 mmol) was placed in THF (25 ml) under nitrogen atmosphere and cooled to -78 ° C. DIBAL-H (1M in THF; 8 ml; 8.00 mmol) was added dropwise over 10 min and the reaction mixture was allowed to stir at -78 ° C for 4 h. The reaction mixture was allowed to warm to room temperature and allowed to stir for nights. The reaction mixture was cooled to -78 ° C and DIBAL-H (1M in THF; 6.5 ml; 6.50 mmol) was added dropwise over 10 min. The reaction mixture was then allowed to warm to room temperature and left to stir for 1.5 h. The reaction mixture was cooled to 0 ° C and quenched with MeOH (10 ml was added dropwise). Saturated Rochelle salt (50 ml) was added and the reaction mixture was allowed to warm to room temperature. Water (50 ml) and DCM (50 ml) were added to the reaction mixture and the layers were separated. The organic layer was washed with brine (50 ml), passed through a hydrophobic frit and concentrated in vacuo to give a colorless oil. The crude product was loaded onto a silica gel column in a minimum amount of DCM and eluted with 5-50% ethyl acetate in cyclohexane. The appropriate fractions were combined and concentrated in vacuo to afford the desired product (876 mg; 2.76 mmol; 89% yield) as a colorless gum.

LCMS (2 min formate method): retention time 0.98 min, [MH] ⁺ 317.

Intermediate 27: 1- (1-tosyl-III-indol-4-yl) ethanone

1- (III-Indol-4-yl) ethan-1-one (500 mg; 3.14 mmol; commercially available from, for example, Activate Scientific) was dissolved in DMF (5 ml) and cooled to 0 ° C on ice bath under nitrogen atmosphere. Sodium hydride (151 mg; 3.77 mmol; 60% dispersion in mineral oil) was added in portions and the reaction mixture was stirred at 0 ° C for 30 min before warming to room temperature for 30 min. Tosyl chloride (719 mg; 3.77 mmol) was added to give an orange suspension (exothermic addition) and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled to 0 ° C in an ice bath and quenched by adding water dropwise (3 ml). The mixture was then distributed between ethyl acetate (20 ml) and sat. aq. LiCl solution (20 ml). The organic layer was separated and aq. the layer was further extracted with ethyl acetate. The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give 1.11 g of a crude brown residue. This was purified by chromatography on silica gel eluting with 5-30% ethyl acetate / cyclohexane to give the desired product (809 mg; 2.323 mmol; 74% yield) as a white solid.

LCMS (2 min formate method): Retention time 1.24 min, [MH] ⁺ 314.

Intermediate 28: 1- (1-tosyl-III-indol-4-yl) ethanol

Sodium borohydride (107 mg; 2.82 mmol) was added to a suspension of 1- (1-tosyl-1H-indol-4-yl) ethan-1-one (803 mg; 2.56 mmol) in ethanol (20 ml). ice bath. The reaction mixture was stirred under nitrogen at room temperature for 1.5 h. THF (17 ml) was added to increase the solubility of the reaction mixture, which was stirred at room temperature for an additional 2 h. An additional portion of sodium borohydride (107 mg; 2, 82 mmol) and the reaction mixture was stirred at room temperature overnight. Added 1M HCl solution (20 ml) and the aqueous solution was extracted with DCM. The combined organic layers were dried (hydrophobic frit) and concentrated to give the desired product (797 mg; 2.274 mmol; 89% yield) as a pink solid.

LC-MS (method 2 min formate): retention time is 1.12 min, [M-H] ^- of 314.2.

Intermediate 29: Methyl 1-tosyl-1H-indole-4-carboxylate

- 35 038888

Methyl 1H-indole-4-carboxylate (5 g; 28.5 mmol; commercially available from, for example, Alfa Aesar) was placed in DMF (50 ml) and cooled in an ice bath. NaH (60% suspension in mineral oil; 1.370 g; 34.2 mmol) was added in portions and the reaction mixture was allowed to stir for 30 min. Tosyl chloride (6.53 g; 34.2 mmol) was added and the reaction mixture was allowed to stir and warm overnight. The reaction mixture was cooled in an ice bath and carefully quenched with water (200 ml). The mixture was extracted with EtOAc (2x250 ml). The combined organic layers were washed with brine (200 ml) and passed through a hydrophobic frit, then concentrated in vacuo to give a brown solid. The crude product was loaded onto a 100 g silica gel cartridge in a minimum amount of DCM and eluted with 5-25% ethyl acetate in cyclohexane. The appropriate fractions were concentrated in vacuo to afford the desired product (6.554 g; 18.90 mmol; 66% yield) as a white solid.

LCMS (2 min high pH method): retention time 1.32 min, [MH] ⁺ 330.2.

Intermediate 30: (1-tosyl-1H-indol-4-yl) methanol

Methyl 1-tosyl-1H-indole-4-carboxylate (6.248 g; 18.97 mmol) was taken up in DCM (200 ml) under nitrogen and cooled to -78 ° C. DIBAL-H (1 M; 83 ml; 83 mmol) was added slowly over about 30 min and the reaction mixture was allowed to stir at -78 ° C for 90 min before being allowed to stir and warm to room temperature over the weekend ... The reaction mixture was cooled in an ice bath and slowly quenched with MeOH (2 ml in 0.1 ml aliquots). Saturated Rochelle salt solution (200 ml) was added and the mixture was stirred and allowed to warm to room temperature for 3 hours. The layers were separated and the organic layer passed through a hydrophobic frit, then concentrated in vacuo to give a yellow oil. The crude product was loaded onto a 100 g silica gel cartridge in a minimum amount of DCM and eluted with 5-50% ethyl acetate in cyclohexane. The appropriate fractions were concentrated in vacuo to afford the desired product (5.172 g; 16.30 mmol; 86% yield) as a white solid.

LCMS (2 min high pH method): retention time 1.07 min, [MH] ⁺ 301.2.

Intermediate 31: Ethyl 1-tosyl-1H-pyrrolo [2,3-b] pyridine-4-carboxylate

Ethyl 1H-pyrrolo [2,3-b] pyridine-4-carboxylate (1.00 g; 5.26 mmol; commercially available from, for example, Alfa Aesar) was placed in DMF (10 ml) and cooled in ice-cold bath. NaH (60% suspension in mineral oil; 0.252 g; 6.31 mmol) was added and the reaction mixture was allowed to stir for 15 min. Tosyl chloride (1.203 g; 6.31 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled in an ice bath and quenched with water (5 ml). The reaction mixture was concentrated in vacuo, brine (50 ml) was added to the residue and it was extracted with ethyl acetate (2x50 ml). This organic layer was dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give a brown solid. The crude product was loaded onto a 50 g silica cartridge with a minimum amount of DCM and eluted with 5-25% (EtOAc: EtOH, 3: 1) in cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give a cream solid. This crude product was taken up in 1: 2 MeOH: DCM (15 ml) and free flowing silica (10 g) was added. The solvent was removed in vacuo and the silica was loaded onto a 100 g ULTRA SNAP cartridge and eluted with 5-25% (EtOAc: EtOH, 3: 1) in cyclohexane. The appropriate fractions were concentrated in vacuo to give the desired product (1.084 g; 2.52 mmol; 48% yield) as a solid

- 36 038888 cream-colored substances.

LCMS (2 min formate method): retention time 1.27 min, [MH] ⁺ 345.1.

Intermediate 32: (1-tosyl-1H-pyrrolo [2,3-b] pyridin-4-yl) methanol

Ethyl 1-tosyl-1H-pyrrolo [2,3-b] pyridine-4-carboxylate (936 mg; 2.72 mmol) was placed in DCM (25 ml) under nitrogen atmosphere and cooled to -78 ° C. DIBAL-H (1M in THF; 27.2 ml; 27.2 mmol) was added dropwise to the reaction mixture and the reaction mixture was left stirring at -78 ° C overnight. The reaction mixture was quenched with MeOH (1 ml was added in small portions) and then allowed to warm to room temperature. Rochelle's salt (saturated in 50 ml water) was added and the mixture was stirred for 15 minutes. The layers were separated and the organic layer was washed with brine (2x25 ml), dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give an orange solid. The aqueous layers were extracted with 10% MeOH in DCM (50 ml). The two resulting organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give an orange oil. The crude products were combined and loaded onto a 25 g silica cartridge with a minimum amount of DCM and eluted with 5-40% (EtOAc: EtOH, 3: 1) in cyclohexane. The appropriate fractions were concentrated in vacuo to give the desired product as a white solid (659 mg; 2.07 mmol; 76% yield).

LCMS (2 min formate method): retention time 0.92 min, [MH] ⁺ 303.1.

Intermediate 33: (S) -Methyl-1- (1- (4-chlorophenyl) ethyl) -3- (methylcarbamoyl) -1Hpyrazole-5-carboxylate

Methyl 3- (methylcarbamoyl) -1H-pyrazole-5-carboxylate (0.5 g; 2.73 mmol) was taken up in THF (20 ml) and acetonitrile (5 ml). (R) -1- (4-chlorophenyl) ethan-1-ol (0.4 ml; 2.96 mmol; commercially available from, for example, Sigma Aldrich) and Ph ₃ P (1.078 g; 4.11 mmol) and the reaction mixture was placed under a nitrogen atmosphere and cooled to 0 ° C. DIAD (0.8 ml; 4.11 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature and allowed to stir for 90 min. EtOAc (25 ml) was added to the reaction mixture, followed by the addition of water (50 ml). The layers were separated and the organic layer was washed with brine (50 ml), dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow oil. The crude product was loaded onto a 100 g ULTRA SNAP cartridge in a minimum amount of DCM and eluted with 5-50% ethyl acetate in cyclohexane. The desired fractions were combined and concentrated in vacuo to give methyl- (S) -1- (1- (4-chlorophenyl) ethyl) 3- (methylcarbamoyl) -1H-pyrazole-5-carboxylate (415 mg; 1.225 mmol; 45% yield ) in the form of a colorless resin.

LCMS (2 min formate method): retention time 1.08 min, [MH] ⁺ 322.4.

The following intermediates were prepared in a manner analogous to the preparation of Intermediate 33

- 37 038888

Intermediate connection LC-MS: (system, retention time, MID 34 O. / y-NH NA Г L (5) -Methyl-3- (methylcarbamoyl) -1- (1- (zheshatolyl) ethyl) -1 // - pyrazole-5-carboxylate Formate, 1.04 min, 302.3 35 o, / yNH (5) -Methyl-3- (methylcarbamoyl) -1- (1- phenylpropyl) -S-pyrazole-5-carboxylate Formate, 1.07 min, 302.2 36 a / XV? 0 ° \ (5) -Methyl-1- (1- (4-fluorophenyl) ethyl) -3- (methyl carbamoyl) -S-pyrazole-5-carboxylate Formate, 1.00 min, 306.1 37 O. / γ-ΝΗ m O \ (5) -Methyl-1- (1- (3-fluorophenyl) ethyl) -3- (methylcarbamoyl) -S-pyrazole-5-carboxylate Formate, 0.99 min, 306.4 38 O. / y-NH X? (5) -Methyl-1- (1- (2-fluorophenyl) ethyl) -3 (methyl carbamoyl) -III-pyrazole-5-carboxylate Formate, 0.99 min, 306.4

- 38 038888

39 o _x y — NH 1 ζ o ^ ° Methyl-3- (methylcarbamoyl) -1 - ((1-tosyl-III-indol-4-yl) methyl) -1 / 7-pyrazole-5-carboxylate Formate, 1.18 min, 467.3 40 η С Methyl 3- (methylcarbamoyl) -1- (1- (1-tosyl-Shindol-4-yl) ethyl) -17 / -pyrazole-5-carboxylate Formate, 1.22 min, MH479 41 7¼¼ o ^ ^{o /} Methyl-3- (methylcarbamoyl) -1 - ((1-tosyl-1H-indol-5-yl) methyl) -1N-pyrazole-5-carboxylate Formate, 1.16 min, 467.5 42 αχ 4 Methyl 3- (methylcarbamoyl) -1- (1- (1-tosyl-Shindol-5-yl) ethyl) -III-pyrazole-5-carboxylate Formate, 1.23 min, [ΜΗ] 'at 479.5

Intermediate 43: (S) -methyl-1- (1- (3-chlorophenyl) ethyl) -3- (methylcarbamoyl) -1Hpyrazole-5-carboxylate

Methyl 3- (methylcarbamoyl) -1H-pyrazole-5-carboxylate (0.5 g; 2.73 mmol), (K) -1- (3-chlorophenyl) ethan 1-ol (0.513 g; 3.28 mmol) , cyanomethylenetributylphosphorane (CMBP) (1.432 ml; 5.46 mmol; commercially available from, for example, TCI) and toluene (10 ml) were added to the reaction vessel. The reaction vessel was sealed and heated in a Biotage Initiator microwave to 150 ° C for 30 minutes. After heating, the reaction mixture was concentrated in vacuo to give a brown oil. The crude product was loaded onto a 100 g ULTRA SNAP cartridge in a minimum amount of DCM and eluted with 5-60% ethyl acetate in cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give methyl- (S) -1- (1- (3-chlorophenyl) ethyl) -3- (methylcarbamoyl) -1H-pyrazole 5-carboxylate (462 mg; 1.364 mmol; 50% yield) as an orange solid.

LCMS (2 min formate method): retention time 1.09 min, [MH] ⁺ 322.2.

The following intermediate compounds were prepared in a manner analogous to the preparation of intermediate 43

- 39 038888

Intermediate connection LC-MS: (system, retention time, MH ⁺ ) 44 o _h _ _η l νΖ ⁴ A / /% N 7 \. Methyl 3- (methylcarbamoyl) -1 - ((1-tosyl-1Hpyrrolo [2,3-c] pyridin-4-yl) methyl) -1H-pyrazole 5-carboxylate Formate, 0.83 min, 468.3 45 \ oA ^ ⁿ Λ, ____ Q O II 1 o Methyl 3- (methylcarbamoyl) -1- (1- (1-tosyl-1Hpyrrolo [2,3-6] pyridin-4-yl) ethyl) -1H-pyrazole- 5carboxylate Formate, 1.11 min, 482.3 46 o _h y — ΝΗ Ν = \ O II / λ O fo 'Methyl 3- (methylcarbamoyl) -1 - ((1-tosyl-1H-pyrrolo [2,3-6] pyridin-4-yl) methyl) -1H -pyrazole-5-carboxylate Formate, 1.06 min, 468.2 47 o / y-NH nA Cl * Λ ⁰ (X) -Methyl 1- (1- (2-chlorophenyl) ethyl) -3- (methylcarbamoyl) -1Н-pyrazole-5-carboxylate Formate, 1.06 min, 322.3 48 O. / y-NH A nA С jL / N-A (5) -Methyl 1- (1- (3-methoxyphenyl) ethyl) -3 (methylcarbamoyl) -1I-pyrazole-5-carboxylate Formate, 0.99 min, 318.2

Intermediate 49: 3- (methylcarbamoyl) -1 - ((1-tosyl-III-indol-4-yl) methyl) -S-pyrazole 5-carboxylic acid

Methyl 3 - (methylcarbamoyl) -1 - ((1-tosyl-1 N-indol-4-yl) methyl) -1 N-pyrazole-5-carboxylate (265 mg; 0.426 mmol) was placed in methanol (2.5 ml) and THF (2.5 ml). Added 1M LiOH in water (0.852 ml; 0.852 mmol) and the mixture was stirred at 50 ° C for 90 min. The reaction mixture was concentrated under water

- 40 038888 kum. The residue was distributed between ethyl acetate and water (10 ml each). The aqueous layer was acidified with 2M HCl and then extracted with ethyl acetate (2x10 ml), dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give the desired product (173.5 mg; 0.326 mmol; 77% yield) as a white solid.

LCMS (2 min formate method): retention time 1.13 min, [MH] ⁺ 453.3.

The following intermediates were prepared in a manner analogous to the preparation of Intermediate 49

Intermediate connection Intermediate used LC-MS: (system, retention time, MH ⁺ ) 50 Ck / y- NH nA o ^on (5) -3- (Methylcarbamoyl) -1- (1 (meta-tol yl) ethyl) -1 // - p and razol-5carboxylic acid a / f 1 Ω Intermediate 34 Formate, 0.86 min, 274.2 51 Ck / nd) o ^ ^he (5) -3- (Methylcarbamoyl) -1- (1phenylpropyl) -1H-pyrazole-5carboxylic acid O. / γ ^ ΝΗ m Intermediate connection 35 Formate, 0.96 min, 288.2

- 41 038888

52 Ok 'y-NH Hub (5) -1- (1- (4-Fluorophenyl) ethyl) -3 (methyl carbamoyl) -III-pyrazole-5carboxylic acid a / y ^ NH XyD O ° \ Intermediate connection 36 Formate, 0.88 min, 292.1 53 o _h / y-NH Soup ^F T χ _Η (5) -1- (1- (3-Fluorophenyl) ethyl) -3 (methyl carbamoyl) -1Н-pyrazole-5carboxylic acid o _h / y-NH ft νΣ / A Intermediate 37 Formate, 0.90 min, 292.4 54 a / y-NH ol F ¹ ΛθΗ (5) -1- (1- (2-Fluorophenyl) ethyl) -3 (methyl carbamoyl) -S-pyrazole-5 carboxylic acid Pt 1 γ-ΝΗ Μ ^F 0 \ Intermediate 38 Formate, 0.89 min, 292.4 55 ° y po) ^ he O ⁰ t (R) -1 - (2 - ((tert-Butyldimethylsilyl) oxy) -1phenylethyl) -3- (methylcarbamoyl) 1H-pyrazole-5-carboxylic acid o _h / smart o / L o- ¹ t Intermediate connection 90 High pH, 0.90 min, 404.6

- 42 038888

56 3- (Methylcarbamoyl) -1- (1- (1-tosylSh-indol-4-yl) ethyl) -Sh-pyrazole-5carboxylic acid Intermediate connection 40 Formate, 1.16 min, MN 465 57 m - / La '\ 7 θ + θΗ 3- (Methylcarbamoyl) -1- (1- (1-tosylLH-pyrrole o [2,3-th] pyridin-4-yl) ethyl) -1Н-pyrazole-5-carboxylic acid ip Oh oh Intermediate connection 45 Formate, 1.06 min, MN 468 58 b _{o O} A ° _H 3- (Methylcarbamoyl) -1 - ((1-tosyl1H-indol-5-yl) methyl) -1H-pyrazole5-carboxylic acid ₀ O ^ S ' ⁰ Vnh soe _O P ° ^X Intermediate 41 Formate, 1.11 min, 453.6 59 ₀ O? S * ° ^ ΝΗ coup ₀ ° F ^N 3- (methylcarbamoyl) -1- (1- (1-tozil1N-indol-5-yl) ethyl) -1H-pyrazol-5karbonovaya acid ₀ Op ⁰ Vnh coui ¹ _o Po ^z Intermediate connection 42 Formate, 1.17 min, [ΜΗ] 'at 465.5

- 43 038888

60 _h about dAAhA hn γ d Aon _of 1 - ((1 // - 11 and rrolo [2,3-6] pyrid in-4- yl) methyl) -3- (methylcarbamoyl) -1Yapirazol-5-carboxylic acid about _h V-NH Intermediate 46 Formate, 0.44 min, 300.1 61 Ο _χ / ^ ΝΗ * (/ -one (X) -1- (1- (4-Chlorophenyl) ethyl) -3 (methyl carbamoyl) -S-pyrazole-5carboxylic acid O. / NH % Intermediate connection 33 Formate, 0.99 min, 308.2 62 Ο _χ /% * _O ^ OH (X) -1- (1- (3-Chlorophenyl) ethyl) -3 (methyl carbamoyl) -S-pyrazole-5carboxylic acid o / ^ NH Ay Intermediate connection 43 Formate, 0.99 min, 308.1 63 Q ¹ Ίί * _o x ° n (X) -1- (1- (2-Chlorophenyl) ethyl) -3 (methyl carbamoyl) -S-pyrazole-5 carboxylic acid Intermediate connection 47 Formate, 0.95 min, 308.2 64 o _h / SyNH G L y _0H (5) -1- (1- (3-Methoxyphenyl) ethyl) -3 (methyl carbamoyl) -S-pyrazole-5carboxylic acid O. / SC% Intermediate connection 48 Formate, 0.88 min, 304.1

Intermediate 65: N ⁵ - ((1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1 - ((1tosyl-1 N-indol-4-yl ) methyl) -1 H-pyrazole-3,5-di-carboxamide

3- (Methylcarbamoyl) -1 - ((1-tosyl-1H-indol-4-yl) methyl) -1H-pyrazole-5-carboxylic acid (173 mg; 0.382 mmol) was placed in DMF (5 ml). DIPEA (0.200 ml; 1.147 mmol) was added followed by HATU (218 mg; 0.573 mmol) and the reaction mixture was left stirring for 5 min giving a brown solution. Then (1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexane-6-amine hydrochloride was added (for the preparation, see preparation of intermediate 94; 57.0 mg; 0.421 mmol) and the reaction mixture was left stirring at room temperature during the night. The reaction mixture was partitioned between ethyl acetate and sodium bicarbonate (15 ml each). The organic layer was washed with 2M HCl (15 ml), brine (15 ml) and then dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by column chromatography on silica gel, eluting with 10-60% mixture (EtOAc: EtOH 3: 1) in cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the desired product.

- 44 038888 (99.7 mg; 0.178 mmol; 46% yield) as a cream solid.

LCMS (2 min formate method): retention time 1.09 min, [MH] ⁺ 534.3.

Intermediate 66: 1 - ((1H-indol-4-yl) methyl) -3- (methylcarbamoyl) -1H-pyrazole-5carboxylic acid

3- (Methylcarbamoyl) -1 - ((1-tosyl-1H-indol-4-yl) methyl) -1H-pyrazole-5-carboxylic acid (139 mg; 0.307 mmol) was placed in THF (6 ml) and methanol ( 3 ml). Cesium carbonate (500 mg; 1.536 mmol) was added and the reaction mixture was left stirring at 70 ° C for 3.5 h. The reaction mixture was concentrated in vacuo, water (10 ml) was added to the residue, which was then acidified with 2N. HCl and extracted with ethyl acetate (2x10 ml). This organic layer was dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give the desired product (91.5 mg; 0.291 mmol; 95% yield) as a pink solid.

LCMS (2 min formate method): retention time 0.75 min, [MH] ⁺ 299.1.

Intermediate 67: (1R, 5S, 6s) -tert-butyl-6- (1 - ((1H-indol-4-yl) methyl) -3 (methylcarbamoyl) -1H-pyrazole-5-carboxamido) -3- azabicyclo [3.1.0] hexane-3-carboxylate

1 - ((1H-Indol-4-yl) methyl) -3- (methylcarbamoyl) -1H-pyrazole-5-carboxylic acid (78.6 mg; 0.263 mmol) was placed in DMF (5 ml). HATU (150 mg; 0.395 mmol) was added followed by DIPEA (0.138 ml; 0.790 mmol) and the reaction mixture was left stirring for 5 min giving a brown solution. Added tert-butyl- (1R, 5S, 6s) -6-amino-3-azabicyclo [3.1.0] hexane-3-carboxylate hydrochloride (68.0 mg; 0.290 mmol; commercially available from, for example, Astatech) and the reaction mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was distributed between ethyl acetate and sodium bicarbonate (10 ml each). The layers were separated and the organic layer was washed with 2N. HCl (10 ml), brine (10 ml) and then dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product as a brown solid. The crude product was loaded onto a 10 g ULTRA SNAP cartridge in the minimum amount of DCM (with a couple of drops of MeOH) and eluted with 5-50% mixture (EtOAc: EtOH 3: 1) in cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the desired product (93.8 mg; 0.186 mmol; 71% yield) as a cream solid.

LCMS (2 min formate method): retention time 1.00 min, [MH] ⁺ 479.

Intermediate 68: 3-Hydroxybicyclo [3.1.0] hexane-6-carboxylic acid

Sodium hydroxide (6 ml; 12.00 mmol; 2M aqueous solution) was added to a solution of ethyl 3hydroxybicyclo [3.1.0] hexane-6-carboxylate (1 g; 5.88 mmol; commercially available from, for example, Fluorochem) in ethanol (10 ml) and the mixture was stirred for 2 h at room temperature, then evaporated in vacuo to half the original volume and acidified with 2M HCl to approximately pH 2. The solution was saturated with sodium chloride (solid was added and the mixture was stirred for 1 h) , then first extracted with 10% MeOH / DCM (5x10 ml) and then EtOAc (5x10 ml). The combined organic layers were dried over sodium sulfate and evaporated in vacuo to give 3-hydroxycyclo [3.1.0] hexane-6-carboxylic acid (0.65 g; 4.57 mmol; 78% yield) as a colorless gum. It was used unrefined in subsequent interactions.

Intermediate 69: 6-aminocyclo [3.1.0] hexan-3-ol

- 45 038888

3-Hydroxybicyclo [3.1.0] hexane-6-carboxylic acid (650 mg; 4.57 mmol) was dissolved in toluene (10 ml) and tert-butanol (10 ml), then Et ₃ N (1.275 ml; 9, 15 mmol) and diphenylphosphorazidate (1.478 ml; 6.86 mmol) and the mixture was heated at 80 ° C overnight. The mixture was diluted with EtOAc (20 ml) and washed with water (20 ml), the solvent was dried and evaporated to give a pale yellow gum. It was dissolved in DCM (10 ml) and loaded onto a column with 50 g of silica, then eluted with a mixture of 0100% EtOAc / cyclohexane and ninhydrin-positive fractions were evaporated under vacuum to obtain three portions of Boc-protected amino acid intermediates containing impurities (each possibly with different diastereomer as the main component), portion A (105 mg), portion B (122 mg), and portion C (85 mg). Each was dissolved in DCM (3 ml) and TFA (1 ml) was added, the solutions were stirred for 1 h, then evaporated in vacuo, and the residues were dissolved in methanol and loaded onto 5 g SCX cartridges. They were washed with methanol and then eluted with 2M methanol solution of ammonia. The eluates were evaporated in vacuo to obtain three portions of the product in the form of pale yellow vitreous substances (each possibly with a different diastereomer as the main component), portion A (15 mg), portion B (12 mg) and portion C (14 mg). The products were used crude and combined in subsequent interactions.

Intermediate 70: tert-butyl- (cyclopent-3-en-1-yloxy) dimethylsilane

Cyclopent-3-en-1-ol (5 g; 59.4 mmol; commercially available from, for example, Astatech) was dissolved in DCM (100 ml) and TBDMS-Cl (8.96 g; 59.4 mmol ) and imidazole (4.86 g; 71.3 mmol), then the resulting suspension was stirred at room temperature over the weekend. The mixture was washed with water (2x100 ml), dried and evaporated in vacuo to give tert-butyl (cyclopent-3en-1-yloxy) dimethylsilane (12.05 g; 60.7 mmol; 102% yield) as a pale yellow liquid.

1H NMR (400 MHz, CDCl ₃ ) δ ppm. 5.68 (s, 2H), 4.50-4.62 (m, 1H), 2.59 (dd, J = 14.9, 6.8 Hz, 2H), 2.232.37 (m, 2H), 0.91 (s, 9H), 0.09 (s, 6 H).

Intermediate 71: (1R, 5S, 6r) -ethyl-3 - ((tert-butyldimethylsilyl) oxy) bicyclo [3.1.0] hexane-6-carboxylate, mixture of diastereomers

Ethyl diazoacetate (6.90 ml; 66.5 mmol) was dissolved in DCM (150 ml) and added dropwise over approximately 5 hours in a mixture of rhodium (R) acetate dimer (1 g; 2.263 mmol) and tert-butyl (cyclopent- 3-en-1yloxy) dimethylsilane (12 g; 60.5 mmol) in DCM (150 ml) at room temperature. The resulting green solution was stirred overnight, then evaporated in vacuo to give a green liquid. It was loaded onto a 340 g silica column and eluted with 0-40% EtOAc / cyclohexane and fractions on TLC plates were visualized by immersion in permanganate solution. The active fractions were evaporated in vacuo to give ethyl (1R, 5S, 6r) -3 - ((tert-butyldimethylsilyl) oxy) bicyclo [3.1.0] hexane-6-carboxylate (5.5 g; 19.33 mmol; yield 32.0%) as a colorless liquid, as a mixture of isomers at the position of the silyl ether (approximately 3: 1 ratio), and it was transferred crude to the next step.

LCMS (2 min high pH method): retention time 0.96 min, [MH] ⁺ absent.

Intermediate 72: (1R, 5S, 6r) -3 - ((tert-butyldimethyl-silyl) oxy) bicyclo [3.1.0] hexane 6-carboxylic acid, diastereomeric mixture

Sodium hydroxide (20 ml; 40.0 mmol; 2M aqueous solution) was added to a solution of ethyl (1R, 5S, 6r) -3 ((tert-butyldimethylsilyl) oxy) bicyclo [3.1.0] hexane-6-carboxylate (5 , 0 g; 17.58 mmol) in ethanol (50 ml) at room temperature and the mixture was stirred for 3 h. TLC analysis confirmed that all starting material was consumed and the mixture was evaporated in vacuo to a volume of about 30 ml, then diluted water (30 ml) and washed with ether (50 ml). After treatment, the ether washings were dried and evaporated in vacuo to give the recovered starting material: ethyl (1R, 5S, 6r) -3 ((tert-butyldimethylsilyl) oxy) bicyclo [3.1.0] hexane-6-carboxylate (3.85 g ). It was dissolved in ethanol (30 ml) and 2M aqueous NaOH solution (20 ml) was added, then the mixture was heated at 70 ° C for 3 h, then evaporated in vacuo. The residue was dissolved in water (50 ml) and washed with ether (50 ml), then the aqueous layer was acidified with 2M HCl (20 ml) and was extracted with EtOAc (2x50 ml). The combined organic layers were dried and evaporated in vacuo to give (1R, 5S, 6r) -3 - ((tert-butyldimethylsilyl) ok

- 46 038888 c) bicyclo [3.1.0] hexane-6-carboxylic acid (1.9 g; 7.41 mmol; 42.2% yield) as a pale yellow solid, NMR analysis indicated a consistent isomer mixture. The product was transferred to the next stage without purification.

Intermediate 73: benzyl ((1R, 5S, 6r) -3 - ((tert-butyldimethylsilyl) oxy) bicyclo [3.1.0] hexan-6-yl) carbamate, diastereomeric mixture

(1R, 5S, 6r) -3 - ((tert-Butyldimethylsilyl) oxy) bicyclo [3.1.0] hexane-6-carboxylic acid (1.8 g; 7.02 mmol) was dissolved in a mixture of toluene (20 ml) and Et ₃ N (1.957 ml; 14.04 mmol), then DPPA (1.815 ml; 8.42 mmol) was added and the mixture was stirred for 30 min at room temperature. Benzyl alcohol (1.095 ml; 10.53 mmol) was added and the mixture was heated at 100 ° C for 4 h, then cooled to room temperature. Ethyl acetate (100 ml) was added and the solution was washed with water (2x100 ml), then dried over sodium sulfate, filtered and the filtrate was evaporated in vacuo to give a pale yellow oil. It was dissolved in DCM (10 ml) and loaded onto a 50 g silica column, then eluted with 0-30% EtOAc / cyclohexane and the product containing fractions (detected by immersion in permanganate solution) were collected and evaporated in vacuo to give benzyl ( (1R, 5S, 6r) -3 - ((tert-butyldimethylsilyl) oxy) bicyclo [3.1.0] hexan-6-yl) carbamate (1.90 g; 5.26 mmol; 75% yield) as a pale yellow oil, NMR corresponds to the desired product as a mixture of isomers in a ratio of about 2: 1. The compound was transferred to the next step without further purification.

LCMS (2 min formate method): retention time 1.56 min, [MH] ⁺ 362.6.

Intermediate 74: (1R, 5S, 6r) -3 - ((tert-butyldimethylsilyl) -oxy) bicyclo [3.1.0] hexan6-amine, diastereomeric mixture

Benzyl - ((1R, 5S, 6r) -3 - ((tert-butyldimethylsilyl) oxy) bicyclo [3.1.0] hexan-6-yl) carbamate (1.9 g; 5.26 mmol) was dissolved in ethanol (100 ml) and hydrogenated in an H-Cube flow reactor at atmospheric pressure and a flow rate of 1 ml / min. The eluate was evaporated in vacuo to give (1R, 5S, 6r) -3 ((tert-butyldimethylsilyl) oxy) bicyclo [3.1.0] hexane-6-amine (1.12 g; 4.92 mmol; 84% yield) in the form of a pale yellow oil. The product is a mixture of unequal amounts of diastereomers at the position of the silyl ether in a ratio of approximately 65:35.

1H NMR (400 MHz, CDCl ₃ ) δ ppm. 4.22 ppm, 1H [A] (broad L, CH), 3.80 ppm. 1H [B] (m, CH), 2.47 ppm, 1H [A] (t, CH), 2.05-1.93 ppm. 2H [A] + 3H [B] (m, 5xCH) 1.75-1.66 ppm. -NH2 [A] + -NH2 [B] + 2xCH [B] 1.62 ppm. 2H, [A] (dd, 2xCH). Both diastereomers have been identified.

1.20-1.15 ppm 2H [A] + 2H [B] (m, 4xCH), 0.86 ppm, 9H [A] (s, 3xCH3) + 9H [B] (s, 3xCH3), 0.00 ppm, 6H [A + B] (s, 2xCH3).

Intermediate 75: N ⁵ - ((1r, 4r) -4-hydroxycyclohexyl) -N ³ -methyl-1- (1- (1-tosyl-1H-indol-4-yl) ethyl) -1H-pyrazole-3 , 5-dicarboxamide

To a solution of 3- (methylcarbamoyl) -1- (1- (1-tosyl-1H-indol-4-yl) ethyl) -1H-pyrazole-5-carboxylic acid (255 mg; 0.547 mmol) in DMF (4 ml) HATU (312 mg; 0.820 mmol) was added followed by the addition of (1r, 4r) -4-aminocyclohexan-1-ol (126 mg; 1.093 mmol; commercially available from, for example, Fluorochem) and DIPEA (0.477 ml; 2, 73 mmol). The resulting reaction mixture was stirred at room temperature in air for 5 h. The reaction mixture was concentrated in vacuo to remove DMF and partitioned between ethyl acetate and saturated aq. LiCl solution. The organic layer was separated, washed with brine, dried (hydrophobic frit) and concentrated to give a crude orange oil. This was purified by chromatography on a silica gel column eluting with 0-50% (25% ethanol in ethyl acetate) / ethyl acetate to give the desired product

- 47 038888 (330 mg; 0.439 mmol; 80% yield) as a pale yellow oil.

LCMS (2 min formate method): retention time 1.07 min, [M + Na] + 586.

The following intermediate compounds were prepared in a manner analogous to the preparation of intermediate 75

Intermediate connection Intermediate used LC-MS: (system, retention time, MH ⁺ ) 76 o / nA „g ~ o pm tv No - ((1 / ?, 55.6g) -3- Oxabicyclo [3.1.0] hexan-6-yl) -1 ((1?) - 2 - ((w / ? esh-butyldimethylsilyl) oxy) -1-phenylethyl) -A ³ -methyl1H-pyrazole-3,5-dicarboxamide a / Α ^ ΝΗ oV) no.o ^ζ θ t Intermediate 55 High pH, 1.29 min, 485.7 77 m Ν ^ ίΙ YA / - h o L IL / \ ..... No-Methyl-No - ((15,25) -2methylcyclopropyl) -1- (1- (1-tosylLH-pyrrolo [2,3-6] pyridin-4yl) ethyl) -1H-pyrazole-3,5dicarboxamide m nA AV W? 'o ^ ^OH Intermediate 57 Formate, 1.11 min, 521.1 78 О Н Vo ⁿ No - ((! / ?, 55.6 g) -3Oxabicyclic o [3.1.0] hexan-6-yl) -A ³ methyl-1 - ((1-tosyl-1I-indol-5yl) methyl ) -1H-pyrazole-3,5 dicarboxamide b. ... О ^ ° V-NH ₀ Λ ° _Η Intermediate 58 Formate, 1.06 min, 534.6

- 48 038888

79 _{0 o} k ° kyn sod ⁿ \ ⁵ - ((15.55.6 /) - 3- Oxabicyclic o [3.1.0] hexan-b-yl) - ^ ³ methyl-1- (1- (1-tosyl-1H- indole-5yl) ethyl) -1H-pyrazole-3,5 dicarboxamide ₀ o <° V ™ vUUO (Λ ° ^η Intermediate 59 Formate, 1.12 min, [ΜΗ] - at 546.5 80 -O-CH o o I ^ - ((15.55.6 ^ -3- Oxabicyclic o [3.1.0] hexan-b-yl) - ^ ³ methyl-1- (1- (1-tosyl-1H- indol-4yl) ethyl) -S-pyrazole-3,5 dicarboxamide <4-94- Intermediate 56 Formate, 1.12 min, MN '546.4 81 C) / D-NH _cl Xb> 2 Ή * Dm 'n o H No - ((1K \ 58 \ 6g *) - 3 - ((tert-Butyldimethylsilyl) oxy) bicyclo [3.1.0] hexan-6-yl ) -1 - ((5) -1 (3-chlorophenyl) ethyl) -A ^{/ 3} -methyl-1Japirazole-3,5-dicarboxamide О / V-NH _a xv? ' _ο ΛθΗ Intermediate 62 Formate, 1.57 min, 517.6 82 o _h / ^ NH OyEdCh J H o H 1 ^ - ((1K, 58.6g) -3 - ((tert-Butyldimethylsilyl) oxy) bicyclo [3.1.0] hexan-b-yl) - ^ ³ methyl-1 - ((5) -1-phenylpropyl) -Spyrazole-3,5-dicarboxamide О / у-ΝΗ ° FУ _О ^ ОН Intermediate 51 High pH, 1.55 min, 497.7

Intermediate 83: 1 - ((1H-pyrrolo [2,3-c] pyridin-4-yl) methyl) -3- (methylcarbamoyl) III-pyrazole-5-carboxylic acid

Methyl 3 - (methylcarbamoyl) -1 - ((1-tosyl-1 H-pyrrolo [2,3-c] pyridin-4-yl) methyl) -1 H-pyrazole-5-carboxylate (106 mg; 0.227 mmol ) was placed in methanol (1.5 ml) and THF (1.5 ml). Added 1M LiOH in water (0.453 ml; 0.453 mmol) and the reaction mixture was left to stir at room temperature overnight. An additional amount of 1M LiOH in water (0.453 ml) was added and the reaction mixture was left stirring for 4 h. The residue was partitioned between water and ethyl acetate (10 ml

- 49 038888 waiting). The aqueous layer was acidified with 2N. HCl and extracted with ethyl acetate (2x15 ml). The aqueous layer was then extracted with 10% MeOH in DCM (2x15 ml) and the aqueous layer was concentrated in vacuo to give a crude residue. The crude product was dissolved in DMSO: MeCN 1: 1 (2 ml), filtered and then purified by MDAP (high pH method). The appropriate fractions were concentrated in vacuo to afford the title compound (22 mg; 0.051 mmol; 23% yield) as a cream solid.

LCMS (2 min formate method): retention time 0.37 min, [MH] ⁺ 300.2.

Intermediate 84: (S) -N ⁵ - (3,3-diethoxypropyl) -N ³ -methyl-1- (1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide

(S) -3- (Methylcarbamoyl) -1- (1-phenylethyl) -1H-pyrazole-5-carboxylic acid (121 mg; 0.443 mmol) was dissolved in DMF (2 ml). HATU (255 mg; 0.671 mmol) was added followed by the addition of 3.3 diethoxypropan-1-amine (0.12 ml; 0.742 mmol; commercially available from e.g. Acros) and then DIPEA (0.39 ml; 2.233 mmol) ... The reaction mixture was stirred under nitrogen atmosphere for 3.25 h. The reaction mixture was partitioned between sat. aqueous LiCl (20 ml), Na ₂ CO ₃ (about 1 ml) and ethyl acetate (20 ml); the layers were separated. The aqueous layer was extracted with additional ethyl acetate (2x20 ml). The organic layers were combined, back-extracted with water (2x10 ml) and filtered through a cartridge equipped with a hydrophobic frit. The filtrate was evaporated in vacuo to give a colorless gum. It was redissolved in dichloromethane and immediately loaded onto the top of a 10 g silica SNAP cartridge and purified by SP4 flash column chromatography (0-60% ethyl acetate / cyclohexane). The appropriate fractions were combined to give (S) -N ⁵ - (3,3-diethoxypropyl) -N ³ -methyl-1- (1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (103 mg; 0.230 mmol; yield 52%).

LCMS (2 min high pH method): retention time 1.05 min, [MH] ⁺ 403.2.

Intermediate 85: 2- (1,3-dihydroxypropan-2-yl) isoindoline-1,3-dione

Isobenzofuran-1,3-dione (4, 62 g; 31.2 mmol; commercially available from, for example, Sigma Aldrich) at room temperature. The reaction mixture was heated to 90 ° C and stirred overnight. The reaction mixture was partitioned between EtOAc (200 ml) and water (250 ml) and the layers were separated. The organic layer was analyzed and shown to contain product. Therefore, the aqueous layer was further extracted with EtOAc (2x100 ml) and then the combined organic layers were subjected to back extraction with water (2x50 ml) and sat. aq. LiCl solution (50 ml). The organic phases were then dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 2- (1,3-dihydroxypropan-2-yl) isoindoline-1,3-dione (3.33 g; 15.05 mmol; 48% yield ) as a cream-colored solid.

LCMS (2 min high pH method): retention time 0.52 min, [MH] ⁺ 222.2.

Intermediate 86: N ⁵ - (2 - ((2r, 5S) -5- (1,3-dioxoisoindolin-2-yl) -1,3-dioxane-2yl) ethyl) -N ³ -methyl-1- ( (S) -1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide

A mixture of (S) -N ⁵ - (3,3-diethoxypropyl) -N ³ -methyl-1- (1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (113 mg; 0.280 mmol), 2- (1 , 3-dihydroxypropan-2-yl) isoindoline-1,3-dione (62 mg; 0.280 mmol) and p-toluenesulfonic acid monohydrate (12 mg; 0.063 mmol) in toluene (3 ml) was stirred at 110 ° C under nitrogen atmosphere for 2 h. The reaction mixture was then cooled to room temperature and

50 038888, the solids were evaporated in vacuo to give a yellow solid. It was partitioned between 10% methanol in DCM (10 ml), water (5 ml) and sat. aqueous Na2CO ₃ (10 ml) and the layers were separated. The aqueous phase was extracted with 10% methanol in DCM (3x10 ml) and ethyl acetate (5 ml). The organic layers were combined and filtered through a cartridge equipped with a hydrophobic frit. The organic layers were concentrated in vacuo to give 138 mg of the crude product. The crude product was taken up in DCM and purified by flash chromatography (10 g SNAP silica cartridge) eluting with 0-100% EtOAc / cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give N ⁵ - (2 - ((2r, 5S) -5- (1,3-dioxoisoindolin-2-yl) -1,3-dioxane-2yl) ethyl) -N ³ - methyl 1 - ((S) -1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (102 mg; 0.154 mmol; 55% yield).

LCMS (2 min high pH method): retention time 1.10 min, [MH] ⁺ 532.2.

Intermediate 87: (S) -N ⁵ - (4,4-diethoxybutyl) -N ³ -methyl-1- (1-phenylethyl) -1H-pyrazole 3.5-dicarboxamide

(S) -3- (Methylcarbamoyl) -1- (1-phenylethyl) -1H-pyrazole-5-carboxylic acid (125 mg; 0.457 mmol) was dissolved in DMF (2 ml). HATU (272 mg; 0.715 mmol) was added followed by the addition of 4.4 diethoxybutan-1-amine (0.13 ml; 0.752 mmol; commercially available from, for example, Sigma Aldrich) and then DIPEA (0.4 ml; 2.290 mmol ). The reaction mixture was stirred under nitrogen atmosphere for 6 hours. Additional HATU (209 mg; 0.549 mmol), 4,4-diethoxybutan-1-amine (0.1 ml; 0.579 mmol) were added and then DIPEA (0.1 ml; 0.573 mmol), then stirred for another 3 hours, the Reaction mixture was distributed between sat. aqueous LiCl (20 ml) and ethyl acetate (20 ml) and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (2x20 ml). The organic layers were combined, back-extracted with water (2x10 ml) and filtered through a cartridge equipped with a hydrophobic frit. The filtrate was evaporated in vacuo to give a colorless gum. It was redissolved in dichloromethane and immediately loaded onto the top of a 10 g silica SNAP cartridge and purified by SP4 flash column chromatography (0-70% ethyl acetate / cyclohexane). The appropriate fractions were combined and concentrated in vacuo to give (S) -N ⁵ - (4,4-diethoxybutyl) -N ³ -methyl-1- (1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (190 mg; 0.411 mmol; yield 90%).

LCMS (2 min high pH method): retention time 1.07 min, [M-H] is 415.3.

Intermediate 88: N ⁵ - (3 - ((2r, 5S) -5- (1,3-dioxoisoindolin-2-yl) -1,3-dioxane-2yl) propyl) -N ³ -methyl-1- ( (S) -1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide

A mixture of (S) -N ⁵ - (4,4-diethoxybutyl) -N ³ -methyl-1- (1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (190 mg; 0.456 mmol), 2- (1 , 3-dihydroxypropan-2-yl) isoindoline-1,3-dione (112 mg; 0.506 mmol) and p-toluenesulfonic acid monohydrate (19 mg; 0.100 mmol) in toluene (4 ml) was stirred at 110 ° C under nitrogen atmosphere for 2 hours. The reaction mixture was then cooled to room temperature and the volatiles were evaporated in vacuo to give a yellow solid. It was partitioned between 10% methanol in DCM (10 ml), water (5 ml) and sat. aqueous Na2CO3 (10 ml) and the layers were separated. The aqueous phase was extracted with 10% methanol in DCM (3x10 ml) and ethyl acetate (5 ml) and the organic layers were combined and filtered through a cartridge equipped with a hydrophobic frit. The organic layers were concentrated in vacuo to give 207 mg of the crude product. The crude product was taken up in DCM and purified by flash chromatography (25 g SNAP silica cartridge) eluting with 0-100% EtOAc / cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give N ⁵ - (3 - ((2r, 5S) -5- (1,3-dioxoisoindolin-2-yl) -1,3-dioxan-2-yl) propyl) N ³ -methyl-1 - ((S) -1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (81 mg; 0.119 mmol; 26% yield).

LCMS (2 min high pH method): retention time 1.12 min, [MH] ⁺ 546.2.

Intermediate 89: (S) -2 - ((tert-butyldimethylsilyl) oxy) -1-phenylethanol

- 51 038888

(S) -1-Phenylethane-1,2-diol (251 mg; 1.817 mmol; commercially available from, for example, Sigma Aldrich) was dissolved in DCM (7 ml), then DMAP (22 mg; 0.180 mmol) was added. The solution was cooled to 0 ° C, then triethylamine (0.380 ml; 2.72 mmol) and TBDMS-Cl (411 mg; 2.72 mmol) in DCM (3 ml) were added dropwise. The reaction mixture was then stirred at room temperature for 2 hours.

_{NH 4} Cl (7 ml) was added to the reaction mixture. The layers were separated and the aqueous layer was back-extracted with DCM (2x10 ml). The combined organic layers were dried and concentrated in vacuo to give 448 mg of the crude product, which was used directly in the next step.

LCMS (2 min high pH method): retention time 1.41 min, [M-H] is 251.1.

Intermediate 90: (R) -methyl-1- (2 - ((tert-butyldimethylsilyl) oxy) -1-phenylethyl) -3 (methylcarbamoyl) -1H-pyrazole-5-carboxylate

Methyl 3- (methylcarbamoyl) -1H-pyrazole-5-carboxylate (216 mg; 1.179 mmol), (S) -2 ((tert-butyldimethylsilyl) oxy) -1-phenylethan-1-ol (327 mg; 1.297 mmol) in toluene (2.5 ml), tri-nbutylphosphine (0.582 ml; 2.359 mmol) and 2- (tributylphosphoranylidene) acetonitrile (0.464 ml; 1.769 mmol). The reaction mixture was heated in a 5 ml microwave tube at 120 ° C for 45 min. Additional (S) -2 - ((tert-butyldimethylsilyl) oxy) -1-phenylethan-1-ol (119 mg; 0.471 mmol) was added to the reaction mixture, followed by heating for 45 min at 120 ° C in a microwave oven. The reaction mixture was concentrated in vacuo to give 1.574 g of a crude product. The crude product was redissolved in DCM and purified by flash chromatography (100 g SNAP silica cartridge) eluting with 0-65% EtOAc: cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give methyl (R) -1- (2 - ((tert-butyldimethylsilyl) oxy) -1-phenylethyl) -3- (methylcarbamoyl) -1H-pyrazole-5-carboxylate (276 mg; 0.562 mmol; yield 48%).

LCMS (2 min formate method): retention time 1.42 min, [MH] ⁺ 418.4.

Intermediate 91: (S) -3- (methoxycarbonyl) -1- (1-phenylethyl) -1H-pyrazole-5-carboxylic acid

LiOH (0.888 g; 21.16 mmol) in water (20 ml) was added to a solution of dimethyl- (S) -1- (1-phenylethyl) -1H pyrazole-3,5-dicarboxylate (6.1 g; 21.16 mmol ) in methanol (50 ml) and 2-MeTHF (50 ml) at 0 ° C and the solution was stirred at 0 ° C for 2 h, then acidified with 2M HCl (12 ml) and evaporated in vacuo to half the original volume. The mixture was further acidified to pH 2, then extracted with EtOAc (2x50 ml) and the combined organic layers were dried and evaporated in vacuo to give a colorless gum. It was dissolved in DCM and loaded onto a 100 g silica column, then eluted with 0-50% (1% AcOH in EtOAc) / cyclohexane and the product-containing fractions were evaporated in vacuo to give (S) -3- (methoxycarbonyl) -1 - (1-phenylethyl) -1H-pyrazole-5-carboxylic acid (4.2 g; 15.31 mmol; 72% yield).

LCMS (2 min formate method): retention time 1.00 min, [MH] ⁺ 275.2.

Intermediate 92: (1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexane-6-carboxylic acid

LiOH (751 mg; 31.4 mmol) was added to a solution of (1R, 5S, 6r) -ethyl-3-oxabicyclo [3.1.0] hexane-6-car

52 038888 bauxylate (1000 mg; 6.27 mmol; commercially available from, for example, Pharmablock) in water (10 ml), THF (10 ml) and MeOH (10 ml) at room temperature. The resulting suspension was stirred for 3 h. To isolate the reaction product, the mixture was evaporated, the remaining crude solid was dissolved in a minimum amount of water and quenched with HCl (5 ml; 25% w / w) and extracted 4 times with a MeOH / DCM solvent mixture, the combined organic phases were dried over a hydrophobic frit, evaporated in vacuo to give the desired compound (1R, 5S, 6r) -3oxabicyclo [3.1.0] hexane-6-carboxylic acid (750 mg; 5.85 mmol; 93% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 12.13 (s, 1H), 3.80 (d, J = 8.6 Hz, 2H), 3.62 (d, J = 8.6 Hz, 2H), 2.002.15 (m, 2H), 1.32 (t, J = 3.1 Hz, 1H).

Intermediate 93: Benzyl- (1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-ylcarbamate

(1R, 5S, 6r) -3-Oxabicyclo [3.1.0] hexane-6-carboxylic acid (340 mg; 2.65 mmol) was dissolved in toluene (12 ml), then Et ₃ N (1.110 ml; 7, 96 mmol), diphenylphosphorazidate (0.686 ml; 3.18 mmol) and benzyl alcohol (0.552 ml; 5.31 mmol) and the mixture was heated under reflux for 2 h.The solution was diluted with EtOAc (10 ml) and washed with water (10 ml ) and NaHCO ₃ solution (10 ml), the organic layer was dried and evaporated and the residue was purified by chromatography on a column with 25 g of silica, eluting with a mixture of 0-50% EtOAc / cyclohexane, and the fractions containing the product were evaporated in vacuo to give benzyl- ( 1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-ylcarbamate (460 mg; 1.972 mmol; 74.3% yield) as a white solid.

LCMS (2 min formate method): retention time 0.83 min, [MH] ⁺ 234.3.

1H NMR (400 MHz, CDCl ₃ ) δ ppm. 7.29-7.41 (m, 5H), 5.11 (br s, 2H), 4.86 (br s, 1H), 3.98 (d, J = 8.3 Hz, 2H), 3.72 (d, J = 8.6 Hz, 2H), 2.45-2.52 (m, 1H), 1.80 (br s, 2H).

Intermediate 94: (1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexane-6-amine hydrochloride

Benzyl- (1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexane-6-ylcarbamate (460 mg; 1.972 mmol) was dissolved in EtOH (20 ml) and the reaction mixture was hydrogenated using an H-Cube flow reactor (parameters : room temperature, 1 bar (0.1 MPa), flow rate 1 ml / min) and a cartridge with 10% Pd / C CatCart 30 as catalyst. The reaction mixture was circulated through an Hcube flow reactor for 1.5 h, then acidified with HCl (7M aqueous; 1.332 mL; 9.86 mmol) and evaporated in vacuo to give an oily solid. The solid was dried in vacuo for 2 days to give the desired product (1R, 5S, 6r) -3oxabicyclo [3.1.0] hexane-6-amine hydrochloride (262 mg; 1.836 mmol; 93% yield) as an off-white solid substances.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 8.48 (br s, 3H), 3.80 (d, J = 8.8 Hz, 2H), 3.59 (d, J = 8.6 Hz, 2H), 2.24 (t, J = 2.3 Hz, 1H) , 2.07 (t, J = 2.6 Hz, 2H).

Intermediate 95: 4-methoxycyclopent-1-ene

Cyclopent-3-en-1-ol (10 g; 119 mmol; commercially available from, for example, Fluorochem) was dissolved in a mixture of DMF (100 ml) and THF (50 ml) and cooled in an ice bath under nitrogen atmosphere, then NaH (60% suspension in mineral oil; 5.71 g; 143 mmol) was added in small portions and the mixture was stirred for 30 min before adding MeI (9.66 ml; 155 mmol). The resulting suspension was stirred at 0 ° C for 2 h, then added to water (500 ml) and extracted with ether (500 ml). The organic layer was washed with water (2x200 ml) and brine (200 ml), dried and evaporated in vacuo to give the desired product as a pale yellow liquid, which was reacted without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ ppm. 5.61-5.82 (m, 2H), 4.13 (dt, J = 6.72, 3.48 Hz, 1H), 3.35 (s, 3H), 2.59 (dd, J = 15.77, 6.72 Hz, 2H ), 2.32-2.47 (m, 2H).

Intermediate 96: Ethyl 3-methoxybicyclo [3.1.0] hexane-6-carboxylate

- 53 038888

Ethyl diazoacetate (82 ml; 119 mmol) was dissolved in DCM (100 ml) and added dropwise to a mixture of 4methoxycyclopent-1-ene (for the preparation, see preparation of intermediate 95; 11.68 g; 119 mmol) and rhodium acetate dimer (II ) (2.63 g; 5.95 mmol) in DCM (100 ml) at room temperature for 4 h, then the mixture was stirred for another 2 h, then washed with water (300 ml) and the organic layer was dried and evaporated in vacuo to obtain a crude, pale green liquid. This was dissolved in cyclohexane and loaded onto a SNAP Ultra 100 g silica column and purified by flash chromatography eluting with 0-20% EtOAc / cyclohexane. The appropriate fractions were evaporated in vacuo to give ethyl 3-methoxybicyclo [3.1.0] hexane-6-carboxylate (1.4 g; 7.60 mmol; 6% yield) as a colorless oil as a mixture of isomers, also containing some residual ethyl diazoacetate. It was subjected to subsequent interactions without any additional purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 4.26 (q, J = 7.09 Hz, 2H), 3.51 (m, J = 7.50, 7.50 Hz, 1H), 3.25 (s, 3H), 2.26 (dd, J = 13.08, 6 , 97 Hz, 2H), 1.89 (td, J = 2.93, 1.22 Hz, 2H), 1.74-1.83 (m, 2H), 1.27-1.34 (m, 4H).

Intermediate 97: 3-methoxybicyclo [3.1.0] hexane-6-carboxylic acid

O - ^{0 =} \ OH

Ethyl 3-methoxybicyclo [3.1.0] hexane-6-carboxylate (for the preparation see preparation of intermediate compound 96; 1.4 g; 7.60 mmol) was dissolved in ethanol (10 ml) and 2M aqueous NaOH solution (10 ml; 20.00 mmol), then the mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was acidified with 2M HCl (aq) (11 ml), then extracted with EtOAc (2x20 ml). The combined organic layers were dried and evaporated in vacuo to give a pale yellow oil that was used directly in the next step.

1H NMR (400 MHz, CDCl ₃ ) δ ppm. 3.54 (m, J = 7.50, 7.50 Hz, 1H), 3.28 (s, 3H), 2.30 (dd, J = 13.20, 7.09 Hz, 2H), 1.99 (td, J = 2 , 93, 1.22 Hz, 2H), 1.74-1.89 (m, 2H), 1.31 (t, J = 2.93 Hz, 1H). An exchangeable proton has not been registered.

Intermediate 98: tert-butyl- (3-methoxybicyclo [3.1.0] hexan-6-yl) carbamate o - y

V / ^NH Λ °

3-Methoxybicyclo [3.1.0] hexane-6-carboxylic acid (for the preparation, see Preparation of Intermediate 97; 0.74 g; 4.74 mmol), diphenylphosphorylazide (1.956 g; 7.11 mmol) and Et ₃ N ( 1.321 ml; 9.48 mmol) was dissolved in toluene (20 ml) and the mixture was stirred for 30 min, then tert-butanol (6 ml) was added and the mixture was heated under reflux for 3 h, then left to stand at room temperature during the night. The mixture was diluted with EtOAc (50 ml), then washed with water and aqueous sodium bicarbonate solution and evaporated in vacuo. The resulting resin was dissolved in DCM and loaded onto a SNAP Ultra 25 g silica column then purified by flash chromatography eluting with 0-30% EtOAc / cyclohexane. Product containing fractions were evaporated in vacuo to give tert-butyl (3-methoxycyclo [3.1.0] hexane-6yl) carbamate (0.45 g; 1.980 mmol; 42% yield) as a colorless solid.

1H NMR (400 MHz, CDCl3) δ ppm. 4.58 (br s, 1H), 3.48 (quin, J = 7.34 Hz, 1H), 3.26 (s, 3H), 2.24 (dd, J = 12.84, 6.97 Hz, 2H), 2.16 ( br s, 1H), 1.71-1.80 (m, 2H), 1.39-1.49 (m, 11H).

Intermediate 99: 3-Methoxybicyclo [3.1.0] hexane-6-amine hydrochloride

tert-Butyl- (3-methoxybicyclo [3.1.0] hexan-6-yl) carbamate (for preparation see preparation

- 54 038888 of intermediate compound 98; 380 mg; 1.672 mmol) was dissolved in HCl (4M in dioxane; 5 ml; 20.00 mmol) and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated to give 3-methoxybicyclo [3.1.0] hexane-6-amine hydrochloride (270 mg; 1.402 mmol; 84% yield) as a light brown solid.

¹ H NMR (400 MHz, DMSC-d6) δ ppm. 8.20 (br s, 3H), 3.54 (m, J = 7.30 Hz, 1H), 3.16 (s, 3H), 2.25 (br s, 1H), 2.05-2.14 (m, 2H), 1.60- 1.70 (m, 4h).

Intermediate 100: 7,7-dimethyl-1,4-dioxaspiro [4.5] decan-8-one

Sodium hydride (60% in mineral oil; 2.79 g; 69.8 mmol) at 0 ° C under nitrogen. The resulting reaction mixture was stirred at room temperature for 1 h followed by the addition of methyl iodide (5.45 ml; 87 mmol). The reaction mixture was stirred at 10 ° C to room temperature for 1.5 hours. The reaction mixture was quenched with saturated ammonium chloride solution (50 ml) and the aqueous layer was extracted with ethyl acetate (2x80 ml). The combined organic layers were washed with brine and dried through a hydrophobic frit. The organic layer was concentrated in vacuo to give approximately 6.8 g of a crude yellow residue. This was purified by SiO ₂ chromatography (100 g Biotage SNAP Ultra cartridge, elution with 5-65% diethyl ether / cyclohexane) to give 7,7-dimethyl1,4-dioxaspiro [4.5] decan-8-one (3.07 g ; 14.16 mmol; 41% yield) as a colorless oil.

LCMS (2 min formate method): retention time 0.78 min, [MH] ⁺ 185.0.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 3.95-4.06 (m, 4H), 2.56-2.64 (m, 2H), 2.02 (d, J = 1.26 Hz, 2H), 1.871.94 (m, 2H), 1.19 (s, 6H).

Intermediate 101: 7,7-dimethyl-1,4-dioxaspiro [4.5] decan-8-ol

To a solution of 7,7-dimethyl-1,4-dioxaspiro [4.5] decan-8-one (for the preparation, see preparation of intermediate 100; 3.04 g; 16.50 mmol) in methanol (10 ml) at 0 ° C (ice bath) sodium borohydride (0.624 g; 16.50 mmol) was added in portions and the resulting reaction mixture was stirred at room temperature for 1 h. Water (10 ml) was added and the methanol was removed in vacuo. The reaction mixture was distributed between water and DCM. The organic layer was separated and the aqueous layer was further extracted with DCM (2x20 ml). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo to give 7,7-dimethyl-1,4-dioxaspiro [4.5] decan8-ol (2.87 g; 13.10 mmol; 79% yield) as a colorless oil ...

LCMS (2 min formate method): retention time 0.62 min, [MH] ⁺ 187.1.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 3.82-4.04 (m, 4H), 3.42 (ddd, J = 8.31, 4.66, 3.40 Hz, 1H), 1.53-1.90 (m, 5H), 1.40-1.50 (m, 2H), 1.03 (br s, 6H).

Intermediate 102: 4-Hydroxy-3,3-dimethylcyclohexanone

HCl ( 2M aqueous solution; 30 ml; 60.0 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was neutralized (to about pH 7) sat. aqueous NaHCO ₃ solution. The aqueous layer was extracted with ethyl acetate (2x40 ml) and the combined organic layers were dried (hydrophobic frit) and concentrated in vacuo to give 4 hydroxy-3,3-dimethylcyclohexan-1-one (2.18 g; 12.26 mmol; 80% yield) in the form of a pale yellow oil.

LCMS (2 min formate method): retention time 0.54 min, [MH] ⁺ 143.0.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 3.74 (dt, J = 6.67, 3.46 Hz, 1H), 2.37-2.67 (m, 2H), 2.22-2.36 (m, 1H),

- 55 038888

2.04-2.18 (m, 2H), 1.97 (dt, J = 13.60, 6.80 Hz, 1H), 1.02 (br s, 6H). An exchangeable proton has not been registered.

Intermediate 103: 4- (benzylamino) -2,2-dimethylcyclohexanol, diastereomeric mixture

4-Hydroxy-3,3-dimethylcyclohexan-1-one (for preparation see preparation of intermediate 102; 124 mg; 0.872 mmol) was dissolved in dichloromethane (2 ml). Phenylmethanamine (0.114 ml; 1.046 mmol) and acetic acid (0.050 ml; 0.872 mmol) were added and the reaction mixture was stirred under N ₂ at room temperature. After 3.5 h, sodium triacetoxyborohydride (222 mg; 1.046 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with sat. aqueous NaHCO ₃ solution (5 ml) and the organic layer was separated. The aqueous layer was further extracted with DCM (2x10 ml) and the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give approximately 270 mg of a crude yellow oil. This was purified by SiO ₂ chromatography (25 g Biotage SNAP cartridge, elution with 0100% (25% EtOH in ethyl acetate) / cyclohexane) to give a product mixture. Desired fractions were concentrated to give 4- (benzylamino) -2,2-dimethylcyclohexanol (63 mg; 0.27 mmol; 26% yield) as a pale yellow oil.

LCMS (2 min formate method): retention time 0.38 min, [MH] ⁺ 234.2.

Intermediate 104: (+/-) - 4-amino-2,2-dimethylcyclohexanol, diastereomeric mixture

4- (Benzylamino) -2,2-dimethylcyclohexan-1-ol (for the preparation, see preparation of intermediate 103; 63 mg; 0.270 mmol) was dissolved in ethyl acetate (6 ml), 10% palladium-carbon (40 mg) was added and the mixture was stirred under a hydrogen atmosphere at room temperature for 21 hours. The reaction mixture was filtered through celite to remove the catalyst and concentrated to give 4-amino-2,2-dimethylcyclohexan-1-ol (35 mg; 0.208 mmol; 77% yield) in the form of a colorless oil in the form of a racemic mixture of diastereomers.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 3.32 (dd, J = 11.58, 4.53 Hz, 1H), 2.78-2.92 (m, 2H), 1.25-1.93 (m, 18 H) 1.06-1.18 (m, 1H), 0.96-1.05 (m, 6H ), 0.88-0.95 (m, 6H).

Intermediate 105: Methyl 1-tosyl-1H-indole-7-carboxylate

Methyl III-indole-7-carboxylate (1000 mg; 5.71 mmol; commercially available from, for example, Apollo Scientific) was placed in DMF (18 ml) and cooled to 0 ° C under nitrogen atmosphere. Sodium hydride (60% suspension in mineral oil; 287 mg; 7.18 mmol) was added in small portions and the reaction mixture was allowed to stir for 15 min. Added tosyl-Cl (1308 mg; 6.86 mmol) and the reaction mixture was allowed to warm to room temperature and left stirring for 16 h. The reaction mixture was cooled to 0 ° C before adding additional sodium hydride (60% suspension in mineral oil; 114 mg; 2.85 mmol). The reaction mixture was stirred for 15 minutes before warming to room temperature. The reaction mixture was stirred for an additional 15 min before adding additional tosyl-Cl (552 mg; 2.90 mmol). The resulting solution was stirred for 2 h. The reaction mixture was then heated to 60 ° C for 1.5 h. The reaction mixture was quenched with water (approximately 6 ml), then partitioned between sat. aqueous LiCl (100 ml) and ethyl acetate (30 ml). The layers were separated and the aqueous layer was extracted two more times with ethyl acetate (2x30 ml). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo to give the crude product as a yellow oil. The crude product was redissolved in dichloromethane and immediately applied to the top of a 100 g silica SNAP cartridge and purified by SP4 flash column chromatography (0-25% ethyl acetate / cyclo

- 56 038888 hexane). The appropriate fractions were combined and concentrated in vacuo to give methyl 1-tosyl-1H-indole-7-carboxylate (1025 mg; 2.80 mmol; 49% yield).

LCMS (2 min high pH method): retention time 1.18 min, [MH] ⁺ 330.1.

Intermediate 106: (1-tosyl-1H-indol-7-yl) methanol

A solution of methyl 1-tosyl-1H-indole-7-carboxylate (for preparation, see preparation of intermediate compound 105; 1025 mg; 3.11 mmol) in dichloromethane (31 ml) under nitrogen atmosphere was cooled to 78 ° C and added dropwise DIBAL-H (1M solution in THF; 7.78 ml; 7.78 mmol) for 15 min and the reaction mixture was stirred at -78 ° C for 1.5 h. The reaction mixture was left stirring for 18 h before adding additional amounts of DIBAL-H (25 wt.% solution in toluene; 4.19 ml; 6.22 mmol). The reaction mixture was stirred for 20 hours. The reaction mixture was quenched with methanol until its temperature was -78 ° C and then allowed to warm to room temperature. The reaction mixture was diluted with Rochelle's salt solution (10 ml) and stirred for 64 h. The layers were separated and the aqueous phase was extracted with DCM (3x20 ml). The combined organic layers were dried through a hydrophobic frit then concentrated in vacuo to give the crude product (1-tosyl-1H-indol-7-yl) methanol (950 mg; 2.84 mmol; 91% yield) as an orange oil which was used as is for subsequent interactions.

LCMS (2 min high pH method): retention time 1.18 min, [M-OH] ⁺ 284.1.

Intermediate 107: Methyl 1-tosyl-1H-indazole-4-carboxylate

Methyl 1H-indazole-4-carboxylate (530 mg; 3.01 mmol; commercially available from, for example, Sigma Aldrich) was placed in DMF (6.4 ml) and cooled to 0 ° C under nitrogen atmosphere. Sodium hydride (60% suspension in mineral oil; 241 mg; 6.02 mmol) was added in small portions and the reaction mixture was allowed to stir for 10 min. Tosyl-Cl (775 mg; 4.07 mmol) was added before stirring for 30 min at 0 ° C. The reaction mixture was left to warm to room temperature and left to stir for 1 hour. The reaction mixture was poured into 250 ml of water before filtration. The precipitate was dried in a vacuum oven overnight to give methyl 1-tosyl-1Nindazole-4-carboxylate (719 mg; 1.959 mmol; 65% yield).

LCMS (2 min high pH method): retention time 1.22 min, [MH] ⁺ 331.1.

Intermediate 108: (1-tosyl-1H-indazol-4-yl) methanol

A solution of methyl 1-tosyl-1H-indazole-4-carboxylate (for preparation see preparation of intermediate compound 107; 804 mg; 2.434 mmol) in dichloromethane (24 ml) under nitrogen atmosphere was cooled to -78 ° C and DIBAL was added dropwise -H (1.637 ml; 2.434 mmol; 25 wt% in toluene) for 15 min and the reaction mixture was stirred at -78 ° C for 62 h. Additional DIBAL-H (3.27 ml; 4.87 mmol ; 25 wt% in toluene) into the reaction mixture at -78 ° C before stirring for 1 hour. The reaction mixture was quenched with methanol until its temperature was -78 ° C and then allowed to warm to room temperature. The reaction mixture was diluted with Rochelle's solution

- 57 038888 salts (10 ml) and stirred for 16 h. The layers were separated and the aqueous phase was extracted with DCM (3x20 ml). The combined organic layers were dried through a hydrophobic frit, then evaporated in vacuo to give (1-tosyl-1H-indazol-4-yl) methanol (686 mg; 2.042 mmol; 84% yield).

LCMS (2 min high pH method): retention time 1.00 min, [MH] ⁺ 303.1.

Intermediate 109: (+/-) - 1- (3-fluoro-2-methylphenyl) ethanol

1- (3-Fluoro-2-methylphenyl) ethan-1-one (1000 mg; 6.57 mmol; commercially available from, for example, Alfa Aesar) was placed in THF (10 ml) and ethanol (10 ml), cooled to 0 ° C and placed under a nitrogen atmosphere. Sodium borohydride (456 mg; 12.05 mmol) was added and the reaction mixture was allowed to stir at room temperature for 1.5 h. The reaction mixture was slowly quenched with 1M HCl to pH 3 before adding water. The layers were separated and the aqueous layer was extracted two more times with DCM (2x20 ml). The organic layers were back-extracted with aqueous sodium bicarbonate solution, passed through a hydrophobic frit and concentrated in vacuo to give a colorless oil as the crude product 1- (3-fluoro-2-methylphenyl) ethan-1-ol (875 mg; 5.11 mmol; yield 78%).

LCMS (2 min formate method): retention time 0.85 min, [MH] ⁺ absent.

Intermediate 110: Ethyl 3- (benzyloxy) bicyclo [3.1.0] hexane-6-carboxylate, mixture of diastereomers

Ethyl diazoacetate (15 ml; 21.69 mmol) was dissolved in DCM (100 ml) and added dropwise to a mixture of ((cyclopent-3-en-1-yloxy) methyl) benzene (3.1 g; 17.79 mmol; available commercially available from, for example, Fluorochem) and rhodium (P) acetate dimer (0.393 g; 0.890 mmol) in DCM (100 ml) at room temperature for 4 hours, then the mixture was stirred for another 2 hours, then washed with water ( 300 ml) and the organic layer was dried and evaporated in vacuo to give a pale green liquid. It was purified using silica gel column chromatography eluting with a 0-20% EtOAc / cyclohexane gradient to give (+/-) - ethyl 3- (benzyloxy) bicyclo [3.1.0] hexane-6-carboxylate (0.91 g ; 3.50 mmol; yield 20%) as a colorless liquid.

LCMS (2 min high pH method): retention time 1.26 min, [MH] ⁺ 261.3.

Intermediate 111: 3- (benzyloxy) bicyclo [3.1.0] hexane-6-carboxylic acid, mixture of diastereomers (+/-) - Ethyl 3- (benzyloxy) bicyclo [3.1.0] hexane-6-carboxylate (relative preparation see preparation of intermediate compound 110; 0.9 g; 3.46 mmol) was dissolved in EtOH (20 ml) and NaOH (5 ml; 10.00 mmol; 2M aqueous) was added, then the mixture was stirred at room temperature overnight ... The solvent was evaporated in vacuo to approximately half the original volume, then acidified with 2M HCl (aq) to pH 4 and extracted with EtOAc (50 ml). The organic layer was dried and evaporated in vacuo to give (+/-) - 3- (benzyloxy) bicyclo [3.1.0] hexane-6-carboxylic acid (0.74 g; 3.19 mmol; 92% yield) as a colorless solids and mixtures of diastereomers.

LCMS (2 min high pH method): retention time 0.56 min, [MH] ⁺ 233.3.

Intermediate 112: tert-butyl- (3- (betyloxy) -bicyclo [3.1.0] hexan-6-yl) carbamate, mixture of diastereomers

3- (Benzyloxy) bicyclo [3.1.0] hexane-6-carboxylic acid (for the preparation see Preparation of Intermediate 111; 0.74 g; 3.19 mmol), diphenylphosphoryl azide (1.140 g; 4.14 mmol) and Et ₃ N (0.888 ml; 6.37 mmol) was dissolved in toluene (20 ml) and the mixture was stirred for 30 min, then tert-butanol (6 ml) was added and the mixture was heated under reflux for 3 h, then left to stand at room temperature overnight. The mixture was diluted with EtOAc then washed

- 58 038888 with water and sat. NaHCO ₃ (aq.) And evaporated in vacuo. The resulting resin was purified using silica gel column chromatography eluting with a 0-30% EtOAc: cyclohexane gradient to give tert-butyl - ((1R, 3r, 5S, 6s) -3- (benzyloxy) bicyclo [3.1.0] hexane- 6-ul) carbamate (0.35 g; 1.154 mmol; yield 36.2%) as a colorless solid and a mixture of diastereomers.

LCMS (2 min high pH method): retention time 1.26 min, [MH] ⁺ 304.3.

Intermediate 113: 3- (benzyloxy) bicyclo [3.1.0] hexane-6-amine, HCl, mixture of diastereomers n

tert-Butyl- (3- (benzyloxy) bicyclo [3.1.0] hexan-6-yl) carbamate (for preparation see preparation of intermediate 112; 350 mg; 1.154 mmol) was dissolved in HCl (4M in dioxane; 5 ml; 20.00 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated to give 3- (benzyloxy) bicyclo [3.1.0] hexane-6-amine hydrochloride (253 mg; 0.897 mmol; 78% yield) as a pale yellow solid and a mixture of diastereomers.

LCMS (2 min high pH method): retention time 0.90 min, [MH] ⁺ 204.2.

Intermediate 114: (+/-) - 7-methyl-1,4-dioxaspiro [4.5] decan-8-one o

about

To a solution of 1,4-dioxaspiro [4.5] decan-8-one (1.04 g; 6.66 mmol; commercially available from suppliers such as Apollo Scientific) in THF (67 ml) under N2 at -78 ° C was added 1M LiHMDS in THF (7.32 ml; 7.32 mmol). The reaction mixture was stirred for 1 h and MeI (0.547 ml; 8.66 mmol) was added dropwise. The reaction mixture was stirred for 3 h at -78 ° C and then allowed to warm to room temperature overnight. Then they quenched sat. NH ₄ Cl solution (aq.) and extracted with EtOAc. The combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo to a brown oil. This oil was purified by column chromatography on silica gel eluting with a gradient of 0 to 32% EtOAc: cyclohexane to give (+/-) - 7-methyl-1,4-dioxaspiro [4.5] decan-8-one (443 mg; 2.60 mmol; yield 39%) as a white solid.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ ppm. 3.95-4.16 (m, 4H), 2.58-2.88 (m, 2H), 2.24-2.41 (m, 1H), 2.04-2.17 (m, 2H), 1.90-2.01 (m, 1H), 1.71 (t, J = 13.1 Hz, 1H), 0.94-1.07 (m, 3H).

Intermediate 115: (+/-) - (trans) -7-methyl-1,4-dioxaspiro [4.5] decan-8-ol one

2M a solution of LiAlH ₄ in THF (1.67 ml; 3.35 mmol). The mixture was stirred for 1.5 h at -78 ° C. Then it was left to warm to 0 ° C, the reaction mixture was carefully quenched with a Rochelle salt solution. EtOAc was added and the layers were separated, the aqueous layer was extracted with EtOAc and the combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo to give (+/-) - (trans) -7-methyl-1,4-dioxaspiro [4.5] decan-8-ol ( 430 mg; 2.397 mmol; 93% yield) as a colorless oil.

1H NMR (600 MHz, DMSO-d6) δ 4.43 (d, J = 5.5 Hz, 1H), 3.88-3.75 (m, 4H), 2.96 (ddt, J = 4.8, 5.7, 10, 1 Hz, 1H), 1.75-1.68 (m, 1H), 1.64-1.60 (m, 1H), 1.63-1.59 (m, 1H), 1.51-1.44 (m, 1H), 1.48-1.41 (m, 1H) , 1.431.35 (m, 1H), 1.19 (t, J = 12.9 Hz, 1H), 0.89 (d, J = 6.6 Hz, 3H).

Intermediate 116: (+/-) - (trans) -4-hydroxy-3-methylcyclohexanone

To a solution of (+/-) - (trans) -7-methyl-1,4-dioxaspiro [4.5] decan-8-ol (for preparation, see Preparation of Intermediate 115; 425 mg; 2.468 mmol) in acetone (7 ml ) H2SO4 (18 ml; 9.00 mmol; 0.5 M) was added and the solution was stirred for 20 h at room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were filtered through

59 038888 hydrophobic frit and concentrated in vacuo to give (+/-) - (trans) -4-hydroxy-3methylcyclohexan-1-one (290 mg; 2.265 mmol; 92% yield) as a yellow oil.

1H NMR (400 MHz, MeOH-d4) δ ppm. 3.93 (d, J = 2.3 Hz, 1H), 3.10 (td, J = 10.2, 4.4 Hz, 1H), 1.90-2.13 (m, 2H), 1.73-1.86 (m, 1H), 1.25-1.59 (m, 2H), 1.09 (t, J = 13.1 Hz, 1H), 0.97-1.03 (m, 3H). An exchangeable proton has not been registered.

Intermediate 117: (S) -N - ((1S, 3R, 4R) -4-hydroxy-3-methylcyclohexyl) -2-methylpropane-2-sulfinamide and (S) -N - ((1S, 3S, 4S) -4-hydroxy-3-methylcyclohexyl) -2-methylpropane-2-sulfinamide (diastereomeric mixture 1: 1)

(+/-) - (trans) -4-Hydroxy-3-methylcyclohexan-1-one (for the preparation, see Preparation of Intermediate 116; 1.99 g; 15.53 mmol) was added to the solution (R) -2- methylpropane-2-sulfinamide (2.304 g; 18.63 mmol) and tetraethoxytitanium (5.43 ml; 25.9 mmol) in THF (30 ml) and the reaction mixture was stirred at 60 ° C for 1.5 h and then at 70 ° C for 1.5 hours. The mixture was cooled to room temperature and then to -78 ° C. A 1M solution of L-selectride in THF (38.8 ml; 38.8 mmol) was added dropwise and the reaction mixture was allowed to slowly warm to room temperature with stirring overnight. The reaction mixture was then cooled to 0 ° C and MeOH was added dropwise. The crude reaction mixture was poured into brine. The resulting slurry was filtered through celite pad and the filter cake washed with EtOAc. The filtrate was then concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo to a yellow oil. This oil was purified using silica gel column chromatography eluting with a gradient of 10 to 42% mixture (25% EtOH in AcOEt): cyclohexane to give (S) -N - ((1S, 3R, 4R) -4-hydroxy-3 -methylcyclohexyl) -2-methylpropane-2sulfinamide and (S) -N - ((1S, 3S, 4S) -4-hydroxy-3-methylcyclohexyl) -2-methylpropane-2-sulfinamide (diastereomeric mixture 1: 1) (303 , 5 mg; 1.301 mmol; yield 8%) as a yellow gum, which was used directly in the next reaction.

Intermediate 118: (1R, 2R, 4S) -4-amino-2-methylcyclohexanol and (1S, 2S, 4S) -4-amino2-methylcyclohexanol (diastereomeric mixture, 1: 1)

4M HCl in dioxane (1 ml; 4.00 mmol) was added to a solution of (S) -N - ((1S, 3R, 4R) -4-hydroxy-3methylcyclohexyl) -2-methylpropane-2-sulfinamide and (S) - N - ((1S, 3S, 4S) -4-hydroxy-3-methylcyclohexyl) -2-methylpropane-2-sulfinamide (1: 1 diastereomeric mixture; for preparation see Preparation of Intermediate 117) (300 mg; 1.286 mmol) in DCM (5 ml) and the reaction mixture was stirred overnight at room temperature. An additional amount of 4M HCl in dioxane (1 ml; 4.00 mmol) was added and the reaction mixture was stirred for 6 h at room temperature. An additional amount of 4M HCl in dioxane (1 ml; 4.00 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo, dissolved in MeOH and passed through a 2 g SCX column (pretreated with MeOH), washing with MeOH and 2M NH3 in MeOH solution. The ammonium fractions were concentrated in vacuo to give (1R, 2R, 4S) -4-amino-2-methylcyclohexanol and (1S, 2S, 4S) -4-amino-2-methylcyclohexanol (1: 1 diastereomeric mixture) (74.5 mg ; 0.577 mmol; 45% yield) as a brown gum.

¹ H NMR (400 MHz, DMSO-d6) δ ppm. 4.17-4.51 (m, 2H), 2.91-3.03 (m, 2H), 2.86 (td, J = 10.2, 4.3 Hz, 2H), 1.61-1.82 (m, 4H), 1.35-1.58 (m , 4H), 1.09-1.28 (m, 4H), 0.95-1.07 (m, 2H), 0.90 (dd, J = 9.4, 6.7 Hz, 6H), 0.610.84 (m, 2H).

Intermediate 119: (R) -1- (3-fluoro-4-methylphenyl) ethanol

(+) - DIP-Cl (B-chlordiisopinocampheylborane) (1.265 g; 3.94 mmol) was placed in THF (20 ml) and cooled to -25 ° C under N2. Added 1- (3-fluoro-4-methylphenyl) ethan-1-one (0.5 g; 3.29 mmol; commercially available from suppliers such as Alfa Aesar) in THF (10 ml) and the reaction mixture was left stirring overnight to warm from -25 ° C to room temperature. Reaction mixture

60 038888 was cooled to -35 ° C and additional (+) - DIP-Cl (1.265 g; 3.94 mmol) in THF (5 ml) was added. The reaction mixture was maintained at -35 to -25 ° C with stirring for 6 hours and then allowed to warm to room temperature overnight. The reaction mixture was quenched with acetaldehyde (0.5 ml; 8.85 mmol) and concentrated in vacuo. The residue was taken up in Et ₂ O (20 ml) and diethanolamine (1.036 g; 9.86 mmol) was added and left stirring for 2 h. The white precipitate was filtered through celite and the filtrate was concentrated in vacuo to give a colorless oil. This oil was purified using silica gel column chromatography eluting with a 0-25% EtOAc: cyclohexane gradient to give (R) -1- (3-fluoro-4-methylphenyl) ethan-1-ol (836 mg; 2.71 mmol ; yield 83%) as a colorless liquid.

LCMS (2 min formate method): retention time 0.89 min, [MH] ⁺ absent.

Intermediate 120: (+/-) - 7-chlorobicyclo [3.2.0] hept-2-en-6-one

Zinc (8.42 g; 129 mmol) was added in small portions over 1 h to a solution of (+/-) - 7,7-dichlorobicyclo [3.2.0] hept-2-en-6-one (24 g; 136 mmol ; commercially available from commercial suppliers such as Alfa Aesar) in AcOH (100 ml) at room temperature. The mixture was stirred for an additional 1 hour, then diluted with water and extracted with diethyl ether. The organic layer was washed with water and sat. sodium bicarbonate solution and brine, then dried and evaporated in vacuo to give (+/-) - 7-chlorobicyclo [3.2.0] hept-2-en-6-one (20 g; 140 mmol; 70% purity) as pale yellow liquid.

Ή NMR (400 MHz, CDCl3) δ ppm 5.89-5.97 (m, 1H), 5.70-5.79 (m, 1H), 5.03-5.14 (m, 1H), 3.78-3.97 (m, 2H), 2.66-2.80 (m, 1H), 2.41-2.55 (m , 1H).

Intermediate 121: (+/-) - bicyclo [3.1.0] hex-2-ene-6-carboxylic acid, diastereomeric mixture

To a stirred mixture of KOH (2.16 g; 38.5 mmol) in 1,4-dioxane (24 ml) and water (10 ml) was added (+/-) - 7-chlorobicyclo [3.2.0] hept- 2-en-6-one (for the preparation, see Preparation of Intermediate 120; 1.307 g; 5.50 mmol). The chlorine-SM in the flask was then washed into the reaction vessel with additional 1,4-dioxane (300 μl). The reaction mixture was stirred for 30 minutes. The reaction mixture was acidified with 2M HCl (aq) to a pH of about 2. The organic layers were extracted with DCM (3x40 ml) and the combined organic layers were left to stand overnight. After 16 h, the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a brown oil. It was further dried under vacuum to give the desired product as a brown waxy solid (+/-) bicyclo [3.1.0] hex-2-ene-6-carboxylic acid (581 mg; 4.68 mmol; 85% yield), which was a mixture of about 40% -endo / about 60% -exo-6-carboxylic acid (required).

LCMS (2 min formate method): (exo) retention time 0.65 min, m / z absent; (endo) retention time is 0.54 min, m / z is absent.

Intermediate 122: (+/-) - benzyl- (cis) -bicyclo [3.1.0] hex-2-en-6-ylcarbamate ° ⁿ

DPPA (26.0 ml; 121 mmol) was added to a solution of (+/-) - bicyclo [3.1.0] hex-2-en-6-carboxylic acid, a mixture of diastereomers, (for preparation, see preparation of intermediate 121; 10 g; 81 mmol) and Et ₃ N (22.46 ml; 161 mmol) in toluene (10 ml) at room temperature and the mixture was stirred for 30 min, then benzyl alcohol (16.75 ml; 161 mmol) was added and the mixture heated under reflux for 3 h. The solution was diluted with EtOAc and washed with water and sat. sodium bicarbonate solution (aq), then dried and evaporated in vacuo to give a brown oil. This oil was purified using silica gel column chromatography eluting with a 0-50% EtOAc: cyclohexane gradient to give (+/-) - benzyl ((cis) bicyclo [3.1.0] hex-2-en-6-yl) carbamate (3.7 g; 16.14 mmol; 20.03% yield) as a colorless solid.

LCMS (2 min formate method): retention time 1.08 min, [MH] ⁺ 230.3.

Intermediate 123: (+/-) - benzyl ((cis) -2-hydroxybicyclo [3.1.0] hexan-6-yl) carbamate

- 61 038888

C o ⁿ it 2-

Borane-methyl sulfide complex (2.299 ml; 24.21 mmol) was added to a solution of (+/-) benzyl ((cis) bicyclo [3.1.0] hex-2-en-6-yl) carbamate (for preparation see preparation of intermediate compounds 122; 3.7 g; 16.14 mmol) in THF (10 ml) at 0 ° C and the mixture was stirred for 2 h, then allowed to warm to room temperature over 30 min. Added water (2 ml) followed by the addition of an aqueous solution of 2M NaOH (16.14 ml; 32.3 mmol). The mixture was cooled in an ice bath, then H ₂ O ₂ (30%; 3.30 ml; 32.3 mmol) was added and the mixture was stirred for an additional 1 h. The mixture was diluted with EtOAc and water and the mixture was vigorously stirred for 30 min, then the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with 5% sodium thiosulfate solution (aq), then dried and evaporated in vacuo to give a gum. This gum was triturated with ether and the resulting colorless solid was collected by filtration. The filtrate was evaporated in vacuo to give a colorless gum which was purified by column chromatography on silica gel eluting with a 0-50% EtOAc: cyclohexane gradient. Slow moving fractions gave a colorless gum (0.53 g) which partially solidified on standing. This material was dissolved in EtOAc and left to stand overnight to give a colorless solid, which was collected by filtration. The filtrate was evaporated in vacuo to give a colorless gum. This resin was purified using silica gel column chromatography eluting with a gradient of 0-50% EtOAc: cyclohexane to give (+/-) - benzyl ((cis) -2-hydroxybicyclo [3.1.0] hexan-6-yl) carbamate ( 180 mg; 0.728 mmol; 5% yield) as a colorless gum.

¹ H NMR (600 MHz, DMSO-d6) δ ppm. 7.19-7.44 (m, 6H), 4.96-5.04 (m, 2H), 4.53 (d, J = 1.0 Hz, 1H), 4.07 (t, J = 4.6 Hz, 1H), 2.09 (br. s, 1H), 1.83 (m, J = 1.0, 1.0 Hz, 1H), 1.62 (dd, J = 12.1, 8.4 Hz, 1H), 1.32-1.40 (m, 3H), 1.09-1.23 (m, 1H).

Intermediate 124: (+/-) - (cis) -6-aminocyclo [3.1.0] hexan-2-ol

H ₂ N - <J ^>

ⁿ OH (+/-) - Benzyl - ((cis) -2-hydroxybicyclo [3.1.0] hexan-6-yl) carbamate (for preparation see preparation of intermediate 123; 180 mg; 0.728 mmol) was dissolved in EtOH ( 10 ml) and 10% Pd / C (35 mg; 0.329 mmol) was added. The reaction mixture was hydrogenated at atmospheric pressure for 6.5 h. The catalyst was filtered off and the reaction mixture was concentrated to give (+/-) - (cis) -6-aminobicyclo [3.1.0] hexan-2-ol (82 mg; 0.728 mmol ; 80% purity) as a pale yellow oil which was used crude in the next step.

Intermediate 125: (+/-) - (trans) -3-methoxycyclopentanamine hydrochloride \ p

Wed HCI nh ₂ (+/-) - tert-Butyl ((trans) -3-methoxycyclopentyl) carbamate (for the preparation, see preparation of intermediate 126; 280 mg; 1.040 mmol) was placed in a solution of 4M hydrochloric acid in dioxane (2 , 5 ml; 10.00 mmol) and stirred for 2 h.The reaction mixture was concentrated in vacuo to give (+/-) - (trans) -3-methoxycyclopentan-1-amine hydrochloride (167 mg; 0.991 mmol; yield 95 %).

1H NMR (400 MHz, DMSO-d6) δ ppm. 8.05 (br s, 3H), 3.85- 3.89 (m, 1H), 3.50-3.57 (m, 1H), 3.17 (s, 3H), 1.89-2.04 (m, 3H), 1.70-1.77 (m, 1H ), 1.55-1.65 (m, 2H).

Intermediate 126: (+/-) - tert-butyl ((trans) -3-methoxycyclopentyl) carbamate

The crushed molecular sieves A were placed under vacuum in a 250 ml round bottom flask and heated with a hair dryer. The flask was allowed to cool and (+/-) - tert-butyl ((trans) -3-hydroxycyclopentyl) carbamate (370 mg; 1.838 mmol; commercially available from, for example, Fluorochem) in anhydrous dichloromethane (13 ml) was added. Added N, N, N8, N8-tetramethylnaphthalene-1,8-diamine (1.357 g; 6.33 mmol)

- 62 038888 and the reaction mixture was cooled to 0 ° C and placed under a nitrogen atmosphere. Added trimethyloxonium tetrafluoroborate (680 mg; 4.60 mmol) and the reaction mixture was allowed to warm to room temperature and stirred rapidly for 20 h. The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). The aqueous layer was extracted with dichloromethane (2x25 ml) and the combined organic layers were washed with 0.5M aqueous HCl (15 ml), saturated sodium bicarbonate solution (20 ml) and brine (30 ml). The organic phase was passed through a hydrophobic frit and concentrated in vacuo to give a yellow oil. The crude product was redissolved in dichloromethane and immediately loaded onto the top of a 25 g silica SNAP cartridge and purified by SP4 flash column chromatography eluting with a gradient of 0-100% ethyl acetate in cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give (+/-) - tert-butyl ((trans) -3-methoxycyclopentyl) carbamate (280 mg; 1.040 mmol; 57% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 6.80 (br d, 1H), 3.84 (q, 1H), 3.75-3.80 (m, 1H), 3.14 (s, 3H), 1.80-1.90 (m, 3H), 1.46-1.56 (m, 2H), 1.38 (s, 9H), 1.29-1.36 (m, 1H).

Intermediate 127: 1- (3- (2-hydroxyethoxy) phenyl) ethanone

3-Hydroxyacetophenone (5.0 g; 36.7 mmol; commercially available from, for example, Sigma Aldrich), ethylene carbonate (4.85 g; 55.1 mmol) and potassium carbonate (5.08 g; 36.7 mmol) was mixed in DMF (50 ml) and heated at 120 ° C overnight under nitrogen atmosphere, then the mixture was diluted with water (200 ml) and extracted with EtOAc (2x100 ml). The combined organic layers were washed with water (200 ml) and brine (200 ml), dried and evaporated in vacuo to give a pale yellow oil. This was dissolved in DCM and loaded onto a 100 g SNAP Ultra column and eluted with 0-100% EtOAc / cyclohexane. Product containing fractions were evaporated in vacuo to give 1- (3- (2-hydroxyethoxy) phenyl) ethan1-one (5.5 g; 30.5 mmol; 83% yield), which was used directly in the next step.

LCMS (2 min high pH method): retention time 0.67 min, [M-H] is 179.1.

Intermediate 128: 1- (3- (2 - ((tert-butyldimethylsilyl) -oxy) ethoxy) phenyl) ethanone

TBDMS-Cl (4.97 g; 33.0 mmol) was added to a mixture of 1- (3- (2-hydroxyethoxy) phenyl) ethan-1-one (for the preparation, see preparation of intermediate 127; 5.4 g; 30 , 0 mmol) and imidazole (2.45 g; 36.0 mmol) in DCM (50 ml) and the mixture was stirred for 2 h, then left to stand over the weekend. The resulting suspension was washed with water (2x100 ml) and the organic layer was dried and evaporated in vacuo to give a colorless oil. This was loaded onto a SNAP Ultra 100 g silica column and purified by flash chromatography eluting with 0-30% EtOAc / cyclohexane. Product containing fractions were evaporated in vacuo to give 1- (3- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) ethan-1-one (6.6 g; 22.41 mmol; 75% yield) as a colorless liquid , which was used directly in the next step.

LCMS (2 min formate method): retention time 1.46 min, [MH] ⁺ 295.3.

Intermediate 129: (+/-) - 1- (3- (2 - ((tert-butyldimethylsilyl) -oxy) ethoxy) phenyl) ethanol

Sodium borohydride (1.27 g; 33.6 mmol) was added to a solution of 1- (3- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) ethan-1-one (for preparation, see preparation of intermediate 128 ; 6.6 g; 22.41 mmol) in ethanol (50 ml) at 0 ° C and the mixture was stirred for 2 h, then quenched by very careful addition of ammonium chloride solution (50 ml; at first slowly and dropwise - violent gas formation ). The resulting mixture was diluted with brine (50 ml) and extracted with EtOAc (2x100 ml), the combined organic layers were dried and evaporated in vacuo to give 1- (3- (2 ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) ethan-1-ol (5.61 g; 18.92 mmol; 84% yield) as a colorless oil which was used directly in the next step.

LCMS (2 min high pH method): retention time 1.41 min, [MH] ⁺ 296.3.

Intermediate 130: (+/-) - methyl-1- (1- (3- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) ethyl) -3- (methylcarbamoyl) -1H-pyrazole-5- carboxylate

- 63 038888

DIAD (1.38 ml; 7.10 mmol) in DCM (10 ml) was added dropwise over 5 min to a solution of methyl 3 (methylcarbamoyl) -1H-pyrazole-5-carboxylate (for preparation, see preparation of intermediate 1 ; 1 g; 5.46 mmol), 1- (3- (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) ethan-1-ol (for the preparation, see the preparation of intermediate 129; 1.942 g; 6, 55 mmol) and triphenylphosphine (1.862 g; 7.10 mmol) in DCM (20 ml) at 0 ° C and the mixture was stirred overnight allowing it to warm to room temperature. The solution was washed with water (20 ml), dried and evaporated in vacuo to give a pale yellow gum. It was dissolved in DCM and loaded onto a SNAP Ultra column with 100 g silica, then eluted with 0-60% EtOAc / cyclohexane and the product-containing fractions were evaporated in vacuo to give (+/-) - methyl-1- (1- (3 - (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) ethyl) -3- (methylcarbamoyl) -1H-pyrazole-5-carboxylate (2.61 g; 5.65 mmol; 104% yield) as pale -yellow resin, which was a mixture of diastereomers, approximately 4: 1 (with additional pyrazole alkylation product as a minor component).

LCMS (2 min formate method): retention time 1.43 min, [MH] ⁺ 462.3.

Intermediate 131: (+/-) - 1- (1- (3- (2 - ((- butyldimethylsilyl) -oxy) ethoxy) phenyl) ethyl) -3 (methylcarbamoyl) -1H-pyrazole-5-carboxylic acid

(+/-) - Methyl 1- (1- (3 - (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) ethyl) -3 - (methylcarbamoyl) -1Hpyrazole-5-carboxylate preparation of intermediate 130; 2.6 g; 5.63 mmol) was dissolved in methanol (30 ml) and NaOH (10 ml; 20.00 mmol; 2M in water) was added, then the mixture was stirred at room temperature for 2 h. The solvent was then evaporated in vacuo. The resulting solid was dissolved in water (30 ml) and washed with ether (2x30 ml), then the aqueous layer was acidified with 2M HCl (aq.) (11 ml) and the resulting mixture was extracted with EtOAc (2x30 ml). The combined organic layers were washed with water, dried and evaporated in vacuo to give (+/-) - 1- (1- (3 - (2 - ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) ethyl) -3 - (methylcarbamoyl) -1H-pyrazole-5carboxylic acid (2.22 g; 4.96 mmol; 88% yield) as a colorless gum, as regioisomers in a ratio of approximately 4: 1 (with additional pyrazole alkylation product as a minor component from the previous step) which turned out to be inseparable at this stage.

LCMS (2 min high pH method): retention time 0.99 min, [MH] ⁺ 448.4.

Intermediate 132: 1- (1- (3- (2 - ((tert-butyldimethylsilyl) -oxy) ethoxy) phenyl) ethyl) N ³ -methyl-N ⁵ - ((1S, 2S) -2-methylcyclopropyl) - 1H-pyrazole-3,5-dicarboxamide, mixture of diastereomers

(+/-) - 1- (1- (3- (2 - ((tert-Butyldimethylsilyl) oxy) ethoxy) phenyl) ethyl) -3- (methylcarbamoyl) -1H-pyrazole-5-carboxylic acid (for obtaining see preparation of intermediate 131; 2 g; 4.47 mmol), (1S, 2S) -2-methylcyclopropan-1-amine hydrochloride (0.625 g; 5.81 mmol), HATU (2.209 g; 5.81 mmol) and Et ₃ N (1.868 ml; 13.40 mmol) was dissolved in DCM (20 ml) and the mixture was stirred for 2 h, then left to stand over the weekend at room temperature. The resulting mixture was stirred with water (50 ml) for 1 h, then the organic layer was separated, dried and evaporated in vacuo to give a pale yellow gum. It was dissolved in DCM and loaded onto a SNAP Ultra 100 g silica column and purified by flash chromatography eluting with 0-100% EtOAc / cyclohexane. Product containing fractions were evaporated in vacuo to give 1- (1- (3- (2 ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) ethyl) -N ³ -methyl-N ⁵ - ((1S, 2S) -methylcyclopropyl) -1H-pyrazole-3,5-dicarboxamide (1.10 g; 2.197 mmol; 49% yield; mixture of diastereomers) as colorless

- 64 038888 solids.

LCMS (2 min formate method): retention time 1.44 min, [MH] ⁺ 501.4.

Examples of

Example 1. N ⁵ - ((1R, 5 S, 6r) -3-Oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl- 1 - ((S) -1-phenylethyl) -1 Hpyrazole -3,5-dicarboxamide

HATU (205 mg; 0.538 mmol) followed by the addition of (1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexane-6-amine hydrochloride (107 mg; 0.789 mmol) and DIPEA (0.313 ml; 1.793 mmol). The resulting reaction mixture was stirred at room temperature in air for 18 hours. The reaction mixture was purified by MDAP (formate method). The fractions containing the desired product were distributed between sat. NaHCO ₃ solution and DCM. The organic layer was separated and the aqueous layer was further extracted with DCM (2x20 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give N ⁵ - ((1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1- ((S) -1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (25 mg; 0.063 mmol; 18% yield) as a white solid.

1H NMR (400 MHz, MeOH-d ₄ ) δ ppm. 7.20-7.32 (m, 5H), 7.09 (s, 1H), 6.59 (d, J = 7.1 Hz, 1H), 3.99 (dd, J = 8.3, 2.7 Hz, 2H), 3.72 ( dt, J = 8.2, 3.5 Hz, 2H), 2.93 (s, 3H), 2.53 (t, J = 2.4 Hz, 1H), 1.92 (d, J = 7.1 Hz, 3H) , 1.85-1.90 (m, 1H), 1.77-1.82 (m, 1H). 2 exchangeable protons have not been registered.

LCMS (2 min formate method): retention time 0.85 min, [MH] ⁺ 355.3.

The crude product remaining after the first injection of MDAP was also purified by MDAP (formate method) and the fractions containing the desired product were partitioned between sat. NaHCO ₃ solution and DCM. The organic layer was separated and the aqueous layer was further extracted with DCM (2x20 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a second crop of N ⁵ - ((1R, 5 S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl - 1 - ((S) -1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (30 mg; 0.076 mmol; 21% yield) as a white solid.

LCMS (2 min formate method): retention time 0.85 min, [MH] ⁺ 355.3.

Example 2. N ⁵ - ((1r, 4S) -4-Hydroxycyclohexyl) -N ³ -methyl-1 - ((S) -1-phenylethyl) -1H-purazole-3,5 dicarboxamide

To a solution of (S) -3- (methylcarbamoyl) -1- (1-phenylethyl) -1H-pyrazole-5-carboxylic acid (451 mg; 1.650 mmol) in DMF (5 ml) was added HATU (941 mg; 2.475 mmol) followed by the addition of (1r, 4r) 4-aminocyclohexanol (trans) (380 mg; 3.30 mmol) and DIPEA (1.441 ml; 8.25 mmol). The resulting reaction mixture was stirred at room temperature in air for 40 min. The reaction mixture was concentrated in vacuo to remove DMF and partitioned between ethyl acetate and saturated aq. LiCl solution. The organic layer was separated, washed with brine, dried (hydrophobic frit) and concentrated to give approximately 1.5 g of the crude product as an orange oil (containing DMF). This was purified by SiO ₂ chromatography (25 g Biotage SNAP cartridge, elution with 20-100% ethyl acetate / cyclohexane followed by elution with 100% ethyl acetate to 12% ethanol / ethyl acetate) to give 447 mg of a colorless oil. It was further purified by MDAP (formate method). The fractions containing the desired product were distributed between sat. NaHCO ₃ solution and DCM. The organic layer was separated and the aqueous layer was further extracted with DCM (2x20 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give N ⁵ - ((1r, 4S) -4-hydroxycyclohexyl) -N ³ -methyl-1 - ((S) -1phenylethyl) -1H-pyrazole- 3,5-dicarboxamide (163 mg; 0.396 mmol; 24% yield) as a white solid.

1H NMR (600 MHz, DMSO-de) δ ppm. 1.16-1.25 (m, 2H), 1.25-1.36 (m, 2H), 1.67-1.80 (m, 2H), 1.78-1.86 (m, 2H), 1.83 (d, J = 6.0 Hz, 3H), 2.77 (d, J = 4.8 Hz, 3H), 3.31-3.39 (m, 1H), 3.57-3.66 (m, 1H), 4.52 (d, J = 4.5 Hz, 1H), 6.67 (q, J = 7.0 Hz, 1H), 7.22-7.25 (m, 1H), 7.23-7.24 (m, 1H), 7.24-7.27 (m, 2H), 7.28-7.31 (m, 2H), 8.11

- 65 038888 (q, J = 4.5 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H).

LCMS (2 min formate method): retention time 0.82 min, [MH] ⁺ 371.3.

Example 3. N ⁵ - ((1R, 3R, 5S, 6r) -3-Hydroxycyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1 - ((S) -1-phenylethyl) 1H- pyrazole-3,5-dicarboxamide

Crude tert-butyl- (3-hydroxybicyclo [3.1.0] hexan-6-yl) carbamate (37 mg; 0.173 mmol) was dissolved in DCM (10 ml) and TFA (1 ml) was added, then the mixture was stirred for 2 h at room temperature. The solvent was evaporated in vacuo to give a pale yellow gum. The crude residue was dissolved in DCM (5 ml), then HATU (86 mg; 0.226 mmol), Et ₃ N (0.048 ml; 0.347 mmol) and (S) -3- (methylcarbamoyl) -1- (1-phenylethyl) - 1H-pyrazole-5-carboxylic acid (47.4 mg; 0.173 mmol) and the mixture was stirred for 2 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by MDAP (high pH method) to give N ⁵ ((1R, 3R, 5S, 6s) -3-hydroxybicyclo [3.1.0] hexan-6-yl) -N ³ -methyl -1 - ((S) -1-phenylethyl) -1H-purazole-3,5-dicarboxamide (3 mg; 8.14 μmol; 5% yield).

% NMR (600 MHz, DMSO-d6) δ ppm 1.36-1.40 (m, 2H), 1.58 (ddt, J = 12.4, 8.3, 4.4, 4.4 Hz, 2H), 1.82 (d, J = 7.0 Hz, 3H), 2.01 (dt, J = 12.6, 7.1 Hz, 2H), 2.42 (dt, J = 3.9, 2.0 Hz, 1H), 2.75 (d, J = 4.6 Hz, 3H), 3.80 (br t, J = 7.0 Hz, 1H), 4.59 (br d, J = 3.3 Hz, 1H), 6.68 (q, J = 7.0 Hz, 1H), 7.19 (s, 1H ), 7.21-7.26 (m, 1H), 7.23-7.26 (m, 2H), 7.27-7.33 (m, 2H), 8.13 (q, J = 4.6 Hz, 1H), 8.42 (d, J = 4 , 0 Hz, 1H).

LCMS (2 min high pH method): retention time 0.79 min, [MH] ⁺ 369.4.

The compounds of the following examples were prepared in a manner analogous to the method for preparing the compound of example 3

- 66 038888

Example Intermediate used LC-MS: (system, retention time, MH ⁺ ) 4 O. / y-NH dbo * No - ((1d, 45) -4-Hydroxycyclohexyl) - А ³ -methyl-1 - ((5) -1- (l <esha-tolyl) ethyl) - III-pyrazole-3, 5-dicarboxamide ck / y ^ NH nA ^^^ Λοη Intermediate 50 Formate, 0.88 min, 385.4 5 O / y-NH> ⁿ No - ((! / ?, 55.6g) -3- Oxabicyclo [3.1.0] hexan-6-yl) -A ³ methyl-1 - ((5) -1-phenylpropyl) -1Npyrazole-3,5-dicarboxamide y-NH oi? > o ^ ^he Intermediate 51 Formate, 0.94 min, 369.3 6 o / y-NH A ⁵ - ((1d, 45) -4-Hydroxycyclohexyl) / U ³ -methyl-1 - ((5) -1-phenylpropyl) -Spyrazole-3,5-dicarboxamide Och / y- NH> o ^ ^he Intermediate 51 Formate, 0.89 min, 385.3 7 a / y-NH LX / ^N X OO c / b ^ - ((1 ^, 55.6 ^ -3- Oxabicyclo [3.1.0] hexan-6-yl) -1 ((5) -1- (4 -fluorophenyl) ethyl) -A ³ -methylSH-pyrazole-3,5-dicarboxamide y-NH Hub o ^he Intermediate 52 Formate, 0.87 min, 373.2

- 67 038888

eight % -NH ^{1 H} ^ - ((1 ^, 55.6 ^ -3- Oxabicyclo [3.1.0] hexan-6-yl) -1 ((5) -1- (3-fluorophenyl) ethyl) -A ³ -methylSH-pyrazole-3,5-dicarboxamide Pts / y-NH gur ' ^G Won Intermediate 53 Formate, 0.87 min, 373.5 9 Q / y-NH уСс f ι Λν ^h № - ((! / ?, 55,6r) -3- Oxabicyclo [3.1.0] hexan-6-yl) -1 ((5) -1- (2-fluorophenyl ) ethyl) -5 ³ -methyl1Н-pyrazole-3,5-dicarboxamide Pts / y-NH At \ 1 _o Aon Intermediate 54 Formate, 0.86 min, 373.6 10 In A nA Λν (5) - \ ⁵ -c11cloprop11l- \ ⁵ -mep1l-1- (1phenylethyl) - 1H-pyrazole-3,5 dicarboxamide O. / γ-NH At ^k О ^ ^he Intermediate 5 High pH, 0.91 min, 313.3 eleven A Cy "k ..... o Ν A ³ -Methyl-A ⁵ - ((15.25) -2methylcyclopropyl) -1 - ((5) -1phenylethyl) - 1H-pyrazole-3,5 dicarboxamide A-nh 1 _o Aon Intermediate 5 Formate, 0.98 min, 327.3

- 68 038888

12 * οΉ ⁿ (lR, 5S, 6s) -mpem-Byx ^ -6- (3 (methylcarbamoyl) -1 - ((5) -1phenylethyl) -S-pyrazole-5carboxamido) -3-azabicyclo [3.1.0] hexane -3-carboxyl at Ok / y-NH 0X7 ¹ (Λ ^ΟΗ Intermediate 5 Formate, 1.11 min, 454 thirteen o, ANH whether: hn γ y J ^ -n, ⁰ H 1 - ((III-Pyrrolo [2,3-c] pyridine-4-11l) methyl) - \ ³ -met11l- \ ⁵ - ((1A. 25) -2-methylcyclopropyl) -1 // - pyrazole-3,5-dicarboxamide o _h Anh LI ⁴ HN A D _o Lon Intermediate 83 High pH, 0.70 min, 353.5 14 o, ANH Ν ^ Υ N = \ ⁴ Χγ 1 - ((III-Pyrrolo [2,3-6] pyridin-4yl) methyl) -A ³ -methyl-N - ((15,25) -2methylcyclopropyl) -1Н -pyrazole-3,5 dicarboxamide o _h X ^N νΆ nA HN Y Τ _o Aon Intermediate 60 Formate, 0.60 min, 353.2 15 о _х / ANH ci-z ^ nA _u / - о XW l 0 Η № - ((l / ?, 55.6r) -3- Oxabicyclo [3.1.0] hexan-6-yl) -1 ((5) -1- (4-chlorophenyl) ethyl) -A ³ -methylIII-pyrazole-3,5-dicarboxamide O. / ANH nA. a Ύ _o Kn Intermediate connection 61 Formate, 0.97 min, 389.3

- 69 038888

sixteen 0. / Anh ^ci oZ cf Afi ⁰ H 1 - ((5) -1- (4-Chlorophenyl) ethyl) -A ⁵ ((1d, 45) -4-hydroxycyclohexyl) -A ^{/ 3} methyl-1H-pyrazole- 3,5 dicarboxamide o _h / ANH nA Χλ / ύ Ύ _ο λθΗ Intermediate 61 Formate, 0.92 min, 405.4 17 0. / y — NH H. OH rA ^N ° H 1 - ((5) -1- (3-Chlorophenyl) ethyl) -A ⁵ ((1d, 4X) -4-hydroxycyclohexyl) -A ³ methyl-1H- pyrazole-3,5 dicarboxamide ο. I Anh ..¼¾ * _o Aon Intermediate 62 Formate, 0.89 min, 405.1 eighteen / ^HN , ~ fl Р ⁿ <3 ^С1 Ύ Ρν'η about n No. - ((1 / ?, 55.6g) -3- Oxabicyclo [3.1.0] hexan-6-yl) -1 ((5) - 1- (3-chlorophenyl) ethyl) -A ^{? 3} -methylIII-pyrazole-3,5-dicarboxamide / HN _Λ z Opp c ^ l Ron Intermediate 62 Formate, 0.94 min, 389.1 nineteen / ^HN , Qi D 1 ₀ Pnh P / ^he No.- (3-Hydroxycyclohexyl) - ^ ³ methyl-1 - ((5) -1-phenylethyl) -Spyrazole-3,5-dicarboxamide, a mixture of diastereomers / HN _Λ z OJQ Ύ _o Won Intermediate 5 Formate, 0.87 min, 371.1

- 70 038888

twenty Οχ Η yN οΑ 1 Al \ IH ° Ν'Ν Η (5) -L ^{/ 3} -Methyl-1- (1-phenylethyl) ^ No- (Sh-pyrazol-4-yl) -Sh-pyrazole-3,5 dicarboxamide / HN ~ se Λ -A Ύ _o Kn Intermediate connection 5 Formate, 0.83 min, 339.0 21 C) Anh Oyf ' ¹ O ^ NH V- ((15.3 /?) -3-Hydroxycyclopentyl) -A ³ -methyl-1 ((5) - 1-phenylethyl) -1H-p and razol-3,5 dicarboxamide / ^HN r nA Ύ _о Aon Intermediate 5 Formate, 0.86 min, 357.1 22 О n VN / ⁴ > ^ОН 1 JL А к) 1 An ⁿ Ό Н l - ((5) -l- (4-Chlorophenyl) ethyl) - ^ ⁵ ((1 / ?, 35.55.6g) -3 - hydroxycyclo [3.1.0] -hexan-6-yl) - \ ⁵ -methyl-1 // - pyrazole-3.5 dicarboxamide about ny nA XayQ Ύ _about Hon Intermediate 61 High pH, 0.93 min, 403.6

- 71 038888

23 about _h U ™ YX about C ^{NH 0} Η (5) -1- (1- (3-Chlorophenyl) ethyl) -L ^{/ 3} methyl-A ⁵ -! Sh-pyrazol-4-yl) -Spyrazole-3,5-dicarboxamide o _h > - ΝΗ ₀ L _0N Intermediate 62 Formate, 0.90 min, 373.5 24 o _h V-NH ΧΧγ ^Ν X sU * ⁰ n (X) -1- (1- (4-Chlorophenyl) ethyl) -A ^{/ 3} - methyl-M- (1 // - pyrazol-4-yl) -1 // pyrazole-3,5-dicarboxamide o,% ΝΗ W o ^ ^he Intermediate 61 Formate, 0.91 min, 373.5 25 O n VN 1 H 0 n 1 - ((5) -1- (4-Chlorophenyl) ethyl) -No ((X ^ 3H ^ A ^ b ^ -3-hydroxycyclo [3.1.0] hexan-6-yl) - / U ³ -methylSH-pyrazole-3,5-dicarboxamide o _h y - ΝΗ sL ^he Intermediate connection 61 High pH, 0.90 min, 403.6 26 o _x ¹ η P% (A) - \ '- Me111l-1- (1-phenyle111l) - \ ⁵ (pyridium-4-yl) -1H-pyrazole-3,5 dicarboxamide O. / Oh 1 L-on Intermediate connection 5 Formate, 0.61 min, 350.1

- 72 038888

27 0. / ^ NH nt ⁰ V / A ^ -D ^ -vshor-Butyl (A ^ -methyl-X-DA) 1-phenylethyl) -III-pyrazole-3,5 dicarboxamide 0. / y-NH ΟγΡ 1 _О У-ОН Intermediate 5 Formate, 1.04 min, 329.1 28 oh, I ’Δ (^ -A ^ -cyclopentyl-A ^ -methyl-X-CXphenylethyl) -III-pyrazole-3,5 dicarboxamide ° Ν-ΝΗ AL 0 Intermediate connection 5 Formate, 1.07 min, 341.1 29 O. / A ^d - (vshor-Butyl) -A ^g3 -methyl-1 - ((5) -1phenylethyl) -17 / -pyrazole-3,5 dicarboxamide, a mixture of diastereomers o / γ-ΝΗ 1 A-he o Intermediate connection 5 Formate, 1.04 min, 329.2 thirty Mon by ^G 0 ^ (ATA ^ -Isobutyl-A ^ -methyl-HD! Phenylethyl) -XY-pyrazole-3,5 dicarboxamide O. / <^ - NH 1 <Mon o Intermediate connection 5 Formate, 1.06 min, 329.1

- 73 038888

31 O. / y-NH OD l ANH δ \ '- Μ en ι l-1 - ((5) -1 - phenylethyl) -No (tetrahydro-2H-pyran-3-yl) -Spyrazole-3,5-dicarboxamide, mixture of diastereomers O. / Ν-ΝΗ * Aon 0 Intermediate connection 5 Formate, 0.91 min, 357.1 32 O / y-NH A (5) -No-Cyclobutyl-A ³ -methyl-1- (1phenylethyl) -III-pyrazole-3,5 dicarboxamide y-NH / b nA. Λ ° Η Intermediate connection 5 Formate, 1.02 min, 327.1 33 O. / ^ NH od n Y (AHL ^ -Methyl-L ^ oxazol-g-yl) -! ^! Phenylethyl) -III-pyrazole-3,5 dicarboxamide o _h / y-NH 1 Aon 0 Intermediate 5 Formate, 0.85 min, 340.1 34 P / y-NH nA OMch 1 _λ Ανη / ⁰ Va ° (5) - \ ⁵ - (3-Me1Ox11propyl) - \ ³ -me111l1- (1-phenylethyl) -1 // - pyrazole-3,5- ° smart 1 A-he o Intermediate connection 5 Formate, 0.90 min, 345.1

- 74 038888

dicarboxamide 35 ° ^ NH out 0¼ d (Α) - \ ⁵ -Μ6ΐιι.ι- \ ⁵ - (1-Μ6ΐιι.ι-1 // - pyrazol-4-yl) -1- (1-phenylethyl) -Spirazol-3, 5-dicarboxamide O. / ^ Λ ^0Η Intermediate 5 Formate, 0.89 min, 353.1 36 a / γ-ΝΗ out 'o ^ n / Y- (2-Hydroxypropyl) -A ³ -methyl-1 ((5) - 1-phenylethyl) - 1 // - pyrazole-3,5 dicarboxamide, a mixture of diastereomers O. / y-NH cut O Intermediate 5 Formate, 0.80 min, 331.1 37 O. / y-NH O (LuL ^ -Methyl-LC-phenylethyl) - ^ ⁵ ((tetrahydro-2 // - pyran-4-yl) methyl) 1 // - pyrazole-3,5-dicarboxamide O. / y- ΝΗ ° 4. Intermediate 5 Formate, 0.90 min, 371.1

- 75 038888

38 0h / y-NH Ή \ A ⁵ -Methyl-A ⁵ - (2- (4-methylmorpholine-2yl) ethyl) -1 - ((5) -1-phenylethyl) -1Hpyrazole-3,5-dicarboxamide, a mixture of diastereomers O. / yNH oH 1 yaon O Intermediate connection 5 Formate, 0.55 min, 400.2 39 Oh / y-NH <4'1 o Yy ^ -one (^ -A ^ -CZ-Hydroxypropyl L ^ -methyl1- (1-phenylethyl) -III-pyrazole-3,5 dicarboxamide θχ ¹ smart M- Intermediate 5 Formate, 0.77 min, 331.1 40 O. / y-NH CI ¹ Li ⁿ \ ⁵ - ((15.55.6g) -3Oxabicyclo [3.1.0] hexan-6-yl) -1 ((5) -1- (2-chlorophenyl) ethyl) -A ³ - methyl III-pyrazole-3,5-dicarboxamide Οχ / minds S Q Intermediate connection 63 Formate, 0.90 min, 389.5 41 o _h Vnh Ουύ σ ^0Η Cl 1 ⁰ Η 1 - ((5) -1- (2-Chlorophenyl) ethyl) -A ^{/ 5} ((1d, 45) -4-hydroxycyclohexyl) -A ^{/ 3} methyl-1 // -pyrazole-3,5 dicarboxamide ^o yNH Intermediate connection 63 Formate, 0.87 min, 449.4

- 76 038888

№ - ((/ ·, 45) -4-r-idroksi 4metiltsiklogeksil!) -A ^3-methyl-1 - ((5) 1-phenyl-ethyl) -m-pyrazol-3,5dikarboksamid

Formate, 0.82 min, 385.2

Intermediate connection 5

^ - ((1 ^, 55.6 ^ -3Oxabicyclo [3.1.0] hexan-6-yl) -1 ((5) -1- (3-methoxyphenyl) ethyl) -A ³ methyl-1 // - pyrazole -3.5 dicarboxamide

Intermediate connection 64

Formate, 0.86 min, 385.3

The compounds of Examples 44-49 were prepared in sequence according to the following method.

(S) -3- (methylcarbamoyl) -1- (1-phenylethyl) -1H-nyrazole-5-carboxylic acid ((0.027 g; 0.1 mmol) x 14 = 383 mg) and HATU ((0.042 g; 0.110 mmol) x 14 = 586 mg). To this tube was added DMF ((0.5 ml) x14 = 7 ml) and DIPEA ((0.050 ml; 0.286 mmol) x 14 = 700 μl). The mixture was stirred for 5 min and then aliquoted into tubes (550 μl), each containing the corresponding pre-weighed amine (0.120 mmol). (Note: additional DIPEA (0.050 ml; 0.286 mmol) was added to the amines, which were in the form of hydrochlorides). The mixture was allowed to react for 66 h. T ₃ P (100 μl; 50 wt% in EtOAc) and DIPEA (0.050 ml; 0.286 mmol) were added and additional amine (0.120 mmol) was added after 5 min. The mixtures were reacted for an additional 24 hours. The reaction mixtures were purified by MDAP (high pH method) and concentrated to give

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Example No. Name Structure Weight (mg) Exit (%) [ΜΗ] ⁺ Rt (min), formate 44 (5) -V ³ -MeiiLi-1- (1phenylethyl) -A ^{/ 5} - (2 (tetrahydro-27 / pyran-4-yl) ethyl) -1Hpyrazole-3,5 dicarboxamide HN ^ Αγγ ^ν 'Ν ην ^ A 6.8 sixteen 385 0.96 45 (5) -No (Cyclopropylmethyl) L'-megyl-1- (1phenylethyl) -Spyrazole-3,5 dicarboxamide Η Ν 'Ay ^Ν ' Ν ^ην Α ^ 6.6 eighteen 327 1.01 46 (A) - \ ⁵ -Pzopropyl- \ ⁵ methyl-1- (1phenylethyl) -Spyrazole-3,5 dicarboxamide ΗΝ TVA / ^Ν 'Ν ηνΑ c7 ~ 21 61 315 0.97 47 (5) -V- (4-Hydroxybicyclo [2.2.2] octan-1-yl) -L ^{/ 3} methyl-1- (1phenylethyl) -! // pyrazole-3,5 dicarboxamide ΗΝ ^ ^Ν ~ Ν ΗΝ— ^ΟΗ thirteen 29 397 0.87 48 V - ((iv.4 /?) - 4-Hydroxycyclohexyl) -7U ³ -methyl-1 ((5) - 1-phenylethyl) -1 // pyrazole-3,5 dicarboxamide ΗΝ ^ ^Ν 'Ν ΗΝ- <U-OH sG eight nineteen 371 0.87 49 \ ⁵ - ((lv.4 /?) - 4-hydroxy-4methylcyclohexyl) \ ³ -methyl-1 - ((5) -1phenylethyl) -! // - pyrazole-3,5 dicarboxamide ΗΝ ^ ^Ν 'Ν ην-Ζ Αοη 0 ^ nineteen 44 385 0.94

Examples 50-64 were prepared as part of the amide preparation sequence using commercially available amines.

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Reagent name Structure Molecular mass Reagent weight (g) mmol Ethanamine h ₂ n ^ 45 0.005 0.120 Propane-Namin 59 0.007 0.120 (+/-) - 4-Aminobutan-2-ol he 89 0.011 0.120 T etrahydro-2H-pyran-4-amine Η ₂ Ν ' ^Χ ^^ 101 0.012 0.120 (+/-) - T etrahydrofuran-3 -amine η ₂ ν ' ^χ ^ ^/ ^ 87 0.010 0.120 (+/-) - 2- (Tetrahydro-2H-pyran-2yl) ethanamine 129 0.016 0.120 (+/-) (tetrahydrofuran-3-yl) methanamine hydrochloride ^η2νχΧ ^ 62ο ^hci 137 0.017 0.120 (+/-) - 2- (Tetrahydro-2H-pyran-3yl) ethanamine 129 0.016 0.120 Oxetane-3-ylmethanamine Η ₂ Ν '^ ^Χ Α \ Χο 87 0.010 0.120 3-Fluorocyclobutanamine, mixture of diastereomers η ₂ νΆ 89 0.011 0.120 from /? eot-Butyl - ((1 g, 4g) -4- (2aminoethyl) cyclohexyl) carbamate Η ₂ Ν 242 0.029 0.120 Oxetane-3 -amine 73 0.009 0.120 2-Cyclopropylethanamine 85 0.010 0.120 2- (1H-Pyrazol-3-yl) ethanamine Η ₂ Ν Ν 111 0.013 0.120 Hydrochloride (1y37?, 4g, 55.7 ^) - 4aminoadamantan-1-ol HE h, J। J HCl 203 0.024 0.120

Method: stock solution (S) -3- (methylcarbαmoyl) -1- (1-phenylethyl) -1H-pyrazole-5-kαcarboxylic acid ((0.027 g; 0.100 mmol) x 18 = 492 mg) and HATU ((0.038 g ; 0.100 mmol) x 18 = 684 mg) was dissolved in DMF ((0.5 ml) x 18 = 9.0 ml). DIPEA (0.052 ml; 0.300 mmol) x18 was added to this stock solution. The tubes were sealed and shaken at room temperature until complete dissolution. After 2 minutes, an aliquot (0.5 ml) of the above stock solution was added to a series of pre-weighed x18 amines (0.120 mmol; see table for amounts) in 1 ml Matrix plastic tubes. Each tube was sealed and shaken to accelerate dissolution, and left to stand overnight for 18 hours at room temperature. T ₃ P (50 wt% EtOAc) 120 μl and DIPEA (0.052 ml; 0.300 mmol) were added to each reaction mixture and left for more than 48 h at room temperature. The reaction mixtures were purified by MDAP (high pH method) to give the final compounds (see table for amounts).

Removal of the Boc protection from the reaction intermediate corresponding to the combination of tert-butyl - ((1r, 4r) -4- (2-aminoethyl) cyclohexyl) carbamate was carried out in DCM (0.5 ml) using 3M HCl in CPME (0.5 ml). A glass microwave vial was used as a reaction vessel. The reaction mixture was left stirring overnight for 22 h at 35 ° C. Additional DCM (0.5 ml) and 3M HCl in CPME (0.5 ml) were added to the reaction mixture and left to stir overnight for 18 h at 35 ° C. The solvent was then removed to dryness under a stream of nitrogen to give the free amine hydrochloride. Additional DCM (0.5 ml) and 3M HCl in CPME (0.5 ml) were added to the solid. The solution was left to stand at room temperature over the weekend. The solvent was removed to dryness to give the free amine hydrochloride (Example 60) as shown in the table below.

Example No. Name Structure Weight (mg) Exit (%) [MH] ⁺ Rt (min), formate 50 (^ -L ^ -Ethyl-A ³ methyl-1- (1phenylethyl) -! // pyrazole-3,5 dicarboxamide HN ^ ⁿ 'N hn ^ eighteen 54 301 0.90 51 (АуД ^ -Meti l-1 - (1 phenylethylutU ⁵ propyl-1 // - pyrazole 3,5-dicarboxamide HN ^ Arvf r- ^N 'N hn ^ 14 40 315 0.98 52 \ ⁵ - (3- HydroxybutylUA ³ methyl-1 - ((5) -1phenylethyl) -1Hpyrazole-3,5dicarboxamide HN ^ o / jy / Y, ^{0H n} 'N ngC \ nineteen 49 345 0.82 53 (Sy \ ³ -Meni.i-1- (1fe11i.leti.l) - \ ⁵ (tetrahydro-2Yapiran-4-yl) -Spirazole-3,5 dicarboxamide HN ^ ⁿ -n hn - ς o 12 31 357 0.89 54 \ '- Methyl-1 - ((A) -1phenylethylutU ⁵ (tetrahydrofuran-3yl) -1 // - pyrazole-3,5 dicarboxamide ΗΝ ' ^N ' N IHN — O '? cT eighteen 48 343 0.86

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55 A ³ -Methyl-1 - ((5) -1phenylethyl) -A ^{/ 5} - (2 (tetrahydro-2Yapiran-2-yl) ethyl) 1 // - pyrazole-3.5dicarboxamide HN ^ ^N 'N HN ^ eighteen 43 385 1.05 56 N-Methyl-1 - ((5) -1phenylethyl) -No ((tetrahydrofuran-3yl) methyl) -1Hpyrazole-3,5 dicarboxamide HN ^ ° Pgud ° ⁿ 'N hn ^ eighteen 44 357 0.87 57 A (-Methyl-X-DA) -! Phenylethyl) -A ^{/ 5} - (2 (ieipariiipo-2 // pyran-3-yl) ethyl) 1 // - pyrazole-3.5 dicarboxamide HN ^ ^N 'N HN ^ 21 49 385 0.99 58 (S) - \ ³ -MeiiLi- \ ⁵ (oxetan-3-ylmethyl) 1- (1-phenylethyl) -Spyrazole-3,5 dicarboxamide HN- Aw ^N 'N VA 17 43 343 0.82 59 (5) - ^ - (3Fluorocyclobutyl) A ^ -methyl-HDC phenylethyl) -! // pyrazole-3,5 dicarboxamide HN ^ Avf ^N 'N hn ^ Q ^ f 7 nineteen 345 0.98 60 Hydrochloride ^ - (2 ((Xr, 45) -4aminocyclohexyl) - HN ^ Ay / ^N 'N hn ^ y — v A- ^λ ..... O ^NH w ^HCI 23 G 47 398 0.60

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ethyl) -A ³ -methyl-1 ((5) -1-phenylethyl) III-pyrazole-3,5 dicarboxamide 61 (5) -No-Methyl-No (oxetan-3-yl) -1- (1phenylethyl) -Spyrazole-3,5 dicarboxamide HN ^ ^Ν 'Ν HN - <% d 14 38 329 0.83 62 (5) -No- (2cyclopropylethyl) A ^ -methyl -! - !! phenylethyl) -Spyrazole-3,5 dicarboxamide HN ^ ° Aguch ° ^ν 'Ν ηνΑ ο sixteen 43 341 1.07 63 (5) -No- (2- (ShPyrazol-3-yl) ethyl) N-methyl-1- (1phenylethyl) -! // pyrazole-3,5 dicarboxamide Η Ν ' ^Ν ' Ν ΗνΑ ν-ΝΙ one 22 54 367 0.82 64 No - ((15.35.5 / ?, 7 /?) - 5G hydroxyadamantan2-yl) -A ^{/ 3} -methyl-1 ((5) -1-phenylethyl) S-pyrazole-3,5 dicarboxamide ΗΝ ^ ^Ν 'Ν ην — pj ηΊ γ Ο ^οη nineteen 41 423 0.89

Example 65 (S) -N ³ , N ⁵ -Dimethyl-1- (1-phenylethyl) -1 H-nurazole-3,5-ducarboxamide

To a suspension of N ³ , N ⁵ -dimethyl-1H-pyrazole-3,5-dicarboxamide (39 mg; 0.214 mmol) in THF (1 ml) were added (R) -1-phenylethanol (40 mg; 0.327 mmol) and triphenylphosphine (90 mg; 0.343 mmol) and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was cooled to 0 ° C and DIAD (0.067 ml; 0.343 mmol) was added. The tube was then heated in a microwave oven at 140 ° C for 15 minutes. The reaction mixture was then heated at 140 ° C for an additional 20 min. An additional portion of (K) -1-phenylethanol (40 mg; 0.327 mmol), triphenylphosphine (90 mg; 0.343 mmol) and DIAD (0.067 ml; 0.343 mmol) were added and the reaction mixture was heated at 140 ° C for 15 min. The solvent was removed in vacuo to give approximately 770 mg of a crude yellow oil. This was purified by SiO ₂ chromatography (25 g Biotage SNAP cartridge, elution with 0100% ethyl acetate / cyclohexane) to give 50 mg of a colorless oil. It was further purified by MDAP (high pH method). Fractions containing the desired product were concentrated in vacuo to give (S) -N ³ , N ⁵ -dimethyl-1- (1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (17 mg; 0.053 mmol; 25% yield ) as a white solid.

LCMS (2 min formate method): retention time 0.82 min, [MH] ⁺ 287.2.

Example 66 1-Benzyl-N ⁵ - ((1r, 4r) -4-hydroxycyclohexyl) -N ³ -methyl-1H-pyrazole-3,5-dicarboxamide

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O I nA / A ™ O ο N

To a solution of 1-benzyl-3- (methylcarbamoyl) -1H-pyrazole-5-carboxylic acid (150 mg; 0.509 mmol) and DIPEA (0.267 ml; 1.527 mmol) in DMF (1 ml), stirred under nitrogen at room temperature , added HATU (290 mg; 0.764 mmol) followed by the addition of (1r, 4r) -4-aminocyclohexanol (70.4 mg; 0.611 mmol) in one portion. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water, then extracted with EtOAc (3x20 ml). The combined organic layer was washed with water (2x15 ml), brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude product. The crude product was triturated with 50% DCM and diethyl ether (3x1 ml) to give a solid which was filtered and dried in vacuo for 15 min to give 1-benzyl-N ⁵ ((1g, 4g) -4-hydroxycyclohexyl) -N ^3- methyl-1H-pyrazole-3,5-dicarboxamide (160 mg; 0.447 mmol; 88% yield) as an off-white solid.

LCMS (4.5 min Method A): Retention time 1.61 min, [MH] ⁺ 357.1.

Example 67 1-Benzyl-N ⁵ -cyclobutyl-N ³ -methyl-1H-pyrazole-3,5-dicarboxamide

SK / nA □

Oh and

To a solution of 1-benzyl-3- (methylcarbamoyl) -1H-pyrazole-5-carboxylic acid (200 mg; 0.733 mmol) and DIPEA (0.384 ml; 2.199 mmol) in DMF (1 ml), stirred under nitrogen at room temperature , added HATU (418 mg; 1.099 mmol) followed by the addition of cyclobutanamine (104 mg; 1.466 mmol; commercially available from, for example, Sigma Aldrich) in one portion. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice water, then extracted with EtOAc (3x20 ml). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude product. The crude product was added to a silica gel 60-120 column and eluted with 65% EtOAc in n-hexane. The collected pure fractions were concentrated in vacuo to give 1-benzyl-N ⁵ -cyclobutyl-N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (84 mg; 0.255 mmol; 35% yield) as a white solid.

LCMS (10 min Method D): Retention time 4.26 min, [MH] ⁺ 313.2. Example 68 (S *) - N ⁵ -cyclopropyl-N ³ -methyl-1- (1-phenylethyl) -1 H-pyrazole-3,5-dicarboxamide

Intermediate 11 was purified by chiral HPLC. The conditions for preparative NF-HPLC (normal phase chromatography) were as follows.

Column / Dimensions: Chiralpak IC (250x30mm), 5 μm.

Mobile phase: n-hexane: ethanol (70:30).

Flow rate: 38 ml / min.

Temperature: ambient.

Wavelength: 249 nm.

Completion time: 18 min.

Solubility: THF plus n-hexane plus ethanol.

The amount of injected sample: 33.0 mg / sample.

Total number of inputs: 10.

The pure fractions corresponding to peak 1 were concentrated in vacuo to give (S *) - N ⁵ cyclopropyl-N ³ -methyl-1- (1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (36 mg; 0.105 mmol; yield 15%) as a white solid.

LCMS (4.5 min, method B): retention time 1.89 min, [MH] ⁺ 313.2.

Example 69. N ⁵ -cyclopropyl-N ³ -methyl-1- (3-methylbenzyl) -1H-pyrazole-3,5-dicarboxamide

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To a solution of N ⁵ -tsiklopropil -metul ^{3-N-1H-pyrazole-3,5-dicarboxamide} (300 mg, 1.366 mmol) in DMF (2 ml), stirred under nitrogen at room temperature was added K ₂ CO ₃ (566 mg; 4.10 mmol) followed by the addition of 1- (bromomethyl) -3-methylbenzene (0.211 ml; 1.640 mmol; commercially available from, for example, Sigma Aldrich) in one portion. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water, then extracted with EtOAc (3x25 ml). The combined organic layer was washed with water (3x15 ml), brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo to give the crude product which was a mixture of 2 regioisomers. They were purified by SFC, chiral HPLC. The conditions for preparative SFC were as follows.

Column / dimensions: LuxCellulose-2 (250x30 mm), 5 μm.

% CO2: 60.0%.

% co-solvent: 40.0% (MeOH).

Total flow rate: 90.0 g / min.

Back pressure: 100.0 bar (10 MPa).

UV: 211 nm.

Accumulation time: 3.8 min.

The amount of injected sample: 16.0 mg.

Solubility: methanol.

Total number of inputs: 20.

Instrument data: manufacturer / model: Thar SFC-200-005.

The pure fractions corresponding to peak 1 were concentrated in vacuo to give N ⁵ cyclopropyl-N ³ -methyl-1- (3-methylbenzyl) -1H-pyrazole-3,5-dicarboxamide (76 mg; 0.238 mmol; 63% yield) in the form of a white solid.

LCMS (4.5 min, method B): retention time 1.90 min, [MH] ⁺ 313.2.

Example 70 1 - ((1 H-Indol-5-yl) methyl) -N ⁵ -cyclopropyl-N ³ -methyl-1H-pyrazole-3,5-dicarboxamide

In a solution of N ⁵ -cyclopropyl-N ³ -methyl-1 - ((1-tosyl-1 H-indol-5-yl) methyl) -1 N-pyrazole-3,5-dicarboxamide (420 mg; 0.666 mmol) in methanol (1 ml), stirring under nitrogen at room temperature, was added NaOH (80 mg; 1.999 mmol) in one portion. The reaction mixture was stirred at 70 ° C for 16 hours. The reaction mixture was cooled to room temperature, then diluted with water (20 ml), then the aqueous layer was extracted with EtOAc (3x15 ml). The combined organic layer was washed with water (3x10 ml), brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo to give the crude product as a mixture of regioisomers. They were purified by SFC, chiral HPLC. The conditions for preparative SFC were as follows.

Column / Dimensions: Chiralpak IC (250x30mm), 5 μm.

% CO ₂ : 50.0%.

% co-solvent: 50.0% (MeOH).

Total flow rate: 60.0 g / min.

Back pressure: 100.0 bar (10 MPa).

UV: 215 nm.

Accumulation time: 6.5 min.

The amount of injected sample: 8.0 mg.

Solubility: MeOH.

Total number of inputs: 40.

The pure fractions corresponding to peak 1 were concentrated in vacuo to give 1 - ((1Hindol-5-yl) methyl) -N ⁵ -cyclopropyl-N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (95 mg; 0.272 mmol ; 85% yield) as an off-white solid.

LCMS (4.5 min, method B): retention time 1.68 min, [MH] ⁺ 338.2.

Example 71 1 - ((1H-Indol-4-yl) methyl) -N ⁵ -cyclopropyl-N ³ -methyl-1H-pyrazole-3,5-dicarboxamide

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In a solution of N ⁵ -cyclopropyl-N ³ -methyl-1 - ((1-tosyl-1 N-indol-4-yl) methyl) -1 H-pyrazole-3,5-dicarboxamide (400 mg; 0.745 mmol) in methanol (1 ml), stirring under nitrogen atmosphere at room temperature, was added NaOH (29.8 mg; 0.745 mmol). The reaction mixture was stirred at 70 ° C for 16 hours. The reaction mixture was diluted with water, then extracted with DCM (3x15 ml). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude mixture of regioisomers (410 mg), which was purified by SFC. The conditions for preparative SFC were as follows.

Column / Dimensions: Chiralpak AD-H (250x21mm), 5 μm.

% CO2: 60.0%.

% co-solvent: 40.0% (MeOH).

Total flow rate: 60.0 g / min.

Back pressure: 100.0 bar (10 MPa).

UV: 215 nm.

Accumulation time: 3.6 min.

The amount of injected sample: 2.6 mg.

Solubility: methanol plus DCM.

Total number of inputs: 34.

The pure fractions corresponding to peak 1 were concentrated in vacuo to give N ⁵ cyclopropyl-N ³ -methyl-1 - ((1-tosyl-1 H-indol-4-yl) methyl) -1 H-pyrazole-3,5- dicarboxamide (400 mg; 0.745 mmol) as an off-white solid.

LCMS (4.5 min, method B): retention time 1.65 min, [MH] ⁺ 338.2.

Example 72. N ⁵ - ((1R, 3S, 5S, 6r) -3-hydroxycyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1 - ((S) -1-phenylethyl) 1 H -pyrazole-3,5-dicarboxamide

O. ! x ^ nh / mon ИХ n ^ / f L ΛΑ

3-Hydroxybicyclo [3.1.0] hexane-6-carboxylic acid (720 mg; 5.06 mmol) was dissolved in toluene (10 ml) and tert-butanol (10 ml), then Et ₃ N (1.412 ml; 10, 13 mmol) and diphenylphosphorazidate (1.637 ml; 7.60 mmol) and the mixture was heated at 80 ° C overnight. The mixture was diluted with EtOAc (20 ml) and washed with water (20 ml), the solvent was dried and evaporated to give a pale yellow gum. It was dissolved in DCM (10 ml) and loaded onto a column with 50 g of silica, then eluted with a mixture of 0100% EtOAc / cyclohexane and ninhydrin-positive fractions were evaporated under vacuum to obtain a mixture of diastereomers of tert-butyl- (3-hydroxybicyclo [3.1.0 ] hexane-6-yl) carbamate, which was used crude in the next step. tert-Butyl- (3-hydroxybicyclo [3.1.0] hexan-6-yl) carbamate (55 mg; 0.258 mmol) (crude) was dissolved in DCM (10 ml) and TFA (1 ml) was added, then the mixture was stirred for 2 hours at room temperature. The solvent was evaporated in vacuo and the residue was dissolved in fresh DCM (10 ml) and Et ₃ N (0.072 ml; 0.516 mmol), HATU (147 mg; 0.387 mmol) and (S) -3- (methylcarbamoyl) -1- (1 -phenylethyl) -1H-pyrazole-5-carboxylic acid (70.5 mg; 0.258 mmol), then the mixture was stirred for 2 hours at room temperature. The reaction mixture was washed with water (10 ml), dried and evaporated in vacuo to give a pale yellow gum. It was purified by MDAP (high pH method) to give N ⁵ - ((1R, 3S, 5S, 6r) -3-hydroxybicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1 - ( (S) -1-phenylethyl) -1 H-pyrazole-3,5-dicarboxamide (16 mg; 0.043 mmol; 17% yield) as a colorless solid.

LCMS (2 min high pH method): retention time 0.84 min, [MH] ⁺ 369.3.

Example 73. N ⁵ - (2 - ((2r, 5S) -5-Amino-1,3-dioxan-2-yl) ethyl) -N ³ -methyl-1 - ((S) -1-phenylethyl) - 1 H-pyrazole-3,5-dicarboxamide

In suspension N ⁵ - (2 - ((2r, 5S) -5- (1,3-dioxoisoindolin-2-yl) -1,3-dioxan-2-yl) ethyl) -N ³ -methyl-1 - ( (S) - 85 038888

1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (102 mg; 0.192 mmol) in ethanol (3 ml) was added hydrazine hydrate (90 μl; 1.836 mmol). The reaction mixture was stirred at 40 ° C for 4 hours. The crude product was filtered and purified by MDAP (high pH method). The fractions containing the desired product were concentrated in vacuo to give N ⁵ - (2 - ((2r, 5S) -5-amino1,3-dioxan-2-yl) ethyl) -N ³ -methyl-1 - ((S) -1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (61 mg; 0.137 mmol; 71% yield).

LCMS (2 min high pH method): retention time 0.78 min, [MH] ⁺ 402.2.

Example 74. N ⁵ - (3 - ((2r, 5S) -5-Amino-1,3-dioxan-2-yl) propyl) -N ³ -methyl-1 - ((S) -1-phenylethyl) - 1H-pyrazole-3,5-dicarboxamide

In suspension N ⁵ - (3 - ((2r, 5S) -5- (1,3-dioxoisoindolin-2-yl) -1,3-dioxan-2-yl) propyl) -N ³ -methyl-1 (( S) -1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (81 mg; 0.148 mmol) in ethanol (3 ml) was added hydrazine hydrate (90 μl; 1.836 mmol). The reaction mixture was stirred at 40 ° C for 19 hours. The crude product was filtered and purified by MDAP (high pH method). The fractions containing the desired product were concentrated in vacuo to give N ⁵ - (3 - ((2r, 5S) -5amino-1,3-dioxan-2-yl) propyl) -N ³ -methyl-1 - ((S) -1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide (42 mg; 0.091 mmol; 61% yield).

LCMS (2 min high pH method): retention time 0.80 min, [MH] ⁺ 416.3.

Example 7 5. N ⁵ - ((1R, 5 S, 6r) -Oxabicyclo [3.1.0] hexan-6-yl) -1 - ((R) -2-hydroxy-1-phenylethyl) -N ³ methyl- 1H-pyrazole-3,5-dicarboxamide

N ⁵ - ((1R, 5S, 6r) -3-Oxabicyclo [3.1.0] hexan-6-yl) -1 - ((R) -2 - ((tert-butyldimethylsilyl) oxy) -1-phenylethyl) - N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (214 mg; 0.442 mmol) was placed in 4M hydrochloric acid in dioxane (500 μl; 2.000 mmol) and left stirring for 1.5 h. The sample was dissolved in MeOH mixture : DMSO 1: 1 (2x1 ml) and purified by MDAP (high pH method). The appropriate fractions were combined and concentrated in vacuo to give N ⁵ - ((1R, 5S, 6r) -3oxabicyclo [3.1.0] hexan-6-yl) -1 - ((R) -2-hydroxy-1-phenylethyl) - N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (68.4 mg; 0.166 mmol; 38% yield) as an eluted second regioisomer.

LCMS (2 min formate method): retention time 0.71 min, [MH] ⁺ 371.2.

Example 76u N ⁵ - ((1R, 5S, 6s) -3-Azabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1 - ((S) -1-phenylethyl) -1Hpyrazole-3, 5-dicarboxamide

To a part of the suspension of tert-butyl- (1R, 5S, 6s) -6- (3- (methylcarbamoyl) -1 - ((S) -1-phenylethyl) -1H-pyrazole-5carboxamido) -3-azabicyclo [3.1.0 ] hexane-3-carboxylate (95 mg; 0.209 mmol) in DCM (2 ml) was added TFA (0.5 ml; 6.49 mmol) and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated and loaded onto SCX cartridge 2 g (pretreated with MeOH). Eluted with MeOH (30 ml) followed by elution with 2M NH3 in MeOH (30 ml). The ammonia fractions containing the product were combined and concentrated to give the title compound (57 mg; 0.145 mmol; 69% yield) as a pale yellow oil.

LCMS (2 min formate method): retention time 0.51 min, [MH] ⁺ 354.4.

Example 77. N ⁵ - ((1R, 5S, 6s) -3-Acetyl-3-azabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1 - ((S) -1-phenylethyl) 1H-pyrazole-3,5-dicarboxamide

- 86 038888

N ⁵ - ((1R, 5S, 6s) -3-Azabicyclo [3.1.0] hexane-6-ul) -N ³ -methyl-1 - ((S) -1-phenulethyl) -1H-pyrazole-3, 5-dicarboxamide (49 mg; 0.139 mmol) was stirred in acetic anhydride (300 μl; 3.18 mmol) at room temperature for 2 h. The reaction mixture was diluted with sat. NaHCO ₃ (aq) and extracted with EtOAc, the organic phase was washed with water, dried using a hydrophobic frit and concentrated to give the title compound (46 mg; 0.105 mmol; 76% yield) as a colorless oil.

LCMS (2 min formate method): retention time 0.77 min, [MH] ⁺ 396.4.

Example 78. 1 - ((1 H-Indol-4-yl) methyl) -N ⁵ - ((1 R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -N ³ - methyl1 H-pyrazole-3,5-dicarboxamide

N ⁵ - ((1R, 5S, 6r) -3-Oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1 - ((1-tosul-1H-indol-4-yl) methyl) -1Hpyrazole-3,5-dicarboxamide (99.7 mg; 0.187 mmol) was taken up in THF (4 ml) and methanol (2 ml). Cesium carbonate (304 mg; 0.934 mmol) was added and the reaction mixture was heated to 73 ° C and left stirring overnight. The reaction mixture was concentrated in vacuo. Water (10 ml) was added to the residue, which was then acidified with 2N. HCl and then extracted with ethyl acetate (2x10 ml). The combined organic layers were dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to afford the title compound (63.8 mg; 0.160 mmol; 85% yield) as a purple solid.

LCMS (2 min formate method): retention time 0.74 min, [MH] ⁺ 380.3.

Example 79. 1 - ((1H-Indol-4-yl) methyl) -N ⁵ - ((1R, 5S, 6s) -3-azabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl- 1Hpyrazole-3,5-dicarboxamide

tert-Butyl- (1R, 5S, 6s) -6- (1 - ((1 H-indol-4-yl) methyl) -3 - (methylcarbamoyl) -1 H-pyrazole-5-carboxamido) -3-azabicyclo [3.1.0] hexane-3-carboxylate (86.5 mg; 0.181 mmol) was taken up in DCM (4 ml). TFA (1 ml; 12.98 mmol) was added and the mixture was left stirring at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The sample was then loaded into methanol and purified by solid phase extraction using a 1 g SCX cartridge, rinsing with methanol, then eluting with 2M ammonia / methanol. The appropriate fractions were combined and evaporated in vacuo to give the crude product as a cream solid. The crude product was taken up in MeOH: DCM 1: 2 (30 ml) and free flowing silica (1 g) was added. The solvent was removed in vacuo and the silica was loaded onto a 10 g ULTRA SNAP cartridge in a minimum amount of DCM and eluted with 0% (2M NH ₃ in methanol) in DCM for 2 column volumes (CV), then with a mixture of 0-20% (2M NH ₃ in methanol) / DCM. The appropriate fractions were combined and concentrated in vacuo to give the desired product 1 - ((1H-indol-4-yl) methyl) -N ⁵ - ((1R, 5S, 6s) -3-azabicyclo [3.1.0] hexane-6- yl) -N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (29.4 mg; 0.070 mmol; 39% yield) as a green solid.

LCMS (2 min formate method): retention time 0.46 min, [MH] ⁺ 379.4.

Example 80 1- (1- (1H-Indol-4-yl) ethyl) -N ⁵ - ((1r, 4r) -4-hydroxycyclohexyl) -N ³ -methyl-1H-pyrazole 3.5-dicarboxamide

- 87 038888

In solution N ⁵ - ((1 r, 4r) -4-hydroxycyclohexyl) -N ³ -methyl-1- (1- (1-tosyl- 1H-indol-4-yl) ethyl) - 1 H-pyrazole-3 , 5-dicarboxamide (330 mg; 0.585 mmol) in methanol (2 ml) and THF (4 ml), Cs ₂ CO ₃ (1546 mg; 4.74 mmol) was added and the reaction mixture was stirred at 70 ° C for 2.5 h. The reaction mixture was concentrated in vacuo and distributed between ethyl acetate and water and washed with brine. The layers were separated and the aqueous layer was further extracted with ethyl acetate (2x15 ml). The organic layers were combined, dried with a hydrophobic frit and concentrated in vacuo to give 153 mg of a crude residue. The crude product was dissolved in DMSO: methanol 1: 1 (2 ml) and purified by MDAP (formate method). The fractions containing the desired product were distributed between sat. NaHCO ₃ solution and DCM. The layers were separated and the aqueous layer was further extracted with two additional portions of DCM (2x15 ml). The organic layers were combined, dried (hydrophobic frit) and concentrated in vacuo to give the title compound (79 mg; 0.193 mmol; 33% yield).

LCMS (2 min formate method): retention time 0.76 min, [MH] ^- 408.

Example 81.1 - ((S *) - 1- (1 H-Indol-4-yl) ethyl) -N ⁵ - ((1 r, 4S) -4-hydroxycyclohexyl) -N ³ -methyl-N-pyrazole -3,5-dicarboxamide (individual enantiomer of unknown configuration at the methyl center)

mg 1- (1- (1 H-indol-4-yl) ethyl) -N ⁵ - ((1 r, 4r) -4-hydroxycyclohexyl) -N ³ -methyl-1 H-pyrazole-3,5-dicarboxamide (for the preparation, see example 80) was separated by chiral column chromatography using the following conditions.

The crude sample was dissolved in EtOH (4 ml) with heating.

Sample: 2 ml of the solution was injected onto the column.

Solvent: 20% EtOH (plus 0.2% isopropylamine) / heptane, flow rate: 30 ml / min. Wavelength: 215 nm.

Column: Chiralpak AD-H 30 mm x 25 cm (5 μm).

Total number of injected samples: 2.

Fractions corresponding to the first eluted peak were combined and evaporated to give the desired product (30 mg).

LC-MS (method 2 min formate): retention time is 0.74 min, [M-H] ^- is 408.

Example 82 1- (1- (1H-Pyrrolo [2,3-b] pyridin-4-yl) ethyl) -N ³ -methyl-N ⁵ - ((1S, 2S) -2-methylcyclopropyl) -1 H -pyrazole-3,5-dicarboxamide

To solution of N-methyl-N ⁵ - ((1 S, 2S) -2-methylcyclopropyl) -1- (1- (1-tosyl-1 H-pyrrolo [2,3-L] pyridin-4yl) ethyl) - 1H-pyrazole-3,5-dicarboxamide (300 mg; 0.576 mmol) in methanol (2 ml) and THF (4 ml) were added Cs ₂ CO ₃ (1502 mg; 4.61 mmol) and the reaction mixture (suspension) was stirred at 70 ° C for 1.5 h. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was additionally extracted with ethyl acetate (2x20 ml). The combined organic layers were dried with a hydrophobic frit and concentrated in vacuo to give 152 mg of a crude residue. This was purified by chromatography on silica gel eluting with 0-100% ethyl acetate / cyclohexane followed by a gradient of 100%

- 88 038888 ethyl acetate to 25% EtOH / ethyl acetate. Fractions containing the desired product were concentrated in vacuo to afford the desired product as a pale yellow solid (74 mg; 28% yield).

LCMS (2 min formate method): retention time 0.65 min, [MH] ⁺ 367.1.

Example 83. 1 - ((S *) - 1- (1H-Pyrrolo [2,3-b] pyridin-4-yl) ethyl) -N ³ -methyl-N ⁵ - ((1S, 2S) -2- methylcyclopropyl) -1H-pyrazole-3,5-dicarboxamide

Example 82 (62 mg) was purified by chiral HPLC. The racemate was dissolved in EtOH (4 ml) with heating. Sample: 2 ml of solution was injected onto the column, solvent: 20% EtOH (plus 0.2% isopropylamine) / heptane (plus 0.2% isopropylamine), flow rate: 30 ml / min, detection wavelength: 215 nm, bandwidth 4 nm, reference 550 nm, bandwidth 100 nm, column: Chiralpak AD-H 30 mm x 25 cm (5 μm), cat # ADH13231). Total number of injected samples: 2. Fractions eluted from 10 to 11 minutes were collected and noted as peak 1. Fractions eluted from 14 to 16 minutes were collected and noted as peak 2. The collected pure fractions were concentrated in vacuo and then transferred to weighed flasks.

Fractions corresponding to peak 1 were collected to give the compound of Example 83 (23 mg).

LCMS (2 min formate method): retention time 0.67 min, [MH] ⁺ 367.2.

Example 84. 1 - ((1H-Indol-5-yl) methyl) -N ⁵ - ((1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl1H- pyrazole-3,5-dicarboxamide

N ⁵ - ((1R, 5S, 6r) -3-Oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1 - ((1-tosyl-1H-indol-5-yl) methyl) -1Hpyrazole-3,5-dicarboxamide (135 mg; 0.253 mmol) was suspended in THF (2 ml) and methanol (1 ml). Cesium carbonate (412 mg; 1.265 mmol) was added and the reaction mixture was left stirring at 70 ° C for 1 hour. The reaction mixture was concentrated in vacuo. Water (20 ml) was added to the residue and extracted with ethyl acetate (2x15 ml). The combined organic layers were dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to afford the desired product (67.4 mg; 0.169 mmol; 67% yield) as a pale brown solid.

LCMS (2 min high pH method): retention time 0.76 min, [MH] ⁺ 380.5.

Example 85. 1- (1- (1H-Indol-5-yl) ethyl) -N ⁵ - ((1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexane-6-yl) -N ³ - methyl 1H-pyrazole-3,5-dicarboxamide

N ⁵ - ((1R, 5S, 6r) -3-Oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1- (1- (1-tosyl-1H-indol-5-yl) ethyl) -1H-pyrazole-3,5-dicarboxamide (117 mg; 0.214 mmol) was taken up in THF (2 ml) and methanol (1 ml). Cesium carbonate (348 mg; 1.068 mmol) was added and the reaction mixture was left stirring at 70 ° C for 2 h. Water (15 ml) was added to the residue and extracted with ethyl acetate (2x15 ml). The combined organic layers were dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give a colorless solid. The crude product was purified by MDAP (formate method). The product was not collected by MDAP, so the waste material was concentrated in vacuo and the residue was purified by MDAP (formate method). The product was not collected by MDAP, so the waste material was concentrated in vacuo and the residue was purified by MDAP (formate method). The corresponding fractions were dried in a nitrogen stream to give 1 (1- (1H-indol-5-yl) ethyl) -N ⁵ - ((1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -N ^3- methyl-1H-pyrazole-3,5 dicarboxamide (12.2 mg; 0.028 mmol; 13% yield) as a white solid.

LCMS (2 min formate method): retention time 0.82 min, [M-H] ^-

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392.

Example 86. 1- (1- (1H-Indol-4-yl) ethyl) -N ⁵ - ((1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -N ³ - methyl1H-pyrazole-3,5-dicarboxamide

To solution N ⁵ - ((1R, 5S) -3-oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1- (1- (1-tosyl-1H-indol-4yl) ethyl) -1H-pyrazole-3,5-dicarboxamide (278 mg; 0.508 mmol) in methanol (2 ml) and THF (4 ml) was added Cs ₂ CO ₃ (1323 mg; 4.06 mmol) and the reaction mixture was stirred at 70 ° C for 2.5 hours. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was additionally extracted with ethyl acetate (2x20 ml). The combined organic layers were dried with a hydrophobic frit and concentrated in vacuo to give 152 mg of a crude residue, which was purified by MDAP (formate method). The fractions containing the desired product were partitioned between saturated NaHCO ₃ solution and DCM. The organic layer was separated and the aqueous layer was further extracted with DCM (2x20 ml). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo to afford the desired product (44 mg; 0.101 mmol; 20% yield) as a light brown solid.

LCMS (high pH method): retention time 0.80 min, [MH] ^- 392.

Example 87. 1 - ((S *) - 1- (1H-Indol-4-yl) ethyl) -N ⁵ - ((1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl ) -N ³ methyl-1H-pyrazole-3,5-dicarboxamide

mg 1- (1- (1H-indol-4-yl) ethyl) -N ⁵ - ((1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl- 1H-pyrazole-3,5-dicarboxamide (for preparation see Example 86) was separated by chiral column chromatography using the following conditions.

The crude sample was dissolved in EtOH (4 ml) with heating.

Sample: 2 ml of the solution was injected onto the column.

Solvent: 20% EtOH / heptane, flow rate: 30 ml / min.

Wavelength: 215 nm.

Column: Chiralpak AD-H 30 mm x 25 cm (5 μm).

Total number of injected samples: 2.

Fractions corresponding to the first eluted peak were combined and evaporated to give the desired product (13 mg).

LCMS (method formate): retention time is 0.80 min, [M-H] ^- is 392.

Example 88 1 - ((S) -1- (3-Chlorophenyl) ethyl) -N ⁵ - ((1R, 3R, 5S, 6r) -3-hydroxybicyclo [3.1.0] hexan-6-yl) N ³ -methyl-1H-pyrazole-3,5-dicarboxamide

N ⁵ - ((1R, 5S, 6r) -3 - ((tert-Butyldimethylsilyl) oxy) bicyclo [3.1.0] hexan-6-yl) -1 - ((S) -1- (3-chlorophenyl) ethyl ) -N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (257 mg; 0.497 mmol) was taken up in 4M hydrochloric acid in dioxane (5 ml; 20.00 mmol) and left to stir at room temperature for 30 min. The reaction mixture was concentrated in vacuo to give a brown gum. The crude product was purified by MDAP (high pH method). The corresponding fractions were concentrated in vacuo to give 1 - ((S) -1- (3-chlorophenyl) ethyl) -N ⁵ - ((1R, 3R, 5S, 6r) -3hydroxybicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (35 mg; 0.083 mmol; 17% yield) as a yellow solid.

LCMS (2 min formate method): retention time 0.89 min, [MH] ⁺ 403.6.

The compound of the following example was prepared in a manner similar to that for the preparation of the compound of example 88

- 90 038888

Intermediate 82 (system, retention time,

Formate,

0.88 min, 383.3

Intermediate used

Hydroxycyclo [3.1.01-hexane-61/7-pyrazole-3,5-dicarboxamide

Example 90. 1 - ((S) -1- (3-Chlorophenyl) ethyl) -N ⁵ - ((1R, 3S, 5S, 6r) -3-hydroxibicyclo [3.1.0] hexan-6-yl) N ³ -methyl-1 H-pyrazole-3,5-dicarboxamide \ - ((। Α 3 /?. 55.6γ) -3yl) -A ³ -methyl-1 - ((5) -1-phenylpropyl) -

N ⁵ - ((1R, 5S, 6r) -3 - ((tert-Butyldimethylsilyl) oxy) bicyclo [3.1.0] hexan-6-yl) -1 - ((S) -1- (3-chlorophenyl) ethyl ) -N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (257 mg; 0.497 mmol) was placed in 4M hydrochloric acid in dioxane (5 ml; 20.00 mmol) and left to stir at room temperature for min. The reaction mixture was concentrated in vacuo to give a brown gum. The crude product was purified by MDAP (high pH method). Desired fractions were concentrated in vacuo to give 1 - ((S) -1- (3-chlorophenyl) ethyl) -N ⁵ - ((1R, 3S, 5S, 6r) -3-hydroxybicyclo [3.1.0] hexane-6- ul) -N ³ -methyl-1H-pyrazole-3,5-dicarboxamide (52.5 mg; 0.124 mmol; yield 24.91%) as a cream solid.

LCMS (2 min formate method): retention time 0.92 min, [MH] ⁺ 403.6.

The compound of the following Example was prepared in a manner similar to that for the preparation of the compound of Example 90.

Example 92 1-Benzyl-N ⁵ -cyclopropyl-N ³ -methyl-1 H-pyrazole-3,5-dicarboxamide

Intermediate connection 82

Intermediate used

Formate,

0.91 min,

LC-MS:

(system, retention time,

Hydroxycyclo [3.1.01-hexane-61/7-pyrazole-3,5-dicarboxamide No. - ((! / ?, 35.55.6g) -3yl) -A ³ -methyl-1 - ((5) -1 -phenylpropyl) -

To a solution of 1-benzyl-3- (methylcarbamoyl) -1H-pyrazole-5-carboxylic acid (1 g; 3.66 mmol) and DIPEA (3.84 ml; 21.99 mmol) in DMF (1 ml), stirring under nitrogen at room temperature, oxalyl chloride (0.642 ml; 7.33 mmol) was added followed by cyclopropanamine (0.418 g; 7.33 mmol) in one portion. The reaction mixture was stirred at room temperature for

- 91 038888 for 16 hours. The reaction mixture was poured into ice water, then extracted with EtOAc (3x20 ml), the combined organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude product. The crude product was added to a silica gel 60-120 column and eluted with 65% EtOAc in n-hexane and the collected pure fractions were concentrated in vacuo to give 1-benzyl-N ⁵ -cyclopropyl-N ³ -methyl-1H-pyrazole 3,5-dicarboxamide ( 901 mg; 2.75 mmol; 75% yield) as an off-white solid.

LCMS (5.5 min Method E): Retention time 2.47 min, [MH] ⁺ 299.3. Examples 93-138.

The compounds of Examples 93-138 were prepared in a manner analogous to the method for preparing the compounds of Examples described above.

Example No. Name Structure [MH] ⁺ Retention time (min), method 93 X-Benzyl-A ^ -methyl-A ⁵ (tetrahydro-2H-pyran-4-yl) III-pyrazole-3,5 dicarboxamide z / I 343.1 1.72 (Method A) 94 1-Κοη3π.ι- \ 9 \ ⁵ -ιιμοιι.ι-1 // - pyrazole-3,5-dicarboxamide ⁰ / = \ HnV m ^/ V and / Y ν ΗΝ ^ θ \ 273.1 1.63 (Method A) 95 X-Benzyl-A ^ -methyl-A ⁵ - ^ (piperidin-4-yl) ethyl) -Spirazole-3,5-dicarboxamide o / e ό ™ ° Ν N 370.2 1.34 (Method A) 96 X-Benzyl-A ^ -isopropyl-A ³ methyl-XH-pyrazole-3,5 dicarboxamide 9 \ O 301.2 1.91 (Method B) 97 X-Benzyl-A ^ -methyl-A ⁵ propyl-XH-pyrazole-3,5 dicarboxamide 9 D Ν, 9 ^HN ^ O 301.2 1.93 (Method B) 98 X-Benzyl-A ^ -ethyl-A ^ -methyl- XY-pyrazole-3,5 dicarboxamide 9 Ц N Р nV ^ hV ί О 287.4 1.77 (Method D) 99 X-Benzyl-A ^ -methyl-A ⁵ (tetrahydrofuran-Z-yl) -X // pyrazole-3,5-dicarboxamide 9 VyJ ³ ° \ 3 '° 329.3 1.69 (Method B)

- 92 038888

one hundred N-Cyclopropyl-1- (4fluorobenzylrA ^ -methyl-EHpyrazole-3,5-dicarboxamide ^ο γΝΗ Anh ⁰ V 317.1 1.82 (Method B) 101 A ^ -cyclopropyl -! - ^ fluorobenzyl EA'-methyl -! // pyrazole-3,5-dicarboxamide \ O ^ ^NH f ^N II Yu \ o V / hn ' 317.1 1.78 (Method E) 102 1- (4-Cyanobenzyl) -A ^{/ 5} cyclopropyl-A ^ -methyl-EH pyrazole-3,5-dicarboxamide \ O ^ ^NH Λ Α} Λ ° 324.1 1.67 (Method B) 103 A ^{/ 5} -cyclopropyl-1- (3methoxybenzylrA ^ -methyl -! // pyrazole-3,5-dicarboxamide O ^ NH <ό / \ N-4 AX ⁷ > 0 HN V 329.1 6.28 (Method C) 104 A ^{/ 5} -cyclopropyl-1- (4methoxybenzylrA ^ -methyl-EHpyrazole-3,5-dicarboxamide one HN ^ O nA y ° HN 329.2 1.82 (Method B) 105 A ^ -Cyclopropyl-A ^ -methyl -! (4-methylbenzyl) -EN-pyrazole 3,5-dicarboxamide oAh VjA Y ⁰ 313.1 6.63 (Method C) 106 A ^{/ 5} -cyclopropyl-1- (2methoxybenzylrA ^ -methyl-EI pyrazole-3,5-dicarboxamide oAn ^HN \ ^ 329.2 1.76 (Method B)

- 93 038888

107 1 - ((1H-Indol-4-yl) methyl) -L ^{/ 5} ((11?, 55, b5) -3-acetyl-3azabicyclo [3.1.0] hexane-6yl ^ A ^ -methyl-HH-pyrazole -3 ^ dicarboxamide IZ χ ZI Z-Z 4 t 421.3 0.69 (Formate method) 108 А ³ -Ethyl-No - ((1d, 45) -4hydroxycyclohexyl) -1 - ((5) 1-phenylethyl) -1L-pyrazole-3,5 dicarboxamide raz 1} ---- About bn 385.3 0.88 (Formate method) 109 ^ - ((1 ^, 55.6 ^ -3- Oxabicyclo [3.1.0] hexane-6yl) -AR-methyl-1 - ((1?) - 1phenylethyl) -1H-pyrazole-3,5 dicarboxamide ..R Z-Z ojn 355.3 0.85 (Formate method) 110 V - ((lr. 4 /?) - 4- Hydroxycyclohexyl) -ARmethyl-1 - ((7?) - 1-phenylethyl) III-pyrazole-3,5 dicarboxamide ... R u.o 1 X AP * ¹ s / 371.3 0.82 (Formate method) 111 \ ⁵ - (1 -Ghydroxypropan-2-yl) A ^ -m eti l-1 - ((5) -1-phenylethyl) 1 // - pyrazole-3.5 dicarboxamide, a mixture of diastereomers -Р Ζ-Ζ z ^ZX 331.1 0.79 (Formate method) 112 (5) -A ^{/ 5} - (/ iresh-Butyl) -A ^{/ 3} methyl-1- (1-phenylethyl) -Spyrazole-3,5-dicarboxamide IZ ^Z zz cP 329.1 1.08 (Formate method)

- 94 038888

113 L ^{/ 5} - ((5) -vshb> p-Butyl) -L ^{/ 3} -methyl1 - ((5) -1-phenylethyl) -1 // pyrazole-3,5-dicarboxamide Z-Z \ ^ Ζ ΖΙ Γΐ ζ 329.2 1.04 (Formate method) 114 No - ((l / ?, 3 / ?, 55.6s) -3- Hydroxycyclo [3.1.0] hexan-6-yl) - \ ⁵ -methyl-1 - ((5) 1-phenylethyl) -1 / / -pyrazole-3,5 dicarboxamide o ^N 'N ΗΝ- <Γ Y ..... he has 369.4 0.79 (High pH Method) 115 (5) -A ⁵ - (2-H hydroxyethyl) -A ³ methyl-1- (1-phenylethyl) -! // pyrazole-3,5-dicarboxamide O u n || yy ^N 'N hn - h ^ he o 317.1 0.75 (Formate method) 116 ^ -L ^ - ^ - Cyanoethyl) - ^ ³ methyl-1- (1-phenylethyl) -1Hpyrazole-3,5-dicarboxamide O n T yy ^N 'N hn ^ Y.' - = n O 326.1 0.86 (Formate method) 117 (5) -No- (2- (1 // - imidazol-4yl) ethyl) -A ³ -methyl-1- (1phenylethyl) -1 // - pyrazole-3,5-dicarboxamide О Н т уу ^N 'v ^hn ^ Anh 367.1 0.53 (Formate method) 118 (5) - \ ³ -Mep1l- \ ⁵ - (3morpholinopropyl) -1- (1phenylethyl) -1 // - pyrazole-3,5 dicarboxamide o O ⁿ T yu ^Ν 'Ν οΑ 400.2 0.54 (Formate method) 119 (5) - ^ ³ -Methyl-1- (1phenylethyl) -D ^{? 5} - (2- (pyridin-4yl) ethyl) -1 // - pyrazole-3,5 dicarboxamide O .0 n τ yy ^Ν 'Ν ΗΝ-h' -C Ν 0 378.1 0.56 (Formate method)

- 95 038888

120 (5) -No- (3- (Dimethylamino) prop11l) - \ ³ -met11L-G (G phenylethyl) -1 // - pyrazole-3,5 dicarboxamide HN ^ O V / H Г ™, ^{v 0} a _n ^z \ 358.1 0.53 (Formate method) 121 (^ - ^ - (r-methoxyethyl) - ^ ³ methyl-1- (1-phenylethyl) -1 // pyrazole-3,5-dicarboxamide o o h η yy ⁿ 'N hn ^ A. / = ( ⁴ w 331.1 0.87 (Formate method) 122 (A) - \ ⁵ - (2- (1 // - im1azol-2yl) ethyl) -A ³ -methyl-1-Clphenyl ethyl) -! // - pyrazole-3,5 dicarboxamide o \ JI _Λ ^H н тУу ^N 'N hnA _n > 0 367.1 0.52 (Formate method) 123 (LuD ^ -Metyl-1 - (1 phenylethyl) -No- (pyridine-4ylmethyl) -1 // - pyrazole-3,5 dicarboxamide 41¼¼ O 364.1 0.56 (Formate method) 124 (5) A ³ -Methyl-1- (1phenylethyl) -A ⁵ - (2- (pyridin-3yl) ethyl) -1 // - pyrazole-3,5 dicarboxamide О P h li yy ^N 'N / = (\ = N w 378.1 0.58 (Formate method) 125 (5) A ³ -Methyl-1- (1phenylethyl) -No- (2- (pyridin-2yl) ethyl) -1 // - pyrazole-3,5 dicarboxamide 0 h li yy, - (/ у ⁿ 'N hnA \ = / cT 378.1 0.59 (Formate method) 126 (5) - \ ⁵ - (2.2-Dif1ore1yl) - \ ³ methyl-1- (1-phenylethyl) -1 // pyrazole-3,5-dicarboxamide 0 ht yy ⁿ 'N hn ^) - ^F / = \ ^F W 337.1 0.95 (Formate method) 127 No.- (2- (4-Acetylmorpholine-2yl) ethyl) -A ³ -methyl-1 - ((5) -1phenylethyl) -1 // - pyrazole-3,5- 0 P \ ^H N / H / = ° ^N 'N HN ^ / —ne ~ 428.2 0.81 (Formate method)

- 96 038888

dicarboxamide, a mixture of diastereomers 128 No. - ((1, 35) -3G hydroxycyclobutyl) - ^ ³ methyl-1 - ((5) -1-phenylethyl) 1 // - pyrazole-3,5 dicarboxamide I about 343.1 0.80 (Formate method) 129 A (-Methyl-L (A) -! Phenylethyl) -A ^{/ 5} - ((tetrahydro2H-pyran-2-yl) methyl) -Spyrazole-3,5-dicarboxamide, a mixture of diastereomers at. O 371.1 ι, οι (Formate method) 130 ^ - ((15.25) -2G hydroxycyclobutyl) -A ^g3 methyl-1 - ((5) -1-phenylethyl) 1 // - pyrazole-3.5 dicarboxamide zz ^z iQ O \\ / O X ZZ b 343.1 0.82 (Formate method) 131 1 - ((5 ^A ) -1- (III-Indol-4yl) ethyl) -V - ((lr, 45) -4hydroxycyclohexyl) - ^ ³ methyl-TH-pyrazole-3,5 dicarboxamide / = \ O HnA. / n4NH ° Yong no MH- 408.3 0.74 (Formate method) 132 1 - ((5) -1- (III-Indol-4yl) ethyl) -A ^{/ 5} - ((15.55.6g) -3oxabicyclic o [3.1.0] hexane-6ylRA ^ -methyl-III-pyrazole- 3 ^ dicarboxamide o n y-N NM / ^: Λ ^r aA'N H O H MH- 392.3 0.77 (Formate method) 133 LU (15,55,6g) -3-Oxabicyclo [3.1.0] hexane-6i l) - \ ³ -m en I l-1 - ((5) -1 (pyridin-2-yl) ethyl) -THpyrazole -3,5-dicarboxamide 0.H Hhh * h about H 356.5 0.67 (High pH Method)

- 97 038888

134 (5) -7U ³ -Methyl-7U ⁵ - (1H-pyrazol4-yl) -1- (1- (pyridin-2yl) ethyl) -1 // - pyrazole-3,5 dicarboxamide about _h y- NH C / & ¹ An about n 340.5 0.53 (Formate method) 135 7Y ³ -Methyl-7Y ⁵ - ((15.25) -2methylcyclopropyl) -1- (1- (1tosyl-III-pyrrolo [2,3b] pyridin-4-yl) ethyl) -1Hpyrazole-3,5-dicarboxamide , a mixture of diastereomers O. n -zy ί γ Λ he 521.1 1, I (Formate method) 136 M - ((1 /?. 55.6g) -3- Oxabicyclo [3.1.0] hexane-6yl) -1 - ((5) -1- (2-methoxyphenyl) ethyl D ^ -methyl-PT-pyrazole 3,5-dicarboxamide o _h n yN riAb A nAg / n He 385.2 0.84 (Formate method) 137 1 - ((1?) - 1- (1H-Pyrrolo [2,3b] pyridin-4-yl) ethyl) -A ³ methyl-7Y ⁵ - ((15,25) -2methylcyclopropyl) -! // pyrazole- 3,5-dicarboxamide O. n № = \ αΑ / ν-ζ / \ hn γ т у he 367.2 0.66 (Formate method) 138 1 - ((5) -1- (3-Chlorophenyl) ethyl) \% (l /?. 3 /?. 55.6v) -3hydroxybicyclo [3.1.0] hexan-6-yl) - \ '- mciii.i -1Npyrazole-3,5-dicarboxamide o O _n n t u. ^N 'N HN— <U A ..... he A'-' zsaZ n o CI 403.6 0.87 (Formate method)

Example 139. N ⁵ - ((1 r, 4S) -4-Methoxycyclohexyl) -N ³ -methyl-1 - ((S) -1-phenylethyl) -1 H-pyrazole-3,5 dicarboxamide

^ Y3- (Methylcarbamoyl1- (1-phenylethyl) -III-pyrazole-5-carboxylic acid (for preparation see intermediate 5; 112 mg; 0.410 mmol) was dissolved in DMF (1 ml) before adding HATU (234 mg; 0.615 Then hydrochloride (1g, 4g) -4-methoxycyclohexan-1-amine (82 mg; 0.445 mmol) was added followed by the addition of DIPEA (0.358 ml; 2.049 mmol) and the reaction mixture was stirred at room temperature for 2 h. purified immediately by MDAP (high pH method). The appropriate fractions were combined and concentrated in vacuo to give N ⁵ - ((1 g, 4S) -4-methoxycyclohexyl) -N ³ -methyl-1 - ((S) - 1-phenylethyl) -1 H-pyrazole-3,5 dicarboxamide (135 mg; 0.316 mmol; 77% yield).

LCMS (2 min formate method): retention time 0.96 min, [MH] ⁺ 385.2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 8.32 (d J = 7.83 Hz, 1H), 8.09-8.17 (m, 1H), 7.20-7.34 (m, 6H), 6.67 (q, J = 7.01 Hz, 1H), 3.60-3.74 (m , 1H), 3.23 (s, 3H), 3.03-3.14 (m, 1H), 2.78 (d, J = 4.65 Hz, 3H), 1.94-2.05 (m, 2H), 1.84 (d, J = 7 , 09 Hz, 4H), 1.71-1.79 (m, 1H), 1.13-1.40 (m, 4H).

Example 140. N ⁵ - ((1R, 5S, 6d) -3-Oxabicyclo [3.1.0] hexan-6-yl) -1- (indolin-4-ylmethyl) -N ³ -methyl-1Hpyrazole-3,5 -dicarboxamide

- 98 038888

- ((1 H-Indol-4-yl) methyl) -N ⁵ - ((1R, 5 S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -N ³ -methyl-1 H β-pyrazole 3,5-dicarboxamide (for the preparation see example 78; 10 mg; 0.026 mmol) was placed in glacial acetic acid (1 ml). Sodium cyanoborohydride (3.31 mg; 0.053 mmol) was added and the reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The aqueous layer was concentrated in vacuo and extracted with 10% MeOH in DCM. The combined organic layers were passed through a hydrophobic frit and concentrated in vacuo to give a crude residue, which was purified by MDAP (high pH method). The appropriate fractions were concentrated in vacuo to give N ⁵ - ((1R, 5 S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -1 - (indolin-4-ylmethyl) -N ³ -methyl- 1 H-pyrazole-3,5-dicarboxamide (3.8 mg; 8.47 μmol; 32% yield) as a white solid.

LCMS (2 min high pH method): retention time 0.69 min, [MH] ⁺ 382.2.

Example 141 1- (1- (3- (2-Hydroxyethoxy) phenyl) ethyl) -N ³ -methyl-N ⁵ - ((1S, 2S) -2-methylcyclopropyl) 1H-pyrazole-3,5-dicarboxamide, mixture of diastereomers

O. / At NH nA

ETC

1- (1- (3- (2 - ((tert-Butyldimethylsilyl) oxy) ethoxy) phenyl) ethyl) -N ³ -methyl-N ⁵ - ((1S, 2S) -methylcyclopropyl) -1H-pyrazole-3, 5-dicarboxamide (for the preparation see intermediate 132; 1.1 g; 2.197 mmol; mixture of diastereomers) was dissolved in DCM (20 ml) and HCl (5 ml; 5.00 mmol; 1M in ether) was added, then the mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo and the residue was dissolved in DCM (10 ml) and loaded onto a SNAP Ultra 25 g silica column eluted with 0-100% (25% EtOH / EtOAc) / cyclohexane , and the product-containing fractions were evaporated in vacuo to give 1- (1- (3- (2-hydroxyethoxy) phenyl) ethyl) -N ³ methyl-N ⁵ - ((1S, 2S) -2-methylcyclopropyl) -1H-pyrazole -3,5-dicarboxamide (0.71 g; 1.837 mmol; 84% yield; mixture of diastereomers) as a colorless solid.

LCMS (2 min formate method): retention time 0.81 min, [M + Na] ⁺ 409.3.

Example 142. (+/-) - N ⁵ - ((1R, 5S, 6r) -3-Oxabicyclo [3.1.0] hexan-6-yl) -1- (1- (3- (2-hydroxyethoxy) phenyl ) ethyl) -N ³ -methyl-1 H-pyrazole-3,5-dicarboxamide

(+/-) - 1 - (1 - (3 - (2 - ((tert-Butyldimethylsilyl) oxy) ethoxy) phenyl) ethyl) -3 - (methylcarbamoyl) -1 H-pyrazole-5-carboxylic acid (regarding the preparation see intermediate 131; 0.27 g; 0.603 mmol), (1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexane-6-amine hydrochloride (0.106 g; 0.784 mmol), HATU (0.298 g; 0.784 mmol) and Et ₃ N (0.252 ml; 1.810 mmol) were dissolved in DCM (20 ml) and the mixture was stirred for 2 h, then left to stand over the weekend at room temperature. The resulting mixture was stirred with water (50 ml) for 1 h, then the organic layer was separated, dried and evaporated in vacuo to give a pale yellow gum. It was dissolved in DCM and loaded onto a SNAP Ultra 100 g silica column and eluted with 0-100% EtOAc / cyclohexane. The product-containing fractions were evaporated in vacuo to give (+/-) - N ⁵ - ((1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan6-yl) -1- (1 - (3 - (2- ((tert-butyldimethylsilyl) oxy) ethoxy) phenyl) ethyl) -N ³ -methyl-1 H-pyrazole-3,5-dicarboxamide (0.14 g; 0.265 mmol; 44% yield) as a colorless solid. This solid was dissolved in DCM (5 ml) and HCl (2 ml; 2.0 mmol; 1M in ether) was added, then the mixture was stirred in

- 99 038888 for 2 hours at room temperature. The solvent was evaporated in vacuo and the crude product was dissolved in DCM and loaded onto a 10 g silica column and purified by flash chromatography eluting with 0-100% (25% EtOH / EtOAc) / cyclohexane. The product-containing fractions were evaporated in vacuo to give (+/-) - N ⁵ - ((1R, 5S, 6r) -3-oxabicyclo [3.1.0] hexan-6-yl) -1- (1- (3- ( 2hydroxyethoxy) phenyl) ethyl) -N ^3- methyl-1H-pyrazole-3,5-dicarboxamide (81 mg; 0.195 mmol; 32% yield) as a colorless foam.

LCMS (2 min formate method): retention time 0.71 min, [MH] 415.4.

The compounds of the following examples were prepared in a manner analogous to the method for preparing the compound of example 1

Example No. Structure and name [MH ⁺ ] Retention time (min) 143 A / (L \ IZ ZX Z-Z 370.0 1.00 (formate method) (5) -A ^{/ 3-} Methyl-A ^{/ 5} - (3-methylisothiazol-5-yl) -1- (1phenylethyl) -1H-pyrazole-3,5-dicarboxamide 144 θκ ^Н VN 7 ⁴ Р— NAU / - \ GP ¹ /> GCD \ I'd / Ny Lfy i J — N Η Ο Η ^ - ((1 ^, 3 ^, 55.6 ^ -3- Methoxycyclic o [ 3.1.0] hexan-b-yl ^ A ^ -methyl1 - ((5) -1-phenylegyl) -! // - pyrazole-3.5 dicarboxamide 493.1 1.30 (high pH method) 145 θκ ^H V ^N \ _ / OH od / An OH (5) - \ ⁵ - (6-Hydroxyspiro [3.3] heptan-2-yl) -No- methyl-1- (1-phenylethyl) -H-pyrazole- 3,5 dicarboxamide, mixture of diastereomers 383.4 0.86 (formate method) 146 θκ ⁿ yN nA A ^ ^on 1 An about n A ^{/ 5} - ((1d, 45) -4- (Hydroxymethyl) cyclohexyl) -A ^{/ 3} - methyl-1 - ((5) -1-phenylethyl) -H- pyrazole-3,5 dicarboxamide 385.3 0.89 (high pH method) 147 Ok ⁿ nA Αν about n (5) -A ^{/ 3} -Methyl-1- (1-phenylethyl) -A ^{/ 5} - (pyridazin-4-yl) -1 // - pyrazole-3.5-d11carboxam11d 351.0 0.81 (formate method)

- 100 038888

148 nX / 7 ° ^H An ⁷ ^ 0 n LA (15 *, 45 *) - 4-Hydroxy-3,3dimethylcyclohexyl) -7U ³ -methyl-1 - ((5) -1phen ylethyl) -Sh-n and razol- 3,5-d and carboxy mid 399.1 0.94 (high pH method) 149 Oh n yN AA nA ,, / -o A 4 Αν ⁷ !! o n \% (1 /?.55/)Γ)-3-Οκχη6ιιιιικ\ι o [3.1.0] hexane-6- yl) - \ ³ -methyl-1 - ((5) -1 - (. / u <7-1Olyl) e1yl) -1 // pyrazole-3,5-dicarboxamide 369.5 0.94 (high pH method) 150 Οχ n CI A \ nA and r ~ ^Q Up to ^F 1 Αν ⁷ η o Η (+/-) - ^ - ((1 ^, 55.6g) -3-Oxabicyclo [3.1.0] hexane-6-yl) -1- (1- (3-chloro-5-fluorophenyl) ethyl) - / U ³ methyl-III-pyrazole-3,5-dicarboxamide 407.2 1.00 (formate method) 151 uh A Du OuQ £ a * A ~ N O n A ^ 5 - ((ls *, 41? *) - 4-Ethyl-4-hydroxycyclohexyl) - AZ-methyl-1 - ((5) -1-phenylethyl) - III-pyrazole-3,5 dicarboxamide 399.2 1.01 (high pH method) 152 Οχ H um nA .on Ομύ a No. - ((1g *, 35 *) - 3-Hydroxycyclobutyl) - / U ³ - 343.0 0.75 (formate method)

- 101 038888

methyl-l - ((5) - (- phenylethyl) -1 // - pyrazole-3.5 dicarboxamide o _h / ANH / HO nA nA ΟγΎ 0 0.75 153 1 Αν OH (5) - \ '- Me1yl- \ ⁵ - (6-oxo-1,6-dihydropyridin-3yl) -1- (1-phenylethyl) -1H-pyrazole-3,5 dicarboxamide o. / A-NH nA / ^^ ^he O ^{s |} Ύ 366.0 (formate method) 0.98 (method with high 154 o ^x n 1 - ((X) -1- (3-Chlorophenyl) ethyl) - ^ - ((1 ^ 45) -4 (hydroxymethyl) cyclohexyl) A ³ -methyl-1Napirazole-3,5-dicarboxamide o. / ANH nX / P ™ С X ^ na ZZ 419.3 pH value) 0.98 155 sg n 1 - ((X) -1- (3-Chlorophenyl) ethyl) -No - ((15.35.4X) -4hydroxy-3-methylcyclohexyl) -A ^{/ 3-} methyl-17 / pyrazole-3,5 -dicarboxamide about. / ANH nA рme СХА р 'An ¹ ' 419.3 (formate method) 0.91 (method with high 156 o ^z n (+/-) - No - ((1d, ZX) -3-Methoxycyclobutyl) A ³ methyl-1- (1-phenylethyl) -17 / -pyrazole-3,5 dicarboxamide 357.2 pH value)

- 102 038888

157 O. I y-NH nA G / \ OH UL ..... 0 Η 1 - ((5) -1- (3-Chlorophenyl) ethyl) -A ⁵ - ((/ irais) -2- (hydroxymethyl) cyclopropyl) -A ³ -methyl-1Hpyrazole-3,5-dicarboxamide, mixture of diastereomers 377.1 0.87 (high pH method) 158 O. / y-NH G UU guon UL ON 1 - ((5) -1- (3-Chlorophenyl) ethyl) -A ^{/ 5} - ((/ irans) -3hydroxycyclopentylHA ^ -methyl-CH-pyrazole3,5-dicarboxamide, mixture of diastereomers 391.3 0.89 (formate method) 159 1 Ογ ^ΝΗ No. li- (+/-) - L ^ - ((11?, 55.6g) -3-Oxabicyclic o [3.1.0] hexan6-yl) -1- (1- (3-fluoro-2 -methyl phenyl) ethyl) -A ³ methyl-III-pyrazole-3,5-dicarboxamide 387.3 0.93 (formate method) 160 / V-NH A Y ^ ^OH ° n \% (lv.4 /?) - 4-rn.ipoiccniinic.ioieKcn.i) -V ³ -Meiii.i- 1 - ((5 *) - 1- (3 - (trifluoromethyl) -phenyl) ethyl) -Spyrazole-3,5-dicarboxamide 387.3 0.93 (formate method)

- 103 038888

161 ΟγΝΗ er » ⁰ bX n A / '-o 1-Benzyl-L ^{/ 5} - ((11?, 55.6g) -3-oxabicyclo [3.1.0] hexan-6-yl) -A ^{/ 3} -methyl- 1/7 pyrazole-3,5-dicarboxamide 341.2 0.80 (formate method) 162 O _h n / = / AN \ J \ 0 nA _u / - (r I Λ Η ",,. / \ X Χ ^ νΑ λα * Υ ^ Ν Π 0 Η Λ4 (Ι Α35 * .55 * .6ν *) - 3- (Benzyl oxy) bicyclic o [3.1.0] hexan-6-yl) -1 - ((5) 1- (3-chlorophenyl) ethyl) -A ^{/ 3} -methyl-1/7-pyrazole3 , 5-dicarboxamide 493.5 1.30 (high pH method) 163 o _h n G 'ΓΎ dA ^{S |} Ύ about n (5) -1- (1- (3-Chlorophenyl) ethyl) - / ^ - (6-hydroxyspiro [3.3] heptan-2-yl) -L ^ -methyl-1 // pyrazole-3,5 β-dicarboxamide, a mixture of diastereomers 417.4 0.97 (formate method) 164 yy nA \ A> ⁿ yJL ^ n 1 An about n No. - ((15,35,45) -4-G hydroxy-3-methylcyclohexyl) - / Y ³ -methyl-1 - ((5) -1-phenylethyl ) -1H-pyrazole-3,5-dicarboxamide 385.3 0.86 (formate method)

- 104 038888

165 o _h n ΝΑ. Ν С X / N'V f ^ν ά 1 λ Ζ = Ν 1 ΕΝ 0 Η (5) -L ^{/ 5} - (2-Ethyl-2Ya-1,2,3-triazol-4-yl) -L ^{/ 3} methyl-1- (1-phenylethyl) -1 // - pyrazole-3,5-dicarboxamide 368.1 1.00 (formate method) 166 Ο Η oj J У ° ^н 0 H № - ((1g *, 45 *) - 4-Ethyl-4-hydroxycyclohexyl) №-methyl-1 - ((5) -1-phenylethyl) -1Н-pyrazole-3, 5dicarboxamide 399.2 0.91 (high pH method) 167 Οχ ⁿ VN J ⁴ > ^0H nA _u / - (ъг ^F ' ^c I YES 0 H ^ - ((15 * 35 *, 55 * 6r *) - 3- Hydroxybi cyclo [3.1.0] hexane-b-ylrA ^ -methyl- 1 - ((5 *) - 1- (3- (trifluoromethyl) -phenyl) ethyl) -Spyrazole-3,5-dicarboxamide 437.2 0.92 (formate method) 168 V nX О Н V - ((15,35,45) -4-G hydroxy-3methylcyclohexyl) -A ^{/ 3} -methyl-1 - ((5) -1- (l <eshatolyl) ethyl) -III-pyrazole- 3,5-dicarboxamide 399.6 0.95 (high pH method) 169 -n Z-Z 403.6 0.93 (high pH method)

- 105 038888

1 - ((5) -1- (3-Fluorophenyl) ethyl) - ^ - ((15.35.45) -4hydroxy-3-methylcyclohexyl ^ DP-methyl-GNpyrazole-3,5-dicarboxamide 170 O. n 4-N ^F nn nA 1 A / 0 Η (+/-) - A ^{/ 5} - ((1d, 4d) -4-Hydroxycyclohexyl) -A ^{/ 3} methyl-1- (1- (4- (trifluoromethyl) phenyl) -ethyl) -Spyrazole-3,5-dicarboxamide 439.1 0.96 (formate method) 171 0 n yN nA l L NZ / \ An ^Z 0 Η ^ - ((15 *, 25 *) - 2- (Γ idroxymethyl) cycle opropyl) - A ^{/ 3} -methyl-1 - ((5) -1 -phenylethyl) -S-pyrazole-3,5-dicarboxamide 343.1 0.78 (high pH method) 172 Pg ⁿ nA χχ ° СG n no ^ n Formate ^ - / US-methyl-D ^ - ^ - methylpyridin-Zyl) -1- (1-phenylethyl) -11 / -pyrazole-3,5 dicarboxamide 364.0 0.75 (formate method) 173 Pt H nA n- ^ 1 An 0 Η (5) A ³ -Methyl-1- (1-phenylethyl) -L ^{/ 5} - (pyridin-3-yl) -III-pyrazole-3,5-dicarboxamide 350.0 0.75 (formate method)

- 106 038888

174 o, I A ^ NH WtV OH \ ⁵ - ((1 /?.55.6g )-3-Oxabits11cl o [3.1.0] hexan-6- yl) -A ³ -methyl-1 - ((5) -1- (orcho-tolyl) ethyl) -17 / pyrazole-3,5-dicarboxamide 369.3 0.90 (formate method) 175 Q. / y-NH XXr γΥ ° ^η * ⁰ Η 1 - ((5) -1- (3-Chlorophenyl) ethyl) -No - ((! / *, 35) -3hydroxycyclobutyl) - \ '- mep1l-1 // - pyrazole 3,5-dicarboxamide 377.2 0.87 (high pH method) 176 O. / γΝΗ nA .on ^FF oU n No - ((1 /?% 35% 55% 6g ^A ) -3- Hydroxycyclo [3.1.0] hexan-6-yl) -A ³ -methyl- 1 - (( 5 *) - 1- (3- (trifluoromethyl) -phenyl) ethyl) -1Нpyrazole-3,5-dicarboxamide 437.2 0.95 (formate method) 177 Uch Λ ~ ΝΗ ^{N =} \ ^x r? X? Η n A ^{/ 5} - ((11?, 55.6 g) -3-Oxabicyclic o [3.1.0] hexane-6yl) -A ³ -methyl-1 - ((5) -1- (yara-tolyl) ethyl ) -1Npyrazole-3,5-dicarboxamide 369.6 0.95 (high pH method) 178 Oak ^{n Υ Ν \ nA ζγ-, Γ α} ^ να 9V ι λ Λν ι Α ~ ν Ο Η 350.0 0.98 (formate method)

- 107 038888

Formate (5) A ³ -methyl-1- (1-phenylethyl) -L ^{/ 5} (pyridin-2-yl) -1 // - pyrazole-3,5 dicarboxamide 179 o _h n A b I Λ — ΝΗ O A ^{/ 5} - ((15.35) -3-Methoxycyclopentyl) -A ^{/ 3} -methyl1 - ((5) -1-phenylethyl) -1 // - pyrazole-3.5dicarboxamide 371.6 0.98 (high pH method) 180 o 1 y-NH nA МУх ο ^ζ Η Η (+/-) - ^ - ((1 ^, 55.6g) -3-Oxabicyclo [3.1.0] hexan6-yl) -1- (1- (4- chloro-3-fluorophenyl) ethyl) -A ³ methyl-1 // - pyrazole-3,5-dicarboxamide 407.3 0.98 (formate method) 181 o A \ K-NH C10D 0 ^x Αγ Ο ^ Ν ^ Η (5) -1- (1- (3-Chlorophenyl) ethyl) -A ^{/ 5-} ethyl-A ^{/ 3} -methyl1 // - pyrazole-3, 5-dicarboxamide 335.2 1.00 (formate method) 182 θν ^H yN o'n (5) -A ^{/ 5} - (3-Ethyl-4-methylisoxazol-5-yl) -A ^{/ 3} methyl-1- (1-phenylethyl) -1 // - pyrazole-3,5 dicarboxamide 382.0 1.06 (formate method) 183 o _h H y ^N \ ^Ni \.-to O n (5) -A ^{/ 3} -Methyl-1- (1-phenylethyl) -A ^{/ 5} - (thiazol-2-yl) 1 // - pyrazol-3, 5-dicarboxamide 356.0 1.00 (formate method)

The compounds of the following examples were prepared in a manner similar to that for the preparation of the compound of example 81

- 108 038888

Example No. Structure and name [MH ⁺ ] Retention time (min) 184 Ok ⁿ y ^ N L _n L Azv ⁿ Y 'OH ^{S |} 1 A / n OH 1 - ((5) -1- (3-Chlorophenyl) ethyl) -No- ((1 /? *, 25 * 55 * 6 /? *) - 2-hydroxybicyclo [3.1.0] hexan-6-yl) -A ³ -methyl1H-pyrazole-3,5-dicarboxamide 403.5 0.94 (high pH method) 185 Ok H £ luu GU ^on U-N * about n 1 - ((X) -1- (3-Chlorophenyl) ethyl) -A ⁵ - ((11? *, 3R *) - 3hydroxycyclopentyl) -A ³ -methyl- 1H-pyrazole 3.5-dicarboxamide 391.3 0.90 (formate method) 186 Ok Н yN ^N A ^ к С L-ΝΑ Ау " ^he 1 An ^z о n D ^{/ 5} - ((15 *, 35 *) - 3-Hydroxycyclopentyl) -D ^{/ 3} mesl-1 - ((5) -1 -phenylegyl) -! // - pyrazole-3.5 dicarboxamide 357.4 0.80 (formate method)

- 109 038888

187 Οχ ⁿ Ύ ^ν \ nA _λ C <χ-0Η ⁰¹ Ύ α ^ / 0 Η 1 - ((5) -1- (3-Chlorophenyl) ethyl) -No - ((15 *, 35 *) - 3hydroxycyclopentyl) A ^3- methyl-1 // - pyrazole 3,5-dicarboxamide 391.3 0.89 (formate method) 188 Οχ ^H YX nA s r ~ ^{Q F} Ξ Ai / h O H \ d (1 /?. 55 /) g) -3-Oxab111111clo | 3.1.0 | -hexane-6- yl) -1 - ((1? ) -1- (3-fluoro-4-methyl phenyl) ethyl) А ³ methyl-17 / -pyrazole-3,5-dicarboxamide 387.2 0.95 (formate method) 189 ° x ¹ yin nA [A ΝΑ OH ..... OH 1 - ((X) -1- (3-Chlorophenyl) ethyl) -A ^{/ 5} - ((15 *, 2X *) - 2 (hydroxymethyl) -cyclopropyl) -L ³ -methyl-1 // pyrazole-3,5-dicarboxamide 439.3 0.95 (formate method) 190 ^{Ο γΝΗ X ΛΑ / Ν \ r} N v N ° JkX nA / '-o \ d (1 / ?. 55 /) d) -3-Oksabi11iklo | 3.1.0 | -hexane-6-yl) -1- ( (5 *) - 1- (3-fluoro-2-methyl phenyl) ethyl) -A ^{/ 3} methyl-1H-pyrazole-3,5-dicarboxamide 387.2 0.92 (formate method)

- 110 038888

191 ° γΝΗ Ί J ΛΑ ^{α hq / η} Ά ^ - ((P ^^ b / TZ-Oxabicycle ο [3.1.0] -hexane-6yl) -1 - ((5 *) - 1- (3-chlorophenyl) - 2-hydroxyethyl) \ '- methyl-1 // - pyrazole-3.5-1carboxam11d 405.5 0.83 (high pH method) 192 ο. / y-NH Puomv 1 An * o ^z Η A ^{/ 5} - ((15 *, 35 *) - 3-Methoxycyclopentyl) -A ^{/ 3} mesl-1 - ((5) -1-phenylegyl) -1 // - pyrazole-3.5 dicarboxamide 371.6 0.97 (high pH method) 193 o _h ^z y-NH F, C_ ^ nX OD mod / O 1 An '^ O Η D ^{/ 5} - ((1g, 45) -4-Hydroxycyclohexyl) - / Y ³ -methyl1 - ((5 *) - 1 - (4- (trifluoromethyl) phenyl) ethyl) -Spyrazole-3,5-dicarboxamide 439.3 0.95 (formate method) 194 o _h / yNH G / yon 1 A * gon A ^{/ 5} - ((15 *, 35 *) - 3-Hydroxycyclopentyl) -. 5 ^ methyl-1 - ((5) -1-phenylethyl) -1H- pyrazole-3,5 dicarboxamide 357.4 0.79 (formate method) 195 A. ° ryd y he 417.3 1.01 (formate method)

- 111 038888

(5) -1- (1- (3-Chlorophenyl) ethyl) - / ^ - (6hydroxyspiro [3.3] heptan-2-yl) -A ^{/ 3-} methyl-1Hpyrazole-3,5-dicarboxamide 196 of _x and y, ^{H, N} VA YA n-Λ? 1 An * h 0 H 1 - ((5 *) - 1- (1H-Indol-5-yl) ethyl) -A ^{/ 5} - ((11?, 55.6g) -3oxabicyclic o [3.1.0] hexane -6-yl) - / U ³ -methyl-1Hpyrazole-3,5-dicarboxamide 394.2 [MH ⁺ ] 0.80 (formate method) 197 Οχ ⁿ Α ^Ν \ f ₃ c ^ a> nA s A ⁰ n। /> nA \ Α / Ά l 1 An h OH ^ - ((l ^ SX ^^ - S-OKcaOHiiHicjiop.l.OJ-reKcaH-eyl) -A ^{/ 3} -methyl-1 - ((5 *) - 1 - (4- (trifluoromethyl) phenyl) ethyl) -EN-pyrazole-3,5-dicarboxamide 437.3 [MH ⁺ ] 0.94 (formate method) 198 Οχ n yy nA _s ^ ο Hu? a ^F 1 An ^/ h OH ^ - ((l ^ SX ^^ - S-OKcaOHiiHicjiop.l.OJ-reKcaH-e- yl) -1 - ((5) -1- (3-fluoro-4-methyl phenyl ) ethyl) -A ^{/ 3} methyl-1H-pyrazole-3,5-dicarboxamide 387.1 [MH ⁺ ] 0.95 (formate method) 199 Οχ Η Ά ^Ν \ СТ / ΝΑ 1 An * о Η *, 3R *) - 3-Methoxycyclic opentyl) - ^ ³ methyl-1 - ((X) -1-phenylethyl) -1Н-pyrazole-3,5 dicarboxamide 371.6 [MH ⁺ ] 0.97 (high pH method)

- 112 038888

200 O. / ANH J .on Ab A ¹ An ' ⁰ Η (5) -1- (1- (3-Chlorophenyl) ethyl) - / ^ - (6hydroxyspiro [3.3] heptan-2-yl) -L ^{/ 3} -methyl- 1Npyrazole-3,5-dicarboxamide - an individual isomer with unknown stereochemistry in the spirocycle 417.3 1.01 (formate method) 201 Pts N -um aYA ' ^ν λ TSc ^ oh ^С1 1 Li'h * Π О Н 1 - ((5) -1- (3-Chlorophenyl) ethyl) -A ^{/ 5} - ((15 *, 21? *, 51? *, 65 *) - 2-hydroxycyclo- [3.1.0] hexan-6-yl) A ³ -methyl-1 // - pyrazole-3,5 dicarboxamide, diastereomer 1 403.5 0.94 (high pH method) 202 Pt N Α ^Ν \ 'A ha ^he L Α ^ ^Ν A A / v An * ^ 0 H (5) -A ^{/ 5} - (6-Hydroxyspiro [3.3] heptan-2-yl) -A ^{/ 3} methyl-1 - (1-phenylethyl) -1 // - pyrazole-3,5-dicarboxamide - an individual isomer with unknown stereochemistry in the spirocycle 383.3 0.85 (formate method) 203 O H yN i Anh on o A ^{/ 5} - ((15 *, 25 *) - 2- (Hydroxymethyl) cyclopropyl) L'-megyl -! - ((5) -1-phenylethyl) -1 // - pyrazole- 3,5 dicarboxamide, diastereomer 1 343.3 0.78 (high pH method)

- 113 038888

204 Οχ n Cl nA _u ХАу А ^F I yN Η О Η \ ⁵ - ((1 /?. 55.6g) -3 - () xabicyclic o [3.1.0] -hexane-6- yl) -1 - ((5 *) - 1- (3-chloro-5-fluorophenyl) ethyl) -A ^{/ 3} methyl-HH-pyrazole-3,5-dicarboxamide 407.3 1.00 (formate method) 205 Οχ n U-N YES nA un ΑΑ_, Ν A aO OH (5) - \ ⁵ - (6-Hydroxyspiro [3.3] heptan-2-yl) -Nomethyl-1- (1-phenylethyl) -11 / - pyrazole-3,5-dicarboxamide - an individual isomer with unidentified stereochemistry in the sirecycle 383.3 0.85 (formate method) 206 o ⁿ yN HELL nA. i Anh he o \ ⁵ - ((1 /? *. 2 /? '^; ) -2- (Hydroxymethyl) cyclopropyl) -D ^{? 3} -methyl-1- ((5) - 1-phenylethyl) - S-pyrazole -3.5 dicarboxamide 343.2 0.78 (high pH method)

The compounds of the following examples were prepared in a manner analogous to the preparation of the compound of example 88

Example No. Structure and name [MH ⁺ ] Retention time (min) 207 Οχ n VN Г ⁴ хОН YES nA and / Ά ХАу А ^F 4 A / n about n 1 - ((5) -1- (3-Fluorophenyl) ethyl) -A ^{/ 5} - 387.6 0.89 (high pH method)

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((1R, 35.55.6g) -3-hydroxybicyclo [3.1.0] hexan-6-yl) -No-methyl-11 / -pyrazole-3,5 dicarboxamide 208 1 ^Ο γΝΗ J Ο-Κ ^Ν A k y bn No. - ((11?, 35.55.6g) -3-Hydroxycyclo- [3.1.0] hexan-6-yl) -No-methyl-1- ( (5) -1- (l <esha-tolyl) ethyl) -III-pyrazole-3,5-dicarboxamide 383.6 0.92 (high pH method) 209 ^Ο γΝΗ _ On on 1 - ((5) -1- (3-Fluorophenyl) ethyl) -No ((11?, 31?, 55.6g) -3-hydroxycyclo [3.1.0] hexan-6-yl ) -No-methyl-1H-pyrazole-3,5 dicarboxamide 387.6 0.86 (high pH method) 210 OyNH w / bX \ = / \ H H * o y / ⁿ \ / bn No. - ((11?, 35.55.6 g) -3-Hydroxycyclo- [3.1.0] hexan-6-yl) -No- methyl-1 - ((5 *) - 1- (4 (trifluoromethyl) phenyl) ethyl) -III-pyrazole-3,5 dicarboxamide 437.2 0.99 (formate method) 211 O. n U-N G ⁴ > ^0H I Xi / h O H No. - ((11?, 31?, 55.6 g) -3-Hydroxycyclo- [3.1.0] hexan-6-yl) -No-methyl -1 - ((5) -1- (l1vshatolyl) ethyl) -11 / -pyrazole-3,5-dicarboxamide 383.5 0.89 (high pH method) 212 O, H y — N G L.NY / Ch, ° ^{n s} Ϊ OH 1 - ((5) -NZ-Chlorophenyl)) ^ (hydroxymethyl) -cyclopropyl) -AZ-methyl-11 / -pyrazole-3, 5-dicarboxamide 377.1 0.87 (high pH method)

The compound of the following Example was prepared in a manner analogous to that for the preparation of the compound of Example 74.

- 115 038888

Example No. Structure and name [MH ⁺ ] Retention time (min) 213 Οχ ⁿ yy nA ОуМ / А ° Л О n ^ - (3 - ((2 ^, 55) -5-amino-1, 3-dioxan-2-yl) propyl) -1 - ((5) -1- (3-chlorophenyl) ethyl) -A ³ methyl-1H-pyrazole-3,5-dicarboxamide 450.6 0.91 (high pH method)

The compounds of the following examples were prepared in a manner similar to that for the preparation of the compound of example 75

Example No. Structure and name [MH ⁺ ] Retention time (min) 214 o, n yN Xi o ° ~ ^{C |} > D 'but ^{x 0 H} 1 - ((1?) - 1- (3-Chlorophenyl) -2-hydroxyethyl) -A ⁵ - ((1d, 37?) - 3-methoxycyclobutyl) -A ³ -methyl-1-Yapirazole -3,5-dicarboxamide 407.2 0.85 (high pH method) 215 Οχ H yy nA s Γ ^ο G U ¹ /> well \) ri HO ^ OH (+/-) - ^ - ((1 ^, 55.6g) -3-Oxabicyclo [3.1.0] hexane-6- yl) -1- (1- (3-chlorophenyl) -2hydroxyethyl) -A ³ -methyl-1H-pyrazole-3,5 dicarboxamide 405.5 0.84 (high pH method) 216 ° h / smart nA, OMe ΑΑχΝΧ (\ A \ __ Y HO ^ O ^ n (+/-) - 1- (1- (3-Chlorophenyl) -2-hydroxyethyl) -A ⁵ - ((1d, 4d) - 4-methoxycyclohexyl) -A ³ -methyl-1Japirazole-3,5-dicarboxamide 435.2 0.90 (high pH method) 217 А / yNH ΑΧί „ОМе L ОНО ^ 1 - ((1?) - 2-Hydroxy-1-phenylethyl) -A ⁵ - ((1d, 41?) - 4methoxycyclohexyl) -A ³ -methyl-1H-pyrazol3, 5-dicarboxamide 401.4 0.79 (formate method)

The compounds of the following examples were prepared in a manner analogous to the preparation of the compound of example 86

- 116 038888

Example No. Structure and name [MH ⁺ ] Retention time (min) 218 O. ⁿ -um nA _s CMQ Mn 'A ⁿ 1 - ((1H-Indol-7-yl) methyl) -L ^{/ 5} - ((15.55.6 g) -3-oxabicyclic o [3.1.0] hexane-b -ylpD ^ -methyl- 1Hpyrazole-3,5-dicarboxamide 80.3 0.89 (formate method) 219 Oh H AU nA s / ° 1 - ((III-indazol-4-yl) methyl) - ^ - ((15.55.6g) -3oxabicyclic o [3.1.0] hexane-b-ylrD ^ -methyl- 1Hpyrazole-3,5-dicarboxamide 81.3 0.66 (formate method)

The compounds of examples 220-261 were prepared in a manner analogous to the method for preparing the compounds of examples described above.

Example No. Structure and name [MH ⁺ ] Retention time (min) 220 О n ^Ξ „Ll / n ⁰ n 1 - ((5 *) - 1- (1H-Indol-5-yl) ethyl) -A ^{/ 5} ((15.55.6g) -3-oxabicyclo [3.1.0 ] -hexan-6-yl) A ^ -methyl-III-pyrazole-3 ^ -dicarboxamide 416.2 [M + Na] 0.80 (formate method)

- 117 038888

221 o / y-NH ^{C |} odOD nA ^ od / odLod ^F 1 Anh ° b \ ⁵ - ((l /?. 55.6r) -3-OKca6iiniiK \ io | 3.1.0 | -ieKcan-6- il) -1 - ((5 *) 1 - (4-chloro-3-fluorophenyl) ethyl) -A ^{/ 3} methyl-III-pyrazole-3,5-dicarboxamide 407.3 0.98 (formate method) 222 u / P od / od O Ν A ^{/ 5} - ((11? *, 45 *) - 4-hydroxy-3,3dimethylcyclohexyl) -A ^{/ 3} -methyl-1 - ((5) -1phenylethyl) -S-pyrazole -3,5-dicarboxamide 399.1 1.01 (high pH method) 223 Ok ⁿ yN SODY (Un (5) -L ^{/ 3-} Methyl-1- (1-phenylethyl) -No- (1,3,4thiadiazol-2-yl) -S-pyrazole-3,5 dicarboxamide 357.0 0.90 (formate method) 224 Mr. A WododAy _o A-nh ₂ (5) -A ^{/ 3} -Methyl-1- (1-phenylethyl) -1H-pyrazole- 3,5-dicarboxamide 273.2 0.77 (formate method)

- 118 038888

225 0 Ό ^Ν = Λ ^ΝχΗ Αορ Η Η 1 - ((III-Benzo [<1] imidazol-4-yl) methyl) -L ^{/ 5} - ((17?, 55.6g) -3-oxabicyclo [3.1.0 ] hexan-6-yl) A ^ -methyl-III-pyrazole-3 ^ -dicarboxamide 365.4 0.67 (high pH method) 226 o d \ ⁵ - ((1 /?. 3 /?. 55.6ν) -3-Γιιιροκ4ΐι6ιιιιικ \ ιο | 3.1.0 | hexane-6-yl) -A ^{/ 3} -methyl-1 - ((5) -1 - (l <esha-tolyl) ethyl) -S-pyrazole-3,5-dicarboxamide 383.6 0.98 (high pH method) 227 Ap Λ and a ⁰ ОУ He! - ((/?) - 1 - (1Н-ИIi о l-4-i l) ethyl l) -No - ((1 /?. 55.6g) - 3-oxabicyclo [3.1 .0] hexan-6-yl) -A ³ -methyl11 / -pyrazole-3,5-dicarboxamide 392.5 0.80 (formate method) 228 o _h A aa An n about n 1 - ((III-Indol-6-yl) methyl) -No - ((11?, 55.6g) -3oxabicyclo [3.1.0] hexan-6-yl) -A ^{/ 3-} methyl-Spirazole-3,5-dicarboxamide 378.3 [M-H] 0.80 (high pH method) 229 UCA Do 'I 437.2 0.94 (formate method)

- 119 038888

\ ⁵ - ((1 /?. ZA.5A.6g) -3-Hy1rox1 | bit11clo | 3.1.0 | hexan-6-yl) -A ³ -methyl-1 - ((1? *) - 1- ( 4 (trifluoromethyl) phenyl) ethyl) -III-pyrazole-3,5 dicarboxamide 230 θκ ^H / he HELL ..... 1 - ((Y1- (3-Fluorophenyl) ethyl) -AU (15, 3Ya, 4 /?) - 4hydroxy-3-methylcyclohexyluD ^ -methyl1H-pyrazole-3,5- dicarboxamide 403.6 0.97 (high pH method) 231 On / y-NH ⁰ N ADH № - ((1A.Z / ?. 4 /?) - 4-r idroksi-3- methylcyclohexyl) -7U ^3-methyl-1 - ((5) -1-pyrazol feniletilu1Ya -3,5-dicarboxamide 385.3 0.91 (formate method) 232 O. n V ^N \ he / AO ..... ¹ Λ ^νη Λ ⁵ - ((1 Λ.3 / Λ4 /?) -4-1 hydroxy-3-methylcyclohexylrL'-methylN-CAUSCH.chs / br / tolyl) ethyl) -S-pyrazole-3,5-dicarboxamide 399.6 1.00 (high pH method) 233 YO n baO> An 1 1 - ((1 // - Indol-5-yl) methyl) -D ^{/ 3} -cyclopropyl D ^ -methyl-III-pyrazole-3 ^ -dicarboxamide 338.2 1.70 (formate method)

- 120 038888

234 A 0, __ ^ν Ά. _N CH. n a4 AAnh HN ^ O \ 1 - ((III-Indol-4-yl) methyl) -LR-cyclopropyl- A ^ -methyl-III-pyrazole-3,5-dicarboxamide 338.2 1.67 (formate method) 235 0. / V-NH r <A № = \ OH _α ΛΛA <A 1 - ((5) -1- (3-Chlorophenyl) ethyl) -A ^ - ((15.31?, 41?) - 4 hydroxy- 3-methylcyclohexyl) -DR-methylIII-pyrazole-3,5-dicarboxamide 419.3 / 420.4 1.02 (formate method) 236 O. / Anh about n A ^ - ((1x, 31?, 45.55) -4-Hydroxy-3,5dimethylcyclohexyl) -A ^{/ 3} -methyl-1 - ((X) -1phenylethyl) -III-pyrazole- 3,5-dicarboxamide 399.6 1.02 (high pH method) 237 o / Anh nA ^F Anh ⁿ b ⁿ \% (1 /?.55.6g )-3-()xabicyclic o | 3.1.01 hexane-6- yl) -1 - ((1? *) - 1- (4 -chloro-3-fluorophenyl) ethyl) -L ^{/ 3} - mesl-1 // - pyrazole-3.5-dicarboxamide 407.3 0.98 (formate method) 238 H \ / Anh [f ⁴ ! UA z ^ ^{0H F} 'sai ⁿ 437.2 0.96 (formate method)

- 121 038888

No - ((11?, 31 /, 55.6 g) -3-Hydroxycyclo [3.1.0] hexan-6-yl) -No-methyl-1 - ((1? *) - 1- (3 (trifluoromethyl) phenyl) ethyl) -1 / 7-pyrazole-3,5 dicarboxamide 239 Ok H ^{0 th} (5) -No- (4-Cyano-3-methylisoxazol-5-yl) -Nomethyl-1- (1-phenylethyl) -1 / 7-pyrazole-3,5 dicarboxamide 379.0 1.00 (formate method) 240 At OJi V ^F a yX ^f О n (5) -No-Methl-1 - (1-phenylethyl) -No- (5 (trifluoromethyl) -1,3,4-thiadiazol-2-yl) -1 // pyrazole-3,5-dicarboxamide 425.0 1.20 (formate method) 241 O / y — NH YU nA .OH ^{FF Ξ n} No - ((11?, 35.55.6g) -3-Hydroxycyclo [3.1.0] hexan-6-yl) -No-methyl-1 - ((1 ? *) - 1- (3 (trifluoromethyl) phenyl) ethyl) -1 / 7-pyrazole-3,5 dicarboxamide 437.2 0.93 (formate method) 242 Ok ^H Cl Ya ^{Νΐ =} \ and A ⁰ jQuQ b / ^F O n \ ⁵ - ((1 /?.55.6g )-3-Oxabicyclic o [3.1.0] hexane-6- yl) -1 - ((/ ? ^: :) -1- (3-chloro-5-fluorophenyl) ethyl) - \ ³ methyl-1/7-pyrazole-3,5-dicarboxamide 407.3 1.00 (formate method)

- 122 038888

243 0.n yN οΑ in Anh ⁰ A / -0 (5) - / ^ - (2,4-Dimethylpyridin-3-yl) -No-methyl-X- (1-phenylethyl) -XH-pyrazole-3,5 dicarboxamide 378.1 0.62 (formate method) 244 0— +. VX -0 ° n A-cyclopropyl-X-Amethoxybenzyl) - ^ ⁵ methyl-1H-pyrazole-3,5-dicarboxamide 329.2 1.84 (formate method) 245 and l <5 nAA A ⁷ n AnA ngL ° \ A-cyclopropyl-A-methyl-X-A methylbenzyl) -X7 / -pyrazole-3,5 dicarboxamide 313.1 6.68 (15 min TFA method) 246 Οχ ⁿ ΑΝ OJQ <A ^f ΑΑγ y _F 1 An about n (5) -A ^{/ 3} -Methyl-X- (X-phenylethyl) -No- (5 (trifluoromethyl) - X, 3,4-oxade iazol-2 -yl) - 1Hpyrazole-3,5-dicarboxamide 409.0 1.05 (formate method)

- 123 038888

247 Η flcrR W> ΝΗ О \ '- ((1 /?.5А.6g )-3-Oxabpppcl o [3.1.0] hexan-6- yl) -1 - ((5) -2-hydroxy-1-phenylethyl ) -A ^{/ 5} mesh-1 // - pyrazole-3.5-1carboxami1 371.3 0.68 (formate method) 248 o _ch n ol 1 Λ ~ ΝΗ ⁰ E / -Yt V ^N (5) - ^ - (3,5-Dimethylisoxazol-4-yl) -A ³ methyl-1- (1-phenylethyl) -III-pyrazole-3 , 5dicarboxamide 368.0 0.95 (formate method) 249 O. / y-NH 0x0 p ^{on Fp} x A ^{/ 5} - ((1d, 45) -4-Hydroxycyclohexyl) -A ^{/ 3} methyl-1 - ((5 *) - 1- (3 (trifluoromethyl) phenyl) ethyl) - Sh-pyrazole-3,5 dicarboxamide 439.3 0.95 (formate method) 250 ^F X ° X ^N \ ^N \ Z \ Z ^OH = A ^{/ 5} - ((1g, 45) -4-Hydroxycyclohexyl) -A ^{/ 3} - methyl-1 - ((5 *) - 1- (4- (trifluoromethyl ) phenyl) ethyl) -S-pyrazole-3,5 dicarboxamide 439.3 0.95 (formate method)

- 124 038888

251 Οχ Η yN Lear ^Η Α ° and ΑΙΑ \ Y (about 1 /?.55.6g)-3-Oksab11ppkl | 3.1.01 hexan-6- yl) -1 - ((1 *) - 1- (3-chlorophenyl? ) -2-hydroxyethyl) - 7Y ^3- methyl-III-pyrazole-3,5-dicarboxamide 405.5 0.83 (high pH method) 252 O ^ NH STAY ^F ° V A ^{/ 3} -cyclopropyl-1- (4-fluorobenzyl) -A ^{/ 5} -methyl-III-pyrazole-3,5-dicarboxamide 317.2 1.86 (formate method) 253 ^Ο γΝΗ ap ^Ν y-NH A ^{/ 3} -cyclopropyl-1- (2-methoxybenzyl) -A ^{/ 5} methyl-III-pyrazole-3,5-dicarboxamide 329.2 1.78 (formate method) 254 Οχ Η ΑΝ αΛυ ί Αν * η ^r \ ο ^ζ Η D ^{/ 5} - ((11?, 55.6 g) -3-Oxabicycle ο [3.1.0] hexane-6-yl) -1 - ((/ g * ) -1- (3-fluoro-2-methylphenyl) ethyl) -7Y ³ methyl-1H-pyrazole-3,5-dicarboxamide 387.2 0.92 (formate method)

- 125 038888

255 no SOD ™ ° V A ^ -Cyclopropyl-L ^ -fluorobenzyl CL ^ -methyl- III-pyrazole-3,5-dicarboxamide 317.1 1.80 (formate method) 256 _H N О 0% ΗΝ ^ (+/-) - А ³ -cyclopropyl-L ^{/ 5} -methyl-1- (1-phenylethyl) -S-pyrazole-3,5-dicarboxamide 313.2 1.92 (formate method) 257 1 ΗΝ ^ Ο χτώ A> ΝΗ ⁰ A A ^{/ 3} -cyclopropyl-A ^{/ 5} -methyl-1- (3methylbenzyl) -III-pyrazole-3,5 dicarboxamide 339.2 1.93 (formate method) 258 Ox n yN x ° 0ΝΗ H ⁿ A ^ - ((11?, 55.6g) -3-Oxabicyclic o [3.1.0] hexane-6yl) -A ^{/ 3} -methyl-1 - ((1,2,3 , 4-tetrahydroquinolin8-yl) methyl) -III-pyrazole-3,5-dicarboxamide 396.2 0.92 (high pH method)

- 126 038888

259 ^H yO CPy ₀ ΗΝ ^ E Benzyl-A ^ -cyclopropyl-A ^ -methyl-P / pyrazole-3,5-dicarboxamide 395.3 3.83 (10 min formate way) 260 HOO ^{NC n} \ 1- (4-Cyanobenzyl) -A ^{/ 3} -cyclopropyl-A ⁵ methyl-III-pyrazole-3,5-dicarboxamide 324.1 1.71 (formate method) 261 1 ΗΝγΟ dA " ^{0 n} \ A ³ -Cyclopropyl-1- (3-methoxybenzyl) -A ^{/ 5} methyl-1I-pyrazole-3,5-dicarboxamide 329.1 6.35 (15 min TFA method)

Biological data.

Compounds of formula (I) can be tested by one or more of the following assays.

Time-resolved fluorescence resonance energy transfer analysis (TR-FRET).

Bromodomain binding was assessed using a time resolved fluorescence resonance energy transfer competitive assay (TR-FRET). To enable this process, a known high affinity small molecule interacting with the entire BET family was labeled with Alexa Fluor® 647, which is a far red fluorescent dye (reference compound X). Reference compound X acts as a bromodomain binding reporter and is an acceptor fluorophore component in the TR-FRET pair. Europium chelate conjugated with an anti-6 * His antibody was used as a donor fluorophore in a TR-FRET pair. The Ahth-6 * H1s antibody selectively binds to an epitope containing 6 histidine residues for purification attached to the N-terminus of each of the tandem bromodomain protein constructs from BET proteins used in this study. The TR-FRET signal is generated when the donor and acceptor fluorophores are in close proximity, between 20 and 80 A, which is achieved in this assay by binding the reference compound X to the bromodomain protein.

Reference compound X. 4 - ((Z) -3- (6 - ((5- (2 - ((4S) -6- (4-Chlorophenyl) -8-methoxy-1-methyl-4H-benzo [f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-4-yl) acetamido) pentyl) amino) -6-oxohexyl) -2 - ((2E, 4E) -5- ( 3,3dimethyl-5-sulfo-1 - (4-sulfobutyl) -3H-indol-1 -ium-2-yl) penta-2,4-diene-1 -ylidene) -3 -methyl-5sulfoindolin-1-yl ) butane-1-sulfonate)

Into solution N- (5-aminopentyl) -2 - ((4S) -6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [f] [1,2,4] tri- 127 038888 ash [4,3-a] [1,4] diazepin-4-yl) acetamide (see preparation of reference compound J WO 2011/054848 A1; 1.7 mg; 3.53 μmol) in DMF (40 μl) was added AlexaFluor647-ONSu solution (2.16 mg; 1.966 μmol) also in DMF (100 μl). The mixture was podslushivaet using DIPEA (1 μl; 5.73 μmol) and stirred overnight on a vortex mixer.

The reaction mixture was evaporated to dryness. The solid was dissolved in MeCN / water / AcOH (5/4/1; less than 1 ml), filtered and loaded onto a C18 Phenomenex Jupiter preparative column and eluted with the following gradient (A: 0.1% trifluoroacetic acid in water, B: 0 , 1% TFA / 90% MeCN / 10% water): flow rate: 10 ml / min, AU (absorption units): 20/10 (214 nm): 5-35%, t = 0 min: B = 5% ; t = 10 min: B = 5%; t = 100 min: B = 35%; t = 115 min: B = 100% (degree of separation: 0.33% / min).

The major component eluted in the range 26-28% B, but appeared to consist of two peaks. The middle fraction (F1.26), which should contain both components, was analyzed by analytical HPLC (spherisorb ODS2, 1 to 35% for 60 min): elution of the single component at 28% B.

Fractions F1.25 / 26 & 27 were combined and evaporated to dryness. Transferred into DMF, evaporated to dryness, triturated with anhydrous ether and the blue solid dried overnight at less than 0.2 mbar (20 Pa): 1.54 mg.

Analytical HPLC (spherisorb ODS2, 1 to 35% B for 60 min): MSM10520-1: [M + H] + (obs.): 661.8 / - corresponding to M-29. This is equivalent to [(M + 2H) / 2] ⁺ for a calculated mass of 1320.984, which corresponds to M-29. This is the standard case with Alexa Fluor 647 and represents the theoretical loss of two methylene groups under mass spectrometer conditions.

Analysis principle. To generate a TR-FRET signal, the donor fluorophore is excited with a laser at λ 337 nm, which further leads to emission at λ 618 nm. If the acceptor fluorophore is in close proximity, energy transfer can occur which results in the emission of Alexa Fluor® 647 at λ 665 nm. In the presence of a competing compound, the reference compound X can be substituted from the binding to the bromodomain. If substitution occurs, the acceptor fluorophore is no longer in close proximity to the donor fluorophore, which interferes with the fluorescent energy transfer and consequent loss of Alexa Fluor® 647 emission at λ 665 nm.

The competition of compounds of formula (I) with reference compound X for binding to the BET family (BRD2, BRD3, BRD4 and BRDT) was evaluated using truncated proteins binding both bromodomain 1 (BD1) and bromodomain 2 (BD2). To control differential binding to either BD1 or BD2, mutations of individual key tyrosine residues to alanine were made in the acetyl-lysine-binding pockets. To confirm this method, a protein with tandem domains of double mutant residues was prepared for each of the members of the BET family. Using a fluorescent polarization method, the binding affinity was determined for each of the single and double mutants for reference compound X. The affinity of tandem double mutant proteins for reference compound X was significantly reduced compared to unmutated wild-type tandem BET proteins (over 1000-fold reduction in Kd) ... The affinity of bromodomain tandem proteins with single mutations for reference compound X was equal to that of the corresponding unmutated BET protein. These data demonstrated that single mutations of tyrosine to alanine reduced the Kd interactions between the mutated bromodomain and reference compound X by more than 1000-fold. In the TR-FRET competition assay, reference compound X was used at a concentration that is equivalent to the Kd for the unmutated bromodomain, which ensures that no binding in the mutant bromodomain is detected.

Protein production. Recombinant human bromodomains [BRD2 (1-473), (Y113A) and (Y386A); BRD3 (1-435), (Y73A) and (Y348A); BRD4 (1-477), (Y97A) and (Y390A) and BRDT (1-397), (Y66A) and (Y309A)] were expressed in E. coli cells (into the pET15b vector for BRD2 / 3/4 and into the pET28a vector for BRDT) with a 6 (His) tag at the N-terminus. The precipitate of bromodomain with His-tag was resuspended in 50 mM HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid) (pH 7.5), 300 mM NaCl, 10 mM imidazole and 1 μm / ml mixture of protease inhibitors, extracted from coli cells using sonication and purified using a high performance chromatography column with nickel immobilized on Sepharose, proteins were washed and then eluted with a linear gradient of 0500 mM imidazole with 50 mM HEPES buffer (pH 7.5), 150 mM NaCl, 500 mM imidazole for 20 column volumes. The final purification was completed with a Superdex 200 preparative SEC column. The purified protein was stored at -80 ° C in 20 mM HEPES pH 7.5 and 100 mM NaCl. Protein identity was confirmed by identifying proteins from peptide mass prints and the calculated molecular weight was confirmed by mass spectrometry.

Protocol for competitive assays TR-FRET bromodomain BRD 2, 3, 4 and T, mutant BD1 + BD2: all components for the analysis were dissolved in an analytical buffer consisting of 50 mm HEPES pH 7.4; 50 mM NaCl, 5% glycerol, 1 mM DTT (dithiothreitol) and 1 mM CHAPS (3 - ((3-cholamidopropyl) dimethylammonium) -1-propanesulfonic acid). Reference compound X was diluted in assay buffer

- 128 038888 pe, containing 20 nM bromodomain tandem protein with single mutations, to a concentration equivalent to 2-Kd for this bromodomain. The solution containing bromodomain and reference compound X was added to dose-dependent dilutions of test compound or vehicle DMSO (this assay uses a maximum of 0.5% DMSO) in 384-well black Greiner low volume microtiter plates and then incubated for 30 minutes at room temperature ... Anti-6 * His antibodies labeled with europium chelate were added in equal volumes of 3 nM to all wells, followed by additional incubation for 30 min at room temperature. TR-FRET was detected using a Perkin Elmer Multimode plate reader by excitation of the donor fluorophore at λ 337 nm and then, after a delay of 50 μs, measuring the emission from donor and acceptor fluorophores at λ 615 and λ 665 nm, respectively. To control these assays, 16 parallel experiments, both without inhibition (vehicle DMSO) and with inhibition (10-IC50 concentrations of the compound of Example 11 from WO 2011 / 054846A1) were included in each microtiter plate for TR-FRET assay.

Then we used the fitting of a four-parameter curve of the following form:

y = a + ((ba) / (1+ (10 ^A x / 10 ^A c) ^A d), where a is the minimum; b is Hill's slope; c is pIC ₅₀ ; and d is the maximum.

All compounds (compound examples) were tested in BRD4 BD1 and BRD4 BD2 TR-FRET assays, essentially as described above. Those of skill in the art will understand that the results of in vitro binding assays and cellular functional activity assays will vary. Therefore, it should be understood that the pIC ₅₀ values given below are experimental only. The pIC ₅₀ values are expressed in log ₁₀ units.

It was found that the compounds of all examples, with the exception of the compounds of examples 131, 242247 and 249-261, have a pIC _{50 of} at least 5.0 in at least one assay described above.

It was found that the compounds of Examples 94, 96, 102, 106, 108-110, 112, 114, 132, 135, 135, 136, 137, 229, 233, 234, 236-241 and 248 have a pIC _{50 of} at least 5, 0 and less than 6.0 in BRD4 BD2.

All other compounds were found to have a pIC _{50 of} at least 6.0 and less than 8.0 in the BRD4 BD2 assay. In particular, the compound of Example 1 was found to have a pIC ₅₀ value of 7.2 in the BRD4 BD2 assay; it has been found that the compound of example 2 has a pIC ₅₀ value of 7.1 in the assay BRD4 BD2; it has been found that the compound of example 3 has a pIC ₅₀ value of 7.5 in the assay BRD4 BD2; and it was found that the compound of Example 139 has a pIC ₅₀ value of 7.4 in the assay BRD4 BD2.

Calculation of selectivity to BRD4 BD2 relative to BRD4 BD1.

Selectivity for BRD4 BD2 relative to BRD4 BD1 was calculated as follows: Selectivity = BRD4 BD2 pICso - BRD4 BD1 pICso

Compounds of all examples, with the exception of compounds of examples 114, 116, 131, 134, 136-138 and 238-261, were found to have a selectivity for BRD4 BD2 relative to BRD4 BD1 of at least 1 log (logarithmic) unit of at least in at least one of the TR-FRET assays described above, and therefore are at least 10 times more selective for BRD4 BD2 over BRD4 BD1.

The compounds of Examples 1-91, 139-219 have been found to have a selectivity for BRD4 BD2 over BRD4 BD1 of at least 2 log units in at least one of the TR-FRET assays described above and are therefore at least at least 100 times more selective for BRD4 BD2 over BRD4 BD1.

The compound of Example 1 was found to have a selectivity for BRD4 BD2 over BRD4 BD1 of 2.8 log units in at least one of the TR-FRET assays described above.

The compound of Example 2 was found to have a selectivity for BRD4 BD2 over BRD4 BD1 of 3.0 log units in at least one of the TR-FRET assays described above.

The compound of Example 3 was found to have a selectivity for BRD4 BD2 over BRD4 BD1 of 3.0 log units in at least one of the TR-FRET assays described above.

The compound of Example 139 was found to have a selectivity for BRD4 BD2 over BRD4 BD1 of 3.0 log units in at least one of the TR-FRET assays described above.

Claims (19)

1. Compound of formula (I) or its salt, where - 129 038888 R ¹ is —C ^ lkyl or cyclopropyl; R ² represents -C ₀ . ₃ αalkylcycloalkyl, where the cycloalkyl group is optionally substituted with one, two or three R ⁵ groups, which may be the same or different; or R ² is —C ₀ .4 alkylheterocyclyl, wherein said heterocyclyl is optionally substituted with one or two R ⁹ groups, which may be the same or different; or R ² is H, —CH3, —C2.6alkyl, optionally substituted with one, two, three, four or five fluoro substituents, —C2.6alkylOR ⁶ , —C2. ₆ αalkylNR ^10а R ^11а , - (CH2) mSO2C1.3αalkul, - (CH2) mSO2NR ¹⁰ R ¹¹ , - (CH2) mC (O) NR ¹⁰ R ¹¹ , - (CH2) mCN, - (CH2) mCO2R ⁶ , - (CH ₂ ) mNHCO ₂ C1.4 alkyl, - (CH ₂ ) _m NHC (O) C ₁ . ₄ alkyl or - (CH ₂ ) _n heteroaryl, wherein said heteroaryl is optionally substituted with one or two R ⁷ groups, which may be the same or different; R ³ is —H, —C1.4alkyl, cyclopropyl, —CH2F, —C1.3alkyl OR ^6, or —C1. ₃ alkylCN; R ⁴ represents a phenyl or heteroaryl group, where each is optionally substituted with one, two or three R ⁷ groups, which may be the same or different; each R ^{5 is} independently halogen, —C0.6alkyl — R ⁸ , —O — C2. ₆ alkyl-R ⁸ , —OCH ₂ phenyl, —CN or —SO ₂ C ₁ . ₃ αalkyl; R ⁶ is H or —C ₁ . ₄ alkyl; each R ^{7 is} independently oxo, halogen, —C1.4αalkyl optionally substituted with one, two or three fluoro substituents, C3.4cycloalkyl, —C0.3alkylOR ⁶ , —OC2. ₃ alkylOR ⁶ , -C0.3 alkylNR ¹⁰ R ¹¹ , -C0. ₃ αalkyl-CONR ¹⁰ R ¹¹ , -CN, -SO2-C1.3alkyl, -SO2NR ¹⁰ R ¹¹ or -SO2phenyl, optionally substituted with -C ₁ . _{4 by} alkyl; R ⁸ is H, —OR ^6, or —NR ¹⁰ R ¹¹ ; each R ⁹ independently represents halogen, -C1.4alkil, cyclopropyl, cyclobutyl, -CH2CF3, -CH2CHF2, -CH2CH2F, -OCH2CH2OR ^6, -CO-zalkilOR ⁶ -So.zalkilNR ^1O R ^11, -NHCH2CH2OR ^6, -NHCO2C1 ^ kil, oxo, —C (O) R ⁶ , —C (O) OR ⁶ or —C (O) NR ¹⁰ R ¹¹ ; R ¹⁰ and R ^{11 are} each independently selected from H and —C ₁ . ₃ alkyl; R ^10a and R ^{11a are} each independently selected from H and —C ₁ . ₃ alkyl; m is an integer selected from 2, 3 or 4; and n is an integer selected from 0, 1, 2, 3, or 4, wherein said cycloalkyl refers to a saturated hydrocarbon mono- or bicyclic ring or a saturated spiro-linked bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8 , 9 or 10 atoms - members of the ring; said heterocyclyl refers to a non-aromatic heterocyclic monocyclic or bicyclic ring system containing 4, 5, 6, 7, 8, 9 or 10 ring member atoms, including one heteroatom and optionally containing an additional heteroatom selected from nitrogen, oxygen or sulfur; and said heteroaryl refers to a monocyclic or bicyclic group having 5, 6, 8, 9, 10, or 11 ring member atoms including 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen, wherein at least part of the group is aromatic. 2. A compound or salt thereof according to claim 1, wherein R ¹ is methyl. 3. A compound or salt thereof according to claim 1 or 2, wherein R ² is —C ₀ . _{3 is an} alkylcycloalkyl group wherein said cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclohexyl or bicyclo [3.1.0] hexanyl, said groups being optionally substituted with 1, 2 or 3 R ⁵ groups which may be the same or different. 4. A compound or salt thereof according to claim 1 or 2, wherein R ² represents a C ₄ _ ₀ alkylheterocyclyl, wherein the heterocyclyl is selected from oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl, piperidinyl, piperazinyl, (1R, 5S ) -3-oxabicyclo [3.1.0] hexanyl and (1R, 5S) -3-azabicyclo [3.1.0] hexanyl, these groups being optionally substituted with one or two R ⁹ groups, which may be the same or different. 5. A compound or a salt thereof according to claim 1 or 2, wherein R ² is methyl, ethyl, propyl, isopropyl, butyl, —CH2CH2CH (CH3) 2, —CH2CH2CH (CH3) 2, —CH2CH2OR ⁶ , —CH2CH2CH2OR ⁶ , -CH2CH (CH3) OR ⁶ , -CH2CH2CH (CH3) OR ⁶ , -CH2CH2CH (CH3) NR ^10a R ^11a , -CH2CH2CH2NR ^10a R ^11a , - (CH2) mSO2CH3, - (CH2) mC (O) NHCH3, - (CH2) mCN, - (CH2) mCO2R ⁶ , - (CH2) mCF3 and - (CH2) mNHCO2C (CH3) 3. 6. A compound or a salt thereof according to claim 1 or 2, wherein R ² is - (CH ₂ ) _n heteroaryl, wherein said heteroaryl group is selected from furanyl, thienyl, pyrrolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl, these groups being optionally substituted with one or two substituents independently selected from halogen, C ₁ . ₄ alkyl, C _3-4 cycloalkyl and -C ₀ groups. ₃ alkylOR ⁶ . 7. A compound or salt thereof according to any one of claims 1 to 6, wherein R ³ is H, methyl, ethyl, —CH2F, —CH2OH, —CH (OH) CH3, —CH2OMe, or —CH2CN. 8. A compound or a salt thereof according to any one of claims 1-7, wherein R ⁴ is unsubstituted phenyl or is phenyl substituted with one or two R ⁷ groups, which may be the same or different, selected from halogen, —C ₁ . ₄ alkyl, group -C ₀ . ₃ alkylOR ⁶ and —CN. - 130 038888 9. A compound or salt thereof according to any one of pi. 1-7, where R ⁴ is a heteroaryl group selected from the group consisting of pyridyl, indolyl and pyrrolopyridinyl, said groups optionally substituted with one, two or three R ⁷ groups, which may be the same or different. 10. The compound according to claim 1, selected from No. - ((^, 48) -4-hydroxycyclohexyl) -No-methyl-1 - ((8) -1-phenylethyl) -1H-pyrazole-3,5-dicarboxamide; N ³ - ((l K, ZK, 58.6 K) -3-hydroxycyclo [3.1.0] hexan-6-yl) -M'-methyl-1 - ((8) -1-phenylethyl) -1H-pyrazole3 , 5-dicarboxamide; No - ((1 R, 5 S, 6R) -3-oxabicyclo [3.1.0] hexan-6-yl) -1 - ((S) -1 - (4-chlorophenyl) ethyl) -No-methyl-1 N-pyrazole 3,5-dicarboxamide; (8) -No-methyl-1- (1-phenylethyl) -No- (1H-pyrazol-4-yl) -1H-pyrazole-3,5-dicarboxamide; 1 - ((8) -1- (4-chlorophenyl) ethyl) -N ⁵ - ((lR, ЗR, 5S, 6R) -3-hydroxibicyclo [3.1.0] hexan-6-yl) -N ³ -methyl -lHpyrazole-3,5-dicarboxamide; 1 - ((- 8) -1 - (3-chlorophenyl) ethyl) -X ⁵ - ((1 R, 3R, 5 S, 6R) -3-hydroxycyclo [3.1.0] hexan-6-yl) -X ^3- methyl1H-pyrazole-3,5-dicarboxamide; N ⁵ - ((lR, ЗR, 5S, 6R) -3-hydroxibicyclo [3.1.0] hexan-6-yl) -N ^3- methyl-l - ((S) -l-phhenylpropyl) -lH-pyrazole- 3,5-dicarboxamide; and N ³ - ((l K, 48) -4-methoxycyclohexyl) -No-methyl-1 - ((8) -1-phenylethyl) -! N-pyrazole-3,5-dicarboxamide, or a salt thereof. 11. The compound according to claim 1, which is N ⁵ - ((lR, 5S, 6R) -3-OKca6HnHKno [3.1.0] reKcaH-6yl) -M ³ -methyl-1 - ((8) -1- phenylethyl) -1H-pyrazole-3,5-dicarboxamide represented by the formula, or a salt thereof. 12. A compound according to any one of pi. 1-11, wherein said salt is a pharmaceutically acceptable salt. 13. A pharmaceutical composition containing a compound according to any one of pi. 1-11 or a pharmaceutically acceptable salt thereof according to and. 12 and one or more pharmaceutically acceptable excipients. 14. A pharmaceutical combination comprising a compound according to any one of pi. 1-11 or a pharmaceutically acceptable salt thereof according to and. 12 together with one or more other therapeutically active agents. 15. The use of a compound according to any one of pi. 1-11 or a pharmaceutically acceptable salt thereof according to i. 12 for treating a disease or condition in which a bromodomain inhibitor is indicated. 16. A method of treating a disease or condition in which a bromodomain inhibitor is indicated in a subject in need thereof, comprising administering a therapeutically effective amount of a compound according to any one of pi. 1-11 or a pharmaceutically acceptable salt thereof according to i.12. 17. The method of treatment according to and. 16, wherein the disease or condition is an acute or chronic autoimmune and / or inflammatory condition. 18. Method of treatment according to and. 16 where the disease or condition is cancer. 19. The method of treatment according to and. 16, wherein the disease or condition is rheumatoid arthritis.