TSHR inhibitors and methods of use thereof

Abstract

Disclosed are compounds that are thyroid stimulating hormone receptor antagonists, and methods useful for preventing or treating a thyroid disease.

Description

[0001] TSHR INHIBITORSAND METHODS OF USE THEREOF

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U. S. Provisional Patent Application No. 63 / 715,386, filed November 1, 2024.

[0004] BACKGROUND

[0005] About 40% of hyperthyroidism patients suffer from Graves' disease (Morbus Basedow), an autoimmune disease in which autoantibodies activate the thyrotropin receptor, mimicking its natural hormone ligand, the thyroid-stimulating hormone (TSH). This pathological activation of TSH-Receptor (TSHR) leads to uncontrolled production of thyroid hormones (e.g., T3 and T4) causing hyperthyroidism. TSH and the TSHR are important proteins for controlling thyroid function. TSHR is primarily expressed in follicular epithelial cells of the thyroid gland but also is expressed in a variety of additional cell types, such as retro-orbital fibroblasts, kidney cells, adipocytes and bone cells. TSH binds to its receptor and leads to the stimulation of second messenger pathways involving predominantly cAMP. Inositol 1,4, 5 -triphosphate (IP3) and diacylglycerol (DAG) pathways are also activated at higher TSH concentrations.

[0006] The treatment of choice applied in the clinics for decades involves thyrostatic drugs that block the production of thyroid hormones. These medications play a role further downstream in the signal cascade of the thyroid upon activation of the TSHR. Since thyroid hormones T3 and T4 are secreted in the thyroid gland, thyrostatic drugs induce an inhibition of their synthesis. Thus, the current primary anti-thyroid treatment does not target the causative molecular activation of the TSHR by autoantibodies and patients are therefore burdened by a rate of at least 5% adverse effects. This demands frequent controls of the thyroid hormone levels and adjustments of thyrostatics dosage. In contrast to these drugs, which regulate the thyroid hormone level, another promising target is the TSHR itself. However, small allosteric antagonists acting directly at the TSHR are not available on the market yet.

[0007] Additionally, about 25% of Graves' disease patients also develop an orbitopathy referred to as “Graves' ophthalmopathy”, a related organ- specific autoimmune disease affecting the appearance and functioning of the eyes. There is considerable evidence that expression of the TSHR in the orbital fibroblasts and orbital adipocytes behind the eye may contribute to this difficult-to-treat orbitopathy, and thyroid stimulating antibodies titer tend to correlate with severity of Grave’s ophthalmopathy. Orbital fibroblast has been recognized as primary target cells of autoimmune attack and TSHR acts as a primary autoantigen in Grave’s ophthalmopathy. The pathological activation of TSHR leads to the production of the extracellular matrix by involvement of hyaluronic acid, fibrosis and swelling of extraocular muscle as well as adipogenesis of orbital fibroblasts (orbital fat expansion). The increase in tissue volume in the orbit often causes diplopia and compression of the optic nerve and exophthalmos. Thus, the TSHR is also potential target for pharmacological intervention of Grave’s ophthalmology and thyroid eye disease.

[0008] Accordingly, there is a need in the art to provide additional means for the treatment of hyperthyroidism, in particular compounds that act as TSHR antagonists.

[0009] SUMMARY

[0010] In some aspects, the present disclosure comprises a compound of Formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt thereof;

[0013] wherein:

[0014] A is 6- to 10-membered aryl or 5- to 10-membered heteroaryl;

[0015] R1is hydrogen, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (C3-Cs)cycloalkyl, 6- to 10-membered aryl(Ci-C3)alkyl, or (C3-Cs)cycloalkyl(Ci-C3)alkyl; wherein (C3-Cs)cycloalkyl and (C3-Cs)cycloalkyl(Ci-C3)alkyl are optionally substituted with one or more instances of halo;

[0016] R2is independently for each occurrence cyano, halo, hydroxy, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-Ce)alkoxy, (Ci-Ce)haloalkoxy, NR5aR5b, C(O)NR5aR5b, OR6a, SR6a, S(O)(NR5a)R5b, S(O)2NR5aR5b, S(O)2R6a, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl(Ci-C3)alkyl, 5- to 10-membered heteroaryl(Ci-C3)alkyl, (C3-Cs)cycloalkyl(Ci-C3)alkyl, 4- to 7-membered heterocycloalkyl (Ci-C3)alkyl, 6- to 10-membered aryl(Ci-C3)alkoxy, 5- to 10-membered heteroaryl(Ci-C3)alkoxy, (C3-Cs)cycloalkyl(Ci-C3)alkoxy, or 4- to 7-membered heterocycloalkyl(Ci-C3)alkoxy; wherein each (Ci-Ce)alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl(Ci-C3)alkyl, 5- to 10-membered heteroaryl(Ci-C3)alkyl, (C3-Cs)cycloalkyl(Ci-C3)alkyl, 4- to 7-membered heterocycloalkyl(Ci-C3)alkyl, 6- to 10-membered aryl(Ci-C3)alkoxy, 5- to 10-membered heteroaryl(Ci-C3)alkoxy, (C3-Cs)cycloalkyl(Ci-C3)alkoxy, or 4- to 7-membered heterocycloalkyl(Ci-C3)alkoxy is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, C(O)NR5aR5b, NR5aR5b, OR6a, SR6a, S(O)2R6a, S(O)(NR5a)R5b, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci-C6)aminoalkyl, (C3-Cs)cycloalkyl, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)haloalkoxy, and (Ci-C6)haloalkoxy(Ci-C6)alkyl;

[0017] R3is hydrogen, halo, NH2, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (Ci-C3)alkoxy, (Ci-C3)alkoxyalkyl, or (Ci-C3)haloalkoxyalkyl;

[0018] R4is hydrogen, halo, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (C3-Cs)cycloalkyl, or (C3-Cs)halocycloalkyl;

[0019] R5aand R5bare independently for each occurrence selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-Cs)cycloalkyl, 6- to 10-membered aryl, and 4- to 7-membered heterocyclyl; or R5aand R5btaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;

[0020] R6ais a 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (C3-Cs)cycloalkyl, or 4- to 7- membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from cyano, halo, -NH2, -OH, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, and (Ci-Ce)alkoxyalkyl;

[0021] Raand Rbare each independently selected from hydrogen, halo, (Ci-C3)alkyl, and (Ci-C3)haloalkyl;

[0022] n is 0, 1, 2, 3, 4, or 5; and

[0023] the absolute stereochemistry at the alpha-ureido lactam chiral center is as shown. In some aspects, provided herein is a compound selected from the following table:

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035] Other aspects of the disclosure comprise a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0036] Other aspects of the disclosure comprise a method of inhibiting a thyroid stimulating hormone receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the disclosure.

[0037] In still other aspects, provided herein is a method for treating hyperthyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention. In some embodiments, the subject has Graves' disease. In more particular embodiments, the subject has Graves' ophthalmopathy. In other embodiments, the subject has Graves' dermopathy. In still other embodiments, the subject has thyroid cancer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0038] Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims.

[0039] DETAILED DESCRIPTION

[0040] Definitions

[0041] For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0042] In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification.

[0043] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0044] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0045] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0046] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0047] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0048] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0049] “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. “R”, “S”, "S*”, “R*”, “E”, “Z”, “cis”, and “trans” indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in “atropisomeric” forms or as “atropisomers.” Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from a mixture of isomers. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.

[0050] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0051] Percent purity by mole fraction is the ratio of the moles of the enantiomer (or diastereomer) or over the moles of the enantiomer (or diastereomer) plus the moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure.

[0052] When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.

[0053] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or14C-enriched carbon are within the scope of this invention.

[0054] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non- pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.

[0055] The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.) In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

[0056] A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0057] The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0058] The term “patient” or “subject” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human.

[0059] An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.

[0060] As used herein, the term “alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. Preferably, “alkyl” refers to a fully saturated acyclic branched or unbranced carbon chain moiety. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Alkyl groups may be substituted or unsubstituted. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0061] As used herein, the term “alkoxy” refers to an alkyl group, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0062] As used herein, the term “alkoxyalkyl”, refers to an alkyl group substituted by an alkoxy group.

[0063] As used herein, the term “heteroaryl” is a term of art and refers to a monocyclic, bicyclic, and polycyclic aromatic group having 3 to 12 total atoms including one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl or tropanyl, and the like. The “heteroaryl” may be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more atoms are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Such heteroaryl groups may be connected to the rest of the molecule through either the aromatic group having one or more heteroatoms in the ring structure or the other cyclic group. For example, heteroaryl includes indole, which comprises a benzene ring and a pyrrole ring that are fused together. An indole substituent may be attached to a parent structure through either the benzene ring or through the pyrrole ring of the indole.

[0064] As used herein, the term “haloalkyl” refers to an alkyl group as hereinbefore defined wherein at least one hydrogen atom is replaced by at least one halogen atom. As used herein, the term “haloalkoxy” refers to an alkoxy group as defined herein substituted with at least one halogen atom. For example, haloalkoxy groups include fluoroalkoxy groups, such as trifluoromethoxy, difluoromethoxy, and the like.

[0065] As used herein, the term “(haloalkoxy)alkyl” refers to an alkyl group substituted with one or more haloakoxy groups.

[0066] As used herein, the term “hydroxy” is a term of art and refers to an -OH group.

[0067] The term “cyano” is a term of art and as used herein refers to -CN.

[0068] As used herein, the term “amino” is a term of art that refers to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

[0069]

[0070] wherein Ra, Rb, and Rceach independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)X-Rd, or Raand Rb, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; Ra represents an aryl, a heteroaryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or a polycyclyl; and x is zero or an integer in the range of 1 to 8. In certain preferred embodiments, the term “amino” refers to -NH2.

[0071] As used herein, the term “aminoalkyl” refers to an alkyl group substituted with one or more one amino groups.

[0072] As used herein, the term “hydroxyalkyl” refers to at least one hydroxy group appended to the parent molecular moiety through an alkyl group as hereinbefore defined substituted with at least one hydroxyl.

[0073] As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene -(CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

[0074] As sued herein, the term “cycloalkyl” means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted. As used herein, the term “(cycloalkyl)alkyl” refers to an alkyl group substituted with one or more cycloalkyl groups. An example of cycloalkylalkyl is cyclohexylmethyl group.

[0075] As used herein, the term “(cycloalkyl)alkoxy” refers to an alkoxy group substituted with one or more cycloalkyl groups.

[0076] As used herein, the term “halocycloalkyl” refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen.

[0077] Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0078] “Alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).

[0079] “Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety.

[0080] The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0081] As used herein, the term “arylalkoxy” or “aryloxy” refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.

[0082] The terms “heterocyclyl” or “heterocyclic group” or “heterocycloalkyl” refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic, which can be completely saturated or which can contain one or more units of unsaturation, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, and having 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. Heterocyclyl groups include, for example, thianthrene, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, indolizine, purine, quinolizine, phthalazine, naphthyridine, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. Heterocycloalkyl groups can be fully saturated or partially saturated. Heterocycloalkyl groups include, for example, bicyclic ring systems having either or both constituent rings saturated (e.g., 2,3-dihydroindole, 4,5,6,7-tetrahydro-benzofuran, decahydroquinoline, and the like) or partially saturated (e.g., octahydroquinoline and the like).

[0083] The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0084] As used herein, the term “heteroaralkyl” or “(heteroaryl)alkyl” is a term of art and refers to an alkyl group substituted with a heteroaryl group, appended to the parent molecular moiety through the alkyl group.

[0085] As used herein, the term “(heteroaryl)alkoxy” refers to an alkoxy group substituted with a heteroaryl group, appended to the parent molecular moiety through the alkoxy group.

[0086] As used herein, the term “(heterocycloalkyl)alkyl” refers to an alkyl group substituted with one or more heterocycloalkyl (i.e., heterocyclyl) groups.

[0087] As used herein, the term “(heterocycloalkyl)alkoxy” refers to an alkoxy group substituted with one or more heterocycloalkyl (i.e., heterocyclyl) groups. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxy carbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamide, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from Ci-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0088] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0089] An “effective amount” is an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments.

[0090] The terms “decrease,” “reduce,” “reduced”, “reduction”, “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference. However, for avoidance of doubt, “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the complete absence of the given entity or parameter as compared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment.

[0091] The terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.

[0092] As used herein, the term “modulate” includes up-regulation and down-regulation, e.g., enhancing or inhibiting a response.

[0093] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Compounds of the Invention

[0094] In some aspects, the present disclosure provides a compound of Formula (I):

[0095]

[0096] or a pharmaceutically acceptable salt thereof;

[0097] wherein:

[0098] A is 6- to 10-membered aryl or 5- to 10-membered heteroaryl;

[0099] R1is hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-Cs)cycloalkyl, 6- to 10-membered aryl(Ci-C3)alkyl, or (C3-Cs)cycloalkyl(Ci-C3)alkyl; wherein (C3-Cs)cycloalkyl and (C3-Cs)cycloalkyl(Ci-C3)alkyl are optionally substituted with one or more instances of halo;

[0100] R2is independently for each occurrence cyano, halo, hydroxy, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-Ce)alkoxy, (Ci-Ce)haloalkoxy, NR5aR5b, C(O)NR5aR5b, OR6a, SR6a, S(O)(NR5a)R5b, S(O)2NR5aR5b, S(O)2R6a, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl(Ci-C3)alkyl, 5- to 10-membered heteroaryl(Ci-C3)alkyl, (C3-Cs)cycloalkyl(Ci-C3)alkyl, 4- to 7-membered heterocycloalkyl (Ci-C3)alkyl, 6- to 10-membered aryl(Ci-C3)alkoxy, 5- to 10-membered heteroaryl(Ci-C3)alkoxy, (C3-Cs)cycloalkyl(Ci-C3)alkoxy, or 4- to 7-membered heterocycloalkyl(Ci-C3)alkoxy; wherein each (Ci-Ce)alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl(Ci-C3)alkyl, 5- to 10-membered heteroaryl(Ci-C3)alkyl, (C3-Cs)cycloalkyl(Ci-C3)alkyl, 4- to 7-membered heterocycloalkyl(Ci-C3)alkyl, 6- to 10-membered aryl(Ci-C3)alkoxy, 5- to 10-membered heteroaryl(Ci-C3)alkoxy, (C3-Cs)cycloalkyl(Ci-C3)alkoxy, or 4- to 7-membered heterocycloalkyl(Ci-C3)alkoxy is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, C(O)NR5aR5b, NR5aR5b, OR6a, SR6a, S(O)2R6a, S(O)(NR5a)R5b, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)aminoalkyl, (C3-Cs)cycloalkyl, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)haloalkoxy, and (Ci-C6)haloalkoxy(Ci-C6)alkyl;

[0101] R3is hydrogen, halo, NH2, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (Ci-C3)alkoxy, (Ci-C3)alkoxyalkyl, or (Ci-C3)haloalkoxyalkyl; R4is hydrogen, halo, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (C3-Cs)cycloalkyl, or (C3-Cs)halocycloalkyl;

[0102] R5aand R5bare independently for each occurrence selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (C3-Cs)cycloalkyl, 6- to 10-membered aryl, and 4- to 7-membered heterocyclyl; or R5aand R5btaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;

[0103] R6ais a 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (C3-Cs)cycloalkyl, or 4- to 7- membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from cyano, halo, -NH2, -OH, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, and (Ci-Ce)alkoxyalkyl;

[0104] Raand Rbare each independently selected from hydrogen, halo, (Ci-C3)alkyl, and (Ci-C3)haloalkyl;

[0105] n is 0, 1, 2, 3, 4, or 5; and

[0106] the absolute stereochemistry at the alpha-ureido lactam chiral center is as shown. In some embodiments, A is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indazolyl, pyridonyl, naphthalenyl, benzoxazolyl, or benzoisothiazolyl.

[0107] In some embodiments, A is phenyl.

[0108] In some embodiments, Raand Rbare each independently selected from hydrogen, fluoro, (Ci-C3)alkyl, and (Ci-C3)fluoroalkyl.

[0109] In some embodiments, Raand Rbare each independently selected from fluoro, (Ci-C3)alkyl, and (Ci-C3)fluoroalkyl.

[0110] In some embodiments, Raand Rbare each hydrogen.

[0111] In some embodiments, Rais methyl and Rbis hydrogen.

[0112] In some embodiments, R1is (Ci-Ce)alkyl, (Ci-C6)fluoroalkyl, (C3-Cs)cycloalkyl, (C3-Cs)cycloalkyl(Ci-C3)alkyl, or 6- to 10-membered aryl(Ci-C3)alkyl.

[0113] In some embodiments, R1is methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl, or benzyl.

[0114] In some embodiments, R1is methyl.

[0115] In some embodiments, R3is hydrogen, (Ci-C3)alkyl, (Ci-C3)haloalkyl, or NH2.

[0116] In some embodiments, R3is hydrogen.

[0117] In some embodiments, R3is methyl.

[0118] In some embodiments, R4is hydrogen.

[0119] In some embodiments, R4is (Ci-C3)alkyl or (Ci-C3)fluoroalkyl. In some embodiments, R4is methyl or trifluoromethyl.

[0120] In some embodiments, the disclosure comprises a structure represented by Formula (I- A):

[0121]

[0122] In some embodiments, R2, independently for each occurrence, is (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, (C3-Cs)cycloalkyl, 6- to 10-membered aryl, 4- to 7- membered heterocyclyl, 6- to 10-membered aryl(Ci-C3)alkyl, or 5- to 10- membered heteroaryl (C i -C3)alkoxy.

[0123] In some embodiments, R2, independently for each occurrence, is halo, -OR6a’ -C(O)NR5aR5b, or NR5aR5b.

[0124] In some embodiments, R2, independently for each occurrence, is fluoro, chloro, cyano, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, phenyl, cyclopropyloxy, phenoxy, benzyloxy, dimethylamido, pyrrolidinyl, piperidinyl, pyridinyl, 1-H-indazolyl, or pyrazolylmethoxy.

[0125] In some embodiments, R5aand R5bare (Ci-C6)alkyl. In further embodiments, R5aand R5bare methyl.

[0126] In some embodiments, R6ais (C3-Cs)cycloalkyl or 6- to 10-membered aryl. In further embodiments, R6ais cyclopropyl or phenyl.

[0127] In some embodiments, n is 0. In alterative embodiments, n is 1. In further alternative embodiments, n is 2. In yet alternative embodiments, n is 3.

[0128] (R2)n- AY^

[0129] In some embodiments, is

[0130]

[0131] ; wherein p is an integer from 0-2; and the dashed bond represents the covalent bond to the carbon atom substituted with R4.

[0132] In some embodiments, (R2)nX — B is selected from the group consisting of:

[0133]

[0134]

[0135] substituted with R4.

[0136] (R2)n- A^M

[0137] In further embodiments, is selected from the group consisting of:

[0138]

[0139]

[0140] wherein the dashed bond represents the covalent bond to the carbon atom substituted with R4.

[0141] In some aspects, the present disclosure comprises a compound according to Formula (Ip):

[0142]

[0143] or a pharmaceutically acceptable salt thereof;

[0144] wherein:

[0145] A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; R1is hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-Cs)cycloalkyl, or (C3-Cs)cycloalkyl(Ci-C3)alkyl; wherein (C3-Cs)cycloalkyl and (C3-Cs)cycloalkyl(Ci-C3)alkyl are optionally substituted with one or more instances of halo;

[0146] R2is independently for each occurrence cyano, halo, hydroxy, (Ci-Ce)alkyl, (Ci-C6)alkoxy, NR5aR5b, C(O)NR5aR5b, OR6a, SR6a, S(O)(NR5a)R5b, S(O)2NR5aR5b, S(O)2R6a, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-Cio)aryl(Ci-C3)alkyl, (C6-Cio)aryl(Ci-C3)alkoxy, (C3-Cs)cycloalkyl, (C3-Cs)cycloalkyl(Ci-C3)alkoxy, or (C3-Cs)cycloalkyl(Ci-C3)alkyl; wherein each (Ci-Ce)alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-Cio)aryl(Ci-C3)alkyl, or (C6-Cio)aryl(Ci-C3)alkoxy is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, C(O)NR5aR5b, NR5aR5b, OR6a, SR6a, S(O)2R6a, S(O)(NR5a)R5b, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-C6)aminoalkyl, (C3-Cs)cycloalkyl, (Ci-Ce)alkoxy, (Ci-Ce)alkoxy(Ci-Ce)alkyl, (Ci-Ce)haloalkoxy, and (Ci-C6)haloalkoxy(Ci-Ce)alkyl;

[0147] R3is hydrogen, halo, NH2, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (Ci-Cs)alkoxy, (Ci-C3)alkoxyalkyl, or (Ci-C3)haloalkoxyalkyl;

[0148] R4is hydrogen, halo, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (C3-Cs)cycloalkyl, or (C3-Cs)halocycloalkyl;

[0149] R5aand R5bare independently for each occurrence selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (C3-Cs)cycloalkyl, (Ce-Cio) aryl, and 4- to 7-membered heterocyclyl; or R5aand R5btaken together with the nitrogen to which they are attached form a 4- to -7 membered heterocycloalkyl;

[0150] R6ais a 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (C3-Cs)cycloalkyl, or 4- to 7- membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from cyano, halo, -NH2, -OH, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, and (Ci-Ce)alkoxyalkyl;

[0151] Raand Rbare each independently selected from hydrogen, halo, (Ci-C3)alkyl, and (Ci-C3)haloalkyl;

[0152] n is 0, 1, 2, 3, 4, or 5; and

[0153] the absolute stereochemistry at the alpha-ureido lactam chiral center is as shown. In some aspects, provided herein is a compound selected from the following table:

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166] or a pharmaceutically acceptable salt thereof.

[0167] Methods of Treatment

[0168] One aspect of the invention provides methods of inhibiting a thyroid stimulating hormone receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0169] Another aspect of the invention comprises treating or preventing a thyroid disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0170] Another aspect of the invention comprises a method of treating hyperthyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0171] In certain embodiments, the subject has Graves' disease.

[0172] In certain embodiments, the subject has Graves' ophthalmopathy.

[0173] In certain embodiments, the subject has Graves' dermopathy.

[0174] In certain embodiments, the subject has thyroid cancer.

[0175] While not being bound by theory, TSHR in thyroid cells, and likely in fibroblasts and adipocytes in the supporting tissue behind the eye (in the retro-orbital space), also are stimulated by TSHR-stimulating antibodies (TSAbs), resulting in Graves' disease. Graves' disease, which is an autoimmune disease that occurs in 1% of the US population, has two important clinical components: 1) hyperthyroidism from stimulation of TSHR on thyroid cells and 2) Graves' orbitopathy (or Graves' ophthalmopathy or thyroid eye disease), which appears to result from stimulation of TSHR on retro-orbital fibroblasts and / or adipocytes.

[0176] Hyperthyroidism, in particular Graves' hyperthyroidism, is a hypermetabolic state that affects virtually every tissue / cell in the body and can lead to, in particular, cardiovascular dysfunction and death.

[0177] Graves' ophthalmopathy, also known as Graves' orbitopathy, occurs in 80% of Graves' hyperthyroid patients as diagnosed by computerized tomographic scan. Symptoms range from mild to moderate to severe to sight- threatening. Protrusion of the eyeball (proptosis) and varying degrees of extra-ocular muscle weakness or paralysis leading to double vision (diplopia) can be disfiguring and incapacitating.

[0178] Graves dermopathy, also known as Pretibial myxedema, thyroid dermopathy, Jadassohn-Dossekker disease or Myxoedema tuberosum, is an infiltrative dermopathy, resulting as a complication of Graves' disease, with an incidence rate of about 1-5% in patients. The disease usually presents itself as a waxy, discolored induration of the skin on the anterior aspect of the lower legs.

[0179] In certain embodiments, a disease that can be treated or prevented by TSHR antagonists is thyroid cancer. While not being bound by theory, TSHR is expressed in thyroid cancer cells and regulates the growth, proliferation and metastatic potential of thyroid cancer cells.

[0180] The thyroid gland is, as is well known, one site of metabolic control within the body. Cancer of the thyroid gland is not particularly common, but the high rate of disease reoccurrence necessitates long-term surveillance. Usually, during treatment for cancer of the thyroid, the majority of the thyroid tumor is removed, but a small amount often remains that must be treated by radioactive iodide therapy. Indeed, thyroid cancer is characterized by a high likelihood of relapses in up to 30% of patients, even after successful therapy.

[0181] In rare cases, the TSHR contains a hereditary mutation that makes it more active than the normal TSHR, resulting in hereditary non-immune hyperthyroidism. TSHR antagonists could be effective treatment for these patients also.

[0182] A “TSHR antagonist” as described herein blocks or inhibits the action of the agonists (TSH or thyroid-stimulating antibodies for TSHR. Small-molecule ligands for the TSHR (antagonists) typically bind to an intra-membrane domain of the receptor, and act by inducing a conformational change rather than simply competing for TSH binding to its extracellular site on the receptor.

[0183] In certain embodiments, the antagonists may be selective antagonists for TSHR (i.e., the compounds do not activate or modulate other hormone receptors, particularly luteinizing hormone / chorionic gonadotropin receptor (LHCGR) and follicle-stimulating hormone receptor (FSHR)).

[0184] In certain embodiments, the antagonists disclosed herein may be used for treating hyperthyroidism in a subject. For example, the antagonists may inhibit mutant TSHRs with higher than normal basal signaling activities (CAMs) that cause an unusual form of hyperthyroidism. In another example, the antagonists may inhibit stimulation by antibodies found in Graves' disease, which is the most common form of hyperthyroidism. In certain embodiments, the TSHR antagonists are useful for treating TSHR-mediated thyroid cancer or hyperthyroidism by blocking TSHR-stimulating antibodies (TSAbs) in Graves' hyperthyroidism.

[0185] In certain embodiments, the compound is administered orally to the subject.

[0186] In certain embodiments, the compound is administered parenterally to the subject. In certain embodiments, the disease is prevented. In other embodiments, the disease is treated.

[0187] Pharmaceutical Compositions, Routes of Administration, and Dosing

[0188] In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of the present disclosure, and a pharmaceutically acceptable carrier.

[0189] In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of any of the disclosed embodiments, and a pharmaceutically acceptable carrier.

[0190] In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier.

[0191] Pharmaceutical compositions of the invention can be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0192] As stated above, an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and / or other therapeutic agent without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein. In certain embodiments, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 2 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 0.5 mg / kg / day to 5 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 1 mg / kg / day to 10 mg / kg / day.

[0193] Generally, daily oral doses of a compound will be, for human subjects, from about 0.01 milligrams / kg per day to 1000 milligrams / kg per day. It is expected that oral doses in the range of 0.5 to 50 milligrams / kg, in one or more administrations per day, will yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound.

[0194] For any compound described herein the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.

[0195] The formulations of the invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0196] For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical.

[0197] For intravenous and other parenteral routes of administration, a compound of the invention can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solutions, e.g., in sterile water or saline, shortly prior to administration.

[0198] For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers.

[0199] Also specifically contemplated are oral dosage forms of the above component or components. The component or components may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the component or components and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N. Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that could be used are poly-l,3-dioxolane and poly-1, 3, 6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol moieties are suitable.

[0200] For the component (or derivative) the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.

[0201] To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as mixed films.

[0202] A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used.

[0203] The therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic could be prepared by compression.

[0204] Colorants and flavoring agents may all be included. For example, the compound of the invention (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.

[0205] One may dilute or increase the volume of the therapeutic with an inert material. These diluents could include carbohydrates, especially mannitol, oc-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.

[0206] Disintegrants may be included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0207] Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic.

[0208] An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.

[0209] Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.

[0210] To aid dissolution of the therapeutic into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride. Potential nonionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios. Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.

[0211] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0212] For topical administration, the compound may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.

[0213] For administration by inhalation, compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0214] Also contemplated herein is pulmonary delivery of the compounds disclosed herein (or salts thereof). The compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of inhaled molecules include Adjei et al., PharmRes 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl.

[0215] 5): 143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (ocl-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a- 1 -proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U. S. Pat. No. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U. S. Pat. No. 5,451,569 (incorporated by reference), issued Sep. 19, 1995 to Wong et al.

[0216] Contemplated for use in the practice of this invention are mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0217] Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Mass.

[0218] All such devices require the use of formulations suitable for the dispensing of the compounds of the invention. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and / or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated. Chemically modified compounds of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.

[0219] Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise a compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol.

[0220] Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant. Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing a compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The compound of the invention (or derivative) should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers (p.m), most preferably 0.5 to 5.m, for most effective delivery to the deep lung.

[0221] Nasal delivery of a pharmaceutical composition of the present invention is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran.

[0222] For nasal administration, a useful device is a small, hard bottle to which a metered dose sprayer is attached. In one embodiment, the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.

[0223] Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.

[0224] The compounds, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0225] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0226] Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0227] The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0228] In addition to the formulations described above, a compound may also be formulated as a depot preparation. Such long-acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0229] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0230] Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-33 (1990).

[0231] The compound of the invention and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt or cocrystal. When used in medicine the salts or cocrystals should be pharmaceutically acceptable, but non- pharmaceutically acceptable salts or cocrystals may conveniently be used to prepare pharmaceutically acceptable salts or cocrystals thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.

[0232] Suitable buffering agents include: acetic acid and a salt (1-2% w / v); citric acid and a salt (1-3% w / v); boric acid and a salt (0.5-2.5% w / v); and phosphoric acid and a salt (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01-0.25% w / v) and thimerosal (0.004-0.02% w / v).

[0233] Pharmaceutical compositions of the invention contain an effective amount of a compound as described herein and optionally therapeutic agents included in a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.

[0234] The therapeutic agent(s), including specifically but not limited to a compound of the invention, may be provided in particles. Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound of the invention or the other therapeutic agent(s) as described herein. The particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic agent(s) also may be dispersed throughout the particles. The therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the compound of the invention in a solution or in a semi-solid state. The particles may be of virtually any shape.

[0235] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, gluten, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly (butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly (octadecyl acrylate).

[0236] The therapeutic agent(s) may be contained in controlled release systems. The term “controlled release” is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term “sustained release” (also referred to as “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term “delayed release” is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”

[0237] Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.

[0238] It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention.

[0239] EXAMPLES

[0240] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0241] Synthesis of Intermediate 1: (S)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II) iodide

[0242]

[0243] Stepi

[0244] Intermediate 1

[0245] Step 1: Preparation of (S)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II) iodide (Intermediate 1)

[0246] To a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (10 g, 30.4 mmol, 1 equiv.) in dimethylformamide (60 mL) was added zinc powder (3.97 g, 60.8 mmol, 2 equiv.) at 0 °C. The reaction was stirred at 25 °C for 16 h. The crude product was used in the next step directly without further purification.

[0247] Synthesis of Intermediate 2: (l-(2-chloro-5-fluorophenyl)ethyl)hydrazine hydrochloride

[0248]

[0249] Scheme 2

[0250]

[0251] Step 1: Preparation of tert-butyl 2-(l-(2-chloro-5-fluorophenyl)ethylidene)hydrazine-l-carboxylate

[0252] To a stirred solution of l-(2-chloro-5-fluorophenyl)ethanone (10.0 g, 57.9 mmol, 1 equiv.) in tetrahydrofuran (50 mL) and heptane (100 mL) was added tert-butoxycarbohydrazide (7.7 g, 57.9 mmol, 1 equiv.) at room temperature under air atmosphere. The mixture was stirred at 75°C for 16h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure to afford the title compound as a black solid (9.0 g). The crude product was used in the next step directly without further purification. LCMS (ESI): m / z [M+H-rBu]+calcd. for C9H8CIFN2O2: 230.03, found 231.10.

[0253] Step 2: Preparation of tert-butyl 2-(l-(2-chloro-5-fluorophenyl)ethyl)hydrazine-l-carboxylate

[0254] To a stirred solution of tert-butyl 2-(l-(2-chloro-5-fluorophenyl)ethyl)hydrazine-l-carboxylate (9.0 g, 31.4 mmol, 1 equiv.) in methanol (50 mL) and acetic acid (50 mL) was added sodium cyanoborohydride (11.8 g, 188.3 mmol, 6 equiv.) at 0 °C. The mixture was stirred at rt under nitrogen for 12h. The resulting mixture was concentrated under reduced pressure. The reaction was diluted with water at rt and extracted with dichloromethane (3 x 200 mL). The residue was washed with brine. The combined organic layers were dried over anhydrous sodium sulfate to afford the title compound as a yellow oil (9.0 g, 99.3% yield). The crude product was used in the next step directly without further purification.

[0255] LCMS (ESI): m / z [M+H-rBu]+calcd. for C9H10CIFN2O2: 232.04, found 233.10.

[0256] Step 3: Preparation of (l-(2-chloro-5-fluorophenyl)ethyl)hydrazine (Intermediate 2) A solution of terr-butyl 2-(l-(2-chloro-5-fluorophenyl)ethyl)hydrazine-l-carboxylate (9.0 g, 31.2 mmol, 1 equiv.) in HC1 (in 1,4-dioxane, 4.0 M) (100 mL) was stirred at rt for 3h. The resulting mixture was concentrated under reduced pressure. This afforded the title hydrochloride compound as a yellow oil (6.9 g, 98.6% yield). The crude product Intermediate 2 was used in the next step directly without further purification.

[0257] LCMS (ESI): m / z [M+H]+calcd. for C8H10ClFN2 188.05, found 189.00.

[0258] Synthesis of Compound 1: (R)-l-(l-(2-chloro-5-fluorobenzyl)-7-methyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0259]

[0260] Intermediate 1 MeLi, Mel Pd(OAc)2, Xphos THF, -78 °C ~ 0 °C DMF, rt Step 3 Step 4

[0261]

[0262]

[0263]

[0264] Step 1: Preparation of l-(2-chloro-5-fluorobenzyl)-lH-pyrazol-5-amine

[0265] To a stirred solution of 3-hydrazinylpropanenitrile (1.53 g, 17.9 mmol, 0.95 equiv.) in tetrahydro furan (20 mL) was added 2-chloro-5-fluorobenzaldehyde (3.00 g, 18.92 mmol, 1 equiv.) at room temperature. The mixture was stirred at rt for 3h under nitrogen. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with te -butyl alcohol (40 mL) at room temperature under nitrogen. The resulting mixture was stirred at 120°C for an additional 2h. The mixture was allowed to cool down to room temperature. The reaction was treated with ice water at 0°C. The resulting mixture was extracted with dichloromethane (3 x 50 mL). The residue was washed with brine (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% petroleum ether in ethyl acetate) to afford the title compound as a yellow oil (3.0 g, 70.3% yield).

[0266] LCMS (ESI): m / z [M+H]+calcd. for C10H9CIFN3: 225.05 m / z, found: 226.00.

[0267] Step 2: Preparation of 4-bromo-l-(2-chloro-5-fluorobenzyl)-lH-pyrazol-5-amine To a stirred solution of l-(2-chloro-5 -fluorobenzyl)- lH-pyrazol-5 -amine (3.00 g, 13.29 mmol, 1 equiv.) in dimethylformamide (40 mL) was added A-Bromosuccinimide (2.60 g, 14.63 mmol, 1.1 equiv.) at room temperature. The mixture was stirred at rt for Ih. The reaction was treated with water at rt. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The residue was washed with brine (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (2.6 g, 64.2% yield).

[0268] LCMS (ESI): m / z calcd. for CioHsBrClFN3: 304.96, found 305.95 [M+H]+.

[0269] Step 3: Preparation of 4-bromo-l-(2-chloro-5-fluorobenzyl)- V-methyl-l H-pyrazol-5-amine

[0270] To a stirred solution of 4-bromo-l-(2-chloro-5 -fluorobenzyl)- lH-pyrazol-5 -amine (2.00 g, 6.57 mmol, 1 equiv.) in tetrahydrofuran (20 mL) was added methyllithium (1.6M in diethoxymethane) (4.5 mL, 7.22 mmol, 1.1 equiv.) dropwise at -78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 0.5h. To above mixture was added CH3I (1.40 g, 9.85 mmol, 1.5 equiv.) in portions at -78°C. The resulting mixture was stirred at -78°C for an additional 10 min. The mixture was stirred at 0°C for 0.5 h under nitrogen. The reaction was treated with sat. ammonium chloride (aq.) at 0°C. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The residue was washed with brine. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (1.2 g, 57.4% yield). LCMS (ESI): m / z [M+H, M+H+2]+calcd. for CiiHioBrClFN3: 316.97, found 317.90, 319.90.

[0271] Step 4: Preparation of tert-butyl (lf)-(l-(2-chloro-5-fluorobenzyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0272] To a stirred solution of 4-bromo-l-(2-chloro-5-fluorobenzyl)-A-methyl-lH-pyrazol-5 -amine (800.0 mg, 2.511 mmol, 1 equiv.), palladium(II) acetate (112.8 mg, 0.502 mmol, 0.2 equiv.) and Xphos (478.9 mg, 1.00 mmol, 0.4 equiv.) in dimethylformamide (10 mL) was added Intermediate 1 (25.1 mL, 12.55 mmol, 5 equiv, 0.5 M in dimethylformamide) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at rt for 12h under nitrogen. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate in petroleum ether) to afford the title compound as a light yellow solid (100.0 mg, 9.7% yield).

[0273] LCMS (ESI): m / z [M+H]+calcd. for C19H22CIFN4O3: 408.14, found 409.10.

[0274] Step 5: Preparation of (lf)-5-amino-l-(2-chloro-5-fluorobenzyl)-7-methyl-l, 4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0275] To a stirred solution of tert-butyl A-[(5R)-l-[(2-chloro-5-fluorophenyl)methyl]-7-methyl-6-oxo-4H,5H-pyrazolo[3,4-b]pyridin-5-yl]carbamate (100 mg, 0.245 mmol, 1 equiv.) in HC1 (in 1,4-dioxane, 4.0 M) (1 mL) at 0°C. The mixture was stirred at rt for Ih. The resulting mixture was concentrated under reduced pressure to afford the title hydrochloride compound as a yellow oil (84 mg, 99% yield). The crude product was used in the next step directly without further purification.

[0276] LCMS (ESI): m / z [M+H]+calcd. for C14H14CIFN4O: 308.08, found 309.10.

[0277] Step 6: Preparation of (lf)-l-(l-(2-chloro-5-fluorobenzyl)-7-methyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 1)

[0278] To a stirred solution of (R)-5-amino- l-(2-chloro-5-fluorobenzyl)-7-methyl- 1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one hydrochloride (85 mg, 0.246 mmol, 1 equiv.) in tetrahydrofuran (1 mL) was added methanesulfonic acid (35.5 mg, 0.369 mmol, 1.5 equiv.) at room temperature. To the above mixture was added isocyanatopotassium (59.9 mg, 0.738 mmol, 3 equiv.) in water (0.1 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for an additional Ih. The reaction was treated with water at rt. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The residue was washed with brine (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (XBridge Prep OBD C18 Column, 12-37% acetonitrile in water with 10 mM ammonium bicarbonate containing 0.05% NHy H2O) to afford the title Compound 1 as a white solid (21.5 mg, 24.9% yield).

[0279] LCMS (ESI): m / z [M+H]+calcd. for C15H15CIFN5O2: 351.09, found 352.05.

[0280] ’H NMR (400 MHz, DMSO-d6) 57.57 (dd, J= 8.8, 5.1 Hz, IH), 7.40 (s, IH), 7.24 (td, J = 8.4, 3.1 Hz, IH), 6.54 (dd, J = 9.3, 3.1 Hz, IH), 6.37 (d, J = 7.0 Hz, IH), 5.80 (s, 2H), 5.52 (s, 2H), 4.25 (dt, J = 13.6, 6.8 Hz, IH), 3.23 (s, 3H), 2.97 (dd, J = 14.5, 6.7 Hz, IH), 2.43 - 2.50 (m, IH).19F NMR (376 MHz, DMSO) 5 (ppm) -114.083.

[0281] Synthesis of Compound 2b and Compound 3: l-((R)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea and l-((R)-l-((R)-l-(2-chloro-5-fluorophenyl)ethyl)-7-methyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0282]

[0283] Step 1: Preparation of ethyl 5-amino-l-(l-(2-chloro-5-fluorophenyl)ethyl)-lH-pyrazole-4-carboxylate

[0284] To a stirred solution of ethyl (2E)-2-cyano-3-ethoxyprop-2-enoate (8.1 g, 47.7 mmol, 0.9 equiv.) in ethyl alcohol (100 mL) was added Diethyl acetate (8.7 g, 67.3 mmol, 1.27 equiv.) and Intermediate 2 hydrochloride (11.9 g, 53.01 mmol, 1 equiv.) at room temperature. The mixture was stirred at 80°C for 2h. The mixture was allowed to cool down to room temperature. The reaction was treated with water at rt. The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The residue was washed with brine. The combined organic layers were dried over anhydrous sodium sulfate to afford the tide compound as a yellow oil (6.0 g, 45.4% yield). The crude product was used in the next step directly without further purification.

[0285] LCMS (ESI): m / z [M+H]+calcd. for C14H15CIFN3O2: 311.08, found 312.10.

[0286] Step 2: Preparation of l-(l-(2-chloro-5-fluorophenyl)ethyl)-lH-pyrazol-5-amine

[0287] A stirred solution of ethyl 5-amino-l-(l-(2-chloro-5-fluorophenyl)ethyl)-lH-pyrazole-4-carboxylate (6.0 g, 18.5 mmol, 1 equiv.) in concentrated HC1 (60 mL) was prepared at room temperature. The mixture was stirred at 80°C overnight. The mixture was allowed to cool down to room temperature. The reaction was treated with ice water at 0°C. The mixture was adjusted to pH = 8 with an ammonium hydroxide solution. The resulting mixture was extracted with dichloromethane (3 x 150 mL). The residue was washed with brine. The combined organic layers were dried over anhydrous sodium sulfate to afford the title compound as a yellow oil (2.8 g, 60.7% yield). The crude product was used in the next step directly without further purification.

[0288] LCMS (ESI): m / z [M+H]+calcd. for C11H11CIFN3: 239.06, found 240.05.

[0289] Step 3: Preparation of 4-bromo-l-(l-(2-chloro-5-fluorophenyl)ethyl)-lH-pyrazol-5-amine

[0290] To a stirred solution of l-(l-(2-chloro-5-fluorophenyl)ethyl)-lH-pyrazol-5-amine (2.8 g, 11.68 mmol, 1 equiv.) in dichloromethane (30 mL) was added A-Bromosuccinimide (2.3 g, 12.85 mmol, 1.1 equiv.) at room temperature. The mixture was stirred at rt for Ih. The reaction was treated with water at rt. The resulting mixture was extracted with dichloromethane (3 x 100 mL). The residue was washed with brine. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (9% ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (1.6 g, 42.9% yield).

[0291] LCMS (ESI): m / z [M+H, M+H+2]+calcd. for CnHioBrClFN3: 316.97, found 317.95, 319.95.

[0292] Step 4: Preparation of 4-bromo-l-( l-(2-chloro-5-fluorophenyl)ethyl)- V-methyl-l II-pyrazol-5-amine

[0293] To a stirred solution of 4-bromo-l-(l-(2-chloro-5-fluorophenyl)ethyl)-lH-pyrazol-5-amine (1.6 g, 5.0 mmol, 1 equiv.) in tetrahydrofuran (20 mL) was added methyl lithium (0.6 M in tetrahydrofuran, 9.2 mL, 5.5 mmol, 1.1 equiv.) dropwise at -78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 0.5 h under nitrogen. To the above mixture was added methyl iodide (1.07 g, 7.53 mmol, 1.5 equiv.) in portions at -78°C. The resulting mixture was stirred at -78°C for an additional 10 min. Then, the mixture was stirred at 0°C for 0.5 h under nitrogen. The reaction was treated with water at 0°C. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The residue was washed with brine. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (1.1 g, 65.9% yield). LCMS (ESI): m / z [M+H, M+H+2]+calcd. for C H BrCIFNv 330.99, found 331.95, 333.95.

[0294] Step 5: Preparation of methyl (21f)-2-((tert-butoxycarbonyl)amino)-3-(l-(l-(2-chloro-5-fluorophenyl)ethyl)-5-(methylamino)-lH-pyrazol-4-yl)propanoate

[0295] To a stirred solution of 4-bromo-l-(l-(2-chloro-5-fluorophenyl)ethyl)-A-methyl-l H-pyrazol-5-amine (1.1 g, 3.31 mmol, 1 equiv.) in dimethylformamide (15 mL) was added palladium(II) acetate (0.15 g, 0.67 mmol, 0.2 equiv.) and Xphos (0.63 g, 1.32 mmol, 0.4 equiv.) at room temperature under nitrogen atmosphere. To the above mixture was added Intermediate 1 (33.1 mL, 16.54 mmol, 5 equiv, 0.5 M in dimethylformamide) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction was treated with water at rt. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The residue was washed with brine. The organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE and ethyl acetate (30%) to afford the title compound as a yellow oil (500 mg, 33.2%).

[0296] LCMS (ESI): m / z [M+H]+calcd. for C21H28CIFN4O4: 454.18, found 455.10.

[0297] Step 6: Preparation of (51f)-5-amino-l-(l-(2-chloro-5-fluorophenyl)ethyl)-7-methyl- 1.4.5.7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0298] The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by reverse phase flash chromatography (C18 silica gel, 10-50% acetonitrile in water) to afford the title compound as a yellow oil (90 mg, 26.4% yield).

[0299] LCMS (ESI): m / z [M+H]+calcd. for C15H16CIFN4O: 322.10, found 323.10.

[0300] Step 7: Preparation of l-((lf)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-7-methyl-6-oxo- 4.5.6.7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 2) and 1-((R)-1-((R)-l-(2-chloro-5-fluorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 3)

[0301] The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by Prep-HPLC with the following conditions (XBridge Prep C18 OBD Column, 23-48% acetonitrile in water with 10 mM ammonium formate) to afford Compound 2 as a white solid (16.1 mg, 17.8% yield). LCMS (ESI): m / z [M+H]+calcd. for C16H17CIFN5O2: 365.11, found 366.05.

[0302] 1H NMR (300 MHz, Methanol-d4) 57.38 - 7.46 (m, 2H), 7.06 (ddd, J = 8.8, 7.8, 3.0 Hz, 1H), 6.66 (dd, J = 9.5, 3.0 Hz, 1H), 6.13 (q, J = 6.8 Hz, 1H), 4.25 (dd, J = 13.5, 6.6 Hz, 1H), 3.47 (s, 3H), 3.06 (dd, 7= 14.7, 6.6 Hz, 1H), 2.57 (ddd, 7= 14.5, 13.5, 0.7 Hz, 1H), 1.96 (d, 7= 6.9 Hz, 3H).

[0303] 19F NMR (282 MHz, CD3OD) 5(ppm): -115.229.

[0304] During purification, Compound 3 was also afforded as white solid (12.7 mg, 14.01% yield). ECMS (ESI): m / z [M+H]+calcd. for C16H17CIFN5O2: 365.11, found 366.10.

[0305] ’H NMR (300 MHz, Methanol-d4) 57.42 - 7.51 (m, 2H), 6.99 - 7.12 (m, 2H), 6.02 (q, 7= 6.8 Hz, 1H), 4.42 (dd, J = 13.7, 6.6 Hz, 1H), 3.17 (s, 3H), 3.09 (dd, J = 14.6, 6.6 Hz, 1H), 2.58 (ddd, 7= 14.5, 13.7, 0.7 Hz, 1H), 1.84 (d, 7= 6.8 Hz, 3H).

[0306] 19F NMR (282 MHz, CD3OD) 5 (ppm): -114.953.

[0307] Synthesis of Compound 4: (R)-l-(l-(2-chloro-5-phenoxybenzyl)-7-methyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0308]

[0309] Scheme 4

[0310]

[0311] Step 1: Preparation of 2-chloro-5-phenoxybenzaldehyde

[0312] To a solution of 5-bromo-2-chlorobenzaldehyde (5.14 g, 22.78 mmol, 1 equiv.) in dioxane (50 mL) was added phenol (4.30 g, 45.57 mmol, 2 equiv.), copper(I) chloride (0.90 g, 9.11 mmol, 0.4 equiv.), A / , A / -Dimethylglycine (0.48 g, 4.56 mmol, 0.2 equiv.) and caesium carbonate (14.85 g, 45.57 mmol, 2 equiv.). The reaction was stirred at 100 °C for 3h under nitrogen. After cooling down to rt, the reaction was treated with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to afford the title compound as a yellow solid (3.02 g, 56.6% yield).

[0313] LCMS (ESI): m / z [M+H]+calcd. for C13H9CIO2: 232.02 m / z, found: 233.00.

[0314] Step 2: Preparation of l-(2-chloro-5-phenoxybenzyl)-lH-pyrazol-5-amine

[0315] To a solution of 2-chloro-5-phenoxybenzaldehyde (1.73 g, 7.31 mmol, 1 equiv.) in tetrahydrofuran (10 mL) was added 3-hydrazinylpropanenitrile (0.60 g, 6.94 mmol, 0.95 equiv.). The reaction was stirred at rt for 3h. The resulting mixture was concentrated under vacuum. The residue was diluted with / -B11OH (40 mL). Then, to the above mixture was added r-BuONa (0.67 g, 6.94 mmol, 0.95 equiv.) in portions over 10 min at room temperature. The resulting mixture was stirred at 120°C for an additional Ih. After cooling down to rt, the reaction was treated with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to afford the tide compound as a yellow solid (280.7 mg, 12.8% yield).

[0316] LCMS (ESI): m / z [M+H]+calcd. for CI6HI4C1N3O: 299.08 m / z, found: 300.05.

[0317] Step 3: Preparation of 4-bromo-l-(2-chloro-5-phenoxybenzyl)-lH-pyrazol-5-amine To a solution of l-(2-chloro-5-phenoxybenzyl)-lH-pyrazol-5-amine (280.7 mg, 0.934 mmol, 1 equiv.) in dichloromethane (10 mL) was added A-Bromosuccinimide (166.3 mg, 0.934 mmol, 1 equiv.). The reaction was stirred at rt for 0.5h. The reaction was treated with water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to afford the title compound as a yellow solid (140 mg, 39.6% yield).

[0318] LCMS (ESI): m / z [M+H, M+H+2]+calcd. for Ci6Hi3BrClN3O: 376.99 m / z, found: 377.90, 379.90.

[0319] Step 4: Preparation of methyl (R)-3-(5-amino-l-(2-chloro-5-phenoxybenzyl)-lH-pyrazol-4-yl)-2-((tert-butoxycarbonyl)amino)propanoate

[0320] To amixture of 4-bromo-l-(2-chloro-5 -phenoxybenzyl)- lH-pyrazol-5 -amine (140.4 mg, 0.370 mmol, 1 equiv.), palladium(II) acetate (16.6 mg, 0.074 mmol, 0.2 equiv.) and Xphos (70.5 mg, 0.148 mmol, 0.4 equiv.) in dimethylformamide (10 mL) was added Intermediate 1 (3.7 mL, 1.850 mmol, 5 equiv, 0.5 M in dimethylformamide) at 0 °C under nitrogen. The reaction was stirred at 80°C for Ih under nitrogen. After cooling down to rt, the reaction was treated with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to afford the title compound as a yellow solid (100.4 mg, 53.9% yield).

[0321] LCMS (ESI): m / z [M+H]+calcd. for C25H29CIN4O5: 500.18 m / z, found: 501.15.

[0322] Step 5: Preparation of tert-butyl (lf)-(l-(2-chloro-5-phenoxybenzyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0323] A solution of methyl (7?)-3-(5-amino-l-(2-chloro-5-phenoxybenzyl)-lH-pyrazol-4-yl)-2-((tert-butoxycarbonyl)amino)propanoate (100.4 mg, 0.200 mmol, 1 equiv.) in acetic acid (10 mL) was stirred at 90 °C for 0.2h. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL). The mixture was neutralized to pH = 7 with saturated sodium bicarbonate (aq.), diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to afford the title compound as a yellow solid (80.4 mg, 85.5% yield).

[0324] LCMS (ESI): m / z [M+H]+calcd. for C24H25CIN4O4: 468.15 m / z, found: 469.10.

[0325] Step 6: Preparation of tert-butyl (lf)-(l-(2-chloro-5-phenoxybenzyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0326] To a solution of tert-butyl N-[(57?)-l-[(2-chloro-5-phenoxyphenyl)methyl]-6-oxo-4H,5H,7H-pyrazolo [3,4-b]pyridin-5-yl] carbamate (90.8 mg, 0.192 mmol, 1 equiv.) in dimethylformamide (5 mL) was added potassium carbonate (79.6 mg, 0.576 mmol, 3 equiv.) and methyl iodide (40.8 mg, 0.288 mmol, 1.5 equiv.). The reaction was stirred at rt for Ih. The reaction was treated with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to afford the title compound as a yellow solid (80 mg, 86.3% yield).

[0327] LCMS (ESI): m / z [M+H]+calcd. for C25H27CIN4O4: 482.17 m / z, found: 483.10.

[0328] Step 7: Preparation of (lf)-5-amino-l-(2-chloro-5-phenoxybenzyl)-7-methyl-l, 4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0329] The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound as white solid (50.3 mg, 78.8% yield).

[0330] LCMS (ESI): m / z [M+H]+calcd. for C20H19CIN4O2: 382.12 m / z, found: 383.05.

[0331] Step 8: Preparation of (lf)-l-(l-(2-chloro-5-phenoxybenzyl)-7-methyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 4)

[0332] The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD Column, 31-56% acetonitrile in water with 10 mM ammonium bicarbonate) to afford the Compound 4 as a white solid (20.0 mg, 35.9% yield).

[0333] LCMS (ESI): m / z [M+H]+calcd. for C21H20CIN5O3: 425.12 m / z, found: 426.12.

[0334] 1H NMR (400 MHz, Methanol-d4) 57.44 (d,. / = 8.8 Hz, IH), 7.32 - 7.41 (m, 2H), 7.30 (s, IH), 7.17 (t, J = 7.4 Hz, IH), 6.90 - 7.01 (m, 3H), 6.05 (d, J = 2.9 Hz, IH), 5.57 (q, J = 17.9 Hz, 2H), 4.22 (dd, J = 13.8, 6.8 Hz, IH), 3.27 (s, 3H), 3.04 (dd, J = 14.7, 6.8 Hz, IH), 2.54 (t, J = 14.2 Hz, IH). Synthesis of Compound 5: (1?)-1-(1-([1, l'-biphenyl]-4-ylmethyl)-7-methyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0335]

[0336] Step 1: Preparation of l-([l,l'-biphenyl]-4-ylmethyl)-lH-pyrazol-5-amine

[0337] A solution of [l,r-biphenyl]-4-carbaldehyde (5.01 g, 27.49 mmol, 1 equiv.) and 3-hydrazinylpropanenitrile (2.22 g, 26.12 mmol, 0.95 equiv.) in tetrahydrofuran (100 mL) was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in tert-butyl alcohol (50 mL). To the above mixture was added sodium terr-butoxide (2.51 g, 26.12 mmol, 0.95 equiv.) in tert-butyl alcohol (100 mL) dropwise over 2 min at room temperature. The resulting mixture was stirred at 120°C for an additional 1 h. The mixture was allowed to cool down to room temperature. The reaction was treated with ice water at 0°C. The resulting mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 1 / 10) to afford the title compound as a yellow oil (1.51 g, 22.0% yield).

[0338] LCMS (ESI): m / z [M+H]+calcd. for C16H15N3: 249.13, found 250.15.

[0339] Step 2: Preparation of l-([l,l'-biphenyl]-4-ylmethyl)-4-bromo-lH-pyrazol-5-amine A solution of l-([l,l'-biphenyl]-4-ylmethyl)-lH-pyrazol-5-amine (1.49 g, 5.98 mmol, 1 equiv.) and A-Bromosuccinimide (1.17 g, 6.57 mmol, 1.1 equiv.) in dichloromethane (20 mL) was stirred at room temperature for 2 h. The reaction was treated with water at room temperature. The resulting mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:1 petroleum ether / ethyl acetate) to afford the title compound as a yellow oil (632 mg, 32.2% yield).

[0340] LCMS (ESI): m / z [M+H, M+H+2]+calcd. for Ci6Hi4BrN3: 327.04, found 327.95, 329.95. Step 3: Preparation of methyl (R)-3-(l-([l,l'-biphenyl]-4-ylmethyl)-5-amino-lH-pyrazol-4-yl)-2-((tert-butoxycarbonyl)amino)propanoate

[0341] To a stirred solution of l-([l, T-biphenyl]-4-ylmethyl)-4-bromo-lH-pyrazol-5-amine (620 mg, 1.889 mmol, 1 equiv.) and palladium(II) acetate (84 mg, 0.378 mmol, 0.2 equiv.) in dimethylformamide (10 mL) was added Xphos (360 mg, 0.756 mmol, 0.4 equiv.) in portions at room temperature. The resulting mixture was stirred at 0 °C for 1 min under nitrogen atmosphere. To the above mixture was added Intermediate 1 (18.7 mL, 9.445 mmol, 5 equiv, 0.5 M in dimethylformamide) dropwise over 1 min at 0 °C. The resulting mixture was stirred at 80 °C for an additional 1 h. The mixture was allowed to cool down to room temperature. The reaction was treated with ice water at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 50mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:1 ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (510 mg, 59.9% yield).

[0342] LCMS (ESI): m / z [M+H]+calcd. for C25H30N4O4: 450.23, found 451.25.

[0343] Step 4: Preparation of tert-butyl (R)-(l-([l, l'-biphenyl]-4-ylmethyl)-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0344] A solution of methyl (7?)-3-(l-([l,l'-biphenyl]-4-ylmethyl)-5-amino-lH-pyrazol-4-yl)-2-((tert-butoxycarbonyl)amino)propanoate (500 mg, 1.110 mmol, 1 equiv.) in AcOH (5 mL) was stirred at 90 °C for 2 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH = 7 with saturated Na2CO t (aq.). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:1 ethyl acetate / PE) to afford the title compound as a yellow oil (430 mg, 92.6% yield).

[0345] LCMS (ESI): m / z [M+H]+calcd. for C24H26N4O3: 418.20, found 419.20.

[0346] Step 5: Preparation of tert-butyl (lf)-(l-([l,l'-biphenyl]-4-ylmethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0347] To a stirred solution of tert-butyl (R)-(l-([l,l'-biphenyl]-4-ylmethyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate (420 mg, 1.004 mmol, 1 equiv.) and potassium carbonate (416 mg, 3.012 mmol, 3 equiv.) in dimethylformamide (5 mL) was added methyl iodide (213 mg, 1.506 mmol, 1.5 equiv.) in portions at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for 1 h. The reaction was treated with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:1 ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (281.2 mg, 64.8% yield).

[0348] LCMS (ESI): m / z [M+H]+calcd. for C25H28N4O3: 432.22, found 433.10.

[0349] Step 6: Preparation of (lf)-l-([l,l'-biphenyl]-4-ylmethyl)-5-amino-7-methyl-l, 4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0350] The transformation was carried out similarly to the synthesis of Compound 1. The crude product was obtained without further purification as hydrochloride as a yellow oil (200.5 mg, 86.8% yield).

[0351] LCMS (ESI): m / z [M+H]+calcd. for C20H20N4O: 332.16, found 333.1.

[0352] Step 7: Preparation of (2?)-l-(l-([l, l'-biphenyl]-4-ylmethyl)-7-methyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 5)

[0353] The transformation was carried out similarly to the synthesis of Compound 1. The crude product was obtained after preparative HPLC (XBridge BEH Shield RP18 Column, 24-44% acetonitrile in water with 10 mM ammonium bicarbonate) to afford the title Compound 5 as a white solid (41.0 mg, 20.2% yield).

[0354] LCMS (ESI): m / z [M+H]+calcd. for C21H21N5O2: 375.17 m / z, found: 376.20. ’H NMR (300 MHz, DMSO-A) 57.75 - 7.61 (m, 4H), 7.51 - 7.41 (m, 2H), 7.41 - 7.29 (m, 2H), 7.16 (d, J = 8.1 Hz, 2H), 6.35 (d, J = 6.9 Hz, 1H), 5.79 (s, 2H), 5.55 (s, 2H), 4.22 (dt, J = 13.5, 6.8 Hz, 1H), 3.25 (s, 3H), 2.98 (dd, J = 14.6, 6.7 Hz, 1H), 2.50 - 2.45 (m, 1H).

[0355] Synthesis of Compound 6: l-((R)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-3,7-dimethyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0356]

[0357] Step 1: Preparation of l-(l-(2-chloro-5-fluorophenyl)ethyl)-3-methyl-lH-pyrazol-5-amine

[0358] To a solution of Intermediate 2 hydrochloride (1.19 g, 5.30 mmol, 1.00 equiv.) in IN HCI (10 mL, 1.00 equiv.) was added 3-aminobut-2-enenitrile (0.47 g, 5.73 mmol, 1.08 equiv.). The reaction was stirred at 100°C for 3h. The mixture was allowed to cool down to rt. The mixture was neutralized to pH = 8 with saturated sodium bicarbonate(aq.), diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / PE) to afford the title compound as a yellow solid (750.4 mg, 55.9% yield).

[0359] LCMS (ESI): m / z [M+H]+calcd. for C12H13CIFN3: 253.08, found 254.10.

[0360] Step 2: Preparation of 4-bromo-l-(l-(2-chloro-5-fluorophenyl)ethyl)-3-methyl-lH-pyrazol-5-amine

[0361] To a solution of l-(l-(2-chloro-5-fluorophenyl)ethyl)-3-methyl-lH-pyrazol-5-amine (750.3 mg, 2.96 mmol, 1 equiv.) in dichloromethane (10 mL) was added A-Bromosuccinimide (526.2 mg, 2.956 mmol, 1 equiv.) at 0 °C. The reaction was stirred at rt for Ih. The reaction was treated with water (30 mL) and extracted with dichloromethane (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to afford the title compound as a yellow solid (450.4 mg, 45.8% yield). LCMS (ESI): m / z [M+H, M+H+2]+calcd. for C12H12B1-CIFN3: 330.99, found 331.95, 333.95.

[0362] Step 3: Preparation of te / 7-butyl ((R)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-3-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0363] To a solution of 4-bromo-l-(l-(2-chloro-5-fluorophenyl)ethyl)-3-methyl-lH-pyrazol-5-amine (450.2 mg, 1.35 mmol, 1 equiv.), palladium(II) acetate (60.8 mg, 0.27 mmol, 0.2 equiv.) and Xphos (258.0 mg, 0.541 mmol, 0.4 equiv.) in dimethylformamide (10 mL) was added Intermediate 1 (2.67 g, 6.77 mmol, 5 equiv.) at 0 °C under nitrogen. The reaction was stirred at 80 °C for Ih under nitrogen. After cooling down to rt, the reaction was treated with water (60 mL) and extracted with ethyl acetate (3 x 60 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to afford the title compound as a yellow solid (200 mg, 34.9% yield).

[0364] LCMS (ESI): m / z [M+H]+calcd. for C20H24CIFN4O3: 422.15, found 423.15.

[0365] Diastereomeric product was also obtained as a yellow solid (130.5 mg, 22.72% yield).

[0366] LCMS (ESI): m / z [M+H]+calcd. for C20H24CIFN4O3: 422.15, found 423.15.

[0367] Step 4: Preparation of te / 7-butyl ((R)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-3,7-dimethyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0368] To a solution of tert-butyl ((7?)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-3-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate (190.5 mg, 0.449 mmol, 1 equiv.) in dimethylformamide (10 mL) was added potassium carbonate (186.3 mg, 1.347 mmol, 3 equiv.) and methyl iodide (95.6 mg, 0.673 mmol, 1.5 equiv.). The reaction was stirred at rt for Ih. The reaction was treated with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to afford the title compound as a yellow solid (110 mg, 56.0% yield).

[0369] LCMS (ESI): m / z [M+H]+calcd. for C21H26CIFN4O3: 436.17, found 437.05.

[0370] Step 5: Preparation of (lf)-5-amino-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-3,7-dimethyl-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0371] The transformation was carried out similarly to the synthesis of Compound 1. The crude product was obtained as hydrochloride salt as a white solid (70.9 mg, 82.9% yield).

[0372] Step 6: Preparation of l-((lf)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-3,7-dimethyl-6-oxo-4,5,6,7-tetrahydro- lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 6)

[0373] The transformation was carried out similarly to the synthesis of Compound 1. The crude product was obtained after preparative HPLC (XBridge Prep C18 OBD Column, 20-45% acetonitrile in water with 10 mM ammonium bicarbonate) to afford the title Compound 6 as a white solid (39.0 mg, 54.3% yield). LCMS (ESI): m / z [M+H]+calcd. for C17H19CIFN5O2: 379.12, found 380.15.

[0374] ‘H NMR (300 MHz, DMSO-d6) 57.49 (dd, J = 8.8, 5.2 Hz, IH), 7.18 (ddd, J = 8.9, 8.0, 3.1 Hz, IH), 6.71 (dd, J = 9.7, 3.1 Hz, IH), 6.32 (d, J = 7.1 Hz, IH), 5.92 (q, J = 6.7 Hz, IH), 5.76 (s, 2H), 4.04 (dt, J = 13.6, 6.9 Hz, IH), 3.34 (s, 3H), 2.82 (dd, J = 14.5, 6.7 Hz, IH), 2.30 -2.42 (m, IH), 2.08 (s, 3H), 1.82 (d, J = 6.7 Hz, 3H).

[0375] 19F NMR (282 MHz, DMSO) 5 (ppm): -113.229.

[0376] Synthesis of Compound 7: (R)-l-(l-(2-chloro-4-phenoxybenzyl)-7-methyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0377]

[0378]

[0379] Step 1: Preparation of 2-chloro-4-phenoxybenzaldehyde

[0380] To a solution of 2-chloro-4-fluorobenzaldehyde (10.0 g, 63.07 mmol, 1 equiv.) in dimethylformamide (100 mL) was added phenol (5.93 g, 63.01 mmol, 1.00 equiv.) and caesium carbonate (61.63 g, 189.15 mmol, 3.00 equiv.). The reaction was stirred at 80 °C for 3h. After cooling down to room temperature, the reaction was treated with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-10% dichloromethane in petroleum ether) to afford the title compound (3.43 g, 23.4% yield).

[0381] LCMS (ESI): m / z [M+H]+calcd. for C13H9CIO2: 232.03, found 233.00.

[0382] Step 2: Preparation of l-(2-chloro-4-phenoxybenzyl)-lH-pyrazol-5-amine

[0383] To a solution of 2-chloro-4-phenoxybenzaldehyde (3.43 g, 14.74 mmol, 1 equiv.) in tetrahydrofuran (40 mL) was added 3-hydrazinylpropanenitrile (1.19 g, 13.98 mmol, 0.95 equiv.). The reaction was stirred at rt for 3h, then concentrated. The resulting mixture was dissolved using tert-butyl alcohol (60 mL), and then sodium tert-butoxide (1.34 g, 13.94 mmol, 0.95 equiv.) was added in portions over 10 min at room temperature. The resulting mixture was stirred at 120°C for an additional Ih. After cooling down to rt, the reaction was treated with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-50% ethyl acetate in petroleum ether) to afford the title compound (2.95 g, 66.8% yield).

[0384] LCMS (ESI): m / z [M+H]+calcd. for CI6HI4C1N3O: 299.08, found 300.10.

[0385] Step 3: Preparation of 4-bromo-l-(2-chloro-4-phenoxybenzyl)-lH-pyrazol-5-amine To a solution of l-(2-chloro-4-phenoxybenzyl)-lH-pyrazol-5-amine (2.95 g, 9.84 mmol, 1 equiv.) in dichloromethane (30 mL) was added 1 -bromopyrrolidine-2, 5-dione (1.75 g, 9.83 mmol, 1.00 equiv.). The reaction was stirred at rt for Ih. The reaction was treated with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% MeOH in dichloromethane) to give the title compound (3.15 g, 84.5% yield).

[0386] LCMS (ESI): m / z [M+H, M+H+2]+calcd. for Ci6Hi3BrClN3O: 376.99, found: 378.00, 380.00.

[0387] Step 4: Preparation of methyl (R)-3-(5-amino-l-(2-chloro-4-phenoxybenzyl)-lH-pyrazol-4-yl)-2-((tert-butoxycarbonyl)amino)propanoate

[0388] To a solution of 4-bromo-l-(2-chloro-4-phenoxybenzyl)-lH-pyrazol-5-amine (1.5 g, 3.96 mmol, 1 equiv.), palladium(II) acetate (0.18 g, 0.80 mmol, 0.20 equiv.), and Xphos (0.75 g, 1.57 mmol, 0.40 equiv.) in dimethylformamide (20 mL) was added Intermediate 1 (39.6 mL, 19.805 mmol, 5 equiv, 0.5 M in dimethylformamide) at 0°C under nitrogen. The reaction was stirred at 25 °C for 16 h under nitrogen, then stirred at 60°C for an additional 1 h. After cooling down to rt, the reaction was treated with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (140 mg, 7.1% yield).

[0389] LCMS (ESI): m / z [M+H]+calcd. for C25H29CIN4O5: 500.18, found 501.20.

[0390] Side-product tert-butyl (7?)-(l-(2-chloro-4-phenoxybenzyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate was also obtained as a yellow oil (580 mg, 49% yield) and combined with product that is obtained after step 5 in this sequence. LCMS (ESI): m / z [M+H]+calcd. for C24H25CIN4O4: 468.16, found 469.25.

[0391] Step 5: Preparation of tert-butyl (R)-(l-(2-chloro-4-phenoxybenzyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0392] A solution of methyl (R)-3-(5-amino-l-(2-chloro-4-phenoxybenzyl)-lH-pyrazol-4-yl)-2-((tert-butoxycarbonyl)amino)propanoate (130 mg, 0.259 mmol, 1 equiv.) in acetic acid (4 mL) was stirred at 90°C for 3h under nitrogen. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL). The mixture was neutralized to pH = 7 with saturated sodium bicarbonate (aq.). The reaction was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (120 mg, 98.6% yield). LCMS (ESI): m / z [M+H]+calcd. for C24H25CIN4O4: 468.16, found 469.30.

[0393] Step 6: Preparation of tert-butyl (R)-(l-(2-chloro-4-phenoxybenzyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0394] To a solution of tert-butyl (R)-(l-(2-chloro-4-phenoxybenzyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate (640 mg, 1.365 mmol, 1 equiv.) in dimethylformamide (10 mL) was added potassium carbonate (565.9 mg, 4.095 mmol, 3.00 equiv.) and methyl iodide (232.5 mg, 1.638 mmol, 1.20 equiv.). The reaction was stirred at rt for 3h. The reaction was treated with water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (480 mg, 72.8% yield).

[0395] LCMS (ESI): m / z [M+H]+calcd. for C25H27CIN4O4: 482.17, found 483.25.

[0396] Step 7: Preparation of (R)-5-amino-l-(2-chloro-4-phenoxybenzyl)-7-methyl-l, 4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0397] The transformation was carried out similarly to the synthesis of Compound 1. The crude product was obtained as yellow oil (190 mg).

[0398] LCMS (ESI): m / z [M+H]+calcd. for C20H19CIN4O2: 382.12, found 383.10.

[0399] Step 8: Preparation of (R)-l-(l-(2-chloro-4-phenoxybenzyl)-7-methyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 7)

[0400] The transformation was carried out similarly to the synthesis of Compound 1. The crude product was obtained after preparative HPLC (YMC-Actus Triart C18 ExRS 49-73% acetonitrile in water with 10 mM ammonium bicarbonate) to afford the title compound Compound 7 (53.5 mg, 25.3% yield).

[0401] LCMS (ESI): m / z [M+H]+calcd. for C21H20CIN5O3: 425.13, found 426.10.

[0402] ’H NMR (300 MHz, Methanol-d4) 57.35 - 7.47 (m, 3H), 7.14 - 7.25 (m, 1H), 7.00 - 7.09 (m, 3H), 6.85 - 6.95 (m, 1H), 6.74 (d, J = 9.0 Hz, 1H), 5.56 (d, J = 3.0 Hz, 2H), 4.35 - 4.48 (m, 1H), 3.29 - 3.35 (m, 3H), 3.04 - 3.17 (m, 1H), 2.54 - 2.69 (m, 1H).

[0403] Synthesis of Compound 8: l-((R)-l-((S)-l-(5-(benzyloxy)-2-chlorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0404]

[0405] Scheme 9

[0406]

[0407] Step 1: Preparation of 4-(benzyloxy)-2-bromo-l-chlorobenzene

[0408] To a stirred mixture of 3-bromo-4-chlorophenol (10.1 g, 48.2 mmol, 1 equiv.) in ethyl alcohol (50 mL) was added 2N sodium hydroxide (24 mL, 1 equiv.) at room temperature. To the above mixture was added benzyl bromide (8.24 g, 48.2 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at room temperature overnight. A new product could be detected by TLC (Rf = 0.3; 1:5 ethyl acetate / petroleum ether). The resulting mixture was concentrated under vacuum, then the reaction was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL), then the organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-20% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (12.1 g, 89.99% yield). Step 2: Preparation of 4-(benzyloxy)-l-chloro-2-(l-ethoxyvinyl) benzene

[0409] To a stirred mixture of 4-(benzyloxy)-2-bromo-l -chlorobenzene (12.10 g, 40.33 mmol, 1 equiv.) and tributyl(l -ethoxy ethenyl) stannane (21.85 g, 60.49 mmol, 1.5 equiv.) in dioxane (60 mL) was added tetrakis(triphenylphosphine)palladium(0) (4.66 g, 4.03 mmol, 0.1 equiv.) in portions at room temperature. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. A new product was observed by TLC (Rf = 0.3; 1: 10 ethyl acetate / petroleum ether). The resulting mixture was cooled to room temperature and used in the next step directly without further purification.

[0410] Step 3: Preparation of l-(5-(benzyloxy)-2-chlorophenyl) ethan-l-one

[0411] To the crude reaction mixture from the previous step was added 1 N hydrochloric acid (60 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction was then diluted with water (20 mL) and extracted with EA (3 x 80 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-20% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (9.10 g, 86.6% yield).

[0412] Step 4: Preparation of tert-butyl 2-(l-(5-(benzyloxy)-2-chlorophenyl)ethylidene)hydrazine-l-carboxylate

[0413] To a stirred mixture of l-(5-(benzyloxy)-2-chlorophenyl) ethan-l-one (9.10 g, 34.5 mmol, 1 equiv.) and tert-butoxycarbohydrazide (13.69 g, 103.6 mmol, 3 equiv.) in THF (40 mL) and heptane (80 mL) was added 6 drops of acetic acid and the reaction was stirred at room temperature. Once the reaction was judged complete by LCMS the reaction mixture was concentrated under reduced pressure to afford the title compound as a yellow oil (9.10 g, 69.5% yield). The crude product was used without further purification.

[0414] Step 5: Preparation of tert-butyl 2-(l-(5-(benzyloxy)-2-chlorophenyl) ethyl) hydrazine-1-carboxylate

[0415] To a stirred mixture of tert-butyl 2-(l-(5-(benzyloxy)-2-chlorophenyl) ethylidene) hydrazine-1 -carboxylate (9.10 g, 24.5 mmol, 1 equiv.) in methanol (50 ml) was added acetic acid (50 mL) at room temperature. Sodium cyanoborohydride (9.25 g, 147 mmol, 6.00 equiv.) was then added at 0 °C, and the resulting mixture was stirred at room temperature for Ih. The reaction mixture was then concentrated under reduced pressure, then sodium bicarbonate solution was added until solution pH = 7. The resulting mixture was diluted with water (100 mL), then extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (7.10 g, 76.76%).

[0416] LCMS (ESI): m / z [M+H]+calcd. for C20H25CIN2O3: 376.16, found: 321.00 [M+H-tBu]+. Step 6: Preparation of (l-(5-(benzyloxy)-2-chlorophenyl) ethyl) hydrazine

[0417] / c / 7- Butyl 2-(l-(5-(benzyloxy)-2-chlorophenyl) ethyl) hydrazine- 1 -carboxylate (5.12 g, 13.5 mmol, 1 equiv.) was dissolved in 4M hydrochloric acid in dioxane (60 mL) and the resulting mixture was stirred at room temperature overnight. The mixture was then concentrated under reduced pressure to afford the hydrochloride salt of the title compound as a white solid, which was used without further purification (3.50 g, 85.5% yield).

[0418] LCMS (ESI): m / z [M+H]+calcd. for C15H17CIN2O: 276.10, found: 277.00.

[0419] Step 7: Preparation of l-(l-(5-(benzyloxy)-2-chlorophenyl) ethyl)- lH-pyrazol-5-amine To a stirred mixture of (l-(5-(benzyloxy)-2-chlorophenyl)ethyl)hydrazine hydrochloride (3.50 g, 11.2 mmol, 1 equiv.) and 3,3-dimethoxypropanenitrile (1.42 g, 12.3 mmol, 1.1 equiv.) in ethanol (96 mL) was added concentrated hydrochloric acid (2.6 mL, 0.144 mmol, 4 equiv.) at room temperature, then the resulting mixture was stirred at 80 °C for 4h. The mixture was then concentrated under reduced pressure and sodium bicarbonate solution was then added until pH = 7. This mixture was diluted with water (100 mL), then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-40% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (2.10 g, 59.1% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H18ClN3O: 327.11, found: 328.10.

[0420] Step 8: Preparation of l-(l-(5-(benzyloxy)-2-chlorophenyl) ethyl) -4-bromo-lH-pyrazol-5-amine

[0421] To a stirred solution of l-(l-(5-(benzyloxy)-2-chlorophenyl) ethyl)- lH-pyrazol-5 -amine (2.10 g, 6.10 mmol, 1 equiv.) in dichloromethane (15 mL) was added 7V-bromosuccinimide (1.19 g, 6.71 mmol, 1.1 equiv.) at 0 °C, and the resulting mixture was stirred at room temperature for Ih. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0-40% ethyl acetate / petroleum ether) to afford the title compound as a red solid (2.30 g, 92.7% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H17BrClN3O: 407.02, found: 407.90.

[0422] Step 9: Preparation of methyl (21f)-3-(5-amino-l-(l-(5-(benzyloxy)-2-chlorophenyl) ethyl)-lH-pyrazol-4-yl)-2-((tert-butoxycarbonyl) amino) propanoate

[0423] To a solution of l-(l-(5-(benzyloxy)-2-chlorophenyl) ethyl)-4-bromo-lH-pyrazol-5-amine (2.12 g, 5.21 mmol, 1 equiv.) and palladium(II) acetate (0.24 g, 1.07 mmol, 0.20 equiv.) in DMF (50 mL) was added XPhos (1.03 g, 2.16 mmol, 0.4 equiv.) in portions at room temperature under a nitrogen atmosphere. To the above mixture was then added Intermediate 1 (33 mL, 15.0 mmol, 3.00 equiv, 0.5 M in DMF) at 0 °C under a nitrogen atmosphere, and the resulting mixture was stirred at 80 °C for Ih under a nitrogen atmosphere. The reaction was then cooled to room temperature, quenched with water (60 mL), and extracted with ethyl acetate (3 x 60 mL). The combined organic extracts were washed with water, brine, dried over sodium suflate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (2.60 g, 80.4% yield).

[0424] LCMS (ESI): m / z [M+H]+calcd. for C27H33CIN4O5: 528.21, found: 529.15.

[0425] Step 10: Preparation of tert-butyl ((51f)-l-(l-(5-(benzyloxy)-2-chlorophenyl) ethyl)-6-oxo- 4.5.6.7-tetrahydro-lH-pyrazolo[3,4-b] pyridin-5-yl)carbamate

[0426] Methyl (27?)-3-(5-amino-l-(l-(5-(benzyloxy)-2-chlorophenyl) ethyl)- IH-pyrazol -4-yl)-2-((tert-butoxycarbonyl) amino) propanoate (2.60 g, 4.92 mmol, 1 equiv.) was dissolved in acetic acid (30 mL) and the resulting solution was stirred at 90 °C for 10 min. The mixture was mixture was cooled to room temperature, then sodium bicarbonate solution was added until pH = 8. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-40% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (2.20 g, 90.1% yield).

[0427] LCMS (ESI): m / z [M+H]+calcd. for C26H29CIN4O4: 496.19, found: 497.35.

[0428] Step 11: Preparation of tert-butyl ((R)-l-((S)-l-(5-(benzyloxy)-2-chlorophenyl) ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0429] To a stirred mixture of tert-butyl ((57?)-l-(l-(5-(benzyloxy)-2-chlorophenyl) ethyl)-6-oxo- 4.5.6.7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate (2.20 g, 4.43 mmol, 1 equiv.) and potassium carbonate (1.84 g, 13.3 mmol, 3 equiv.) in DMF (30 mL) was added methyl iodide (0.94 g, 6.64 mmol, 1.5 equiv.) and the resulting mixture was stirred at room temperature for Ih. The reaction was then quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound as the second eluting isomer as a yellow oil (900.2 mg, 39.79% yield).

[0430] LCMS (ESI): m / z [M+H]+calcd. for C27H31CIN4O4: 510.20, found: 511.15.

[0431] Step 12: (R)-5-amino-l-((S)-l-(5-(benzyloxy)-2-chlorophenyl)ethyl)-7-methyl-l, 4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0432] / c / 7- Butyl ((7?)-l-((S)-l-(5-(benzyloxy)-2-chlorophenyl) ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b] pyridin-5-yl)carbamate (900.2 mg, 1.761 mmol, 1 equiv.) was dissolved in a solution of 4M hydrochloride acid in 1,4-dioxane (10 mL) and the resulting solution was stirred at room temperature for 3 h. The reaction mixture was then concentrated under reduced pressure to afford the hydrochloride salt of the title compound as a light yellow solid (500 mg, 91.7% yield).

[0433] LCMS (ESI): m / z [M+H]+calcd. for C22H23CIN4O2: 410.15, found: 411.10.

[0434] Step 13: Preparation of l-((R)-l-((S)-l-(5-(benzyloxy)-2-chlorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 8)

[0435] To a stirred solution of (7?)-5-amino- 1 -(( )- 1 -(5-(benzyloxy)-2-chlorophenyl) ethyl)-7-methyl-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one hydrochloride (300.1 mg, 0.730 mmol, 1 equiv.) in THF (10 ml ) and water (0.5 mL) were added potassium cyanate (136.03 mg, 1.678 mmol, 3 equiv.) and methanesulfonic acid (96.70 mg, 1.006 mmol, 1.5 equiv.) and the reaction was stirred at room temperature for Ih. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XBridge Prep OBD C18 column, 35-55% acetonitrile / water with 0.05% ammonium bicarbonate) to afford Compound 8 as a white solid (52.2 mg, 23.6% yield).

[0436] LCMS (ESI): m / z [M+H]+calcd. for C23H24CIN5O3: 453.16, found: 454.15.1H NMR (300 MHz, DMSO-A) 57.30 - 7.42 (m, 7H), 6.96 (dd, J = 8.8, 3.0 Hz, 1H), 6.24 -6.38 (m, 2H), 5.92 - 6.08 (m, 1H), 5.80 (s, 2H), 4.90 - 5.08 (m, 2H), 3.90 - 4.15 (m, 1H), 3.33 (s, 3H), 2.80 - 3.00 (m, 1H), 2.35 - 2.47 (m, 1H), 1.83 (d, J = 6.6 Hz, 3H).

[0437] Synthesis of Compound 9: l-((R)-l-((S)-l-(2-chloro-4-cyclopropylphenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0438]

[0439] Step 1: Preparation of l-(2-chloro-4-cyclopropylphenyl)ethenone

[0440] To a stirred solution of l-(4-bromo-2-chlorophenyl)ethanone (3.00 g, 12.8 mmol, 1 equiv.) and cyclopropylboronic acid (1.32 g, 15.4 mmol, 1.2 equiv.) in toluene (30 mL) and water (3 mL) were added palladium(II) acetate (0.14 g, 0.642 mmol, 0.05 equiv.), tricyclohexylphosphane (0.36 g, 1.29 mmol, 0.1 equiv.), and potassium phosphate tribasic (9.55 g, 44.97 mmol, 3.5 equiv.) in portions at room temperature, then the resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The reaction was then cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (3 x50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% ethyl acetate / petroleum ether) to afford the title compound as a colorless oil (2.00 g, 79.97% yield).

[0441] LCMS (ESI): m / z [M+H]+calcd. for C11H11CIO: 194.05, found 194.95.

[0442] Step 2: Preparation of (LR)-l-(2-chloro-4-cyclopropylphenyl)ethanol

[0443] To a stirred solution of (3aS)-l-methyl-3,3-diphenyl-hexahydropyrrolo[ 1,2-c][l,3,2]oxazaborole (569.5 mg, 1.027 mmol, 0.2 equiv.) in THF (10 mL) was added borane dimethyl sulfide complex (2.0 M in THF, 1.17 g, 7.705 mmol, 1.5 equiv.) and l-(2-chloro-4-cyclopropylphenyl)ethanone (2.00 g, 5.14 mmol, 1 equiv.) in portions at 0 °C, then the resulting mixture was stirred at 0 °C for 1 h. The reaction was then quenched by addition of ice water (30 mL) at 0 °C and the resulting solution was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford the tide compound as a colorless oil (1.60 g, 79.2% yield). LCMS (ESI): m / z [M+H]+calcd. for C11H13CIO: 196.07, found 179.1 [M+H-0H]+.

[0444] Step 3: Preparation of V'-( / c / 7-butoxycarbonyl)-V-|( l. S)-l-(2-chloro-4-cyclopropylphenyl)ethyl]tert-butoxycarbohydrazide

[0445] To a stirred solution of (17?)-l-(2-chloro-4-cyclopropylphenyl)ethanol (1.59 g, 8.08 mmol, 1 equiv.) and triphenylphosphine (3.18 g, 12.1 mmol, 1.5 equiv.) in acetonitrile (20 mL) was added di-terr-butyl diazene- 1,2-di carboxylate (2.79 g, 12.1 mmol, 1.5 equiv.) in portions at room temperature under a nitrogen atmosphere, then the resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound as a colorless oil (2.20 g, 66.2% yield).

[0446] LCMS (ESI): m / z [M-H]’ calcd. for C21H31C1N2O4: 410.20, found 409.1.

[0447] Step 4: Preparation of [(lS)-l-(2-chloro-4-cyclopropylphenyl)ethyl]hydrazine

[0448] A solution of M-(tert-butoxycarbonyl)-A-[(lS)-l-(2-chloro-4-cyclopropylphenyl)ethyl]tert-butoxycarbohydrazide (2.19 g, 5.33 mmol, 1 equiv.) in 4M hydrochloride acid in 1,4-dioxane (25 mL) was stirred at room temperature for 1 h. The mixture was then concentrated under reduced pressure to afford the hydrochloride salt of the title compound as an off-white solid, which was used without further purification (1.20 g, 91.6% yield).

[0449] LCMS (ESI): m / z [M+H]+calcd. for C11H15CIN2: 210.09, found 211.1.

[0450] Step 5: Preparation of 2-[(lS)-l-(2-chloro-4-cyclopropylphenyl)ethyl]pyrazol-3-amine To a stirred solution of [( IS)- 1 -(2-chl n )-4-cyclopropyl phenyl )ethy 1 ] hydrazine hydrochloride (1.17 g, 4.75 mmol, 1 equiv.) and 3,3-diethoxypropanenitrile (0.68 g, 4.75 mmol, 1 equiv.) in ethanol (10 mL) was added concentrated hydrochloric acid (1.58 mL, 18.98 mmol, 4 equiv.) dropwise at room temperature. The resulting mixture was then stirred at 80 °C for 3 h. The mixture was then cooled to room temperature and the pH adjusted to 8 by the addition of sodium bicarbonate solution. The resulting solution was then diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-40% ethyl acetate / petroleum ether) to afford the title compound as a colorless oil (800.0 mg, 64.4% yield).

[0451] LCMS (ESI): m / z [M+H]+calcd. for C14H16CIN3: 261.10, found 262.05.

[0452] Step 6: Preparation of 4-bromo-2-[(lS)-l-(2-chloro-4-cyclopropylphenyl)ethyl]pyrazol-3-amine

[0453] To a stirred solution of 2-[( 1 S)- 1 -(2-chloro-4-cyclopropylphenyl)ethyl ]pyrazol-3-amine (790.0 mg, 3.018 mmol, 1 equiv.) in dichloromethane (8 mL) was added A-bromosuccinimide (590.9 mg, 3.320 mmol, 1.1 equiv.) in portions at 0 °C, and the resulting mixture was stirred at room temperature for 5 min. The reaction mixture was then concentrated under reduced pressure and the residue was purified by silica gel chromatography (0-20% ethyl acetate / petroleum ether) to afford the title compound as a colorless oil (700.0 mg, 68.1% yield). LCMS (ESI): m / z [M+H]+calcd. for Ci4Hi5BrClN3: 341.01, found 342.0.

[0454] Step 7: Preparation of tert-butyl A^-[(51f)-l-[(lS)-l-(2-chloro-4-cyclopropylphenyl)ethyl]- 6-oxo-4H,5H,7H-pyrazolo[3,4-b]pyridin-5-yl]carbamate

[0455] To a stirred solution of 4-bromo-2-[(lS)-l-(2-chloro-4-cyclopropylphenyl)ethyl]pyrazol-3-amine (690.0 mg, 2.026 mmol, 1 equiv.) in DMF (10 mL) was added XPhos (193.1 mg, 0.405 mmol, 0.2 equiv.) and palladium(II) acetate (45.5 mg, 0.203 mmol, 0.1 equiv.) in portions at room temperature under a nitrogen atmosphere, then Intermediate 1 (0.5 M in DMF, 16.2 mF, 8.104 mmol, 4 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was then cooled to room temperature and filtered, then the filter cake was washed with ethyl acetate (3 x 20 mL). The filtrate was concentrated under reduced pressure then water (30 mL) was added and the resulting solution was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-40% ethyl acetate / petroleum ether) to afford the tide compound as a light yellow oil (700.0 mg, 80.20% yield).

[0456] LCMS (ESI): m / z [M+H]+calcd. for C22H27CIN4O3: 430.18, found 431.20.

[0457] Step 8: Preparation of tert-butyl iV-[(51f)-l-[(lS)-l-(2-chloro-4-cyclopropylphenyl)ethyl]- 7-methyl-6-oxo-4H,5H-pyrazolo[3,4-b]pyridin-5-yl]carbamate

[0458] To a stirred solution of tert-butyl W-[(57?)-l-[(lS)-l-(2-chloro-4-cyclopropylphenyl)ethyl]-6-oxo-4H,5H,7H-pyrazolo[3,4-b]pyridin-5-yl]carbamate (690.0 mg, 1.601 mmol, 1 equiv.) and potassium carbonate (663.9 mg, 4.803 mmol, 3 equiv.) in DMF (8 mL) was added methyl iodide (340.9 mg, 2.401 mmol, 1.5 equiv.) dropwise at room temperature, and the resulting mixture was stirred at room temperature for 2 h. The reaction was then quenched with water (20 mL) and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 ethyl acetate / petroleum ether) to afford the title compound as an off-white oil (300.0 mg, 42.11% yield).

[0459] LCMS (ESI): m / z [M+H]+calcd. for C23H29CIN4O3: 444.19, found: 445.20. Step 9: Preparation of (51f)-5-amino-l-[(lS)-l-(2-chloro-4-cyclopropylphenyl)ethyl]-7-methyl-4H,5H-pyrazolo[3,4-b]pyridin-6-one

[0460] A solution of tert-butyl A-[(57?)-l-[(lS)-l-(2-chloro-4-cyclopropylphenyl)ethyl]-7-methyl-6-oxo-4H,5H-pyrazolo[3,4-b]pyridin-5-yl]carbamate (200.0 mg, 0.337 mmol, 1 equiv.) was dissolved in 4M hydrochloric acid in 1,4-dioxane (3 mL) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then pH adjusted to 8 with sodium bicarbonate solution, and the resulting solution was diluted with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as an off-white solid, which was used without further purification (150.0 mg, 96.80% yield).

[0461] LCMS (ESI): m / z [M+H]+calcd. for C18H21C1N4O: 344.14, found: 345.15.

[0462] Step 10: Preparation of l-((R)-l-((S)-l-(2-chloro-4-cyclopropylphenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0463] To a stirred solution of (57?)-5-amino-l-[(lS)-l-(2-chloro-4-cyclopropylphenyl)ethyl]-7-methyl-4H,5H-pyrazolo[3,4-b]pyridin-6-one (140.0 mg, 0.406 mmol, 1 equiv.) in THF (2 mL) was added potassium cyanate (98.8 mg, 1.218 mmol, 3 equiv.) and methanesulfonic acid (58.5 mg, 0.609 mmol, 1.5 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 xlO mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Xbridge Prep Shield RP18 150 mm x 30 mm x 5 pm column, 23-43% acetonitrile / water with 10 mM ammonium bicarbate) to afford the title compound as a white solid (32.4 mg, 20.6% yield).

[0464] LCMS (ESI): m / z [M+H]+calcd. for C19H22CIN5O2: 387.15, found: 388.15.

[0465] ’H NMR (300 MHz, DMSO-A) 57.37 - 7.14 (m, 2H), 7.01 - 6.98 (m, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.32 (d, J = 6.9 Hz, 1H), 5.98 (q, J = 6.6 Hz, 1H), 5.78 (s, 2H), 4.04 - 3.99 (m, 1H), 3.33 (s, 3H), 2.94 - 2.87 (m, 1H), 2.50 - 2.38 (m, 1H), 1.90 - 1.81 (m, 4H), 0.99 - 0.90 (m, 2H), 0.74 - 0.63 (m, 2H). Synthesis of Compound 10: l-((R)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-7-(cyclopropylmethyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0466]

[0467] Step 1: Preparation of 4-bromo-l-(l-(2-chloro-5-fluorophenyl)ethyl)-lH-pyrazol-5-amine

[0468] A mixture of l-(l-(2-chloro-5-fluorophenyl)ethyl)-lH-pyrazol-5-amine (6.5 g, 27.1 mmol, 1 equiv.) and 1 -bromopyrrolidine-2, 5 -dione (7.0 g, 39.3 mmol, 1.45 equiv.) in dichlromethane (50 mL) was stirred at room temperature for 30 min. The reaction mixture was then concentrated under reduced pressure and the residue was purified by silica gel chromatography (1:5 ethyl acetate / petroleum ether) to afford the tide compound as a light red solid (7.5 g, 86.8% yield).

[0469] Step 2: Preparation of (51f)-5-amino-l-[(lS)-l-(2-chloro-5-fluorophenyl)ethyl]-7-(cyclopropylmethyl)-4H,5H-pyrazolo[3,4-b]pyridin-6-one

[0470] To a stirred solution of 4-bromo-l-(l-(2-chloro-5-fluorophenyl)ethyl)-lH-pyrazol-5-amine (1.00 g, 3.14 mmol, 1 equiv.) in DMF (10 mL) was added palladium(II) acetate (0.14 g, 0.628 mmol, 0.2 equiv.), XPhos (0.60 g, 1.26 mmol, 0.4 equiv.) and Intermediate 1 (19.90 mL, 9.957 mmol, 3 equiv, 0.5M in DMF) dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred at 80 °C for 1 h under nitrogen, then was cooled to room temperature. The reaction was quenched with saturated ammonium chloride solution (50 mL) and the resulting mixture was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concetated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as the first eluting diastereomer as a yellow oil (450 mg, 35.1% yield).

[0471] LCMS (ESI): m / z [M+H]+calcd. for C19H22CIFN4O3: 408.14, found: 409.10.

[0472] Step 3: Preparation of tert-butyl iV-[(51f)-l-[(lS)-l-(2-chloro-5-fluorophenyl)ethyl]-7-(cyclopropylmethyl)-6-oxo-4H,5H-pyrazolo[3,4-b]pyridin-5-yl]carbamate

[0473] To a solution of tert-butyl A-[(57?)-l-[(lS)-l-(2-chloro-5-fluorophenyl)ethyl]-6-oxo-4H,5H,7H-pyrazolo[3,4-b]pyridin-5-yl]carbamate (190.0 mg, 0.465 mmol, 1 equiv.) in DMF (2 mL) were added (bromomethyl)cyclopropane (75.3 mg, 0.558 mmol, 1.2 equiv.) and potassium carbonate (192.7 mg, 1.39 mmol, 3 equiv.), and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (100 mg, 46.5% yield).

[0474] LCMS (ESI): m / z [M+H]+calcd. for C23H28CIFN4O3: 462.18, found: 463.20.

[0475] Step 4: Preparation of (51f)-5-amino-l-[(lS)-l-(2-chloro-5-fluorophenyl)ethyl]-7-(cyclopropylmethyl)-4H,5H-pyrazolo[3,4-b]pyridin-6-one

[0476] A solution of tert-butyl A-[(57?)-l-[(lS)-l-(2-chloro-5-fluorophenyl)ethyl]-7-(cyclopropylmethyl)-6-oxo-4H,5H-pyrazolo[3,4-b]pyridin-5-yl]carbamate (90.0 mg, 0.194 mmol, 1 equiv.) in 4 M hydrochloric acid in 1,4-dioxane (2 mL) was stirred at room temperature for 1 h. The reaction was adjusted to pH = 7 with sodium bicarbonate solution (10% aq.) at 0 °C, then extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as a yellow oil, which was used without further purification (70 mg, 99.2% yield). LCMS (ESI): m / z [M+H]+calcd. for C21H20CIFN4O: 362.13, found: 363.10. Step 5: Preparation of l-((R)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-7-(cyclopropylmethyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 10)

[0477] To a solution of (5R)-5-amino-l-[(lS)-l-(2-chloro-5-fluorophenyl)ethyl]-7-(cyclopropylmethyl)-4H,5H-pyrazolo[3,4-b]pyridin-6-one (70.0 mg, 0.193 mmol, 1 equiv.) in THF (2 mL) and water (0.2 mL) were added potassium isocyanate (47.0 mg, 0.579 mmol, 3.00 equiv.) and methanesulfonic acid (20 mg, 0.208 mmol, 1.08 equiv.)., then the reaction was stirred at room temperature for 1 h. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (YMC Triart C 18150 mm x 30 mm, 5 pm column, 23-53% water / acetonitrile with 10 mM bicarbonate) to afford Compound 10 as a white solid (31.8 mg, 40.6% yield). LCMS (ESI): m / z [M+H]+calcd. for C19H21CIFN5O2: 405.14, found: 406.10.

[0478] ’H NMR (300 MHz, DMSO-d6) 57.58 - 7.43 (m, 2H), 7.27 - 7.14 (m, 1H), 6.65 - 6.54 (m, 1H), 6.45 - 6.37 (m, 1H), 5.94 - 5.82 (m, 1H), 5.77 (s, 2H), 4.13 - 3.93 (m, 2H), 3.60 - 3.47 (m, 1H), 3.01 - 2.88 (m, 1H), 2.49 - 2.34 (m, 1H), 1.89 (d, J = 6.7 Hz, 3H), 1.23 - 0.79 (m, 1H), 0.60 - 0.07 (m, 3H).

[0479] 19F NMR (282 MHz, DMSO-d6) 5 -113.434.

[0480] Synthesis of Compound 11: l-((R)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-7-cyclopropyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0481]

[0482] Scheme 12

[0483]

[0484] Step 1: Preparation of tert-butyl ((R)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-7-cyclopropyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate To a stirred solution of tert-butyl ((ft)- 1 -((£)- l-(2-chloro-5-fhiorophenyl)ethyl)-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate (370.0 mg, 0.905 mmol, 1 equiv.) and cyclopropylboronic acid (155.5 mg, 1.810 mmol, 2 equiv.) in dichloromethane (8 mL) were added pyridine (143.2 mg, 1.810 mmol, 2 equiv.) and copper(II) trifluoroacetate (556.7 mg, 1.810 mmol, 2 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 24 h, then the reaction was quenched with water (20 mL) and the resulting mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as a colorless oil (230.0 mg, 56.65% yield).

[0485] LCMS (ESI): m / z [M+H]+calcd. for C22H26CIFN4O3: 448.17, found: 449.3.

[0486] Step 2: Preparation of (R)-5-amino-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-7-cyclopropyl-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0487] A mixture of tert-butyl (7?)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-7-cyclopropyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-ylcarbamate (220.0 mg, 0.513 mmol, 1 equiv.) in 4 M hydrochloric acid in 1,4-dioxane (5 mL) was stirred at room temperature for 3 h. The resulting mixture was then concentrated under reduced pressure to afford the hydrochloride salt of the title compound as alight yellow solid (168.0 mg, 89.10% yield). LCMS (ESI): m / z [M+H]+calcd. for CI7HISC1FN4O: 348.12, found: 349.10. Step 3: Preparation of l-((R)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-7-cyclopropyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 11)

[0488] To a stirred solution of (R)-5 -amino- 1 -((£)- 1 -(2-chloro-5 -fluorophenyl)ethyl)-7-cy clopropyl-4,5-dihydro-lH-pyrazolo[3,4-b]pyridin-6(7H)-one hydrochloride (158.2 mg, 0.411 mmol, 1 equiv.) in THF (2 mL) and water (2 mL) were added potassium cyanate (100.0 mg, 1.234 mmol, 3 equiv.) and methanesulfonic acid (78.9 mg, 0.822 mmol, 2 equiv.) and the reaction was stirred at room temperature for 1 h. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (YMC Triart C18 ExRs Column, 20mm x 250 mm x 5 pm, 30-52% acetonitrile / water with 0.1% ammonium bicarbonate) to afford Compound 11 as a white solid (52.4 mg, 32.6% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H19CIFN5O2: 391.12, found: 392.15.

[0489] 1H NMR (300 MHz, DMSO-A) 57.50 - 7.65 (m, 1H), 7.38 - 7.48 (m, 1H), 7.10 - 7.30 (m, 1 H), 6.70 - 6.90 (m, 1H), 6.20 - 6.40 (m, 2H), 5.70 (s, 2 H), 3.80 - 4.02 (m, 1 H), 2.70 - 3.00 (m, 2H), 2.25 - 2.50 (m, 1H), 1.75 (d, J = 6.7 Hz, 3H), 1.00 - 1.30 (m, 2H), 0.50 - 0.80 (m, 2H).

[0490] 19F NMR (282 MHz, DMSO-d6) 5 -113.50.

[0491] Synthesis of Compound 12: l-((R)-l-((S)-l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0492]

[0493] Scheme 13

[0494]

[0495] Step 1: Preparation of l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethan-l-ol

[0496] To a solution of 2-bromo-4-fluoro-l -(trifluoromethoxy )benzene (4 g, 15.5 mmol, 1 equiv.) in THF (50 mL) was added n-butyllithium (6.82 ml, 17.0 mmol, 1.1 equiv, 2.5 M in THF) at -78 °C under nitrogen and the solution was stirred for 1 h. Acetaldehyde (6.2 ml, 31.0 mmol, 2 equiv, 5 M in THF) was then added at -78 °C and the resulting mixture was stirred at 0 °C for 2 h. The reaction was warmed to room temperature and quenched with water (100 mL), then the resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (2.48 g, 71.4% yield).

[0497] Step 2: Preparation of di-A / 7-butyl l-(l-(5-fluoro-2- (trifluoromethoxy)phenyl)ethyl)hydrazine-l,2-dicarboxylate

[0498] To a solution of l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethan-l-ol (2.48 g, 11.1 mmol, 1 equiv.) in acetonitrile (30 mL) was added triphenylphosphine (4.35 g, 16.6 mmol, 1.5 equiv.) under nitrogen and the mixture was stirred at room temperature for 30 min. Di-tert-butyl diazene- 1,2-dicarboxylate (3.82 g, 16.6 mmol, 1.5 equiv.) was then added at 0 °C and the resulting mixture was stirred at room temperature for 2 h. The reaction was then quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (4.5 g, 92.8% yield).

[0499] LCMS (ESI): m / z [M+H]+calcd. for C19H26F4N2O5: 438.18, found 283.00 [M+H-tBu-Boc]+.

[0500] Step 3: Preparation of (l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)hydrazine

[0501] To a stirred solution of di-tert-butyl l-(l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)hydrazine-l,2-dicarboxylate (4.3 g, 9.82 mmol) in methanol (45 mL) was added acetyl chloride (4.5 ml) at 0 °C. The mixture was stirred at room temperature for 5 min, then a 1:5 mixture of concentrated hydrochloric acid in methanol (39.3 mL) was added at 0 °C. The reaction mixture was stirred at 50 °C for 2 h, then was cooled to room temperature and concentrated under reduced pressure to afford the hydrochloride salt of the tide compound as a white solid, which was used without further purification (2.56 g, 95.2% yield).

[0502] LCMS (ESI): m / z [M+H]+calcd. for C9H10F4N2O: 238.07, found 239.00.

[0503] Step 4: Preparation of l-(l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-lH-pyrazol-5-amine

[0504] To a stirred solution of (l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)hydrazine hydrochloride (2.5 g, 9.11 mmol, 1 equiv.) and 3,3-diethoxypropanenitrile (1.3 g, 9.11 mmol, 1 equiv.) in ethanol (40 mL) was added concentrated hydrochloric acid (3.1 mL, 36.43 mmol, 4 equiv.) in portions at 0 °C, and the resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. Sodium bicarbonate (100 mL) was then added, and the resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as a white solid (2.2 g, 83.6% yield). LCMS (ESI): m / z [M+H]+calcd. for C12H11F4N3O: 289.08, found 290.10. Step 5: Preparation of 4-bromo-l-(l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-lH-pyrazol-5-amine

[0505] To a stirred solution of l-(l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-lH-pyrazol-5-amine (2.2 g, 7.61 mmol, 1 equiv.) in dichloromethane (15 ml) was added 7V-bromosuccinimide (1.22 g, 6.85 mmol, 0.9 equiv.) at 0 °C, and the resulting mixture was stirred at 0 °C for 30 min. The reaction was then quenched with water (50 mL), and the resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the tide compound as a yellow oil (2.33 g, 79.8% yield). LCMS (ESI): m / z [M+H]+calcd. for Ci2Hi0BrF4N3O: 366.99, found 368.05.

[0506] Step 6: Preparation of tert-butyl ((51f)-l-(l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0507] To a stirred solution of 4-bromo-l-(l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-lH-pyrazol-5 -amine (620 mg, 4.08 mmol, 1 equiv.), palladium(II) acetate (183.0 mg, 0.815 mmol, 0.2 equiv.) and XPhos ( 777.3 mg, 1.630 mmol, 0.4 equiv.) in DMF (10 mL) was added Intermediate 1 (24.5 mL, 12.2 mmol, 3 equiv, 0.5 M in DMF) dropwise at 0 °C under a nitrogen atmosphere, and the resulting mixture was stirred at 80 °C for 1.5 h. The reaction was then cooled to room temperature, quenched with saturated ammonium chloride solution, filtered, and the filter cake was washed with ethyl acetate (3 x 10 mL). The filtrate was extracted with ethyl acetate (3 x 50 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (640 mg, 34.2% yield). LCMS (ESI): m / z [M+H]+calcd. for C20H22F4N4O4: 458.16, found 459.35.

[0508] Step 7: Preparation of tert-butyl ((R)-l-((S)-l-(5-fluoro-2- (trifluoromethoxy)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0509] To a stirred solution of tert-butyl ((57?)-l-(l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate (630 mg, 1.38 mmol, 1 equiv.) and potassium carbonate (569.5 mg, 4.127 mmol, 3 equiv.) in DMF (10 mL) was added methyl iodide (234.4 mg, 1.651 mmol, 1.2 equiv.) in portions, then the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (30 mL), and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as the second eluting diastereomer as a yellow oil (260 mg, 40.0% yield).

[0510] LCMS (ESI): m / z [M+H]+calcd. for C21H24F4N4O4: 472.17, found:473.30.

[0511] Step 8: Preparation of (lf)-5-amino-l-((S)-l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-7-methyl-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0512] A solution of tert-butyl ((!?)- 1 -(( )- 1 -(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate (250 mg, 0.530 mmol, 1 equiv.) in 4 M hydrochloric acid in 1,4-dioxane(3 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to afford the hydrochloride salt of the title compound as a yellow oil, which was used without further purification (200 mg, 92.4% yield).

[0513] LCMS (ESI): m / z [M+H]+calcd. for C16H16F4N4O2: 372.12, found: 373.20.

[0514] Step 8: Preparation of l-((R)-l-((S)-l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 12) To a stirred solution of (7?)-5-amino-l-((S)-l-(5-fluoro-2-(trifluoromethoxy)phenyl)ethyl)-7-methyl-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one hydrochloride (190 mg, 0.465 mmol, 1 equiv.) and potassium isocyanate (113 mg, 1.39 mmol, 3 equiv.) in THF (2 mL) and water (2 ml) was added methanesulfonic acid (67 mg, 0.698 mmol, 1.5 equiv.) in portions at 0 °C, and the resulting mixture was stirred at room temperature for 1 h. The reaction was then warmed to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XBridge Prep OBD C18 Column 20*250 mm, 5 pm, 28-49% acetonitrile / water with 0.1% formic acid) to afford Compound 12 as a white solid (32.9 mg, 17.1% yield).

[0515] LCMS (ESI): m / z [M+H]+calcd. for C17H17F4N5O3: 415.13, found: 416.05.

[0516] ‘H-NMR (400 MHz, DMSO-A) 57.37 - 7.45 (m, 1H), 7.24 - 7.35 (m, 2H), 7.15 - 7.22 (m, 1H), 6.36 (d, J = 6.9 Hz, 1H), 5.91 - 6.01 (m, 1H), 5.80 (s, 2H), 4.00 - 4.11 (m, 1H), 3.42 (s, 3H), 2.83 - 2.94 (m, 1H), 2.35 - 2.47 (m, 1H), 1.89 (d, J= 6.7 Hz, 3H).19F-NMR (376 MHz, DMSO-A) 5 -56.32, -113.71.

[0517] Synthesis of Compound 13: l-((R)-l-((S)-l-(3-chloronaphthalen-2-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0518]

[0519] Step 1: Preparation of 2-chloro-3-(l-ethoxyethenyl)naphthalene

[0520] To a solution of 2-bromo-3-chloronaphthalene (3.20 g, 13.8 mmol, 1 equiv.) and tributyl(l-ethoxyethenyl)stannane (7.50 g, 20.7 mmol, 1.49 equiv.) in 1,4-di oxane (30 mL) was added bis(triphenylphosphine)palladium(II) dichloride (968.3 mg, 1.379 mmol, 0.10 equiv.). The reaction was stirred at 100 °C for 1 h under nitrogen. The reaction was then cooled to room temperature and the entire reaction mixture was carried directly to the next step.

[0521] LCMS (ESI): m / z [M+H]+calcd. for C14H13CIO: 232.07, found: 233.10.

[0522] Step 2: Preparation of l-(3-chloronaphthalen-2-yl)ethenone

[0523] A solution of 2-chloro-3-(l-ethoxyethenyl)naphthalene (3.00 g, 12.9 mmol, 1 equiv.) in IN hydrochloric acid (30 mL) was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated, then sodium bicarbonate solution (100 mL) was added the resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound (2.50 g, 94.8% yield).

[0524] LCMS (ESI): m / z [M+H]+calcd. for C12H9CIO: 204.03, found: 205.05.

[0525] Step 3: Preparation of (lR)-l-(3-chloronaphthalen-2-yl)ethanol

[0526] To a solution of (S)- l-methyl-3,3-diphenylhexahydropyrrolo[ 1,2-c] [ l,3,2]oxazaborole( 1.35 g, 4.89 mmol, 0.40 equiv.) in THF (30 mL) was added borane dimethyl sulfide complex (2.0 M in THF, 9.16 mL, 18.3 mmol, 1.5 equiv.) at 0 °C, then l-(3-chloronaphthalen-2-yl)ethanone (2.50 g, 12.2 mmol, 1 equiv.) was added at 0 °C and the reaction was stirred at 0 °C for 1 h. The reaction was then quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (30-70% ethyl acetate / petroleum ether) to afford the title compound (2.40 g, 95.1% yield).

[0527] Step 4: Preparation of V'-( / c / 7-butoxycarbonyl)-V-|( l. S)-l-(3-chloronaphthalen-2-yDethyl |Z / 7-butoxv carbohydrazide

[0528] To a solution of (17?)-l-(3-chloronaphthalen-2-yl)ethanol (2.40 g, 11.6 mmol, 1 equiv.) and triphenylphosphine (4.60 g, 17.5 mmol, 1.51 equiv.) in acetonitrile (50 mL) was added di-tert-butyl azodicarboxylate (4.10 g, 17.8 mmol, 1.53 equiv.) at 0 °C under nitrogen, then the reaction was stirred at 25 °C for 3 h under nitrogen. The reaction was then quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-60% ethyl acetate / petroleum ether) to afford the title compound (4.80 g, 98.2% yield). LCMS (ESI): m / z [M-H]’ calcd. for C22H29CIN2O4: 420.18, found: 419.10.

[0529] Step 5: Preparation of [(lS)-l-(3-chloronaphthalen-2-yl)ethyl]hydrazine

[0530] To a solution of M-(terr-butoxycarbonyl)-A^-[(lS)-l-(3-chloronaphthalen-2-yl)ethyl]terr-butoxycarbohydrazide (4.80 g, 11.4 mmol, 1 equiv.) in methanol (65 mL) were added acetyl chloride (5.40 g, 68.8 mmol, 6.03 equiv.) and 1 M hydrochloric acid in methanol (45.6 mL, 45.6 mmol, 4 equiv.) in portions at 0 °C, then the reaction was stirred at 50 °C for 3 h. The reaction mixture was then cooled to room temperature and concentrated under vacuum to afford the hydrochloride salt of the title compound as a yellow oil, which was used without further purification (2.90 g, 99.4% yield).

[0531] LCMS (ESI): m / z [M+H]+calcd. for C12H13CIN2: 220.08, found: 221.05.

[0532] Step 6: Preparation of 2-[(lS)-l-(3-chloronaphthalen-2-yl)ethyl]pyrazol-3-amine To a solution of [( IS)- l-(3-chloronaphthalen-2-yl)ethyl]hydrazine hydrochloride (2.90 g, 11.3 mmol, 1 equiv.) and 3,3-diethoxypropanenitrile (1.80 g, 12.6 mmol, 1.11 equiv.) in ethanol (50 mL) was added concentrated hydrochloric acid (3.8 mL, 45.6 mmol, 4.03 equiv.) and the reaction was stirred at 80 °C for 1 h. The reaction mixture was then cooled to room temperature and was adjusted to pH = 7 with saturated sodium bicarbonate solution, then the resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (30-70% ethyl acetate / petroleum ether) to afford the title compound (2.40 g, 77.9% yield).

[0533] LCMS (ESI): m / z [M+H]+calcd. for C15H14CIN3: 271.09, found: 272.15.

[0534] Step 7: Preparation of 4-bromo-2-[(lS)-l-(3-chloronaphthalen-2-yl)ethyl]pyrazol-3-amine

[0535] To a solution of 2-[(lS)-l-(3-chloronaphthalen-2-yl)ethyl]pyrazol-3-amine (2.40 g, 8.83 mmol, 1 equiv.) in dichloromethane (20 mL) was added 7V-bromosuccinimide (1.60 g, 8.99 mmol, 1.02 equiv.) at 0 °C, then the reaction was stirred at 25 °C for 0.5 h. The reaction was then quenched with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (30-70% ethyl acetate / petroleum ether) to afford the title compound (2.70 g, 87.2% yield).

[0536] LCMS (ESI): m / z [M+H]+calcd. for CisHnBrCIN 351.00, found: 352.00. Step 8: Preparation of tert-butyl / V-[(5 / f)-l-[(lS)-l-(3-chloronaphthalen-2-yl)ethyl]-6-oxo-4H,5H,7H-pyrazolo[3,4-b]pyridin-5-yl]carbamate

[0537] To a solution of 4-bromo-2-[(lS)-l-(3-chloronaphthalen-2-yl)ethyl]pyrazol-3-amine (1.00 g, 2.85 mmol, 1 equiv.) in DMF (20 mL) were added palladium(II) acetate (128.1 mg, 0.571 mmol, 0.20 equiv.) and XPhos (543.9 mg, 1.141 mmol, 0.40 equiv.), then Intermediate 1 (33.0 mL, 14.3 mmol, 5.00 equiv, 0.5 M in DMF) was added at 0 °C under nitrogen and the reaction was stirred at 80 °C for 1 h under nitrogen. The reaction mixture was then cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20-60% ethyl acetate / petroleum ether) to afford the title compound (900.0 mg, 71.57% yield).

[0538] LCMS (ESI): m / z [M+H]+calcd. for C23H25CIN4O3: 440.16, found: 441.15.

[0539] Step 9: Preparation of tert-butyl A^-[(5 / f)-l-[(lS)-l-(3-chloronaphthalen-2-yl)ethyl]-7-methyl-6-oxo-4H,5H-pyrazolo[3,4-b]pyridin-5-yl]carbamate

[0540] To a solution of tert-butyl A-[(57?)-l-[(lS)-l-(3-chloronaphthalen-2-yl)ethyl]-6-oxo-4H,5H,7H-pyrazolo[3,4-b]pyridin-5-yl]carbamate (500.0 mg, 1.134 mmol, 1 equiv.) and potassium carbonate (470.2 mg, 3.402 mmol, 3.00 equiv.) in DMF (10 mL) was added methyl iodide (193.2 mg, 1.361 mmol, 1.20 equiv.) at 0 °C, then the reaction was stirred at 25 °C for 1 h. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20-60% ethyl acetate / petroleum ether) to afford the title compound (460.0 mg, 89.16% yield).

[0541] LCMS (ESI): m / z [M+H]+calcd. for C24H27CIN4O3: 454.18, found: 455.10.

[0542] Step 10: Preparation of (5 / f)-5-amino-l-[(lS)-l-(3-chloronaphthalen-2-yl)ethyl]-7-methyl-4H,5H-pyrazolo[3,4-b]pyridin-6-one

[0543] A solution of terr-butyl A-[(57?)-l-[(lS)-l-(3-chloronaphthalen-2-yl)ethyl]-7-methyl-6-oxo-4H,5H-pyrazolo[3,4-b]pyridin-5-yl]carbamate (440.0 mg, 0.967 mmol, 1 equiv.) in 4 M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25 °C for 1 h. The reaction was adjusted to pH = 8 with saturated sodium bicarbonate solution, then the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford the title compound as a yellow oil which was used without further purification (340.0 mg, 99.13% yield).

[0544] LCMS (ESI): m / z [M+H]+calcd. for C19H19CIN4O: 354.12, found: 355.10.

[0545] Step 11: Preparation of l-((R)-l-((S)-l-(3-chloronaphthalen-2-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 13)

[0546] To a solution of (5R)-5-amino-l-[(lS)-l-(3-chloronaphthalen-2-yl)ethyl]-7-methyl-4H,5H-pyrazolo[3,4-b]pyridin-6-one (300.0 mg, 0.845 mmol, 1 equiv.) in THF (10 mL) and water (2 mL) were added potassium isocyanate (205.7 mg, 2.536 mmol, 3.00 equiv.) and methanesulfonic acid (97.5 mg, 1.02 mmol, 1.20 equiv.) and the reaction was stirred at 25 °C for 1 h. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (YMC Triart C18 ExRs Column 150 mm x 30 mm x 5 pm, 26-50% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 13 as a white solid (49.0 mg, 14.6% yield). LCMS (ESI): m / z [M+H]+calcd. for C20H20CIN5O2: 397.13, found: 398.10.

[0547] 1H NMR (300 MHz, Methanol-^) 57.96 (s, 1H), 7.85 - 7.73 (m, 2H), 7.61 - 7.36 (m, 4H), 6.34 - 6.18 (m, 1H), 4.31 - 4.13 (m, 1H), 3.49 (s, 3H), 3.15 - 2.99 (m, 1H), 2.69 - 2.50 (m, 1H), 2.08 (d, J = 6.8 Hz, 3H).

[0548] Synthesis of Compound 14: l-((R)-l-((S)-l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0549]

[0550] Scheme 15

[0551]

[0552] Step 1: Preparation of 5-bromo-6-chloro-2-methylbenzo[d]oxazole

[0553] To a solution of 2-amino-4-bromo-5 -chlorophenol (2.60 g, 11.7 mmol, 1 equiv.) and 1,1,1-trimethoxyethane (2.81 g, 23.4 mmol, 2 equiv.) in ethanol (20 mL) was added ytterbium(III) trifluoromethanesulfonate (72.5 mg, 0.117 mmol, 0.01 equiv.), then the resulting mixture was stirred at 90 °C for 2 h. The reaction was then cooled to room temperature, quenched with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound as a yellow solid (2.60 g, 90.3% yield).

[0554] LCMS (ESI): m / z [M+H]+calcd. for C8H5BrClNO: 246.92, found: 247.90.

[0555] Step 2: Preparation of l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethan-l-ol

[0556] To a stirred solution of 5-bromo-6-chloro-2-methylbenzo[d]oxazole (2.20 g, 8.93 mmol, 1 equiv.) in THF (12 mL) was added isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 8.97 mL, 1.3 equiv.) in portions at -45 °C under a nitrogen atmosphere, and the resulting mixture was stirred at -45 °C for 30 min under a nitrogen atmosphere. Acetaldehyde (1.77 g, 40.2 mmol, 4.5 equiv.) was then added at -45 °C and the resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was then quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (50-100% ethyl acetate / petroleum ether) to afford the title compound as a colorless oil (720.0 mg, 38.11% yield).

[0557] LCMS (ESI): m / z [M+H]+calcd. for C10H10CINO2: 211.04, found: 212.05.

[0558] Step 3: Preparation of di-tert-butyl l-(l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)hydrazine-l,2-dicarboxylate

[0559] To a solution of l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethan-l-ol (710.0 mg, 3.355 mmol, 1.00 equiv.) in acetonitrile (15 mL) were added di-tert-butyl azodicarboxylate (386.2 mg, 1.677 mmol, 0.50 equiv.) and triphenylphosphine (1.76 g, 6.71 mmol, 2 equiv.) under nitrogen and the reaction was stirred at room temperature for 3 h under a nitrogen atmosphere. The reaction was then quenched with water (30 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound as a yellow solid (910.0 mg, 63.69% yield).

[0560] LCMS (ESI): m / z [M+H]+calcd. for C20H28CIN3O5: 425.2, found: 314.00 [M+H-tBu- tBu]+.

[0561] Step 4: Preparation of 6-chloro-5-(l-hydrazineylethyl)-2-methylbenzo[d]oxazole

[0562] A mixture of di-tert-butyl l-(l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)hydrazine-l,2-dicarboxylate (900.0 mg, 2.113 mmol, 1 equiv.) in 4 M hydrochloric acid in 1,4-dioxane (8 mL) was stirred at room temperature for 3 h. The reaction mixture was then concentrated under reduced pressure to afford the hydrochloride salt of the title compound as a light yellow solid (510.0 mg, 92.05% yield).

[0563] LCMS (ESI): m / z [M+H]+calcd. for C10H12CIN3O: 225.07, found: 226.05.

[0564] Step 5: Preparation of l-(l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)-lH-pyrazol-5-amine

[0565] To a stirred solution of 2-chloroacrylonitrile (222.6 mg, 2.530 mmol, 1.30 equiv.) and 6-chloro-5-(l-hydrazineylethyl)-2-methylbenzo[d]oxazole hydrochloride (510.0 mg, 1.946 mmol, 1.00 equiv.) in ethanol (10 mL) was added sodium acetate (478.7 mg, 5.838 mmol, 3.00 equiv.) in portions at room temperature, and the resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was then cooled to room temperature and adjusted to pH = 8 with saturated sodium bicarbonate. Water (30 mL) was then added and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (50-100% ethyl acetate / petroleum ether) to afford the title compound as a white solid (190.0 mg, 30.99% yield).

[0566] LCMS (ESI): m / z [M+H]+calcd. for C13H13CIN4O: 276.08, found: 277.05.

[0567] Step 6: Preparation of 4-bromo-l-(l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)-lH-pyrazol-5-amine

[0568] To a stirred solution of l-(l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)-lH-pyrazol-5-amine (900.0 mg, 3.252 mmol, 1 equiv.) in dichloromethane (6 mL) was added N-bromosuccinimide (578.9 mg, 3.252 mmol, 1 equiv.) at 0 °C, then the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by silica gel chromatography (0-40% yield) to afford the title compound as a red solid (800.0 mg, 69.17% yield).

[0569] LCMS (ESI): m / z [M+H]+calcd. for Ci3Hi2BrClN4O: 355.99, found: 356.85.

[0570] Step 7: Preparation of tert-butyl ((51f)-l-(l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0571] To a stirred solution of 4-bromo-l-(l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)-lH-pyrazol-5 -amine (300.0 mg, 0.844 mmol, 1 equiv.) and palladium(II) acetate (37.9 mg, 0.169 mmol, 0.2 equiv.) in DMF (3 mL) were added XPhos (160.9 mg, 0.338 mmol, 0.4 equiv.) and Intermediate 1 (8.5 mL, 4.225 mmol, 5 equiv, 0.5 M in DMF) dropwise at 0 °C under a nitrogen atmosphere, then the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was then cooled to room temperature, quenched with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-70% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (240.0 mg, 63.80% yield).

[0572] LCMS (ESI): m / z [M+H]+calcd. for C21H24CIN5O4: 445.15, found: 446.10.

[0573] Step 8: Preparation of tert-butyl ((R)-l-((S)-l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate To a stirred solution of tert-butyl ((57?)-l-(l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate (230.0 mg, 0.516 mmol, 1 equiv.) and potassium carbonate (213.9 mg, 1.548 mmol, 3 equiv.) in DMF (3 mL) was added methyl iodide (109.8 mg, 0.774 mmol, 1.5 equiv.) dropwise at room temperature, then the reaction mixture was stirred 1 h. The reaction was then quenched with water and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as the first eluting isomer as a yellow oil (100.0 mg, 42.15% yield).

[0574] LCMS (ESI): m / z [M+H]+calcd. for C22H26CIN5O4: 459.17, found: 460.15.

[0575] Step 9: Preparation of (R)-5-amino-l-((S)-l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)-7-methyl-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0576] To a stirred solution of tert-butyl ((7?)-l-((S)-l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate (70.0 mg, 0.152 mmol, 1 equiv.) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.2 mL) dropwise at room temperature, then the mixture was stirred at room temperature for 1 h. The reaction mixture was adjusted to pH = 7 with sodium bicarbonate solution, and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford the title compound, which was used without further purification (50.0 mg, 90.0% yield).

[0577] LCMS (ESI): m / z [M+H]+calcd. for C17H18CIN5O2: 359.11, found: 360.00.

[0578] Step 10: Preparation of l-((R)-l-((S)-l-(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 14) To a stirred solution of (7?)-5-amino- 1 -(( )- 1 -(6-chloro-2-methylbenzo[d]oxazol-5-yl)ethyl)-7-methyl-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one (50.0 mg, 0.139 mmol, 1 equiv.) in THF (1 mL) were added methanesulfonic acid (20.0 mg, 0.209 mmol, 1.5 equiv.) and potassium isocyanate (33.8 mg, 0.417 mmol, 3 equiv, dissolved in 1 mL of water) dropwise at room temperature, then the mixture was stirred for 1 h. The reaction was then quenched with water and extracted with 10:1 dichloromethane / methanol (3 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XBridge Prep OBD C18 Column, 30*150 mm, 5 pm, 12-37% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 14 as a white solid (11.6 mg, 20.7% yield).

[0579] LCMS (ESI): m / z [M+H]+calcd. for C18H19CIN6O3: 402.12, found: 403.10.1H NMR (300 MHz, DMSO-A) 57.91 (s, 1H), 7.42 (s, 1H), 6.94 (s, 1H), 6.33 (d, J = 7.0 Hz, 1H), 6.13 (q, J = 6.6 Hz, 1H), 5.79 (s, 2H), 3.99 (dt, J = 13.6, 6.7 Hz, 1H), 3.36 (s, 3H), 2.92 (dd, J = 14.6, 6.6 Hz, 1H), 2.58 (s, 3H), 2.43 (d, J = 14.1 Hz, 1H), 1.91 (d, J = 6.6 Hz, 3H).

[0580] Synthesis of Compound 15: (R)-l-(l-((3-chloro-[l,r-biphenyl]-4-yl)methyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0581]

[0582] Step 1: Preparation of 3-chloro-[l,l'-biphenyl]-4-carbaldehyde

[0583] To a solution of 4-bromo-2-chlorobenzaldehyde (5.00 g, 22.78 mmol, 1 equiv.) in dioxane (50 mL) and water (10 mL) was added phenyl boronic acid (2.78 g, 22.78 mmol, 1 equiv.), l, T-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (3.33 g, 4.55 mmol, 0.2 equiv.) and potassium carbonate (7.87 g, 56.95 mmol, 2.5 equiv.). The resulting mixture was maintained under nitrogen and stirred at 80 °C for 2h. The mixture was allowed to cool down to room temperature. The mixture was treated with water (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 30-60%) to afford the title compound 3-chloro-[l,l'-biphenyl]-4-carbaldehyde as a yellow oil (4.18 g, 84.6% yield).

[0584] LCMS (ESI): m / z [M+H]+calcd. for C13H9CIO: 216.03, found: 217.10.

[0585] Step 2: Preparation of l-((3-chloro-[l,l'-biphenyl]-4-yl)methyl)-lH-pyrazol-5-amine To a solution of 3-chloro-[l,l'-biphenyl]-4-carbaldehyde (4.18 g, 19.29 mmol, 1 equiv.) in tetrahydrofuran (50 mL) was added 3-hydrazinylpropanenitrile (1.54 g, 18.20 mmol, 0.95 equiv.) at 25 °C and the mixture stirred for 3h. The resulting mixture was concentrated under reduced pressure. To the above mixture was added tert-butanol (50 mL) and sodium tert-butoxide (1.74 g, 18.20 mmol, 0.95 equiv.) in portions at 25 °C. The resulting mixture was stirred at 120 °C for additional Ih. The mixture was allowed to cool down to room temperature. The mixture was treated with water (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 50-70%) to afford the title compound as a yellow oil (3.37 g, 61.5% yield).

[0586] LCMS (ESI): m / z [M+H]+calcd. for C16H14CIN3: 283.09, found: 284.10.

[0587] Step 3: Preparation of 4-bromo-l-((3-chloro-[l,l'-biphenyl]-4-yl)methyl)-lH-pyrazol-5-amine

[0588] To a solution of l-((3-chloro-[l, T-biphenyl]-4-yl)methyl)-lH-pyrazol-5-amine (3.37 g, 11.87 mmol, 1 equiv.) in dichloromethane (20 mL) was added A^-bromosuccinimide (1.90 g, 10.71 mmol, 0.9 equiv.) at 0 °C. The resulting mixture was stirred at 25 °C for 2h. The mixture was treated with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 70-80%) to afford the title compound as a yellow oil (2.1 g, 48.7% yield).

[0589] LCMS (ESI): m / z [M+H, M+H+2]+calcd. for Ci6Hi3BrClN3: 361.00, found: 362.00, 364.00. Step 4: Preparation of tert-butyl (lf)-(l-((3-chloro-[l,l'-biphenyl]-4-yl)methyl)-6-oxo- 4.5.6.7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0590] To a stirred solution of 4-bromo-l-((3-chloro-[l, T-biphenyl]-4-yl)methyl)-lH-pyrazol-5-amine (2.10 g, 5.79 mmol, 1 equiv.) and palladium (II) acetate (0.20 g, 0.87 mmol, 0.2 equiv.) in dimethyl formamide (16 mL) was added Xphos (0.84 g, 1.75 mmol, 0.4 equiv.) in portions at room temperature. The resulting mixture was stirred at 0 °C for 1 min under nitrogen atmosphere. To the above mixture was added Intermediate 1 (26.2 mL, 13.15 mmol, 3 equiv, 0.5 M in dimethylformamide) dropwise over 5 min at 0 °C. The resulting mixture was stirred at 80 °C for additional 2h. The mixture was allowed to cool down to room temperature, and was then treated with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 50-70%) to afford the title compound as a yellow oil (1.2 g, 45.8% yield).

[0591] LCMS (ESI): m / z [M+H]+calcd. for C24H25CIN4O3: 452.16, found: 453.20.

[0592] Step 5: Preparation of tert-butyl (lf)-(l-((3-chloro-[l,l'-biphenyl]-4-yl)methyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0593] To a solution of tert-butyl (7?)-(l-((3-chloro-[l, T-biphenyl]-4-yl)methyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate (1.20 g, 2.65 mmol, 1 equiv.) in dimethylformamide (15 mL) was added potassium carbonate (1.10 g, 7.96 mmol, 3 equiv.) and methyl iodide (565.5 mg, 3.98 mmol, 1.5 equiv.). The resulting mixture was stirred at 25 °C for 2 h, then treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 60-80%) to afford the tide compound (780 mg, 59.5% yield).

[0594] LCMS (ESI): m / z [M+H]+calcd. for C25H27CIN4O3: 466.18, found: 467.20.

[0595] Step 6: Preparation of (lf)-5-amino-l-((3-chloro-[l,l'-biphenyl]-4-yl)methyl)-7-methyl- 1.4.5.7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0596] To a solution of te -butyl (7?)-(l-((3-chloro-[l,l'-biphenyl]-4-yl)methyl)-7-methyl-6-oxo- 4.5.6.7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate (770.0 mg, 1.64 mmol, 1 equiv.) in hydrogen chloride (4.0 M in 1,4-dioxane, 10 mL) was stirred at 25 °C for 1 h. The reaction was adjusted to pH = 7 using sodium bicarbonate (10% aqueous solution) at 0 °C, then extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as a yellow oil (460 mg, 76.0% yield).

[0597] LCMS (ESI): m / z [M+H]+calcd. for C12H13CIFN: 366.12, found: 367.10.

[0598] Step 7: Preparation of (R)-l-(l-((3-chloro-[l,r-biphenyl]-4-yl)methyl)-7-methyl-6-oxo- 4.5.6.7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 15)

[0599] To a stirred solution of (7?)-5-amino-l-((3-chloro-[l, T-biphenyl]-4-yl)methyl)-7-methyl- 1.4.5.7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one (450.0 mg, 1.22 mmol, 1 equiv.) and methanesulfonic acid (141.4 mg, 1.47 mmol, 1.2 equiv.) in tetrahydrofuran (5 mL) and water (1 mL) was added potassium isocyanate (298.5 mg, 3.68 mmol, 3 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was treated with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (XB ridge Prep C18 OBD Column, 19*250 mm, 5 pm, 28-53% (v / v) acetonitrile and water containing NH4HCO3 (10 mM)) to afford Compound 15 as a white solid (154.5 mg, 30.7% yield).

[0600] LCMS (ESI): m / z [M+H]+calcd. for C21H20CIN5O2: 409.13, found: 410.10.

[0601] 1H NMR (300 MHz, DMSO-rfe) 57.81 (d, J = 1.8 Hz, 1H), 7.75 - 7.60 (m, 3H), 7.53 - 7.34 (m, 4H), 6.80 (d, J = 8.1 Hz, 1H), 6.37 (d, J = 6.9 Hz, 1H), 5.80 (s, 2H), 5.58 (d, J = 1.8 Hz, 2H), 4.27 (dt, J = 13.5, 6.7 Hz, 1H), 3.26 (s, 3H), 3.00 (dd, J = 14.6, 6.7 Hz, 1H).

[0602] Synthesis of Compound 16: l-((R)-l-((S)-l-(4-(lH-indazol-6-yl)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0603]

[0604] Scheme 17

[0605] 8

[0606]

[0607] Compound 45 Compound 16

[0608] Step 1: Preparation of l-((lf)-l-((S)-l-(4-(lH-indazol-6-yl) phenyl) ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b] pyridin-5-yl) urea (Compound 16)

[0609] To a solution of Compound 45 (200 mg, 0.575 mmol, 1 equiv.) and lH-indazol-6-ylboronic acid (186.3 mg, 1.15 mmol, 2.00 equiv.) in 1,4-dioxane (4 mL) and water (1 mL) was added Xphos (27.4 mg, 0.057 mmol, 0.10 equiv.), Xphos Pd G3 (48.67 mg, 0.057 mmol, 0.10 equiv.) and tripotassium phosphate (305.15 mg, 1.438 mmol, 2.50 equiv.). The reaction was stirred at 80 °C for 3h under nitrogen. After cooling down to room temperature, the mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Xbridge Prep Shield RP185pm OBD 30*150mm column, 17-33% (v / v) actetonitrile and water containing ammonium bicarbonate (10 mM)) to afford Compound 16 (71.3 mg, 28.8% yield).

[0610] LCMS (ESI): m / z [M+H]+calcd. for C23H23N7O2: 429.19, found: 430.20.

[0611] ’H NMR (400 MHz, DMSO-O 5 13.13 (s, 1H), 8.08 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.64 -7.73 (m, 3H), 7.35 - 7.43 (m, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.35 (d, J = 8.0 Hz, 1H), 5.83 -5.92 (m, 1H), 5.79 (s, 2H), 4.05 - 4.16 (m, 1H), 3.40 (s, 3H), 2.89 - 2.99 (m, 1H), 2.40 - 2.48 (m, 1H), 1.90 (d, J = 8.0 Hz, 3H).

[0612] Synthesis of Compound 17: l-((R)-7-benzyl-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0613]

[0614] Scheme 18

[0615]

[0616] Step 1: Preparation of ( f)-l-(2-chloro-5-fluorophenyl)ethan-l-ol

[0617] To a solution of (3aS)-l-methyl-3,3-diphenyl-hexahydropyrrolo[ l,2-c][ l,3,2]oxazaborole (6.43 g, 23.19 mmol, 0.20 equiv.) in tetrahydrofurane (200 mL) was added borane dimethyl sulfide complex (2.0M in tetrahydrofurane, 87.0 mL, 173.9 mmol, 1.50 equiv.) and l-(2-chloro-5-fluorophenyl)ethanone (20.0 g, 115.94 mmol, 1 equiv.) at 0 °C. The reaction was stirred at 0 °C for Ih. The reaction was monitored by TLC. The reaction was treated with water and ice at 0 °C, then diluted further with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-30%) to afford the title compound as a white oil (20.0 g, 98.8% yield). Step 2: Preparation of di-tert-butyl (S)-l-(l-(2-chloro-5-fluorophenyl)ethyl)hydrazine-1,2-dicarboxylate

[0618] To a solution of (7?)-l-(2-chloro-5-fluorophenyl)ethan-l-ol (20.0 g, 114.54 mmol, 1 equiv.) and triphenylphosphine (45.0 g, 171.8 mmol, 1.50 equiv.) in acetonitrile (250 mL) was added di-tert-butyl diazene- 1,2-dicarboxylate (39.56 g, 171.822 mmol, 1.5 equiv.) in acetonitrile (80 mL) at 0 °C under nitrogen. The reaction was stirred at 30 °C for 3 h under nitrogen. Quenched with water (500 mL) and extracted with ethyl acetate (3 x 800 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-15%) to afford the title compound as a colorless oil (38.0 g, 85.3% yield).

[0619] LCMS (ESI): m / z [M+H-tBu-Boc]+calcd. for C18H26CIFN2O4: 388.15, found 232.90.

[0620] Step 3: Preparation of (S)-(l-(2-chloro-5-fluorophenyl)ethyl)hydrazine hydrochloride A solution of di-tert-butyl (S)-l-(l-(2-chloro-5-fluorophenyl)ethyl)hydrazine-l,2-dicarboxylate (38.0 g, 97.7 mmol, 1 equiv.) in hydrogen chloride (in 1,4-dioxane, 4.0M, 400 mL) was stirred at room temperature for 3h. The resulting mixture was concentrated under reduced pressure. This title compound was afforded as a white solid without further purification (18.3 g, 83.2% yield).

[0621] LC / MS: m / z [M+H]+calcd. for C8H10CIFN2: 188.05, found: 189.10.

[0622] Step 4: Preparation of (S)-l-(l-(2-chloro-5-fluorophenyl)ethyl)-lH-pyrazol-5-amine To a solution of (S)-( l-(2-chloro-5-fluorophenyl)ethyl)hydrazine hydrochloride (18.3 g, 81.3 mmol, 1 equiv.) in ethanol (200 mL) was added 3,3-diethoxypropanenitrile (11.6 g, 81.3 mmol, 1 equiv.) and hydrogen chloride (12N, 27.1 mL, 325.5 mmol, 4 equiv.). The reaction was stirred at 80 °C for 3h. The mixture was allowed to cool down to room temperature. The mixture was basified to pH = 8 with saturated, aqueous sodium bicarbonate. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 x 500 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-40%) to afford the title compound as a light-yellow oil (13.0 g, 66.7% yield).

[0623] LC / MS: m / z [M+H]+calcd. for C11H11CIFN3: 239.06, found: 239.90.

[0624] - Ill - Step 5: Preparation of 4-bromo-2-[(lS)-l-(2-chloro-5-fluorophenyl)ethyl]pyrazol-3-amine

[0625] A mixture of 2-[(lS)-l-(2-chloro-5-fhiorophenyl)ethyl]pyrazol-3-amine (6.5 g, 27.1 mmol, 1 equiv.) and 1 -bromopyrrolidine-2, 5-dione (7.0 g, 39.3 mmol, 1.4 equiv.) in dichloromethane (50 mL) was stirred at room temperature for 30 min. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate, 5:1) to afford the title compound as alight red solid (7.5 g, 86.8% yield).

[0626] TLC: R / = 0.3 (ethyl acetate / petroleum ether, 1:3).

[0627] Step 6: Preparation of tert-butyl ((R)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate

[0628] To a stirred solution of 4-bromo-2-[(lS)-l-(2-chloro-5-fluorophenyl)ethyl]pyrazol-3-amine (1.0 g, 3.1 mmol, 1 equiv.) in dimethylformamide (10 mL) was added palladium(II) acetate (0.14 g, 0.62 mmol, 0.2 equiv.), Xphos (0.60 g, 1.25 mmol, 0.4 equiv.) and Intermediate 1 (19.9 mL, 9.95 mmol, 3 equiv, 0.5M in dimethylformamide) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at 80 °C for Ih under nitrogen. The mixture was allowed to cool down to room temperature. The reaction was quenched with saturated, aqueous ammonium chloride (50 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 80 mL). The residue was washed with brine. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-100%) to afford the title compound as a yellow oil (450 mg, 35.0% yield).

[0629] LC / MS: m / z [M+H]+calcd. for C19H22CIFN4O3: 408.14, found: 409.10.

[0630] Step 7: Preparation of tert-butyl A-[(51f)-7-benzyl-l-[(lS)-l-(2-chloro-5-fluorophenyl)ethyl]-6-oxo-4H,5H-pyrazolo[3,4-b]pyridin-5-yl]carbamate

[0631] To a solution of tert-butyl A-[(5R)-l-[(lS)-l-(2-chloro-5-fluorophenyl)ethyl]-6-oxo-4H,5H,7H-pyrazolo[3,4-b]pyridin-5-yl]carbamate (155.0 mg, 0.37 mmol, 1 equiv.) in dimethylformamide (3 mL) was added benzyl bromide (77.8 mg, 0.455 mmol, 1.2 equiv.) and potassium carbonate (157.1 mg, 1.13 mmol, 3 equiv.). The resulting mixture was stirred at 25 °C for 2h. The mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-100%) to afford the title compound as a yellow oil (150 mg, 79.3% yield).

[0632] LCMS (ESI): m / z [M+H]+calcd. for C26H28CIFN4O3: 498.18, found: 499.25.

[0633] Step 8: Preparation of (51f)-5-amino-7-benzyl-l-[(lS)-l-(2-chloro-5-fluorophenyl)ethyl]-4H,5H-pyrazolo[3,4-b]pyridin-6-one

[0634] A solution of tert-butyl A-[(5R)-7-benzyl-l-[(lS)-l-(2-chloro-5-fluorophenyl)ethyl]-6-oxo-4H,5H-pyrazolo[3,4-b]pyridin-5-yl]carbamate (110.0 mg, 0.22 mmol, 1 equiv.) in hydrogen chloride (4.0 M in 1,4-dioxane, 2 mL) was stirred at 25 °C for 1 h. The reaction was adjusted to pH = 7 with sodium bicarbonate (10% aqueous) at 0 °C, then extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as a yellow oil (79 mg, 89.8% yield). LCMS (ESI): m / z [M+H]+calcd. for C21H20CIFN4O: 398.13, found: 399.05.

[0635] Step 9: Preparation of l-((R)-7-benzyl-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 17)

[0636] To a solution of (5R)-5-amino-7-benzyl-l-[(lS)-l-(2-chloro-5-fluorophenyl)ethyl]-4H,5H-pyrazolo[3,4-b]pyridin-6-one (79.0 mg, 0.19 mmol, 1 equiv.) in tetrahydrofurane (2 mL) and water (0.2 mL) was added potassium isocyanate (17.7 mg, 0.21 mmol, 1.10 equiv.), methanesulfonic acid (57.1 mg, 0.59 mmol, 3.00 equiv.). The reaction was stirred at 25 °C for Ih. The mixture was treated with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XBridge Prep C18 OBD 250 mm x 19 mm, 5pm column, 33-58% (v / v) water containing ammonium bicarbonate (10 mM) and acetonitrile) to afford l-((5R)-7-benzyl-l-(l-(2-chloro-5-fluorophenyl)ethyl)-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (60 mg), which was separated by chiral-HPLC (CHIRAL ART Cellulose-SB, 2*25 cm, 5 pm column, 30% (v / v) hexanes (containing 0.5% 2M ammonia in methanol) and ethanol) to afford the title Compound 17 as a white solid and as first compound to elute (31.6 mg, 36.1% yield).

[0637] LCMS (ESI): m / z [M+H]+calcd. for C22H21CIFN5O2: 441.14, found: 442.15.1H NMR (300 MHz, DMSO-rfe) 57.53 - 7.38 (m, 2H), 7.36 - 7.05 (m, 6H), 6.66 - 6.55 (m, 1H), 6.50 - 6.41 (m, 1H), 5.81 (s, 2H), 5.71 - 5.58 (m, 1H), 5.53 - 5.39 (m, 1H), 4.90 - 4.78 (m, 1H), 4.33 - 4.18 (m, 1H), 3.07 - 2.92 (m, 1H), 2.62 (m, 1H), 1.65 - 1.56 (m, 3H).

[0638] 19F NMR (282 MHz, DMSO-O 5 -113.680.

[0639] Synthesis of Compound 18 and Compound 19: l-((41f,51f)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-4,7-dimethyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea and l-((4S,51f)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-4,7-dimethyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0640]

[0641] Step 1: Preparation of (S)- 1-( l-(2-chloro-5-fluorophenvl)ethvl)-\-methvl-l H-pyrazol-5-amine

[0642] To a solution of (S)- 1 -( 1 -(2-chloro-5-fluorophenyl)ethyl)- 1 H-pyrazol-5-ami ne (prepared using methods described for Compound 17, 2.06 g, 8.59 mmol, 1 equiv.) in tetrahydrofuran (20 mL) was added methyllithium (3.0 M in ethyl ether, 3.14 mL, 9.45 mmol, 1.10 equiv.) at -78 °C under nitrogen. The reaction was stirred at -78 °C for 0.5 h under nitrogen. To the above mixture was added methyl iodide (1.83 g, 12.89 mmol, 1.50 equiv.) in portions at -78°C under nitrogen. The resulting mixture was stirred at 0 °C for additional 30 min. The reaction was quenched by the addition of ammonium chloride (saturated, aqueous solution, 10 mL) at 0 °C. The mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-50%) to afford the title compound as a yellow solid (1.57 g, 72.0% yield).

[0643] LC / MS: m / z [M+H]+calcd. for C12H13CIFN3: 253.08, found: 254.05.

[0644] Step 2: Preparation of l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-4,7-dimethyl-6-oxo- 4.5.6.7-tetrahydro-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid

[0645] To a solution of (S)-l-(l-(2-chloro-5-fluorophenyl)ethyl)-N-methyl-lH-pyrazol-5 -amine (1.57 g, 6.19 mmol, 1 equiv.) in methanol (20 mL) was added 2,2-dimethyl-l,3-dioxane-4,6-dione (892.4 mg, 6.19 mmol, 1 equiv.) and acetaldehyde (272.8 mg, 6.19 mmol, 1 equiv.). The reaction was stirred at 65 °C for 12h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Cl 8 silica gel; acetonitrile in water, 10-50%, 10 min; 254 nm detection). The title compound was afforded as a white solid (900.1 mg, 39.7% yield).

[0646] LCMS: m / z [M+H]+calcd. for C24H28FN3O: 365.09, found: 366.00.

[0647] Step 3: Preparation of 5-amino-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-4,7-dimethyl- 1.4.5.7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0648] To a solution of l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-4, 7-dimethyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid (900.3 mg, 2.46 mmol, 1 equiv.) in benzene (10 mL) was added triethylamide (572.8 mg, 5.66 mmol, 2.3 equiv.) and diphenylphosphoryl azide (1.56 g, 5.69 mmol, 2.3 equiv.). The reaction was stirred at 50 °C for 4h under nitrogen. Then, to the above mixture was added dibutyltin dilaurate (155.5 mg, 0.24 mmol, 0.1 equiv.) and hydrogen chloride (10 mL, 6N). The resulting mixture was stirred at 80 °C for additional 3h. The mixture was allowed to cool down to room temperature. The mixture was basified to pH = 8 with sodium bicarbonate (saturated, aqueous). The mixture was treated with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol / dichloromethane, 0-20%) to afford the title compound as a mixture of diastereomers as a yellow solid (590.1 mg, 71.2% yield).

[0649] LCMS: m / z [M+H]+calcd. for C16H18ClFN4O: 336.12, found: 337.05.

[0650] Step 4: Preparation of l-((41f,51f)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-4,7-dimethyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea and l-((4S,51f)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-4,7-dimethyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 18 and Compound 19)

[0651] To a solution of 5-amino-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-4,7-dimethyl-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one (100.2 mg, 0.29 mmol, 1 equiv.) in tetrahydrofuran (5 mL) and water (0.5 mL) was added potassium cyanate (60.2 mg, 0.74 mmol, 2.5 equiv.) and methanesulfonic acid (37.1 mg, 0.38 mmol, 1.3 equiv.). The reaction was stirred at room temperature for Ih. The mixture was treated with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm column, 15-45% (v / v) acetonitrile and water containing 10 mM ammonium bicarbonate) to afford Compound 18 as first eluting compound as a white solid (15.7 mg, 13.9% yield).

[0652] LCMS: m / z [M+H]+calcd. for C17H19CIFN5O2: 379.12, found: 380.15.

[0653] 1H NMR (400 MHz, MeOD) 57.30 - 7.66 (m, 2H), 7.05 (ddd, J = 8.8, 7.8, 3.1 Hz, IH), 6.68 (dd, J = 9.6, 3.0 Hz, IH), 6.12 (q, J = 6.8 Hz, IH), 3.97 (d, J = 12.8 Hz, IH), 3.45 (s, 3H), 2.83 (dq, J = 13.2, 6.7 Hz, IH), 1.94 (d, J = 6.9 Hz, 3H), 1.33 (d, J = 6.7 Hz, 3H).

[0654] 19F NMR (376 MHz, MeOD) 5(ppm): -115.170.

[0655] Compound 19 was afforded as second eluting compound as a white solid (3.5 mg, 3.4%yield). LCMS: m / z [M+H]+calcd. for C17H19CIFN5O2: 379.12, found: 380.15.

[0656] 1H NMR (400 MHz, MeOD) 57.43 (s, IH), 7.42 (dd, J = 8.8, 5.0 Hz, IH), 6.90 - 7.20 (m, IH), 6.66 (dd, J = 9.5, 3.1 Hz, IH), 6.10 (q, J = 6.8 Hz, IH), 4.37 (d, J = 5.7 Hz, IH), 3.45 (s, 3H), 3.18 - 3.21 (m, IH), 1.94 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 7.1 Hz, 3H).19F NMR (376 MHz, MeOD) 5(ppm): -115.253.

[0657] Synthesis of Compound 20: l-((lf)-l-((S)-l-(5-fluoro-2-(trifluoromethyl)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0658]

[0659] Step 1 and 2: Preparation of l-[5-fluoro-2-(trifluoromethyl)phenyl]ethenone

[0660] To a solution of 2-bromo-4-fluoro-l-(trifluoromethyl)benzene (10 g, 41.2 mmol, 1 equiv.) in 1,4-dioxane (100 mL) were added methyl tributyl(l -ethoxy ethenyl)stannane (19.32 g, 53.50 mmol, 1.3 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (2.89 g, 4.12 mmol, 0.1 equiv.) under nitrogen, then the reaction was stirred at 100 °C for 16 h under nitrogen. The reaction mixture was then cooled to room temperature, 2 N hydrochloric acid (100 mL) was added, and the reaction was stirred at 25 °C for 2 h. The reaction mixture was then diluted with water (300 mL) and extracted with ethyl acetate (3 x 400 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (4.5 g, 53.1% yield).

[0661] Step 3: Preparation of l-[5-fluoro-2-(trifluoromethyl)phenyl]ethanol

[0662] To a solution of l-[5-fluoro-2-(trifluoromethyl)phenyl]ethanone (6 g, 29.1 mmol, 1 equiv.) in methanol (80 mL) was added sodium borohydride (2.20 g, 58.2 mmol, 2 equiv.) at 0 °C, then the reaction was stirred at 25 °C for 1 h. The reaction was then quenched with water (150 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (3.1 g, 51.2% yield).

[0663] Preparation of l-((lf)-l-((S)-l-(5-fluoro-2-(trifluoromethyl)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 20)

[0664] The remaining steps were carried out similarly to previously described reactions, then the final product was purified by preparative HPLC (XSelect CSH Prep Phenyl-Hexl OBD Prep Column 30 mm X 150 mm, 5 pm. 20-35% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 20 as a white solid (51.4 mg).

[0665] LCMS (ESI): m / z [M+H]+calcd. for C17H17F4N5O2: 399.13, found: 400.10.

[0666] 1H NMR (400 MHz, DMSO-A) 57.83 (dd, J = 8.9, 5.5 Hz, 1H), 7.43 (s, 1H), 7.42 - 7.34 (m, 1H), 7.12 (dd, 7= 10.5, 2.7 Hz, 1H), 6.35 (d, J = 7.0 Hz, 1H), 6.03 (q, J = 6.6 Hz, 1H), 5.79 (s, 2H), 4.02 (dt, J = 13.6, 6.7 Hz, 1H), 3.36 (s, 3H), 2.89 (dd, 7= 14.6, 6.5 Hz, 1H), 2.49 - 2.39 (m, 1H), 1.93 (d, J = 6.7 Hz, 3H).

[0667] 19F NMR (282 MHz, DMSO-76) 5 -56.68, -105.82. Synthesis of Compound 21: l-((R)-l-((7f)-l-(2-chloro-5-fluorophenyl)-2,2,2-trifluoroethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0668]

[0669] Step 1: Preparation of iV'-(2,2,2-trifluoroethylidene)benzohydrazide

[0670] To a solution of trifluoroacetaldehyde hydrate (5 g, 43.1 mmol, 1 equiv.) in methanol (50 mL) was added benzohydrazide (5.87 g, 43.1 mmol, 1 equiv.) and 4A molecular sieves (1 g), then the reaction was stirred at 75 °C for 24 h. The reaction mixture was then cooled to room temperature, filtered to remove the molecular sieves, quenched with water (200 mL) and extracted with dichloromethane (3 x 200 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (2.8 g, 30.1% yield).

[0671] Step 2: Preparation of iV'-(l-(2-chloro-5-fluorophenyl)-2,2,2-trifluoroethyl)benzohydrazide

[0672] To a solution of 2-bromo-l-chloro-4-fluorobenzene (13.56 g, 64.77 mmol, 5 equiv.) in THF (30 mL) was added isopropylmagnesium chloride lithium chloride complex (49.8 mL, 64.8 mmol, 5 equiv.) at 0 °C under nitrogen, then the reaction was stirred at 25 °C for 1 h.7V-(2,2,2-trifluoroethylidene)benzohydrazide (2.8 g, 12.9 mmol, 1 equiv.) was then added dropwise at 0 °C and the reaction was stirred at 25 °C for 1 h. The reaction was then quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford the tide compound as a yellow oil (3.5 g, 78.1% yield). LCMS (ESI): m / z [M+H]+calcd. for C15H11CIF4N2O: 346.05, found: 347.00.

[0673] Step 3: Preparation of (l-(2-chloro-5-fluorophenyl)-2,2,2-trifluoroethyl)hydrazine To A^-[l-(2-chloro-5-fluorophenyl)-2,2,2-trifluoroethyl]benzohydrazide (3.5 g, 10.1 mmol, 1 equiv.) was added concentrated hydrochloric acid (100 mL), then the reaction was stirred at 80 °C for 72 h. The resulting mixture was then concentrated under reduced pressure to afford the hydrochloride salt of the tide compound which was used without further purification (2.3 g, 93.9% yield).

[0674] LCMS (ESI): m / z [M+H]+calcd. for CsIEC fe 242.02, found: 243.05.

[0675] Preparation of l-((R)-l-((R)-l-(2-chloro-5-fluorophenyl)-2,2,2-trifluoroethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 21)

[0676] The remaining steps were carried out similarly to previously described reactions to afford a mixture of diastereomers of the final product. This mixture was first purified by preparative HPLC (XBridge BEH Shield RP1830*150 mm, 5pm column, 18-48% acetonitrile / water with 10 mM ammonium bicarbonate), then the diastereomers were separated by chiral HPLC (CHIRALPAK IE 2*25 cm, 5 pm column, Solvent A (30%): hexanes with 0.5% 2M ammonium in methanol; Solvent B (70%): ethanol) to afford Compound 21 as the first eluting isomer as a white solid (19.9 mg).

[0677] LCMS (ESI): m / z [M+H]+calcd. for C16H14CIF4N5O2: 419.08, found: 420.15.1H NMR (300 MHz, DMSO-A) 57.59 - 7.73 (m, 1H), 7.47 - 7.58 (m, 2H), 7.34 - 7.47 (m, 1H), 6.73 - 6.88 (m, 1H), 6.35 (d, J = 7.1 Hz, 1H), 5.79 (s, 2H), 4.03 - 4.20 (m, 1H), 3.50 (s, 3H), 2.83 - 2.97 (m, 1H), 2.52 - 2.60 (m, 1H).

[0678] 19F NMR (282 MHz, DMSO-A) 5-67.49, -112.91.

[0679] Synthesis of Compound 22: l-((R)-l-((S)-l-(5-chloro-2-fluoro-[l, T-biphenyl]-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0680]

[0681] Scheme 22

[0682]

[0683] Step 1: Preparation of l-(4-bromo-2-chloro-5-fluorophenyl)ethan-l-ol

[0684] To a solution of 4-bromo-2-chloro-5-fluorobenzaldehyde (9 g, 37.9 mmol, 1 equiv.) in tetrahydrofuran (100 mL) was added methylmagnesium bromide (1.0 M in THF, 42.2 mL) at -78 °C under nitrogen, then the reaction was stirred at room temperature under nitrogen for 2 h. The reaction was then quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the tide compound as a yellow oil (8.5 g, 88.5% yield). LCMS (ESI): m / z [M+H]+calcd. for CsH7BrClFO: 253.93, found: 254.85.

[0685] Preparation of l-((R)-l-((S)-l-(5-chloro-2-fluoro-[l,r-biphenyl]-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 22)

[0686] The remaining steps were carried out similarly to previously described reactions. Following Step 8 the resulting mixture of diastereomers was separated by silica gel chromatography to afford terz-butyl N-[(5R)-l-[(lS)-l-{5-chloro-2-fluoro-[ 1, T -biphenyl] -4-yl} ethyl] -7-methyl-6-oxo-4H,5H-pyrazolo[3,4-b] pyridin-5-yl] carbamate as the second eluting isomer. Following Step 10 the product was purified by preparative HPEC (XBridge Prep OBD C18 Column, 30*150 mm, 5 pm, 31-51% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 22 as a white solid (66.4 mg).

[0687] ECMS (ESI): m / z [M+H]+calcd. for C22H21CIFN5O2: 441.14, found: 442.15.

[0688] 1H NMR (400 MHz, DMSO-rfe) 57.63 (d, J= 8.0 Hz, 1H), 7.54 - 7.60 (m, 2H), 7.39 - 7.52 (m, 4H), 6.90 (d, J = 12.0 Hz, 1H), 6.36 (d, J = 8.0 Hz, 1H), 6.00 - 6.10 (m, 1H), 5.80 (s, 2H), 4.05 - 4.16 (m, 1H), 3.44 (s, 3H), 2.88 - 2.96 (m, 1H), 2.40 - 2.48 (m, 1H), 1.91 (d, J = 8.0 Hz, 3H).

[0689] 19F NMR (376 MHz, DMSO-rfe) 5 -118.73.

[0690] Synthesis of Compound 23: l-((R)-l-((S)-l-(2-cyclopropyl-5-fluorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0691]

[0692] Scheme 23

[0693]

[0694] Step 1: Preparation of 2-cyclopropyl-5-fluorobenzaldehyde

[0695] To a solution of 2-bromo-5 -fluorobenzaldehyde (7.00 g, 34.5 mmol, 1 equiv.), cyclopropylboronic acid (6.13 g, 71.4 mmol, 2.07 equiv.) in toluene (70 mL) and water (10 mL) was added palladium(II) acetate (774.1 mg, 3.448 mmol, 0.10 equiv.) and potassium phosphate tribasic (22.03 g, 103.8 mmol, 3.01 equiv.), then the reaction was stirred at 90 °C for 3 h under nitrogen. The reaction mixture was then quenched with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound (5.00 g, 88.3% yield).

[0696] Step 2: Preparation of l-(2-cyclopropyl-5-fluorophenyl)ethanol

[0697] To a solution of 2-cyclopropyl-5-fluorobenzaldehyde (5.00 g, 30.5 mmol, 1 equiv.) in tetrahydrofuran (80 mL) was added methylmagnesium bromide (1.0 M in THF, 36.5 mL, 36.5 mmol, 1.20 equiv.) at -78 °C, then the reaction was stirred at 25 °C for 1 h. The reaction was then quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20-60% ethyl acetate / petroleum ether) to afford the title compound (5.20 g, 94.7% yield).

[0698] Preparation of l-((R)-l-((S)-l-(2-cyclopropyl-5-fluorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 23)

[0699] The remaining steps were carried out similarly to previously described reactions. Following Step 7 the resulting mixture of diastereomers was separated by silica gel chromatography (30-70% ethyl acetate / petroleum ether) to afford tert-butyl N-[(5R)-l-[(lS)-l-(2-cyclopropyl-5-fluorophenyl)ethyl]-6-oxo-4H,5H,7H-pyrazolo[3,4-b]pyridin-5-yl]carbamate as the second eluting isomer. Following the final step the product was purified by preparative HPLC (XBridge Prep C18 OBD Column 250 mm x 19 mm x 5 pm, 25-50% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 23 as a white solid (54.7 mg).

[0700] LCMS (ESI): m / z [M+H]+calcd. for C19H22FN5O2: 371.18, found: 372.10.

[0701] 1H NMR (300 MHz, Methanol-^) 57.41 (s, 1H), 7.09 - 6.96 (m, 1H), 6.97 - 6.81 (m, 1H), 6.57 - 6.46 (m, 1H), 6.40 - 6.21 (m, 1H), 4.32 - 4.17 (m, 1H), 3.48 (s, 3H), 3.15 - 2.99 (m, 1H), 2.67 - 2.46 (m, 1H), 1.98 (d, J = 6.8 Hz, 3H), 1.94 - 1.82 (m, 1H), 1.11 - 0.90 (m, 2H), 0.83 - 0.53 (m, 2H).

[0702] 19F NMR (282 MHz, Methanol-^) 5 -118.04.

[0703] Synthesis of Compound 24: l-((R)-l-((S)-l-(2-cyclobutyl-5-fluorophenyl)ethyl)-7-methyl- 6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0704]

[0705] Scheme 24

[0706]

[0707] Step 5: Preparation of l-(l-(2-cyclobutyl-5-fluorophenyl)ethyl)-lH-pyrazol-5-amine To a solution of l-(l-(2-bromo-5-fluorophenyl)ethyl)-lH-pyrazol-5-amine (800 mg, 2.816 mmol, 1 equiv, prepared as previously described) in DMF (10 mL) were added 2-cyclobutyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.03 g, 5.63 mmol, 2 equiv.), Ir[dF(CF3)ppy (dtbpy))PF6 (157.9 mg, 0.141 mmol, 0.05 equiv.), (4,4'-dtbbpy)NiC12 (112.0 mg, 0.282 mmol, 0.1 equiv.) and morpholine (367.9 mg, 4.224 mmol, 1.5 equiv.) under nitrogen, then The reaction was stirred at room temperature under LED irradiation for 3 h. The reaction was then quenched with water (100 tmL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% ethyl acetate / petroleum ether) to afford the tide compound as a white solid (340 mg, 46.6% yield). LCMS (ESI): m / z [M+H]+calcd. for CisHisFNs: 259.15, found: 260.15.

[0708] Preparation of l-((lf)-l-((S)-l-(2-cyclobutyl-5-fluorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 24)

[0709] The remaining steps were carried out similarly to previously described reactions. Following Step 8 the mixture of diastereomers was separated by silica gel chromatography (1:1 ethyl acetate / petroleum ether) to afford tert-butyl ((R)-l-((S)-l-(2-cyclobutyl-5-fluorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate as the second eluting isomer. Following the final step the product was purified by preparative HPLC (XSelect CSH C18 Column, 30*150 mm, 5pm, 28-53% acetonitrile / water with 0.1% formic acid) to afford Compound 24 as a white solid (35.5 mg).

[0710] LCMS (ESI): m / z [M+H]+calcd. for C20H24FN5O2: 385.19 m / z, found: 386.20 [M+H]+.1H NMR (400 MHz, DMSO-tfc) 57.58-7.56 (m, J = 1H), 7.47 (s, 1H), 7.12-7.10 (m, 1H), 6.75-6.70 (m, 1H), 6.34 (d, J = 8.0 Hz, 1H), 5.97 (q, J = 8.0 Hz, 1H), 5.78 (s, 2H), 4.22-4.18 (m, 1H), 3.84-3.82 (m, 1H), 2.98-2.94 (m, 4H), 2.45-2.43 (m, 1H), 2.39 - 1.93 (m, 5H), 1.86 (t, J = 9.3 Hz, 1H), 1.68 (d, J = 6.6 Hz, 3H).

[0711] 19F NMR (376 MHz, DMSO-tfc) 5 -116.05.

[0712] Synthesis of Compound 25: l-((R)-l-((S)-l-(5-fluoro-2-methylphenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0713]

[0714] Scheme 25

[0715]

[0716] Step 1: Preparation of l-(5-fluoro-2-methylphenyl)ethan-l-one

[0717] To a solution of l-(2-bromo-5-fluorophenyl)ethan-l-one (6.00 g, 27.6 mmol, 1.00 equiv.) in toluene (70 mL) and water (10 mL) were added methylboronic acid (8.27 g, 138 mmol, 5 equiv.), palladium(II) acetate (0.62 g, 2.76 mmol, 0.1 equiv.), potassium phosphate tribasic (17.60 g, 82.94 mmol, 3 equiv.) and di(l-adamantyl)-iV-butylphosphine (1.98 g, 5.53 mmol, 0.2 equiv.), and the reaction was stirred at 90 °C for 12 h under nitrogen. The reaction was then cooled to room temperature, quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as a white solid (2.75 g, 65.4% yield).

[0718] Preparation of l-((R)-l-((S)-l-(5-fluoro-2-methylphenyl)ethyl)-7-methyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 25)

[0719] The remaining steps were carried out similarly to previously described reactions. Following the final step the product was purified by preparative HPLC (YMC Triart C 18 ExRs Column, 30*150 mm, 5 um, 25-45% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 25 as a white solid (98.1 mg). LCMS (ESI): m / z [M+H]+calcd. for C17H20FN5O2: 345.16, found 346.20.

[0720] 1H NMR (400 MHz, DMSO-A) 57.38 (s, 1H), 7.20 (d, J = 8.5 Hz, 1H), 6.98 (t, J = 8.4, 1H), 6.42 - 6.30 (m, 2H), 5.90 (t, J = 6.6 Hz, 1H), 5.79 (s, 2H), 4.03-4.00 (m, 1H), 3.32 (s, 3H), 2.92-2.85 (m, 1H), 2.44-2.40 (m, 1H), 2.22 (s, 3H), 1.81 (d, J= 6.6 Hz, 3H).

[0721] 19F NMR (376 MHz, DMSO-A) 5 -116.39.

[0722] Synthesis of Compound 26: l-((R)-l-((S)-l-(2-chloro-5-fluoro-4- (trifluoromethoxy)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0723]

[0724] Scheme 26

[0725]

[0726] Step 1: Preparation of 2-bromo-4-fluoro-5-(trifluoromethoxy)aniline

[0727] To a stirred solution of 4-fluoro-3-(trifluoromethoxy)aniline (5.01 g, 25.7 mmol, 1 equiv.) in acetonitrile (30 mL) was added 7V-bromosuccinimide (4.80 g, 26.9 mmol, 1.05 equiv.) in portions at 0 °C under a nitrogen atmosphere, then the reaction was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (1:5 ethyl acetate / petroleum, ether) to the title compound as a yellow oil (6.50 g, 92.7% yield).

[0728] LCMS (ESI): m / z [M+H]+calcd. for C7H4BrF4NO: 272.94, found: 273.90. Step 2: Preparation of l-bromo-2-chloro-5-fluoro-4-(trifluoromethoxy)benzene

[0729] To a stirred solution of 2-bromo-4-fluoro-5-(trifluoromethoxy)aniline (6.50 g, 23.7 mmol, 1 equiv.) in acetonitrile (50 mL) was added copper(I) chloride (7.05 g, 71.2 mmol, 3 equiv.) followed by addition of isoamyl nitrite (8.33 g, 71.2 mmol, 3.00 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (30 mL). The reaction mixture was then diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography, (1:10 ethyl acetate / petroleum ether) to afford the tide compound as a yellow oil (3.01 g, 43.2% yield). Preparation of l-((R)-l-((S)-l-(2-cyclopropyl-5-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 26)

[0730] The remaining steps were carried out similarly to previously described reactions. Following the final step the product was purified by preparative HPLC (Xbridge Prep Shield RP18 5pm OBD 30*150mm column, 25-41% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 26 as a white solid (19.9 mg).

[0731] LCMS (ESI): m / z [M+H]+calcd. for C17H16CIF4N5O3: 449.09, found: 450.10.

[0732] ’H NMR (400 MHz, DMSO-rfe) 57.78 - 8.24 (m, 1H), 7.32 - 7.48 (m, 1H), 7.10 - 7.30 (m, 1H), 6.29 - 6.51 (m, 1H), 5.95 - 6.10 (m, 1H), 5.70 - 5.91 (m, 2H), 4.01 -4.19 (m, 1H), 3.40 - 3.52 (m, 3H), 2.84 - 2.98 (m, 1H), 2.38 - 2.47 (m, 1H), 1.80 - 1.98 (m, 3H).

[0733] 19F NMR (376 MHz, DMSO-A) 5 -58.03, -129.64.

[0734] Synthesis of Compound 27: l-((R)-l-((S)-l-(2-chloro-4-cyclopropoxy-5-fluorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0735]

[0736] Scheme 27

[0737]

[0738] Step 1: Preparation of l-(2-chloro-4-cyclopropoxy-5-fluorophenyl)ethan-l-one

[0739] To a solution of l-(2-chloro-4,5-difluorophenyl)ethan-l-one (2.05 g, 10.8 mmol, 1 equiv.) in DMSO (20 mL) were added cyclopropanol (499.8 mg, 8.606 mmol, 0.8 equiv.) and cesium carbonate (3.50 g, 10.8 mmol, 1 equiv.) and the resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was then cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound as a white solid (901.2 mg, 36.64% yield).

[0740] LCMS (ESI): m / z [M+H]+calcd. for C11H10CIFO2: 228.04, found 229.00.

[0741] Preparation of l-((R)-l-((S)-l-(4-cyclopropoxy-2-cyclopropyl-5-fluorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 27) The remaining steps were carried out similarly to previously described reactions. Following the final step the product was purified by preparative HPLC (Xbridge Prep Shield RP18 5pm OBD 30*150mm column, 25-41% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 27 as a white solid (59.1 mg).

[0742] LCMS (ESI): m / z [M+H]+calcd. for C19H21CIFN5O3: 421.13, found: 422.10.

[0743] 1H NMR (400 MHz, DMSO-A) 57.45 (dd, J = 7.6, 2.0 Hz, 1H), 7.37 (s, 1H), 6.75 (d, J = 12.0 Hz, 1H), 6.34 (d, J = 7.0 Hz, 1H), 5.90 - 6.10 (m, 1H), 5.79 (s, 2H), 3.90 - 4.18 (m, 2H), 3.40 (s, 3H), 2.81 - 3.00 (m, 1H), 2.40 - 2.50 (m, 1H), 1.84 (d, J = 6.6 Hz, 3H), 0.65 - 0.91 (m, 4H).

[0744] 19F NMR (376 MHz, DMSO-A) 5 -135.04.

[0745] Synthesis of Compound 28: l-((lf)-l-((S)-l-(2-chloro-5-fluoro-4-(pyridin-2-yl)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0746]

[0747] Scheme 28

[0748] 11

[0749]

[0750] Step 1: Preparation of 4-bromo-2-chloro-5-fluoro -methoxy-A^-methylbenzamide To a solution of 4-bromo-2-chloro-5-fluorobenzoic acid (10 g, 39.45 mmol, 1 equiv.) in dimethylformamide (100 mL) was added A%Ldiniethylhydroxylamine hydrochloride (5.77 g, 59.18 mmol, 1.5 equiv.), <9-(7-Aza-lH-benzotriazol-l-yl)-A,iV,iV, A'-tetramethyluronium hexafluorophosphate (18.0 g, 47.3 mmol, 1.2 equiv.), and A-A-diisopropylethylamine (30.6 g, 236.7 mmol, 6 equiv.). The reaction was stirred at 25 °C for 1 h. The mixture was treated with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-100%) to afford the title compound as a yellow oil (9 g, 76% yield).

[0751] LCMS (ESI): m / z [M+H, M+H+2]+calcd. for CoHsBrCIFNCh: 294.94, found: 295.94, 297.94. Step 2: Preparation of l-(4-bromo-2-chloro-5-fluorophenyl)ethan-l-one To a solution of 4-bromo-2-chloro-5-fluoro- / V-methoxy-iV-methylbenzamide (9 g, 30.352 mmol, 1 equiv.) in tetrahydrofuran (90 mL) was added methylmagnesium bromide (1.0 M in tetrahydrofuran) (75.8 mL, 75.8 mmol, 2.50 equiv.) under nitrogen at 0 °C. The reaction was stirred at 25 °C for 1 h. The mixture was treated with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-70%) to afford the title compound as a yellow oil (6.5 g, 85.1% yield).

[0752] LCMS (ESI): m / z [M+H, M+H+2]+calcd. for CsHsBrCIFO: 249.92, found: 250.90, 252.90.

[0753] Step 3-6: Preparation of (S)-l-(l-(4-bromo-2-chloro-5-fluorophenyl)ethyl)-lH-pyrazol-5-amine

[0754] (S)-l-(l-(4-bromo-2-chloro-5-fluorophenyl)ethyl)-lH-pyrazol-5-amine was prepared accordingly to procedures described above.

[0755] LCMS (ESI): m / z [M+H, M+H+2]+calcd. for CiiHioBrClFN3: 316.97, found: 317.90, 319.90.

[0756] Step 7: Preparation of (S)-l-(l-(2-chloro-5-fluoro-4-(pyridin-2-yl)phenyl)ethyl)-lH-pyrazol-5-amine

[0757] To a solution of (S)-l-(l-(4-bromo-2-chloro-5-fluorophenyl)ethyl)-lH-pyrazol-5-amine (680 mg, 2.13 mmol, 1 equiv.) in dimethylformamide (10 mL) was added pyridin-2-ylboronic acid (1.8 g, 14.94 mmol, 7.00 equiv.) and palladium(II) acetate (47.9 mg, 0.21 mmol, 0.1 equiv.), 1, T-bis(diphenylphosphino)ferrocene (236.6 mg, 0.42 mmol, 0.2 equiv.), copper(I) chloride (211.3 mg, 2.135 mmol, 1 equiv.) and caesium carbonate (1.4 g, 4.27 mmol, 2 equiv.). The reaction was stirred at 100 °C for 1 h under nitrogen. The mixture was allowed to cool down to room temperature. The mixture was treated with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-50%) to afford the title compound as a yellow oil (500 mg, 73.9% yield).

[0758] LCMS (ESI): m / z [M+H]+calcd. for Ci6Hi4ClFN4: 316.09, found: 317.09. Step 8-13: Preparation of l-((R)-l-((S)-l-(2-chloro-5-fluoro-4-(pyridin-2-yl)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 28)

[0759] Compound 28 was prepared according to procedures described above. The tide Compound 28 was purified by preparative HPLC (XBridge BEH Shield RP1830*150 mm, 5pm column, 13-43% (v / v) acetonitrile and water (containing lOmmol / L ammonium bicarbonate) and isolated as a white solid (21.4 mg, 26.6% yield).

[0760] LCMS (ESI): m / z [M+H]+calcd. for C21H20CIFN6O2: 442.13, found: 443.15.

[0761] 1H NMR (300 MHz, DMSO) 58.64 - 8.79 (m, 1H), 7.75 - 8.05 (m, 3H), 7.37 - 7.50 (m, 2H), 6.88 (d, J = 12.0 Hz, 1H), 6.35 (d, J = 6.9 Hz, 1H), 6.02 - 6.16 (m, 1H), 5.79 (s, 2H), 4.02 -4.16 (m, 1H), 3.38 (d, 7 = 27.6 Hz, 3H), 2.85 - 3.02 (m, 1H), 2.36 - 2.48 (m, 1H), 1.92 (d, J = 6.7 Hz, 3H).

[0762] 19F NMR (282 MHz, DMSO) 5 -117.38.

[0763] Synthesis of Compound 29: 5-chloro-2-fluoro-V.. V-dimethyl-4-((. S)-l-(( / ?)-7-methyl-6-oxo-5-ureido-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-l-yl)ethyl)benzamide

[0764]

[0765] Scheme 2912

[0766]

[0767] Step 1: Preparation of 4-bromo-5-chloro-2-f'luoro- \.\ -climethvlbenzamicle

[0768] To a solution of 4-bromo-5-chloro-2-fluorobenzoic acid (3 g, 11.83 mmol, 1 equiv.) in dimethylformamide (50 mL) was added <9-(7-Aza-lH-benzotriazol-l-yl)-A, A, A', A'-tetramethyluronium hexafluorophosphate (9.00 g, 23.67 mmol, 2.0 equiv.), diisopropylethylamine (3.06 g, 23.67 mmol, 2.0 equiv.), and dimethylamine hydrochloride (1.16 g, 14.20 mmol, 1.2 equiv.) at 0 °C. The resulting mixture was stirred at 20 °C for 2 h. The reaction was monitored by TLC. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 1:3) to afford the title compound as a yellow solid (3 g, 90.35% yield). LCMS: m / z [M+H, M+H+2]+calcd. for CgHgBrCIFNO: 278.95, found 279.90, 281.90. Step 2-12: Preparation of 5-chloro-2-f'luoro-V.. V-dimethyl-4-((. S)-l-(( / ?)-7-methyl-6-oxo-5-ureido-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-l-yl)ethyl)benzamide (Compound 29)

[0769] The title Compound 29 was prepared according to previously described procedures. The title Compound 29 was purified by preparative HPLC (YMC Triart C 18 ExRs Column 150 mm x 30 mm x 5 pm column, 15-32% (v / v) acetonitrile and water containing 0.05% ammonium bicarbonate) and afforded as a white solid (40 mg, 30.0% yield).

[0770] LCMS: m / z [M+H]+calcd. for C19H22CIFN6O3: 436.14, found 437.05.

[0771] 1H NMR (400 MHz, DMSO-d6) 57.54 (d, J = 6.0 Hz, 1H), 7.38 (s, 1H), 6.91 (d, J = 10.1 Hz, 1H), 6.34 (d, J = 6.9 Hz, 1H), 5.96 - 6.06 (m, 1H), 5.79 (s, 2H), 4.02 - 4.13 (m, 1H), 3.41 (s, 3H), 2.97 (s, 3H), 2.86 - 2.94 (m, 1H), 2.81 (s, 3H), 2.38 - 2.50 (m, 1H), 1.88 (d, J = 6.7 Hz, 3H).

[0772] 19F NMR (376 MHz, DMSO) 5 (ppm): -116.973.

[0773] Synthesis of Compound 30: l-((lf)-l-((S)-l-(6-chloro-l-methyl-lH-indazol-5-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0774]

[0775] Scheme 3013

[0776]

[0777] Step 1: Preparation of 5-bromo-6-chloro-l-methyl-lH-indazole and 5-bromo-6-chloro-2-methyl-2H-indazole

[0778] To a solution of 5-bromo-6-chloro-lH-indazole (7.60 g, 32.83 mmol, 1 equiv.) in dimethylformamide (100 mL) was added methyl iodide (6.99 g, 49.24 mmol, 1.5 equiv.) and potassium carbonate (13.61 g, 98.49 mmol, 3 equiv.). The reaction was stirred at room temperature for 3h. The mixture was treated with water (150 mL) and extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-60%) to give 5-bromo-6-chloro-l-methyl-lH-indazole as a yellow oil (5.1 g, 63.2% yield).

[0779] LCMS (ESI): m / z [M+H, M+H+2]+calcd. for CsIEBrC 243.94, found: 244.95, 246.95.

[0780] 5-bromo-6-chloro-2-methyl-2H-indazole was also obtained during the purification as a yellow oil (2.5 g, 31.02% yield).

[0781] LCMS (ESI): m / z [M+H, M+H+2]+calcd. for CsHeBrC 243.94, found: 244.95, 246.95.

[0782] Step 2-11: Preparation of l-((R)-l-((S)-l-(6-chloro-l-methyl-lH-indazol-5-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 30) Step 2-11 were performed as described in above procedures. Compound 30 was purified by preparative HPLC (XBridge Prep OBD C1830*150 mm 5 pm column, 6-36% (v / v) acetonitrile and water containing lOmmol / L ammonium bicarbonate) and afforded as a white solid (43.9 mg, 30.1% yield).

[0783] LCMS (ESI): m / z [M+H]+calcd. for C18H20CIN7O2: 401.14, found: 402.15.

[0784] ’H NMR (300 MHz, DMSO-fife) 5 7.82 - 8.12 (m, 2H), 7.17 - 7.46 (m, 2H), 6.27 - 6.40 (m, 1H), 6.08 - 6.19 (m, 1H), 5.77 (s, 2H), 3.91 - 4.11 (m, 4H), 3.37 - 2.42 (m, 3H), 2.82 - 3.00 (m, 1H), 2.39 - 2.49 (m, 1H), 1.92 (d, J = 6.7 Hz, 3H).

[0785] Synthesis of Compound 31: l-((R)-l-((S)-l-(6-chloro-2-methyl-2H-indazol-5-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0786]

[0787] Scheme 31

[0788] 14

[0789]

[0790] Step 1-10: Preparation of l-((R)-l-((R)-l-(6-chloro-2-methyl-2H-indazol-5-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 31) Compound 31 was synthesized according to procedures described previously, using starting material 5-bromo-6-chloro-2-methyl-2H-indazole which was obtained during step 1 in the synthesis of Compound 30. Compound 31 was purified by preparative HPLC (YMC Triart C18 ExRs 30*150 mm, 5 um column 13- 34% (v / v) acetonitrile and water with lOmmol / L ammonium bicarbonate) and afforded in 41.0% yield (29.9 mg)

[0791] LCMS (ESI): m / z [M+H]+calcd. for C18H20CIN7O2: 401.14, found: 402.15.

[0792] ’H NMR (300 MHz, DMSO-&) 58.38 (s, 1H), 7.73 (s, 1H), 7.38 (s, 1H), 7.17 (s, 1H), 6.29 - 6.39 (m, 1H), 6.01 - 6.15 (m, 1H), 5.78 (s, 2H), 4.13 (s, 3H), 3.97 - 4.07 (m, 1H), 3.35 - 3.37 (m, 3H), 2.88 - 2.99 (m, 1H), 2.39 - 2.43 (m, 1H), 1.91 (d, J= 6.7 Hz, 3H). Synthesis of Compound 32: (R)-l-(l-((3-chloronaphthalen-2-yl)methyl)-7-methyl-6-oxo- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0793]

[0794] Step 1: Preparation of 3-chloronaphthalene-2-carbaldehyde

[0795] To a solution of 2-bromo-3-chloronaphthalene (1.40 g, 5.79 mmol, 1 equiv.) in tetrahydrofuran (30 mL) was added isopropylmagnesium chloride lithium chloride complex (in tetrahydrofuran, 1.3 M, 6.8 mL, 8.84 mmol, 1.52 equiv.) at 0 °C under nitrogen. The reaction was stirred at 0 °C for Ih under nitrogen. Then dimethylformamide (635.6 mg, 8.69 mmol, 1.50 equiv.) was added at -78 °C. The reaction was stirred at -78 °C for 3h under nitrogen. The mixture was treated with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-50%) to afford the title compound (580.0 mg, 52.4% yield).

[0796] LCMS (ESI): m / z [M+H]+calcd. for C11H7CIO: 190.02, found: 191.05. Step 2-7: Preparation of (R)-l-(l-((3-chloronaphthalen-2-yl)methyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 32) Compound 32 was prepared using procedures as described above. After purification by preparative HPLC (XBridge Prep OBD C18 Column 250 mm x 19 mm x 5 pm column, 24-47% (v / v) acetonitrile and water containing lOmmol / L ammonium bicarbonate), Compound 32 was afforded as a white solid (33.3 mg, 14.7% yield).

[0797] LCMS (ESI): m / z [M+H]+calcd. for C19H18CIN5O2: 383.11, found: 384.10.

[0798] 1H NMR (300 MHz, MeOD) 58.03 (s, 1H), 7.90 - 7.72 (m, 2H), 7.61 - 7.45 (m, 3H), 7.22 (s, 1H), 5.78 - 5.72 (m, 2H), 4.54 - 4.41 (m, 1H), 3.31 - 3.29 (m, 3H), 3.23 - 3.10 (m, 1H), 2.75 - 2.59 (m, 1H).

[0799] Synthesis of Compound 33: l-((R)-l-((S)-l-(5-chloro-2-methoxypyridin-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0800]

[0801] Scheme 3316

[0802]

[0803] Step 1: Preparation of 4-bromo-5-chloro-2-methoxypyridine

[0804] To a solution of 4-bromo-2-methoxypyridine (5.00 g, 26.59 mmol, 1 equiv.) in dimethylformamide (50 mL) was added 7V-chlorosuccinimide (7.10 g, 53.18 mmol, 2 equiv.). The reaction was stirred at room temperature for Ih under nitrogen, and then treated with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-50%) to afford the title compound as a white solid (5.20 g, 87.9% yield).

[0805] LCMS (ESI): m / z [M+H, M+H+2]+calcd. for C6H5BrClNO: 220.92, found 221.90, 223.90. Step 2-13: Preparation of l-((R)-l-((S)-l-(5-chloro-2-methoxypyridin-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 33) Compound 33 was synthesized using procedures described above. After purification by preparative HPLC (YMC Triart C18 ExRs Column, 30*150 mm, 5 um, 17-40% (v / v) acetonitrile and water containing 10 mmoL / L ammonium bicarbonate) Compound 33 was afforded as a white solid (25.0 mg, 13.8% yield).

[0806] LCMS (ESI): m / z [M+H]+calcd. for C16H19CIN6O3: 378.12, found 379.10.

[0807] 1H NMR (400 MHz, DMSO-O 58.21 (s, 1H), 7.39 (s, 1H), 6.34 (d, J = 6.9 Hz, 1H), 6.22 (s, 1H), 5.95 (q, J = 6.7 Hz, 1H), 5.79 (s, 2H), 4.05 (t, J = 6.7 Hz, 1H), 3.81 (s, 3H), 3.36 (s, 3H), 2.92-2.90 (m, 1H), 2.45 (d, J= 14.0 Hz, 1H), 1.85 (d, J = 6.7 Hz, 3H).

[0808] Synthesis of Compound 34: (R)-l-(l-((5-chlorobenzo[c]isothiazol-6-yl)methyl)-7-methyl- 6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0809]

[0810] Step 1: Preparation of methyl 5-chlorobenzo[c]isothiazole-6-carboxylate

[0811] A mixture of methanesulfonamide (7.2 g, 75.69 mmol, 7.56 equiv.), thionyl chloride (8 mL, 110.1 mmol, 11.0 equiv.) and toluene (10 mL) was stirred at 120 °C for 18h under nitrogen. After cooling to room temperature, toluene was removed under reduced pressure. To a solution of methyl 5-amino-2-chloro-4-methylbenzoate (2 g, 10.0 mmol, 1.0 equiv.) in toluene (40 mL) was added thionyl chloride (8 mL, 110 mmol, 11.0 equiv.) dropwise at 0 °C. After the addition was complete, the reaction mixture was heated at 120 °C for 18h. Pyridine (1 mL, 12.4 mmol, 1.2 equiv.) and the crude A-sulfinylmethanesulfonamide from the above reaction were added to the mixture. The resulting solution was then stirred at 120 °C for 18h. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate (100 mL), and washed with water (2 x 100 mL). The organic layer was washed with brine (100 mL), dried with sodium sulfate and concentrated in vacuum to give the crude product which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 1 / 10) to afford the title compound as a yellow solid.

[0812] LCMS (ESI): m / z [M+H]+calcd. for C9H6CINO2S: 226.98, found 228.00.

[0813] Step 2: Preparation of (5-chlorobenzo[c]isothiazol-6-yl) methanol

[0814] To a solution of methyl 5-chloro-2,l-benzothiazole-6-carboxylate (2 g, 8.7 mmol, 1 equiv.) in tetrahydrofuran (200 mL) was added diisobutylaluminium hydride (17.6 mL, 17.5 mmol, 2 equiv, 1.0 M in dichloromethane) at -78 °C. The reaction was stirred at -78 °C for 3h under nitrogen. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-70%) to afford the title compound (1.4 g, 79.8% yield).

[0815] LCMS (ESI): m / z [M+H]+calcd. for CSH6C1NOS: 198.99, found 199.90.

[0816] Step 3: Preparation of 5-chloro-2,l-benzothiazole-6-carbaldehyde

[0817] To a solution of (5-chloro-2,l-benzothiazol-6-yl) methanol (1.7 g, 8.51 mmol, 1 equiv.) in dichloromethane (50 mL) was added Dess-Martin periodinane (10.8 g, 25.5 mmol, 3 equiv.). The reaction was stirred at rt for 3h under nitrogen. After cooling down to room temperature, the mixture was treated with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-100%) to afford the title compound (1.4 g, 83.1% yield).

[0818] Step 4-10: Preparation of (R)-5-amino-l-((5-chlorobenzo[c]isothiazol-6-yl) methyl)-7-methyl-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-b] pyridin-6-one (Compound 34) Compound 34 was prepared similarly to procedures reported above. After purification by preparative HPLC (XBridge Shield RP18 OBD 250 mm x 19 mm x 5 pm column, 9-39% (v / v) acetonitrile and water containing 10 mmoL / L ammonium bicarbonate), Compound 34 was afforded (8.3 mg, 7.3% yield).

[0819] LCMS (ESI): m / z [M+H]+calcd. for CieHisCINeChS: 390.18, found 391.10.

[0820] 1H NMR (400 MHz, MeOD) 59.56 (s, 1H), 8.06 (s, 1H), 7.48 (s, 1H), 7.08 (s, 1H), 5.68 (s, 2H), 4.47 (dd, J = 13.5, 6.7 Hz, 1H), 3.23-3.33 (m, 3H), 3.14 (dd, J = 14.7, 6.8 Hz, 1H), 2.66 (t, J= 14.1 Hz, 1H), 1.28 (s, 1H), 0.93 - 0.83 (m, 1H).

[0821] Synthesis of Compound 35: l-((R)-l-((S)-l-(3-chloro-6-methoxypyridin-2-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0822]

[0823] Scheme 35

[0824]

[0825] Step 1: Preparation of 2-bromo-3-chloro-6-methoxypyridine

[0826] Chlorotrimethylsilane (11.5 g, 106.0 mmol, 4 equiv.) was dissolved in methanol (60 mL) at 0 °C. The reaction was stirred at room temperature for 30 min. To the above mixture was added 6-bromo-5-chloropyridin-2-amine (5.5 g, 26.5 mmol, 1 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for additional 15 min. To the above mixture was added sodium nitrite (0.73 g, 10.6 mmol, 0.4 equiv.) dropwise at room temperature. The resulting mixture was stirred at 50 °C for additional 3h. The mixture was allowed to cool down to room temperature, and then treated with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-30%) to afford the title compound as a yellow solid (4.61 g, 78.1% yield).

[0827] LCMS (ESI): m / z [M+H, M+H+2]+calcd. for C6H5BrClNO: 220.92, found: 222.00, 224.00.

[0828] Step 2-11: Preparation of l-((R)-l-((S)-l-(3-chloro-6-methoxypyridin-2-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 35) Compound 35 was prepared similarly to procedures reported above. After purification by preparative HPLC (YMC Triart C18 ExRs 30*150 mm, 5 um column, 7-37% (v / v) acetonitrile and water containing lOmmol / L ammonium bicarbonate), a mixture of diastereomers was obtained (35 mg, 22.1% yield), that was further purified by chiral HPLC (CHIRAL ART Cellulose-SB, 2*25 cm, 5 pm, 30% (v / v) ethanol and hexanes containing 0.5% 2M ammonia in methanol) to afford the tide Compound 35 as second eluting compound as a white solid (26.5 mg, 75.7% yield)

[0829] LCMS (ESI): m / z [M+H]+calcd. for C16H19CIN6O3: 378.12, found: 379.15.

[0830] 1H NMR (300 MHz, DMSO-&) 57.75 (d, J = 8.7 Hz, 1H), 7.26 (s, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.35 (d, J = 6.9 Hz, 1H), 5.98 - 6.10 (m, 1H), 5.78 (s, 2H), 4.00 - 4.19 (m, 1H), 3.77 (s, 3H), 3.39 (s, 3H), 2.80 - 2.92 (m, 1H), 2.39 - 2.48 (m, 1H), 1.90 (d, J = 6.7 Hz, 3H).

[0831] Synthesis of Compound 36: l-((R)-7-methyl-6-oxo-l-((S)-l-(2- (trifluoromethyl)phenyl)ethyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0832]

[0833] Scheme 36

[0834]

[0835]

[0836] HCI / dioxane MsOH, THF / H2O

[0837] Step 8

[0838] Step 9

[0839]

[0840]

[0841] All reactions were carried out similarly to previously described reactions. Following Step 7 the resulting mixture of diastereomers was separated by silica gel chromatography (0-22% ethylacetate / petroleum ether) to afford tert-butyl A-[(5R)-7-methyl-6-oxo-l-[(lS)-l-[2-(trifluoromethyl)phenyl]ethyl]-4H,5H-pyrazolo[3,4-b]pyridin-5-yl]carbamate as the second eluting isomer. Following the final step the product was purified by preparative HPLC (XBridge Prep C18 OBD Column, 19*250 mm, 5pm, 20-45% acetonitrile / water with 0.05% ammonium bicarbonate) to afford Compound 36 as a white solid (101.2 mg).

[0842] LCMS (ESI): m / z [M+H]+calcd. for C17H18F3N5O2: 381.14, found: 382.15.

[0843] ’H NMR (400 MHz, DMSO-tfc) 57.73 (dd, J = 8.0, 1.3 Hz, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.42 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.34 (d, J = 7.0 Hz, 1H), 6.05 (q, J = 6.6 Hz, 1H), 5.79 (s, 2H), 3.99 (dt, J = 13.5, 6.7 Hz, 1H), 3.33 (s, 3H), 2.90 (dd, 7= 14.6, 6.5 Hz, 1H), 2.44 (t, J= 14.1 Hz, 1H), 1.92 (d, J= 6.7 Hz, 3H).19F NMR (376 MHz, DMSO-tfc) 5(ppm): 57.0092.

[0844] Synthesis of Compound 37: l-((lf)-l-((S)-l-(2-chloro-5-(trifluoromethyl)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0845]

[0846] All reactions were carried out similarly to previously described reactions. Following Step 9 the resulting mixture of diastereomers was separated by silica gel chromatography (1:1 ethyl acetate / petroleum ether) to afford tert-butyl A-[(5R)-l-[(lS)-l-[2-chloro-5-(trifluoromethyl) phenyl] ethyl]-7-methyl-6-oxo-4H,5H-pyrazolo[3,4-b] pyridin-5-yl] carbamate as the second eluting isomer. Following the final step the product was purified by preparative HPLC (XBridge Prep OBD C18 Column 30*150 mm, 5 pm, 22-44% acetonitrile / water with 10 mM ammonium bicarbonate and 0.05% ammonia) to afford Compound 37 as a white solid (75.4 mg).

[0847] LCMS (ESI): m / z [M+H]+calcd. for C17H17CIF3N5O2: 415.10, found: 416.15.

[0848] 1H NMR (300 MHz, DMSO-tfc) 57.72 (d, J = 1.9 Hz, 2H), 7.42 (s, 1H), 7.16 (d, J = 1.8 Hz, 1H), 6.34 (d, J = 6.9 Hz, 1H), 6.11 (q, J = 6.7 Hz, 1H), 5.78 (s, 2H), 4.02 (dt, J = 13.4, 6.7 Hz, 1H), 3.38 (s, 3H), 2.92 (dd, J = 14.6, 6.6 Hz, 1H), 2.42 (d, J = 14.1 Hz, 1H), 1.91 (d, J = 6.7 Hz, 3H).

[0849] 19F NMR (282 MHz, DMSO-de) 5 -61.285.

[0850] Synthesis of Compound 38: l-((R)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-7-ethyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0851]

[0852] Scheme 38

[0853]

[0854] All reactions were carried out similarly to previously described reactions. Following the final step the resulting product was purified by preparative HPLC (Xselect CSH Phenyl Hexy Column, 19*250 mm, 5 pm, 27-46% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 38 as a white solid (21.0 mg).

[0855] LCMS (ESI): m / z [M+H]+calcd. for C17H19CIFN5O2: 379.12, found 380.05.

[0856] ’H NMR (400 MHz, DMSO-A) 5 6.50 - 6.80 (m, 2H), 6.15 - 6.30 (m, 1H), 5.65 - 5.85 (m, 1H), 5.00 - 5.20 (m, 1H), 3.30 - 3.53 (m, 2H), 2.80 - 3.05 (m, 1H), 2.15 - 2.33 (m, 1H), 1.60 - 1.80 (m, 1H), 1.05 - 1.20 (m, 3H), 0.30 - 0.45 (m, 3H).

[0857] 19F NMR (282 MHz, DMSO-A) 5 -115.09.

[0858] Synthesis of Compound 39: l-((lf)-l-((S)-l-([l,l'-biphenyl]-4-yl)ethyl)-7-methyl-6-oxo- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0859]

[0860] Scheme 39

[0861]

[0862] All reactions were carried out similarly to previously described reactions. Following Step 8 the resulting mixture of diastereomers was separated by silica gel chromatography (1:1 ethyl acetate / petroleum ether) to afford tert-butyl ((7?)-l-((S)-l-([l,l'-biphenyl]-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate as the second eluting isomer. Following the final step the resulting product was purified by preparative HPLC (XBridge Prep OBD C18 Column 30*150 mm, 5 pm; 31-56% acetonitrile / water with 0.1% formic acid) to afford Compound 39 as a white solid (31.1 mg).

[0863] LCMS (ESI): m / z [M+H]+calcd. for C22H23N5O2: 389.19, found: 390.15.

[0864] 1H-NMR (400 MHz, DMSO-tfc) 57.57 - 7.66 (m, 4H), 7.38 - 7.48 (m, 3H), 7.28 - 7.37 (m, 1H), 7.10 (d, J = 8.0 Hz, 2H), 6.35 (d, J = 7.0 Hz, 1H), 5.85 - 5.97 (m, 1H), 5.72 - 5.84 (m, 2H), 4.00 - 4.19 (m, 1H), 3.37 - 3.39 (m, 3H), 2.88 - 2.99 (m, 1H), 2.36 - 2.48 (m, 1H), 1.89 (d, J = 6.7 Hz, 3H).

[0865] Synthesis of Compound 40: l-((R)-l-((S)-l-(2-chloro-4-cyclopropyl-5-fluorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0866]

[0867] All reactions were carried out similarly to previously described reactions. Following Step 5 the resulting mixture of diastereomers was separated by silica gel chromatography (1:5 ethyl acetate / petroleum ether) to afford tert-butyl ((7?)-l-((S)-l-(2-chloro-4-cyclopropyl-5-fluorophenyl)ethyl)-6-oxo-4,5,6,7 -tetrahydro- 1 H-pyrazolo [3,4-b]pyridin-5 -yl)carbamate as the second eluting isomer. Following the final step, the resulting product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 30*150 mm, 5 pm, 31-51% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 40 as a white solid (44.9 mg).

[0868] LCMS (ESI): m / z [M+H]+calcd. for C19H21CIFN5O2: 405.14, found:406.10.

[0869] 1H NMR (400 MHz, DMSO-A) 57.38 (s, 1H), 6.95 - 7.12 (m, 1H), 6.50 - 6.72 (m, 1H), 6.18 - 6.42 (m, 1H), 5.90 - 6.04 (m, 1H), 5.68 - 5.88 (m, 2H), 3.99 - 4.22 (m, 1H), 3.36 - 3.46 (m, 3H), 2.82 - 2.98 (m, 1H), 2.40 - 2.47 (m, 1H), 1.94 - 1.08 (m, 1H), 1.78 - 1.90 (m, 3H), 0.90 - 1.02 (m, 2H), 0.72 - 0.85 (m, 2H).

[0870] 19F NMR (376 MHz, DMSO-A) 5 -121.00.

[0871] Synthesis of Compound 41: l-((R)-7-methyl-6-oxo-l-((S)-l-phenylethyl)-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0872]

[0873] Scheme 41

[0874]

[0875] All reactions were carried out similarly to previously described reactions. Following Step 7 the resulting mixture of diastereomers was separated by silica gel chromatography (0-40% ethyl acetate / petroleum ether) to afford tert-butyl ((7?)-7-methyl-6-oxo-l-((S)-l-phenylethyl)-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b] pyridin-5-yl) carbamate as the second eluting isomer. Following the final step the product was purified by preparative HPLC (XB ridge Shield RP18 OBD 250 mm x 19 mm x 10 pm column, 55-65% methanol / water with 0.05% ammonium bicarbonate) to afford Compound 41 as a white solid (39.7 mg).

[0876] LCMS (ESI): m / z [M+H]+calcd. for C16H19N5O2: 313.15, found: 314.10.

[0877] 1H NMR (300 MHz, DMSO-tfc) 57.14 - 7.41 (m, 4H), 6.94 - 7.04 (m, 2H), 6.32 (d, J = 6.9 Hz, 1H), 5.75 - 5.86 (m, 3H), 3.90 - 4.18 (m, 1H), 3.33 (s, 3H), 2.85 - 3.00 (m, 1H), 2.38 -2.50 (m, 1H), 1.85 (d, J = 6.8 Hz, 3H). Synthesis of Compound 42: l-((R)-l-((S)-l-(2-chloro-4-(trifluoromethyl)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0878]

[0879] All reactions were carried out similarly to previously described reactions. Following Step 7 the resulting diastereomers were separated by silica gel chromatography (0.50% ethyl acetate / petroleum ether) to afford tert-butyl A-[(57?)-l-[(lS)-l-[2-chloro-4-(trifluoromethyl)phenyl]ethyl]-6-oxo-4H,5H,7H-pyrazolo[3,4-b]pyridin-5-yl]carbamate as the first eluting isomer. Following the final step the resulting product was purified by preparative HPLC (XBridge Prep OBD C18 Column 30 mm x 150 mm x 5 pm, 25-41% acetonitrile / water with 10 mM ammonium bicarbonate and 0.05% ammonia) to afford Compound 42 as a white solid (32.3 mg).

[0880] LCMS (ESI): m / z [M+H]+calcd. for C17H17CIF3N5O2: 415.10, found 416.15.1H NMR (400 MHz, DMSO-A) 57.89 (d, J = 1.9 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.41 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.34 (d, J = 6.9 Hz, 1H), 6.12 (q, J = 6.7 Hz, 1H), 5.78 (s, 2H), 4.07 (dt, J = 13.5, 6.7 Hz, 1H), 3.37 (s, 3H), 2.93 (dd, J = 14.6, 6.6 Hz, 1H), 2.50 - 2.39 (m, 1H), 1.90 (d, J= 6.7 Hz, 3H).

[0881] 19F NMR (282 MHz, DMSO-A) 5 -61.21.

[0882] Synthesis of Compound 43: l-((lf)-l-((S)-l-(3',5-dichloro-2-fluoro-[l,l'-biphenyl]-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0883]

[0884] Scheme 43

[0885]

[0886] All reactions were carried out similarly to previously described reactions. Following Step 5 the resulting mixture of diastereomers were separated by silica gel chromatography (1:1 ethyl acetate / petroleum ether) to afford tert-butyl ((R)-l-((S)-l-(3',5-dichloro-2-fluoro-[l,l'-biphenyl]-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate as the second eluting isomer. Following the final step the resulting product was purified by preparative HPLC (YMC Triart C18 ExRs Column 250 mm x 19 mm x 5 pm, 40-60% acetonitrile / water with 0.05% ammonium bicarbonate) to afford Compound 43 as a white solid (25.1 mg).

[0887] LCMS (ESI): m / z [M+H]+calcd. for C22H20CI2FN5O2: 475.10, found 476.10.

[0888] 1H NMR (400 MHz, DMSO-tfc) 57.71 (d, J = 7.1 Hz, 1H), 7.66 (s, 1H), 7.47 - 7.59 (m, 3H), 7.41 (s, 1H), 6.91 (d, J = 11.4 Hz, 1H), 6.36 (d, J = 6.9 Hz, 1H), 6.01 - 6.10 (m, 1H), 5.80 (s, 2H), 4.04 - 4.15 (m, 1H), 3.44 (s, 3H), 2.88 - 2.97 (m, 1H), 2.40 - 2.48 (m, 1H), 1.91 (d, J = 6.7 Hz, 3H).

[0889] 19F NMR (376 MHz, DMSO-tfc) 5 (ppm): -118.4504. Synthesis of Compound 44: l-((R)-l-((S)-l-(2-ethyl-5-fluorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0890]

[0891] All reactions were carried out similarly to previously described reactions. Following Step 4 the resulting mixture of diastereomers was separated by silica gel chromatography (1:2 ethyl acetate / petroleum ether) to afford tert-butyl ((7?)-l-((S)-l-(2-ethyl-5-fluorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate as the second eluting isomer. Following the final step the resulting product was purified by preparative HPLC (XBridge Prep OBD C18 Column 30*150 mm, 5 pm; 20-40% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 44 as a white solid (21.6 mg).

[0892] LCMS (ESI): m / z [M+H]+calcd. for C18H22FN5O2: 359.18, found: 360.10.

[0893] 1H-NMR (300 MHz, DMSO-d6) 57.37 (s, 1H), 7.20 - 7.31 (m, 1H), 6.99 - 7.11 (m, 1H), 6.46 - 6.56 (m, 1H), 6.34 (d, J = 7.0 Hz, 1H), 5.92 - 6.05 (m, 1H), 5.79 (s, 2H), 3.97 - 4.12 (m, 1H), 3.32 - 3.34 (m, 1H), 2.85 - 2.98 (m 1H), 2.52 - 2.74 (m, 2H), 2.37 - 3.48 (m, 1H), 1.83 (d, J = 6.7 Hz, 3H), 1.01 - 1.12 (m, 3H).

[0894] 19F-NMR (282 MHz, DMSO-A) 5 -116.54.

[0895] Synthesis of Compound 45: l-((R)-l-((S)-l-(4-chlorophenyl)ethyl)-7-methyl-6-oxo- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0896]

[0897] All reactions were carried out similarly to previously described reactions. Following Step 7 the resulting mixture of diastereomers was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford terr-butyl ((ft)- 1 -((£)- l-(4-chlorophenyl) ethyl)-7-methyl-6- oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b] pyridin-5-yl) carbamate as the second eluting isomer. Following the final step the resulting product was purified by preparative HPLC (XBridge Prep C18 OBD Column, 19*250 mm, 5pm, 22-47% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 45 as a white solid (36.9 mg).

[0898] LCMS (ESI): m / z [M+H]+calcd. for CieHisClNsCfi: 347.1, found: 348.10.

[0899] 1H NMR (400 MHz, DMSO-A) 57.37 (d, J = 12.0 Hz, 3H), 7.03 (d, J = 8.0 Hz, 2H), 6.33 (d, J = 8.0 Hz, 1H), 5.76 - 5.86 (m, 3H), 4.02 - 4.13 (m, 1H), 3.34 (m, 3H), 2.87 - 2.96 (m, 1H), 2.37 - 2.49 (m, 1H), 1.84 (d, J = 8.0 Hz, 3H).

[0900] Synthesis of Compound 46: l-((R)-l-((S)-l-(2,6-dichlorophenyl)ethyl)-7-methyl-6-oxo- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0901]

[0902] Scheme 46

[0903]

[0904] All reactions were carried out similarly to previously described reactions. Following Step 7 the resulting mixture of diastereomers was separated by silica gel chromatography (0-45% ethyl acetate / petroleum ether) to afford tert-butyl ((7?)-l-((S)-l-(2,6-dichlorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate as the second eluting isomer. Following the final step the resulting product was purified by preparative HPLC (XSelect CSH C18 Column 250 mm x 19 mm x 5 pm, 20-44% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 46 as a white solid (10.9 mg).

[0905] LCMS (ESI): m / z [M+H]+calcd. for C16H17CI2N5O2: 381.08, found: 382.10.1H NMR (300 MHz, Methanol-^) 57.37 - 7.44 (m, 3H), 7.26 - 7.34 (m, 1H), 6.31 - 6.49 (m, 1H), 4.20 - 4.38 (m, 1H), 3.00 - 3.12 (m, 4H), 2.39 - 2.61 (m, 1H), 1.94 - 2.11 (m, 3H).

[0906] Synthesis of Compound 47: l-((R)-l-((S)-l-(2-chloro-5-fluorophenyl)ethyl)-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0907]

[0908] All reactions were carried out similarly to previously described reactions. Following the final step the resulting product was purified by preparative HPLC (YMC Triart C 18 Column, 30 mm x 150 mm x 5 um, 3% to 25% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 47 as a white solid (11.5 mg).

[0909] LCMS (ESI): m / z [M+H]+calcd. for C15H15CIFN5O2: 351.1, found: 352.10.

[0910] ‘H NMR (300 MHz, DMSO-A) 5 11.01 (s, 1H), 7.40 - 7.62 (m, 1H), 7.29 (s, 1H), 7.10- 7.20 (m, 1H), 6.80 - 7.00 (m, 1H), 6.18 - 6.40 (m, 1H), 5.82 - 6.00 (m, 1H), 5.68 - 5.80 (m, 2H), 4.18 (dt, J= 13.8, 7.2 Hz, 1H), 2.90 - 3.10 (m, 1H), 2.30 - 2.50 (m, 1H), 1.71 (d, J = 6.8 Hz, 3H).

[0911] 19F NMR (282 MHz, DMSO-d6) 5 -114.10. Synthesis of Compound 48: l-((R)-l-((S)-l-(2-cyano-5-fluorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0912]

[0913] All reactions were carried out similarly to previously described reactions. Following Step 5 the resulting mixture of diastereomers was separated by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford tert-butyl A-[(5R)-l-[(lS)-l-(2-cyano-5-fluorophenyl)ethyl]-7-methyl-6-oxo-4H,5H-pyrazolo[3,4-b]pyridin-5-yl]carbamate as the second eluting isomer. Following the final step the resulting product was purified by preparative HPLC (YMC Triart C18 ExRs Column 150 mm x 30 mm x 5 pm, 15-31% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 48 as a white solid (27.4 mg).

[0914] LCMS (ESI): m / z [M+H]+calcd. for C17H17FN6O2: 356.14, found: 357.10.

[0915] 1H NMR (300 MHz, DMSO-tfc) 57.93 (dd, J = 8.6, 5.6 Hz, 1H), 7.48 - 7.32 (m, 2H), 7.18 (dd, J= 10.0, 2.6 Hz, 1H), 6.34 (d, J = 6.7 Hz, 1H), 6.04 (q, J = 6.7 Hz, 1H), 5.78 (s, 2H), 4.11 (dt, J = 13.4, 6.6 Hz, 1H), 3.45 (s, 3H), 2.91 (dd, J = 14.6, 6.6 Hz, 1H), 2.40 (t, J = 14.1 Hz, 1H), 1.92 (d, J= 6.7 Hz, 3H).

[0916] 19F NMR (282 MHz, DMSO-A) 5 -102.281.

[0917] Synthesis of Compound 49: l-((R)-l-((S)-l-(5-chloro-3'-cyano-2-fluoro-[l,r-biphenyl]-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0918]

[0919] All reactions were carried out similarly to previously described reactions. Following Step 4 the resulting mixture of diastereomers was separated by silica gel chromatography (0-22% ethyl acetate / petroleum ether) to afford tert-butyl ((2?)-l-((S)-l-(5-chloro-3'-cyano-2-fluoro-[l,l'- biphenyl]-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)carbamate as the second eluting isomer. Following the final step the resulting product was purified by preparative HPLC (XBridge Prep C18 OBD Column, 19*250 mm, 5pm, 28-53% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 49 as a white solid (46.0 mg).

[0920] LCMS (ESI): m / z [M+H]+calcd. for C23H20CIFN6O2: 466.13, found: 467.20.

[0921] 1H NMR (400 MHz, DMSO-d6) 58.08 (s, 1H), 7.84 - 7.98 (m, 2H), 7.77 (d, J = 7.1 Hz, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.42 (s, 1H), 6.92 (d, J = 11.4 Hz, 1H), 6.37 (d, J = 6.9 Hz, 1H), 6.07 (q, J = 6.7 Hz, 1H), 5.80 (s, 2H), 4.10 (dt, J = 13.6, 6.8 Hz, 1H), 3.44 (s, 3H), 2.93 (dd, J = 14.6, 6.6 Hz, 1H), 2.45 (d, J= 14.1 Hz, 1H), 1.91 (d, J = 6.7 Hz, 3H).

[0922] Synthesis of Compound 50: l-((lf)-l-((S)-l-(4',5-dichloro-2-fluoro-[l,l'-biphenyl]-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0923]

[0924] Scheme 50

[0925]

[0926] All reactions were carried out similarly to previously described reactions. Following Step 4 the resulting mixture of diastereomers was separated by silica gel chromatography (20-60% ethyl acetate / petroleum ether) to afford tert-butyl A-[(5R)-l-[(lS)-l-{4',5-dichloro-2-fluoro-[l,r-biphenyl]-4-yl }ethyl]-7-methyl-6-oxo-4H,5H-pyrazolo[3,4-b]pyridin-5-yl]carbamate as the second eluting isomer. Following the final step the resulting product was purified by preparative HPLC (XBridge Prep C18 OBD Column 150 mm x 30 mm x 5 pm, 32-62% acetonitrile / water with 10 mM ammonium bicarbonate) to afford Compound 50 as a white solid (38.5 mg).

[0927] LCMS (ESI): m / z [M+H]+calcd. for C22H20CI2FN5O2: 475.10, found: 476.15.

[0928] 1H NMR (300 MHz, Methanol-^) 57.61 - 7.38 (m, 6H), 6.81 (d, J= 11.3 Hz, 1H), 6.23 - 6.09 (m, 1H), 4.35 - 4.20 (m, 1H), 3.51 (s, 3H), 3.15 - 2.99 (m, 1H), 2.66 - 2.50 (m, 1H), 2.00 (d, J = 6.8 Hz, 3H).

[0929] 19F NMR (282 MHz, Methanol-^) 5 -119.71. Synthesis of Compound 51: l-((lf)-l-((S)-l-(2',5-dichloro-2-fluoro-[l,l'-biphenyl]-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0930]

[0931] Step 1-7: Preparation of l-((lf)-l-((S)-l-(2',5-dichloro-2-fluoro-[l,l'-biphenyl]-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 51)

[0932] Compound 51 was prepared similarly to procedures reported above. After purification by preparative HPLC (YMC Triart C18 ExRs Column, 30*150 mm, 5 um column, 37-52% (v / v) acetonitrile and water with 10 mmoL / L ammonium bicarbonate), the title Compound 51 was afforded as white solid (28.8 mg, 21.8% yield).

[0933] LCMS (ESI): m / z [M+H]+calcd. for C22H20CI2FN5O2: 475.1, found: 476.05.

[0934] 1H NMR (400 MHz, DMSO-d6) 57.39 - 7.63 (m, 6H), 7.00 (d, J = 4.0 Hz, 1H), 6.36 (d, J = 8.0 Hz, 1H), 6.02 - 6.11 (m, 1H), 5.79 (s, 2H), 4.05 - 4.16 (m, 1H), 3.46 (s, 3H), 2.88 - 2.98 (m, 1H), 2.40 - 2.49 (m, 1H), 1.93 (d, J= 8.0 Hz, 3H).

[0935] 19F NMR (376 MHz, DMSO) 5 -114.70.

[0936] Synthesis of Compound 52: l-((R)-l-((S)-l-(2-chloro-5-methoxyphenyl)ethyl)-7-ethyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0937]

[0938] Scheme 52

[0939]

[0940] Step 1-10: Preparation of l-(( f)-l-((S)-l-(2-chloro-5-methoxyphenyl)ethyl)-7-ethyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 52) Compound 52 was prepared similarly to procedures reported above. After purification by preparative HPLC (XBridge Prep OBD C18 Column, 19 x 250 mm x 5 pm column, 24-47% (v / v) acetonitrile and water with 0.05% ammonium bicarbonate), the title Compound 52 was afforded as white solid (76.2 mg, 71.4% yield).

[0941] LCMS (ESI): m / z [M+H]+calcd. for C18H22CIN5O3: 391.14, found: 392.20.

[0942] 1H NMR (300 MHz, DMSO-A) 57.30 - 7.50 (m, 2H), 6.80 - 7.00 (m, 1H), 6.30 - 6.50 (m, 1H), 6.00 - 6.10 (m, 1H), 5.60 - 5.80 (m, 3H), 3.90 - 4.20 (m, 2H), 3.54 - 3.65 (m, 3H), 2.90 - 3.00 (m, 1H), 2.38 - 2.50 (m, 1H), 2.08 (s, 1H), 1.70 - 1.90 (m, 3H), 1.10 (t, J = 7.1 Hz, 3H). Synthesis of Compound 53: (R)-l-(7-methyl-l-(naphthalen-2-ylmethyl)-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0943]

[0944] Step 1-6: Preparation of (R)-l-(7-methyl-l-(naphthalen-2-ylmethyl)-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 53)

[0945] Compound 53 was prepared similarly to procedures reported above. After purification by preparative HPLC (YMC Triart C18 ExRs Column, 30*150 mm, 5 um column, 13-43% (v / v) methanol and water containing 0.05% ammonium bicarbonate), a mixture of enantiomers was obtained (30.0 mg, 10.5% yield), that was further purified by chiral HPLC (CHIRALPAK IE, 2*25 cm, 5 pm column, 50% (v / v) ethanol: dichloromethane (1:1) and hexanes (containing 0.5% 2M ammonia in methanol) to afford, as first eluting compound, the title Compound 53 (10.6 mg, 35.3% yield).

[0946] LCMS (ESI): m / z [M+H]+calcd. for C19H19N5O2: 349.15, found: 350.15.1H NMR (400 MHz, Methanol-d4) 57.83 - 7.90 (m, 2H), 7.79 - 7.83 (m, 1H), 7.44 - 7.54 (m, 4H), 7.21 - 7.28 (m, 1H), 5.71 (s, 2H), 4.35 - 4.44 (m, 1H), 3.32 - 3.33 (m, 3H), 3.08 - 3.18 (m, 1H), 2.63 (t, J = 14.2 Hz, 1H).

[0947] Synthesis of Compound 54: l-((R)-l-((S)-l-(2-chloro-5-fluoro-4-methoxyphenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0948]

[0949] Scheme 54

[0950]

[0951] Step 1-11: Preparation of l-(( f)-l-((S)-l-(2-chloro-5-fluoro-4-methoxyphenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 54) Compound 54 was prepared similarly to procedures reported above. After purification by preparative HPLC (YMC Triart C18 ExRs Column, 30*150 mm, 5 um column, 27-39% (v / v) acetonitrile and water containing 10 mmoL / L ammonium bicarbonate), the title Compound 54 was afforded as white solid (63.7 mg, 37.8% yield).

[0952] LCMS (ESI): m / z [M+H]+calcd. for C17H19CIFN5O3: 395.12, found: 396.10.1H NMR (400 MHz, DMSO-d6) 57.37 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 12.0 Hz, 1H), 6.34 (d, J = 8.0 Hz, 1H), 5.90 - 6.00 (m, 1H), 5.79 (s, 2H), 3.98 - 4.09 (m, 1H), 3.84 (s, 3H), 3.32 - 3.41 (m, 2H), 2.84 - 2.94 (m, 1H), 2.38 - 2.49 (m, 2H), 1.84 (d, J = 8.0 Hz, 3H).

[0953] 19F NMR (376 MHz, DMSO) 5 -135.40.

[0954] Synthesis of Compound 55: l-((R)-l-((S)-l-(4-(terFbutyl)-2-chlorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0955]

[0956] Scheme 55

[0957]

[0958] IZn.

[0959] I®

[0960]

[0961]

[0962] Step 1-12: Preparation of l-((lf)-l-((S)-l-(4-(tert-butyl)-2-chlorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 55) Compound 55 was prepared similarly to procedures reported above. After purification by preparative HPLC (XBridge Shield RP18 OBD 250 mm x 19 mm x 10 pm column, 55-65% (v / v) methanol and water containing 0.05% ammonium bicarbonate), the title Compound 55 was afforded as white solid (51.6 mg, 29.1% yield).

[0963] LCMS (ESI): m / z [M+H]+calcd. for C20H26CIN5O2: 403.18, found: 404.15.

[0964] 1H NMR (300 MHz, DMSO-A) 57.30 - 7.43 (m, 3H), 6.83 (d, J = 8.2 Hz, 1H), 6.35 (d, J = 6.9Hz, 1H), 5.95 - 6.07(m, 1H), 5.79 (s, 2H), 3.98 - 4.15 (m, 1H), 3.38 (s, 3H), 2.82 - 3.00 (m, 1H), 2.40 - 2.50 (m, 1H), 1.85 (d, J = 6.7 Hz, 3H), 1.24 (s, 9H).

[0965] Synthesis of Compound 56: l-((R)-l-((S)-l-(2-chloro-4,5-difluorophenyl)ethyl)-7-methyl- 6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0966]

[0967] Scheme 56

[0968] 24

[0969]

[0970] Step 1-9: Preparation of l-((lf)-l-((S)-l-(2-chloro-4,5-difluorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 56) Compound 56 was prepared similarly to procedures reported above. After purification by preparative HPLC (XBridge Prep OBD Cis 30*150 mm, 5pm column, 19-35% (v / v) acetonitrile and water containing lOmmol / L ammonium bicarbonate), the title Compound 56 was afforded as white solid (22.5 mg, 18.1% yield).

[0971] LCMS (ESI): m / z [M+H]+calcd. for C16H16CIF2N5O2: 383.10, found: 384.10.

[0972] 1H NMR (300 MHz, DMSO-A) 57.67 - 7.82 (m, 1H), 7.38 (s, 1H), 6.97 - 7.12 (m, 1H), 6.35 (d, J = 6.9 Hz, 1H), 5.93 - 6.06 (m, 1H), 5.79 (s, 2H), 3.99 - 4.17 (m, 1H), 3.40 (s, 3H), 2.82 - 2.98 (m, 1H), 2.31 - 2.47 (m, 1H), 1.86 (d, J = 6.7 Hz, 3H).

[0973] 19F NMR (282 MHz, DMSO) 5 -136.30, 138.06.

[0974] Synthesis of Compound 57: (lf)-l-(l-((5-chloro-2-fluoro-[l,l'-biphenyl]-4-yl)methyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0975]

[0976] Scheme 5725

[0977]

[0978] Step 1-7: Preparation of (lf)-l-(l-((5-chloro-2-fluoro-[l,l'-biphenyl]-4-yl)methyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 57) Compound 57 was prepared similarly to procedures reported above. After purification by column chromatography on silica gel (methanol / dichloromethane, 0-15%), the title Compound 57 was afforded as white solid (395.9 mg, 48.1% yield).

[0979] LCMS (ESI): m / z [M+H]+calcd. for C21H19CIFN5O2: 427.12, found: 428.10.

[0980] 1H NMR (400 MHz, DMSO) 57.69 (d, J = 7.0 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.53 - 7.38 (m, 4H), 6.69 (d, J = 11.0 Hz, 1H), 6.38 (d, J = 6.9 Hz, 1H), 5.80 (s, 2H), 5.56 (s, 2H), 4.34 - 4.21 (m, 1H), 3.29 (s, 3H), 3.03 - 2.92 (m, 1H), 2.55 - 2.47 (m, 1H).

[0981] 19F NMR (376 MHz, DMSO) 5 -119.21. Synthesis of Compound 58: l-((R)-l-((S)-l-(5-cyclopropyl-2-fluoro-[l,r-biphenyl]-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0982]

[0983] Step 1-3: Preparation of l-((lf)-l-((S)-l-(5-cyclopropyl-2-fluoro-[l,l'-biphenyl]-4-yl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 58)

[0984] Compound 58 was prepared similarly to procedures reported above. After purification by preparative HPLC (XSelect CSH C18 Column 250 mm x 19 mm x 5 pm column, 40-62% (v / v) acetonitrile and water with lOmmol / L ammonium bicarbonate), the title Compound 58 was afforded as white solid (15.2 mg, 17.2% yield).

[0985] LCMS (ESI): m / z [M+H]+calcd. for C25H26FN5O2: 447.21, found: 448.25.

[0986] 1H NMR (300 MHz, MeOD) 57.30 - 7.53 (m, 6H), 7.03 - 7.12 (m, 1H), 6.62 - 6.72 (m, 1H), 6.27 - 6.40 (m, 1H), 4.22 - 4.35 (m, 1H), 3.53 (s, 3H), 3.01 - 3.14 (m, 1H), 2.60 (t, J = 14.1 Hz, 1H), 2.00 - 2.06 (m, 3H), 1.85 - 1.99 (m, 1H), 0.89 - 1.13 (m, 2H), 0.66 - 0.85 (m, 2H).

[0987] 19F NMR (282 MHz, MeOD) 5 -122.76. Synthesis of Compound 59: l-((lf)-l-((S)-l-(2-chloro-5-fluoro-4- (trifluoromethyl)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0988]

[0989] Scheme 5927

[0990]

[0991] Step 1-10: Preparation of l-((R)-l-((S)-l-(2-chloro-5-fluoro-4- (trifluoromethyl)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 59)

[0992] Compound 59 was prepared similarly to procedures reported above. After purification by preparative HPLC (XBridge Prep OBD C18 Column, 30*150 mm, 5pm THF column, 26-42% (v / v) acetonitrile and water containing 10 mmoL / L ammonium bicarbonate), the title Compound 59 was afforded as white solid (48.1 mg, 28.8% yield).

[0993] LCMS (ESI): m / z [M+H]+calcd. for C17H16CIF4N5O2: 433.09, found: 434.10.1H NMR (400 MHz, DMSO) d 7.94 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.13 (d, J = 12.0 Hz, 1H), 6.35 (d, J = 4.0 Hz, 1H), 6.02 - 6.12 (m, 1H), 5.79 (s, 2H), 4.05 - 4.16 (m, 1H), 3.42 (s, 3H), 2.86 - 2.96 (m, 1H), 2.38 - 2.50 (m, 1H), 1.90 (d, J = 8.0 Hz, 3H).

[0994] 19F NMR (376 MHz, DMSO) 5 -60.19, -116.21.

[0995] Synthesis of Compound 60: l-((R)-l-((S)-l-(2-chloro-5-fluoro-4-(pyridin-4-yl)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[0996]

[0997] Step 1-8: Preparation of l-((R)-l-((S)-l-(2-chloro-5-fluoro-4-(pyridin-4-yl)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 60) Compound 60 was prepared similarly to procedures reported above. After purification by preparative HPLC (YMC Triart C18 150 mm x 30 mm, 5pm column, 33-58% (v / v) water (containing 0.1% formic acid) and acetonitrile), the tide Compound 60 was afforded as first eluting diastereomer as white solid (3.5 mg, 2.8% yield).

[0998] LCMS (ESI): m / z [M+H]+calcd. for C21H20CIFN6O2:442.13, found: 443.15.

[0999] ’H NMR (300 MHz, DMSO-rfe) 5 8.77 - 8.33 (m, 2H), 7.78 (d, J = 7.1 Hz, 1H), 7.66 - 7.57 (m, 2H), 7.42 (s, 1H), 6.95 (d, J = 11.6 Hz, 1H), 6.38 (d, J = 6.9 Hz, 1H), 6.11 - 6.01 (m, 1H), 5.80 (s, 2H), 4.17 -4.02 (m, 1H), 3.44 (s, 3H), 2.99 - 2.86 (m, 1H), 2.49 - 2.38 (m, 1H), 1.92 (d, J = 6.7 Hz, 3H).

[1000] 19F NMR (282 MHz, DMSO-&) 5 -117.943

[1001] Synthesis of Compound 61: l-((R)-l-((S)-l-(2-chloro-5-fluoro-4-(pyridin-3-yl)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[1002]

[1003] Scheme 6129

[1004]

[1005] Step 1-6: Preparation of l-((lf)-l-((S)-l-(2-chloro-5-fluoro-4-(pyridin-3-yl)phenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 61) Compound 61 was prepared similarly to procedures reported above. After purification by preparative HPLC (XBridge Prep C18 OBD Column 250 mm x 19 mm x 5 pm column, 21-43% (v / v) acetonitrile and water containing lOmmol / L ammonium bicarbonate), the title Compound 61 was afforded as white solid (38.7 mg, 34.9% yield).

[1006] LCMS (ESI): m / z [M+H]+calcd. for C21H20CIFN6O2: 442.13, found: 443.15.

[1007] 1H NMR (300 MHz, Methanol-^) 58.82 - 8.49 (m, 2H), 8.12 - 7.96 (m, 1H), 7.73 - 7.37 (m, 3H), 6.87 (d, J = 11.3 Hz, 1H), 6.29 - 6.05 (m, 1H), 4.38 - 4.17 (m, 1H), 3.52 (s, 3H), 3.15 -2.99 (m, 1H), 2.69 - 2.48 (m, 1H), 2.01 (d, J = 6.8 Hz, 3H).

[1008] 19F NMR (282 MHz, MeOD) 5 -119.93. Synthesis of Compound 62: (lf)-l-(l-((5-chloro-2-fluoro-[l,l'-biphenyl]-4-yl)methyl)-7-ethyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[1009]

[1010] Step 1-3: Preparation of (lf)-l-(l-((5-chloro-2-fluoro-[l,l'-biphenyl]-4-yl)methyl)-7-ethyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 62) Compound 62 was prepared similarly to procedures reported above. After purification by preparative HPLC (XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm, 25-55% (v / v) acetonitrile and water containing 10 mmoL / L ammonium bicarbonate), the title Compound 62 was afforded as white solid (65.5 mg, 32.8% yield).

[1011] LCMS (ESI): m / z [M+H]+calcd. for C22H21CIFN5O2: 441.14, found: 442.10.

[1012] 1H NMR (400 MHz, DMSO-d6) 57.71 (d, J = 8.0 Hz, 1H), 7.55 - 7.61 (m, 2H), 7.40 - 7.53 (m, 4H), 6.66 (d, J= 12.0 Hz, 1H), 6.40 (d, J = 4.0 Hz, 1H), 5.81 (s, 2H), 5.42 - 5.55 (m, 2H), 4.20 - 4.31 (m, 1H), 3.75 - 3.89 (m, 1H), 3.60 - 3.73 (m, 1H), 2.92 - 3.02 (m, 1H), 2.42 - 2.50 (m, 1H), 1.03 - 1.11 (m, 3H).

[1013] 19F NMR (376 MHz, DMSO) 5 -119.20.

[1014] Synthesis of Compound 63: (R)-l-(l-([l, T-biphenyl]-4-ylmethyl)-7-ethyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[1015]

[1016] Step 1-3: Preparation of (lf)-l-(l-([l,l'-biphenyl]-4-ylmethyl)-7-ethyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 63)

[1017] Compound 63 was prepared similarly to procedures reported above. After purification by preparative HPLC (XBridge BEH Shield RP18 Column 150 mm x 30 mm x 5 pm column, 19-49% (v / v) acetonitrile and water containing 10 mmol / L ammonium bicarbonate), the title Compound 63 was afforded as white solid (10.6 mg, 18.8% yield). LCMS (ESI): m / z [M+H]+calcd. for C22H23N5O2: 389.19, found 390.20.

[1018] ’H NMR (300 MHz, DMSO-A) 57.71 - 7.61 (m, 4H), 7.51 - 7.35 (m, 4H), 7.16 (d, J = 8.1 Hz, 2H), 6.37 (d, J = 7.0 Hz, 1H), 5.80 (s, 2H), 5.49 (s, 2H), 4.22 (dt, J = 13.5, 6.7 Hz, 1H), 3.89 (dd, J = 14.5, 7.2 Hz, 1H), 3.72 - 3.50 (m, 1H), 2.98 (dd, J = 14.5, 6.6 Hz, 1H), 2.43 (d, J = 14.2 Hz, 1H), 0.98 (t, J = 7.0 Hz, 3H).

[1019] Synthesis of Compound 64: l-((R)-l-((S)-l-(2-chlorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[1020]

[1021] Scheme 64

[1022]

[1023] "C''NK HCI / dioxane MsOH, THF / H2O

[1024] Step 8 Step 9

[1025]

[1026]

[1027] Step 1-9: Preparation of l-((R)-l-((S)-l-(2-chlorophenyl)ethyl)-7-methyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 64)

[1028] Compound 64 was prepared similarly to procedures reported above. After purification by preparative HPLC (XBridge Prep C18 OBD 250 mm x 19 mm, 5pm column, 18-43% (v / v) water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile), the title Compound 64 was afforded as white solid (23.1 mg, 20.2% yield).

[1029] LCMS (ESI): m / z [M+H]+calcd. for C16H18ClN5O2: 347.11, found: 348.15.

[1030] 1H NMR (300 MHz, DMSO-dfe) 57.51 - 7.43 (m, 1H), 7.40 (s, 1H), 7.36 - 7.24 (m, 2H), 6.80 - 6.70 (m, 1H), 6.33 (d, J = 6.9 Hz, 1H), 6.12 - 5.99 (m, 1H), 5.79 (s, 2H), 4.10 - 3.95 (m, 1H), 3.38 - 3.34 (m, 3H), 2.98 - 2.85 (m, 1H), 2.48 - 2.37 (m, 1H), 1.86 (d, J = 6.7 Hz, 3H). Synthesis of Compound 65: l-((R)-l-((R)-l-(2-chloro-4-cyclopropylphenyl)-2,2,2-trifluoroethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[1031]

[1032] Scheme 6532

[1033]

[1034] Step 1-10: Preparation of l-((R)-l-((R)-l-(2-chloro-4-cyclopropylphenyl)-2,2,2-trifluoroethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 65)

[1035] Compound 65 was prepared similarly to procedures reported above. After purification by preparative HPLC (YMC Triart C18 ExRs Column, 30*150 mm, 5 um column, 35-57% (v / v) acetonitrile and water containing 10 mmoL / L ammonium bicarbonate), the title Compound 65 was afforded as white solid (62.3 mg, 19.3% yield).

[1036] LCMS(ESI): m / z [M+H]+calcd. for C19H19CIF3N5O2: 441.12, found: 442.15.

[1037] ’H NMR (300 MHz, DMSO) 57.52 (d, J = 9.4 Hz, 2H), 7.27 (d, J = 1.9 Hz, 1H), 7.13 (dd, J = 8.3, 1.9 Hz, 1H), 6.72 (q, J = 7.1 Hz, 1H), 6.34 (d, J = 7.1 Hz, 1H), 5.79 (s, 2H), 4.06 (dt, J = 13.6, 6.8 Hz, 1H), 3.48 (s, 3H), 2.88 (dd, 7= 14.6, 6.6 Hz, 1H), 2.46 (d, J = 14.1 Hz, 1H), 1.93 (td, J = 8.4, 4.3 Hz, 1H), 0.92 - 1.05 (m, 2H), 0.69 - 0.80 (m, 2H).19F NMR (282 MHz, DMSO) 5(ppm): -67.304.

[1038] Synthesis of Compound 66: (R)-l-(l-(2-chloro-5-fluoro-4-(6-methoxypyridin-3-yl)benzyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[1039]

[1040] Step 1-7: Preparation of (R)-l-(l-(2-chloro-5-fluoro-4-(6-methoxypyridin-3-yl)benzyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 66) Compound 66 was prepared similarly to procedures reported above. After purification by preparative HPLC (XBridge BEH Shield RP18 Column, 19*250 mm, 5 pm, 22-52% (v / v) acetonitrile and water containing lOmmol / E ammonium bicarbonate), the title Compound 66 was afforded as white solid (29.6 mg, 13.4% yield).

[1041] LCMS (ESI): m / z [M+H]+calcd. for C21H20CIFN6O3: 458.13, found 459.20.

[1042] 1H NMR (300 MHz, DMSO-rfe) 58.40 (s, 1H), 7.89 - 8.00 (m, 1H), 7.65 - 7.80 (m, 1H), 7.42 (s, 1H), 6.87 - 7.00 (m, 1H), 6.60 - 6.78 (m, 1H), 6.30 - 6.45 (m, 1H), 5.81 (s, 2H), 5.56 (s, 2H), 4.20 - 4.35 (m, 1H), 3.85 - 3.95 (m, 3H), 3.27 - 3.30 (m, 3H), 2.90 - 3.07 (m, 1H), 2.50 - 3.57 (m, 1H).

[1043] 19F NMR (282 MHz, DMSO-O 5 -119.08.

[1044] Synthesis of Compound 67: l-((R)-l-((S)-l-(5-((lH-pyrazol-4-yl)methoxy)-2-chlorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[1045]

[1046] Scheme 67

[1047]

[1048] Step 1: Preparation of l-((R)-l-((S)-l-(2-chloro-5-hydroxyphenyl)ethyl)-7-methyl-6-oxo- 4.5.6.7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea

[1049] To a solution of Compound 8 (200 mg, 0.441 mmol, 1 equiv.) in dichloromethane (5 mL) was added boron trichloride (1.0 M in methylene chloride, 1.1 mL, 1.103 mmol, 2.5 equiv.) under nitrogen. The reaction was stirred at 25 °C for Ih. The mixture neutralized to pH = 7 with sodium bicarbonate solution and then treated with water (20 mL) and extracted with dichloromethane / methanol (10:1, 3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product (150 mg) was used in the next step directly without further purification.

[1050] LCMS (ESI): m / z [M+H]+calcd. for CieHisClNsCh: 363.11, found: 364.0.

[1051] Step 2: Preparation of tert-butyl 4-((4-chloro-3-((S)-l-((R)-7-methyl-6-oxo-5-ureido- 4.5.6.7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-l-yl)ethyl)phenoxy)methyl)-lH-pyrazole-1 -carboxylate

[1052] To a solution of l-((R)-l-((S)-l-(2-chloro-5-hydroxyphenyl)ethyl)-7-methyl-6-oxo-4, 5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (140 mg, 0.386 mmol, 1 equiv.) in dimethylformamide (4 mL) was added tert-butyl 4-(bromomethyl)pyrazole-l -carboxylate (161.4 mg, 0.618 mmol, 1.5 equiv.) and potassium carbonate (170.95 mg, 1.236 mmol, 3 equiv.). The reaction was stirred at 25 °C for Ih and then treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane / methanol, 0-20%) afford the title compound as a yellow oil (60 mg, 28.6% yield).

[1053] LCMS (ESI): m / z [M+H]+calcd. for C25H30CIN7O5: 543.20, found: 544.1.

[1054] Step 3: Preparation of l-((R)-l-((S)-l-(5-((lH-pyrazol-4-yl)methoxy)-2-chlorophenyl)ethyl)-7-methyl-6-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-b]pyridin-5-yl)urea (Compound 67)

[1055] To tert-butyl 4-((4-chloro-3-((S)-l-((R)-7-methyl-6-oxo-5-ureido-4,5,6,7-tetrahydro-lH-pyrazolo [3,4-b] pyridin- 1 -yl)ethyl)phenoxy)methyl)- 1 H-pyrazole- 1 -carboxylate (50 mg, 0.092 mmol, 1 equiv.) was added dichloromethane (8 mL) and trifluoroacetic acid (2 mL). The reaction was stirred at 25 °C for Ih. The resulting mixture was concentrated under reduced pressure. The mixture was neutralized to pH = 7 with sodium bicarbonate and then treated with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XBridge Prep OBD Cis 30*150 mm, 5pm column, 45-70% (v / v) methanol and water containing 10 mmoL / L ammonium bicarbonate) to afford the title Compound 67 (9.9 mg, 24.2% yield) as a white solid.

[1056] LCMS (ESI): m / z [M+H]+calcd. for C20H22CIN7O3: 443.15, found: 444.10.

[1057] ’H NMR (300 MHz, CD3CN) 511.12 - 12.74 (m, IH), 7.33 - 7.47 (m, 3H), 7.22 - 7.32 (m, IH), 6.74 - 6.91 (m, IH), 6.21 - 6.31 (m, IH), 5.97 - 6.12 (m, IH), 5.79 - 5.94 (m, IH), 4.82 -5.11 (m, 4H), 3.91 - 4.09 (m, IH), 3.32 - 3.44 (m, 3H), 3.03 - 3.19 (m, IH), 2.40 - 2.56 (m, IH), 1.83 - 1.92 (m, 3H).

[1058] hTSHR TR-FRET cAMP Assay

[1059] Assays were performed using Expi293F Inducible cells (Invitrogen) stably expressing hTSHR via a pcZeo TetO DNA plasmid. Cell lines were maintained in suspension in Expi293 Expression Medium (ThermoFisher Scientific) supplemented with 10 pg / mL Blasticidin and 10 pg / mL Zeocin and incubated at 37°C, 8% CO2, with shaking. hTSHR cells were incubated overnight at 32°C, 5% CO2, with shaking, but without Doxycycline. Assay-ready aliquots were prepared by harvesting each cell type separately 24-hours post-induction. Cells were pelleted at 4°C, resuspended in Expi293 Expression media + 10% DMSO, aliquoted, and kept frozen at -80°C until ready for use.

[1060] For the assay, concentration-response curves of test and reference compounds were added to 384-well plates using an Echo 650 liquid handler (Beckman Coulter) and backfilled with DMSO to a final concentration of 0.5%. cAMP was measured using the cisbio cAMP Gs dynamic HTRF kit (PerkinElmer) according to manufacturer instructions. Aliquots of frozen hTSHR cells were quickly thawed and washed with phosphate-buffered saline (Sigma- Aldrich) to remove media and DMSO. The cells were resuspended in kit-supplied Stimulation Buffer at 0.8 x 106cells / mL. 7.5 pF of the hTSHR cell dilution were added to each well of the assay plate and incubated with the compounds for 15 minutes in a 37°C, 0% CO2 incubator. 2.5 pF of Vehicle control or an ECso concentration of recombinant human anti-TSHR antibody (M22, Creative Biolabs) was added to stimulate cAMP production. Cells were incubated for 30 minutes at 37°C, 0% CO2. Following this incubation, the cells were lysed and accumulated cAMP was detected through the addition of kit-supplied lysis buffer containing d2 -reagent and Eu-cryptate antibody. The HTRF signal was quantified using a BMG Clariostar plate reader optimized for HTRF assays. The HTRF ratio was determined by dividing the signal output at 655 nm by that at 620 nm. Data were normalized to the signal produced by the ECso concentration of either M22 or FSH (0% inhibition) and vehicle (no agonist, 100% inhibition).

[1061] Compound 1 had an activity bin of ** (*** = pICso >7; ** = pICso 6-7; and * = pICso <6). Further results are shown in Table 1. The results demonstrate the diverse compounds have surprising activity ranges.

[1062] Table 1. Compound characterization and activity range yielded from the hTSHR TR- FRET cAMP assay.

[1063]

[1064]

[1065]

[1066]

[1067]

[1068]

[1069]

[1070]

[1071]

[1072]

[1073] INCORPORATION BY REFERENCE

[1074] All of the U. S. patents and U. S. and PCT patent application publications cited herein are hereby incorporated by reference.

[1075] EQUIVALENTS

[1076] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. CLAIMS2.We claim:

1. A compound according to Formula (I):

5.

6. or a pharmaceutically acceptable salt thereof;7.wherein:8.A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl;9.R1is hydrogen, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C3-Cs)cycloalkyl, 6- to 10-membered aryl(Ci-C3)alkyl, or (C3-Cs)cycloalkyl(Ci-C3)alkyl; wherein (C3-Cs)cycloalkyl and (C3-Cs)cycloalkyl(Ci-C3)alkyl are optionally substituted with one or more instances of halo;10.R2is independently for each occurrence cyano, halo, hydroxy, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, (Ci-C6)haloalkoxy, NR5aR5b, C(O)NR5aR5b, OR6a, SR6a, S(O)(NR5a)R5b, S(O)2NR5aR5b, S(O)2R6a, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl(Ci-C3)alkyl, 5- to 10-membered heteroaryl(Ci-C3)alkyl, (C3-Cs)cycloalkyl(Ci-C3)alkyl, 4- to 7-membered heterocycloalkyl(Ci-C3)alkyl, 6- to 10-membered aryl(Ci-C3)alkoxy, 5- to 10-membered heteroaryl(Ci-C3)alkoxy, (C3-Cs)cycloalkyl(Ci-C3)alkoxy, or 4- to 7-membered heterocycloalkyl(Ci-C3)alkoxy; wherein each (Ci-Ce)alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (C3-Cs)cycloalkyl, 4- to 7-membered heterocycloalkyl, 6-to 10-membered aryl(Ci-C3)alkyl, 5- to 10-membered heteroaryl(Ci-C3)alkyl, (C3-Cs)cycloalkyl(Ci-C3)alkyl, 4- to 7-membered heterocycloalkyl(Ci-C3)alkyl, 6- to 10-membered aryl(Ci-C3)alkoxy, 5- to 10-membered heteroaryl(Ci-C3)alkoxy, (C3-Cs)cycloalkyl(Ci-C3)alkoxy, or 4- to 7-membered heterocycloalkyl(Ci-C3)alkoxy is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, C(O)NR5aR5b, NR5aR5b, OR6a, SR6a, S(O)2R6a, S(O)(NR5a)R5b, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)aminoalkyl, (C3-Cs)cycloalkyl, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkoxy, and (Ci-C6)haloalkoxy(Ci-C6)alkyl; R3is hydrogen, halo, NH2, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (Ci-C3)alkoxy, (Ci-C3)alkoxyalkyl, or (Ci-C3)haloalkoxyalkyl;11.R4is hydrogen, halo, (Ci-C3)alkyl, (Ci-C3)haloalkyl, (C3-Cs)cycloalkyl, or (C3-Cs)halocycloalkyl;12.R5aand R5bare independently for each occurrence selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (C3-Cs)cycloalkyl, 6- to 10-membered aryl, and 4- to 7-membered heterocyclyl; or R5aand R5btaken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl;13.R6ais a 6- to 10-membered aryl, 5- to 10-membered heteroaryl, (C3-Cs)cycloalkyl, or 4- to 7- membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from cyano, halo, -NH2, -OH, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, and (Ci-Ce)alkoxyalkyl;14.Raand Rbare each independently selected from hydrogen, halo, (Ci-C3)alkyl, and (Ci-C3)haloalkyl;15.n is 0, 1, 2, 3, 4, or 5; and16.the absolute stereochemistry at the alpha-ureido lactam chiral center is as shown.

2. The compound of claim 1, wherein A is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indazolyl, pyridonyl, naphthalenyl, benzoxazolyl, or benzoisothiazolyl.

3. The compound of claim 1 or 2, wherein A is phenyl.

4. The compound of any one of claims 1-3, wherein Raand Rbare each independently selected from hydrogen, fluoro, (Ci-C3)alkyl, and (Ci-C3)fluoroalkyl.

5. The compound of any one of claims 1-4, wherein Raand Rbare each hydrogen.

6. The compound of any one of claims 1-4, wherein Rais methyl and Rbis hydrogen.

7. The compound of any one of claims 1-6, wherein R1is (Ci-Ce)alkyl, (Ci- C6)fluoroalkyl, (C3-Cs)cycloalkyl, (C3-Cs)cycloalkyl(Ci-C3)alkyl, or 6- to 10-membered aryl(Ci-C3)alkyl.

8. The compound of any one of claims 1-7, wherein R1is methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl, or benzyl.

9. The compound of any one of claims 1-8, wherein R1is methyl.

10. The compound of any one of claims 1-9, wherein R3is hydrogen, (Ci-C3)alkyl, (Ci- C3)haloalkyl, or NH2.

11. The compound of any one of claims 1-10, wherein R3is hydrogen.

12. The compound of any one of claims 1-10, wherein R3is methyl.

13. The compound of any one of claims 1-12, wherein R4is hydrogen.

14. The compound of any one of claims 1-12, wherein R4is (Ci-C3)alkyl or (Ci-C3)fluoroalkyl.

15. The compound of claim 14, wherein R4is methyl or trifluoromethyl.

16. The compound of any one of claims 1-15, having the structure represented by Formula (I-A):

34.

17. The compound of any one of claims 1-16, wherein R2, independently for each occurrence, is (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, (C3-Cs)cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 7- membered heterocycloalkyl, 6- to 10-membered aryl(Ci-C3)alkyl, or 5- to 10-membered heteroaryl(Ci-C3)alkoxy.

18. The compound of any one of claims 1-16, wherein R2, independently for each occurrence, is halo, OR6a, -C(O)NR5aR5b, or NR5aR5b.

19. The compound of any one of claims 1-16, wherein R2, independently for each occurrence, is fluoro, chloro, cyano, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, phenyl, cyclopropyloxy, phenoxy, benzyloxy, dimethylamido, pyrrolidinyl, piperidinyl, pyridinyl, 1-H-indazolyl, or pyrazolylmethoxy.

20. The compound of any one of claims 1-16 and 18, wherein R5aand R5bare (Ci-C6)alkyl.

21. The compound of claim 20, wherein R5aand R5bare methyl.

22. The compound of any one of claims 1-16 and 18, wherein R6ais (C3-Cs)cycloalkyl or 6- to 10-membered aryl.

23. The compound of claim 22, wherein R6ais cyclopropyl or phenyl.

24. The compound of any one of claims 1-16, wherein n is 0.

25. The compound of any one of claims 1-23, wherein n is 1.

26. The compound of any one of claims 1-23, wherein n is 2.

27. The compound of any one of claims 1-23, wherein n is 3.46.(R2)n- ^A 28. The compound of any one of claims 1-23 and 25-27, wherein is48.

49. wherein p is an integer from 0-2; and50.the dashed bond represents the covalent bond to the carbon atom substituted with R4.51.(R2)n- A^A29. The compound of claim 1, wherein is selected from the group consisting of:

53.

56.

57. substituted with R4.

30. The compound of claim 1 or 29, wherein60.

61. is selected from the group consisting of:

63.

31. A compound selected from the following table:

67.

87.

105.

122.

136.

157.

176.

193.

212.

229.

249. 251.; or a pharmaceutically acceptable salt thereof.

32. A method of inhibiting a thyroid stimulating hormone receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-31 or a pharmaceutically acceptable salt thereof.

33. A method of treating hyperthyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-31 or a pharmaceutically acceptable salt thereof.

34. The method of claim 32 or 33, wherein the subject has Graves' disease.

35. The method of claim 34, wherein the subject has Graves' ophthalmopathy.

36. The method of claim 34 or 35, wherein the subject has Graves' dermopathy.

37. The method of any one of claims 32-36, wherein the subject has thyroid cancer.

38. A pharmaceutical composition, comprising a compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

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