Patent Application
20250154109
The application relates generally to sodium channel blocking compounds, derivatives thereof, and the use of such compounds as pharmacological agents.
Millions of people suffer from conditions associated with pain, itch, and/or cough. Pain can be a symptom or cause of conditions such as neuropathy, hyperalgesia, and opioid use disorders. In many cases, drugs used to treat such condition fail to provide relief or produce intolerable side effects. Therefore, existing treatments are inadequate for many patients who suffer from a variety of conditions.
The invention provides compounds that are useful for treatment of conditions associated with aberrant activity of voltage gated sodium channel Nav1.8, such as pain, itch, and cough.
In one aspect, the invention provides a compound of Formula (I):
In certain embodiments, R1 is selected from H and C1-C3 alkyl
In certain embodiments, R1 is H.
In certain embodiments, R2 is H.
In various embodiments, if the A ring is a heteroaryl, it contains one or more nitrogen atom in a ring. In certain embodiments, the A ring contains one nitrogen atom. In certain embodiments, such nitrogen atom may be in the form of an N-oxide, wherein the N-oxide is selected from a group consisting of pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide, pyridazinyl N-oxide. In certain embodiments, the A ring may include further substituents.
In various embodiments, ring C is optionally fused to at least one ring selected from the group consisting of: an optionally saturated carbocyclyl containing 5-6 ring members or an optionally saturated heterocyclyl containing 5-6 ring members and 1-4 optionally charged heteroatoms.
In certain embodiments, R2 is selected from H or formula (II):
In various embodiments, R2 is selected from a group consisting of: H, —C(═O)NH2, —C(═O)NHR′, —C(═O)NR′R″, —C(═O)OH, alkylamino, and —S(═O)R′.
In various embodiments, R2 is selected from H or Formula (II):
In certain embodiments, R2 is represented by Formula (II):
In certain embodiments, R2 is represented by Formula (II) (described above), wherein X1 is not O and/or X2 is not O.
In certain embodiments, R2 is represented by Formula (II) (described above), wherein X1 is not NH or NR′ and X2 is not NH or NR′.
In certain embodiments, ring A is an optionally substituted aryl.
In certain embodiments, ring A is an optionally substituted heteroaryl with one heteroatom.
In certain embodiments, ring A is an optionally substituted heteroaryl with two heteroatoms.
In certain embodiments, ring A is substituted with at least trifluoromethyl.
In certain embodiments, trifluoromethyl is the only substitution on ring A.
In certain embodiments, ring A is substituted with at least cyclopropylmethyl.
In certain embodiments, A is represented by the following Formula(s):
In certain embodiments, ring A is an optionally substituted five (5) or more membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from N, O, or S.
In certain embodiments, ring A is represented by the following Formula(s):
In certain embodiments, ring A is represented by the following Formula(s):
In certain embodiments, ring A is represented by the following Formula(s):
In certain embodiments, ring A is represented by the following Formula(s):
In certain embodiments, ring A is represented by the following Formula(s):
In certain embodiments, ring A is represented by the following Formula(s):
In certain embodiments, ring A is selected from the group consisting of
In certain embodiments, ring B is selected from the group consisting of pyrrolidine, azetidine, piperidine, piperazine, azepane, azocane, morpholine, thiomorpholine, oxazepane, isoindoline, dihydroisoquinoline, octahydroisoindole, azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane, azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]octane, diazabicyclo-[3.2.1]octane, azabicyclo[3.2.0]heptane, oxa-azabicyclo[3.2.1]octane, azaspiro[2.5]octane, azaspiro[2.6]nonane, azaspiro[3.5]nonane, oxa-azaspiro[3.5]nonane, oxa-azaspiro[4.5]decane, dihydrothieno[3,2-c]pyridine, dihydrothiazolo[4,5-c]pyridine, dihydrooxazolo[4,5-c]pyridine, dihydroimidazo[1,2-a]pyrazine, hexahydrofuro[3,2-b]pyrrole, hexahydrocyclopenta[c]pyrrole, and azatricyclo[4.3.1.13,8]undecane.
In certain embodiments, ring C is phenyl.
In certain embodiments, ring C is pyridyl.
In certain embodiments, in Formula (II), X1 and X2 are O.
In certain embodiments, in Formula (II), X1 is O and X2 is NH.
In certain embodiments, the compound of Formula (I) is further described as Formula (III):
In certain embodiments, substituted or unsubstituted B is selected from a group consisting of:
In certain embodiments, substituted or unsubstituted C is selected from a group consisting of:
In certain embodiments, R1 is H.
In certain embodiments, R2 is selected from a group consisting of: H,
In certain embodiments, R2 is selected from a group consisting of: H,
In certain embodiments, R2 is:
In certain embodiments, ring C comprises additional substitutions, i.e., substitutions in wherein the substitutions are selected from a group consisting of H, halo, and alkyl. In certain embodiments, the said halo substitution in ring C is F.
In certain embodiments, the one or more substitutions on the ring A ring are selected from a group consisting of: halo, cyano, haloalkyl, cyanoalkyl, substituted or unsubstituted C1-C6 alkyl, aryl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C3-C6 heteroaryl, and a combination thereof, wherein the heterocycloalkyl and heteroaryl comprise one or more hetero atoms selected from a group consisting of: N, O, or S.
In certain embodiments, the one or more substitutions on the ring A are selected from a group consisting of: methyl, trifluoromethyl, chloro, fluoro, bromo, C1-C6 alkyl, phenyl, cycloalkyl, methyl pyrazole, and fused 1,4-dioxane.
In certain embodiments, the one or more substitutions on the ring A are selected from a group consisting of: —CH3, —CF3, —Cl, —Br, —F, —CH2—CH2—CH═CH2, phenyl, —CH2—CN, —C(O)—NH2,
and any combination thereof.
In certain embodiments, the compound of Formula (I) is selected from the group consisting of:
In certain embodiments, the compound of the invention is selected from a group consisting of:
In certain embodiments, the compound of the invention is selected from a group consisting of:
In another aspect, the invention provides inhibitors of a voltage gated sodium channel Nav1.8. The inhibitors may have a defined chemical structure, such as the structure of any of the compounds described above.
In another aspect, the invention provides methods of treating a condition in a subject by providing to a subject having a condition a compound of the invention, such as any of those described above.
The condition may be associated with aberrant activity of voltage gated sodium channels.
The condition may be abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute itch, acute pain, acute pain in major trauma/injury, airways hyperreactivity, allergic dermatitis, allergies, ankylosing spondylitis, asthma, atopy, Behcets disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic itch, chronic low back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndromes, constant unilateral facial pain with additional attacks, contact dermatitis, cough, dental pain, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, distal sensory polyneuropathy (DSP) associated with highly active antiretroviral therapy (HAART), Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, Fabry disease, facet joint syndrome, failed back surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, inherited erythromelalgia, irritable bowel syndrome, irritable bowel syndrome, itch, juvenile idiopathic arthritis, mastocytosis, melorheostosis, migraine, multiple sclerosis, musculoskeletal damage, myofascial orofacial pain, neurodegeneration following ischemia, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, pachyonychia congenita, pain, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful joint arthroplasties, pancreatitis, Parkinson
disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, postoperative pain, post-stroke pain, post-surgical pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud
disease, renal colic, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, subacute cough, temporomandibular joint disorders, tension-type headache, trigeminal neuralgia, vascular leg ulcers, vulvodynia, or whiplash associated disorder. In another aspect, the invention provides methods of making a medicament using a compound of the invention, such as any of those described above.
In another aspect the invention provides products comprising a compound of the invention, such as any of those described above, for treatment of a condition, such as any of those described above, in a subject.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this presently described subject matter belongs. The definitions provided below are intended to supplement and illustrate, not preclude, the definitions that would be apparent to one of ordinary skill in the art upon review of the present disclosure.
Unless otherwise stated, the moieties described below are optionally substituted, i.e., they may be substituted at one or more positions. The terms substituted, whether preceded by the term “optionally” or not, and substituent, as used herein, refer to the ability to change one or more functional groups for another functional group or groups on a molecule, provided that the valency of all atoms is maintained. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. The substituents also may be further substituted (e.g., an aryl group substituent may have another substituent off it, such as another aryl group, which is further substituted at one or more positions).
When the term “independently selected” is used, the substituents being referred to (e.g., R groups, such as groups R1, R2, and the like, or variables, such as “m” and “n”), can be identical or different. For example, both R1 and R2 can be substituted alkyls, or R1 can be hydrogen and R2 can be a substituted alkyl, and the like.
The terms “a,” “an,” or “a(n),” when used in reference to a group of substituents herein, mean at least one. For example, where a compound is substituted with “an” alkyl or aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.
A named “R” or group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein. For the purposes of illustration, certain representative “R” groups as set forth above are defined below.
Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.
Unless otherwise explicitly defined, a “substituent group,” as used herein, includes a functional group selected from one or more of the following moieties, which are defined herein.
The term hydrocarbon, as used herein, refers to any chemical group comprising hydrogen and carbon. The hydrocarbon may be substituted or unsubstituted. As would be known to one skilled in the art, all valences must be satisfied in making any substitutions. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, ally 1, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, and the like.
The term “alkyl” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain, acyclic or cyclic saturated hydrocarbon group, or combination thereof, and can include di- and multivalent groups, having the number of carbon atoms designated (e.g., C1-C10 means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons). In particular embodiments, the term “alkyl” refers to C1-20 inclusive, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons, linear (i.e., “straight-chain”), branched, or cyclic saturated hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom.
Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologues and isomers thereof.
“Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl, or propyl, is attached to a linear alkyl chain. “Lower alkyl” refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. “Higher alkyl” refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
Alkyl groups can optionally be substituted (a “substituted alkyl”) with one or more alkyl group substituents, which can be the same or different. The term “alkyl group substituent” includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as “alkylaminoalkyl”), or aryl.
Thus, the term “substituted alkyl” includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto.
The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain having from 1 to 20 carbon atoms or heteroatoms or a cyclic hydrocarbon group having from 3 to 15 carbon atoms or heteroatoms, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom, such as O, N, P, Si or S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) 0, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, —CH2—CH2—O—CH3, —CH2—CH2—NH—CH3, —CH2—CH2—N(CH3)—CH3, —CH2—S—CH2—CH3, —CH2—CH2—S(O)—CH3, —CH2—CH2—S(O)2—CH3, —CH═CH—O—CH3, —Si(CH3)3, —CH2—CH═N—OCH3, —CH═CH—N(CH3)—CH3, O—CH3, —O—CH2—CH3, and —CN. Up to two or three heteroatoms may be consecutive, such as, for example, —CH2—NH—OCH3 and —CH2—O—Si(CH3)3.
As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as —C(O)NR′, —NR′R″, —OR′, —SR, —S(O)R, and/or —S(O2)R′.
“Cycloalkyl” refers to a saturated monocyclic or multicyclic ring system of from about 3 to about 15 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group also can be optionally substituted with an alkyl group substituent as defined herein, oxo, and/or alkylene. There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyeiohexenyl, cycloheptyl, and the like.
The term “cycloalkylalkyl,” as used herein, refers to a cycloalkyl group as defined above, which is attached to the parent molecular moiety through an alkylene moiety, also as defined above, e.g., a C1-20 alkylene moiety. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.
The term “carbocyclyl” refers to a monocyclic or multicyclic ring system of from about 3 to about 15 ring members in which all ring members are carbon atoms. Unless otherwise specified, a carbocyclyl may be saturated, partially saturated (i.e., have one or more double or triple bonds), or aromatic.
The term “heterocyclyl” refers to a monocyclic or multicyclic ring system of from about 3 to about 15 ring members in which at least one ring member is a heteroatom, such as N, O, or S.
Unless otherwise specified, a heterocyclyl may be saturated, partially saturated (i.e., have one or more double or triple bonds), or aromatic. Examples of saturated and partially unsaturated non-aromatic heterocyclic groups include, but are not limited to, 3-oxetanyl, 2-oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, dihydropyranyl, tetrahydropyranyl, thio-dihydropyranyl, thio-tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 4,5,6-tetrahydropyrimidinyl, 2,3-dihydrofuranyl, dihydrothienyl, dihydropyridinyl, tetrahydropyridinyl, isoxazolidinyl, pyrazolidinyl, tetrazolyl, imidazolyl, isothiozolyl, triazolyl, azabicyclo-octanyl, diazabicyclo-octanyl, and all alkyl, alkoxy, haloalkyl and haloalkoxy substituted derivatives of any of the aforementioned groups.
The terms “cycloheteroalkyl” and “heterocycloalkyl” refer to a saturated ring system, such as a 3- to 10-member cycloalkyl ring system, that include one or more heteroatoms. The heteroatoms may be the same or different and may be nitrogen (N), oxygen (O), or sulfur (S).
Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyi), 1-piperidmyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The cycloheteroalkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkyl rings and/or non-aromatic hydrocarbon rings. Heterocyclic rings include those having from one to three heteroatoms, such as oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Examples include, but are not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like.
An unsaturated hydrocarbon, carbocyclyl, or heterocyclyl has one or more double bonds or triple bonds. Examples of unsaturated hydrocarbons include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
The term “alkenyl” as used herein refers to a monovalent group derived from a C2-C20 inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen molecule. Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl.
The term “cycloalkenyl” as used herein refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.
The term “alkynyl” as used herein refers to a monovalent group derived from a straight or branched C2-C20 hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond. Examples of “alkynyl” include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl groups, and the like.
The term “alkylene” by itself or a part of another substituent refers to a straight or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group can be straight, branched, or cyclic. The alkylene group also can be optionally unsaturated and/or substituted with one or more “alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (—CH2—); ethylene (—CH2—CH2—); propylene (CH2)3, cyclohexylene (—C6H10—, —CH═CH—CH═CH—, —CH═CH—CH2—, —CH2CH2CH2CH2CH2—, —CH2CH2CH(CH2CH2CH3)CH2—, —(CH2)q-N(R)—(CH2)r-, wherein each of q and r is independently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxyl (—O—CH2—O—); and ethylenedioxyl (—O—(CH2)2—O—).
The term “heteroalkylene” by itself or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited by, —CH2—CH2—S—CH2—CH2— and —CH2—S—CH2—CH2—NH—CH2—. For heteroalkylene groups, heteroatoms also can occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O)OR′— represents both —C(O)OR′— and —R′OC(O)—.
The term “spirocyclyl” refers to a polycyclic compound in which two rings have a single atom, e.g., carbon, as the only common member of two rings. Thus, a “spirocycloalkyl” refers to a cycloalkyl group with two rings having a single carbon in common, and a “spiroheterocycloalkyl” or “spiroheterocycloalkyl” refers to a cycloheteroalkyl group with two rings having a single carbon or other atom, e.g., nitrogen, in common.
The term “aryl” means, unless otherwise stated, an aromatic hydrocarbon substituent that can be a single ring or multiple rings (such as from 1 to 3 rings), which are fused together or linked covalently.
The term “heteroaryl” refers to and groups (or rings) that contain from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyndyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzoihiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-qumolyl, and 6-quinolyl.
Substituents for each of above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms “arylene” and “heteroarylene” refer to the divalent forms of aryl and heteroaryl, respectively.
Where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g., “3 to 7 membered”), the term “member” refers to a carbon atom or heteroatom.
Each of the above terms is meant to include both substituted and unsubstituted forms of the indicated group. In some instances, the groups are explicitly defined as substituted, for example, “substituted aryl.” The optional substituents are provided below.
Substituents can be one or more of a variety of groups selected from, but not limited to: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″—SR′, -halogen, —SiR′R″R″, —OC(O)R, —C(O)R, —CO2R—C(O)NR′R″, —OC(O)NR′R″, —NR″C(O)R, —NR′—C(O)NR″R′, —NR″C(O)OR′, —NR—C(NR′R″)═NR″′, —S(O)R, —S(O)2R′, —S(O)2NR′R″, —NRSO2R′, —CN, CF3, fluorinated C1-C4 alkyl, and —NO2 in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such groups. R′, R″, R″′ and R″″ each may independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. Other non-limiting examples of substituents include (C1-C6)alkyl, (C2-C5)alkenyl, (C3-C5)alkynyl, halogen, halo(C1-C6)alkyl, hydroxy, —O(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C5)cycloalkyl, (C6-C10)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (C1-C6)alkyl-OH, (C1-C6)alkyl-O—(C1-C6)alkyl, (C1-C6)alkyl(C6-C10)aryl, —C(O)(C1-C6)alkyl, —C(O)NR′R″, —S(O)(C1-C6)alkyl, —S(O)NR′R″, —S(O)2(C1-C6)alkyl, —S(O)2NR′R″, —O(C1-C6)alkyl-S(O)(C1-C6)alkyl, —O(C1-C6)alkyl-S(O)NR′R″, —O(C1-C6)alkyl-S(O)2(C1-C6)alkyl, and —O(C1-C6)alkyl-S(0)2NR′R″. As used herein, an “alkoxy” group is an alkyl attached to the remainder of the molecule through a divalent oxygen.
When a compound of the disclosure includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R″′ and R″″ groups when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of ordinary skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e. g., —CF3 and —CH2CF3) and acyl (e.g., —C(O)CH3, —C(O)CF3, —C(O)CH2CH3, and the like).
Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)—(CRR′)q—U—, wherein T and U are independently —NR—, —O—, —CRR′— or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B—, wherein A and B are independently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)2—, —S(O)2NR′— or a single bond, and r is an integer of from 1 to 4.
One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —(CRR′)s-X′—(C″R″′)d-, where s and d are independently integers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)2—, or —S(O)2NR′—. The substituents R, R′, R″ and R″ may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
As used herein, the term “acyl” refers to an organic acid group wherein the —OH of the carboxyl group has been replaced with another substituent and has the general formula RC(═O)—, wherein R is an alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic, or aromatic heterocyclic group as defined herein). As such, the term “acyl” specifically includes aryl acyl groups, such as a 2-(furan-2-yl)acetyl)- and a 2-phenylacetyl group. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups also are intended to include amides, —RC(═O)NR, esters, —RC(═O)OR′, ketones, —RC(═O)R′, and aldehydes, —RC(═O)H.
The terms “alkoxyl” or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O—) or unsaturated (i.e., alkenyl-O— and alkynyl-O—) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include C1-C20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, and n-pentoxyl, neopentoxyl, n-hexoxyl, and the like.
The term “alkoxy alkyl” as used herein refers to an alkyl-O-alkyl ether, for example, a methoxy ethyl or an ethoxymethyl group.
“Aryloxyl” refers to an aryl-O— group wherein the aryl group is as previously described, including a substituted aryl. The term “aryloxyl” as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.
“Aralkyl” refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described and includes substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.
“Aralkyloxyl” refers to an aralkyl-O— group wherein the aralkyl group is as previously described. An exemplar) aralkyloxyl group is benzyloxyl, i.e., C6H5CH2—O—. An aralkyloxyl group can optionally be substituted.
“Alkoxycarbonyl” refers to an alkyl-O—C(═O)— group. Exemplary alkoxy carbonyl groups include methoxycarbonyl, ethoxy carbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl.
“Aryloxycarbonyl” refers to an aryl-O—C(═O)— group. Exemplary aryloxy carbonyl groups include phenoxy- and naphthoxy-carbonyl.
“Aralkoxycarbonyl” refers to an aralkyl —O—C(═O)— group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
“Carbamoyl” refers to an amide group of the formula —C(═O)NH2.
“Alkylcarbamoyl” refers to a R′RN—C(═O) group wherein one of R and R′ is hydrogen and the other of R and R′ is alkyl and/or substituted alkyl as previously described. “Dialkylcarbamoyl” refers to a R′RN—C(═O)— group wherein each of R and R′ is independently alkyl and/or substituted alkyl as previously described.
The term “carbonyldioxyl,” as used herein, refers to a carbonate group of the formula —OC(═O)—OR.
“Acyloxyl” refers to an acyl-O— group wherein acyl is as previously described.
The term “amino” refers to the —NH2 group and refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic groups. For example, the terms “acyl amino” and “alkylamino” refer to specific N-substituted organic groups with acyl and alkyl substituent groups respectively.
An “aminoalkyl” as used herein refers to an amino group covalently bound to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure —NHR′ wherein R′ is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure —NR′R″, wherein R′ and R″ are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure —NR′R″R″′, wherein R′, R″, and R″′ are each independently selected from the group consisting of alkyl groups. Additionally, R′, R″, and/or R″′ taken together may optionally be —(CH2)k where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropyl amino, piperidino, trimethylamino, and propylamine.
The amino group is —NR′R″, wherein R′ and R″ are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
The terms alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S—) or unsaturated (i.e., alkenyl-S— and alkynyl-S—) group attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
“Acylamino” refers to an acyl-NH— group wherein acyl is as previously described. “Aroylamino” refers to an aroyl-NH— group wherein aroyl is as previously described.
The term “carbonyl” refers to the —C(═O)— group, and can include an aldehyde group represented by the general formula R—C(═O)H.
The term “carboxyl” refers to the COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety.
The term “cyano” refers to the —CN group.
The terms “halo,” “halide,” and “halogen” refer to fluoro, chloro, bromo, and iodo groups.
The term “haloalkyl” refers to an alkyl group substituted with one or more halogens.
Additionally, the term “haloalkyl,” includes monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-4)alkyl” includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
The terms “halocycloalky” and “cyclohaloalkyl” refer to a cycloalkly group with one or more halogens.
The term “hydroxyl” refers to the —OH group.
The term “hydroxy alkyl” refers to an alkyl group substituted with an —OH group.
The term “mercapto” refers to the —SH group.
The term “oxo” refers to an oxygen atom that is double bonded to a carbon atom or to another element.
The term “nitro” refers to the —NO2 group.
The term “thio” refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom.
The term “sulfate” refers to the —SO4 group.
The term thiohydroxyl or thiol, as used herein, refers to a group of the formula —SH.
More particularly, the term “sulfide” refers to compound having a group of the formula —SR.
The term “sulfone” refers to compound having a sulfonyl group —S(O2)R′.
The term “sulfoxide” refers to a compound having a sulfinyl group —S(O)R
The term ureido refers to a urea group of the formula —NH—CO—NH2.
Throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, congeners, and optical- and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.
Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined, m terms of absolute stereochemistry, as (R)- or (S)- or, as D- or L- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and/or isolate. The present disclosure is meant to include compounds in racemic, scalemic, and optically pure forms. Optically active (R)- and (S)-, or D- and L-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefenic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium, and which are readily converted from one isomeric form to another.
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, compounds having the present structures with the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this disclosure.
The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example, tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
The compounds of the present disclosure may exist as salts, and particularly as pharmaceutically acceptable salts. The present disclosure includes such salts. Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (−)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in art. Also included are base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or m a suitable inert solvent or by ion exchange. Examples of acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
In addition to salt forms, the present disclosure provides compounds that are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
The term “protecting group” refers to chemical moieties that block some or all reactive moieties of a compound and prevent such moieties from participating in chemical reactions until the protective group is removed, for example, those moieties listed and described in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley & Sons (1999). It may be advantageous, where different protecting groups are employed, that each (different) protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions allow differential removal of such protecting groups.
For example, protective groups can be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as tert-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co existing amino groups may be blocked with fluoride labile silyl carbamates.
Allyl blocking groups are useful in the presence of acid- and base-protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a palladium(O)-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
The invention provides compounds that modulate, e.g., inhibit, the activity of voltage gated sodium channels. In certain embodiments, the compound has the structure of Formula (I):
In certain embodiments, R1 is selected from H and C1-C3 alkyl
In certain embodiments, R1 is H.
In certain embodiments, R2 is H.
In various embodiments, if the A ring is a heteroaryl, it contains one or more nitrogen atom in a ring. In certain embodiments, the A ring contains one nitrogen atom. In certain embodiments, such nitrogen atom may be in the form of an N-oxide, wherein the N-oxide is selected from a group consisting of pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide, pyridazinyl N-oxide. In certain embodiments, the A ring may include further substituents.
In various embodiments, ring C is optionally fused to at least one selected from the group consisting of: an optionally saturated carbocyclyl containing 5-6 ring members or an optionally saturated heterocyclyl containing 5-6 ring members and 1-4 optionally charged heteroatoms.
In certain embodiments, R2 is selected from H or formula (II):
In various embodiments, R2 is selected from a group consisting of: H, —C(═O)NH2, —C(═O)NHR′, —C(═O)NR′R″, —C(═O)OH, alkylamino, and —S(═O)R′.
In various embodiments, R2 is selected from H or Formula (II):
In certain embodiments, R2 is represented by Formula (II):
In certain embodiments, R2 is represented by Formula (II) (described above), wherein X1 is not O and/or X2 is not O.
In certain embodiments, R2 is represented by Formula (II) (described above), wherein X1 is not NH or NR′ and X2 is not NH or NR′. In certain embodiments, ring A is an optionally substituted aryl.
In certain embodiments, ring A is an optionally substituted heteroaryl with one heteroatom.
In certain embodiments, ring A is an optionally substituted heteroaryl with two heteroatoms.
In certain embodiments, ring A is substituted with at least triflouoromethyl. In certain embodiments, trifluoromethyl is the only substitution on ring A.
In certain embodiments, ring A is substituted with at least cyclopropylmethyl.
In certain embodiments, A is represented by the following Formula(s):
In certain embodiments, ring A is an optionally substituted five (5) or more membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from N, O, or S.
In certain embodiments, ring A is represented by the following Formula(s):
In certain embodiments, ring A is represented by the following Formula(s):
In certain embodiments, ring A is represented by the following Formula(s):
In certain embodiments, ring A is represented by the following Formula(s):
In certain embodiments, ring A is represented by the following Formula(s):
In certain embodiments, ring A is represented by the following formula(s):
In certain embodiments, ring A is selected from the group consisting of:
In certain embodiments, ring B is selected from the group consisting of pyrrolidine, azetidine, piperidine, piperazine, azepane, azocane, morpholine, thiomorpholine, oxazepane, isoindoline, dihydroisoquinoline, octahydroisoindole, azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane, azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]octane, diazabicyclo-[3.2.1]octane, azabicyclo[3.2.0]heptane, oxa-azabicyclo[3.2.1]octane, azaspiro[2.5]octane, azaspiro[2.6]nonane, azaspiro[3.5]nonane, oxa-azaspiro[3.5]nonane, oxa-azaspiro[4.5]decane, dihydrothieno[3,2-c]pyridine, dihydrothiazolo[4,5-c]pyridine, dihydrooxazolo[4,5-c]pyridine, dihydroimidazo[1,2-a]pyrazine, hexahydrofuro [3,2-b]pyrrole, hexahydrocyclopenta[c]pyrrole, and azatricyclo[4.3.1.13,8]undecane.
In certain embodiments, ring C is phenyl.
In certain embodiments, ring C is pyridyl.
In certain embodiments, in Formula (II), X1 and X2 are O.
In certain embodiments, in Formula (II), X1 is O and X2 is NH.
In certain embodiments, the compound of Formula (I) is further described as Formula (III):
In certain embodiments, substituted or unsubstituted B is selected from a group consisting of:
In certain embodiments, substituted or unsubstituted C is selected from a group consisting of:
In certain embodiments, R1 is H.
In certain embodiments, R2 is selected from a group consisting of: H,
In certain embodiments, R2 is selected from a group consisting of H,
In certain embodiments, R2 is:
In certain embodiments, ring C comprises additional substitutions, i.e., substitutions in wherein the substitutions are selected from a group consisting of H, halo, and alkyl. In certain embodiments, the said halo substitution in ring C is F.
In certain embodiments, the one or more substitutions on the ring A ring are selected from a group consisting of: halo, cyano, haloalkyl, cyanoalkyl, substituted or unsubstituted C1-C6 alkyl, aryl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C3-C6 heteroaryl, and a combination thereof, wherein the heterocycloalkyl and heteroaryl comprise one or more hetero atoms selected from a group consisting of: N, O, or S.
In certain embodiments, the one or more substitutions on the ring A are selected from a group consisting of: methyl, trifluoromethyl, chloro, fluoro, bromo, C1-C6 alkyl, phenyl, cycloalkyl, methyl pyrazole, fused 1,4 dioxane, and methylcyano.
In certain embodiments, the one or more substitutions on the ring A are selected from a group consisting of: —CH3, —CF3, —Cl, —Br, —F, —CH2—CH2—CH═CH2, phenyl, —CH2—CN, —C(═O)—NH2,
and any combination thereof.
In another aspect, the invention provides inhibitors of a voltage gated sodium channel Nav1.8. The inhibitors may have a defined chemical structure, such as the structure of any of the compounds described above.
In another aspect, the invention provides methods of treating a condition in a subject by providing to a subject having a condition a compound of the invention, such as any of those described above.
In another aspect the invention provides products comprising a compound of the invention, such as any of those described above, for treatment of a condition, such as any of those described above, in a subject.
In certain embodiments, the compound of Formula (I) is selected from the group consisting of:
In certain embodiments, the compound of the invention is selected from a group consisting of:
In certain embodiments, the compound of the invention is selected from a group consisting of:
The invention provides pharmaceutical compositions containing compounds of the inventions, such as those described above. The pharmaceutical composition may be in a form suitable for oral use, for example, as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, and preserving agents, to provide pharmaceutically elegant and palatable preparations. Tablets contain the compounds in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated, or they may be coated by known techniques to delay disintegration in the stomach and absorption lower down in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874, the contents of which are incorporated herein by reference, to form osmotic therapeutic tablets for control release. Preparation and administration of compounds is discussed in U.S. Pat. No. 6,214,841 and U.S. Pub. No. 2003/0232877, the contents of which are incorporated herein by reference.
Formulations for oral use may also be presented as hard gelatin capsules in which the compounds are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the compounds are mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
An alternative oral formulation, where control of gastrointestinal tract hydrolysis of the compound is sought, can be achieved using a controlled-release formulation, where a compound of the invention is encapsulated in an enteric coating.
Aqueous suspensions may contain the compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the compounds in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compounds in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring, and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, and agents for flavoring and/or coloring. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
In certain embodiments, the formulation is a sustained release formulation. In certain embodiments, the formulation is not a sustained release formulation. In certain embodiments, the formulation is not injectable. In certain embodiments, the formulation does not contain particles having a D50 (volume weighted median diameter) of less than 10 microns. In certain embodiments, the formulation does not contain a polymer surface stabilizer. In certain embodiments, the formulation is not an aqueous suspension.
The composition may be formulated for administration by a particular mechanism. The composition may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical, nasal, or pulmonary administration. The composition may be formulated for administration by injection or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).
The composition may be formulated a single daily dosage. The composition may be formulated for multiple daily dosages, e.g., two, three, four, five, six or more daily dosages.
The invention provides methods of treating a condition in a subject using compounds of the invention. The methods are useful for treating any condition associated with aberrant, e.g., increased, activity of voltage gated sodium channel Nav1.8. Conditions associated with increased activity at voltage gated sodium channels and the use of inhibitors to treat such conditions is known in the art and described in, for example, International Patent Publication Nos. WO 2020/014243, WO 2020/014246, WO 2020/092187, the contents of each of which are incorporated herein by reference.
For example and without limitation, the condition may be abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute itch, acute pain, acute pain in major trauma/injury, airways hyperreactivity, allergic dermatitis, allergies, ankylosing spondylitis, asthma, atopy, Behcet disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic itch, chronic low back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndromes, constant unilateral facial pain with additional attacks, contact dermatitis, cough, dental pain, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, distal sensory polyneuropathy (DSP) associated with highly active antiretroviral therapy (HAART), Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, Fabry
disease, facet joint syndrome, failed back surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, inherited erythromelalgia, irritable bowel syndrome, irritable bowel syndrome, itch, juvenile idiopathic arthritis, mastocytosis, melorheostosis, migraine, multiple sclerosis, musculoskeletal damage, myofascial orofacial pain, neurodegeneration following ischemia, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, pachyonychia congenita, pain, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful joint arthroplasties, pancreatitis, Parkinson
disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, postoperative pain, post-stroke pain, post-surgical pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud
disease, renal colic, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, subacute cough, temporomandibular joint disorders, tension-type headache, trigeminal neuralgia, vascular leg ulcers, vulvodynia, or whiplash associated disorder.
Methods of treating a condition in a subject may include providing a composition of the invention to a subject. The composition may be provided to a subject by any suitable route or mode of administration. For example and without limitation, the composition may be provided buccally, dermally, enterally, intraarterially, intramuscularly, intraocularly, intravenously, nasally, orally, parenterally, pulmonarily, rectally, subcutaneously, topically, transdermally, by injection, or with or on an implantable medical device.
The composition may be provided according to a dosing regimen. A dosing regimen may include one or more of a dosage, a dosing frequency, and a duration.
Doses may be provided at any suitable interval. For example and without limitation, doses may be provided once per day, twice per day, three times per day, four times per day, five times per day, six times per day, eight times per day, once every 48 hours, once every 36 hours, once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 4 hours, once every 3 hours, once every two days, once every three days, once every four days, once every five days, once every week, twice per week, three times per week, four times per week, or five times per week.
The dose may be provided in a single dosage, i.e., the dose may be provided as a single tablet, capsule, pill, etc. Alternatively, the dose may be provided in a divided dosage, i.e., the dose may be provided as multiple tablets, capsules, pills, etc.
The dosing may continue for a defined period. For example and without limitation, doses may be provided for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months or more.
Methods of making the compounds of the present invention, and intermediates used in their synthesis, are provided in the General Synthetic Schemes and Specific Syntheses Procedures below. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Otherwise, their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide. “dry” glassware means oven/desiccator dried. Solvents were ACS grade unless otherwise noted.
All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry nitrogen or dry argon and were stirred magnetically unless otherwise indicated. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Yields are not optimized. The chemical names were generated using the ChemDraw Professional 19.1, available from PerkinElmer or chemAxon.
Reactions were monitored by thin layer chromatography (TLC) using 0.25 mm silica gel 60 F254 plates purchased from EMD MILLIPORE™. Purification was performed with Biotage Isolera One Flash Chromatography Instrument or purified using one of the preparative HPLC methods mentioned below.
Equipment: Shimadzu LCMS 2020 mass-directed preparative HPLC System; column: Gemini 5 um C18 column, 150*21.2 mm; General gradient: 30% to 90% MeCN/H2O containing 0.1% HCOOH, gradient may be slight adjusted for specific compound; Flow rate: 20 mL/min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm;
Equipment: Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um C18 column, 150*21.2 mm; General gradient: 30% to 90% MeCN/H2O containing 0.1% TFA, gradient may be slight adjusted for specific compound; Flow rate: 20 mL/min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm.
Equipment: Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um C18 column, 150×21.2 mm; General gradient: 30% to 90% MeCN/H2O containing 0.05% ammonia, gradient may be slight adjusted for specific compound; Flow rate: 20 mL/min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm. Analytical LCMC were collected using one of following methods—
Equipment: Shimadzu LCMS 2020 Mass Spectrometer; Column: HALO C18 2.7 μm, 3.0 mm×30 mm; Mobile Phase: MeCN (0.05% HCOOH)-Water (0.05% HCOOH); Gradient: MeCN from 5% to 95% over 1.4 min, hold 0.6 min, total run time is 2.5 min; Flow rate: 1.8 mL/min; Column temperature: 50° C.; Wavelength: 214 and 254 nm PDA.
Equipment: Shimadzu LCMS 2020 Mass Spectrometer; XBridge BEH C18 2.5 μm, 3.0 mm×30 mm Mobile Phase: MeCN-Water (0.1% NH4OH); Gradient: MeCN from 5% to 95% over 1.8 min, hold 0.7 min, total run time is 3.0 min; Flow rate: 1.0 mL/min; Column temperature: 50° C.; Wavelength: 214 and 254 nm PDA.
Equipment: Shimadzu LCMS 2020 Mass Spectrometer; Column: HALO C18 2.7 μm, 3.0 mm×30 mm Mobile Phase: MeCN (0.05% TFA)-Water (0.05% TFA); Gradient: MeCN from 5% to 95% over 1.4 min, hold 0.6 min, total run time is 2.5 min; Flow rate: 1.8 mL/min; Column temperature: 50° C.; Wavelength: 214 and 254 nm PDA.
Column: Daicel chiralpak-AS-H 5 μm 250×20 mm; Mobile Phase: CO2/MeOH [0.1% NH3 (7M in MeOH)], CO02/MeOH ratio varies for different compounds; Oven temperature: 40° C.; Flow rate: 38 mL/min.
Column: Daicel chiralpak-OJ-H 5 μm 250*20 mm; Mobile Phase: CO2/MeOH (0.1% HCOOH), CO02/MeOH ratio varies for different compounds; Oven temperature: 40° C.; Flow rate: 38 mL/min.
Column: Daicel chiralpak-OD-H 5 μm 250×20 mm; Mobile Phase: CO02/MeOH, ratio varies for different compounds; Oven temperature: 40° C.; Flow rate: 38 mL/min.
Column: Daicel chiralpak-AD-H 5 μm 250×20 mm; Mobile Phase: CO02/i-PrOH, ratio varies for different compounds; Oven temperature: 40° C.; Flow rate: 38 mL/min.
Column: Daicel chiralpak-IC 5 μm 250×20 mm; Mobile Phase: CO02/EtOH, ratio varies for different compounds; Oven temperature: 40° C.; Flow rate: 38 mL/min.
Unless otherwise stated, 1H nuclear magnetic resonance spectroscopy (NMR) spectra were recorded on a Bruker AVANCE NEO 400 MHz Digital NMR Spectrometer. Chemical shifts, 6, are quoted in parts per million (ppm) relative to TMS and calibrated using residual un-deuterated solvent as an internal reference. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz.
When the following abbreviations are used herein, they have the following meaning:
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. The present invention further provides processes for the preparation of compounds of structural Formula I as defined above. In some cases, the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for the purpose of illustration only and are not to be construed as limitations on the disclosed invention.
As illustrated in Scheme A, in general, compounds of the invention can be prepared by reacting substituted cyclic amines (B) using base such as DIEA or inorganic base such as K2CO3 or Cs2CO3 to afford intermediate A-2. Intermediate A-2 can be converted to corresponding acid A-3 by treating A-2 with base such as KOH in aqueous EtOH or MeOH. Intermediates A-4, A-5 and A-7 can be formed either by treating A-3 and amine C, utilizing amide coupling conditions or by activation of appropriately functionalized carboxylic acid A-3 with (COCl)2 or POCl3 and with amine C base such as DIEA or pyridine in DCM. Intermediate A-4 can be prepared directly by treating A-2 and amine C in presence of Me3Al and toluene as a solvent. The compounds of formula A-4 and A-5 are independently treated with ammonium carbonate and PIDA in methanol to deliver compound of formula A-6. The compounds of formula A-6 can also be formed from intermediate A-7 by removing a protecting group, such as Boc under acidic conditions.
As illustrated in Scheme B, in general, compounds of the invention can be prepared by activation of appropriately functionalized carboxylic acid A-3 in dioxane with either (COCl)2 or SOCl2 followed by addition of NH4OH to afford B-1. Intermediate B-1 can then be brought together with materials of variously substituted Br compounds, utilizing Xantphos-Pd-G2 mediated coupling conditions to deliver intermediate A-4 and A-7. The compounds of formula A-4 treated with ammonium carbonate and PIDA in methanol to deliver compound of formula A-6. The compounds of formula A-6 can also be formed from intermediate A-7 by removing a protecting group, such as Boc under acidic conditions.
As further illustrated in Scheme C, in general, compounds of the invention can be prepared by derivatization of compounds of formula A-6 with R3 or R′ substituents. Acylation of A-6 with an activated acid such as an acid chloride and TEA followed by removal of any protecting groups would provide compounds of formula A-8 or A-9. When A-8 or A-9 are an N-acylated sulfoximine, the carbonyl group may be reduced with borane to a methylene group (CH2) to provide the corresponding N-alkyl derivative. Alternatively, N-alkyl derivatives may be obtained by alkylation with an alkyl halide such as, but not limited to, methyl iodide and a base such as diisopropylethylamineor Pd mediated coupling of A-6 with alkyl boronic acids.
Step 1. methyl 3-(azepan-1-yl)-6-chloropyridazine-4-carboxylate: To a solution of methyl 3,6-dichloropyridazine-4-carboxylate (2.50 g, 12.1 mmol) was in dioxane (20 mL) was added azepane (1.26 g, 12.7 mmol) followed by DIEA (4.21 mL, 24.2 mmol) at rt. The mixture was stirred at rt for further 3 h, at the end of this period solvent was evaporated and the crude was chromatographed over SiO2 with a gradient of 0-25% EtOAc in DCM to provide methyl 3-(azepan-1-yl)-6-chloropyridazine-4-carboxylate (2.86 g, 87.8%). 1H NMR (300 MHz, CDCl3) δ 7.40 (s, 1H), 4.03 (s, 1H), 3.92 (s, 3H), 3.58-3.48 (m, 5H), 1.86 (qd, J=6.2, 5.4, 2.4 Hz, 5H), 1.60-1.47 (m, 5H)
Step 2. methyl 3-(azepan-1-yl)-6-iodopyridazine-4-carboxylate: A mixture of methyl 3-(azepan-1-yl)-6-chloropyridazine-4-carboxylate (3.26 g, 12.1 mmol) and HI (25 mL, 57% v/v) was stirred 50 to 55° C. overnight, cooled to rt and the solid separated was filtered and washed with water (2×20 mL). The filtered cake was dissolved in EtOAc, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure to give methyl 3-(azepan-1-yl)-6-iodopyridazine-4-carboxylate (2.16 g, 49.52%). LCMS: m/z 362.1[M+H]+
Step 3. methyl 3-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate: To a mixture of methyl 3-(azepan-1-yl)-6-iodopyridazine-4-carboxylate (2.16 g, 5.98 mmol) in HMPA (25 mL), CuI (1.62 g, 8.49 mmol) was added tetrabutylammoniumiodide (1.10 g, 2.99 mmol) under nitrogen, the reaction mixture was degassed for 5 min to the above mixture methyl 2,2-difluoro-2-(fluorosulfonyl) acetate(7.61 mL, 59.8 mmol) was added slowly and stirred at 90° C. for 1.5 h. The mixture was filtered and washed with EtOAc (3×100 mL), to the filtrate water (50 mL) was added and extracted with EtOAc (3×120 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was evaporated, and the residue was chromatographed over SiO2 eluting with a gradient of 0-20% EtOAc in Hexanes to afford methyl 3-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (0.667 g, 37%). LCMS: m/z 304.1[M+H]+
Step 4: 3-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a solution of methyl 3-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate in a mixture of MeOH:THF:H2O (1:2:1, v/v) 20 mL was added LiOH·H2O at rt. Then the mixture was stirred at 50° C. for 2 h, at the end of this period reaction mixture was cooled to rt and the solvent was evaporated. The solid material was suspended in water (10 mL) and pH was adjusted to 3 using 1N HCl solution. The mixture was extracted with EtOAc (3×50 mL), combined EtOAc was washed with brine (30 mL) and dried over Na2SO4, filtered and solvent evaporated to give 3-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.489 g, 77%). 1HNMR (300 MHz, DMSO-d6) δ 7.86 (s, 1H), 3.63 (t, J=5.6 Hz, 4H), 1.90-1.71 (m, 4H), 1.60-1.36 (m, 4H)
Step 5. 3-(azepan-1-yl)-N-[3-(methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide: To a mixture of 3-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.100 g, 0.346 mmol), 3-(methylsulfanyl)aniline (0.0529 g, 0.380 mmol) and HATU (0.263 g, 0.691 mmol) in DMF(3 mL) was added DIEA (0.151 mL, 0.864 mmol) at rt and stirring continued further for 6 h. At the end of this period water(5 mL) was added ands extracted with EtOAc (2×25 mL), combined EtOAc layer was washed with 1M LiCl (20 mL) followed by brine(20 mL) and dried over Na2SO4, filtered and solvent evaporated under reduced pressure. The crude product was chromatographed over SiO2 with a gradient of EtOAc in DCM to provide 3-(azepan-1-yl)-N-[3-(methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.128 g, 90%). LCMS: m/z 411.4[M+H]+
Step 6. 3-(azepan-1-yl)-N-{3-[imino(methyl)oxo-λ6-sulfanyl]phenyl}-6-(trifluoromethyl)pyridazine-4-carboxamide: To a solution of 3-(azepan-1-yl)-N-[3-(methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.110 g, 0.268 mmol) in MeOH (5 mL) was added (NH4)2CO3 (0.0386 g, 0.402 mmol) and PIDA (0.199 g, 0.616 mmol) at rt. The mixture was stirred for 2 h at rt. The solvent was evaporated to dryness and the crude was chromatographed over SiO2 with a gradient of 0-15 MeOH in DCM to provide 3-(azepan-1-yl)-N-{3-[imino(methyl)oxo-λ6-sulfanyl]phenyl}-6-(trifluoromethyl)pyridazine-4-carboxamide (15.4 g, 13%). 1H NMR (300 MHz, CDCl3) δ 8.83 (s, 1H), 8.22-8.02 (m, 2H), 7.81 (dt, J=8.0, 1.2 Hz, 1H), 7.70 (s, 1H), 7.60 (t, J=8.0 Hz, 1H), 3.68 (t, J=5.7 Hz, 4H), 3.12 (s, 3H), 1.85 (s, 4H), 1.54(bs, 4H). LC-MS: m/z 442.5[M+H]+
Step 1: 3-(azepan-1-yl)-N-[2-(methylsulfanyl)pyridin-4-yl]-6-(trifluoromethyl)pyridazine-4-carboxamide: To a mixture of 3-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.100 g, 0.346 mmol), HATU(0.263 g, 0.691 mmol) and 2-(methylsulfanyl)pyridin-4-amine (0.0485 g, 0.346 mmol) in DMF(3 mL) was added DIEA(0.151 ml, 0.864 mmol) at rt. The mixture was stirred at rt for 16 h. At the end of this period water (5 mL) was added and extracted with EtOAc (2×25 mL), EtOAc layers were combined and washed with 1M LiCi (10 mL) followed by brine and dried (Na2SO4) filtered and the solvent evaporated to give crude product. The crude was chromatographed over SiO2 with a gradient of 0-20% EtOAc in DCM to provide 3-(azepan-1-yl)-N-[2-(methylsulfanyl)pyridin-4-yl]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.030 g, 21%). LC-MS: m/z 412.2[M+H]+
Step 2: 3-(azepan-1-yl)-N-{2-[imino(methyl)oxo-λ6-sulfanyl]pyridin-4-yl}-6-(trifluoromethyl)pyridazine-4-carboxamide: To a solution of 3-(azepan-1-yl)-N-[2-(methylsulfanyl)pyridin-4-yl]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.026 g, 0.0632 mmol) in MeOH (5 mL) was added (NH4)4CO3(0.0911 g, 0.0948 mmol) and PIDA (0.0468 g, 0.145 mmol) at rt. The mixture was stirred for 2 h at rt. The solvent was evaporated to dryness and the crude was chromatographed over SiO2 with a gradient of 0-15 MeOH in DCM to provide 3-(azepan-1-yl)-N-{2-[imino(methyl)oxo-λ6-sulfanyl]pyridin-4-yl}-6-(trifluoromethyl)pyridazine-4-carboxamide (0.121 g, 43.3%) 1H NMR (300 MHz, CDCl3) δ 9.61 (s, 1H), 8.65 (d, J=5.5 Hz, 1H), 8.20 (dd, J=5.5, 2.0 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.74 (s, 1H), 3.63 (q, J=4.8, 4.3 Hz, 4H), 3.26 (s, 3H), 1.85 (bs, 4H), 1.54(bs, 4H). LC-MS: m/z 443.5[M+H]+
Step 1: 1-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane: A mixture of 2,6-dichloro-3-(trifluoromethyl)pyridine (1.0 g, 4.6 mmol), 4,4-difluoroazepane hydrochloride (0.95 g, 5.5 mmol) and DIEA (1.19 g, 9.2 mmol) in dioxane (20 mL) was heated at 80° C. for 5 hours. Then the mixture was concentrated and residue was purified by flash column chromatography on silica gel (PE/EtOAc=5/1) to give 1-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane (900 mg, 62.5%). LCMS (ESI) calcd. for C12H13ClF5N2 [M+H]+ m/z 315.07, found 315.05.
Step 2: 4,4-difluoro-1-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)azepane: A mixture of 1-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane (850 mg, 2.7 mmol), trimethylboroxine (3.39 g, 27 mmol), Pd(dppf)Cl2 (98.73 mg, 0.135 mmol) and K2CO3 (1.12 g, 8.1 mmol) in dioxane/H2O (4/1, 25 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After cooling to ambient temperature, the mixture was filtered through celite, and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=5/1) to give the 4,4-difluoro-1-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)azepane (800 mg, 91%). LCMS (ESI) calcd. for C13H16F5N2 [M+H]+ m/z 295.13, found 295.00.
Step 3: 1-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane: To a solution of 4,4-difluoro-1-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)azepane (700 mg, 2.38 mmol) in DCM (15 mL) was added NBS (508 mg, 2.85 mmol). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated and directly purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give the 1-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane (650 mg, 65.9%). LCMS (ESI) calcd. for C13H15BrF5N2 [M+H]+ m/z 373.04, found 372.95.
Step 4: Ethyl 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinate: A mixture of 1-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane (600 mg, 1.6 mmol), Pd(dppf)Cl2 (58.5 mg, 0.08 mmol) and triethylamine (485 mg, 4.8 mmol) in EtOH (10 mL) was heated at 110° C. under an atmosphere of CO (30 atm) for 16 hours in a high-pressure reactor. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give ethyl 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinate (550 mg, 94%). LCMS (ESI) calcd. for C16H20F5N2O2 [M+H]+ m/z 367.15, found 367.00.
Step 5: 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid: To a solution of ethyl 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinate (550 mg, 1.5 mmol) in MeOH/H2O (1/1, 20 mL) was added KOH (0.84 g, 15 mmol) at room temperature. The mixture was heated at 70° C. for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH=3-4 with 1 N HCl and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (420 mg, 83%). LCMS (ESI) calcd. for C14H16F5N2O2 [M+H]+ m/z 339.12, found 338.95.
Step 6: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (120 mg, 0.35 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate Int-3 (115 mg, 0.43 mmol) in pyridine (6 mL) was added POCl3 (0.3 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The mixture was quenched with water (60 mL) and extracted with EtOAc (40 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/2) to provide tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (57 mg, 24.4% o) as a yellow oil. LCMS (ESI) calcd. for C26H32F5N4O4S [M+H]+ m/z 591.21, found 591.10.
Step 7: 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: To a solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (57 mg, 0.10 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The final mixture was concentrated in vacuum and purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 50% to 80% MeCN/H2O containing 0.1% formic acid) to afford 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl) nicotinamide (11.3 mg, 23.2%) as a white solid. LCMS (ESI) calcd. for C21H24F5N4O2S [M+H]+ m/z 491.15, found 491.05. 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.31 (s, 1H), 8.04-7.85 (m, 2H), 7.67 (d, J=7.8 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 3.71 (s, 2H), 3.59-3.33 (m, 5H), 3.13 (s, 3H), 2.40-2.67 (m, 2H), 2.03-1.83 (m, 4H).
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (250 mg, 0.740 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)λ6-sulfaneylidene)carbamate (220 mg, 0.814 mmol) in pyridine (4 mL) was added POCl3 (375 L) dropwise at 50° C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 27.5%) as a yellow oil. LCMS (ESI) calcd. for C26H32F5N4O4S [M+H]+ m/z 591.21, found 591.15.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.200 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the filtrate was diluted with water (5 mL) and extracted with DCM (5 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to obtain (R)-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (55 mg, 56.12%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.29 (s, 1H), 7.94-7.82 (m, 2H), 7.65 (d, J=8 Hz, 1H), 7.59-7.55 (m, 1H), 4.20 (s, 1H), 3.49-3.47 (m, 2H), 3.33-3.31 (m, 2H), 3.05 (s, 3H), 2.33 (s, 3H), 1.96-1.92 (m, 2H), 1.89-1.86 (m, 4H). LCMS (ESI) calcd. for C21H24F5N4O2S [M+H]+ m/z 491.16, found 490.95.
Step 1: tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (250 mg, 0.644 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (208.76 mg, 0.773 mmol) in pyridine (4 mL) was added POCl3 (500 L) dropwise at 50° C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (130 mg, 34.21%) as a white oil. LCMS (ESI) calcd. for C26H32F5N4O4S [M+H]+ m/z 591.21, found 591.40.
Step 2: (S)-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: A solution of tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (130 mg, 0.22 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to obtain (S)-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (62 mg, 57.51%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.29 (s, 1H), 7.95 (d, J=10.5 Hz, 2H), 7.70-7.52 (m, 2H), 4.27 (bs, 1H), 3.71 (s, 2H), 3.47 (t, J=5.5 Hz, 2H), 3.07 (s, 3H), 2.52 (s, 3H), 2.33 (s, 2H), 2.04-1.81 (m, 4H). LCMS (ESI) calcd. for C21H24F5N4O2S [M+H]+ m/z 491.16, found 491.20.
Step 1: methyl 6-chloro-3-(4,4-difluoroazepan-1-yl)pyridazine-4-carboxylate: To a solution of methyl 3,6-dichloropyridazine-4-carboxylate (2 g, 9.7 mmol) and 4,4-difluoroazepane hydrochloride (2.0 g, 11.6 mmol) in 1,4-dioxane (30 mL) was added DIEA (3.75 g, 29.1 mmol). The mixture was heated at 80° C. for 4 hours. LCMS showed the reaction was completed. The mixture was concentrated and purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give the methyl 6-chloro-3-(4,4-difluoroazepan-1-yl)pyridazine-4-carboxylate (1.6 g, 54.1%) as a yellow solid. LCMS (ESI) calcd. for C12H15ClF2N3O2 [M+H]+ m/z 306.08, found 305.90.
Step 2: methyl 3-(4,4-difluoroazepan-1-yl)-6-iodopyridazine-4-carboxylate: A solution of methyl 6-chloro-3-(4,4-difluoroazepan-1-yl)pyridazine-4-carboxylate (1.6 g, 5.2 mmol) in HI (15 mL, 57% aqueous solution) was heated at 40° C. for overnight. After cooling to ambient temperature, the precipitate was collected by filtration, washed with water, and dried under vacuum to give the methyl 3-(4,4-difluoroazepan-1-yl)-6-iodopyridazine-4-carboxylate (1.8 g, 87.4%) as a yellow solid. LCMS (ESI) calcd. for C12H15IF2N3O2 [M+H]+ m/z 398.02, found 397.85.
Step 3: methyl 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate. A solution of methyl 3-(4,4-difluoroazepan-1-yl)-6-iodopyridazine-4-carboxylate (1.8 g, 4.5 mmol), Cu (0.87 g, 13.6 mmol) and [Ph2SCF3]+[OTf]− (3.6 g, 9.0 mmol) in DMF (20 mL) was heated at 60° C. for 5 hours. LCMS showed the reaction was completed. Then the mixture was filtered through celite. The filtrate was diluted with water and extracted with EtOAc (80 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc/PE=1/4) to give methyl 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (1.2 g, 78.9%) as a yellow solid. LCMS (ESI) calcd. for C12H14F3F2N3O2 [M+H]+ m/z 340.11, found 339.95.
Step 4: 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a solution of methyl 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (800 mg, 2.35 mmol) in MeOH/H2O (1/1, 20 mL) was added KOH (1.05 g, 18.8 mmol) at room temperature. The mixture was heated at 70° C. for 5 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (620 mg, 81.2%) as a yellow solid. LCMS (ESI) calcd. for C12H13F5N3O2 [M+H]+ m/z 326.09, found 325.95.
Step 5: To a solution of 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (80 mg, 0.246 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (66.5 mg, 0.246 mmol) in pyridine (2.5 mL) was added POCl3 (20 uL) at 0° C. The mixture was stirred at 0° C. for 1 hour. LCMS showed the reaction was completed. The final mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried with sodium sulfate, concentrated to give the crude intermediate. The crude intermediate was dissolved in DCM (3 mL) and added TFA (1 mL). The solution was stirred at room temperature for 1 hour then concentrated and purified by Prep-HPLC (Column: Gemini-C18, 150×21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 20%-38%-60%) to give the title compound (18.1 mg, 15.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.71 (d, J=7.9 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 4.25 (s, 1H), 3.87 (m, 2H), 3.58 (m, 2H), 3.06 (s, 3H), 2.36 (m, 2H), 2.12-1.86 (m, 4H). LCMS (ESI) calcd. for C19H21F5N5O2S [M+H]+ m/z 478.13, found 478.05.
Step 1: methyl 3,6-dichloro-5-methylpyridazine-4-carboxylate: To a solution of methyl 3,6-dichloropyridazine-4-carboxylate (1 g, 4.86 mmol) in DMSO (10 mL) was added MeNO2(1.48 g, 24.3 mmol). The mixture was stirred at room temperature for 30 min. Then TEA (0.74 g, 7.29 mmol) was added dropwise to the reaction at 0° C. The reaction was stirred at room temperature for 3 h. After the reaction was completed, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give methyl 3,6-dichloro-5-methylpyridazine-4-carboxylate (0.9 g, 84.3%) as a white solid. LCMS (ESI) calcd. for C7H7C12N2O2 [M+H]+ m/z 220.99, found 220.85.
Step 2: methyl 3-(azepan-1-yl)-6-chloro-5-methylpyridazine-4-carboxylate: To a solution of methyl 3,6-dichloro-5-methylpyridazine-4-carboxylate (900 mg, 4.09 mmol) and azepane (484 mg, 4.89 mmol) in 1,4-dioxane (10 mL) was added DIEA (1583 mg, 12.27 mmol). The mixture was heated at 80° C. for 4 hours. LCMS showed the reaction was completed. The mixture was concentrated and purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give the methyl 3-(azepan-1-yl)-6-chloro-5-methylpyridazine-4-carboxylate (680 mg, 58.8%) as yellow solid. LCMS (ESI) calcd. for C13H19ClN3O2 [M+H]+ m/z 284.11, found 284.10.
Step 3: methyl 3-(azepan-1-yl)-6-iodo-5-methylpyridazine-4-carboxylate: A solution of methyl 3-(azepan-1-yl)-6-chloro-5-methylpyridazine-4-carboxylate (680 mg, 2.4 mmol) in HI (10 mL, 57% aqueous solution) was heated at 40° C. for overnight. After cooling to ambient temperature, the precipitate was collected by filtration, washed with water, and dried under vacuum to give the methyl 3-(azepan-1-yl)-6-iodo-5-methylpyridazine-4-carboxylate (500 mg, 55.5%) as a yellow solid. LCMS (ESI) calcd. for C13H19IN3O2 [M+H]+ m/z 376.05, found 376.10.
Step 4: methyl 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate: A solution of methyl 3-(azepan-1-yl)-6-iodo-5-methylpyridazine-4-carboxylate (500 mg, 1.33 mmol), Cu (257 mg, 4.02 mmol) and [Ph2SCF3]+[OTf]− (1064 mg, 2.66 mmol) in DMF (10 mL) was heated at 60° C. for 5 hours. LCMS showed the reaction was completed. Then the mixture was filtered through celite. The filtrate was diluted with water (40 mL) and extracted with EtOAc (40 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc/PE=4/1) to give methyl 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (350 mg, 82.7%) as a yellow solid. LCMS (ESI) calcd. for C14H19F3N3O2 [M+H]+ m/z 318.14, found 318.05.
Step 5: 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl) pyridazine-4-carboxylic acid: To a solution of methyl 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (350 mg, 1.1 mmol) in MeOH/H2O (1/1, 8 mL) was added KOH (580 mg, 8.8 mmol) at room temperature. The mixture was heated at 70° C. for 5 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove the MeOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (250 mg, 74.8%) as a yellow solid. LCMS (ESI) calcd. for C13H17F3N3O2 [M+H]+ m/z 304.12, found 304.05.
Step 6: tert-butyl ((3-(3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.33 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (89 mg, 0.33 mmol) in pyridine (4 mL) was added POCl3 (30 uL) at room temperature. The mixture was heated at 60° C. for 1 hour. LCMS showed the reaction was completed. The final mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried with sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc/PE=1/2) to give tert-butyl((3-(3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl)(oxo)-λ6-sulfaneylidene) carbamate (20 mg, 10.9%) as a yellow oil. LCMS (ESI) calcd. for C25H32F3N5O4S [M+H]+ m/z 556.22, found [M+H]+ 556.15.
Step 7: 3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: To a solution of tert-butyl ((3-(3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (20 mg, 0.04 mmol) in DCM (2 mL) was added TFA (0.4 mL) at 0° C. The mixture was stirred room temperate for 2 hours. The mixture was concentrated and the residue was purified by Prep-HPLC (Column: Gemini-C18, 150×21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 30%-40%-70%) to give 3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (5 mg, 30.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.28 (s, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 4.34 (s, 1H), 3.73 (t, J=5.9 Hz, 4H), 3.08 (s, 3H), 2.30 (s, 3H), 1.76 (s, 4H), 1.49 (s, 4H). LCMS (ESI) calcd. for C20H25F3N5O2S [M+H]+ m/z 456.17, found 456.05.
To a solution of 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.33 mmol) in DCM (2 mL) was added oxalyl chloride (30 L) at room temperature. The mixture was stirred at room temperature for 30 minutes, then concentrated under reduced pressure. The resulting residue was dissolved in THE (1 mL) and added dropwise to a mixture of (3-aminophenyl)(imino)(methyl)-λ6-sulfanone (73 mg, 0.43 mmol) and DIEA (64 mg, 0.49 mmol) in THE (1 mL). The mixture was stirred at 40° C. for 2 h. LCMS showed the reaction was completed. The final mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried with sodium sulfate and concentrated. The residue was purified by Prep-HPLC (Column: Gemini-C18, 150×21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 20%-38%-60%) to give N-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)-3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (10 mg, 6.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (t, J=7.9 Hz, 1H), 7.17 (s, 1H), 7.10 (d, J=7.7 Hz, 1H), 6.88 (dd, J=8.1, 1.9 Hz, 1H), 5.79 (s, 2H), 3.75-3.62 (m, 4H), 3.60 (s, 3H), 2.27 (s, 3H), 1.74 (s, 4H), 1.56-1.37 (m, 4H). LCMS (ESI) calcd. for C20H25F3N5O2S [M+H]+ m/z 456.17, found 456.00.
Step 1: methyl 4-(azepan-1-yl)-6-chloropyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (5 g, 24.3 mmol) and azepane (2.89 g, 29.2 mmol) in 1,4-dioxane (60 mL) was added DIEA (9.4 g, 72.9 mmol). The mixture was heated at 80° C. for 4 hours. LCMS showed the reaction was completed. The mixture was concentrated and purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give the methyl 4-(azepan-1-yl)-6-chloropyridazine-3-carboxylate (3.5 g, 53.8%) as a yellow solid. LCMS (ESI) calcd. for C12H17ClN3O2 [M+H]+ m/z 270.10, found 270.05.
Step 2: methyl 4-(azepan-1-yl)-6-iodopyridazine-3-carboxylate: A solution of methyl 4-(azepan-1-yl)-6-chloropyridazine-3-carboxylate (3.5 g, 11.8 mmol) in HI (30 mL, 57% aqueous solution) was stirred at 40° C. for overnight. After cooling to ambient temperature, the precipitate was collected by filtration, washed with water and dried under vacuum to give the methyl 4-(azepan-1-yl)-6-iodopyridazine-3-carboxylate (3.5 g, 82.2%) as a yellow solid. LCMS (ESI) calcd. for C12H17IN3O2 [M+H]+ m/z 362.03, found 362.00.
Step 3: methyl 4-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxylate: A solution of methyl 4-(azepan-1-yl)-6-iodopyridazine-3-carboxylate (2.5 g, 6.9 mmol), Cu (1.35 g, 20.7 mmol) and [Ph2SCF3]+[OTf]− (5.5 g, 13.8 mmol) in DMF (30 mL) was heated at 60° C. for 5 hours. LCMS showed the reaction was completed. Then the mixture was filtered through celite. The filtrate was diluted with water and extracted with EtOAc (80 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc/PE=1/3) to give methyl 4-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxylate (1 g, 47.7%) as a yellow solid. LCMS (ESI) calcd. for C13H17F3N3O2 [M+H]+ m/z 304.12, found 303.95.
Step 4: 4-(azepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide. To a solution of tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate 534 mg, 1.98 mmol) in toluene (5 mL) was added Me3Al (1M in hexane, 2.18 mL, 2.18 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 0.5 h. Then a solution of methyl 4-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxylate (200 mg, 0.66 mmol) in toluene (3 mL) was added at the same temperature. The resulting mixture was heated at 90° C. for 2 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, concentrated, purified by prep-HPLC (Column: Gemini-C18, 150×21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 20%-38%-60%) to give 4-(azepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (60 mg, 20.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.37 (s, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.34 (s, 1H), 4.22 (s, 1H), 3.64-3.48 (m, 4H), 3.07 (s, 3H), 1.74 (s, 4H), 1.48 (s, 4H). LCMS (ESI) calcd. for C19H23F3N5O2S [M+H]+ m/z 442.14, found 442.00.
Step 1: tert-butyl (R)-((3-(3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.330 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (133.70 mg, 0.495 mmol) in pyridine (2 mL) was added dropwise added POCl3 (150 L) at 50° C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 32.72%) as a yellow oil. LCMS (ESI) calcd. for C25H33F3N5O4S [M+H]+ m/z 556.22, found 556.40.
Step 2: (R)-3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of tert-butyl (R)-((3-(3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (60 mg, 0.108 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE/EtOAc=1/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (R)-3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (15 mg, 30%, 96.05% purity, 99% ee) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.27 (s, 1H), 7.92-7.85 (m, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 4.26 (s, 1H), 3.73 (t, J=5.8 Hz, 4H), 3.07 (s, 3H), 2.30 (s, 3H), 1.76 (s, 4H), 1.49 (s, 4H). LCMS (ESI) calcd. for C20H23F3N5O2S [M−H]− m/z 454.15, found 454.10.
Step 1: tert-butyl (S)-((3-(3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A mixture of 3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.330 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (133.70 mg, 0.495 mmol) in pyridine (2 mL) was added POCl3 (150 μL) at 50° C. The reaction was monitored by LCMS.
After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combine organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (S)-((3-(3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (47 mg, 25.7%) as a yellow oil. LCMS (ESI) calcd. for C25H33F3N5O4S [M+H]+ m/z 556.22, found 556.15.
Step 2: (S)-3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of tert-butyl (S)-((3-(3-(azepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (47 mg, 0.08 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the filtrate was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE/EtOAc=1/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (S)-3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (18 mg, 49.45%, 98% purity, 100% ee) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.27 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.64-7.60 (m, 1H), 4.26 (s, 1H), 3.74-3.71 (m, 4H), 3.07 (s, 3H), 2.29 (s, 3H), 1.76 (s, 4H), 1.49 (s, 4H). LCMS (ESI) calcd. for C20H25F3N5O2S [M+H]+ m/z 456.17, found 456.10.
Step 1: methyl 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate: A mixture of methyl 2-chloro-6-methylnicotinate (1.3 g, 7 mmol) and 6-azaspiro[2.5]octane hydrochloride (1.03 g, 7 mmol) in 1,4-dioxane (20 mL) was added DIEA (1.82 g, 14 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (40 mL) and extracted with DCM (40 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to provide methyl 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (1 g, 55.6%) as a white solid. LCMS (ESI) calcd. for C15H21N2O2 [M+H]+ m/z 261.16, found 260.95.
Step 2: methyl 5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate: To a mixture of methyl 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (0.950 g, 3.64 mmol) in DMF (10 mL) was added NCS (0.534 g, 4 mmol). The reaction mixture was stirred at room temperature for 8 hours. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give methyl 5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (0.750 g, 70.0%) as a white oil. LCMS (ESI) calcd. for C15H20ClN2O2 [M+H]+ m/z 295.12, found 294.95.
Step 3: 5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid: To a solution methyl 5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (0.700 g, 2.5 mmol) in MeOH/H2O (1/1, 15 mL) was added KOH (0.561 g, 25 mmol) at room temperature. The mixture was heated at 60° C. for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (20 mL). Then the aqueous phase was adjusted to pH=3 with 1N HCl and extracted with DCM (20 mL×3). The combined organic phases were dried with Na2SO4 and concentrated under reduced pressure to give 5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (560 mg, 79.6%) as a white solid. LCMS (ESI) calcd. for C14H18ClN2O2 [M+H]+ m/z 281.10, found 280.95.
Step 4: tert-butyl ((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a mixture of 5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (500 mg, 1.78 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (723 mg, 2.67 mmol) in pyridine (4 mL) at room temperature was added POCl3 (750 L). The reaction mixture was stirred at room temperature for 2 hours. Then the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl ((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 12.64%) as a yellow oil. LCMS (ESI) calcd. for C26H34ClN4O4S [M+H]+ m/z 533.20, found 533.05.
Step 5: 5-chloro-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide: A solution of tert-butyl ((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.23 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE/EtOAc=1/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.1% formic acid) to afford the title compound (41 mg, 41.44%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.39 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.60-7.56 (m, 1H), 4.21 (s, 1H), 3.36-3.32 (m, 4H), 3.05 (s, 3H), 2.46 (s, 3H), 1.38-1.35 (s, 4H), 0.28 (s, 4H). LCMS (ESI) calcd. for C21H26ClN4O2S [M+H]+ m/z 433.14, found 433.05.
Step 1: methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate: A mixture of methyl 2,6-dichloronicotinate 1 (2.0 g, 9.7 mmol), 4,4-difluoroazepane hydrochloride (1.67 g, 9.7 mmol) and DIEA (3.75 g, 29.1 mmol) in dioxane (25 mL) was heated at 80° C. for 5 hours. Then the mixture was concentrated and directly purified by flash column chromatography on silica gel (PE/EtOAc=6/1) to give methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate (2.22 g, 67%). LCMS (ESI) calcd. for C13H16ClF2N2O2 [M+H]+ m/z 305.09, found 305.90.
Step 2: methyl 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinate: A mixture of Zn power (2.2 g, 33.6 mmol) and 12 (850 mg, 3.36 mmol) in a 250 mL three-necked flask was evacuated and backfilled with N2 three times and then charged with N2. The flask was heated carefully with a hot air blower until 12 was sublimated. Then a solution of (bromomethyl)cyclopropane (2.27 g, 16.8 mmol) in DMF (8 mL) was added intermediately via a syringe. The mixture was stirred for 10 minutes while keeping the temperature was about 80° C. Then the heater and stirrer were removed. The upper layer clear solution was added dropwise into a stirred solution of methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate (1.7 g, 5.6 mmol), CuI (320 mg, 1.68 mmol) and Pd(pph3)2C12 (390 mg, 0.56 mmol) in DMF (4 mL) under an atmosphere of N2. The mixture was heated at 110° C. for 5 hours. Then the mixture was quenched with water (80 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated to give the crude. The residue was purified by silica gel column chromatography (PE/EA, 4/1) to afford methyl 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinate (1.3 g, 64%) as a white solid. LCMS (ESI) calcd. for C17H23F2N2O2 [M+H]+ m/z 325.17, found 325.25.
Step 3: 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinic acid: To a solution of methyl 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinate (400 mg, 1.23 mmol) in MeOH/H2O (1/1, 8 mL) was added KOH (0.69 g, 12.3 mmol) at room temperature. The mixture was heated at 70° C. for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinic acid (360 mg, 84.7%). LCMS (ESI) calcd. for C16H21F2N2O2 [M+H]+ m/z 311.16, found 311.00.
Step 4: 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamide: To a solution of 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinic acid (100 mg, 0.32 mmol) in DCM (5 mL) and DMF (10 L) was added oxalyl chloride (81.84 mg, 0.64 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. After the reaction was completed, the mixture was concentrated to remove the solvent. Then the residue was dissolved in THE (5 mL) and was added to vigorously stirred NH3—H2O (2 mL). The mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum to give crude 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamide (96 mg, 86.7%) which was used in the next step without further purification. LCMS (ESI) calcd. for C16H22F2N3O [M+H]+ m/z 310.17, found 309.95.
Step 5: tert-butyl ((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamide 5 (90 mg, 0.29 mmol), tert-butyl ((3-bromophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (195 mg, 0.58 mmol), Cs2CO3 (285 mg, 0.87 mmol) and Xantphos-Pd-G2 (26 mg, 0.029 mmol) in 1,4-dioxane (5 mL) was heated at 110° C. for overnight under an atmosphere of N2. LCMS showed the reaction was completed. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give tert-butyl ((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamido) phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 27%) as a yellow oil. LCMS (ESI) calcd. for C28H37F2N4O4S [M+H]+ m/z 563.25, found 563.20.
Step 6: 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: To a solution of tert-butyl ((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 0.089 mmol) in DCM (3 mL) was added TFA (1 mL) at rt. The mixture was stirred room temperature for 2 hours. The resulting mixture was concentrated and the residue was purified by prep-HPLC (Column: Gemini-C18, 150×21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 50%-80%) to give 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl) phenyl)nicotinamide (15 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.34 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.63 (m, 2H), 7.56-7.61 (t, J=7.9 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 5.93-5.81 (m, 1H), 5.08-4.94 (m, 2H), 4.19 (s, 1H), 3.63 (s, 2H), 3.42 (t, J=5.7 Hz, 2H), 3.05 (s, 3H), 2.73 (t, J=7.5 Hz, 2H), 2.48-2.42 (m, 2H), 2.39-2.26 (m, 2H), 2.01-1.80 (m, 4H). LCMS (ESI) calcd. for C23H29F2N4O2S [M+H]+ m/z 463.20, found 463.10.
Step 1: methyl 6-chloro-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate (3): A mixture of methyl 3,6-dichloropyridazine-4-carboxylate (1.5 g, 7.2 mmol) and 6-azaspiro[2.5]octane hydrochloride (1.06 g, 7.2 mmol) in 1,4-dioxane (20 mL) was added DIEA (1.87 g, 14.4 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give methyl 6-chloro-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate (1.1 g, 54.37%) as a yellow oil. LCMS (ESI) calcd. for C13H17ClN3O2 [M+H]+ m/z 282.10, found 281.95.
Step 2: methyl 6-iodo-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate: To a solution of methyl 6-chloro-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate (1.1 g, 3.91 mmol) was added HI (55%, 10 mL) at room temperature. The mixture was heated at 40° C. for 10 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (20 mL×3). The combined organic phases were dried with Na2SO4 and concentrated under reduced pressure to give crude methyl 6-iodo-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate (800 mg, 54.9%) as a yellow solid which was used directly in next Step without further purification. LCMS (ESI) calcd. for C13H17IN3O2 [M+H]+ m/z 374.04, found 373.90.
Step 3: methyl 3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate: A mixture of methyl 6-iodo-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate (600 mg, 1.6 mmol) and Cu (30.7 mg, 4.8 mmol) and [Ph2SCF3]+[OTf]− (123 mg, 3.2 mmol) in DMF (10 mL) was heated at 60° C. for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (40 mL) and extracted with DCM (40 mL×3). The combined organic phases were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give methyl 3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (330 mg, 65.6%) as a yellow solid. LCMS (ESI) calcd. for C14H17F3N3O2 [M+H]+ m/z 316.13, found 316.00.
Step 4: 3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a solution methyl 3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (330 mg, 1.05 mmol) in MeOH/H2O (10 mL) was added KOH (560 mg, 10 mmol) at room temperature. The mixture was heated at 70° C. for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water and extracted with DCM (20 mL). The aqueous phase was adjusted to pH=3 with 1N HCl and extracted with DCM (20 mL×3). The combined organic phases were dried with Na2SO4 and concentrated under reduced pressure to give 3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (240 mg, 75.9%) as a white solid. LCMS (ESI) calcd. for C13H15F3N3O2 [M+H]+ m/z 302.11, found 301.90.
Step 5: tert-butyl ((3-(3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A mixture of 3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (240 mg, 0.8 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (325 mg, 1.2 mmol) in pyridine (4 mL) was added POCl3 (350 L) at room temperature. The mixture was stirred at room for 2 hours. Then the mixture was diluted with water (4 mL) and extracted with DCM (4 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl ((3-(3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)--λ6-sulfaneylidene)carbamate (85 mg, 19.1%) as a yellow oil. LCMS (ESI) calcd. for C25H31F3N5O4S [M+H]+ m/z 554.21, found 554.10.
Step 6: N-(3-(S-methylsulfonimidoyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of tert-butyl ((3-(3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (85 mg, 0.153 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was first purified by flash chromatography on silica gel (PE/EtOAc=1/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.1% formic acid) to obtain N-(3-(S-methylsulfonimidoyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (44 mg, purity 98.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.29 (s, 1H), 8.02 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 4.25 (s, 1H), 3.71-3.67 (m, 4H), 3.06 (s, 3H), 1.46-1.42 (m, 4H), 0.35 (s, 4H). LCMS (ESI) calcd. for C20H23F3N5O2S [M+H]+ m/z 454.15, found 454.10.
Step 1: methyl 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate: A mixture of methyl 2-chloro-6-methylnicotinate (1.0 g, 5.4 mmol), 4,4-difluoroazepane hydrochloride (1.11 g, 6.4 mmol) and DIEA (1.39 g, 10.8 mmol) in dioxane (20 mL) was heated at 80° C. for 5 hours. Then the mixture was concentrated, and the residue was purified by flash column chromatography on silica gel (PE/EtOAc=5/1) to give methyl 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (720 mg, 42.6%). LCMS (ESI) calcd. for C14H18F2N2O2 [M+H]+ m/z 285.14, found 285.15.
Step 2: methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate: To a solution of methyl 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (700 mg, 2.46 mmol) in DMF (10 mL) was added NCS (394 mg, 2.95 mmol). The mixture was stirred for 5 hours at room temperature. Then the mixture was diluted with water (40 mL) and extracted with DCM (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated to give the crude. The crude was purified by silica gel column chromatography (PE/EtOAc, 4/1) to afford methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (680 mg, 78%) as a yellow solid. LCMS (ESI) calcd. for C14H18ClF2N2O2 [M+H]+ m/z 319.10, found 319.00.
Step 3: 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid: To a solution of methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (650 mg, 2.03 mmol) in MeOH/H2O (1/1, 10 mL) was added KOH (1.14 g, 20.4 mmol) at room temperature. The mixture was heated at 70° C. for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (600 mg, 86.9%). LCMS (ESI) calcd. for C13H16ClF2N2O2 [M+H]+ m/z 305.09, found 304.90.
Step 4: tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (120 mg, 0.39 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (160 mg, 0.59 mmol) in pyridine (6 mL) was added POCl3 (0.3 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The mixture was quenched with water (60 mL) and extracted with EtOAc (40 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/2) to provide tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamido)phenyl)(methyl)(oxo)-_6-sulfaneylidene)carbamate (65 mg, 27%) as a yellow oil. LCMS (ESI) calcd. for C25H32ClF2N4O4S [M+H]+ m/z 557.18, found 557.15.
Step 5: 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: To a solution of tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamido) phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (65 mg, 0.12 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The final mixture was concentrated in vacuum and purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 50% to 80% MeCN/H2O containing 0.1% formic acid) to afford 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (10.1 mg, 18.8%) as a white solid. LCMS (ESI) calcd. for C20H24ClF2N4O2S [M+H]+ m/z 457.13, found 457.00. 1H NMR (400 MHz, DMSO-d6) δ 0.74 (s, 1H), 8.32 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.77 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 3.64-3.57 (m, 2H), 3.42-3.38 (m, 2H), 3.09 (s, 3H), 2.45 (s, 3H), 2.35-2.25 (m, 2H), 2.02-1.89 (m, 2H), 1.87-1.80 (m, 2H).
Step 1: tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (250 mg, 0.820 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (244 mg, 0.902 mmol) in pyridine (4 mL) was added POCl3 (373 L) at 50° C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 26.3%) as a yellow oil. LCMS (ESI) calcd. for C25H32ClF2N4O4S [M+H]+ m/z 557.18, found 557.10.
Step 2: (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.210 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the filtrate was diluted with water (5 mL) and extracted with DCM (5 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to obtain (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (67 mg, 69.8%, 100% ee) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 10.72 (s, 1H), 8.30 (s, 1H), 7.93 (d, J=8 Hz, 1H), 7.77 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.59-7.55 (m, 1H), 4.21 (s, 1H), 3.62-3.60 (m, 2H), 3.42-3.39 (m, 2H), 3.05 (s, 3H), 2.28 (s, 3H), 2.29-2.26 (m, 2H), 1.95-1.91 (m, 2H), 1.85-1.73 (m, 2H). LCMS (ESI) calcd. for C20H24ClF2N4O2 [M+H]+ m/z 457.13, found 456.90.
Step 1: tert-butyl (S)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (250 mg, 0.8224 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (266.447 mg, 0.9868 mmol) in pyridine (5 mL) was added dropwise added POCl3 (500 L) dropwise at room temperature. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (S)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 32.80%) as a white solid. LCMS (ESI) calcd. for C25H32ClF2N4O4S [M+H]+ m/z 557.17, found 557.05.
Step 2: (S)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (S)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.27 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to give (S)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (54.5 mg, 44.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.31 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 3.61 (dd, J=6.4, 3.6 Hz, 2H), 3.40 (s, 2H), 3.09 (s, 3H), 2.45 (s, 3H), 2.30 (d, J=14.7 Hz, 2H), 1.95 (t, J=12.2 Hz, 2H), 1.88-1.78 (m, 2H). LCMS (ESI) calcd. for C20H24ClF2N4O2S [M+H]+ m/z 457.12, found 457.20.
Step 1: tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.31 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (91 mg, 0.34 mmol) in pyridine (5 mL) was added POCl3 (50 L) dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to provide tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (82 mg, 45.8%) as a yellow solid. LCMS (ESI) calcd. for C24H29F5N5O4S [M+H]+ m/z 578.19, found 578.05.
Step 2: (R)-3-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: To a solution of tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.16 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The mixture was stirred at room temperature for 1 hours. LCMS showed the reaction was completed. The final mixture was concentrated in vacuum and purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.1% formic acid) to afford (R)-3-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (38 mg, 50%, 99% ee) as a white solid. LCMS (ESI) calcd. for C19H21F5N5O2S [M+H]+ m/z 478.14, found 478.25. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 4.25 (s, 1H), 3.87 (s, 2H), 3.58 (t, J=5.7 Hz, 2H), 3.06 (s, 3H), 2.39 (s, 2H), 2.19-1.98 (m, 2H), 1.96-1.85 (d, J=5.1 Hz, 2H).
Step 1: tert-butyl (S)-((3-(3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate To a solution of 3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.31 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (91 mg, 0.34 mmol) in pyridine (5 mL) was added POCl3 (50 L) dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/2) to provide tert-butyl (S)-((3-(3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 50.8%) as a yellow solid. LCMS (ESI) calcd. for C19H21F5N5O2S [M-Boc+H]+ m/z 478.14, found 478.05.
Step 2: (S)-3-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: To a solution of tert-butyl (S)-((3-(3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.16 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was completed. The final mixture was concentrated in vacuum and purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.1% formic acid) to afford (S)-3-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (53 mg, 71.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.28 (s, 1H), 8.08 (s, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 3.87 (s, 2H), 3.58 (t, J=5.4 Hz, 2H), 3.10 (s, 3H), 2.45-2.31 (m, 2H), 2.12-2.00 (m, 2H), 1.98-1.88 (m, 2H). LCMS (ESI) calcd. for C19H21F5N5O2S [M+H]+ m/z 478.14, found 478.50.
Step 1: methyl 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylate: A mixture of methyl 6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylate (600 mg, 1.88 mmol) and phenylboronic acid (1.146 g, 9.401 mmol) in 1,4-dioxane/H2O (4/1, 10 mL), potassium carbonate (779 mg, 5.641 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (137 mg, 0.188 mmol) was heated at 100° C. for 6 h under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=3/1) to give methyl 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylate (600 mg, 88.2%) as a white oil. LCMS (ESI) calcd. for C19H22F2N3O2 [M+H]+ m/z 362.17, found 362.00.
Step 2: 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylic acid: To a solution methyl 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylate (0.550 g, 1.519 mmol) in MeOH/H2O (1/1, 10 mL) was added KOH (0.852 g, 15.19 mmol) at room temperature. The mixture was heated at 70° C. for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (10 mL). Then the aqueous phase was adjusted to pH=3 with 1N HCl and extracted with DCM (10 mL×3). The combined organic phases were dried with Na2SO4 and concentrated under reduced pressure to give 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylic acid (500 mg, 65.8%) as a white solid. LCMS (ESI) calcd. for C18H20F2N3O2 [M+H]+ m/z 348.15, found 348.00.
Step 3: 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxamide: A solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxylic acid (450 mg, 1.293 mmol) in SOCl2 (5 mL) was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated. The residue was diluted with THE and added dropwise to a stirred solution of ammonium hydroxide (5 mL). Then the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxamide (420 mg, 93.8%) as a white solid. LCMS (ESI) calcd. for C18H21F2N4O [M+H]+ m/z 347.17, found 347.05.
Step 4. 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)-6-phenylpyridazine-4-carboxamide: A solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-phenylpyridazine-4-carboxamide (400 mg, 1.152 mmol) in dioxane (8 mL) was added 1-bromo-3-(methylsulfinyl)benzene (946 mg, 3.456 mmol), cesium carbonate (975 mg, 2.995 mmol) and Xantphos-Pd-G2 (204 mg, 0.230 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 16 hours under nitrogen. The reaction was monitored by LCMS. After the reaction was completed, the filtrate was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)-6-phenylpyridazine-4-carboxamide (120 mg, 21.5%) as a white solid. LCMS (ESI) calcd. for C25H27F2N4O2S [M+H]+ m/z 485.18, found 485.10.
Step 5: 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-phenylpyridazine-4-carboxamide: To a solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)-6-phenylpyridazine-4-carboxamide (120 mg, 0.247 mmol) in MeOH (5 mL) was added PhI(OAc)2 (199 mg, 0.618 mmol) and ammonium carbamate (58 mg, 0.741 mmol) at room temperature. The reaction mixture was heated at 70° C. for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (5 mL), and extracted with DCM (5 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE/EtOAc=1/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to afford 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-phenylpyridazine-4-carboxamide (28 mg, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.08 (s, 1H), 8.32 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 7.59-7.57 (m, 2H), 7.55-7.51 (m, 2H), 7.49-7.46 (m, 1H), 4.24 (s, 1H), 3.78-3.76 (m, 2H), 3.67-3.64 (m, 2H), 3.06 (s, 3H), 2.35-2.32 (m, 2H), 2.19 (s, 3H), 2.06-2.04 (m, 2H), 1.89-1.87 (m, 2H). LCMS (ESI) calcd. for C25H28F2N5O2S [M+H]+ m/z 500.20, found 499.95.
Step 1: methyl 6-chloro-4-(4,4-difluoroazepan-1-yl)pyridazine-3-carboxylate: To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (5.0 g, 24.3 mmol) and 4,4-difluoroazepane hydrogen chloride (4.98 g, 29.2 mmol) in 1,4-dioxane (50 mL) was added DIEA (6.27 g, 48.6 mmol). The mixture was heated at 80° C. for 4 hours. LCMS showed the reaction was completed. The mixture was concentrated and purified by flash column chromatography on silica gel (PE/EtOAc=15/1) to give the methyl 6-chloro-4-(4,4-difluoroazepan-1-yl)pyridazine-3-carboxylate (4.8 g, 64.9%) as a white solid. LCMS (ESI) calcd. for C12H15ClF2N3O2 [M+H]+ m/z 306.08, found 305.90.
Step 2: 6-chloro-4-(4,4-difluoroazepan-1-yl)pyridazine-3-carboxamide: A solution of methyl 6-chloro-4-(4,4-difluoroazepan-1-yl)pyridazine-3-carboxylate (4.8 g, 15.7 mmol) in NH3-MeOH (7M, 15 mL) was heated at 60° C. for 16 hours in a high-pressure reactor. The reaction mixture was concentrated to give crude 6-chloro-4-(4,4-difluoroazepan-1-yl)pyridazine-3-carboxamide (4.8 g) which was used in the next Step without purification. LCMS (ESI) calcd. for C11H14ClF2N4O [M+H]+ m/z 291.08, found 290.95.
Step 3: 4-(4,4-difluoroazepan-1-yl)-6-iodopyridazine-3-carboxamide: A solution of 6-chloro-4-(4,4-difluoroazepan-1-yl)pyridazine-3-carboxamide (2.5 g, 8.62 mmol) in HI (10 mL, 57% aqueous solution) was heated at 40° C. for 5 hours. After cooling to ambient temperature, the precipitate was collected by filtration, washed with water, and dried under vacuum to give the 4-(4,4-difluoroazepan-1-yl)-6-iodopyridazine-3-carboxamide (2.2 g, 66.8%) as a white solid. LCMS (ESI) calcd. for C11H14F2IN4O [M+H]+ m/z 383.02, found 382.85.
Step 4: 4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide: A mixture of 4-(4,4-difluoroazepan-1-yl)-6-iodopyridazine-3-carboxamide (2.2 g, 5.76 mmol), Cu (1.1 g, 17.28 mmol) and [Ph2SCF3]+[OTf]− (4.6 g, 11.52 mmol) in DMF (15 mL) was heated at 60° C. for 5 hours. LCMS showed the reaction was completed. Then the mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (80 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc/PE=5/1) to give 4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (1.3 g, 69.5%) as a yellow oil. LCMS (ESI) calcd. for C12H14F5N4O [M+H]+ m/z 325.11, found 324.95.
Step 5: 4-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfinyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide: A solution of 4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (200 mg, 0.60 mmol), 1-bromo-3-(methylsulfinyl)benzene (262 mg, 1.2 mmol), Cs2CO3 (587 mg, 1.8 mmol) and Xantphos-Pd-G2 (55 mg, 0.06 mmol) in 1,4-dioxane (6 mL) was heated at 100° C. for overnight under an atmosphere of N2. LCMS showed the reaction was completed. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=4/1) to give 4-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfinyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (120 mg, 43%) as an white oil. LCMS (ESI) calcd. for C19H20F5N4O2S [M+H]+ m/z 463.12, found 463.00.
Step 6: 4-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide: To a solution of 4-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfinyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (120 mg, 0.25 mmol) in MeOH (5 mL) was added PhI(OAc)2 (347.49 mg, 1.08 mmol) and ammonium carbamate (100.98 mg, 1.29 mmol) at room temperature. The reaction mixture was heated at 70° C. for 3 hours. Then the mixture was cooled to room temperature, diluted with water (20 mL) and extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 50% to 55% ACN-H2O containing 0.1% FA) to afford 4-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (15 mg, 12.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.38 (s, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.43 (s, 1H), 4.25 (s, 1H), 3.67 (s, 2H), 3.56 (t, J=5.7 Hz, 2H), 3.07 (s, 3H), 2.37-2.23 (m, 2H), 2.12-1.00 (m, 2H), 1.94-1.84 (s, 2H). LCMS (ESI) calcd. for C19H21F5N5O2S [M+H]+ m/z 478.14, found 478.05.
Step 1. methyl 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylate: A mixture of methyl 6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylate (600 mg, 1.880 mmol) and cyclopropylboronic acid (323 mg, 3.760 mmol) in THE (10 mL) was added potassium phosphate (797 mg, 3.760 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (137 mg, 0.188 mmol) under nitrogen at room temperature. After addition, the reaction mixture was heated at 90° C. in a microwave reactor for 1 hour. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=3/1) to give methyl 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylate (550 mg, 90.0%) as a white oil. LCMS (ESI) calcd. for C16H22F2N3O2 [M+H]+ m/z 326.17, found 326.00.
Step 2: 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylic acid: To a solution to methyl 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylate (500 mg, 1.538 mmol) in MeOH/H2O (1/1, 10 mL) was added KOH (861 mg, 15.38 mmol) at room temperature. The mixture was heated at 70° C. for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (10 mL). Then the aqueous phase was adjusted to pH=3 with 1N HCl and extracted with DCM (10 mL×3). The combined organic phases were dried with Na2SO4 and concentrated under reduced pressure to give 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylic acid (380 mg, 79.5%) as a white solid. LCMS (ESI) calcd. for C15H20F2N3O2 [M+H]+ m/z 312.15, found 312.00.
Step 3: 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamide: A solution of 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylic acid (350 mg, 1.125 mmol) in SOCl2 (5 mL) was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under vacuum. The residue was dissolved in THE (3 mL) and added dropwise to a stirred solution of ammonium hydroxide (5 mL). Then the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the filtrate was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamide (280 mg, 80.4%) as a white solid. LCMS (ESI) calcd. for C15H21F2N4O [M+H]+ m/z 311.17, found 311.05.
Step 4: 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)pyridazine-4-carboxamide: A solution of give 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamide (250 mg, 0.803 mmol) in dioxane (8 mL) was added 1-bromo-3-(methylsulfinyl)benzene (526 mg, 2.411 mmol), cesium carbonate (678 mg, 2.087 mmol) and Xantphos-Pd-G2 (143 mg, 0.161 mmol) at room temperature. The reaction mixture was heated at 100° C. under nitrogen for 16 hours. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)pyridazine-4-carboxamide (90 mg, 25.1%) as a white solid. LCMS (ESI) calcd. for C22H27F2N4O2S [M+H]+ m/z 449.18, found 450.10.
Step 5: 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide: To a solution of 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(methylsulfinyl)phenyl)pyridazine-4-carboxamide (90 mg, 0.200 mmol) in MeOH (5 mL) was added PhI(OAc)2 (161 mg, 0.501 mmol) and ammonium carbamate (46 mg, 0.600 mmol) at room temperature. The reaction mixture was heated at 70° C. for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (15 mL), and extracted with DCM (15 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE/EtOAc=1/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to afford 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide (52 mg, 56%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.39 (s, 1H), 7.92 (d, J=8 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.70-7.66 (m, 1H), 3.67-3.63 (m, 2H), 3.58-3.55 (m, 2H), 2.50 (s, 3H), 2.33 (s, 3H), 2.29-2.15 (m, 3H), 2.01-2.00 (m, 2H), 1.83-1.81 (m, 2H), 1.01-0.98 (m, 4H). LCMS (ESI) calcd. for C22H28F2N5O2S [M+H]+ m/z 464.20, found 464.00.
Step 1: 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinic acid: To a solution of methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate (200 mg, 0.66 mmol) in THF/H2O (1/1, 10 mL) was added KOH (368 mg, 6.6 mmol) at room temperature. The mixture was heated at 80° C. for 16 hours. After the reaction was complete, the mixture was concentrated to remove most of the THF. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, concentrated under reduced pressure to afford 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinic acid (180 mg, 94.7% yield) as a white solid. LCMS (ESI) calcd. for C12H14ClF2N2O2 [M+H]+ m/z 291.07, found 290.95.
Step 2: tert-butyl (S)-((3-(6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinic acid (120 mg, 0.41 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (224 mg, 0.83 mmol) in pyridine (5 mL) was added POCl3 (100 L) dropwise at 0° C. The reaction solution was stirred at 0° C. for 1 hour. After the reaction was complete, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (S)-((3-(6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (110 mg, 49.5%) as a yellow oil. LCMS (ESI) calcd. for C24H29ClF2N4O4SNa [M+H]+ m/z 565.16, found 565.10.
Step 3: tert-butyl (S)-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture tert-butyl (S)-((3-(6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.167 mmol), (cyclopropylmethyl)trifluoroborate potassium (83 mg, 0.52 mmol), cesium carbonate (163 mg, 0.5 mmol), Pd(OAc)2 (15 mg, 0.07 mmol) and Ru-phos (24 mg, 0.052 mmol) in toluene/H2O (10/1, 11 mL) was heated at 100° C. for 16 h under an atmosphere of N2. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give tert-butyl (S)-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 53.8%) as a yellow oil. LCMS (ESI) calcd. for C28H37F2N4O4S [M+H]+ m/z 563.25, found 563.20.
Step 4: (S)-6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (S)-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 0.09 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated, and the residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 85% MeCN/H2O containing 0.1% trifluoroacetic acid) to provide (S)-6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (13.3 mg, 32.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.34 (s, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.73-7.47 (m, 3H), 6.70 (d, J=7.6 Hz, 1H), 4.18 (s, 1H), 3.63 (s, 2H), 3.42 (t, J=5.8 Hz, 2H), 3.04 (s, 3H), 2.53 (d, J=7.0 Hz, 2H), 2.32 (t, J=10.9 Hz, 2H), 2.03-1.90 (m, 2H), 1.89-1.76 (m, 2H), 1.12-1.02 (m, 1H), 0.58-0.39 (m, 2H), 0.26-0.17 (m, 2H). LCMS (ESI) calcd. for C23H29F2N4O2S [M+H]+ m/z 463.20, found 463.10.
Step 1: tert-butyl (R)-((3-(6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinic acid (150 mg, 0.52 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (279 mg, 1.03 mmol) in pyridine (5 mL) was added POCl3 (100 L) dropwise at 0° C. The reaction solution was stirred at 0° C. for 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (R)-((3-(6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (140 mg, 49.8%) as a yellow oil. LCMS (ESI) calcd. for C24H29ClF2N4O4SNa [M+Na]+ m/z 565.16, found 565.10.
Step 2: tert-butyl (R)-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture tert-butyl (R)-((3-(6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (140 mg, 0.26 mmol), (cyclopropylmethyl)trifluoroborate potassium (83 mg, 0.52 mmol), cesium carbonate (250 mg, 0.78 mmol), Pd(OAc)2 (15 mg, 0.07 mmol) and Ru-phos (24 mg, 0.052 mmol) in toluene/H2O (10/1, 11 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give tert-butyl (R)-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (75 mg, 51.3%). LCMS (ESI) calcd. for C28H37F2N4O4S [M+H]+ m/z 563.25, found 563.25.
Step 3: (R)-6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (75 mg, 0.13 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated and the residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 85% MeCN/H2O containing 0.1% trifluoroacetic acid) to provide (R)-6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (26.2 mg, 39%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.34 (s, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.73-7.47 (m, 3H), 6.70 (d, J=7.6 Hz, 1H), 4.18 (s, 1H), 3.63 (s, 2H), 3.42 (t, J=5.8 Hz, 2H), 3.04 (s, 3H), 2.53 (d, J=7.0 Hz, 2H), 2.32 (t, J=10.9 Hz, 2H), 2.03-1.90 (m, 2H), 1.89-1.76 (m, 2H), 1.12-1.02 (m, 1H), 0.58-0.39 (m, 2H), 0.26-0.17 (m, 2H). LCMS (ESI) calcd. for C23H29F2N4O2S [M+H]+ m/z 463.20, found 463.15.
Step 1: 6-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane: A mixture of 2,6-dichloro-3-(trifluoromethyl)pyridine (3 g, 13.95 mmol) and 6-azaspiro[2.5]octane hydrochloride (2.06 g, 13.95 mmol) in 1,4-dioxane (50 mL) was added DIEA (3.60 g, 27.90 mmol) at room temperature. The reaction mixture was heated at 80° C. for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (100 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=20/1) to provide 6-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (2.5 g, 61.6%) as a yellow oil. LCMS (ESI) calcd. for C13H15ClF3N2 [M+H]+ m/z 291.09, found 291.00.
Step 2: 6-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane: A mixture of 6-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (2.5 g, 8.59 mmol), trimethylboroxine (10.78 g, 85.9 mmol), Pd(dppf)Cl2 (628 mg, 0.86 mmol) and K2CO3 (3.55 g, 25.77 mmol) in dioxane/H2O (4/1, 25 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=20/1) to give the 6-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (1.9 g, 81.6%) as a yellow oil. LCMS (ESI) calcd. for C14H18F3N2 [M+H]+ m/z 271.14, found 271.10.
Step 3: 6-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane: To a solution of 6-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (1.9 g, 7.01 mmol) in DCM (30 mL) was added NBS (1.37 g, 7.71 mmol). The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated and directly purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give the 6-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (1.5 g, 65.9%) as a yellow oil. LCMS (ESI) calcd. for C14H17BrF3N2 [M+H]+ m/z 351.05, found 351.00.
Step 4: ethyl 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinate: A mixture of 6-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-azaspiro[2.5]octane (1.5 g, 4.30 mmol), Pd(dppf)Cl2 (157.16 mg, 0.21 mmol) and triethylamine (1.30 g, 12.9 mmol) in EtOH (10 mL) was heated at 110° C. under an atmosphere of CO (30 atm) for 16 hours in a high-pressure reactor. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give ethyl 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinate (1.3 g, 94%) as a yellow solid. LCMS (ESI) calcd. for C17H22F3N2O2 [M+H]+ m/z 343.17, found 343.15.
Step 5: 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinic acid: To a solution of ethyl 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinate (1.3 g, 3.79 mmol) in MeOH/H2O (1/1, 40 mL) was added KOH (2.12 g, 37.9 mmol) at room temperature. The mixture was heated at 70° C. for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove MeOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinic acid (900 mg, 75.4%) as a yellow solid. LCMS (ESI) calcd. for C15H18F3N2O2 [M+H]+ m/z 315.13, found 315.15.
Step 6: tert-butyl (methyl(3-(6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate: To a mixture of 6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinic acid (250 mg, 0.7936 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (322.62 mg, 1.1904 mmol) in pyridine (8 mL) was added POCl3 (750 L) at room temperature.
The reaction mixture was stirred at room temperature for 2 hours. Then the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (methyl(3-(6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate (190 mg, 42.2%) as a yellow solid. LCMS (ESI) calcd. for C27H34F3N4O4S [M+H]+ m/z 567.23, found 567.15.
Step 7: 6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinamide: A solution of tert-butyl (methyl(3-(6-methyl-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate (190 mg, 0.3351 mmol) in DCM (6 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 40% to 85% ACN-H2O containing 0.1% formic acid) to afford (50 mg, 32%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.34 (s, 1H), 7.97-7.86 (m, 2H), 7.65 (d, J=7.8 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 3.64-3.52 (m, 4H), 3.07 (s, 3H), 2.50 (s, 3H), 1.41-1.32 (m, 4H), 0.31 (s, 4H). LCMS (ESI) calcd. for C22H26F3N4O2S [M+H]+ m/z 467.18, found 467.10.
Step 1: tert-butyl (R)-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A mixture of 5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (250 mg, 0.892 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (265 mg, 0.982 mmol) in pyridine (4 mL) was added POCl3 (375 L) at 50° C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 25.3%) as a yellow oil. LCMS (ESI) calcd. for C26H34ClN4O4S [M+H]+ m/z 533.20, found 533.15.
Step 2: (R)-5-chloro-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide: A solution of tert-butyl (R)-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.225 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to obtain (R)-5-chloro-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (70 mg, 71.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 10.82 (s, 1H), 8.41 (s, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.80 (s, 1H), 7.67 (d, J=8 Hz, 1H), 7.62-7.58 (m, 1H), 3.36-3.33 (m, 4H), 3.11 (s, 3H), 2.46 (s, 3H), 1.38-1.36 (m, 4H), 0.29 (s, 4H). LCMS (ESI) calcd. for C21H26ClN4O2S [M+H]+ m/z 433.15, found 433.05.
Step 1: tert-butyl (S)-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (200 mg, 0.7143 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (232.29 mg, 0.8571 mmol) in pyridine (5 mL) was added POCl3 (500 μL) dropwise at room temperature. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (S)-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 31.5%) as a white solid. LCMS (ESI) calcd. for C26H34ClN4O4S [M+H]+ m/z 533.20, found 533.15.
Step 2: (S)-5-chloro-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide: A solution of tert-butyl (S)-((3-(5-chloro-6-methyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.2169 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 45% to 95% ACN-H2O containing 0.1% formic acid) to provide (S)-5-chloro-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (42 mg, 44.72%) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 10.81 (s, 1H), 8.39 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 3.36 (d, J=5.2 Hz, 4H), 3.06 (s, 3H), 2.47 (s, 3H), 1.43-1.31 (m, 4H), 0.29 (s, 4H). LCMS (ESI) calcd. for C21H26ClN4O2S [M+H]+ m/z 433.15, found 433.10.
Step 1: ethyl 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate: A solution of ethyl 3-chloro-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (800 mg, 2.99 mmol), 4,4-difluoroazepane hydrochloride (613 mg, 3.58 mmol) and DIEA (1155 mg, 8.96 mmol) in dioxane (10 mL) was heated at 80° C. for 1 h. LCMS showed the reaction was completed. The mixture concentrated under vacuum and purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to provide ethyl 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (800 mg, 73.1%) as a yellow solid. LCMS (ESI) calcd. for C15H19F5N3O2 [M+H]+ m/z 368.14, found 367.95.
Step 2: 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a solution of ethyl 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (800 mg, 2.48 mmol) in MeOH/H2O (1/1, 10 mL) was added KOH (872 mg, 21.80 mmol) at room temperature. The mixture was heated at 70° C. for 5 hours. After the reaction was completed, the mixture was concentrated to remove most MeOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (600 mg, 81.2%) as a yellow solid. LCMS (ESI) calcd. for C13H15F5N3O2 [M+H]+ m/z 340.11, found 340.00.
Step 3: tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (200 mg, 0.59 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (175 mg, 0.65 mmol) in pyridine (10 mL) was added POCl3 (100 L) dropwise at 50° C. The mixture was heated at 50° C. for 2 hours. LCMS showed the reaction was completed. The mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/3) to provide tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 25.9%) as a yellow solid. LCMS (ESI) calcd. for C20H23F5N5O2S [M-Boc+H]+ m/z 492.15, found 492.15.
Step 4: (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: To a solution of tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.15 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was completed. The final mixture was concentrated in vacuum and purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% ammonium hydroxide) to afford (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (15 mg, 20.3%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.27 (s, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 4.28 (s, 1H), 3.85 (s, 2H), 3.69 (t, J=5.9 Hz, 2H), 3.08 (s, 3H), 2.33 (s, 3H), 2.11-1.99 (m, 2H), 1.93-1.81 (m, 2H), 1.23 (s, 2H). LCMS (ESI) calcd. for C20H23F5N5O2S [M+H]+ m/z 492.15, found 492.10.
Step 1: tert-butyl (S)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (200 mg, 0.59 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (191.16 mg, 0.708 mmol) in pyridine (3.2 mL) was added POCl3 (400 L) dropwise at 50° C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (S)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 34.2%) as a yellow solid. LCMS (ESI) calcd. for C25H31F5N5O4S [M+H]+ m/z 592.19, found 592.15.
Step 2: (S)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of give tert-butyl (S)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.203 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to obtain (S)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (20 mg, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.27 (s, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 3.85 (s, 2H), 3.69 (t, J=5.8 Hz, 2H), 3.08 (s, 3H), 2.37 (d, J=16.1 Hz, 2H), 2.33 (s, 3H), 2.12-2.02 (m, 2H), 1.92-1.85 (m, 2H). LCMS (ESI) calcd. for C20H23F5N5O2S [M+H]+ m/z 492.15, found 492.00.
Step 1: tert-butyl (S)-((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinic acid (175 mg, 0.564 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (168 mg, 0.620 mmol) in pyridine (4 mL) was added POCl3 (250 L) at 50° C. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (S)-((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 25.15%) as a yellow oil. LCMS (ESI) calcd. for C28H37F2N4O4S [M+H]+ m/z 563.25, found 563.20.
Step 2: (S)-6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (S)-((3-(6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 0.143 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to obtain (S)-6-(3-buten-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (23 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.37 (s, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.66-7.56 (m, 2H), 6.65 (d, J=8 Hz, 1H), 5.92-5.82 (m, 1H), 5.07-4.95 (m, 2H), 3.64-3.62 (m, 2H), 3.43-3.40 (m, 2H), 3.14 (s, 3H), 2.74-2.67 (m, 2H), 2.45-2.43 (m, 2H), 2.34-2.32 (s, 2H), 1.93-1.84 (m, 4H). LCMS (ESI) calcd. for C23H29F2N4O2S [M+H]+ m/z 463.20, found 463.10.
A mixture of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (150 mg, 0.44 mmol) and pyridazin-4-amine (84 mg, 0.88 mmol) in pyridine (6 mL) was added POCl3 (150 μL) dropwise at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the resulting solution was diluted with water (40 mL) and extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (DCM/MeOH=20/1) then further purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 35% to 75% ACN-H2O containing 0.1% TFA) to give 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (25.2 mg, 13%) as a white solid. LCMS (ESI) calcd. for C17H18F5N6O [M+H]+ m/z 417.15, found 417.00. 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 9.31 (d, J=2.3 Hz, 1H), 9.18 (d, J=5.9 Hz, 1H), 8.07 (dd, J=5.8, 2.7 Hz, 1H), 3.83 (s, 2H), 3.61 (t, J=5.9 Hz, 2H), 2.37 (d, J=15.7 Hz, 2H), 2.32 (s, 3H), 2.16-1.94 (m, 2H), 1.94-1.79 (m, 2H).
Step 1: pyridazin-4-yl trifluoromethanesulfonate: To a solution of pyridazin-4-ol (300 mg, 3.12 mmol) and Et3N (630 mg, 6.24 mmol) in DCM (20 mL) was added Tf2O (1056 mg, 3.74 mmol) at 0° C. The mixture was stirred at the same temperature for 30 minutes. The mixture was quenched with water (20 mL) and extracted with DCM (20 mL×2). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to provide pyridazin-4-yl trifluoromethane sulfinate (100 mg, 14% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J=8.5 Hz, 1H), 8.17 (d, J=2.7 Hz, 1H), 6.63 (dd, J=8.6, 2.8 Hz, 1H).
Step 2: 4-(4,4-difluoroazepan-1-yl)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide: To a solution of 4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl) pyridazine-3-carboxamide (100 mg, 0.31 mmol), pyridazin-4-yl trifluoromethane sulfinate (100 mg, 0.46 mmol) and Cs2CO3 (202 mg, 0.62 mmol) in 1,4-dioxane (5 mL) was added Xantphos-Pd-G2 (53 mg, 0.06 mmol). Then the mixture was heated at 100° C. for 16 hours under an atmosphere of N2. The resulting mixture was filtered through celite. The filtrate was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE/EtOAc=1/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to afford 4-(4,4-difluoroazepan-1-yl)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (7 mg, 6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 9.51 (d, J=2.2 Hz, 1H), 9.13 (d, J=5.9 Hz, 1H), 8.10 (dd, J=5.8, 2.5 Hz, 1H), 7.49 (s, 1H), 3.71-3.60 (m, 2H), 3.49 (t, J=5.6 Hz, 2H), 2.32 (s, 2H), 2.04 (t, J=12.4 Hz, 2H), 1.90 (d, J=4.9 Hz, 2H). LCMS (ESI) calcd. for C16H16F5N6O [M+H]+ m/z 403.12, found 402.95.
Step 1: ethyl 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate: A solution of ethyl 2-chloro-4-methyl-6-(trifluoromethyl)nicotinate (prepared by a known method WO2019166822) (800 mg, 2.9962 mmol), 4,4-difluoroazepane hydrochloride (1.03 g, 5.99 mmol) and DIEA (1.16 g, 8.99 mmol) in dioxane (12 mL) was heated at 100° C. for 4 hours. LCMS showed the reaction was completed. The mixture concentrated under vacuum and purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to provide ethyl 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (710 mg, 64.74%) as a yellow solid. LCMS (ESI) calcd. for C16H20F5N2O2 [M+H]+ m/z 367.15, found 367.10.
Step 2: 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid: To a solution of ethyl 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (710 mg, 1.94 mmol) in THF/H2O (1/1, 10 mL) was added KOH (1.09 g, 19.40 mmol) at room temperature. The mixture was heated at 70° C. for 5 hours. After the reaction was completed, the mixture was concentrated to remove most THF. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (540 mg, 82.4%) as a yellow solid. LCMS (ESI) calcd. for C14H16F5N2O2 [M+H]+ m/z 339.12, found 339.05.
Step 3: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-6 (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (100 mg, 0.2958 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (96.21 mg, 0.3550 mmol) in pyridine (3 mL) was added POCl3 (100 L) dropwise at room temperature. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 29%) as a yellow solid. LCMS (ESI) calcd. for C26H32F5N4O4S [M+H]+ m/z 591.22, found 591.15.
Step 4: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl) nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 0.0846 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 50% to 55% ACN-H2O containing 0.1% formic acid) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (14.4 mg, 34.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.33 (s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.16 (s, 1H), 3.68-3.63 (m, 2H), 3.58 (t, J=6.0 Hz, 2H), 3.10 (s, 3H), 2.36-2.21 (m, 5H), 2.06-1.95 (m, 2H), 1.88-1.75 (m, 2H). LCMS (ESI) calcd. for C21H24F5N4O2S [M+H]+ m/z 491.16, found 491.00.
Step 1: tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A mixture of 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (150 mg, 0.4438 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (144.32 mg, 0.5325 mmol) in pyridine (3 mL) was added POCl3 (100 L) dropwise at room temperature. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6sulfaneylidene)carbamate (50 mg, 19.06%) as a yellow solid. LCMS (ESI) calcd. for C26H32F5N4O4S [M+H]+ m/z 591.22, found 591.15.
Step 2: (S)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 0.0846 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 50% to 55% ACN-H2O containing 0.1% formic acid) to provide (S)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (20.6 mg, 49.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.33 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.72-7.57 (m, 2H), 7.16 (s, 1H), 3.65 (d, J=7.9 Hz, 2H), 3.58 (t, J=6.0 Hz, 2H), 3.09 (s, 3H), 2.36-2.20 (m, 5H), 2.08-1.94 (m, 2H), 1.87-1.77 (m, 2H). LCMS (ESI) calcd. for C21H24F5N4O2S [M+H]+ m/z 491.16, found 491.00.
Step 1: tert-butyl (R)-((3-(6-(but-3-en-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 6-(but-3-en-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinic acid (250 mg, 0.806 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (239 mg, 0.887 mmol) in pyridine (4 mL) was added POCl3 (350 L) at 50° C. The mixture was stirred at room temperature for 1 h, then cooled to room temperature. The resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-((3-(6-(but-3-en-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 13%) as a yellow oil. LCMS (ESI) calcd. for C28H37F2N4O4S [M+H]+ m/z 563.25, found 563.15.
Step 2: (R)-6-(but-3-en-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(6-(but-3-en-1-yl)-2-(4,4-difluoroazepan-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 0.143 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 50% to 80% ACN-H2O containing 0.1% formic acid) to obtain (R)-6-(but-3-en-1-yl)-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (23 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.43 (s, 1H), 7.68-7.63 (m, 1H), 7.62-7.61 (m, 3H), 6.66 (d, J=7.6 Hz, 1H), 5.89-5.82 (m, 1H), 5.02-4.95 (m, 2H), 3.64-3.62 (m, 2H), 3.43-3.40 (m, 2H), 3.31 (s, 3H), 2.75-2.71 (m, 2H), 2.45-2.43 (m, 2H), 2.42-2.32 (m, 2H), 1.93-1.84 (m, 4H). LCMS (ESI) calcd. for C23H29F2N4O2S [M+H]+ m/z 463.20, found 463.05.
Step 1: 4-(azepan-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl) pyridazine-3-carboxamide: To a solution of 2-methoxypyridin-4-amine (368 mg, 2.97 mmol) in toluene (4 mL) was added Me3Al (1M in hexane, 3.26 mL, 3.26 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 0.5 h. Then a solution of methyl 4-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxylate (300 mg, 0.99 mmol) in toluene (2 mL) was added at the same temperature. The mixture was heated at 90° C. for 2 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, concentrated, and purified by silica gel column chromatography (eluting with EtOAc/PE=1/1) to give 4-(azepan-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl) pyridazine-3-carboxamide (300 mg, 76.9%) as a yellow solid. LCMS (ESI) calcd. for C18H21F3N5O2 [M+H]+ m/z 396.16, found 396.00.
Step 2: 4-(azepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide: To a solution of 4-(azepan-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide 7 (200 mg, 0.51 mmol) in ACN (3 mL) was added TMSI (141 mg, 1.01 mmol) at room temperature. The mixture was heated at 50° C. for 5 hours. LCMS showed the reaction was completed. The final mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried with sodium sulfate, concentrated, and purified by Prep-HPLC (Column: Gemini-C18, 150×21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 20%-38%-60%) to give 4-(azepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (15 mg, 7.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 11.05 (s, 1H), 7.35 (t, J=3.5 Hz, 2H), 6.84 (d, J=1.9 Hz, 1H), 6.44 (dd, J=7.2, 1.8 Hz, 1H), 3.57-3.50 (m, 4H), 1.74 (s, 4H), 1.48 (s, 4H). LCMS (ESI) calcd. for C17H19F3N5O2 [M+H]+ m/z 382.15, found 382.00.
To a solution of 3-(methylsulfonyl)aniline (338 mg, 1.98 mmol) in toluene (5 mL) was added Me3Al (1M in hexane, 2.18 mL, 2.18 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 0.5 h. Then a solution of methyl 4-(azepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxylate (200 mg, 0.66 mmol) in toluene (3 mL) was added at the same temperature. The resulting mixture was heated at 90° C. for 2 hours. LCMS showed the reaction was completed. The mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, concentrated, purified by prep-HPLC (Column: Gemini-C18, 150×21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 20%-38%-60%) to give 4-(azepan-1-yl)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (80 mg, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.39 (s, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.76-7.62 (m, 2H), 7.36 (s, 1H), 3.63-3.52 (m, 4H), 3.24 (s, 3H), 1.74 (s, 4H), 1.47 (s, 4H). LCMS (ESI) calcd. for C19H22F3N4O3S [M+H]+ m/z 443.13, found 443.10.
Step 1: A mixture of 4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (250 mg, 0.62 mmol), 3-bromobenzonitrile (335 mg, 1.86 mmol), Cs2CO3(606 mg, 1.86 mmol) and Xantphos-Pd-G2 (52 mg, 0.06 mmol) in 1,4-dioxane (5 mL) was heated at 100° C. overnight under an atmosphere of N2. LCMS showed the reaction was completed. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=4/1) to give N-(3-cyanophenyl)-4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (200 mg, 75.7%) as a white solid. LCMS (ESI) calcd. for C19H17F5N5O [M+H]+ m/z 426.14, found 426.00.
Step 2: N-(3-carbamoylphenyl)-4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide: To a solution of N-(3-cyanophenyl)-4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (100 mg, 0.24 mmol) in DMSO (5 mL) was added K2CO3 (100 mg, 0.72 mmol) and H2O2(30% solution, 0.5 mL). The solution was stirred at room temperature for 4 hours. LCMS showed the reaction was completed. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Column: Gemini-C18, 150×21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.05% NH3), Gradient: 20%-80%) to give N-(3-carbamoylphenyl)-4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (40 mg, 38%) as a white solid. LCMS (ESI) calcd. for C19H20F5N5O2 [M+H]+ m/z 444.15, found 444.30. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.41 (s, 2H), 3.72-3.63 (m, 2H), 3.58 (t, J=5.7 Hz, 2H), 2.37-2.24 (m, 2H), 2.13-2.19 (m, 2H), 1.93-1.84 (m, 2H).
A solution of 4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (100 mg, 0.30 mmol), 1-bromo-3-(methylsulfonyl)benzene (143 mg, 0.61 mmol), Cs2CO3 (293 mg, 0.9 mmol) and Xantphos-Pd-G2 (27 mg, 0.03 mmol) in 1,4-dioxane (3 mL) was heated at 100° C. overnight under an atmosphere of N2. LCMS showed the reaction was complete. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (Column: Gemini-C18, 150×21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.05% FA), Gradient: 35%-85%) to give 4-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-3-carboxamide (36 mg, 25%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.40 (s, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.88-7.61 (m, 2H), 7.44 (s, 1H), 3.70-3.63 (m, 2H), 3.55 (t, J=5.7 Hz, 2H), 3.24 (s, 3H), 2.37-2.24 (s, 2H), 2.16-1.96 (m, 2H), 1.94-1.83 (m, 2H). LCMS (ESI) calcd. for C19H20F5N4O3S [M+H]+ m/z 479.12, found 479.05.
Step 1: 4-(4,4-difluoroazepan-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide: A mixture of 4-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (250 mg, 0.77 mmol), 4-bromo-2-methoxypyridine (215 mg, 1.16 mmol), Cs2CO3 (625 mg, 1.93 mmol) and Xantphos-Pd-G2 (18 mg, 0.02 mmol) in dioxane (5 mL) was heated at 100° C. for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/3) to provide 4-(4,4-difluoroazepan-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (200 mg, 61.9%) as a yellow solid. LCMS (ESI) calcd. for C18H19F5N5O2 [M+H]+ m/z 432.15, found 432.10.
Step 2: 4-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide: To a solution of 4-(4,4-difluoroazepan-1-yl)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl) pyridazine-3-carboxamide (150 mg, 0.35 mmol) in MeCN (2 mL) was added TMSI (97 mg, 0.70 mmol) at room temperature. The mixture was heated at 50° C. for 5 hours. LCMS showed the reaction was completed. The final mixture was concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (DCM/MeOH=10/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150×21.2 mm, eluting with 30% to 90% ACN-H2O containing 0.1% formic acid) to afford 4-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-3-carboxamide (62 mg, 43%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 11.08 (s, 1H), 7.44 (s, 1H), 7.36 (d, J=7.0 Hz, 1H), 6.86 (d, J=1.8 Hz, 1H), 6.47 (d, J=7.1 Hz, 1H), 3.70-3.58 (m, 2H), 3.51 (t, J=5.6 Hz, 2H), 2.36-2.24 (m, 2H), 2.11-2.01 (m, 2H), 1.92-1.85 (m, 2H). LCMS (ESI) calcd. for C17H17F5N5O2 [M+H]+ m/z 418.13, found 418.05.
Step 1: methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate: To a solution of methyl 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (500 mg, 1.42 mmol) in MeCN (10 mL) was added NCS (228 mg, 1.70 mmol) at 25° C. The mixture was heated at 60° C. for 6 hours. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL×2). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to provide methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (450 mg, 79.0%) as a yellow solid. LCMS (ESI) calcd. for C16H19ClF5N2O2 [M+H]+ m/z 401.11, found 400.95.
Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid: To a solution of ethyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (450 mg, 1.12 mmol) in THF/EtOH/H2O (1/1, 10 mL) was added KOH (1.25 g, 22.44 mmol) at room temperature. The mixture was heated at 80° C. for 5 hours. After the reaction was completed, the mixture was concentrated to remove most THE and EtOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (350 mg, 83.7%) as a yellow solid. LCMS (ESI) calcd. for C14H15ClF5N2O2 [M+H]+ m/z 373.08, found 373.05.
Step 3: tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A mixture of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (200 mg, 0.73 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (174 mg, 0.87 mmol) in pyridine (5 mL) was added POCl3 (150 L) dropwise at room temperature. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (50 mg, 28.6%) as a yellow solid. LCMS (ESI) calcd. for C26H30ClF5N4O4SNa [M+H]+ m/z 647.15, found 647.10.
Step 4: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 0.08 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 85% MeCN/H2O containing 0.1% formic acid) to provide 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (14.1 mg, 33.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.29 (s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 4.24 (s, 1H), 3.62 (dt, J=12.0, 5.3 Hz, 4H), 3.07 (s, 3H), 2.41-2.21 (m, 5H), 2.08-1.96 (m, 2H), 1.86-1.78 (m, 2H). LCMS (ESI) calcd. for C21H23ClF5N4O2S [M+H]+ m/z 525.12, found 525.10.
Step 1: 2-(4,4-dimethoxybutan-2-ylidene)malononitrile: To a stirred solution of 4,4-dimethoxybutan-2-one (100 g, 0.76 mol), acetic acid ((4.54 g, 0.076 mol) and malononitrile (45 g, 0.68 mol) in toluene (250 mL) was added piperidine (6.44 g, 0.076 mol) in portions over 20 minutes. The reaction mixture was stirred overnight at room temperature. The mixture was washed with H2O (200 mL), dried over Na2SO4 and concentrated in vacuo to afford the crude 2-(4,4-dimethoxybutan-2-ylidene)malononitrile (50 g) which was used directly in the next step.
Step 2: 4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile: Crude 2-(4,4-dimethoxybutan-2-ylidene)malononitrile (50 g, about 278 mmol) was added dropwise to a stirred solution of concentrated H2SO4 (30 mL) at a rate that the reaction temperature did not exceed 30° C. The reaction mixture was then heated at 50° C. for 2 h. The resulting reaction mixture was cooled to room temperature and added slowly into ice-H2O (200 mL). The precipitate was collected by filtration, washed with water, and dried under vacuum to give the 4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (25 g, 67%) as white solid. LCMS (ESI) calcd. for C7H7N2O [M+H]+ m/z 135.06, found 134.95.
Step 3: 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid: A solution of 4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (25 g, 187 mmol) in 50% aqueous H2SO4 (40 mL) was heated at 120° C. for 8 hours. Then the reaction mixture was cooled to room temperature slowly poured into ice-water. The precipitate was collected by filtration, washed with water, and dried under vacuum to give crude 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (15 g, 52.1% yield) which was used in the next step without further purification. LCMS (ESI) calcd. for C7H7NO3 [M+H]+ m/z 154.05, found 154.0.
Step 4: methyl 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate: To a solution of 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (10 g, 65.3 mmol) in MeOH (120 mL) was added SOC2 (15 mL) dropwise. Then the mixture was heated at 65° C. for 16 hours. LCMS showed the reaction was completed. The mixture was concentrated to give the crude. The crude was diluted with ice-water, extracted with DCM (3×80 mL). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford crude methyl 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (10 g, 91.7%) which was used in the next step without further purification. LCMS (ESI) calcd. for C5H10NO3 [M+H]+ m/z 168.07, found 168.0.
Step 5: methyl 5-bromo-4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate: To a solution of methyl 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (10.0 g, 59.8 mmol) in DCM (100 mL) was added NBS (10.64 g, 59.8 mmol) at 0° C. The solution was stirred at the same temperature for 30 minutes. Then the mixture was washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford crude methyl 5-bromo-4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (16.5 g, 80% purity, 89.6%). LCMS (ESI) calcd. for C8H8BrNO3 [M+H]+ m/z 245.98, found 246.
Step 6: methyl 5-bromo-2-chloro-4-methylnicotinate: A solution of methyl 5-bromo-4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (4.0 g, 16.3 mmol) in phenyl dichlorophosphate (30 mL) was heated at 170° C. for 4 hours. The solution was cooled to room temperature, diluted with water, and extracted with DCM (2×70 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, concentrated under reduced pressure to afford the crude. The crude was purified by flash column chromatography on silica gel (PE/EtOAc=12/1) to give methyl 5-bromo-2-chloro-4-methylnicotinate (2.7 g, 63.2%). LCMS (ESI) calcd. for C8H8BrClNO2 [M+H]+ m/z 263.94, found 263.75.
Step 7: 5-bromo-2-chloro-4-methylnicotinic acid: To a solution of methyl 5-bromo-2-chloro-4-methylnicotinate (1.5 g, 5.7 mmol) in THF/H2O (1/1, 30 mL) was added KOH (3.19 g, 57 mmol) at room temperature. The mixture was heated at 80° C. for 16 hours. After the reaction was completed, the mixture was concentrated to remove most THF. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford 5-bromo-2-chloro-4-methylnicotinic acid (1.30 g, 90.9%) as a white solid. LCMS (ESI) calcd. for C7H6BrClNO2 [M+H]+ m/z 249.93, found 251.85.
Step 8: 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid: A solution of 5-bromo-2-chloro-4-methylnicotinic acid (400 mg, 1.59 mmol), 4,4-difluoroazepane hydrochloride (543 mg, 3.18 mmol), K2CO3 (1.43 g, 10.34 mmol) and DIEA (821 mg, 6.36 mmol) in NMP (10 mL) was heated at 140° C. for 6 hours. LCMS showed the reaction was completed. The mixture concentrated under vacuum and directly purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to provide 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (320 mg, 60% purity, 34.7% yield) as a yellow solid. LCMS (ESI) calcd. for C13H16BrF2N2O2 [M+H]+ m/z 351.04, found 350.9.
Step 9: tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (150 mg, 0.43 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (232 mg, 0.86 mmol) in pyridine (3 mL) was added POCl3 (100 L) dropwise at 50° C. The reaction solution was stirred at 50° C. for 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 31%) as a yellow solid. LCMS (ESI) calcd. for C25H32BrF2N4O4S [M+H]+ m/z 603.13, found 603.05.
Step 10: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-phenylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 0.083 mmol), phenylboronic acid (31 mg, 0.25 mmol), potassium carbonate (34.5 mg, 0.25 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (6 mg, 0.008 mmol) in 1,4-dioxane/H2O (4/1, 2 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=3/1) to give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-phenylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (40 mg, 80%) as a white oil. LCMS (ESI) calcd. for C31H37F2N4O4S [M+H]+ m/z 599.25, found 599.20.
Step 11: 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-phenylnicotinamide: A solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-phenylnicotinamido) phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (40 mg, 0.067 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 85% ACN-H2O containing 0.1% FA) to provide 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-phenylnicotinamide (14.5 mg, 42.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.47 (t, J=7.4 Hz, 2H), 7.37 (dd, J=19.8, 7.2 Hz, 3H), 4.22 (s, 1H), 3.58 (s, 4H), 3.06 (s, 3H), 2.31 (d, J=13.4 Hz, 2H), 2.15 (s, 3H), 2.01 (s, 2H), 1.82 (d, J=5.8 Hz, 2H). LCMS (ESI) calcd. for C26H29F2N4O2S [M+H]+ m/z 499.20, found 499.10.
Step 1: tert-butyl (R)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A mixture of (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (150 mg, 0.31 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (87 mg, 0.46 mmol) in DMF (10 mL) was added HATU (175 mg, 0.46 mmol) and DIEA (120 mg, 0.93 mmol). The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (110 mg, 53.6%) as a white oil. LCMS (ESI) calcd. for C28H36F5N6O5S [M+H]+ m/z 663.24, found 663.20.
Step 2: (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of tert-butyl (R)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (110 mg, 0.16 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% NH3) to obtain (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (51.3 mg, 56.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 8.29 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.75-7.66 (m, 2H), 2.85 (s, 2H), 3.68 (t, J=6.0 Hz, 2H), 3.47 (s, 3H), 3.19 (s, 2H), 2.41-2.30 (m, 5H), 2.23 (s, 3 H), 2.14-1.97 (m, 2H), 1.95-1.83 (m, 2H). LCMS (ESI) calcd. for C23H28F5N6O3S [M+H]+ m/z 563.19, found 563.
Step 1: tert-butyl (S)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A mixture of (S)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide(100 mg, 0.204 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (66 mg, 0.346 mmol) in DMF (10 mL) was added HATU (101 mg, 0.265 mmol) and DIEA (85 mg, 0.653 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (S)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (85 mg, 62.96%) as a white oil. LCMS (ESI) calcd. for C28H36F5N6O5S [M+H]+ m/z 663.24, found 663.15.
Step 2: (S)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of tert-butyl (S)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (85 mg, 0.128 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (S)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (43.98 mg, 60.93%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.39 (bs, 1H), 8.28 (s, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.67-7.63 (m, 2H), 3.85-3.78 (m, 2H), 3.71-3.68 (m, 2H), 3.45 (s, 3H), 3.14 (s, 2H), 2.40-2.38 (m, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 2.08-2.01 (m, 2H), 1.89-1.87 (m, 2H). LCMS (ESI) calcd. for C23H28F5N6O3S [M+H]+ m/z 563.19, found 563.15.
Step 1: tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (2 g, 5.75 mmol) in DCM (20 mL) was added (COCl)2 (1.3 g, 10.34 mmol) and DMF (0.05 mL). The mixture was stirred at room temperature for 0.5 h. Then the mixture was concentrated in vacuum. The residue was diluted with THE (20 mL) and added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (1.7 g, 6.33 mmol) and DIEA (2.2 g, 17.25 mmol) in THE (20 mL). The reaction solution was heated at 50° C. for 1 hour. After the reaction was completed, the resulting solution was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/2) to give tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (2.1 g, 61.05%) as a yellow solid. LCMS (ESI) calcd. for C25H32BrF2N4O4S [M+H]+ m/z 603.13, found 603.00.
Step 2: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (900 mg, 1.5 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (378 mg, 3.0 mmol), K2CO3 (621 mg, 4.5 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (120 mg, 0.16 mmol) in 1,4-dioxane/H2O (4/1, 40 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL×3). The combine organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to provide tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (750 mg, 83%) as a white oil. LCMS (ESI) calcd. for C29H37F2N6O4S [M+H]+ m/z 603.26, found 603.15.
Step 3: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (650 mg, 1.08 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (50 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 85% MeCN/H2O containing 0.1% formic acid) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (311 mg, 57.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.37 (s, 1H), 8.17 (s, 1H), 7.89 (d, J=3.4 Hz, 2H), 7.67 (d, J=7.8 Hz, 1H), 7.63-7.55 (m, 2H), 4.22 (s, 1H), 3.88 (s, 3H), 3.65-3.49 (m, 4H), 3.06 (s, 3H), 2.30-2.24 (m, 5H), 1.98 (t, J=11.3 Hz, 2H), 1.80 (d, J=5.6 Hz, 2H). LCMS (ESI) calcd. for C24H29F2N6O2S [M+H]+ m/z 503.20, found 503.15.
Step 1: tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A solution of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (60 mg, 0.12 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (45.2 mg, 0.24 mmol) and HATU (59 mg, 0.155 mmol) in DMF (5 mL) was added DIEA (46.3 mg, 0.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (55 mg, 68%) as a yellow oil. LCMS (ESI) calcd. for C32H42F2N7O5S [M+H]+ m/z 674.29, found 674.25.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide: To a solution of tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (55 mg, 0.17 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 75% MeCN/H2O containing 0.05% NH3) to afford (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide (15.3 mg, 16%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.38 (s, 1H), 8.18 (s, 1H), 7.98 (dt, J=6.5, 2.1 Hz, 1H), 7.90 (s, 1H), 7.67 (dd, J=9.6, 4.2 Hz, 2H), 7.61 (s, 1H), 3.89 (s, 3H), 3.68-3.58 (m, 2H), 3.54 (t, J=6.1 Hz, 2H), 3.45 (s, 3H), 3.20 (s, 2H), 2.32-2.19 (m, 8H), 1.99 (dd, J=15.6, 9.9 Hz, 2H), 1.80 (d, J=5.7 Hz, 2H). LCMS (ESI) calcd. for C27H34F2N7O3S [M+H]+ m/z 574.24, found 574.20.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.33 mmol), (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (120 mg, 0.67 mmol), K2CO3 (93 mg, 0.67 mmol) and Pd(dppf)Cl2 (22 mg, 0.03 mmol) in dioxane (8 mL) and H2O (2 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1 to 1/2) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (190 mg, 87.7%) as a yellow solid. LCMS (ESI) calcd. for C33H39F2N4O6S [M+H]+ m/z 657.26, found 657.15
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (190 mg, 0.29 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The half of residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 90% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (23.1 mg, 29%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.71-7.52 (m, 2H), 6.93 (d, J=8.2 Hz, 1H), 6.86-6.72 (m, 2H), 4.28 (s, 4H), 4.21 (s, 1H), 3.68-3.49 (m, 4H), 3.05 (s, 3H), 2.31-2.20 (m, 2H), 2.15 (s, 3H), 2.07-1.95 (m, 2H), 1.84-1.76 (m, 2H). LCMS (ESI) calcd. for C28H31F2N4O4S [M+H]+ m/z 557.21, found 557.15.
Step 1: tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide(100 mg, 0.18 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (41 mg, 0.22 mmol) in DMF (10 mL) was added HATU (103 mg, 0.27 mmol) and DIEA (70 mg, 0.54 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (75 mg, 57.2%) as a yellow solid. LCMS (ESI) calcd. for C36H44F2N5O7S [M+H]+ m/z 728.30, found 728.25.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (75 mg, 0.10 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to obtain (R)-2-(4,4-difluoroazepan-1-yl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide (30.3 mg, 48.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.39 (s, 1H), 8.10-7.91 (m, 2H), 7.72-7.60 (m, 2H), 6.93 (d, J=8.2 Hz, 1H), 6.85-6.72 (m, 2H), 4.28 (s, 4H), 3.68-3.51 (m, 4H), 3.45 (s, 3H), 3.19 (s, 2H), 2.35-2.19 (m, 5H), 2.15 (s, 3H), 2.07-1.94 (m, 2H), 1.84-1.76 (m, 2H). LCMS (ESI) calcd. for C31H36F2N5O5S [M+H]+ m/z 628.24, found 628.15.
Step 1: tert-butyl (R)-((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (500 mg, 0.83 mmol), (4-cyanophenyl)boronic acid (380 mg, 2.50 mmol), potassium carbonate (345 mg, 2.50 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (130 mg, 0.17 mmol) in 1,4-dioxane/H2O (4/1, 50 mL) was heated at 100° C. for 6 hours under an atmosphere of N2. After the reaction was completed, the mixture was diluted with water (200 mL) and extracted with DCM (80 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (510 mg, 98%) as a yellow solid. LCMS (ESI) calcd. for C32H36F2N5O4S [M+H]+ m/z 624.24, found 624.20.
Step 2: (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (510 mg, 0.82 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with DCM (50 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (245 mg, 57%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.93-7.89 (m, 3H), 7.67 (d, J=7.6 Hz, 1H), 7.60-7.56 (m, 3H), 4.22 (s, 1H), 3.68-3.66 (m, 2H), 3.61-3.58 (m, 2H), 3.06 (s, 3H), 2.32-2.29 (m, 2H), 2.16 (s, 3H), 2.02-2.00 (m, 2H), 1.83-1.82 (m, 2H). LCMS (ESI) calcd. for C27H28F2N5O2S [M+H]+ m/z 524.19, found 524.15.
Step 1: tert-butyl (R)-(2-(((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A mixture of (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (130 mg, 0.25 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (94.5 mg, 0.5 mmol) and HATU (141.6 mg, 0.37 mmol) in DMF (3 mL) was added DIEA (96.3 mg, 0.74 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-(2-(((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (100 mg, 57.6%) as a yellow solid. LCMS (ESI) calcd. for C35H41F2N6O5S [M+H]+ m/z 695.28, found 695.25.
Step 2: (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-(2-(((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (100 mg, 0.144 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide (55.3 mg, 64.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.38 (s, 1H), 8.14 (s, 1H), 8.00-7.96 (m, 1H), 7.93 (d, J=8.1 Hz, 2H), 7.68-7.63 (m, 2H), 7.58 (d, J=8.1 Hz, 2H), 3.68 (d, J=4.5 Hz, 2H), 3.59 (t, J=6.0 Hz, 2H), 3.45 (s, 3H), 3.19 (s, 2H), 2.31 (d, J=7.6 Hz, 2H), 2.23 (s, 3H), 2.16 (s, 3H), 2.06-1.96 (m, 2H), 1.86-1.80 (m, 2H). LCMS (ESI) calcd. for C30H33F2N6O3S [M+H]+ m/z 595.23, found 595.15.
Step 1: tert-butyl (R)-3-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)azetidine-1-carboxylate: To a mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (100 mg, 0.199 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (80 mg, 0.398 mmol) and HATU (151 mg, 0.398 mmol) in DMF (5 mL) was added DIEA (77 mg, 0.597 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/4) to give tert-butyl (R)-3-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6--sulfaneylidene)carbamoyl)azetidine-1-carboxylate (92 mg, 67.65%) as a yellow oil. LCMS (ESI) calcd. for C33H42F2N7O5S [M+H]+ m/z 686.30, found 686.20.
Step 2: (R)-N-(3-(N-(azetidine-3-carbonyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide formate: A solution of tert-butyl (R)-3-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)azetidine-1-carboxylate (92 mg, 0.134 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-N-(3-(N-(azetidine-3-carbonyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide formate (45 mg, 57.69%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 8.09 (d, J=7.3 Hz, 1H), 7.90 (s, 1H), 7.73-7.65 (m, 2H), 7.61 (s, 1H), 3.98-3.78 (m, 8H), 3.63-3.53 (m, 5H), 3.48 (s, 3H), 2.33-2.18 (m, 5H), 2.07-1.94 (m, 2H), 1.85-1.74 (m, 2H). LCMS (ESI) calcd. for C28H34F2N7O3S [M+H]+ m/z 586.24, found 586.15.
Step 1: tert-butyl (R)-(1-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate: To a mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (100 mg, 0.20 mmol), 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (81 mg, 0.40 mmol) and HATU (151 mg, 0.40 mmol) in DMF (5 mL) was added DIEA (77 mg, 0.60 mmol). The mixture was stirred at 50° C. for 16 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1 to 1/4) to give tert-butyl (R)-(1-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate (85 mg, 62.04%) as a yellow oil. LCMS (ESI) calcd. for C33H44F2N7O5S [M+H]+ m/z 688.31, found 688.25.
Step 2: (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide formate: A solution of tert-butyl (R)-(1-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate (85 mg, 0.12 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide formate (30.5 mg, 43.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.44 (d, J=1.6 Hz, 1H), 8.33 (d, J=3.7 Hz, 1H), 8.18 (d, J=2.6 Hz, 1H), 8.03-7.87 (m, 2H), 7.75-7.57 (m, 3H), 3.88 (s, 3H), 3.63-3.58 (m, 2 H), 3.56-3.52 (m, 2H), 3.49 (s, 3H), 2.34-2.21 (m, 5H), 2.09-1.93 (m, 2H), 1.87-1.74 (m, 2H), 1.40-1.27 (m, 6H). LCMS (ESI) calcd. for C28H36F2N7O3S [M+H]+ m/z 588.26, found 588.20.
Step 1: tert-butyl (R)-(1-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclopropyl)carbamate: To a mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (100 mg, 0.20 mmol), 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid (80 mg, 0.40 mmol) and HATU (151 mg, 0.40 mmol) in DMF (5 mL) was added DIEA (77 mg, 0.60 mmol). The mixture was stirred at 50° C. for 16 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/4) to give tert-butyl (R)-(1-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclopropyl)carbamate (85 mg, 62.5%) as a yellow oil. LCMS (ESI) calcd. for C33H42F2N7O5S [M+H]+ m/z 686.30, found 686.25.
Step 2: (R)-N-(3-(N-(1-aminocyclopropane-1-carbonyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide formate: A solution of tert-butyl (R)-(1-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclopropyl)carbamate (85 mg, 0.12 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-N-(3-(N-(1-aminocyclopropane-1-carbonyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide formate (52.3 mg, 72.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.38 (s, 1H), 8.18 (s, 2H), 7.98 (d, J=5.9 Hz, 1H), 7.90 (s, 1H), 7.69-7.62 (m, 2H), 7.61 (s, 1H), 3.89 (s, 3H), 3.65-3.59 (m, 2H), 3.55 (t, J=5.9 Hz, 2H), 3.44 (s, 3H), 2.32-2.15 (m, 5H), 2.06-1.91 (m, 2H), 1.85-1.76 (m, 2H), 1.29-1.17 (m, 2H), 0.87-0.79 (m, 2H). LCMS (ESI) calcd. for C28H34F2N7O3S [M+H]+ m/z 586.24, found 586.20.
To a mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (120 mg, 0.24 mmol), oxetane-3-carboxylic acid (49 mg, 0.48 mmol) and HATU (182 mg, 0.48 mmol) in DMF (5 mL) was added DIEA (92 mg, 0.72 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/4) to give the crude product. Then the residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methyl-N-(oxetane-3-carbonyl)sulfonimidoyl)phenyl)nicotinamide (85.2 mg, 60.87%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.97 (d, J=6.4 Hz, 1H), 7.90 (s, 1H), 7.71-7.64 (m, 2H), 7.61 (s, 1H), 4.71-4.58 (m, 4H), 3.88 (s, 3H), 3.85-3.77 (m, 1H), 3.63-3.58 (m, 2H), 3.54 (t, J=5.9 Hz, 2H), 3.48 (s, 3H), 2.31-2.19 (m, 5H), 2.06-1.93 (m, 2H), 1.85-1.74 (m, 2H). LCMS (ESI) calcd. for C28H33F2N6O4S [M+H]+ m/z 587.23, found 587.15.
Step 1: tert-butyl (R)-(1-(((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate: A mixture of (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (100 mg, 0.19 mmol), 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (77.6 mg, 0.38 mmol) and HATU (109 mg, 0.29 mmol) in DMF (3 mL) was added DIEA (74 mg, 0.57 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 16 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-(1-(((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate (95 mg, 70.6%) as a yellow solid. LCMS (ESI) calcd. for C36H43F2N6O5S [M+H]+ m/z 709.30, found 709.20.
Step 2: (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide: A solution of tert-butyl (R)-(1-(((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate (95 mg, 0.13 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (41.3 mg, 67.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.41 (s, 1H), 8.14 (s, 1H), 7.93 (d, J=8.4 Hz, 3H), 7.69-7.64 (m, 2H), 7.58 (d, J=8.3 Hz, 2H), 3.71-3.64 (m, 2H), 3.59 (t, J=6.0 Hz, 2H), 3.43 (s, 3H), 2.36-2.27 (m, 2H), 2.16 (s, 3H), 2.06-1.96 (m, 2H), 1.87-1.67 (m, 4H), 1.20 (d, J=3.6 Hz, 6H). LCMS (ESI) calcd. for C31H35F2N6O3S [M+H]+ m/z 609.25, found 609.20.
Step 1: ethyl 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate: A solution of ethyl 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (1.4 g, 3.82 mmol) and NBS (817 mg, 4.59 mmol) in MeCN (30 mL) was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The mixture was diluted with water (60 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=5/1) to provide ethyl 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (1.6 g, 94.1%) as yellow solid. LCMS (ESI) calcd. for C16H19BrF5N2O2 [M+H]+ m/z 447.06, found 447.05.
Step 2: 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid: To a solution of ethyl 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (1.6 g, 3.59 mmol) in EtOH/THF/H2O (1/1/1, 30 mL) was added KOH (2.01 g, 35.9 mmol) at 25° C. The mixture was heated at 80° C. for 16 hours. After the reaction was completed, the mixture was concentrated to remove most EtOH/THF. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (1.2 g, 80.1%) as a yellow solid. LCMS (ESI) calcd. for C14H15BrF5N2O2 [M+H]+ m/z 417.03, found 417.00.
Step 3: tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (600 mg, 1.44 mmol) in SOCl2 (6 mL) was heated to 80° C. for 0.5 h. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in DCM (5 mL) was added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (465 mg, 1.72 mmol) and TEA (436 mg, 4.30 mmol) in DCM (6 mL) at 0° C. The resulting mixture was stirred at 40° C. for 2 hours. Then the mixture was quenched with water (50 mL) and extracted with DCM (50 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (450 mg, 32.7%) as a yellow solid. LCMS (ESI) calcd. for C26H31BrF5N4O4S [M+H]+ m/z 671.12, found 671.05.
Step 4: tert-butyl (R)-((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.299 mmol), Zn(CN)2 (39 mg, 0.329 mmol), Pd2(dba)3 (55 mg, 0.060 mmol) in DMA (2 mL) was heated at 120° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate(110 mg, 53.8%) as a yellow solid. LCMS (ESI) calcd. for C27H30F5N5O4SNa [M+Na]+ m/z 618.19, found 638.15.
Step 5: (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (110 mg, 0.179 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 80% MeCN/H2O containing 0.1% formic acid) to provide (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (72.1 mg, 76.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.27 (s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.71 (d, J=7.9 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 4.26 (s, 1H), 3.69 (t, J=25.8 Hz, 4H), 3.07 (s, 3H), 2.47 (s, 3H), 2.32 (d, J=8.9 Hz, 2H), 2.08-1.99 (m, 2H), 1.86 (s, 2H). LCMS (ESI) calcd. for C22H23F5N5O2S [M+H]+ m/z 516.15, found 516.35.
Step 1: tert-butyl (R)-3-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl) azetidine-1-carboxylate: A solution of (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl) phenyl)-6-(trifluoromethyl)nicotinamide (95 mg, 0.18 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (75 mg, 0.37 mmol), HATU (140 mg, 0.37 mmol) and DIEA (71 mg, 0.55 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (40 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=95/5) to provide tert-butyl (R)-3-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl) azetidine-1-carboxylate (100 mg, 77.7%) as brown oil. LCMS (ESI) calcd. for C31H35F5N6O5SNa [M+Na]+ m/z 721.22, found 721.20.
Step 2: (R)-N-(3-(N-(azetidine-3-carbonyl)-S-methylsulfonimidoyl)phenyl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide formate A solution of tert-butyl (R)-3-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)azetidine-1-carboxylate (100 mg, 0.14 mmol) in DCM (4 mL) was added TFA (0.4 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-N-(3-(N-(azetidine-3-carbonyl)-S-methylsulfonimidoyl)phenyl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide formate (38.72 mg, 43.74%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.53 (d, J=9.3 Hz, 2H), 7.88 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 4.28-4.15 (m, 4H), 3.90-3.77 (m, 2H), 3.74-3.69 (m, 3H), 3.48 (s, 3H), 2.54 (s, 3H), 2.36-2.26 (m, 2H), 2.09-1.88 (m, 4H). LCMS (ESI) calcd. for C26H28F5N6O3S [M+H]+ m/z 599.19, found 599.15.
Step 1: tert-butyl (R)-(3-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-3-oxopropyl)carbamate: A solution of (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (110 mg, 0.21 mmol), 3-((tert-butoxycarbonyl)amino)propanoic acid (61 mg, 0.32 mmol), HATU (162 mg, 0.43 mmol) and DIEA (83 mg, 0.64 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=95/5) to provide tert-butyl (R)-(3-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-3-oxopropyl)carbamate (100 mg, 63.2%) as brown oil. LCMS (ESI) calcd. for C30H36F5N6O5S [M+H]+ m/z 687.24, found 687.10.
Step 2: (R)-N-(3-(N-(3-aminopropanoyl)-S-methylsulfonimidoyl)phenyl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide formate: A solution of tert-butyl (R)-(3-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-3-oxopropyl)carbamate (100 mg, 0.15 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-N-(3-(N-(3-aminopropanoyl)-S-methylsulfonimidoyl)phenyl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide formate (31.3 mg, 36.2%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.53 (s, 2H), 7.91-7.84 (m, 1H), 7.83-7.86 (m, 1H), 7.69 (t, J=8.0 Hz, 1H), 3.84 (s, 2H), 3.77-3.71 (m, 2H), 3.47 (s, 3H), 3.15 (t, J=6.5 Hz, 2H), 2.76 (t, J=6.5 Hz, 2H), 2.55 (s, 3H), 2.39-2.25 (m, 2H), 2.11-1.87 (m, 4H). LCMS (ESI) calcd. for C25H28F5N6O3S [M+H]+ m/z 587.19, found 586.95.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,4-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol), (3,4-difluorophenyl)boronic acid (52.5 mg, 0.33 mmol), K2CO3 (68.9 mg, 0.5 mmol) and Pd(dppf)Cl2 (24.3 mg, 0.03 mmol) in 1,4-dioxane/H2O (4/1, 5 mL) was heated at 100° C. for 5 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,4-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (86 mg, 81.6%) as a yellow oil. LCMS (ESI) calcd. for C31H35F4N4O4S [M+H]+ m/z 635.23, found 635.10.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,4-difluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,4-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (86 mg, 0.136 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,4-difluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (21.1 mg, 29%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.37 (s, 1H), 8.10 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.56-7.49 (m, 1H), 7.49-7.43 (m, 1H), 7.21-7.17 (m, 1H), 4.22 (s, 1H), 3.68-3.64 (m, 2H), 3.59 (t, J=6.1 Hz, 2H), 3.06 (s, 3H), 2.37-2.22 (m, 2H), 2.16 (s, 3H), 2.07-1.94 (m, 2H), 1.85-1.79 (m, 2H). LCMS (ESI) calcd. for C26H27F4N4O2S [M+H]+ m/z 535.18, found 535.15
Step 1: tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,4-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,4-difluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (140 mg, 0.26 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (99.1 mg, 0.52 mmol) and HATU (149.4 mg, 0.39 mmol) in DMF (3 mL) was added DIEA (101.6 mg, 0.79 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,4-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (120 mg, 55.5%) as a yellow solid. LCMS (ESI) calcd. for C34H40F4N5O5S [M+H]+ m/z 706.27, found 706.25.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,4-difluorophenyl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,4-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (120 mg, 0.17 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,4-difluorophenyl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide (56.2 mg, 64.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.99 (dd, J=6.8, 2.1 Hz, 1H), 7.70-7.63 (m, 2H), 7.56-7.42 (m, 2H), 7.23-7.16 (m, 1H), 3.70-3.64 (m, 2H), 3.58 (t, J=6.0 Hz, 2H), 3.46 (s, 3H), 3.20 (s, 2H), 2.39-2.7 (m, 2H), 2.24 (s, 3H), 2.17 (s, 3H), 2.08-1.95 (m, 2H), 1.87-1.77 (m, 2H). LCMS (ESI) calcd. for C29H32F4N5O3S [M+H]+ m/z 606.22, found 606.15.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,5-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate(100 mg, 0.17 mmol), (3,5-difluorophenyl)boronic acid (53 mg, 0.33 mmol), K2CO3, (69 mg, 0.5 mmol) and Pd(dppf)Cl2 (24 mg, 0.03 mmol) in 1,4-dioxane/H2O (4/1, 5 mL) was heated at 100° C. for 5 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,5-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 64.8%) as a yellow oil. LCMS (ESI) calcd. for C31H35F4N4O4S [M+H]+ m/z 635.23, found 635.20.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,5-difluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,5-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 0.11 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,5-difluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (33.2 mg, 56.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.12 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.70-7.53 (dt, J=15.8, 8.0 Hz, 2H), 7.33-7.19 (m, 1H), 7.15-7.04 (m, 2H), 4.22 (s, 1H), 3.70-3.55 (m, 4H), 3.06 (d, J=0.7 Hz, 3H), 2.32-2.23 (m, 2H), 2.18 (s, 3H), 2.07-1.95 (m, 2H), 1.88-1.76 (m, 2H). LCMS (ESI) calcd. for C26H27F4N4O2S [M+H]+ m/z 535.18, found 535.10
Step 1: tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,5-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,5-difluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (130 mg, 0.24 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (55 mg, 0.29 mmol) in DMF (5 mL) was added HATU (137 mg, 0.36 mmol) and DIEA (93 mg, 0.72 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,5-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (105 mg, 61.9%) as a yellow solid. LCMS (ESI) calcd. for C34H40F4N5O5S [M+H]+ m/z 706.27, found 706.20.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,5-difluorophenyl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,5-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (105 mg, 0.15 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to obtain (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,5-difluorophenyl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide (53.5 mg, 58.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.39 (d, J=10.8 Hz, 1H), 8.13 (s, 1H), 8.02-7.93 (m, 1H), 7.71-7.62 (m, 2H), 7.27 (t, J=9.5 Hz, 1H), 7.11 (d, J=6.8 Hz, 2H), 3.69-3.56 (m, 4H), 3.45 (s, 3H), 3.19 (s, 2H), 2.35-2.18 (m, 8H), 2.07-1.95 (m, 2H), 1.86-1.78 (m, 2H). LCMS (ESI) calcd. for C29H32F4N5O3S [M+H]+ m/z 606.22, found 606.15.
Step 1: tert-butyl (R)-((3-(5-(cyclopropylethynyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido) phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.33 mmol), ethynylcyclopropane (66 mg, 0.80 mmol), DBU (150 mg, 0.99 mmol) and Pd(PPh3)4 (20 mg, 0.03 mmol) in 1,4-dioxane (4 mL) was heated at 100° C. for 16 h under an atmosphere of N2.
After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (40 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give tert-butyl (R)-((3-(5-(cyclopropylethynyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (210 mg, 81.6%) as a yellow solid. LCMS (ESI) calcd. for C30H37F2N4O4S [M+H]+ m/z 587.25, found 587.25.
Step 2: (R)-5-(cyclopropylethynyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-(cyclopropylethynyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (210 mg, 0.35 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford (R)-5-(cyclopropylethynyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (200 mg, crude) as a yellow solid. LCMS (ESI) calcd. for C25H29F2N4O2S [M+H]+ m/z 487.20, found 487.10.
Step 1: tert-butyl (R)-(2-(((3-(5-(cyclopropylethynyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl) (methyl) carbamate: A solution of (R)-5-(cyclopropylethynyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (200 mg, 0.41 mmol) in DMF (2 mL) was added N-(tert-butoxycarbonyl)-N-methylglycine (117 mg, 0.66 mmol), DIEA (169 mg, 1.23 mmol) and HATU (277 mg, 0.82 mmol) at 0° C. The resulting mixture was stirred at 25° C. for 1 hour. Then the mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to afford tert-butyl (R)-(2-(((3-(5-(cyclopropylethynyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (120 mg, 38.4%) as a yellow solid. LCMS (ESI) calcd. for C33H42F2N5O5S [M+H]+ m/z 658.29, found 658.25.
Step 2: (R)-5-(cyclopropylethynyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-(2-(((3-(5-(cyclopropylethynyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (120 mg, 0.18 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.05% NH3) to provide (R)-5-(cyclopropylethynyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide (35.5 mg, 37.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.35 (s, 1H), 8.17 (s, 1H), 7.96 (d, J=7.3 Hz, 1H), 7.67 (t, J=7.2 Hz, 2H), 3.66-3.59 (m, 2H), 3.56-3.51 (m, 2H), 3.46 (s, 3H), 3.19 (s, 2H), 2.29-2.19 (m, 8H), 2.03-1.94 (m, 2H), 1.83-1.76 (m, 2H), 1.61-1.53 (m, 1H), 0.92-0.87 (m, 2H), 0.74-0.69 (m, 2H). LCMS (ESI) calcd. for C28H34F2N5O3S [M+H]+ m/z 558.23, found 558.20.
Step 1: tert-butyl (R)-(2-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A mixture of (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (100 mg, 0.19 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (74 mg, 0.39 mmol) in DMF (10 mL) was added HATU (96 mg, 0.252 mmol) and DIEA (80 mg, 0.621 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(2-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (105 mg, 78.9%) as a white oil. LCMS (ESI) calcd. for C30H34F5N6O5S [M−H]+ m/z 685.13, found 685.10.
Step 2: (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-(2-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (105 mg, 0.15 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (46.1 mg, 51.79%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.60-7.56 (m, 1H), 3.78-3.75 (m, 2H), 3.66-3.63 (m, 2H), 3.34 (s, 3H), 3.26 (s, 2H), 2.45 (s, 3H), 2.26 (s, 3H), 2.26-2.21 (m, 2H), 1.96-1.89 (m, 2H), 1.86-1.83 (m, 2H). LCMS (ESI) calcd. for C25H28F5N6O3S [M+H]+ m/z 587.28, found 587.15.
Step 1: tert-butyl (R)-(1-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclopropyl)carbamate: A mixture of (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (110 mg, 0.21 mmol) and 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid (37 mg, 0.32 mmol) in DMF (10 mL) was added HATU (162 mg, 0.43 mmol) and DIEA (82 mg, 0.64 mmol). The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the resulting solution was diluted with water (40 mL) and extracted with DCM (40 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(1-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclopropyl)carbamate (105 mg, 80.32%) as a colorless oil. LCMS (ESI) calcd. for C31H36F5N6O5S [M−H]+ m/z 699.24, found 699.10.
Step 2: (R)-N-(3-(N-(1-aminocyclopropane-1-carbonyl)-S-methylsulfonimidoyl)phenyl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-(1-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclopropyl)carbamate (105 mg, 0.15 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (R)-N-(3-(N-(1-aminocyclopropane-1-carbonyl)-S-methylsulfonimidoyl)phenyl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide formate (60.5 mg, 66.56%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.17-11.04 (m, 1H), 8.31 (s, 1H), 8.23-8.16 (m, 1H), 7.94 (d, J=6.9 Hz, 1H), 7.70 (q, J=8.6, 7.9 Hz, 2H), 3.88-3.71 (m, 2H), 3.66 (t, J=5.5 Hz, 2H), 3.46 (s, 3H), 2.48 (s, 3H), 2.36-2.22 (m, 2H), 2.10-1.96 (m, 2H), 1.91-1.80 (m, 2H), 1.28-1.18 (m, 2H), 0.92-0.79 (m, 2H). LCMS (ESI) calcd. for C26H28F5N6O3S [M+H]+ m/z 599.19, found 599.20.
Step 1: tert-butyl (R)-((3-(5-(4-chlorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol), (4-chlorophenyl) boronic acid (32 mg, 0.20 mmol), K2CO3 (46 mg, 0.33 mmol) and Pd(dppf)Cl2 (12 mg, 0.02 mmol) in dioxane (10 mL) and H2O (2.5 mL) was heated at 100° C. for 6 hours. LCMS showed the reaction was completed. Then the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((3-(5-(4-chlorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 85.71%) as yellow oil. LCMS (ESI) calcd. for C31H36ClF2N4O4S [M+H]+ m/z 633.21, found 633.10.
Step 2: (R)-5-(4-chlorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-(4-chlorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.14 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3·H2O) to provide (R)-5-(4-chlorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (45.07 mg, 58.27%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.37 (s, 1H), 8.08 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.52 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 4.22 (s, 1H), 3.70-3.62 (m, 2H), 3.61-3.54 (m, 2H), 3.06 (s, 3H), 2.31-2.23 (m, 2H), 2.15 (s, 3H), 2.06-1.96 (m, 2H), 1.85-1.76 (m, 2H). LCMS (ESI) calcd. for C26H28ClF2N4O2S [M+H]+ m/z 533.16, found 533.15.
Step 1: tert-butyl (R)-(2-(((3-(5-(4-chlorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A solution of (R)-5-(4-chlorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (110 mg, 0.21 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (78 mg, 0.41 mmol), HATU (157 mg, 0.41 mmol) and DIEA (80 mg, 0.62 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (40 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-(2-(((3-(5-(4-chlorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (110 mg, 75.86%) as yellow oil. LCMS (ESI) calcd. for C34H41ClF2N5O5S [M+H]+ m/z 704.25, found 704.20.
Step 2: (R)-5-(4-chlorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-(2-(((3-(5-(4-chlorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (110 mg, 0.16 mmol) in DCM (2 mL) was added TFA (0.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-5-(4-chlorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide formate (36.88 mg, 98.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.39 (d, J=9.4 Hz, 2H), 8.08 (s, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.71-7.63 (m, 2H), 7.52 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 3.66 (s, 2H), 3.58 (t, J=5.7 Hz, 2H), 3.47 (s, 3H), 3.28 (s, 2H), 2.36-2.21 (s, 5H), 2.15 (s, 3H), 2.06-1.95 (m, 2H), 1.86-1.76 (m, 2H). LCMS (ESI) calcd. for C29H33ClF2N5O3S [M+H]+ m/z 604.20, found 604.15.
Step 1: tert-butyl (R)-((3-(5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (300 mg, 0.49 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (234 mg, 0.99 mmol), K2CO3 (207 mg, 1.49 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (37 mg, 0.05 mmol) in 1,4-dioxane/H2O (4/1, 15 mL) was heated at 100° C. for 6 hours under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (80 mL) and extracted with EA (40 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-((3-(5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (300 mg, 95.54%) as a yellow solid. LCMS (ESI) calcd. for C31H39F2N6O4S [M+H]+ m/z 629.27, found 629.35.
Step 2: (R)-5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.16 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (20 mL) and extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (R)-5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (60.7 mg, 71.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.37 (s, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.62-7.53 (m, 2H), 4.22 (s, 1H), 3.79-3.74 (m, 1H), 3.64-3.51 (m, 4H), 3.06 (s, 3H), 2.34-2.20 (m, 5H), 2.05-1.92 (m, 2H), 1.86-1.72 (m, 2H), 1.13-1.05 (m, 2H), 1.03-0.94 (m, 2H). LCMS (ESI) calcd. for C26H31F2N6O2S [M+H]+ m/z 529.22, found 529.20.
Step 1: tert-butyl (R)-(2-(((3-(5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A mixture of (R)-5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (140 mg, 0.27 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (100 mg, 0.53 mmol) and HATU (201 mg, 0.53 mmol) in DMF (3 mL) was added DIEA (104 mg, 0.81 mmol) at room temperature. The reaction mixture was heated at 50° C. for 2 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-(2-(((3-(5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (140 mg, 75.68%) as a yellow solid. LCMS (ESI) calcd. for C34H44F2N7O5S [M+H]+ m/z 700.31, found 700.25.
Step 2: (R)-5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-(2-(((3-(5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (140 mg, 0.20 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (R)-5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide (82.5 mg, 68.75%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.38 (s, 1H), 8.18 (s, 1H), 8.01-7.95 (m, 2H), 7.69-7.63 (m, 2H), 7.60 (d, J=0.5 Hz, 1H), 3.80-3.72 (m, 1H), 3.63-3.58 (m, 2H), 3.54 (t, J=6.1 Hz, 2H), 3.45 (s, 3H), 3.19 (s, 2H), 2.34-2.17 (m, 8H), 2.06-1.92 (m, 2H), 1.84-1.74 (m, 2H), 1.12-1.05 (m, 2H), 1.02-0.94 (m, 2H). LCMS (ESI) calcd. for C29H36F2N7O3S [M+H]+ m/z 600.26, found 600.40.
Step 1: tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (300 mg, 0.54 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (204 mg, 1.62 mmol), K2CO3 (224 mg, 1.62 mmol) and Pd(dppf)Cl2 (36 mg, 0.05 mmol) in 1,4-dioxane (20 mL) and H2O (5 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (40 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (290 mg, 89.2%) as a yellow solid. LCMS (ESI) calcd. for C28H36F2N7O4S [M+H]+ m/z 604.25, found 604.15.
Step 2: (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide: A solution of tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (290 mg, 0.48 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum to give the crude product. Half of the crude product was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% NH3) to provide (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide (15.1 mg, 12.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 7.88 (d, J=7.5 Hz, 2H), 7.70 (d, J=8.0 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 4.25 (s, 1H), 3.92 (s, 3H), 3.76-3.68 (m, 2H), 3.62 (t, J=6.0 Hz, 2H), 3.07 (s, 3H), 2.36-2.87 (s, 5H), 2.09-1.98 (m, 2H), 1.88-1.79 (m, 2H). LCMS (ESI) calcd. for C23H27F2N7O2S [M+H]+ m/z 504.20, found 504.10.
Step 1: tert-butyl (R)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A mixture of (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide (90 mg, 0.18 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (68 mg, 0.36 mmol) and HATU (103 mg, 0.27 mmol) in DMF (3 mL) was added DIEA (70 mg, 0.54 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM, 0 to 10%) to give tert-butyl (R)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (95 mg, 78.31%) as a yellow oil. LCMS (ESI) calcd. for C31H41F2N8O5S [M+H]+ m/z 675.29, found 675.30.
Step 2: (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)pyridazine-4-carboxamide: A solution of tert-butyl (R)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (95 mg, 0.14 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.05% NH3) to provide (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)pyridazine-4-carboxamide (30.20 mg, 37.58%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.48 (t, J=1.9 Hz, 1H), 8.06 (s, 1H), 8.02-7.95 (m, 1H), 7.91 (s, 1H), 7.89-7.81 (m, 1H), 7.71 (t, J=8.0 Hz, 1H), 4.00 (s, 3H), 3.86-3.79 (m, 2H), 3.73 (t, J=6.1 Hz, 2H), 3.47 (s, 3H), 3.40 (s, 2H), 2.44 (s, 3H), 2.41 (s, 3H), 2.39-2.29 (m, 2H), 2.15-2.07 (m, 2H), 1.99-1.95 (m, 2H). LCMS (ESI) calcd. for C26H33F2N8O3S [M+H]+ m/z 575.24, found 575.20.
Step 1: tert-butyl (R)-(1-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclobutyl)carbamate: A solution of (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (80 mg, 0.16 mmol), 1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (50 mg, 0.23 mmol), HATU (118 mg, 0.31 mmol) and DIEA (60 mg, 0.47 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (40 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=95/5) to provide tert-butyl (R)-(1-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclobutyl)carbamate (60 mg, 54.19%) as brown oil. LCMS (ESI) calcd. for C32H38F5N6O5S [M+H]+ m/z 713.26, found 713.15.
Step 2: (R)-N-(3-(N-(1-aminocyclobutane-1-carbonyl)-S-methylsulfonimidoyl)phenyl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-(1-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclobutyl)carbamate (60 mg, 0.08 mmol) in DCM (4 mL) was added TFA (0.4 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-N-(3-(N-(1-aminocyclobutane-1-carbonyl)-S-methylsulfonimidoyl)phenyl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide (16.20 mg, 31.39%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.38 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.77-7.65 (m, 2H), 3.75 (s, 2H), 3.65 (t, J=5.8 Hz, 2H), 3.50 (s, 3H), 2.47 (s, 3H), 2.45-2.37 (m, 2H), 2.36-2.23 (m, 2H), 2.10-1.96 (m, 2H), 1.94-1.72 (m, 6H). LCMS (ESI) calcd. for C27H30F5N6O3S [M+H]+ m/z 613.20, found 613.00.
Step 1: tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate: A solution of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (100 mg, 0.19 mmol), (tert-butoxycarbonyl)glycine (53 mg, 0.29 mmol), HATU (151 mg, 0.39 mmol) and DIEA (77 mg, 0.59 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (40 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=95/5) to provide tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (70 mg, 47.99%) as yellow solid. LCMS (ESI) calcd. for C31H40F2N7O5S [M+H]+ m/z 660.28, found 660.25.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: A solution of tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (70 mg, 0.11 mmol) in DCM (4 mL) was added TFA (0.4 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 80% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (20 mg, 21.33%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 8.01 (d, J=6.8 Hz, 1H), 7.90 (s, 1H), 7.66 (d, J=6.7 Hz, 2H), 7.61 (s, 1H), 3.88 (s, 3H), 3.61 (s, 2H), 3.54 (t, J=6.0 Hz, 2H), 3.45 (s, 3H), 3.23 (s, 2H), 2.34-2.26 (m, 2H), 2.25 (s, 3H), 2.06-1.94 (m, 2H), 1.84-1.74 (m, 2H). LCMS (ESI) calcd. for C26H32F2N7O3S [M+H]+ m/z 560.23, found 560.15.
Step 1: tert-butyl ((R)-1-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (100 mg, 0.19 mmol), (tert-butoxycarbonyl)-D-alanine (53 mg, 0.29 mmol) and HATU (144 mg, 0.38 mmol) in DMF (3 mL) was added DIEA (74 mg, 0.57 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM, 0 to 10%) to give tert-butyl ((R)-1-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (90 mg, 72.31%) as a yellow solid. LCMS (ESI) calcd. for C32H42F2N7O5S [M+H]+ m/z 674.29, found 675.20.
Step 2: N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: A solution of tert-butyl ((R)-1-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (95 mg, 0.14 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.05% NH3) to provide N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (20.20 mg, 27.58%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.38 (s, 1H), 8.18 (s, 1H), 7.98 (dd, J=7.1, 2.1 Hz, 1H), 7.90 (s, 1H), 7.68 (dd, J=10.8, 4.6 Hz, 2H), 7.61 (s, 1H), 3.88 (s, 3H), 3.62-3.58 (m, 2H), 3.54 (t, J=6.1 Hz, 2H), 3.45 (s, 3H), 3.29 (d, J=6.9 Hz, 1H), 2.35-2.26 (m, 2H), 2.25 (s, 3H), 2.04-1.94 (s, 2H), 1.82-1.76 (m, 2H), 1.18 (d, J=6.9 Hz, 3H). LCMS (ESI) calcd. for C27H34F2N7O3S [M+H]+ m/z 574.24, found 574.00.
Step 1: tert-butyl ((S)-1-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate: To a solution of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (100 mg, 0.20 mmol), (tert-butoxycarbonyl)-L-alanine (95 mg, 0.50 mmol) and HATU (114 mg, 0.30 mmol) in DMF (3 mL) and was added DIEA (77 mg, 0.60 mmol). Then the mixture was stirred at 25° C. for 3 hours. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (3×6 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with MeOH/DCM, 0 to 10%) to give tert-butyl ((S)-1-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (110 mg, 781.72%) as a yellow oil. LCMS (ESI) calcd. for C32H42F2N7O5S [M+H]+ m/z 674.29, found 674.20.
Step 2: N-(3-((R)-N-(L-alanyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide formate: A solution of tert-butyl ((S)-1-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (110 mg, 0.16 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*19 mm, eluting with 20% to 45% ACN/H2O containing 0.1% FA) to provide N-(3-((R)-N-(L-alanyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide formate (35.80 mg, 36.14% o) as a white solid. 1H NMR (400 MHz, CD3OD, ppm) δ 8.64 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.95-7.86 (m, 1H), 7.84-7.74 (m, 2H), 7.71 (t, J=8.0 Hz, 1H), 7.60 (s, 1H), 3.97 (s, 3H), 3.96-3.90 (m, 1H), 3.69-3.64 (m, 2H), 3.62 (t, J=6.2 Hz, 2H), 3.53 (d, J=10.4 Hz, 3H), 2.36 (s, 3H), 2.34-2.23 (m, 2H), 2.12-2.00 (m, 2H), 1.95-1.85 (m, 2H), 1.59 (t, J=6.9 Hz, 3H). LCMS (ESI) calcd. for C27H33F2N7O3SNa [M+Na]+ m/z 596.22, found 595.95.
Step 1: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzoic acid: A mixture of 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (1.2 g, 4.96 mmol), 4,4-difluoroazepane hydrochloride (933 mg, 5.45 mmol) and DIEA (1.9 g, 14.88 mmol) in DMSO (20 mL) was heated at 120° C. for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (60 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/4) to provide 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzoic acid (800 mg, 45.20%) as a yellow solid. LCMS (ESI) calcd. for C14H14ClF5NO2 [M+H]+ m/z 358.07, found 357.90.
Step 2: tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzoic acid (150 mg, 0.42 mmol) in DCM (5 mL) was added Oxalyl chloride (96 mg, 0.76 mmol) and DMF (0.02 mL). The mixture was stirred at room temperature for 1 h. Then the mixture was concentrated in vacuum. The residue was diluted with THF (5 mL) and added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (125 mg, 0.46 mmol) and DIEA (163 mg, 1.26 mmol) in THE (3 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 49.02%) as a yellow oil. LCMS (ESI) calcd. for C21H22ClF5N3O2S [M+H-Boc]+ m/z 510.11, found 510.00.
Step 3: (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: To a solution of tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo) λ6-sulfaneylidene)carbamate (100 mg, 0.16 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.05% NH3) to provide (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (56 mg, 67.47%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.34 (t, J=1.7 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.73-7.65 (m, 2H), 7.60 (t, J=7.9 Hz, 1H), 7.34 (s, 1H), 4.23 (s, 1H), 3.44-3.35 (m, 4H), 3.05 (s, 3H), 2.29-2.17 (m, 2H), 2.10-1.98 (m, 2H), 1.85-1.72 (m, 2H). LCMS (ESI) calcd. for C21H22ClF5N3O2S [M+H]+ m/z 510.11, found 510.05.
Step 1: 6-fluoro-2-methyl-3-nitrobenzoic acid: To a solution of fuming HNO3 (0.69 mL, 15.6 mmol) in sulfuric acid (4.4 mL) was added a solution of 2-fluoro-6-methylbenzoic acid (1.6 g, 10.4 mmol) in concentrated sulfuric acid (15 mL) at 0° C. and the mixture was stirred at 0° C. for 30 min. Then the mixture was poured into ice water (50 mL). The precipitate was collected by filtration, washed with water, and dried under vacuum to provide 6-fluoro-2-methyl-3-nitrobenzoic acid (1.7 g, 82.1%) as a yellow solid. LCMS (ESI) calcd. for C8H5FNO4 [M−H]-m/z 198.02, found 198.05.
Step 2: 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-nitrobenzoic acid: A mixture of 6-fluoro-2-methyl-3-nitrobenzoic acid (1.7 g, 8.54 mmol) and 4,4-difluoroazepane hydrochloride (1.76 g, 10.24 mmol) in NMP (30 mL) was added DIEA (5.52 g, 42.68 mmol) and K2CO3 (5.90 g, 42.68 mmol) at room temperature. The reaction mixture was heated at 140° C. for 16 hours. After the reaction was completed, the solution was adjusted to pH=5-6 with 1N HCl and extracted with DCM (150 mL×2). The combined organic layers were washed with brine (150 mL×3), dried over sodium sulfate, then concentrated and purified by flash column chromatography on silica gel (DCM/MeOH=20/1 to 10/1) to give 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-nitrobenzoic acid (1.6 g, 55.9%) as a white solid. LCMS (ESI) calcd. for C14H17F2N2O4 [M+H]+ m/z 315.12, found 315.05.
Step 3: methyl 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-nitrobenzoate: To a solution of 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-nitrobenzoic acid (1.6 g, 5.09 mmol) in DMF (20 mL) was added K2CO3 (1.41 g, 10.18 mmol) and Mel (1.08 g, 7.64 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was completed, solution was diluting with DCM (100 mL) and washed with brine (100 mL×3), dried over sodium sulfate, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1 to 1/3) to provide methyl 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-nitrobenzoate (1.5 g, 89.7%) as a light-yellow solid. LCMS (ESI) calcd. for C15H19F2N2O4 [M+H]+ m/z 329.13, found 329.10.
Step 4: methyl 3-amino-6-(4,4-difluoroazepan-1-yl)-2-methylbenzoate: A solution of methyl 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-nitrobenzoate (1.4 g, 4.26 mmol) in MeOH (30 mL) and water (10 mL) was added NH4Cl (1.60 g, 29.85 mmol), Fe (1.19 g, 21.32 mmol). The mixture was heated to 60° C. for 1 hour. After the reaction was completed, the mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide methyl 3-amino-6-(4,4-difluoroazepan-1-yl)-2-methylbenzoate (1.2 g, 94.3%) as a yellow solid. LCMS (ESI) calcd. for C15H21F2N2O2 [M+H]+m/z 299.16, found 299.10.
Step 5: methyl 6-(4,4-difluoroazepan-1-yl)-3-iodo-2-methylbenzoate: To a solution of TsOH·H2O (1.53 g, 8.04 mmol) and methyl 3-amino-6-(4,4-difluoroazepan-1-yl)-2-methylbenzoate (800 mg, 2.68 mmol) in MeCN (30 mL) was added a solution of NaNO2 (370 mg, 5.36 mmol) and KI (1.11 g, 6.70 mmol) in H2O (5 mL) at 0° C. The mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the mixture was quenched with water (100 mL), adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the solution was extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1 to 1/1) to provide methyl 6-(4,4-difluoroazepan-1-yl)-3-iodo-2-methylbenzoate (500 mg, 45.6%) as yellow solid. LCMS (ESI) calcd. for C15H19F2INO2 [M+H]+ m/z 410.05, found 410.00.
Step 6: methyl 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoate: A mixture of methyl 6-(4,4-difluoroazepan-1-yl)-3-iodo-2-methylbenzoate (400 mg, 0.98 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (184 mg, 1.47 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was added potassium carbonate (405 mg, 2.93 mmol) and Pd(dppf)Cl2 (143 mg, 0.20 mmol). Then the mixture was heated at 100° C. for 6 hours under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give methyl 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoate (300 mg, 84.5%) as a yellow oil. LCMS (ESI) calcd. for C19H24F2N3O2 [M+H]+ m/z 364.19, found 364.10.
Step 7: 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoic acid: To a solution of methyl 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoate (200 mg, 0.55 mmol) in MeOH/H2O (1/1, 10 mL) was added KOH (309 mg, 5.50 mmol) at room temperature. The reaction mixture was heated at 80° C. for 18 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=3-4 with aqueous HCl (1M). Then the solution was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoic acid (150 mg, 78.00%) as a white solid. LCMS (ESI) calcd. for C18H22F2N3O2 [M+H]+ m/z 350.17, found 350.10.
Step 8: tert-butyl (R)-((3-(6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzoic acid (150 mg, 0.43 mmol) in DCM (5 mL) was added oxalyl chloride (163 mg, 1.29 mmol) and DMF (20 L). The mixture was stirred at room temperature for 0.5 hour. Then the mixture was concentrated under vacuum. The residue was dissolved in THE (5 mL) and added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (139 mg, 0.52 mmol) and TEA (217 mg, 2.15 mmol) in THE (5 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (R)-((3-(6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 58.1%) as a yellow oil. LCMS (ESI) calcd. for C30H38F2N5O4S [M+H]+ m/z 602.26, found 602.15.
Step 9: (R)-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)benzamide: A solution of tert-butyl (R)-((3-(6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.25 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% NH4OH) to obtain (R)-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)benzamide (42.5 mg, 33.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.44 (s, 1H), 7.88 (d, J=7.3 Hz, 2H), 7.66-7.51 (m, 3H), 7.35 (d, J=8.3 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 4.19 (s, 1H), 3.88 (s, 3H), 3.17-3.08 (m, 4H), 3.03 (s, 3H), 2.28 (s, 3H), 2.13-1.88 (m, 4H), 1.68 (m, 2H). LCMS (ESI) calcd. for C25H30F2N5O2S [M+H]+ m/z 502.21, found 502.15.
Step 1: methyl 3-(azepan-1-yl)-5-methyl-6-(3-methylthiophen-2-yl)pyridazine-4-carboxylate: A mixture of methyl 3-(azepan-1-yl)-6-iodo-5-methylpyridazine-4-carboxylate (450 mg, 1.20 mmol) and (3-methylthiophen-2-yl)boronic acid (340 mg, 2.400 mmol) in 1,4-dioxane/H2O (4/1, 20 mL), potassium carbonate (324 mg, 2.400 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (87 mg, 0.12 mmol) was heated at 100° C. for 6 hours under an atmosphere of N2. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combine organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give methyl 3-(azepan-1-yl)-5-methyl-6-(3-methylthiophen-2-yl)pyridazine-4-carboxylate (320 mg, 77.29%) as a white solid. LCMS (ESI) calcd. for C18H24N3O2S [M+H]+ m/z 346.15, found 346.00.
Step 2: 3-(azepan-1-yl)-5-methyl-6-(3-methylthiophen-2-yl)pyridazine-4-carboxylic acid: To a solution of methyl 3-(azepan-1-yl)-5-methyl-6-(3-methylthiophen-2-yl)pyridazine-4-carboxylate (270 mg, 0.783 mmol) in MeOH/H2O (1/1, 8 mL) was added KOH (438 mg, 7.83 mmol) at room temperature. The mixture was heated at 70° C. for 5 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove most MeOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 3-(azepan-1-yl)-5-methyl-6-(3-methylthiophen-2-yl)pyridazine-4-carboxylic acid (180 mg, 69.49%) as a white solid. LCMS (ESI) calcd. for C17H22N3O2S [M+H]+ m/z 332.14, found 332.05.
Step 3: tert-butyl ((3-(3-(azepan-1-yl)-5-methyl-6-(3-methylthiophen-2-yl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 3-(azepan-1-yl)-5-methyl-6-(3-methylthiophen-2-yl)pyridazine-4-carboxylic acid (130 mg, 0.392 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (159 mg, 0.589 mmol) in pyridine (4 mL) was added POCl3 (305 L) at 50° C. The mixture was heated at 50° C. for 1 hour. LCMS showed the reaction was completed. The final mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried with sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc/PE=1/2) to give tert-butyl ((3-(3-(azepan-1-yl)-5-methyl-6-(3-methylthiophen-2-yl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 21.83%) as a yellow oil. LCMS (ESI) calcd. for C29H38N5O4S2 [M+H]+ m/z 584.23, found 584.15.
Step 4: 3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(3-methylthiophen-2-yl)pyridazine-4-carboxamide: To a solution of the tert-rt-butyl ((3-(3-(azepan-1-yl)-5-methyl-6-(3-methylthiophen-2-yl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 0.086 mmol) in DCM (2 mL) was added TFA (0.4 mL) at 0° C. The mixture was stirred room temperate for 2 hours. Then the mixture was concentrated and the residue was purified by prep-HPLC (Column: Gemini-C18, 150×21.2 mm, 5 um; Mobile Phase: ACN-H2O (0.1% FA), Gradient: 30%-40%-70%) to give 3-(azepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(3-methylthiophen-2-yl)pyridazine-4-carboxamide (3 mg, 12.20%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.30 (s, 1H), 7.89-7.88 (m, 1H), 7.70-7.68 (m, 1H), 7.60-7.58 (m, 2H), 7.05-7.03 (m, 1H), 4.24 (s, 1H), 3.70-3.68 (m, 4H), 3.07-3.05 (m, 4H), 2.09-2.07 (m, 4H), 1.77 (s, 3H), 1.51 (s, 3H), 1.23 (s, 3H). LCMS (ESI) calcd. for C24H30N5O2S2 [M+H]+ m/z 484.18, found 484.15.
Step 1: methyl 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinate: A mixture of methyl 2,6-dichloronicotinate (2.0 g, 9.75 mmol) and 6-azaspiro[2.5]octane hydrochloride (1.43 g, 9.75 mmol) in MeCN (20 mL) was added DIEA (2.52 g, 19.5 mmol) at room temperature. The reaction mixture was stirred at 25° C. for 16 hours. After the reaction was completed, the mixture was diluted with water (40 mL) and extracted with DCM (40 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to provide methyl 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (1.67 g, 61.1%) as a yellow solid. LCMS (ESI) calcd. for C14H18ClN2O2 [M+H]+ m/z 281.11, found 281.05.
Step 2: 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid: To a solution methyl 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (1.6 g, 5.69 mmol) in THF/H2O (1/1, 15 mL) was added KOH (3.18 g, 56.9 mmol) at room temperature. The mixture was heated at 70° C. for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (20 mL). Then the aqueous phase was adjusted to pH=3 with 1N HCl and extracted with DCM (20 mL×3). The combined organic phases were dried with Na2SO4 and concentrated under reduced pressure to give 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (1.4 g, 79.56%) as a yellow solid. LCMS (ESI) calcd. for C13H16ClN2O2 [M+H]+ m/z 267.09, found 266.95.
Step 3: tert-butyl ((3-(6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (300 mg, 1.12 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (364 mg, 1.34 mmol) in pyridine (5 mL) was added POCl3 (100 L) dropwise at 0° C. The reaction solution was stirred at 0° C. for 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl ((3-(6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 49.8%) as a yellow oil. LCMS (ESI) calcd. for C25H32ClN4O4S [M+Na]+ m/z 519.19, found 519.10.
Step 4: tert-butyl ((3-(6-(cyclopropylmethyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture tert-butyl ((3-(6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (180 mg, 0.34 mmol), (cyclopropylmethyl)trifluoroborate potassium (110 mg, 0.68 mmol), cesium carbonate (332 mg, 1.02 mmol), Pd(OAc)2 (23 mg, 0.10 mmol) and Ru-phos (32 mg, 0.068 mmol) in toluene/H2O (10/1, 11 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give tert-butyl ((3-(6-(cyclopropylmethyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 51.3%). LCMS (ESI) calcd. for C29H39N4O4S [M+H]+ m/z 539.27, found 539.25.
Step 5: 6-(cyclopropylmethyl)-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide: A solution of tert-butyl ((3-(6-(cyclopropylmethyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.17 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated, and the residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 85% MeCN/H2O containing 0.1% trifluoroacetic acid) to provide 6-(cyclopropylmethyl)-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (45.2 mg, 60.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.49 (s, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.67-7.53 (m, 2H), 6.90 (d, J=7.7 Hz, 1H), 4.20 (s, 1H), 3.33 (s, 4H), 3.05 (s, 3H), 2.57 (d, J=7.0 Hz, 2H), 1.39 (s, 4H), 1.08 (s, 1H), 0.48 (d, J=7.7 Hz, 2H), 0.35-0.16 (m, 6H). LCMS (ESI) calcd. for C24H31N4O2S [M+H]+ m/z 439.22, found 439.10.
Step 1: tert-butyl ((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6--sulfaneylidene)carbamate (100 mg, 0.167 mmol), (4-cyanophenyl)boronic acid (38 mg, 0.250 mmol), potassium carbonate (58 mg, 0.418 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (13 mg, 0.017 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 6 hours under an atmosphere of N2. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (74 mg, 71.15%) as a yellow oil. LCMS (ESI) calcd. for C32H36F2N5O4S [M+H]+ m/z 624.24, found 624.20.
Step 2: 5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (74 mg, 0.119 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (24.5 mg, 39.52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.93-7.89 (m, 3H), 7.67 (d, J=7.6 Hz, 1H), 7.60-7.56 (m, 3H), 4.22 (s, 1H), 3.68-3.66 (m, 2H), 3.61-3.58 (m, 2H), 3.06 (s, 3H), 2.32-2.29 (m, 2H), 2.16 (s, 3H), 2.02-2.00 (m, 2H), 1.83-1.82 (m, 2H). LCMS (ESI) calcd. for C27H28F2N5O2S [M+H]+ m/z 524.19, found 524.15.
Step 1: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.167 mmol), (3-fluorophenyl)boronic acid (35 mg, 0.250 mmol), potassium carbonate (58 mg, 0.418 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (13 mg, 0.017 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 6 hours under an atmosphere of N2. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (65 mg, 63.72%) as a yellow oil. LCMS (ESI) calcd. for C31H36F3N4O4S [M+H]+ m/z 617.23, found 617.25.
Step 2: 2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (65 mg, 0.106 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (25.1 mg, 46.29%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.66 (d, J=8 Hz, 1H), 7.58-7.56 (m, 1H), 7.53-7.47 (m, 1H), 4.22 (s, 1H), 3.65-3.60 (m, 2H), 3.58-3.57 (m, 2H), 3.05 (s, 3H), 2.32-2.26 (m, 2H), 2.16 (s, 3H), 2.00-1.96 (m, 2H), 1.83-1.81 (m, 2H). LCMS (ESI) calcd. for C26H28F3N4O2S [M+H]+ m/z 517.18, found 517.15.
Step 1: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.166 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (63 mg, 0.50 mmol), potassium carbonate (69.0 mg, 0.50 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (12 mg, 0.016 mmol) in 1,4-dioxane/H2O (4/1, 4 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combine organic phases were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6--sulfaneylidene)carbamate (78 mg, 78%) as a white oil. LCMS (ESI) calcd. for C29H37F2N6O4S [M+H]+ m/z 603.26, found 603.15.
Step 2: 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (78 mg, 0.13 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 85% MeCN/H2O containing 0.1% formic acid) to provide 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (23.5 mg, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.37 (s, 1H), 8.17 (s, 1H), 7.89 (d, J=3.4 Hz, 2H), 7.67 (d, J=7.8 Hz, 1H), 7.63-7.55 (m, 2H), 4.22 (s, 1H), 3.88 (s, 3H), 3.65-3.49 (m, 4H), 3.06 (s, 3H), 2.27 (d, J=16.4 Hz, 5H), 1.98 (t, J=11.3 Hz, 2H), 1.80 (d, J=5.6 Hz, 2H). LCMS (ESI) calcd. for C24H29F2N6O2S [M+H]+ m/z 503.21, found 503.15.
Step 1: tert-butyl ((3-(6-(4,4-difluoroazepan-1-yl)-4-methyl-[3,3bipyridine]-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.166 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (102.5 mg, 0.50 mmol), potassium carbonate (69.0 mg, 0.50 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (12 mg, 0.016 mmol) in 1,4-dioxane/H2O (4/1, 4 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combine organic phases were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((3-(6-(4,4-difluoroazepan-1-yl)-4-methyl-[3,3
bipyridine]-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (85 mg, 85.4%) as a white oil. LCMS (ESI) calcd. for C30H36F2N5O4S [M+H]+ m/z 600.25, found 600.20.
Step 2: 6-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-[3,3bipyridine]-5-carboxamide: A solution of tert-butyl ((3-(6-(4,4-difluoroazepan-1-yl)-4-methyl-[3,3
bipyridine]-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (85 mg, 0.14 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 85% MeCN/H2O containing 0.1% formic acid) to provide 6-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-[3,3-bipyridine]-5-carboxamide (22.3 mg, 32%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.65-8.52 (m, 2H), 8.38 (s, 1H), 8.13 (s, 1H), 7.86 (dd, J=37.2, 7.9 Hz, 2H), 7.67 (d, J=7.8 Hz, 1H), 7.62-7.47 (m, 2H), 3.70-3.58 (m, 4H), 3.07 (s, 3H), 2.30 (t, J=10.9 Hz, 2H), 2.16 (s, 3H), 2.00 (dd, J=14.7, 7.3 Hz, 2H), 1.83 (d, J=5.4 Hz, 2H). LCMS (ESI) calcd. for C25H28F2N5O2S [M+H]+ m/z 500.20, found 500.10.
Step 1: tert-butyl ((3-(6-(4,4-difluoroazepan-1-yl)-4-methyl-[3,4bipyridine]-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.200 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (61 mg, 0.300 mmol), potassium carbonate (69 mg, 0.500 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (15 mg, 0.020 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 6 hours under an atmosphere of N2. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((3-(6-(4,4-difluoroazepan-1-yl)-4-methyl-[3,4
bipyridine]-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 74.89%) as a yellow oil. LCMS (ESI) calcd. for C30H36F2N5O4S [M+H]+ m/z 600.24, found 600.20.
Step 2: 6-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-[3,4bipyridine]-5-carboxamide: A solution of give tert-butyl ((3-(6-(4,4-difluoroazepan-1-yl)-4-methyl-[3,4
bipyridine]-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.150 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 6-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-[3,4
bipyridine]-5-carboxamide (39.85 mg, 53.13%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.64 (d, J=5.2 Hz, 2H), 8.36 (s, 1H), 8.15 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.60-7.56 (m, 1H), 7.41 (d, J=5.6 Hz, 2H), 4.22 (s, 1H), 3.69-3.66 (m, 2H), 3.60-3.58 (m, 2H), 3.06 (s, 3H), 2.32-2.29 (m, 2H), 2.19 (s, 3H), 2.03-1.96 (m, 2H), 1.84-1.82 (m, 2H). LCMS (ESI) calcd. for C25H28F2N5O2S [M+H]+ m/z 500.19, found 500.10.
□ A solution of tert--butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 0.1 mmol) in DCM (2 mL) was added TFA (0.5 mL) at room temperature. The solution was stirred at room temperature for 2 hours. Then the solution was concentrated and the residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (25.7 mg, 51%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.31 (d, J=4.2 Hz, 2H), 7.89 (d, J=8.2 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 4.27 (s, 1H), 3.66-3.46 (m, 4H), 3.06 (s, 3H), 2.28 (d, J=12.4 Hz, 5H), 1.98 (s, 2H), 1.80 (d, J=5.6 Hz, 2H). LCMS (ESI) calcd. for C20H24BrF2N4O2S [M+H]+ m/z 501.07, found 501.05
Step 1: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(4-(difluoromethyl)phenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.166 mmol), (4-(difluoromethyl)phenyl)boronic acid (43 mg, 0.249 mmol), potassium carbonate (92 mg, 0.664 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (12 mg, 0.017 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 6 hours under an atmosphere of N2. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(4-(difluoromethyl)phenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 74%) as a yellow oil. LCMS (ESI) calcd. for C32H37F4N4O4S [M+H]+ m/z 649.24, found 649.20.
Step 2: 2-(4,4-difluoroazepan-1-yl)-5-(4-(difluoromethyl)phenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(4-(difluoromethyl)phenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 0.123 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The solution was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 2-(4,4-difluoroazepan-1-yl)-5-(4-(difluoromethyl)phenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (28 mg, 41%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.66 (d, J=7.9 Hz, 3H), 7.59 (d, J=7.9 Hz, 1H), 7.50 (d, J=7.9 Hz, 2H), 7.10 (s, 1H), 4.22 (s, 1H), 3.66 (s, 2H), 3.59 (t, J=6.0 Hz, 2H), 3.06 (s, 3H), 2.31 (d, J=13.6 Hz, 2H), 2.16 (s, 3H), 2.01 (s, 2H), 1.82 (s, 2H). LCMS (ESI) calcd. for C27H29F4N4O2S [M+H]+ m/z 549.19, found 549.15.
Step 1: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(4-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.167 mmol), (4-fluorophenyl)boronic acid (35 mg, 0.250 mmol), potassium carbonate (57 mg, 0.417 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (12 mg, 0.017 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was concentrated under vacuum. The residue was directly purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(4-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 67.96%) as a yellow solid. LCMS (ESI) calcd. for C31H36F3N4O4S [M+H]+ m/z 617.24, found 617.20.
Step 2: 2-(4,4-difluoroazepan-1-yl)-5-(4-fluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(4-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 0.113 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The solution was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 2-(4,4-difluoroazepan-1-yl)-5-(4-fluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (38 mg, 64.85%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.37 (s, 1H), 8.07 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.70-7.54 (m, 2H), 7.42-7.25 (m, 4H), 4.22 (s, 1H), 3.71-3.49 (m, 4H), 3.06 (s, 3H), 2.35-2.22 (m, 2H), 2.14 (s, 3H), 2.07-1.95 (m, 2H), 1.86-1.76 (m, 2H). LCMS (ESI) calcd. for C26H28F3N4O2S [M+H]+ m/z 517.19, found 517.15.
Step 1: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-3-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.167 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (52 mg, 0.250 mmol), potassium carbonate (57 mg, 0.417 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (12 mg, 0.017 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 16 hours under an atmosphere of N2.
After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-3-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 79.76%) as a yellow solid. LCMS (ESI) calcd. for C29H37F2N6O4S [M+H]+ m/z 603.26, found 603.30.
Step 2: 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-3-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-3-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 0.133 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The solution was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-3-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (40 mg, 59.97%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.68-7.55 (m, 2H), 6.44 (d, J=2.1 Hz, 1H), 4.22 (s, 1H), 3.89 (s, 3H), 3.66-3.52 (m, 4H), 3.06 (s, 3H), 2.38-2.19 (m, 5H), 2.07-1.95 (m, 2H), 1.81 (d, J=5.5 Hz, 2H). LCMS (ESI) calcd. for C24H29F2N6O2S [M+H]+ m/z 503.20, found 503.10.
Step 1: tert-butyl (S)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (200 mg, 0.57 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (309 mg, 1.15 mmol) in pyridine (4 mL) was added POCl3 (150 L) dropwise at 50° C. The reaction was stirred at 50° C. for 1 hour. After the reaction was completed, the resulting solution was quenched with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (S)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 28.99%) as a yellow solid. LCMS (ESI) calcd. for C25H32BrF2N4O4S [M+H]+ m/z 603.13, found 603.10.
Step 2: tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (S)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.167 mmol), 2-oxa-6-azaspiro[3.3]heptane (25 mg, 0.250 mmol), potassium carbonate (57 mg, 0.417 mmol), S-Phos (7 mg, 0.017 mmol) and Pd(dba)3 (10 mg, 0.017 mmol) in 1,4-dioxane (10 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 87.38%) as a yellow oil. LCMS (ESI) calcd. for C30H40F2N5O5S [M+H]+ m/z 620.27, found 620.25.
Step 3: (S)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)nicotinamide: A solution of tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.145 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The mixture was stirred at room temperature for 2 h hours then concentrated under vacuum. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (S)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)nicotinamide (43 mg, 56.97%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.37 (s, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.62-7.53 (m, 2H), 4.72 (s, 4H), 4.21 (s, 1H), 4.00 (s, 4H), 3.42-3.36 (m, 4H), 3.05 (s, 3H), 2.23-2.11 (m, 2H), 2.07 (s, 3H), 2.03-1.91 (m, 2H), 1.77-1.66 (m, 2H). LCMS (ESI) calcd. for C25H32F2N5O3S [M+H]+ m/z 520.22, found 520.20.
Step 1: tert-butyl ((3-(5-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.166 mmol), (3-cyanophenyl)boronic acid (37 mg, 0.249 mmol), potassium carbonate (92 mg, 0.664 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (12 mg, 0.017 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 6 hours under an atmosphere of N2. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((3-(5-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 77%) as a yellow oil. LCMS (ESI) calcd. for C32H36F2N5O4S [M+H]+ m/z 624.24, found 624.20.
Step 2: 5-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl) phenyl) nicotinamide: A solution of tert-butyl ((3-(5-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6--sulfaneylidene)carbamate (80 mg, 0.128 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The solution was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 5-(3-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (35 mg, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.95-7.77 (m, 3H), 7.75-7.63 (m, 3H), 7.59 (t, J=7.9 Hz, 1H), 4.31 (s, 1H), 3.67 (s, 2H), 3.60 (t, J=6.1 Hz, 2H), 3.07 (s, 3H), 2.31 (d, J=12.2 Hz, 2H), 2.16 (s, 3H), 2.00 (s, 2H), 1.83 (d, J=5.5 Hz, 2H). LCMS (ESI) calcd. for C27H28F2N5O2S [M+H]+ m/z 524.19, found 524.20.
Step 1: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(2-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6--sulfaneylidene)carbamate: A mixture tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.16 mmol), (2-fluorophenyl)boronic acid (35 mg, 0.25 mmol), K2CO3 (23 mg, 0.16 mmol) and Pd(dppf)Cl2 (12 mg, 0.02 mmol) in dioxane/H2O (10/1, 11 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(2-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 51.3%). LCMS (ESI) calcd. for C31H36F3N4O4S [M+H]+ m/z 617.24, found 617.30.
Step 2: Preparation of 2-(4,4-difluoroazepan-1-yl)-5-(2-fluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(2-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6--sulfaneylidene)carbamate (60 mg, 0.10 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated, and the residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 85% MeCN/H2O containing 0.1% trifluoroacetic acid) to provide 2-(4,4-difluoroazepan-1-yl)-5-(2-fluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (19 mg, 37%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.38 (s, 1H), 8.06 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.51-7.43 (m, 1H), 7.36-7.28 (m, 3H), 4.21 (s, 1H), 3.67 (s, 2H), 3.59 (t, J=6.1 Hz, 2H), 3.06 (s, 3H), 2.31 (d, J=13.4 Hz, 2H), 2.06 (s, 3H), 2.01 (s, 2H), 1.83 (d, J=5.6 Hz, 2H). LCMS (ESI) calcd. for C26H28F3N4O2S [M+H]+ m/z 517.19, found 517.10.
Step 1: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(4-methoxyphenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol), (4-methoxyphenyl)boronic acid (39 mg, 0.26 mmol), K2CO3 (69 mg, 0.50 mmol) and PdCl2(dppf) (12 mg, 0.02 mmol) in dioxane/H2O (10/1, 11 mL) was heated at 100° C. for 16 h under an atmosphere of N2. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(4-methoxyphenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 53.8%) as a yellow solid. LCMS (ESI) calcd. for C32H39F2N4O5S [M+H]+ m/z 629.26, found 629.20.
Step 2: 2-(4,4-difluoroazepan-1-yl)-5-(4-methoxyphenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(4-methoxyphenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 0.13 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was dissolved in THE (2 mL) then adjusted to pH=8-9 with saturated aqueous NaHCO3. The resulting solution was extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H2O containing 0.05% NH4OH) to give 2-(4,4-difluoroazepan-1-yl)-5-(4-methoxyphenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (20 mg, 29%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.38 (s, 1H), 8.05 (s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.68-7.55 (m, 2H), 7.26 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.6 Hz, 2H), 4.21 (s, 1H), 3.80 (s, 3H), 3.63 (s, 2H), 3.57 (t, J=6.1 Hz, 2H), 3.05 (s, 3H), 2.28 (s, 2H), 2.15 (s, 3H), 2.00 (s, 2H), 1.81 (s, 2H). LCMS (ESI) calcd. for C27H31F2N4O3S [M+H]+ m/z 529.21, found 529.15.
Step 1: methyl 6-chloro-5-methyl-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate: To a solution of methyl 3,6-dichloro-5-methylpyridazine-4-carboxylate (1.0 g, 4.52 mmol) and 6-azaspiro[2.5]octane hydrochloride (0.68 g, 4.6 mmol) in dioxane (20 mL) was added DIEA (2.91 g, 22.62 mmol). The mixture was heated at 80° C. for 2 hours. LCMS showed the reaction was completed. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (70 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1 to 2/1) to provide methyl 6-chloro-5-methyl-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate (0.5 g, 31.11%) as a white solid. LCMS (ESI) calcd. for C14H19ClN3O2 [M+H]+ m/z 296.11, found 296.00.
Step 2: methyl 6-iodo-5-methyl-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate: To a mixture of NaI (2.02 g, 13.52 mmol) in MeCN (10 mL) was added CH3COCl(0.40 g, 5.07 mmol) in MeCN (5 mL). Then a solution of methyl 6-chloro-5-methyl-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate (0.5 g, 1.69 mmol) in MeCN (10 mL) was added dropwise to the mixture at room temperature. The mixture was stirred at room temperature for 0.5 h. LCMS showed the reaction was completed. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to provide methyl 6-iodo-5-methyl-3-(6-azaspiro[2.5]octan-6-yl)pyridazine-4-carboxylate (370 mg, 62.04%) as a yellow oil. LCMS (ESI) calcd. for C14H19IN3O2 [M+H]+ m/z 388.05, found 387.90.
Step 3: methyl 5-methyl-3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate: A solution of methyl 6-iodo-5-methyl-3-(6-azaspiro [2.5]octan-6-yl)pyridazine-4-carboxylate (350 mg, 0.90 mmol), CuI (343 mg, 1.81 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.38 g, 7.2 mmol) in DMF (5 mL) was heated at 120° C. for 2 hours. LCMS showed the reaction was completed. Then the mixture was filtered through celite. The filtrate was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=4/1) to provide methyl 5-methyl-3-(6-azaspiro [2.5]octan-6-yl)-6-(trifluoromethyl) pyridazine-4-carboxylate (200 mg, 52.94%) as a yellow solid. LCMS (ESI) calcd. for C15H19F3N3O2 [M+H]+ m/z 330.14, found 330.00.
Step 4: 5-methyl-3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a solution of methyl 5-methyl-3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (200 mg, 0.61 mmol) in MeOH/H2O (1/1, 4 mL) was added KOH (272 mg, 4.86 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hours. After the reaction was completed, the mixture was concentrated to remove most MeOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to provide crude 5-methyl-3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (200 mg) as a yellow solid which was used in next step without further purification. LCMS (ESI) calcd. for C14H17F3N3O2 [M+H]+ m/z 316.13, found 315.95.
Step 5: tert-butyl (methyl(3-(5-methyl-3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 5-methyl-3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (200 mg, 0.63 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (205 mg, 0.76 mmol) in pyridine (10 mL) was added POCl3 (10 mg, 0.063 mmol). The mixture was stirred at room temperate for 1 hours. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=5/1) to afford tert-butyl (methyl(3-(5-methyl-3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 21.95%) as a yellow solid. LCMS (ESI) calcd. for C26H33F3N5O4S [M+H]+ m/z 569.22, found 568.25.
Step 6: 5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide: To a solution of tert-butyl (methyl(3-(5-methyl-3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 0.12 mmol) in DCM (1 mL) was added TFA (0.3 mL) at 0° C. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 85% MeCN/H2O containing 0.1% formic acid) to provide 5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (29 mg, 33.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.30 (s, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.72 (d, J=7.4 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 4.26 (s, 1H), 3.76-3.62 (m, 4H), 3.07 (s, 3H), 2.33 (s, 3H), 1.43-1.32 (m, 4H), 0.31 (s, 4H). LCMS (ESI) calcd. for C21H25F3N5O2S [M+H]+ m/z 468.17, found 468.05.
Step 1: methyl 5-chloro-2-hydroxy-4-methylnicotinate: To a solution of methyl 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (5.0 g, 30 mmol) in DCM (50 mL) was added NCS (4.0 g, 30 mmol) at 0° C. The mixture was stirred at the same temperature for 60 minutes. Then the mixture was quenched with water (50 mL) and extracted with DCM (2×50 mL). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by triturate in PE/EtOAc (3/1) to provide methyl 5-chloro-2-hydroxy-4-methylnicotinate (4 g, 66%) as a light brown solid. LCMS (ESI) calcd. for C8H9ClNO3 [M+H]+ m/z 202.03, found 202.10.
Step 2: methyl 2,5-dichloro-4-methylnicotinate: A solution of methyl 5-chloro-2-hydroxy-4-methylnicotinate (2.0 g, 10 mmol) in phenyl dichlorophosphate (10 mL) was heated to 170° C. for 2 h. The resulting solution was cooled to room temperature, quenched with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to provide methyl 2,5-dichloro-4-methylnicotinate (1 g, 45%) as a light-yellow oil. LCMS (ESI) calcd. for C8H8Cl2NO2 [M+H]+ m/z 219.99, found 219.80.
Step 3: 2,5-dichloro-4-methylnicotinic acid: To a solution of methyl 2,5-dichloro-4-methylnicotinate (500 mg, 2.3 mmol) in MeOH/H2O (v/v, 10 mL) was added KOH (129 mg, 23 mmol) at room temperature. The mixture was heated at 70° C. for 5 hours. After the reaction was completed, the mixture was concentrated to remove most MeOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford 2,5-dichloro-4-methylnicotinic acid (400 mg, 85.6%) as a white solid. LCMS (ESI) calcd. for C7H6C12NO2 [M+H]+ m/z 205.98, found 206.05.
Step 4: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid: A solution of 2,5-dichloro-4-methylnicotinic acid (400 mg, 1.94 mmol), 4,4-difluoroazepane hydrochloride (498 mg, 2.91 mmol), K2CO3 (1.61 g, 11.64 mmol) and DIEA (1.0 g, 7.76 mmol) in NMP (10 mL) was heated at 140° C. for 6 hours. LCMS showed the reaction was completed. The mixture concentrated under vacuum and directly purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/2) to provide 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (300 mg, 40%) as a yellow solid. LCMS (ESI) calcd. for C13H16ClF2N2O2 [M+H]+ m/z 305.09, found 305.05.
Step 5: tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (300 mg, 0.98 mmol) and tert-butyl ((3-aminophenyl) (methyl)(oxo)-λ6-sulfaneylidene) carbamate (264 mg, 0.98 mmol) in pyridine (6 mL) was added POCl3 (200 L) dropwise at 50° C. The reaction solution was stirred at 50° C. for 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 22.8%) as a yellow solid. LCMS (ESI) calcd. for C25H32ClF2N4O4S [M+H]+ m/z 557.18, found 557.15.
Step 6: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 0.089 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 85% MeCN/H2O containing 0.1% formic acid) to provide 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (14.9 mg, 36.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 4.23 (s, 1H), 3.60 (s, 2H), 3.53 (t, J=6.1 Hz, 2H), 3.07 (s, 3H), 2.28 (s, 5H), 1.98 (s, 2H), 1.80 (d, J=5.5 Hz, 2H). LCMS (ESI) calcd. for C20H24ClF2N4O2S [M+H]+ m/z 457.13, found 457.15.
Step 1: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(p-tolyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.166 mmol), p-tolylboronic acid (68.0 mg, 0.50 mmol), K2CO3 (69.0 mg, 0.50 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (12 mg, 0.016 mmol) in 1,4-dioxane/H2O (4/1, 4 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(p-tolyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 88.5%) as a white oil. LCMS (ESI) calcd. for C32H39F2N4O4S [M+H]+ m/z 613.27, found 613.35.
Step 2: 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(p-tolyl)nicotinamide: A solution of give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(p-tolyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.147 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(p-tolyl)nicotinamide (50.59 mg, 67.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.38 (s, 1H), 8.05 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.27 (d, J=7.9 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 4.22 (s, 1H), 3.64 (d, J=2.5 Hz, 2H), 3.57 (t, J=6.1 Hz, 2H), 3.05 (s, 3H), 2.35 (s, 3H), 2.28 (s, 2H), 2.15 (s, 3H), 2.00 (s, 2H), 1.82 (d, J=5.5 Hz, 2H). LCMS (ESI) calcd. for C27H31F2N4O2S [M+H]+ m/z 513.21, found 513.20.
Step 1: tert-butyl ((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.167 mmol), Zn(CN)2 (39 mg, 0.334 mmol), tBuXPhos-Pd-G3 (13 mg, 0.017 mmol) in THF/H2O (4/1, 10 mL) was heated at 70° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 76.92%) as a yellow oil. LCMS (ESI) calcd. for C26H32F2N5O4S [M+H]+ m/z 548.21, found 548.20.
Step 2: 5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 0.128 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The solution was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (20.5 mg, 32.79%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.56 (s, 1H), 8.29 (t, J=1.8 Hz, 1H), 7.93-7.84 (m, 1H), 7.74-7.65 (m, 1H), 7.60 (t, J=7.9 Hz, 1H), 4.24 (s, 1H), 3.62-3.32 (m, 4H), 3.06 (d, J=0.9 Hz, 3H), 2.40-2.21 (m, 5H), 2.08-1.93 (m, 2H), 1.89-1.78 (m, 2H). LCMS (ESI) calcd. for C21H24F2N5O2S [M+H]+ m/z 448.16, found 448.05.
Step 1: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(thiazol-2-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.16 mmol), 2-(tributylstannyl)thiazole (125 mg, 0.32 mmol) and Pd(PPh3)4 (20 mg, 0.02 mmol) in toluene (5 mL) was heated at 110° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(thiazol-2-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (75 mg, 77.3%). LCMS (ESI) calcd. for C28H34F2N5O4S2 [M+H]+ m/z 606.20, found 606.15.
Step 2: 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(thiazol-2-yl)nicotinamide: A solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(thiazol-2-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (75 mg, 0.12 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated, and the residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 95% MeCN/H2O containing 0.1% NH3) to provide 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(thiazol-2-yl)nicotinamide (17.5 mg, 29.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.48 (s, 1H), 8.36 (s, 1H), 7.97 (d, J=3.3 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.82 (d, J=3.3 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 4.23 (s, 1H), 3.75-3.60 (m, 4H), 3.07 (s, 3H), 2.43 (s, 3H), 2.31 (t, J=16.0 Hz, 2H), 2.09-1.96 (m, 2H), 1.87-1.80 (m, 2H). LCMS (ESI) calcd. for C23H26F2N5O2S2 [M+H]+ m/z 506.15, found 506.05.
Step 1: tert-butyl((3-(6
(4,4-difluoroazepan-1-yl)-4
methyl-[2,3
bipyridine]-5
carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.16 mmol), 2-(tributylstannyl)pyridine (118 mg, 0.32 mmol) and Pd(PPh3)4 (20 mg, 0.02 mmol) in toluene (5 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give tert-butyl ((3-(6
(4,4
difluoroazepan-1-yl)-4
methyl-[2,3
bipyridine]-5
carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (52 mg, 54.2% y) as a white oil. LCMS (ESI) calcd. for C30H36F2N5O4S [M+H]+ m/z 600.25, found 600.25.
Step 2: 6(4,4-difluoroazepan-1-yl)-4
methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-[2,3
bipyridine]-5
carboxamide: A solution of tert-butyl ((3-(61-(4,4-difluoroazepan-1-yl)-4
methyl-[2,3
bipyridine]-5
carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (52 mg, 0.09 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated, and the residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.1% NH3) to provide 6
(4,4-difluoroazepan-1-yl)-4
methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-[2,3
bipyridine]-5
carboxamide (16.58 mg, 36.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.67 (d, J=4.7 Hz, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 7.95-7.83 (m, 2H), 7.67 (d, J=7.9 Hz, 1H), 7.63-7.49 (m, 2H), 7.36 (dd, J=7.4, 4.9 Hz, 1H), 4.22 (s, 1H), 3.72-3.57 (m, 4H), 3.06 (s, 3H), 2.38-2.22 (m, 5H), 2.10-1.95 (m, 2H), 1.83 (dt, J=11.2, 5.8 Hz, 2H). LCMS (ESI) calcd. for C25H28F2N5O2S [M+H]+ m/z 500.19, found 500.10.
Step 1: methyl 5-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate: To a solution of methyl 3-chloro-5-methyl-6-(trifluoromethyl) pyridazine-4-carboxylate (400 mg, 1.57 mmol) in 1,4-dioxane (5 mL) was added 2-oxa-6-azaspiro [3.3]heptane (186 mg, 1.88 mmol) and DIPEA (304 mg, 2.35 mmol). The mixture was heated to 100° C. and stirred for 2 hours. Then the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide methyl 5-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (400 mg, 88%) as a light brown solid. LCMS (ESI) calcd. for C13H15F3N3O3 [M+H]+ m/z 318.11, found 318.05.
Step 2: 5-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a solution of methyl 5-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylate (400 mg, 1.26 mmol) in MeOH/H2O (1/1, 10 mL) was added KOH (705 mg, 12.6 mmol) at room temperature. The mixture was heated at 70° C. for 5 hours. After the reaction was completed, the mixture was concentrated to remove most MeOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford 5-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (300 mg, 78.5%) as a white solid. LCMS (ESI) calcd. for C12H13F3N3O3 [M+H]+ m/z 304.09, found 304.00.
Step 3: 5-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide: To a solution of 5-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (200 mg, 0.66 mmol) and HATU (300 mg, 0.79 mmol) in DMF (5 mL) was added DIPEA (128 mg, 0.99 mmol). The mixture was heated to 40° C. and stirred for 2 hours. Then NH3-MeOH (3.3 mL, 7M) was added, the mixture was stirred for 5 hours at 40° C. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 5-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (120 mg, 60.3%) as a yellow solid. LCMS (ESI) calcd. for C12H14F3N4O2 [M+H]+m/z 303.11, found 303.10.
Step 4: 5-methyl-N-(3-(methylsulfinyl)phenyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of 5-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (120 mg, 0.40 mmol), 1-bromo-3-(methylsulfinyl) benzene (105 mg, 0.48 mmol), Cs2CO3 (261 mg, 0.80 mmol), XantPhos (46 mg, 0.08 mmol) and Pd2(dba)3 (37 mg, 0.04 mmol) in DMF (2 mL) was heated at 100° C. overnight under an atmosphere of N2. LCMS showed the reaction was completed. The mixture was filtered through celite, and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 5-methyl-N-(3-(methylsulfinyl)phenyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (90 mg, 51.7%) as a yellow oil. LCMS (ESI) calcd. for C19H20F3N4O3S [M+H]+ m/z 441.12, found 441.10.
Step 5: 5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide: To a solution of 5-methyl-N-(3-(methylsulfinyl)phenyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (90 mg, 0.20 mmol) in MeOH (5 mL) was added PhI(OAc)2 (161 mg, 0.5 mmol) and ammonium carbamate (47 mg, 0.6 mmol) at room temperature. The reaction mixture was heated at 70° C. for 3 hours. Then the mixture was cooled to room temperature, diluted with water (20 mL) and extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 55% MeCN/H2O containing 0.1% formic acid) to afford 5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (17.9 mg, 19.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.39 (s, 1H), 7.97 (d, J=9.1 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 4.69 (s, 4H), 4.37 (s, 4H), 3.38 (s, 3H), 2.28 (s, 3H). LCMS (ESI) calcd. for C19H21F3N5O3S [M+H]+ m/z 456.13, found 456.10.
Step 1: 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide: A solution of 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid (200 mg, 0.59 mmol) in DCM (5 mL) and DMF (1 drop) was added dropwise oxalyl chloride (86 μL) at 0° C. The mixture was stirred at 0° C. for 1 hour. Then the mixture was concentrated to remove the solvent. Then the residue was dissolved in THE (5 mL) and was added to vigorously stirred NH3—H2O (5 mL). The mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum to give crude 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide (190 mg) which was used directly in next step. LCMS (ESI) calcd. for C14H17F5N3O [M+H]+ m/z 338.13, found 338.05.
Step 2: 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-(methylsulfinyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide: A solution of 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide (175 mg, 0.52 mmol) in 1,4-dioxane (8 mL) was added 4-bromo-2-(methylsulfinyl)pyridine (457.38 mg, 1.53 mmol), Cs2CO3 (440.5 mg, 1.35 mmol) and XantPhos-Pd-G2 (92.4 mg, 0.1 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours under nitrogen. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-(methylsulfinyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide (120 mg, 48.5%) as a white solid. LCMS (ESI) calcd. for C20H22F5N4O2S [M+H]+ m/z 477.14, found 477.10.
Step 3: 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide: To a solution of 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-(methylsulfinyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide (120 mg, 0.252 mmol) in MeOH (5 mL) was added PhI(OAc)2 (203 mg, 0.63 mmol) and ammonium carbamate (59 mg, 0.756 mmol) at room temperature. The reaction mixture was heated at 70° C. for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (5 mL), and extracted with DCM (5 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE/EtOAc=1/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 90% MeCN/H2O containing 0.05% NH3) to afford 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide (45.5 mg, 36.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.60 (d, J=5.5 Hz, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.01 (s, 1H), 7.87 (dd, J=5.5, 2.0 Hz, 1H), 4.35 (s, 1H), 3.73-3.67 (m, 2H), 3.41 (t, J=5.6 Hz, 2H), 3.14 (d, J=0.9 Hz, 3H), 2.52 (d, J=1.4 Hz, 3H), 2.38-2.27 (m, 2H), 1.95 (s, 2H), 1.88 (d, J=5.3 Hz, 2H). LCMS (ESI) calcd. for C20H23F5N5O2S [M+H]+ m/z 492.15, found 492.20.
Step 1: 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (250 mg, 0.7374 mmol) in DCM (5 mL) was added oxalyl chloride (0.3 mL) and DMF (1 drop) at room temperature. After addition, the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated. The residue was diluted with THE and added dropwise to a stirred solution of ammonium hydroxide (5 mL). Then the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (200 mg, 80.10%) as a yellow solid. LCMS (ESI) calcd. for C13H16F5N4O [M+H]+ m/z 339.12, found 339.10.
Step 2: 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(2-(methylsulfinyl)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (180 mg, 0.5325 mmol) in 1,4-dioxane (10 mL) was added 4-bromo-2-(methylsulfinyl)pyridine (349 mg, 1.597 mmol), cesium carbonate (451 mg, 1.3845 mmol) and Xantphos-Pd-G2 (94 mg, 0.1065 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours under nitrogen. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(2-(methylsulfinyl)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (120 mg, 47.24%) as a yellow oil. LCMS (ESI) calcd. for C19H21F5N5O2S [M+H]+ m/z 478.13, found 478.15.
Step 3: 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide: To a solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(2-(methylsulfinyl)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (120 mg, 0.251 mmol) in MeOH (5 mL) was added PhI(OAc)2 (202 mg, 0.627 mmol) and ammonium carbamate (58 mg, 0.753 mmol) at room temperature. The reaction mixture was heated at 70° C. for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (5 mL), and extracted with DCM (5 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE/EtOAc=1/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 95% MeCN/H2O containing 0.1% formic acid) to afford 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (54.46 mg, 41.57%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.66 (d, J=5.2 Hz, 1H), 8.35 (d, J=1.6 Hz, 1H), 7.80 (dd, J=5.2 Hz, 1.6 Hz, 1H), 4.42 (s, 1H), 3.83-3.81 (m, 2 H), 3.64-3.61 (m, 2H), 3.15 (s, 3H), 1.83-1.81 (m, 2H), 2.31 (s, 3H), 2.08-2.04 (m, 2H), 1.89-1.87 (m, 2H). LCMS (ESI) calcd. for C19H22F5N6O2S [M+H]+ m/z 493.14, found 493.10.
Step 1: tert-butyl (S)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (120 mg, 0.34 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (112 mg, 0.41 mmol) in pyridine (5 mL) was added POCl3 (100 L) dropwise at 50° C. The reaction solution was stirred at 50° C. 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (S)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 29.3%) as a yellow solid. LCMS (ESI) calcd. for C25H32BrF2N4O4S [M+H]+ m/z 603.13, found 603.10.
Step 2: tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-phenylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (S)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 0.10 mmol), phenylboronic acid (61 mg, 0.50 mmol), K2CO3 (42 mg, 0.30 mmol) and Pd(dppf)Cl2 (7 mg, 0.01 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was concentrated under vacuum. The residue was directly purified by flash column chromatography on silica gel (PE/EtAOc=3/1) to give tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-phenylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (30 mg, 50.1%) as a yellow solid. LCMS (ESI) calcd. for C31H37F2N4O4S [M+H]+ m/z 599.25, found 599.25.
Step 3: (S)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-phenylnicotinamide: A solution of tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-phenylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (30 mg, 0.05 mmol) in DCM (3 mL) was added TFA (0.3 mL) at: room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated, and the residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H2O containing 0.1% NH3) to provide (S)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-phenylnicotinamide (14.28 mg, 57.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.47 (t, J=7.4 Hz, 2H), 7.42-7.30 (m, 3H), 4.22 (s, 1H), 3.69-3.54 (m, 4H), 3.06 (s, 3H), 2.29 (t, J=16.1 Hz, 2H), 2.16 (s, 3H), 2.05-1.96 (m, 2H), 1.86-1.76 (m, 2H). LCMS (ESI) calcd. for C26H29F2N4O2S [M+H]+ m/z 499.20, found 499.10.
Step 1: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(2,6-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.333 mmol), (2,6-difluorophenyl)boronic acid (105 mg, 0.667 mmol), tBuOK (75 mg, 0.667 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (24 mg, 0.033 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 90° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(2,6-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (30 mg, 14.22%) as a yellow solid. LCMS (ESI) calcd. for C31H35F4N4O4S [M+H]+ m/z 635.23, found 635.20.
Step 2: 2-(4,4-difluoroazepan-1-yl)-5-(2,6-difluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-5-(2,6-difluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (30 mg, 0.047 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The solution was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 2-(4,4-difluoroazepan-1-yl)-5-(2,6-difluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (7 mg, 28.48%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.38 (t, J=1.8 Hz, 1H), 8.08 (s, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.69-7.49 (m, 3H), 7.25 (t, J=7.9 Hz, 2H), 4.24 (s, 1H), 3.70-3.57 (m, 4H), 3.06 (s, 3H), 2.36-2.24 (m, 2H), 2.08-1.98 (m, 5H), 1.86-1.78 (m, 2H). LCMS (ESI) calcd. for C26H27F4N4O2S [M+H]+ m/z 535.18, found 535.15.
Step 1: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.333 mmol), (2,6-difluorophenyl)boronic acid (105 mg, 0.667 mmol), t-BuOK (75 mg, 0.667 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (24 mg, 0.033 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 90° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/2) to give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 45.98%, yellow solid) as a byproduct of Suzuki coupling. LCMS (ESI) calcd. for C25H33F2N4O4S [M+H]+ m/z 523.22, found 523.15.
Step 2: 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate 11 (80 mg, 0.153 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The solution was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (22 mg, 34.38%) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 10.78 (s, 1H), 8.37 (s, 1H), 8.08 (d, J=4.9 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.72-7.55 (m, 2H), 6.69 (d, J=5.0 Hz, 1H), 3.63-3.57 (m, 2H), 3.52 (t, J=6.1 Hz, 2H), 3.13 (s, 3H), 2.30-2.18 (m, 5H), 2.06-1.93 (m, 2H), 1.84-1.73 (m, 2H). LCMS (ESI) calcd. for C20H25F2N4O2S [M+H]+ m/z 423.17, found 423.05.
Step 1: methyl 2-chloro-4,6-dimethylnicotinate: To a solution of 2-chloro-4,6-dimethylnicotinic acid (2 g, 10.81 mmol) and K2CO3 (4.48 g, 32.43 mmol) in DMF (20 mL) was added Mel(3.07 g, 21.62 mmol) dropwise. Then the mixture was heated at 70° C. for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water, extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc/PE, 0 to 10%) to give methyl 2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate (1.6 g, 74.38%) as a colorless oil. LCMS (ESI) calcd. for C9H11ClNO2 [M+H]+ m/z 200.05, found 200.10.
Step 2: methyl 2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate: A solution of methyl 2-chloro-4,6-dimethylnicotinate (1 g, 5.03 mmol), 4,4-difluoroazepane hydrochloride (1.29 g, 7.54 mmol), Cs2CO3 (8.17 g, 25.15 mmol), Pd2(dba)3 (0.46 g, 0.50 mmol) and SPhos (0.41 g, 1.00 mmol) in dioxane (10 mL) was stirred at 110° C. for 12 h under N2 atmosphere. Then the mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc/PE, 0 to 20%) to give methyl 2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate (0.4 g, 26.64%) as a yellow solid. LCMS (ESI) calcd. for C15H21F2N2O2 [M+H]+ m/z 299.16, found 299.15.
Step 3: methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate: A solution of methyl 2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate (400 mg, 1.34 mmol) and NCS (270 mg, 2.01 mmol) in MeCN (5 mL) was heated at 60° C. for 12 h. Then the mixture was diluted with water, extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc/PE, 0 to 20%) to give methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate (260 mg, 58.44%) as a yellow solid. LCMS (ESI) calcd. for C15H20ClF2N2O2 [M+H]+ m/z 333.12, found 333.00.
Step 4: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinic acid: To a solution of methyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate (260 mg, 0.78 mmol) in THF/EtOH (1/1, 4 mL) was added KOH (874 mg, 15.60 mmol) at room temperature. The mixture was heated at 70° C. for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove THE and EtOH. The residue was dissolved in H2O (4 mL) and adjusted to pH=3-4 with 1N HCl and extracted with EtOAc (5 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to give 5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinic acid (200 mg, 80.63%). LCMS (ESI) calcd. for C14H18ClF2N2O2 [M+H]+ m/z 319.10, found 319.10.
Step 5: tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinic acid (200 mg, 0.63 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (255 mg, 0.95 mmol) in pyridine (10 mL) was added POCl3 (1 mL) dropwise at 50° C. The reaction solution was stirred at 50° C. for 1 hour. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (130 mg, 36%) as a yellow solid. LCMS (ESI) calcd. for C26H34ClF2N4O4S [M+H]+ m/z 571.19, found 571.20.
Step 6: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (130 mg, 0.228 mmol) in DCM (2 mL) was added TFA (0.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HIPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to afford 5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (40 mg, 37.33%) as a white solid. LCMS (ESI) calcd. for C21H26ClF2N4O2S [M+H]+ m/z 471.14, found 471.15. 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.32 (t, J=1.8 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.62 (m, J=15.8, 8.0 Hz, 2H), 4.23 (s, 1H), 3.56 (m, J=31.8, 8.7, 4.4 Hz, 4H), 3.05 (s, 3H), 2.46 (s, 3H), 2.26 (d, J=8.9 Hz, 5H), 2.03-1.92 (m, 2H), 1.84-1.73 (m, 2H).
Step 1: 4-bromopyridine-2-sulfonamide: To a stirred solution of 2-(benzylthio)-4-bromopyridine (5.0 g, 17.9 mmoL) in DCM (60 mL), AcOH (8.6 mL) and water (17 mL) was added 1,3-dichloro-5,5-imethyl-imidazolidine-2,4-dione (10.5 g, 53.7 mmol) slowly at 0° C. The mixture was stirred at room temperature for overnight. Then the mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude sulfonyl chloride. The crude sulfonyl chloride was dissolved in THE (20 mL) and added dropwise to stirred 28% ammonia (20 mL). The solution was stirred at room temperature for 30 min. Then the mixture was diluted with water (40 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum to give the crude 4-bromopyridine-2-sulfonamide (5 g) which was used directly in next step without further purification. LCMS (ESI) calcd. for C5H6BrN2O2S [M+H]+ m/z 236.93, found 236.90.
Step 2: 4-bromo-N-(tert-butyldimethylsilyl)pyridine-2-sulfonamide: To a solution of 4-bromopyridine-2-sulfonamide (5.0 g, 18.9 mmol) and DIEA (3.67 g, 28.4 mmol) in DCM (30 mL) was added TBSCl (3.4 g, 22.7 mmol) at room temperature. The solution as stirred at room temperature for 3 hours. Then the mixture was diluted with water (40 mL) and extracted with DCM (40 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1 to 5/1) to give 4-bromo-N-(tert-butyldimethylsilyl)pyridine-2-sulfonamide (4.5 g, 67%) as a white solid. LCMS (ESI) calcd. for C11H20BrN2O2SSi [M+H]+ m/z 351.02, found 351.00.
Step 3: 4-bromo-N(tert-butyldimethylsilyl)-N-methylpyridine-2-sulfonimidamide: To a 500 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added a solution of Ph3PCl2 (3.1 g, 9.3 mmol) in chloroform (40 mL). This was followed by the addition of DIEA (1.88 g, 18.6 mmol) dropwise with stirring at room temperature. The resulting solution was stirred for 10 min at room temperature, then the reaction solution was cooled to 0° C. To this ice-cold solution was added a solution of 4-bromo-N-(tert-butyldimethylsilyl)pyridine-2-sulfonamide (814 mg, 2.32 mmol) in chloroform (8 mL) dropwise at 0° C. The resulting solution was stirred for 30 min at 0° C. Then methylamine (10 mL, 2M in THF) was added at the same temperature. The solution was stirred for 1 hour at room temperature. The resulting solution was diluted with water (40 mL) and extracted with DCM (40 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give 4-bromo-N
(tert-butyldimethylsilyl)-N-methylpyridine-2-sulfonimidamide (450 mg, 53.4%) as a white solid. LCMS (ESI) calcd. for C12H23BrN3OSSi [M+H]+ m/z 364.05, found 363.90.
Step 4: N-(2-(N(tert-butyldimethylsilyl)-N-methylsulfamidimidoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide: A solution of 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide (125 mg, 0.371 mmol) in dioxane (10 mL) was 4-bromo-N
tert-butyldimethylsilyl)-N-methylpyridine-2-sulfonimidamide (202 mg, 0.556 mmol), cesium carbonate (314 mg, 0.9644 mmol) and XantPhos-Pd-G2 (66 mg, 0.074 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours under nitrogen. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give N-(2-(N
(tert-butyldimethylsilyl)-N-methylsulfamidimidoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide (60 mg, 26.08%) as a yellow oil. LCMS (ESI) calcd. for C26H38F5N6O2SSi [M+H]+ m/z 621.24, found 621.20.
Step 5: 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-(N-methylsulfamidimidoyl) pyridine-4-yl)-5-(trifluoromethyl)nicotinamide: To a solution of N-(2-(N(tert-butyldimethylsilyl)-N-methylsulfamidimidoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide (60 mg, 0.097 mmol) in 1,4-dioxane (5 mL) was added 4M HCl-dioxane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 95% MeCN/H2O containing 0.1% formic acid) to afford 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-(N-methylsulfamidimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide (21.5 mg, 44.79%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (bs, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 7.97 (s, 1H), 7.78 (s, 1H), 6.83 (bs, 1H), 4.21 (bs, 1H), 3.69-3.68 (m, 2H), 3.33-3.32 (m, 2H), 2.49 (s, 3H), 2.47 (s, 3H), 2.32-2.30 (m, 2H), 1.95-1.91 (m, 2H), 1.87-1.86 (m, 2H). LCMS (ESI) calcd. for C20H24F5N6O2S [M+H]+ m/z 507.16, found 507.10.
Step 1: tert-butyl (S)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (250 mg, 0.676 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (274 mg, 1.013 mmol) in pyridine (15 mL) was added POCl3 (450 L) at 50° C. After the reaction was completed, the mixture was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (S)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (40 mg, 9.47%) as a yellow oil. LCMS (ESI) calcd. for C26H29ClF5N4O4S [M−H]− m/z 623.15, found 623.35.
Step 2: (S)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl (S)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (40 mg, 0.064 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 80% MeCN/H2O containing 0.1% formic acid) to (S)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (12.5 mg, 37.87%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.28 (s, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.70 (d, J=7.3 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 4.24 (s, 1H), 3.65 (s, 2H), 3.58 (t, J=6.0 Hz, 2H), 3.06 (s, 3H), 2.36 (s, 3H), 2.31 (d, J=18.2 Hz, 2H), 2.08-1.95 (m, 2H), 1.86-1.77 (m, 2H). LCMS (ESI) calcd. for C21H23ClF5N4O2S [M+H]+ m/z 525.11, found 525.15.
Step 1: tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (250 mg, 0.6756 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (274 mg, 1.0134 mmol) in pyridine (15 mL) was added POCl3 (450 L) at 50° C. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (25 mL) and extracted with DCM (25 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (40 mg, 9.47%) as a yellow oil. LCMS (ESI) calcd. for C26H31ClF5N4O4S [M+H]+ m/z 625.17, found 525.10.
Step 2: (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (40 mg, 0.0641 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 80% MeCN/H2O containing 0.1% formic acid) to (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (7.5 mg, 27.87%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.29 (s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 4.25 (s, 1H), 3.65 (s, 2H), 3.58 (t, J=6.1 Hz, 2H), 3.07 (s, 3H), 2.36 (s, 3H), 2.33-2.28 (m, 2H), 2.05-1.98 (m, 2H), 1.82 (d, J=6.0 Hz, 2H). LCMS (ESI) calcd. for C21H23ClF5N4O2S [M+H]+ m/z 525.11, found 525.05.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 0.117 mmol), (3-fluorophenyl)boronic acid (49.0 mg, 0.35 mmol), potassium carbonate (47.3 mg, 0.35 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (17.1 mg, 0.0234 mmol) in 1,4-dioxane/H2O (4/1, 4 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 83.15%) as a white oil. LCMS (ESI) calcd. for C31H36F3N4O4S [M+H]+ m/z 617.24, found 617.20.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 0.0974 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Then the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 90% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (11.2 mg, 22.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.51 (dd, J=14.3, 7.9 Hz, 1H), 7.25-7.17 (m, 3H), 4.23 (s, 1H), 3.66 (dd, J=6.5, 3.6 Hz, 2H), 3.59 (t, J=6.1 Hz, 2H), 3.06 (s, 3H), 2.35-2.23 (m, 2H), 2.17 (s, 3H), 2.09-1.96 (m, 2H), 1.83 (d, J=5.7 Hz, 2H). LCMS (ESI) calcd. for C26H28F3N4O2S [M+H]+ m/z 517.19, found 517.15
Step 1: tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (S)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.167 mmol), (3-fluorophenyl)boronic acid (117 mg, 0.833 mmol), potassium carbonate (69 mg, 0.501 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (13 mg, 0.0167 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 6 hours under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (68 mg, 66.67%) as a yellow oil. LCMS (ESI) calcd. for C31H36F3N4O4S [M+H]+ m/z 617.24, found 617.20.
Step 2: (S)-2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (S)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (68 mg, 0.110 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (S)-2-(4,4-difluoroazepan-1-yl)-5-(3-fluorophenyl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (12.5 mg, 22.32%) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 10.88 (s, 1H), 8.38-8.36 (m, 1H), 8.10 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.66 (d, J=8 Hz, 1H), 7.58-7.56 (m, 1H), 7.51-7.47 (m, 1H), 7.24-7.17 (m, 3H), 4.22 (s, 1H), 3.67-3.65 (m, 2H), 3.60-3.57 (m, 2H), 3.06 (s, 3H), 2.32-2.26 (m, 2H), 2.14 (s, 3H), 2.07-1.96 (m, 2H), 1.83-1.82 (m, 2H). LCMS (ESI) calcd. for C26H28F3N4O2S [M+H]+ m/z 517.19, found 517.10.
Step 1: 5-fluoro-2-(tributylstannyl)pyridine: To a mixture of 2-bromo-5-fluoropyridine (1 g, 5.714 mmol) in THE (15 mL) was added n-BuLi (2.86 mL, 6.587 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 0.5 h. Then tributylchlorostannane (2.15 g, 6.587 mmol) was added to the mixture at −78° C. The mixture was stirred at room temperature for 2 hours under an atmosphere of N2. After the reaction was completed, the mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=10/1) to give 5-fluoro-2-(tributylstannyl)pyridine (1.1 g, 49.77%) as a colorless oil. LCMS (ESI) calcd. for C17H31FNSn [M+H]+ m/z 388.14, found 386.05.
Step 2: tert-butyl ((3-(6(4,4-difluoroazepan-1-yl)-5-fluoro-4
methyl-[2,3
bipyridine]-5
carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.167 mmol), 5-fluoro-2-(tributylstannyl)pyridine (389 mg, 1.002 mmol), Pd(PPh3)4 (19 mg, 0.017 mmol) in toluene (10 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((3-(6
(4,4-difluoroazepan-1-yl)-5-fluoro-4
methyl-[2,3
bipyridine]-5
carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 67.96%) as a yellow oil. LCMS (ESI) calcd. for C30H35F3N5O4S [M+H]+ m/z 618.24, found 618.20.
Step 3: 6(4,4-difluoroazepan-1-yl)-5-fluoro-4
methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-[2,3
bipyridine]-5
carboxamide: A solution of tert-butyl ((3-(6
(4,4-difluoroazepan-1-yl)-5-fluoro-4
methyl-[2,3
bipyridine]-5
carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 0.113 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The solution was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 61-(4,4-difluoroazepan-1-yl)-5-fluoro-4
methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-[2,3
bipyridine]-5
carboxamide (30.4 mg, 51.88%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.73-8.66 (m, 1H), 8.53 (d, J=4.8 Hz, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.59 (td, J=7.9, 2.0 Hz, 1H), 7.52-7.42 (m, 1H), 4.23 (s, 1H), 3.69 (dd, J=5.1, 2.6 Hz, 2H), 3.61 (t, J=5.3 Hz, 2H), 3.06 (d, J=1.2 Hz, 3H), 2.39-2.25 (m, 2H), 2.12-2.07 (m, 3H), 2.06-1.95 (m, 2H), 1.88-1.78 (m, 2H). LCMS (ESI) calcd. for C25H27F3N5O2S [M+H]+ m/z 518.19, found 518.10.
Step 1: tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(3-methylthiophen-2-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.33 mmol), (3-methylthiophen-2-yl)boronic acid (95 mg, 0.66 mmol), t-BuOK (75 mg, 0.66 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (24 mg, 0.033 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/2) to give tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(3-methylthiophen-2-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 49.0%) as a yellow solid. LCMS (ESI) calcd. for C30H37F2N4O4S2 [M+H]+ m/z 619.22, found 619.20.
Step 2: 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(3-methylthiophen-2-yl)nicotinamide: A solution of tert-butyl ((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(3-methylthiophen-2-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 0.09 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The solution was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.1% NH3) to obtain 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(3-methylthiophen-2-yl)nicotinamide (27.9 mg, 99.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 10.88 (s, 1H), 8.35 (t, J=1.8 Hz, 1H), 8.06 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.52 (d, J=5.1 Hz, 1H), 7.03 (d, J=5.1 Hz, 1H), 4.23 (s, 1H), 3.71-3.62 (m, 2H), 3.59 (t, J=6.1 Hz, 2H), 3.06 (s, 3H), 2.29 (t, J=13.2 Hz, 2H), 2.07 (d, J=3.2 Hz, 3H), 2.04-1.96 (m, 5H), 1.86-1.78 (m, 2H). LCMS (ESI) calcd. for C25H29F2N4O2S2 [M+H]+ m/z 519.17, found 519.10.
Step 1: 4-bromo-Ntert-butyldimethylsilyl)pyridine-2-sulfonimidamide: To a 250 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added a solution of Ph3PCl2 (1.13 g, 3.4 mmol) in chloroform (24 mL). This was followed by the addition of TEA (0.96 mL) dropwise with stirring at room temperature. The resulting solution was stirred for 10 min at room temperature, then the reaction solution was cooled to 0° C. To this ice-cold solution was added a solution of 4-bromo-N-(tert-butyldimethylsilyl)pyridine-2-sulfonamide (600 mg, 1.7 mmol) in chloroform (8 mL) dropwise at 0° C. The resulting solution was stirred for 30 min at 25° C. And then ammonia gas was introduced into the reaction system. The solution was stirred for 1 hour at room temperature. The resulting solution was diluted with water (40 mL) and extracted with DCM (40 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give 4-bromo-N
(tert-butyldimethylsilyl)pyridine-2-sulfonimidamide (300 mg, 50.5%) as a white solid. LCMS (ESI) calcd. for C11H21BrN3OSSi [M+H]+ m/z 352.04, found 352.00.
Step 2: tert-butyl (4-bromo-N-(tert-butyldimethylsilyl)pyridine-2-sulfonimidoyl)carbamate: A solution of 4-bromo-Ntert-butyldimethylsilyl)pyridine-2-sulfonimidamide (300 mg, 0.86 mmol) and DMAP (126 mg, 1.03 mmol) in THE (5 mL) was added di-tert-butyl dicarbonate (750 mg, 3.44 mmol) at room temperature. The solution as stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (4-bromo-N-(tert-butyldimethylsilyl)pyridine-2-sulfonimidoyl)carbamate (250 mg, 64.7%) as a white solid. LCMS (ESI) calcd. for C16H29BrN3O3SSi [M+H]+ m/z 450.09, found 450.05.
Step 3: tert-butyl (N-(tert-butyldimethylsilyl)-4-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)pyridine-2-sulfonimidoyl)carbamate: A solution of 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide (165 mg, 0.49 mmol) in dioxane (10 mL) was added tert-butyl (4-bromo-N-(tert-butyldimethylsilyl)pyridine-2-sulfonimidoyl)carbamate (220 mg, 0.49 mmol), cesium carbonate (415 mg, 1.27 mmol) and XantPhos-Pd-G2 (43.5 mg, 0.049 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours under nitrogen. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (N-(tert-butyldimethylsilyl)-4-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)pyridine-2-sulfonimidoyl)carbamate (120 mg, 34.7%) as a yellow oil. LCMS (ESI) calcd. for C30H44F5N6O4SSi [M+H]+ m/z 707.28, found 707.35.
Step 4: 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamidimidoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide: To a solution of tert-butyl (N-(tert-butyldimethylsilyl)-4-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)pyridine-2-sulfonimidoyl)carbamate (100 mg, 0.14 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 95% MeCN/H2O containing 0.05% NH3) to afford 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamidimidoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide (33.2 mg, 48.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.55 (d, J=5.4 Hz, 1H), 8.34 (d, J=1.5 Hz, 1H), 8.00 (s, 1H), 7.82 (dd, J=5.4, 1.8 Hz, 1H), 6.71 (s, 2H), 3.74-3.67 (m, 2H), 3.41 (t, J=5.3 Hz, 2H), 2.52 (s, 3H), 2.33 (s, 2H), 1.94 (d, J=15.4 Hz, 2H), 1.88 (d, J=4.5 Hz, 2H). LCMS (ESI) calcd. for C19H22F5N6O2S [M+H]+ m/z 493.15, found 493.10.
Step 1: 3-bromo-N-(tert-butyldimethylsilyl)benzenesulfonamide: To a solution of 3-bromobenzenesulfonamide (5.0 g, 21.2 mmol) and DIEA (4.11 g, 31.8 mmol) in DCM (30 mL) was added TBSCl (3.84 g, 25.4 mmol) at room temperature. The solution as stirred at room temperature for 3 hours. Then the mixture was diluted with water (40 mL) and extracted with DCM (40 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1 to 5/1) to give 3-bromo-N-(tert-butyldimethylsilyl)benzenesulfonamide (4.7 g, 63.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (t, J=1.8 Hz, 1H), 7.74-7.66 (m, 3H), 7.45 (t, J=7.9 Hz, 1H), 0.76 (s, 9H), 0.00 (s, 6H)
Step 2: 3-bromo-N(tert-butyldimethylsilyl)benzenesulfonimidamide: To a 500 mL 3-necked round-bottom flask purged and maintained with an atmosphere of nitrogen, was added a solution of Ph3PCl2 (6 g, 18.1 mmol) in chloroform (40 mL). This was followed by the addition of Et3N (2.30 g, 22.8 mmol) dropwise with stirring at room temperature. The resulting solution was stirred for 10 min at room temperature, then the reaction solution was cooled to 0° C. To this ice-cold solution was added a solution of 3-bromo-N-(tert-butyldimethylsilyl)benzenesulfonamide (4 g, 11.4 mmol) in chloroform (8 mL) dropwise at 0° C. The resulting solution was stirred for 30 min at 25° C. And then ammonia gas was introduced into the reaction system. The solution was stirred for 1 hour at room temperature. The resulting solution was diluted with water (40 mL) and extracted with DCM (40 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give 3-bromo-N
(tert-butyldimethylsilyl)benzenesulfonimidamide (2 g, 50.4%) as a white solid. LCMS (ESI) calcd. for C12H22BrN2OSSi [M+H]+ m/z 351.04, found 350.95.
Step 3: tert-butyl (3-bromo-N-(tert-butyldimethylsilyl)phenylsulfonimidoyl)(tert-butoxycarbonyl)carbamate: A solution of 3-bromo-Ntert-butyldimethylsilyl)benzenesulfonimidamide (2 g, 5.73 mmol), DMAP (839 mg, 6.87 mmol) and di-tert-butyl dicarbonate (4.99 g, 22.92 mmol) in THE (20 mL) stirred at room temperature for 3 hours. Then the mixture was diluted with water (40 mL) and extracted with DCM (40 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=20/1) to give tert-butyl (3-bromo-N-(tert-butyldimethylsilyl)phenylsulfonimidoyl)(tert-butoxycarbonyl)carbamate(1.29 g, 41.0%) as a white solid. LCMS (ESI) calcd. for C22H38BrN2O5SSi [M+H]+ m/z 551.15, found 551.15.
Step 4: tert-butyl (tert-butoxycarbonyl)(3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenylsulfonimidoyl)carbamate: A mixture of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (150 mg, 0.44 mmol), tert-butyl (3-bromo-N-(tert-butyldimethylsilyl)phenylsulfonimidoyl)(tert-butoxycarbonyl)carbamate (362 mg, 0.66 mmol), Cs2CO3 (287 mg, 0.88 mmol) and Xantphos-Pd-G2 (35 mg, 0.044 mmol) in 1,4-dioxane (10 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was concentrated under vacuum. The residue was directly purified by flash column chromatography on silica gel (PE/EtOAc=1/2) to give tert-butyl (tert-butoxycarbonyl)(3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenylsulfonimidoyl)carbamate (75 mg, 24.6%) as a yellow solid. LCMS (ESI) calcd. for C29H38F5N6O6S [M+H]+ m/z 693.25, found 693.20.
Step 5: 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-sulfamidimidoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of tert-butyl (tert-butoxycarbonyl)(3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenylsulfonimidoyl)carbamate (75 mg, 0.11 mmol) in 1,4-dioxane (1 mL) was added 4M HCl dioxane (1 mL) at room temperature. The solution was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 95% MeCN/H2O containing 0.1% NH3) to obtain 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-sulfamidimidoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (18.3 mg, 33.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.04 (s, 1H), 8.27-8.23 (m, 1H), 7.76-7.71 (m, 2H), 7.51 (s, 1H), 3.85 (s, 2H), 3.71 (s, 2H), 2.41-2.34 (m, 2H), 2.32 (s, 3H), 2.11-2.03 (m, 2H), 1.91-1.86 (m, 2H). LCMS (ESI) calcd. for C19H22F5N6O2S [M+H]+ m/z 493.15, found 493.05.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate(80 mg, 0.133 mmol), 2-oxa-6-azaspiro[3.3]heptane (20 mg, 0.200 mmol), Cs2CO3 (130 mg, 0.400 mmol) and Pd2(dba)3 (12 mg, 0.013 mmol), S-Phos (5 mg, 0.013 mmol) in 1,4-dioxane (10 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 73.17%) as a yellow oil. LCMS (ESI) calcd. for C30H40F2N5O5S [M+H]+ m/z 620.27, found 620.25.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 0.097 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The solution was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)nicotinamide (28 mg, 56.80%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.36 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.68-7.62 (m, 1H), 7.60-7.52 (m, 2H), 4.71 (s, 4H), 4.21 (s, 1H), 3.99 (s, 4H), 3.34 (s, 4H), 3.04 (s, 3H), 2.24-2.12 (m, 2H), 2.06 (s, 3H), 2.03-1.92 (m, 2H), 1.76-1.66 (m, 2H). LCMS (ESI) calcd. for C25H32F2N5O3S [M+H]+ m/z 520.22, found 520.35.
3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-phenylpyridazine-4-carboxamide (40 mg) was purified by Chiral SFC (chiralpak-AS-H, 150*21.2 mm, eluting with 25% CO02-MeOH containing 0.1% formic acid). The first elution was lyophilized to afford (S)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-phenylpyridazine-4-carboxamide (13.7 mg, 34%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.33-8.31 (m, 1H), 7.89 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.63-7.59 (m, 1H), 7.57-7.46 (m, 5H), 4.26 (s, 1H), 3.79-3.77 (m, 2H), 3.67-3.64 (m, 2H), 3.07 (s, 3H), 2.35-2.33 (m, 2H), 2.19 (s, 3H), 2.06-2.04 (m, 2H), 1.88-1.86 (m, 2H). LCMS (ESI) calcd. for C25H28F2N5O2S [M+H]+ m/z 500.19, found 500.15. and the second elution was lyophilized to afford (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-phenylpyridazine-4-carboxamide (13.3 mg, 33%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.33-8.31 (m, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.63-7.59 (m, 1H), 7.57-7.53 (m, 2H), 7.51-7.48 (m, 2H), 7.48-7.46 (m, 1H), 4.25 (s, 1H), 3.79-3.77 (m, 2H), 3.67-3.64 (m, 2H), 3.07 (s, 3H), 2.35-2.33 (m, 2H), 2.19 (s, 3H), 2.06-2.04 (m, 2H), 1.88-1.86 (m, 2H). LCMS (ESI) calcd. for C25H28F2N5O2S [M+H]+ m/z 500.19, found 500.15.
Step 1: A solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (250 mg, 0.74 mmol) in dioxane (12 mL) was added tert-butyl (4-bromo-N-(tert-butyldimethylsilyl)pyridine-2-sulfonimidoyl)carbamate (367 mg, 0.81 mmol), cesium carbonate (626 mg, 1.92 mmol) and XantPhos-Pd-G2 (65.7 mg, 0.074 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours under nitrogen. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (N-(tert-butyldimethylsilyl)-4-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine-2-sulfonimidoyl)carbamate (180 mg, 34.4%) as a yellow oil. LCMS (ESI) calcd. for C29H43F5N7O4SSi [M+H]+ m/z 708.28, found 708.25.
Step 2: To a solution of tert-butyl (N-(tert-butyldimethylsilyl)-4-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine-2-sulfonimidoyl)carbamate (180 mg, 0.25 mmol) in DCM (7.5 mL) was added TFA (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 85% MeCN/H2O containing 0.05% NH3) to afford 3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(2-sulfamidimidoylpyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (53.5 mg, 42.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.53 (s, 1H), 8.25 (s, 1H), 7.78-7.63 (m, 1H), 5.8-6.9 (bs, 2H), 3.84 (s, 2H), 3.68 (s, 2H), 2.33 (s, 2H), 2.30 (s, 3H), 2.06 (d, J=13.6 Hz, 2H), 1.87 (d, J=5.3 Hz, 2H). LCMS (ESI) calcd. for C18H21F5N7O2S [M+H]+ m/z 494.14, found 494.10.
Step 1: (3-bromophenyl)(methyl)-λ4-sulfanimine: To a solution of ethyl (Z)-N-((mesitylsulfonyl)oxy)acetimidate (4.4 g, 15.4 mmol) in dioxane (15 mL) was added HClO4 (70%, 15 mL) dropwise at 0° C. The mixture was stirred 0° C. for 15 minutes. The mixture was quenched with cold water (30 mL) and extracted with DCM (15 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate. Then a solution of (3-bromophenyl)(methyl)sulfane (2 g, 9.85 mmol) in DCM (15 mL) was added dropwise to the mixture at 0° C. The mixture was stirred at room temperature for 2 h. After the reaction was completed, half of the DCM was evaporated, and diethyl ether (50 mL) was added to the mixture. After storing at 0° C. overnight, the crystal precipitation was collected and dried under vacuum to provide (3-bromophenyl)(methyl)-λ4-sulfanimine (1.5 g, 70%) was crystallized upon storage at 0° C. overnight. LCMS (ESI) calcd. for C7H9BrNS [M+H]+ m/z 219.96, found 219.90.
Step 2: (3-bromophenyl)(methyl)-λ6-sulfanediimine: To a solution of (3-bromophenyl)(methyl)-λ4-sulfanimine (1.5 g, 6.88 mmol) in DMF (15 mL) was added NCS (1.1 g, 0.008 mol) and Na2CO3 (4.3 g, 0.041 mol) at 0° C. under N2. The mixture was stirred at 0° C. for 15 minutes. Then (Me3Si)2NH (3.3 g, 0.021 mol) was added to the mixture at 0° C. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 5% to 30% MeCN/H2O containing 0.05% NH3) to provide (3-bromophenyl)(methyl)-λ6-sulfanediimine (200 mg, 12.48% yield) as a white solid. LCMS (ESI) calcd. for C7H10BrN2S [M+H]+ m/z 232.98, found 232.85.
Step 3: di-tert-butyl ((3-bromophenyl)(methyl)-λ6-sulfanediylidene)dicarbamate: A (3-bromophenyl)(methyl)-λ6-sulfanediimine (200 mg, 0.862 mmol), t-BuOK (241 mg, 2.155 mmol) and Boc2O (563 mg, 2.586 mmol) in THE (10 mL) was stirred at room temperature for 16 h. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=3/1) to give di-tert-butyl ((3-bromophenyl)(methyl)-λ6-sulfanediylidene)dicarbamate (80 mg, 21.51%) as a yellow solid. LCMS (ESI) calcd. for C17H26BrN2O4S [M+H]+ m/z 433.08, found 433.00.
Step 1: di-tert-butyl ((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)-λ6-sulfanediylidene)dicarbamate: A mixture of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (80 mg, 0.237 mmol), di-tert-butyl ((3-bromophenyl)(methyl)-λ6-sulfanediylidene)dicarbamate (80 mg, 0.185 mmol), Cs2CO3 (231 mg, 0.711 mmol) and Xantphos-Pd-G2 (21 mg, 0.024 mmol) in dioxane (10 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give di-tert-butyl ((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)-λ6-sulfanediylidene)dicarbamate (30 mg, 18.41%) as a yellow oil. LCMS (ESI) calcd. for C30H40F5N6O5S [M+H]+ m/z 691.27, found 691.15.
Step 2: 3-(4,4-difluoroazepan-1-yl)-N-{3-[diimino(methyl)-λ6-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of di-tert-butyl ((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)-λ6-sulfanediylidene)dicarbamate (30 mg, 0.043 mmol) in DCM (2 mL) was added TFA (0.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 95% MeCN/H2O containing 0.1% formic acid) to provide 3-(4,4-difluoroazepan-1-yl)-N-{3-[diimino(methyl)-λ6-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (3.1 mg, 14.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.35 (s, 1H), 7.86 (dd, J=17.8, 7.9 Hz, 2H), 7.59 (td, J=7.9, 2.9 Hz, 1H), 3.85 (s, 2H), 3.69 (s, 2H), 3.02 (d, J=2.9 Hz, 3H), 2.33 (s, 5H), 2.14-2.00 (m, 2H), 1.88 (s, 2H). LCMS (ESI) calcd. for C20H24F5N6OS [M+H]+ m/z 491.16, found 491.05.
Step 1: tert-butyl (tert-butoxycarbonyl)(3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)phenylsulfonimidoyl)carbamate: A solution of 2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide (200 mg, 0.593 mmol) in dioxane (10 mL) was tert-butyl (3-bromo-N-(tert-butyldimethylsilyl)phenylsulfonimidoyl)(tert-butoxycarbonyl)carbamate (975 mg, 1.779 mmol), cesium carbonate (502 mg, 1.542 mmol) and XantPhos-Pd-G2 (106 mg, 0.119 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours under nitrogen. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (tert-butoxycarbonyl)(3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)phenylsulfonimidoyl)carbamate (100 mg, 24.39%) as a white oil. LCMS (ESI) calcd. for C30H39F5N5O6S [M+H]+ m/z 692.25, found 692.20.
Step 2: 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-sulfamidimidoylphenyl)-5-(trifluoromethyl)nicotinamide: To a solution of tert-butyl (tert-butoxycarbonyl)(3-(2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamido)phenylsulfonimidoyl)carbamate (50 mg, 0.072 mmol) in 1,4-dioxane (5 mL) was added 4M HCl-dioxane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 95% MeCN/H2O containing 0.1% formic acid) to afford 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-sulfamidimidoylphenyl)-5-(trifluoromethyl)nicotinamide (16.23 mg, 54.10%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.28-8.26 (m, 1H), 7.90 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.64 (d, J=8 Hz, 1H), 7.50-7.46 (m, 1H), 6.5-5.5 (bs, 2H), 3.72-3.70 (m, 2H), 3.49-3.46 (m, 2H), 2.49 (s, 3H), 2.33-2.30 (m, 2H), 1.98-1.92 (m, 2H), 1.88-1.87 (m, 2H). LCMS (ESI) calcd. for C20H23F5N5O2S [M+H]+ m/z 492.15, found 492.10.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-phenylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol), phenylboronic acid (41 mg, 0.34 mmol), K2CO3 (47 mg, 0.34 mmol) and Pd(dppf)Cl2 (7 mg, 0.01 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was concentrated under vacuum. The residue was directly purified by flash column chromatography on silica gel (PE/EtAOc=3/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-phenylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 83.6%) as a yellow solid. LCMS (ESI) calcd. for C31H37F2N4O4S [M+H]+ m/z 599.25, found 599.20.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-phenylnicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-phenylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate(50 mg, 0.08 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated, and the residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H2O containing 0.1% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-phenylnicotinamide (16.25 mg, 40.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.47 (t, J=7.3 Hz, 2H), 7.42-7.31 (m, 3H), 4.22 (s, 1H), 3.71-3.54 (m, 4H), 3.06 (s, 3H), 2.36-2.21 (m, 2H), 2.15 (s, 3H), 2.09-1.94 (m, 2H), 1.87-1.73 (m, 2H). LCMS (ESI) calcd. for C26H29F2N4O2S [M+H]+ m/z 499.20, found 499.15.
Step 1: tert-butyl (R)-((3-(5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 0.133 mmol), tert-butyldimethyl(prop-2-yn-1-yloxy)silane (45 mg, 0.267 mmol), DBU (41 mg, 0.267 mmol) and Pd(PPh3)4 (15 mg, 0.013 mmol) in DMSO (5 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-((3-(5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 54.35%) as a yellow oil. LCMS (ESI) calcd. for C34H49F2N4O5SSi [M+H]+ m/z 691.31, found 691.30.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(3-hydroxyprop-1-yn-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 0.072 mmol) in 1,4-dioxane (3 mL) was added HCl-1,4-dioxane (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-2-(4,4-difluoroazepan-1-yl)-5-(3-hydroxyprop-1-yn-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (15.2 mg, 35.59%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.34 (t, J=1.8 Hz, 1H), 8.22 (s, 1H), 7.89 (d, J=8.9 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 5.33 (t, J=5.9 Hz, 1H), 4.33 (d, J=5.9 Hz, 2H), 4.23 (s, 1H), 3.65 (dd, J=6.4, 3.9 Hz, 2H), 3.56 (t, J=6.1 Hz, 2H), 3.06 (d, J=0.7 Hz, 3H), 2.35-2.20 (m, 5H), 2.04-1.94 (m, 2H), 1.84-1.76 (m, 2H). LCMS (ESI) calcd. for C23H27F2N4O3S [M+H]+ m/z 477.18, found 477.15.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3-(dimethylamino)prop-1-yn-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol), N,N-dimethylprop-2-yn-1-amine (16 mg, 0.19 mmol) and DBU (57 mg, 0.37 mmol) in DMSO (2 mL) was added Pd(PPh3)4 (10 mg, 0.0085 mmol). Then the mixture was heated at 100° C. for 12 hours under N2. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (3×5 mL). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with MeOH/DCM, 0 to 10%) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3-(dimethylamino)prop-1-yn-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate(70 mg, 68.29% yield) as a yellow oil. LCMS (ESI) calcd. for C30H40F2N5O4S [M+H]+ m/z 604.28, found 604.25.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(3-(dimethylamino)prop-1-yn-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3-(dimethylamino)prop-1-yn-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 0.12 mmol) in DCM (2 mL) was added TFA (0.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H2O containing 0.05% NH3) to afford (R)-2-(4,4-difluoroazepan-1-yl)-5-(3-(dimethylamino)prop-1-yn-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (20.17 mg, 33.42%) as a white solid. LCMS (ESI) calcd. for C25H32F2N5O2S [M+H]+ m/z 504.22, found 504.25. 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.28 (d, J=33.4 Hz, 2H), 7.89 (d, J=7.4 Hz, 1H), 7.69-7.57 (m, 2H), 4.23 (s, 1H), 3.68-3.54 (m, 4H), 3.49 (s, 2H), 3.06 (s, 3H), 2.33 (s, 3H), 2.24 (s, 6H), 1.99 (d, J=7.8 Hz, 2H), 1.81 (d, J=4.9 Hz, 2H), 1.23 (s, 2H).
Step 1: tert-butyl (R)-((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.167 mmol), Zn(CN)2 (39 mg, 0.333 mmol), tBuXPhos-Pd-G3 (14 mg, 0.017 mmol) in THF/H2O (4/1, 5 mL) was heated at 70° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 65.93%) as a yellow oil. LCMS (ESI) calcd. for C26H32F2N5O4S [M+H]+ m/z 548.21, found 548.15.
Step 2: (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 0.109 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (38.5 mg, 77.55%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 4.24 (s, 1H), 3.74 (s, 2H), 3.62 (t, J=5.8 Hz, 2H), 3.07 (s, 3H), 2.37 (s, 3H), 2.35-2.21 (m, 2H), 2.07-1.93 (m, 2H), 1.88-1.79 (m, 2H). LCMS (ESI) calcd. for C21H24F2N5O2S [M+H]+ m/z 448.16, found 448.00.
Step 1: tert-butyl (R)-(2-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A mixture of (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (110 mg, 0.246 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (70 mg, 0.369 mmol), HATU (187 mg, 0.492 mmol) and DIEA (95 mg, 0.738 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (R)-(2-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (90 mg, 59.21%) as a yellow oil. LCMS (ESI) calcd. for C29H37F2N6O5S [M+H]+ m/z 619.25, found 619.20.
Step 2: (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-(2-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (90 mg, 0.145 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)nicotinamide (62 mg, 82.12%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 7.97 (d, J=7.7 Hz, 1H), 7.69 (dt, J=15.6, 7.9 Hz, 2H), 3.74 (s, 2H), 3.61 (t, J=5.8 Hz, 2H), 3.50 (s, 3H), 3.41 (s, 2H), 2.37 (s, 3H), 2.33 (s, 3H), 2.31-2.22 (m, 2H), 2.06-1.95 (m, 2H), 1.89-1.79 (m, 2H). LCMS (ESI) calcd. for C24H29F2N6O3S [M+H]+ m/z 519.20, found 519.15.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(prop-1-yn-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.199 mmol), tributyl(prop-1-yn-1-yl)stannane (79 mg, 0.239 mmol) and Pd(PPh3)4 (23.0 mg, 0.02 mmol) in toluene (6 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(prop-1-yn-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 62.5%) as a yellow oil. LCMS (ESI) calcd. for C28H35F2N4O4S [M+H]+ m/z 561.23, found 561.15.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(prop-1-yn-1-yl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(prop-1-yn-1-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 0.125 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(prop-1-yn-1-yl)nicotinamide (25.2 mg, 43.86%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 4.22 (s, 1H), 3.62 (d, J=5.2 Hz, 2H), 3.55 (t, J=5.9 Hz, 2H), 3.06 (s, 3H), 2.29 (s, 3H), 2.28-2.17 (m, 2H), 2.08 (s, 3H), 2.04-1.93 (m, 2H), 1.84-1.74 (m, 2H). LCMS (ESI) calcd. for C23H27F2N4O2S [M+H]+ m/z 461.18, found 461.05.
Step 1: methyl 3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)bicyclo[1.1.1]pentane-1-carboxylate: A solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (200 mg, 0.59 mmol), methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (125.8 mg, 0.71 mmol) and HATU (336 mg, 0.89 mmol) in DMF (5 mL) was added DIEA (228 mg, 1.77 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give methyl 3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)bicyclo[1.1.1]pentane-1-carboxylate (110 mg, 40.3%) as a yellow oil. LCMS (ESI) calcd. for C20H24F5N4O3 [M+H]+ m/z 463.18, found 463.15.
Step 2: N-(3-carbamoylbicyclo[1.1.1]pentan-1-yl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of methyl 3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)bicyclo[1.1.1]pentane-1-carboxylate (110 mg, 0.24 mmol) in 7M NH3 MeOH solution (5 mL) was heated at 100° C. for 8 hours in a sealed tube. After the reaction was completed, the mixture was concentrated. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 80% MeCN/H2O containing 0.1% formic acid) to provide N-(3-carbamoylbicyclo[1.1.1]pentan-1-yl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide(56.6 mg, 52.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.31 (s, 1H), 7.02 (s, 1H), 3.84-3.76 (m, 2H), 3.68 (t, J=6.0 Hz, 2H), 2.39-2.28 (m, 2H), 2.24 (d, J=1.2 Hz, 3H), 2.21 (s, 6H), 2.13-2.02 (m, 2H), 1.95-1.87 (m, 2H). LCMS (ESI) calcd. for C19H23F5N5O2 [M+H]+ m/z 448.18, found 448.05.
Step 1: tert-butyl (R)-((3-(5-carbamoyl-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.183 mmol), K2CO3 (76 mg, 0.548 mmol) and 30% H2O2 (2 mL) in DMSO (5 mL) was stirred at room temperature for 4 h. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/5) to give tert-butyl (R)-((3-(5-carbamoyl-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (92 mg, 87.62%) as a yellow oil. LCMS (ESI) calcd. for C26H34F2N5O5S [M+H]+ m/z 566.22, found 566.20.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N3-(3-(S-methylsulfonimidoyl)phenyl) pyridine-3,5-dicarboxamide: A solution of tert-butyl (R)-((3-(5-carbamoyl-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (92 mg, 0.163 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N3-(3-(S-methylsulfonimidoyl)phenyl)pyridine-3,5-dicarboxamide (61 mg, 80.58%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.77 (s, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.34 (s, 1H), 4.23 (s, 1H), 3.65 (s, 2H), 3.57 (t, J=5.9 Hz, 2H), 3.06 (s, 3H), 2.32 (s, 3H), 2.31-2.22 (m, 2H), 2.05-1.92 (m, 2H), 1.86-1.77 (m, 2H). LCMS (ESI) calcd. for C21H26F2N5O3S [M+H]+ m/z 466.17, found 466.15.
A solution of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.150 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% NH3·H2O) to obtain (R)-5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (30.51 mg, 34.94%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.29 (t, J=2.0 Hz, 1H), 7.91-7.85 (m, 1H), 7.70 (dt, J=8.0, 1.3 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 4.32-4.20 (m, 1H), 3.67-3.52 (m, 4H), 3.07 (s, 3H), 2.40 (s, 3H), 2.33-2.23 (m, 2H), 2.09-1.95 (m, 2H), 1.86-1.77 (m, 2H). LCMS (ESI) calcd. for C21H23BrF5N4O2S [M+H]+ m/z 571.06, found 571.05.
Step 1: tert-butyl (R)-((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.224 mmol), (4-cyanophenyl)boronic acid (0.098 g, 0.672 mmol), t-BuOK (51 mg, 0.448 mmol), Pd(dppf)Cl2 (17 mg, 0.022 mmol) in dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 45.1%) as a yellow solid. LCMS (ESI) calcd. for C33H34F5N5O4SNa [M+Na]+ m/z 714.22, found 714.15.
Step 2: (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 0.109 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 80% MeCN/H2O containing 0.1% formic acid) to provide (R)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (21.3 mg, 35.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.34 (s, 1H), 7.96 (d, J=8.6 Hz, 2H), 7.89 (d, J=8.1 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.45 (d, J=7.0 Hz, 2H), 3.73-3.61 (m, 4H), 3.07 (s, 3H), 2.37-2.26 (m, 2H), 2.11-1.98 (m, 2H), 1.91 (s, 3H), 1.88-1.79 (m, 2H). LCMS (ESI) calcd. for C28H27F5N5O2S [M+H]+ m/z 592.18, found 592.15.
Step 1: 3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)bicyclo[1.1.1]pentane-1-carboxylic acid: A mixture of methyl 3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)bicyclo[1.1.1]pentane-1-carboxylate (100 mg, 0.212 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (40 mg, 0.318 mmol), K2CO3 (88 mg, 0.637 mmol) and Pd(dppf)Cl2 (16 mg, 0.021 mmol) in dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=9/1) to give 3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)bicyclo[1.1.1]pentane-1-carboxylic acid (60 mg, 61.86%) as a yellow solid. LCMS (ESI) calcd. for C23H28F2N5O3 [M+H]+ m/z 460.21, found 460.10.
Step 2: N-(3-carbamoylbicyclo[1.1.1]pentan-1-yl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: A solution of 3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)bicyclo[1.1.1]pentane-1-carboxylic acid (60 mg, 0.130 mmol) in DCM (6 mL) and DMF (0.02 mL) was added oxalyl chloride (33 mg, 0.261 mmol). The solution was stirred at room temperature for 30 min. Then the solution was concentrated under vacuum. The residue was diluted with THE (5 mL) and added to a stirred solution of 28% NH3—H2O (2 mL) in THE (5 mL). The mixture was stirred at room temperature for 3 hours. Then the mixture was quenched with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 80% MeCN/H2O containing 0.1% formic acid) to provide N-(3-carbamoylbicyclo[1.1.1]pentan-1-yl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (21.4 mg, 35.67%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.56 (s, 1H), 7.28 (s, 1H), 6.99 (s, 1H), 3.87 (s, 3H), 3.61-3.46 (m, 4H), 2.29-2.14 (m, 11H), 2.10-1.97 (m, 2H), 1.86-1.80 (m, 2H). LCMS (ESI) calcd. for C23H29F2N6O2 [M+H]+ m/z 459.23, found 459.10.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.299 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (188 mg, 1.50 mmol) in 1,4-dioxane/H2O (4/1, 10 mL), cesium carbonate (195 mg, 0.598 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (22 mg, 0.030 mmol) was heated at 100° C. for 6 hours under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6--sulfaneylidene)carbamate (150 mg, 75.00%) as a yellow oil. LCMS (ESI) calcd. for C30H36F5N6O4S [M+H]+ m/z 671.24, found 671.20.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.179 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (44.21 mg, 43.13%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.35 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.58-7.60 (m, 1H), 7.36 (s, 1H), 4.24 (s, 1H), 3.89 (s, 3H), 3.68-3.66 (m, 2H), 3.62-3.59 (m, 2H), 3.06 (s, 3H), 2.31-2.29 (m, 2H), 2.03 (s, 3H), 1.99-1.97 (m, 2H), 1.84-1.82 (m, 2H). LCMS (ESI) calcd. for C25H28F5N6O2S [M+H]+ m/z 571.19, found 571.20.
Step 1: methyl 3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)bicyclo[1.1.1]pentane-1-carboxylate: A solution of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (700 mg, 2.01 mmol) in DCM (10 mL) and DMF (0.05 mL) was added oxalyl chloride (383 mg, 3.17 mmol). The solution was stirred at room temperature for 30 min. Then the solution was concentrated under vacuum. The residue was diluted with THE (5 mL) and added to a stirred solution of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (427 mg, 2.41 mmol) and DIEA (778 mg, 6.03 mmol) in THE (5 mL). The mixture was heated at 50° C. for 1 h. Then the mixture was quenched with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/4) to provide methyl 3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)bicyclo[1.1.1]pentane-1-carboxylate (750 mg, 79.20%) as a yellow solid. LCMS (ESI) calcd. for C20H25BrF2N3O3 [M+H]+ m/z 474.10, found 475.05.
Step 2: 5-bromo-N-(3-carbamoylbicyclo[1.1.1]pentan-1-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide: A mixture of methyl 3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)bicyclo[1.1.1]pentane-1-carboxylate(750 mg, 1.59 mmol) in 7M NH3-MeOH (10 mL) was heated at 100° C. for 8 hours in a sealed tube. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/4) to give 5-bromo-N-(3-carbamoylbicyclo[1.1.1]pentan-1-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (700 mg, 96.42%) as a yellow solid. LCMS (ESI) calcd. for C19H24BrF2N4O2 [M+H]+ m/z 459.10, found 458.95.
Step 3: N-(3-carbamoylbicyclo[1.1.1]pentan-1-yl)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide: A solution of 5-bromo-N-(3-carbamoylbicyclo[1.1.1]pentan-1-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (120 mg, 0.26 mmol), (4-cyanophenyl)boronic acid (76 mg, 0.52 mmol), Pd(dppf)Cl2 (19 mg, 0.026 mmol) and K2CO3 (108 mg, 0.78 mmol) in dioxane (2 mL) and H2O (0.5 mL) was heated at 100° C. for 12 h under N2 atmosphere. Then the mixture was diluted with water and extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*19 mm, eluting with 20% to 70% MeCN/H2O containing 0.1% FA) to afford N-(3-carbamoylbicyclo[1.1.1]pentan-1-yl)-5-(4-cyanophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (57.4 mg, 23.04%) as a white solid. LCMS (ESI) calcd. for C26H28F2N5O2 [M+H]+ m/z 480.22, found 480.20. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.02 (s, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.28 (s, 1H), 6.99 (s, 1H), 3.69-3.53 (m, 4H), 2.37-2.22 (m, 2H), 2.19 (s, 6H), 2.10-1.99 (m, 5H), 1.91-1.81 (m, 2H).
Step 1: methyl 2-chloro-4-(4,4-difluoroazepan-1-yl)-6-methylpyrimidine-5-carboxylate: A solution of methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (3.50 g, 15.83 mmol), 4,4-difluoroazepane hydrochloride (2.71 g, 15.83 mmol) and DIPEA (5.11 g, 39.58 mmol) in dioxane (50 mL) was heated at 50° C. for 6 hours. LCMS showed the reaction was completed. The mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=5/1) to provide methyl 2-chloro-4-(4,4-difluoroazepan-1-yl)-6-methylpyrimidine-5-carboxylate (3.6 g, 67.55%) as white solid. LCMS (ESI) calcd. for C13H17ClF2N3O2 [M+H]+ m/z 320.10, found 320.10.
Step 2: methyl 4-(4,4-difluoroazepan-1-yl)-2-iodo-6-methylpyrimidine-5-carboxylate: A solution of methyl 2-chloro-4-(4,4-difluoroazepan-1-yl)-6-methylpyrimidine-5-carboxylate (1 g, 3.13 mmol) in 57% hydriodic acid (5 mL) was stirred at 25° C. for 48 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=5/1) to provide methyl 4-(4,4-difluoroazepan-1-yl)-2-iodo-6-methylpyrimidine-5-carboxylate (670 mg, 50.08%) as a brown solid. LCMS (ESI) calcd. for C13H17F2IN3O2 [M+H]+ m/z 411.04, found 412.00.
Step 3: methyl 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate: A solution of methyl 4-(4,4-difluoroazepan-1-yl)-2-iodo-6-methylpyrimidine-5-carboxylate (670 mg, 1.63 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (626 mg, 3.26 mmol) and CuI (619 mg, 3.26 mmol) in DMF (10 mL) heated at 150° C. for 2 hours under an atmosphere of N2. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (60 mL×3). The combined organic phases were washed with brine (60 mL×3), dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to provide methyl 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate (380 mg, 66.26%) as a brown solid. LCMS (ESI) calcd. for C14H17F5N3O2 [M+H]+ m/z 354.12, found 354.10.
Step 4: 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic acid: To a solution of methyl 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate (380 mg, 1.08 mmol) in MeOH/H2O (1/1, 4 mL) was added KOH (603 mg, 10.76 mmol) at room temperature. The mixture was heated at 70° C. for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove most MeOH. The residue was dissolved with H2O (10 mL), adjusted to pH=3-4 with 1N HCl and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried with Na2S04, and concentrated under reduced pressure to give 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic acid (310 mg, 40.74%). LCMS (ESI) calcd. for C13H15F5N3O2 [M+H]+ m/z 340.11, found 340.10.
Step 5: tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic acid (150 mg, 0.44 mmol) in DCM (3 mL) and DMF (one drop) was added oxalyl chloride (119 mg, 1 mmol). The solution was stirred at room temperature for 5 min. Then the solution was added to a stirred solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (180 mg, 0.68 mmol) and Et3N (141 mg, 1.39 mmol) in DCM (3 mL) at 0° C. The resulting mixture was stirred at 25° C. for 1 hour. Then the mixture was quenched with water (20 mL) and extracted with DCM (20 mL×2). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (98 mg, 37.73%) as a brown oil. LCMS (ESI) calcd. for C25H31F5N5O4S [M+H]+ m/z 592.20, found 592.15.
Step 6: (R)-4-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)pyrimidine-5-carboxamide: A solution of tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (98 mg, 0.166 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 80% MeCN/H2O containing 0.1% NH3·H2O) to provide (R)-4-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)pyrimidine-5-carboxamide (75.4 mg, 88.28%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.27 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.72-7.55 (m, 2H), 4.24 (s, 1H), 3.85-3.62 (m, 4H), 3.07 (s, 3H), 2.41 (s, 3H), 2.28 (d, J=15.2 Hz, 2H), 2.11-1.99 (m, 2H), 1.90-1.80 (m, 2H). LCMS (ESI) calcd. for C20H23F5N5O2S [M+H]+ m/z 492.15, found 492.10.
A mixture of 5-bromo-N-(3-carbamoylbicyclo[1.1.1]pentan-1-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (100 mg, 0.219 mmol), Zn(CN)2 (51 mg, 0.439 mmol) and t-Bu-XPhos-Pd-G3 (17 mg, 0.022 mmol) in THF/H2O (4/1, 10 mL) was heated at 70° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 80% MeCN/H2O containing 0.1% formic acid) to provide N-(3-carbamoylbicyclo[1.1.1]pentan-1-yl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (57.8 mg, 65.68%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.45 (d, J=1.2 Hz, 1H), 7.29 (s, 1H), 7.00 (s, 1H), 3.74-3.59 (m, 4H), 2.32-2.19 (m, 11H), 2.08-1.97 (m, 2H), 1.90-1.82 (m, 2H). LCMS (ESI) calcd. for C20H24F2N5O2 [M+H]+ m/z 404.19, found 404.05.
Step 1: methyl 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methylpyridazine-4-carboxylate: A mixture of methyl 6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylate (800 mg, 2.50 mmol) and (4-methoxyphenyl)boronic acid (570 mg, 3.75 mmol) in 1,4-dioxane/H2O (4/1, 20 mL), potassium carbonate (1036 mg, 7.50 mmol) and Pd(dppf)Cl2·DCM (183 mg, 0.250 mmol) was heated at 100° C. for 6 h under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases was washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=3/1) to give methyl 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methylpyridazine-4-carboxylate (830 mg, 84.69%) as a white oil. LCMS (ESI) calcd. for C20H24F2N3O3 [M+H]+ m/z 392.18, found 392.25.
Step 2: 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methylpyridazine-4-carboxylic acid: To a solution methyl 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methylpyridazine-4-carboxylate (800 mg, 2.04 mmol) in MeOH/H2O (1/1, 10 mL) was added KOH (1144.64 mg, 20.40 mmol) at room temperature. The mixture was heated at 70° C. for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with DCM (10 mL). Then the aqueous phase was adjusted to pH=3 with 1N HCl and extracted with DCM (10 mL×3). The combined organic phases was dried with Na2SO4 and concentrated under reduced pressure to give crude 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methylpyridazine-4-carboxylic acid (670 mg, 87.13%) as a white solid. LCMS (ESI) calcd. for C19H22F2N3O3 [M+H]+ m/z 378.16, found 378.10.
Step 3: 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methylpyridazine-4-carboxamide: A solution of 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methylpyridazine-4-carboxylic acid (650 mg, 1.719 mmol) in DMF (10 mL) was added HATU (850 mg, 2.235 mmol), DIEA (710 mg, 5.500 mmol) and NH3-MeOH (5 mL) at room temperature. The mixture was heated at 40° C. for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water 2 mL) and extracted with DCM (20 mL×3). The combined organic phases was washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methylpyridazine-4-carboxamide (500 mg, 76.92%) as a white solid. LCMS (ESI) calcd. for C19H23F2N4O2 [M+H]+ m/z 377.18, found 377.05.
Step 4: 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methyl-N-(3-(methylsulfinyl)phenyl)pyridazine-4-carboxamide: A solution of 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methylpyridazine-4-carboxamide (450 mg, 1.194 mmol) in dioxane (8 mL) was added 1-bromo-3-(methylsulfinyl)benzene (785 mg, 3.582 mmol), Cs2CO3 (1011 mg, 3.104 mmol) and Xantphos-Pd-G2 (212 mg, 0.239 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 16 hours under nitrogen. The reaction was monitored by LCMS. After the reaction was completed, the filtrate was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases was washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methyl-N-(3-(methylsulfinyl)phenyl)pyridazine-4-carboxamide (300 mg, 48.86%) as a white solid. LCMS (ESI) calcd. for C26H29F2N4O3S [M+H]+ m/z 515.19, found 515.10.
Step 5: 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide: To a solution of 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methyl-N-(3-(methylsulfinyl)phenyl)pyridazine-4-carboxamide (280 mg, 0.544 mmol) in MeOH (5 mL) was added PhI(OAc)2 (438 mg, 1.359 mmol) and ammonium carbamate (127 mg, 1.632 mmol) at room temperature. The reaction mixture was heated at 70° C. for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (5 mL), and extracted with DCM (5 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE/EtOAc=1/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.1% formic acid) to afford 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide (60 mg, 20.83%) as a white solid. LCMS (ESI) calcd. for C26H30F2N5O3S [M+H]+ m/z 530.20, found 530.15.
Step 6: (S)-3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide and (R)-3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide: A racemic mixture of 3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide (60 mg) was purified by Chiral SFC (chiralpak-AD-H, 150*21.2 mm, eluting with 40% CO02-MeOH containing 0.1% NH3). The first eluting isomer was lyophilized to afford (S)-3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide (16.2 mg, 95.0% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.32-8.31 (m, 1H), 7.88 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.60-7.58 (m, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 4.25 (s, 1H), 3.82 (s, 3H), 3.78-3.75 (m, 2H), 3.66-3.63 (m, 2H), 3.06 (s, 3H), 2.33-2.32 (m, 2H), 2.19 (s, 3H), 2.05-2.03 (m, 2H), 1.87-1.85 (m, 2H). LCMS (ESI) calcd. for C26H30F2N5O3S [M+H]+ m/z 530.20, found 530.15. The second eluting isomer was lyophilized to afford (R)-3-(4,4-difluoroazepan-1-yl)-6-(4-methoxyphenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide (21.5 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.32-8.31 (m, 1H), 7.89 (d, J=9.2 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.60-7.58 (m, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 4.25 (s, 1H), 3.82 (s, 3H), 3.77-3.75 (m, 2H), 3.66-3.63 (m, 2H), 3.06 (s, 3H), 2.33-2.32 (m, 2H), 2.19 (s, 3H), 2.05-2.03 (m, 2H), 1.87-1.85 (m, 2H). LCMS (ESI) calcd. for C26H30F2N5O3S [M+H]+ m/z 530.20, found 530.15.
Step 1: tert-butyl (R)-((3-(6-cyano-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.358 mmol), Zn(CN)2 (42 mg, 0.358 mmol), Pd2(dba)3 (66 mg, 0.072 mmol), DPPF (79 mg, 0.143 mmol) and Zn (5 mg, 0.072 mmol) in DMA (2 mL) was heated at 120° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(6-cyano-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 76.4%) as a colorless oil. LCMS (ESI) calcd. for C25H31F2N6O4S [M+H]+ m/z 549.21, found 549.20.
Step 2: (R)-6-cyano-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide: A solution of tert-butyl (R)-((3-(6-cyano-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.274 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 80% MeCN/H2O containing 0.1% NH3—H2O) to provide (R)-6-cyano-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide (27.4 mg, 22.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.21 (s, 1H), 7.83 (s, 1H), 7.71-7.48 (m, 2H), 4.21 (s, 1H), 3.95-8.82 (m, 2H), 3.76-3.64 (m, 2H), 3.06 (s, 3H), 2.39-2.30 (m, 5H), 2.11-2.00 (m, 2H), 1.94-1.85 (m, 2H). LCMS (ESI) calcd. for C20H23F2N6O2S [M+H]+ m/z 449.16, found 449.05.
Step 1: Preparation of tert-butyl 3,6-dichloropyridazine-4-carboxylate: A mixture of 3,6-dichloropyridazine-4-carboxylic acid (20 g, 0.10 mol) in DCM (200 mL) was added dropwise t-BuOH (76.7 g, 10.4 mol) and DMAP (1.27 g, 0.01 mol) at 0° C. The mixture was stirred at 0° C. for 10 minutes, then DCC (42.8 g, 0.21 mol) was added dropwise. The resulting mixture was stirred at room temperature for 4 hours. Then the mixture was filtered through celite, and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to tert-butyl 3,6-dichloropyridazine-4-carboxylate (17 g, 68.5%) as a white solid. LCMS (ESI) calcd. for C9H11C12N2O2 [M+H]+ m/z 249.02, found 249.00.
Step 2: tert-butyl 3,6-dichloro-5-methylpyridazine-4-carboxylate: A solution of tert-butyl 3,6-dichloropyridazine-4-carboxylate (15 g, 60.2 mmol) in DMSO (150 mL) was added dropwise MeNO2 (18.4 g, 301 mmol) at room temperature. The mixture was stirred for 30 minutes and added dropwise TEA (9.14 g, 90.3 mmol) at 0° C. Then the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was quenched with water (200 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/EtOAc, 10/1) to afford tert-butyl 3,6-dichloro-5-methylpyridazine-4-carboxylate (10 g, 63.4%) as a yellow solid. LCMS (ESI) calcd. for C10H13C12N2O2 [M+H]+ m/z 263.03, found 263.00.
Step 3: 3,6-dichloro-5-methylpyridazine-4-carboxylic acid: A solution of tert-butyl 3,6-dichloro-5-methylpyridazine-4-carboxylate (3 g, 11.4 mmol) in DCM (30 mL) was added TFA (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated to afford crude 3,6-dichloro-5-methylpyridazine-4-carboxylic acid (2 g, 85.6%) as yellow solid. LCMS (ESI) calcd. for C6H5C2N2O2 [M+H]+ m/z 206.97, found 206.90.
Step 4: tert-butyl (R)-((3-(3,6-dichloro-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of crude 3,6-dichloro-5-methylpyridazine-4-carboxylic acid (500 mg, 2.42 mmol) in DCM (5 mL) and DMF (10 uL) was added oxalyl chloride (460 mg, 3.62 mmol) at 0° C. The mixture was stirred at room temperature for 5 minutes. Then the solution was added dropwise to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (653 mg, 2.42 mmol) and Et3N (733 mg, 7.25 mmol). The mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated to give the crude. The crude was purified by silica gel column chromatography (PE/EtOAc, 1/1) to afford tert-butyl (R)-((3-(3,6-dichloro-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (300 mg, 27%) as a yellow solid. LCMS (ESI) calcd. for C18H19Cl2N4O4S [M−H]− m/z 457.05, found 457.00.
Step 5: tert-butyl (R)-((3-(6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture tert-butyl (R)-((3-(3,6-dichloro-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (300 mg, 0.66 mmol) and 4,4-difluoroazepane hydrochloride (162.3 mg, 0.99 mmol) in 1,4-dioxane (6 mL) was added DBU (300 mg, 1.98 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours. Then the mixture was concentrated and directly purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 55.4%). LCMS (ESI) calcd. C24H31ClF2N5O4S [M+H]+ m/z 558.17, found 558.15.
Step 6: tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of tert-butyl (R)-((3-(6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6sulfaneylidene)carbamate (100 mg, 0.18 mmol), 2-oxa-6-azaspiro[3.3]heptane (35.6 mg, 0.36 mmol), K2CO3(74.3 mg, 0.54 mmol), S-Phos (14.7 mg, 0.036 mmol) and Pd2(dba)3(16.4 mg, 0.018 mmol) in 1,4-dioxane (3 mL) was heated at 100° C. for overnight under an atmosphere of N2. LCMS showed the reaction was completed. The mixture was filtered through celite, and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/2) to give tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 49%) as a yellow oil. LCMS (ESI) calcd. for C29H39F2N6O5S [M+H]+ m/z 621.27, found 621.25.
Step 7: (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridazine-4-carboxamide: A solution of tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 0.08 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 80% ACN/H2O containing 0.05% NH3) to (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridazine-4-carboxamide (9.5 mg, 22.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.32 (s, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 4.66 (s, 4H), 4.26 (s, 1H), 4.15 (s, 4H), 3.31-3.28 (m, 4H), 3.08 (s, 3H), 2.34-2.21 (m, 4H), 2.15 (s, 3H), 1.84 (d, J=5.2 Hz, 2H). LCMS (ESI) calcd. for C24H31F2N6O3S [M+H]+ m/z 521.22, found 521.15.
Step 1: tert-butyl 6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylate: A mixture of tert-butyl 3,6-dichloro-5-methylpyridazine-4-carboxylate (1 g, 3.9 mmol) and 4,4-difluoroazepane hydrochloride (1 g, 5.85 mmol) in 1,4-dioxane (15 mL) was added DIEA (2.52 g, 19.5 mmol) at room temperature. The reaction mixture was heated at 100° C. for 16 hours. Then the mixture was concentrated and directly purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl 6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylate (700 mg, 49.7%) as a white solid. LCMS (ESI) calcd. for C16H23ClF2N3O2 [M+H]+ m/z 362.14, found 362.05.
Step 2: tert-butyl 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxylate: A solution of tert-butyl 6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxylate (700 mg, 1.93 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (292.4 mg, 2.32 mmol), K2CO3 (1068 mg, 7.74 mmol) and Pd(dppf)Cl2 (283 mg, 0.39 mmol) in 1,4-dioxane/H2O (4/1, 15 mL) was heated at 100° C. for overnight under an atmosphere of N2. LCMS showed the reaction was completed. The mixture was filtered through celite, and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/2) to give tert-butyl 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxylate (500 mg, 63.7%) as a yellow oil. LCMS (ESI) calcd. for C20H28F2N5O2 [M+H]+ m/z 408.22, found 408.20.
Step 3: 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxylic acid: To a solution of tert-butyl 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxylate (500 mg, 1.229 mmol) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solution was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum to give the crude 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxylic acid (300 mg) as a yellow solid. LCMS (ESI) calcd. for C16H20F2N5O2 [M+H]+ m/z 352.16, found 352.15.
Step 4: methyl 3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxamido)bicyclo[1.1.1]pentane-1-carboxylate: A solution of 3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxylic acid (150 mg, 0.426 mmol) in DCM (6 mL) and DMF (0.02 mL) was added oxalyl chloride (97 mg, 0.767 mmol). The solution was stirred at room temperature for 30 min. Then the solution was concentrated under vacuum. The residue was diluted with THF (5 mL) and added to a stirred solution of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (123 mg, 0.639 mmol) and DIEA (165 mg, 1.278 mmol) in THE (5 mL). The mixture was stirred at room temperature for 3 hours. Then the mixture was quenched with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1 to 1/3) to give methyl 3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxamido)bicyclo[1.1.1]pentane-1-carboxylate 7 (100 mg, 49.50%) as a yellow solid. LCMS (ESI) calcd. for C23H29F2N6O3 [M+H]+ m/z 475.23, found 475.15.
Step 5: N-(3-carbamoylbicyclo[1.1.1]pentan-1-yl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxamide: A solution of methyl 3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxamido)bicyclo[1.1.1]pentane-1-carboxylate (100 mg, 0.211 mmol) in 7M NH3-MeOH (5 mL) was heated at 100° C. for 8 hours in a sealed tube. Then the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 80% MeCN/H2O containing 0.1% formic acid) to provide N-(3-carbamoylbicyclo[1.1.1]pentan-1-yl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine-4-carboxamide (33 mg, 34.38% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.28 (s, 1H), 8.13 (s, 1H), 7.85 (s, 1H), 7.30 (s, 1H), 7.01 (s, 1H), 3.91 (s, 3H), 3.72-3.65 (m, 2H), 3.61 (t, J=6.1 Hz, 2H), 2.37-2.27 (m, 2H), 2.23 (s, 3H), 2.21 (s, 6H), 2.12-2.01 (m, 2H), 1.92-1.82 (m, 2H). LCMS (ESI) calcd. for C22H28F2N7O2 [M+H]+ m/z 460.23, found 460.10.
3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)bicyclo[1.1.1]pentane-1-carboxylic acid: A mixture of methyl 3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)bicyclo[1.1.1]pentane-1-carboxylate (30 mg, 0.064 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (12 mg, 0.095 mmol), K2CO3 (26 mg, 0.191 mmol) and Pd(dppf)Cl2 (5 mg, 0.006 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 80% MeCN/H2O containing 0.1% formic acid) to provide 3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)bicyclo[1.1.1]pentane-1-carboxylic acid (12 mg, 41.38%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.08 (s, 1H), 8.07 (s, 1H), 7.85 (s, 1H), 7.56 (s, 1H), 3.87 (s, 3H), 3.59-3.51 (m, 4H), 2.25 (s, 8H), 2.17 (s, 3H), 2.09-1.98 (m, 2H), 1.88-1.80 (m, 2H). LCMS (ESI) calcd. for C23H28F2N5O3 [M+H]+ m/z 460.21, found 460.10.
Step 1: tert-butyl (S)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic acid (100 mg, 0.295 mmol) in DCM (3 mL) and DMF (one drop) was added oxalyl chloride (127 mg, 1 mmol). The solution was stirred at room temperature for 5 min. Then the solution was added to a stirred solution of tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (159 mg, 0.59 mmol) and TEA (141 mg, 1.39 mmol) in DCM (3 mL) at 0° C. The resulting mixture was stirred at 25° C. for 1 hour. Then the mixture was quenched with water (10 mL) and extracted with DCM (10 mL×2). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (S)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 34.4% yield) as a brown oil. LCMS (ESI) calcd. for C25H31F5N5O4S [M+H]+ m/z 592.20, found 592.10.
Step 2: (S)-4-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)pyrimidine-5-carboxamide: A solution of tert-butyl (S)-(3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 0.101 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 80% MeCN/H2O containing 0.1% NH3·H2O) to provide (S)-4-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)pyrimidine-5-carboxamide (31.5 mg, 63.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.28 (s, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.65 (dt, J=15.8, 7.9 Hz, 2H), 4.25 (s, 1H), 3.83-3.54 (m, 4H), 3.07 (s, 3H), 2.41 (s, 3H), 2.35-2.24 (m, 2H), 2.12-1.99 (m, 2H), 1.90-1.78 (m, 2H). LCMS (ESI) calcd. for C20H23F5N5O2S [M+H]+ m/z 492.15, found 492.10.
Step 1: tert-butyl ((1R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.25 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (70 mg, 0.50 mmol), K2CO3 (69 mg, 0.50 mmol) and Pd(dppf)Cl2 (18 mg, 0.02 mmol) in dioxane (8 mL) and H2O (2 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/2) to give tert-butyl ((1R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (110 mg, 65.3%) as a yellow solid. LCMS (ESI) calcd. for C33H43F2N6O5S [M+H]+ m/z 673.30, found 673.25.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(1H-pyrazol-4-yl)nicotinamide: A solution of tert-butyl ((1R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (110 mg, 0.16 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.1% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(1H-pyrazol-4-yl)nicotinamide (41.4 mg, 52.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 10.85 (s, 1H), 8.37 (t, J=1.8 Hz, 1H), 8.19 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.80 (s, 2H), 7.66 (d, J=8.0 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 4.22 (s, 1H), 3.63-3.50 (m, 4H), 3.06 (s, 3H), 2.31-2.18 (m, 5H), 2.09-1.90 (m, 2H), 1.87-1.71 (m, 2H). LCMS (ESI) calcd. for C23H27F2N6O2S [M+H]+ m/z 489.19, found 489.10.
Step 1: 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid: A solution of 5-bromo-2-chloro-4-methylnicotinic acid (4.00 g, 15.9 mmol), 4,4-difluoroazepane hydrochloride (5.43 g, 31.8 mmol), K2CO3 (13.20 g, 95.4 mmol) and DIEA (8.21 g, 63.6 mmol) in NMP (120 mL) was heated at 140° C. for 6 hours. LCMS showed the reaction was completed. The mixture was diluted with water. Then pH of the resulting mixture was adjusted to 4 with 2N aqueous HCl. The solution was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford the crude. The crude was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to provide 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (1.6 g, 28.6%) as a yellow solid. LCMS (ESI) calcd. for C13H16BrF2N2O2 [M+H]+ m/z 351.04, found 348.90.
Step 2: tert-butyl (S)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (1.60 g, 4.58 mmol) and tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (2.48 g, 9.17 mmol) in pyridine (30 mL) was added POCl3 (500 L) dropwise at 50° C. The reaction solution was stirred at 50° C. for 2 hours. After the reaction was completed, the resulting solution was diluted with water (200 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (S)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (1.55 g, 56.4%) as a yellow solid. LCMS (ESI) calcd. for C25H32BrF2N4O4S [M+H]+ m/z 603.13, found 601.05.
Step 3: (S)-5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (S)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.1% NH3) to give (S)-5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (30.6 mg, 38.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.37-8.24 (m, 2H), 7.89 (d, J=9.0 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 4.23 (s, 1H), 3.63-3.48 (m, 4H), 3.06 (s, 3H), 2.31-2.18 (m, 5H), 2.06-1.92 (m, 2H), 1.84-1.74 (m, 2H). LCMS (ESI) calcd. for C20H24BrF2N4O2S [M+H]+ m/z 501.08, found 500.95.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (73.3 mg, 0.33 mmol), K2CO3 (68.9 mg, 0.5 mmol) and Pd(dppf)Cl2 (24.3 mg, 0.03 mmol) in 1,4-dioxane/H2O (4/1, 5 mL) was heated at 100° C. for 5 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (82 mg, 78.3%) as a yellow oil. LCMS (ESI) calcd. for C30H39F2N6O4S [M+H]+ m/z 617.27, found 617.20.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (82 mg, 0.133 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 85% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (45.2 mg, 65.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.63 (s, 1H), 7.58 (t, J=7.9 Hz, 1H), 4.23 (s, 1H), 3.80 (s, 3H), 3.64-3.53 (m, 4H), 3.06 (s, 3H), 2.29-2.23 (m, 2H), 2.10 (s, 3H), 2.06 (s, 3H), 2.03-1.94 (m, 2H), 1.84-1.75 (m, 2H). LCMS (ESI) calcd. for C25H31F2N6O2S [M+H]+ m/z 517.22, found 517.15
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(oxazol-5-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate(100 mg, 0.17 mmol), oxazole (23 mg, 0.33 mmol), KOAc (50 mg, 0.51 mmol) and Pd(OAc)2 (6 mg, 0.03 mmol) in DMA (5 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/5) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(oxazol-5-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (65 mg, 65.31% yield) as a yellow oil. LCMS (ESI) calcd. for C28H34F2N5O5S [M+H]+ m/z 590.23, found 590.15.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(oxazol-5-yl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(oxazol-5-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (65 mg, 0.11 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(oxazol-5-yl)nicotinamide (11.2 mg, 20.74%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.40 (s, 1H), 4.24 (s, 1H), 3.72-3.65 (m, 2H), 3.61 (t, J=5.9 Hz, 2H), 3.06 (s, 3H), 2.35-2.21 (m, 5H), 2.08-1.94 (m, 2H), 1.88-1.77 (m, 2H). LCMS (ESI) calcd. for C23H26F2N5O3S [M+H]+ m/z 490.17, found 490.15.
Step 1: 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid: A mixture of 2,6-dichloro-4-methylnicotinic acid (1 g, 4.95 mmol) and 4,4-difluoroazepane hydrochloride (916 mg, 5.34 mmol) in NMP (15 mL) was added DIEA (1.88 g, 14.56 mmol) and K2CO3 (2.01 g, 14.56 mmol) at room temperature. The reaction mixture was heated at 140° C. for 16 hours. After the reaction was completed, the solution was diluting with DCM (100 mL) and washed with brine (100 mL×3), dried over sodium sulfate, then concentrated and purified by flash column chromatography on silica gel (PE/EtOAc=1/1 to 1/3) to give 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (1.1 g, 66.9%) as a white solid. LCMS (ESI) calcd. for C13H16ClF2N2O2 [M+H]+ m/z 305.09, found 304.95.
Step 2: tert-butyl (R)-((3-(6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (700 mg, 2.30 mmol) and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (748 mg, 2.76 mmol) in pyridine (6 mL) was added POCl3 (100 L) dropwise at 0° C. The reaction solution was stirred at 0° C. for 2 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (R)-((3-(6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (500 mg, 39.0%) as a yellow solid. LCMS (ESI) calcd. for C25H32ClF2N4O4S [M+H]+ m/z 557.18, found 557.20
Step 3: tert-butyl (R)-((3-(6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of tert-butyl (R)-((3-(6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (300 mg, 0.54 mmol), Zn(CN)2 (126 mg, 1.08 mmol) and tBuXphos-pd-G3 (87 mg, 0.11 mmol) in THF/H2O (4/1, 5 mL) was heated at 70° C. overnight under an atmosphere of N2. LCMS showed the reaction was completed. The mixture was filtered through celite, and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/2) to give tert-butyl (R)-((3-(6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 67.8%) as a yellow oil. LCMS (ESI) calcd. for C26H32F2N5O4S [M+H]+ m/z 548.22, found 548.20
Step 4: (R)-6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.18 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (5 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.1% NH3) to give (R)-6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (30.6 mg, 37.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.29 (t, J=2.0 Hz, 1H), 7.89 (dd, J=8.1, 2.2 Hz, 1H), 7.72-7.66 (m, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.33 (s, 1H), 4.24 (s, 1H), 3.68-3.59 (m, 2H), 3.56 (t, J=6.1 Hz, 2H), 3.06 (s, 3H), 2.34-2.22 (m, 5H), 2.08-1.96 (m, 2H), 1.86-1.75 (m, 2H). LCMS (ESI) calcd. for C21H24F2N5O2S [M+H]+ m/z 448.16, found 448.05.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,3-difluoroazetidin-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.250 mmol) and 3,3-difluoroazetidine hydrochloride (220 mg, 1.25 mmol) in 1,4-dioxane (10 mL) was added Cs2CO3 (540 mg, 1.25 mmol), Pd2(dba)3 (40 mg, 0.025 mmol) and X-Phos (40 mg, 0.05 mmol). The mixture was heated at 100° C. for 6 hours under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,3-difluoroazetidin-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (77 mg, 49.00%) as a yellow oil. LCMS (ESI) calcd. for C28H36F4N5O4S [M+H]+ m/z 614.24, found 614.15.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,3-difluoroazetidin-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,3-difluoroazetidin-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (77 mg, 0.125 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,3-difluoroazetidin-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (32.8 mg, 50.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.35-8.34 (m, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.57 (t, J=8 Hz, 1H), 4.28 (t, J=12.4 Hz, 4H), 4.21 (s, 1H), 3.46-3.43 (m, 2H), 3.41-3.38 (m, 2H), 3.04 (s, 3H), 2.22-2.16 (m, 2H), 2.08 (s, 3H), 1.98-1.92 (m, 2H), 1.76-1.72 (m, 2H). LCMS (ESI) calcd. for
Step 1: methyl 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate: A mixture of methyl 2-chloro-4-(4,4-difluoroazepan-1-yl)-6-methylpyrimidine-5-carboxylate (300 mg, 0.94 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (178 mg, 1.41 mmol), K2CO3 (259 mg, 1.88 mmol), Pd(dppf)Cl2 (66 mg, 0.09 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give methyl 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (280 mg, 81.6% yield) as a yellow solid. LCMS (ESI) calcd. for C17H21F2N5O2Na [M+Na]+ m/z 366.17, found 366.10.
Step 2: 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylic acid: To a solution of methyl 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (280 mg, 0.76 mmol) in MeOH/H2O (1/1, 10 mL) was added KOH (428 mg, 7.65 mmol) at room temperature. The mixture was heated at 70° C. for 16 hours. After the reaction was completed, the mixture was concentrated to remove most MeOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylic acid (190 mg, 71.0%) as a yellow solid. LCMS (ESI) calcd. for C16H20F2N5O2 [M+H]+ m/z 352.16, found 352.15.
Step 3: tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylic acid (100 mg, 0.28 mmol) in SOCl2 (2 mL) was heated to 80° C. and stirred for 1 hour. Then the solution was concentrated under vacuum to provide the chloride intermediate. The chloride intermediate was added to a stirred solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (91 mg, 0.34 mmol) and DIEA (72 mg, 0.56 mmol) in DCM (2 mL) at 0° C. The resulting mixture was stirred at 25° C. for 1 hour. Then the mixture was quenched with water (10 mL) and extracted with DCM (10 mL×2). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to afford tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (65 mg, 38.4%) as a yellow solid. LCMS (ESI) calcd. for C28H36F2N7O4S [M+H]+ m/z 604.25, found 604.25.
Step 4: (R)-4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)pyrimidine-5-carboxamide: A solution of tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (65 mg, 0.11 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.05% NH3) to provide (R)-4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)pyrimidine-5-carboxamide (20.8 mg, 37.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.31 (s, 2H), 7.97 (s, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 4.23 (s, 1H), 3.90 (s, 3H), 3.77 (s, 2H), 3.62 (t, J=6.0 Hz, 2H), 3.06 (s, 3H), 2.41-2.25 (m, 5H), 2.11-1.95 (m, 2H), 1.89-1.79 (m, 2H). LCMS (ESI) calcd. for C23H28F2N7O2S [M+H]+ m/z 504.20, found 504.15.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of tert-butyl (R)-((3-(6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido) phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.27 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (40 mg, 0.32 mmol), K2CO3 (74 mg, 0.54 mmol) and Pd(dppf)Cl2 (20 mg, 0.03 mmol) in 1,4-dioxane (10 mL) and H2O (2.5 mL) was heated at 100° C. for 6 hours. LCMS showed the reaction was completed. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/10) to provide tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 74.07%) as yellow oil. LCMS (ESI) calcd. for C29H37F2N6O4S [M+H]+ m/z 603.26, found 603.25.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.20 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 20% to 95% MeCN/H2O containing 0.05% NH3·H2O) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (53.25 mg, 52.26% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.37 (t, J=1.8 Hz, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 6.97 (s, 1H), 4.40 (bs, 1H), 3.89 (s, 3H), 3.67-3.65 (m, 2H), 3.55 (t, J=6.1 Hz, 2H), 3.07 (s, 3H), 2.33-2.34 (m, 2H), 2.25 (s, 3H), 2.00-1.94 (m, 2H), 1.84-1.81 (m, 2H). LCMS (ESI) calcd. for C24H29F2N6O2S [M+H]+ m/z 503.21, found 503.15.
Step 1: tert-butyl ((1R)-(3-(2-(4,4-difluoroazepan-1-yl)-5-(3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido) phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol), (3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)boronic acid (112 mg, 0.50 mmol), K2CO3 (69 mg, 0.50 mmol), Pd(dppf)Cl2 (22 mg, 0.02 mmol) in dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (50 mL) and extracted with EtOAc (40 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give tert-butyl ((1R)-(3-(2-(4,4-difluoroazepan-1-yl)-5-(3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (98 mg, 57.1%) as a yellow solid. LCMS (ESI) calcd. for C35H47F2N6O5S [M+H]+ m/z 701.33, found 701.20.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,5-dimethyl-1H-pyrazol-4-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl ((1R)-(3-(2-(4,4-difluoroazepan-1-yl)-5-(3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (98 mg, 0.14 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 80% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,5-dimethyl-1H-pyrazol-4-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (41.5 mg, 57.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.36 (s, 1H), 7.93 (d, J=5.7 Hz, 2H), 7.67-7.56 (m, 2H), 4.22 (s, 1H), 3.65-3.53 (m, 4H), 3.05 (s, 3H), 2.32-2.18 (m, 2H), 2.09-1.91 (m, 11H), 1.87-1.72 (m, 2H). LCMS (ESI) calcd. for C25H31F2N6O2S [M+H]+ m/z 517.22, found 517.15.
Step 1: tert-butyl (R)-((3-(6-carbamoyl-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido) phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.18 mmol), K2CO3 (76 mg, 0.55 mmol) and 30% H2O2(2 mL) in DMSO (5 mL) was stirred at room temperature for 4 hour. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/5) to give tert-butyl (R)-((3-(6-carbamoyl-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (72 mg, 69.51%) as a yellow oil. LCMS (ESI) calcd. for C26H34F2N5O5S [M+H]+ m/z 566.23, found 566.20.
Step 2: (R)-6-(4,4-difluoroazepan-1-yl)-4-methyl-N5-(3-(S-methylsulfonimidoyl)phenyl)pyridine-2,5-dicarboxamide: A solution of tert-butyl (R)-((3-(6-carbamoyl-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (72 mg, 0.13 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-6-(4,4-difluoroazepan-1-yl)-4-methyl-N5-(3-(S-methylsulfonimidoyl)phenyl)pyridine-2,5-dicarboxamide (26.1 mg, 43.93%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.33 (d, J=1.7 Hz, 1H), 7.93-7.79 (m, 2H), 7.69-7.55 (m, 3H), 7.31 (s, 1H), 4.23 (s, 1H), 3.76-3.66 (m, 2H), 3.59 (t, J=6.0 Hz, 2H), 3.06 (s, 3H), 2.35-2.20 (s, 5H), 2.06-1.92 (m, 2H), 1.86-1.74 (m, 2H). LCMS (ESI) calcd. for C21H26F2N5O3S [M+H]+ m/z 466.17, found 466.05.
Step 1: tert-butyl (R)-((3-(6-(4-cyanophenyl)-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.27 mmol), (4-cyanophenyl)boronic acid (79 mg, 0.54 mmol), K2CO3 (112 mg, 0.81 mmol) and Pd(dppf)Cl2 (18 mg, 0.02 mmol) in dioxane (8 mL) and H2O (2 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (40 mL) and extracted with EtOAc (40 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(6-(4-cyanophenyl)-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (98 mg, 58.3%) as a yellow solid. LCMS (ESI) calcd. for C31H35F2N6O4S [M+H]+ m/z 625.24, found 625.15.
Step 2: (R)-6-(4-cyanophenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide: A solution of tert-butyl (R)-((3-(6-(4-cyanophenyl)-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (98 mg, 0.16 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 90% MeCN/H2O containing 0.1% NH3) to provide (R)-6-(4-cyanophenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide (21.3 mg, 25.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.31 (s, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.89 (d, J=7.9 Hz, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.71 (d, J=7.6 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 4.25 (s, 1H), 3.87-3.78 (m, 2H), 3.70-3.61 (m, 2H), 3.07 (s, 3H), 2.43-2.27 (m, 2H), 2.21 (s, 3H), 2.11-1.97 (m, 2H), 1.91-1.83 (m, 2H). LCMS (ESI) calcd. for C26H27F2N6O2S [M+H]+ m/z 525.19, found 525.15.
Step 1: ethyl 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate: A mixture of ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (1 g, 4.06 mmol) and 4,4-difluoroazepane hydrochloride (834 mg, 4.87 mmol) in 1,4-dioxane (20 mL) was added DIEA (1.05 g, 8.12 mmol) at room temperature. The reaction mixture was heated at 100° C. for 4 hours. Then the mixture was concentrated and directly purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give ethyl 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (1.3 g, 92.5%) as a yellow solid. LCMS (ESI) calcd. for C15H22F2N3O2S [M+H]+ m/z 346.14, found 345.95.
Step 2: 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylthio)pyrimidine-5-carboxylic acid: To a solution of ethyl 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (1.3 g, 3.75 mmol) in EtOH/H2O (1/1, 20 mL) was added KOH (421 mg, 7.50 mmol) at room temperature. The mixture was heated at 70° C. for 16 hours. After the reaction was completed, the mixture was concentrated to remove most EtOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (40 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylthio)pyrimidine-5-carboxylic acid (860 mg, 72.1%) as a yellow solid. LCMS (ESI) calcd. for C13H18F2N3O2S [M+H]+ m/z 318.11, found 317.95.
Step 3: tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylthio)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylthio)pyrimidine-5-carboxylic acid (860 mg, 2.70 mmol) in DCM (10 mL) and DMF (20 uL) was added oxalyl chloride (446 mg, 3.51 mmol) at 0° C. The mixture was stirred at room temperature for 5 minutes. Then the solution was added dropwise to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (878 mg, 3.24 mmol) and Et3N (545 mg, 5.40 mmol). The mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (20 mL) and extracted with DCM (40 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated to give the crude. The crude was purified by silica gel column chromatography (PE/EtOAc, 1/1) to afford tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylthio)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (750 mg, 48.7%) as a yellow solid. LCMS (ESI) calcd. for C25H34F2N5O4S2 [M+H]+ m/z 570.20, found 570.15.
Step 4: tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylsulfonyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylthio)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (750 mg, 1.32 mmol) and m-CPBA (273 mg, 1.58 mmol) in DCM (20 mL) was stirred at room temperature for 2 hours. Then the mixture was concentrated and directly purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylsulfonyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (530 mg, 66.7%) as a yellow solid. LCMS (ESI) calcd. for C25H34F2N5O6S2 [M+H]+ m/z 602.19, found 602.15.
Step 5: tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-morpholinopyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylsulfonyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.16 mmol) and morpholine (30 mg, 0.33 mmol) in DMF (5 mL) was heated at 100° C. for 6 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=4/1) to give tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-morpholinopyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (75 mg, 76.9%) as a yellow solid. LCMS (ESI) calcd. for C28H39F2N6O5S [M+H]+ m/z 609.27, found 609.25.
Step 6: (R)-4-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-morpholinopyrimidine-5-carboxamide: A solution of tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-morpholinopyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (75 mg, 0.12 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.05% NH3) to provide (R)-4-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-morpholinopyrimidine-5-carboxamide (26.5 mg, 37.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.31 (t, J=1.8 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 4.20 (s, 1H), 3.70-3.60 (m, 10H), 3.53 (t, J=6.1 Hz, 2H), 3.05 (s, 3H), 2.31-2.14 (m, 5H), 2.04-1.93 (m, 2H), 1.85-1.76 (m, 2H). LCMS (ESI) calcd. for C23H31F2N6O3S [M+H]+ m/z 509.22, found 509.20.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,5-dimethylisoxazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6--sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (35 mg, 0.25 mmol), KF (29 mg, 0.50 mmol) and Pd(DTBPF)Cl2 (22 mg, 0.03 mmol) in DMSO (4 mL) and H2O (1 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (40 mL) and extracted with EtOAc (40 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,5-dimethylisoxazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (64 mg, 62.2%) as a yellow solid. LCMS (ESI) calcd. for C30H38F2N5O5S [M+H]+ m/z 618.26, found 618.20.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,5-dimethylisoxazol-4-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(3,5-dimethylisoxazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (64 mg, 0.16 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 90% MeCN/H2O containing 0.1% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-5-(3,5-dimethylisoxazol-4-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (50.3 mg, 91.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.34 (t, J=1.8 Hz, 1H), 8.02 (s, 1H), 7.96-7.89 (m, 1H), 7.69-7.64 (m, 1H), 7.59 (t, J=7.9 Hz, 1H), 4.23 (s, 1H), 3.70-3.51 (m, 4H), 3.08-3.00 (m, 3H), 2.35-2.20 (m, 5H), 2.14-1.91 (m, 8H), 1.87-1.77 (m, 2H). LCMS (ESI) calcd. for C25H30F2N5O3S [M+H]+ m/z 518.21, found 517.95.
Step 1: tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((1R)-(3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylsulfinyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol) and 1-methylpiperazine (34 mg, 0.34 mmol) in DMF (5 mL) was heated at 80° C. for 6 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=4/1) to give tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (56 mg, 53%) as a yellow solid. LCMS (ESI) calcd. for C29H42F2N7O4S [M+H]+ m/z 622.30, found 622.20.
Step 2: (R)-4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(4-methylpiperazin-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)pyrimidine-5-carboxamide: A solution of tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (56 mg, 0.09 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 80% MeCN/H2O containing 0.05% NH3) to provide (R)-4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(4-methylpiperazin-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)pyrimidine-5-carboxamide (11.50 mg, 24.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.31 (t, J=1.8 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.55 (t, J=7.9 Hz, 1H), 4.20 (s, 1H), 3.77-3.65 (m, 4H), 3.65-3.50 (m, 4H), 3.05 (s, 3H), 2.37-2.24 (m, 6H), 2.23-2.15 (m, 6H), 2.05-1.91 (m, 2H), 1.86-1.74 (m, 2H). LCMS (ESI) calcd. for C24H34F2N7O2S [M+H]+ m/z 522.25, found 522.20.
Step 1: tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((1R)-(3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylsulfinyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol), 3,3-difluoroazetidine hydrochloride (44 mg, 0.34 mmol) and Et3N (52 mg, 0.51 mmol) in THE (5 mL) was heated at 80° C. for 16 hours in sealed tube. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=4/1) to give tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (54 mg, 51.6%) as a yellow solid. LCMS (ESI) calcd. for C27H35F4N6O4S [M+H]+ m/z 615.24, found 615.15.
Step 2: (R)-4-(4,4-difluoroazepan-1-yl)-2-(3,3-difluoroazetidin-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyrimidine-5-carboxamide: A solution of tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (54 mg, 0.08 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 80% MeCN/H2O containing 0.05% NH3) to provide (R)-4-(4,4-difluoroazepan-1-yl)-2-(3,3-difluoroazetidin-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyrimidine-5-carboxamide (17.20 mg, 38.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.30 (s, 1H), 7.86 (d, J=7.3 Hz, 1H), 7.70-7.52 (m, 2H), 4.41 (t, J=12.4 Hz, 4H), 4.22 (s, 1H), 3.69-3.53 (m, 4H), 3.06 (s, 3H), 2.34-2.19 (m, 5H), 2.06-1.92 (m, 2H), 1.86-1.74 (m, 2H). LCMS (ESI) calcd. for C22H27F4N6O2S [M+H]+ m/z 515.19, found 515.20.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(1,3-dimethyl-1H-pyrazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (250 mg, 0.41 mmol), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (202.5 mg, 0.83 mmol), potassium carbonate (172 mg, 1.2 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (30 mg, 0.04 mmol) in 1,4-dioxane/H2O (4/1, 15 mL) was heated at 100° C. for 5 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combine organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (260 mg, 98%) as a yellow oil. LCMS (ESI) calcd. for C29H35F4N6O4S [M+H]+ m/z 639.24, found 639.15.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 0.13 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-5-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (30.6 mg, 43.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.48-8.33 (m, 2H), 8.23 (s, 1H), 8.08-7.64 (m, 5H), 7.59 (t, J=7.8 Hz, 1H), 4.23 (s, 1H), 3.69-3.53 (m, 4H), 3.06 (s, 3H), 2.26 (s, 5H), 1.99 (s, 2H), 1.81 (s, 2H). LCMS (ESI) calcd. for C24H27F4N6O2S [M+H]+ m/z 539.19, found 539.15
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (260 mg, 0.43 mmol), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (312 mg, 1.32 mmol) and K2CO3 (182 mg, 1.32 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL) was added Pd(dppf)Cl2 (28 mg, 0.03 mmol). Then the mixture was heated at 100° C. for 12 hours under N2. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with MeOH/DCM, 0 to 10%) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (250 mg, 39.68%) as a yellow oil. LCMS (ESI) calcd. for C31H41F2N6O4S [M+H]+ m/z 631.28, found 631.20.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6--sulfaneylidene)carbamate (120 mg, 0.19 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.05% NH3) to provide (59.9 mg, 59.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.37 (t, J=1.8 Hz, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.59 (dd, J=13.4, 5.4 Hz, 2H), 4.55-4.49 (m, 1H), 4.22 (s, 1H), 3.63-3.52 (m, 4H), 3.06 (s, 3H), 2.37-2.17 (m, 5H), 2.15-1.92 (m, 2H), 1.87-1.75 (m, 2H), 1.46 (s, 3H), 1.45 (s, 3H). LCMS (ESI) calcd. for C26H33F2N6O2S [M+H]+ m/z 531.23, found 531.20.
Step 1: tert-butyl (R)-((3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(piperazin-1-yl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl ((1R)-(3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylsulfinyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol) and piperazine (29 mg, 0.34 mmol) in THE (5 mL) was heated at 80° C. for 16 hours in a sealed tube. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=4/1) to give tert-butyl ((1R)-(3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylsulfinyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (53 mg, 51.6%) as a yellow solid. LCMS (ESI) calcd. for C28H40F2N7O4S [M+H]+ m/z 608.29, found 608.20.
Step 2: (R)-4-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(piperazin-1-yl)pyrimidine-5-carboxamide. A solution of tert-butyl ((1R)-(3-(4-(4,4-difluoroazepan-1-yl)-6-methyl-2-(methylsulfinyl)pyrimidine-5-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (54 mg, 0.08 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 80% MeCN/H2O containing 0.05% NH3) to provide (R)-4-(4,4-difluoroazepan-1-yl)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(piperazin-1-yl)pyrimidine-5-carboxamide (13.30 mg, 32.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.31 (s, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.69-7.49 (m, 2H), 4.20 (s, 1H), 3.68-3.48 (m, 8H), 3.05 (s, 3H), 2.79-2.58 (m, 4H), 2.32-2.16 (m, 5H), 2.05-1.90 (m, 2H), 1.84-1.73 (m, 2H). LCMS (ESI) calcd. for C23H32F2N7O2S [M+H]+ m/z 508.23, found 508.10.
Step 1: 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid: A solution of 2,6-dichloro-4-methylnicotinic acid (3.00 g, 14.56 mmol), 4,4-4,4-difluoroazepane hydrochloride (3.00 g, 17.47 mmol), K2CO3 (10.06 g, 72.81 mmol) and DIEA (9.41 g, 63.6 mmol) in NMP (40 mL) was heated at 140° C. for 6 hours. LCMS showed the reaction was completed. The mixture was diluted with water. The mixture was adjusted to pH=3-4 with 2N HCl. The solution was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford the crude. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to provide 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (3.20 g, 72.12%) as a white solid. LCMS (ESI) calcd. for C13H16ClF2N2O2 [M+H]+ m/z 305.09, found 305.05.
Step 2: 5,6-dichloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid: A solution of 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (2.00 g, 6.56 mmol) in MeCN (40 mL) was added NCS (964 mg, 7.22 mmol) at room temperature. The reaction mixture was heated to 70° C. for 5 hours. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (80 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford the crude. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=4/1) to provide 5,6-dichloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (1.10 g, 49.4%) as a brown solid. LCMS (ESI) calcd. for C13H15C12F2N2O2 [M+H]+ m/z 339.05, found 339.05.
Step 3: tert-butyl (R)-((3-(5,6-dichloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 5,6-dichloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (200 mg, 0.59 mmol) in DCM (5 mL) was added DMF (4 drop) and oxalyl chloride (112 mg, 0.88 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. Then the solution was added dropwise to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (653 mg, 2.42 mmol) and DIEA (229 mg, 1.77 mmol) in THE (10 mL). The mixture was heated to 50° C. for 5 hours. After the reaction was completed, the resulting solution was diluted with water (80 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=10/1) to give tert-butyl (R)-((3-(5,6-dichloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (95 mg, 27.2%). LCMS (ESI) calcd. for C25H31C12F2N4O4S [M+H]+ m/z 591.14, found 591.10.
Step 4: tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of tert-butyl (R)-((3-(5,6-dichloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 0.10 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (25 mg, 0.20 mmol), Cs2CO3 (98 mg, 0.30 mmol) and Pd(dppf)Cl2 (13 mg, 0.02 mmol) in dioxane (4 mL) and H2O (1 mL) was heated at 100° C. for 6 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1 to 1/1) to provide tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (49 mg, 90.03%) as yellow oil. LCMS (ESI) calcd. for C29H36ClF2N6O4S [M+H]+ m/z 637.22, found 637.15.
Step 5: (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (49 mg, 0.077 mmol) in DCM (2 mL) was added TFA (0.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 20% to 95% MeCN/H2O containing 0.05% NH3·H2O) to provide (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (20.4 mg, 49.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.45 (s, 1H), 8.33 (t, J=1.8 Hz, 1H), 8.11 (d, J=0.6 Hz, 1H), 7.89 (d, J=9.0 Hz, 1H), 7.69-7.54 (m, 2H), 4.23 (s, 1H), 3.93 (s, 3H), 3.70-3.51 (m, 4H), 3.06 (s, 3H), 2.36-2.26 (m, 5H), 2.06-1.94 (m, 2H), 1.87-1.78 (m, 2H). LCMS (ESI) calcd. for C24H28ClF2N6O2S [M+H]+ m/z 537.17, found 537.10.
Step 1: 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide: A solution of 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinic acid (500 mg, 1.48 mmol) in DMF (20 mL) was added HATU (1.03 g, 1.92 mmol), DIEA (856 mg, 4.74 mmol) and NH3-MeOH (10 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was diluted with water (100 mL) and extracted with DCM (40 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (410 mg, 82.0%) as a white solid. LCMS (ESI) calcd. for C14H17F5N3O [M+H]+ m/z 338.13, found 338.00.
Step 2: 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(methylsulfinyl)phenyl)-5-(trifluoromethyl)nicotinamide: A solution of 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (400 mg, 1.18 mmol) in dioxane (10 mL) was added 1-bromo-3-(methylsulfinyl)benzene (1.20 g, 3.08 mmol), Cs2CO3 (2.03 g, 3.55 mmol) and Xantphos-Pd-G2 (180 mg, 0.12 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 16 hours under N2. After the reaction was completed, the mixture was diluted with water (50 mL) and extracted with DCM (40 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(methylsulfinyl)phenyl)-5-(trifluoromethyl)nicotinamide (280 mg, 49.73%) as a white solid. LCMS (ESI) calcd. for C21H23F5N3O2S [M+H]+ m/z 476.15, found 475.90.
Step 3: 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: To a solution of 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(methylsulfinyl)phenyl)-5-(trifluoromethyl)nicotinamide (280 mg, 0.59 mmol) in MeOH (10 mL) was added PhI(OAc)2 (670 mg, 1.47 mmol) and ammonium carbamate (195 mg, 1.76 mmol) at room temperature. The reaction mixture was heated at 70° C. for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (50 mL) and extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give the crude. The residue was further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.1% formic acid) to afford 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (120 mg, 41.7%) as a white solid. LCMS (ESI) calcd. for C21H24F5N4O2S [M+H]+ m/z 491.16, found 491.10.
Step 4: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide and (S)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (120 mg, 0.24 mmol) purified by prep-Chiral-SFC (chiralpak-AS-H, 150*21.2 mm, eluting with 30% CO02-MeOH containing 0.1% NH3). The first elution was lyophilized to afford (S)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (63.5 mg, 52.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.45 (s, 1H), 8.31 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.69 (d, J=8 Hz, 1H), 7.62-7.58 (m, 1H), 4.23 (s, 1H), 3.74-3.71 (m, 2H), 3.64-3.61 (m, 2H), 3.06 (s, 3H), 2.32 (s, 3H), 2.29-2.25 (m, 2H), 2.03-1.96 (m, 2H), 1.86-1.81 (m, 2H). LCMS (ESI) calcd. for C21H24F5N4O2S [M+H]+ m/z 491.16, found 491.05. The second elution was lyophilized to afford (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide(56.2 mg, 46.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.45 (s, 1H), 8.31 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.69 (d, J=8 Hz, 1H), 7.62-7.58 (m, 1H), 4.23 (s, 1H), 3.74-3.71 (m, 2H), 3.64-3.61 (m, 2H), 3.06 (s, 3H), 2.32 (s, 3H), 2.29-2.25 (m, 2H), 2.07-1.96 (m, 2H), 1.86-1.81 (m, 2H). LCMS (ESI) calcd. for C21H24F5N4O2S [M+H]+ m/z 491.16, found 491.05.
Step 1: 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide: To a solution of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (1 g, 2.8 mmol) in DMF (10 mL) was added HATU (1.4 g, 3.7 mmol), DIEA (1.2 g, 9 mmol) and NH3-MeOH (10 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was diluted with water (80 mL) and extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (800 mg, 82.13%) as a white solid. LCMS (ESI) calcd. for C13H17BrF2N3O [M+H]+ m/z 350.05, found 349.90.
Step 2: 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: A mixture of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (800 mg, 2.30 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (725 mg, 5.75 mmol), K3PO4 (1.59 g, 6.9 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (168 mg, 0.23 mmol) in 1,4-dioxane/H2O (10/1, 20 mL) was heated at 100° C. in a microwave reactor for 6 hours under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (80 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=3/1) to give 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (650 mg, 76.5%) as a white oil. LCMS (ESI) calcd. for C17H22F2N5O [M+H]+ m/z 350.18, found 350.00.
Step 3: tert-butyl (tert-butoxycarbonyl)(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenylsulfonimidoyl)carbamate: To a solution of 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (200 mg, 0.57 mmol) in dioxane (10 mL) was added tert-butyl (3-bromo-N-(tert-butyldimethylsilyl)phenylsulfonimidoyl)(tert-butoxycarbonyl)carbamate (313 mg, 0.57 mmol), cesium carbonate (484 mg, 1.49 mmol) and Xantphos-Pd-G2 (101 mg, 0.12 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 16 hours under nitrogen. The reaction was monitored by LCMS. After the reaction was completed, the filtrate was diluted with water (80 mL) and extracted with EtOAc (50 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (tert-butoxycarbonyl)(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenylsulfonimidoyl)carbamate (150 mg, 37.31%) as a white solid. LCMS (ESI) calcd. for C33H44F2N7O6S [M+H]+ m/z 704.31, found 704.20.
Step 4: 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-sulfamidimidoylphenyl)nicotinamide. A solution of tert-butyl (tert-butoxycarbonyl)(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenylsulfonimidoyl)carbamate (150 mg, 0.21 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 90% MeCN/H2O containing 0.1% NH3) to provide 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-sulfamidimidoylphenyl)nicotinamide (35.4 mg, 33.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.37 (s, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.75 (d, J=8 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 7.60 (s, 1H), 7.50-7.46 (m, 1H), 5.80 (bs, 2H), 3.88 (s, 3H), 3.63-3.60 (m, 2H), 3.57-3.54 (m, 2H), 2.32-2.34 (m, 2H), 2.24 (s, 3H), 2.02-1.99 (m, 2H), 1.81-1.79 (m, 2H). LCMS (ESI) calcd. for C23H28F2N7O2S [M+H]+ m/z 504.20, found 504.10.
Step 1: tert-butyl (R)-((3-(5-(4-chloro-3-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.25 mmol), (4-chloro-3-fluorophenyl)boronic acid (87 mg, 0.5 mmol), K2CO3 (69 mg, 0.5 mmol) and Pd(dppf)Cl2 (15 mg, 0.02 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (80 mL) and extracted with EA (40 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-((3-(5-(4-chloro-3-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 55.3%) as a yellow solid. LCMS (ESI) calcd. for C31H35ClF3N4O4S [M+H]+ m/z 651.20, found 651.10.
Step 2: (R)-5-(4-chloro-3-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-(4-chloro-3-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.14 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to (R)-5-(4-chloro-3-fluorophenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (51.3 mg, 71.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.12 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.71-7.63 (m, 2H), 7.58 (t, J=7.9 Hz, 1H), 7.45 (dd, J=10.3, 1.9 Hz, 1H), 7.22 (dd, J=8.3, 1.6 Hz, 1H), 4.23 (s, 1H), 3.71-3.55 (m, 4H), 3.06 (s, 3H), 2.33-2.22 (m, 2H), 2.17 (s, 3H), 2.06-1.94 (m, 2H), 1.86-1.78 (m, 2H). LCMS (ESI) calcd. for C26H27ClF3N4O2S [M+H]+ m/z 551.15, found 551.05.
Step 1: tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-6-(4-(difluoromethyl)phenyl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.27 mmol), (4-(difluoromethyl)phenyl)boronic acid (69 mg, 0.41 mmol), K2CO3 (112 mg, 0.81 mmol) and Pd(dppf)Cl2 (18 mg, 0.02 mmol) in dioxane (8 mL) and H2O (2 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (40 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-6-(4-(difluoromethyl)phenyl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 51.13%) as a yellow solid. LCMS (ESI) calcd. for C31H36F4N5O4S [M+H]+ m/z 650.24, found 650.15.
Step 2: (R)-3-(4,4-difluoroazepan-1-yl)-6-(4-(difluoromethyl)phenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide: A solution of tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-6-(4-(difluoromethyl)phenyl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (98 mg, 0.16 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 90% MeCN/H2O containing 0.1% NH3) to provide (R)-3-(4,4-difluoroazepan-1-yl)-6-(4-(difluoromethyl)phenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide (35.8 mg, 40.7% y) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.33 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.74-7.69 (m, 5H), 7.63-7.59 (m, 1H), 7.13 (t, J=5.6 Hz, 1H), 4.25 (s, 1H), 3.81-3.79 (m, 2H), 3.69-3.66 (m, 2H), 3.07 (s, 3H), 2.39-2.33 (m, 2H), 2.21 (s, 3H), 2.07-2.01 (m, 2H), 1.89-1.88 (m, 2H). LCMS (ESI) calcd. for C26H28F4N5O2S [M+H]+ m/z 550.19, found 550.15.
Step 1: methyl 2-(4,4-difluoroazepan-1-yl)-5-fluoro-4-methylnicotinate: To a solution of methyl 5-amino-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinate (600 mg, 2.0 mmol) in THE (10 mL) was added nitrosyl tetrafluoroborate (282 mg, 2.4 mmol) at 0° C. Then the mixture was stirred at 0° C. for 1 hour. The resulting brown precipitate was collected by filtration and washed with THF. Then the filter cake was heated to 150° C. for 0.5 h. After the reaction was completed, the mixture was cooled to room temperature. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give methyl 2-(4,4-difluoroazepan-1-yl)-5-fluoro-4-methylnicotinate (150 mg, 24.7%) as a yellow solid. LCMS (ESI) calcd. for C14H18F3N2O2 [M+H]+ m/z 303.13, found 302.75.
Step 2: 2-(4,4-difluoroazepan-1-yl)-5-fluoro-4-methylnicotinic acid: A solution of methyl 2-(4,4-difluoroazepan-1-yl)-5-fluoro-4-methylnicotinate (150 mg, 0.5 mmol) and KOH (280 mg, 5 mmol) in MeOH/H2O (1/1, 4 mL) was heated at 70° C. for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The residue was adjusted to pH=3-4 with aqueous HCl (1M). Then the solution was extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum to give crude 2-(4,4-difluoroazepan-1-yl)-5-fluoro-4-methylnicotinic acid (110 mg) as a yellow oil. LCMS (ESI) calcd. for C13H16F3N2O2 [M+H]+ m/z 289.12, found 288.75.
Step 3: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-fluoro-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 2-(4,4-difluoroazepan-1-yl)-5-fluoro-4-methylnicotinic acid (100 mg, 0.35 mmol) in DCM (5 mL) was added oxalyl chloride (80 mg, 0.62 mmol) and DMF (0.02 mL). The mixture was stirred at room temperature for 1 h. Then the mixture was concentrated under vacuum. The residue was diluted with THE (3 mL) and added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (104 mg, 0.38 mmol) and DIEA (135 mg, 1.04 mmol) in THE (3 mL). The mixture was heated at 50° C. for 1 hour. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-fluoro-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 42.8%) as a yellow solid. LCMS (ESI) calcd. for C25H32F3N4O4S [M+H]+ m/z 541.21, found 541.15.
Step 4: (R)-2-(4,4-difluoroazepan-1-yl)-5-fluoro-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-5-fluoro-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 0.15 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 80% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-5-fluoro-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (32.5 mg, 49.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.33 (t, J=1.8 Hz, 1H), 8.18 (s, 1H), 7.93-7.86 (m, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 4.23 (s, 1H), 3.58-3.52 (m, 2H), 3.48 (t, J=6.1 Hz, 2H), 3.06 (s, 3H), 2.29-2.14 (m, 5H), 2.05-1.92 (m, 2H), 1.83-1.71 (m, 2H). LCMS (ESI) calcd. for C20H24F3N4O2S [M+H]+ m/z 441.16, found 441.10.
Step 1: ethyl 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate: A solution of ethyl 2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (1.4 g, 3.82 mmol) and NBS (817 mg, 4.59 mmol) in MeCN (30 mL) was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The mixture was diluted with water (60 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=5/1) to provide ethyl 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (1.6 g, 94.1%) as yellow solid. LCMS (ESI) calcd. for C16H19BrF5N2O2 [M+H]+ m/z 447.06, found 447.05.
Step 2: 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid: To a solution of ethyl 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinate (1.6 g, 3.59 mmol) in EtOH/THF/H2O (1/1/1, 30 mL) was added KOH (2.01 g, 35.9 mmol) at 25° C. The mixture was heated at 80° C. for 16 hours. After the reaction was completed, the mixture was concentrated to remove most EtOH/THF. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (1.2 g, 80.1%) as a yellow solid. LCMS (ESI) calcd. for C14H15BrF5N2O2 [M+H]+ m/z 417.03, found 417.00.
Step 3: tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinic acid (600 mg, 1.44 mmol) in SOCl2 (6 mL) was heated to 80° C. for 0.5 h. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in DCM (5 mL) was added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (465 mg, 1.72 mmol) and TEA (436 mg, 4.30 mmol) in DCM (6 mL) at 0° C. The resulting mixture was stirred at 40° C. for 2 hours. Then the mixture was quenched with water (50 mL) and extracted with DCM (50 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (450 mg, 32.7%) as a yellow solid. LCMS (ESI) calcd. for C26H31BrF5N4O4S [M+H]+ m/z 671.12, found 671.05.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(4-(trifluoromethyl)phenyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol), (4-(trifluoromethyl)phenyl)boronic acid (63.1 mg, 0.33 mmol), potassium carbonate (162.5 mg, 0.5 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (24.3 mg, 0.03 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated at 100° C. for 5 h under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (50 mL×3). The combine organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(4-(trifluoromethyl)phenyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate 2 (96 mg, 86.6%) as a yellow oil. LCMS (ESI) calcd. for C32H36F5N4O4S [M+H]+ m/z 667.24, found 667.20.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(4-(trifluoromethyl)phenyl)nicotinamide: A solution of give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(4-(trifluoromethyl)phenyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (96 mg, 0.15 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(4-(trifluoromethyl)phenyl)nicotinamide (45.3 mg, 55.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.37 (s, 1H), 8.13 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.85-7.79 (m, 2H), 7.67 (d, J=7.9 Hz, 1H), 7.63-7.56 (m, 3H), 4.23 (s, 1H), 3.71-3.65 (m, 2H), 3.60 (t, J=6.0 Hz, 2H), 3.06 (s, 3H), 2.36-2.27 (m, 2H), 2.17 (s, 3H), 2.09-1.96 (m, 2H), 1.89-1.78 (m, 2H). LCMS (ESI) calcd. for C27H28F5N4O2S [M+H]+ m/z 567.19, found 567.15.
Step 1: tert-butyl (R)-((3-(5,6-dicyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of tert-butyl (R)-((3-(5,6-dichloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol), Zn(CN)2 (40 mg, 0.34 mmol) and tBuXPhos-Pd-G3 (27 mg, 0.03 mmol) in THE (8 mL) and H2O (2 mL) was heated at 50° C. for 6 hours. LCMS showed the reaction was completed. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((3-(5,6-dicyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 61.88%) as a yellow solid. LCMS (ESI) calcd. for C27H30F2N6O4SNa [M+H]+ m/z 595.19, found 595.15.
Step 2: (R)-5,6-dicyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5,6-dicyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (60 mg, 0.10 mmol) in DCM (2 mL) was added TFA (0.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3·H2O) to provide (R)-5,6-dicyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (24.2 mg, 48.85%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.25 (s, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.76-7.67 (m, 1H), 7.62 (t, J=7.9 Hz, 1H), 4.26 (s, 1H), 3.69 (d, J=45.8 Hz, 4H), 3.07 (s, 3H), 2.43 (s, 3H), 2.36-2.22 (m, 2H), 2.12-1.95 (m, 2H), 1.92-1.77 (m, 2H). LCMS (ESI) calcd. for C22H23F2N6O2S [M+H]+ m/z 473.16, found 473.10.
Step 1: tert-butyl (R)-((3-(5-chloro-6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of tert-butyl (R)-((3-(5,6-dichloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol), Zn(CN)2 (20 mg, 0.17 mmol) and tBuXPhos-Pd-G3 (27 mg, 0.03 mmol) in THE (8 mL) and H2O (2 mL) was heated at 50° C. for 6 hours. LCMS showed the reaction was completed. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((3-(5-chloro-6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (20 mg, 20.33%) as a yellow solid. LCMS (ESI) calcd. for C26H30ClF2N5O4SNa [M+Na]+ m/z 604.17, found 604.10.
Step 2: (R)-5-chloro-6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-chloro-6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (20 mg, 0.03 mmol) in DCM (2 mL) was added TFA (0.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3·H2O) to provide (R)-5-chloro-6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (5.2 mg, 30.32%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.27 (d, J=1.7 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 4.25 (s, 1H), 3.62 (d, J=5.1 Hz, 2H), 3.56 (t, J=6.0 Hz, 2H), 3.06 (d, J=0.6 Hz, 3H), 2.34 (s, 3H), 2.31-2.18 (m, 2H), 2.07-1.94 (m, 2H), 1.87-1.76 (m, 2H). LCMS (ESI) calcd. for C21H23ClF2N5O2S [M+H]+ m/z 482.13, found 482.05.
Step 1: methyl 5-bromo-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate: A solution of methyl 2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate (700 mg, 2.35 mmol) and NBS (459 mg, 2.58 mmol) in MeCN (10 mL) was stirred heated at 80° C. for 2 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=5/1) to provide methyl 5-bromo-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate (780 mg, 88.1%) as yellow solid. LCMS (ESI) calcd. for C15H20BrF2N2O2 [M+H]+ m/z 377.07, found 377.00.
Step 2: 5-bromo-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinic acid: To a solution of methyl 5-bromo-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate (780 mg, 2.07 mmol) in MeOH/H2O (1/1, 10 mL) was added KOH (1.16 g, 20.68 mmol) at 25° C. The mixture was heated at 80° C. for 16 hours. After the reaction was completed, the mixture was concentrated to remove most MeOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to afford 5-bromo-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinic acid (650 mg, 86.6%) as a yellow solid. LCMS (ESI) calcd. for C14H18BrF2N2O2 [M+H]+ m/z 363.05, found 363.00.
Step 3: tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinic acid (650 mg, 1.79 mmol) in DCM (10 mL) was added oxalyl chloride (1.14 g, 8.95 mmol) and DMF (20 L). The mixture was stirred at room temperature for 0.5 hour. Then the mixture was concentrated under vacuum. The residue was dissolved in DCM (10 mL) and added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (583 mg, 2.15 mmol) and TEA (906 mg, 8.95 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (570 mg, 51.7%) as a yellow oil. LCMS (ESI) calcd. for C26H34BrF2N4O4S [M+H]+ m/z 615.15, found 615.10.
Step 4: (R)-5-bromo-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (110 mg, 0.18 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% NH4OH) to obtain (R)-5-bromo-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (50.2 mg, 54.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.32 (t, J=1.8 Hz, 1H), 7.91-7.83 (m, 1H), 7.69-7.54 (m, 2H), 4.23 (s, 1H), 3.63-3.45 (m, 4H), 3.05 (s, 3H), 2.51 (s, 3H), 2.34-2.19 (m, 5H), 2.04-1.91 (m, 2H), 1.82-1.73 (m, 2H). LCMS (ESI) calcd. for C21H26BrF2N4O2S [M+H]+ m/z 517.09, found 517.05.
Step 1: methyl 5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinate: A mixture of Zn power (2.8 g, 0.044 mol) and 12 (250 mg, 0.984 mmol) in a 250 mL three-necked flask was evacuated and backfilled with N2 three times and then charged with N2. The flask was heated carefully with a hot air blower until 12 was sublimated. Then a solution of tert-butyl 3-iodoazetidine-1-carboxylate (1.5 g, 0.0053 mol) in DMF (5 mL) was added intermediately via a syringe. The mixture was stirred for 10 minutes at room temperature. Then the heater and stirrer were removed. The upper layer clear solution was added dropwise into a stirred solution of methyl 2-(4,4-difluoroazepan-1-yl)-5-iodo-4-methylnicotinate (1 g, 0.0024 mol), CuI (200 mg, 1.053 mmol) and Pd(pph3)2C12 (200 mg, 0.284 mmol) in DMF (4 mL) under an atmosphere of N2. The mixture was heated at 80° C. for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give methyl 5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinate (700 mg, 70.38%) as a white oil. LCMS (ESI) calcd. for C22H32F2N3O4 [M+H]+ m/z 440.24, found 440.10.
Step 2: 5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid: To a solution of methyl 5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinate (700 mg, 1.59 mmol) in MeOH/H2O (v:v=1:1, 20 mL) was added potassium hydroxide (892 mg, 15.90 mmol) at room temperature. The mixture was stirred for 10 hours at 80° C. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature, the reaction was extracted with DCM (20 mL), then the aqueous phase was adjusted to pH=3 with 1 N HCl and extracted with DCM (20 mL×3). The organic phase was dried with Na2SO4 and concentrated under reduced pressure to give 5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (550 mg, 81.24%) as a white solid. LCMS (ESI) calcd. for C21H30F2N3O4 [M+H]+ m/z 426.22, found 426.10.
Step 3: tert-butyl 3-(5-carbamoyl-6-(4,4-difluoroazepan-1-yl)-4-methylpyridin-3-yl)azetidine-1-carboxylate: A solution of 5-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (550 mg, 1.291 mmol) in DMF (20 mL) was added HATU (638 mg, 1.678 mmol), DIEA (534 mg, 4.131 mmol) and NH3-MeOH (20 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was cooled to room temperature and the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl 3-(5-carbamoyl-6-(4,4-difluoroazepan-1-yl)-4-methylpyridin-3-yl)azetidine-1-carboxylate (480 mg, 87.59%) as a yellow solid. LCMS (ESI) calcd. for C21H31F2N4O3 [M+H]+ m/z 425.24, found 425.10.
Step 4: tert-butyl 3-(6-(4,4-difluoroazepan-1-yl)-4-methyl-5-((3-(methylsulfinyl)phenyl)carbamoyl)pyridin-3-yl)azetidine-1-carboxylate: A solution of tert-butyl 3-(5-carbamoyl-6-(4,4-difluoroazepan-1-yl)-4-methylpyridin-3-yl)azetidine-1-carboxylate (480 mg, 1.129 mmol) in dioxane (10 mL) was added 1-bromo-3-(methylsulfinyl)benzene (749 mg, 3.388 mmol), cesium carbonate (956 mg, 2.935 mmol) and Xantphos-Pd-G2 (100 mg, 0.113 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 16 hours under nitrogen. The reaction was monitored by LCMS. After the reaction was completed, the filtrate was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl 3-(6-(4,4-difluoroazepan-1-yl)-4-methyl-5-((3-(methylsulfinyl)phenyl)carbamoyl)pyridin-3-yl)azetidine-1-carboxylate (250 mg, 39.37%) as a yellow oil. LCMS (ESI) calcd. for C28H37F2N4O4S [M+H]+ m/z 563.25, found 563.15.
Step 5: tert-butyl 3-(6-(4,4-difluoroazepan-1-yl)-4-methyl-5-((3-(S-methylsulfonimidoyl)phenyl)carbamoyl)pyridin-3-yl)azetidine-1-carboxylate: To a solution of tert-butyl 3-(6-(4,4-difluoroazepan-1-yl)-4-methyl-5-((3-(methylsulfinyl)phenyl)carbamoyl)pyridin-3-yl)azetidine-1-carboxylate (250 mg, 0.444 mmol) in MeOH (10 mL) was added PhI(OAc)2 (358 mg, 1.110 mmol) and ammonium carbamate (104 mg, 1.332 mmol) at room temperature. The reaction mixture was heated at 70° C. for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (10 mL), and extracted with DCM (10 mL×3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE/EtOAc=1/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.1% formic acid) to afford tert-butyl 3-(6-(4,4-difluoroazepan-1-yl)-4-methyl-5-((3-(S-methylsulfonimidoyl)phenyl)carbamoyl)pyridin-3-yl)azetidine-1-carboxylate (70 mg, 27.34%) as a white oil. LCMS (ESI) calcd. for C28H38F2N5O4S [M+H]+ m/z 578.26, found 578.20.
Step 6: 5-(azetidin-3-yl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl 3-(6-(4,4-difluoroazepan-1-yl)-4-methyl-5-((3-(S-methylsulfonimidoyl)phenyl)carbamoyl)pyridin-3-yl)azetidine-1-carboxylate (70 mg, 0.121 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% NH3) to afford 5-(azetidin-3-yl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (4.20 mg, 7.17%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.59-7.55 (m, 1H), 4.21 (s, 1H), 3.94-3.92 (m, 1H), 3.71-3.67 (m, 4H), 3.55-3.49 (m, 2H), 3.36-3.35 (m, 2H), 3.05 (s, 3H), 2.23-2.05 (m, 2H), 2.06 (s, 3H), 1.99-1.91 (m, 2H), 178-1.76 (m, 2H). LCMS (ESI) calcd. for C23H30F2N5O2S [M+H]+ m/z 478.21, found 478.05.
Step 1: tert-butyl (3-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1,1,1-trifluoro-3-oxopropan-2-yl)carbamate: To a solution of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (150 mg, 0.30 mmol), 2-((tert-butoxycarbonyl)amino)-3,3,3-trifluoropropanoic acid (109 mg, 0.45 mmol) and TCFH (148 mg, 0.61 mmol) in MeCN (5 mL) and was added NMI (50 mg, 0.61 mmol). Then the mixture was stirred at 25° C. for 3 hours. LCMS showed the reaction was completed. The mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/4) to provide tert-butyl (3-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1,1,1-trifluoro-3-oxopropan-2-yl)carbamate (130 mg, 59.91%) as a yellow oil. LCMS (ESI) calcd. for C32H39F5N7O5S [M+H]+ m/z 728.27, found 728.25.
Step 2: N-(3-((R)-N-(2-amino-3,3,3-trifluoropropanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: To a solution of tert-butyl (3-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1,1,1-trifluoro-3-oxopropan-2-yl)carbamate (130 mg, 0.18 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.05% NH3) to provide N-(3-((R)-N-(2-amino-3,3,3-trifluoropropanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (68 mg, 60.71%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (d, J=1.4 Hz, 1H), 8.43 (d, J=1.6 Hz, 1H), 8.18 (s, 1H), 8.02-7.94 (m, 1H), 7.90 (s, 1H), 7.71-7.64 (m, 2H), 7.61 (s, 1H), 4.00-3.91 (m, 1H), 3.89 (s, 3H), 3.64-3.57 (m, 2H), 3.57-3.49 (m, 5H), 2.34-2.16 (m, 7H), 2.06-1.93 (m, 2H), 1.85-1.72 (m, 2H). LCMS (ESI) calcd. for C27H31F5N7O3S [M+H]+ m/z 628.22, found 628.10.
Step 1: tert-butyl (R)-(2-(((3-(6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: To a solution of (R)-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)benzamide (70 mg, 0.14 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (32 mg, 0.17 mmol) and HATU (106 mg, 0.28 mmol) in DMF (3 mL) and was added DIEA (54 mg, 0.42 mmol). Then the mixture was stirred at 25° C. for 5 hours. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (3×6 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE/EtOAc, 40% to 70%) to give tert-butyl (R)-(2-(((3-(6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (60 mg, 80.2%) as a yellow oil. LCMS (ESI) calcd. for C33H43F2N6O5S [M+H]+ m/z 673.30, found 673.20.
Step 2: (R)-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)benzamide: A solution of tert-butyl (R)-(2-(((3-(6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (60 mg, 0.09 mmol) in DCM (3 mL) was added TFA (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% NH4OH) to obtain (R)-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)benzamide (31.3 mg, 61.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.44 (s, 1H), 7.98 (dt, J=5.2, 2.7 Hz, 1H), 7.90 (s, 1H), 7.67-7.61 (m, 2H), 7.59 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 3.88 (s, 3H), 3.42 (s, 3H), 3.20 (s, 2H), 3.16-3.09 (m, 4H), 2.30-2.20 (m, 6H), 2.12-1.88 (m, 4H), 1.71-1.62 (m, 2H). LCMS (ESI) calcd. for C28H35F2N6O3S [M+H]+ m/z 573.25, found 573.05.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.17 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole (87 mg, 0.33 mmol), K2CO3 (46 mg, 0.33 mmol) and Pd(dppf)Cl2 (12 mg, 0.02 mmol) in dioxane (8 mL) and H2O (2 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (40 mL) and extracted with EtOAc (40 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 47.5%) as a yellow solid. LCMS (ESI) calcd. for C29H34F5N6O4S [M+H]+ m/z 657.23, found 657.25.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)nicotinamide. A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 0.08 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 25% to 75% MeCN/H2O containing 0.1% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)nicotinamide (15.30 mg, 34.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.69 (s, 1H), 8.42-8.16 (m, 3H), 7.90 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 4.23 (s, 1H), 3.72-3.55 (m, 4H), 3.06 (s, 3H), 2.31-2.21 (m, 5H), 2.06-1.95 (m, 2H), 1.85-1.76 (m, 2H). LCMS (ESI) calcd. for C24H26F5N6O2S [M+H]+ m/z 557.18, found 557.05.
Step 1: tert-butyl (R)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate: A mixture of (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (80 mg, 0.16 mmol) and (tert-butoxycarbonyl)glycine (57 mg, 0.32 mmol) in DMF (5 mL) was added HATU (91 mg, 0.24 mmol) and DIEA (62 mg, 0.48 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (70 mg, 67.4%) as a yellow solid. LCMS (ESI) calcd. for C27H34F5N6O5S [M+H]+ m/z 649.23, found 649.20.
Step 2: (R)-3-(4,4-difluoroazepan-1-yl)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of tert-butyl (R)-(2-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (70 mg, 0.11 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.05% NH3) to obtain (R)-3-(4,4-difluoroazepan-1-yl)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (18.5 mg, 30.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.26 (s, 1H), 7.96 (d, J=7.7 Hz, 1H), 7.79-7.61 (m, 2H), 3.85 (s, 2H), 3.69 (s, 2H), 3.46 (s, 3H), 3.23 (s, 2H), 2.38-2.27 (m, 5H), 2.12-2.01 (m, 2H), 1.93-1.85 (m, 2H). LCMS (ESI) calcd. for C22H26F5N6O3S [M+H]+ m/z 549.17, found 549.10.
Step 1: tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(2-methyloxazol-5-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.167 mmol) and 2-methyloxazole (50 mg, 0.501 mmol) in DMA (10 mL) was added Pd(OAc)2 (5 mg, 0.017 mmol) and KOAc (60 mg, 0.501 mmol). The mixture was heated at 100° C. for 6 hours under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(2-methyloxazol-5-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 49.00%) as a yellow solid. LCMS (ESI) calcd. for C29H36F2N5O5S [M+H]+ m/z 604.24, found 604.25.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(2-methyloxazol-5-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(2-methyloxazol-5-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.149 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(2-methyloxazol-5-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (44.7 mg, 50.10%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.36-8.35 (m, 2H), 7.91 (d, J=8.8 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.22 (s, 1H), 4.23 (s, 1H), 3.69-3.66 (m, 2H), 3.61-3.58 (m, 2H), 3.06 (s, 3H), 2.47 (s, 3H), 2.33-2.32 (m, 2H), 2.29 (s, 3H), 2.00-1.99 (m, 2H), 1.83-1.82 (m, 2H). LCMS (ESI) calcd. for C24H28F2N5O3S [M+H]+ m/z 504.19, found 504.15.
2-((tert-butyldimethylsilyl)oxy)acetic acid: To a solution of 2-hydroxyacetic acid (1 g, 13.16 mmol) and imidazole (2.68 g, 39.47 mmol) in DCM (15 mL) was added TBSCl (2.38 g, 15.79 mmol) at 0° C. Then the mixture was stirred at 25° C. for 16 hours. After the reaction was completed. The mixture was diluted with water and extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum to give crude 2-((tert-butyldimethylsilyl)oxy)acetic acid (1.6 g) which was used directly in next step without further purification.
To a solution of (S)-2-hydroxypropanoic acid (1 g, 11.11 mmol) and imidazole (2.27 g, 33.32 mmol) in DCM (15 mL) was added TBSCl (2.00 g, 13.33 mmol) at 0° C. Then the mixture was heated at 25° C. for 16 hours. After the reaction was completed, the mixture was diluted with water and extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum to give crude (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (1.4 g) which was used directly in next step without further purification.
Step 1: N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A mixture of (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (100 mg, 0.20 mmol) and (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (83 mg, 0.41 mmol) in DMF (5 mL) was added HATU (116 mg, 0.31 mmol) and DIEA (79 mg, 0.61 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (80 mg, 52.2%) as a yellow solid. LCMS (ESI) calcd. for C29H41F5N5O4SSi [M+H]+ m/z 678.26, found 678.20.
Step 2: 3-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (80 mg, 0.12 mmol) in THE (3 mL) and H2O (1 mL) was added AcOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (30 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H2O containing 0.05% NH3) to obtain 3-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (29.2 mg, 43.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.30 (d, J=1.8 Hz, 1H), 7.98-7.91 (m, 1H), 7.77-7.66 (m, 2H), 4.74 (d, J=5.4 Hz, 1H), 4.03 (dd, J=6.8, 5.4 Hz, 1H), 3.85 (s, 2H), 3.68 (t, J=5.9 Hz, 2H), 3.49 (s, 3H), 2.41-2.29 (m, 5H), 2.14-2.01 (m, 2H), 1.94-1.83 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS (ESI) calcd. for C23H27F5N5O4S [M+H]+ m/z 564.17, found 564.05.
Step 1: tert-butyl (R)-(1-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclobutyl)carbamate: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (50 mg, 0.10 mmol) and 1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (37 mg, 0.17 mmol) in DMF (5 mL) was added HATU (50 mg, 0.13 mmol) and DIEA (42 mg, 0.32 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(1-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclobutyl)carbamate (40 mg, 62.5%) as a white oil. LCMS (ESI) calcd. for C31H39F5N5O5S [M+H]+ m/z 688.26, found 688.20.
Step 2: (R)-N-(3-(N-(1-aminocyclobutane-1-carbonyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide. A solution of tert-butyl (R)-(1-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclobutyl)carbamate (40 mg, 0.06 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (R)-N-(3-(N-(1-aminocyclobutane-1-carbonyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (26.7 mg, 72.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.72-7.66 (m, 2H), 3.74-3.71 (m, 2H), 3.62-3.60 (m, 2H), 3.48 (s, 3H), 2.34-2.30 (m, 5H), 2.03-2.00 (m, 2H), 1.98-1.94 (m, 2H), 1.79-1.70 (m, 6H). LCMS (ESI) calcd. for C26H31F5N5O3S [M+H]+ m/z 588.21, found 588.10.
Step 1: tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (50 mg, 0.10 mmol) and (tert-butoxycarbonyl)glycine (30 mg, 0.17 mmol) in DMF (5 mL) was added HATU (50 mg, 0.13 mmol) and DIEA (42 mg, 0.32 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (40 mg, 62.5%) as a white oil. LCMS (ESI) calcd. for C28H35F5N5O5S [M+H]+ m/z 648.23, found 648.10.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (40 mg, 0.06 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide (17.5 mg, 54.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 7.99 (d, J=7.2 Hz, 1H), 7.71-7.65 (m, 2H), 3.74-3.71 (m, 2H), 3.62-3.60 (m, 2H), 3.46 (s, 3H), 3.24 (s, 2H), 2.32 (s, 3H), 2.32-2.30 (m, 2H), 2.03-2.00 (m, 2H), 1.88-1.83 (m, 2H). LCMS (ESI) calcd. for C23H27F5N5O3S [M+H]+ m/z 548.18, found 548.10.
Step 1: tert-butyl ((R)-1-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (60 mg, 0.12 mmol), (tert-butoxycarbonyl)-D-alanine (35 mg, 0.18 mmol) and HATU (91 mg, 0.24 mmol) in DMF (3 mL) was added DIEA (46 mg, 0.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to provide tert-butyl ((R)-1-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (75 mg, 82.4%) as a yellow solid. LCMS (ESI) calcd. for C29H37F5N5O5S [M+H]+ m/z 662.25, found 662.10.
Step 2: N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide: To a solution of tert-butyl ((R)-1-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (75 mg, 0.11 mmol) in DCM (3 mL) was added TFA (0.3 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (20 mg, 31.45%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.73-7.63 (m, 2H), 3.72 (s, 2H), 3.62 (t, J=5.8 Hz, 2H), 3.46 (s, 3H), 2.36-2.23 (m, 5H), 2.07-1.94 (m, 3H), 1.89-1.80 (m, 2H), 1.18 (d, J=6.9 Hz, 3H). LCMS (ESI) calcd. for C24H29F5N5O3S [M+H]+ m/z 562.19, found 562.15.
Step 1: tert-butyl ((R)-1-(((R)-(3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate: A mixture of (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (100 mg, 0.20 mmol) and (tert-butoxycarbonyl)-D-alanine (77 mg, 0.41 mmol) in DMF (5 mL) was added HATU (116 mg, 0.31 mmol) and DIEA (79 mg, 0.61 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl ((R)-1-(((R)-(3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (80 mg, 53.4%) as a yellow solid. LCMS (ESI) calcd. for C28H36F5N6O5S [M+H]+ m/z 663.24, found 663.25.
Step 2: N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide. A solution of tert-butyl ((R)-1-(((R)-(3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-1-oxopropan-2-yl)carbamate (80 mg, 0.12 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H2O containing 0.05% NH3) to N-(3-((R)-N-(D-alanyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (26.4 mg, 38.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ11.24 (s, 1H), 8.36 (s, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.82-7.68 (m, 2H), 6.72 (s, 2H), 3.85 (s, 2H), 3.73-3.64 (m, 3H), 3.56 (s, 3H), 2.40-2.30 (m, 5H), 2.13-2.01 (m, 2H), 1.93-1.83 (m, 2H), 1.35 (d, J=7.1 Hz, 3H). LCMS (ESI) calcd. for C23H28F5N6O3S [M+H]+ m/z 563.19, found 563.10.
Step 1: tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (100 mg, 0.19 mmol) and (tert-butoxycarbonyl)glycine (51 mg, 0.29 mmol) in DMF (5 mL) was added HATU (147 mg, 0.39 mmol) and DIEA (75 mg, 0.58 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (80 mg, 57.0%) as a yellow solid. LCMS (ESI) calcd. for C32H39F5N7O5S [M+H]+ m/z 728.27, found 728.20
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (80 mg, 0.11 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 80% MeCN/H2O containing 0.1% NH3·H2O) to obtain (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-glycyl-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide (30.5 mg, 44.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.39-8.28 (m, 1H), 8.04-7.91 (m, 1H), 7.75-7.62 (m, 3H), 7.36 (s, 1H), 3.90 (s, 3H), 3.71-3.56 (m, 4H), 3.45 (s, 3H), 3.23 (s, 2H), 2.38-2.24 (m, 2H), 2.09-1.96 (m, 5H), 1.88-1.79 (m, 2H). LCMS (ESI) calcd. for C27H30F5N7O3S [M+H]+ m/z 628.22, found 628.15.
Step 1: 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid: A mixture of 2,6-dichloro-4-methylnicotinic acid (4.0 g, 19.51 mmol), 4,4-difluoroazepane hydrochloride (4.0 g, 23.41 mmol), K2CO3 (8.0 g, 58.53 mmol) and DIEA (6.3 g, 48.78 mmol) in NMP (60 mL) was heated at 140° C. for 8 hours under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (150 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=50/1) to give 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (4.5 g, 75.89%) as a yellow solid. LCMS (ESI) calcd. for C13H16ClF2N2O2 [M+H]+ m/z 305.09, found 304.90.
Step 2: 2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinic acid: A mixture of 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (4.5 g, 14.80 mmol), Trimethylboroxine (5.6 g, 44.37 mmol), K2CO3 (6.1 g, 44.41 mmol) and Pd(dppf)Cl2 (1.1 g, 1.48 mmol) in 1,4-dioxane/H2O (4/1, 60 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (150 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=10/1) to give 2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinic acid (3.2 g, 76.19%) as a yellow solid. LCMS (ESI) calcd. for C14H19F2N2O2 [M+H]+ m/z 285.14, found 284.95.
Step 3: methyl 2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate: A mixture of 2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinic acid (3.2 g, 11.27 mmol), K2CO3 (4.7 g, 33.80 mmol) and Mel (3.2 g, 22.54 mmol) in DMF (40 mL) was heated at 80° C. for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/10) to give methyl 2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate (2.8 g, 83.58%) as a yellow solid. LCMS (ESI) calcd. for C15H21F2N2O2 [M+H]+ m/z 299.16, found 298.75.
Step 4: methyl 2-(4,4-difluoroazepan-1-yl)-5-iodo-4,6-dimethylnicotinate: To a solution of methyl 2-(4,4-difluoroazepan-1-yl)-4,6-dimethylnicotinate (2.5 g, 8.39 mmol) in DCM (30 mL) was added NIS (2.1 g, 9.23 mmol). The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The resulting solution was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=5/1) to give methyl 2-(4,4-difluoroazepan-1-yl)-5-iodo-4,6-dimethylnicotinate (3.1 g, 87.32%) as a yellow solid. LCMS (ESI) calcd. for C15H20F2IN2O2 [M+H]+ m/z 425.05, found 424.75.
Step 5: methyl 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-5-(trifluoromethyl)nicotinate: A mixture of methyl 2-(4,4-difluoroazepan-1-yl)-5-iodo-4,6-dimethylnicotinate (2 g, 4.72 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (4.5 g, 23.58 mmol) and CuI (1.8 g, 9.44 mmol) in DMF (30 mL) was heated at 120° C. for 3 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (80 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=5/1) to give methyl 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-5-(trifluoromethyl)nicotinate (1.4 g, 80.46%) as a yellow solid. LCMS (ESI) calcd. for C16H20F5N2O2 [M+H]+ m/z 367.14, found 366.95.
Step 6: 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-5-(trifluoromethyl)nicotinic acid: A solution of methyl 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-5-(trifluoromethyl)nicotinate (1.4 g, 3.81 mmol) in NH3-MeOH (30 mL) was heated at 130° C. for 8 hours in a high-pressure reactor. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/2) to give 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-5-(trifluoromethyl)nicotinic acid (600 mg, 44.78%) as a yellow solid. LCMS (ESI) calcd. for C15H18F5N2O2 [M+H]+ m/z 353.13, found 352.80.
Step 7: 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-5-(trifluoromethyl)nicotinamide: To a mixture of 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-5-(trifluoromethyl)nicotinic acid (600 mg, 1.70 mmol), HATU (1.3 g, 3.41 mmol) and DIEA (660 mg, 5.11 mmol) in DMF (20 mL) was added NH3-MeOH (7M, 10 mL). The reaction was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/3) to give 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-5-(trifluoromethyl)nicotinamide (440 mg, 73.58%) as a yellow solid. LCMS (ESI) calcd. for C15H19F5N3O [M+H]+ m/z 352.15, found 351.90.
Step 8: 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(methylsulfinyl)phenyl)-5-(trifluoromethyl)nicotinamide: A mixture of 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-5-(trifluoromethyl)nicotinamide (440 mg, 1.25 mmol), 1-bromo-3-(methylsulfinyl)benzene (410 mg, 1.88 mmol), Cs2CO3 (1.2 g, 3.75 mmol) and Xantphos-Pd-G2 (111 mg, 0.13 mmol) in 1,4-dioxane (10 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(methylsulfinyl)phenyl)-5-(trifluoromethyl)nicotinamide (350 mg, 57.19%) as a yellow solid. LCMS (ESI) calcd. for C22H25F5N3O2S [M+H]+ m/z 490.16, found 490.05.
Step 9: 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: A mixture of 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(methylsulfinyl)phenyl)-5-(trifluoromethyl)nicotinamide (350 mg, 0.71 mmol), PhI(OAc)2 (710 mg, 2.14 mmol) and NH2CO2NH4 (167 mg, 2.14 mmol) in MeOH (10 mL) was heated at 70° C. for 16 hours under an atmosphere of N2. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE/EtOAc=1/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to give 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (160 mg, 44.44%) as a white solid. LCMS (ESI) calcd. for C22H26F5N4O2S [M+H]+ m/z 505.17, found 505.05.
Step 10: (S)-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide and (R)-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: 2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide was further purified by Chiral-Prep-HPLC (Daicel 1H, 4.6*250 mm, eluting with 20% CO02-MeOH containing 0.1% NH3) to afford first eluting isomer (S)-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.32 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 4.24 (s, 1H), 3.71 (s, 2H), 3.59 (d, J=5.3 Hz, 2H), 3.06 (s, 3H), 2.52 (s, 3H), 2.36-2.21 (m, 5H), 2.06-1.91 (m, 2H), 1.86-1.72 (m, 2H). LCMS (ESI) calcd. for C22H26F5N4O2S [M+H]+ m/z 505.17, found 505.00 and the second eluting isomer (R)-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.32 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 4.23 (s, 1H), 3.71 (s, 2H), 3.60 (t, J=5.8 Hz, 2H), 3.06 (s, 3H), 2.52 (s, 3H), 2.35-2.22 (m, 5H), 2.06-1.92 (m, 2H), 1.87-1.75 (m, 2H). LCMS (ESI) calcd. for C22H26F5N4O2S [M+H]+ m/z 505.17, found 505.00.
Step 1: tert-butyl (R)-(1-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (50 mg, 0.10 mmol) and 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (35 mg, 0.17 mmol) in DMF (5 mL) was added HATU (50 mg, 0.13 mmol) and DIEA (42 mg, 0.32 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(1-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate (40 mg, 57.97%) as a white oil. LCMS (ESI) calcd. for C30H39F5N5O5S [M+H]+ m/z 676.26, found 676.15.
Step 2: (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide A solution of tert-butyl (R)-(1-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate (40 mg, 0.06 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (15.2 mg, 44.18%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 7.93 (d, J=7.3 Hz, 1H), 7.74-7.62 (m, 2H), 3.75-3.68 (m, 2H), 3.63 (t, J=6.0 Hz, 2H), 3.44 (s, 3H), 2.35-2.22 (m, 5H), 2.06-1.93 (m, 2H), 1.92-1.71 (m, 4H), 1.21 (d, J=3.9 Hz, 6H). LCMS (ESI) calcd. for C25H31F5N5O3S [M+H]+ m/z 576.21, found 576.10.
Step 1: 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(methylsulfinyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide: A solution of 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (680 mg, 2.02 mmol) in dioxane (8 mL) was added 4-bromo-2-(methylsulfinyl)pyridine (423 mg, 2.02 mmol), cesium carbonate (1970 mg, 6.06 mmol) and Xantphos-Pd-G2 (180 mg, 0.202 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 16 hours under nitrogen. The reaction was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combine organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(methylsulfinyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide (750 mg, 77.88%) as a white solid. LCMS (ESI) calcd. for C20H22F5N4O2S [M+H]+ m/z 477.14, found 477.00.
Step 2: 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide: To a solution of 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(methylsulfinyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide (750 mg, 1.57 mmol) in MeOH (10 mL) was added PhI(OAc)2 (1266 mg, 3.93 mmol) and ammonium carbamate (364 mg, 4.72 mmol) at room temperature. The reaction mixture was heated at 70° C. for 1 hour. After the reaction was completed, the mixture was diluted with water (25 mL), and extracted with DCM (25 mL×3). The combine organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (PE/EtOAc=1/1), then further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide (220 mg, 37.78%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.63 (d, J=5.6 Hz, 1H), 8.48 (s, 1H), 8.39 (d, J=1.6 Hz, 1H), 7.82 (dd, J=5.6, 1.6 Hz, 1H), 4.40 (s, 1H), 3.71-3.69 (m, 2H), 3.57-3.55 (m, 2H), 3.15 (s, 3H), 2.32-2.30 (m, 5H), 2.02-1.95 (m, 2H), 1.84-1.81 (m, 2H). LCMS (ESI) calcd. for C20H23F5N5O2S [M+H]+ m/z 492.15, found 492.05.
Step 3: (S)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide and (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide: 2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide was further purified by Chiral-Prep-HPLC (1H-40% D-2.5, 4.6*250 mm, eluting with 35% CO02-MeOH containing 0.1% NH3) to afford first eluting isomer (S)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide (53.40 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.63 (d, J=5.6 Hz, 1H), 8.48 (s, 1H), 8.39 (d, J=1.6 Hz, 1H), 7.82 (dd, J=5.6, 1.6 Hz, 1H), 4.40 (s, 1H), 3.71-3.69 (m, 2H), 3.57-3.55 (m, 2H), 3.15 (s, 3H), 2.32-2.30 (m, 5H), 2.02-1.95 (m, 2H), 1.84-1.81 (m, 2H). LCMS (ESI) calcd. for C20H23F5N5O2S [M+H]+ m/z 492.15, found 492.05 and the second eluting isomer (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide (51.20 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.63 (d, J=5.6 Hz, 1H), 8.48 (s, 1H), 8.39 (d, J=1.6 Hz, 1H), 7.82 (dd, J=5.6, 1.6 Hz, 1H), 4.40 (s, 1H), 3.71-3.69 (m, 2H), 3.57-3.55 (m, 2H), 3.15 (s, 3H), 2.32-2.30 (m, 5H), 2.02-1.95 (m, 2H), 1.84-1.81 (m, 2H). LCMS (ESI) calcd. for C20H23F5N5O2S [M+H]+ m/z 492.15, found 492.05.
Step 1: tert-butyl (S)-2-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)pyrrolidine-1-carboxylate: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (100 mg, 0.19 mmol) and (tert-butoxycarbonyl)-L-proline (61 mg, 0.29 mmol) in DMF (5 mL) was added HATU (147 mg, 0.39 mmol) and DIEA (75 mg, 0.58 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (S)-2-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)pyrrolidine-1-carboxylate (70 mg, 48.0%) as a yellow solid. LCMS (ESI) calcd. for C35H43F5N7O5S [M+H]+ m/z 768.30, found 768.20.
Step 2: N-(3-((R)-N-(L-prolyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl (S)-2-(((R)-(3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)pyrrolidine-1-carboxylate (70 mg, 0.09 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 80% MeCN/H2O containing 0.1% NH3·H2O) to obtain N-(3-((R)-N-(L-prolyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide (26.2 mg, 42.0%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.40 (s, 1H), 7.92-7.85 (m, 1H), 7.73-7.63 (m, 3H), 7.36 (s, 1H), 3.90 (s, 3H), 3.70-3.57 (m, 4H), 3.52 (dd, J=8.5, 5.9 Hz, 1H), 3.45 (s, 3H), 2.94-2.84 (m, 1H), 2.69-2.58 (m, 1H), 2.37-2.24 (m, 2H), 2.10-1.94 (m, 6H), 1.89-1.69 (m, 4H), 1.65-1.44 (m, 2H). LCMS (ESI) calcd. for C30H35F5N7O3S [M+H]+ m/z 668.25, found 668.20.
Step 1: (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (100 mg, 0.20 mmol) and 2-((tert-butyldimethylsilyl)oxy)acetic acid (78 mg, 0.41 mmol) in DMF (5 mL) was added HATU (116 mg, 0.31 mmol) and DIEA (79 mg, 0.61 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide (80 mg, 52.2%) as a yellow solid. LCMS (ESI) calcd. for C33H44F5N6O4SSi [M+H]+ m/z 743.28, found 743.15.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide: A solution of (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide (80 mg, 0.12 mmol) in THF (3 mL) and H2O (1 mL) was added AcOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (30 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H2O containing 0.05% NH3) to obtain (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide (24.2 mg, 40.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.32 (s, 1H), 8.01-7.95 (m, 1H), 7.71-7.65 (m, 3H), 7.36 (s, 1H), 4.79 (t, J=6.3 Hz, 1H), 3.94 (d, J=6.3 Hz, 2H), 3.90 (s, 3H), 3.68 (s, 2H), 3.61 (t, J=6.0 Hz, 2H), 3.46 (s, 3H), 2.32 (s, 2H), 2.10-2.00 (m, 5H), 1.84 (d, J=5.7 Hz, 2H). LCMS (ESI) calcd. for C27H30F5N6O4S [M+H]+ m/z 629.20, found 629.10.
Step 1: N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide(100 mg, 0.20 mmol) and (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (208 mg, 1.02 mmol) in DMF (5 mL) was added HATU (101 mg, 0.26 mmol) and DIEA (84 mg, 0.64 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (60 mg, 44.44%) as a white oil. LCMS (ESI) calcd. for C30H42F5N4O4SSi [M+H]+ m/z 677.26, found 677.05.
Step 2: 2-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide: A solution of N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (60 mg, 0.09 mmol) in THE (0.5 mL) was added AcOH (1.5 mL) and H2O (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 2-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide (35.60 mg, 70.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 7.96-7.93 (m, 1H), 7.69-7.68 (m, 2H), 4.71 (d, J=5.6 Hz, 1H), 4.05-4.02 (m, 1H), 3.74-3.71 (m, 2H), 3.62-3.60 (m, 2H), 3.46 (s, 3H), 2.34-2.30 (m, 5H), 2.07-1.96 (m, 2H), 1.85-1.83 (m, 2H)), 1.25 (d, J=6.8 Hz, 3H). LCMS (ESI) calcd. for C24H28F5N4O4S [M+H]+ m/z 563.18, found 563.05.
Step 1: N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (100 mg, 0.20 mmol) and (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (208 mg, 1.02 mmol) in DMF (5 mL) was added HATU (101 mg, 0.26 mmol) and DIEA (84 mg, 0.64 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (60 mg, 44.44%) as a white oil. LCMS (ESI) calcd. for C30H42F5N4O4SSi [M+H]+ m/z 677.26, found 677.10.
Step 2: 2-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide. A solution of N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (60 mg, 0.09 mmol) in THE (0.5 mL) was added AcOH (1.5 mL) and H2O (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain 2-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide (17.80 mg, 35.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.46 (s, 1H), 8.34-8.33 (m, 1H), 7.98-7.95 (m, 1H), 7.71-7.65 (m, 2H), 4.73 (d, J=5.2 Hz, 1H), 4.04-4.01 (m, 1H), 3.74-3.71 (m, 2H), 3.62-3.60 (m, 2H), 3.47 (s, 3H), 2.32-2.30 (m, 5H), 2.03-2.00 (m, 2H), 1.84-1.82 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS (ESI) calcd. for C24H28F5N4O4S [M+H]+ m/z 563.18, found 563.00.
Step 1: tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (80 mg, 0.16 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (50 mg, 0.28 mmol) in DMF (5 mL) was added HATU (81 mg, 0.21 mmol) and DIEA (68 mg, 0.51 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (40 mg, 39.21%) as a white oil. LCMS (ESI) calcd. for C29H37F5N5O5S [M+H]+ m/z 662.25, found 662.10.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide. A solution of tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (40 mg, 0.06 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% NH4OH) to obtain (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (5.30 mg, 15.15%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.46 (s, 1H), 8.36-8.33 (m, 1H), 7.98-7.96 (m, 1H), 7.71-7.65 (m, 2H), 3.74-3.71 (m, 2H), 3.62-3.60 (m, 2H), 3.46 (s, 3H), 3.21 (s, 2H), 2.34-2.30 (m, 5H), 2.24 (s, 3H), 2.02-1.98 (m, 2H), 1.85-1.81 (m, 2H). LCMS (ESI) calcd. for C24H29F5N5O3S [M+H]+ m/z 562.19, found 562.10.
Step 1: (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (90 mg, 0.18 mmol) and 2-((tert-butyldimethylsilyl)oxy)acetic acid (175 mg, 0.92 mmol) in DMF (5 mL) was added HATU (91 mg, 0.24 mmol) and DIEA (76 mg, 0.59 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (60 mg, 50.42%) as white oil. LCMS (ESI) calcd. for C29H40F5N4O4SSi [M+H]+ m/z 663.25, found 663.10.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide: A solution of (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (60 mg, 0.09 mmol) in THE (0.5 mL) was added CH3CO2H (1.5 mL) and H2O (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide (11.30 mg, 22.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.46 (s, 1H), 8.32-8.29 (m, 1H), 8.01-7.99 (m, 1H), 7.71-7.67 (m, 2H), 4.79-4.76 (m, 1H), 3.94 (d, J=6.4 Hz, 2H), 3.73-3.71 (m, 2H), 3.64-3.61 (m, 2H), 3.47 (s, 3H), 2.34-2.30 (m, 5H), 2.03-2.00 (m, 2H), 1.85-1.83 (m, 2H). LCMS (ESI) calcd. for C23H26F5N4O4S [M+H]+ m/z 549.16, found 549.05.
Step 1: (R)-5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (500 mg, 0.75 mmol) in DCM (6 mL) was added TFA (0.6 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide (R)-5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (400 mg, 94.2%) as a yellow solid. LCMS (ESI) calcd. for C21H23BrF5N4O2S [M+H]+ m/z 569.07, found 570.75.
Step 2: tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate: A solution of (R)-5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (400 mg, 0.70 mmol), (tert-butoxycarbonyl)glycine (248 mg, 1.41 mmol), HATU (401 mg, 1.05 mmol) and DIEA (272 mg, 2.11 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to provide tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (410 mg, 72.3%) as yellow solid. LCMS (ESI) calcd. for C28H34BrF5N5O5S [M+H]+ m/z 726.14, found 727.95.
Step 3: tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)carbamate: A solution of tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (400 mg, 0.55 mmol) in THE (10 mL) was added BH3-THF (1.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to provide tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)carbamate (160 mg, 40.8%) as a yellow solid. LCMS (ESI) calcd. for C28H36BrF5N5O4S [M+H]+ m/z 712.16, found 712.00.
Step 4: (R)-N-(3-(N-(2-aminoethyl)-S-methylsulfonimidoyl)phenyl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide. A mixture of tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)carbamate (160 mg, 0.22 mmol), CuCN (201 mg, 2.24 mmol) in DMA (10 mL) was heated to 150° C. and stirred for 2 hours under an atmosphere of N2. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 40% MeCN/H2O containing 0.1% formic acid) to provide (R)-N-(3-(N-(2-aminoethyl)-S-methylsulfonimidoyl)phenyl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide (22.3 mg, 17.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.23 (s, 1H), 8.01-7.91 (m, 1H), 7.66 (d, J=4.9 Hz, 2H), 3.84-3.63 (m, 4H), 3.19 (s, 3H), 3.09-2.69 (m, 4H), 2.47 (s, 3H), 2.36-2.24 (m, 2H), 2.11-1.95 (m, 2H), 1.93-1.80 (m, 2H). 1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 8.41 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.77-7.65 (m, 2H), 3.90-3.72 (m, 4H), 3.24 (s, 3H), 3.22-3.07 (m, 2H), 3.05 (d, J=4.9 Hz, 2H), 2.55 (s, 3H), 2.39-2.27 (m, 2H), 2.09-1.91 (m, 4H). LCMS (ESI) calcd. for C24H28F5N6O2S [M+H]+ m/z 559.19, found 559.00.
Step 1: ethyl 2-bromo-5-fluoro-3-methylisonicotinate: A solution of 2-bromo-5-fluoro-3-methylpyridine (4 g, 21.17 mmol) in THE (30 mL) at −78° C. under an atmosphere of N2 was added dropwise a solution of LDA (19.7 mL). The mixture was stirred at −78° C. for 1 hour. Then a solution of ethyl carbonochloridate (6.87 g, 63.31 mmol) in THE (10 mL) was added dropwise. The reaction mixture was stirred at 25° C. for 2 hours. After the reaction was completed, the reaction was quenched with saturated NH4Cl (80 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over sodium sulfate and evaporated to give a residue, which was purified by flash column chromatography on silica gel (PE/EtAOc=10/1) to give ethyl 2-bromo-5-fluoro-3-methylisonicotinate (1.2 g, 21.9%) as white oil. LCMS (ESI) calcd. for C9H10BrFNO2 [M+H]+ m/z 261.99, found 261.80.
Step 2: ethyl 5-fluoro-3-methyl-2-(trifluoromethyl)isonicotinate: A mixture of ethyl 2-bromo-5-fluoro-3-methylisonicotinate (1.2 g, 4.58 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (4.42 g, 23.01 mmol) and CuI (1.75 g, 9.19 mmol) in DMF (15 mL) was heated to 120° C. and refluxed for 5 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with EtOAc (50 mL) and washed with water (50 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to provide ethyl 5-fluoro-3-methyl-2-(trifluoromethyl)isonicotinate (950 mg, 82.3%) as white oil. LCMS (ESI) calcd. for C10H10F4NO2 [M+H]+ m/z 252.07, found 251.60.
Step 3: ethyl 5-(4,4-difluoroazepan-1-yl)-3-methyl-2-(trifluoromethyl)isonicotinate: A solution of ethyl 5-fluoro-3-methyl-2-(trifluoromethyl)isonicotinate (950 mg, 3.78 mmol), 4,4-difluoroazepane hydrochloride (1.3 g, 7.57 mmol), K2CO3 (3.1 g, 22.46 mmol) and DIEA (2.9 g, 22.44 mmol) in NMP (15 mL) was heated to 120° C. and refluxed for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with EtOAc (50 mL) and washed with water (50 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide ethyl 5-(4,4-difluoroazepan-1-yl)-3-methyl-2-(trifluoromethyl)isonicotinate (500 mg, 36%) as a white solid. LCMS (ESI) calcd. for C16H20F5N2O2 [M+H]+ m/z 367.15, found 366.95.
Step 4: 5-(4,4-difluoroazepan-1-yl)-3-methyl-2-(trifluoromethyl)isonicotinic acid: A solution of ethyl 5-(4,4-difluoroazepan-1-yl)-3-methyl-2-(trifluoromethyl)isonicotinate (450 mg, 1.23 mmol) in THF/H2O/EtOH (1/1/1, 12 mL) was added KOH (689 mg, 12.28 mmol) at room temperature. The reaction mixture was heated to 80° C. and refluxed for 16 hours. After the reaction was completed, the residue was adjusted to pH4-5 with 3M HCl. Then the aqueous solution was extracted with DCM (30 mL×3). The combine organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum to give 5-(4,4-difluoroazepan-1-yl)-3-methyl-2-(trifluoromethyl)isonicotinic acid (400 mg, 98.6%) as a white solid. LCMS (ESI) calcd. for C14H16F5N2O2 [M+H]+ m/z 339.12, found 338.95.
Step 5: tert-butyl (R)-((3-(5-(4,4-difluoroazepan-1-yl)-3-methyl-2-(trifluoromethyl)isonicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 5-(4,4-difluoroazepan-1-yl)-3-methyl-2-(trifluoromethyl)isonicotinic acid (200 mg, 0.59 mmol) in SOCl2 (5 mL) was heated to 80° C. and stirred for 2 hours. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THE (2 mL) was added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (240 mg, 0.89 mmol) and DIEA (382 mg, 2.96 mmol) in THE (3 mL) at 0° C. The resulting mixture was stirred at 25° C. for 16 hours. Then the mixture was quenched with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((3-(5-(4,4-difluoroazepan-1-yl)-3-methyl-2-(trifluoromethyl)isonicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (160 mg, 46% yield) as white oil. LCMS (ESI) calcd. for C26H32F5N4O4S [M+H]+ m/z 591.21, found 591.10.
Step 6: (R)-5-(4,4-difluoroazepan-1-yl)-3-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)isonicotinamide: A solution of tert-butyl (R)-((3-(5-(4,4-difluoroazepan-1-yl)-3-methyl-2-(trifluoromethyl)isonicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (160 mg, 0.27 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.05% NH3) to provide (R)-5-(4,4-difluoroazepan-1-yl)-3-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)isonicotinamide (43.5 mg, 32.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.33 (s, 2H), 7.89 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 4.25 (s, 1H), 3.56-3.44 (m, 4H), 3.06 (s, 3H), 2.33 (s, 3H), 2.21 (s, 2H), 2.11-1.99 (m, 2H), 1.81 (d, J=5.5 Hz, 2H). LCMS (ESI) calcd. for C21H24F5N4O2S [M+H]+ m/z 491.16, found 491.00.
Step 1: (R)-N-(3-(N-(2-chloroacetyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A mixture of (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (200 mg, 0.41 mmol) and TEA (124 mg, 1.22 mmol) in DCM (10 mL) was added 2-chloroacetyl chloride (51 mg, 0.45 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to provide (R)-N-(3-(N-(2-chloroacetyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (150 mg, 64.9%) as a yellow solid. LCMS (ESI) calcd. for C22H24ClF5N5O3S [M+H]+ m/z 568.12, found 568.05.
Step 2: (R)-3-(4,4-difluoroazepan-1-yl)-N-(3-(N-(2-(3,3-difluoroazetidin-1-yl)acetyl)-S-methylsulfonimidoyl)phenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A mixture of (R)-N-(3-(N-(2-chloroacetyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (140 mg, 0.25 mmol), KI (82 mg, 0.50 mmol) and K2CO3 (68 mg, 0.50 mmol) in DMF (5 mL) was added 3,3-difluoroazetidine hydrochloride (64 mg, 0.50 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (15 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 85% MeCN/H2O containing 0.05% NH3) to provide (R)-3-(4,4-difluoroazepan-1-yl)-N-(3-(N-(2-(3,3-difluoroazetidin-1-yl)acetyl)-S-methylsulfonimidoyl)phenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (34.60 mg, 22.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.29 (s, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.76-7.66 (m, 2H), 3.85 (s, 2H), 3.71-3.60 (m, 6H), 3.47 (s, 3H), 3.37 (s, 2H), 2.44-2.31 (m, 5H), 2.12-2.01 (m, 2H), 1.94-1.83 (m, 2H). LCMS (ESI) calcd. for C25H28F7N6O3S [M+H]+ m/z 625.19, found 625.10.
Step 1: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzoic acid: A solution of 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (300 mg, 1.23 mmol), 4,4-difluoroazepane hydrochloride (380 mg, 2.22 mmol), and DIEA (637 mg, 4.93 mmol) in DMSO (6 mL) was heated to 120° C. and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with EtOAc (50 mL) and washed with water (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzoic acid (180 mg, 40.7%) as yellow oil. LCMS (ESI) calcd. for C14H14ClF5NO2 [M+H]+ m/z 358.07, found 358.00.
Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamide: A solution of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzoic acid (180 mg, 0.50 mmol) in SOCl2 (5 mL) was heated to 80° C. and stirred for 0.5 hour. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THE (5 mL) was added to a solution of THE (5 mL) in NH3·H2O (5 mL) at 0° C. The resulting mixture was stirred at 25° C. for 1 hour. Then the mixture was quenched with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamide (84 mg, 46.8%) as yellow oil. LCMS (ESI) calcd. for C14H15ClF5N2O [M+H]+ m/z 357.08, found 357.00.
Step 3: tert-butyl (R)-((4-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamide (84 mg, 0.24 mmol), tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (79 mg, 0.24 mmol), Cs2CO3 (200 mg, 0.61 mmol) and Xantphos-Pd-G2 (42 mg, 0.05 mmol) in 1,4-dioxane (5 mL) was heated to 100° C. and stirred for 2 hours under nitrogen. After the reaction was completed, the mixture was filtered through celite. The filtrate was concentrated and residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((4-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (110 mg, 91.6%) as yellow solid. LCMS (ESI) calcd. for C25H29ClF5N4O4S [M+H]+ m/z 611.15, found 611.10.
Step 4: (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide: A solution of tert-butyl (R)-((4-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (110 mg, 0.18 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.05% NH3) to provide (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (35.60 mg, 38.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 8.38 (s, 1H), 7.82 (d, 1H), 7.72 (s, 1H), 7.34 (s, 1H), 4.33 (s, 1H), 3.44-3.38 (m, 2H), 3.36 (t, J=5.8 Hz, 2H), 3.14 (s, 3H), 2.31-2.15 (m, 2H), 2.12-1.98 (m, 2H), 1.84-1.74 (m, 2H). LCMS (ESI) calcd. for C20H21ClF5N4O2S [M+H]+ m/z 511.10, found 511.00.
Step 1: 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide. A solution of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (400 mg, 1.15 mmol) in SOCl2 (3 mL) was heated to 80° C. and stirred for 2 hours. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THF (2 mL) was added to NH3·H2O (6 mL) at 0° C. The resulting mixture was stirred at 25° C. for 2 hours. Then the mixture was quenched with water (30 mL) and extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (300 mg, 71.5%) as a yellow solid. LCMS (ESI) calcd. for C13H17BrF2N3O [M+H]+ m/z 348.05, found 349.85
Step 2: 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: A solution of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (300 mg, 0.86 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (217 mg, 1.72 mmol), K2CO3 (357 mg, 2.59 mmol) and Pd(dppf)Cl2 (63 mg, 0.09 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated to 100° C. and refluxed for 16 hours under nitrogen. After the reaction was completed, the mixture was cooled to room temperature. The mixture was quenched with water (30 mL) and extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (200 mg, 63.2%) as a white solid. LCMS (ESI) calcd. for C17H22F2N5O [M+H]+ m/z 350.18, found 350.05.
Step 3: tert-butyl (R)-((4-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (200 mg, 0.57 mmol), tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (289 mg, 0.86 mmol), Cs2CO3 (560 mg, 1.72 mmol) and Xantphos-Pd-G2 (51 mg, 0.06 mmol) in 1,4-dioxane (6 mL) was heated to 100° C. and refluxed for 16 hours under nitrogen. After the reaction was completed, the mixture was cooled to room temperature. The mixture was quenched with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((4-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (180 mg, 49.5%) as a white solid. LCMS (ESI) calcd. for C28H36F2N7O4S [M+H]+ m/z 604.25, found 604.15.
Step 4: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)nicotinamide: A solution of tert-butyl (R)-((4-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (180 mg, 0.30 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 70% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)nicotinamide(96.70 mg, 64.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 8.61 (d, J=5.4 Hz, 1H), 8.43 (m, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.82 (m, 1H), 7.61 (s, 1H), 4.38 (s, 1H), 3.88 (s, 3H), 3.62-3.48 (m, 4H), 3.15 (s, 3H), 2.33-2.22 (m, 5H), 2.08-1.96 (m, 2H), 1.80 (m, 2H). LCMS (ESI) calcd. for C23H28F2N7O2S [M+H]+ m/z 504.20, found 504.10.
Step 1: 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide: A solution of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (500 mg, 1.44 mmol) in SOCl2 (5 mL) was heated to 80° C. and refluxed for 2 hours. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THE (2 mL) was added to a solution of NH3·H2O (8 mL) in THE (8 mL) at 0° C. The resulting mixture was stirred at 25° C. for 2 hours. Then the mixture was quenched with water (30 mL) and extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (380 mg, 72.5%) as a yellow solid. LCMS (ESI) calcd. for C13H17BrF2N3O [M+H]+ m/z 348.05, found 347.80.
Step 2: 5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide: A solution of 5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (330 mg, 0.95 mmol) and CuCN (849 mg, 9.48 mmol) in DMA (5 mL) was heated to 150° C. and stirred for 16 hours under nitrogen. After the reaction was completed, the resulting solution was diluted with EtOAc (15 mL) and filtered through celite. The filtrate was washed with water (15 mL×3) and combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (200 mg, 71.7%) as a yellow solid. LCMS (ESI) calcd. for C14H17F2N4O [M+H]+ m/z 295.14, found 294.90.
Step 3: tert-butyl (R)-((4-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (150 mg, 0.51 mmol), tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (257 mg, 0.76 mmol), Cs2CO3 (498 mg, 1.53 mmol) and Xantphos-Pd-G2 (45 mg, 0.05 mmol) in dioxane (5 mL) was heated to 100° C. and refluxed for 4 hours under nitrogen. After the reaction was completed, the mixture was concentrated. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((4-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 71.3%) as a yellow solid. LCMS (ESI) calcd. for C25H31F2N6O4S [M+H]+ m/z 549.21, found 549.10.
Step 4: (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)nicotinamide: A solution of tert-butyl (R)-((4-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (180 mg, 0.33 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 70% MeCN/H2O containing 0.05% NH3) to provide (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)nicotinamide (73.36 mg, 50%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.63 (d, J=5.4 Hz, 1H), 8.58 (s, 1H), 8.37 (d, J=1.7 Hz, 1H), 7.82 (dd, J=5.4, 1.9 Hz, 1H), 4.40 (s, 1H), 3.72 (s, 2H), 3.57 (t, J=5.6 Hz, 2H), 3.15 (s, 3H), 2.37 (s, 3H), 2.34-2.23 (m, 2H), 2.08-1.94 (m, 2H), 1.89-1.77 (m, 2H). LCMS (ESI) calcd. for C20H23F2N6O2S [M+H]+ m/z 449.16, found 449.05.
Step 1: (R)-N-(3-(N-(2-chloroacetyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (110 mg, 0.22 mmol) and Et3N (68 mg, 0.67 mmol) in DCM (5 mL) was added 2-chloroacetyl chloride (76 mg, 0.67 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to provide (R)-N-(3-(N-(2-chloroacetyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (100 mg, 77.8%) as a yellow solid. LCMS (ESI) calcd. for C23H25ClF5N4O3S [M+H]+ m/z 567.13, found 567.1.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-(2-(3,3-difluoroazetidin-1-yl)acetyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide: A mixture of (R)-N-(3-(N-(2-chloroacetyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (90 mg, 0.16 mmol), KI (53 mg, 0.32 mmol) and K2CO3 (44 mg, 0.32 mmol) in DMF (5 mL) was added 3,3-difluoroazetidine hydrochloride (41 mg, 0.32 mmol) at room temperature. The reaction mixture was heated to 40° C. and stirred for 16 hours. After the reaction was completed, the resulting solution was diluted with water (15 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 80% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-(2-(3,3-difluoroazetidin-1-yl)acetyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(trifluoromethyl)nicotinamide (61.20 mg, 61.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 7.96 (dt, J=6.8, 2.1 Hz, 1H), 7.73-7.63 (m, 2H), 3.75-3.60 (m, 8H), 3.46 (s, 3H), 3.36 (s, 2H), 2.35-2.23 (m, 5H), 2.08-1.96 (m, 2H), 1.88-1.78 (m, 2H). LCMS (ESI) calcd. for C26H29F7N5O3S [M+H]+ m/z 624.19, found 624.1.
Step 1: tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A solution of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (300 mg, 0.60 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (226 mg, 1.19 mmol), HATU (340 mg, 0.90 mmol) and DIEA (231 mg, 1.79 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (220 mg, 54.7%) as a yellow solid. LCMS (ESI) calcd. for C32H42F2N7O5S [M+H]+ m/z 674.30, found 674.20.
Step 2: tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)(methyl)carbamate: A solution of tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (180 mg, 0.27 mmol) in THE (5 mL) was added BH3-THF (1 mL) at 0° C. The reaction mixture was stirred at 0° C. for 4 hours. LCMS showed the reaction was completed. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)(methyl)carbamate (50 mg, 28.4%) as a yellow solid. LCMS (ESI) calcd. for C32H44F2N7O4S [M+H]+ m/z 660.32, found 660.20.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methyl-N-(2-(methylamino)ethyl)sulfonimidoyl)phenyl)nicotinamide: A mixture of tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)(methyl)carbamate (50 mg, 0.08 mmol) in DCM (4 mL) was added TFA (0.8 mL) at room temperature. The reaction mixture was stirred at 25° C. for 2 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 80% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methyl-N-(2-(methylamino)ethyl)sulfonimidoyl)phenyl)nicotinamide (3.20 mg, 7.52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.30 (s, 1H), 8.18 (s, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.64-7.56 (m, 3H), 3.89 (s, 3H), 3.60-3.52 (m, 4H), 3.13 (s, 3H), 2.90-2.73 (m, 2H), 2.55-2.50 (m, 2H), 2.32-2.20 (m, 8H), 2.04-1.94 (m, 2H), 1.82-1.75 (m, 2H). LCMS (ESI) calcd. for C27H36F2N7O2S [M+H]+ m/z 560.26, found 560.2.
Step 1: 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide: A solution of 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (800 mg, 2.63 mmol) in SOCl2 (5 mL) was heated to 80° C. and stirred for 2 hours. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THF (2 mL) was added to NH3·H2O (6 mL) at 0° C. The resulting mixture was stirred at 25° C. for 2 hours. Then the mixture was quenched with water (30 mL) and extracted with DCM (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (500 mg, 62.1%) as a yellow solid. LCMS (ESI) calcd. for C13H17ClF2N3O [M+H]+ m/z 304.10, found 303.9
Step 2: 6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide: A solution of 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (500 mg, 1.65 mmol) and CuCN (1.47 g, 16.46 mmol) in DMA (20 mL) was heated to 150° C. and stirred for 16 hours under nitrogen. After the reaction was completed, the mixture was cooled to room temperature. The mixture was quenched with water (60 mL) and extracted with DCM (60 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (110 mg, 22.5%) as a white solid. LCMS (ESI) calcd. for C14H17F2N4O [M+H]+ m/z 295.14, found 295.1.
Step 3: tert-butyl (R)-((4-(6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (100 mg, 0.34 mmol), tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (229 mg, 0.68 mmol), Cs2CO3 (221 mg, 0.68 mmol) and Xantphos-Pd-G2 (30 mg, 0.03 mmol) in 1,4-dioxane (5 mL) was heated to 100° C. and refluxed for 16 hours under nitrogen. After the reaction was completed, the mixture was cooled to room temperature. The mixture was quenched with water (15 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((4-(6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 53.5%) as a white solid. LCMS (ESI) calcd. for C25H31F2N6O4S [M+H]+ m/z 549.21, found 549.2.
Step 4: (R)-6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)nicotinamide. A solution of tert-butyl (R)-((4-(6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.18 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 70% MeCN/H2O containing 0.05% NH3) to provide (R)-6-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)nicotinamide (70.40 mg, 83.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.62 (d, J=5.4 Hz, 1H), 8.36 (s, 1H), 7.81 (d, J=3.8 Hz, 1H), 7.31 (s, 1H), 4.29 (s, 1 H), 3.66-3.48 (m, 4H), 3.15 (s, 3H), 2.34-2.20 (m, 5H), 2.07-1.94 (m, 2H), 1.86-1.77 (m, 2H). LCMS (ESI) calcd. for C20H23F2N6O2S [M+H]+ m/z 449.16, found 449.1.
Step 1: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide: A solution of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzoic acid (400 mg, 1.12 mmol), 4-fluoro-3-(methylthio)aniline (176 mg, 1.12 mmol) in pyridine (5 mL) was added POCl3 (257 mg, 1.68 mmol) at 0° C. The reaction solution was stirred at room temperature for 2 hours. Then the mixture was quenched with water (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=5/1) to provide 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (220 mg, 39.59%) as a yellow oil. LCMS (ESI) calcd. for C21H20ClF6N2OS [M+H]+ m/z 497.09, found 497.0.
Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylsulfinyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-(trifluoromethyl)benzamide (400 mg, 0.81 mmol) in DCM (10 mL) was added m-CPBA (194 mg, 1.13 mmol) at 0° C. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=4/1) to give 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylsulfinyl)phenyl)-4-(trifluoromethyl)benzamide (200 mg, 50.0%) as a white solid. LCMS (ESI) calcd. for C21H20ClF6N2O2S [M+H]− m/z 513.09, found 513.1.
Step 3: (S)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylsulfinyl)phenyl)-4-(trifluoromethyl)benzamide & (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylsulfinyl)phenyl)-4-(trifluoromethyl)benzamide: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylsulfinyl)phenyl)-4-(trifluoromethyl)benzamide was further purified by Chiral-Prep-SFC ((R,R)-Whelk-01, 20 mm I.D.*250 mm L, 5 m, eluting with 30% MeOH/CO2 containing 0.1% NH3) to give (S)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylsulfinyl)phenyl)-4-(trifluoromethyl)benzamide (45.0 mg) as the first elution. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.14 (dd, J=6.1, 2.7 Hz, 1H), 7.92-7.84 (m, 1H), 7.71 (s, 1H), 7.40 (t, J=9.1 Hz, 1H), 7.34 (s, 1H), 3.46-3.34 (m, 4H), 2.83 (s, 3H), 2.23 (d, J=6.5 Hz, 2H), 2.13-1.99 (m, 2H), 1.81 (d, J=5.3 Hz, 2H). LCMS (ESI) calcd. for C21H20ClF6N2O2S [M+H]+ m/z 513.08, found 513.1 and (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylsulfinyl)phenyl)-4-(trifluoromethyl)benzamide (42.0 mg) as the second elution. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.14 (dd, J=6.0, 2.5 Hz, 1H), 7.92-7.84 (m, 1H), 7.71 (s, 1H), 7.40 (t, J=9.1 Hz, 1H), 7.34 (s, 1H), 3.47-3.34 (m, 4H), 2.83 (s, 3H), 2.22 (dd, J=8.5, 5.5 Hz, 2H), 2.13-1.99 (m, 2H), 1.81 (d, J=5.2 Hz, 2H). LCMS (ESI) calcd. for C21H20ClF6N2O2S [M+H]+ m/z 513.08, found 513.1.
Step 1: ethyl 2-bromo-3-chloro-5-fluoroisonicotinate. To a solution of 2-bromo-3-chloro-5-fluoropyridine (7 g, 0.033 mol) in THF (50 mL) was added LDA (3.88 g, 0.036 mmol) dropwise at −78° C. under N2 atmosphere. The solution was stirred at the same temperature for 1 hour. Then to the solution was added ethyl carbonochloridate (5.35 g, 0.050 mol) at −78. The resulting solution was slowly warmed to room temperature and stirred for 2 hours. The final mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (50 mL×3). Then the combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give ethyl 2-bromo-3-chloro-5-fluoroisonicotinate (5 g, 53.94%) as a yellow oil. LCMS (ESI) calcd. for ClH7BrClFNO2 [M+H]t m/z 281.93, found 281.90.
Step 2: ethyl 2-bromo-3-chloro-5-(4,4-difluoroazepan-1-yl)isonicotinate: A solution of ethyl 2-bromo-3-chloro-5-fluoroisonicotinate (5 g, 0.018 mol) and DIEA (6.85 g, 0.53 mol) in DMSO (20 ml) was added 4,4-difluoroazepane hydrochloride (6.07 g, 0.035 mol). Then the mixture was heated at 100° C. for 10 hours. After the reaction was completed, the resulting solution was diluted with water (60 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give ethyl 2-bromo-3-chloro-5-(4,4-difluoroazepan-1-yl)isonicotinate (1.2 g, 16.8%) as a yellow solid. LCMS (ESI) calcd. for C14H17BrClF2N2O2 [M+H]+ m/z 399.01, found 398.80.
Step 3: ethyl 3-chloro-5-(4,4-difluoroazepan-1-yl)-2-(trifluoromethyl)isonicotinate: A solution of ethyl 2-bromo-3-chloro-5-(4,4-difluoroazepan-1-yl)isonicotinate (1.2 g, 0.003 mol) and CuI (1.15 g, 0.006 mol) in DMF (10 ml) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.90 g, 0.015 mol) at 100° C. and stirred for 10 hours under N2. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give ethyl 3-chloro-5-(4,4-difluoroazepan-1-yl)-2-(trifluoromethyl)isonicotinate (0.9 g, 77.6%) as a yellow solid. LCMS (ESI) calcd. for C15H17ClF5N2O2 [M+H]+ m/z 387.09, found 387.00.
Step 4: 3-chloro-5-(4,4-difluoroazepan-1-yl)-2-(trifluoromethyl)isonicotinic acid: A solution of ethyl 3-chloro-5-(4,4-difluoroazepan-1-yl)-2-(trifluoromethyl)isonicotinate (900 mg, 2.33 mmol) in THF/H2O/EtOH=1:1:1 (9 ml) was added KOH (1301 mg, 23.30 mmol). The mixture was heated at 70° C. for 16 hours. After the reaction was completed, the organic solvent was removed under reduced pressure. The aqueous solution was adjusted to pH 2-3 with 2N HCl (10 mL). Then the solution was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=10/1) to give 3-chloro-5-(4,4-difluoroazepan-1-yl)-2-(trifluoromethyl)isonicotinic acid (410 mg, 49.2%) as a yellow solid. LCMS (ESI) calcd. for C13H13ClF5N2O2 [M+H]+ m/z 359.06, found 358.70.
Step 5: 3-chloro-5-(4,4-difluoroazepan-1-yl)-2-(trifluoromethyl)isonicotinamide: A solution of 3-chloro-5-(4,4-difluoroazepan-1-yl)-2-(trifluoromethyl)isonicotinic acid (410 mg, 1.15 mmol), HATU (869 mg, 2.29 mmol) and DIEA (739 mg, 5.72 mmol) in DMF (5 ml) was added NH3-MeOH (7M, 1 mL) at 25° C. The mixture was stirred at the same temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 3-chloro-5-(4,4-difluoroazepan-1-yl)-2-(trifluoromethyl)isonicotinamide (200 mg, 44.0%) as a yellow solid. LCMS (ESI) calcd. for C13H14ClF5N3O [M+H]+ m/z 358.07, found 357.90.
Step 6: 3-chloro-5-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfinyl)phenyl)-2-(trifluoromethyl)isonicotinamide: A mixture of 3-chloro-5-(4,4-difluoroazepan-1-yl)-2-(trifluoromethyl)isonicotinamide (200 mg, 0.56 mmol), Cs2CO3 (547 mg, 1.68 mmol) and Xantohos-Pd-G2 (99 mg, 0.11 mmol) in 1,4-dioxane (5 mL) was added 1-bromo-3-(methylsulfinyl)benzene (306 mg, 1.40 mmol). The mixture was heated at 100° C. for 16 hours under N2. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/5 to 1/1) to give 3-chloro-5-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfinyl)phenyl)-2-(trifluoromethyl)isonicotinamide (130 mg, 42.2%) as a yellow solid. LCMS (ESI) calcd. for C20H20ClF5N3O2S [M+H]+ m/z 496.09, found 495.80.
Step 7: 3-chloro-5-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)isonicotinamide: A solution of 3-chloro-5-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfinyl)phenyl)-2-(trifluoromethyl)isonicotinamide (130 mg, 0.26 mmol), PhI(OAc)2 (211 mg, 0.66 mmol) in MeOH (3 ml) was added ammonium carbamate (61 mg, 0.79 mmol). Then the solution was heated at 70° C. for 16 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. Then the residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H2O containing 0.05% NH3-H2O) to obtain 3-chloro-5-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)isonicotinamide (44 mg, 32.8%) as a white solid. LCMS (ESI) calcd. for C20H21ClF5N4O2S [M+H]+ m/z 511.10, found 511.00.
Step 8: (S)-3-chloro-5-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)isonicotinamide and (R)-3-chloro-5-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)isonicotinamide: 3-chloro-5-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)isonicotinamide was further purified by Chiral-Prep-SFC (DAICEL 1H, 20 mm I.D.*250 mm L, 5 m, eluting with 30% MeOH/CO2 containing 0.1% NH3) to provide (S)-3-chloro-5-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)isonicotinamide (15.2 mg) as the first elution. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 4.26 (s, 1H), 3.68-3.54 (m, 4H), 3.07 (s, 3H), 2.32-2.20 (m, 2H), 2.15-2.00 (m, 2H), 1.90-1.80 (m, 2H). LCMS (ESI) calcd. for C20H21ClF5N4O2S [M+H]+ m/z 511.10, found 511.00 and (R)-3-chloro-5-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(trifluoromethyl)isonicotinamide (19.4 mg) as the second elution. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 4.26 (s, 1H), 3.66-3.52 (m, 4H), 3.07 (s, 3H), 2.33-2.20 (m, 2H), 2.15-2.00 (m, 2H), 1.90-1.80 (m, 2H). LCMS (ESI) calcd. for C20H21ClF5N4O2S [M+H]+ m/z 511.10, found 511.00.
A solution of tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)carbamate (60 mg, 0.09 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 70% ACN/H2O containing 0.1% TFA) to provide (R)-N-(3-(N-(2-aminoethyl)-S-methylsulfonimidoyl)phenyl)-5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide 2,2,2-trifluoroacetate (31.2 mg, 61.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.32 (s, 2H), 7.92-7.85 (m, 1H), 7.80-7.68 (m, 3H), 7.67-7.62 (m, 2H), 3.66-3.48 (m, 4H), 3.21 (s, 3H), 3.08-2.83 (m, 4H), 2.35-2.17 (m, 5H), 2.09-1.91 (m, 2H), 1.86-1.72 (m, 2H). LCMS (ESI) calcd. for C22H29BrF2N5O2S [M+H]+ m/z 544.12, found 546.1.
Step 1: tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate. A solution of (R)-5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (400 mg, 0.80 mmol), (tert-butoxycarbonyl)glycine (280 mg, 1.60 mmol), HATU (455 mg, 1.20 mmol) and DIEA (309 mg, 2.39 mmol) in DMF (8 mL) was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (450 mg, 85.5%) as a yellow solid. LCMS (ESI) calcd. for C27H35BrF2N5O5S [M+H]+ m/z 658.15, found 660.0.
Step 2: tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)carbamate: A solution of tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)carbamate (450 mg, 0.68 mmol) in THE (6 mL) was added BH3-THF (1.2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. LCMS showed the reaction was completed. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-16-sulfaneylidene)amino)ethyl)carbamate (340 mg, 77.2%) as a yellow solid. LCMS (ESI) calcd. for C27H37BrF2N5O4S [M+H]+ m/z 644.17, found 644.1.
Step 3: tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)carbamate: A solution of tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)carbamate (250 mg, 0.39 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (98 mg, 0.78 mmol), K2CO3 (161 mg, 1.16 mmol) and Pd(dppf)Cl2-DCM (32 mg, 0.04 mmol) in MeCN (6 mL) was heated to 80° C. and refluxed for 16 hours. After the reaction was completed, the mixture was concentrated. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)carbamate (200 mg, 79.8%) as a yellow solid. LCMS (ESI) calcd. for C31H42F2N7O4S [M+H]+ m/z 646.30, found 646.2.
Step 4: (R)-N-(3-(N-(2-aminoethyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide 2,2,2-trifluoroacetate: A solution of tert-butyl (R)-(2-(((3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)carbamate (200 mg, 0.31 mmol) in DCM (6 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 20% to 60% ACN/H2O containing 0.1% TFA) to provide (R)-N-(3-(N-(2-aminoethyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide 2,2,2-trifluoroacetate (115.60 mg, 68.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.36 (s, 1H), 8.18 (s, 1H), 7.93-7.87 (m, 2H), 7.78-7.66 (m, 3H), 7.65-7.60 (m, 3H), 3.89 (s, 3H), 3.64-3.50 (m, 4H), 3.21 (s, 3H), 3.10-2.82 (m, 4H), 2.33-2.21 (m, 5H), 2.08-1.95 (m, 2H), 1.85-1.74 (m, 2H). LCMS (ESI) calcd. for C26H34F2N7O2S [M+H]+ m/z 546.25, found 546.2.
Step 1: tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A solution of (R)-5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (400 mg, 0.80 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (302 mg, 1.60 mmol), HATU (455 mg, 1.20 mmol) and DIEA (309 mg, 2.39 mmol) in DMF (8 mL) was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (460 mg, 85.6%) as a yellow solid. LCMS (ESI) calcd. for C28H37BrF2N5O5S [M+H]+ m/z 672.17, found 672.00.
Step 2: tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)(methyl)carbamate: A solution of tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (460 mg, 0.68 mmol) in THE (6 mL) was added BH3 in Dimethyl sulfide (1.2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 6 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)(methyl)carbamate (300 mg, 66.6%) as a yellow solid. LCMS (ESI) calcd. for C28H39BrF2N5O4S [M+H]+ m/z 658.19, found 660.1.
Step 3: provide (R)-5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(2-(methylamino)ethyl)sulfonimidoyl)phenyl)nicotinamide 2,2,2-trifluoroacetate: A solution of tert-butyl (R)-(2-(((3-(5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)ethyl)(methyl)carbamate (60 mg, 0.09 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 70% ACN/H2O containing 0.1% TFA) to provide (R)-5-bromo-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methyl-N-(2-(methylamino)ethyl)sulfonimidoyl)phenyl)nicotinamide 2,2,2-trifluoroacetate (31.5 mg, 61.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.33 (d, J=4.8 Hz, 4H), 7.88 (dt, J=6.9, 2.2 Hz, 1H), 7.69-7.62 (m, 2H), 3.67-3.45 (m, 4H), 3.22 (s, 3H), 3.13-2.89 (m, 4H), 2.58 (t, J=5.5 Hz, 3H), 2.34-2.19 (m, 5H), 2.05-1.92 (m, 2H), 1.84-1.73 (m, 2H). LCMS (ESI) calcd. for C23H31BrF2N5O2S [M+H]+ m/z 558.13, found 560.10.
Step 1: 5,6-dichloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide: A solution of 5,6-dichloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (300 mg, 0.88 mmol) in SOCl2 (5 mL) was heated to 80° C. and stirred for 2 hours. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate was added to a stirred solution of NH3·H2O (5 mL) in THE (8 mL) at 0° C. The resulting mixture was stirred at 25° C. for 0.5 hour. Then the mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide 5,6-dichloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (260 mg, 86.96%) as a yellow solid. LCMS (ESI) calcd. for C13H16C12F2N3O [M+H]+ m/z 338.07, found 338.0.
Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide: A solution of 5,6-dichloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinamide (260 mg, 0.77 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (194 mg, 1.54 mmol), Cs2CO3 (751 mg, 2.31 mmol) and Pd(dppf)Cl2 (113 mg, 0.15 mmol) in 1,4-dioxane (10 mL) and H2O (2.5 mL) was heated to 100° C. and refluxed for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide (170 mg, 57.63%) as a yellow solid. LCMS (ESI) calcd. for C17H21ClF2N5O [M+H]+ m/z 384.14, found 384.0.
Step 3: tert-butyl (R)-((4-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide (170 mg, 0.44 mmol), tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (164 mg, 0.49 mmol), Cs2CO3 (433 mg, 1.33 mmol) and Xantphos-Pd-G2 (79 mg, 0.09 mmol) in 1,4-dioxane (8 mL) was heated to 100° C. and refluxed for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((4-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 70.92%) as yellow oil. LCMS (ESI) calcd. for C28H35ClF2N7O4S [M+H]+ m/z 638.21, found 638.2.
Step 4: (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)nicotinamide: A solution of tert-butyl (R)-((4-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.31 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 20% to 95% MeCN/H2O containing 0.05% NH3·H2O) to provide (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)nicotinamide (126.50 mg, 75.03%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 8.62 (d, J=5.4 Hz, 1H), 8.46 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.11 (s, 1H), 7.82 (dd, J=5.4, 2.0 Hz, 1H), 4.38 (s, 1H), 3.93 (s, 3H), 3.70-3.62 (m, 2H), 3.52 (t, J=6.0 Hz, 2H), 3.15 (s, 3H), 2.32 (s, 5H), 2.06-1.94 (m, 2H), 1.86-1.76 (m, 2H). LCMS (ESI) calcd. for C23H27ClF2N7O2S [M+H]+ m/z 538.16, found 538.1.
Step 1: 5-bromo-2-chloro-N-(4-fluoro-3-(methylthio)phenyl)-4-methylnicotinamide: A solution of 5-bromo-2-chloro-4-methylnicotinic acid (500 mg, 2.0 mmol) in SOCl2 (6 mL) was heated to 80° C. for 1 hour. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THF (5 mL) was added to a solution of 4-fluoro-3-(methylthio)aniline (313.8 mg, 2.0 mmol) and DIEA (1.3 g, 10.0 mmol) in THF (5 mL) at 0° C. The resulting mixture was stirred at 25° C. for 2 hours. Then the mixture was quenched with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 5-bromo-2-chloro-N-(4-fluoro-3-(methylthio)phenyl)-4-methylnicotinamide (500 mg, 64.4%) as a white solid. LCMS (ESI) calcd. for C14H12BrClFN2OS [M+H]+ m/z 388.95, found 390.8.
Step 2: 5-bromo-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-methylnicotinamide: A solution of 5-bromo-2-chloro-N-(4-fluoro-3-(methylthio)phenyl)-4-methylnicotinamide (500 mg, 1.28 mmol), 4,4-difluoroazepane hydrochloride (330 mg, 1.92 mmol), K2CO3 (532 mg, 3.85 mmol) and DIEA (497.5 mg, 3.85 mmol) in NMP (8 mL) was heated to 140° C. and refluxed for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with EtOAc (30 mL) and washed with water (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/2) to provide 5-bromo-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-methylnicotinamide (260 mg, 41.7%) as a white solid. LCMS (ESI) calcd. for C20H22BrF3N3OS [M+H]+ m/z 490.06, found 490.0.
Step 3: 2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: A solution of 5-bromo-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-methylnicotinamide (260 mg, 0.53 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (134.1 mg, 1.06 mmol), K2CO3 (220.7 mg, 1.6 mmol) and Pd(dppf)Cl2 (39 mg, 0.05 mmol) in 1,4-dioxane/H2O (4/1, 10 mL) was heated to 100° C. and stirred for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combine organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1 to 1/3) to give 2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (200 mg, 77.1%) as a yellow solid. LCMS (ESI) calcd. for C24H27F3N5OS [M+H]+ m/z 490.19, found 490.1.
Step 4: 2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: A solution of 2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(methylthio)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (200 mg, 0.41 mmol), PhI(OAc)2 (394.7 mg, 1.2 mmol), and AcONH4 (63 mg, 0.82 mmol) in EtOH (6 mL) was heated to 50° C. and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combine organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 25% to 80% MeCN/H2O containing 0.05% NH3) give 2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (80 mg, 37.7%) as a white solid. LCMS (ESI) calcd. for C24H28F3N6O2S [M+H]+ m/z 521.19, found 521.1.
Step 5: (S)-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide and (R)-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: 2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide was further purified by Chiral-Prep-SFC (DAICEL OJ-H, 20 mm I.D.*250 mm L, 5 m, eluting with 75/25 CO02/MeOH containing 0.1% NH3) to give and (S)-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (35.3 mg) as the first elution. 1H NMR (400 MHz, DMSO-d6) 10.85 (s, 1H), 8.31 (dd, J=6.5, 2.7 Hz, 1H), 8.17 (s, 1H), 7.98-7.91 (m, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 7.44 (t, J=9.3 Hz, 1H), 4.70 (s, 1H), 3.88 (s, 3H), 3.63-3.52 (m, 4H), 3.19 (s, 3H), 2.32-2.20 (m, 5H), 2.07-1.94 (m, 2H), 1.84-1.74 (m, 2H). LCMS (ESI) calcd. for C24H28F3N6O2S [M+H]+ m/z 521.19, found 521.1 and (R)-2-(4,4-difluoroazepan-1-yl)-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (30.1 mg) as the second elution. 1H NMR (400 MHz, DMSO-d6) 10.85 (s, 1H), 8.32 (d, J=6.4 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 7.98-7.91 (m, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 7.44 (t, J=9.3 Hz, 1H), 4.71 (s, 1H), 3.89 (d, J=2.1 Hz, 3H), 3.65-3.51 (m, 4H), 3.20 (s, 3H), 2.35-2.18 (m, 5H), 2.06-1.93 (m, 2H), 1.85-1.74 (m, 2H). LCMS (ESI) calcd. for C24H28F3N6O2S [M+H]+ m/z 521.19, found 521.2.
Step 1: tert-butyl (R)-((3-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (600 mg, 2.47 mmol) in SOCl2 (6 mL) was heated to 80° C. and stirred for 0.5 hour. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate in THE (2 mL) was added to a stirred solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (738 mg, 2.72 mmol) and DIEA (1.59 g, 12.37 mmol) in THE (10 mL) at 0° C. The resulting mixture was stirred at 25° C. for 1 hour. Then the mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/2) to provide tert-butyl (R)-((3-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (550 mg, 44.89%) as a white solid. LCMS (ESI) calcd. for C20H19ClF4N2O4SNa [M+Na]m/z 517.06, found 516.8.
Step 2: tert-butyl ((R)-(3-(5-chloro-4-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.30 mmol) and (S)-2-(trifluoromethyl)morpholine (116 mg, 0.61 mmol) in DMSO (2 mL) was added DIEA (391 mg, 3.02 mmol) at room temperature. The reaction mixture was heated to 100° C. and stirred for 24 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((R)-(3-(5-chloro-4-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 41.9%) as a yellow solid. LCMS (ESI) calcd. for C25H27ClF6N3O5S [M+H]+ m/z 630.13, found 630.1.
Step 3: 5-chloro-N-(3-((R)—S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)benzamide: A solution of tert-butyl ((R)-(3-(5-chloro-4-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (80 mg, 0.13 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 80% MeCN/H2O containing 0.05% NH3) to provide 5-chloro-N-(3-((R)—S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)benzamide (23.4 mg, 34.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.39 (s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.85 (s, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.65-7.57 (m, 2H), 4.24 (s, 1H), 4.20-4.11 (m, 1H), 4.06-3.96 (m, 1H), 3.64-3.53 (m, 1H), 3.48-3.41 (m, 1H), 3.23-3.08 (m, 3H), 3.06 (s, 3H). LCMS (ESI) calcd. for C20H19ClF6N3O3S [M+H]+ m/z 530.07, found 530.0.
Step 1: tert-butyl ((R)-(3-(5-chloro-4-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.30 mmol) and (R)-2-(trifluoromethyl)morpholine (124 mg, 0.80 mmol) in DMSO (2 mL) was added DIEA (547 mg, 4.24 mmol) at room temperature. The reaction mixture was heated to 100° C. and stirred for 24 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((R)-(3-(5-chloro-4-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 37.1%) as a yellow solid. LCMS (ESI) calcd. for C25H27ClF6N3O5S [M+H]+ m/z 630.13, found 630.0.
Step 2: 5-chloro-N-(3-((R)—S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)benzamide: A solution of tert-butyl ((R)-(3-(5-chloro-4-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 0.11 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 80% MeCN/H2O containing 0.05% NH3) to provide 5-chloro-N-(3-((R)—S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)benzamide (26.2 mg, 44.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.39 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.66-7.57 (m, 2H), 4.24 (s, 1H), 4.21-4.13 (m, 1H), 4.13-3.95 (m, 1H), 3.69-3.49 (m, 1H), 3.49-3.38 (m, 1H), 3.20-3.03 (m, 6H). LCMS (ESI) calcd. for C20H19ClF6N3O3S [M+H]+ m/z 530.07, found 530.0.
Step 1: 5-chloro-2-fluoro-4-(trifluoromethyl)benzamide: A solution of 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (500 mg, 2.07 mmol) in DCM (10 mL) was added DMF (2 drops) and oxalyl chloride (0.7 mL) at room temperature. After addition, the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated. The residue was dissolved in THF (10 mL) and added dropwise to a stirred solution of ammonium hydroxide (5 mL). Then the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combine organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1 to 1/2) to give 5-chloro-2-fluoro-4-(trifluoromethyl)benzamide (450 mg, 90.36%) as a white solid.
Step 2: tert-butyl (R)-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 5-chloro-2-fluoro-4-(trifluoromethyl)benzamide (450 mg, 1.86 mmol) in 1,4-dioxane (10 mL) was added tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (745 mg, 2.23 mmol), Cs2CO3 (1.8 g, 5.58 mmol) and Xantphos-Pd-G2 (165 mg, 0.18 mol) at room temperature under nitrogen. Then the reaction mixture was heated to 100° C. and stirred for 16 hours under nitrogen. The reaction was monitored by LCMS. After the reaction was completed, the filtrate was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combine organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (500 mg, 54.23%) as a yellow solid. LCMS (ESI) calcd. for C19H19ClF4N3O4S [M+H]+ m/z 496.07, found 495.9.
Step 3: tert-butyl ((R)-(4-(5-chloro-4-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.30 mmol) and (R)-2-(trifluoromethyl)morpholine (116 mg, 0.61 mmol) in DMSO (2 mL) was added DIEA (391 mg, 3.02 mmol) at room temperature. Then the reaction mixture was heated to 100° C. and stirred for 24 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1 to 1/2) to give tert-butyl ((R)-(4-(5-chloro-4-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (70 mg, 36.6%) as a yellow solid. LCMS (ESI) calcd. for C24H26ClF6N4O5S [M+H]+ m/z 631.12, found 631.1.
Step 4: 5-chloro-N-(2-((R)—S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)benzamide: A solution of tert-butyl ((R)-(4-(5-chloro-4-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (70 mg, 0.11 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 80% MeCN/H2O containing 0.05% NH3) to provide 5-chloro-N-(2-((R)—S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)benzamide (17.8 mg, 30.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.62 (d, J=5.3 Hz, 1H), 8.43 (s, 1H), 7.91-7.76 (m, 2H), 7.61 (s, 1H), 4.37 (s, 1H), 4.23-4.12 (m, 1H), 4.03-3.95 (m, 1H), 3.60-3.50 (m, 1H), 3.46-3.40 (m, 1H), 3.15 (s, 3H), 3.14-2.99 (m, 3H). LCMS (ESI) calcd. for C19H18ClF6N4O3S [M+H]+ m/z 531.07, found 531.1.
Step 1: tert-butyl ((R)-(4-(5-chloro-4-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((4-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.30 mmol) and (S)-2-(trifluoromethyl)morpholine hydrochloride (116 mg, 0.61 mmol) in DMSO (2 mL) was added DIEA (391 mg, 3.02 mmol) at room temperature. The reaction mixture was heated to 100° C. and stirred for 24 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give tert-butyl ((R)-(4-(5-chloro-4-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 36.6%) as a yellow solid. LCMS (ESI) calcd. for C24H26ClF6N4O5S [M+H]+ m/z 631.12, found 631.1.
Step 2: 5-chloro-N-(2-((R)—S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)benzamide. A solution of tert-butyl ((R)-(4-(5-chloro-4-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (70 mg, 0.11 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 60% to 90% MeCN/H2O containing 0.05% NH3·H2O) to provide 5-chloro-N-(2-((R)—S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)benzamide (12.5 mg, 21.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.64 (d, J=5.4 Hz, 1H), 8.45 (s, 1H), 7.96-7.75 (m, 2H), 7.62 (s, 1H), 4.38 (s, 1H), 4.25-4.11 (m, 1H), 4.05-3.93 (m, 1H), 3.62-3.51 (m, 1H), 3.47-3.38 (m, 1H), 3.15 (s, 3H), 3.14-2.98 (m, 3H). LCMS (ESI) calcd. for C19H18ClF6N4O3S [M+H]+ m/z 531.07, found 531.0.
Step 1: tert-butyl (R)-((3-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of tert-butyl (R)-((3-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.30 mmol), 4-(trifluoromethyl)piperidine (46 mg, 0.30 mmol) and DIEA (157 mg, 1.21 mmol) in DMSO (10 mL) was heated to 100° C. and stirred for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to provide tert-butyl (R)-((3-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)phenyl)(methyl)(oxo)-λ6-)carbamate (100 mg, 52.52%) as yellow oil. LCMS (ESI) calcd. for C26H29ClF6N3O4S [M+H]+ m/z 628.15, found 628.1.
Step 2: (R)-5-chloro-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide: A solution of tert-butyl (R)-((3-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.16 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated and the residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL*3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 60% MeCN/H2O containing 0.05% NH3) to provide (R)-5-chloro-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide (39.6 mg, 51.30%). 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.42 (s, 1H), 7.89-7.82 (m, 2H), 7.70-7.58 (m, 2H), 7.47 (s, 1H), 4.21 (s, 1H), 3.42-3.32 (m, 2H), 3.04 (s, 3H), 2.93-2.84 (m, 2H), 2.46-2.35 (m, 1H), 1.89-1.81 (m, 2H), 1.61-1.43 (m, 2H). LCMS (ESI) calcd. for C21H21ClF6N3O2S [M+H]+ m/z 528.09, found 528.0.
Step 1: 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid: A mixture of 2,6-dichloro-4-methylnicotinic acid (1 g, 4.88 mmol) and 4,4-difluoroazepane (790 mg, 5.86 mmol) in NMP (20 mL) was added DIEA (3.15 g, 24.4 mmol) at room temperature. The mixture was heated to 140° C. and stirred for 6 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was cooled and diluted with water (40 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=20/1 to 10/1) to give 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (1 g, 67.1%) as a yellow solid. LCMS (ESI) calcd. C13H16ClF2N2O2 for [M+H]+ m/z 305.09, found 305.1.
Step 2: methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinate: A solution of 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinic acid (1 g, 3.29 mmol) in DMF (20 mL) was added K2CO3 (1.36 g, 9.87 mmol) and CH3I (701 mg, 4.94 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (40 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1 to 5/1) to give methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinate (800 mg, 76.5%) as yellow oil. LCMS (ESI) calcd. for C14H18ClF2N2O2 [M+H]+ m/z 319.10, found 318.7.
Step 3: methyl 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinate: A solution of methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinate (800 mg, 2.52 mmol), cyclopropylboronic acid (650 mg, 7.56 mmol), K2CO3 (1.39 g, 10.1 mmol) and Pd(dppf)Cl2 (368 mg, 0.50 mmol) in 1,4-dioxane/H2O=4:1 (20 mL) was stirred under nitrogen. The reaction mixture was stirred to 100° C. and stirred for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was cooled and diluted with water (40 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1 to 4/1) to give methyl 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinate (500 mg, 61.2%) as yellow oil. LCMS (ESI) calcd. for C17H23F2N2O2 [M+H]+ m/z 325.17, found 324.8.
Step 4: methyl 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-5-iodo-4-methylnicotinate: A solution of methyl 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methylnicotinate (500 mg, 1.54 mmol) in MeCN (10 mL) was added NIS (415.8 mg, 1.85 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=20/1 to 10/1) to give methyl 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-5-iodo-4-methylnicotinate (400 mg, 57.8%) as yellow oil. LCMS (ESI) calcd. for C17H22F2IN2O2 [M+H]+ m/z 451.07, found 450.8.
Step 5: methyl 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinate: A solution of methyl 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-5-iodo-4-methylnicotinate (400 mg, 0.89 mmol) and CuI (339 mg, 1.78 mmol) in DMF (10 ml) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (867.8 mg, 4.45 mmol) at room temperature. The reaction mixture was heated to 120° C. and stirred for 5 hours under N2. After the reaction was completed, the resulting solution was cooled and diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1 to 5/1) to give methyl 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinate (250 mg, 71.7%) as yellow solid. LCMS (ESI) calcd. for C18H22F5N2O2 [M+H]+ m/z 393.16, found 393.0.
Step 6: 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinic acid: A solution of methyl 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinate (250 mg, 0.64 mmol) in DMSO/H2O=1/1 (6 mL) was added KOH (2.87 g, 51.2 mmol) at room temperature. The reaction mixture was heated to 100° C. and stirred for 1 hour. After the reaction was completed, the reaction mixture was adjusted to pH=3-4 with aqueous HCl (1M). Then the solution was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum to obtain 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinic acid (180 mg, 74.2%) as a yellow solid which was used without further purification. LCMS (ESI) calcd. for C17H20F5N2O2 [M+H]+ m/z 379.14, found 379.1.
Step 7: 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl) nicotinamide: A solution of 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinic acid (180 mg, 0.48 mmol), HATU (328.3 mg, 0.86 mmol) and DIEA (309.6 mg, 2.4 mmol) in DMF (5 ml) was added NH3-MeOH (7 M, 1 mL). The solution was stirred for 16 hours at room temperature. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=5/1 to 1/1) to give 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (150 mg, 82.6%) as a yellow solid. LCMS (ESI) calcd. for C17H21F5N3O [M+H]+ m/z 378.16, found 377.8.
Step 8: tert-butyl (R)-((4-(6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (150 mg, 0.40 mmol), Cs2CO3 (391 mg, 1.20 mmol), Xantphos-Pd-G2 (72 mg, 0.08 mmol) and tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.60 mmol) in 1,4-dioxane (5 ml) was heated to 100° C. and stirred for 16 hours under N2. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1 to 1/2) to give tert-butyl (R)-((4-(6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (130 mg, 82.6%) as yellow solid. LCMS (ESI) calcd. for C28H35F5N5O4S [M+H]+ m/z 632.23, found 632.1.
Step 9: (R)-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-((4-(6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (130 mg, 0.21 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H2O containing 0.05% NH3·H2O) to obtain (R)-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide (38 mg, 33.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.61 (d, J=5.4 Hz, 1H), 8.38 (d, J=1.8 Hz, 1H), 7.81 (dd, J=5.4, 1.9 Hz, 1H), 4.37 (s, 1H), 3.63 (s, 2H), 3.53-3.47 (m, 2H), 3.15 (s, 3H), 2.31-2.15 (m, 6H), 2.04-1.89 (m, 2H), 1.83-1.74 (m, 2H), 1.07 (s, 2H), 1.02-0.96 (m, 2H). LCMS (ESI) calcd. for C23H27F5N5O2S [M+H]+ m/z 532.18, found 532.1.
Step 1: tert-butyl (S)-((4-(6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (150 mg, 0.40 mmol), Cs2CO3 (391 mg, 1.20 mmol), Xantphos-Pd-G2 (72 mg, 0.08 mmol) and tert-butyl (S)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.60 mmol) in 1,4-dioxane (5 ml) was heated to 100° C. and stirred for 16 hours under N2. After the reaction was completed, the resulting solution was cooled and diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (S)-((4-(6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (130 mg, 82.6%) as a yellow solid. LCMS (ESI) calcd. for C28H35F5N5O4S [M+H]+ m/z 632.24, found 632.05.
Step 2: (S)-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide: A solution of give tert-butyl (S)-((4-(6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (130 mg, 0.21 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H2O containing 0.05% NH3·H2O) to obtain (S)-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide (50 mg, 44.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.61 (d, J=5.4 Hz, 1H), 8.38 (d, J=1.8 Hz, 1H), 7.81 (dd, J=5.4, 2.0 Hz, 1H), 4.37 (s, 1H), 3.64 (s, 2H), 3.50 (s, 2H), 3.15 (s, 3H), 2.31-2.15 (m, 6H), 2.02-1.90 (m, 2H), 1.86-1.70 (m, 2H), 1.08 (s, 2H), 1.03-0.91 (m, 2H). LCMS (ESI) calcd. for C23H27F5N5O2S [M+H]+ m/z 532.18, found 532.10.
Step 1: tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of tert-butyl (R)-((3-(5-chloro-2-fluoro-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.30 mmol), 4,4-difluoropiperidine (183 mg, 1.51 mmol) and DIEA (195 mg, 1.51 mmol) in DMSO (5 mL) was heated to 100° C. and stirred for 16 hours. LCMS showed the reaction was completed. The mixture was cooled and diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to provide tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (130 mg, 71.9%) as yellow solid. LCMS (ESI) calcd. for C25H28ClF5N3O4S [M+H]+ m/z 596.14, found 596.1.
Step 2: (R)-5-chloro-2-(4,4-difluoropiperidin-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (130 mg, 0.22 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 50% ACN/H2O containing 0.1% TFA) to provide (R)-5-chloro-2-(4,4-difluoropiperidin-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (65 mg, 60.0%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.41 (d, J=1.7 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.81 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.53 (s, 1H), 4.23 (s, 1H), 3.20 (d, J=4.9 Hz, 4H), 3.06 (s, 3H), 2.09-1.94 (m, 4H). LCMS (ESI) calcd. for C20H20ClF5N3O2S [M+H]+ m/z 496.09, found 496.0.
Step 1: 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(methylsulfinyl)phenyl)-5-(trifluoromethyl)nicotinamide: A solution of 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (200 mg, 0.53 mmol), Cs2CO3 (522 mg, 1.59 mmol), Xantphos-Pd-G2 (96 mg, 0.11 mmol) and 1-bromo-3-(methylsulfinyl)benzene (140 mg, 0.64 mmol) in 1,4-dioxane (5 mL) was heated to 80° C. and stirred for 16 hours under N2. After the reaction was completed, the resulting solution diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1 to 1/2) to give 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(methylsulfinyl)phenyl)-5-(trifluoromethyl)nicotinamide (200 mg, 73.3%) as a yellow solid. LCMS (ESI) calcd. for C24H27F5N3O2S [M+H]+ m/z 516.17, found 515.9.
Step 2: 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: A solution of 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(methylsulfinyl)phenyl)-5-(trifluoromethyl)nicotinamide (200 mg, 0.39 mmol) in MeOH (10 mL) was added ammonium carbamate (73 mg, 1.17 mmol) and PhI(OAc)2 (314 mg, 0.98 mmol) at room temperature. The reaction mixture was heated to 70° C. and stirred for 16 hours. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (160 mg, 77.4%) as a yellow solid. LCMS (ESI) calcd. for C24H28F5N4O2S [M+H]+ m/z 531.18, found 531.2.
Step 3: (S)-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide and (R)-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide was further purified by Chiral-Prep-SFC ((R,R)-Whelk-01, 20 mm*250 mm L, 5 m, eluting with 75% CO02/MeOH containing 0.1% NH3) to provide (S)-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (64.3 mg) as the first elution: H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.31 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 4.22 (s, 1H), 3.70-3.50 (m, 4H), 3.06 (s, 3H), 2.33-2.27 (m, 3H), 2.27-2.15 (m, 3H), 2.03-1.91 (m, 2H), 1.83-1.74 (m, 2H), 1.07 (s, 2H), 1.03-0.90 (m, 2H). LCMS (ESI) calcd. for C24H28F5N4O2S [M+H]+ m/z 531.18, found 531.1 and (R)-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (62.3 mg) as the second elution. 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.31 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 4.21 (s, 1H), 3.68-3.52 (m, 4H), 3.06 (s, 3H), 2.31-2.27 (m, 3H), 2.26-2.16 (m, 3 H), 2.03-1.89 (m, 2H), 1.83-1.75 (m, 2H), 1.07 (s, 2H), 1.01-0.92 (m, 2H). LCMS (ESI) calcd. for C24H28F5N4O2S [M+H]+ m/z 531.18, found 531.1.
Step 1: tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(p-tolyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of tert-butyl (R)-((3-(6-chloro-3-(4,4-difluoroazepan-1-yl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.27 mmol), p-tolylboronic acid (74 mg, 0.54 mmol), K2CO3 (112 mg, 0.81 mmol) and Pd(dppf)Cl2 (18 mg, 0.02 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL) was heated at 100° C. for 16 hours under an atmosphere of N2. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (40 mL) and extracted with EtOAc (40 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(p-tolyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (105 mg, 63.6%) as a yellow solid. LCMS (ESI) calcd. for C31H38F2N5O4S [M+H]+ m/z 614.26, found 614.20.
Step 2: (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(p-tolyl)pyridazine-4-carboxamide: A solution of tert-butyl (R)-((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(p-tolyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (105 mg, 0.17 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 35% to 90% MeCN/H2O containing 0.1% NH3) to provide (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(p-tolyl)pyridazine-4-carboxamide (36.7 mg, 42.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.32 (s, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 4.25 (s, 1H), 3.84-3.70 (m, 2H), 3.65 (t, J=6.0 Hz, 2H), 3.06 (s, 3H), 2.44-2.25 (m, 5H), 2.19 (s, 3H), 2.14-2.00 (m, 2H), 1.92-1.80 (m, 2H). LCMS (ESI) calcd. for C26H30F2N5O2S [M+H]+ m/z 514.21, found 514.15.
Step 1: tert-butyl 2,4-difluoronicotinate: To a solution of 2,4-difluoropyridine (5 g, 43.4 mmol) in THE (30 mL) at −78° C. under an atmosphere of N2 was added a solution of LDA (32.2 mL, 2M in THF). The mixture was stirred at −78° C. for 10 min. Then a solution of Boc2O (28.4 g, 130.2 mmol) in THE (20 mL) was added to the solution dropwise. The reaction mixture was stirred at 25° C. for 15 min. After the reaction was completed, the reaction was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc (150 mL×3). The combined organic layers were dried over sodium sulfate and evaporated to give the crude which was purified by flash column chromatography on silica gel (PE/EtAOc=10/1) to give tert-butyl 2,4-difluoronicotinate (7.3 g, 78.2%) as white oil. LCMS (ESI) calcd. for C10H12F2NO2 [M+H]+ m/z 216.09, found 215.90.
Step 2: tert-butyl 5-chloro-2,4-difluoronicotinate: To a solution of tert-butyl 2,4-difluoronicotinate (1.5 g, 7 mmol) in THE (15 mL) was added LDA (5.2 mL, 2M, in THF) at −78° C. under an atmosphere of N2. The mixture was stirred at −78° C. for 30 min. Then a solution of hexachloroethane (2.07 g, 8.75 mmol) in THE (10 mL) was added to the mixture dropwise. The reaction mixture was stirred at 25° C. for 1 hour. After the reaction was completed, the solution was quenched with saturated NH4Cl (80 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over sodium sulfate and evaporated to give the crude which was purified by flash column chromatography on silica gel (PE/EtAOc=10/1) to give tert-butyl 5-chloro-2,4-difluoronicotinate (600 mg, 34.4%) as white oil. LCMS (ESI) calcd. for C10H11ClF2NO2 [M+H]+ m/z 250.05, found 250.00.
Step 3: tert-butyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-fluoronicotinate: A mixture of tert-butyl 5-chloro-2,4-difluoronicotinate (300 mg, 1.2 mmol), 4,4-difluoroazepane hydrochloride (247 mg, 1.44 mmol) and DIEA (464.5 mg, 3.6 mmol) in 1,4-dioxane (5 mL) was heated at 100° C. for 5 hours. After the reaction was completed, the mixture was cooled to room temperature. Then the mixture was concentrated to give the crude. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give tert-butyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-fluoronicotinate (400 mg, 91.6%). LCMS (ESI) calcd. for C16H21ClF3N2O2 [M+H]+ m/z 365.13, found 365.10.
Step 4: 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-fluoronicotinic acid: A solution of tert-butyl 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-fluoronicotinate (400 mg, 1.1 mmol) in DCM (3 mL) was added TFA (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated to give 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-fluoronicotinic acid (320 mg, 94.4%) as a white solid. LCMS (ESI) calcd. for C12H13ClF3N2O2 [M+H]+ m/z 309.06, found 308.75.
Step 5: tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-fluoronicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-fluoronicotinic acid (260 mg, 0.84 mmol) in SOCl2 (5 mL) was heated at 80° C. for 0.5 h. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THF (2 mL) was added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (274.3 mg, 1.01 mmol) and Et3N (255.7 mg, 2.53 mmol) in THE (3 mL) at 0° C. The resulting mixture was stirred at 25° C. for 1 h. Then the mixture was quenched with water (50 mL) and extracted with DCM (50 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-fluoronicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 31.8%) as a white oil. LCMS (ESI) calcd. for C24H29ClF3N4O4S [M+H]+ m/z 561.16, found 561.10.
Step 6: (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-fluoro-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: A solution of tert-butyl (R)-((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-fluoronicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (150 mg, 0.27 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.05% NH3) to provide (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-fluoro-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (40.5 mg, 32.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.36 (d, J=10.1 Hz, 1H), 8.26 (d, J=1.9 Hz, 1H), 7.92-7.86 (m, 1H), 7.72-7.66 (m, 1H), 7.61 (s, 1H), 4.24 (s, 1H), 3.73-3.60 (m, 2 H), 3.53 (s, 2H), 3.07 (s, 3H), 2.35-2.26 (m, 2H), 2.06-1.93 (m, 2H), 1.88-1.79 (m, 2H). LCMS (ESI) calcd. for C19H21ClF3N4O2S [M+H]+ m/z 461.10, found 461.05.
Step 1: tert-butyl (R)-(1-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate: A solution of (R)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (200 mg, 0.39 mmol), 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (95 mg, 0.47 mmol), HATU (221 mg, 0.58 mmol) and DIEA (150 mg, 1.16 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (40 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=95/5) to provide tert-butyl (R)-(1-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate (75 mg, 27.6%) as brown oil. LCMS (ESI) calcd. for C31H38F5N6O5S [M+H]+ m/z 701.26, found 701.25.
Step 2: (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide formate: A solution of tert-butyl (R)-(1-(((3-(5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate (75 mg, 0.11 mmol) in DCM (4 mL) was added TFA (0.4 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 30% to 95% MeCN/H2O containing 0.1% formic acid) to provide (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-4-methyl-6-(trifluoromethyl)nicotinamide formate (31.2 mg, 48.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.43 (s, 1H), 8.11 (s, 3H), 7.90 (d, J=8.1 Hz, 1H), 7.79-7.68 (m, 2H), 3.88-3.61 (m, 4H), 3.59 (s, 3H), 2.47 (s, 3H), 2.38-2.23 (m, 2H), 2.11-1.98 (m, 2H), 1.91-1.79 (m, 2H), 1.49 (s, 3H), 1.45 (s, 3H). LCMS (ESI) calcd. for C26H30F5N6O3S [M+H]+ m/z 601.20, found 601.15.
Step 1: tert-butyl (R)-(2-(((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate: A mixture of (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (100 mg, 0.196 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (63 mg, 0.334 mmol) in DMF (5 mL) was added HATU (97 mg, 0.26 mmol) and DIEA (81 mg, 0.62 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(2-(((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (80 mg, 70.17%) as a white oil. LCMS (ESI) calcd. for C 29H35ClF5N4O5S [M+H]+ m/z 681.19, found 681.00.
Step 2: (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of tert-butyl (R)-(2-(((3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6--sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (80 mg, 0.14 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain (R)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (37.5 mg, 46.25%) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 10.97 (s, 1H), 8.36 (s, 1H), 7.99-7.97 (m, 1H), 7.72-7.65 (m, 3H), 7.34 (s, 1H), 3.46 (s, 3H), 3.43-3.40 (m, 2H), 3.39-3.36 (m, 2H), 3.20 (s, 2H), 2.20-2.25 (m, 5H), 2.08-2.05 (m, 2H), 1.82-1.80 (m, 2H). LCMS (ESI) calcd. for C24H27ClF5N4O3S [M+H]+ m/z 581.14, found 581.10.
Step 1: (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: To a solution of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (200 mg, 0.40 mmol), 2-((tert-butyldimethylsilyl)oxy)acetic acid (378 mg, 1.99 mmol) and HATU (303 mg, 0.80 mmol) in DMF (5 mL) and was added DIEA (154 mg, 1.20 mmol). Then the mixture was heated at 25° C. for 2 hours. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (110 mg, 38.46%) as a yellow oil. LCMS (ESI) calcd. for C32H45F2N6O4SSi [M+H]+ m/z 675.30, found 675.25.
Step 2: (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: To a solution of (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (110 mg, 0.16 mmol) in THE (1 mL) was added H2O (3 mL) and AcOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*19 mm, eluting with 20% to 30% ACN/H2O containing 0.1% formic acid) to provide (R)-2-(4,4-difluoroazepan-1-yl)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (45 mg, 49.45%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 8.04-7.96 (m, 1H), 7.90 (s, 1H), 7.70-7.63 (m, 2H), 7.61 (s, 1H), 4.78 (t, J=6.3 Hz, 1H), 3.95 (d, J=6.3 Hz, 2H), 3.88 (s, 3H), 3.61 (dd, J=6.5, 3.8 Hz, 2H), 3.54 (t, J=6.1 Hz, 2H), 3.46 (s, 3H), 2.34-2.20 (m, 5H), 2.07-1.93 (m, 2H), 1.86-1.75 (m, 2H). LCMS (ESI) calcd. for C26H31F2N6O4S [M+H]+ m/z 561.21, found 561.05.
Step 1: N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: To a solution of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (200 mg, 0.40 mmol), (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (406 mg, 1.99 mmol) and HATU (303 mg, 0.80 mmol) in DMF (5 mL) was added DIEA (154 mg, 1.20 mmol). Then the mixture was heated at 25° C. for 2 hours. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (110 mg, 40.15%) as a yellow oil. LCMS (ESI) calcd. for C33H47F2N6O4SSi [M+H]+ m/z 689.31, found 689.25
Step 2: 2-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: To a solution of N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (110 mg, 0.16 mmol) in THE (1 mL) was added H2O (3 mL) and AcOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*19 mm, eluting with 20% to 30% ACN/H2O containing 0.1% formic acid) to provide 2-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (47 mg, 51.25%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.39 (s, 1H), 8.18 (s, 1H), 8.01-7.95 (m, 1H), 7.90 (s, 1H), 7.70-7.63 (m, 2H), 7.61 (s, 1H), 4.71 (d, J=5.3 Hz, 1H), 4.08-3.99 (m, 1H), 3.88 (s, 3H), 3.65-3.57 (m, 2H), 3.54 (t, J=6.1 Hz, 2H), 3.47 (s, 3H), 2.34-2.18 (m, 5H), 2.07-1.93 (m, 2H), 1.86-1.73 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS (ESI) calcd. for C27H33F2N6O4S [M+H]+ m/z 575.23, found 575.15.
Step 1: N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: To a solution of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (200 mg, 0.40 mmol), (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (406 mg, 1.99 mmol) and HATU (303 mg, 0.80 mmol) in DMF (5 mL) was added DIEA (154 mg, 1.20 mmol). Then the mixture was heated at 25° C. for 2 hours. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4--1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (120 mg, 43.8%) as a yellow oil. LCMS (ESI) calcd. for C33H47F2N6O4SSi [M+H]+ m/z 689.31, found 689.25.
Step 2: 2-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide: To a solution of N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (120 mg, 0.17 mmol) in THE (1 mL) was added H2O (3 mL) and AcOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*19 mm, eluting with 20% to 30% ACN/H2O containing 0.1% formic acid) to provide 2-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide (72 mg, 71.86%) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 10.94 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.99-7.93 (m, 1H), 7.90 (s, 1H), 7.70-7.63 (m, 2H), 7.61 (d, J=0.6 Hz, 1H), 4.69 (d, J=5.5 Hz, 1H), 4.11-3.98 (m, 1H), 3.88 (s, 3H), 3.65-3.58 (m, 2H), 3.54 (t, J=6.0 Hz, 2H), 3.45 (s, 3H), 2.35-2.20 (m, 5H), 2.06-1.91 (m, 2H), 1.87-1.74 (m, 2H), 1.26 (d, J=6.8 Hz, 3H). LCMS (ESI) calcd. for C27H33F2N6O4S [M+H]+ m/z 575.23, found 575.05.
Step 1: (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A mixture of (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (100 mg, 0.20 mmol) and 2-((tert-butyldimethylsilyl)oxy)acetic acid (77 mg, 0.40 mmol) in DMF (5 mL) was added HATU (114 mg, 0.30 mmol) and DIEA (77 mg, 0.60 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (80 mg, 60.2%) as a yellow solid. LCMS (ESI) calcd. for C28H39F5N5O4SSi [M+H]+ m/z 664.24, found 664.20.
Step 2: (R)-3-(4,4-difluoroazepan-1-yl)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of (R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (80 mg, 0.12 mmol) in THE (1 mL) and H2O (3 mL) was added AcOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (30 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 80% MeCN/H2O containing 0.05% NH3) to obtain (R)-3-(4,4-difluoroazepan-1-yl)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfonimidoyl)phenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide(20.5 mg, 31%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 8.26 (s, 1H), 7.98 (d, J=7.7 Hz, 1H), 7.77-7.66 (m, 2H), 4.81 (t, J=6.3 Hz, 1H), 3.95 (d, J=6.2 Hz, 2H), 3.91-3.63 (m, 4H), 3.48 (s, 3H), 2.46-2.28 (m, 5H), 2.12-2.01 (m, 2H), 1.95-1.83 (m, 2H). LCMS (ESI) calcd. for C22H25F5N5O4S [M+H]+ m/z 550.16, found 549.95.
Step 1: N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A mixture of (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (100 mg, 0.20 mmol) and (S)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (82 mg, 0.40 mmol) in DMF (5 mL) was added HATU (114 mg, 0.30 mmol) and DIEA (77 mg, 0.60 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (80 mg, 58.9%) as a yellow solid. LCMS (ESI) calcd. for C29H41F5N5O4SSi [M+H]+ m/z 678.25, found 678.20.
Step 2: 3-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of N-(3-((R)-N-((S)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (80 mg, 0.12 mmol) in THE (1 mL) and H2O (3 mL) was added AcOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 80% MeCN/H2O containing 0.1% formic acid) to obtain 3-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((S)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (21.5 mg, 31.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 8.31 (s, 1H), 7.98-7.86 (m, 1H), 7.79-7.63 (m, 2H), 4.72 (d, J=5.5 Hz, 1H), 4.04 (dd, J=6.8, 5.7 Hz, 1H), 3.94-3.61 (m, 4H), 3.46 (s, 3H), 2.43-2.29 (m, 5H), 2.13-2.00 (m, 2H), 1.94-1.82 (m, 2H), 1.25 (d, J=6.8 Hz, 3H). LCMS (ESI) calcd. for C23H27F5N5O4S [M+H]+ m/z 564.17, found 564.00.
Step 1: tert-butyl (R)-(1-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-_6-sulfaneylidene)carbamoyl)cyclobutyl)carbamate: A mixture of (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (80 mg, 0.16 mmol) and 1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (69 mg, 0.32 mmol) in DMF (5 mL) was added HATU (91 mg, 0.24 mmol) and DIEA (62 mg, 0.48 mmol). The mixture was heated at 50° C. for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (40 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(1-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclobutyl)carbamate (80 mg, 72.5%) as a yellow solid. LCMS (ESI) calcd. for C30H38F5N6O5S [M+H]+ m/z 689.26, found 689.10.
Step 2: (R)-N-(3-(N-(1-aminocyclobutane-1-carbonyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of tert-butyl (R)-(1-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamoyl)cyclobutyl)carbamate (80 mg, 0.12 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H2O containing 0.05% NH3) to obtain (R)-N-(3-(N-(1-aminocyclobutane-1-carbonyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (23.6 mg, 33.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 8.34 (s, 1H), 7.89 (s, 1H), 7.80-7.61 (m, 2H), 3.91-3.79 (m, 2H), 3.74-3.64 (m, 2H), 3.47 (s, 3H), 2.38-2.30 (m, 5H), 2.12-1.97 (m, 4H), 1.95-1.60 (m, 8H). LCMS (ESI) calcd. for C25H30F5N6O3S [M+H]+ m/z 589.20, found 589.20.
Step 1: tert-butyl (R)-(1-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate: A mixture of (R)-3-(4,4-difluoroazepan-1-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (80 mg, 0.16 mmol) and 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (65 mg, 0.32 mmol) in DMF (5 mL) was added HATU (91 mg, 0.24 mmol) and DIEA (62 mg, 0.48 mmol). The mixture was heated at 50° C. for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-(1-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate (60 mg, 55.3%) as a yellow solid. LCMS (ESI) calcd. for C29H38F5N6O5S [M+H]+ m/z 677.25, found 677.30.
Step 2: (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of tert-butyl (R)-(1-(((3-(3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)amino)-2-methyl-1-oxopropan-2-yl)carbamate (60 mg, 0.09 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H2O containing 0.05% NH3) to obtain (R)-N-(3-(N-(2-amino-2-methylpropanoyl)-S-methylsulfonimidoyl)phenyl)-3-(4,4-difluoroazepan-1-yl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (11.3 mg, 24.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.32 (s, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.76-7.63 (m, 2H), 3.95-3.64 (m, 4H), 3.44 (s, 3H), 2.39-2.30 (m, 5H), 2.14-2.01 (m, 2H), 1.92-1.83 (m, 2H), 1.75 (s, 2H), 1.20 (d, J=4.1 Hz, 6H). LCMS (ESI) calcd. for C24H30F5N6O3S [M+H]+ m/z 577.20, found 577.15.
Step 1: N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide: A mixture of (R)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (100 mg, 0.18 mmol) and (R)-2-((tert-butyldimethylsilyl)oxy)propanoic acid (54 mg, 0.26 mmol) in DMF (5 mL) was added HATU (133 mg, 0.35 mmol) and DIEA (68 mg, 0.53 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide (66 mg, 49.7%) as a yellow solid. LCMS (ESI) calcd. for C34H46F5N6O4SSi [M+H]+ m/z 757.30, found 757.10.
Step 2: 2-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide: A mixture of N-(3-((R)-N-((R)-2-((tert-butyldimethylsilyl)oxy)propanoyl)-S-methylsulfonimidoyl)phenyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide (66 mg, 0.09 mmol) in THF (3 mL) and H2O (1 mL) was added AcOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (30 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H2O containing 0.1% formic acid) to obtain 2-(4,4-difluoroazepan-1-yl)-N-(3-((R)-N-((R)-2-hydroxypropanoyl)-S-methylsulfonimidoyl)phenyl)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)nicotinamide (13.2 mg, 23.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.40 (s, 1H), 8.02-7.96 (m, 1H), 7.77-7.68 (m, 3H), 7.40 (s, 1H), 4.79 (d, J=5.3 Hz, 1H), 4.11-4.03 (m, 1H), 3.94 (s, 3H), 3.72 (s, 2H), 3.65 (t, J=5.9 Hz, 2H), 3.51 (s, 3H), 2.41-2.29 (m, 2H), 2.13-2.02 (m, 5H), 1.91-1.83 (m, 2H), 1.31 (d, J=6.8 Hz, 3H). LCMS (ESI) calcd. for C28H32F5N6O4S [M+H]+ m/z 643.21, found 643.10.
Step 1: methyl (S)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinate: A mixture of methyl 2-chloro-4-methyl-5-(trifluoromethyl)nicotinate (160 mg, 0.63 mmol), (S)-2-(trifluoromethyl)morpholine (196 mg, 1.26 mmol) and DIEA (815 mg, 6.31 mmol) in DMSO (3 mL) was heated to 100° C. and stirred for 5 hours. Then the mixture was quenched with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to afford methyl (S)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinate (110 mg, 46.90%) as a yellow solid. LCMS (ESI) calcd. for C14H18F6N2O3 [M+H]+ m/z 373.10, found 372.9.
Step 2: (S)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinic acid: To a solution of methyl (S)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinate (110 mg, 0.30 mmol) in DMSO (2 mL) was added KOH (336 mg, 6.00 mmol) in H2O (2 mL) at 25° C. The mixture was heated to 80° C. and stirred for 2 hours. After the reaction was completed, the aqueous phase was adjusted to pH=3-4 with 1N HCl, extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under vacuum to afford (S)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinic acid (100 mg, 93.1%) as yellow oil. LCMS (ESI) calcd. for C13H13F6N2O3 [M+H]+ m/z 359.09, found 359.0.
Step 3: (S)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinamide: A solution of (S)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinic acid (100 mg, 0.28 mmol) in SOCl2 (3 mL) was heated to 80° C. and stirred for 2 hours. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THE (3 mL) was added to NH3·H2O (3 mL) at 0° C. The resulting mixture was stirred at 25° C. for 1 hour. Then the mixture was quenched with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/2) to provide (S)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinamide (90 mg, 90.0%) as yellow oil. LCMS (ESI) calcd. for C13H14F6N3O2 [M+H]+ m/z 358.10, found 357.9.
Step 4: tert-butyl ((R)-methyl(4-(4-methyl-5-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)nicotinamido)pyridin-2-yl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of (S)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinamide (90 mg, 0.25 mmol), tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (102 mg, 0.30 mmol), Cs2CO3 (246 mg, 0.76 mmol) and Xantphos-Pd-G2 (22 mg, 0.03 mmol) in 1,4-dioxane (5 mL) was heated to 100° C. and refluxed for 4 hours under nitrogen. After the reaction was completed, the mixture was concentrated. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl ((R)-methyl(4-(4-methyl-5-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)nicotinamido)pyridin-2-yl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 58.9%) as a yellow solid. LCMS (ESI) calcd. for C24H28F6N5O5S [M+H]+ m/z 612.17, found 612.0.
Step 5: 4-methyl-N-(2-((R)—S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)nicotinamide: A solution of tert-butyl ((R)-methyl(4-(4-methyl-5-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)nicotinamido)pyridin-2-yl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.15 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 80% MeCN/H2O containing 0.05% NH3) to provide 4-methyl-N-(2-((R)—S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)nicotinamide (55.00 mg, 71.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.68-8.57 (m, 2H), 8.39 (d, J=1.5 Hz, 1H), 7.83 (dd, J=5.4, 1.9 Hz, 1H), 4.39 (s, 1H), 4.24-4.12 (m, 2H), 4.00-3.92 (m, 1H), 3.83-3.74 (m, 1H), 3.60-3.50 (m, 1H), 3.25-3.11 (m, 5H), 2.36 (s, 3H). LCMS (ESI) calcd. for C19H20F6N5O3S [M+H]+ m/z 512.12, found 512.1.
Step 1: methyl (R)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinate: A mixture of methyl 2-chloro-4-methyl-5-(trifluoromethyl)nicotinate (300 mg, 1.18 mmol) and (R)-2-(trifluoromethyl)morpholine (367 mg, 2.37 mmol) in DMSO (5 mL) was added DIEA (459 mg, 3.55 mmol) at room temperature. Then the reaction mixture was heated to 100° C. and stirred for 16 hours. After the reaction was completed, the resulting solution was diluted with water (15 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtAOc=1/1) to give methyl (R)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinate (300 mg, 68.1%) as a yellow solid. LCMS (ESI) calcd. for C14H15F6N2O3 [M+H]+ m/z 373.10, found 373.1.
Step 2: (R)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinic acid: To a solution of methyl (R)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinate (300 mg, 0.81 mmol) in DMSO/H2O (1/1, 10 mL) was added KOH (904 mg, 16.10 mmol). The reaction mixture was heated to 80° C. and stirred for 16 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=3-4 with aqueous HCl (1 M). Then the solution was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide (R)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinic acid (250 mg, 86.6%) as a yellow solid. LCMS (ESI) calcd. for C13H13F6N2O3 [M+H]+ m/z 359.09, found 359.1.
Step 3: tert-butyl ((R)-methyl(3-(4-methyl-5-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)nicotinamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of (R)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinic acid (120 mg, 0.34 mmol) in SOCl2 (3 mL) was heated to 80° C. and stirred for 1 hour. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate in THE (3 mL) was added to a stirred solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (109 mg, 0.40 mmol) and DIEA (130 mg, 1.01 mmol) in THE (3 mL) at 25° C. The resulting mixture was heated to 50° C. and stirred for 16 hours. Then the mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/2) to provide tert-butyl ((R)-methyl(3-(4-methyl-5-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)nicotinamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 44%) as a white solid. LCMS (ESI) calcd. for C25H29F6N4O5S [M+H]+ m/z 611.18, found 611.1.
Step 4: 4-methyl-N-(3-((R)—S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)nicotinamide: A solution of tert-butyl ((R)-methyl(3-(4-methyl-5-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)nicotinamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.15 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 80% MeCN/H2O containing 0.05% NH3) to provide 4-methyl-N-(3-((R)—S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)nicotinamide (24.00 mg, 31.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.58 (s, 1H), 8.33 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.71 (d, J=7.9 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 4.27-4.12 (m, 3H), 4.00-3.85 (m, 2H), 3.62-3.52 (m, 1H), 3.23-3.12 (m, 2H), 3.06 (s, 3H), 2.37 (s, 3H). LCMS (ESI) calcd. for C20H21F6N4O3S [M+H]+ m/z 511.13, found 511.0.
Step 1: (R)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinamide: A solution of (R)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinic acid (120 mg, 0.34 mmol) in SOCl2 (3 mL) was heated to 80° C. and stirred for 1 hour. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate in THF (3 mL) was added to a stirred solution of NH4OH (3 mL) at 25° C. The resulting mixture was stirred at 25° C. for 2 hours. Then the mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to provide (R)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinamide (100 mg, 83.5%) as a white solid. LCMS (ESI) calcd. for C13H14F6N3O2 [M+H]+ m/z 358.10, found 357.9.
Step 2: tert-butyl ((R)-methyl(4-(4-methyl-5-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)nicotinamido)pyridin-2-yl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of (R)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinamide (100 mg, 0.28 mmol) in 1,4-dioxane (5 mL) was added tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (141 mg, 0.42 mmol), Cs2CO3 (274 mg, 0.84 mmol) and Xantphos-Pd-G2 (25 mg, 0.03 mmol) at room temperature under nitrogen. Then the reaction mixture was heated to 100° C. and stirred for 16 hours under nitrogen. The reaction was monitored by LCMS. After the reaction was completed, the filtrate was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combine organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl ((R)-methyl(4-(4-methyl-5-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)nicotinamido)pyridin-2-yl)(oxo)-λ6-sulfaneylidene)carbamate (110 mg, 64.3%) as a yellow solid. LCMS (ESI) calcd. for C24H28F6N5O5S [M+H]+ m/z 612.17, found 612.1.
Step 3: 4-methyl-N-(2-((R)—S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)nicotinamide: A solution of tert-butyl ((R)-methyl(4-(4-methyl-5-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)nicotinamido)pyridin-2-yl)(oxo)-λ6-sulfaneylidene)carbamate (110 mg, 0.18 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 80% MeCN/H2O containing 0.05% NH3) to provide 4-methyl-N-(2-((R)—S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)-2-((R)-2-(trifluoromethyl)morpholino)nicotinamide (37.00 mg, 40.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.70-8.56 (m, 2H), 8.40 (d, J=1.7 Hz, 1H), 7.83 (dd, J=5.2, 1.9 Hz, 1H), 4.40 (s, 1H), 4.26-4.10 (m, 2H), 4.03-3.91 (m, 1H), 3.84-3.73 (m, 1H), 3.61-3.49 (m, 1H), 3.24-3.11 (m, 5H), 2.36 (s, 3H). LCMS (ESI) calcd. for C19H20F6N5O3S [M+H]+ m/z 512.12, found 512.1.
Step 1: tert-butyl ((R)-methyl(3-(4-methyl-5-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)nicotinamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of (S)-4-methyl-5-(trifluoromethyl)-2-(2-(trifluoromethyl)morpholino)nicotinic acid (60 mg, 0.17 mmol) in SOCl2 (1 mL) was heated at 80° C. for 2 hours. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THF (1 mL) was added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (45.3 mg, 0.17 mmol) and DIEA (108.2 mg, 0.84 mmol) in THE (1 mL) at 0° C. The resulting mixture was stirred at 50° C. for 16 hours. Then the mixture was quenched with water (50 mL) and extracted with DCM (50 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl ((R)-methyl(3-(4-methyl-5-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)nicotinamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 48.9%) as a white solid. LCMS (ESI) calcd. for C25H29F6N4O5S [M+H]+ m/z 611.18, found 611.1.
Step 2: 4-methyl-N-(3-((R)—S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)nicotinamide: A solution of tert-butyl ((R)-methyl(3-(4-methyl-5-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)nicotinamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate (50 mg, 0.08 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 80% MeCN/H2O containing 0.05% NH3) to obtain 4-methyl-N-(3-((R)—S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)-2-((S)-2-(trifluoromethyl)morpholino)nicotinamide (6.00 mg, 14.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.58 (s, 1H), 8.35-8.30 (m, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.71 (d, J=7.9 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 4.27-4.12 (m, 3H), 4.03-3.83 (m, 2H), 3.61-3.52 (m, 1H), 3.23-3.11 (m, 2H), 3.06 (s, 3H), 2.37 (s, 3H). LCMS (ESI) calcd. for C20H21F6N4O3S [M+H]+ m/z 511.13, found 511.1.
Step 1: methyl 2-(4,4-difluoropiperidin-1-yl)-4-methyl-5-nitronicotinate: A solution of methyl 2-chloro-4-methyl-5-nitronicotinate (3 g, 13 mmol), 4,4-difluoropiperidine (3 g, 19.5 mmol) and DIEA (5 g, 39 mmol) in 1,4-dioxane (30 mL) was heated to 100° C. and stirred for 3 hours. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give methyl 2-(4,4-difluoropiperidin-1-yl)-4-methyl-5-nitronicotinate (3.1 g, 65.4%) as white solid. LCMS (ESI) calcd. for C13H16F2N3O4 [M+H]+ m/z 316.11, found 315.9
Step 2: methyl 5-amino-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinate: A solution of methyl 2-(4,4-difluoropiperidin-1-yl)-4-methyl-5-nitronicotinate (3 g, 8.6 mmol) in MeOH (30 mL) and water (10 mL) was added NH4Cl (2.3 g, 43 mmol), Fe (2.16 g, 38.7 mmol). The mixture was heated at 60° C. for 4 hours. After the reaction was completed. The mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide methyl 5-amino-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinate (1.5 g, 44.2%) as a yellow solid. LCMS (ESI) calcd. for C13H18F2N3O2 [M+H]+ m/z 286.14, found 285.9.
Step 3: methyl 2-(4,4-difluoropiperidin-1-yl)-5-iodo-4-methylnicotinate: To a solution of NaNO2 (0.87 g, 12.6 mmol) and KI (2.61 g, 15.7 mmol) in H2O (4 mL) stirred at 0° C. was added a solution of p-TsOH·H2O (3.6 g, 18.9 mmol) and methyl 5-amino-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinate (1.8 g, 6.3 mmol) in MeCN (4 mL) dropwise. The reaction mixture was stirred at 25° C. for 2 h. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give methyl 2-(4,4-difluoropiperidin-1-yl)-5-iodo-4-methylnicotinate (2 g, 79.3%) as yellow solid. LCMS (ESI) calcd. for C13H16F2IN2O2[M+H]+ m/z 397.02, found 396.8.
Step 4: methyl 2-(4,4-difluoropiperidin-1-yl)-4-methyl-5-(trifluoromethyl)nicotinate: A solution of methyl 2-(4,4-difluoropiperidin-1-yl)-5-iodo-4-methylnicotinate (2 g, 5 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (4.80 mg, 25 mmol) and CuI (1.90 mg, 10 mmol) in DMF (50 mL) was heated to 120° C. and stirred for 5 hours under N2. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give methyl 2-(4,4-difluoropiperidin-1-yl)-4-methyl-5-(trifluoromethyl)nicotinate (1.3 g, 76%) as yellow oil. LCMS (ESI) calcd. for C14H16F5N2O2[M+H]+ m/z 339.12, found 396.8
Step 5: 2-(4,4-difluoropiperidin-1-yl)-4-methyl-5-(trifluoromethyl)nicotinic acid: To a solution of methyl 2-(4,4-difluoropiperidin-1-yl)-4-methyl-5-(trifluoromethyl)nicotinate (1.3 g, 3.8 mmol) and KOH (2.13 g, 38 mmol) in MeOH/H2O (1/1, 20 mL) was heated to 80° C. and stirred for 16 hours. After the reaction was completed, the mixture was cooled and adjusted to pH=3-4 with 1N HCl and then extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried with Na2SO4, concentrated under reduced pressure to give 2-(4,4-difluoropiperidin-1-yl)-4-methyl-5-(trifluoromethyl)nicotinic acid (1 g, 81.5%) as yellow oil which was used without further purification. LCMS (ESI) calcd. for C13H14F5N2O2 [M+H]+ m/z 325.10, found 325.1.
Step 6: tert-butyl (R)-((3-(2-(4,4-difluoropiperidin-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 2-(4,4-difluoropiperidin-1-yl)-4-methyl-5-(trifluoromethyl)nicotinic acid (200 mg, 0.61 mmol) in SOCl2 (5 mL) was heated to 80° C. and stirred for 2 hours. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THF (5 mL) was added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (249 mg, 0.92 mmol) and DIEA (238 mg, 1.84 mmol) in THE (5 mL). The resulting mixture was stirred at 50° C. for 16 hours. Then the mixture was quenched with water (20 mL) and then extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1 to 1/2) to provide tert-butyl (R)-((3-(2-(4,4-difluoropiperidin-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 56.32%) as a yellow solid. LCMS (ESI) calcd. for C25H30F5N4O4S [M+H]+ m/z 577.19, found 0.577.1
Step 7: (R)-2-(4,4-difluoropiperidin-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-(4,4-difluoropiperidin-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.35 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 55% to 80% MeCN/H2O containing 0.05% NH3) to provide (R)-2-(4,4-difluoropiperidin-1-yl)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (82.8 mg, 49.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.53 (s, 1H), 8.35 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 4.24 (s, 1H), 3.73-3.52 (m, 4H), 3.07 (s, 3H), 2.36 (s, 3H), 2.05-1.90 (m, 4H). LCMS (ESI) calcd. for C20H22F5N4O2S [M+H]+ m/z 477.14, found 477.0.
Step 1: methyl 4-methyl-5-nitro-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinate: A solution of methyl 2-chloro-4-methyl-5-nitronicotinate (3 g, 13 mmol), 4-(trifluoromethyl)piperidine (3 g, 19.5 mmol) and DIEA (5 g, 39 mmol) in 1,4-dioxane (30 mL) was heated to 100° C. and stirred for 3 hours. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give methyl 4-methyl-5-nitro-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinate (3.1 g, 65.4%) as white solid. LCMS (ESI) calcd. for C14H17F3N3O4 [M+H]+ m/z 348.12, found 348.1.
Step 2: methyl 5-amino-4-methyl-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinate: A solution of methyl 4-methyl-5-nitro-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinate (3 g, 8.6 mmol) in MeOH (30 mL) and water (10 mL) was added NH4Cl (2.3 g, 43 mmol), Fe (2.16 g, 38.7 mmol). The mixture was heated at 60° C. for 4 hours. After the reaction was completed. The mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide methyl 5-amino-4-methyl-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinate (1.5 g, 44.2%) as a yellow solid. LCMS (ESI) calcd. for C14H19F3N3O2 [M+H]+ m/z 318.15, found 318.1.
Step 3: methyl 5-iodo-4-methyl-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinate: To a solution of methyl 5-amino-4-methyl-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinate (1.5 g, 4.7 mmol) and p-TsOH·H2O (2.68 g, 14.1 mmol) in MeCN (18 mL) stirred at 0° C. was added a solution of NaNO2 (0.65 g, 9.4 mmol) and KI (1.95 g, 11.8 mmol) in H2O (4 mL) dropwise. The reaction mixture was stirred at 25° C. for 2 h. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give methyl 5-iodo-4-methyl-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinate (1.2 g, 57.5%) as yellow solid. LCMS (ESI) calcd. for C14H17F3IN2O2 [M+H]+ m/z 429.03, found 429.0.
Step 4: methyl 4-methyl-5-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinate: A solution of methyl 5-iodo-4-methyl-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinate (1.2 g, 2.8 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.69 g, 14 mmol) and CuI (1.07 mg, 5.6 mmol) in DMF (15 mL) was heated to 100° C. and stirred for 5 hours under N2. LCMS showed the reaction was completed. The mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give methyl 4-methyl-5-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinate (0.8 g, 71.4%) as yellow oil. LCMS (ESI) calcd. for C15H17F6N2O2 [M+H]+ m/z 371.12, found 371.1.
Step 5: 4-methyl-5-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinic acid: To a solution of methyl 4-methyl-5-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinate (800 mg, 2.16 mmol) and KOH (1.2 g, 21.6 mmol) in MeOH/H2O/THF (1/1/1, 25 mL) was heated to 70° C. and stirred for 16 hours. After the reaction was completed, the mixture was cooled and adjusted to pH=3-4 with 1N HCl and then extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried with Na2SO4, concentrated under reduced pressure to give 4-methyl-5-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinic acid (750 mg, 97.3% yield) as yellow oil which was used without further purification. LCMS (ESI) calcd. for C14H15F6N2O2 [M+H]+ m/z 357.11, found 356.9.
Step 6: tert-butyl (R)-(methyl(3-(4-methyl-5-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 4-methyl-5-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinic acid (200 mg, 0.56 mmol) in SOCl2 (5 mL) was heated to 80° C. and stirred for 2 hours. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THE (5 mL) was added to a solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (104.8 mg, 0.62 mmol) and DIEA (361.8 mg, 2.80 mmol) in THE (5 mL). The resulting mixture was heated at 50° C. for 16 hours. Then the mixture was quenched with water (20 mL) and then extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-(methyl(3-(4-methyl-5-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 58.7%) as a yellow solid. LCMS (ESI) calcd. for C26H31F6N4O4S [M+H]+ m/z 609.20, found 609.0
Step 7: (R)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinamide: A solution of tert-butyl (R)-(methyl(3-(4-methyl-5-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinamido)phenyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.33 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 80% MeCN/H2O containing 0.05% NH3) to provide (R)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)nicotinamide(75.2 mg, 45.0%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 4.25-4.13 (m, 3H), 3.05 (s, 3H), 3.03-2.93 (m, 2H), 2.63-2.52 (m, 1H), 2.35 (s, 3H), 1.85-1.74 (m, 2H), 1.48-1.32 (m, 2H). LCMS (ESI) calcd. for C21H23F6N4O2S [M+H]+ m/z 509.15, found 509.1.
Step 1: 5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide: A solution of 5-chloro-2-fluoro-4-(trifluoromethyl)benzamide (3 g, 12.4 mmol), 4-(trifluoromethyl)piperidine (1.99 g, 13.0 mmol), and DIEA (4.01 g, 31.0 mmol) in DMSO (50 mL) was heated to 120° C. and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide (3.0 g, 64.52%) as yellow solid. LCMS (ESI) calcd. for C14H14ClF6N2O [M+H]+ m/z 375.07, found 375.0.
Step 2: tert-butyl (R)-((4-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide (200 mg, 0.53 mmol), tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (187 mg, 0.56 mmol), Cs2CO3 (452 mg, 1.39 mmol) and Xantphos-Pd-G2 (95 mg, 0.11 mmol) in 1,4-dioxane (5 mL) was stirred at 100° C. for 2 hours under nitrogen. After the reaction was completed, the mixture was filtered through celite. The filtrate was concentrated and residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((4-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 59.68% yield) as a yellow solid. LCMS (ESI) calcd. for C25H28ClF6N4O4S [M+H]+ m/z 629.14, found 629.1.
Step 3: (R)-5-chloro-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide: A solution of tert-butyl (R)-((4-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.32 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (R)-5-chloro-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide (58.40 mg, 34.78%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.64 (d, J=5.4 Hz, 1H), 8.50 (s, 1H), 7.84 (s, 1H), 7.78 (dd, J=5.4, 1.7 Hz, 1H), 7.49 (s, 1H), 4.36 (s, 1H), 3.36 (d, J=11.8 Hz, 2H), 3.14 (s, 3H), 2.90 (t, J=12.0 Hz, 2H), 2.47-2.35 (m, 1H), 1.84 (d, J=11.9 Hz, 2H), 1.56-1.38 (m, 2H). LCMS (ESI) calcd. for C20H20ClF6N4O2S [M+H]+ m/z 529.09, found 529.1.
Step 1: tert-butyl (S)-((4-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide (200 mg, 0.53 mmol), tert-butyl (S)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (187 mg, 0.56 mmol), Cs2CO3 (452 mg, 1.39 mmol) and Xantphos-Pd-G2 (95 mg, 0.11 mmol) in 1,4-dioxane (5 mL) was heated to 100° C. and refluxed for 2 hours under nitrogen. After the reaction was completed, the mixture was filtered through celite. The filtrate was concentrated and residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (S)-((4-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)pyridin-2-yl)(methyl)(oxo)-16-sulfaneylidene)carbamate (200 mg, 59.68%) as a yellow solid. LCMS (ESI) calcd. for C25H28ClF6N4O4S [M+H]+ m/z 629.14, found 629.1.
Step 2: (S)-5-chloro-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide: A solution of tert-butyl (S)-((4-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.32 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (S)-5-chloro-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide (84.30 mg, 50.18%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.64 (d, J=5.4 Hz, 1H), 8.51 (s, 1H), 7.84 (s, 1H), 7.78 (dd, J=5.3, 1.6 Hz, 1H), 7.49 (s, 1H), 4.36 (s, 1H), 3.36 (d, J=11.8 Hz, 2H), 3.14 (s, 3H), 2.90 (t, J=12.0 Hz, 2H), 2.46-2.38 (m, 1H), 1.85 (d, J=11.9 Hz, 2H), 1.57-1.36 (m, 2H). LCMS (ESI) calcd. for C20H20ClF6N4O2S [M+H]+ m/z 529.09, found 529.1.
Step 1: tert-butyl (R)-((5-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzoic acid (150 mg, 0.40 mmol), tert-butyl (R)-((5-amino-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (138 mg, 0.48 mmol), HATU (273 mg, 0.72 mmol) and DIEA (155 mg, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (R)-((5-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 69.8%) as a yellow solid. LCMS (ESI) calcd. for C26H28ClF7N3O4S [M+H]+ m/z 646.14, found 646.1.
Step 2: (R)-5-chloro-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide: A solution of tert-butyl (R)-((5-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.37 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-IPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (R)-5-chloro-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide (60 mg, 29.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 10.88 (s, 1H), 8.38 (dd, J=6.5, 2.6 Hz, 1H), 7.96-7.84 (m, 1H), 7.80 (s, 1H), 7.52-7.43 (m, 2H), 4.67 (s, 1H), 3.40-3.86 (m, 2H), 3.19 (s, 3H), 2.91-2.86 (m, 2H), 2.52-2.47 (m, 1H), 1.87-1.83 (m, 2H), 1.57-1.39 (m, 2H). LCMS (ESI) calcd. for C21H20ClF7N3O2S [M+H]+ m/z 546.08, found 546.1.
Step 1: tert-butyl (S)-((5-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzoic acid (150 mg, 0.40 mmol), tert-butyl (S)-((5-amino-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (138 mg, 0.48 mmol), HATU (273 mg, 0.72 mmol) and DIEA (155 mg, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/2) to give tert-butyl (S)-((5-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 69.8%) as a yellow solid. LCMS (ESI) calcd. for C26H28ClF7N3O4S [M+H]+ m/z 646.14, found 646.1.
Step 2: (S)-5-chloro-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide: A solution of tert-butyl (S)-((5-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.37 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (S)-5-chloro-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide (65 mg, 32.2%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.38 (dd, J=6.5, 2.7 Hz, 1H), 7.97-7.84 (m, 1H), 7.80 (s, 1H), 7.55-7.25 (m, 2H), 4.67 (s, 1H), 3.40-3.36 (m, 2H), 3.19 (s, 3H), 2.92-2.87 (m, 2H), 2.47-2.37 (m, 1H), 1.87-1.83 (m, 2H), 1.56-1.43 (m, 2H). LCMS (ESI) calcd. for C21H20ClF7N3O2S [M+H]+ m/z 546.08, found 546.0.
Step 1: 5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamide: A solution of 5-chloro-2-fluoro-4-(trifluoromethyl)benzamide (3 g, 12.4 mmol), 4,4-difluoropiperidine (1.65 g, 13.7 mmol) and DIEA (4.01 g, 31.0 mmol) in DMSO (50 mL) was heated to 120° C. and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (200 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1 to 1/2) to provide 5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamide (3.0 g, 70.42%) as a yellow solid. LCMS (ESI) calcd. for C13H13ClF5N2O [M+H]+ m/z 343.06, found 343.1.
Step 2: tert-butyl (S)-((4-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamide (200 mg, 0.58 mmol), tert-butyl (S)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (206 mg, 0.61 mmol), Cs2CO3 (494 mg, 1.52 mmol) and Xantphos-Pd-G2 (104 mg, 0.12 mmol) in 1,4-dioxane (5 mL) was heated to 100° C. and stirred for 2 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered through celite. The filtrate was concentrated and residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to provide tert-butyl (S)-((4-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 57.30%) as a yellow solid. LCMS (ESI) calcd. for C24H27ClF5N4O4S [M+H]+ m/z 597.14, found 597.1.
Step 3: (S)-5-chloro-2-(4,4-difluoropiperidin-1-yl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide: To a solution of tert-butyl (S)-((4-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.33 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (S)-5-chloro-2-(4,4-difluoropiperidin-1-yl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (102 mg, 64.21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 7.85 (s, 2H), 7.56 (s, 1H), 3.36 (s, 3H), 3.20 (d, J=5.0 Hz, 4H), 2.04-1.92 (m, 4H). LCMS (ESI) calcd. for C19H19ClF5N4O2S [M+H]+ m/z 497.08, found 497.1.
Step 1: tert-butyl (R)-((4-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamide (200 mg, 0.58 mmol), tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (206 mg, 0.61 mmol), Cs2CO3 (494 mg, 1.52 mmol) and Xantphos-Pd-G2 (104 mg, 0.12 mmol) in 1,4-dioxane (5 mL) was heated to 100° C. and stirred for 2 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered through celite. The filtrate was concentrated and residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((4-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 57.30%) as a yellow solid. LCMS (ESI) calcd. for C24H27ClF5N4O4S [M+H]+ m/z 597.14, found 597.1.
Step 2: (R)-5-chloro-2-(4,4-difluoropiperidin-1-yl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide: A solution of tert-butyl (R)-((4-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (200 mg, 0.33 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (R)-5-chloro-2-(4,4-difluoropiperidin-1-yl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (95 mg, 58.77%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.70 (d, J=5.4 Hz, 1H), 8.56 (s, 1H), 7.85 (s, 2H), 7.56 (s, 1H), 3.36 (s, 3H), 3.28-3.14 (m, 4H), 2.07-1.91 (m, 4H). LCMS (ESI) calcd. for C19H19ClF5N4O2S [M+H]+ m/z 497.08, found 497.1.
Step 1: tert-butyl (S)-((5-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzoic acid (100 mg, 0.29 mmol), tert-butyl (S)-((5-amino-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (126 mg, 0.44 mmol), HATU (166 mg, 0.44 mmol) and DIEA (113 mg, 0.87 mmol) in DMF (5 mL) stirred 25° C. for 16 h. After the reaction was completed, the mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (S)-((5-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 55.9%) as yellow solid. LCMS (ESI) calcd. for C25H26ClF6N3NaO4S [M+Na]+ m/z 636.11, found 636.0.
Step 2: (S)-5-chloro-2-(4,4-difluoropiperidin-1-yl)-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of tert-butyl (S)-((5-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.16 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 60% to 95% MeCN/H2O containing 0.05% NH3) to provide (S)-5-chloro-2-(4,4-difluoropiperidin-1-yl)-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (25.9 mg, 31.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.41-8.29 (m, 1H), 7.98-7.88 (m, 1H), 7.80 (s, 1H), 7.56-7.41 (m, 2H), 4.70 (s, 1H), 3.26-3.16 (m, 7H), 2.10-1.93 (m, 4H). LCMS (ESI) calcd. for C20H19ClF6N3O2S [M+H]+ m/z 514.08, found 514.0.
Step 1: methyl 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-nitrobenzoate. A solution of methyl 6-fluoro-2-methyl-3-nitrobenzoate (8 g, 37.5 mmol), 4,4-difluoroazepane hydrochloride (7.08 g, 41.3 mmol), and cesium carbonate (36.65 g, 112.5 mmol) in DMF (100 mL) was heated to 50° C. and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=4/1) to provide methyl 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-nitrobenzoate (7.5 g, 60.80%) as yellow solid. LCMS (ESI) calcd. for C15H19F2N2O4 [M+H]+ m/z 329.12, found 329.1.
Step 2: methyl 3-amino-6-(4,4-difluoroazepan-1-yl)-2-methylbenzoate: A solution of methyl 6-(4,4-difluoroazepan-1-yl)-2-methyl-3-nitrobenzoate (7.9 g, 24.1 mmol) in MeOH (90 mL) and water (30 mL) was added NH4Cl (6.45 g, 120.5 mmol), Fe (6.06 g, 108.5 mmol). The mixture was heated at 60° C. for 5 hours. After the reaction was completed. The mixture was filtered through celite. The filtrate was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide methyl 3-amino-6-(4,4-difluoroazepan-1-yl)-2-methylbenzoate (6 g, 83.40%) as a yellow solid which was used directly in next step without further purification. LCMS (ESI) calcd. For C15H21F2N2O2 [M+H]+ m/z 299.15, found 299.1.
Step 3: methyl 3-amino-4-chloro-6-(4,4-difluoroazepan-1-yl)-2-methylbenzoate: A solution of methyl 3-amino-6-(4,4-difluoroazepan-1-yl)-2-methylbenzoate (3.7 g, 12.4 mmol) and NCS (1.99 g, 14.9 mmol) in MeCN (80 mL) was heated to 60° C. and stirred for 6 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to provide methyl 3-amino-4-chloro-6-(4,4-difluoroazepan-1-yl)-2-methylbenzoate (1.5 g, 36.29%) as yellow oil. LCMS (ESI) calcd. for C15H20ClF2N2O2 [M+H]+ m/z 333.11, found 333.0.
Step 4: methyl 3-amino-4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methylbenzoate: To a solution of methyl 3-amino-4-chloro-6-(4,4-difluoroazepan-1-yl)-2-methylbenzoate (1.5 g, 4.51 mmol) and cyclopropylboronic acid (387 mg, 4.51 mmol) in toluene (20 mL) was added K3PO4 (1.91 g, 9.02 mmol), S-Phos (185 mg, 0.45 mmol), Pd2(dba)3 (413 mg, 0.45 mmol) and H2O (5 mL) at room temperature. The mixture was heated at 100° C. for 16 h under an atmosphere of N2. After the reaction was completed, the mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to provide methyl 3-amino-4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methylbenzoate (1 g, 65.56%) as yellow oil. LCMS (ESI) calcd. for C18H25F2N2O2 [M+H]+ m/z 339.18, found 339.2.
Step 5: methyl 4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-3-iodo-2-methylbenzoate: To a solution of methyl 3-amino-4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methylbenzoate (620 mg, 1.83 mmol) in THE (10 mL) was added I2 (698 mg, 2.75 mmol. The reaction solution was stirred at room temperature for 0.5 h. Then t-BuONO (283 mg, 2.75 mmol) was added, and the reaction solution was heated at 80° C. for 1 hour. After the reaction was completed, the mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to provide methyl 4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-3-iodo-2-methylbenzoate (300 mg, 36.44% yield) as yellow oil. LCMS (ESI) calcd. for C18H23F21NO2 [M+H]+ m/z 450.07, found 450.0.
Step 6: methyl 4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzoate: To a solution of methyl 4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-3-iodo-2-methylbenzoate (400 mg, 0.89 mmol) and CuI (339 mg, 1.78 mmol) in DMF (10 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.05 g, 10.68 mmol) dropwise at room temperature under an atmosphere of N2. The mixture was heated at 100° C. for 2 hours. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to give methyl 4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzoate (245 mg, 70.31%). LCMS (ESI) calcd. for C19H23F5NO2 [M+H]+ m/z 392.16, found 392.1.
Step 7: 4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzoic acid: To a solution of methyl 4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzoate (100 mg, 0.26 mmol) in DMSO/H2O (1/1, 10 mL) was added KOH (143 mg, 2.56 mmol) at room temperature. The mixture was stirred at 80° C. for 3 hours. After the reaction was completed. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried with Na2SO4, concentrated under reduced pressure to give 4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzoic acid (80 mg, 82.97%) as a yellow solid. LCMS (ESI) calcd. for C18H21F5NO2 [M+H]+ m/z 378.14, found 378.2.
Step 8: 4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzamide: A solution of 4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzoic acid (80 mg, 0.21 mmol) in SOCl2 (5 mL) was heated to 80° C. and stirred for 0.5 hour. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THE (5 mL) was added to a solution of THF (5 mL) in NH3·H2O (5 mL) and at 0° C. The resulting mixture was stirred at 25° C. for 1 hour. Then the mixture was quenched with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzamide (70 mg, 87.74%) as yellow oil. LCMS (ESI) calcd. for C18H22F5N2O [M+H]+ m/z 377.16, found 377.2.
Step 9: tert-butyl (R)-((4-(4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzamide (70 mg, 0.19 mmol), tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (66 mg, 0.20 mmol), Cs2CO3 (158 mg, 0.48 mmol) and Xantphos-Pd-G2 (33 mg, 0.04 mmol) in 1,4-dioxane (5 mL) was stirred at 100° C. for 2 hours under nitrogen. After the reaction was completed, the mixture was filtered through celite. The filtrate was concentrated and residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((4-(4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 85.11%) as a yellow solid. LCMS (ESI) calcd. for C29H36F5N4O4S [M+H]+ m/z 631.23, found 631.3.
Step 10: (R)-4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-3-(trifluoromethyl)benzamide: A solution of tert-butyl (R)-((4-(4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.16 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-IPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (R)-4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-3-(trifluoromethyl)benzamide (20 mg, 23.82%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.60 (d, J=5.3 Hz, 1H), 8.43 (s, 1H), 7.80 (d, J=4.1 Hz, 1H), 6.85 (s, 1H), 4.35 (s, 1H), 3.30-3.18 (m, 4H), 3.13 (s, 3H), 2.32 (d, J=2.9 Hz, 3H), 2.22-1.92 (m, 5H), 1.75-1.61 (m, 2H), 0.97 (d, J=7.4 Hz, 2H), 0.73 (d, J=4.9 Hz, 2H). LCMS (ESI) calcd. for C24H28F5N4O2S [M+H]+ m/z 531.18, found 531.2.
Step 1: tert-butyl (S)-((3-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzoic acid (150 mg, 0.40 mmol), tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (130 mg, 0.48 mmol), HATU (273 mg, 0.72 mmol) and DIEA (155 mg, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give tert-butyl (S)-((3-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (180 mg, 64.5%) as a yellow solid. LCMS (ESI) calcd. for C26H29ClF6N3O4S [M+H]+ m/z 628.15, found 628.00.
Step 2: (S)-5-chloro-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide: A solution of tert-butyl (S)-((3-(5-chloro-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (180 mg, 0.29 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (S)-5-chloro-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)piperidin-1-yl)benzamide (70 mg, 45.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.42 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.82 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.48 (s, 1H), 4.21 (s, 1H), 3.40-3.36 (m, 2H), 3.05 (s, 3H), 2.93-2.87 (m, 2H), 2.47-2.37 (m, 1H), 1.88-1.82 (m, 2H), 1.58-1.44 (m, 2H). LCMS (ESI) calcd. for C21H21ClF6N3O2S [M+H]+ m/z 528.09, found
Step 1: methyl (trans)-3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)cyclobutane-1-carboxylate: A mixture of 5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzoic acid (200 mg, 0.56 mmol) and methyl (trans)-3-aminocyclobutane-1-carboxylate (110 mg, 0.67 mmol) in DMF (5 mL) was added HATU (277 mg, 0.73 mmol) and DIEA (232 mg, 1.80 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give methyl (trans)-3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)cyclobutane-1-carboxylate (210 mg, 79.85%) as white oil. LCMS (ESI) calcd. for C20H23ClF5N2O3 [M+H]+ m/z 469.13, found 469.0.
Step 2: (trans)-3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)cyclobutane-1-carboxylic acid: A solution of methyl (trans)-3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)cyclobutane-1-carboxylate 2 (210 mg, 0.45 mmol) in THF/H2O (1:1, 10 mL) was added KOH (239 mg, 4.50 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the reaction was extracted with DCM (20 mL), then the aqueous phase was adjusted to pH=3 with 1 N HCl and extracted with DCM (20 mL×3). The organic phase was dried with Na2SO4 and concentrated under vacuum to give (trans)-3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)cyclobutane-1-carboxylic acid (180 mg, 87.80%) as a white solid. LCMS (ESI) calcd. for C19H21ClF5N2O3 [M+H]+ m/z 455.12, found 455.05.
Step 3: N-((trans)-3-carbamoylcyclobutyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamide: A solution of (trans)-3-(5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamido)cyclobutane-1-carboxylic acid (180 mg, 0.40 mmol) in DMF (5 mL) was added HATU (218 mg, 0.51 mmol), DIEA (183 mg, 1.28 mmol) and NH3-MeOH (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN/H2O containing 0.1% formic acid) to obtain N-((trans)-3-carbamoylcyclobutyl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-4-(trifluoromethyl)benzamide (39.20 mg, 22.22%) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.84 (d, J=7.5 Hz, 1H), 7.45 (s, 1H), 7.26 (s, 2H), 6.79 (s, 1H), 4.49-4.43 (m, 1H), 3.37-3.33 (m, 2H), 3.30 (s, 3H), 2.90-2.83 (m, 1H), 2.41-2.35 (m, 2H), 2.26-2.08 (m, 6H), 1.85-1.79 (m, 2H). LCMS (ESI) calcd. for C19H22ClF5N3O2 [M+H]+ m/z 454.13, found 454.0.
Step 1: tert-butyl (S)-((4-(4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzamide (50 mg, 0.13 mmol), tert-butyl (S)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (47 mg, 0.14 mmol), Cs2CO3 (113 mg, 0.35 mmol) and Xantphos-Pd-G2 (24 mg, 0.03 mmol) in 1,4-dioxane (5 mL) was heated at 100° C. for 2 hours under nitrogen. After the reaction was completed, the mixture was filtered through celite. The filtrate was concentrated and residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (S)-((4-(4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (40 mg, 47.63%) as a yellow solid. LCMS (ESI) calcd. for C29H36F5N4O4S [M+H]+ m/z 631.23, found 631.2.
Step 2: (S)-4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-3-(trifluoromethyl)benzamide: A solution of tert-butyl (S)-((4-(4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-3-(trifluoromethyl)benzamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (40 mg, 0.06 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (S)-4-cyclopropyl-6-(4,4-difluoroazepan-1-yl)-2-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-3-(trifluoromethyl)benzamide (2.8 mg, 8.37%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.61 (d, J=5.4 Hz, 1H), 8.43 (d, J=1.7 Hz, 1H), 7.81 (dd, J=5.5, 2.0 Hz, 1H), 6.85 (s, 1H), 4.35 (s, 1H), 3.25 (dd, J=12.3, 6.7 Hz, 4H), 3.13 (s, 3H), 2.35-2.30 (m, 3H), 2.19-1.93 (m, 5H), 1.74-1.65 (m, 2H), 0.98 (dd, J=8.5, 1.5 Hz, 2H), 0.73 (d, J=5.0 Hz, 2H). LCMS (ESI) calcd. for C24H28F5N4O2S [M+H]+ m/z 531.18, found 531.2.
Step 1: 5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzoic acid: A solution of 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (200 mg, 0.82 mmol), 4,4-difluoropiperidine (200 mg, 1.65 mmol) and DIEA (533 mg, 4.12 mmol) in DMSO (5 mL) was heated at 100° C. for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide 5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzoic acid (180 mg, 63.5%) as yellow solid. LCMS (ESI) calcd. for C13H12ClF5NO2 [M+H]+ m/z 344.05, found 344.0.
Step 2: tert-butyl (R)-((5-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: To a solution of 5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzoic acid (100 mg, 0.29 mmol), tert-butyl (R)-((5-amino-2-fluorophenyl)(methyl)(oxo)-16-sulfaneylidene)carbamate (126 mg, 0.44 mmol), HATU (166 mg, 0.44 mmol) and DIEA (113 mg, 0.87 mmol) in DMF (5 mL) stirred 25° C. for 16 h. After the reaction was completed, the mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give tert-butyl (R)-((5-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 50.9%) as yellow solid. LCMS (ESI) calcd. for C25H26ClF6N3NaO4S [M+Na]+ m/z 636.11, found 636.0.
Step 3: (R)-5-chloro-2-(4,4-difluoropiperidin-1-yl)-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of tert-butyl (R)-((5-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)-2-fluorophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (100 mg, 0.16 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 60% to 95% MeCN/H2O containing 0.05% NH3) to provide (R)-5-chloro-2-(4,4-difluoropiperidin-1-yl)-N-(4-fluoro-3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (59.5 mg, 31.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.41-8.29 (m, 1H), 7.98-7.88 (m, 1H), 7.80 (s, 1H), 7.56-7.41 (m, 2H), 4.70 (s, 1H), 3.26-3.16 (m, 7H), 2.10-1.93 (m, 4H). LCMS (ESI) calcd. for C20H19ClF6N3O2S [M+H]+ m/z 514.08, found 514.0.
Step 1: tert-butyl (S)-((3-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate: A solution of 5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzoic acid (180 mg, 0.52 mmol), tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (213 mg, 0.78 mmol), HATU (299 mg, 0.78 mmol) and DIEA (203 mg, 1.57 mmol) in DMF (5 mL) was stirred at 25° C. for 16 hours. After the reaction was completed, the resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (S)-((3-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 38.3%) as yellow solid. LCMS (ESI) calcd. for C25H28ClF5N3O4S [M+H]+ m/z 596.14, found 596.1.
Step 2: (S)-5-chloro-2-(4,4-difluoropiperidin-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide: A solution of tert-butyl (S)-((3-(5-chloro-2-(4,4-difluoropiperidin-1-yl)-4-(trifluoromethyl)benzamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.20 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 90% MeCN/H2O containing 0.05% NH3) to provide (S)-5-chloro-2-(4,4-difluoropiperidin-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (43 mg, 43.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.41 (t, J=1.7 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.81 (s, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.53 (s, 1H), 4.23 (s, 1H), 3.26-3.14 (m, 4H), 3.06 (s, 3H), 2.10-1.95 (m, 4H). LCMS (ESI) calcd. for C20H20ClF5N3O2S [M+H]+ m/z 496.09, found 496.1.
Step 1: methyl (trans)-3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)cyclobutane-1-carboxylate: A mixture of 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinic acid (200 mg, 0.59 mmol) and methyl (trans)-3-aminocyclobutane-1-carboxylate hydrochloride (117 mg, 0.71 mmol) in DMF (5 mL) was added HATU (293 mg, 0.77 mmol) and DIEA (244 mg, 1.89 mmol). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give methyl (trans)-3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)cyclobutane-1-carboxylate (180 mg, 0.68%) as white oil. LCMS (ESI) calcd. for C20H25F5N3O3 [M+H]+ m/z 450.18, found 450.10.
Step 2: (trans)-3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)cyclobutane-1-carboxylic acid: A solution of methyl (trans)-3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)cyclobutane-1-carboxylate (180 mg, 0.40 mmol) in t-BuOH/THF/H2O (1/1/1, 10 mL) was added KOH (224 mg, 4.0 mmol) at room temperature. The mixture was stirred for 2 hours at room temperature. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature, the reaction was extracted with DCM (20 mL), then the aqueous phase was adjusted to pH=3 with 1 N HCl and extracted with DCM (20 mL×3). The organic phase was dried with Na2SO4 and concentrated under vacuum to provide crude product (150 mg, 86.2% yield) as white solid. 1/3 of the above product (50 mg, 0.11 mmol) was further purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 85% MeCN/H2O containing 0.1% FA) to provide (trans)-3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)cyclobutane-1-carboxylic acid (7 mg) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.94 (d, J=7.3 Hz, 1H), 8.36 (s, 1H), 4.53-4.41 (m, 1H), 3.71-3.57 (m, 4H), 3.00-2.89 (m, 1H), 2.46-2.40 (m, 2H), 2.32-2.17 (m, 7H), 2.07-1.94 (m, 2H), 1.89-1.80 (m, 2H). LCMS (ESI) calcd. for C19H23F5N3O3 [M+H]+ m/z 436.17, found 436.2.
A mixture of (trans)-3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)cyclobutane-1-carboxylic acid (100 mg, 0.23 mmol) and HATU (131 mg, 0.34 mmol) in DMF (5 mL) was added NH3-MeOH (7M, 2 mL) and DIEA (148.4 mg, 1.15 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 70% MeCN/H2O containing 0.05% NH3) to provide N-((trans)-3-carbamoylcyclobutyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (27 mg, 27.1%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J=7.2 Hz, 1H), 8.36 (s, 1H), 7.24 (s, 1H), 6.80 (s, 1H), 4.56-4.37 (m, 1H), 3.72-3.57 (m, 4H), 2.93-2.82 (m, 1H), 2.41-2.34 (m, 2H), 2.32-2.20 (m, 5H), 2.18-2.10 (m, 2H), 2.07-1.97 (m, 2H), 1.89-1.78 (m, 2H). LCMS (ESI) calcd. for C19H24F5N4O2 [M+H]+ m/z 435.18, found 435.1
Step 1: methyl 4-methyl-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-5-(trifluoromethyl)nicotinate: A solution of methyl 2-chloro-4-methyl-5-(trifluoromethyl)nicotinate (1 g, 3.91 mmol), 1-(2,2,2-trifluoroethyl)-1,4-diazepane hydrochloride (1.28 g, 5.85 mmol) and DIEA (2.52 g, 19.52 mmol) in DMSO (20 mL) was heated to 100° C. and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide methyl 4-methyl-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-11-yl)-5-(trifluoromethyl)nicotinate (900 mg, 58.97%) as yellow oil. LCMS (ESI) calcd. for C16H20F6N3O 2 [M+H]+ m/z 400.15, found 400.0.
Step 2: 4-methyl-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-5-(trifluoromethyl)nicotinic acid: A solution of methyl 4-methyl-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-5-(trifluoromethyl)nicotinate (500 mg, 1.25 mmol) in DMSO/H2O (1/1, 10 mL) was added KOH (3.51 g, 62.61 mmol). Then the solution was heated to 100° C. and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting solution was adjusted to pH=3-4 with saturated HCl (1 M) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to give 4-methyl-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-5-(trifluoromethyl)nicotinic acid (400 mg, 89.55%) as yellow solid which was used without further purification. LCMS (ESI) calcd. for C15H18F6N3O2 [M+H]+ m/z 386.13, found 385.7.
Step 3: 4-methyl-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-5-(trifluoromethyl)nicotinamide: A solution of 4-methyl-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-5-(trifluoromethyl)nicotinic acid (380 mg, 0.99 mmol) in SOCl2 (10 mL) was heated to 80° C. and stirred for 2 hours. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate dissolved in THE (10 mL) was added to NH3·H2O (3 mL) at 0° C. The resulting mixture was stirred at 25° C. for 1 hour. Then the mixture was quenched with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/2) to provide 4-methyl-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-5-(trifluoromethyl)nicotinamide (200 mg, 52.77%) as yellow oil. LCMS (ESI) calcd. for C15H19F6N4O [M+H]+ m/z 385.15, found 385.1.
Step 4: tert-butyl (R)-(methyl(4-(4-methyl-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)(oxo)-λ6-sulfaneylidene)carbamate: A mixture of 4-methyl-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-5-(trifluoromethyl)nicotinamide (200 mg, 0.52 mmol), tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (262 mg, 0.78 mmol), Cs2CO3 (452 mg, 1.39 mmol) and Xantphos-Pd-G2 (98 mg, 0.11 mmol) in 1,4-dioxane (5 mL) was stirred at 100° C. for 2 hours under nitrogen. After the reaction was completed, the mixture was filtered through celite. The filtrate was concentrated and residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-(methyl(4-(4-methyl-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)(oxo)-λ6-sulfaneylidene)carbamate (220 mg, 66.08%) as a yellow solid. LCMS (ESI) calcd. for C26H33F6N6O4S [M+H]+ m/z 639.22, found 639.2.
Step 5: (R)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-5-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-(methyl(4-(4-methyl-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)(oxo)-λ6-sulfaneylidene)carbamate (210 mg, 0.33 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH=8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN/H2O containing 0.05% NH3) to provide (R)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-2-(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)-5-(trifluoromethyl)nicotinamide (65.0 mg, 36.77%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.63 (d, J=5.4 Hz, 1H), 8.45 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 7.81 (dd, J=5.5, 2.0 Hz, 1H), 4.39 (s, 1H), 3.69-3.59 (m, 4H), 3.30-3.21 (m, 2H), 3.15 (s, 3H), 3.00-2.91 (m, 2H), 2.79-2.72 (m, 2H), 2.30 (s, 3H), 1.85-1.76 (m, 2H). LCMS (ESI) calcd. for C21H25F6N6O2S [M+H]+ m/z 539.17, found 539.2.
Step 1: methyl (cis)-3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)cyclobutane-1-carboxylate: A mixture of 2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinic acid (200 mg, 0.59 mmol) and methyl (cis)-3-aminocyclobutane-1-carboxylate (153 mg, 1.18 mmol) in DMF (5 mL) was added HATU (337 mg, 0.89 mmol) and DIEA (229 mg, 1.77 mmol). The mixture was heated to 80° C. and stirred for 24 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1 to 1/1) to give methyl (cis)-3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)cyclobutane-1-carboxylate (150 mg, 56.9%) as a yellow solid. LCMS (ESI) calcd. for C20H25F5N3O3 [M+H]+ m/z 450.18, found 450.1.
Step 2: (cis)-3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)cyclobutane-1-carboxylic acid: To a solution of methyl (cis)-3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)cyclobutane-1-carboxylate (150 mg, 0.33 mmol) in t-BuOH/THF/H2O (1:1:1, 10 mL) was added KOH (187.3 mg, 3.34 mmol) at room temperature. The mixture was stirred for 2 hours at room temperature. The reaction was monitored by LCMS. After the reaction was completed, the mixture was cooled to room temperature, the reaction was extracted with DCM (20 mL), then the aqueous phase was adjusted to pH=3 with 1 N HCl and extracted with DCM (20 mL×3). The combined organic layers were dried with Na2SO4 and concentrated under vacuum to give (cis)-3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)cyclobutane-1-carboxylic acid (140 mg, 96.3%) as a white solid. LCMS (ESI) calcd. for C19H23F5N3O3 [M+H]+ m/z 436.17, found 436.10.
Step 3: N-((cis)-3-carbamoylcyclobutyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide: To a solution of (cis)-3-(2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamido)cyclobutane-1-carboxylic acid (140 mg, 0.32 mmol) and HATU (183 mg, 0.48 mmol) in DMF (5 mL) was added NH3-MeOH (7M, 5 mL) and DIEA (208 mg, 1.61 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (15 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 60% MeCN/H2O containing 0.05% NH3) to provide N-((cis)-3-carbamoylcyclobutyl)-2-(4,4-difluoroazepan-1-yl)-4-methyl-5-(trifluoromethyl)nicotinamide (28.6 mg, 20.5%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J=7.3 Hz, 1H), 8.35 (s, 1H), 7.22 (s, 1H), 6.75 (s, 1H), 4.33-4.14 (m, 1H), 3.74-3.55 (m, 4H), 2.73-2.62 (m, 1H), 2.40-2.19 (m, 7H), 2.10-1.97 (m, 4H), 1.89-1.76 (m, 2H). LCMS (ESI) calcd. for C19H24F5N4O2 [M+H]+ m/z 435.18, found 435.1.
The potency of the examples listed above are assayed against human Nav1.8 using either SyncroPatch384PE assay or Sophion QPatch II assay described below.
Compounds were tested on recombinant human Nav1.8/b3 stably transfected CHO cells using the SyncroPatch384PE system (Nanion Technologies), an automated patch clamp device. Cells were cultured at 37° C./5% CO2 in Ham's F-12 supplemented with 10% fetal bovine serum, 100 U/mL penicillin G sodium, 100 mg/mL streptomycin sulfate and selection antibiotics (0.01 mg/mL Blasticidin, 0.4 mg/mL Zeocin and 0.25 mg/mL Hygromycin). On the day of the recordings, cells in culture dishes were washed twice with Hank's Balanced Salt Solution (HBSS) and treated with Accutase for approximately 20 minutes. Immediately before use in the SynchroPatch384PE using an 8-hole NPC-384 chip, the cells were washed in HBSS to remove the Accutase and re-suspended in extracellular solution. All experiments were performed at ambient temperature. Intracellular solution contained (mM): CsCl, 50; CsF, 90; MgCl2, 5; EGTA, 1; HEPES, 10; pH adjusted to 7.2 with CsOH. Extracellular solution contained (mM): NaCl, 137; KCl, 4.0; CaCl2), 3.8; MgCl2, 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH. 100 nM tetrodotoxin (TTX) was added to the extracellular solution to block endogenous TTX-sensitive sodium currents.
Compounds were tested in quadruplicate in 0.3% DMSO and 0.03% pluronic Acid. Compounds were diluted 1:3.33 in extracellular solution to create an 8-point concentration response curve. Each plate contained a historical positive control and up to ten compounds. 300 μM tetracaine and 0.3% DMSO+0.03% pluronic acid were used as high and low controls respectively.
Whole cell patch clamp recordings were conducted according to Nanion's standard procedure for SyncroPatch384PE®. Cells were held at a holding potential of −120 mV. A depolarization step to 10 mV for 30 ms was applied (P1 measurement), followed by a hyperpolarization step to −100 mV for 100 ms. An inactivation step at −35 mV for 10 sec was applied before stepping to −100 mV for 20 ms, followed by a step to 10 mV for 30 ms (P2 measurement) and then back to −100 mV for 30 ms. Sweep interval was 15 sec. Following establishment of the whole-cell configuration in extracellular solution, cells were washed in extracellular solution containing 0.3% DMSO and 0.03% pluronic acid to stabilize the baseline current. Compounds were then applied by the SynchroPatch384 PE system into each well and the current was recorded for five minutes in extracellular solution, followed by application of tetracaine to achieve full block at the end of experiment. The potency of the compounds was assessed on two read-outs, resting state block (P1 measurement) or inactivated state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO+pluronic acid) controls.
Examples 1 to 219 and Examples 225 to 236 are assayed using SyncroPatch384PE assay described above.
Compounds were tested on recombinant human Nav1.8/01 stably transfected HEK293 (Eurofins, CYL3025, St. Charles, MO) cells using the Qpatch II system (Sophion Bioscience A/S, Ballerup—Denmark), an automated patch clamp device. Cells were cultured at 37° C./5% CO2 in DMEM/F-12 supplemented with 10% fetal bovine serum, lx Non-Essential Amino Acids, and selection antibiotics (0.625 μg/mL Puromycin, 400 μg/mL Geneticin, and 100 μg/mL Hygromycin). One or two days prior to recording, cells were moved to a lower temperature 30° C./5% CO2 incubator to increase surface expression of the channels. On the day of the recordings, cells in culture dishes were washed twice with Ca2+—Mg2+ free DPBS and treated with Detachin (Genlantis, San Diego) for 3 minutes and then resuspended in Serum Free Medium (EX-CELL® ACF CHO Medium for Cell Culture (Sigma-Aldrich) supplemented with 0.04 mg/mL soybean trypsin Inhibitor and 25 mM HEPES (all components supplied by Sigma-Aldrich, St. Louis, MO) and allowed to recover for a minimum of 20 minutes in the onboard Qstirrer. All experiments were performed at ambient temperature. Intracellular solution contained (mM): CsCl, 50; CsF, 90; MgCl2, 2; EGTA, 5; HEPES, 10; pH adjusted to 7.2 with CsOH. Extracellular solution contained (mM): NaCl, 137; KCl, 4; CaCl2), 3.8; MgCl2, 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH. 500 nM tetrodotoxin (TTX) was added to the extracellular solution to block endogenous TTX-sensitive sodium currents.
Compounds were tested in an interleaved manner across two cohorts of wells to develop an aggregate 8-point concentration response curve. Final concentrations include 0.5% DMSO and 0.03% pluronic Acid. The concentration range spanned a range from 0.01-300 nM. Compounds were diluted 1:10 with extracellular solution within their respective cohort. (R)-2-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide served as a positive control while DMSO (0.5% by volume) served as a vehicle control to ascertain assay performance.
Whole cell patch clamp recordings were conducted according to Sophion standard procedure for Qpatch II®. Cells were held at a holding potential of −120 mV. A depolarizing step to 10 mV for 30 ms was applied (TP1 measurement), followed by a hyperpolarization step to −100 mV for 20 ms. Due to instability observed at long depolarized potentials, there were no second TP2 measurements attempted. Inter-sweep interval was 15 sec. Following establishment of the whole-cell configuration in extracellular solution, cells were washed twice in extracellular solution containing 0.5% DMSO and 0.03% pluronic acid to stabilize the baseline current. Compounds were then applied by the Qpatch II system into each well in an ascending manner within cohort and the current was recorded for five minutes for each concentration. Percent of current remaining was determined by taking the average of the last 5 sweeps within each concentration and normalizing to the latest pre-compound saline period. The potency of the compounds was assessed on resting state block (TP1 measurement) only to obtain IC50 values. Wells whose initial sodium current magnitude were below 2 nA or whole cell resistance fell below 100 MQ were excluded from analysis.
Examples 220 to 224, Examples 237 to 257 and Example 259 are assayed using Sophion Qpatch II assay described above.
Table 1 shows the potency of compounds against human Nav1.8, where “A” represents an IC50 less than or equal to 5 nM, “B” represents an IC50 greater than 5 nM to less than or equal to 50 nM, “C” represents an IC50 greater than 50 nM to less than or equal to 100 nM, “D” represents an IC50 greater than 100 nM to less than or equal to 200 nM, “E” represents an IC50 greater than 200 nM.
It is well known that plasma protein binding modulates the effective drug concentrations at pharmacological target sites (J. Pham Sci (2013) 102, 2953-2994). Free drug theory holds that, absent active uptake mechanisms, free drug in plasma is equal to free drug concentration in tissues and only unbound drug in tissue is contributory to target receptor binding and pharmacologic activity (Expert Opin. Drug Discov. (2007) 2, 51-64). In general, drugs of a given potency against a biological target having reduced plasma protein binding can affect pharmacology with lower total plasma concentrations than comparable drugs with higher plasma protein binding. Hence, increasing the plasma free fraction can have a favorable impact on a drug's effective modulation of a biological target and the resulting pharmacologic activity per dose.
In the present invention, without being bound by any mechanism, unexpected increases in plasma drug free fraction (reduced drug-plasma protein binding) have been found for compounds of Formula I when R2 is a sulfoximine. For example, in certain embodiments of the invention, wherein R2 is
and wherein, X1 is O and X2 is NH. As demonstrated from the data below, the compounds comprising R2 is sulfoximine has a better free plasma concentration as compared to the compounds of Formula (I), wherein R2 is sulfonamido, i.e., (X1 and X2 are O and R4 is NH2).
Table 2 presents sulfoximine compounds of the invention alongside comparator sulfonamide compounds. Table 3 presents the human and rat plasma protein binding data (% unbound) for the compounds of Table 2.
Comparator compounds A, B, C have been previously reported as inhibitors of Na, 1.8 in WO2020/092667. Comparator D, not previously reported, is offered as an additional sulfonamido example. As indicated in Table 3, sulfoximines of the present invention, namely Example 101, Example 17 and Example 4 exhibit free fractions of 1.8, 1.7, and 0.9% in an assay measuring human plasma protein binding. Further, Example 101, Compound E, Example 4, and Example 17 exhibit plasma free fractions of 3.55, 37.8, 3.0, and 1.9% respectively in an assay measuring rat plasma protein binding. In contrast, the comparator sulfonamido Compounds A, B, C, and D have been found to exhibit plasma free fractions of 0.24, 17.4, 0.53, and 0.31% respectively in an assay measuring human plasma protein binding and 0.52, 15.8, 1.62, and 0.31% respectively in an assay measuring rat plasma protein binding.
1Human Plasma binding was measured by equilibrium dialysis as generally described by Jitendra Kumar et al., J Bioequiv Availab (2012), S14.
2Fold increase is reported as the ratios of Ex 101/Compound A; Ex 17/Compound C; Ex 4/Compound D
3Rat Plasma binding was measured by equilibrium dialysis as generally described by Jitendra Kumar et al., J Bioequiv Availab (2012), S14.
4Fold increase is reported as the ratios of Ex 101/Compound A; Compound E/Compound B; Ex 17/Compound C; Ex 4/Compound D
5Compound E is the racemate of Examples 18 and 19.
Thus, on a comparable structural basis, sulfoximine compounds of the invention in Table 3 exhibit 2.9-7.5 fold higher plasma free fractions in human plasma and 1.9-6.8 fold higher plasma free fractions in rat plasma than sulfonamide comparator compounds. This unexpected increase in plasma free fraction improves the drug-like properties of sulfoximines of Formula I versus analogous sulfonamides.
References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure.
All such documents are hereby incorporated herein by reference in their entirety for all purposes.
Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification, and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2023/012172 | 2/2/2023 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63354509 | Jun 2022 | US | |
| 63306695 | Feb 2022 | US |
