Classifications

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  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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  • A61K31/4965—Non-condensed pyrazines
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D487/04—Ortho-condensed systems

Definitions

• the present disclosure provides a compound represented by the structure of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
• R 3 and R 4 are each independently selected from (a), (b), (c), and (d):
• C x-y when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
• C 1-6 alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.
• - C x-y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain.
• an aromatic ring e.g., phenyl
• a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
• Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl.
• Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.
• the cycloalkenyl may be attached to the rest of the molecule by a single bond.
• monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
• Cycloalkenyl may be optionally substituted by one or more substituents such as those substituents described herein.
• a “C x-y carbocycle” is meant to include groups that contain from x to y carbons in a ring.
• heteroaryl refers to a radical derived from a 3- to 12-membered aromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S.
• the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof.
• the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof.
• the heteroaryl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof.
• the heteroaryl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof.
• haloalkyl or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, di chi orom ethyl, bromom ethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
• the alkyl part of the fluoroalkyl radical is optionally further substituted.
• salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
• Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
• Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
• the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
• Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.
• R 1 and R 2 are each independently selected from (iv), (v), (vi) and (vii):
• R 3 and R 4 are each independently selected from (a), (b), (c), and (d):
• C 3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR 17B , -SR 17B , -N(R 17B ) 2 , -C(O)R 17B , -C(O)OR 17B , -OC(O)R 17B , - OC(O)N(R 17B ) 2, -C(O)N(R 17B ) 2 , -N(R 17B )C(O)R 17B , -N(R 17B )C(O)OR 17B , - N(R 17B )C(O)N(R 17B ) 2 , -N(R 17B )S(O) 2 (R 17B ), -S(O)R 17B , -S(O) 2 R 17B , -S(O) 2 N(R 17B ) 2 , -NO 2 , and -CN;
• one of R 1 or R 2 is C 1-6 alkyl substituted with a 5- to 6-membered saturated heterocycle wherein the 5- to 6-membered saturated heterocycle selected from pyrrolidine, pyrroline, pyrazoline, imidazoline, tetrahydrofuran, dioxolane, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine, any one of which is optionally substituted.
• the 5- to 6-membered saturated heterocycle selected from pyrrolidine, pyrroline, pyrazoline, imidazoline, tetrahydrofuran, dioxolane, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine, any one of which
• R 1 is hydrogen; and R 2 is C 1-6 alkyl substituted with a 5- to 6-membered saturated heterocycle wherein the 5- to 6-membered saturated heterocycle selected from pyrrolidine, pyrroline, pyrazoline, imidazoline, tetrahydrofuran, dioxolane, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine, any one of which is optionally substituted.
• R 1 is hydrogen; and R 2 is represented by
• one of R 1 or R 2 is a 5- to 6- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR 14B , -N(R 14B ) 2 , -C(O)R 14B , -C(O)OR 14B , -NO 2 , and -CN.
• one of R 1 or R 2 is 5- to 6-membered heterocycle selected from pyrrolidine, pyrroline, pyrazoline, imidazoline, tetrahydrofuran, dioxolane, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, dioxane, thiane, dithiane, morpholine, and thiomorpholine, any one of which is optionally substituted.
• one of R 1 or R 2 is represented by
• A is selected from a 5- to 6-membered heterocycle optionally substituted with one more substituents independently selected from (i), (ii), and (iii):
• R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently selected at each occurrence from (I), (II) and (III):
• A is selected from optionally substituted 5- to 6-membered heteroaryl.
• the optionally substituted 5- to 6-membered heteroaryl of A comprises one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combination thereof.
• the optionally substituted 5- to 6-membered heteroaryl of A comprises one or more heteroatoms selected from nitrogen, oxygen, and combination thereof.
• the optionally substituted 5- to 6- membered heteroaryl of A comprises one or more heteroatoms selected from nitrogen, sulfur, and combination thereof.
• the optionally substituted 5- to 6-membered heteroaryl of A comprises one or more heteroatoms selected from oxygen, sulfur, and combination thereof. In some embodiments, the optionally substituted 5- to 6-membered heteroaryl of A comprises one or more nitrogen heteroatoms. In some embodiments, the optionally substituted 5- to 6-membered heteroaryl of A comprises one or more heteroatoms selected from nitrogen and oxygen.
• A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (ii) C 1 -io alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , C(O)OR 11 , -OC(O)R 11 , -OC(O)N(R 11 ) 2, - C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)N(R 11 ) 2 , -N(R 11 )S(O) 2 (R 11 ), - S(O)R 11 , -S(O) 2 R 11
• A is selected from 5- to 6-memebred heteroaryl optionally substituted with one or more substituents independently selected from (ii) C 1 -io alkyl optionally substituted with one or more substituents independently selected from C 3-10 carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -SR 11 , - N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -OC(O)N(R 11 ) 2, -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , - N(R 11 )C(O)OR 11 , -N(R 11 )C(O)N(R 11 ) 2 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O
• the 5- to 6-membered heterocycle of A is substituted with one or more substituents.
• B is selected from - CH(R A )(R b ) and each of R A and R B are independently selected from: methyl, ethyl, propyl, and isopropyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 13 , -SR 13 , -N(R 13 )2, -C(O)R 13 , -NO2, and -CN; and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 13 , -SR 13 , - N(R 13 ) 2 , -C(O)R 13 , -NO2, and -CN.
• R 1 and R 2 are each independently C1-3 alkyl optionally substituted with a substituent independently selected from halogen, -OR 14 , -SR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -NO2, and -CN.
• R 1 and R 2 are each independently selected from: hydrogen and In some embodiments, R 1 and R 2 are each selected from hydrogen, and . In some embodiments, R 1 and R 2 are each independently selected from: hydrogen, In ⁇ and some embodiments, R 1 and R 2 are each independently selected from: hydrogen, . In some embodiments, R 1 and R 2 are selected from different substituents. In some embodiments, one of R 1 and R 2 , is hydrogen. In some embodiments, one of R 1 and R 2 , is C1-3 alkyl. In some embodiments, one of R 1 and R 2 is selected from methyl, ethyl, and propyl. In some embodiments, one of R 1 and R 2 is methyl.
• each of R 3 and R 4 is selected from (c).
• each of R 3 and R 4 is selected from C 2 -6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 15 , -SR 15 , - N(R 15 ) 2 , -C(O)R 15 , -C(O)-O-C 1-6-alkyl, -OC(O)R 15 , -OC(O)N(R 15 ) 2 -C(O)N(R 15 ) 2 , -N(R 15 )C(O)R 15 , -N(R 15 )C(O)OR 15 , -N(R 15 )C(O)N(R 15 ) 2 , -N(R 15 )S(O) 2 (R 15 ), -S(O)R 15 , -S(O)R 15 , -S(O)
• C 1 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 3 ⁇ 4 -CN;
• R 3 and R 4 are each independently selected from (a) and (b):
• C 1 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 3 ⁇ 4 -CN;
• one of R 3 and R 4 is hydrogen, and the other of R 3 and R 4 is selected from C 1 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 3 ⁇ 4 -CN;
• R 3 and R 4 are hydrogen and
• R 3 and R 4 are each independently selected from (a) and (c):
• C 1 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)-O-C 1 .
• R 3 and R 4 are each independently selected from (b) and (c):
• R 3 and R 4 are each independently selected from (a), (b), and (c):
• R 3 and R 4 are each independently selected from (a), (b), (c), and (d):
• R 3 or R 4 is selected
• R 3 or R 4 is selected from C 2 -6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)N(R 15 ) 2 , -N(R 15 )C(O)OR 15 , -NO 2 , -CN; C 3-6 carbocycle and 3- to 6-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 15 , -SR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2 , and -CN.
• R 3 or R 4 is selected embodiments, R 3 or R 4 is selected from
• the optionally substituted 4- to 12-membered heterocycle optionally comprises more than one heteroatom selected from oxygen and nitrogen. In some embodiments, the optionally substituted 4- to 12-membered heterocycle optionally comprises more than one heteroatom selected from oxygen and sulfur. In some embodiments, the optionally substituted 4- to 12-membered heterocycle comprises more than one heteroatom selected from nitrogen and sulfur. In some embodiments, the optionally substituted 4- to 12-membered heterocycle optionally comprises at least one additional heteroatom selected from oxygen, nitrogen, sulfur, and any combination thereof. In some embodiments, the optionally substituted 4- to 12-membered heterocycle comprises one nitrogen heteroatom.
• the 4- to 12-membered heterocycle is selected from a saturated 4- to 8-membered heterocycle and 6- to 12-membered unsaturated heterocycle, any one of one which is optionally substituted.
• the R 3 and R 4 of R 4 come together to form a saturated 4- to 8-membered heterocycle any one of which is optionally substituted.
• R 3 and R 4 come together to form a saturated 4- to 8-membered heterocycle and the saturated 4- to 8-membered heterocycle is selected from azetidine, oxetane, pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, morpholine, oxazepane, and azaspiro[3.3]heptane, any one of which is optionally substituted with one substituents independently selected from chloro, fluoro, -OR 16 , -N(R 16 )2, -C(O)OR 16 , - C(O)N(R 16 ) 2 , -N(R 16 )C(O)R 16 , -NO2, and -CN; and C
• R 3 and R 4 of r4 come together to form the saturated 4- to 8-membered heterocycle and the 4- to 8-membered heterocycle is selected from:
• R 3 and R 4 of R 4 come together to form the saturated 4- to 8-membered heterocycle and R 4 is selected from:
• R 3 and R 4 of R come together to form an unsaturated 4- to 12-membered heterocycle and R is represented
• the present disclosure provides a compound represented by the structure of Formula (II): or a pharmaceutically acceptable salt thereof, wherein A, B, R 1 , R 2 , R 3 , R 4 , and n are as defined in
• R 5 is selected from: halogen, -OR 17 , -SR 17 , -N(R 17 ) 2 , -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2, -C(O)N(R 17 ) 2 , -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 ) 2 , -N(R 17 )S(O) 2 (R 17 ), -S(O)R 17 , -S(O) 2 R 17 , -S(O) 2 N(R 17 ) 2 , -NO 2 , and -CN; C 1-6 alkyl and C 2-6 alkenyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 17 , -
• R 5 is selected from and . In some embodiments, R 5 is .In some embodiments, R 5 is . In some embodiments,
• Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
• Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.
• the compounds of Formula (I), (I-a), or (II), have some or all of the 3 ⁇ 4 atoms replaced with 2 H atoms.
• the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
• compounds or salts of Formula (I), (I-a), or (II) may be prodrugs.
• prodrug is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure.
• One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
• the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal.
• the present disclosure provides methods of producing the above-defined compounds.
• the compounds may be synthesized using conventional techniques.
• these compounds are conveniently synthesized from readily available starting materials.
• compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen.
• Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate.
• the pharmaceutical compositions can also include the compounds, salts or conjugates in a free-base form or pharmaceutically-acceptable salt form.
• Pharmaceutical compositions as often further can comprise more than one active compound (e.g., a compound, salt or conjugate and other agents) as necessary for the particular indication being treated.
• the active compounds can have complementary activities that do not adversely affect each other. Such molecules can be present in combination in amounts that are effective for the purpose intended.
• the present disclosure provides a method of a method of treating an inflammatory disease or condition in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (I), (I-a), or (II) or a pharmaceutical composition thereof.
• Step 1 Synthesis of Methyl 2-(4-amino-3-fluorophenyl)acetate: To a solution of 2-(4- amino-3-fhiorophenyl)acetic acid (300 mg, 1.77 mmol, l.OOeq) in MeOH (4.00 mL) was added drop-wise SOCh (253 mg, 2.13 mmol, 154 uL, 1.20eq). The mixture was stirred at 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure to afford methyl 2-(4-amino-3- fluorophenyl)acetate (300 mg, 1.6 mmol, 92% yield) as a yellow solid.
• LCMS [M+H] + 184.2 m/z
• Step 3 Synthesis of Methyl (S)-2-(4-(2-amino-2-cycloheptylacetamido)-3- fluorophenyl)acetate: To a solution of methyl (S)-2-(4-(2-((tert-butoxycarbonyl)amino)-2- cycloheptylacetamido)-3-fluorophenyl)acetate (600 mg, 1.37 mmol, l.OOeq) in DCM (5.00 mL) was added HCl/dioxane (4.00 M, 3.44 mL, lO.Oeq) at 0 °C. The mixture was stirred at RT for 2 h.
• Step 5 Synthesis of (S)-2-(4-(2-cycloheptyl-2-(l-ethyl-lH-pyrazole-5- carboxamido)acetamido)-3-fluorophenyl)acetic acid: To a solution of methyl (S)-2-(4-(2- cycloheptyl-2-(l-ethyl-lH-pyrazole-5-carboxamido)acetamido)-3-fluorophenyl)acetate (100 mg, 218 umol, 1.00 eq) in MeOH (4.00 mL) was added a solution of LiOH/ThO (10.9 mg, 261 umol, 1.20 eq) in 3 ⁇ 40 (1.00 mL) at 0 °C.
• Step 6 Synthesis of (S)-N-(l-cycloheptyl-2-((2-fluoro-4-(2-(methyl(2,2,2- trifluoroethyl)amino)-2-oxoethyl)phenyl)amino)-2-oxoethyl)-l-ethyl-lH-pyrazole-5-carboxamide (1).
• Example 18 Synthesis of Compound 17 [0224] N-((S)- 1 , 1 -di cyclopropyl -3 -((4-((S)- 1 -((2,2-difluoroethyl)amino)- 1 -oxopropan-2-yl)-2- fluorophenyl)amino)-3-oxopropan-2-yl)-l -isopropyl- lH-pyrazole-5-carboxamide (17).
• Example 34 Synthesis of Compound 33 [0243] N-((S)-l,l-dicyclopropyl-3-((2-fluoro-4-((S)-l-(3-fluoro-3-(hydroxymethyl)azetidin-l-yl)- l-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-l-isopropyl-lH-pyrazole-5-carboxamide (33).
• Example 48 Synthesis of Compound 47 [0257] N-((2S)-l,l-dicyclopropyl-3-((2-fluoro-4-((2S)-l-(4-fluoro-2-(trifluoromethyl)pyrrolidin-l- yl)-l-oxopropan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-l-isopropyl-lH-pyrazole-5-carboxamide (47).
• Example 53 Synthesis of Compound 52 [0262] N-((S)-l,l-dicyclopropyl-3-((2-fluoro-4-((S)-l-oxo-l-((3-(trifluoromethyl)azetidin-3- yl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-l-isopropyl-lH-pyrazole-5-carboxamide (52).
• Examples synthesized according to General Scheme A employ a carboxylic acid and an amine in the first step followed by an amino acid in step 3 and a carboxylic acid in step 5. Starting materials are listed in order of use.
• l-ethyl-4-fluoro-lH-pyrazole-5-carboxylic acid l-Ethyl-lH-pyrazole-5-carboxylic acid (0.500 g, 3.57 mmol, l.OOeq) and Select F (2.53 g, 7.14 mmol, 2.00eq) were added to a microwave reaction vial and diluted with MeCN (8.00 mL) and AcOH (3 mL). The sealed tube was heated at 110 °C for 6 h under microwave. The reaction mixture was diluted with FhO and extracted with EtOAc.
• Example 87 Synthesis of Compound 85 l-fluoro-4-(l-methoxybut-l-en-2-yl)benzene.
• l-(4-fluorophenyl)propan-l-one 400 g, 2.63 mol, 363 mL, 1.00 eq
• THF 2000 mL
• t-BuOK 442 g, 3.94 mol, 1.50 eq
• (methoxymethyl)triphenylphosphonium chloride (1.17 kg, 3.42 mol, 1.30 eq). The mixture was stirred at 0-5°C for 2 h.
• (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(4-fluorophenyl)pentanoic acid To a solution of (2S)-2- amino-3-(4-fluorophenyl)pentanoic acid hydrochloride salt (200 g, crude) in THF (1200 mL) and LhO (1200 mL) was added B0C2O (413 g, 1.89 mol, 435 mL) and K2CO3 (523 g, 3.79 mol). The mixture was stirred at 15-25°C for 3 h.
• the title compound was isolated as a single stereoisomer by chiral SFC purification of 25.0 g of the mixture (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); eluting with 15% of 0.1%NH 3 H 2 O in ethanol).
• the title compound (12.0 g, 38.5 mmol, 48.0% yield) was obtained as the first eluting isomer and an off-white solid.
• N-Methoxy-N-methylcyclobutanecarboxamide N-Methoxy-N-methylcyclobutanecarboxamide.
• cyclobutanecarboxylic acid 75.0 g, 749 mmol, 71.4 mL, 1.00 eq
• DCM 350 mL
• N,O-dimethylhydroxylamine hydrochloride 87.7 g, 899 mmol, 1.20 eq
• EDCI 215 g, 1.12 mol, 1.50 eq
• TEA 114 g, 1.12 mol, 156 mL, 1.50 eq
• reaction mixture was stirred at 30 °C for 12 h.
• the reaction mixture was treated with H2O and extracted with DCM.
• the combined organic layers were washed with brine, dried over Na 2 SC> 4 , filtered, and concentrated under reduced pressure.
• the residue was purified by chiral SFC purification (column: (S,S)Whelk-O1 (250 mm x 30 mm, 5 um); mobile phase: 5% to 40% [0.05% diethylamine in MeOH]) to afford the first eluting isomer of (S)-N-((lS)-l-cyano-2-cyclobutylbutyl)-2- methylpropane-2-sulfmamide (3.20 g, 12.5 mmol, 32.8% yield, 99.7% purity) as a light yellow oil and the second eluting isomer of (S)-N-((lS)-l-cyano-2-cyclobutylbutyl)-2-methylpropane-2- sulfmamide (3.00 g, 11.7 mmol, 30.8% yield, 100% purity) as a light yellow oil.
• Methyl l-(2-(3,3-difluoroazetidin-l-yl)ethyl)-lH-pyrazole-5-carboxylate Methyl l-(2- bromoethyl)-lH-pyrazole-5-carboxylate (100 mg, 429 umol, l.OOeq), 3,3-difluoroazetidine hydrochloride (111 mg, 858 umol, 2.00eq), and DIEA (277 mg, 2.15 mmol, 374 uL, 5.00eq) were taken up into a microwave reaction vial in IPA (3.00 mL). The sealed tube was heated at 100 °C for 8 h under microwave heating.
• reaction mixture was filtered, concentrated under reduced pressure, and purified by prep-HPLC (eluting with 10-40% ACN in water with 10 mM ammonium carbonate) to afford methyl l-(2-(lH- imidazol-l-yl)ethyl)-lH-pyrazole-5-carboxylate (120 mg, 545 umol, 42.3% yield) as a colorless oil.
• LCMS [M+H] + 221.1 m/z.
• the title compound was prepared from the second eluting, single stereoisomer of tert-butyl 3-(5-(((S)- 1 , 1 -di cyclopropyl-3 -((2-fluoro-4-((S)- 1 -oxo- 1 -((2,2,2-trifluoroethyl)amino)propan-2- yl)phenyl)amino)-3-oxopropan-2-yl)carbamoyl)-lH-pyrazol-l-yl)piperidine-l-carboxylate(29 mg, 41.86 umol, leq), which was diluted in 0.5 mL DCM and treated with 4 M HC1 in dioxane (100 uL, lOeq).
• Example 108 Synthesis of Compound 105 [0345] N-((2S)-l,l-dicyclopropyl-3-((2-fluoro-4-(3-methoxy-l-oxo-l-((2,2,2- trifluoroethyl)amino)propan-2-yl)phenyl)amino)-3-oxopropan-2-yl)-l-isopropyl-lH-pyrazole-5- carboxamide (105).
• reaction mixture was diluted by ThO, extracted by EtOAc, washed by ThO, dried over anhydrous NaiSCL, and concentrated under reduced pressure to give a residue.
• LCMS [M+H] + 577.2 m/z.
• Title compound was isolated as the first eluting, single stereoisomer by chiral SFC purification (column: REGIS (S ⁇ S) WHELK-Ol (250x25 mm, 10 um); mobile phase: 15% [0.1% NH3H2O in IP A]).
• LCMS [M+H] + 577.2 m/z.
• the mixture was warmed to RT and stirred for 2 h.
• the reaction mixture was treated with sat. aq. NaiSCb and adjusted the pH of the solution to 3 with 1 N HC1.
• the mixture was extracted with DCM, the combined organic layer was washed with water and brine, dried over NaiSCE, and concentrated under reduced pressure to give a residue.

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