Synthesis of TYK2 inhibitors and their intermediates

Abstract

Described herein are methods for the synthesis of tyrosine protein kinase 2 (TYK2) inhibitors, intermediate compounds in the synthesis, and methods for making the intermediates. Also provided are pharma- ceutically acceptable compositions comprising the compounds prepared by the synthesis methods, and methods for using the compositions to treat disorders.

Description

[Technical field]

[0001] Claiming priority This application claims priority to U.S. Provisional Application No. 63 / 269,946, filed March 25, 2022, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present disclosure relates to methods for synthesizing tyrosine protein kinase 2 (TYK2) inhibitors, intermediate compounds in the synthesis, and methods for making the intermediates. Also provided are pharma- ceutically acceptable compositions comprising compounds prepared by the synthesis methods, and methods of using the compositions to treat disorders. [Background technology]

[0003] Protein kinases constitute a large family of structurally related enzymes responsible for the control of various signaling processes within cells. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Nearly all kinases contain a similar catalytic domain of 250-300 amino acids. These kinases can be classified into families according to the substrates they phosphorylate (e.g., protein tyrosines, protein serine / threonines, lipids, etc.).

[0004] Generally, protein kinases mediate intracellular signaling by effecting phosphoryl transfer from nucleoside triphosphates to protein acceptors involved in signaling pathways. These phosphorylation events act as molecular on / off switches that can modulate or regulate the biological function of target proteins. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, UV radiation, bacterial endotoxins, and H2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α)), and growth factors (e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to cell growth, migration, differentiation, hormone secretion, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

[0005] Many diseases are associated with abnormal cellular responses triggered by kinase-mediated events, including, but not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases.

[0006] TYK2 catalyzes the phosphorylation of STAT proteins downstream of a number of cytokine receptors, including type I interferon receptors, IL-12 receptors, and IL-23 receptors. Activation of TYK2-dependent receptors by their cytokine ligands activates STAT-dependent transcriptional and cellular functional responses that are specific to the receptor and cell type in which TYK2 is expressed. Cytokine signaling pathways regulated by TYK2 play important roles in several immune-mediated disorders. The cytokine IL-12 is essential for the development of type 1 T helper cells (Th1), which produce interferon-gamma, the main effector molecule in systemic autoimmune disorders, such as systemic lupus erythematosus. The cytokine IL-23 is central to the expansion and survival of Th17 cells and innate lymphoid cells, both of which have been shown to play important pathogenic roles in autoimmunity. Stimulation of IL-23 promotes the production of key proinflammatory cytokines by Th17 cells, including IL-17A, IL-17F, and IL-22, all of which are important effector molecules for the pathogenesis of conditions such as psoriasis, psoriatic arthritis, and spondyloarthritis. Inhibition of TYK2 is predicted to affect multiple immune-mediated disorders through its effects on the IL-23 / Th17 / Th22 axis, IL-12-mediated Th1 function, and type I interferon-driven regulation of multiple immune pathways and cell types.

[0007] Compound 1 shown below [ka] is a TYK2 inhibitor. See U.S. Patent No. 11,046,698. There remains a need for synthetic methods that can efficiently yield large amounts (e.g., kilograms or more) of Compound 1 for further clinical studies and therapeutic use. The present disclosure fulfills this need and provides other related advantages. Summary of the Invention

[0008] In one embodiment, the compound 1 produced by the methods disclosed herein: [ka] or a pharma- ceutically acceptable salt or solvate thereof as described herein.

[0009] In one embodiment, the compound 1: [ka] or a pharma- ceutically acceptable salt or solvate thereof are described herein.

[0010] In another embodiment, a compound of formula I [ka] Described herein are methods for preparing compounds, or a pharma- ceutically acceptable salt thereof, where PG is a suitable amino protecting group, as defined herein, or a pharma- ceutically acceptable salt thereof.

[0011] In another embodiment, a compound of formula II [ka] Described herein are methods for preparing compounds, or a pharma- ceutically acceptable salt thereof, where PG is a suitable amino protecting group, as defined herein, or a pharma- ceutically acceptable salt thereof.

[0012] In one embodiment, a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, Described herein are compounds in which PG is a suitable amino protecting group, or a pharma- ceutically acceptable salt thereof.

[0013] In one embodiment, a compound of formula II [ka] or a pharma- ceutically acceptable salt thereof, Described herein are compounds, or a pharma- ceutically acceptable salt thereof, in which PG is a suitable amino protecting group, as defined herein.

[0014] In another aspect, a method of inhibiting TYK2 protein kinase or a mutant thereof in a patient is described, the method comprising administering to the patient compound 1, [ka] or a pharma- ceutically acceptable salt or solvate thereof in a therapeutically effective amount, and Compound 1 is produced by the methods described herein.

[0015] Other aspects, embodiments, and features will become apparent from the following description, drawings, and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Detailed Description Compound 1, shown below, is an oral, allosteric, selective TYK2 inhibitor for the treatment of psoriasis, psoriatic arthritis, and other inflammatory and autoimmune diseases. Currently, there are no approved TYK2 inhibitors, and compound 1 is the most selective TYK2 inhibitor currently in clinical development. Furthermore, the selectivity of compound 1 and its potential to provide higher levels of TYK2 inhibition for longer periods with once-daily (QD) dosing may provide clinical and ultimately commercial advantages over other TYK2 inhibitors in development. TYK2 is a member of the Janus kinase (JAK) family of kinases, a type of intracellular signaling protein that regulates chronic inflammation in inflammatory and autoimmune diseases. Inhibition of JAKs can be effective in treating inflammatory and autoimmune diseases, but it can also raise on-target safety issues by modulating diverse cytokine pathways. As a result, JAK inhibitors have been established as oral therapeutics for numerous inflammatory and autoimmune diseases, but their clinical utility is limited by increased risk of infection and other side effects, resulting in the U.S. Food and Drug Administration (FDA) mandating boxed warnings and dosage restrictions as part of their labeling. Designing selective JAK inhibitors that directly and specifically inhibit the intended kinase function is challenging due to the structural similarity between the catalytic sites (orthosteric or JH1 sites) in the JAK catalytic domain for drug targeting. Based on human genetic data and growing clinical evidence on the selectivity of allosteric TYK2 inhibitors, the present approach of selective allosteric inhibition of TYK2 provides an optimal balance of achieving potent efficacy while potentially avoiding safety concerns associated with broad inhibition of JAKs for the treatment of multiple inflammatory and autoimmune diseases. Therefore, a robust, scalable, and enantioselective synthetic procedure to generate compounds for further testing is critical to use this compound in research and clinical settings.

[0017] U.S. Patent No. 11,046,698, the entirety of which is incorporated herein by reference, describes certain compounds that are therapeutically useful. Such compounds include Compound 1, [ka] or a pharma- ceutically acceptable salt thereof.

[0018] Compound 1 is referred to as I-908 in US 11,046,698, and an alternative synthesis of compound 1, which differs from the improved synthesis described herein, is described in detail in Example 40 of US 11,046,698. It would be desirable to provide improved methods of synthesizing compound 1, or a pharma- ceutically acceptable salt or solvate thereof. Accordingly, methods of synthesizing such compounds and their pharma- ceutically acceptable salts are described herein.

[0019] In some embodiments, improved methods of preparing compound 1, or a pharma- ceutically acceptable salt or solvate thereof, are described, which produce compound 1 in higher yield, fewer steps, milder conditions, and / or greater generality (greater structural diversity of desirable compounds). In some embodiments, methods of preparing compound 1, or a pharma- ceutically acceptable salt or solvate thereof, as further described herein, are described.

[0020] In another aspect, there are provided intermediates useful for preparing compound 1. Such intermediates include those described in detail below.

[0021] In another aspect, described herein is compound 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein the compound is prepared according to the synthetic methods described herein. In another aspect, described herein is a pharmaceutical composition comprising compound 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein the compound is prepared according to the synthetic methods described herein.

[0022] The compounds prepared by the methods of the present invention, as well as their pharma- ceutically acceptable salts and pharmaceutical compositions, are useful for treating, preventing, ameliorating, or promoting recovery from a variety of injuries, diseases, and disorders, including those described herein.

[0023] Compounds and Definitions Compounds include those generally described herein, and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In addition, general principles of organic chemistry are covered in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999 and March's Advanced Organic Chemistry, 5th Ed. th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0024] "Aliphatic" or "aliphatic group," as used herein, refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation but is not aromatic (also referred to herein as "carbocyclic" or "alicyclic") and has one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0025] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, that is saturated or has one or more units of unsaturation and shares one or more atoms between the two rings of the ring system. That is, the term includes any permissible ring fusion, e.g., ortho-fused or spiro-cyclic. As used herein, the term "heterobicyclic" is a bicyclic ring that is a subset of "bicyclic" and requires that one or more heteroatoms are present in one or both rings of the bicyclic ring. Such heteroatoms may be present at the junction of the rings, are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms, e.g., sulfones and sulfonates), phosphorus (including oxidized forms, e.g., phosphates), boron, and the like. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system having at least one bridge, i.e., saturated or partially unsaturated carbocyclic or heterocyclic. As defined by IUPAC, a "bridge" is an unbranched chain of atoms, or an atom or valence bond, connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system (except hydrogen) that is attached to three or more skeletal atoms. In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups shown below, where each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents as defined for aliphatic groups. Additionally or alternatively, any of the substitutable nitrogens of the bridged bicyclic group are optionally substituted. Exemplary bicycles include the following: [ka] Exemplary bridged bicyclic groups include: [ka]

[0026] The term "lower alkyl" refers to any straight or branched chain C 1-4 refers to an alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0027] The term "lower haloalkyl" refers to a straight or branched chain C alkyl group substituted with one or more halogen atoms. 1-4 Refers to an alkyl group.

[0028] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (nitrogen in any oxidized form, sulfur, phosphorus, or silicon, the quaternization of any basic nitrogen, or a substitutable nitrogen of a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including as in N-substituted pyrrolidinyl)).

[0029] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0030] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. A "substituted" alkylene chain is a polymethylene group in which one or more of the methylene hydrogen atoms has been replaced with a substituent. Suitable substituents include those groups described below for substituted aliphatic groups.

[0031] The term "alkenylene" refers to a divalent alkenyl group having at least one carbon-carbon double bond. Unless otherwise specified, the double bond may be cis or trans. In some embodiments, an alkenylene group has one carbon-carbon double bond. In some embodiments, the double bond is cis. In some embodiments, the double bond is trans. A substituted alkenylene chain is a polymethylene group containing at least one double bond, in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those groups described below for substituted aliphatic groups.

[0032] The term "alkynylene" refers to a divalent alkynyl group having at least one carbon-carbon triple bond. The carbon-carbon triple bond may be intermediate or terminal in the alkynylene group, i.e., between two carbon atoms at either end or in the middle of the chain or carbon atom. A substituted alkynylene chain is a polymethylene group containing at least one triple bond, one or more of whose hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups. In some embodiments, the triple bond is at the terminal position, and the hydrogen of the alkynyl is optionally replaced by a substituent.

[0033] The term "halogen" means F, Cl, Br or I.

[0034] The term "aryl" used alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, and in which each ring in the system contains 3 to 7 ring members. The term "aryl" may also be used synonymously with the term "aryl ring". In certain embodiments, "aryl" refers to an aromatic ring system that may bear one or more substituents, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthoimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0035] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, 6, 10, or 14 pi electrons shared in a cyclic arrangement, and, in addition to carbon atoms, 1 to 5 heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0036] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably 1-4, heteroatoms as defined above. The term "nitrogen" when used in reference to a ring atom of a heterocycle includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or . + It may be NR (as in N-substituted pyrrolidinyl).

[0037] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings, e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions independently are optionally substituted.

[0038] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to include rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0039] As described herein, compounds may include "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more of the hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a given group, the substituents may be either the same group or different groups at all positions. The combinations of substituents envisioned are preferably those that result in the formation of stable compounds or chemically feasible compounds. The term "stable", as used herein, refers to a compound that is substantially unchanged when subjected to conditions that allow for the production, detection, and, in certain embodiments, the recovery, purification, and use of the compound for one or more of the purposes disclosed herein.

[0040] Each optional substituent on a substitutable carbon is independently selected from halogen, -(CH2), 0-4 R°, -(CH2) 0-4 OR°, -O(CH2) 0-4 R°, -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR°)2, -(CH2) 0-4 SR°, -(CH2) 0-4 Ph (optionally substituted with R°), -(CH2) 0-4 O(CH2) 0-1 Ph (optionally substituted with R°), -CH=CHPh (optionally substituted with R°), -(CH2) 0-4O(CH2) 0-1 -pyridyl (optionally substituted with R°), -NO2, -CN, -N3, -(CH2) 0-4 N(R°)2, -(CH2) 0-4 N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2) 0-4 N(R°)C(O)NR°2, -N(R°)C(S)NR°2, -(CH2) 0-4 N(R°)C(O)OR°, -N(R°)N(R°)C(O)R°, -N(R°)N(R°)C(O)NR°2, -N(R°)N(R°)C(O)OR°, -(CH2) 0-4 C(O)R°, -C(S)R°, -(CH2) 0-4 C(O)OR°, -(CH2) 0-4 C(O)SR°, -(CH2) 0-4 C(O)OSiR°3, -(CH2) 0-4 OC(O)R°, -OC(O)(CH2) 0-4 SR-, SC(S)SR°, -(CH2) 0-4 SC(O)R°, -(CH2) 0-4 C(O)NR°2, -C(S)NR°2, -C(S)SR°, -SC(S)SR°, -(CH2) 0-4 OC(O)NR°2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -C(NOR°)R°, -(CH2) 0-4 SSR°, -(CH2) 0-4 S(O)2R°, -(CH2) 0-4 S(O)2OR°, -(CH2) 0-4 OS(O)2R°, -S(O)2NR°2, -(CH2) 0-4 S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(OR°)R°, -C(NH)NR°2, -P(O)2R°, -P(O)R°2, -OP(O)R°2, -OP(O)(OR°)2, SiR°3, -(linear or branched C 1-4 alkylene)ON(R°)2, or -(straight or branched chain C 1-4 is a monovalent substituent selected from alkylene)C(O)ON(R°)2.

[0041] Each R° is independently hydrogen, C 1-6 Aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, when R° is present independently twice, it is taken together with the intervening atom(s) to form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which R° is optionally substituted by a divalent substituent (selected from =O and =S) on a saturated carbon atom of R°, or each R° is selected from halogen, -(CH2) 0-2 R ● , -(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 S.R. ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● 、 -(Linear or branched chain C 1-4 Alkylene)C(O)OR ● , or -SSR ● is optionally substituted with a monovalent substituent independently selected from:

[0042] Each R ● is independent, C 1-4 Aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, or any substituents on saturated carbons are ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 A divalent substituent independently selected from S- or attached to adjacent substitutable carbons of an "optionally substituted" group is -O(CR * 2) 2-3 O- and R * Each independently represents hydrogen, C 1-6 It is selected from an aliphatic group, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0043] R * But, C 1-6 When it is an aliphatic group, R * is halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2 or -NO2, each R ● is independent, C 1-4Aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, when preceded by "halo", is substituted only with one or more halogens.

[0044] The optional substituents on the substitutable nitrogen are independently -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † and each R † are independently hydrogen, C 1-6 an aliphatic group, an unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R † When there are 2 independently occurring R† together with the intervening atom(s) form an unsubstituted 3-12 membered mono- or bicyclic saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; R † C 1-6 When it is an aliphatic group, R † is halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2 or -NO2, each R ●is independent, C 1-4 Aliphatic group, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, when preceded by "halo", is substituted only with one or more halogens.

[0045] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharma- ceutically acceptable non-toxic acid addition salts are the salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic or malonic acids, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of the salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0046] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+ (C 1-4 Representative alkali metal or alkaline earth metal salts include the sodium, lithium, potassium, calcium, magnesium salts, and the like. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0047] Unless otherwise specified, a structure depicted herein is also intended to include all isomers of that structure (e.g., enantiomers, diastereomers, and geometric (or conformational) isomers), such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers of the compounds of the invention are contemplated, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures. Unless otherwise specified, all tautomers of the compounds are contemplated. In addition, unless otherwise specified, a structure depicted herein is also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the invention may be substituted or unsubstituted by hydrogen, such as by the replacement of hydrogen by deuterium or tritium, or by the replacement of hydrogen by hydrogen or by the replacement of hydrogen by hydrogen. 13 C-enriched carbon or 14 Replacement of carbon with C-enriched carbon is envisioned. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents.

[0048] Description of exemplary embodiments In one embodiment, the compound 1 produced by the methods disclosed herein: [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0049] In one embodiment, a compound of formula I [ka] or a pharma- ceutically acceptable salt thereof, Compounds, or pharma- ceutically acceptable salts thereof, are described in which PG is a suitable amino protecting group.

[0050] In certain embodiments, PG is t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl. In certain embodiments, PG is t-butyloxycarbonyl (BOC).

[0051] In one embodiment, the compound 2 [ka] or a pharma- ceutically acceptable salt thereof is described.

[0052] In one embodiment, a compound of formula II [ka] or a pharma- ceutically acceptable salt thereof, Compounds, or pharma- ceutically acceptable salts thereof, are described in which PG is a suitable amino protecting group.

[0053] In certain embodiments, PG is t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl. In certain embodiments, PG is t-butyloxycarbonyl (BOC).

[0054] In one embodiment, compound 6 [ka] or a pharma- ceutically acceptable salt thereof is described.

[0055] In one embodiment, a compound of formula III [ka] or a pharma- ceutically acceptable salt thereof, Compounds, or pharma- ceutically acceptable salts thereof, are described in which PG is a suitable amino protecting group.

[0056] The compound of formula III is represented by the following compound 8: [ka] or by N-protection of a pharma- ceutically acceptable salt or ester thereof.

[0057] In one embodiment, the compound 1' shown below is produced by the methods disclosed herein: [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0058] In one embodiment, a compound of formula I' [ka] or a pharma- ceutically acceptable salt thereof, Compounds, or pharma- ceutically acceptable salts thereof, are described in which PG is a suitable amino protecting group.

[0059] In certain embodiments, PG is t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl. In certain embodiments, PG is t-butyloxycarbonyl (BOC).

[0060] In one embodiment, compound 2' [ka] or a pharma- ceutically acceptable salt thereof is described.

[0061] In one embodiment, a compound of formula II' [ka] or a pharma- ceutically acceptable salt thereof, Compounds, or pharma- ceutically acceptable salts thereof, are described in which PG is a suitable amino protecting group.

[0062] In certain embodiments, PG is t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl. In certain embodiments, PG is t-butyloxycarbonyl (BOC).

[0063] In one embodiment, compound 6' [ka] or a pharma- ceutically acceptable salt thereof is described.

[0064] In one embodiment, a compound of formula III [ka] or a pharma- ceutically acceptable salt thereof, Compounds, or pharma- ceutically acceptable salts thereof, are described in which PG is a suitable amino protecting group.

[0065] Compounds of formula III may be prepared by N-protection of compound 8 below. [ka]

[0066] According to the embodiments described herein, the protecting groups described above (e.g., PG or PG 1 For deprotection or addition of a protecting group, see Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3 rdedition, John Wiley & Sons, 1999, each of which is incorporated herein by reference in its entirety. In some embodiments, the protecting group is a suitable amino-protecting group.

[0067] As used herein, the phrase "suitable amino protecting group" is well known in the art and when taken together with the nitrogen attached to the amino, the protecting group includes, but is not limited to, aralkylamines, carbamates, allylamines, amides, etc. Examples of mono-protecting groups for amines include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, benzoyl, etc. Examples of di-protecting groups for amines include amines substituted with two substituents independently selected from the groups listed above as mono-protecting groups, and further include cyclic imides, such as phthalimide, maleimide, succinimide, 2,2,5,5-tetramethyl-1,2,5-azadisilolidine, azide, and the like. It will be apparent that acid hydrolysis of an amino protecting group will result in the formation of its salt compound. For example, when an amino protecting group is removed by treatment with an acid, such as hydrochloric acid, the resulting amine compound will be formed as its hydrochloride salt. Those skilled in the art will recognize that a wide variety of acids are useful for removing acid-labile amino protecting groups, and therefore a wide variety of salt forms are envisioned.

[0068] In another aspect, a compound selected from one of the compounds in Table 1, or a pharma- ceutically acceptable salt thereof, is described. [Table 1]

[0069] Exemplary Synthetic Methods As described above, the present invention provides methods for synthesizing Compound 1 and compounds of Formula I, I', II, II', or III, and pharma- ceutically acceptable salts thereof. In some embodiments, compounds of the present invention are generally prepared according to Scheme 1, shown below. Scheme 1 [ka]

[0070] In Scheme 1 above, PG is as defined and described in the embodiments of the present invention, and includes nitrogen protecting groups known to those of skill in the art.

[0071] In one embodiment, the compound 1: [ka] or a pharma- ceutically acceptable salt or solvate thereof, which comprises the steps of: [ka] or a pharma- ceutically acceptable salt thereof, wherein PG is a suitable amino protecting group, or a pharma- ceutically acceptable salt thereof.

[0072] In certain embodiments, PG is t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl. In certain embodiments, PG is t-butyloxycarbonyl (BOC).

[0073] In certain embodiments, the compound of formula I is compound 2 [ka] or a pharma- ceutically acceptable salt thereof.

[0074] In some embodiments, the deprotection includes hydrogenolysis, contact with an acid (e.g., HCl), contact with a base (e.g., piperidine, ammonia, K2CO3, or methylamine), or heating. In accordance with embodiments described herein, the deprotection of the protecting group (e.g., PG) can be carried out according to the methods described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3 rd Protective groups and their deprotection methods are described in detail in the American Chemical Society, Vol. 13, No. 1, 1999, edition, John Wiley & Sons, 1999, which is incorporated herein by reference in its entirety. In some embodiments, the protecting group is a suitable amino protecting group. The deprotection may be carried out in any of the following solvents: In some embodiments, the deprotection is carried out in an alcohol selected from methanol, ethanol, propanol, butanol, pentanol, or hexanol. In some embodiments, the deprotection is carried out in ethanol.

[0075] In certain embodiments, the method comprises: a) a compound of formula II: [ka] or a pharma- ceutically acceptable salt thereof, wherein PG is a suitable amino protecting group, and [ka] and cross-coupling the compound of formula I: b) a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof; and Includes.

[0076] In certain embodiments, the compound of formula II is compound 6 [ka] or a pharma- ceutically acceptable salt thereof.

[0077] In one embodiment, the compound 1' shown below: [ka] or a pharma- ceutically acceptable salt or solvate thereof, which comprises the step of: [ka] or a pharma- ceutically acceptable salt thereof, wherein PG is a suitable amino protecting group, or a pharma- ceutically acceptable salt thereof.

[0078] In certain embodiments, PG is t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl. In certain embodiments, PG is t-butyloxycarbonyl (BOC).

[0079] In certain embodiments, the compound of formula I' is compound 2' [ka] or a pharma- ceutically acceptable salt thereof.

[0080] In some embodiments, the deprotection includes hydrogenolysis, contact with an acid (e.g., HCl), contact with a base (e.g., piperidine, ammonia, K2CO3, or methylamine), or heating. In accordance with embodiments described herein, the deprotection of the protecting group (e.g., PG) can be carried out according to the methods described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3 rd Protective groups and their deprotection methods are described in detail in the American Chemical Society, Vol. 13, No. 1, 1999, edition, John Wiley & Sons, 1999, which is incorporated herein by reference in its entirety. In some embodiments, the protecting group is a suitable amino protecting group. The deprotection may be carried out in any of the following solvents: In some embodiments, the deprotection is carried out in an alcohol selected from methanol, ethanol, propanol, butanol, pentanol, or hexanol. In some embodiments, the deprotection is carried out in ethanol.

[0081] In certain embodiments, the method comprises: c) a compound of formula II' [ka] or a pharma- ceutically acceptable salt thereof, wherein PG is a suitable amino protecting group, and [ka] and cross-coupling the compound of formula I' to form a compound of formula I' d) a compound of formula I' [ka] or a pharma- ceutically acceptable salt thereof; and Includes.

[0082] In certain embodiments, the compound of formula II' is compound 6' [ka] or a pharma- ceutically acceptable salt thereof.

[0083] In some embodiments, the cross-coupling includes a metal-catalyzed cross-coupling reaction. In certain embodiments, the cross-coupling includes a palladium-catalyzed cross-coupling (e.g., Buchwald-Hartwig cross-coupling). In some embodiments, the method includes contacting a palladium compound, a ligand, a compound of formula II or II', and compound 4. In some embodiments, the palladium compound includes Pd(OAc)2 (palladium acetate(II)), Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0)), PdCl2[P(o-Tol)3]2 (dichlorobis(tri-o-tolylphosphine)palladium(II)), Pd(dba)2 (bis(dibenzylideneacetone)palladium(0)), Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0)), or Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)). In some embodiments, the palladium compound comprises Pd(OAc) 2 .

[0084] In some embodiments, the ligand is xantphos, diphenylphosphino binaphthyl (BINAP), diphenylphosphinoferrocene (DPPF), tri(o-tolyl)phosphine, [ka] wherein "Cy" is cyclohexyl, or any palladium cross-coupling ligand known to one of skill in the art, including but not limited to those described in Hartwig, JF (2008), "Evolution of a Fourth Generation Catalyst for the Amination and Thioetherification of Aryl Halides", Acc. Chem. Res., 41(11):1534-1544 and Surry, DS; Buchwald, SL (2008), "Biaryl Phosphane Ligands in Palladium-Catalyzed Amination", Angew. Chem. Int. Ed., 47(34):6338-6361, the disclosures of which are incorporated herein by reference in their entireties. In some embodiments, the ligand is Xantphos. Xantphos has the formula: [ka] In the formula, "Ph" is phenyl.

[0085] In some embodiments, the method further comprises contacting the palladium compound, the ligand, compound 4, and / or the compound of formula II or II' with a salt. In some embodiments, the salt is NaOt-Bu, LiHMDS, KOH, K2CO3, NaOH, Cs2CO3, or any other salt described in the publications above, in Hartwig et al., or in Surrey et al. In some embodiments, the salt is K2CO3.

[0086] In certain embodiments, the palladium-catalyzed cross-coupling comprises contacting Pd(OAc)2, Xantphos, K2CO3, compound 4, and a compound of formula II or II' in a suitable organic solvent. In some embodiments, the solvent includes DME (1,2-dimethoxyethane). In certain embodiments, the compound of formula I or I' (the cross-coupling product) is washed with N-Ac-L-cysteine ​​(NAC).

[0087] In certain embodiments, the method further comprises distilling the NAC washed compound of formula I or I' dissolved in an organic solvent (i.e., THF) and contacting with activated carbon. In certain embodiments, the compound of formula I or I' and activated carbon are heated. In certain embodiments, the heating is to a temperature of about 40°C to about 50°C, about 50°C to about 60°C, about 60°C to about 70°C, or about 70°C to about 80°C.

[0088] In certain embodiments, the compound of formula I or I' is contacted with activated carbon. In certain embodiments, the compound of formula I or I' is contacted with 3-mercaptopropylethylsulfide silica (SPM32). The contacting may be after contacting with activated carbon. In certain embodiments, the compound of formula I or I' is heated during contact with the activated carbon. In certain embodiments, the heating is to a temperature of about 40°C to about 50°C, about 50°C to about 60°C, about 60°C to about 70°C, or about 70°C to about 80°C. In certain embodiments, the compound of formula I or I' is triturated after contacting with SPM32. The trituration may be from one or more of the following solvents: In certain embodiments, the trituration of the compound of formula I or I' is from methyl t-butyl ether (MTBE). In certain embodiments, the trituration comprises heating to a temperature of about 40° C. to about 50° C., about 50° C. to about 60° C., about 60° C. to about 70° C., or about 70° C. to about 80° C. In certain embodiments, the trituration further comprises cooling the heated compound of Formula I or I' to a temperature of about 0° C. to about 10° C., about 10° C. to about 20° C., or about 20° C. to about 30° C.

[0089] In certain embodiments, the cross-coupled compound of formula I or I' is dissolved in a suitable organic solvent, i.e., the solvents listed below, before and / or after contact with coal or SPM32. In some embodiments, the solvent is DCM (dichloromethane).

[0090] The above cross-coupling methods, palladium compounds, ligands and salts can be prepared as known in the art, for example as described in Palladium-Catalyzed Coupling Reactions, A. Molnar, 1999. st edition, Wiley-VCH, 2013, each of which is incorporated herein by reference in its entirety.

[0091] In certain embodiments, the method comprises: a) a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof, wherein PG is a suitable amino protecting group, is reacted with compound 5 [ka] or a pharma- ceutically acceptable salt thereof, Producing a compound of formula II: b) a compound of formula II: [ka] or a pharma- ceutically acceptable salt thereof, wherein PG is a suitable amino protecting group, and [ka] or a pharma- ceutically acceptable salt thereof to produce a compound of formula I: c) a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof; and Includes.

[0092] In certain embodiments, the compound of formula III is compound 7, shown below. [ka]

[0093] In certain embodiments, the method comprises: d) a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof, wherein PG is a suitable amino protecting group, is reacted with compound 5' [ka] or a pharma- ceutically acceptable salt thereof, Producing a compound of formula II': e) a compound of formula II' [ka] or a pharma- ceutically acceptable salt thereof, wherein PG is a suitable amino protecting group, and [ka] or a pharma- ceutically acceptable salt thereof to produce a compound of formula I': f) a compound of formula I' [ka] or a pharma- ceutically acceptable salt thereof; and Includes.

[0094] In certain embodiments, the compound of formula III is compound 7, shown below. [ka]

[0095] In some embodiments, the compound of formula II or II' is triturated from an alkane after amidation. The trituration may be prior to subsequent cross-coupling. The alkane may be selected from butane, pentane, hexane, heptane, octane, nonane, decane, or mixtures thereof. In some embodiments, the compound of formula II or II' is triturated from heptane after amidation. In some embodiments, the compound of formula II or II' is triturated from n-heptane after amidation. In some embodiments, the compound of formula II or II' is triturated from n-heptane after amidation, the heptane being at a temperature of about 16°C to about 18°C, about 18°C ​​to about 20°C, about 20°C to about 22°C, or about 22°C to about 24°C.

[0096] Amidation is known to those skilled in the art to include hydrolyzing a carboxylic acid with an amine to form an amide bond. In certain embodiments, the amidation includes treating the compound of formula III and compound 5 or 5' with a base. In some embodiments, the base includes diisopropylethylamine (DIPEA), triethylamine (TEA) or pyridine. In some embodiments, the base includes DIPEA. In some embodiments, the amidation further includes contacting the compound of formula III, compound 5 or 5', and base with T3P (propylphosphonic anhydride). In some embodiments, the amidation is neat. In some embodiments, the amidation is performed in the following solvent (i.e., DCM).

[0097] In some embodiments, the amidation is carried out at a temperature of about -10°C to about -5°C, about -5°C to about 0°C, about 0°C to about 5°C, about 5°C to about 10°C, or at about room temperature (22°C).

[0098] Synthesis of intermediates In another embodiment, the compound of formula I: [ka] A method is described for preparing compounds of the formula II, wherein PG is a suitable amino protecting group, which method comprises the steps of: [ka] or a pharma- ceutically acceptable salt thereof and the following compound 4 [ka] or a pharma- ceutically acceptable salt thereof.

[0099] The cross-coupling may be carried out using any of the conditions, reagents, ligands, catalysts, salts or additives described above.

[0100] In certain embodiments, the method comprises: a) a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof and the following compound 5 [ka] or a pharma- ceutically acceptable salt thereof, Producing a compound of formula II: b) a compound of formula II: [ka] or a pharma- ceutically acceptable salt thereof and the following compound 4 [ka] or a pharma- ceutically acceptable salt thereof, Producing a compound of formula I; Includes.

[0101] The amidation and / or cross-coupling may be carried out using any of the conditions, reagents or additives described above.

[0102] In another embodiment, a compound of formula II [ka] or a pharma- ceutically acceptable salt thereof, which comprises reacting a compound of formula III [ka] or a pharma- ceutically acceptable salt thereof, [ka] or a pharma- ceutically acceptable salt thereof to produce a compound of formula II; Includes.

[0103] In another embodiment, the compound is of formula I': [ka] A method is described for preparing compounds of the formula II', wherein PG is a suitable amino protecting group, which method comprises the step of preparing a compound of the formula II' [ka] or a pharma- ceutically acceptable salt thereof and the following compound 4 [ka] or a pharma- ceutically acceptable salt thereof.

[0104] The cross-coupling may be carried out using any of the conditions, reagents, ligands, catalysts, salts or additives described above.

[0105] In certain embodiments, the method comprises: c) a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof, [ka] or a pharma- ceutically acceptable salt thereof, Producing a compound of formula II': d) a compound of formula II' [ka] or a pharma- ceutically acceptable salt thereof and the following compound 4 [ka] or a pharma- ceutically acceptable salt thereof, Producing a compound of formula I'; Includes.

[0106] The amidation and / or cross-coupling may be carried out using any of the conditions, reagents or additives described above.

[0107] In another embodiment, a compound of formula II' [ka] or a pharma- ceutically acceptable salt thereof, which comprises reacting a compound of formula III [ka] or a pharma- ceutically acceptable salt thereof, [ka] or a pharma- ceutically acceptable salt thereof to produce a compound of formula II'.

[0108] Amidation may be carried out using any of the conditions, reagents or additives described above.

[0109] In some embodiments, the compound of formula II or II' is triturated from heptane after amidation. In some embodiments, the compound of formula II or II' is triturated from n-heptane after amidation. In some embodiments, the compound of formula II or II' is triturated from n-heptane after amidation, where the heptane is at a temperature of about 16°C to about 18°C, about 18°C ​​to about 20°C, about 20°C to about 22°C, or about 22°C to about 24°C.

[0110] In certain embodiments, the amidation comprises treating the compound of formula III and compound 5 or 5' with a base. In some embodiments, the base comprises diisopropylethylamine (DIPEA), triethylamine (TEA) or pyridine. In some embodiments, the base comprises DIPEA. The amidation and cross-coupling may be carried out using any of the conditions, reagents or additives described above.

[0111] In any of the above preparation methods, the reaction may be carried out neat or in a solvent. A suitable medium is a solvent or mixture of solvents that, when combined with the compound to be combined, can facilitate the reaction between the medium and the compound. The suitable solvent can solubilize one or more of the reaction components, or the suitable solvent can facilitate the stirring of a suspension of one or more of the reaction components. Examples of suitable solvents are protic solvents, halogenated hydrocarbons, ethers, esters, aromatic hydrocarbons, polar or non-polar aprotic solvents, or any mixture thereof. Such mixtures include, for example, mixtures of protic and aprotic solvents, such as benzene / methanol / water, benzene / water, DME / water, etc.

[0112] Such suitable solvents, and others, may be substituted and are well known in the art, see, for example, "Advanced Organic Chemistry," Jerry March, 5 th edition, John Wiley and Sons, NY.

[0113] Use, Preparation and Administration Pharmaceutically acceptable compositions According to another embodiment, provided is a composition comprising a compound produced by the method of the present invention and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition is such that it is effective to measurably inhibit TYK2 protein kinase or a variant thereof in a biological sample or a patient. In certain embodiments, the amount of the compound in the composition is such that it is effective to measurably inhibit TYK2 protein kinase or a variant thereof in a biological sample or a patient. In certain embodiments, the composition is formulated for administration to a patient in need of such a composition. In some embodiments, the composition is formulated for oral administration to a patient.

[0114] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0115] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the composition include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0116] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound (Compound 1) that, upon administration to a recipient, is capable of providing, either directly or indirectly, the compound, or an inhibitory active metabolite or residue thereof.

[0117] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of TYK2 protein kinase or a variant thereof.

[0118] The compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations may be as sterile injectable solutions or suspensions in non-toxic acceptable parenteral diluents or solvents, for example as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspending media.

[0119] For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful for the preparation of injectables, since they are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylene versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspending agents. Other surfactants commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms, such as Tween, Span, and other emulsifiers or bioavailability enhancers, may also be used for formulation purposes.

[0120] The pharmaceutically acceptable composition may be orally administered in any of the acceptable oral dosage forms, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dry cornstarch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners, flavors or colorants may also be added.

[0121] Alternatively, the pharma- ceutically acceptable composition may be administered in the form of a suppository for rectal administration. These suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol.

[0122] Pharmaceutically acceptable compositions may be administered topically, especially when the therapeutic target includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0123] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches may also be used.

[0124] The provided pharma- ceutically acceptable composition may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers for topical application.Carriers for topical administration of Compound 1 include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, the provided pharma- ceutically acceptable composition may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharma- ceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0125] The pharmacy acceptable compositions provided may be formulated for ophthalmic use as micronized suspensions in isotonic, pH-adjusted, sterile saline, or preferably as solutions in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, the pharmacy acceptable compositions may be formulated for ophthalmic use in an ointment, such as petrolatum.

[0126] The pharma- ceutically acceptable compositions may also be administered by nasal aerosol or inhalation.Such compositions may be prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0127] Most preferably, the pharma- ceutically acceptable composition is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharma- ceutically acceptable composition is administered without food. In other embodiments, the pharma- ceutically acceptable composition is administered with food.

[0128] The amount of compound that may be combined with a carrier material to produce a composition in a single dosage form can vary depending on the host being treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated to allow a dosage of 0.01-100 mg / kg body weight / day of inhibitor to be administered to a patient receiving these compositions.

[0129] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific Compound 1 used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.

[0130] Uses of the Compounds and Pharmaceutically Acceptable Compositions Compound 1 and compositions described herein are generally useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by compound 1 and methods of the present invention is TYK2.

[0131] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors and type I and type III interferon receptors and is activated by these receptors upon cytokine binding. Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitin)), and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF).Velasquez et al.,“A protein kinase in the interferon α / β signaling pathway,”Cell (1992)70:313、Stahl et al.“Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β receptor components,”Science(1994)263:92、Finbloom et al.,“IL-10 induces the tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of Stat1 and Stat3 complexes in human T cells and monocytes,”J.Immunol.(1995)155:1079、Bacon et al.,“Interleukin 12(IL-12)induces tyrosine phosphorylation of Jak2 and Tyk2:differential use of Janus family kinases by IL-2 and IL-12,”J.Exp.Med.(1995)181:399、Welham et al.,“Interleukin-13 signal transduction in lymphohemopoietic cells:similarities and differences in signal transduction with interleukin-4 and insulin,”J.Biol.Chem.(1995)270:12286、Parham et al.,“A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit,IL-23R,”J.Immunol.(2002)168:5699。Activated TYK2 then phosphorylates additional signaling proteins, such as STAT family members, including STAT1, STAT2, STAT4 and STAT6.

[0132] Activation of TYK2 by IL-23 has been linked to inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis. Duerr et al., "A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene," Science (2006) 314:1461-1463. TYK2, as a downstream effector of IL-23, is also involved in psoriasis, ankylosing spondylitis and Behcet's disease. Cho et al., “Genomics and the multifactorial nature of human auto-immune disease,” N. Engl. J. Med (2011) 365: 1612-1623; Cortes et al., “Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci,” Nat. Genet. (2013) 45(7): 730-738; Remmers et al., “Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease,” Nat. Genet. (2010) 42: 698-702. A genome-wide association study of 2,622 individuals with psoriasis identified an association between disease susceptibility and TYK2. Strange et al., “A genome-wide association study identifies a new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1,” Nat. Genet. (2010) 42:985-992. TYK2 knockout or TYK2 inhibition with tyrphostin significantly reduces dermatitis induced by both IL-23 and IL-22.Ishisaki et al., “Tyk2 is a therapeutic target for pseniasis-like skin inflammation,” Intl. Immunol. (2013), doi:10.1093 / intimm / dxt062.

[0133] TYK2 is also involved in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucus hypersecretion are mediated by IL-13-induced TYK2 activation (which in turn activates STAT6). Zhang et al., “Docking protein Gab2 regulates mucin expression and goblet cell hyperplasia through TYK2 / STAT6 pathway,” FASEB J. (2012) 26:1-11.

[0134] Reduced TYK2 activity protects joints from collagen antibody-induced arthritis (a model of human rheumatoid arthritis). Mechanistically, reduced TYK2 activity reduces T h 1 / T h The production of 17-related cytokines, matrix metalloproteinases, and other important inflammatory markers was reduced. Ishizaki et al., “Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice,” Intl. Immunol. (2011) 23(9):575-582.

[0135] TYK2 knockout mice were completely resistant to experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) and showed a lack of CD4 T cell infiltration in the spinal cord compared to controls, suggesting that TYK2 is essential for pathogenic CD4-mediated disease development in MS. Oyamada et al., “Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis,” J. Immunol. (2009) 183: 7539-7546. This supports previous studies that have linked increased expression of TYK2 to MS susceptibility. Ban et al., “Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor,” Eur J. Hum. Genet. (2009) 17: 1309-1313. Loss-of-function mutations in TYK2 result in reduced neuronal demyelination and increased remyelination, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0136] TYK2 is the only signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduced footpad thickness induced by methylated BSA injection, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice.

[0137] Joint linkage and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder) showed a strong and significant correlation between loss-of-function mutations in TYK2 and reduced prevalence of SLE in families with affected members. Sigurdsson et al., “Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupis Erythematosus,” Am. J. Hum. Genet. (2005) 76:528-537. Genome-wide association studies of individuals from an SLE cohort versus an unaffected cohort showed a significant correlation between the TYK2 locus and SLE. Graham et al., “Association of NCF2,IKZF1,IRF8,IFIH1,and TYK2 with Systemic Lupus Erythematosus,” PLoS Genetics(2011)7(10):e1002341.

[0138] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice showed reduced cytotoxic T cell responses and accelerated tumor development. However, these effects were associated with efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors may be highly suitable for the treatment of autoimmune disorders or graft rejection. Although other JAK family members, such as JAK3, have similar roles in the immune system, TYK2 has been suggested as a better target than other members, as it is involved in more or less closely related signaling pathways, resulting in fewer off-target effects than other members. Simma et al.“Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumor Surveillance,”Cancer Res.(2009)69:203-211.

[0139] However, contrary to the reduced tumor surveillance observed by Simma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly dependent on IL-10 via STAT1-mediated signaling by TYK2 to maintain cancer cell survival through upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. Specific activating mutations in TYK2 that promote cancer cell survival include mutations in the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required for improved cancer cell survival, as conversion did not occur with TYK2 enzymes characterized by kinase-dead mutations (M978Y or M978F) in addition to an activating mutation (E957D). Sanda et al. “TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia,” Cancer Disc. (2013)3(5):564-577.

[0140] That is, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10-dependent and / or BCL2-dependent tumors, such as 70% of adult T-cell leukemia cases. Fontan et al. “Discovering What Makes STAT Signaling TYK in T-ALL,” Cancer Disc. (2013) 3: 494-496.

[0141] TYK2-mediated STAT3 signaling has also been shown to mediate amyloid-β (Aβ) peptide-induced neuronal cell death. After Aβ administration, decreased phosphorylation of STAT3 by TYK2 reduced neuronal cell death, and increased phosphorylation of STAT3 was observed in postmortem brains of Alzheimer's patients. Wan et al. “Tyk / STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer's Disease,” J.Neurosci.(2010)30(20):6873-6881.

[0142] Inhibition of the JAK-STAT signaling pathway is also involved in hair growth and reversal of hair loss associated with alopecia areata. Xing et al., “Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition,” Nat. Med. (2014) 20: 1043-1049; Harel et al., “Pharmacologic inhibition of JAK-STAT signaling promotes hair growth,” Sci. Adv. (2015) 1(9): e1500973.

[0143] Thus, compounds that inhibit the activity of TYK2 would be beneficial, particularly those that have selectivity over JAK2. Such compounds should provide a pharmacological response that successfully treats one or more of the conditions described herein without the side effects associated with inhibition of JAK2.

[0144] Although TYK2 inhibitors are known in the art, there remains a need to provide new inhibitors with more effective or beneficial pharmacologic properties, such as compounds with improved activity, selectivity over other JAK kinases (particularly JAK2) and ADMET properties (absorption, distribution, metabolism, excretion and / or toxicity). That is, in some embodiments, compound 1, an inhibitor of TYK2, exhibits selectivity over JAK2.

[0145] The activity of compound 1 utilized in the present invention as a TYK2 inhibitor or variant thereof may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity and / or subsequent functional consequences or ATPase activity of activated TYK2 or variants thereof. Alternative in vitro assays quantify the ability of the inhibitor to bind to TYK2. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / TYK2 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by performing a competition experiment in which novel inhibitors are incubated with TYK2 bound to a known radioligand. Representative in vitro and in vivo assays useful for assaying TYK2 inhibitors include, for example, those described and disclosed in the references incorporated herein in their entireties by reference.

[0146] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder as described herein, or one or more of its symptoms. In some embodiments, treatment may be administered after one or more symptoms have manifested. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may continue after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0147] Compound 1 is an inhibitor of TYK2 and is therefore useful for treating one or more disorders associated with the activity of TYK2 or a mutant thereof. Thus, in certain embodiments, a method for treating a TYK2-mediated disorder comprises administering to a patient in need of treatment Compound 1 or a pharma- ceutically acceptable composition thereof produced by the methods described herein.

[0148] As used herein, the term "TYK2-mediated" disorders, diseases and / or conditions, as used herein, refers to any disease or other deleterious condition in which TYK2 or a variant thereof is known to play a role. Accordingly, another embodiment relates to treating or reducing the severity of one or more diseases in which TYK2 or a variant thereof is known to play a role. Such TYK2-mediated disorders include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplant-related disorders.

[0149] In some embodiments, a method of treating one or more disorders, the disorders being selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, and a disorder associated with transplantation, the method comprising administering to a patient in need of treatment a pharmaceutical composition comprising an effective amount of compound 1, or a pharma- ceutical acceptable salt thereof, produced by the methods of the invention.

[0150] In some embodiments, the disorder is an autoimmune disorder, hi some embodiments, the disorder is selected from type 1 diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0151] In some embodiments, the disorder is an inflammatory disorder, hi some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, or inflammatory bowel disease.

[0152] In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments, the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, or essential thrombocytosis.

[0153] In some embodiments, the disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[0154] In some embodiments, the disorder is a neurological disorder, hi some embodiments, the neurological disorder is Alzheimer's disease.

[0155] In some embodiments, the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation to the FERM domain, the JH2 domain, or the kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0156] In some embodiments, the disorder is associated with transplantation. In some embodiments, the disorder is associated with transplantation is transplant rejection or graft-versus-host disease.

[0157] In some embodiments, the disorder is associated with type I interferon, IL-10, IL-12 or IL-23 signaling. In some embodiments, the disorder is associated with type I interferon signaling. In some embodiments, the disorder is associated with IL-10 signaling. In some embodiments, the disorder is associated with IL-12 signaling. In some embodiments, the disorder is associated with IL-23 signaling.

[0158] Compound 1 produced by the methods of the present invention is also useful for the treatment of inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, cutaneous lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0159] Compound 1 produced by the method of the present invention may also be used to treat other diseases or conditions, such as diseases or conditions having an inflammatory component, such as ophthalmic diseases and conditions, such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal keratoconjunctivitis, diseases affecting the nose, including allergic rhinitis, as well as autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, among others. inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disorders, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome).For example, idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous diseases, endometriosis, leptospirosis renal disease, glaucoma, retinal diseases, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic and exercise-induced), acute lung disorders, acute respiratory distress. Distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, eye allergies, silica-induced disease, COPD (damage, airway inflammation, bronchial hyperresponsiveness, remodeling or reduction in disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopy dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, sweat gland abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis In some embodiments, the composition may be used to treat inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology, including inflammatory bowel disease, myelitis, myocarditis, myositis, nephritis, ovariitis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis.

[0160] In some embodiments, the inflammatory disease that can be treated according to the method is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS) and osteoarthritis.

[0161] In some embodiments, the inflammatory disease that can be treated according to the method is T h 1 or T h In some embodiments, the disease is mediated by T h The 17 mediated disease is selected from cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0162] In some embodiments, inflammatory diseases that can be treated according to the method are selected from Sjogren's syndrome, allergic disorders, osteoarthritis, eye conditions such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, and diseases affecting the nose, such as allergic rhinitis.

[0163] Further described herein is the use of compound 1, or a pharma- ceutically acceptable salt thereof, or a hydrate or solvate thereof, as defined in the present invention, for the preparation of a medicament for the treatment of an autoimmune disorder, an inflammatory disorder or a proliferative disorder, or a disorder commonly occurring in connection with transplantation.

[0164] Combination therapy Depending on the particular condition or disease being treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with Compound 1 and compositions produced by the methods of the invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0165] In certain embodiments, the provided combinations, or compositions thereof, are administered in combination with another therapeutic agent.

[0166] Examples of drugs that may be combined with the combination include, but are not limited to, drugs for treating Alzheimer's disease, such as Aricept® and Excelon®, drugs for treating HIV, such as ritonavir, drugs for treating Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine, drugs for treating multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone, drugs for treating asthma, such as albuterol and Singulair®, drugs for treating schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol, anti-inflammatory drugs, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine, immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine, neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole and antiparkinsonian agents, drugs for treating cardiovascular diseases such as beta-blockers, AC E inhibitors, diuretics, nitrates, calcium channel blockers and statins, agents for treating liver disease such as corticosteroids, cholestyramine, interferons and antivirals, agents for treating blood disorders such as corticosteroids, anti-leukemia agents and growth factors, agents that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e. metabolic degradation inhibitors) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir), and agents for treating immune deficiency disorders such as gamma globulins.

[0167] In certain embodiments, the combination therapy or a pharma- ceutically acceptable composition thereof is administered in combination with a monoclonal antibody or a siRNA pharmaceutical.

[0168] These additional agents may be administered separately from the combination therapy provided as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form mixed together with the compound in a single composition. When administered as part of a multiple dose regimen, these two active agents may be provided simultaneously, sequentially, or within a period of one another, typically within 5 hours of the other.

[0169] As used herein, the terms "combination," "in combination," and related terms refer to simultaneous or sequential administration of therapeutic agents. For example, a combination may be administered simultaneously or sequentially with another therapeutic agent, either in separate unit dosage forms or together in a single unit dosage form.

[0170] The amount of additional therapeutic agent present in the compositions of the invention will be no more than the amount that would normally be administered in a composition containing that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will be in the range of about 50% to 100% of the amount that would normally be present in a composition containing that agent as the only therapeutically active agent.

[0171] In one embodiment, a composition comprising Compound 1 and one or more additional therapeutic agents is contemplated. The therapeutic agents may be administered together with Compound 1, or may be administered before or after administration of Compound 1. Suitable therapeutic agents are described in more detail below. In certain embodiments, Compound 1 may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, Compound 1 may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0172] In another embodiment, a method is described for treating an inflammatory disease, disorder, or condition by administering to a patient in need of treatment Compound 1 and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents, including, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat, cyclosporine ... Stats (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine ( Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), as well as “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), (registered trademark), certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T-cell" agents such as abatacept (Orencia®), "anti-IL-6" agents,for example tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine. , alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycols (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil®), HFAs), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate, azepam (Beclovent®, Qvar® and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®) and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®,Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtricitabine), riva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®) and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®) and etravirine (Intelence®), nucleoside reverse transcriptase inhibitors such as tenofovir (Viread®), ), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®) and tipiravir. Nabil (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®) and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®);or any combination thereof.

[0173] In another embodiment, described is a method of treating rheumatoid arthritis, comprising administering to a patient in need of treatment Compound 1 and a combination of nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials, such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts, such as aurothioglucose (Solganal®), aurothiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (I muran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), and and one or more additional therapeutic agents selected from adalimumab (Humira®), "anti-IL-1" agents, such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies, such as rituximab (Rituxan®), "anti-T cell" agents, such as abatacept (Orencia®), and "anti-IL-6" agents, such as tocilizumab (Actemra®).

[0174] In some embodiments, described are methods of treating osteoarthritis, comprising administering to a patient in need of treatment Compound 1 and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies, such as tanezumab.

[0175] In some embodiments, described are methods of treating cutaneous lupus erythematosus or systemic lupus erythematosus, comprising administering to a patient in need of treatment Compound 1 and an effective amount of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials, such as hydrocortis ... The method includes administering oxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and one or more additional therapeutic agents selected from anticoagulants, such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0176] In some embodiments, described are methods of treating Crohn's disease, ulcerative colitis or inflammatory bowel disease, comprising administering to a patient in need of treatment Compound 1 and one or more additional therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal agents such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0177] In some embodiments, described is a method of treating asthma, comprising administering to a patient in need of such treatment Compound 1 and one or more of the following: Singulair®; a beta-2 agonist, such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®); an anticholinergic agent, such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®); an inhaled corticosteroid, such as prednisone, prednisolone, beta dipropionate, or a combination of these. and one or more additional therapeutic agents selected from clomethasone (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®), and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[0178] In some embodiments, described is a method of treating COPD, comprising administering to a patient in need of treatment Compound 1 and a beta-2 agonist, such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), an anticholinergic agent, such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), a methylxanthine, such as theofilin, and one or more additional therapeutic agents selected from aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent, Qvar, and Vanceril), triamcinolone acetonide (Azmacort), mometasone (Asthmanex), budesonide (Pulmocort), flunisolide (Aerobid), Afviar, Symbicort, and Dulera.

[0179] In another embodiment, described is a method of treating a hematological malignancy comprising administering to a patient in need of treatment Compound 1 and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0180] In another embodiment, described is a method of treating a solid tumor comprising administering to a patient in need of treatment Compound 1 and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0181] In another embodiment, described is a method of treating a hematological malignancy comprising administering to a patient in need of treatment Compound 1 and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma" Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

[0182] In another embodiment, described is a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need of treatment Compound 1 and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0183] In another embodiment, described is a method of treating multiple myeloma, comprising administering to a patient in need of treatment compound 1 and one or more additional therapeutic agents selected from bortezomib (Velcade®) and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).

[0184] In another embodiment, described is a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof Compound 1 and a BTK inhibitor, the disease being, for example, inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, and rheumatoid arthritis. encephalomyelitis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated cerebrospinal meningitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerular nephropathy, fetal Endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immune deficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g. allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, dust mites or cockroach umbrellas), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis , asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, sweat gland abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia,Polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B-cell proliferative disorders such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasma cell myeloma, Cellular tumors, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia or lymphomatoid granulomatosis, breast cancer, prostate cancer or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of the bone and joints (including but not limited to, rheumatoid arthritis, seronegative spondyloarthropathy (ankylosing spondylitis, psoriatic arthritis and Reiter's disease) (including pulmonary embolism), systemic sclerosis, osteoporosis, bone cancer, bone metastasis, thromboembolic disorders (e.g., myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, cerebral infarction, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, deep vein thrombosis), pelvic inflammatory disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease , irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and autoimmune thrombocytopenic conditions, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes mellitus, septic shock, cutaneous lupus erythematosus,The method is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, scleroderma, mycosis fungoides, and acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury).

[0185] In another embodiment, described is a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof compound 1, prepared according to the methods disclosed herein, and a PI3K inhibitor, wherein the disease is selected from cancer, a neurodegenerative disorder, an angiogenesis disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), a liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder.

[0186] In another embodiment, described is a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof compound 1, prepared according to the methods disclosed herein, and a PI3K inhibitor, the disease being a benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, abdomen, stomach tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, myeloma, leukemia ... tumors, cancer of the gastrointestinal tract, particularly colon cancer or colorectal adenoma, tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, epithelial plasma neoplasms, adenomas, adenocarcinomas, keratoacanthomas, epidermoid carcinomas, large cell carcinomas, non-small cell lung cancer, lymphomas (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also known as Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, Cowden syndrome, Lhermitte-Dacros disease, and Bannayan-Zonana syndrome, or diseases in which the PI3K / PKB pathway is aberrantly activated Disease, asthma of any type or origin (including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection), acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, chronic obstructive airways disease or chronic obstructive pulmonary disease (COPD, COAD or COLD) (chronic bronchitis or chronic bronchitis-associated dyspnea, emphysema, and airway obstruction resulting from other medications, especially other inhaled medications). bronchitis of any kind or origin (including but not limited to acute, arachidic, catarrhal, croupus, chronic or elongated bronchitis), pneumoconiosis of any kind or origin (inflammatory diseases of the lungs, whether chronic or acute, often accompanied by airway obstruction, caused by repeated inhalation of dust, generally of an occupational nature, including, for example, aluminum lung disease, anthracosis, asbestosis, stone disease, ptilosis, siderosis, silicosis, tobacco poisoning and byssinosis), Löffler's syndrome, eosinophilic, pneumonia,Parasitic (especially metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granulomas and eosinophil-related disorders affecting the airways (resulting from drug reactions), psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, diseases affecting the nose (including allergic rhinitis), inflammatory diseases involving an autoimmune reaction or having an autoimmune component or etiology (autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, Scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca, and vernal conjunctivitis), interstitial pulmonary fibrosis, The method is selected from psoriatic arthritis, glomerulonephritis (with or without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change nephropathy), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic cerebral infarction, congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia.

[0187] In some embodiments, described are methods of treating or reducing the severity of a disease, comprising administering to a patient in need thereof compound 1 prepared according to the methods disclosed herein and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the disorder is a proliferative disorder, lupus or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological neoplasm, or solid tumor.

[0188] In some embodiments, described are methods of treating or reducing the severity of a disease, comprising administering to a patient in need thereof a TYK2 pseudokinase (JH2) domain binding compound and a TYK2 kinase (JH1) domain binding compound. In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the JH2 domain binds to compound 1 prepared according to the methods disclosed herein. Other suitable JH2 domain binding compounds include those described in WO2014074660A1, WO2014074661A1, WO2015089143A1, each of which is incorporated herein by reference in its entirety. Suitable JH1 domain binding compounds include those described in WO2015131080A1, each of which is incorporated herein by reference in its entirety.

[0189] Compound 1 and compositions according to the methods disclosed herein may be administered in any amount and by any route of administration effective for treating or reducing the severity of autoimmune, inflammatory, proliferative, endocrine, neurological, and transplant-related disorders. The exact amount required will vary from subject to subject, depending on the subject's race, age, and general condition, the severity of the infection, the specific drug, its method of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The term "dosage unit form" as used herein refers to a physically discrete pharmaceutical unit appropriate for the patient to be treated. However, it will be understood that the total daily usage of the compounds and compositions will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the activity of the specific compound used, the specific composition used, the age, weight, general health, sex and diet of the patient, the time of administration, route of administration and rate of excretion of the specific compound used, the duration of the treatment, drugs used in combination or concomitantly with the specific compound used, and similar factors well known in the medical art. The term "patient", as used herein, means an animal, preferably a mammalian animal, and most preferably a human.

[0190] Pharmaceutically acceptable compositions can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powder, ointment or drops), orally as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds may be administered orally or parenterally, at dosage levels of about 0.01 mg to about 50 mg per kg of subject body weight per day, and preferably about 1 mg to about 25 mg per kg, one or more times per day, to produce the desired therapeutic effect.

[0191] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions may also contain adjuvants, such as wetting agents, emulsifying agents, suspending agents, sweeteners, flavoring agents, and odor-correcting agents.

[0192] Injectable preparations, for example, sterile aqueous or oleaginous injection suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can be as sterile injectable solutions, suspensions or emulsions in non-toxic acceptable parenteral diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution (USP) and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

[0193] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water, or other injectable sterile medium prior to use.

[0194] To prolong the effect of Compound 1, it may be desirable to slow the absorption of the compound injected subcutaneously or intramuscularly. This may be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on the size and crystalline form of the crystals. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the release rate of Compound 1 can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with living tissue.

[0195] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing compound 1 prepared by the methods of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at ambient temperature but liquid at body temperature and thus will melt in the rectum or vaginal cavity releasing the active compound.

[0196] The solid dosage form for oral administration includes capsules, tablets, pills, powders and granules.In such solid dosage forms, active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) filler or extender, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) moisturizer, such as glycerol, d) disintegrant, such as agar, calcium carbonate, Potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarders such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0197] Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells well known in the pharmaceutical art, such as enteric coatings and other coatings. These dosage forms may optionally contain opacifying agents, and may also be of a composition that releases the active ingredient(s) only, or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0198] The active compound of the present invention may also be in microencapsulated form with one or more of the excipients described above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells well known in the pharmaceutical art, such as enteric coatings, release controlling coatings and other coatings. In such solid dosage forms, the active compound may be admixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also contain, as is normal practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. These dosage forms may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0199] The topical or transdermal dosage forms of Compound 1 prepared by the method of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and, if necessary, any necessary preservatives or buffers. Ophthalmic formulations, eye drops and ear drops are also contemplated within the scope. In addition, contemplated is the use of transdermal patches, which have the added advantage of providing a controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the amount of the compound that penetrates the skin. The rate can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0200] According to one embodiment, described is a method of inhibiting protein kinase activity in a biological sample, comprising contacting the biological sample with compound 1 prepared by a method of the invention, or a composition comprising said compound.

[0201] According to another embodiment, a method of inhibiting the activity of TYK2 or a mutant thereof in a biological sample is contemplated, comprising contacting said biological sample with a compound or a composition comprising said compound. In a particular embodiment, described is a method of irreversibly inhibiting the activity of TYK2 or a mutant thereof in a biological sample, comprising contacting said biological sample with compound 1 prepared by the method of the invention, or a composition comprising said compound.

[0202] In another embodiment, described are methods of selectively inhibiting TYK2 over one or more of JAK1, JAK2, and JAK3. In some embodiments, compound 1 produced by the methods of the invention is more than 2-fold selective over JAK1 / 2 / 3. In some embodiments, the compound is more than 5-fold selective over JAK1 / 2 / 3. In some embodiments, the compound is more than 10-fold selective over JAK1 / 2 / 3. In some embodiments, the compound is more than 50-fold selective over JAK1 / 2 / 3. In some embodiments, the compound is more than 100-fold selective over JAK1 / 2 / 3.

[0203] The term "biological sample" as used herein includes, but is not limited to, cell culture medium or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0204] Inhibiting the activity of TYK2 (or a variant thereof) in a biological sample is useful for a variety of purposes known to those of skill in the art, including, but not limited to, blood transfusion, organ transplantation, biological sample storage, and biological assays.

[0205] Another embodiment relates to a method of inhibiting protein kinase activity in a patient, comprising administering to the patient compound 1 prepared by a method of the invention, or a composition comprising said compound.

[0206] Another embodiment relates to a method of inhibiting the activity of TYK2 or a mutant thereof in a patient, comprising administering to said patient compound 1 prepared by the methods of the invention, or a composition comprising said compound. According to certain embodiments, a method of reversibly or irreversibly inhibiting one or more activities of TYK2 or a mutant thereof in a patient, comprising administering to said patient compound 1 prepared by the methods of the invention, or a composition comprising said compound. In other embodiments, provided is a method for treating a disorder mediated by TYK2 or a mutant thereof in a patient in need of such treatment, comprising administering to said patient compound 1 prepared by the methods of the invention, or a pharma- ceutically acceptable composition thereof. Such disorders are described in detail herein.

[0207] Depending on the particular condition, or disease, being treated, additional therapeutic agents that are normally administered to treat that condition may be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0208] Compound 1 prepared by the method of the present invention may be used to advantage in combination with other therapeutic compounds. In some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active compounds, alkylating compounds, histone deacetylase inhibitors, compounds inducing cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, antitumor antimetabolites, platin compounds, compounds targeting / reducing protein or lipid kinase activity, and further angiogenesis inhibitor compounds, compounds targeting, reducing or inhibiting protein or lipid phosphatase activity, gonadorelin agonists, antiandrogens, methionine aminopeptidase inhibitors. agents, matrix metalloproteinase inhibitors, bisphosphonates, biological response modifiers, antiproliferative antibodies, heparanase inhibitors, inhibitors of Ras oncogenic isoforms, telomerase inhibitors, proteasome inhibitors, compounds for use in the treatment of hematological malignancies, compounds which target, reduce or inhibit the activity of Flt-3, Hsp90 inhibitors, e.g., 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma These include, but are not limited to, temozolomide (Temodal®), kinesin spindle protein inhibitors such as SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx), MEK inhibitors such as ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer), and leucovorin.The term "aromatase inhibitors" as used herein relates to compounds that inhibit estrogen production, for example the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. This term includes, but is not limited to, steroids, in particular atamestane, exemestane and formestane, and nonsteroids, in particular aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is sold under the trade name Aromasin™. Formestane is sold under the trade name Lentaron™. Fadrozole is sold under the trade name Afema™. Anastrozole is sold under the trade name Arimidex™. Letrozole is sold under the trade name Femara™ or Femar™. Aminoglutethimide is sold under the trade name Orimeten.TM.. Combinations that include chemotherapeutic agents that are aromatase inhibitors are particularly useful in the treatment of hormone receptor positive tumors, such as tumors of the breast.

[0209] The term "antiestrogen" as used herein refers to a compound that antagonizes the action of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is sold under the trade name Nolvadex. Raloxifene hydrochloride is sold under the trade name Evista. Fulvestrant can be administered under the trade name Faslodex. Combinations that include chemotherapeutic agents that are antiestrogens are particularly useful for treating estrogen receptor positive tumors, such as breast tumors.

[0210] The term "antiandrogen" as used herein refers to any substance capable of inhibiting the biological action of male hormones, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[0211] The term "topoisomerase I inhibitors" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the polymeric camptothecin conjugate PNU-166148. For example, irinotecan can be administered in its marketed form, for example, under the trade name Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[0212] The term "topoisomerase II inhibitors" as used herein includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and rosoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is sold under the trade name Etopophos™. Teniposide is sold under the trade name VM 26-Bristol. Doxorubicin is sold under the trade name Acriblastin™ or Adriamycin™. Epirubicin is sold under the trade name Farmorubicin™. Idarubicin is sold under the trade name Zavedos™. Mitoxantrone is sold under the trade name Novantron.

[0213] The term "microtubule activator" refers to microtubule stabilizing compounds, microtubule destabilizing compounds and microtubule polymerization inhibitors, including, but not limited to, taxanes, such as paclitaxel and docetaxel, vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine, discodermolide, colchicine, and epothilones, and derivatives thereof. Paclitaxel is sold under the trade name Taxol™. Docetaxel is sold under the trade name Taxotere™. Vinblastine sulfate is sold under the trade name Vinblastin RP™. Vincristine sulfate is sold under the trade name Farmistin™.

[0214] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin™. Ifosfamide is sold under the trade name Holoxan™.

[0215] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including, but not limited to, suberoylanilide hydroxamic acid (SAHA).

[0216] The term "antineoplastic antimetabolites" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed. Capecitabine is sold under the trade name Xeloda™. Gemcitabine is sold under the trade name Gemzar™.

[0217] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum, and oxaliplatin. For example, carboplatin can be administered in the form as it is marketed, e.g., under the trade name Carboplat™. For example, oxaliplatin can be administered in the form as it is marketed, e.g., under the trade name Eloxatin™.

[0218] The term "compounds which target / reduce protein or lipid kinase activity or protein or lipid phosphatase activity or further angiogenesis inhibitory compounds" as used herein includes inhibitors of protein tyrosine kinases and / or serine and / or threonine kinases or lipid kinase inhibitors, such as a) compounds which target, reduce or inhibit the activity of platelet derived growth factor receptors (PDGFRs), e.g. compounds which target, reduce or inhibit the activity of PDGFRs, in particular b) compounds which target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFRs); c) compounds which target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), for example compounds which target, reduce or inhibit the activity of IGF-IR, in particular compounds which inhibit the kinase activity of the IGF-I receptor or compounds which inhibit the kinase activity of the IGF-I receptor or Antibodies targeting the extracellular domain of the growth factor, d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family or ephrin B4 inhibitors, e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family, f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase, g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, e.g. imatinib, h) PDGFR family i) compounds which target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is a member of the c-Kit receptor tyrosine kinase family, for example compounds which target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds which inhibit the c-Kit receptor, for example imatinib, i) compounds which target, reduce or inhibit the activity of members of the c-Abl family, their gene fusion products (for example BCR-Abl kinase) and mutants, for example compounds which target or reduce the activity of c-Abl family members and their gene fusion products,j) compounds which target, reduce or inhibit the activity of protein kinase C (PKC) and members of the Raf family of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, members of the PI3K, SYK, BTK and TEC families, and / or members of the cyclin-dependent kinase family (CDK) (e.g. stauroside kinases such as midostaurin); Examples of further compounds include UCN-01, safingol, BAY43-9006, bryostatin 1, perifosine, irmofosine, RO318220 and RO320432, GO6976, lsis3521, LY333531 / LY379196, isoquinoline compounds, FTI, PD184352 or QAN697 (P13K inhibitors), or AT7519 (CDK inhibitors), k) compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors (e.g. compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors include imatinib mesylate (Gleevec™), tyrphostins, e.g. Tyrphostin A23 / RG-50810, AG99, Tyrphostin AG213, Tyrphostin AG1748, Tyrphostin AG 490, Tyrphostin B44, Tyrphostin B44(+) enantiomer, Tyrphostin AG 555, AG494, Tyrphostin AG556, AG957, and Adafostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester, NSC680410, Adafostin); l) targeting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants;Compounds that reduce or inhibit (e.g., compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, in particular compounds, proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4, or that bind to EGF or EGF-related ligands, CP358774, ZD1839, ZM105180, trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, O SI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, as well as 7H-pyrrolo-[2,3-d]pyrimidine derivatives), m) compounds which target, reduce or inhibit the activity of the c-Met receptor, for example compounds which target, reduce or inhibit the activity of c-Met, in particular compounds which inhibit the kinase activity of the c-Met receptor, or antibodies which target the extracellular domain of c-Met or which bind to HGF, n) 1 compounds that target, reduce or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK) (including, but not limited to, PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib and ruxolitinib); o) compounds that target, reduce or inhibit the kinase activity of PI3 kinase (PI3K) (including, but not limited to, ATU-027, SF-1126, D S-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765 and idelalisib), and q) compounds that target, reduce or inhibit the signaling action of the Hedgehog protein (Hh) or Smoothened receptor (SMO) pathways, including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (salidegib),These include, but are not limited to,

[0219] The term "PI3K inhibitor", as used herein, includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to, PI3K alpha, PI3K gamma, PI3K delta, PI3K beta, PI3K-C2 alpha, PI3K-C2 beta, PI3K-C2 gamma, Vps34, p110-alpha, p110-beta, p110-gamma, p110-delta, p85-alpha, p85-beta, p55-gamma, p150, p101, and p87. Examples of PI3K inhibitors include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0220] The term "BTK inhibitor", as used herein, includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0221] The term "SYK inhibitors", as used herein, includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607 and fostamatinib.

[0222] The term "Bcl-2 inhibitors", as used herein, includes compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's Pan-Bcl-2 inhibitors, curcumin (and analogs thereof), Bcl-2 / Bcl-xL dual inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof, see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of In some embodiments, the Bcl-2 inhibitor is a small molecule drug. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0223] Further examples of BTK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2008039218 and WO2011090760, which are incorporated by reference herein in their entireties.

[0224] Further examples of SYK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2003063794, WO2005007623 and WO2006078846, which are incorporated herein by reference in their entireties.

[0225] Further examples of PI3K inhibitor compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entireties of which are incorporated herein by reference.

[0226] Further examples of JAK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, which are incorporated by reference in their entireties.

[0227] Additional anti-angiogenic compounds include compounds that have another mechanism for their activity, e.g., a mechanism unrelated to the inhibition of protein or lipid kinases, such as thalidomide (Thalomid™) and TNP-470.

[0228] Examples of proteasome inhibitors useful for use in combination with compound 1 prepared by the methods of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0229] Compounds which target, decrease or inhibit the activity of protein or lipid phosphatases are eg inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or a derivative thereof.

[0230] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, γ-tocotrienol or δ-tocotrienol.

[0231] The term cyclooxygenase inhibitors as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenyl acetic acids and derivatives, such as celecoxib (Celebrex™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenyl acetic acids, such as lumiracoxib, which is 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid.

[0232] The term "bisphosphonates" as used herein includes, but is not limited to, etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid. Etidronic acid is sold under the trade name Didronel™. Clodronic acid is sold under the trade name Bonefos™. Tiludronic acid is sold under the trade name Skelid™. Pamidronic acid is sold under the trade name Aredia™. Alendronic acid is sold under the trade name Fosamax™. Ibandronic acid is sold under the trade name Bondranat™. Risedronic acid is sold under the trade name Actonel™. Zoledronic acid is sold under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0233] The term "heparanase inhibitors" as used herein refers to compounds that target, reduce or inhibit the degradation of heparin sulfate. This term includes, but is not limited to, PI-88. The term "biological response modifiers" as used herein refers to lymphokines or interferons.

[0234] The term "inhibitor of oncogenic isoform of Ras" such as H-Ras, K-Ras or N-Ras, as used herein, refers to a compound that targets, reduces or inhibits the oncogenic activity of Ras, such as "farnesyltransferase inhibitors", for example, L-744832, DK8G557 or R115777 (Zarnestra™). The term "telomerase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of telomerase. Compounds that target, reduce or inhibit the activity of telomerase are particularly compounds that inhibit telomerase receptor, such as telomestatin.

[0235] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of methionine aminopeptidase. Compounds that target, reduces or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0236] The term "proteasome inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of the proteasome. Compounds that target, reduces or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade™) and MLN341.

[0237] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) as used herein includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its oral bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC683551), BMS-279251, BAY12-9566, TAA211, MMI270B or AAJ996.

[0238] The term "compounds for use in the treatment of hematological malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R), interferons, 1-β-D-arabinofuransylcytosine (ara-c) and busulfan, ALK inhibitors, which are compounds that target, reduce or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.

[0239] Compounds which target, decrease or inhibit the activity of the FLT-3R-like tyrosine kinase receptor are in particular compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0240] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90, compounds that degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin proteosome pathway. Compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 are in particular compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives, other geldanamycin-related compounds, radicicol and HDAC inhibitors.

[0241] The term "antiproliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, Erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 antibodies. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, provided that they exhibit the desired biological activity.

[0242] For the treatment of acute myeloid leukemia (AML), the compound of the present invention can be used in combination with standard leukemia therapy, in particular in combination with therapy used in the treatment of AML.In particular, compound 1 prepared by the method of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum and PKC412.In some embodiments, the method is a method for treating AML associated with ITD and / or D835Y mutation, comprising administering compound 1 prepared by the method of the present invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), staurosporine derivatives (e.g., midostaurin or lestaurtinib), sorafenib, tanzutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitor is selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.

[0243] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue, which is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogues hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, reduce or inhibit the activity of histone deacetylase (HDAC) inhibitors, for example, sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and compounds disclosed in US6,552,065, including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, particularly the lactate salt. Somatostatin receptor antagonists, as used herein, refer to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Approaches that damage tumor cells refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and below means ionizing radiation that occurs either as electromagnetic waves (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy and is known in the art. Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1, pp. 248-275 (1993).

[0244] Also included are EDG binders and ribonucleotide reductase inhibitors. The term "EDG binders" as used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitors" refers to pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are in particular hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0245] In particular, these compounds, proteins or monoclonal antibodies of VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharma- ceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate, Angiostatin™, Endostatin™, anthranilic acid amide, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers, such as Macugon, FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI4610), and bevacizumab (Avastin™).

[0246] Photodynamic therapy, as used herein, refers to therapy that uses certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0247] Angiogenesis inhibitory steroids, as used herein, refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0248] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0249] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists, biological response modifiers, preferably lymphokines or interferons, antisense oligonucleotides or oligonucleotide derivatives, shRNA or siRNA, or miscellaneous compounds, or compounds with other or unknown mechanisms of action.

[0250] Compound 1 prepared by the method of the present invention is also useful as a combination therapeutic compound, in particular in the treatment of obstructive or inflammatory airway diseases, such as those mentioned above, in combination with other drug substances, such as anti-inflammatory, bronchodilatory or antihistamine drug substances, for example, as an enhancer of the therapeutic activity of such drugs or as a means of reducing the required dosage or potential side effects of such drugs. Compound 1 prepared by the method of the present invention may be mixed with the other drug substances in a pharmaceutical composition, or may be administered separately, before, simultaneously with or after the other drug substances. Thus, provided is a combination of compound 1 prepared by the method of the present invention as described above with an anti-inflammatory, bronchodilatory, antihistamine or antitussive drug substance, wherein the compound and the drug substance are present in the same pharmaceutical composition or in different pharmaceutical compositions.

[0251] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, non-steroidal glucocorticoid receptor agonists, LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL284, ONO4057, SB209247, LTD4 antagonists such as montelukast and zafirlukast, PDE4 inhibitors such as cilomilast (Ariflo®, GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Allophylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID (trademark) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Suitable bronchodilators include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxitropium bromide, tiotropium salts and CHF4226 (Chiesi), as well as glycopyrrolate.

[0252] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratadine, diphenhydramine, fexofenadine hydrochloride, acrivastine, astemizole, azelastine, ebastine, epinastine, mizolastine, and terfenadine.

[0253] Other useful combinations of compounds with anti-inflammatory agents are with antagonists of chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9, CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0254] The structures of the active compounds, identified by code number, generic name or trade name, can be obtained from the current edition of the standard compendium "The Merck Index", or from databases such as Patents International (eg IMS World Publications).

[0255] Compound 1 prepared by the method of the present invention may be used in combination with known therapeutic processes, such as administration of hormones or irradiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that are poorly sensitive to radiation therapy.

[0256] Compound 1 prepared by the method of the present invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy being in the form of a fixed combination, a time-delayed or independent administration of compound 1 prepared by the method of the present invention and one or more other therapeutic compounds, or a fixed combination administered in combination with one or more other therapeutic compounds. Compound 1 prepared by the method of the present invention can be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention or a combination thereof, particularly for the treatment of tumors, or in addition. Long-term therapy is also possible in the context of other therapeutic strategies as described above, such as adjuvant therapy. Another possible treatment is therapy to maintain the patient's condition after tumor regression or even after chemopreventive therapy, for example in patients at risk.

[0257] These additional agents may be administered as part of a multiple dose regimen, separate from the composition containing the compound as described herein. Alternatively, these agents may be part of a single dosage form, mixed together in a single composition with compound 1 prepared by the method of the present invention. When administered as part of a multiple dose regimen, these two active agents may be provided simultaneously, sequentially, or within a period of one another, typically within 5 hours of the other.

[0258] As used herein, the terms "combination", "combined" and related terms refer to simultaneous or sequential administration of therapeutic agents. For example, compound 1 prepared by the method of the present invention may be administered simultaneously or sequentially with another therapeutic agent, either in separate unit dosage forms or together in one unit dosage form. Thus, one unit dosage form includes compound 1 prepared by the method of the present invention, the additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0259] The amounts of any of the compounds of the invention and additional therapeutic agents (in compositions containing additional therapeutic agents as described above) that may be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the composition should be formulated so that a dosage of 0.01-100 mg / kg of body weight / day of the compound of the invention can be administered.

[0260] In those compositions that include an additional therapeutic agent, the additional therapeutic agent and compound 1 prepared by the methods described herein may act synergistically. Thus, the amount of additional therapeutic agent in such compositions will be less than that required for monotherapy using only that therapeutic agent. In such compositions, the additional therapeutic agent may be administered at a dosage of 0.01-1,000 μg / kg body weight / day.

[0261] The amount of additional therapeutic agent present in a composition comprising Compound 1 prepared by the methods of the invention will not be greater than the amount that would normally be administered in a composition containing that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in a composition disclosed herein will be in the range of about 50% to 100% of the amount that would normally be present in a composition containing that agent as the only therapeutically active agent.

[0262] Compound 1 or a pharmaceutical composition thereof prepared by the method of the present invention may be incorporated into a composition for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, are used to eliminate restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharma- ceutically acceptable composition that includes a kinase inhibitor. An implantable device coated with Compound 1 is another embodiment.

[0263] In some embodiments, a medicament is provided that includes at least Compound 1, or a pharma- ceutically acceptable salt or solvate thereof, prepared by the methods described herein, and a pharma- ceutically acceptable carrier.

[0264] Any of the features of each aspect of the invention apply to all other aspects mutatis mutandis.

[0265] In order that the invention described herein may be more fully understood, the following examples are set forth, it being understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. EXAMPLES

[0266] Example 1: Synthesis of Compound 1 Scheme 2 below illustrates detailed synthetic procedures for producing compounds 6, 2 and 1. Scheme 2: Detailed synthetic procedure for the synthesis of compound 1 [ka] Step 1: Synthesis of Compound 6 [ka]

[0267] Compound 7 may be prepared as shown in the scheme below. [ka] The overall yield was 29.2%. Using this process, compound 7 was prepared on a 60.0 kg scale starting with 140.0 kg of ethyl 3-amino-1H-pyrazole-4-carboxylate. The campaign produced 29.31 kg of 7 with a chemical purity of 99.0% and 41.16 kg of 7 with a chemical purity of 98.8%.

[0268] Compound 7 (1.9 Kg, 5.82 mol, 1.00 eq), the hydrochloride salt of compound 5 (800.9 g, 5.82 mol, 1.00 eq), DIPEA (4.5 Kg, 34.92 mol, 6.00 eq), T3P (50% in EtOAc) (7.4 Kg, 11.64 mol, 2.00 eq) were dissolved in DCM (50.3 Kg, 48.0 L, 20 vol) at 0 ± 5 °C.

[0269] After stirring at 0±5° C. for 1 h, HPLC (30 min method, UV 242 nm) of the reaction sample showed the desired product, compound 6, to be 81%.

[0270] After stirring the reaction for an additional hour at 0±5° C., HPLC of a second reaction sample showed 82% of the desired product, compound 6, and 18% of starting material, compound 7, plus the two activated ester intermediates. At this stage, Applicants proceeded to a water quench.

[0271] Quenching and workup of the reaction The reaction mixture was quenched with water (3.8Kg, 3.8L, 2vol). The DCM was distilled and the residue was dissolved in EtOAc (68.6Kg, 76.1L, 40vol). The organic layer was washed with 20% aqueous K2CO3 (33.4Kg, 15vol), 10% K2CO3 (2x19.0Kg, 2x10vol).

[0272] HPLC analysis of the organic layer showed 99.05% desired product, compound 6, with 1% starting material, compound 7, and two by-product activated ester intermediates combined.

[0273] The organic layer passed a purity test and was washed successively with water (9.5 Kg, 5 vol) and brine (2 x 9.5 Kg, 2 x 5 vol). The resulting organic layer was filtered through a silica plug (5.7 Kg, 2% (w / w)) topped with 5.0 Kg of sand. The silica plug was washed with EtOAc (34.4 Kg, 38.0 L, 20 vol).

[0274] Trituration in n-heptane The combined filtrate was concentrated to approximately 6 L (3.2 vol). n-heptane (7.8 Kg, 11.4 L, 6 vol) was slowly charged over a period of 30 min. The mixture was stirred at 20±5° C. for at least 2 h (actual stirring time: overnight, 15.4 h). The solid was collected by filtration and washed with n-heptane [2×5.2 Kg (2×7.6 L, 2×4 vol)].

[0275] Drying and infusion After drying in a vacuum tray dryer at 43°C for 23 hours, a sample was removed for LOD (limit of detection) testing, which showed an LOD result of 0.35%. The material was injected to give the product compound 6, 1.73 Kg, as a white solid in 72.4% yield. 1 H NMR (DMSO-d6)ppm: 1.29 (s, 9H), 1.51 (m, 2H), 2.04 (m, 2H), 3.22 (s, 3H), 3.32 (s, 3H), 3.84 (m, 1H), 4.28 (m, 1H), 7.53 (s, 1H), 8.03 (d, 1H), 8.63 (s, 1H)

[0276] Step 2: Synthesis of Compound 2 [ka] Compound 4 may be prepared as shown in the scheme below. [ka] The overall yield was 74.5%. Using the above route, 3 x 20 kg of 4 were delivered. Batch production was started with approximately 18.0 kg (corrected by assay) of 3-aminopyridin-2-ol and approximately 22.2 kg of 2-fluoropyridine. The produced campaigns were 23.91 kg of 4 with 99.8% chromatographic purity, 22.84 kg of 4 with 99.8% chromatographic purity, and 22.90 kg of 4 with 99.8% chromatographic purity, respectively.

[0277] Compound 6 (1.7 Kg, 4.15 mol, 1.00 eq), compound 4 (799.3 g, 4.27 mol, 1.03 eq), Pd(OAc)2 (18.0 g, 0.08 mol, 0.020 eq), Xantphos (46.3 g, 0.08 mol, 0.020 eq), K2CO3 (1.26 Kg, 9.13 mol, 2.20 eq) in DME (26.5 Kg, 30.6 L, 18 vol) at 80 ± 5 °C were combined in a 50 gallon tank. The reaction was completed after 4 hours at 80 °C. HPLC (UV 266 nm) analysis of the reaction mixture showed 0.06% compound 6 remaining.

[0278] Two crude populations After confirming the completion of the reaction, the reaction mixture was cooled to 20±5° C. and stirred at 20±5° C. for at least 30 minutes. The solids were filtered and washed twice with MTBE (4.2 Kg and 3.6 Kg) to obtain "first batch crude solids". The filtrate was returned to the 50 gallon reactor. The mixture was concentrated until no distillate was observed. DME (3.3 Kg) and MTBE (5.6 Kg) were injected. The mixture was stirred at 20±5° C. for at least 30 minutes. The solids were collected by filtration and washed with MTBE (6.1 Kg) to obtain "second batch crude solids".

[0279] Extraction with DCM The two resulting crude solid crops were combined and transferred to the 50 gallon reactor. DCM (37.9 Kg) and water (28.5 Kg) were added. The mixture was stirred at 20±5° C. for at least 15 minutes and then allowed to settle for phase separation. The mixture was left to settle overnight (17.5 hours) to eliminate the emulsion.

[0280] After decanting the DCM layer, the aqueous layer was back-extracted twice with DCM (12.6 Kg each time), the first back-extraction was allowed to stand for 6 hours and the second back-extraction was allowed to stand overnight (15 hours).

[0281] Optionally, the DCM / water mixture can be filtered through Celite to remove insoluble solids before phase separation. Lab experiments have shown that the phase separation is much faster after filtering and removing the insoluble solids. In addition, product loss due to unclear phase separation can be avoided.

[0282] Washing with N-Ac-L-Cys aqueous solution, water and brine The combined product in DCM solution was washed three times (38.0 Kg each time) with 10% N-Ac-L-cysteine ​​(NAC) aqueous solution. After standing for 30 minutes, a clear phase separation was obtained. The DCM layer was then washed successively with water (19.0 Kg) and saturated aqueous NaCl solution (19.0 Kg).

[0283] Treatment with activated carbon After treatment with NAC, washing with water and brine, the product solution in DCM was distilled and solvent exchanged to THF (2 times with 5.1 Kg of THF). Activated carbon (340.0 g, 20 wt% for 1.7 Kg of compound 6 as starting material) and THF (30.4 Kg, 34.2 L, 20 vol for 1.7 Kg of compound 6 as starting material) were injected. The mixture was heated to 60±5° C. and stirred at 60±5° C. for at least 6 hours (overnight, stirred for about 18 hours). Subsequently, the mixture was cooled to 20±5° C. and the coal was filtered off through Celite (3.2 Kg). The Celite pad was washed with THF (5.0 Kg). A sample of the THF solution was taken. The sample solution was concentrated and tested for palladium (Pd) content analysis. The Pd content was found to be less than 7.88 ppm.

[0284] Processing in SPM32 Three treatments with SPM32 (570 g SPM32 per treatment) were carried out in THF for at least 6 hours at 60±5° C. After cooling to 20±5° C., the scavenger SPM32 was filtered off through Celite and the Celite was washed with THF. The three treatments were as follows:

[0285] First treatment with SPM32 (570g of SPM32): 18 hours at 60±5℃, Celite: 2.4Kg, THF for washing Celite: 7.3Kg

[0286] Second treatment with SPM32 (570g SPM32): 20.4 hours at 60±5℃, Celite: 1.5Kg, THF for washing Celite: 7.2Kg

[0287] 3rd treatment with SPM32 (570g SPM32): 21 hours at 60±5℃, Celite: 1.5Kg, THF for washing Celite: 8.1Kg

[0288] A sample of the THF solution was removed. The sample solution was concentrated and tested for Pd content analysis. The Pd content was found to be less than 7.94 ppm.

[0289] distillation

[0290] After treatment with SPM32, the THF solution was concentrated in a 50 gallon tank to approximately 20 L. The THF solution was transferred to a clean drum. The tank was rinsed with THF (10.4 Kg) and the rinse was transferred to the drum. The product was isolated in a 100 L reactor as follows:

[0291] Distillation in a 100 L reactor: The THF solution in the drum was transferred to a 100 L reactor and concentrated under vacuum to about 10 L. MTBE (14.8 Kg, 20.0 L) was injected and the mixture was concentrated to about 10 L. The distillation with MTBE exchange was repeated two more times (14.8 Kg MTBE each time, concentrated to about 10 L).

[0292] Trituration in MTBE After distillation of the solvent (approximately 10 L remained), MTBE (11.1 Kg, 15 L) was injected. The mixture was heated to 50±5° C. and stirred at 50±5° C. for 1 hour. After cooling to 20±5° C., the mixture was stirred at 20±5° C. overnight (19.5 hours). The batch was filtered and the wet cake was washed twice with MTBE (2.8 Kg and 4.8 Kg, respectively). A sample of the wet cake was removed and analyzed by HPLC, which showed a purity of 99.29%.

[0293] Drying and infusion The material was dried in a vacuum tray dryer at up to 45° C. for at least 16 hours. After drying at 43° C. for 21.7 hours, a sample was removed for LOD testing, which showed an LOD of 0.88%. The material was poured. 1.5 Kg of compound 2 was obtained as an off-white solid, with a yield of 65.2%. 1 H NMR (DMSO-d6)ppm: 1.33 (s, 9H), 1.50 (m, 2H), 2.10 (m, 2H), 3.21 (s, 3H), 3.25 (s, 3H), 3.77 (m, 1H), 4.34 (m, 1H), 6.49 (m, 1H), 7.18 (s, 1H), 7.55 (dd, 1H), 7.71 (dd, 1H), 7.88 (d, 1H), 8.0 (d, 1H), 8.05 (dd, 1H), 8.29 (s, 1H), 8.5 (dd, 1H), 8.65 (dd, 1H), 9.75 (s, 1H)

[0294] Synthesis of Reagent Compound 5 Compound 5 used in the above protocol can be prepared from cyclobutanone according to the scheme and sequence shown below. [ka]

[0295] Cyclobutanone was converted to 2-bromocyclobutan-1-one by the following steps: DCM (1330 kg, 10 vol.) was injected into a 2000 L stainless steel reactor under N2 protection, followed by sequential injection of cyclobutanone (100 Kg, 1.0 eq.) and TEA (216.6 kg, 1.5 eq.). Cooled to -15 to -25 °C. TMSOTf (381.1 kg, 1.2 eq.) was added dropwise to the reactor at -15 to -25 °C for about 7 hours. Stirred at -15 to -25 °C for 2 hours. N-bromosuccinimide (NBS) (253.3 kg, 1.0 eq.) was injected in portions at -15 to -25 °C for about 16 hours. Stirred at -15 to -25 °C for 2 hours. After heating to 0-10°C, soft water (200 kg, 2 vol.) was injected and stirred for 20 min at 10-20°C. The mixture was transferred to a 3000 L glass-lined reactor, water (300 kg, 3.0 vol.) was injected and stirred for 20 min at 20-30°C. The lower organic layer was separated and collected. The organic layer was washed with soft water (500 kg, 5 vol.). 0.5 N HCl (533 kg, 5 vol.) was injected into the organic layer and stirred for 1 h at 10-20°C. The lower organic layer was separated and collected. The organic layer was washed with soft water (500 kg, 5 vol.). The organic layer was washed with 10% brine (535 kg, 5 vol.). The organic layer was concentrated 2-3 times under vacuum at ≤35°C. DCM (665 kg, 5 vol.) was charged and concentrated 1-2 fold under vacuum at <35°C. This procedure was repeated twice to remove water. Sampled for KF (criterion: KF <0.5%, result: <0.01%). The residue was collected to give 2-bromocyclobutan-1-one as a light brown oil (331.8 kg in DCM, assay: 32%, 106.3 kg, KF <0.01%, assay yield: 50%).

[0296] 2-Bromocyclobutan-1-one was converted to 2-(dibenzylamino)cyclobutan-1-one according to the following steps: DCM (707 kg, 5 vol.) was injected into a 3000 L glass-lined reactor under N2 protection, followed by Bn2NH (140 kg, 1.0 eq.) and DIPEA (115 kg, 1.25 eq.). 2-Bromocyclobutan-1-one (106 kg, 1.0 eq.) was injected into the reactor at 15-25 °C. Stirred at 15-25 °C for 16 h. Concentrated under vacuum at <40 °C by 4-5 times. Injected EtOAc (572 kg, 6 vol.) and then concentrated under vacuum at <40 °C by 4-5 times. Injected EtOAc (572 kg, 6 vol.). Washed once with water (636 kg, 6 vol.) (separated emulsified layer into aqueous layer). Washed once with 2% brine (649 kg, 6 vol.). EtOAc was extracted with 1N HCl (2×636 L, 1×318 L, 2×6 vol., 1×3 vol.) and the aqueous layers were combined. The pH of the aqueous phase was adjusted to 9-10 with 20% NaOH. NaCl (212 kg, 2 w / w) was charged and stirred until the solids were dissolved. The aqueous layer was extracted once with THF (755 kg, 8 vol.). The aqueous layer was extracted once more with THF (472 kg, 5 vol.). The organic layers were combined and washed once with 10% brine (340 kg, 3 vol.). The organic layer was collected to give a pale yellow solution of 2-(dibenzylamino)cyclobutan-1-one (1155 kg of THF solution, assay: 14.98%, 173 kg of 5028-2 (corrected assay), purity: 93.0% (BnNH: 3.0%), KF: 7.9%, assay yield: 92%), which was used in the next reaction sequence.

[0297] 2-(dibenzylamino)cyclobutan-1-one was converted to racemic trans-2-(dibenzylamino)cyclobutan-1-ol according to the following sequence: A solution of 2-(dibenzylamino)cyclobutan-1-one (775 kg, containing 116 kg of 2-(dibenzylamino)cyclobutan-1-one) obtained from the above sequence was pumped into a 2000 L stainless steel reactor under N2 protection. Soft water (47 kg, 0.41 vol., from a THF solution containing 0.59 vol. of water) and THF (266 kg, 2.68 vol.) were pumped into the reactor. It was cooled to -50°C to -60°C. NaBH4 (16.5 kg, 1.0 eq.) was pumped into the reactor in portions at -50°C to -60°C. It was stirred for 1 h at -50°C to -60°C. The temperature was raised to -10°C and the reaction was quenched by dropwise addition of acetone (90.5 kg, 1 vol.). Soft water (406 kg, 3.5 vol.) was injected into the reaction below 30°C. MTBE (429 kg, 5 vol.) was injected to dilute the reaction mixture. The mixture was separated, the aqueous layer was extracted with MTBE (172 kg, 2 vol.) and the organic layers were combined. The organic layer was washed with 5% brine (300 kg, 2.5 vol.). The organic phase was washed with 20% brine (348 kg, 2.5 vol.). The organic layer was concentrated under vacuum below 45°C to 220 L (1.9 vol., target: 1-2 vol.). n-heptane (6.0 vol.) was injected. n-heptane (3.0 vol.) was injected. Concentrated 4-5 times under vacuum below 45°C. Inject n-heptane (3.0 vol.). Stir at 15-25°C until copious amounts of solids precipitated (>3 h). Heat to 40-45°C and stir until material (that stuck to the reactor walls) was in the system, then inject n-heptane (2.0 vol.). Cool to 10-20°C and stir >3 h. Filter and wash the filter cake with n-heptane (2.0 vol.). Dry under vacuum below 35°C until KF was 0.5% or less, then sample for LOD and record the results.The product was collected to give racemic trans-2-(dibenzylamino)cyclobutan-1-ol as an off-white solid (66.0 kg, P: 98.7% (Bn2NH: 0.51%, cis: 0.56%), isolated yield: 56.4%).

[0298] Racemic trans-2-(dibenzylamino)cyclobutan-1-ol was enzymatically chiral resolved according to the following sequence: Acetone (1422 kg, 20 vol.) was injected into a 3000 L reactor under N2 protection. Stirred for 20 min and sampled for KF (criterion: KF 0.5% or less, result: KF 0.30%). Racemic trans-2-(dibenzylamino)cyclobutan-1-ol (95.8 kg, 1.0 eq.) was injected into the reactor under N2 protection. Enzyme lipase Novozyme 435 (18.84 kg, 0.2 w / w) was injected into the reactor under N2 protection. Stirred for 0.5 h at 20-25 °C. Succinic anhydride (23.3 kg, 0.65 eq.) was injected into the reactor under N2 protection at 20-25 °C. Stirred for 26 h at 20-25°C. Filtered and the filter cake was washed three times with MTBE (1 vol.). Water (1.0 eq.) was poured into the filtrate. All filtrates were collected and concentrated 1-3 times under vacuum below 40°C. MTBE (5.0 vol.) was poured into the residue and concentrated 1-3 times under vacuum below 40°C. The procedure was repeated twice. The residue was diluted with MTBE (10 vol.) and 2.5% aqueous K2CO3 (6 vol.) and then stirred for 0.5 h at 10-15°C. The MTBE phase was separated and extracted with 2.5% aqueous K2CO3 (2 x 6 vol.) at 10-15°C to ensure that the ester was not found in MTBE. All aqueous phases were combined and washed with MTBE (2 x 2 vol.) (Note: the solid at the interface was separated into the aqueous phase). Solid NaOH (4.0 eq.) was injected in portions into the aqueous phase below 10°C. Stirring was continued for more than 4 hours at 15-20°C. The reaction mixture was extracted once with MTBE (5.0 vol.). The reaction mixture was extracted once more with MTBE (3.0 vol.) (solids at the interface were separated into the aqueous phase). All MTBE phases were combined and washed with water (2 x 2 vol.). The MTBE phase was concentrated under vacuum 2-2.5 times below 40°C. Heptane (5 vol.) was injected into the residue and the system was concentrated under vacuum 3-3.5 times below 40°C. Heptane (5 vol.) was injected into the residue and the system was concentrated under vacuum 3.5-4 times below 40°C. Heptane (5 vol.) was injected into the residue and the system was concentrated under vacuum 3.5-4 times below 40°C. Heptane (5 vol.) was injected into the residue and stirred for 6 hours at 15-25°C.The mixture was filtered and the filter cake was washed once with n-heptane (0.5 vol.). The filter cake was collected and the cake was dried under vacuum until KF was 0.5% or less, then sampled for LOD and the result was recorded. The product was collected to give an off-white chiral resolved solid (1R,2R)-2-(dibenzylamino)cyclobutan-1-ol (61.93 kg, KF: 0.1%, LOD: 0.75%, HPLC purity: 99.9%, chiral purity: 99.7%, isolated yield: 33.5%).

[0299] (1R,2R)-2-(dibenzylamino)cyclobutan-1-ol was converted to (1R,2R)-N,N-dibenzyl-2-methoxycyclobutan-1-amine according to the following sequence: 2-MeTHF (588 kg, 12.0 vol.) was injected into a 2000 L glass-lined reactor under N2 protection. Stirred for 15 min. (1R,2R)-2-(dibenzylamino)cyclobutan-1-ol (57.0 kg, 1.0 eq.) was injected into the reactor. Stirred for 20 min to obtain a clear solution. The reaction was cooled to -5 to 0 °C. t-BuOK (33.52 kg, 1.4 eq.) was injected into the reactor in portions at 0 ± 5 °C. Stirred for 2 h at 0 to 5 °C. CH3I (42.35 kg, 1.4 eq.) was added dropwise to the reactor at 0±5°C. Stirred for 4 h at 5±5°C. Soft water (5.0 vol.) was injected at 0-30°C and stirred for 30 min. The organic layer was separated and collected. The aqueous layer was extracted with MTBE (3 vol.). The organic phase was collected and washed with soft water (2×2.5 vol.). It was washed with brine (2.5 vol.) (the emulsion layer was collected separately during the brine wash). The emulsion layer was extracted with MTBE (2 vol.). The organic layer was collected. It was filtered through an activated charcoal filter. The organic phase was concentrated 4-6 times under vacuum at below 50°C. Methanol (10.0 vol.) was injected into the reactor and concentrated 4-6 times under vacuum at below 55°C (jacket temperature). Methanol (10.0 vol.) was injected into the reactor and concentrated 4-6 times under vacuum at below 55° C. (jacket temperature). The concentrated residue was collected to give a solution of (1R,2R)-N,N-dibenzyl-2-methoxycyclobutan-1-amine in MeOH with an HPLC purity of 99.9%.

[0300] Compound 5 was prepared from (1R,2R)-N,N-dibenzyl-2-methoxycyclobutan-1-amine according to the following sequence: A solution of (1R,2R)-N,N-dibenzyl-2-methoxycyclobutan-1-amine (30.0 kg (calculated at 100% conversion)) in MeOH (approximately 150 L, 5 vol., obtained from the sequence above) was injected into a 1000 L autoclave under N2 atmosphere, followed by MeOH (14 vol.). 20% wet Pd(OH)2 / C (50% water, 3.0 kg, 0.1 w / w, wet weight basis) was injected into the autoclave under N2 atmosphere, followed by rinsing the feed port with MeOH (1.0 vol.). Stir and inject H2 (1.0 MPa) into the autoclave. Stir for approximately 24 h at 20-30 °C. Filtered and washed the filter cake with MeOH (3×1.0 vol.) under N2 atmosphere. Collected the filtrate. Dropped 4.0 N HCl (g) in MeOH (2.0 eq.) to the filtrate at 20-30°C. Stirred for 2 h at 20-30°C. Combined another batch. Concentrated the reaction mixture 3.5-4.5 times. Injected toluene (5.0 vol.) and then concentrated the reaction mixture 3.5-4.5 times. Repeated the process once more to remove water in the mixture. Sampled for KF (base: 0.10%, result: 0.07%). Injected MTBE (5.0 vol.) and then concentrated the reaction mixture 5.5-6.5 times and then injected MTBE (1 vol.). Stirred for 3 h at 15-25°C. Filtered and washed the cake with MTBE (2 vol.). The filter cake was collected and dried under vacuum for 16 h at 40-50° C. The cake was collected to give a pale pink solid compound 5 (26.92 kg, purity: 98.1 (GC), chiral purity: 99.9% (by extraction), KF: 0.1%, isolated yield: 91.8%).

[0301] Step 3: Synthesis of Compound 1 [ka] Compound 2 (1.5 Kg, 2.68 mol, 1.00 eq) in 3.3 M HCl / EtOH solution (19.1 Kg, 30.6 L, 15 vol) at 40±5° C. was injected into a 100 L reactor. After 21 h at 40° C., the reaction was complete. HPLC (UV 266 nm) analysis of the reaction mixture showed 99.55% product compound 1. No starting material compound 2 peak was detected by HPLC. The main impurity peak (0.32%) of the reaction mixture was the peak at 6.932 min (RRT: 0.454). The impurity peak was also seen in the HPLC of the working reaction (0.29%, RRT: 0.47), and after filtering the HCl salt of compound 1, the impurity was completely removed.

[0302] Filtration of HCl salt Once the reaction was confirmed to be complete, the mixture was cooled to 20±5° C. and stirred at 20±5° C. for at least 30 minutes. The HCl salt of compound 1 was collected by filtration. The filtration was very slow and took 5.6 hours to filter. The wet cake was washed with EtOH (1st wash: 1.8 Kg, 2nd wash: 0.8 Kg).

[0303] Neutralization with K2CO3 aqueous solution The HCl salt of compound 1 was suspended in 0.5N aqueous K2CO3 (30.0 Kg). The mixture was stirred at 20±5°C for at least 1 hour, and a pH of 1.85 was observed. An additional amount of 0.5N aqueous K2CO3 (42.1 Kg) was injected until a pH of 10 or higher was observed (actual pH: 10.05). The mixture was stirred at 20±5°C for at least 12 hours (actual stirring time: 17 hours). The solid was collected by filtration. The filtration was very slow and took 5.9 hours to filter. The wet cake was washed twice with water (1st wash: 3.0 Kg, 2nd wash: 4.5 Kg). The wet cake was returned to the 100 L reactor and slurried again in water (17.0 Kg) for 1 hour. The solid was collected by filtration. The wet cake was washed twice with water (1st wash: 4.5 Kg, 2nd wash: 1.1 Kg) and EtOH (1.2 Kg). The wet cake was dried in a tray dryer at 60° C. or less for at least 16 hours.

[0304] Dryness Test (1): After drying at 58°C for 16.4 hours, a sample was removed for KF testing for informational purposes only (KF result: 12.55%).

[0305] Dryness Test (2): After drying at 58°C for an additional 23.2 hours (total 39.6 hours), a second sample was removed for informational purposes only (KF result: 1.12%). This procedure was performed with deviation (Deviation Report #19-111). The material was poured, giving 1.14 Kg of compound 1 in 92.7% yield (before conversion of form).

[0306] Morphological transformation The dried solid compound 1 (1.14 Kg) was transferred to a 22 L glass reactor and EtOH (8.99 Kg, 11.4 L, 10 vol per 1.14 Kg solid) was added. The mixture was stirred at 60±5° C. for 3 hours. After cooling to 20±5° C. and stirring at 20±5° C. for 9.5 hours, a sample was removed and XRPD analysis showed crystalline material.

[0307] The solid was collected by filtration. The filter cake was transferred to lined trays and dried in a tray dryer at 60° C. or less for at least 16 hours. After drying at 57° C. for 92.7 hours, a sample was removed for LOD testing and showed an LOD of 0.20%. The material was considered dry and poured. 1.1 Kg of compound 1 was obtained as an off-white solid with a recovery of 96.5%. The overall yield of step 3 including reaction, neutralization and form conversion was 89.4%. NMR peak assignments for compound 1 Numbering system for NMR peak assignments: [ka] [Table 2] [Table 3]

[0308] While applicants have described a number of embodiments, it will be apparent that applicants' basic examples may be modified to produce other embodiments that utilize the compounds and methods described. It will therefore be understood that the scope of the invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

1. Compound 1: 【Chemistry 1】 or a method for preparing a pharmaceutically acceptable salt or solvate thereof, a) Equation III: 【Transformation 6】 Compound 5: 【Transformation 7】 or amidate with a pharmaceutically acceptable salt thereof, formula II: 【Transformation 8】 A step of producing the compound, wherein PG is an appropriate amino protecting group, b) The compound of formula II or a pharmaceutically acceptable salt thereof, and compound 4: 【Chemistry 9】 Cross-coupling and, equation I: 【Chemistry 10】 The process of producing the compound, c) A method comprising the step of deprotecting a compound of formula I or a pharmaceutically acceptable salt thereof to produce compound 1.

2. The method according to claim 1, wherein PG is t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl.

3. The method according to claim 1, wherein PG is t-butyloxycarbonyl (BOC).

4. Compound I is compound 2: 【Chemistry 11】 or a pharmaceutically acceptable salt thereof, and / or Compound II is compound 6: 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, and / or Compound III is compound 7: 【Chemistry 13】 The method according to any one of claims 1 to 3, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof.

5. Equation I 【Chemistry 14】 A method for preparing a compound or a pharmaceutically acceptable salt thereof (wherein PG is a suitable amino protecting group), a) Equation III: 【Chemistry 17】 Compound 5: [Chemistry 18] or amidate with a pharmaceutically acceptable salt thereof, formula II: 【Chemistry 19】 To produce the compound, b) Compound of formula II or a pharmaceutically acceptable salt thereof, and compound 4: 【Chemistry 20】 Cross-coupling with a pharmaceutically acceptable salt thereof to produce the compound of formula I, Methods that include...

6. Formula II: 【Chemistry 21】 A method for preparing a compound of or a pharmaceutically acceptable salt thereof (wherein PG is a suitable amino protecting group), wherein formula III: 【Chemistry 22】 Compound 5: 【Chemistry 23】 or amidation with a pharmaceutically acceptable salt thereof to produce the compound of formula II, Methods that include...

7. The method according to any one of claims 5 or 6, wherein PG is t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl.

8. The method according to any one of claims 5 or 6, wherein PG is t-butyloxycarbonyl (BOC).

9. Compound I is compound 2: 【Chemistry 24】 The method according to claim 5, or a pharmaceutically acceptable salt thereof.

10. Compound II is compound 6: 【Chemistry 25】 or a pharmaceutically acceptable salt thereof, and / or Compound III is compound 7: 【Chemistry 26】 The method according to any one of claims 5 or 9, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof.

11. Compound 1 produced by the method described in any one of claims 1 to 3 【Chemistry 27】 or a pharmaceutically acceptable salt or solvate thereof.

12. Formula I: 【Chemistry 28】 Compounds thereof or pharmaceutically acceptable salts or solvates thereof (PG being a suitable amino protecting group).

13. Compound I is compound 2: 【Chemistry 29】 The compound according to claim 12, or a pharmaceutically acceptable salt thereof.

14. Formula II: 【Transformation 30】 Compounds thereof or pharmaceutically acceptable salts or solvates thereof (wherein PG is a suitable amino protecting group).

15. Compound II is compound 6: 【Chemistry 31】 The compound according to claim 14, or a pharmaceutically acceptable salt or solvate thereof.

16. The compound according to claim 12 or 14, wherein PG is t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, or benzoyl, for example, PG is t-butyloxycarbonyl (BOC).

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