CTPS1 inhibitors and uses thereof

Abstract

The present invention provides compounds, compositions thereof, and methods of using them for inhibiting CPTS1 and treating CPTS1-mediated disorders. It has now been discovered that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as inhibitors of CTPS1 kinase. In certain embodiments, the present invention provides compounds of the formulas presented herein. The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful for treating various diseases, disorders, or conditions associated with the regulation of CTPS1. Such diseases, disorders, or conditions include those described herein.

Description

[Technical Field]

[0001] Citation of Related Applications This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 104,878, filed October 23, 2020, the entire contents of which are incorporated herein by reference.

[0002] Technical field of the invention The present invention relates to compounds and methods useful for antagonizing CTP synthease 1 (CTPS1). The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, and methods of using the compositions in the treatment of various disorders. [Background technology]

[0003] Background of the Invention All cells, whether prokaryotic or eukaryotic in origin, utilize nucleotides as key building blocks for cellular metabolic processes, such as the synthesis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), membrane lipid biosynthesis, and as a cellular reservoir of biochemical energy for many important enzymatic processes. The primary cellular metabolic requirement for nucleotides has led to the development of many therapeutic agents that target various aspects of nucleotide biosynthesis, which have been successfully used to treat numerous diseases, such as cancer or autoimmune diseases.

[0004] The cellular pool of the pyrimidine nucleotide CTP (cytidine 5'-triphosphate) is derived from two sources: either via a salvage pathway or a de novo biosynthetic pathway that depends on the enzyme CTP synthase (or synthetase). In humans, two isoforms of CTP synthase exist: CTPS1 and CTPS2. These enzymes catalyze the conversion of the pyrimidine UTP (uridine 5'-triphosphate) to CTP, convert glutamine to L-glutamate, and convert ATP to ADP (adenosine 5'-diphosphate) in a series of coupled reactions utilizing the substrates glutamine and ATP (adenosine 5'-triphosphate). The specific biological roles of the two different isoforms of CTP synthase in humans have not yet been fully delineated.

[0005] The immune system in multicellular organisms has evolved to provide protection from a wide variety of infectious pathogens. This process generally requires the recognition of pathogens by various immune cells, often followed by the amplification and long-term propagation of the immune response through the rapid expansion, proliferation, and differentiation of responding immune cells. Within this process, the activity of CTP synthase appears to play a key role in providing sufficient CTP for the rapid expansion of immune lymphocytes after activation via a de novo biosynthetic pathway.

[0006] Clinical data demonstrating that CTPS1 is a key enzyme for supporting lymphocyte proliferation in humans have been provided through the identification of a homozygous loss-of-function mutation (rs145092287) in this enzyme, which causes a severe immunodeficiency characterized by a severely impaired ability of activated T or B cells to proliferate in response to antigen receptor-mediated activation. The absence of any other reported clinical phenotypes outside the immune system in homozygous carriers indicates a specific role for CTPS1 in supporting immune cell expansion and proliferation and suggests that CTPS1 activity may not be important outside the immune system in humans or may be compensated for by CTPS2 activity.

[0007] Given the known therapeutic benefits of therapeutics targeting nucleotide synthesis and the key role of CTP synthase in de novo CTP production to fuel cellular metabolic needs, CTPS1 represents a novel class of target for drugs with therapeutic potential, particularly in the context of immune disorders. Pathogenic immune cells, such as autoreactive T or B cells, drive or are components of a variety of diseases, including autoimmune diseases, severe allergic reactions, cardiovascular and metabolic disorders, progressive neurological diseases, and hematological cancers. Inhibition of CTPS1 may provide therapeutic benefits in these and other diseases, and the specific role of CTPS1 in select immune cell subsets may also highlight the potential for an improved therapeutic index over other clinical therapeutics that more broadly target nucleotide biosynthesis. Summary of the Invention [Means for solving the problem]

[0008] Summary of the Invention It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of CTPS1 kinase. In certain embodiments, the present invention provides compounds of the formulae presented herein.

[0009] The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful for treating various diseases, disorders, or conditions associated with the regulation of CTPS1, including those described herein. DETAILED DESCRIPTION OF THE INVENTION

[0010] Detailed Description of Specific Embodiments 1. General Description of Certain Embodiments of the Invention: In certain aspects, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formula I, ring A, ring B, ring C, L, R 1 , R A , R B , R C Each of m, n, and p, both alone and in combination, is as defined below and as described in embodiments herein.

[0011] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0012] In some embodiments, the present invention provides a method of treating a CTPS1-mediated disease, disorder, or condition, comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof. 2. Compounds and Definitions:

[0013] The compounds of the present invention include those generally described above and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise specified, the following definitions shall apply. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Edition, eds. Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0014] The term "aliphatic" or "aliphatic group," as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted, hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl"), having 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 still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") 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 rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, saturated or unsaturated, alkyl, alkenyl, alkynyl groups, and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl).

[0015] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system (i.e., carbocyclic or heterocyclic) that is saturated or partially unsaturated and has at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms, or a single atom, or a valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (other than hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, in which each group is attached to the remainder of the molecule at any suitable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents, such as those described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic rings include: [ka] Examples include:

[0016] The term "lower alkyl" refers to C 1~4 " refers to a straight or branched chain alkyl group of the formula: Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0017] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1~4 The term "alkyl" refers to a straight or branched chain alkyl group.

[0018] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form 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 +(as in N-substituted pyrrolidinyl)).

[0019] The term "unsaturated," as used herein, means a moiety having one or more units of unsaturation.

[0020] As used herein, the term "divalent C 1~8 (or C 1~6 ) saturated or unsaturated, straight or branched hydrocarbon chains" refers to straight or branched divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0021] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) 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 methylene hydrogens are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0022] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0023] The term "halogen" means F, Cl, Br, or I.

[0024] The term "aryl," used alone or as part of a larger moiety, as in "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 each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, and anthracyl, which may bear one or more substituents. As used herein, and included within its scope, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0025] The terms "heteroaryl" and "heteroara-," used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to carbon atoms. 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 "heteroara-," as used herein, also encompass groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, and the radical or point of attachment, unless otherwise specified, is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. 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, and tetrahydroisoquinolinyl. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any 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.

[0026] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having zero to three heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl) or NH (as in pyrrolidinyl). + It may also be NR (as in N-substituted pyrrolidinyl).

[0027] A heterocyclic ring can be attached to its parent group at any heteroatom or carbon atom that results in a stable structure, and any of these 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, 2-oxa-6-azaspiro[3.3]heptane, 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.

[0028] 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 encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0029] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety have been 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 specified group, the substituents may be either the same or different at each position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0030] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH) 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 (which is R ○ -(CH2) 0~4 O(CH2) 0~1 Ph (which is R ○ -CH=CHPh (which may be substituted with R ○ -(CH2) 0~4 O(CH2) 0~1 -pyridyl (which is R ○which may be replaced by); -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 ○ ; -N(R ○ )C(NR ○ )N(R ○ )2; -(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)NR ○ 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;-(C 1~4 straight or branched chain alkylene)ON(R ○ )2; or -(C 1~4 straight or branched chain alkylene)C(O)ON(R ○ )2, where each R ○ may be substituted as defined below and independently represent hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R ○two independent occurrences of together with the atom(s) between them form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0031] R ○ (R ○ Suitable monovalent substituents on the ring formed by two independent occurrences of (a ring formed by two independent occurrences of together with the atom between them) are independently 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 SR ● , -(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 ● , -(C 1~4 straight or branched chain alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0032] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═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 S-. Here R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 and an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having an aliphatic or 0-4 heteroatom independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2~3 O-, where R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 It is selected from an aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0033] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C which may be substituted as defined below 1~6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † two independent occurrences of together with the atom(s) between them form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] R † Suitable substituents on the aliphatic group are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids, inorganic bases, organic acids, and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or formed by using other methods used in the art, such as ion exchange. Other pharmaceutically 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 suitable salts include phosphate, 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.

[0037] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carbonates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0038] Unless otherwise stated, structures depicted herein are also meant to encompass all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0039] Unless otherwise indicated, divalent structures or functional groups depicted herein are meant to include either orientation at the point of attachment (e.g., the group [ka] is part of a Markush group attached to groups "A" and "B", [ka] (including both).

[0040] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, structures of the present invention in which hydrogen is replaced by deuterium or tritium, or in which carbon is replaced by 13 C or 14 Compounds having the invention in which C is replaced with an enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools according to the invention, as probes in biological assays, or as therapeutic agents.

[0041] As used herein, a "CTPS1 antagonist" or "CTPS1 inhibitor" refers to a molecule that reduces, inhibits, or otherwise diminishes one or more of the biological activities of CTPS1. Antagonism using a CTPS1 antagonist does not necessarily indicate complete elimination of CTPS1 activity. In fact, the activity may be reduced by a statistically significant amount, including at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% reduction in CTPS1 activity compared to an appropriate control. The compounds of the present disclosure directly bind to CTPS1 and inhibit its activity.

[0042] By "specific antagonist" is intended an agent that reduces, inhibits, or otherwise diminishes the activity of a defined target to a greater extent than the activity of an unrelated target. For example, a CTPS1-specific antagonist reduces at least one biological activity of CTPS1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein. In some embodiments, the IC of the antagonist for the target is 50 is the IC of this antagonist against non-targets 50 of approximately 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001%, or less.

[0043] The compounds of the present invention can be tethered to a detectable moiety. It is understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that a detectable moiety can be attached to a provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently linked to a detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing carbonate, amino, thiol, or hydroxyl moieties, to name a few. It is understood that such moieties can be attached directly to a provided compound or via a tethering group such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached via click chemistry. In some embodiments, such moieties can be attached via 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

[0044] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that can be detected, such as primary and secondary labels. Radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), primary labels, such as mass tags and fluorescent labels, are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0045] As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a secondary intermediate to generate a detectable signal. For biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. For antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radioactive fluorescence resonance energy transfer (FRET), and the second group generates the signal that is detected.

[0046] As used herein, the terms "fluorescent label," "fluorescent dye," and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY530 / 550, BODIPY558 / 568, BODIPY564 / 570, BODIPY576 / 589, BODIPY581 / 591, BODIPY630 / 650, BODIPY650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl, dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, eosin, erythrosine, fluorescein, FAM, hydrochloride Examples of suitable dyes include, but are not limited to, roxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, Lissamine rhodamine B, Marina Blue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

[0047] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection technology.Examples of mass tag include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipeconic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and their derivatives.The synthesis and usefulness of these mass tags are described in U.S. Patent No. 4,650,750, U.S. Patent No. 4,709,016, U.S. Patent No. 5,360,8191, U.S. Patent No. 5,516,931, U.S. Patent No. 5,602,273, U.S. Patent No. 5,604,104, U.S. Patent No. 5,610,020 and U.S. Patent No. 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides of various lengths and base compositions, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, in the appropriate mass range (100-2000 daltons) may be used as mass tags.

[0048] The terms "measurable affinity" and "measurably inhibit," as used herein, refer to a measurable change in CTPS1 activity between a sample containing a compound of the present invention or a composition thereof and CTPS1 and an equivalent sample containing CTPS1 in the absence of the compound or composition thereof. 3. Description of Exemplary Embodiments:

[0049] As noted above, in certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I: R 1 is C 1~6aliphatic; 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is selected from q instances of R A is replaced by; Ring A is selected from phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is [ka] and; where R L , R L’ , and R L” are each independently hydrogen, —CN, halogen, or an optionally substituted group, and the optionally substituted group is C 1~6 aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R L Group, R L’ groups, and R L” two of the groups, together with the atoms to which they are each attached, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R L , RL’ , and R L” One of the following is R B together with to form a 7- to 10-membered saturated or partially unsaturated fused bicyclic ring; Ring B is selected from phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 11-membered saturated or partially unsaturated, fused, bridged, or spiro bicyclic carbocyclic ring; a 7- to 11-membered fused bicyclic aryl ring; a 7- to 11-membered saturated or partially unsaturated, fused, bridged, or spiro bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is selected from phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or the bond between ring B and ring C is absent, and ring B and ring C together form a 7- to 11-membered saturated or partially unsaturated, fused, bridged, or spiro bicyclic carbocyclic ring; a 7- to 11-membered fused bicyclic aryl ring; a 7- to 11-membered saturated or partially unsaturated, fused, bridged, or spiro bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R A, R B , and R C Each example independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C( -O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or R C Each example of C 1~6 aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; nitrogen, oxygen and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is an optionally substituted group selected from r instances of R and s instances of R. D is replaced by; R DEach instance of is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R )C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; Each R is independently hydrogen, —CN, halogen, or an optionally substituted group, and the optionally substituted group is C 1~6 Aliphatic; phenyl; naphthalenyl; 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 4 heteroatoms; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 11-membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups, together with the atoms to which each R is attached, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, or 2; each q is independently 0, 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; and each s is independently 0, 1, 2, 3, or 4; however, R 1 But C 1~6 an aliphatic or 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; Sulfonamide moiety [ka] wherein the R group is hydrogen or para-methoxybenzyl; L, [ka] and R L Group and R L’ group, or R L Group and R L” and L, taken together with the atom to which they are each attached, do not form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or L is [ka] and; Ring B is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and when ring C is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is attached to ring B in the para position relative to the L group; Ring A and its R A The substituents are [ka] except where * is [ka] represents a bond to the moiety, and ** represents a bond to the [ka] Represents a bond to a moiety.

[0050] In some embodiments, the present invention provides a compound of formula I': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I': R 1 is C 1~6 aliphatic; 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is selected from q instances of R A is replaced by; Ring A is selected from phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is [ka] and; where R L , R L’ , and R L” are each independently hydrogen, —CN, halogen, or an optionally substituted group, and the optionally substituted group is C 1~6 aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R L Group, R L’ groups, and R L” two of the groups, together with the atoms to which they are each attached, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R L , R L’ , and R L” One of the following is R B together with to form a 7- to 10-membered saturated or partially unsaturated fused bicyclic ring; Ring B is selected from phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 11-membered saturated or partially unsaturated, fused, bridged, or spiro bicyclic carbocyclic ring; a 7- to 11-membered fused bicyclic aryl ring; a 7- to 11-membered saturated or partially unsaturated, fused, bridged, or spiro bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is selected from phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or the bond between ring B and ring C is absent, and ring B and ring C together form a 7- to 11-membered saturated or partially unsaturated, fused, bridged, or spiro bicyclic carbocyclic ring; a 7- to 11-membered fused bicyclic aryl ring; a 7- to 11-membered saturated or partially unsaturated, fused, bridged, or spiro bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R A , R B , and R CEach example independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C( -O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or R C Each example of C 1~6 aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is selected from r instances of R and s instances of R. D or two R C The group is each R Coptionally taken together with the atom to which it is attached to form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 7-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R D Each instance of is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R )C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; Each R is independently hydrogen, —CN, halogen, or an optionally substituted group, and the optionally substituted group is C 1~6Aliphatic; phenyl; naphthalenyl; 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 4 heteroatoms; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 11-membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups, together with the atoms to which each R is attached, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, or 2; each q is independently 0, 1, 2, 3, or 4; each r is independently 0, 1, 2, 3, or 4; and each s is independently 0, 1, 2, 3, or 4; however, R 1 But C 1~6 an aliphatic or 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; Sulfonamide moiety [ka] wherein the R group is hydrogen or para-methoxybenzyl; L, [ka] and R L Group and R L’ group, or R L Group and R L” and L, taken together with the atom to which they are each attached, do not form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or L is [ka] and; Ring B is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and when ring C is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is attached to ring B in the para position relative to the L group; Ring A and its R A The substituents are [ka] except where * is [ka] represents a bond to the moiety, and ** represents a bond to the [ka] Represents a bond to a moiety.

[0051] In certain embodiments, R 1 is C 1~6aliphatic; 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is selected from q instances of R A is replaced by .

[0052] In certain embodiments, R 1 is C 1~6 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; each of which is selected from q instances of R A is replaced by .

[0053] In certain embodiments, R 1 is C 1~6 haloalkyl, cyclopropyl, cyclobutyl, aziridinyl, azetidinyl, oxiranyl, and oxetanyl; each of which is selected from q instances of R A is replaced by .

[0054] In certain embodiments, R 1 -CF3, -CHF2, [ka] is.

[0055] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0056] In certain embodiments, Ring A is selected from phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0057] In some embodiments, Ring A is phenyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, furanyl, furazanyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,6-oxadiazolyl, 1,2,7-oxadiazolyl, 1,2,8-oxadiazolyl, 1,2,9-oxadiazolyl, 1,2,10-oxadiazolyl, 1,2,11-oxadiazolyl, 1,2,12-oxadiazolyl, 1,2,13-oxadiazolyl, 1,2,14-oxadiazolyl, 1,2,15-oxadiazolyl, 1,2,16-oxadiazolyl, 1,2,17-oxadiazolyl, 1,2,18-oxadiazolyl, 1,2,19-oxadiazolyl, 1,2,20-oxadiazolyl, 1,2,21-oxadiazolyl, 1,2,22-ox -oxadiazolyl; selected from 1,2,5 oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrimidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl.

[0058] In some embodiments, Ring A is phenyl, benzimidazolyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl. selected from 1,2,5 oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrimidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, and thiazolyl;

[0059] In some embodiments, Ring A is selected from phenyl, pyrazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and indolyl.

[0060] In certain embodiments, ring A is [ka] is.

[0061] In certain embodiments, ring A is [ka] [ka] is.

[0062] In certain embodiments, ring A is [ka] is.

[0063] In certain embodiments, ring A is [ka] is.

[0064] In certain embodiments, ring A is [ka] is.

[0065] In some embodiments, ring A is selected from those depicted in Table 1 below.

[0066] In some embodiments, L is [ka] is.

[0067] In some embodiments, L is [ka] is.

[0068] In some embodiments, L is [ka] is.

[0069] In some embodiments, L is [ka] is.

[0070] In certain embodiments, L is [ka] [ka] is.

[0071] In certain embodiments, L is [ka] [ka] [ka] [ka] is.

[0072] In certain embodiments, L is [ka] is.

[0073] In some embodiments, R L’ and R L” Each of the [ka] [ka] , halogen, or optionally substituted C 1~6 It is aliphatic.

[0074] In some embodiments, R L’ and R L” Each of is independently hydrogen, F, -CN, -Me, or -Et.

[0075] In some embodiments, R L , R L’ , and R L” One of the following is R B What came together with [ka] is.

[0076] In some embodiments, L is selected from those depicted in Table 1 below.

[0077] In some embodiments, Ring B is selected from phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 11-membered saturated or partially unsaturated fused, bridged, or spiro bicyclic carbocyclic ring; a 7- to 11-membered fused bicyclic aryl ring; a 7- to 11-membered saturated or partially unsaturated fused, bridged, or spiro bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0078] In some embodiments, Ring B is selected from phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 11-membered saturated or partially unsaturated fused, bridged, or spiro bicyclic carbocyclic ring; a 7- to 11-membered saturated or partially unsaturated fused, bridged, or spiro bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0079] In some embodiments, Ring B is phenyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, decahydroquinolinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isoindolinyl, isoindolinonyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyridinyl, Imidinyl, piperazinyl, piperazinonyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyrazolopyridinyl, pyridazinyl, pyridinyl, pyridinonyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroisoquinolinyl, tetra and selected from hydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or bicyclo[1.1.1]pentanyl.

[0080] In some embodiments, Ring B is selected from phenyl, isoindolinyl, isoindolinonyl, 1,3,4-oxadiazolyl, oxazolyl, piperazinyl, piperazinonly, pyrazinyl, pyrazolyl, pyrazolopyridinyl, pyridinyl, pyridinonyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 1,3,4-thiadiazolyl, thiazolyl, or bicyclo[1.1.1]pentanyl.

[0081] In certain embodiments, ring B is [ka] [ka] is.

[0082] In certain embodiments, ring B is [ka] is.

[0083] In certain embodiments, Ring B is a 5-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-membered monocyclic heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0084] In certain embodiments, ring B is [ka] [ka] is.

[0085] In some embodiments, ring B is selected from those depicted in Table 1 below.

[0086] In certain embodiments, Ring C is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0087] In certain embodiments, Ring C is selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazopyrimidine, 1H-indazolyl, indolenyl, and the like. yl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl , oxazolidinyl, oxazolyl, oxazolidinyl, oxetanyl, pyrimidinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, pyrrolopyridine, quinazolinyl, quinolinyl, 4H-quinolizinyl, tetrahydro furanyl, tetrahydropyranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, or azetidinyl.

[0088] In certain embodiments, Ring C is imidazolyl, imidazopyrimidine, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; -1,2,5 oxadiazolyl, 1,3,4-oxadiazolyl, piperidinyl, pyrazinyl, pyrrolidinyl, pyrrolopyridine, or azetidinyl.

[0089] In certain embodiments, ring C is [ka] is.

[0090] In certain embodiments, ring C is [ka] is.

[0091] In certain embodiments, ring C is [ka] is.

[0092] In certain embodiments, ring C is [ka] [ka] is.

[0093] In some embodiments, ring C is selected from those depicted in Table 1 below.

[0094] In some embodiments, the bond between ring B and ring C is absent, and ring B and ring C together form a 7- to 11-membered saturated or partially unsaturated, fused, bridged, or spiro bicyclic carbocyclic ring; a 7- to 11-membered fused bicyclic aryl ring; a 7- to 11-membered saturated or partially unsaturated, fused, bridged, or spiro bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0095] In some embodiments, ring B and ring C together form indanyl, tetrahydronaphthyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, decahydroquinolinyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, naphthalenyl, octahydroisoquinolinyl, pteridinyl, purinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl, or tetrahydroquinolinyl.

[0096] In some embodiments, the bond between ring B and ring C is absent, and ring B and ring C together form isoquinolinyl, naphthalenyl, or quinolinyl.

[0097] In some embodiments, the bond between ring B and ring C is absent, and ring B and ring C together form: [ka] [ka] Form.

[0098] In some embodiments, the bond between ring B and ring C is absent, and ring B and ring C together form: [ka] Form.

[0099] In some embodiments, the bond between ring B and ring C is absent, and ring B and ring C together form: [ka] Form.

[0100] In some embodiments, ring B and ring C taken together are selected from those depicted in Table 1 below.

[0101] As generally defined above, R A Each example independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C( -O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or R A Each example of C 1~6aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; nitrogen, oxygen and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is an optionally substituted group selected from r instances of R and s instances of R. D is replaced by .

[0102] In some embodiments, R A Each example independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C( -O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or R A Each example of C 1~6aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from an aryl ring; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0103] In some embodiments, R A Each instance of is independently -F or -OCH3.

[0104] In some embodiments, R A Each example is selected from those illustrated in Table 1 below.

[0105] As generally defined above, R B Each example independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C( -O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or R BEach example of C 1~6 aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; nitrogen, oxygen and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is an optionally substituted group selected from r instances of R and s instances of R. D is replaced by .

[0106] In some embodiments, R B Each example independently represents oxo, halogen, -CN, -NO2, -OR, -OCH3, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R )C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or R B Each example of C 1~6aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from an aryl ring; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0107] In some embodiments, R B Each example is a halogen or C 1~6 It is aliphatic.

[0108] In some embodiments, R B Each instance of is -F or -Me.

[0109] In some embodiments, R B is -CH2N(CH3)2.

[0110] In some embodiments, R B Each example is selected from those illustrated in Table 1 below.

[0111] As generally defined above, R CEach example independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C( -O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or R C Each example of C 1~6 aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; nitrogen, oxygen and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is an optionally substituted group selected from r instances of R and s instances of R. D is replaced by .

[0112] In some embodiments, R CEach example independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C( -O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or R C Each example of C 1~6 aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. an optionally substituted group selected from an aryl ring; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0113] In some embodiments, R C Each example is -OR, optionally substituted C 1~6 It is an aliphatic or optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur.

[0114] In some embodiments, R C Examples of each are -Me, -Et, -Pr, -CF3, -OMe, -OEt, -OiPr, azetidine, or pyrrolidine.

[0115] In some embodiments, R C Each example is -CH2CHF2,

[0116] In some embodiments, R C Each example is selected from those illustrated in Table 1 below.

[0117] As generally defined above, R D Each instance of is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R )C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2.

[0118] In some embodiments, R D means oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O )R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2.

[0119] In some embodiments, R D is selected from those illustrated in Table 1 below.

[0120] As generally defined above, each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 Aliphatic; phenyl; naphthalenyl; 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 4 heteroatoms; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 11-membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Two R groups on the same nitrogen, together with the nitrogen, form an optionally substituted 4- to 7-membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0121] In some embodiments, R is selected from those depicted in Table 1 below.

[0122] As generally defined above, each hydrogen bonded to a carbon can optionally be independently replaced by deuterium.

[0123] In some embodiments, the hydrogen bonded to the carbon is replaced by deuterium.

[0124] As generally defined above, m is 0, 1, or 2.

[0125] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0126] In some embodiments, m is selected from those depicted in Table 1 below.

[0127] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0128] In some embodiments, n is selected from those depicted in Table 1 below.

[0129] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0130] In some embodiments, p is selected from those depicted in Table 1 below.

[0131] As generally defined above, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0. In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0132] In some embodiments, q is selected from those depicted in Table 1 below.

[0133] As generally defined above, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0. In some embodiments, r is 1, 2, 3, or 4. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4.

[0134] In some embodiments, r is selected from those depicted in Table 1 below.

[0135] As generally defined above, s is 0, 1, 2, 3, or 4. In some embodiments, s is 0. In some embodiments, s is 1, 2, 3, or 4. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4.

[0136] In some embodiments, s is selected from those depicted in Table 1 below.

[0137] In some embodiments, the present invention provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II, R 1, ring A, ring B, ring C, R A , R B , R C , R L , R L’ , R L” Each of m, n, and p, both alone and in combination, is as defined above and as described in embodiments herein.

[0138] In some embodiments, the present invention provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula III, R 1 , ring A, ring B, ring C, R A , R B , R C , R L , R L’ , R L” Each of m, n, and p, both alone and in combination, is as defined above and as described in embodiments herein.

[0139] In some embodiments, the present invention provides a compound of formula IV: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula IV, R 1 , ring A, ring B, ring C, R A , R B , R C , R L , R L’ , R L” Each of m, n, and p, both alone and in combination, is as defined above and as described in embodiments herein.

[0140] In some embodiments, the present invention provides a compound of formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula V, R1 , ring A, ring B, ring C, R A , R B , R C , R L , R L’ , R L” Each of m, n, and p, both alone and in combination, is as defined above and as described in embodiments herein.

[0141] In some embodiments, the present invention provides a compound of formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula VI, R 1 , ring A, ring B, ring C, R A , R B , R C , R L , R L’ , R L” Each of m, n, and p, both alone and in combination, is as defined above and as described in embodiments herein.

[0142] Exemplary compounds of the present invention are set forth in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

[0143] In some embodiments, the present invention provides compounds set forth in Table 2: [Table 2-1] [Table 2-2] [Table 2-3]

[0144] In some embodiments, the method employs a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the method employs a compound set forth in Table 1 above. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0145] In some embodiments, the present invention provides a compound of Formula I as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, for use as a medicament.

[0146] In some embodiments, the present invention provides a compound of formula I, as described herein, or a pharmaceutical composition, as described herein, for use in a method for inhibiting CTPS1, as described herein, in a method for enhancing an immune response in a patient in need thereof, as described herein, and / or in a method for treating a CTPS1-dependent disorder, as described herein.

[0147] In some embodiments, the present invention provides a compound of formula I, as described herein, or a pharmaceutical composition, as described herein, for use in a method for inhibiting CTPS1, as described herein.

[0148] In some embodiments, the present invention provides a compound of formula I, as described herein, or a pharmaceutical composition, as described herein, for use in a method for enhancing an immune response in a patient in need thereof.

[0149] In some embodiments, the present invention provides a compound of formula I, as described herein, or a pharmaceutical composition, as described herein, for use in a method for treating a CTPS1-dependent disorder, as described herein.

[0150] In some embodiments, the present invention also provides the use of a compound of formula I described herein, or a pharmaceutical composition described herein, for the manufacture of a medicament for inhibiting CTPS1, for enhancing an immune response in a patient in need thereof, and / or for treating a CTPS1-dependent disorder.

[0151] In some embodiments, the present invention also provides the use of a compound of Formula I described herein, or a pharmaceutical composition described herein, for the manufacture of a medicament for inhibiting CTPS1.

[0152] In some embodiments, the present invention also provides the use of a compound of formula I, as described herein, or a pharmaceutical composition, as described herein, for the manufacture of a medicament for enhancing an immune response in a patient in need thereof.

[0153] In some embodiments, the present invention also provides the use of a compound of formula I described herein, or a pharmaceutical composition described herein, for the manufacture of a medicament for treating a CTPS1-dependent disorder.

[0154] In some embodiments, the present invention also provides the use of a compound of formula I, as described herein, or a pharmaceutical composition, as described herein, in a method for inhibiting CTPS1, as described herein, in a method for enhancing an immune response in a patient in need thereof, as described herein, and / or in a method for treating a CTPS1-dependent disorder, as described herein.

[0155] In some embodiments, the present invention also provides the use of a compound of formula I, as described herein, or a pharmaceutical composition, as described herein, in a method for inhibiting CTPS1, as described herein.

[0156] In some embodiments, the present invention also provides the use of a compound of formula I, as described herein, or a pharmaceutical composition, as described herein, in a method for enhancing an immune response in a patient in need thereof.

[0157] In some embodiments, the present invention also provides the use of a compound of formula I described herein, or a pharmaceutical composition described herein, in a method for treating a CTPS1-dependent disorder described herein. 4. General Methods of Providing the Compounds

[0158] The compounds of the invention may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by methods described in detail in the Examples herein. 5. Use, Prescription and Administration Pharmaceutically Acceptable Compositions

[0159] According to another embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is an amount effective to measurably inhibit CTPS1 or a mutant thereof in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present invention is an amount effective to measurably inhibit CTPS1 or a mutant thereof in a biological sample or in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0160] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0161] 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 can be used in the compositions of this invention include 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, electrolytes such as salts or 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.

[0162] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, directly or indirectly, the compound of this invention or an inhibitory active metabolite or residue thereof.

[0163] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of CTPS1 or a mutant thereof.

[0164] The subject matter disclosed herein includes the prodrugs, metabolites, derivatives, and pharmaceutically acceptable salts of the compounds of the present invention.Metabolites include compounds produced by a process comprising contacting the compounds of the present invention with mammals for a sufficient time to obtain their metabolic products.When the compounds of the present invention are bases, desired pharmaceutically acceptable salts can be prepared by any suitable method available in the art, such as treating the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, and phosphoric acid, or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid or galacturonic acid, alpha hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, or sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid. If the compound of the invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, by treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide. Representative examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0165] The compounds of the present invention may be in the form of a "prodrug," which includes compounds having a moiety that can be metabolized in vivo. Generally, prodrugs are metabolized in vivo by esterases or other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19). Prodrugs can be prepared in situ during the final isolation and purification of compounds, or can be prepared by separately reacting the purified compound in its free acid form or at a hydroxyl with a suitable esterifying reagent. A hydroxyl group can be converted to an ester by treatment with a carboxylic acid. Examples of prodrug moieties include saturated and unsaturated, branched or unbranched lower alkyl ester moieties (e.g., propionate ester), lower alkenyl ester, di-lower alkyl-amino lower alkyl ester (e.g., dimethylaminoethyl ester), acylamino lower alkyl ester (e.g., acetyloxymethyl ester), acyloxy lower alkyl ester (e.g., pivaloyloxymethyl ester), aryl ester (phenyl ester), aryl-lower alkyl ester (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl ester, lower alkyl amide, di-lower alkyl amide, and hydroxyamide. Prodrugs that are converted to active forms in vivo by other mechanisms are also encompassed. In some aspects, the compounds of the present invention are prodrugs of any of the formulas herein.

[0166] The compositions of the present invention can 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 of this invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0167] For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, especially in their polyoxyethylated forms, are useful for preparing injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions. Other commonly used surfactants, such as Tween®, Span®, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0168] The pharmaceutically acceptable composition of this invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiers and suspending agents.If desired, certain sweeteners, flavorings or coloring agents can also be added.

[0169] Alternatively, the pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These 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.

[0170] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0171] Topical application for the lower intestinal tract may be in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches may also be used.

[0172] For topical application, the provided pharmaceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, the provided pharmaceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically 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.

[0173] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated into an ointment such as petrolatum.

[0174] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0175] Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of this invention are administered with food.

[0176] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg of body weight per day of the inhibitor can be administered to a patient receiving these compositions.

[0177] It should also be understood that the specific dosage and treatment regimen for any particular patient will vary depending on a variety of factors, including the activity of the specific compounds employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also vary depending on the particular compound in the composition. Uses of the Compounds and Pharmaceutically Acceptable Compositions

[0178] All cells, whether prokaryotic or eukaryotic, utilize nucleotides for cellular metabolic processes, such as the synthesis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), as key building blocks for membrane lipid biosynthesis, and as a cellular reservoir of biochemical energy for many important enzymatic processes. Two classes of nucleotides exist: those containing either purine (e.g., guanine or adenine) or pyrimidine (e.g., cytosine or thymine) bases, and both classes are important for various metabolic processes. Nucleotides can be further phosphorylated by kinases to provide mono-, di-, or triphosphorylated forms, which are also utilized in biosynthetic processes. Perhaps one of the most well-known uses of nucleotide triphosphates is as a building block for DNA within cells. Based on the important role of nucleotides within cells, numerous therapeutic agents have been developed to target different aspects of nucleotide synthesis; some inhibit the production of purine nucleotides, some inhibit the production of pyrimidine nucleotides, or some simultaneously inhibit both classes. These include compounds such as leflunomide / teriflunomide, methotrexate, and azathioprine.

[0179] The pyrimidine nucleotide CTP (cytidine 5'-triphosphate) is a precursor required for the anabolic synthesis of both DNA and RNA, as well as for the sialylation of phospholipids and proteins. CTP is derived from two sources: a salvage pathway and a de novo synthesis pathway dependent on the enzyme CTP synthase (Evans and Guy 2004; Higgins, et al. 2007; Ostrander, et al. 1998). In humans, CTP synthase has two highly homologous isoforms (CTPS1 and CTPS2), both of which perform the same enzymatic reaction; however, evidence suggests that the cellular and metabolic regulation of these two isoforms may be distinct. CTP synthase exists as two isozymes in humans and other eukaryotes, but the detailed functional differences between these two isoforms in cell and tissue biology have not yet been fully delineated (van Kuilenburg, et al. 2000).

[0180] CTPS1 and CTPS2 catalyze the conversion of uridine triphosphate (UTP) and glutamine to cytidine triphosphate (CTP) and L-glutamate, with the concomitant hydrolysis of ATP to ADP: [ka]

[0181] CTP synthase has two functional activities: an N-terminal synthetase domain and a C-terminal glutaminase domain, and the active enzyme is composed of a homotetramer (Kursula, et al., 2006). The synthetase domain of the enzyme transfers a phosphate from adenosine triphosphate (ATP) to the 4-position of UTP to generate the activated intermediate 4-phospho-UTP. The glutaminase domain of the enzyme generates ammonia from glutamine via a covalently linked thioester intermediate, preserving the active site cysteine ​​and generating glutamate. The generated ammonium can either be transferred from the glutaminase domain through the enzyme tunnel to the synthetase domain or derived from external ammonium. The ammonium can then be used by the synthetase domain to generate CTP from 4-phospho-UTP (Lieberman, 1956).

[0182] Numerous studies have highlighted the key role of nucleotide synthesis and CTP synthase activity in several aspects of normal and disease cell biology, particularly in cellular contexts with the high metabolic demands of replication and division, which necessitate the activation of de novo nucleotide synthesis. For example, CTPS activity has been shown to be upregulated in a range of tumor types, both hematological and non-hematological in origin, suggesting that de novo pyrimidine biosynthesis is required to support the aggressive growth and division of cancer cells. While the mechanistic drivers, cell types, and tissue origins of cancer are clearly diverse, the underlying consequence is a disruption of cell division control that allows inappropriate proliferation.

[0183] The process of tumorigenesis is highly complex, requiring the careful coordination of multiple pathways, many of which have yet to be fully characterized. Ultimately, every cell division requires efficient replication of the cell's DNA and other components, a metabolically demanding process. Interfering with a cell's ability to replicate by targeting nucleic acid synthesis has been a central approach to cancer treatment for many years, and examples of therapeutic agents that act in this way are 6-thioguanine, 6-mercaptopurine, 5-fluorouracil, cytarabine, gemcitabine, and methotrexate.

[0184] Currently, the precise role that CTPS1 and / or CTPS2 may play in cancer is not fully defined. Several nonselective inhibitors of CTP synthase have previously been developed for oncology indications, even progressing to Phase I / II clinical trials, but these have been hindered by toxicity, poor pharmacokinetic characteristics, or limited efficacy. Most of these early inhibitors are nucleoside analog prodrugs (3-deazauridine, cyclopentenylcytosine, carbozine), which are converted to active triphosphorylated metabolites by kinases involved in pyrimidine synthesis. Other inhibitors (e.g., activin or 6-diazo-5-oxo-L-norleucine) are reactive analogs of glutamine that irreversibly inhibit the glutaminase domain of CTPS and other glutamine-utilizing enzymes.

[0185] Given the high metabolic demands of proliferating cancer cells and data suggesting CTP synthase activity in many tumor types, selective CTPS inhibitors may offer an attractive alternative approach for tumor treatment. Compounds with differential activity against CTPS1 and / or CTPS2 may offer important opportunities for targeting different tumors depending on their relative dependence on these two enzymes.

[0186] In addition to cancer biology, extensive literature highlights the role of nucleotide synthesis and CTP synthase activity in immune biology and disease. The immune system in multicellular organisms has evolved to provide protection from a wide variety of infectious pathogens. This process generally requires recognition of pathogens by various immune cells, often followed by amplification and long-term propagation of the immune response via rapid expansion, proliferation, and differentiation of responding immune cells. Within this process, CTP synthase activity appears to play a key role in DNA synthesis and the rapid expansion of lymphocytes after activation (Fairbanks, et al. 1995; van den Berg, et al. 1995).

[0187] Direct clinical confirmation comes from genetic trials in which a rare, loss-of-function homozygous mutation (rs145092287) in this enzyme causes a severe immunodeficiency characterized by a severely impaired ability of activated T or B cells to proliferate in response to antigen receptor-mediated activation. Furthermore, activated CTPS1-deficient cells from patients have reduced levels of intracellular CTP compared with normal controls, and normal T cell proliferation can be restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by adding exogenous cytidine. CTPS1 mRNA and protein expression have been found to be very low in resting lymphocytes but rapidly upregulated after activation. CTPS1 expression in other tissues is generally low, and it is unknown whether expression in other tissues is similarly inducible. CTPS2 appears to be expressed ubiquitously but at low levels in many cells and tissues, and normal levels of CTPS2 do not compensate for mutant CTPS1 in immune cells, supporting a critical role for CTPS1 in immune populations affected in homozygous patients (Martin, et al. 2014). In summary, these findings suggest that CTPS1 activity is important for meeting the metabolic demand for CTP required by several key immune cell populations when they are activated and required to proliferate.

[0188] Normally, the immune response is tightly regulated to ensure sufficient activity to protect against infection while simultaneously preventing overactivation or inappropriate recognition of host proteins and cells. In certain diseases or conditions, control of this process may be ineffective, resulting in immune-mediated pathology. A wide variety of human diseases and pathologies are thought to result from these types of inappropriate immune responses and are generally classified as autoimmune diseases or conditions.

[0189] Given the role that pathogenic immune cells, such as autoreactive T and B lymphocytes, are thought to play in a wide range of autoimmune and other diseases, CTPS1 represents a potential therapeutic target for a novel class of immunosuppressants. Specific CTPS1 inhibitors may therefore offer a novel approach for functional inhibition of activated lymphocytes, as well as other specific immune cell populations shown to be deficient in CTPS1-deficient patients, such as NK (natural killer), MAIT (mucosal-associated invariant T), and iNK (invariant natural killer) cells (Martin, et al. 2014).

[0190] In addition to its role in cancer and immune biology, CTPS1 has also been suggested to play a role in vascular smooth muscle cell proliferation (restenosis) after vascular injury or surgery (Tang, et al. 2013).

[0191] To date, no specific CTP synthase inhibitors have been described in detail or clinically tested. Available data strongly suggest that CTPS1 inhibitors can reduce the proliferation of pathogenic immune and cancer cell populations, and potentially other targeted cell populations. Therefore, CTPS1 inhibitors are expected to be useful for the treatment or prevention of a wide range of indications in which pathology is driven by these populations. CTPS1 inhibitors may represent a unique approach for inhibiting selected components of the immune system, such as proliferating pathogenic autoreactive lymphocytes. This may be useful in a number of diseases, such as immune-mediated rejection of transplanted cells, organs, and tissues, graft-versus-host disease or reactions, and immune-driven allergies and autoimmune diseases. Furthermore, the apparent specificity of CTPS1 function in immune cells may suggest that CTPS1 inhibitors may exhibit an improved therapeutic index over other clinically used nonspecific nucleotide inhibitors, such as leflunomide or azathioprine. Finally, CTPS1 inhibitors may offer therapeutic potential in a wide range of cancer indications, particularly those of hematopoietic origin, and may help improve recovery from vascular injury or surgery, as well as reduce morbidity and mortality associated with neointima formation and restenosis.

[0192] The present disclosure provides methods for modulating (e.g., inhibiting) CTPS1 activity, comprising administering to a patient a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In certain embodiments, the compounds and compositions described herein are useful for inhibiting CTPS1.

[0193] In one embodiment, the subject matter disclosed herein relates to a method for inhibiting CTPS1, comprising contacting CTPS1 with an effective amount of a compound of the present invention described herein, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. Such a method comprises contacting CTPS1 with an effective amount of a compound of the present disclosure. The compound can be contacted with CTPS1 in vitro or in vivo by administering the compound to a subject.

[0194] In one aspect, the present invention provides a method of treating a disease or disorder mediated by CTPS1 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0195] In another aspect, the present invention provides a method of treating a disease or disorder associated with CTPS1 regulation in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0196] In certain embodiments, the disease or disorder is selected from rejection of transplanted cells and tissues, transplant-associated diseases or disorders, allergies and autoimmune diseases.

[0197] In one embodiment, the disease or disorder is rejection of transplanted cells and tissues. In certain embodiments, the subject may have received a transplant selected from the group consisting of heart, kidney, lung, liver, pancreas, pancreatic islets, brain tissue, stomach, large intestine, small intestine, cornea, skin, trachea, bone, bone marrow (or any other source of hematopoietic progenitor cells and stem cells, including hematopoietic cells mobilized from bone marrow to peripheral blood or umbilical cord blood cells), muscle, and bladder. In certain embodiments, the compounds of the present invention are used to prevent or suppress immune responses associated with rejection of donor tissue, cell, graft, or organ transplants in subjects.

[0198] In certain embodiments, the disease or disorder is a transplant-related disease or disorder. In some embodiments, transplant-related diseases or disorders include graft-versus-host disease (GVHD), such as GVHD associated with bone marrow transplantation, and immune disorders resulting from or associated with the rejection of organ, tissue, or cell transplants (e.g., autografts or xenografts of tissue or cells), including transplants of skin, muscle, neurons, islets, organs, liver parenchyma cells, etc., as well as host-versus-graft disease (HVGD). In certain embodiments, the compounds of the present invention are used to prevent or predict acute rejection of such transplants in recipients and / or for long-term sustained therapy to prevent rejection of such transplants in recipients (e.g., inhibiting rejection of insulin-producing islet cell transplants from donors in target recipients suffering from diabetes). In some embodiments, the compounds of the present invention prevent host-versus-graft disease (HVGD) and graft-versus-host disease (GVHD).

[0199] In certain embodiments, the compounds of the invention are administered to a subject before, after, and / or during transplantation. In some embodiments, the compounds of the invention are administered to a subject on a periodic basis before and / or after transplantation.

[0200] In another embodiment, the disease or disorder is an allergy.

[0201] In certain embodiments, the autoimmune diseases treated by the compounds of the invention include Addison's disease, adult-onset Still's disease, alopecia areata, Alzheimer's disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, ankylosing spondylitis, antiphospholipid syndrome (Hughes syndrome), aplastic anemia, arthritis, asthma, atherosclerosis, atherosclerotic plaques, atopic dermatitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune hypophysitis (lymphocytic hypophysitis), autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis, autoimmune orchitis, autoinflammatory diseases requiring immunosuppressive treatment, azoospermia, Behcet's disease, Buerger's disease, bullous pemphigoid, cardiomyopathy, cardiovascular disease, and refractory celiac disease (types I and II). Celiac disease, including celiac disease, chronic fatigue immune deficiency syndrome (CFIDS), chronic idiopathic polyneuropathy, chronic inflammatory demyelinating polyneuropathy (CIPD), chronic relapsing polyneuropathy (Guillain-Barré syndrome), Churg-Strauss syndrome (CSS), cicatricial pemphigoid, cold agglutinin disease (CAD), chronic obstructive pulmonary disease (COPD), CREST syndrome, cryoglobulinemia syndrome, cutaneous lupus, dermatitis herpetiformis, dermatomyositis, eczema, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, Evans syndrome, exophthalmos, fibromyalgia, Goodpasture syndrome, Graves' disease, hemophagocytic lymphohistiocytosis (HLH) (including type 1 hemophagocytic lymphohistiocytosis), histiocytosis / histiocytic disorders, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura Thrombocytopenia purpura (ITP), IgA nephropathy, immunoproliferative or immunoproliferative disorders, inflammatory bowel disease (IBD), interstitial lung disease, juvenile arthritis, juvenile idiopathic arthritis (JIA), Kawasaki disease, Lambert-Eaton myasthenic syndrome, lichen planus, localized scleroderma, lupus nephritis, Meniere's disease, microangiopathic hemolytic anemia, microscopic polyangitis, Miller Fisher syndrome / acute disseminated cerebrospinal radiculopathyEncephalomyeloradiculopathy), mixed connective tissue disease, multiple sclerosis (MS), muscular rheumatism, myalgic encephalomyelitis (ME), myasthenia gravis, eye inflammation, pemphigus foliaceus, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome (Whitaker syndrome), polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis / autoimmune bile duct disease, primary glomerulonephritis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, pure red cell aplasia, Raynaud's syndrome phenomenon, Reiter's syndrome / reactive arthritis, relapsing polychondritis, restenosis, rheumatic fever, rheumatoid disease, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleroderma / systemic sclerosis, Sjögren's syndrome, stiff-man syndrome, Sweet's syndrome (febrile neutrophilic dermatosis), systemic lupus erythematosus (SLE), systemic sclerosis, Takayasu's arteritis, temporal arteritis / giant cell arteritis, thyroiditis, type 1 diabetes, type 2 diabetes, uveitis, vasculitis, vitiligo, Wegener's granulomatosis, or X-linked lymphoproliferative disease.

[0202] In some embodiments, the disease treated by the compounds of the present invention is driven by T cell activation and proliferation and is selected from alopecia areata, atopic dermatitis, eczema, psoriasis, lichen planus, psoriatic arthritis, vitiligo, uveitis, ankylosing spondylitis, Reiter's syndrome / reactive arthritis, aplastic anemia, autoimmune lymphoproliferative syndromes / disorders, hemophagocytic lymphohistiocytosis, type 1 diabetes, and refractory celiac disease. In some embodiments, the disease is acute rejection of transplanted tissues and transplanted organs, acute graft-versus-host disease (GVHD) after transplantation of bone marrow cells or any other source of allogeneic cells, including hematopoietic progenitor cells and / or stem cells.

[0203] In certain embodiments, diseases treated by the compounds of the invention are driven by the activation and proliferation of both T and B cells and include allergies, cicatricial pemphigoid, bullous pemphigoid, epidermolysis bullosa acquisita, pemphigus foliaceus, pemphigus vulgaris, dermatitis herpetiformis, ANCA-associated vasculitis and microscopic polyangiitis, vasculitis, Wegener's granulomatosis; Churg-Strauss syndrome (CSS), polyarteritis nodosa, cryoglobulinemia and essential mixed cryoglobulinemia, systemic lupus erythematosus (SLE), antiphospholipid syndrome (Hughes' syndrome), cutaneous lupus, lupus nephritis, mixed connective tissue disease, thyroiditis, Hashimoto's thyroiditis, Graves' disease, exophthalmos, autoimmune hemolytic anemia, autoimmune neutropenia, ITP, pernicious anemia, pure red cell aplasia (PRC). anemia), microangiopathic hemolytic anemia, primary glomerulonephritis, Buerger's disease, Goodpasture's syndrome, IgA nephropathy, chronic idiopathic polyneuropathy, chronic inflammatory demyelinating polyneuropathy (CIPD), chronic relapsing polyneuropathy (Guillain-Barré syndrome), Miller Fisher syndrome, stiff-man syndrome, Lambert-Eaton myasthenic syndrome, and myasthenia gravis.

[0204] In certain embodiments, the diseases treated by the compounds of the invention are Addison's disease, autoimmune oophoritis and azoospermia, polyglandular syndrome (Whitaker's syndrome), Schmidt's syndrome, autoimmune myocarditis, cardiomyopathy, Kawasaki's disease, rheumatoid arthritis, Sjogren's syndrome, mixed connective tissue disease, polymyositis and dermatomyositis, polychondritis, primary glomerulonephritis, multiple sclerosis, autoimmune hepatitis, primary biliary cirrhosis / autoimmune bile duct disease, fulminant rejection of transplanted organs, chronic rejection of grafts or transplants, and chronic graft-versus-host reaction / disease after transplantation of bone marrow cells or hematopoietic progenitor cells.

[0205] In certain embodiments, the diseases treated by the compounds of the invention are COPD, idiopathic pulmonary fibrosis, interstitial lung disease, sarcoidosis, adult-onset Still's disease, juvenile idiopathic arthritis, systemic sclerosis, CREST syndrome in which B cells and pathogenic antibodies may also play a role, Sweet's syndrome; Takayasu's arteritis, temporal arteritis / giant cell arteritis, ulcerative cholangitis, inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis, primary sclerosing cholangitis, Alzheimer's disease, cardiovascular syndromes, type 2 diabetes, restenosis, chronic fatigue and immune deficiency syndrome (CFIDS), autoimmune lymphoproliferative syndrome, and X-linked lymphoproliferative disorder.

[0206] In certain embodiments, the disease treated by the compounds of the present invention is an inflammatory skin disease, such as psoriasis or lichen planus; acute and / or chronic GVHD, such as steroid-resistant acute GVHD; acute lymphoproliferative syndrome; systemic lupus erythematosus, lupus nephritis, or cutaneous lupus; or transplantation. Furthermore, the disease or disorder may be selected from myasthenia gravis, multiple sclerosis, and scleroderma / systemic sclerosis.

[0207] In certain aspects, the present invention provides methods of treating cell proliferative disorders, including cancer, benign papillomatosis, gestational trophoblastic disease, and benign neoplastic diseases, such as cutaneous papillomas (warts) and genital papillomas.

[0208] In one aspect, provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

[0209] In the methods described herein, a compound of the present invention or a pharmaceutical composition thereof is administered to a subject with cancer.

[0210] In certain embodiments, the cancer is selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematological malignancies, and renal cell carcinoma.

[0211] In certain embodiments, the cancer is acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet's syndrome, T-cell non-Hodgkin's lymphoma (natural killer / T-cell lymphoma, adult-onset T-cell leukemia / lymphoma, enteropathy type T-cell lymphoma, lymphoma, hepatosplenic T-cell lymphoma, and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell non-Hodgkin's lymphoma (including Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), hairy cell leukemia, Hodgkin's lymphoma, lymphoblastic lymphoma, lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue lymphoma, multiple myeloma, myelodysplastic syndrome, plasma cell myeloma, primary mediastinal large B-cell lymphoma, chronic myeloproliferative syndromes (e.g., chronic myelogenous leukemia, primary myelofibrosis, essential thrombocythemia, polycytemia vera), and chronic lymphocytic leukemia.

[0212] In some embodiments, the cancer is a non-hematological cancer selected from bladder cancer, breast, melanoma, neuroblastoma, malignant pleural mesothelioma, and sarcoma.

[0213] Examples of cancers that can be treated using the compounds of the present disclosure include bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, cancer of the fallopian tubes, cancer of the endometrium, endometrial cancer, cancer of the cervix, cancer of the vagina, cancer of the vulva, Hodgkin's disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic or acute leukemia, childhood These include, but are not limited to, stage 1 solid tumors, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, cancer of the renal pelvis, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, tumors of the spinal axis, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers (including those induced by asbestos), and combinations of these cancers.

[0214] In some embodiments, cancers treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of these cancers.

[0215] In certain embodiments, the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer, or sarcoma. In other embodiments, the cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumor, acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia, melanoma, tumors of the breast, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, and cholangiocarcinoma.

[0216] In certain embodiments, the cancer is selected from brain and spinal cord cancer, head and neck cancer, leukemia and blood cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, liver and bile duct cancer, kidney and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, glandular cancer, thyroid cancer, cardiac tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancer, and cancer of unknown primary site (cancer in which metastasis is found but the site of original cancer is unknown). In certain embodiments, the cancer is in an adult patient. In further embodiments, the cancer is in a pediatric patient. In certain embodiments, the cancer is associated with AIDS.

[0217] In further embodiments, the cancer is selected from cancers of the brain and spinal cord. In certain embodiments, the cancer is selected from the group consisting of atypical astrocytoma, glioblastoma, atypical astrocytoma, and estheosioneuroblastoma (olfactory blastoma). In certain embodiments, the brain cancer is selected from the group consisting of astrocytic tumors (e.g., heavy cell astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, atypical astrocytoma, atypical astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult-onset glioblastoma, and primary pediatric glioblastoma), oligodendroglial tumors (e.g., oligodendroglioma and anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., glioma ... tumors (e.g., oligoastrocytoma and anaplastic oligoastrocytoma), ependymoma (e.g., myxopapillary ependymoma and anaplastic ependymoma); medulloblastoma, primitive neuroectodermal tumor, schwannoma, meningioma, atypical meningioma, anaplastic meningioma, pituitary adenoma, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, visual pathway and hypothalmic glioma, and primary central nervous system lymphoma. In certain examples of these embodiments, the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and supratentorial primitive neuroectodermal tumor (sPNET).

[0218] In certain embodiments, the cancer is selected from nasopharyngeal cancer, cancer of the nasal cavity and paranasal sinuses, hypopharyngeal cancer, oral cancer (e.g., squamous cell carcinoma, lymphoma, and sarcoma), lip cancer, oropharyngeal cancer, salivary gland tumors, cancer of the larynx (e.g., laryngeal squamous cell carcinoma, rhabdomyosarcoma), and head and neck cancer, including eye or ocular cancer. In certain embodiments, the eye cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.

[0219] In certain embodiments, the cancer is selected from leukemia and blood cancer. In certain embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPN), post-MPN AML, post-MDS AML, del(5q)-related high-risk MDS or AML, blast phase chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerhans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms, including plasmacytoma and multiple myeloma. The leukemias described herein can be acute or chronic.

[0220] In certain embodiments, the cancer is selected from a skin cancer, hi certain embodiments, the skin cancer is selected from the group consisting of melanoma, squamous cell carcinoma, and basal cell carcinoma.

[0221] In certain embodiments, the cancer is selected from cancers of the reproductive system. In certain embodiments, the cancer is selected from the group consisting of breast cancer, cervical cancer, vaginal cancer, ovarian cancer, prostate cancer, penile cancer, and testicular cancer. In certain examples of these embodiments, the cancer is breast cancer selected from the group consisting of ductal carcinoma and phyllodes tumor. In certain examples of these embodiments, the breast cancer may be male or female breast cancer. In certain examples of these embodiments, the cancer is cervical cancer selected from the group consisting of squamous cell carcinoma and adenocarcinoma. In certain examples of these embodiments, the cancer is ovarian cancer selected from the group consisting of epithelial cancers.

[0222] In certain embodiments, the cancer is selected from cancers of the gastrointestinal system. In certain embodiments, the cancer is selected from the group consisting of esophageal cancer, gastric cancer (also known as stomach cancer), gastrointestinal carcinoid tumor, pancreatic cancer, gallbladder cancer, colorectal cancer, and anal cancer. In exemplary of these embodiments, the cancer is selected from the group consisting of pancreatic cancer, including esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gastric lymphoma, gastrointestinal lymphoma, pancreatic solid pseudopapillary tumor, pancreatoblastoma, islet cell tumor, acinar cell carcinoma, and tubular adenocarcinoma, gallbladder adenocarcinoma, colorectal adenocarcinoma, and anal squamous cell carcinoma.

[0223] In certain embodiments, the cancer is selected from liver and bile duct cancer. In certain embodiments, the cancer is liver cancer (hepatocellular carcinoma). In certain embodiments, the cancer is bile duct cancer (cholangiocarcinoma); in examples of these embodiments, the bile duct cancer is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.

[0224] In certain embodiments, the cancer is selected from kidney and bladder cancer. In certain embodiments, the cancer is a kidney cancer selected from the group consisting of renal cell carcinoma, Wilms' tumor, and transitional cell carcinoma. In certain embodiments, the cancer is a bladder cancer selected from the group consisting of urethelial carcinoma (transitional cell carcinoma), squamous cell carcinoma, and adenocarcinoma.

[0225] In certain embodiments, the cancer is selected from bone cancer, hi certain embodiments, the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing's sarcoma, and chordoma.

[0226] In certain embodiments, the cancer is selected from lung cancer. In certain embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, bronchial tumor, and pleuropulmonary blastoma.

[0227] In certain embodiments, the cancer is selected from the group consisting of malignant mesothelioma, epithelioid mesothelioma, and sarcoma.

[0228] In certain embodiments, the cancer is selected from a sarcoma, hi certain embodiments, the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of the tendon sheath, and Kaposi's sarcoma.

[0229] In certain embodiments, the cancer is selected from lymphoma. In certain embodiments, the cancer is selected from the group consisting of Hodgkin's lymphoma (e.g., Reed-Sternberg cell), non-Hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sézary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphoma, and primary central nervous system lymphoma.

[0230] In certain embodiments, the cancer is selected from a glandular cancer, hi certain embodiments, the cancer is selected from the group consisting of adrenocortical carcinoma, pheochromocytoma, paraganglioma, pituitary tumor, thymoma, and thymic carcinoma.

[0231] In certain embodiments, the cancer is selected from thyroid cancer. In certain embodiments, the thyroid cancer is selected from the group consisting of medullary thyroid cancer, papillary thyroid cancer, and follicular thyroid cancer.

[0232] In certain embodiments, the cancer is selected from a germ cell tumor. In certain embodiments, the cancer is selected from the group consisting of malignant extracranial germ cell tumor and malignant extragonadal germ cell tumor. In certain examples of these embodiments, the malignant extragonadal germ cell tumor is selected from the group consisting of nonseminoma and seminoma.

[0233] In certain embodiments, the cancer is selected from a cardiac tumor, hi certain embodiments, the cardiac tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosarcoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

[0234] In certain embodiments, the cell proliferative disorder is selected from benign papillomatosis, benign neoplastic disease, and gestational trophoblastic disease. In certain embodiments, the benign neoplastic disease is selected from cutaneous papillomas (warts) and genital papillomas. In certain embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidiform mole and gestational trophoblastic neoplasia (e.g., mole destructive, choriocarcinoma, pelvic trophoblastic tumor, epithelioid trophoblastic tumor).

[0235] In some embodiments, the subject has melanoma. The melanoma may be at an early stage or a late stage. In some embodiments, the subject has colorectal cancer. The colorectal cancer may be at an early stage or a late stage. In some embodiments, the subject has non-small cell lung cancer. The non-small cell lung cancer may be at an early stage or a late stage. In some embodiments, the subject has pancreatic cancer. The pancreatic cancer may be at an early stage or a late stage. In some embodiments, the subject has a hematological malignancy. The hematological malignancy may be at an early stage or a late stage. In some embodiments, the subject has ovarian cancer. The ovarian cancer may be at an early stage or a late stage. In some embodiments, the subject has breast cancer. The breast cancer may be at an early stage or a late stage. In some embodiments, the subject has renal cell carcinoma. The renal cell carcinoma may be at an early stage or a late stage. In some embodiments, the cancer has a high level of T-cell infiltration.

[0236] In some embodiments, cancers treatable with the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma), kidney cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-resistant prostate cancer), breast cancer, triple-negative breast cancer, colon cancer, and lung cancer (e.g., non-small cell lung cancer and small cell lung cancer). Additionally, the present disclosure encompasses refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure.

[0237] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0238] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0239] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0240] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondroitin hamartoma, and mesothelioma.

[0241] Exemplary gastrointestinal cancers include cancer of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), cancer of the stomach (carcinoma, lymphoma, leiomyosarcoma), cancer of the pancreas (tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), cancer of the small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), cancer of the large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0242] Exemplary genitourinary tract cancers include kidney (adenocarcinoma, Wilms' tumor [nephroblastoma]), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma).

[0243] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0244] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (chondromyxosteosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor.

[0245] Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (atypical astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Dacros disease.

[0246] Exemplary gynecological cancers include cancer of the uterus (endometrial carcinoma), cancer of the cervix (cervical carcinoma, preneoplastic cervical dysplasia), cancer of the ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), cancer of the vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), cancer of the vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), and cancer of the fallopian tubes (carcinoma).

[0247] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloid. In some embodiments, diseases and indications treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.

[0248] Exemplary head and neck cancers include, but are not limited to, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancer, thyroid and parathyroid cancer.

[0249] In some embodiments, CTPS inhibitors can be used to treat tumors that produce PGE2 (e.g., tumors overexpressing Cox-2) and / or adenosine (tumors overexpressing CD73 and CD39). Cox-2 overexpression has been detected in numerous tumors, such as colorectal cancer, breast cancer, pancreatic cancer, and lung cancer, and correlates with poor prognosis. COX-2 overexpression has been reported in hematological cancer models, such as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia), as well as in patient blast cells. CD73 is upregulated in various human cancers, including colon, lung, pancreatic, and ovarian cancers. Importantly, higher CD73 expression levels are associated with tumor neovascularization, invasiveness, and metastasis, as well as shorter patient survival in breast cancer.

[0250] In certain embodiments, the present invention provides a method of treating a disease or disorder mediated by CTPS1 in a subject, wherein the treatment reduces T cell and / or B cell proliferation, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0251] In certain embodiments, the present invention provides a method of reducing T cell and / or B cell proliferation, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0252] In certain embodiments, the present invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, or derivative thereof, in the manufacture of a medicament for reducing T cell and / or B cell proliferation in a subject.

[0253] In certain embodiments, the compounds of the present invention are used to enhance recovery from vascular injury or surgery, and to reduce the morbidity and mortality associated with neointima and restenosis in subjects.For example, the compounds of formula (I) can be used to prevent, reduce, or inhibit neointima formation.Before inserting or implanting a medical device with a composition containing an effective amount of a compound of formula (I), the medical device can be treated with the purpose of preventing, reducing, or inhibiting neointima formation after inserting or implanting the device or implant into a subject.The device can be a device that is temporarily inserted into a subject, or a device that is permanently implanted.In some embodiments, the device is a surgical device.Examples of medical devices include, but are not limited to, needles, cannulas, catheters, shunts, balloons, and implants such as stents and valves.

[0254] In some embodiments, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0255] In certain embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, for use in the treatment or prevention of a disease or disorder provided herein.

[0256] In certain embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, for use as a pharmaceutical for the treatment or prevention of a disease or disorder provided herein.

[0257] In certain embodiments, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, in the manufacture of a medicament for the inhibition of CTPS1 in a subject.

[0258] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases mentioned herein, for example, in individuals who may be predisposed to the disease, condition, or disorder but who have not yet experienced or displayed the pathology or symptoms of the disease.

[0259] The compounds of the present disclosure can be administered by any suitable method known in the art. In some embodiments, the compounds of the present invention, or pharmaceutically acceptable salts, prodrugs, metabolites, or derivatives thereof, are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intracavity, intratumorally, or intranasally.

[0260] In some embodiments, the CTPS1 antagonist is administered continuously. In other embodiments, the CTPS1 antagonist is administered intermittently. Moreover, treatment of a subject with an effective amount of a CTPS1 antagonist can include a single treatment or can include a series of treatments.

[0261] It will be understood that the appropriate dose of the active compound depends on numerous factors within the knowledge of an ordinary human or veterinarian. The dose(s) of the active compound will vary depending, for example, on the age, weight, general health, sex, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combinations.

[0262] It will also be understood that the effective dosage of the compounds of the invention, or pharmaceutically acceptable salts, prodrugs, metabolites, or derivatives thereof, used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may be effected by, and become apparent from, the results of diagnostic assays.

[0263] In some embodiments, the CTPS1 antagonist is administered to a subject at a dose between about 0.001 μg / kg and about 1000 mg / kg, including, but not limited to, about 0.001 μg / kg, 0.01 μg / kg, 0.05 μg / kg, 0.1 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 25 μg / kg, 50 μg / kg, 100 μg / kg, 250 μg / kg, 500 μg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, and 200 mg / kg.

[0264] In the methods described herein, the methods may further comprise administering a chemotherapeutic agent to the subject. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject simultaneously with the compound or composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject before administration of the compound or composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject after administration of the compound or composition.

[0265] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. 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., taking into account a history of the symptoms and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay the recurrence of the symptoms.

[0266] As used herein, the term "prophylaxis" or "preventing" is used to mean preventing the symptoms of a disease or disorder in a subject or preventing the recurrence of symptoms of a disease or disorder in an afflicted subject, and is not limited to complete prevention of affliction.

[0267] The term "administration" or "administering" includes routes of introducing a compound(s) into a subject to perform their intended function. Examples of routes of administration that may be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0268] The term "effective amount" includes an amount that is effective, at the dosage and for the period required, to achieve the desired result. The effective amount of a compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimal therapeutic response.

[0269] The phrases "systemic administration," "systemically administered," "peripheral administration," and "peripherally administered," as used herein, refer to administering a compound(s), drug(s), or other substance so that the compound(s), drug(s), or other substance enters a patient's system and is therefore subject to metabolism and other similar processes.

[0270] The phrase "therapeutically effective amount" refers to the amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) attenuates, improves, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein.In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down to a certain extent, and preferably stop) the infiltration of cancer cells into peripheral organs; inhibit (i.e., slow down to a certain extent, and preferably stop) the metastasis of tumors; inhibit tumor growth to a certain extent; and / or alleviate one or more of the symptoms associated with cancer to a certain extent.To the extent that a drug can prevent the growth and / or kill existing cancer cells, the drug can be cytostatic and / or cytotoxic. With respect to cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0271] The term "subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In certain embodiments, the subject is a human. Combination therapy

[0272] Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, can be administered in combination with the compounds and 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."

[0273] In certain embodiments, the provided combinations, or compositions thereof, are administered in combination with another therapeutic agent.

[0274] Examples of drugs with which the combinations of this invention may be combined 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, trihexephendyl, 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, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents agents); agents for treating cardiovascular disease, such as beta-blockers, ACE 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., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and agents for treating immune deficiency disorders, such as gamma globulins.

[0275] In certain embodiments, the combination therapy of the invention, or a pharmaceutically acceptable composition thereof, is administered in combination with a monoclonal antibody or siRNA therapeutic agent.

[0276] 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 compounds of this invention in a single composition. When administered as part of a multiple dose regimen, the two active agents may be given simultaneously, sequentially, or within a period of each other, usually within 5 hours of each other.

[0277] As used herein, the terms "combination," "in combination," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, a combination of the invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.

[0278] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0279] In one embodiment, the present invention provides a composition comprising a compound of Formula I and one or more additional therapeutic agents. The therapeutic agents can be administered together with the compound of Formula I, or before or after the administration of the compound of Formula I. Suitable therapeutic agents are described in more detail below. In certain embodiments, the compound of Formula I can 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, the compound of formula I can 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.

[0280] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), colchicine (Colcrys®), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), probenecid, allopurinol, febuxostat, etc. (febuxostat) (Uloric®), sulfasalazine (Azulfidine®), antimalarials (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®) )), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Gibberish®), fluconazole (Fenix ​​... Mabs (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), canakinumab (Ilaris®), anti-Jak inhibitors (e.g., tofacitinib), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g.,Abatacept (Orencia®), “anti-IL-6” agents (e.g., tocilizumab (Actemra®)), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies (e.g., tanezumab), anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)), antidiarrheal drugs (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders (e.g., cholestyramine), alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives (e.g., milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), anticholinergics or antispasmodics (e.g., dicyclomine (Bentyl®)), Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids (e.g., beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®)), Afviar®, Symbicort®, Dulera®,Cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), IgE antibodies (e.g., omalizumab (Xolair®)), nucleoside reverse transcriptase inhibitors (e.g., zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®) ), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors (e.g., delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (nev airapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors (e.g., tenofovir (Viread®)), protease inhibitors (e.g., amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), trademark), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors (e.g., enfuvirtide (Fuzeon®) and maraviroc (Selzentry®)), integrase inhibitors (e.g., raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), or any combination(s) thereof.

[0281] In another embodiment, the present invention provides a method of treating rheumatoid arthritis by administering to a patient in need thereof a compound of Formula I and nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), sulfasalazine (Azulfidine®), antimalarials (e.g., benzodiazepines), benzocaine (benzocaine), benzodiazepines (e.g., benzocaine), benzocaine ( ... For example, hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®)), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), (R), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), and adalimumab (Humira®)), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g., abatacept (Orencia®)), and "anti-IL-6" agents (e.g., tocilizumab (Actemra®)).

[0282] In some embodiments, the present invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies (e.g., tanezumab).

[0283] In some embodiments, the present invention provides a method of treating cutaneous lupus erythematosus or systemic lupus erythematosus by administering to a patient in need thereof a compound of Formula I and a combination of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), antimalarials (e.g., hydroxychloroquine, and administering one or more additional therapeutic agents selected from fluticasone (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)).

[0284] In some embodiments, the present invention provides a method of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease by administering to a patient in need thereof a compound of Formula I and mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal drugs (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile acid binders (e.g., cholestyramine, alosetron (Lotronex®), lubiprostone (Amiti®), or other anti-inflammatory drugs (e.g., benzodiazepines, benzocaine ... za®), laxatives (e.g., milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), and one or more additional therapeutic agents selected from anticholinergics or antispasmodics (e.g., dicyclomine (Bentyl®), anti-TNF therapeutics, steroids, and antibiotics (e.g., Flagyl or ciprofloxacin).

[0285] In some embodiments, the present invention provides a method of treating asthma by administering to a patient in need thereof a compound of Formula I and one or more of Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate), or steroids (e.g., benzodiazepines, benzocaine ... (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®), cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), and IgE antibodies (e.g., omalizumab (Xolair®)).

[0286] In some embodiments, the present invention provides a method of treating COPD, comprising administering to a patient in need thereof a compound of Formula I and a beta-2 agonist (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), an anticholinergic (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), a methylxanthine (e.g., theophylline (Theo and aminophylline), inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®).

[0287] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I 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.

[0288] In another embodiment, the present invention provides a method of treating a solid tumor, comprising administering to a patient in need thereof a compound of Formula I 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.

[0289] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I 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).

[0290] In another embodiment, the invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a compound of Formula I 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.

[0291] In another embodiment, the present invention provides a method of treating multiple myeloma, comprising administering to a patient in need thereof a compound of formula I 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®).

[0292] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a BTK inhibitor, wherein the disease is selected from the group consisting of 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, and inflammatory bowel disease. thyroiditis), Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated cerebrospinal meningitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, 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, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, house dust mites, or cockroach calyx) calyx), 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, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitisMyocarditis, 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 (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Walde's lymphoma M. Lundstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, 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, mastocytoma) alveolar sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases (including but not limited to rheumatoid arthritis, seronegative spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases), thromboembolic disorders (e.g., myocardial infarction, angina pectoris, re-occlusion after angioplasty, restenosis after angioplasty, re-occlusion after aortocoronary artery bypass, restenosis after aortocoronary artery bypass, stroke, transient ischemia, peripheral arterial occlusive disorder , pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis (cholocystitis), 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 polyglandulardisease) (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile In some embodiments, the disease is selected from the group consisting of chronic arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0293] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is selected from cancer, a neurodegenative disorder, an angiogenic 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), liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder.

[0294] In another embodiment, the invention provides a method of treating or lessening the severity of a disease, comprising the step of administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is a benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid gland, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, particularly colon cancer or colorectal adenoma or head and neck tumor, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, intraepithelial neoplasia, character), adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, Cowden syndrome, Lhermitte-Dudos disease Diseases including Banayan-Zonana syndrome or diseases in which the PI3K / PKB pathway is abnormally activated, asthma of any type or onset, including both intrinsic (non-allergic) 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 airway disease or chronic obstructive lung diseasedisease (COPD, COAD or COLD) (including associated chronic bronchitis or dyspnea), emphysema, and exacerbations of airway overactivity as a result of other medications (especially other inhaled medications), bronchitis of any type or occurrence (including but not limited to acute, arachidic, catarrhal, croupus, chronic or tuberculous bronchitis), pneumoconiosis of any type or occurrence (an inflammatory, generally occupational, lung disease, whether chronic or acute, frequently associated with airway obstruction and caused by repeated inhalation of dust) (including, for example, aluminum lung disease, anthracosis, asbestosis, stone disease, ptilosis, siderosis, silicosis, tabacosis and byssinosis), Loffler's syndromesyndrome), eosinophilic pneumonia, parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophil-related disorders affecting the airways caused by eosinophilic granulomas and drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, eosinophilic granulomas, eosinophil-associated disorders affecting the respiratory tract caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, eosinophilic granulomas ... Diseases affecting the nose, including erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, allergic rhinitis, and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, multiple cartilage degeneration, inflammation, 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, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome (including, for example, idiopathic nephrotic syndrome or minimal change nephropathy)), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, as well as neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia.

[0295] In some embodiments, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I 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.

[0296] 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-binding compound is a compound of Formula I. Other suitable JH2 domain-binding compounds include those described in WO2014074660A1, WO2014074661A1, and 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.

[0297] According to the method of the present invention, the compounds and compositions can be administered in any amount and by any route of administration effective for treating or reducing the severity of autoimmune, inflammatory, proliferative, endocrine, neurological, or transplant-related disorders. The exact amount required varies from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the specific drug, its mode of administration, etc. The compounds of the present invention are preferably formulated into unit dosage forms for ease of administration and uniformity of dosage. The term "unit dosage form" as used herein refers to a physically separate unit of drug appropriate for the patient to be treated. However, it is understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The effective dose level specific to 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 excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound used, and similar factors well known in the medical field. The term "patient", as used herein, means an animal, preferably a mammal, most preferably a human.

[0298] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention can 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, preferably about 1 mg to about 25 mg per kg, one or more times daily to obtain the desired therapeutic effect.

[0299] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, 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, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, as well as sweeteners, flavoring agents and fragrances.

[0300] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be injectable sterile solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such 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. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0301] Injectable preparations can be sterilized prior to use, 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.

[0302] To prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can 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 dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved 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. The compound release rate can be controlled depending on the ratio of compound to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0303] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of this 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 therefore melts in the rectum or vaginal cavity and releases the active compound.

[0304] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as, for example, 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 comprise buffering agents.

[0305] Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be composed so that they release 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 for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc.

[0306] The active compound may be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is common practice, such dosage forms may contain 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. They 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.

[0307] Dosage forms for topical or transdermal administration of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of this invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing 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 flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0308] According to one embodiment, the present invention relates to a method of inhibiting protein kinase activity in a biological sample, comprising the step of contacting said biological sample with a compound of this invention or a composition comprising said compound.

[0309] According to another embodiment, the present invention relates to a method for inhibiting the activity of CTPS 1 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of this invention or a composition comprising said compound. In certain embodiments, the present invention relates to a method for irreversibly inhibiting the activity of CTPS 1 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of this invention or a composition comprising said compound.

[0310] The term "biological sample," as used herein, includes, but is not limited to, a cell culture or extract thereof; a biopsy or extract thereof obtained from a mammal; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0311] Inhibition of the activity of CTPS 1 (or a variant thereof) in a biological sample is useful for a variety of purposes known to those skilled in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0312] Another embodiment of the invention relates to a method of inhibiting protein kinase activity in a patient, comprising administering to said patient a compound of the present invention, or a composition comprising said compound.

[0313] According to another embodiment, the present invention provides a method for inhibiting the activity of CTPS1 or a mutant thereof in a patient, comprising administering to the patient a compound of the present invention or a composition comprising said compound. According to certain embodiments, the present invention provides a method for reversibly or irreversibly inhibiting the activity of CTPS1 or one or more mutants thereof in a patient, comprising administering to the patient a compound of the present invention or a composition comprising said compound. In other embodiments, the present invention provides a method for treating a disorder mediated by CTPS1 or a mutant thereof in a patient in need thereof, comprising administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0314] Depending upon the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may also 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."

[0315] The compounds of the present invention can also be advantageously used in combination with other therapeutic compounds.In some embodiments, the other therapeutic compounds are antiproliferative compounds.Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platin compounds; compounds that target / reduce protein kinase activity or lipid kinase activity and further antiangiogenic compounds; compounds that target, reduce or inhibit the activity of protein phosphatases or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine aminopeptides. putidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease, 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 Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors (e.g., SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx)); MEK inhibitors (e.g., ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer) and leucovorin).The term "aromatase inhibitor" as used herein refers to a compound that inhibits 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, particularly atamestane, exemestane, and formestane, and nonsteroids, particularly aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is commercially available under the trade name Aromasin™. Formestane is commercially available under the trade name Lentaron™. Fadrozole is commercially available under the trade name Afema™. Anastrozole is commercially available under the trade name Arimidex™. Letrozole is commercially available under the trade name Femara™ or Femar™. Aminoglutethimide is commercially available under the trade name Orimeten™. Combinations of the present invention which include a chemotherapeutic agent that is an aromatase inhibitor are particularly useful for the treatment of hormone receptor positive tumors, e.g., breast tumors.

[0316] The term "antiestrogen" as used herein refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is commercially available under the trade name Nolvadex™. Raloxifene hydrochloride is commercially available under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combination of the present invention, which includes a chemotherapeutic agent that is an antiestrogen, is particularly useful for treating estrogen receptor-positive tumors, such as breast tumors.

[0317] The term "antiandrogen," as used herein, relates to any substance capable of inhibiting the biological effects of androgens, 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™.

[0318] The term "topoisomerase I inhibitor" 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. Irinotecan can be administered, for example, in the form as it is marketed, for example, under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[0319] The term "topoisomerase II inhibitors", as used herein, includes, but is not limited to, anthracyclines (e.g., doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is commercially available under the trade name Etopophos™. Teniposide is commercially available under the trade name VM 26-Bristol. Doxorubicin is commercially available under the trade name Acriblastin™ or Adriamycin™. Epirubicin is commercially available under the trade name Farmorubicin™. Idarubicin is commercially available under the trade name Zavedos™. Mitoxantrone is commercially available under the trade name Novantron.

[0320] The term "microtubule active agent" refers to microtubule-stabilizing compounds, microtubule-destabilizing compounds, and microtubulin 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 their derivatives. Paclitaxel is commercially available under the trade name Taxol™. Docetaxel is commercially available under the trade name Taxotere™. Vinblastine sulfate is commercially available under the trade name Vinblastin RP™. Vincristine sulfate is commercially available under the trade name Farmistin™.

[0321] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is commercially available under the trade name Cyclostin™. Ifosfamide is commercially available under the trade name Holoxan™.

[0322] 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).

[0323] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (e.g., 5-azacytidine and decitabine), methotrexate and edatrexate, and folate antagonists (e.g., pemetrexed). Capecitabine is commercially available under the trade name Xeloda™. Gemcitabine is commercially available under the trade name Gemzar™.

[0324] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Eloxatin™.

[0325] The term "compounds which target / reduce the activity of protein kinases or lipid kinases; or compounds which target / reduce the activity of protein phosphatases or lipid phosphatases; or further anti-angiogenic compounds", as used herein, includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors, 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 compounds which inhibit PDGF receptors, such as N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib, SU101, SU6668 and GFB-111); 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) (e.g., For example, compounds that target, reduce or inhibit the activity of IGF-IR, in particular compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factors; 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, for example imatinib; h) compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family (for example compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, for example imatinib);i) Compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and mutants (e.g., compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (ParkeDavis); or dasatinib (BMS-354825); j) compounds (including staurosporine derivatives, e.g., midostaurin) that target, decrease, or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK, and TEC families, and / or members of the cyclin-dependent kinase family (CDK); further exemplary compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, for example, compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors such as imatinib mesylate (Gleevec™) or tyrphostins (e.g., tyrphostin A23 / RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44 (+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG 556, AG957) and adaphostine (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); l) compounds that target, decrease or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and mutants thereof, for example, compounds that target, decrease or inhibit the activity of the epidermal growth factor receptor family are in particular compounds, proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family, e.g., EGF receptor, ErbB2, ErbB3 and ErbB4, or that bind to EGF or EGF-related ligands (e.g., CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-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, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives); m) compounds that target, decrease or inhibit the activity of the c-Met receptor, for example, compounds that target, decrease or inhibit the activity of c-Met, particularly compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) one or more JAK family members (JAK1 / J o) compounds that target, decrease, or inhibit the kinase activity of PI3 kinase (PI AK2 / 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); Compounds that target, decrease or inhibit the kinase activity of 3K (including but 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);and q) compounds that target, decrease, or inhibit the signaling effects of the Hedgehog (Hh) or Smoothened receptor (SMO) pathways (including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib));

[0326] The term "PI3K inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family (including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87). Examples of PI3K inhibitors useful in the present invention 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.

[0327] 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.

[0328] The term "SYK inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0329] The term "Bcl-2 inhibitor", as used herein, refers to 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), dual Bcl-2 / Bcl-xL 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), the TW series of compounds (Univ. of In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0330] Further examples of BTK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2008039218 and WO2011090760, which are incorporated herein by reference in their entireties.

[0331] Further examples of SYK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2003063794, WO2005007623, and WO2006078846, which are incorporated herein by reference in their entireties.

[0332] Further examples of PI3K inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, which are incorporated by reference in their entireties.

[0333] Further examples of JAK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, which are incorporated by reference in their entireties.

[0334] Additional anti-angiogenic compounds include compounds that have another mechanism for their activity, for example, a mechanism unrelated to protein kinase inhibition or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[0335] Examples of useful proteasome inhibitors for use in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0336] Compounds which target, decrease or inhibit the activity of protein or lipid phosphatases are eg inhibitors of phosphatase 1, inhibitors of phosphatase 2A or inhibitors of CDC25 (eg okadaic acid or a derivative thereof).

[0337] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-, γ- or δ-tocopherol, or α-, γ- or δ-tocotrienol.

[0338] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid, lumiracoxib.

[0339] The term "bisphosphonate," as used herein, includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is commercially available under the trade name Didronel™. Clodronic acid is commercially available under the trade name Bonefos™. Tiludronic acid is commercially available under the trade name Skelid™. Pamidronic acid is commercially available under the trade name Aredia™. Alendronic acid is commercially available under the trade name Fosamax™. Ibandronic acid is commercially available under the trade name Bondranat™. Risedronic acid is commercially available under the trade name Actonel™. Zoledronic acid is commercially available under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0340] The term "heparanase inhibitor," as used herein, refers to a compound that targets, decreases, or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. The term "biological response modifier," as used herein, refers to lymphokines or interferons.

[0341] The term "inhibitor of Ras oncogenic isoforms" (e.g., H-Ras, K-Ras, or N-Ras) as used herein refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras; for example, "farnesyltransferase inhibitors" such as L-744832, DK8G557, or R115777 (Zarnestra™). The term "telomerase inhibitor" as used herein refers to compounds that target, reduce, or inhibit the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase are particularly compounds that inhibit the telomerase receptor, such as telomestatin.

[0342] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, decreases or inhibits the activity of methionine aminopeptidase. Compounds that target, decreases or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0343] 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 MLN 341.

[0344] 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 (e.g., the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996).

[0345] The term "compounds used 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, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.

[0346] Compounds that target, decrease or inhibit the activity of FLT-3R are, in particular, compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0347] The term "HSP90 inhibitor," 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.

[0348] 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. Antibody refers to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.

[0349] For the treatment of acute myeloid leukemia (AML), the compound of the present invention can be used in combination with standard leukemia therapy, particularly in combination with the therapy used for the treatment of AML.In particular, the compound 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 present invention provides a method for treating AML associated with ITD and / or D835Y mutation, comprising administering the compound 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.

[0350] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue that is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogue of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, reduce or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (previously FR901228), trichostatin A, and the 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 its pharmaceutically acceptable salt, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salt, particularly lactate.Somatostatin receptor antagonists as used herein refer to compounds that target, treat or inhibit somatostatin receptors, such as octreotide and SOM230.Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, eds., Devita et al., 4th ed., Vol. 1, pp. 248-275 (1993).

[0351] Also included are EDG binders and ribonucleotide reductase inhibitors.The term "EDG binder" as used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720.The term "ribonucleotide reductase inhibitor" refers to pyrimidine nucleoside analogs 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.The ribonucleotide reductase inhibitor is particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivative.

[0352] In particular, VEGF compounds, proteins or monoclonal antibodies such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically 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 (e.g., rhuMAb and RHUFab), VEGF aptamers (e.g., Macugon); FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610), and bevacizumab (Avastin™) are also included.

[0353] Photodynamic therapy, as used herein, refers to the use of 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.

[0354] Antiangiogenic steroids, as used herein, refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0355] Corticosteroid-containing implants refer to compounds such as fluocinolone and dexamethasone.

[0356] 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.

[0357] The compounds of the present invention are also useful as co-therapeutic compounds for use in combination with other drug substances, such as anti-inflammatory, bronchodilator, or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airway diseases such as those mentioned hereinabove, e.g., as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dosage or potential side effects of such drugs. The compounds of the present invention may be mixed with other drug substances in a given pharmaceutical composition, or may be administered separately, before, simultaneously with, or after the other drug substances. Thus, the present invention includes combinations of the compounds of the present invention, as described hereinabove, with anti-inflammatory, bronchodilator, antihistamine, or antitussive drug substances, wherein the compounds of the present invention and the drug substances are in the same or different pharmaceutical compositions.

[0358] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids (e.g., budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate); non-steroidal glucocorticoid receptor agonists; LTB4 antagonists (e.g., LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247); LTD4 antagonists (e.g., montelukast and zafirlukast); PDE4 inhibitors (e.g., cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Allofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo)); A2a agonists; A2b antagonists; and beta-2 adrenoceptor agonists (e.g., albuterol (salbutamol), metaproterenol, terbutaline, salmeterol Suitable bronchodilator drugs include anticholinergic or antimuscarinic compounds, especially ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

[0359] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[0360] Other useful combinations of the compounds of the invention with anti-inflammatory drugs 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 and 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).

[0361] The structures of 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 (e.g. IMS World Publications).

[0362] The compounds of the present invention can also be used in combination with known therapeutic processes, such as the administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiation therapy.

[0363] The compound of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combined therapy can be in the form of a fixed combination, or the compound of the present invention and one or more other therapeutic compounds are administered alternately or independently, or in the form of a fixed combination administered in combination with one or more other therapeutic compounds.Otherwise or in addition, the compound of the present invention can be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for tumor treatment.As described above, in the context of other treatment strategies, long-term treatment is possible, as well as adjuvant treatment.Other possible treatments are treatments to maintain the patient's condition after tumor regression, or even chemopreventive treatment, for example, in patients at risk.

[0364] These additional agents can be administered separately from the compound-containing compositions of this invention, as part of a multiple dose regimen. Alternatively, these agents can be part of a single dosage form, mixed together with the compound of this invention in a single composition. When administered as part of a multiple dose regimen, the two active agents may be given simultaneously, sequentially, or within a period of each other, usually within 5 hours of each other.

[0365] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention can be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0366] The amounts of both the compounds of the present invention and additional therapeutic agents (in compositions containing such additional therapeutic agents) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions of this invention should be formulated so that a dosage of between 0.01-100 mg / kg of body weight per day of the compound of the present invention can be administered.

[0367] In these compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention may act synergistically. Therefore, the amount of the additional therapeutic agent in such compositions is less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, the additional therapeutic agent can be administered at a dosage of between 0.01 and 1,000 μg per kg of body weight per day.

[0368] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0369] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. For example, vascular stents are used to overcome restenosis (re-narrowing of the blood vessel wall after injury). However, patients using stents or other implantable devices are at risk of blood clot formation or platelet activation. These unwanted effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with the compounds of this invention is another embodiment of the present invention. [Example]

[0370] Example As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. While the general methods illustrate the synthesis of certain compounds of the invention, it is understood that the following general methods, and other methods known to those of skill in the art, can be applied to all compounds and each subclass and species of these compounds as described herein. Additional compounds of the invention were prepared by methods substantially similar to those described herein in the Examples and methods known to those of skill in the art. Example 1. Synthesis of intermediates. Synthesis of Int-1. [ka]

[0371] An 8 mL vial was charged with Ir[dF(Me)ppy](dtbbpy)PF (7.0 mg, 0.006 mmol, 0.01 equiv.), NiCl·glyme (7.0 mg, 0.034 mmol, 0.05 equiv.), dtbbpy (9.0 mg, 0.034 mmol, 0.05 equiv.), 2,4-dichloropyrimidine (100 mg, 0.671 mmol, 1.00 equiv.), Boc-Pro-OH (216 mg, 1.000 mmol, 1.50 equiv.), DBU (153 mg, 1.000 mmol, 1.50 equiv.), and DMA (3.0 mL). The reaction mixture was degassed by bubbling a stream of nitrogen through it for 20 min and then irradiated in a Merck photoreactor for 24 h. LCMS indicated that 40% of the desired product Int-1 had been formed. Synthesis of Int-2. [ka]

[0372] To a solution of tert-butyl 1-(2-chloropyrimidin-4-yl)cyclopropylcarbamate (540 mg, 2 mmol, 1.00 equiv.) and cyclopropanesulfonamide (564 mg, 4 mmol, 2 equiv.) in 1,4-dioxane (15 mL), CsCO (1.956 g, 6 mmol, 3 equiv.), t-BuXPhos (85.6 mg, 0.2 mmol, 0.1 equiv.), and [Pd(ally)Cl] (36.6 mg, 0.1 mmol, 0.05 equiv.) were added at room temperature under a nitrogen atmosphere. The reaction mixture was degassed with nitrogen three times and stirred at 60 °C overnight. The reaction was monitored by TLC and LCMS. After completion, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:1) to afford 470 mg (66.38%) of tert-butyl 1-(2-(cyclopentanesulfonamido)pyrimidin-4-yl)cyclopropylcarbamate (Int-2) as a yellow solid. Synthesis of Int-3. [ka]

[0373] To a solution of tert-butyl 1-(2-bromothiazol-4-yl)cyclopropylcarbamate (2.5 g, 7.837 mmol, 1.00 equiv.) and cyclopropanesulfonamide (1.897 g, 15.674 mmol, 2 equiv.) in 1,4-dioxane (60 mL), CsCO (7.665 g, 23.511 mmol, 3 equiv.), t-BuXPhos (335.5 mg, 0.784 mmol, 0.1 equiv.), and [Pd(ally)Cl] (143.42 mg, 0.392 mmol, 0.05 equiv.) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 60 °C overnight. The reaction was monitored by TLC and LCMS. After completion, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (1:1) to afford 1.5 g (56.41%) of tert-butyl 1-(2-(cyclopentanesulfonamido)thiazol-4-yl)cyclopropylcarbamate (Int-3) as a yellow solid. Synthesis of 27.3. [ka]

[0374] To a stirred solution of methyl 4-(cyclopentanesulfonamido)picolinate (257 mg, 1 mmol, 1 equiv.) in tetrahydrofuran (10 mL) and water (2 mL) was added lithium hydroxide (48 mg, 2 mmol, 2 equiv.). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water. The pH of the solution was adjusted to 3 with 1N hydrochloric acid. The solid was collected by filtration to give 4-(cyclopentanesulfonamido)picolinic acid (27.3) as an off-white solid. (140 mg, 57%), MS (ES): m / z 243 [M+H] + . Synthesis of 28.3. [ka]

[0375] To a solution of 2-chloro-6-ethoxypyrazine (1.59 g, 10 mmol, 1 equiv.) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.63 g, 12 mmol, 1.2 equiv.) in 1,4-dioxane (40 mL) and water (10 mL) was added potassium carbonate (4.14 g, 30 mmol, 3 equiv.) and Pd(dppf)Cl-CHCl (406 mg, 0.5 mmol, 0.05 equiv.). The resulting solution was stirred at 80 °C for 2 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the compound was eluted with 30% ethyl acetate in petroleum ether to give 4-(6-ethoxypyrazin-2-yl)aniline (28.3) as an off-white solid (1.76 g, 82%), MS(ES): m / z 216 [M+H] + . Synthesis of Int A.1. [ka]

[0376] Synthesis of Int A.1. To a stirred mixture of ethyl 2-(4-bromopyridin-2-yl)acetate (5 g, 20.5 mmol, 1 eq.) in acetic acid (70 ml) was added dropwise sodium nitrite (1.7 g, 24.7 mmol, 1.2 eq.) in water (35 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The mixture was basified to pH 7 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give ethyl (E)-ethyl 2-(4-bromopyridin-2-yl)-2-(hydroxyimino)acetate (Int.A.1, 5.35 g, 95%) as a yellow oil. MS (ES): m / z 273 [M+H] + .

[0377] Synthesis of Int A.3. To a stirred mixture of Int A.1 (5.35 g, 19.6 mmol, 1 equiv.) in ethanol (50 mL) and water (5 mL), zinc powder (2.55 g, 39.2 mmol, 2 equiv.) was added portionwise and acetic acid (5 mL) was added dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 hour. Then, triethylamine (5 mL, 36 mmol, 1.8 equiv.) and di-tert-butyl pyrocarbonate (5 g, 39.2 mmol, 2.0 equiv.) were added at 0° C. The resulting mixture was basified to pH 8 with saturated aqueous sodium bicarbonate and stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 20% ethyl acetate in petroleum ether) to give ethyl 2-(4-bromopyridin-2-yl)-2-((tert-butoxycarbonyl)amino)acetate (Int A.3, 2.35 g, 33%) as a yellow solid. MS (ES): m / z 359 [M+H] + .

[0378] Synthesis of Int A.4. To a stirred mixture of Int A.3 (5.1 g, 14.2 mmol, 1 equiv.) in ethanol (10 mL) and tetrahydrofuran (100 mL), sodium borohydride (5.11 g, 142 mmol, 10 equiv.) and lithium chloride (5.9 g, 142 mmol, 10 equiv.) were added at 0° C. The resulting mixture was stirred at 50° C. overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with 50% ethyl acetate in petroleum ether) to afford ethyl tert-butyl (1-(4-bromopyridin-2-yl)-2-hydroxyethyl)carbamate (Int A.4, 3.35 g, 74%) as a yellow solid. MS (ES): m / z 317 [M+H] + .

[0379] Synthesis of Int A.5. To a solution of imidazole (3.2 g, 46.8 mmol, 6 equiv.) in dichloromethane (50 mL) was added thionyl chloride (1N in dichloromethane, 24 mL, 23.4 mmol, 3 equiv.) dropwise at 0° C. The mixture was stirred at 0° C. for 1 hour, after which Int A.4 (2.48 g, 7.8 mmol, 1 equiv.) in dichloromethane (10 mL) was added dropwise at −10° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous citric acid and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica (eluting with 80% acetonitrile in water) to give 4-(4-bromopyridin-2-yl)-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2-oxide (Int A.5, 2 g, 71%) as a pale yellow solid. MS (ES): m / z 363 [M+H] + .

[0380] Synthesis of Int A. To a solution of Int A.5 (1.7 g, 4.7 mmol, 1 equiv.) in acetonitrile (50 mL) was added a solution of ruthenium(III) chloride (0.1 g, 0.5 mmol, 0.1 equiv.) and sodium tetroxoiodate (1.1 g, 5.2 mmol, 1.1 equiv.) in water (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with ethyl acetate) to afford tert-butyl 4-(4-bromopyridin-2-yl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (Int. A, 1.6 g, 90%) as a pale yellow solid. MS(ES): m / z 379 [M+H] + . Synthesis of Int.B. [ka]

[0381] Synthesis of Int B.1. To a stirred mixture of Int A.3 (1.3 g, 3.62 mmol, 1 equiv.) and 147.1 (1.3 g, 5.43 mmol, 1.5 equiv.) in 1,4-dioxane (20 mL), potassium phosphate tribasic (1.54 g, 7.24 mmol, 2 equiv.), XantPhos (419 mg, 0.72 mmol, 0.2 equiv.), and Pd(OAc) (81 mg, 0.36 mmol, 0.1 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on C18 silica (eluting with acetonitrile / water, 7 / 1) to give ethyl 2-((tert-butoxycarbonyl)amino)-2-(4-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyridin-2-yl)acetate (Int B.1, 1.1 g, 58%) as a white solid. MS (ES): m / z 520 [M+H] + .

[0382] Synthesis of Int B.2. To a stirred mixture of Int B.1 (300 mg, 0.58 mmol, 1 equiv.) in THF (3 mL) and ethanol (0.3 mL), lithium chloride (49 mg, 1.15 mmol, 2 equiv.) and sodium borohydride (87 mg, 2.31 mmol, 4 equiv.) were added portionwise at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with ice-water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with petroleum ether / ethyl acetate, 1 / 1) to afford tert-butyl (2-hydroxy-1-(4-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyridin-2-yl)ethyl)carbamate (Int B.2, 200 mg, 72%) as a white solid. MS(ES): m / z 478 [M+H] + .

[0383] Synthesis of Int B.3. To a solution of imidazole (940 mg, 13.8 mmol, 6 equiv.) in dichloromethane (12 mL) was added thionyl chloride (1N in dichloromethane, 7 mL, 7.0 mmol, 3 equiv.) dropwise at 0° C. The mixture was stirred at 0° C. for 1 hour, and then Int B.2 (1.1 g, 2.30 mmol, 1 equiv.) in dichloromethane (10 mL) was added dropwise at −10° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous citric acid and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 75% ethyl acetate in petroleum ether) to give 4-(4-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyridin-2-yl)-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2-oxide (Int B.3, 900 mg, 75%) as a pale yellow solid. MS (ES): m / z 524 [M+H] + .

[0384] Synthesis of Int B. To a solution of Int B.3 (1.0 g, 1.91 mmol, 1 equiv.) in acetonitrile (10 mL) was added a solution of ruthenium(III) chloride (24 mg, 0.12 mmol, 0.06 equiv.) and sodium iodate tetroxide (449 mg, 2.10 mmol, 1.1 equiv.) in water (4 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 75% ethyl acetate in petroleum ether) to give 4-(4-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyridin-2-yl)-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2,2-dioxide (Int B, 920 mg, 89%) as a pale yellow oil. MS (ES): m / z 540 [M+H] + . Synthesis of Int.F. [ka]

[0385] Synthesis of Int. F. A solution of 1-(4-chloropyridin-2-yl)ethanone (1 g, 6.43 mmol, 1 equiv.) and DMA-DMF (0.22 g, 9.64 mmol, 1.5 equiv.) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 2 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were concentrated under reduced pressure to give (E)-1-(4-chloropyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (Int. F, 1.2 g, 90%) as a colorless oil, which was used directly in the next step without further purification. MS (ES): m / z 211 [M+H] + . Example 2: Synthesis of N-(4-(1-(5-(6-ethoxypyrazin-2-yl)-1-oxoisoindolin-2-yl)propyl)thiazol-2-yl)cyclopropanesulfonamide (I-6). [ka]

[0386] Synthesis of 2.2. To a solution of N-(4-(1-aminopropyl)thiazol-2-yl)cyclopropanesulfonamide (150.0 mg, 0.58 mmol, 1.0 equiv.) and methyl 4-bromo-2-(bromomethyl)benzoate (177.5 mg, 0.58 mmol, 1 equiv.) in ethanol (5 mL) was added triethylamine (175.8 mg, 1.74 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 12 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 column; mobile phase, water (10% NH4HCO3) and ACN (28% ACN to 41% in 10 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and concentrated under reduced pressure to give N-(4-(1-(5-bromo-1-oxoisoindolin-2-yl)propyl)thiazol-2-yl)cyclopropanesulfonamide as a yellow solid (100 mg, 38%), MS(ES): m / z 456 / 458 [M+H] + .

[0387] Synthesis of I-6. To a solution of 2.2 (100.0 mg, 0.22 mmol, 1.0 equiv.) and 2-ethoxy-6-(tributylstannyl)pyrazine (182.2 mg, 0.44 mmol, 2.0 equiv.) in toluene (5 mL), Pd(PPh3)4 (25.4 mg, 0.02 mmol, 0.1 equiv.) was added at room temperature. The reaction mixture was stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The product was purified by Prep-HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase, water (0.1% FA) and ACN (21% ACN to 33% in 7 minutes); UV detection at 254 / 220 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid (22 mg, 20%), MS(ES): m / z 500 [M+H] + ; 1H NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.31 (s, 1H), 8.28 (d, J=8 Hz, 1H), 8.19 (s, 1H), 7.94 (d, J=8 Hz, 1H), 6.76 (s, 1H), 5.33-5.28 (m, 1H), 4.64-4.60 (m, 1H), 4.57 (q, J=7.2 Hz, 2H), 4.41-4.36 (m, 1H), 2.64-2.57 (m, 1H), 2.24-2.10 (m, 2H), 1.50 (t, J=7.2 Hz, 1H), 1.10-1.06 (m, 2H), 1.01 (t, J=7.2 Hz, 3H), 0.98-0.92 (m, 2H). Example 3: Synthesis of N-(1-(2-(cyclopentanesulfonamido)thiazol-4-yl)cyclopropyl)-2-naphthamide (I-1). [ka]

[0388] Synthesis of I-1. To a solution of N-(4-(1-aminocyclopropyl)thiazol-2-yl)cyclopropanesulfonamide hydrochloride (3.1, 50.0 mg, 0.17 mmol, 1.0 equiv.) and 2-naphthoic acid (29.3 mg, 0.17 mmol, 1.0 equiv.) in acetonitrile (5 mL), TCFH (95.2 mg, 0.34 mmol, 2.0 equiv.) and NMI (140.2 mg, 1.71 mmol, 10.0 equiv.) were added at room temperature. The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase, water (10% NH4HCO3) and ACN (35% ACN to 48% in 7 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid. (8.9 mg, 13%), MS(ES): m / z 414 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 8.02-7.91 (m, 4H), 7.64-7.57 (m, 2H), 6.48 (s, 1H), 2.65-2.58 (m, 1H), 1.47-1.30 (m, 4H), 1.11-1.07 (m, 2H), 0.97-0.92 (m, 2H). Example 4: Synthesis of N-(1-(2-(cyclopentanesulfonamido)thiazol-4-yl)cyclopropyl)quinoline-2-carboxamide (I-2). [ka]

[0389] Synthesis of I-2. To a solution of 3.1 (100.0 mg, 0.34 mmol, 1.0 equiv.) and quinoline-2-carboxylic acid (58.6 mg, 0.34 mmol, 1.0 equiv.) in acetonitrile (5 mL), TCFH (190.4 mg, 0.68 mmol, 2.0 equiv.) and NMI (280.4 mg, 3.42 mmol, 10.0 equiv.) were added at room temperature. The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase, water (10% NH4HCO3) and ACN (31% ACN to 42% in 7 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid. (32.2 mg, 23%), MS(ES): m / z 415 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.49 (d, J=8.4 Hz, 1H), 8.20 (d, J=8.8 Hz, 2H), 8.02 (d, J=8 Hz, 1H), 7.88-7.84 (m, 1H), 7.74-7.70 (m, 1H), 6.54 (s, 1H), 2.63-2.56 (m, 1H), 1.48-1.39 (m, 4H), 1.10-1.06 (m, 2H), 0.97-0.92 (m, 2H). Example 5: Synthesis of N-(1-(2-(cyclopentanesulfonamido)thiazol-4-yl)cyclopropyl)isoquinoline-3-carboxamide (I-3). [ka]

[0390] Synthesis of I-3. To a solution of 3.1 (50.0 mg, 0.17 mmol, 1.0 equiv.) and isoquinoline-3-carboxylic acid (29.3 mg, 0.17 mmol, 1.0 equiv.) in acetonitrile (5 mL), TCFH (95.2 mg, 0.34 mmol, 2.0 equiv.) and NMI (140.2 mg, 1.71 mmol, 10.0 equiv.) were added at room temperature. The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10% NH4HCO3) and ACN (33% ACN to 45% in 7 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid (13.3 mg, 19%), MS(ES): m / z 415 [M+H]. + ; 1 H NMR (400 MHz, CD3OD) δ 9.31 (s, 1H), 8.57 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 8.10 (d, J=8 Hz, 1H), 7.89-7.80 (m, 4H), 6.53 (s, 1H), 2.62-2.56 (m, 1H), 1.47-1.36 (m, 4H), 1.13-1.06 (m, 2H), 1.00-0.90 (m, 2H). Example 6: Synthesis of N-(1-(2-(cyclopentanesulfonamido)thiazol-4-yl)cyclopropyl)quinoline-3-carboxamide (I-5). [ka]

[0391] Synthesis of I-5. To a solution of 3.1 (50.0 mg, 0.17 mmol, 1.0 equiv.) and quinoline-3-carboxylic acid (29.3 mg, 0.17 mmol, 1.0 equiv.) in acetonitrile (5 mL), TCFH (95.2 mg, 0.34 mmol, 2.0 equiv.) and NMI (140.2 mg, 1.71 mmol, 10.0 equiv.) were added at room temperature. The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10% NH4HCO3) and ACN (32% ACN to 44% in 7 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid (11.7 mg, 17%), MS(ES): m / z 415 [M+H]. + ; 1 H NMR (400 MHz, d6-DMSO) δ 9.41 (s, 1H), 9.31 (s, 1H), 8.88 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 7.88 (t, J=8.4 Hz, 1H), 7.71 (t, J=8.4 Hz, 1H), 6.45 (s, 1H), 2.61-2.51 (m, 1H), 1.43-1.37 (m, 2H), 1.32-1.26 (m, 2H), 0.93-0.85 (m, 4H). Example 7: Synthesis of N-(1-(2-(cyclopentanesulfonamido)thiazol-4-yl)cyclopropyl)quinoline-6-carboxamide (I-9). [ka]

[0392] Synthesis of I-9. To a solution of 3.1 (80.0 mg, 0.27 mmol, 1.0 equiv.) and quinoline-6-carboxylic acid (46.7 mg, 0.27 mmol, 1.0 equiv.) in acetonitrile (5 mL), TCFH (151.2 mg, 0.54 mmol, 2.0 equiv.) and NMI (221.4 mg, 2.70 mmol, 10.0 equiv.) were added at room temperature. The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10% NH4HCO3) and ACN (30% ACN to 41% in 7 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid (25.0 mg, 22%), MS(ES): m / z 415 [M+H]. + ; 1 H NMR (400 MHz, CD3OD) δ 8.97 (dd, J=4.4, 1.6 Hz, 1H), 8.56-8.50 (m, 2H), 8.22 (dd, J=8.8, 2.0 Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.65 (dd, J=4.4, 1.6 Hz, 1H), 6.52 (s, 1H), 2.68-2.58 (m, 1H), 1.48-1.28 (m, 4H), 1.12-1.08 (m, 2H), 1.05-0.94 (m, 2H). Example 8: Synthesis of N-(1-(2-(cyclopentanesulfonamido)thiazol-4-yl)cyclopropyl)isoquinoline-6-carboxamide (I-4). [ka]

[0393] Synthesis of I-4. To a solution of 3.1 (50.0 mg, 0.17 mmol, 1.0 equiv.) and isoquinoline-6-carboxylic acid (29.4 mg, 0.17 mmol, 1.0 equiv.) in acetonitrile (5 mL), TCFH (95.2 mg, 0.34 mmol, 2.0 equiv.) and NMI (139.4 mg, 1.70 mmol, 10.0 equiv.) were added at room temperature. The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10% NH4HCO3) and ACN (31% ACN to 46% in 7 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid (11.7 mg, 17%), MS(ES): m / z 415 [M+H]. + ; 1 H NMR (300 MHz, d6-DMSO) δ 12.28 (br s, 1H), 9.40 (s, 1H), 9.34 (s, 1H), 8.58 (d, J=5.7 Hz, 1H), 8.50 (s, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.92 (d, J=5.7 Hz, 1H), 6.43 (s, 1H), 2.62-2.54 (m, 1H), 1.41-1.23 (m, 4H), 1.01-0.84 (m, 4H). Example 9: Synthesis of N-(1-(2-(cyclopentanesulfonamido)thiazol-4-yl)cyclopropyl)isoquinoline-7-carboxamide (I-7). [ka]

[0394] Synthesis of I-7. To a solution of 3.1 (80.0 mg, 0.27 mmol, 1.0 equiv.) and isoquinoline-7-carboxylic acid (46.7 mg, 0.27 mmol, 1.0 equiv.) in acetonitrile (5 mL), TCFH (151.2 mg, 0.54 mmol, 2.0 equiv.) and NMI (221.4 mg, 2.70 mmol, 10.0 equiv.) were added at room temperature. The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase, water (10% NH4HCO3) and ACN (33% ACN to 48% in 7 min); UV detection at 254 / 220 nm. Fractions containing the product were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid. (25.9 mg, 23%), MS(ES): m / z 415 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 9.37 (s, 1H), 8.64 (s, 1H), 8.55 (d, J=6.0 Hz, 1H), 8.23 ​​(d, J=8.4 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.91 (d, J=6.0 Hz, 1H), 6.53 (s, 1H), 2.65-2.58 (m, 1H), 1.52-1.37 (m, 4H), 1.04-1.08 (m, 2H), 1.03-0.94 (m, 2H). Example 10: Synthesis of N-(1-(2-(cyclopentanesulfonamido)thiazol-4-yl)cyclopropyl)quinoline-7-carboxamide (I-10). [ka]

[0395] Synthesis of I-10. To a solution of 3.1 (50.0 mg, 0.17 mmol, 1.0 equiv.) and quinoline-7-carboxylic acid (29.4 mg, 0.17 mmol, 1.0 equiv.) in acetonitrile (5 mL), TCFH (95.2 mg, 0.34 mmol, 2.0 equiv.) and NMI (139.4 mg, 1.70 mmol, 10.0 equiv.) were added at room temperature. The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10% NH4HCO3) and ACN (31% ACN to 43% in 7 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid (11.2 mg, 16%), MS(ES): m / z 415 [M+H]. + ; 1 H NMR (400 MHz, CD3OD) δ 8.98 (d, J=4.4 Hz, 1H), 8.45 (d, J=8 Hz, 2H), 8.13-8.03 (m, 2H), 7.65 (dd, J=8.4, 4.0 Hz, 1H), 6.53 (s, 1H), 2.65-2.58 (m, 1H), 1.48-1.37 (m, 4H), 1.18-1.04 (m, 2H), 1.02-0.94 (m, 2H). Example 11: Synthesis of 6-(1-(2-(cyclopentanesulfonamido)thiazol-4-yl)cyclopropylcarbamoyl)isoquinoline 2-oxide (I-11). [ka]

[0396] Synthesis of 11.1. To a solution of methyl isoquinoline-6-carboxylate (1.67 g, 8.93 mmol, 1.0 equiv.) in dichloromethane (40 mL) was added 3-chloroperoxybenzoic acid (2.30 g, 13.40 mmol, 1.5 equiv.) at room temperature. The resulting solution was stirred at room temperature for 16 hours. The mixture was quenched with saturated aqueous sodium thiosulfate monohydrate, then adjusted to pH 8 with saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the compound was eluted with 50% ethyl acetate in petroleum ether to give 6-(methoxycarbonyl)isoquinoline 2-oxide as a yellow solid. (0.54 g, 30%), MS (ES): m / z 204 [M+H] + .

[0397] Synthesis of 11.2. To a solution of 11.1 (240.0 mg, 1.18 mmol, 1.0 equiv) in tetrahydrofuran (12 mL) and water (3 mL) was added lithium hydroxide (85.0 mg, 3.54 mmol, 3.0 equiv). The resulting solution was stirred at 60°C for 4 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water. The pH of the solution was adjusted to 3 with 1N hydrochloric acid. The solid was collected by filtration and dried in an oven at 45°C to give 6-carboxyisoquinoline 2-oxide as an off-white solid. (0.12 g, 54%), MS (ES): m / z 190 [M+H] + .

[0398] Synthesis of I-11. To a solution of 3.1 (80.0 mg, 0.27 mmol, 1.0 equiv.) and 11.2 (51.3 mg, 0.27 mmol, 1.0 equiv.) in acetonitrile (5 mL), TCFH (151.2 mg, 0.54 mmol, 2.0 equiv.) and NMI (221.4 mg, 2.70 mmol, 10.0 equiv.) were added at room temperature. The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase, water (10% NH4HCO3 + 0.1% NH3 . HO) and ACN (22% ACN to 33% in 7 min); UV detection at 254 / 220 nm. Product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid. (37.1 mg, 32%), MS(ES): m / z 431 [M+H] + ; 1 H NMR (300 MHz, d6-DMSO) δ 9.28 (s, 1H), 9.02 (s, 1H), 8.49 (s, 1H), 8.21 (d, J=1.5 Hz, 1H), 8.16-8.03 (m, 2H), 7.95 (d, J=8.7 Hz, 1H), 6.26 (s, 1H), 2.47-2.42 (m, 1H), 1.42-1.34 (m, 2H), 1.24-1.18 (m, 2H), 0.92-0.78 (m, 4H). Example 12: Synthesis of N-(1-(2-(cyclopentanesulfonamido)thiazol-4-yl)cyclopropyl)-5-(4-methyl-1H-imidazol-1-yl)picolinamide (I-8). [ka]

[0399] Synthesis of 12.1. To a solution of methyl 5-bromopyridine-2-carboxylate (500.0 mg, 2.31 mmol, 1.0 equiv.) and 4-methyl-1H-imidazole (380.0 mg, 4.63 mmol, 2.0 equiv.) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.51 g, 4.63 mmol, 2.0 equiv.) and copper iodide (881.5 mg, 4.63 mmol, 2.0 equiv.) at room temperature. The resulting mixture was stirred at 120° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 column; mobile phase, water (0.1% FA) and ACN (15% ACN to 28% in 10 min); UV detection at 254 / 220 nm. Product-containing fractions were combined and concentrated under reduced pressure to give 5-(4-methyl-1H-imidazol-1-yl)picolinic acid as a green solid (70.0 mg, 15%), MS (ES): m / z 204 [M+H]. + .

[0400] Synthesis of I-8. To a solution of 12.1 (70.0 mg, 0.34 mmol, 1.0 equiv.) and 3.1 (100.3 mg, 0.34 mmol, 1.0 equiv.) in acetonitrile (10 mL) was added TCFH (190.4 mg, 0.68 mmol, 2.0 equiv.) and NMI (278.8 mg, 3.40 mmol, 10.0 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The product was purified by Prep-HPLC using the following conditions: Column, SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm; Mobile phase, water (0.1% FA) and ACN (7% ACN to 17% in 7 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid (25.6 mg, 17%), MS(ES): m / z 445 [M+H]. + ; 1H NMR (300 MHz, d6-DMSO) δ 12.27 (br s, 1H), 9.30 (s, 1H), 8.98 (s, 1H), 8.39 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.21-8.09 (m, 1H), 7.67 (s, 1H), 6.41 (s, 1H), 2.61-2.55 (m, 1H), 2.19 (s, 3H), 1.37-1.24 (m, 4H), 0.89-0.88 (m, 4H). Example 13: Synthesis of N-(4-(1-(5-(6-ethoxypyrazin-2-yl)-1-oxoisoindolin-2-yl)cyclopropyl)thiazol-2-yl)cyclopropanesulfonamide (I-13). [ka]

[0401] Synthesis of 13.1. To a solution of 3.1 (222.0 mg, 0.75 mmol, 1.0 equiv.) and methyl 4-bromo-2-(bromomethyl)benzoate (230.0 mg, 0.75 mmol, 1.0 equiv.) in ethanol (10 mL) was added triethylamine (303.0 mg, 3.00 mmol, 4.0 equiv.) at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 column; mobile phase, water (10% NH4HCO3) and ACN (35% ACN to 48% in 10 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and concentrated under reduced pressure to give N-(4-(1-(5-bromo-1-oxoisoindolin-2-yl)cyclopropyl)thiazol-2-yl)cyclopropanesulfonamide as a yellow solid (100.0 mg, 29%), MS(ES): m / z 454 / 456 [M+H] + .

[0402] Synthesis of I-13. To a solution of 13.1 (100.0 mg, 0.22 mmol, 1.0 equiv.) and 2-ethoxy-6-(tributylstannyl)pyrazine (13.2, 273.3 mg, 0.66 mmol, 3.0 equiv.) in toluene (10 mL) was added Pd(PPh3)4 (23.1 mg, 0.02 mmol, 0.1 equiv.) at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The product was purified by Prep-HPLC using the following conditions: column, SunFire Prep C18 OBD column, 19 x 150 mm, 5 μm; mobile phase, water (0.1% FA) and ACN (27% ACN to 41% in 7 min); UV detection at 254 / 220 nm. Fractions containing the product were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid. (29 mg, 27%), MS(ES): m / z 498 [M+H] + ; 1 H NMR (400 MHz, d6-DMSO) δ 12.27 (br s, 1H), 8.91 (s, 1H), 8.35 (s, 1H), 8.32 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 6.35 (s, 1H), 4.67 (s, 2H), 4.51 (q, J=7.2 Hz, 2H), 2.59-2.51 (m, 1H), 1.52-1.45 (m, 4H), 1.42 (t, J=7.2 Hz, 3H), 0.95-0.88 (m, 4H). Example 14: Synthesis of (R)—N-(4-(1-(5-(6-ethoxypyrazin-2-yl)-1-oxoisoindolin-2-yl)propyl)thiazol-2-yl)cyclopropanesulfonamide (I-12) and (S)—N-(4-(1-(5-(6-ethoxypyrazin-2-yl)-1-oxoisoindolin-2-yl)propyl)thiazol-2-yl)cyclopropanesulfonamide (I-12a). [ka]

[0403] Separation of I-12 and I-12a. Compound I-6 (17.0 mg, 0.03 mmol, 1.00 equiv.) was separated by chiral preparative HPLC using the following conditions: column, CHIRALPAK AS-H, 2 × 25 mm, 5 μm; mobile phase, Hex (0.1% FA):ethanol = 80:20; detector, UV 254 / 220 nm. Product-containing fractions were combined and concentrated under reduced pressure to give (R)—N-(4-(1-(5-(6-ethoxypyrazin-2-yl)-1-oxoisoindolin-2-yl)propyl)thiazol-2-yl)cyclopropanesulfonamide (3.9 mg, 23%, first peak) and (S)—N-(4-(1-(5-(6-ethoxypyrazin-2-yl)-1-oxoisoindolin-2-yl)propyl)thiazol-2-yl)cyclopropanesulfonamide (0.9 mg, 5%, second peak) as a white solid.

[0404] I-12: MS(ES): m / z 500 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.31 (s, 1H), 8.28 (d, J=8 Hz, 1H), 8.19 (s, 1H), 7.94 (d, J=8 Hz, 1H), 6.76 (s, 1H), 5.32-5.28 (m, 1H), 4.65-4.60 (m, 1H), 4.57 (q, J=7.2 Hz, 2H), 4.41-4.36 (m, 1H), 2.62-2.58 (m, 1H), 2.21-2.11 (m, 2H), 1.49 (t, J=7.2 Hz, 3H), 1.11-1.08 (m, 2H), 1.03 (t, J=7.2 Hz, 3H), 0.97-0.93 (m, 2H).

[0405] I-12a: MS(ES): m / z 500 [M+H] + ; 1H NMR (400 MHz, CD3OD) δ 8.75 (s, 1H), 8.32 (s, 1H), 8.28 (d, J=8.4 Hz, 1H), 8.19 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 6.75 (s, 1H), 5.32-5.28 (m, 1H), 4.65-4.60 (m, 1H), 4.57 (q, J=7.2 Hz, 2H), 4.42-4.37 (m, 1H), 2.64-2.57 (m, 1H), 2.24-2.06 (m, 2H), 1.49 (t, J=6.8 Hz, 3H), 1.11-1.08 (m, 2H), 1.03 (t, J=7.2 Hz, 3H), 0.97-0.93 (m, 2H). Example 15: Synthesis of 5-(6-ethoxypyrazin-2-yl)-N-(1-(2-(N-methylcyclopropanesulfonamido)thiazol-4-yl)cyclopropyl)picolinamide (I-14). [ka]

[0406] Synthesis of 15.2. To a solution of ethyl 1-(2-bromothiazol-4-yl)cyclopropane-1-carboxylate (15.1, 1.10 g, 4.00 mmol, 1.00 equiv.) and cyclopropanesulfonamide (968.0 mg, 8.00 mmol, 2.0 equiv.) in 1,4-dioxane (20 mL), cesium carbonate (3.91 g, 12.00 mmol, 3.0 equiv.), t-BuXPhos (0.17 g, 0.40 mmol, 0.1 equiv.), and [Pd(ally)Cl] (73.7 mg, 0.20 mmol, 0.05 equiv.) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 16 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the compound was eluted with 50% ethyl acetate in petroleum ether to give ethyl 1-(2-(cyclopentanesulfonamido)thiazol-4-yl)cyclopropane-1-carboxylate (15.2) as a yellow solid (0.85 g, 67%), MS(ES): m / z 317 [M+H] + .

[0407] Synthesis of 15.3. To a solution of 15.2 (0.85 g, 2.69 mmol, 1.0 equiv.) in N,N-dimethylformamide (10 mL) was added sodium hydride (60%, 129.2 mg, 3.23 mmol, 1.2 equiv.). After 30 minutes, iodomethane (573.7 mg, 4.04 mmol, 1.5 equiv.) was added. The resulting solution was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the compound was eluted with 30% ethyl acetate in petroleum ether to give ethyl 1-(2-(N-methylcyclopropanesulfonamido)thiazol-4-yl)cyclopropane-1-carboxylate (15.3) as a yellow solid. (0.68g, 77%), MS(ES):m / z331[M+H] + .

[0408] Synthesis of 15.4. To a solution of 15.3 (0.68 g, 2.06 mmol, 1.0 equiv.) in tetrahydrofuran (10 mL) and water (2 mL) was added lithiumol (148.3 mg, 6.18 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was diluted with water. The pH of the solution was adjusted to 3 with 1 N hydrochloric acid. The solid was collected by filtration to give 1-(2-(N-methylcyclopropanesulfonamido)thiazol-4-yl)cyclopropane-1-carboxylic acid (15.4) as an off-white solid. (0.45 g, 72%), MS (ES): m / z 303 [M+H] + .

[0409] Synthesis of 15.5. To a solution of 15.4 (0.45 g, 1.49 mmol, 1.0 equiv.), trimethylamine (180.8 mg, 1.79 mmol, 1.2 equiv.), toluene (10 mL), and 2-methylpropan-2-ol (10 mL) was added diphenylphosphoryl azide (0.41 g, 1.49 mmol, 1.0 equiv.) at room temperature. The resulting solution was stirred at 100° C. for 16 hours. The mixture was cooled to room temperature. The pH of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the compound was eluted with 40% ethyl acetate in petroleum ether to give tert-butyl (1-(2-(N-methylcyclopropanesulfonamido)thiazol-4-yl)cyclopropyl)carbamate (15.5) as a yellow oil (0.25 g, 45%), MS(ES): m / z 374 [M+H] + .

[0410] Synthesis of 15.6. A solution of 15.5 (0.25 g, 0.67 mmol, 1.0 equiv) in hydrochloric acid (4.0 M, 10 mL) in 1,4-dioxane was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give N-(4-(1-aminocyclopropyl)thiazol-2-yl)-N-methylcyclopropanesulfonamide hydrochloride as an off-white solid. (207.1 mg, 100%), MS (ES): m / z 274 [M+H] + .

[0411] Synthesis of I-14. To a solution of 15.6 (49.1 mg, 0.18 mmol, 1.0 equiv.) and 5-(6-ethoxypyrazin-2-yl)picolinic acid (15.7, 44.1 mg, 0.18 mmol, 1.0 equiv.) in acetonitrile (5 mL), TCFH (100.8 mg, 0.36 mmol, 2.0 equiv.) and NMI (147.6 mg, 1.80 mmol, 10.0 equiv.) were added at room temperature. The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase, water (10% NH4HCO3) and ACN (38% ACN to 47% in 8 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid. (12.9 mg, 14%), MS(ES): m / z 501 [M+H] + ; 1H NMR (400 MHz, d6-DMSO) δ 9.70 (s, 1H), 9.34 (s, 1H), 8.99 (s, 1H), 8.67 (dd, J=8.4 Hz, 1H), 8.37 (s, 1H), 8.12 (dd, J=8.4 Hz, 1H), 6.90 (s, 1H), 4.51 (q, J=7.2 Hz, 2H), 3.65 (s, 3H), 2.63-2.55 (m, 1H), 1.42 (t, J=7.2 Hz, 3H), 1.38-1.32 (m, 4H), 0.97-0.86 (m, 4H). Example 16: Synthesis of N-((4-(cyclopentanesulfonamido)pyridin-2-yl)methyl)-4-(6-ethoxypyrazin-2-yl)benzamide (I-15). [ka]

[0412] Synthesis of 16.1. To a solution of 2-chloro-6-ethoxypyrazine (3.16 g, 20 mmol, 1 equiv.) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (6.28 g, 24 mmol, 1.2 equiv.) in 1,4-dioxane (80 mL) and water (20 mL) was added potassium carbonate (8.28 g, 60 mmol, 3 equiv.) and Pd(dppf)Cl2CH2Cl2 (1.63 g, 2 mmol, 0.1 equiv.). The resulting solution was stirred at 80 °C for 2 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the compound was eluted with 20% ethyl acetate in petroleum ether to give methyl 4-(6-ethoxypyrazin-2-yl)benzoate (16.1) as an off-white solid (4.18 g, 78%), MS (ES): m / z 259 [M+H] + .

[0413] Synthesis of 16.2. To a solution of 16.1 (4.18 g, 15.6 mmol, 1 equiv.) in tetrahydrofuran (80 mL) and water (20 mL) was added lithiol (1.13 g, 46.86 mmol, 3 equiv.). The resulting solution was stirred at 60° C. for 4 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water. The pH of the solution was adjusted to 3 with 1N hydrochloric acid. The solid was collected by filtration to give 4-(6-ethoxypyrazin-2-yl)benzoic acid (16.2) as a white solid. (2.72 g, 69%), MS (ES): m / z 245 [M+H] + .

[0414] Synthesis of 16.3. To a solution of 4-aminopicolinonitrile (1.19 g, 10 mmol, 1 equiv.) in pyridine (20 mL) was added 4-dimethylaminopyridine (122 mg, 1 mmol, 0.1 equiv.) and cyclopropanesulfonyl chloride (4.21 g, 30 mmol, 3 equiv.) at 0 °C. The resulting solution was stirred at 50 °C for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 column; mobile phase, water (0.1% FA) and ACN (5% ACN to 30% in 20 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and concentrated under reduced pressure to give N-(2-cyanopyridin-4-yl)cyclopropanesulfonamide (16.3) as a yellow solid. (1.2g, 53%), MS(ES): m / z224[M+H] + .

[0415] Synthesis of 16.4. A solution of 16.3 (1 g, 4.48 mmol, 1 equiv.) in methanol (25 mL) and ammonium hydroxide (5 mL) was flushed with nitrogen three times. Palladium on carbon (200 mg) was added to the solution, which was then flushed with hydrogen. The mixture was stirred at room temperature under an atmosphere of hydrogen for 2 hours. The solid was filtered off, and the solution was concentrated under reduced pressure to give crude N-(2-(aminomethyl)pyridin-4-yl)cyclopropanesulfonamide (16.4) as a yellow solid. (900 mg, 88%), MS (ES): m / z 228 [M+H] + .

[0416] Synthesis of I-15. To a solution of 16.4 (100 mg, 0.44 mmol, 1 equiv.) in pyridine (2 mL), 16.2 (118.2 mg, 0.48 mmol, 1.1 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (126.5 mg, 0.66 mmol, 1.5 equiv.) were added at room temperature. The resulting solution was stirred at 80 °C for 1 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column: YMC-Actus Triart C18 30x250, 5um; Mobile phase: Water (0.1% NH4HCO3 + 0.1% NH3.H2O) and ACN (15% ACN to 45% in 7 min); UV detection at 254 / 210 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid. (67.6 mg, 33%), MS(ES): m / z 454 [M+H] + ; 1H NMR (400 MHz, d6-DMSO) δ 10.83 (brs, 1H), 9.24 (t, J = 6.0 Hz, 1H), 8.89 (s, 1H), 8.31-8.19 (m, 4H), 8.05 (d, J = 8.4 Hz 2H), 7.08-6.98 (m, 2H), 4.55-4.45 (m, 4H), 2.72-2.65 (m, 1H), 1.41 (t, J = 7.0 Hz, 3H), 0.99-0.89 (m, 4H). Example 17: Synthesis of N-[(4-cyclopropanesulfonamidopyridin-2-yl)methyl]-5-(6-ethoxypyrazin-2-yl)pyridine-2-carboxamide (I-16). [ka]

[0417] Synthesis of I-16. To a solution of N-(2-(aminomethyl)pyridin-4-yl)cyclopropanesulfonamide (16.4, 44.5 mg, 0.19 mmol, 1 equiv.) in pyridine (2 mL), 5-(6-ethoxypyrazin-2-yl)pyridine-2-carboxylic acid (15.7, 48 mg, 0.19 mmol, 1 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (75 mg, 0.38 mmol, 2 equiv.) were added at room temperature. The resulting solution was stirred at 80° C. for 1 hour. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column: YMC-Actus Triart C18 30 x 250, 5 um; Mobile phase: Water (0.1% NH4HCO3 + 0.1% NH3.H2O) and ACN (22% ACN to 33% in 7 min); UV detection at 254 / 210 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid. (37.7 mg, 42%), MS(ES): m / z 455 [M+H] + ; 1H NMR (400 MHz, d6-DMSO) δ 10.92 (brs, 1H), 9.47 (t, J = 6.0 Hz, 1H), 9.41 (d, J = 1.6 Hz, 1H), 9.01 (s, 1H), 8.71 (dd, J = 8.4, 2.4 Hz, 1H), 8.37 (s, 1H), 8.25-8.19 (m, 2H), 7.02 (d, J = 3.2 Hz, 2H), 4.57-4.49 (m, 4H), 2.74-2.67 (m, 1H), 1.42 (t, J = 6.8 Hz, 3H), 0.98-0.95 (m, 4H). Example 18: Synthesis of N-((5-(cyclopentanesulfonamido)pyridin-3-yl)methyl)-5-(6-ethoxypyrazin-2-yl)picolinamide (I-26). [ka]

[0418] Synthesis of 18.1. To a solution of 5-aminonicotinonitrile (1.19 g, 10 mmol, 1 equiv.) in pyridine (20 mL) was added 4-dimethylaminopyridine (122 mg, 1 mmol, 0.1 equiv.) and cyclopropanesulfonyl chloride (4.21 g, 30 mmol, 3 equiv.) at 0 °C. The resulting solution was stirred at 50 °C for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 column; mobile phase, water (0.1% FA) and ACN (5% ACN to 30% in 20 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and concentrated under reduced pressure to give N-(5-cyanopyridin-3-yl)cyclopropanesulfonamide (18.1) as a yellow solid. (1.2g, 53%), MS(ES): m / z224[M+H] + .

[0419] Synthesis of 18.2. A solution of 18.1 (1 g, 4.48 mmol, 1 equiv.) in methanol (25 mL) and ammonium hydroxide (5 mL) was flushed with nitrogen three times. Palladium on carbon (100 mg, 0.94 mmol, 0.21 equiv.) was added to the solution, which was then flushed with hydrogen. The mixture was stirred at room temperature under an atmosphere of hydrogen for 2 hours. The solid was filtered off, and the solution was concentrated under reduced pressure to give N-[5-(aminomethyl)pyridin-3-yl]cyclopropanesulfonamide (18.2) as a yellow solid. (900 mg, 88%), MS (ES): m / z 228 [M+H] + .

[0420] Synthesis of I-26. To a solution of 5-(6-ethoxypyrazin-2-yl)pyridine-2-carboxylic acid (15.7, 50 mg, 0.2 mmol, 1 equiv.) in pyridine (1 mL) was added 18.2 (50.9 mg, 0.22 mmol, 1.1 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58.6 mg, 0.31 mmol, 1.5 equiv.) at room temperature. The resulting solution was stirred at 80 °C for 1 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column: YMC-Actus Triart C18 30x250, 5um; Mobile phase: Water (0.1% NH4HCO3 + 0.1% NH3.H2O) and ACN (15% ACN to 45% in 7 min); UV detection at 254 / 210 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid. (36.5 mg, 39%), MS(ES): m / z 455 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 9.98 (brs, 1H), 9.57 (t, J = 8.4 Hz, 1H), 9.37 (d, J = 2.4 Hz, 1H), 9.01 (s, 1H), 8.69 (dd, J = 11.2, 2.8 Hz, 1H), 8.35-8.29 (m, 3H), 8.19 (d, J = 8.2 Hz, 1H), 7.64 (s, 1H), 4.52 (m, 4H), 2.68-2.58 (m, 1H), 1.42 (t, J = 7.0 Hz, 3H), 0.93-0.82 (m, 4H). Example 19: Synthesis of 5-(6-ethoxypyrazin-2-yl)-N-((4-((trifluoromethyl)sulfonamido)pyridin-2-yl)methyl)picolinamide (I-23). [ka]

[0421] Synthesis of 19.1. To a solution of 4-aminopicolinonitrile (240 mg, 2 mmol, 1 equiv.) in pyridine (6 mL) was added 4-dimethylaminopyridine (24.6 mg, 0.2 mmol, 0.1 equiv.) and cyclopropanesulfonyl chloride (678.9 mg, 4 mmol, 4 equiv.) at 0° C. The resulting solution was stirred at 50° C. for 12 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 column; mobile phase, water (0.1% FA) and ACN (5% ACN to 30% in 20 min); UV detection at 254 / 220 nm. Product-containing fractions were combined and concentrated under reduced pressure to give N-(2-cyanopyridin-4-yl)-1,1,1-trifluoromethanesulfonamide (19.1) as a yellow oil. (200mg, 39%), MS(ES): m / z252[M+H] + .

[0422] Synthesis of 19.2. A solution of 19.1 (200 mg, 0.79 mmol, 1 equiv.) in methanol (6 mL) and ammonium hydroxide (2 mL) was flushed with nitrogen three times. Palladium on carbon (20 mg) was added to the solution, which was then flushed with hydrogen. The mixture was stirred at room temperature under an atmosphere of hydrogen for 2 hours. The solid was filtered off, and the solution was concentrated under reduced pressure to give crude N-(2-(aminomethyl)pyridin-4-yl)-1,1,1-trifluoromethanesulfonamide (19.2) as a green solid. (100 mg, 49%), MS (ES): m / z 256 [M+H] + .

[0423] Synthesis of Compound I-23. To a solution of 5-(6-ethoxypyrazin-2-yl)picolinic acid (15.7, 50 mg, 0.2 mmol, 1 equiv.) in pyridine (1 mL), 19.2 (57.2 mg, 0.22 mmol, 1.1 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58.6 mg, 0.31 mmol, 1.5 equiv.) were added at room temperature. The resulting solution was stirred at 80 °C for 1 hour. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: Column: YMC-Actus Triart C18 30x250, 5um; Mobile phase: Water (0.1% NH4HCO3 + 0.1% NH3.H2O) and ACN (15% ACN to 33% in 10 min); UV detection at 254 / 210 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as an off-white solid. (28 mg, 28%), MS(ES): m / z 483 [M+H] + ; 1H NMR (300 MHz, CD3OD) δ 9.38 (d, J = 2.0 Hz, 1H), 8.81 (s, 1H), 8.66 (dd, J = 8.4, 2.1 Hz, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 8.12 (d, J = 6.0 Hz, 1H), 7.24-7.14 (m, 2H), 4.69 (s, 2H), 4.59 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H). Example 20: Synthesis of N-[(4-cyclopropanesulfonamidopyridin-2-yl)methyl]-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide (I-25). [ka]

[0424] Synthesis of Compound I-25. To a stirred solution of N-[2-(aminomethyl)pyridin-4-yl]cyclopropanesulfonamide (16.4, 43.3 mg, 0.19 mmol, 1 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (73.1 mg, 0.38 mmol, 2 equiv.) in pyridine was added 4-(6-ethoxypyrazin-2-yl)-2-fluorobenzoic acid (20.1, 50 mg, 0.19 mmol, 1 equiv.). The final reaction mixture was irradiated with microwave radiation at 80 °C for 2 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product (30 mg) was purified by prep-HPLC using the following conditions: Column: YMC-Actus Triart C18 30x250, 5um; Mobile phase: Water (0.1% NH4HCO3) and ACN (15% ACN to 35% in 10 min), UV detection at 254 / 210 nm. Fractions containing the product were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound as a white solid. (12.1 mg, 13%), MS(ES): m / z 472 [M+H] + ;1 H NMR (400 MHz, d6-DMSO) δ 10.77 (br, 1H), 8.99 (m, 1H), 8.94 (s, 1H), 8.33 (s, 1H), 8.19 (d, J = 5.6 Hz, 1H), 8.11-8.07 (m, 2H), 7.88-7.84 (m, 1H), 7.06 (s, 1H), 6.97 (dd, J = 5.6 Hz, J = 1.6 Hz, 1H), 4.54-4.89 (m, 4H), 2.71-2.64 (m, 1H), 1.42 (t, J = 7.2 Hz, 3H), 1.24-1.16 (m, 4H). Example 21: Synthesis of N-[(4-cyclopropanesulfonamidopyridin-2-yl)methyl]-4-(6-ethoxypyrazin-2-yl)piperazine-1-carboxamide (I-27). [ka]

[0425] Synthesis of Compound 21.1. To a stirred mixture of 2-chloro-6-ethoxy-pyrazine (790 mg, 4.98 mmol, 1 equiv.) and tert-butyl piperazine-1-carboxylate (1.12 g, 6.01 mmol, 1.2 equiv.) in dimethyl sulfoxide (15 mL), N,N-diisopropylethylamine (1.74 mL, 13.42 mmol, 2 equiv.) was added at room temperature. The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 column; mobile phase, water (10 mmol / L NH4HCO3) and ACN (5% ACN to 20% in 10 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and concentrated under reduced pressure to give tert-butyl 4-(6-ethoxypyrazin-2-yl)piperazine-1-carboxylate (21.1, 880 mg, 57%) as a white solid. MS (ES): m / z 309 [M+H] + .

[0426] Synthesis of 21.2. To a stirred mixture of 21.1 (880 mg, 2.85 mmol, 1 equiv.) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The pH of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 2-ethoxy-6-(piperazin-1-yl)pyrazine (21.2, 660 mg, 89%) as a brown oil. MS (ES): m / z 209 [M+H] + .

[0427] Synthesis of I-27. To a stirred mixture of 21.2 (45 mg, 0.22 mmol, 1 equiv.) in tetrahydrofuran (3 mL), triphosgene (20.8 mg, 0.07 mmol, 0.3 equiv.), triethylamine (0.12 mL), and N-[2-(aminomethyl)pyridin-4-yl]cyclopropanesulfonamide (16.4, 74.9 mg, 0.33 mmol, 1.5 equiv.) were added at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The pH of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase, water (0.1% NH4HCO3) and ACN (8% ACN to 35% in 10 min); UV detection at 254 / 220 nm. Fractions containing the product were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound (20.2 mg, 20%) as a white solid. MS (ES): m / z 462 [M+H] + ; 1H NMR (300 MHz, d6-DMSO) δ 8.09 (d, J = 6.0 Hz, 1H), 7.82 (s, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.31-7.29 (m, 1H), 6.92-6.88 (m, 2H), 4.31-4.23 (m, 4H), 3.56-3.50 (m, 8H), 2.63-2.56 (m, 1H), 1.33-1.29 (m, 3H), 0.92-0.91 (m, 4H). Example 22: Synthesis of N-[(4-cyclopropanesulfonamidopyridin-2-yl)methyl]-5-(6-methoxypyrazin-2-yl)pyridine-2-carboxamide (I-24). [ka]

[0428] Synthesis of 22.1. To a stirred mixture of 2-chloro-6-methoxy-pyrazine (432 mg, 2.98 mmol, 1 equiv.) and methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (786.2 mg, 2.98 mmol, 1 equiv.) in 1,4-dioxane (12 mL) and water (3 mL), potassium carbonate (1.2 g, 8.96 mmol, 3 equiv.) and Pd(dppf)Cl2CHCl2 (218.6 mg, 0.29 mmol, 0.1 equiv.) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the compound was eluted with 20% ethyl acetate in petroleum ether to give methyl 5-(6-methoxypyrazin-2-yl)pyridine-2-carboxylate (22.1) as a white solid (440 mg, 60%), MS(ES): m / z 246 [M+H] + .

[0429] Synthesis of 22.2. To a stirred mixture of 22.1 (440 mg, 1.79 mmol, 1 equiv.) in tetrahydrofuran (24 mL) and water (6 mL), lithium thiol (214.8 mg, 8.97 mmol, 5 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at 60° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water. The pH of the solution was adjusted to 3 with 1N hydrochloric acid. The solid was collected by filtration to give 5-(6-methoxypyrazin-2-yl)pyridine-2-carboxylic acid (22.2) as a white solid. (397 mg, 95%), MS (ES): m / z 232 [M+H] + .

[0430] Synthesis of I-24. To a stirred mixture of 22.2 (38 mg, 0.16 mmol, 1.1 equiv.) and N-[2-(aminomethyl)pyridin-4-yl]cyclopropanesulfonamide (16.4, 34 mg, 0.15 mmol, 1 equiv.) in pyridine (1 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (57.4 mg, 0.3 mmol, 2 equiv.) was added at room temperature. The resulting mixture was stirred at 80 °C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 column; mobile phase, water (10 mmol / L NH4HCO3) and ACN (10% ACN to 50% in 10 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and concentrated under reduced pressure. The residue was purified by Prep-HPLC using the following conditions: column, YMC-Actus Triart C18 30x250, 5um; mobile phase, water (10mmol / L NH4HCO3) and ACN (15% ACN to 35% in 7 minutes); UV detection at 254 / 220nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound (20.3mg, 30%) as a white solid. MS(ES): m / z 441 [M+H] + ; 1H NMR (300 MHz, d6-DMSO) δ 10.84 (br, 1H), 9.49 (t, J = 6.1 Hz, 1H), 9.42 (d, J = 1.8 Hz, 1H), 9.03 (s, 1H), 8.73 (dd, J = 8.1, 2.1 Hz, 1H), 8.40 (s, 1H), 8.28-8.16 (m, 2H), 7.03 (s, 2H), 4.57 (d, J = 6.0 Hz, 2H), 4.06 (s, 3H), 2.72-2.68 (m, 1H), 1.03-0.86 (m, 4H). Example 23: Synthesis of N-[(6-cyclopropanesulfonamidopyrimidin-4-yl)methyl]-5-(6-ethoxypyrazin-2-yl)pyridine-2-carboxamide (I-22). [ka]

[0431] Synthesis of 23.1. To a stirred solution of 6-bromopyrimidin-4-amine (870 mg, 5 mmol, 1 equiv.) and zinc cyanide (1.17 g, 10 mmol, 2 equiv.) in dimethylformamide (20 mL) was added Pd(PPh3)4 (577.8 mg, 0.5 mmol, 0.1 equiv.) at room temperature. The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 12 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 column; mobile phase, water (10 mmol / L NH4HCO3) and ACN (5% ACN to 30% in 20 min); UV detection at 254 / 220 nm. Product-containing fractions were combined and concentrated under reduced pressure to give 6-aminopyrimidine-4-carbonitrile (23.1) as a white solid. (200mg, 33%), MS(ES):m / z121[M+H] + .

[0432] Synthesis of Compound 23.2. To a stirred solution of 23.1 (200 mg, 1.66 mmol, 1 equiv.) in dimethylformamide (2 mL) and tetrahydrofuran (4 mL) was added sodium hydride (60%, 79.9 mg, 3.33 mmol, 2 equiv.) at 0° C. The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 0.5 hours. Then, cyclopropanesulfonyl chloride (702.23 mg, 4.99 mmol, 3 equiv.) was added dropwise at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 column; mobile phase, water (0.1% FA) and ACN (5% ACN to 15% in 20 min); UV detection at 254 / 220 nm. Product-containing fractions were combined and concentrated under reduced pressure to give N-(6-cyanopyrimidin-4-yl)cyclopropanesulfonamide (23.2) as a yellow oil (50 mg, 13%), MS (ES): m / z 225 [M+H]. + .

[0433] Synthesis of 23.3. A solution of 23.2 (350 mg, 1.56 mmol, 1 equiv.) in methanol (25 mL) and ammonium hydroxide (5 mL) was flushed with nitrogen three times. Palladium on carbon (40 mg) was added to the solution, which was then flushed with hydrogen. The mixture was stirred at room temperature under an atmosphere of hydrogen for 2 hours. The solid was filtered off, and the solution was concentrated under reduced pressure to give crude N-[6-(aminomethyl)pyrimidin-4-yl]cyclopropanesulfonamide (23.3) as a pale green solid. (350 mg, 98%), MS (ES): m / z 229 [M+H] + .

[0434] Synthesis of Compound I-22. A mixture of 23.2 (238 mg, 1.04 mmol, 1 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (399.7 mg, 2.08 mmol, 2 equiv.), and 5-(6-ethoxypyrazin-2-yl)pyridine-2-carboxylic acid (15.7, 255.6 mg, 1.04 mmol, 1 equiv.) in pyridine (5 mL) was stirred at 80 °C for 0.5 h. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 100% gradient over 10 min; detector, UV 254 nm. The crude product (50 mg) was purified by Prep-HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 19 x 250 mm, 5 μm; Mobile phase: Water (0.1% FA) and CAN (50% to 70% in 10 min), UV detection at 254 / 210 nm. The product-containing fractions were combined and partially evaporated in vacuo and lyophilized overnight to give the title compound (27 mg, 5%) as a white solid. MS (ES): m / z 456 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.2 (brs, 1H), 9.55 (t, J = 6.1 Hz, 1H), 9.41 (d, J = 2.1 Hz, 1H), 9.03 (s, 1H), 8.72 (dd, J = 8.2, 2.3 Hz, 2H), 8.38 (s, 1H), 8.21 (d, J = 8.2 Hz, 1H), 6.95 (s, 1H), 4.55-4.50 (m, 4H), 3.05-2.98 (m, 1H), 1.43 (t, J = 7.0 Hz, 3H), 1.04-1.01 (m, 4H). Example 24: Synthesis of N-[(4-cyclopropanesulfonamidopyridin-2-yl)methyl]-4-(6-ethoxypyrazin-2-yl)-2-oxopiperazine-1-carboxamide (I-28). [ka]

[0435] Synthesis of 24.1. To a stirred solution of 2-chloro-6-ethoxy-pyrazine (790 mg, 5 mmol, 1 equiv.) and piperazin-2-one (750 mg, 7.5 mmol, 1.5 equiv.) in dimethyl sulfoxide was added N,N-diisopropylethylamine (1.94 g, 15 mmol, 3 equiv.). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere overnight. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, water (0.1% NH4HCO3) and ACN (20% ACN to 35% in 25 min). The product-containing fractions were concentrated under reduced pressure to give 4-(6-ethoxypyrazin-2-yl)piperazin-2-one (24.1) as a yellow-green solid (560 mg, 50%). MS (ES): m / z 223 [M+H]. + .

[0436] Synthesis of 24.2. To a stirred solution of 24.1 (444 mg, 2 mmol, 1 equiv.) and 4-nitrophenyl carbonochloridate (1.62 g, 8 mmol, 4 equiv.) in dichloromethane, trimethylamine (1.01 g, 10 mmol, 5 equiv.) and 4-dimethylaminopyridine (24.8 mg, 0.2 mmol, 0.1 equiv.) were added. The resulting mixture was stirred at room temperature for 3 h. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, water (10 mmol / L NH4HCO3) and ACN (10% ACN to 50% in 20 min); UV detection at 254 / 220 nm. The mixture was concentrated under reduced pressure to give 4-nitrophenyl 4-(6-ethoxypyrazin-2-yl)-2-oxopiperazine-1-carboxylate (24.2) as a yellow solid. (200mg, 26%), MS(ES):m / z388[M+H] + .

[0437] Synthesis of I-28. To a stirred solution of N-[2-(aminomethyl)pyridin-4-yl]cyclopropanesulfonamide (16.4, 29.9 mg, 0.13 mmol, 1 equiv.) in dichloromethane (1 mL) and dimethylacetamide (0.1 mL) was added trimethylamine (40 mg, 0.4 mmol, 3 equiv.) and 24.2 (51 mg, 0.13 mmol, 1 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product (32 mg) was purified by prep-HPLC using the following conditions: Column: SunFire Prep C18 OBD column, 19 x 150 mm 5 um, mobile phase water (0.1% FA) and ACN (31% ACN to 45% in 10 min); UV detection at 254 / 210 nm; the title compound was obtained as a white solid. (12.8 mg, 20%). MS (ES): m / z 476 [M+H] + , 1 H NMR (400 MHz, d6-DMSO) δ 9.59 (t, J = 5.6 Hz, 1H), 8.23-8.19 (m, 1H), 7.75 (s, 1H), 7.53 (s, 1H), 7.01 (d, J =5.6 Hz, 2H), 4.46 (d, J = 5.2 Hz, 2H), 4.41 (s, 2H), 4.32 (q, J = 7.0 Hz, 2H), 3.97 (dd, J = 6.8, 4.1 Hz, 2H), 3.78 (dd, J = 6.8, 4.1 Hz, 2H), 2.77-2.68 (m, 1H), 1.33 (t, J = 7.0 Hz, 3H), 1.03-0.89 (m, 4H). Example 25: Synthesis of N-[[4-(difluoromethanesulfonamido)pyridin-2-yl]methyl]-5-(6-ethoxypyrazin-2-yl)pyridine-2-carboxamide (I-30). [ka]

[0438] Synthesis of 25.1. To a stirred solution of 4-aminopyridine-2-carbonitrile (240 mg, 2 mmol, 1 equiv.) and 4-dimethylaminopyridine (24.6 mg, 0.2 mmol, 0.1 equiv.) in pyridine (2 mL) was added difluoromethanesulfonyl chloride (606.4 mg, 4 mmol, 2 equiv.) at 0° C. The resulting mixture was stirred at 50° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and purified by reverse-phase flash chromatography using the following conditions: column, C18 column; mobile phase, water (0.1% FA) and ACN (10% ACN to 50% in 10 min); UV detection at 254 / 220 nm. The product-containing fractions were combined and concentrated under reduced pressure to give N-(2-cyanopyridin-4-yl)-1,1-difluoromethanesulfonamide (25.1) as a brown oil. (50.5mg, 10%), MS(ES):m / z232[MH] - .

[0439] Synthesis of 25.2. A stirred mixture of 25.1 (100 mg, 0.43 mmol, 1 equiv.) in methanol (10 mL) and ammonium hydroxide (3 mL) was flushed with nitrogen three times. Palladium on carbon (10 mg) was added to the solution, which was then flushed with hydrogen. The mixture was stirred at room temperature under an atmosphere of hydrogen for 2 hours. The solid was filtered off, and the solution was concentrated under reduced pressure to give crude N-[2-(aminomethyl)pyridin-4-yl]-1,1-difluoromethanesulfonamide (25.2) as a brown solid. (37 mg, 36%), MS (ES): m / z 238 [M+H] + .

[0440] Synthesis of I-30. To a stirred mixture of 25.2 (25 mg, 0.1 mmol, 1 equiv.) and 5-(6-ethoxypyrazin-2-yl)pyridine-2-carboxylic acid (15.7, 12.9 mg, 0.05 mmol, 0.5 equiv.) in N,N-dimethylformamide (2 mL), 1-hydroxybenzotriazole (21.3 mg, 0.15 mmol, 1.5 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30.3 mg, 0.15 mmol, 1.5 equiv.) were added at room temperature. The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC using the following conditions: ...

Claims

1. Formula I: 【Chemistry 316】 or a pharma- ceutically acceptable salt thereof, wherein in formula I: R １ is -CF3, -CHF2, 【Chemical 337】 Selected from: Ring A is selected from a 6-membered monocyclic heteroaryl ring having 1 or 2 nitrogen atoms or phenyl; L is, 【Hua 338-1】 【Hua 338-2】 【Hua 338-3】 【Hua 338-4】 and Ring B is selected from phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 11-membered saturated or partially unsaturated fused, bridged, or spiro bicyclic carbocyclic ring; a 7- to 11-membered fused bicyclic aryl ring; a 7- to 11-membered saturated or partially unsaturated fused, bridged, or spiro bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is selected from a 6-membered monocyclic heteroaryl ring having 1 to 4 nitrogen atoms; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R Ａ , R Ｂ , and R Ｃ Each instance is independently oxo, halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ N.R. ２ , -S(O)R, -S(O)NR ２ , -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)C(NR)NR ２ , -N(R)NR ２ , -N(R)S(O) ２ N.R. ２ , -N(R)S(O) ２ R, -N=S(O)R ２ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR ２ , -P(O)(R)OR or -P(O)R ２ or R Ｃ Each instance of is independently １～６ aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 6- to 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is selected from r instances of R and s instances of R. Ｄ or two R Ｃ The group is each R Ｃ optionally taken together with the atom to which it is attached to form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 7-membered heteroaryl ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R Ｄ Each instance is independently oxo, halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ N.R. ２ , -S(O)R, -S(O)NR ２ , -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)C(NR)NR ２ , -N(R)NR ２ , -N(R)S(O) ２ N.R. ２ , -N(R)S(O) ２ R, -N=S(O)R ２ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR ２ , -P(O)(R)OR or -P(O)R ２ and Each R is independently hydrogen, —CN, halogen, or an optionally substituted group, the optionally substituted group being C １～６ aliphatic; phenyl; naphthalenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 4 heteroatoms; a 5- to 8-membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 10-membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6- to 11-membered saturated or partially unsaturated bicyclic carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups, together with the atoms to which each R is attached, form an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, or 2; each r is independently 0, 1, 2, 3, or 4; and each s is independently 0, 1, 2, 3, or 4; however: R １ but, 【Chemical 339】 and Sulfonamide moiety 【Chemistry 318】 R group is hydrogen or para-methoxybenzyl; L, 【Hua 340-1】 or L is 【Hua 340-2】 and Ring B is phenyl or a 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Ring C is a 6-membered monocyclic heteroaryl ring having 1 to 4 nitrogen atoms and is attached to Ring B at the para position relative to the L group; Ring A and its R Ａ The substituents are 【Chemical 341】 Other than, where * is 【Chemistry 322】 represents a bond to the moiety, and ** represents 【Chemistry 323】 Represents a bond to a moiety, A compound or a pharma- ceutically acceptable salt thereof.

2. R １ But -CHF ２ ,or 【Chemical 342】 2. The compound of claim 1, wherein:

3. Ring A is 【Chemical 343】 2. The compound of claim 1, wherein:

4. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Ring B is selected from phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7- to 11-membered fused bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

5. Ring B is 【Chemical 344】 2. The compound of claim 1, wherein:

6. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Ring C is a 6-membered monocyclic heteroaryl ring having 1 to 4 nitrogen atoms.

7. Ring C is 【Chemical 345】 2. The compound of claim 1, wherein: 【Request 8】 【Chemistry 346-1】 【Hua 346-2】 【Hua 346-3】 【Hua 346-4】 【Hua 346-5】 【Hua 346-6】 【Hua 346-7】 【Hua 346-8】 【Hua 346-9】 【Chemistry 346-10】 【Hua 346-11】 【Hua 346-12】 【Chemistry 346-13】 【Chemistry 346-14】 【Chemistry 346-15】 【Hua 346-16】 【Chemistry 346-17】 【Hua 346-18】 【Hua 346-19】 【Hua 346-20】 【Hua 346-21】 【Hua 346-22】 【Hua 346-23】 【Hua 346-24】 【Hua 346-25】 【Hua 346-26】 【Chemistry 346-27】 【Hua 346-28】 【Hua 346-29】 【Chemistry 346-30】 【Chemistry 346-31】 【Chemistry 346-32】 【Chemistry 346-33】 【Chemistry 346-34】 【Chemistry 346-35】 【Hua 346-36】 【Chemistry 346-37】 【Chemistry 346-38】 【Chemistry 346-39】 【Chemistry 346-40】 or a pharma- ceutically acceptable salt thereof. 【Request 9】 【Hua 347-1】 【Hua 347-2】 or a pharma- ceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

11. A composition comprising a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for use as a medicament.

12. A composition comprising a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for use in treating a CPTS1-mediated disorder, disease, or condition in a patient, said use comprising administering said composition or pharmaceutical composition to said patient.

13. The composition of claim 12, wherein the disease is selected from rejection of transplanted cells and tissues, transplant-associated diseases or disorders, allergies and autoimmune diseases.

14. The composition of claim 13, wherein the disorder is graft-versus-host disease (GVHD).

15. The disease or disorder is selected from the group consisting of Addison's disease, adult-onset Still's disease, alopecia areata, Alzheimer's disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, ankylosing spondylitis, antiphospholipid syndrome (Hughes syndrome), aplastic anemia, arthritis, asthma, atherosclerosis, atherosclerotic plaques, atopic dermatitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune hypophysitis (lymphocytic hypophysitis), autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis, autoimmune orchitis, and immunosuppressive treatment. Autoinflammatory diseases requiring treatment, azoospermia, Behcet's disease, Buerger's disease, bullous pemphigoid, cardiomyopathy, cardiovascular disease, celiac disease including refractory celiac disease (types I and II), chronic fatigue immune deficiency syndrome (CFIDS), chronic idiopathic polyneuropathy, chronic inflammatory demyelinating polyneuropathy (CIPD), chronic relapsing polyneuropathy (Guillain-Barre syndrome), Churg-Strauss syndrome (CSS), cicatricial pemphigoid, cold agglutinin disease (CAD), chronic obstructive pulmonary disease (COPD), CREST syndrome, cryoglobulin syndrome, cutaneous lupus, herpetiformis Dermatitis, dermatomyositis, eczema, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, Evans syndrome, exophthalmos, fibromyalgia, Goodpasture's syndrome, Graves' disease, hemophagocytic lymphohistiocytosis (HLH) (including type 1 hemophagocytic lymphohistiocytosis), histiocytosis / histiocytic disorders, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, immunoproliferative or immunoproliferative diseases, inflammatory bowel disease (IBD), interstitial lung disease, juvenile arthritis, juvenile idiopathic arthritis (JIA), Kawasaki disease, Lambert-Eaton myasthenic syndrome, lichen planus psoriasis, localized scleroderma, lupus nephritis, Meniere's disease, microangiopathy, microscopic polyangiitis, Miller Fisher syndrome / acute disseminated cerebrospinal radiculopathy, mixed connective tissue disease, multiple sclerosis (MS), muscular rheumatism, myalgic encephalomyelitis (ME), myasthenia gravis, eye inflammation, pemphigus foliaceus, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome (Whitaker syndrome), polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis / autoimmune bile duct disease, primary glomerulonephritis, primary sclerosing cholangitis, psoriasis,14. The composition of claim 13, wherein the disease is psoriatic arthritis, pure red cell aplasia, Raynaud's phenomenon, Reiter's syndrome / reactive arthritis, relapsing polychondritis, restenosis, rheumatic fever, rheumatic disease, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleroderma / systemic sclerosis, Sjogren's syndrome, stiff-man syndrome, Sweet's syndrome (febrile neutrophilic dermatosis), systemic lupus erythematosus (SLE), systemic scleroderma, Takayasu's arteritis, temporal arteritis / giant cell arteritis, thyroiditis, type 1 diabetes, type 2 diabetes, uveitis, vasculitis, vitiligo, Wegener's granulomatosis, or X-linked lymphoproliferative disease.

16. 11. Use of a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, in the manufacture of a medicament for the treatment of a CPTS1-mediated disorder, disease, or condition in a patient.

17. 17. The use according to claim 16, wherein the disease is selected from rejection of transplanted cells and tissues, transplant-associated diseases or disorders, allergies and autoimmune diseases.

18. 18. The use according to claim 17, wherein the disorder is graft-versus-host disease (GVHD).

19. The disease or disorder is selected from the group consisting of Addison's disease, adult-onset Still's disease, alopecia areata, Alzheimer's disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, ankylosing spondylitis, antiphospholipid syndrome (Hughes syndrome), aplastic anemia, arthritis, asthma, atherosclerosis, atherosclerotic plaques, atopic dermatitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune hypophysitis (lymphocytic hypophysitis), autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis, autoimmune orchitis, and immunosuppressive treatment. Autoinflammatory diseases requiring treatment, azoospermia, Behcet's disease, Buerger's disease, bullous pemphigoid, cardiomyopathy, cardiovascular disease, celiac disease including refractory celiac disease (types I and II), chronic fatigue immune deficiency syndrome (CFIDS), chronic idiopathic polyneuropathy, chronic inflammatory demyelinating polyneuropathy (CIPD), chronic relapsing polyneuropathy (Guillain-Barre syndrome), Churg-Strauss syndrome (CSS), cicatricial pemphigoid, cold agglutinin disease (CAD), chronic obstructive pulmonary disease (COPD), CREST syndrome, cryoglobulin syndrome, cutaneous lupus, herpetiformis Dermatitis, dermatomyositis, eczema, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, Evans syndrome, exophthalmos, fibromyalgia, Goodpasture's syndrome, Graves' disease, hemophagocytic lymphohistiocytosis (HLH) (including type 1 hemophagocytic lymphohistiocytosis), histiocytosis / histiocytic disorders, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, immunoproliferative or immunoproliferative diseases, inflammatory bowel disease (IBD), interstitial lung disease, juvenile arthritis, juvenile idiopathic arthritis (JIA), Kawasaki disease, Lambert-Eaton myasthenic syndrome, lichen planus psoriasis, localized scleroderma, lupus nephritis, Meniere's disease, microangiopathy, microscopic polyangiitis, Miller Fisher syndrome / acute disseminated cerebrospinal radiculopathy, mixed connective tissue disease, multiple sclerosis (MS), muscular rheumatism, myalgic encephalomyelitis (ME), myasthenia gravis, eye inflammation, pemphigus foliaceus, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome (Whitaker syndrome), polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis / autoimmune bile duct disease, primary glomerulonephritis, primary sclerosing cholangitis, psoriasis,18. The use according to claim 17, which is for the treatment of psoriatic arthritis, pure red cell aplasia, Raynaud's phenomenon, Reiter's syndrome / reactive arthritis, relapsing polychondritis, restenosis, rheumatic fever, rheumatic disease, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleroderma / systemic sclerosis, Sjogren's syndrome, stiff-man syndrome, Sweet's syndrome (febrile neutrophilic dermatosis), systemic lupus erythematosus (SLE), systemic scleroderma, Takayasu's arteritis, temporal arteritis / giant cell arteritis, thyroiditis, type 1 diabetes, type 2 diabetes, uveitis, vasculitis, vitiligo, Wegener's granulomatosis, or X-linked lymphoproliferative disorder.

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