JP2024520457A - Sulfur-containing heteroaromatic tricyclic KRAS inhibitors - Google Patents

Abstract

The present embodiments provide compounds of formula I, pharmaceutical compositions of the compounds, and methods for treating diseases such as cancer.

Description

Embodiments herein relate to compounds, compositions, and methods for the treatment of RAS-mediated diseases. In particular, embodiments herein relate to compounds and methods for treating diseases such as cancer by targeting oncogenic mutants of the K-RAS isoform.

Ras proteins are small guanine nucleotide-binding proteins that function as molecular switches by cycling between active GTP-bound and inactive GDP-bound structures. Ras signaling is controlled by a balance between activation by guanine nucleotide exchange factors (GEFs), usually by Sons of Sevenless (SOS), and inactivation by GTPase-activating proteins (GAPs), such as neurofibromin or p120GAP. Ras proteins play a key role in controlling cell proliferation, differentiation, and survival. Dysregulation of the Ras signaling pathway is almost exclusively associated with disease. Hyperactivating somatic mutations of Ras are one of the most common lesions in human cancer. Most of these mutations have been shown to reduce the sensitivity of Ras to GAP stimulation, reducing its intrinsic GTPase activity and leading to an increase in the active GTP-bound population. Mutations in any one of the three Ras isoforms (K-Ras, N-Ras, or H-Ras) have been shown to cause oncogenic transformation, with K-Ras mutations being the most common in human cancers. For example, K-Ras mutations are known to be frequently associated with pancreatic cancer, colon cancer, and non-small cell lung cancer. Similarly, H-Ras mutations are common in cancers such as papillary thyroid cancer, lung cancer, and skin cancer. Finally, N-Ras mutations occur frequently in hepatocellular carcinoma.

K-Ras is the most frequently mutated oncoprotein in human cancers. Thus, there is a need to develop selective inhibitors of mutant KRAS. The present embodiments meet this and other needs.

（式中、
Ｚは、ＯまたはＳであり、
ｍは、１または２であり、
ｐは、１または２であり、
Ｌ^１は、

であり、
ｋは、０～４の整数であり、Ｒ^１のそれぞれは独立して、メチル、シアノメチル、Ｃ_２～Ｃ_４アルキル、シアノ、シクロアルキル、ハロ、ハロアルキル、トリフルオロメチル、及びアルコキシから選択され、または、任意の２つのＲ^１が結合して、架橋もしくはスピロ環にＳ、ＳＯ_２、ＯもしくはＮから選択されるヘテロ原子を必要に応じて含む縮合環、架橋もしくはスピロ環構造を形成し、架橋またはスピロ環構造は、必要に応じてオキソで置換され、
Ｒ^２のそれぞれは、アルキル、Ｎ－アルキルアミノ、Ｎ，Ｎ－ジアルキルアミノ、アルキルアミドアルキル、アリールアミドアルキル、－ＯＣＨ_２ＣＯＮＲＲ’からなる群から独立して選択され、Ｒ及びＲ’は独立して、水素、アルキル、ならびにいずれも必要に応じて置換されたシクロアルキル、アルキルスルホンアミドアルキル、アリールスルホンアミドアルキル、Ｎ－アルキルアミノアルキル、Ｎ，Ｎ－ジアルキルアミノアルキル、アルコキシ、アルコキシアルキル、シクロアルキル、アルキルシクロアルキル、ヒドロキシアルキル、ハロゲン、ハロアルキル、アリール、アリールオキシ、アラルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル、ヘテロシクリルアルキル、及びヘテロアリールオキシから選択され、または、ｍが２の場合、２つのＲ^２が結合して、Ｎ、Ｏ、もしくはＳから選択される１～３個のヘテロ原子を必要に応じて含むスピロ環式３～６員環を形成し、
Ｒ^３、Ｒ^４、Ｒ^５、及びＲ^６は独立して、ハロゲン、水素、ヒドロキシル、アルコキシ、アルキル、シクロアルキル、アミノ、Ｎ－アルキルアミノ、Ｃ－アミド（－ＣＯＮＲＲ’）、Ｎ－アミド（－ＮＨＣＯＲ）、尿素（－ＮＨＣＯＮＨＲ）、エーテル（－ＯＲ）、スルホンアミド（－ＮＨＳＯ_２Ｒもしくは－ＳＯ_２ＮＨＲ）、及びＣＦ_３から選択され、各Ｒ及びＲ’は独立して、水素、アルキル、またはシクロアルキルであり、または
任意の２つの隣接するＲ^３、Ｒ^４、Ｒ^５、もしくはＲ^６は、Ｎ、ＯもしくはＳから選択される０～３個のヘテロ原子を含む、必要に応じて置換された縮合５員環もしくは６員環を形成し、
ただし、Ｒ^３、Ｒ^４、Ｒ^５、またはＲ^６の１つが２－キナゾリノンへの結合である場合、
Ｒ^７は、アルキル、シアノ、シクロアルキル、ハロゲン、ハロアルキル、トリフルオロメチル、及びアルコキシである） （Ｉ） In one aspect, the present embodiments provide a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof:

(Wherein,
Z is O or S;
m is 1 or 2;
p is 1 or 2;
^L1 is

and
k is an integer from 0 to 4, each R ¹ is independently selected from methyl, cyanomethyl, C ₂ -C ₄ alkyl, cyano, cycloalkyl, halo, haloalkyl, trifluoromethyl, and alkoxy, or any two R ¹ are joined to form a fused ring, bridged, or spiro ring structure optionally containing a heteroatom selected from S, SO ₂ , O, or N in the bridge or spiro ring, and the bridge or spiro ring structure is optionally substituted with oxo;
each R ² is independently selected from the group consisting of alkyl, N-alkylamino, N,N-dialkylamino, alkylamidoalkyl, arylamidoalkyl, -OCH ₂ CONRR', where R and R' are independently selected from hydrogen, alkyl, and cycloalkyl, alkylsulfonamidoalkyl, arylsulfonamidoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halogen, haloalkyl, aryl, aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and heteroaryloxy, each of which is optionally substituted; or when m is 2, two R ² are joined to form a spirocyclic 3-6 membered ring optionally containing 1-3 heteroatoms selected from N, O, or S;
R ³ , R ⁴ , R ⁵ , and R ⁶ are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino, C-amido (-CONRR'), N-amido (-NHCOR), urea (-NHCONHR), ether (-OR), sulfonamido (-NHSO ₂ R or -SO ₂ NHR), and CF ₃ , where each R and R' is independently hydrogen, alkyl, or cycloalkyl; or any two adjacent R ³ , R ⁴ , R ⁵ , or R ⁶ form an optionally substituted fused 5- or 6-membered ring containing 0-3 heteroatoms selected from N, O, or S;
With the proviso that when one of R ³ , R ⁴ , R ⁵ , or R ⁶ is a bond to the 2-quinazolinone,
^R7 is alkyl, cyano, cycloalkyl, halogen, haloalkyl, trifluoromethyl, and alkoxy. (I)

In another aspect, the present invention provides a pharmaceutical composition comprising a pharma- ceutical effective amount of a compound disclosed herein, or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable excipient.

In another embodiment, the present invention provides a method of treating a subject having cancer, wherein the cancer is characterized by the presence of a KRAS G12C mutation, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

In another embodiment, the present invention provides a method for preparing a medicament for treating a subject having cancer, the cancer being characterized by the presence of a KRAS G12C mutation, using a medicament comprising a compound disclosed herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

In another embodiment, the present invention provides a use of a compound disclosed herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for the preparation of a medicament for treating cancer in a subject characterized by the presence of a KRAS G12C mutation.

In another embodiment, the present embodiments provide a compound disclosed herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating cancer in a subject, wherein the cancer is characterized by a KRAS G12C mutation.

I. Overview The present embodiments provide inhibitors of KRAS G12C that exhibit good selectivity over wild-type KRAS and are useful in the treatment of cancers characterized by KRAS G12C mutations.

II. Definitions Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. Furthermore, any method or material similar or equivalent to the method or material described herein can be used to practice the present invention. For the purposes of the present invention, the following terms are defined.

As used herein, "a," "an," or "the" includes aspects of one member as well as aspects of multiple members. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a cell" includes a plurality of such cells, a reference to "the agent" includes a reference to one or more agents known to those of skill in the art, and so forth.

"Alkyl" refers to a straight or branched chain saturated aliphatic group having the number of carbon atoms indicated. Alkyl can contain any number of carbons, such _{as C1-2} , _C1-3 , _C1-4 , C1-5, C1-6, _C1-7, C1-8 _{, C1-9, C1-10} , _C2-3 , _C2-4 , _{C2-5 , C2-6} , _C3-4 , _{C3-5 , C3-6} , _{C4-5 , C4-6} , and _C5-6 . For example, _C1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and the like. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.

"Alkylene" refers to a straight or branched chain saturated aliphatic group having the number of carbon atoms indicated and linking at least two other groups, i.e., divalent hydrocarbon groups. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For example, a straight chain alkylene can be a divalent group of -(CH ₂ ) _n -, where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. Alkylene groups can be substituted or unsubstituted.

"Alkenyl" refers to a straight or branched chain hydrocarbon having at least two carbon atoms and _at least one double bond. Alkenyl can contain any number of carbons, such as _C2 , _C2-3 , _C2-4 , _C2-5 , _{C2-6, C2-7} , C2-8, C2-9, _C2-10 , _C3 , _C3-4 , _C3-5 , _{C3-6 , C4} , _C4-5 , _C4-6 , _C5 , _C5-6 , and _C6 . Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, ₅ or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.

"Alkenylene" refers to an alkenyl group, as defined above, that links at least two other groups, i.e., divalent hydrocarbon groups. The two moieties linked to the alkenylene can be attached to the same atom or different atoms of the alkenylene. Alkenylene groups include, but are not limited to, ethenylene, propenylene, isopropenylene, butenylene, isobutenylene, sec-butenylene, pentenylene, and hexenylene. Alkenylene groups can be substituted or unsubstituted.

"Alkynyl" refers to a straight or branched chain hydrocarbon having at least two carbon atoms and at least one triple bond. Alkynyl can contain _any number of carbons, such as _C2 , _C2-3 , _C2-4 , _C2-5 , _C2-6 , C2-7, C2-8 _{, C2-9, C2-10} , _{C3 , C3-4} , _C3-5 , C3-6 _{, C4} , _C4-5 , _C4-6 , _{C5, C5-6 ,} and _C6 . Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted.

"Alkynylene" refers to an alkynyl group, as defined above, that links at least two other groups, i.e., divalent hydrocarbon groups. The two moieties linked to the alkynylene can be attached to the same atom or different atoms of the alkynylene. Alkynylene groups include, but are not limited to, ethynylene, propynylene, isopropynylene, butynylene, sec-butynylene, pentynylene, and hexynylene. Alkynylene groups can be substituted or unsubstituted.

"Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to its point of attachment, i.e., alkyl-O-. As with the alkyl group, the alkoxy group can have any suitable number of carbon atoms, such as C _1-6 . Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like. Alkoxy groups can be further substituted with a variety of substituents described herein. Alkoxy groups can be substituted or unsubstituted.

"Alkoxyalkyl" refers to a group having an alkyl component and an alkoxy component, where the alkyl component bonds the alkoxy component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene that bonds to _the alkoxy component and to the point of attachment. The alkyl component can contain any number of carbons, such as _C0-6 , _C1-2 , _C1-3 , _C1-4 , _C1-5 , _C1-6 , _C2-3 , C2-4, _{C2-5, C2-6, C3-4, C3-5 , C3-6 , C4-5, C4-6} , and _C5-6 . The alkoxy component is as defined above. Examples of alkoxyalkyl groups include, but are not limited to, 2-ethoxy-ethyl and methoxymethyl.

"Alkylhydroxy" or "hydroxyalkyl" refers to an alkyl group, as defined above, in which at least one of the hydrogen atoms has been replaced with a hydroxy group. With respect to the alkyl group, the alkylhydroxy group can have any suitable number of carbon atoms, such as C _1-6 . Exemplary alkylhydroxy groups include, but are not limited to, hydroxymethyl, hydroxyethyl (hydroxy is in the 1- or 2-position), hydroxypropyl (hydroxy is in the 1-, 2- or 3-position), hydroxybutyl (hydroxy is in the 1-, 2-, 3- or 4-position), hydroxypentyl (hydroxy is in the 1-, 2-, 3-, 4- or 5-position), hydroxyhexyl (hydroxy is in the 1-, 2-, 3-, 4-, 5- or 6-position), 1,2-dihydroxyethyl, and the like.

"Halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

"Haloalkyl" refers to an alkyl, as defined above, in which some or all of the hydrogen atoms have been replaced with halogen atoms. With respect to the alkyl group, the haloalkyl group can have any suitable number of carbon atoms, such as C _1-6 . For example, haloalkyl includes trifluoromethyl, fluoromethyl, and the like. In some cases, the term "perfluoro" may be used to define a compound or group in which all hydrogens have been replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

"Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms have been replaced with halogen atoms. As with the alkyl group, the haloalkoxy group can have any suitable number of carbon atoms, such as C _1-6 . The alkoxy group can be substituted with one, two, three, or more halogens. When all hydrogens are replaced with halogens, e.g., fluorine, the compound is persubstituted, e.g., perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like.

"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic, fused bicyclic or bridged polycyclic ring assembly containing 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyls include any number _of carbons, such as _C3-6 , _{C4-6, C5-6 , C3-8} , _C4-8 , _C5-8 , C6-8, _C3-9 , _C3-10 , _C3-11 , and _C3-12 . Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can have one or more double or triple bonds within the ring and can be partially unsaturated. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene. When cycloalkyl is a saturated monocyclic C _3-8 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When cycloalkyl is a saturated monocyclic C _3-6 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.

"Cycloalkylene" refers to a cycloalkyl group having the indicated number of carbon atoms and linking at least two other groups, i.e., a divalent group. The two moieties linked to the cycloalkylene can be linked to the same atom or different atoms of the cycloalkylene group. Examples of cycloalkylene rings include cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene, among others. The cycloalkylene group can be linked 1,1, 1,2, 1,3, or 1,4. For example, the cyclohexylene ring can adopt many conformations, including boat and chair conformations. The chair conformation of cyclohexylene can have substituents in an axial or equatorial orientation. The divalent nature of cycloalkylene gives rise to cis and trans formations, with cis referring to both substituents being on the same side (top or bottom) of the cycloalkylene ring and trans referring to the substituents being on opposite sides of the cycloalkylene ring. For example, cis-1,2- and cis-1,4-cyclohexylene can have one substituent in the axial orientation and another in the equatorial orientation, and trans-1,2- and trans-1,4-cyclohexylene can have both substituents in the axial or equatorial orientation. Cis-1,3-cyclohexylene can have both substituents in the axial or equatorial orientation, and trans-1,3-cyclohexylene can have one substituent in the axial orientation and another in the equatorial orientation. The cyclohexylene group can be substituted or unsubstituted.

"Alkyl-cycloalkyl" refers to a group having an alkyl component and a cycloalkyl component, where the alkyl component bonds to the cycloalkyl component at the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene that bonds to the cycloalkyl component and to the point of attachment. In some cases, the alkyl component can be absent. The alkyl component can contain any _{number of carbons} , such as _C1-6 , _C1-2 , _C1-3 , _{C1-4 , C1-5} , _C2-3 , _{C2-4 , C2-5, C2-6} , C3-4, _{C3-5, C3-6, C4-5 , C4-6} , and _C5-6 . The cycloalkyl component is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

"Heterocycloalkyl" or "heterocyclyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. Additional heteroatoms are also useful and include, but are not limited to, B, Al, Si, and P. Heteroatoms such as, but not limited to, -S(O)- and -S(O) ₂ - are also oxidized. Heterocycloalkyl groups can contain any number of ring atoms, for example, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Heterocycloalkyl groups can contain any suitable number of heteroatoms, for example, 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Heterocycloalkyl groups can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, dithiane, and hexahydro-1H-pyrrolidine. Heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with C _1-6 alkyl or oxo (=O), among others.

The heterocycloalkyl group can be attached via any position on the ring. For example, aziridine can be 1- or 2-aziridine, azetidine can be 1- or 2-azetidine, pyrrolidine can be 1-, 2-, or 3-pyrrolidine, piperidine can be 1-, 2-, 3-, or 4-piperidine, pyrazolidine can be 1-, 2-, 3-, or 4-pyrazolidine, imidazolidine can be 1-, 2-, 3-, or 4-imidazolidine, piperazine can be 1-, 2-, 3-, or 4-piperazine, tetrahydrofuran can be 1- or 2-tetrahydrofuran, oxazolidine can be 2-, 3-, 4-, or 5-oxazolidine, isoxazolidine can be 2-, 3-, 4-, or 5-isoxazolidine, thiazolidine can be 2-, 3-, 4-, or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4-, or 5-isothiazolidine, and morpholine can be 2-, 3-, or 4-morpholine.

When a heterocycloalkyl contains 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. Heterocycloalkyls can also form rings with 5 to 6 ring members and 1 to 2 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, and hexahydro-1H-pyrrolidine.

"Heterocycloalkylene" refers to a heterocycloalkyl group, as defined above, that is linked to at least two other groups. The two moieties linked to the heterocycloalkylene can be linked to the same atom or to different atoms of the heterocycloalkylene. The heterocycloalkylene group can be substituted or unsubstituted.

"Alkyl-heterocycloalkyl" refers to a group having an alkyl component and a heterocycloalkyl component, where the alkyl component bonds the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene that bonds to _the heterocycloalkyl component and to the point of attachment. The alkyl component can contain any number of carbons, such as _C0-6 , _{C1-2 , C1-3} , _C1-4 , _C1-5 , _{C1-6, C2-3, C2-4} , _C2-5 , C2-6 _{, C3-4, C3-5, C3-6} , C4-5, _C4-6 , and _C5-6 . In some cases, the alkyl component can be absent. The heterocycloalkyl component is as defined above. The alkyl-heterocycloalkyl group can be substituted or unsubstituted.

"Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can contain any suitable number of ring atoms, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or joined by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with methylene linking groups. Some aryl groups, such as phenyl, naphthyl, or biphenyl, have 6 to 12 ring members. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. Aryl groups can be substituted or unsubstituted.

"Alkyl-aryl" refers to a group having an alkyl component and an aryl component, where the alkyl component bonds the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene that bonds to the aryl component and to the point of attachment. The alkyl component can contain any number of carbons, such as _{C0-6 , C1-2 , C1-3} , _C1-4 , _{C1-5 , C1-6} , _C2-3 , C2-4, C2-5, _{C2-6 ,} C3-4 _{, C3-5, C3-6 ,} C4-5 _{, C4-6} , and _C5-6 . In some cases, the alkyl component can be absent. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethyl-benzene. The alkyl-aryl group can be substituted or unsubstituted.

"Arylene" refers to an aryl group, as defined above, that links at least two other groups. The two moieties that are linked to the aryl can be linked to the same atom or different atoms of the aryl. An arylene group can be substituted or unsubstituted.

"Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where 1 to 5 of the ring atoms are heteroatoms such as N, O, or S. Additional heteroatoms are also useful, including, but not limited to, B, Al, Si, and P. Heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O) ₂ -. Heteroaryl groups can contain any number of ring atoms, for example, 5 to 6, 5 to 8, 6 to 8, 5 to 9, 5 to 10, 5 to 11, or 5 to 12 ring members. Heteroaryl groups can contain any suitable number of heteroatoms, for example, 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5, etc. Heteroaryl groups can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can also be fused to aromatic ring systems such as a phenyl ring to form groups including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings joined by a bond, such as bipyridine.The heteroaryl group can be substituted or unsubstituted.

Heteroaryl groups can be attached through any position on the ring. For example, pyrrole is 1-, 2-, and 3-pyrrole, pyridine is 2-, 3-, and 4-pyridine, imidazole is 1-, 2-, 4-, and 5-imidazole, pyrazole is 1-, 3-, 4-, and 5-pyrazole, triazole is 1-, 4-, and 5-triazole, tetrazole is 1- and 5-tetrazole, pyrimidine is 2-, 4-, 5-, and 6-pyrimidine, pyridazine is 3- and 4-pyridazine, 1,2,3-triazine is 4- and 5-triazine, 1,2,4-triazine is 3-, 5-, and 6-triazine, 1,3,5-triazine is 2-triazine, thiophene is 2- and 3-thiophene, furan is 2- and and 3-furan, thiazole includes 2-, 4-, and 5-thiazole, isothiazole includes 3-, 4-, and 5-isothiazole, oxazole includes 2-, 4-, and 5-oxazole, isoxazole includes 3-, 4-, and 5-isoxazole, indole includes 1-, 2-, and 3-indole, isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3-, and 4-quinoline, isoquinoline includes 1-, 3-, and 4-isoquinoline, quinazoline includes 2- and 4-quinoazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes 2- and 3-benzofuran.

Some heteroaryl groups include those having 5 to 10 ring members and 1 to 3 ring atoms containing N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those with 5 to 8 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those with 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine. Additionally, other heteroaryl groups include those having 5-6 ring members and 1-2 ring atoms containing N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

Some heteroaryl groups contain 5 to 10 ring members and only nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline. Other heteroaryl groups contain 5 to 10 ring members and only oxygen heteroatoms, such as furan and benzofuran. Some other heteroaryl groups contain 5 to 10 ring members and only sulfur heteroatoms, such as thiophene and benzothiophene. Additionally, other heteroaryl groups contain 5 to 10 ring members and at least 2 heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, cinnoline, and the like.

"Heteroarylene" refers to a heteroaryl group, as defined above, that links at least two other groups. The two moieties that are linked to the heteroaryl are linked to different atoms of the heteroaryl. The heteroarylene group may be substituted or unsubstituted.

"Alkyl-heteroaryl" refers to a group having an alkyl component and a heteroaryl component, where the alkyl component bonds the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene that bonds to the heteroaryl component and to the point of attachment. The alkyl component can contain any number of carbons, such as _C0-6 , _C1-2 , _{C1-3 , C1-4 , C1-5, C1-6} , _{C2-3, C2-4, C2-5 , C2-6 , C3-4 , C3-5, C3-6} , C4-5, _C4-6 , and _C5-6 . In some cases, the alkyl component can be absent. The heteroaryl component is as defined herein. The alkyl-heteroaryl group can be substituted or unsubstituted.

The groups defined above may be optionally substituted with any suitable number and type of substituents. Representative substituents include halogen, haloalkyl, haloalkoxy, -OR', =O, -OC(O)R', -(O)R', -O ₂ R', -ONR'R", -OC(O)NR'R", =NR', =N-OR', -NR'R", -NR"C(O)R', -NR'-(O)NR"R"', -NR"C(O)OR', -NH-(NH ₂ )=NH, -NR'C(NH ₂ )=NH, -NH-(NH ₂ )=NR', -SR', -S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R", -NR'S(O) ₂ R", -N ₃ and -NO. Examples of such rings include, but are not limited to, _2. R', R", and R'" each independently represent hydrogen, unsubstituted alkyl, for example, unsubstituted _C1-6 alkyl. Alternatively, R' and R", or R" and R'", when attached to the same nitrogen, combine with the nitrogen to which they are attached to form a heterocycloalkyl or heteroaryl ring as defined above.

"Salt" refers to an acid or base salt of a compound that can be used in the methods disclosed herein. Specific examples of pharma-ceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It is understood that pharma-ceutically acceptable salts are non-toxic. Further information regarding suitable pharma-ceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

Pharmaceutically acceptable salts of the acidic compounds disclosed herein are salts formed with bases, i.e., cationic salts such as alkali metal salts and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.

Similarly, acid addition salts of mineral acids, organic carboxylic acids and organic sulfonic acids, such as hydrochloric acid, methanesulfonic acid, maleic acid, etc., are also possible, so long as a basic group such as pyridyl is part of the structure.

The neutral form of the compound 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, but otherwise the salts are equivalent to the parent form of the compound for purposes of the present embodiments.

Certain compounds disclosed herein have asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the embodiments of the invention.

"Hydrate" refers to a compound that is complexed with at least one water molecule. The compounds disclosed herein can be complexed with 1-10 water molecules.

As used herein, "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

"Pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to and absorption by a subject. Pharmaceutical excipients useful in this embodiment include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, and coloring agents. One of skill in the art will recognize that other pharmaceutical excipients are useful in this embodiment.

"Treate," "treating," and "treatment" refer to indications of success in treating or ameliorating an injury, medical condition, state, or symptom (e.g., pain), including objective or subjective parameters such as relief, sedation, relief of symptoms, or making the symptom, injury, medical condition, or condition more tolerable to the patient, reducing the frequency or duration of the symptom or condition, or, in some circumstances, preventing the onset of the symptom. Treatment or amelioration of symptoms can be based on objective or subjective parameters, including, for example, the results of a physical exam.

"Administration" refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or implantation of a sustained release device, e.g., a mini-osmotic pump, into a subject.

"Therapeutically effective amount or dose" or "therapeutically sufficient amount or dose" or "effective or sufficient amount or dose" refers to a dose that produces the therapeutic effect for which it is administered. The exact dose will depend on the purpose of the treatment, and can be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Co., 1999). (See Wilkins.) In sensitized cells, the therapeutically effective amount is often lower than the conventional therapeutically effective amount in non-sensitized cells.

"Subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

（式中、
ｍは、１または２であり、
ｐは、１または２であり、
Ｌ^１は、

であり、
ｋは、０～４の整数であり、Ｒ^１のそれぞれは独立して、メチル、シアノメチル、Ｃ_２～Ｃ_４アルキル、シアノ、シクロアルキル、ハロ、ハロアルキル、トリフルオロメチル、及びアルコキシから選択され、または、任意の２つのＲ^１が結合して、架橋もしくはスピロ環にＳ、ＳＯ_２、ＯもしくはＮから選択されるヘテロ原子を必要に応じて含む縮合環、架橋もしくはスピロ環構造を形成し、架橋またはスピロ環構造は、必要に応じてオキソで置換され、
Ｒ^２は、いずれも必要に応じて置換されたアルキル、Ｎ－アルキルアミノ、Ｎ，Ｎ－ジアルキルアミノ、アルキルアミドアルキル、アリールアミドアルキル、アルキルスルホンアミドアルキル、アリールスルホンアミドアルキル、Ｎ－アルキルアミノアルキル、Ｎ，Ｎ－ジアルキルアミノアルキル、アルコキシ、アルコキシアルキル、シクロアルキル、アルキルシクロアルキル、ヒドロキシアルキル、ハロゲン、ハロアルキル、アリール、アラルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクリル、及びヘテロシクリルアルキルからなる群から選択され、または、ｍが２の場合、２つのＲ^２が結合して、Ｎ、Ｏ、もしくはＳから選択される１～３個のヘテロ原子を必要に応じて含むスピロ環式３～６員環を形成し、
Ｒ^３、Ｒ^４、Ｒ^５、及びＲ^６は独立して、ハロゲン、水素、ヒドロキシル、アルコキシ、アルキル、シクロアルキル、アミノ、Ｎ－アルキルアミノ、Ｃ－アミド（－ＣＯＮＲＲ’）、Ｎ－アミド（－ＮＨＣＯＲ）、尿素（－ＮＨＣＯＮＨＲ）、エーテル（－ＯＲ）、スルホンアミド（－ＮＨＳＯ_２Ｒもしくは－ＳＯ_２ＮＨＲ）、及びＣＦ_３から選択され、各Ｒ及びＲ’は独立して、水素、アルキル、またはシクロアルキルであり、または
任意の２つの隣接するＲ^３、Ｒ^４、Ｒ^５、もしくはＲ^６は、Ｎ、ＯもしくはＳから選択される０～３個のヘテロ原子を含む、必要に応じて置換された縮合５員環もしくは６員環を形成し、
ただし、Ｒ^３、Ｒ^４、Ｒ^５、またはＲ^６の１つが２－キナゾリノンへの結合である場合、
Ｒ^７は、アルキル、シアノ、シクロアルキル、ハロゲン、ハロアルキル、トリフルオロメチル、及びアルコキシである） III. Compounds The present embodiments provide compounds of formula (I) and pharma- ceutically acceptable salts thereof.

(Wherein,
m is 1 or 2;
p is 1 or 2;
^L1 is

and
k is an integer from 0 to 4, each R ¹ is independently selected from methyl, cyanomethyl, C ₂ -C ₄ alkyl, cyano, cycloalkyl, halo, haloalkyl, trifluoromethyl, and alkoxy, or any two R ¹ are joined to form a fused ring, bridged, or spiro ring structure optionally containing a heteroatom selected from S, SO ₂ , O, or N in the bridge or spiro ring, and the bridge or spiro ring structure is optionally substituted with oxo;
^R2 is selected from the group consisting of alkyl, N-alkylamino, N,N-dialkylamino, alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl, arylsulfonamidoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halogen, haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each of which is optionally substituted; or when m is 2, two ^R2 are joined to form a spirocyclic 3-6 membered ring optionally containing 1-3 heteroatoms selected from N, O, or S;
R ³ , R ⁴ , R ⁵ , and R ⁶ are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino, C-amido (-CONRR'), N-amido (-NHCOR), urea (-NHCONHR), ether (-OR), sulfonamido (-NHSO ₂ R or -SO ₂ NHR), and CF ₃ , where each R and R' is independently hydrogen, alkyl, or cycloalkyl; or any two adjacent R ³ , R ⁴ , R ⁵ , or R ⁶ form an optionally substituted fused 5- or 6-membered ring containing 0-3 heteroatoms selected from N, O, or S;
With the proviso that when one of R ³ , R ⁴ , R ⁵ , or R ⁶ is a bond to the 2-quinazolinone,
^R7 is alkyl, cyano, cycloalkyl, halogen, haloalkyl, trifluoromethyl, and alkoxy.

（式中、Ａｒ^１は、Ｃ結合アリール、ヘテロアリール、複素環、または炭素環であり、
ｎは、０～３の整数であり、及び
Ｒ^１０のそれぞれは、アルキル、アミノ、シアノハロゲン、トリフルオロメチル、ヘテロシクリルから独立して選択され、または２つのＲ^１０が結合して、二環式縮合複素環を形成する） In embodiments, provided herein are compounds having the formula (IIa) and pharma- ceutically acceptable salts thereof:

wherein Ar ¹ is a C-linked aryl, heteroaryl, heterocycle, or carbocycle;
n is an integer from 0 to 3, and each R ¹⁰ is independently selected from alkyl, amino, cyanohalogen, trifluoromethyl, heterocyclyl, or two R ¹⁰ are joined to form a bicyclic fused heterocycle.

（式中、Ａｒ^２は、Ｎ－結合ヘテロアリールまたは複素環であり、
ｎは、０～３の整数であり、及び
Ｒ^１０のそれぞれは、アルキル、アミノ、シアノハロゲン、トリフルオロメチル、及びヘテロシクリルから独立して選択され、または２つのＲ^１０が結合して、二環式縮合複素環を形成する） In embodiments, provided herein are compounds having the formula (IIb) or a pharma- ceutically acceptable salt thereof:

wherein ^Ar2 is an N-linked heteroaryl or heterocycle;
n is an integer from 0 to 3, and each R ¹⁰ is independently selected from alkyl, amino, cyanohalogen, trifluoromethyl, and heterocyclyl, or two R ¹⁰ are joined to form a bicyclic fused heterocycle.

（式中、Ａｒ^３は、アリールまたはヘテロアリールであり、
ｎは、０～３の整数であり、及び
Ｒ^１０のそれぞれは、アルキル、アミノ、シアノハロゲン、トリフルオロメチル、ヘテロシクリルから独立して選択され、または２つのＲ^１０が結合して、二環式縮合複素環を形成する） In embodiments, provided herein are compounds having the formula (IIc) or a pharma- ceutically acceptable salt thereof:

wherein ^Ar3 is aryl or heteroaryl;
n is an integer from 0 to 3, and each R ¹⁰ is independently selected from alkyl, amino, cyanohalogen, trifluoromethyl, heterocyclyl, or two R ¹⁰ are joined to form a bicyclic fused heterocycle.

In an embodiment, n is 1. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4.

In an embodiment, p is 1. In an embodiment, p is 2.

から選択され、

は、Ｌ^１の２つの窒素原子のいずれかを介して結合される。 In an embodiment, ^L1 is

is selected from

is bonded via any of the two nitrogen atoms of ^L1 .

Ｃ結合アリールまたはヘテロアリール、Ｎ結合ヘテロアリールまたはヘテロシクリルから選択され、Ｒ及びＲ’は独立して、水素、アルキル、及びシクロアルキルから選択される。 In embodiments, R ² is methoxy, amino, MeOCH ₂ —, EtOCH ₂ —, MeO(CH ₂ ) ₂ NH—,

is selected from C-linked aryl or heteroaryl, N-linked heteroaryl or heterocyclyl, and R and R' are independently selected from hydrogen, alkyl, and cycloalkyl.

から選択される縮合チオフェンを定義し、
式中、Ｗ、Ｘ、Ｙ、及びＺのそれぞれは独立して、Ｃ＝Ｏ、ＮＨ、Ｏ、Ｓ、ＣＨ、Ｃ－Ｑから選択され、Ｑは、アミノ、ハロゲン、メチル、－Ｏ－アルキル、－Ｏ－シクロアルキル、またはトリフルオロメチルである。 In an embodiment, R ³ , R ⁴ , R ⁵ , and R ⁶ are

defines a fused thiophene selected from
wherein each of W, X, Y, and Z is independently selected from C═O, NH, O, S, CH, CQ, where Q is amino, halogen, methyl, —O-alkyl, —O-cycloalkyl, or trifluoromethyl.

から選択されるチオフェンを定義し、Ｘは、水素、クロロ、メチル、またはＣＦ_３、

である。 In an embodiment, R ³ , R ⁴ , R ⁵ , and R ⁶ are

X is hydrogen, chloro, methyl, or CF ₃ ,

It is.

In embodiments, the compounds disclosed herein include the following compounds, or pharma- ceutically acceptable salts thereof:

In embodiments, the compounds disclosed herein include the following additional compounds, or pharma- ceutically acceptable salts thereof:

The compounds disclosed herein can exist as salts. The present embodiments include such salts, which may be pharma- ceutically acceptable salts. Examples of applicable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or racemic mixtures, succinate, benzoate, and mixtures thereof, including salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art. Also included are base addition salts, such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds disclosed herein contain relatively basic functional groups, acid addition salts can be prepared by contacting the neutral form of such a compound, neat or in a suitable inert solvent, with a sufficient amount of the desired acid. Examples of acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and those derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galactunolonic acid. Certain compounds disclosed herein contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

Other salts include acid or base salts of the compounds used in the methods of the present invention. Specific examples of pharma-ceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It is understood that pharma-ceutically acceptable salts are non-toxic. Further information regarding suitable pharma-ceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

Pharmaceutically acceptable salts include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds disclosed herein. When the compounds disclosed herein contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharma-ceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds disclosed herein contain relatively basic functional groups, 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 in a suitable inert solvent. Examples of pharma-ceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids, and salts derived from relatively non-toxic organic acids such as 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 arginates, and salts of organic acids such as glucuronic or galactunolonic acid (see, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds disclosed herein contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

The neutral form of the compound is preferably 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 disclosed herein can exist in unsolvated and solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present embodiments. Certain compounds disclosed herein can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present embodiments and are intended to be within the scope of the present embodiments.

Certain compounds disclosed herein have asymmetric carbon atoms (optical centers) or double bonds, and stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)- with respect to amino acids, or as (D)- or (L)-, and individual isomers, are encompassed within the scope of the present embodiments. The compounds disclosed herein do not include compounds known in the art to be too unstable to synthesize and/or isolate. The present embodiments are meant to include compounds in racemic and optically pure form. Optically active (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The compounds disclosed herein can be provided as mixtures of atropisomers, or can be pure atropisomers.

Isomers include compounds that have the same number and kinds of atoms, and thus the same molecular weight, but differ in the structural arrangement or configuration of the atoms.

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. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds according to the present invention are within the scope of the present embodiments.

Unless otherwise stated, the compounds disclosed herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds disclosed herein may be labeled with radioactive or stable isotopes, such as, for example, deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I), fluorine-18 ( ¹⁸ F), nitrogen-15 ( ¹⁵ N), oxygen-17 ( ¹⁷ O), oxygen-18 ( ¹⁸ O), carbon-13 ( ¹³ C), or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the scope of the present embodiments.

In addition to salt forms, embodiments of the present invention provide compounds that are in the form of prodrugs. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds disclosed herein. Additionally, prodrugs can be converted to the compounds disclosed herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds disclosed herein when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

The compounds disclosed herein can be prepared by a variety of methods as illustrated in the exemplary synthetic reaction schemes shown and described below. The starting materials and reagents used in preparing these compounds are generally available from commercial suppliers such as Aldrich Chemical Co. or are described in detail in Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R. C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds.) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, vol. 1-40, or by methods known to those skilled in the art. The following synthetic reaction schemes are merely illustrative of some of the ways in which the compounds disclosed herein can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to those skilled in the art in view of the disclosure contained herein.

For illustrative purposes, the following reaction schemes provide routes for synthesizing the compounds and key intermediates disclosed herein. For more detailed descriptions of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes can be used. Although some specific starting materials and reagents are shown in the schemes and described below, other starting materials and reagents can be substituted to provide a variety of derivatives or reaction conditions. Additionally, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

The starting materials and intermediates of the synthetic reaction schemes can be isolated and purified if necessary using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless otherwise specified, the reactions described herein are preferably carried out under an inert atmosphere, at atmospheric pressure, at a reaction temperature range of about -78°C to about 150°C, more preferably about 0°C to about 125°C, and most preferably and conveniently at about room temperature (or ambient temperature), or about 20°C.

Some compounds in the following schemes are shown using generalized substituents, however, one of ordinary skill in the art will readily appreciate that the nature of the substituents can be varied to provide a variety of compounds contemplated in the present embodiments. Additionally, the reaction conditions are illustrative and alternative conditions are well known. The reaction sequences in the following examples are not intended to limit the scope of the claimed embodiments.

IV. Pharmaceutical Formulations In some embodiments, a pharmaceutical composition comprises any one of the compounds disclosed herein and a pharma- ceutically acceptable excipient.

In some embodiments, a pharmaceutical composition is provided that includes a pharma- ceutical effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable excipient.

In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent.

In some embodiments, the additional therapeutic agent is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is an anti-microtubule agent, a platinum coordination complex, an alkylating agent, an antibiotic agent, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hormone or hormone analog, a signal transduction pathway inhibitor, a non-receptor tyrosine kinase angiogenesis inhibitor, an immunotherapeutic agent, a proapoptotic agent, an LDH-A inhibitor, a fatty acid biosynthesis inhibitor, a cell cycle signaling inhibitor, an HDAC inhibitor, a proteasome inhibitor, or a cancer metabolism inhibitor. In some embodiments, the chemotherapeutic agent is cisplatin, carboplatin, doxorubicin, ionizing radiation, docetaxel, or paclitaxel.

The compounds disclosed herein can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, troches, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by the patient. The compounds disclosed herein can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. The compounds described herein can also be administered by inhalation, e.g., intranasally. Additionally, the compounds disclosed herein can be administered transdermally. The compounds disclosed herein can also be administered by ocular, vaginal, and rectal routes, including suppositories, injections, powders, and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Thus, the present embodiments also provide pharmaceutical compositions comprising one or more pharma- ceutically acceptable carriers and/or excipients and either a compound of formula I or a pharma- ceutically acceptable salt of a compound of formula I.

For preparing pharmaceutical compositions from the compounds disclosed herein, pharma- ceutically acceptable carriers can be either solid or liquid. Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, surfactants, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Details of formulation and administration techniques are well described in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

In powders, the carrier is a finely divided solid that is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties and additional excipients as required in suitable proportions and compacted into the desired shape and size.

The powders, capsules and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. The term "preparation" is intended to include formulations of the active compound with an encapsulating material as a carrier, providing a capsule in which the active ingredient is surrounded by the carrier with or without other excipients, thus associating with the carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

Suitable solid excipients are carbohydrate or protein fillers including, but not limited to, sugars including lactose, sucrose, mannitol, or sorbitol; starches from corn, wheat, rice, potato, or other plants; celluloses such as methylcellulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose; gums including gum arabic and gum tragacanth; and proteins such as gelatin and collagen. Disintegrating or solubilizing agents can be added if desired, such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

The dragee cores are provided with suitable coatings such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and concentrated sugar solutions which may also contain suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for product identification or to characterize the amount of active compound (i.e., dosage). The pharmaceutical preparations can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and a coating such as glycerol or sorbitol. The push-fit capsules can contain the compound disclosed herein mixed with fillers or binders such as lactose or starch, lubricants such as talc or magnesium stearate, and, if necessary, stabilizers. In soft capsules, the compound disclosed herein can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol, with or without stabilizers.

To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into suitable sized molds, allowed to cool and thereby solidify.

Liquid preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use may be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents as required. Aqueous suspensions suitable for oral use are prepared by dispersing the finely divided active ingredient in water using viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, as well as dispersing or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as 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, aspartame, or saccharin. The preparations may be adjusted for osmolality.

Also included are solid preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

Oily suspensions can be formulated by suspending the compounds disclosed herein in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, such as liquid paraffin, or mixtures thereof. Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents, such as glycerol, sorbitol, or sucrose, can be added to provide a palatable oral preparation. These preparations can be preserved by the addition of an antioxidant, such as ascorbic acid. For examples of injectable oil vehicles, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. Pharmaceutical preparations can be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, as described above, or a mineral oil, or mixtures thereof. Suitable emulsifying agents include natural gums such as gum acacia and gum tragacanth, natural phospholipids such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweetening and flavoring agents, similar to syrup and elixir combinations. Such formulations can also contain a demulcent, preservative, or coloring agent.

The compounds disclosed herein can be delivered transdermally, topically, and in formulations as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

The compounds disclosed herein can also be delivered as microspheres for sustained release in the body. For example, the microspheres can be administered via intradermal injection of drug-containing microspheres for sustained subcutaneous release (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), as biodegradable injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995), or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both the transdermal and intradermal routes allow for continuous delivery over weeks or months.

Pharmaceutical formulations of the compounds disclosed herein can be provided as salts and can be formed with many acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base form. In other cases, the preparations can be lyophilized powders in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol, pH range 4.5-5.5, mixed with a buffer prior to use.

Pharmaceutical formulations of the compounds disclosed herein may be provided as salts, which may be formed with bases, i.e., cationic salts such as alkali metal and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.

In some embodiments, formulations of compounds disclosed herein can be delivered by using liposomes that fuse with the cell membrane or are endocytosed, i.e., by using ligands that bind to cell surface membrane protein receptors that trigger endocytosis, that bind to the liposome, or that bind directly to the oligonucleotide. Liposomes can be used to focus the delivery of GR modulators to target cells in vivo, especially if the liposome surface carries a ligand specific for the target cell or is otherwise preferentially directed to a particular organ. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

The amount of active ingredient in a unit dose preparation may vary or be adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 1,000 mg, and most typically from 10 mg to 500 mg, depending on the particular application and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

The dosing regimen also takes into account pharmacokinetic parameters well known in the art, i.e., rate of absorption, bioavailability, metabolism, clearance, etc. (see, e.g., Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fourtherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108; see latest edition of Remington's, supra). Current technology allows the clinician to determine the dosing regimen for the individual patient, the GR and/or MR modulator, and the disease or condition being treated.

Single or multiple dose formulations of the compounds disclosed herein can be administered at doses and frequencies according to the patient's needs and tolerance. The formulation should provide a sufficient amount of active agent to effectively treat the disease state. Thus, in one embodiment, pharmaceutical formulations for oral administration of the compounds disclosed herein are at a daily dose between about 0.5 and about 30 mg per kg of body weight per day. In another embodiment, doses of about 1 mg to about 20 mg per kg of body weight per patient per day are used. Lower doses can be used, particularly when the drug is administered to an anatomically isolated site such as the cerebrospinal fluid (CSF) space, as opposed to being administered orally, into the bloodstream, into a body cavity, or into the lumen of an organ. Substantially higher doses can be used for local administration. Actual methods for preparing formulations containing the compounds disclosed herein for parenteral administration are known or apparent to those skilled in the art and are described in detail by publications such as Remington's, supra. See also Nieman, In "Receptor Mediated Antisteroid Action," Agarwal, et al., eds., De Gruyter, New York (1987).

The compounds described herein may be used in combination with each other, in combination with other active agents known to be useful in modulating the glucocorticoid receptor, or in combination with adjuvants that are not effective alone but may contribute to the effectiveness of the active agent.

In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second active agent. Co-administration includes administering two active agents simultaneously, near simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition that includes both active agents. In some embodiments, the active agents can be formulated separately. In some embodiments, the active and/or adjunct agents can be combined or conjugated to each other.

After a pharmaceutical composition containing a compound disclosed herein has been formulated in one or more acceptable carriers, it can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of a compound of Formula I, such labeling would include, for example, instructions regarding the amount, frequency and method of administration.

In some embodiments, the compositions disclosed herein are useful for parenteral administration, such as intravenous (IV) administration or administration to a cavity or lumen of an organ. Formulations for administration generally comprise a solution of the compositions disclosed herein dissolved in one or more pharma- ceutically acceptable carriers. Acceptable vehicles and solvents that can be used include water and Ringer's solution, which is isotonic sodium chloride. Additionally, sterile fixed oils can be conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid can be used in the preparation of injectables as well. These solutions are sterile and usually free of undesirable matter. These formulations can be sterilized by conventional, well-known sterilization techniques. The formulations can contain pharma-ceutically acceptable auxiliary substances necessary to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like. The concentration of the composition in these formulations can vary widely and is selected primarily based on fluid volume, viscosity, body weight, etc., according to the particular mode of administration selected and the needs of the patient. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. The suspension can be formulated according to conventional techniques using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol.

In some embodiments, formulations of the compositions disclosed herein can be delivered by using liposomes that fuse with cell membranes or are endocytosed, i.e., by using ligands that bind to cell surface membrane protein receptors that trigger endocytosis, that bind to the liposomes, or that bind directly to the oligonucleotides. Liposomes can be used to focus the delivery of the compositions disclosed herein to target cells in vivo, especially if the liposome surface carries a ligand specific to the target cell or is otherwise preferentially directed to a particular organ. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

V. Methods In some embodiments, a method of treating a disorder or condition in a subject is provided, the method comprising administering to a human a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

In some embodiments, a method is provided for inhibiting KRAS G12C activity in a cell, comprising contacting a cell in which inhibition of KRAS G12C activity is desired with an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

In some embodiments, a method is provided for inhibiting KRAS G12C activity in a cell, comprising contacting a cell in which inhibition of KRAS G12C activity is desired with a pharmaceutical composition disclosed herein.

In some embodiments, a method of treating a KRAS G12C-associated cancer is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

In some embodiments, a method of treating a KRAS G12C-associated cancer is provided, comprising administering to a patient in need thereof a pharmaceutical composition disclosed herein.

In some embodiments, a method of treating a subject having a cancer characterized by the presence of a KRAS G12C mutation is provided, the method comprising administering to a human a therapeutically effective amount of a compound of any one of formula (I) or formula (II) or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition disclosed herein.

In some embodiments, a method is provided for preparing a medicament for treating a subject having a cancer characterized by the presence of a KRAS G12C mutation, the compound comprising Formula (I) or Formula (II) or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition.

In some embodiments, there is provided a use of a compound of formula (I) or formula (II) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for the preparation of a medicament for the treatment of a human having a cancer characterized by the presence of a KRAS G12C mutation.

In some embodiments, there is provided a compound of formula (I) or formula (II) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating a subject having a cancer characterized by the presence of a KRAS G12C mutation.

In some embodiments, a method of treating cancer in a patient in need thereof is provided, the method comprising: (a) determining that the cancer is associated with a KRAS G12C mutation (e.g., a KRAS G12C-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound disclosed herein.

In some embodiments, a method of treating cancer in a patient in need thereof is provided, the method comprising: (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRAS G12C-associated cancer); and (b) administering to the patient a pharmaceutical composition disclosed herein.

In some embodiments, the cancer is cardiac cancer (sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, teratoma), lung cancer (bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma), gastrointestinal cancer (esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma) , hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma)), genitourinary tract cancer (kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testis (spermoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma)), liver cancer (hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma), bile duct cancer (gallbladder cancer, ampullary cancer, cholangiocarcinoma), bone cancer (osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, cartilage cancer) Sarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroid exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumor), nervous system cancer (skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma), gynecological cancer (uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, sarcoma) Lutli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma)), blood cancer (blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma)), skin cancer (malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, melanocystic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis), or adrenal gland cancer (neuroblastoma).

In some embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, or pancreatic cancer.

In certain embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of symptoms and/or taking into account genetic or other susceptibility factors). Treatment can also be continued after symptoms have subsided, for example, to prevent or delay recurrence.

The compounds of formula (I) or formula (II) or pharma- ceutically acceptable salts thereof may be inhibitors of KRAS G12C. For example, the inhibitory constant (Ki) of the compounds disclosed herein may be less than about 50 μM, or less than about 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or less than about 1 μM. The inhibitory constant (Ki) of the compounds disclosed herein may be less than about 1,000 nM, or less than about 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or less than about 1 nM. The inhibition constant (Ki) of the compounds disclosed herein may be less than about 1 nM, or less than about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or less than about 0.1 nM.

The compounds of formula (I) or formula (II) or pharma- ceutically acceptable salts thereof may be selective inhibitors of KRAS G12C. For example, the KRAS G12C inhibition constant (IC50) of the compounds disclosed herein may be at least 2-fold, or at least 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100-fold less than the inhibition constant of one or more of KRAS wild-type, or NRAS, or HRAS. The KRAS G12C inhibition constant (Ki) of the compounds disclosed herein may also be at least 100-fold, or at least 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 10,000-fold less than the inhibition constant of one or more of KRAS wild-type, or NRAS, or HRAS.

A. Combination Therapy for Cancer The compounds disclosed herein or their salts can be used alone or in combination with other drugs for treatment. For example, the second drug of the pharmaceutical combination formulation or dosing regimen can have complementary activity to the compounds disclosed herein so that they do not adversely affect each other. The compounds can be administered together as a single pharmaceutical composition or separately. In one embodiment, the compounds or pharmaceutically acceptable salts can be co-administered with cytotoxic drugs to treat proliferative diseases and cancer.

The term "co-administration" refers to simultaneous administration, or separate sequential administration in any manner, of a compound disclosed herein or a salt thereof with additional active pharmaceutical ingredient(s), including cytotoxic agents and radiation therapy. When administration is not simultaneous, the compounds are administered in close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form; for example, one compound may be administered topically and another compound may be administered orally.

These additional agents may be administered separately from the compound-containing compositions of the present invention as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form mixed with the compounds disclosed herein in a single composition. When administered as part of a multiple dose regimen, the two active agents may be administered simultaneously, sequentially, or within a period of time, usually within 5 hours of each other.

As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to embodiments herein. For example, the compounds disclosed herein may be administered simultaneously with another therapeutic agent, or sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present embodiments provide a single unit dosage form that includes a compound of Formula I, an additional therapeutic agent, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

The amount of both the compound of the invention and the additional therapeutic agent that can be combined with the carrier materials to produce a single dosage form (in compositions containing additional therapeutic agents as described above) can vary depending on the host treated and the particular mode of administration. In certain embodiments, the compositions disclosed herein are formulated so that a dose of 0.01-100 mg/kg body weight/day of the invention can be administered.

Typically, any drug that is active against the disease or condition to be treated can be co-administered. Examples of such drugs are described in Cancer Principles and Practice of Oncology, edited by V. T. Devita and S. Hellman, ^6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. Those skilled in the art can identify which drug combinations are useful based on the specific characteristics of the drugs and the disease involved.

In one embodiment, the method of treatment comprises the co-administration of a compound disclosed herein or a pharma- ceutically acceptable salt thereof with at least one cytotoxic agent.As used herein, the term "cytotoxic agent" refers to a substance that inhibits or blocks cell function and/or causes cell death or destruction.Cytotoxic agents include, but are not limited to, radioisotopes (e.g., ^At211 , ^I131 , ^I125 , ^Y90 , ^Re186 , ^Re188 , ^Sm153 , ^Bi212 , ^P32 , ^Pb212 , and radioisotopes of Lu), chemotherapeutic agents, growth inhibitors, enzymes such as nucleases and their fragments, and small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin (including their fragments and/or mutants).

Exemplary cytotoxic agents may be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutics, pro-apoptotic agents, LDH-A inhibitors, fatty acid biosynthesis inhibitors, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and cancer metabolism inhibitors.

"Chemotherapeutic agents" include chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), mefetal bovine serum albumin (MEGA ... Imatinib silate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide, alkylsulfonates such as busulfan, improsulfan, and piposulfan, aziridines such as benzodopa, carboquone, meturedopa, and uredopa, ethylenimines and methylamelamines (altretamine, triethylenemelamine, triethylenephosphamide, suforamide, triethylenethiophosphoramide, and trimethylmelamine), acetogenins (especially bullatacin and bullatacinone), camptothecins (including topotecan and irinotecan), bryostatin, kallistatin, CC-1065 (including its azozelesin, carzelesin, and bizelesin synthetic analogs), cryptophycins (especially cryptophycin 1 and cryptophycin 8), corticosteroids (including prednisone and prednisolone), Cyproterone acetate, 5α-reductase (including finasteride and dutasteride), vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatins, aldesleukin, talc duocarmycins (including synthetic analogs KW-2189 and CB1-TM1), eleutherobin, pancratistatin, sarcodictiin, spongiostatins, nitrogen mustards, such as chlorambucil, chromafazine, chlorophosphamide , estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicine, phenesterine, prednimustine, trofosfamide, uracil mustard, nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine, antibiotics such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γ1I and calicheamicin ω1I (Angew Chem. Intl. Ed. Engl. 1994) 33:183-186), dynemicins including dynemicin A, bisphosphonates such as clodronate, esperamicins, and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), antibiotics such as aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholinosidase, ... nodoxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), mitomycins such as epirubicin, esorubicin, idarubicin, marcelomycin, and mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potofilomycin, puromycin, keramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, antimetabolites such as methotrexate and 5-fluorouracil (5-FU), denopterin, methotrexate, folic acid analogues such as folate, pteropterin, trimetrexate, purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, and other pyrimidine analogues, calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone, and other androgens, adrenal antidrugs such as aminoglutethimide, mitotane, trilostane, and other folic acid replacement fluids, aceglatone, aldophosphamide, and other Licoside, aminolevulinic acid, eniluracil, amsacrine, bestravcil, bisantrene, edatrexate, defofamine, demecolcine, diaziquone, elfomitin, elliptinium acetate, epothilone, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidynin, maytansinoids such as maytansine and ansamitocin, mitoguazone, mitoxantrone, mopidanol, nitraelin, pentostatin, fenameth, pirarubicin, rosoxantrone, podophyllic acid, 2-ethylhydrazide, procarbazine, PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg. ), razoxane, rhizoxin, schizofiran, spirogermanium, tenuazonic acid, triazicon, 2,2',2"-trichlorotriethylamine, trichothecenes (especially T-2 toxin, veraculin A, roridin A, and anguidine), urethanes, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside ("Ara-C"), cyclophosphamide, thiotepa, taxoids such as TAXOL (paclitaxel, Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (chromophore free), albumin engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (docetaxel, Sanofi-Aventis), chlorambucil, GEMZAR® (gemcitabine), 6-thioguanine, mercaptopurine, methotrexate, platinum analogs such as cisplatin and carboplatin, vinblastine, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, NAVELBINE® (vinorelbine), novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine (XELODA®), ibandronate, CPT-11, the topoisomerase inhibitor RFS 2000, difluoromethylornithine (DMFO), retinoids such as retinoic acid, and pharma- ceutically acceptable salts, acids, and derivatives of any of the above.

Chemotherapeutic agents include (i) anti-hormonal agents that act to control or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX®, tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxyfene, ketoxifene, LY117018, onapristone, and FARESTON® (including toremifine citrate); (ii) agents that inhibit estrogen production in the adrenal glands; Aromatase inhibitors, which inhibit the aromatase enzyme they regulate, such as 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane, Pfizer), formestany, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole, Novartis), and ARIMIDEX® (anastrozole, AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, e.g., PKC-alpha, Ralf, and H. -Ras, (vii) ribozymes, such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors, (viii) vaccines, such as gene therapy vaccines, e.g., ALLOVECTIIN®, LEUVECTIN®, and VAXID®, PROLEUKIN®, rIL-2, topoisomerase 1 inhibitors, such as LURTOTECAN®, ABARELIX® rmRH, and (ix) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

Chemotherapeutic agents also include antibodies, such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexar, Corixia), and the antibody drug conjugate gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies that have therapeutic potential as drugs in combination with the compounds disclosed herein include apolizumab, acelizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidofusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motavizumab, , natalizumab, nimotuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resivizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucotuzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and interleukin-12 and anti-interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories), which is an exclusively human sequence recombinant full-length IgG ₁ lambda antibody genetically modified to recognize the p40 protein.

Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise directly interact with EGFR and prevent or reduce its signaling activity, alternatively referred to as "EGFR antagonists." Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see U.S. Pat. No. 4,943,533 (Mendelsohn et al.)), as well as variants thereof, such as chimeric 225 (C225 or cetuximab, ERBUTIX®) and reshaped human 225 (H225) (see WO 96/40210 (Imclone Systems)). Inc.), IMC-11F8, fully human EGFR targeting antibody (Imclone), antibodies that bind to type II mutant EGFR (U.S. Pat. No. 5,212,290), humanized and chimeric antibodies that bind to EGFR as described in U.S. Pat. No. 5,891,996, and human antibodies that bind to EGFR, such as ABX-EGF or panitumumab (see WO 98/50433 (Abgenix/Amgen)), EMD 55900 (Stragliotto et al. Eur. J. Cancer 2007, 14, 1111-112, and U.S. Pat. No. 5,891,996). 32A:636-640 (1996)), the humanized EGFR antibody EMD7200 (matuzumab) (EMD/Merck) directed against EGFR which competes with both EGF and TGF-alpha for EGFR binding, the human EGFR antibody HuMax-EGFR (GenMab), the fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3 and described in U.S. Pat. No. 6,235,883, MDX-447 (Medarex Inc), and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). Anti-EGFR antibodies may be conjugated to a cytotoxic agent, thereby producing an immunoconjugate (see, for example, European Patent No. 659,439 A2, Merck Patent GmbH). EGFR antagonists are disclosed in U.S. Patent Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,8 Nos. 6,66,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, and in PCT publications such as WO 98/14451, WO 98/50038, WO 99/09016, and WO 99/24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals), PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer). Inc.), ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca), ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca), BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol), (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine), CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide), EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinazolinyl]-4-(dimethylamino)-2-butynamide) (Wyeth), AG1478 (Pfizer), AG1571 (SU 5271, Pfizer), dual EGFR/HER2 tyrosine kinase inhibitors, such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2-methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

Chemotherapeutic agents include EGFR targeted drugs as described in the previous paragraph, small molecule HER2 tyrosine kinase inhibitors such as TAK165 available from Takeda, CP-724,714 (oral selective inhibitor of ErbB2 receptor tyrosine kinase) (Pfizer and OSI), dual HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds to EGFR but inhibits both HER2 and EGFR overexpressing cells, lapatinib (GSK572016, available from Glaxo-SmithKline), oral HER2 and EGFR tyrosine kinase inhibitor, PKI-166 (available from Novartis), pan-HER inhibitors such as canertinib (CI-1033, Pharmacia), Raf-1 inhibitors such as ISIS which inhibits Raf-1 signaling. antisense drug ISIS-5132 available from Pharmaceuticals; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC® available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT® available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584 available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitors CI-1040 (available from Pharmacia); quinazolines such as PD 153035, 4-(3-chloroanilino)quinazolines; pyridopyrimidines, pyrimidopyrimidines, pyrrolopyrimidines such as CGP 59326, CGP 60261, and CGP 62706, pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines, curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide), tyrphostins containing a nitrothiophene moiety, PD-0183805 (Warner-Lambert), antisense molecules (e.g., those that bind to HER-encoding nucleic acids), quinoxalines (U.S. Pat. No. 5,804,396), tryphostins (U.S. Pat. No. 5,804,396), pan-HER inhibitors such as ZD6474 (Astra Zeneca), PTK-787 (Novartis/Schering AG), CI-1033 (Pfizer), Affinitac (ISIS 3521, Isis/Lilly), imatinib mesylate (GLEEVEC®), PKI 166 (Novartis), GW2016 (Glaxo SmithKline), CI-1033 (Pfizer), EKB-569 (Wyeth), semaxinib (Pfizer), ZD6474 (AstraZeneca), PTK-787 (Novartis/Schering AG), INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®), or other medicaments disclosed in U.S. Pat. No. 5,804,396, WO 1999/09016 (American Cyanamid), WO 1998/43960 (American "Tyrosine kinase inhibitors" include those described in any of the patent publications such as WO1997/38983 (Warner Lambert), WO1999/06378 (Warner Lambert), WO1999/06396 (Warner Lambert), WO1996/30347 (Pfizer, Inc), WO1996/33978 (Zeneca), WO1996/3397 (Zeneca), and WO1996/33980 (Zeneca).

Chemotherapeutic agents include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa- 2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharma- ceutically acceptable salts thereof.

Chemotherapeutic agents include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone 17-valerate, aclomethasone propionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasone-17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate, immunoselective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomer form (feG) (IMULAN Antirheumatic drugs (e.g., azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers (e.g., etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi )), interleukin 1 (IL-1) blockers (e.g., anakinra (Kineret)), T cell costimulation blockers (e.g., abatacept (Orencia)), interleukin 6 (IL-6) blockers (e.g., tocilizumab (ACTEMERA®)), interleukin 13 (IL-13) blockers (e.g., lebrikizumab), interferon alpha (IFN) blockers (e.g., rontalizumab), beta 7 integrin blockers (e.g., rhuMAb Beta7), IgE pathway blockers (e.g., anti-M1 prime), secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1/β2 blockers (e.g., anti-lymphotoxin alpha (LTa)), radioisotopes (e.g., At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and radioisotopes of Lu), various investigational drugs (e.g., thioplatin, PS-341, phenylbutyrate, ET-18-OCH ₃ , or farnesyltransferase inhibitors (L-739749, L-744832)), polyphenols (e.g., quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavins, flavanols, procyanidins, betulinic acid and its derivatives), autophagy inhibitors (e.g., chloroquine), delta-9-tetrahydrocannabinol (dronabinol, MARINOL®), beta-lapachone, lapachol, colchicine, betulinic acid, acetylcamptothecin, scopolectin, and 9-aminocamptothecin), podophyllotoxin, tegafur (UFTORAL®), bexarotene (TARGRETIN®), bisphosphonates (e.g., clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDRO®), CAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®)), as well as epidermal growth factor receptor (EGF-R), vaccines (e.g., THERATOPE® vaccine), perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341), CCI-779, tipifarnib (R11577), orafenib, ABT510, Bcl-2 inhibitors such as oblimersen sodium (GENASENSE®), pixantrone, farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASAR™), and pharma- ceutically acceptable salts, acids, or derivatives of any of the above, as well as combinations of two or more of the above, such as CHOP (short for the combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone), and FOLFOX (short for a treatment regimen using oxaliplatin (ELOXATIN™) in combination with 5-FU and leucovorin).

Chemotherapeutic agents also include nonsteroidal anti-inflammatory drugs that have sedative, antipyretic, and anti-inflammatory effects. NSAIDs include nonselective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs may be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathy, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headaches and migraines, post-operative pain, mild to moderate pain due to inflammation and tissue injury, fever, ileus, and renal colic.

In certain embodiments, chemotherapeutic agents include, but are not limited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, interferons, platinum derivatives, taxanes (e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g., etoposide), cisplatin, mTOR inhibitors (e.g., rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, camptothecin, cisplatin, metronidazole, and imatinib mesylate, among others. In another embodiment, the compounds disclosed herein are administered in combination with a biologic agent, such as bevacizumab or panitumumab.

In certain embodiments, the compounds disclosed herein or pharma- ceutically acceptable compositions thereof are selected from the group consisting of abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, BCG live, bevacizumab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calsterone, capecitabine, camptothecin, carboplatin, carmustine, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, dactinomycin, sirolimus, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin hydrochloride, dromostanolone propionate, epirubicin, epoetin alfa, erotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, hitrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, interferon Terferon alfa-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, porphyrin It is administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of the following: marsodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronic acid, or zoledronic acid.

Chemotherapeutic agents also include drugs for treating Alzheimer's disease, such as donepezil hydrochloride and rivastigmine; drugs for treating Parkinson's disease, such as L-dopa/carbidopa, entacapone, lopinrol, pramipexole, bromocriptine, pergolide, trihexefendyl, and amantadine; drugs for treating multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), glatiramer acetate, and mitoxantrone; drugs for treating asthma, such as albuterol and montelukast sodium; drugs for treating schizophrenia, such as Zyprexa, Risperdal, Seroquel, and Haloperidol; corticosteroids, TNF inhibitors, IL-1 Also included are anti-inflammatory drugs such as RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinson's drugs; drugs for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; drugs for treating liver disease such as corticosteroids, cholestyramine, interferons, and antivirals; drugs for treating blood disorders such as corticosteroids, anti-leukemia drugs, and growth factors; and drugs for treating immune deficiency disorders such as gamma globulin.

Additionally, the chemotherapeutic agents include pharma- ceutically acceptable salts, acids, or derivatives of any of the chemotherapeutic agents described herein, as well as combinations of two or more thereof.

VI. Examples Synthetic Procedures

スキームＩＩ

スキームＩＩでは、Ｘは、ハロゲンまたはメシレート、トリフレートなどの擬ハロゲンである。 General Procedures Compounds of formula I can be prepared from commercially available reagents using the synthetic methods and reaction schemes herein, or using other reagents and conventional methods known to those skilled in the art. For example, compounds of the present invention can be prepared according to the general reactions of Schemes I and II utilizing conventional cross-coupling chemistry.
Scheme I
Compounds of formula (I)

Scheme II

In Scheme II, X is a halogen or pseudohalogen, such as mesylate, triflate, and the like.

０℃でジクロロメタン（１ｍＬ）中の（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－メトキシ－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オン（０．０９５ｍｍｏｌ）の溶液に、トリエチルアミン（０．５７ｍｍｏｌ）及び塩化アクリロイル（０．１９ｍｍｏｌ）を加えた。反応混合物を室温で２時間撹拌した。溶媒を真空中で除去して残渣を得て、これを分取ＨＰＬＣで精製して、表題化合物を収率３９％で黄色固体として得た。
ｍ／ｚ （ＥＳＩ， ＋ｖｅ）＝ ５９９．０ ［Ｍ＋Ｈ］＋；１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ８．００ （ｓ， １Ｈ）， ７．８８ （ｓ， １Ｈ）， ７．１５ （ｓ， １Ｈ）， ６．８１ （ｄｄ， Ｊ ＝ １６．０， ８．０ Ｈｚ， １Ｈ）， ６．１９ （ｄｄ， Ｊ ＝ １６．０， ４．０ Ｈｚ， １Ｈ）， ５．７４ （ｄｄ， Ｊ ＝ ８．０， ４．０ Ｈｚ， １Ｈ）， ４．６６ － ４．４５ （ｍ， ３Ｈ）， ４．０５ － ３．９４ （ｍ， ２Ｈ）， ３．８９ － ３．８１ （ｍ， １Ｈ）， ３．３２ （ｓ， ５Ｈ）， ３．２８ － ３．２４ （ｍ， ２Ｈ）， ３．１７ （ｓ， １Ｈ）， １．３９ （ｓ， ６Ｈ）。 Example 1: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (E1).

To a solution of (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (0.095 mmol) in dichloromethane (1 mL) at 0° C. was added triethylamine (0.57 mmol) and acryloyl chloride (0.19 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo to give a residue which was purified by preparative HPLC to give the title compound as a yellow solid in 39% yield.
m/z (ESI, +ve) = 599.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.88 (s, 1H), 7.15 (s, 1H), 6.81 (dd, J = 16.0, 8.0 Hz, 1H), 6.19 (dd, J = 16.0, 4.0 Hz, 1H), 5.74 (dd, J = 8.0, 4.0 Hz, 1H), 4.66 - 4.45 (m, 3H), 4.05 - 3.94 (m, 2H), 3.89 - 3.81 (m, 1H), 3.32 (s, 5H), 3.28 - 3.24 (m, 2H), 3.17 (s, 1H), 1.39 (s, 6H).

Step 1: (3-chlorothiophen-2-yl)triisopropylsilane To a solution of 3-chlorothiophene (73.4 mmol) in THF (50 mL) at −78° C. was added LDA (73.4 mmol) and after 1 h at −78° C., chlorotriisopropylsilane was added. The mixture was stirred at room temperature for 16 h, quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound in 90% yield.

Step 2: (3-Chloro-5-iodothiophen-2-yl)triisopropylsilane To a solution of (3-chlorothiophen-2-yl)triisopropylsilane (8.4 mmol) in THF (20 mL) at -78 °C was added LDA (10.08 mol). The reaction mixture was stirred at -78 °C for 2 h. A solution of iodine (10.92 mmol) in THF (5 mL) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed three times with saturated aqueous Na ₂ S ₂ O ₃ solution, dried over sodium sulfate and concentrated to give a residue which was purified by silica gel chromatography to give the title compound as a colorless oil in 91% yield.

Step 3: Methyl 2-amino-4-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-5-(trifluoromethyl)benzoate _A mixture of methyl 2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoate (0.14 mol), (3-chloro-5-iodothiophen-2-yl)triisopropylsilane (0.11 mol), Pd(dppf)Cl ₂ (24.5 mmol) and K ₃ PO ₄ (0.37 mol) in 1,4-dioxane:H 2 O (300 mL:30 mL) was stirred at 100° C. for 16 h. The mixture was cooled to room temperature and the solid was filtered. The filtrate was concentrated to give a residue which was purified by silica gel chromatography to give the title compound as a yellow solid in 63% yield. m/z (ESI, +ve) = 492.1 [M+H]+.

Step 4: Methyl 2-amino-4-(4-chlorothiophen-2-yl)-5-(trifluoromethyl)benzoate. To a solution of methyl 2-amino-4-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-5-(trifluoromethyl)benzoate (4.9 mmol) in THF (30 mL) was added TBAF (14.7 mmol). The mixture was stirred at room temperature for 3 h, diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and the volatiles were removed under reduced pressure to give a residue which was purified by silica gel chromatography to give the title compound as a white solid in 97% yield. m/z (ESI, +ve)=336.0 [M+H]+.

Step 5: Methyl 2-amino-4-(4-chlorothiophen-2-yl)-3-iodo-5-(trifluoromethyl)benzoate. To a mixture of methyl 2-amino-4-(4-chlorothiophen-2-yl)-5-(trifluoromethyl)benzoate (27.1 mmol) in AcOH (100 mL) was added N-iodosuccinamide (44.4 mol). The reaction was stirred at room temperature for 36 h and the volatiles were removed under reduced pressure. The resulting residue was redissolved in ethyl acetate and washed successively with saturated aqueous Na ₂ S ₂ O ₃ , water and brine. The organic layer was dried over sodium sulfate and concentrated to give a residue which was purified by silica gel chromatography (0-15% ethyl acetate in hexanes) to give the title compound as a white solid in 35% yield. m/z (ESI, +ve)=461.9 [M+H]+.

Step 6: 2-amino-4-(4-chlorothiophen-2-yl)-3-iodo-5-(trifluoromethyl)benzoic acid To a mixture of methyl 2-amino-4-(4-chlorothiophen-2-yl)-3-iodo-5-(trifluoromethyl)benzoate (23.8 mmol) in MeOH:THF (30 mL:30 mL) was added 0.01 M aqueous NaOH (0.238 mol) and the reaction was stirred at room temperature for 30 min. The pH of the mixture was adjusted to 5 by adding 6 M HCl and the solution was extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated to give the title compound in 96% yield as a yellow solid. m/z (ESI, +ve)=447.9 [M+H]+.

Step 7: 7-(4-chlorothiophen-2-yl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione. A mixture of 2-amino-4-(4-chlorothiophen-2-yl)-3-iodo-5-(trifluoromethyl)benzoic acid (20.4 mmol) and urea (1.67 mol) was heated at 200° C. for 2 h. The reaction was cooled to 90° C. and diluted with 600 mL of methanol:ethyl acetate (1:1). The mixture was allowed to cool slowly to room temperature and stirred for an additional 3 h. After filtration, the volatiles were removed under reduced pressure and the crude material was purified by reverse phase silica gel chromatography to afford the title compound in 50% yield as a white solid. m/z (ESI, +ve)=472.8 [M+H]+.

Step 8: (S)-7-(4-chlorothiophen-2-yl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione To a solution of 7-(4-chlorothiophen-2-yl)-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (0.0124 mol), cuprous iodide (470 mg, 0.0024 mol) and potassium carbonate (5.14 g, 00.0372 mol) in isopropyl alcohol (30 ml) and ethylene glycol (60 ml) was added (S)-3-mercapto-2-methoxypropan-1-ol (0.0372 mol). The reaction mixture was stirred at 85° C. for 36 hours. The mixture was concentrated under reduced pressure and the crude material was purified by reverse column to give the title compound as a white solid in 39% yield. m/z (ESI, +ve) = 467.0 [M+H]+.

Step 9: (S)-11-(4-chlorothiophen-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione. To a solution of triphenylphosphine (6.4 mmol) in THF (10 ml) cooled to 0° C. was added N,N-diisopropylethylamine (6.4 mmol) and the mixture was stirred for 30 min. (S)-7-(4-chlorothiophen-2-yl)-8-((3-hydroxy-2-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (6.4 mmol) was added and stirred at 0° C. for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse column chromatography to give the title compound as a white solid in 77% yield. m/z (ESI, +ve) = 449.0 [M+H]+.

Step 10: (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one To a solution of (S)-11-(4-chlorothiophen-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6,8(7H)-dione (0.05 mmol) in toluene (1 mL) was added N,N-diisopropylethylamine (1.0 mmol) and POCl3 (1 mL). The reaction mixture was stirred at 120° C. for 1.5 h, cooled to room temperature, and concentrated to give a residue which was dissolved in dichloroethane (1 mL) and added to a solution of (2R,6S)-2,6-dimethylpiperazine (0.35 mmol) and N,N-diisopropylethylamine (1.0 mmol) in dichloroethane (1 mL). The reaction mixture was stirred at room temperature for 1 h, concentrated, and the resulting solid was purified by silica gel chromatography to give the title compound in 51% yield as a yellow solid. m/z (ESI, +ve)=545.1 [M+H]+.

アセトニトリル（２ｍＬ）中の（１２Ｓ）－８－（４－クロロ－２－チエニル）－４－［（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル］－１２－（メトキシメチル）－７－（トリフルオロメチル）－１０－チア－１，３－ジアザトリシクロ［７．３．１．０５，１３］トリデカ－３，５（１３），６，８－テトラエン－２－オン；２，２，２－トリフルオロ酢酸（０．０５ｍｍｏｌ）の０℃溶液にジイソプロピルエチルアミン（０．４６ｍｍｏｌ）、続いて塩化アクリロイル（０．１４ｍｍｏｌ）を加えた。反応物を０℃で２０分間撹拌し、酢酸エチルで希釈し、水で洗浄した。有機層を硫酸ナトリウムで乾燥させ、減圧下で濃縮して残渣を得て、これをＨＰＬＣで精製した。表題化合物を収率３６％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ５９９．１ ［Ｍ＋Ｈ］^＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＭｅＯＤ） δ ８．０２ （ｓ， １Ｈ）， ７．５０ （ｓ， １Ｈ）， ６．９０ （ブロード １重線， １Ｈ）， ６．７４ （ｄｄ， Ｊ ＝ １６．７， １０．６ Ｈｚ， １Ｈ）， ６．１９ （ｄ， Ｊ ＝ １６．７， ２．０ Ｈｚ， １Ｈ）， ５．７１ （ｄ， Ｊ＝ １０．６， ２．０ Ｈｚ， １Ｈ）， ５．２５ （ｓ， １Ｈ）， ４．６９－４．４７ （ｍ， ２Ｈ）， ４．２４ （ｄ， １６ Ｈｚ， １Ｈ）， ４．１５ （ｄ， １６ Ｈｚ， １Ｈ）， ３．６７－３．６２ （ｍ， １Ｈ）， ３．５４－３．５０ （ｍ， １Ｈ）， ３．４０ （ｍ， １Ｈ）， ３．３６－３．２３ （ｍ， ５Ｈ）， ３．０２ （ｄｄ， Ｊ＝ １４， ３．０ Ｈｚ， １Ｈ）， １．４７ （ｄ， Ｊ＝ ６．９ Ｈｚ， ６Ｈ）， １．３１ （ｄ， Ｊ＝ ６．９ Ｈｚ， ３Ｈ）。 Example 2: (S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(4-chlorothiophen-2-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one (E2)

To a 0° C. solution of (12S)-8-(4-chloro-2-thienyl)-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-12-(methoxymethyl)-7-(trifluoromethyl)-10-thia-1,3-diazatricyclo[7.3.1.05,13]trideca-3,5(13),6,8-tetraen-2-one; 2,2,2-trifluoroacetic acid (0.05 mmol) in acetonitrile (2 mL) was added diisopropylethylamine (0.46 mmol) followed by acryloyl chloride (0.14 mmol). The reaction was stirred at 0° C. for 20 min, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a residue which was purified by HPLC. The title compound was isolated as a white solid in 36% yield. MS (ESI) m/z: 599.1 [M+H] ⁺ . 1H NMR (400 MHz, MeOD) δ 8.02 (s, 1H), 7.50 (s, 1H), 6.90 (broad singlet, 1H), 6.74 (dd, J = 16.7, 10.6 Hz, 1H), 6.19 (d, J = 16.7, 2.0 Hz, 1H), 5.71 (d, J = 10.6, 2.0 Hz, 1H), 5.25 (s, 1H), 4.69-4.47 (m, 2H), 4.24 (d, 16 Hz, 1H), 4.15 (d, 16 Hz, 1H), 3.67-3.62 (m, 1H), 3.54-3.50 (m, 1H), 3.40 (m, 1H), 3.36-3.23 (m, 5H), 3.02 (dd, J = 14, 3.0 Hz, 1H), 1.47 (d, J = 6.9 Hz, 6H), 1.31 (d, J = 6.9 Hz, 3H).

Step 1: Methyl 2-acetamido-4-chloro-5-iodobenzoate. To a mixture of methyl 2-amino-4-chloro-5-iodobenzoate (161 mmol) in AcOH (500 mL) was added Ac ₂ O (193 mmol). The mixture was stirred at 100° C. for 16 h, cooled to room temperature, filtered and washed with hexane to give the title compound as a white solid in 62% yield. MS (ESI) m/z: 353.9 [M+H] ⁺ .

Step 2: Methyl 2-acetamido-4-chloro-5-(trifluoromethyl)benzoate To a mixture of methyl 2-acetamido-4-chloro-5-iodobenzoate (99 mmol) in DMF (350 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (396 mmol), HMPA (396 mmol) and CuI (79 mmol). The mixture was stirred at 90° C. for 16 h, poured into water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (1-5% ethyl acetate in hexanes) to afford the title compound as a white solid in 84% yield. MS (ESI) m/z: 296.0 [M+H] ⁺ .

Step 3: Methyl 2-amino-4-chloro-5-(trifluoromethyl)benzoate A mixture of methyl 2-acetamido-4-chloro-5-(trifluoromethyl)benzoate (68 mmol) in HCl/MeOH (200 mL) was stirred at 70 °C for 2 h. The mixture was concentrated and the residue was treated with saturated aqueous NaHCO ₃ (100 mL). The resulting mixture was extracted three times with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulfate. The volatiles were evaporated under reduced pressure to afford the title compound as a yellow solid in quantitative yield. MS (ESI) m/z: 254.0 [M+H] ⁺

Step 4: Methyl 2-amino-4-chloro-3-iodo-5-(trifluoromethyl)benzoate To a solution of methyl 2-amino-4-chloro-5-(trifluoromethyl)benzoate (110 mmol) in acetic acid (280 mL) was added N-iodosuccinimide (143 mmol). The mixture was stirred at 50° C. for 16 hours. The reaction mixture was poured into water, extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was washed with hexane to afford the title compound as a white solid in quantitative yield. MS (ESI) m/z: 379.9 [M+H] ⁺

Step 5: 2-Amino-4-chloro-3-iodo-5-(trifluoromethyl)benzoic acid To a solution of methyl 2-amino-4-chloro-3-iodo-5-(trifluoromethyl)benzoate (66 mmol) in dioxane (200 mL) and water (200 mL) was added solid sodium hydroxide (132 mmol). The mixture was stirred at 90° C. for 3 h. After completion, the solution was poured into water and the pH was adjusted to 4-5. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound in 95% yield as a yellow solid. MS (ESI) m/z: 365.9 [M+H] ⁺

Step 6: 7-Chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione A mixture of 2-amino-4-chloro-3-iodo-5-(trifluoromethyl)benzoic acid (14 mmol) and urea (274 mmol) was stirred at 200° C. for 5 h, cooled to 80° C., and treated with water (100 mL). The mixture was stirred for an additional 1 h, cooled to room temperature, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (20% ethyl acetate in hexanes) to afford the title compound as a white solid in 33% yield. MS (ESI) m/z: 388.8 [M-H]-

Step 7: (R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (51.2 mmol) in dioxane (800 mL) was added potassium carbonate (153.6 mmol), (R)-1-mercapto-3-methoxypropan-2-ol (92.1 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (10.24 mmol) and tris(dibenzylideneacetone)dipalladium (5.1 mmol). The mixture was stirred at 55° C. for 18 hours. After completion, the insoluble material was filtered off and the filtrate was concentrated, the pH adjusted to 4 with acetic acid, extracted with ethyl acetate and washed with brine. Evaporation of the volatiles gave a residue which was crystallized (dichloromethane/methanol=1/10) to give the title compound in 73% yield as a white solid. MS (ESI) m/z: 385.0 [M+H]+.

Step 8: (S)-10-Chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione. To a mixture of (R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (89.5 mmol) and triphenylphosphoranylidene (134.3 mmol) in tetrahydrofuran (500 mL) at 0° C. was added diethyl azodicarboxylate (134.3 mmol). The mixture was stirred at 0° C. for 45 minutes. After completion, the mixture was poured into ice water (300 mL) and extracted three times with ethyl acetate. After concentration, the residue was recrystallized (dichloromethane/methanol=1/10) to give the title compound as a white solid in 73% yield. MS (ESI): m/z 367.0 [M+H] ⁺ .

Step 9: (2S,6R)-tert-Butyl-4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate To a mixture of (S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5,7(3H,6H)-dione (27.32 mmol) and potassium carbonate (273.2 mmol) in acetonitrile (500 mL) at 0 °C was added 4-methylbenzenesulfonic anhydride (40.98 mmol). The mixture was stirred at 0° C. for 30 min and at 30° C. for 4 h, after which (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (54.64 mmol) was added and the resulting mixture was stirred at 0° C. for an additional 2 h. The mixture was filtered through a Celite pad and the filtrate was concentrated. The residue was purified by silica gel chromatography (1-3% methanol in dichloromethane) to afford the title compound in quantitative yield as a white solid. This material was used in the following step without further purification. MS (ESI) m/z 563.5 [M+H] ⁺ .

Step 10: tert-Butyl (2S,6R)-4-((S)-10-(4-chlorothiophen-2-yl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate tert-Butyl (2S,6R)-4-[(12S)-8-chloro-12-(methoxymethyl)-2-oxo-7-(trifluoromethyl)-10-thia-1,3-diazatricyclo[7.3.1.05,13]trideca-3,5(13),6,8-tetraen-4-yl]-2,6-dimethyl-piperazine-1-carboxylate (0.07 mmol), RuPhos G4 (0.01 mmol), potassium phosphate (0.22 mmol), and (4-chloro-2-thienyl)boronic acid (0.22 mmol) were dissolved in dioxane (2 mL) and water (0.5 mL) and the mixture was degassed with nitrogen for 2 minutes. The reaction was stirred at 80° C. for 1 hour, cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to give a residue which was purified by HPLC to give the title compound as a tan solid in 62% yield.

Step 11: (S)-10-(4-chlorothiophen-2-yl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one To a stirred solution of tert-butyl (2S,6R)-4-[(12S)-8-(4-chloro-2-thienyl)-12-(methoxymethyl)-2-methylene-7-(trifluoromethyl)-10-thia-1,3-diazatricyclo[7.3.1.05,13]trideca-3,5(13),6,8-tetraen-4-yl]-2,6-dimethyl-piperazine-1-carboxylate (0.05 mmol) in dichloromethane (3 mL) was added TFA (0.3 mL) and the reaction was stirred at room temperature for 45 min. The volatiles were removed under reduced pressure to give an orange residue which was used in the following step without further purification.

反応スキーム１

（Ｒ）－１－メルカプト－３－メトキシプロパン－２－オール（２）
０℃でテトラヒドロフラン（８００ｍＬ）中の（Ｓ）－２－（メトキシメチル）オキシラン（５０ｇ、５６８．２ｍｍｏｌ）の混合物に１，１，１，３，３，３－ヘキサメチルジシラチアン（１１９．４ｇ、６８１．８ｍｍｏｌ）及びフッ化テトラブチルアンモニウム（テトラヒドロフラン中、１．０Ｍ、１７０．６ｍＬ、１７０．５ｍｍｏｌ）を加えた。混合物を室温で２時間撹拌した。完了後、混合物を水（３０００ｍＬ）に注ぎ、酢酸エチル（３×８００ｍＬ）で抽出した。組み合わせた有機相をブライン（８００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させた。濾過及び濃縮後、残渣を石油エーテル／酢酸エチル＝３／１を用いるシリカゲルカラムで精製して、（Ｒ）－１－メルカプト－３－メトキシプロパン－２－オール（７０．０ｇ、粗製）を無色の油として得た。^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＣＤＣｌ_３） δ ３．８６－３．８２ （ｍ， １Ｈ）， ３．４９－３．４６ （ｍ， １Ｈ）， ３．４１－３．３７ （ｍ， ４Ｈ）， ２．７１－２．６４ （ｍ， １Ｈ）， １．５５－１．５０ （ｍ， １Ｈ）。 Example 3: (S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-10-(5-methylthiophen-2-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (E3)

Reaction Scheme 1

(R)-1-mercapto-3-methoxypropan-2-ol (2)
1,1,1,3,3,3-Hexamethyldisilathiane (119.4 g, 681.8 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 170.6 mL, 170.5 mmol) were added to a mixture of (S)-2-(methoxymethyl)oxirane (50 g, 568.2 mmol) in tetrahydrofuran (800 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. After completion, the mixture was poured into water (3000 mL) and extracted with ethyl acetate (3×800 mL). The combined organic phase was washed with brine (800 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on a silica gel column with petroleum ether/ethyl acetate=3/1 to give (R)-1-mercapto-3-methoxypropan-2-ol (70.0 g, crude) as a colorless oil. ^1H NMR (300 MHz, _CDCl3 ) δ 3.86-3.82 (m, 1H), 3.49-3.46 (m, 1H), 3.41-3.37 (m, 4H), 2.71-2.64 (m, 1H), 1.55-1.50 (m, 1H).

(R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (4)
To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (3) (20 g, 51.2 mmol) in dioxane (800 mL) was added potassium carbonate (21.2 g, 153.6 mmol), (R)-1-mercapto-3-methoxypropan-2-ol (11.26 g, 92.1 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (5.93 g, 10.24 mmol) and tris(dibenzylideneacetone)dipalladium (4.7 g, 5.1 mmol). The mixture was stirred at 55° C. under nitrogen atmosphere for 18 hours. After completion, the insoluble material was filtered off. The filtrate was then concentrated and the residue was adjusted to pH=4 with acetic acid, extracted with ethyl acetate (1000 mL) and washed with brine (500 mL). The organic phase was concentrated and recrystallized (dichloromethane/methanol=1/10). The mixture was filtered and the filter cake was collected to give (R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (4) (14 g, yield: 71%) as a white solid. MS (ESI) m/z 385.0 [M+H] ⁺ .

(S)-10-Chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione (5)
To a mixture of (R)-7-chloro-8-((2-hydroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (4) (34.4 g, 89.5 mmol) and triphenylphosphoranylidene (35.2 g, 134.3 mmol) in tetrahydrofuran (500 mL) at 0° C. was added diethyl azodicarboxylate (23.3 g, 134.3 mmol). The mixture was stirred at 0° C. for 45 minutes. After completion, the mixture was poured into ice water (300 mL) and extracted with ethyl acetate (3×500 mL). After concentration, the residue was recrystallized (dichloromethane/methanol=1/10), the mixture was filtered, and the filter cake was collected to give (S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione (24.0 g, 73% yield) as a white solid. MS (ESI): m/z 367.0 [M+H] ⁺ .

(2S,6R)-tert-butyl-4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate (6)
4-Methylbenzenesulfonic anhydride (13.4 g, 40.98 mmol) was added to a mixture of (S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione (10 g, 27.32 mmol) and potassium carbonate (37.7 g, 273.2 mmol) in acetonitrile (500 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes and at 30° C. for 4 hours. After completion, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (11.7 g, 54.64 mmol) was added to the reaction solution. The reaction mixture was stirred at 0° C. for 2 hours. After completion, the mixture was filtered through a celite pad and the filtrate was concentrated. The residue was purified by chromatography column (dichloromethane/methanol=100/1-30/1) to give (2S,6R)-tert-butyl-4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate (15 g, crude) as a pale white solid. MS (ESI) m/z 563.5 [M+H] ⁺ .

(2S,6R)-tert-butyl-4-((S)-3-(methoxymethyl)-10-(5-methylthiophen-2-yl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate (7)
To a mixture of (2S,6R)-tert-butyl-4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate (6) (200 mg, 0.35 mmol) in a solution of 1,4-dioxane (6 mL) and water (1 mL) was added tripotassium phosphate (780 mg, 3.5 mmol), (5-methylthiophen-2-yl)boronic acid (497 mg, 3.5 mmol), and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (41 mg, 0.52 mmol). The mixture was stirred at 85° C. for 4 hours under nitrogen atmosphere. After completion, the mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 30/1) to give (2S,6R)-tert-butyl-4-((S)-3-(methoxymethyl)-10-(5-methylthiophen-2-yl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate (7) (200 mg, crude) as a yellow solid. MS (ESI) m/z 625.5 [M+H] ⁺ .

(S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-10-(5-methylthiophen-2-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (8)
Trifluoroacetic acid (1 mL) was added to a mixture of (2S,6R)-tert-butyl-4-((S)-3-(methoxymethyl)-10-(5-methylthiophen-2-yl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate (200 mg, 0.32 mmol) in dichloromethane (3 ml) at 0° C. The reaction solution was stirred at room temperature for 30 minutes. After completion, the mixture was concentrated. The residue was redissolved in dichloromethane and dried over Na ₂ SO ₄ . After concentration, the residue was purified by column (dichloromethane/methanol=15:1) to give (S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-10-(5-methylthiophen-2-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (8) (150 mg, yield: 89%) as a yellow solid. MS (ESI) m/z 525.3 [M+H] ⁺ .

(S)-7-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-10-(5-methylthiophen-2-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (Example 3)
Acrylic anhydride (36 mg, 0.28 mmol) was added to a mixture of (S)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-10-(5-methylthiophen-2-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (100 mg, 0.19 mmol) and triethylamine (28 mg, 0.28 mmol) in dichloromethane (3 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes. After completion, the mixture was poured into ice water (1 mL) and extracted with ethyl acetate (3×5 mL). After concentration, the residue was purified with a chromatography column (dichloromethane/methanol=60/1 to 30/1) to obtain (S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-10-(5-methylthiophen-2-yl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (Example 3) (48 mg, yield: 44%) as a white powder. MS (ESI) m/z 579.3 [M+H]+; ^1H NMR (400 MHz, _CDCl3 ) δ 8.03 (s, 1H), 6.82 (s, 2H), 6.62 (dd, J = 10.4 Hz, J = 16.4 Hz, 1H), 6.40 (dd, J = 1.6 Hz, J = 16.4 Hz, 1H), 5.77 (dd, J = 1.6 Hz, J = 10.4 Hz, 1H), 5.42-5.38 (m, 1H), 4.78-4.54 (m, 2H), 4.20-4.15 (m, 2H), 3.72-3.62 (m, 2H), 3.40 (s, 3H), 3.38-3.28 (m, 3H), 2.96 (dd, J = 2.8 Hz, J = 13.6 Hz, 1H), 2.57 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.46 (d, J = 6.8 Hz, 3H).

（２Ｓ，６Ｒ）－ｔｅｒｔ－ブチル－４－（（Ｓ）－１０－（５－クロロチオフェン－２－イル）－３－（メトキシメチル）－５－オキソ－９－（トリフルオロメチル）－３，５－ジヒドロ－２Ｈ－［１，４］チアジノ［２，３，４－ｉｊ］キナゾリン－７－イル）－２，６－ジメチルピペラジン－１－カルボキシレート（２）
１，４－ジオキサン（１５ｍＬ）及び水（２ｍＬ）の溶液中の（２Ｓ，６Ｒ）－ｔｅｒｔ－ブチル－４－（（Ｓ）－１０－クロロ－３－（メトキシメチル）－５－オキソ－９－（トリフルオロメチル）－３，５－ジヒドロ－２Ｈ－［１，４］チアジノ［２，３，４－ｉｊ］キナゾリン－７－イル）－２，６－ジメチルピペラジン－１－カルボキシレート（４００ｍｇ、０．７１ｍｍｏｌ）の混合物にリン酸三カリウム（１．５ｇ、７．１ｍｍｏｌ）、（５－クロロチオフェン－２－イル）ボロン酸（４９７ｍｇ、３．５ｍｍｏｌ）、及びクロロ（２－ジシクロヘキシルホスフィノ－２’，６’－ジイソプロポキシ－１，１’－ビフェニル）［２－（２’－アミノ－１，１’－ビフェニル）］パラジウム（ＩＩ）（８３ｍｇ、０．１ｍｍｏｌ）を加えた。混合物を窒素雰囲気下、８５℃で４時間撹拌した。完了後、混合物を濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール＝１００／１～３０／１）で精製して、（２Ｓ，６Ｒ）－ｔｅｒｔ－ブチル－４－（（Ｓ）－１０－（５－クロロチオフェン－２－イル）－３－（メトキシメチル）－５－オキソ－９－（トリフルオロメチル）－３，５－ジヒドロ－２Ｈ－［１，４］チアジノ［２，３，４－ｉｊ］キナゾリン－７－イル）－２，６－ジメチルピペラジン－１－カルボキシレート（２）（４５０ｍｇ、粗製）を黄色固体として得た。ＭＳ （ＥＳＩ） ｍ／ｚ ６４５．５［Ｍ＋Ｈ］^＋。 Example 4: (S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-chlorothiophen-2-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (E4)

(2S,6R)-tert-butyl-4-((S)-10-(5-chlorothiophen-2-yl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate (2)
To a mixture of (2S,6R)-tert-butyl-4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate (400 mg, 0.71 mmol) in a solution of 1,4-dioxane (15 mL) and water (2 mL) was added tripotassium phosphate (1.5 g, 7.1 mmol), (5-chlorothiophen-2-yl)boronic acid (497 mg, 3.5 mmol), and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (83 mg, 0.1 mmol). The mixture was stirred at 85° C. for 4 hours under nitrogen atmosphere. After completion, the mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=100/1 to 30/1) to give (2S,6R)-tert-butyl-4-((S)-10-(5-chlorothiophen-2-yl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate (2) (450 mg, crude) as a yellow solid. MS (ESI) m/z 645.5 [M+H] ⁺ .

(S)-10-(5-chlorothiophen-2-yl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (3)
Trifluoroacetic acid (1 mL) was added to a mixture of (2S,6R)-tert-butyl-4-((S)-10-(5-chlorothiophen-2-yl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-3,5-dihydro-2H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-2,6-dimethylpiperazine-1-carboxylate (2) (450 mg, 0.69 mmol) in dichloromethane (3 ml) at 0° C. The reaction solution was stirred at room temperature for 30 minutes. After completion, the mixture was concentrated and the residue was purified by column (dichloromethane/methanol=15:1) to give (S)-10-(5-chlorothiophen-2-yl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (3) (350 mg, crude) as a yellow solid. MS (ESI) m/z 544.9 [M+H] ⁺ .

(S)-7-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-10-(5-chlorothiophen-2-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (4)
Acrylic anhydride (121 mg, 0.96 mmol) was added to a mixture of (S)-10-(5-chlorothiophen-2-yl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (350 mg, 0.64 mmol) and triethylamine (97 mg, 0.96 mmol) in dichloromethane (3 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes. After completion, the mixture was poured into ice water (1 mL) and extracted with ethyl acetate (3×5 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography column (dichloromethane/methanol=60/1 to 30/1) to give (S)-10-(5-chlorothiophen-2-yl)-7-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1,4]thiazino[2,3,4-ij]quinazolin-5(3H)-one (4) (88 mg, yield: 24%) as a yellow powder. MS (ESI) m/z 599.9 [M+H]+; ^1H NMR (400 MHz, _CDCl3 ) δ 8.03 (s, 1H), 6.98 (d, J = 4.0 Hz, 1H), 6.81 (d, J = 3.2 Hz, 1H), 6.61 (dd, J = 10.8 Hz, J = 16.8 Hz, 1H), 6.40 (dd, J = 2.0 Hz, J = 16.8 Hz, 1H), 5.77 (dd, J = 2.0 Hz, J = 10.4 Hz, 1H), 5.46-5.41 (m, 1H), 4.82-4.48 (m, 2H), 4.17 (t, J = 13.6 Hz, 2H), 3.70-3.62 (m, 2H), 3.40-3.28 (m, 6H), 2.96 (dd, J = 2.8 Hz, J = 13.2 Hz, 1H), 1.61 (d, J = 6.8 Hz, 3H), 1.46 (d, J = 7.2 Hz, 3H).

ステップ１：ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレート

ジオキサン（５ｍＬ）及び水（０．１ｍＬ）中のｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレート（０．３２ｍｍｏｌ）、（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）ボロン酸（１．２８ｍｍｏｌ）、リン酸カリウム（０．９６ｍｍｏｌ）、及びＲｕｐｈｏｓ Ｐｄ Ｇ４（０．０３ｍｍｏｌ）の混合物を脱気し、窒素で３回パージした。混合物を８０℃で３０分間撹拌し、揮発性物質を減圧下で除去して残渣を得て、これを分取ＴＬＣ（ヘキサン中の６５％酢酸エチル）で精製した。表題化合物を収率６３％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ８６５．３ ［Ｍ＋１］＋。 Example 23: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Step 1: tert-Butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

A mixture of tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (0.32 mmol), (4-chloro-5-(triisopropylsilyl)thiophen-2-yl)boronic acid (1.28 mmol), potassium phosphate (0.96 mmol), and Ruphos Pd G4 (0.03 mmol) in dioxane (5 mL) and water (0.1 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 80° C. for 30 min and the volatiles were removed under reduced pressure to give a residue which was purified by preparative TLC (65% ethyl acetate in hexanes). The title compound was isolated in 63% yield as a white solid. MS (ESI) m/z: 865.3 [M+1]+.

テトラヒドロフラン（５ｍＬ）中のｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレート（０．２０ｍｍｏｌ）の溶液にＴＨＦ（０．３ｍＬ）中の１Ｍのフッ化テトラブチルアンモニウムの溶液を加えた。混合物を室温で３０分間撹拌し、揮発性物質を減圧下で除去し、得られた残渣を分取ＴＬＣ（ヘキサン中の６０％酢酸エチル）で精製して、表題化合物を収率７２％で無色の半固体として得た。ＭＳ （ＥＳＩ） ｍ／ｚ： ７０９．２ ［Ｍ＋１］＋ Step 2: tert-Butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

To a solution of tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (0.20 mmol) in tetrahydrofuran (5 mL) was added a solution of 1 M tetrabutylammonium fluoride in THF (0.3 mL). The mixture was stirred at room temperature for 30 min, the volatiles were removed under reduced pressure, and the resulting residue was purified by preparative TLC (60% ethyl acetate in hexanes) to afford the title compound in 72% yield as a colorless semi-solid. MS (ESI) m/z: 709.2 [M+1]+

ジクロロメタン（６ｍＬ）中のｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロチオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレート（０．１４ｍｍｏｌ）の溶液にトリフルオロ酢酸（２ｍＬ）を加えた。３０分後、揮発性物質を減圧下で除去して、表題化合物を収率９９％で黄色の油として得た。この物質を更に精製することなく以下のステップで使用した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６０９．２ ［Ｍ＋１］＋。 Step 3: (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

To a solution of tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (0.14 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL). After 30 min, the volatiles were removed under reduced pressure to afford the title compound in 99% yield as a yellow oil. This material was used in the following step without further purification. MS (ESI) m/z: 609.2 [M+1]+.

ジクロロメタン（２ｍＬ）中の（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オン（０．１４ｍｍｏｌ）の溶液にトリエチルアミン（０．４３ｍｍｏｌ）及びプロパ－２－エノイルクロリド（０．２１ｍｍｏｌ）を加えた。３０分後、揮発性物質を減圧下で除去して残渣を得て、これを分取ＴＬＣ（ヘキサン中の１００％酢酸エチル）で精製した。表題化合物を収率６７％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６６３．４ ［Ｍ＋１］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ８．５２ （ｄ， Ｊ ＝ ４．８ Ｈｚ， ２Ｈ）， ８．０６ （ｓ， １Ｈ）， ７．３４ （ｓ， １Ｈ）， ７．００ （ｔ， Ｊ ＝ ４．８ Ｈｚ， １Ｈ）， ６．９２ （ｓ， １Ｈ）， ６．６３ （ｄｄ， Ｊ ＝ １０．４， １６．４ Ｈｚ， １Ｈ）， ６．４７ － ６．３７ （ｍ， １Ｈ）， ５．８４ － ５．６９ （ｍ， ２Ｈ）， ４．９５ － ４．５３ （ｍ， ４Ｈ）， ４．２１ （ｄ， Ｊ ＝ １３．２ Ｈｚ， ２Ｈ）， ３．６０ （ｄｄ， Ｊ ＝ ２．８， １３．６ Ｈｚ， １Ｈ）， ３．４５ － ３．３２ （ｍ， ２Ｈ）， ３．１９ － ３．０６ （ｍ， １Ｈ）， １．６４ － １．６０ （ｍ， ３Ｈ）， １．４８ （ｄ， Ｊ ＝ ６．４ Ｈｚ， ３Ｈ） Step 4: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

To a solution of (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (0.14 mmol) in dichloromethane (2 mL) was added triethylamine (0.43 mmol) and prop-2-enoyl chloride (0.21 mmol). After 30 min, the volatiles were removed under reduced pressure to give a residue which was purified by preparative TLC (100% ethyl acetate in hexanes). The title compound was isolated in 67% yield as a white solid. MS (ESI) m/z: 663.4 [M+1]+. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.8 Hz, 2H), 8.06 (s, 1H), 7.34 (s, 1H), 7.00 (t, J = 4.8 Hz, 1H), 6.92 (s, 1H), 6.63 (dd, J = 10.4, 16.4 Hz, 1H), 6.47 - 6.37 (m, 1H), 5.84 - 5.69 (m, 2H), 4.95 - 4.53 (m, 4H), 4.21 (d, J = 13.2 Hz, 2H), 3.60 (dd, J = 2.8, 13.6 Hz, 1H), 3.45 - 3.32 (m, 2H), 3.19 - 3.06 (m, 1H), 1.64 - 1.60 (m, 3H), 1.48 (d, J = 6.4 Hz, 3H)

反応スキーム

（Ｓ）－１－（１－（ベンジルオキシ）－３－（トリチルチオ）プロパン－２－イル）－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン（２）
０℃でテトラヒドロフラン（３４０ｍＬ）中の（Ｒ）－１－（ベンジルオキシ）－３－（トリチルチオ）プロパン－２－オール（３０ｇ、６８．１８ｍｍｏｌ）、１Ｈ－ピラゾロ［３，４－ｂ］ピリジン（９．７４ｇ、８１．８５ｍｍｏｌ）及びトリフェニルホスフィン（５３．６ｇ、２０４．６ｍｍｏｌ）の混合物に（Ｅ）－ジエチルジアゼン－１，２－ジカルボキシレート（３５．６ｇ、２０４．６ｍｍｏｌ）を加えた。混合物を窒素雰囲気下、室温で１２時間撹拌した。完了後、混合物を水（３００ｍＬ）でクエンチし、ジクロロメタン（１００ｍＬ×３）で抽出した。有機相を減圧下で濃縮した。残渣を、石油エーテル／酢酸エチル＝１０／１を用いるシリカゲルカラムで精製して、（Ｓ）－１－（１－（ベンジルオキシ）－３－（トリチルチオ）プロパン－２－イル）－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン（２）（２３．３６ｇ、収率６３％）を無色の油として得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ_３） δ ８．５１－８．４９ （ｍ， １Ｈ）， ８．０２－８．００ （ｍ， ２Ｈ）， ７．４３－７．３２ （ｍ， ６Ｈ）， ７．２４－６．９９ （ｍ， １５Ｈ）， ４．３６－４．２６ （ｍ， ３Ｈ）， ３．７９－３．６４ （ｍ， ２Ｈ）， ３．２０－３．１５ （ｍ， １Ｈ）， ２．７２－２．６８ （ｍ， １Ｈ）。 Example 24: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Reaction scheme

(S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-1H-pyrazolo[3,4-b]pyridine (2)
To a mixture of (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (30 g, 68.18 mmol), 1H-pyrazolo[3,4-b]pyridine (9.74 g, 81.85 mmol) and triphenylphosphine (53.6 g, 204.6 mmol) in tetrahydrofuran (340 mL) at 0° C. was added (E)-diethyldiazene-1,2-dicarboxylate (35.6 g, 204.6 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 12 hours. After completion, the mixture was quenched with water (300 mL) and extracted with dichloromethane (100 mL×3). The organic phase was concentrated under reduced pressure. The residue was purified on a silica gel column with petroleum ether/ethyl acetate=10/1 to give (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-1H-pyrazolo[3,4-b]pyridine (2) (23.36 g, yield 63%) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 8.51-8.49 (m, 1H), 8.02-8.00 (m, 2H), 7.43-7.32 (m, 6H), 7.24-6.99 (m, 15H), 4.36-4.26 (m, 3H), 3.79-3.64 (m, 2H), 3.20-3.15 (m, 1H), 2.72-2.68 (m, 1H).

(S)-3-(benzyloxy)-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)propane-1-thiol (3)
Triethylsilane (15 g, 129.3 mmol) was added to a mixture of (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-1H-pyrazolo[3,4-b]pyridine (2) (23.36 g, 43.18 mmol) in dichloromethane (90 mL) and 2,2,2-trifluoroacetic acid (30 mL) at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for 10 minutes. After completion, the mixture was concentrated under reduced pressure and adjusted to PH=8 with NH ₃ ^.MeOH . The mixture was then extracted with ethyl acetate (60 mL×3). After concentration, the residue was purified on a silica gel column with petroleum ether/ethyl acetate=10/1 to give (S)-3-(benzyloxy)-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)propane-1-thiol (3) (11 g, 85% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 8.56-8.64 (m, 1H), 8.08-8.05 (m, 2H), 7.29-7.12 (m, 6H), 5.39-5.35 (m, 1H), 4.53-4.45 (m, 2H), 4.01-3.93 (m, 2H), 3.35-3.13 (m, 2H), 1.27-1.22 (m, 1H).

(S)-8-((3-(benzyloxy)-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (4)
To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-diol (3) (8 g, 20.51 mmol) in 1,4-dioxane (100 mL) was added potassium carbonate (8.5 g, 61.59 mmol), (S)-3-(benzyloxy)-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)propane-1-thiol (11 g, 36.79 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.78 g, 3.08 mmol) and tris(dibenzylideneacetone)dipalladium (1.87 g, 2.04 mmol). The mixture was stirred at 60° C. under nitrogen atmosphere for 18 hours. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1) to give (S)-8-((3-(benzyloxy)-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (4) (15 g, crude) as a red oil. MS (ESI): m/z 563 [M-H] ⁻ .

(S)-7-Chloro-8-((3-hydroxy-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (5)
A solution of (S)-8-((3-(benzyloxy)-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (4) (15 g, 26.69 mmol) in trifluoroacetic acid (120 mL). The mixture was stirred at 80° C. for 18 hours. After completion, the mixture was concentrated and adjusted to PH=7-8 at 0° C. After concentration, the residue was purified on a silica gel column with dichloromethane/methanol=40/1 to give (S)-7-chloro-8-((3-hydroxy-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (5) (7.67 g, 26% yield for two steps) as a yellow solid. MS (ESI): m/z 472 [M−H] ⁻ .

(S)-11-Chloro-8-hydroxy-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (6)
To a mixture of (S)-7-chloro-8-((3-hydroxy-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (5) (7.57 g, 16.07 mmol) and triphenylphosphine (12.6 g, 48.09 mmol) in tetrahydrofuran (300 mL) at 0° C. was added diethyl azodicarboxylate (8.4 g, 48.28 mmol). The mixture was stirred at 0° C. for 45 minutes. After completion, the mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL×3). After concentration, the residue was purified on C18 using 30-95% acetonitrile in water to give (S)-11-chloro-8-hydroxy-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (6) (6 g, 82% yield) as a white solid. ^1H NMR (400 MHz, _CDCl3 ) δ 12.12 (s, 1H), 8.61-8.60 (m, 1H), 8.32-8.23 (m, 2H), 8.09 (s, 1H), 7.32-7.29 (m, 1H), 5.69-5.63 (m, 1H), 5.14-4.22 (m, 3H), 3.59 (s, 1H).

(2S,6R)-tert-butyl-4-((S)-11-chloro-6-oxo-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (7)
To a mixture of (S)-11-chloro-8-hydroxy-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (6) (3 g, 6.62 mmol) and potassium carbonate (9.2 g, 66.7 mmol) in acetonitrile (120 mL) and dichloromethane (80 mL) was added 2,4,6-triisopropylphenyl 4-methylbenzenesulfonate (4 g, 13.2 mmol). The mixture was stirred at 35° C. for 5 hours. After completion, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (2.2 g, 10.3 mmol) was added to the reaction solution. The reaction mixture was stirred at 35° C. for 1 hour. After completion, the mixture was poured into ice water (200 mL) and extracted with ethyl acetate (100 mL×3). After concentration, the residue was purified on a C18 column with 20-95% acetonitrile in water to give (2S,6R)-tert-butyl-4-((S)-11-chloro-6-oxo-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (7) (3.92 g, 91% yield) as a yellow solid. MS (ESI) m/z 650 [M+H] ⁺ .

(2S,6R)-tert-butyl-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8).
(2S,6R)-tert-butyl-4-((S)-11-chloro-6-oxo-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (7) (400 mg, 0.61 mL) in 1,4-dioxane (10 mL) and water (1 mL). To a solution of 1.5 mmol) of 1,2-dichloro-5-(triisopropylsilyl)thiophen-2-yl)boronic acid (586 mg, 1.84 mmol), and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (49 mg, 0.062 mmol) were added. The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol=60/1) to give (2S,6R)-tert-butyl-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8) (200 mg, 37% yield) as a yellow solid. MS (ESI) m/z 888.2 [M+H] ⁺ .

(2S,6R)-tert-butyl-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9)
Tetrabutylammonium fluoride (0.35 mL, 1.0 M solution in tetrahydrofuran) was added to a mixture of (2S,6R)-tert-butyl-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8) (200 mg, 0.23 mmol) in tetrahydrofuran (5 mL) at 0° C. The reaction solution was stirred at 0° C. for 1 hour. After completion, the mixture was concentrated and extracted with ethyl acetate (50 mL×3). The organic phase was concentrated and the residue was purified on a C18 column with 20% to 95% acetonitrile in water to give (2S,6R)-tert-butyl-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9) (130 mg, 77% yield) as a pale yellow solid. MS (ESI) m/z 732.2 [M+H] ⁺ .

(S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin)-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (10)
Trifluoroacetic acid (2 mL) was added to a mixture of (2S,6R)-tert-butyl-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9) (130 mg, 0.178 mmol) in dichloromethane (5 ml) at 0° C. The mixture was stirred at room temperature for 1 hour. After completion, the mixture was concentrated and adjusted to pH=7-8 at 0° C. After concentration, the residue was purified on a silica gel column with dichloromethane/methanol=30/1 to give (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin)-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (10) (92 mg, 82% yield) as a yellow oil. MS (ESI) m/z 632.2 [M+H] ⁺ .

(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (11)
Acrylic anhydride (27 mg, 0.219 mmol) was added to a mixture of (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin)-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (10) (92 mg, 0.146 mmol) and triethylamine (29 mg, 0.292 mmol) in dichloromethane (2 ml) at 0° C. The mixture was stirred at 0° C. for 1 h. After completion, the mixture was poured into ice water (30 mL) and extracted with dichloromethane (10 mL×3). Concentration and purification of the residue by preparative high performance liquid chromatography (20% to 95% acetonitrile in water) gave (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(1H-pyrazolo[3,4-b]pyridin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (11) (28 mg, 28% yield) as a white solid. MS (ESI) m/z 686.1 [M+H] ⁺ . ^1H NMR (400 MHz, _CDCl3 ) δ 8.53 (d, J = 4.0 Hz, 1H), 8.10-8.04 (m, 3H), 7.34 (s, 1H), 7.18-7.15 (dd, J = 8.0 Hz, 4.4 Hz, 1H), 7.02-6.88 (m, 1H), 6.67-6.60 (m, 1H), 6.42 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.78 (dd, J = 10.4 Hz, 2.0 Hz, 2H), 5.54-5.28 (m, 1H), 5.10 (d, J = 13.6 Hz, 1H), 4.80-4.44 (m, 2H), 4.17 (d, J = 13.2 Hz, 2H), 3.91-3.57 (m, 1H), 3.40-3.33 (m, 3H), 1.59-1.58 (m, 6H).

反応スキーム

（Ｒ）－１－（ベンジルオキシ）－３－（トリチルチオ）プロパン－２－オール（２）
メタノール（２５０ｍＬ）における（Ｓ）－２－（（ベンジルオキシ）メチル）オキシラン（２５ｇ、１５２．４ｍｍｏｌ）及びフッ化カリウム（１７．７ｇ、３０４．８ｍｍｏｌ）の混合物にトリフェニルメタンチオール（４２ｇ、１５２．４ｍｍｏｌ）を加えた。この混合物を室温で１８時間撹拌した。完成後、混合物を減圧下で濃縮し、石油エーテル／酢酸エチル＝５／１のシリカゲルカラムで精製すると、（Ｒ）－１－（ベンジルオキシ）－３－（トリチルチオ）プロパン－２－オール（２）（６０ｇ、収率９０％）が無色の油として得られた。^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ_３） δ ７．４４－７．３８ （ｍ， ６Ｈ）， ７．３５－７．１８ （ｍ， １４Ｈ）， ４．４６ （ｓ， ２Ｈ）， ３．５８－３．４８ （ｍ， １Ｈ）， ３．３７－３．２６ （ｍ， ２Ｈ）， ２．４５－２．３５ （ｍ， ２Ｈ）。 Example 25: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Reaction scheme

(R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (2)
To a mixture of (S)-2-((benzyloxy)methyl)oxirane (25 g, 152.4 mmol) and potassium fluoride (17.7 g, 304.8 mmol) in methanol (250 mL) was added triphenylmethanethiol (42 g, 152.4 mmol). The mixture was stirred at room temperature for 18 hours. After workup, the mixture was concentrated under reduced pressure and purified on a silica gel column with petroleum ether/ethyl acetate=5/1 to give (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (2) (60 g, 90% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.44-7.38 (m, 6H), 7.35-7.18 (m, 14H), 4.46 (s, 2H), 3.58-3.48 (m, 1H), 3.37-3.26 (m, 2H), 2.45-2.35 (m, 2H).

(S)-2-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (3)
To a mixture of [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (5.5 g, 41 mmol) and triphenylphosphine (13.4 g, 51 mmol) in tetrahydrofuran (400 mL) at 0° C. under nitrogen atmosphere, diethyl azodicarboxylate (8.8 g, 51 mmol) was added. The mixture was stirred at room temperature for 10 minutes, and then (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (2) (15 g, 34 mmol) was added. The mixture was stirred for 2 hours. After completion, the mixture was poured into ice water (300 mL) and extracted with ethyl acetate (150 mL×3). After concentration, the residue was purified on a silica gel column with petroleum ether/ethyl acetate=50/1 to give crude (S)-2-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (3) (16.5 g, crude) as a white solid. MS (ESI): m/z 558.2 [M+H] ⁺ .

(S)-2-(1-(benzyloxy)-3-mercaptopropan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (4)
To a mixture of (S)-2-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (3) (165 g, 30 mmol) and triethylsilane (17.4 g, 150 mmol) in dichloromethane (300 mL) was added trifluoroacetic acid (30 mL). The mixture was stirred at room temperature for 2 hours. After completion, the mixture was concentrated and adjusted to pH=7-8 at 0° C. After concentration, the residue was purified on a silica gel column with petroleum ether/ethyl acetate=2/1 to give (S)-2-(1-(benzyloxy)-3-mercaptopropan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (4) (7.9 g, 85% yield). MS (ESI): m/z 316.1 [M+H] ^<+> .

(S)-2-(1-(benzyloxy)-3-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (5).
To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-diol (4.5 g, 11 mmol) in 1,4-dioxane (200 mL) was added potassium carbonate (4.6 g, 33 mmol), (S)-2-(1-(benzyloxy)-3-mercaptopropan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (4) (55 g, 17 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (1.2 g, 1.03 mmol) and tris(dibenzylideneacetone)dipalladium (0.92 g, 1.0 mmol). The mixture was stirred at 60° C. under nitrogen atmosphere for 18 hours. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give (S)-2-(1-(benzyloxy)-3-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (5) (6.2 g, 93% yield) as a pale yellow solid. MS (ESI): m/z 578.1 [M+H] ⁺ .

(S)-2-(1-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)-3-hydroxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (6)
A solution of (S)-2-(1-(benzyloxy)-3-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)propan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (5) (6.2 g, 10 mmol) in trifluoroacetic acid (50 mL). The mixture was stirred at 80° C. for 18 hours. After completion, the mixture was concentrated and adjusted to pH=7-8 at 0° C. After concentration, the residue was purified on a silica gel column with dichloromethane/methanol=10/1 to give (S)-2-(1-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)-3-hydroxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (6) (3.6 g, 69% yield) as a yellow solid. MS (ESI): m/z 488.1 [M+H] ⁺ .

(S)-11-Chloro-8-hydroxy-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (7).
Diethyl azodicarboxylate (4.9 g, 28.6 mmol) was added to a mixture of (S)-2-(1-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)-3-hydroxypropan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (6) (3.5 g, 7.1 mmol) and triphenylphosphine (7.5 g, 28.6 mmol) in tetrahydrofuran (130 mL) at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. After completion, the mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL×3). Upon concentration, the residue was purified on C18 using 30-95% acetonitrile in water to give (S)-11-chloro-3-(4-fluorophenoxy)-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (7) (2.6 g, 78% yield) as a yellow solid. MS (ESI): m/z 470. [M+H] ⁺ .

(2S,6R)-tert-butyl-4-((S)-11-chloro-6-oxo-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8).
To a mixture of ((S)-11-chloro-3-(4-fluorophenoxy)-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (7) (2.4 g, 5.1 mmol) and potassium carbonate (7.0 g, 51 mmol) in acetonitrile (100 mL) was added 4-methylbenzenesulfonic anhydride (4.9 g, 15.3 mmol). The mixture was stirred at 35° C. for 8 hours. After completion, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (3.8 g, 17.8 mmol) was added to the reaction solution. The reaction mixture was stirred at 35° C. for 8 hours. C. for overnight. After completion, the mixture was poured into ice water (200 mL) and extracted with ethyl acetate (100 mL.times.3). On concentration, the residue was purified on a C18 column using 20-95% acetonitrile in water to give (2S,6R)-tert-butyl-4-((S)-11-chloro-6-oxo-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8) (2.3 g, 72% yield) as a pale yellow solid. MS (ESI) m/z 666.2 [M+H].sup ^.+ .

(2S,6R)-tert-butyl-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-[ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9)
(2S,6R)-tert-butyl-4-((S)-11-chloro-6-oxo-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8) (3 To a solution of 50 mg, 0.53 mmol) of tripotassium phosphate (337 mg, 1.59 mmol), (4-chloro-5-(triisopropylsilyl)thiophen-2-yl)boronic acid (507 mg, 1.59 mmol), and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (41 mg, 0.053 mmol) were added. The mixture was stirred at 80° C. for 1 hour under a nitrogen atmosphere. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol=60/1) to give (2S,6R)-tert-butyl-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-[ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9) (250 mg, crude) as a yellow solid. MS (ESI) m/z 904.1 [M+H] ⁺ .

(2S,6R)-tert-butyl-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (10)
Tetrabutylammonium fluoride (0.34 mL, 1.0 M solution in tetrahydrofuran) was added to a mixture of (2S,6R)-tert-butyl-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9) (250 mg, 0.28 mmol) in tetrahydrofuran (5 mL) at 0° C. The reaction solution was stirred at 0° C. for 1 hour. After completion, the mixture was concentrated and extracted with ethyl acetate (50 mL×3). Upon concentration, the residue was purified on a C18 column with 20% to 95% acetonitrile in water to give (2S,6R)-tert-butyl-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (10) (150 mg, 38% yield for two steps) as a pale yellow solid. MS (ESI) m/z 748.2 [M+H] ⁺ .

(S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (11)
Trifluoroacetic acid (2 mL) was added to a mixture of (2S,6R)-tert-butyl-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (10) (150 mg, 0.20 mmol) in dichloromethane (6 mL) at 25° C. The mixture was stirred at 25° C. for 1 hour. After completion, the mixture was concentrated and the pH was adjusted to 8 with ammonia in methanol at 0° C. The mixture was concentrated and purified by silica gel column chromatography (dichloromethane/methanol=30/1) to give (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (11) (80 mg, 62% yield) as a yellow solid. MS (ESI) m/z 648.2 [M+H] ⁺ .

(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (12)
To a mixture of (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (11) (80 mg, 0.12 mmol) in dichloromethane (6 ml) at 0° C. was added triethylamine (24 mg, 0.24 mmol) and acrylic anhydride (23 mg, 0.18 mmol). The mixture was stirred at 25° C. for 1 hour. After completion, the mixture was added methanol at 25° C. and concentrated. The mixture was purified by preparative high performance liquid chromatography (20% to 95% acetonitrile in water) to give (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (12) (24 mg, 0.034 mmol, 28% yield) as a pale yellow powder. MS (ESI) m/z 702.3 [M+H] ⁺ . ^1H NMR (400 MHz, _CDCl3 ) δ 8.09 (s, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.34 (s, 1H), 7.10-7.00 (m, 2H), 6.96-6.95 (m, 1H), 6.65-6.59 (m, 1H), 6.49 (t, J = 7.2 Hz, 1H), 6.41 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.78 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 5.35-5.27 (m, 1H), 5.25-5.08 (m, 1H), 5.02-4.90 (m, 1H), 4.90-4.50 (m, 2H), 4.15 (d, J = 13.2 Hz, 2H), 3.85-3.00 (m, 4H), 1.60-1.40 (m, 6H).

反応スキーム

（３－クロロチオフェン－２－イル）トリイソプロピルシラン（２）
リチウムジイソプロピルアミド（２２１．３７ｍＬ、４４２．７４ｍｍｏｌ、テトラヒドロフラン／ｎ－ヘプタン中の２．０Ｍ溶液）を、窒素雰囲気下、－７８℃でテトラヒドロフラン（１．０５Ｌ）中の３－クロロチオフェン（５０ｇ、４２１．６６ｍｍｏｌ）の溶液にゆっくり加えた。混合物を－７８℃で１時間撹拌し、次いで塩化トリイソプロピルシリル（８５．３６ｇ、４４２．７４ｍｍｏｌ）を加えた。混合物をゆっくりと室温まで温め、一晩撹拌した。完了後、飽和塩化アンモニウム水溶液（８００ｍＬ）をゆっくり加え、酢酸エチル（１Ｌ×３）で抽出した。濃縮後、残渣をシリカゲルカラム（石油エーテル／酢酸エチル＝５００／１）で精製して、（３－クロロチオフェン－２－イル）トリイソプロピルシラン（２）（５７ｇ、収率４９％）を無色の油として得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ_３） δ ７．５２ （ｄ， Ｊ ＝ ４．８ Ｈｚ， １Ｈ）， ７．０４ （ｄ， Ｊ ＝ ４．８ Ｈｚ， １Ｈ）， １．５７－１．５１ （ｍ， ３Ｈ）， １．１２ （ｄ， Ｊ ＝ ８．０ Ｈｚ，１８ Ｈ）。 Example 26: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Reaction scheme

(3-chlorothiophen-2-yl)triisopropylsilane (2)
Lithium diisopropylamide (221.37 mL, 442.74 mmol, 2.0 M solution in tetrahydrofuran/n-heptane) was slowly added to a solution of 3-chlorothiophene (50 g, 421.66 mmol) in tetrahydrofuran (1.05 L) at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C. for 1 h, then triisopropylsilyl chloride (85.36 g, 442.74 mmol) was added. The mixture was slowly warmed to room temperature and stirred overnight. After completion, saturated aqueous ammonium chloride solution (800 mL) was slowly added and extracted with ethyl acetate (1 L×3). After concentration, the residue was purified on a silica gel column (petroleum ether/ethyl acetate=500/1) to give (3-chlorothiophen-2-yl)triisopropylsilane (2) (57 g, 49% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.52 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 4.8 Hz, 1H), 1.57-1.51 (m, 3H), 1.12 (d, J = 8.0 Hz, 18H).

(4-Chloro-5-(triisopropylsilyl)thiophen-2-yl)boronic acid (3)
Lithium diisopropylamide (10.91 mL, 21.83 mmol, 2.0 M solution in tetrahydrofuran/n-heptane) was slowly added to a solution of (3-chlorothiophen-2-yl)triisopropylsilane (2) (5 g, 18.19 mmol) in tetrahydrofuran (90 mL) at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C. for 1 h, then trimethyl borate (2.27 g, 21.83 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 1 h. After completion, saturated aqueous ammonium chloride solution (10 mL) was slowly added. After concentration, the residue was purified on a silica gel column (dichloromethane/methanol=50/1) to give (4-chloro-5-(triisopropylsilyl)thiophen-2-yl)boronic acid (3) (3.5 g, 60% yield) as a pale yellow oil. ^1H NMR (400 MHz, CD3OD) δ 7.53 (s, 1H), 1.59-1.52 (m, 3H), 1.13 (d, J=8.0 Hz, 18H).

(R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (5)
To a mixture of (S)-2-((benzyloxy)methyl)oxirane (25 g, 152.4 mmol) and potassium fluoride (17.7 g, 304.8 mmol) in methanol (250 mL) was added triphenylmethanethiol (42 g, 152.4 mmol). The mixture was stirred at room temperature for 18 hours. After completion, the mixture was concentrated under reduced pressure and purified on a silica gel column with petroleum ether/ethyl acetate=5/1 to give (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (5) (60 g, 90% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.44-7.38 (m, 6H), 7.35-7.18 (m, 14H), 4.46 (s, 2H), 3.58-3.48 (m, 1H), 3.37-3.26 (m, 2H), 2.45-2.35 (m, 2H).

(S)-2-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)isoindoline-1,3-dione (6)
Diethyl azodicarboxylate (8.9 g, 51.1 mmol) was added to a mixture of isoindoline-1,3-dione (6.0 g, 40.9 mmol) and triphenylphosphine (13.3 g, 51.1 mmol) in tetrahydrofuran (400 mL) at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 10 minutes, and then (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (5) (15 g, 34.1 mmol) was added. The mixture was stirred for 2 hours. After completion, the mixture was poured into ice water (300 mL) and extracted with ethyl acetate (150 mL×3). After concentration, the residue was purified on a silica gel column with petroleum ether/ethyl acetate=50/1 to give crude (S)-2-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)isoindoline-1,3-dione (6) (19.0 g, crude) as a colorless oil. MS (ESI) m/z 570.2 [M+H] ⁺ .

(S)-2-(1-(benzyloxy)-3-mercaptopropan-2-yl)isoindolin-1-one (7)
To a solution of (S)-2-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)isoindoline-1,3-dione (6) (18.0 g, 31.66 mmol) in acetic acid (250 mL) at 0° C. was added zinc (30.8 g, 474 mmol). The mixture was stirred at 100° C. for 4 hours. After completion, the mixture was concentrated, adjusted to pH=7-8 at 0° C. and extracted with dichloroethane. After concentration, the residue was purified on a silica gel column with petroleum ether/ethyl acetate=3/1 to give (S)-2-(1-(benzyloxy)-3-mercaptopropan-2-yl)isoindolin-1-one (7) (3.7 g, 37% yield) as a yellow oil. MS (ESI) m/z 314.1 [M+H] ⁺ .

(S)-2-(1-(benzyloxy)-3-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)propan-2-yl)isoindolin-1-one (8)
To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-diol (4.6 g, 12 mmol) in 1,4-dioxane (200 mL) was added potassium carbonate (11.8 g, 36 mmol), (S)-2-(1-(benzyloxy)-3-mercaptopropan-2-yl)isoindolin-1-one (7) (4.7 g, 15 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.4 g, 1.6 mmol) and tris(dibenzylideneacetone)dipalladium (1.1 g, 1.2 mmol). The mixture was stirred at 60° C. under nitrogen atmosphere for 18 hours. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate=3/1) to give (S)-2-(1-(benzyloxy)-3-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)propan-2-yl)isoindolin-1-one (8) (4.6 g, 66% yield) as a pale yellow solid. MS (ESI) m/z 576.1 [M+H] ⁺ .

(S)-2-(1-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)-3-hydroxypropan-2-yl)isoindolin-1-one (9)
A solution of (S)-2-(1-(benzyloxy)-3-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)propan-2-yl)isoindolin-1-one (8) (4.5 g, 7.8 mmol) in trifluoroacetic acid (100 mL). The mixture was stirred at 80° C. for 18 hours. After completion, the mixture was concentrated and adjusted to pH=7-8 at 0° C. After concentration, the residue was purified on a silica gel column with dichloromethane/ethyl acetate=1/2 to give (S)-2-(1-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)-3-hydroxypropan-2-yl)isoindolin-1-one (9) (2.8 g, 75% yield) as a yellow solid. MS (ESI): m/z 486.1 [M+H] ⁺ .

(S)-11-Chloro-8-hydroxy-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (10)
To a mixture of (S)-2-(1-((7-chloro-2,4-dihydroxy-6-(trifluoromethyl)quinazolin-8-yl)thio)-3-hydroxypropan-2-yl)isoindolin-1-one (9) (2.6 g, 5.3 mmol) and triphenylphosphine (5.6 g, 21.4 mmol) in tetrahydrofuran (100 mL) at 0° C. under nitrogen atmosphere, diethyl azodicarboxylate (3.7 g, 21.4 mmol) was added. The mixture was stirred at room temperature for 3 hours. After completion, the mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL×3). Upon concentration, the residue was purified on C18 using 30-95% acetonitrile in water to give (S)-11-chloro-8-hydroxy-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (10) (2.0 g, 83% yield) as a yellow solid. MS (ESI) m/z 468.2 [M+H] ⁺ .

(2S,6R)-tert-butyl-4-((S)-11-chloro-6-oxo-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (11)
To a mixture of (S)-11-chloro-8-hydroxy-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (10) (500 mg, 1.06 mmol) and DIEA (690.38 mg, 5.34 mmol) in toluene (20 mL) was added phosphoryl trichloride (1.31 g, 8.547 mmol). The mixture was stirred at 120° C. for 4 hours. After completion, the mixture was concentrated and the residue was added to the solution. The reaction mixture was stirred at 35° C. for 1 hour. After completion, the mixture was poured into ice water (100 mL) and extracted with ethyl acetate (50 mL×3). Upon concentration, the residue was purified on a C18 column with 20-95% acetonitrile in water to give (2S,6R)-tert-butyl-4-((S)-11-chloro-6-oxo-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (11) (532 mg, 75% yield) as a pale yellow solid. MS (ESI) m/z 664.1 [M+H] ⁺ .

(2S,6R)-tert-butyl-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (12)
(2S,6R)-tert-butyl-4-((S)-11-chloro-6-oxo-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (11) (350 mg, 0.53 m) in 1,4-dioxane (5 mL) and water (0.5 mL). To a solution of 1,2-dichloro-5-(triisopropylsilyl)thiophen-2-yl)boronic acid (507 mg, 1.59 mmol), tripotassium phosphate (337 mg, 1.59 mmol), (4-chloro-5-(triisopropylsilyl)thiophen-2-yl)boronic acid (507 mg, 1.59 mmol), and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (41 mg, 0.053 mmol) were added. The mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol=60/1) to give (2S,6R)-tert-butyl-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (12) (190 mg, 40% yield) as a yellow solid. MS (ESI) m/z 902.1 [M+H] ⁺ .

(2S,6R)-tert-butyl-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (13)
Tetrabutylammonium fluoride (0.23 mL, 1.0 M solution in tetrahydrofuran) was added to a mixture of (2S,6R)-tert-butyl-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (12) (190 mg, 0.21 mmol) in tetrahydrofuran (5 mL) at 0° C. The reaction solution was stirred at 0° C. for 1 hour. After completion, the mixture was concentrated and extracted with ethyl acetate (100 mL×3). Upon concentration, the residue was purified on a C18 column with 20% to 95% acetonitrile in water to give (2S,6R)-tert-butyl-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (13) (110 mg, 70% yield) as a pale yellow solid. MS (ESI) m/z 746.2 [M+H] ⁺ .

(S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (14)
Trifluoroacetic acid (2 mL) was added to a mixture of (2S,6R)-tert-butyl-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (13) (110 mg, 0.15 mmol) in dichloromethane (6 mL) at 0° C. The reaction solution was stirred at room temperature for 1 h. After completion, the mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to give (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (14) (62 mg, 64% yield) as a pale yellow solid. MS (ESI) m/z 646.2 [M+H] ⁺ .

(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (15)
Acrylic anhydride (18 mg, 0.144 mmol) was added to a mixture of (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (14) (62 mg, 0.096 mmol) and triethylamine (19 mg, 0.192 mmol) in dichloromethane (3 ml) at 0° C. The mixture was stirred at 0° C. for 1 h. After completion, the mixture was poured into ice water (10 mL) and extracted with dichloromethane (10 mL×3). Concentration and purification of the residue by preparative high performance liquid chromatography (20% to 95% acetonitrile in water) afforded (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(1-oxoisoindolin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (15) (20 mg, 30% yield) as a white solid. MS (ESI) m/z 700.3 [M+H] ⁺ . ^1H NMR (400 MHz, _CDCl3 ) δ 8.09 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.57-7.52 (m, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.36 (s, 1H), 7.00-6.93 (m, 1H), 6.66-6.60 (m, 1H), 6.44-6.40 (m, 1H), 5.79 (dd, J = 10.4 Hz, 2.0 Hz, 1H), 5.20-4.15 (m, 10H), 3.43-3.37 (m, 3H), 1.57-1.56 (m, 6H).

反応スキーム

（Ｒ）－１－（ベンジルオキシ）－３－（トリチルチオ）プロパン－２－オール（２）
メタノール（２５０ｍＬ）における（Ｓ）－２－（（ベンジルオキシ）メチル）オキシラン（２５ｇ、１５２．４ｍｍｏｌ）及びフッ化カリウム（１７．７ｇ、３０４．８ｍｍｏｌ）の混合物にトリフェニルメタンチオール（４２ｇ、１５２．４ｍｍｏｌ）を加えた。この混合物を室温で１８時間撹拌した。完成後、混合物を減圧下で濃縮し、石油エーテル／酢酸エチル＝５／１のシリカゲルカラムで精製し、（Ｒ）－１－（ベンジルオキシ）－３－（トリチルチオ）プロパン－２－オール（２）（６０ｇ、収率９０％）を無色の油として得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ_３） δ ７．４４－７．３８ （ｍ， ６Ｈ）， ７．３５－７．１８ （ｍ， １４Ｈ）， ４．４６ （ｓ， ２Ｈ）， ３．５８－３．４８ （ｍ， １Ｈ）， ３．３７－３．２６ （ｍ， ２Ｈ）， ２．４５－２．３５ （ｍ， ２Ｈ）。 Example 27: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(1H-benzo[d]imidazol-1-yl)-11-(4-chlorothiophen)-2-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one

Reaction scheme

(R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (2)
To a mixture of (S)-2-((benzyloxy)methyl)oxirane (25 g, 152.4 mmol) and potassium fluoride (17.7 g, 304.8 mmol) in methanol (250 mL) was added triphenylmethanethiol (42 g, 152.4 mmol). The mixture was stirred at room temperature for 18 hours. After completion, the mixture was concentrated under reduced pressure and purified on a silica gel column with petroleum ether/ethyl acetate=5/1 to give (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (2) (60 g, 90% yield) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.44-7.38 (m, 6H), 7.35-7.18 (m, 14H), 4.46 (s, 2H), 3.58-3.48 (m, 1H), 3.37-3.26 (m, 2H), 2.45-2.35 (m, 2H).

(S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-1H-benzo[d]imidazole (3)
Diethyl azodicarboxylate (16.6 g, 95.46 mmol) was added to a mixture of 1H-benzo[d]imidazole (8.45 g, 71.59 mmol) and triphenylphosphine (25.0 g, 95.46 mmol) in tetrahydrofuran (470 mL) at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 10 minutes, and then (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (2) (21 g, 47.73 mmol) was added. The mixture was stirred for 2 hours. After completion, the mixture was poured into ice water (300 mL) and extracted with ethyl acetate (150 mL×3). After concentration, the residue was purified on a silica gel column with petroleum ether/ethyl acetate=30/1 to give (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-1H-benzo[d]imidazole (3) (12.4 g, 48% yield) as a yellow oil. MS (ESI) m/z 541.0 [M+H] ⁺ .

(S)-2-(1H-benzo[d]imidazol-1-yl)-3-(benzyloxy)propane-1-thiol (4)
To a mixture of (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-1H-benzo[d]imidazole (3) (12.47 g, 23.1 mmol) and triethylsilane (6.7 g, 57.7 mmol) in dichloromethane (230 mL) was added trifluoroacetic acid (26.3 g, 231 mmol). The mixture was stirred at room temperature for 3 hours. After completion, the mixture was concentrated and adjusted to pH=7-8 at 0° C. After concentration, the residue was purified on a silica gel column with petroleum ether/ethyl acetate=10/1 to give (S)-2-(1H-benzo[d]imidazol-1-yl)-3-(benzyloxy)propane-1-thiol (4) (3.95, 57% yield) as a yellow oil. MS (ESI) m/z 299.2 [M+H] ⁺ .

(S)-8-((2-(1H-benzo[d]imidazol-1-yl)-3-(benzyloxy)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (5)
To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-diol (2.87 g, 7.36 mmol) in 1,4-dioxane (73 mL) was added potassium carbonate (3.0 g, 22.08 mmol), (S)-2-(1H-benzo[d]imidazol-1-yl)-3-(benzyloxy)propane-1-thiol (4) (3.95 g, 13.26 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (639 mg, 1.10 mmol) and tris(dibenzylideneacetone)dipalladium (674 mg, 0.736 mmol). The mixture was stirred at 60° C. under nitrogen atmosphere for 18 hours. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate=3/1) to give (S)-8-((2-(1H-benzo[d]imidazol-1-yl)-3-(benzyloxy)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (5) (3.8 g, 93% yield) as a pale yellow solid. MS (ESI) m/z 561 [M+H] ⁺ .

(S)-8-((2-(1H-benzo[d]imidazol-1-yl)-3-hydroxypropyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (6)
A solution of (S)-8-((2-(1H-benzo[d]imidazol-1-yl)-3-(benzyloxy)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (5) (3.8 g, 6.78 mmol) in trifluoroacetic acid (55 mL). The mixture was stirred at 80° C. for 18 hours. After completion, the mixture was concentrated and adjusted to pH=7-8 at 0° C. After concentration, the residue was purified on a silica gel column using dichloromethane/ethyl acetate=1/2 to give (S)-8-((2-(1H-benzo[d]imidazol-1-yl)-3-hydroxypropyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (6) (2.5 g, 78% yield) as a yellow solid. MS (ESI): m/z 471.0 [M+H] ⁺ .

(S)-3-(1H-benzo[d]imidazol-1-yl)-11-chloro-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (7)
To a mixture of (S)-8-((2-(1H-benzo[d]imidazol-1-yl)-3-hydroxypropyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (6) (2.56 g, 5.45 mmol) and triphenylphosphine (5.7 g, 21.78 mmol) in tetrahydrofuran (750 mL) at 0° C. was added diethyl azodicarboxylate (3.79 g, 21.78 mmol). The mixture was stirred at 0° C. for 45 minutes. After completion, the mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL×3). Upon concentration, the residue was purified on C18 using 30-95% acetonitrile in water to give (S)-3-(1H-benzo[d]imidazol-1-yl)-11-chloro-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (7) (840 mg, 34% yield) as a yellow solid. MS (ESI) m/z 451.3 [M-H] ^- .

(2S,6R)-tert-Butyl-4-((S)-3-(1H-benzo[d]imidazol-1-yl)-11-chloro-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8)
To a mixture of (S)-3-(1H-benzo[d]imidazol-1-yl)-11-chloro-8-hydroxy-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (7) (680 mg, 1.5 mmol) and potassium carbonate (2.07 g, 15.0 mmol) in acetonitrile (50 mL) was added 2,4,6-triisopropylbenzenesulfonyl chloride (908 mg, 3.0 mmol). The mixture was stirred at 35° C. for 4 hours. After completion, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (802 mg, 3.75 mmol) was added to the reaction solution. The reaction mixture was stirred at 35° C. for 1 hour. After completion, the mixture was poured into ice water (200 mL) and extracted with ethyl acetate (100 mL×3). Upon concentration, the residue was purified on a C18 column with 20-95% acetonitrile in water to give (2S,6R)-tert-butyl-4-((S)-3-(1H-benzo[d]imidazol-1-yl)-11-chloro-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8) (486 mg, 50% yield) as a pale yellow solid. MS (ESI) m/z 649.2 [M+H] ⁺ .

(2S,6R)-tert-butyl-4-((S)-3-(1H-benzo[d]imidazol-1-yl)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9)
(2S,6R)-tert-butyl-4-((S)-3-(1H-benzo[d]imidazol-1-yl)-11-chloro-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8) (350 mg, 0.54 mL) in 1,4-dioxane (5 mL) and water (0.5 mL). To a solution of 1,2-dichloro-5-(triisopropylsilyl)thiophen-2-yl)boronic acid (515 mg, 1.62 mmol), tripotassium phosphate (343 mg, 1.62 mmol), (4-chloro-5-(triisopropylsilyl)thiophen-2-yl)boronic acid (515 mg, 1.62 mmol), and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (42 mg, 0.054 mmol) were added. The mixture was stirred at 80°C under nitrogen atmosphere for 1 hour. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol=60/1) to give (2S,6R)-tert-butyl-4-((S)-3-(1H-benzo[d]imidazol-1-yl)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9) (197 mg, 41% yield) as a yellow solid. MS (ESI) m/z 888 [M+H] ⁺ .

(2S,6R)-tert-Butyl-4-((S)-3-(1H-benzo[d]imidazol-1-yl)-11-(4-chlorothiophen-2-yl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (10)
Tetrabutylammonium fluoride (0.24 mL) was added to a mixture of (2S,6R)-tert-butyl-4-((S)-3-(1H-benzo[d]imidazol-1-yl)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9) (197 mg, 0.22 mmol) in tetrahydrofuran (5 mL) at 0° C. The reaction solution was stirred at 0° C. for 1 hour. After completion, the mixture was concentrated and extracted with ethyl acetate (100 mL×3). Upon concentration, the residue was purified on a C18 column with 20% to 95% acetonitrile in water to give (2S,6R)-tert-butyl-4-((S)-3-(1H-benzo[d]imidazol-1-yl)-11-(4-chlorothiophen-2-yl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (10) (81 mg, 50% yield) as a pale yellow solid. MS (ESI) m/z 731.2 [M+H] ⁺ .

(S)-3-(1H-benzo[d]imidazol-1-yl)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (11)
Trifluoroacetic acid (1 mL) was added to a mixture of (2S,6R)-tert-butyl-4-((S)-3-(1H-benzo[d]imidazol-1-yl)-11-(4-chlorothiophen-2-yl)-6-oxo-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (10) (81 mg, 0.11 mmol) in dichloromethane (3 mL) at 0° C. The reaction solution was stirred at room temperature for 1 h. After completion, the mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give (S)-3-(1H-benzo[d]imidazol-1-yl)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (11) (60 mg, crude) as a pale yellow solid. MS (ESI) m/z 631.2 [M+H] ⁺ .

(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(1H-benzo[d]imidazol-1-yl)-11-(4-chlorothiophene)-2-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (12)
Acrylic anhydride (42 mg, 0.33 mmol) was added to a mixture of (S)-3-(1H-benzo[d]imidazol-1-yl)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (11) (60 mg, crude) and triethylamine (56 mg, 0.55 mmol) in dichloromethane (5 ml) at 0° C. The mixture was stirred at 0° C. for 1 h. After completion, the mixture was poured into ice water (30 mL) and extracted with dichloromethane (30 mL×3). Concentration and purification of the residue by preparative high performance liquid chromatography (20% to 95% acetonitrile in water) gave (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3-(1H-benzo[d]imidazol-1-yl)-11-(4-chlorothiophene)-2-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (12) (2.5 mg, 3% yield) as a white solid. MS (ESI) m/z 685.8 [M+H] ⁺ . ^1H NMR (400 MHz, _CDCl3 ) δ 8.21 (s, 1H), 8.13 (s, 1H), 7.83-7.79 (m, 1H), 7.60-7.54 (m, 1H), 7.40-7.32 (m, 4H), 6.66-6.59 (m, 1H), 6.43 (dd, J = 16.4 Hz, 1.6 Hz, 1H), 5.81 (dd, J = 10.8 Hz, 1.6 Hz, 1H), 5.39-5.32 (m, 4H), 5.12-4.95 (m, 3H), 4.76-4.61 (m, 2H), 4.24-4.17 (m, 2H), 2.01-2.00 (m, 6H).

反応スキーム

（Ｓ）－（２－アジド－３－（ベンジルオキシ）プロピル）（トリチル）スルファン（２）
窒素雰囲気下、０℃でテトラヒドロフラン（４００ｍＬ）中の（Ｒ）－１－（ベンジルオキシ）－３－（トリチルチオ）プロパン－２－オール（１）（２０ｇ、４５．４５ｍｍｏｌ）及びトリフェニルホスフィン（３０ｇ、１１３．６ｍｍｏｌ）の混合物にアゾジカルボン酸ジエチル（３０ｍＬ、１１３．６ｍｍｏｌ）を加えた。混合物を室温で１０分間撹拌し、次いで、ＤＰＰＡ（１１ｍＬ、４７．７３ｍｍｏｌ）を加えた。混合物を２時間撹拌した。完了後、この混合物を氷水（３００ｍＬ）に注ぎ、酢酸エチル（１５０ｍＬ×３）で抽出した。濃縮後、残渣を石油エーテル／酢酸エチル＝２０／１を用いるシリカゲルカラムで精製して、粗製（Ｓ）－（３－（ベンジルオキシ）－２－（４－フルオロフェノキシ）プロピル）（トリチル）スルファン（２）（１６．５ｇ、粗製）を黄色の油として得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ，ＣＤＣｌ_３） δ ７．４３－７．１９ （ｍ， ２０Ｈ）， ４．５２－４．４９ （ｍ， １Ｈ）， ４．４５ （ｓ， ２Ｈ）， ３．３９－３．３５ （ｍ， ２Ｈ）， ２．４１－２．３６ （ｍ， ２Ｈ）。 Example 28: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(1H-1,2,3)-triazol-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one

Reaction scheme

(S)-(2-azido-3-(benzyloxy)propyl)(trityl)sulfane (2)
Diethyl azodicarboxylate (30 mL, 113.6 mmol) was added to a mixture of (R)-1-(benzyloxy)-3-(tritylthio)propan-2-ol (1) (20 g, 45.45 mmol) and triphenylphosphine (30 g, 113.6 mmol) in tetrahydrofuran (400 mL) at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 10 minutes, and then DPPA (11 mL, 47.73 mmol) was added. The mixture was stirred for 2 hours. After completion, the mixture was poured into ice water (300 mL) and extracted with ethyl acetate (150 mL×3). After concentration, the residue was purified on a silica gel column with petroleum ether/ethyl acetate=20/1 to give crude (S)-(3-(benzyloxy)-2-(4-fluorophenoxy)propyl)(trityl)sulfane (2) (16.5 g, crude) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.43-7.19 (m, 20H), 4.52-4.49 (m, 1H), 4.45 (s, 2H), 3.39-3.35 (m, 2H), 2.41-2.36 (m, 2H).

(S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-5-(trimethylsilyl)-1H-1,2,3-triazole (3)
To a solution of (S)-(2-azido-3-(benzyloxy)propyl)(trityl)sulfane (2) (16.5 g, 35.48 mmol) in toluene (70 mL) was added ethynyltrimethylsilane (13 mL, 88.71 mmol). The mixture was stirred at 100° C. for 16 hours. After completion, the mixture was concentrated and purified on a silica gel column with petroleum ether/ethyl acetate=15/1 to give the product (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-5-(trimethylsilyl)-1H-1,2,3-triazole (3) (14.1 g, 55% yield for two steps) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.40-7.19 (m, 20H), 7.12-7.09 (m, 1H), 4.43 (s, 2H), 4.13-4.09 (m, 1H), 3.70-3.59 (m, 2H), 2.87-2.83 (m, 2H), 1.26 (s, 9H).

(S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-1H-1,2,3-triazole (4)
To a solution of (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-5-(trimethylsilyl)-1H-1,2,3-triazole (3) (14.1 g, 24.87 mmol) in tetrahydrofuran (70 mL) was added tetrabutylammonium fluoride (9.2 g, 35 mmol). The mixture was stirred at 40° C. for 2 hours. After completion, the mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL×3). After concentration, the residue was purified on a silica gel column with petroleum ether/ethyl acetate=10/1 to give (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-1H-1,2,3-triazole (4) (12 g, 98% yield). ^1H NMR (400 MHz, _CDCl3 ) δ 7.61 (s, 1H), 7.40-7.19 (m, 20H), 7.13-7.11 (m, 1H), 4.35 (s, 2H), 4.15-4.01 (m, 1H), 3.75-3.57 (m, 2H), 2.87-2.84 (m, 2H).

(S)-3-(benzyloxy)-2-(1H-1,2,3-triazol-1-yl)propane-1-thiol (5)
To a mixture of (S)-1-(1-(benzyloxy)-3-(tritylthio)propan-2-yl)-1H-1,2,3-triazole (4) (12 g, 24.87 mmol) and triethylsilane (2.9 g, 24.87 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (40 mL). The mixture was stirred at room temperature for 2 hours. After completion, the mixture was concentrated and adjusted to pH=7-8 at 0° C. After concentration, the residue was purified on a silica gel column with petroleum ether/ethyl acetate=5/1 to give (S)-3-(benzyloxy)-2-(1H-1,2,3-triazol-1-yl)propane-1-thiol (5) (5 g, 83% yield) as a yellow oil. ^1H NMR (400 MHz, _CDCl3 ) δ 7.73-7.71 (m, 2H), 7.38-7.28 (m, 4H), 7.25-7.23 (m, 1H), 4.82-4.80 (m, 1H), 4.55-4.47 (m, 2H), 3.99-3.86 (m, 2H), 3.17-3.09 (m, 2H), 2.05 (s, 1H).

(S)-8-((3-(benzyloxy)-2-(1H-1,2,3-triazol-1-yl)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (6)
To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-diol (5.3 g, 13.39 mmol) in 1,4-dioxane (100 mL) was added potassium carbonate (5.5 g, 40.17 mmol), (S)-3-(benzyloxy)-2-(1H-1,2,3-triazol-1-yl)propane-1-thiol (5) (5 g, 20.08 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (1.17 g, 2.01 mmol) and tris(dibenzylideneacetone)dipalladium (1.23 g, 1.34 mmol). The mixture was stirred at 60° C. under nitrogen atmosphere for 18 hours. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate=4/1) to give (S)-8-((3-(benzyloxy)-2-(1H-1,2,3-triazol-1-yl)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (6) (6.8 g, 97% yield) as a pale yellow solid. MS (ESI) m/z 512.0 [M+H] ⁺ .

(S)-7-Chloro-8-((3-hydroxy-2-(1H-1,2,3-triazol-1-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (7)
A solution of (S)-8-((3-(benzyloxy)-2-(1H-1,2,3-triazol-1-yl)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4-diol (6) (6.8 g, 13.70 mmol) in trifluoroacetic acid (12 mL). The mixture was stirred at 80° C. for 18 hours. After completion, the mixture was concentrated and adjusted to pH=7-8 at 0° C. After concentration, the residue was purified on a silica gel column with dichloromethane/ethyl acetate=1/2 to give (S)-7-chloro-8-((3-hydroxy-2-(1H-1,2,3-triazol-1-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (7) (6.0 g, crude) as a yellow solid. MS (ESI): m/z 422.1 [M+H] ⁺ .

(S)-11-Chloro-8-hydroxy-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (8)
To a mixture of (S)-7-chloro-8-((3-hydroxy-2-(1H-1,2,3-triazol-1-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (7) (6.0 g, 13.54 mmol) and triphenylphosphine (11.0 g, 40.62 mmol) in tetrahydrofuran (400 mL) at 0° C. was added diethyl azodicarboxylate (11 mL, 40.62 mmol). The mixture was stirred at 0° C. for 45 minutes. After completion, the mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL×3). The organic phase was concentrated and the residue was purified on C18 with 30-95% acetonitrile in water to give (S)-11-chloro-8-hydroxy-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (8) (4.2 g, 76% yield for two steps) as a yellow solid. MS (ESI) m/z 402.0 [M−H] ⁺ .

(2S,6R)-tert-Butyl-4-((S)-11-chloro-6-oxo-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9)
To a mixture of (S)-11-chloro-8-hydroxy-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (8) (2.4 g, 5.96 mmol) and potassium carbonate (8.23 g, 59.6 mmol) in acetonitrile (50 mL) was added 2,4,6-tris(prop-2-yl)benzenesulfonyl chloride (7.22 g, 23.82 mmol). The mixture was stirred at 35° C. for 4 hours. After completion, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (5.1 g, 23.82 mmol) was added to the reaction solution. The reaction mixture was stirred at 35° C. for 1 hour. After completion, the mixture was poured into ice water (200 mL) and extracted with ethyl acetate (100 mL×3). Upon concentration, the residue was purified on a C18 column using 20-95% acetonitrile in water to give (2S,6R)-tert-butyl-4-((S)-11-chloro-6-oxo-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9) (1.5 g, 43% yield) as a pale yellow solid. MS (ESI) m/z 600.3 [M+H] ⁺ .

(2S,6R)-tert-butyl-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (10)
(2S,6R)-tert-butyl-4-((S)-11-chloro-6-oxo-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9) (200 mg, 0.3 mL) in 1,4-dioxane (3 mL) and water (0.5 mL). To a solution of 1,3 mmol) of 1,3-dichloro-5-(triisopropylsilyl)thiophen-2-yl)boronic acid (430 mg, 1.34 mmol), tripotassium phosphate (270 mg, 1.0 mmol), (4-chloro-5-(triisopropylsilyl)thiophen-2-yl)boronic acid (430 mg, 1.34 mmol), and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (40 mg, 0.05 mmol) were added. The mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to give (2S,6R)-tert-butyl-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (10) (175 mg, 63% yield) as a yellow solid. MS (ESI) m/z 838.0 [M+H] ⁺ .

(2S,6R)-tert-butyl-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (11)
To a solution of (2S,6R)-tert-butyl-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (10) (150 mg, 0.2 mmol) in tetrahydrofuran (1 mL) was added tetrabutylammonium fluoride (130 mg, 0.5 mmol). The mixture was stirred at 40° C. for 2 hours. After completion, the mixture was poured into ice water (5 mL) and extracted with ethyl acetate (10 mL×3). After concentration, the residue was purified on a silica gel column with dichloromethane/methanol=80/1 to give (2S,6R)-tert-butyl-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (11) (150 mg, crude) as a yellow solid. MS (ESI) m/z 682.2 [M+H] ⁺ .

(S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (12)
Trifluoroacetic acid (1 mL) was added to a mixture of (2S,6R)-tert-butyl-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (11) (150 mg, crude) in dichloromethane (1 mL) at 0° C. The reaction solution was stirred at room temperature for 1 h. After completion, the mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol=15/1) to give (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (12) (80 mg, 69% yield for two steps) as a pale yellow solid. MS (ESI) m/z 582.3 [M+H] ⁺ .

(S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (13)
Acrylic anhydride (26 mg, 0.207 mmol) was added to a mixture of (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (12) (80 mg, 0.138 mmol) and triethylamine (28 mg, 0.275 mmol) in dichloromethane (2 ml) at 0° C. The mixture was stirred at 0° C. for 1 h. After completion, the mixture was poured into ice water (10 mL) and extracted with dichloromethane (10 mL×3). Concentration and purification of the residue by preparative high performance liquid chromatography (20% to 95% acetonitrile in water) afforded (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(1H-1,2,3-triazol-1-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (13) (12 mg, 14% yield) as a white solid. MS (ESI) m/z 636.2 [M+H] ⁺ . ^1H NMR (400 MHz, _CDCl3 ) δ 8.11 (s, 1H), 7.87-7.77 (m, 2H), 7.36 (s, 1H), 6.98 (s, 1H), 6.67-6.59 (m, 1H), 6.42 (dd, J = 16.4 Hz, 2.0 Hz, 1H), 5.79 (dd, J = 10.4 Hz, 1.6 Hz 1H), 5.64-5.42 (m, 1H), 5.29-5.17 (m, 1H), 5.11-4.95 (m, 1H), 4.79-4.64 (m, 2H), 4.21-4.18 (m, 2H), 3.80-3.67 (m, 1H), 3.41-3.38 (m, 3H), 1.55-1.54 (m, 6H).

ステップ１：（Ｓ）－２－（（１－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－３－（トリチルチオ）プロパン－２－イル）オキシ）ピラジン

０℃のＴＨＦ（１００ｍＬ）中の（Ｓ）－１－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－３－（トリチルチオ）プロパン－２－オール（１７ｍｍｏｌ）の溶液に水素化ナトリウム（４２ｍｍｏｌ）を加えた。３０分後、２－フルオロピラジン（２５．５ｍｍｏｌ）を加え、混合物を室温で１６時間撹拌した。反応物を水で希釈し、酢酸エチルで抽出し、組み合わせた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮して、表題化合物を収率９３％で白色固体として得た。ＭＳ （ＥＳＩ） ｍ／ｚ： ６６７．０ ［Ｍ＋１］＋。 Example 29: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Step 1: (S)-2-((1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)pyrazine

To a solution of (S)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-ol (17 mmol) in THF (100 mL) at 0° C. was added sodium hydride (42 mmol). After 30 min, 2-fluoropyrazine (25.5 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction was diluted with water, extracted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound in 93% yield as a white solid. MS (ESI) m/z: 667.0 [M+1]+.

０℃のＴＦＡ（３０ｍＬ）及びジクロロメタン（９０ｍＬ）中の（Ｓ）－２－（（１－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－３－（トリチルチオ）プロパン－２－イル）オキシ）ピラジン（１９ｍｍｏｌ）の溶液にトリエチルシラン（３７ｍｍｏｌ）を加えた。反応物を６０分かけて室温に到達させ、その時点で水を加えた。混合物をジクロロメタンで３回抽出し、組み合わせた有機層をブラインで洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮して残渣を得て、これをシリカゲルクロマトグラフィー（ジクロロメタン中の０～１０％メタノール）で精製して、表題化合物を収率９０％で黄色の油として得た。ＭＳ （ＥＳＩ） ｍ／ｚ： ４２５．０ ［Ｍ＋１］＋。 Step 2: (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(pyrazin-2-yloxy)propane-1-thiol

To a solution of (S)-2-((1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)pyrazine (19 mmol) in TFA (30 mL) and dichloromethane (90 mL) at 0° C. was added triethylsilane (37 mmol). The reaction was allowed to reach room temperature over 60 min, at which point water was added. The mixture was extracted three times with dichloromethane and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (0-10% methanol in dichloromethane) to afford the title compound in 90% yield as a yellow oil. MS (ESI) m/z: 425.0 [M+1]+.

１００℃でジオキサン（２０ｍＬ）中の７－クロロ－８－ヨード－６－（トリフルオロメチル）キナゾリン－２，４（１Ｈ，３Ｈ）－ジオン（６．１０ｍｍｏｌ）、（Ｓ）－３－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－２－（ピラジン－２－イルオキシ）プロパン－１－チオール（９．１ｍｍｏｌ）、キサントホス（１．２ｍｍｏｌ）、ジイソプロピルエチルアミン（２４．４ｍｍｏｌ）及びＰｄ２（ｄｂａ）３（０．０６ｍｍｏｌ）の混合物を２時間撹拌した。反応物を室温まで冷却し、揮発性物質を減圧下で除去して残渣を得て、これを逆相クロマトグラフィー（水中の０～１００％アセトニトリル）で精製した。表題化合物を収率９３％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６８１．０ ［Ｍ＋１］＋。 Step 3: (S)-8-((3-((tert-butyldiphenylsilyl)oxy)-2-(pyrazin-2-yloxy)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

A mixture of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (6.10 mmol), (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(pyrazin-2-yloxy)propane-1-thiol (9.1 mmol), Xantphos (1.2 mmol), diisopropylethylamine (24.4 mmol) and Pd2(dba)3 (0.06 mmol) in dioxane (20 mL) was stirred at 100° C. for 2 h. The reaction was cooled to room temperature and the volatiles removed under reduced pressure to give a residue which was purified by reverse phase chromatography (0-100% acetonitrile in water). The title compound was isolated in 93% yield as a yellow solid. MS (ESI) m/z: 681.0 [M+1]+.

ＴＨＦ（１ｍＬ）中の（Ｓ）－８－（（３－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－２－（ピラジン－２－イルオキシ）プロピル）チオ）－７－クロロ－６－（トリフルオロメチル）キナゾリン－２，４（１Ｈ，３Ｈ）－ジオン（５．０ｍｍｏｌ）の溶液にＴＨＦ（１５ｍＬ）中の１ＭのＴＢＡＦ溶液を加えた。１時間後、反応混合物を水で希釈し、酢酸エチルで抽出し、組み合わせた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮して、表題化合物を収率４４％で茶色固体として得た。ＭＳ （ＥＳＩ） ｍ／ｚ： ４４９．０ ［Ｍ＋１］＋。 Step 4: (S)-7-Chloro-8-((3-hydroxy-2-(pyrazin-2-yloxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

To a solution of (S)-8-((3-((tert-butyldiphenylsilyl)oxy)-2-(pyrazin-2-yloxy)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (5.0 mmol) in THF (1 mL) was added 1 M TBAF solution in THF (15 mL). After 1 h, the reaction mixture was diluted with water, extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound in 44% yield as a brown solid. MS (ESI) m/z: 449.0 [M+1]+.

ＴＨＦ（５ｍＬ）中のトリフェニルホスフィン（３．６１ｍｍｏｌ）の０℃溶液にＴＨＦ（５ｍＬ）中のＤＩＡＤ（３．８１ｍｍｏｌ）の０℃溶液を加えた。１０分後、（Ｓ）－７－クロロ－８－（（３－ヒドロキシ－２－（ピラジン－２－イルオキシ）プロピル）チオ）－６－（トリフルオロメチル）キナゾリン－２，４（１Ｈ，３Ｈ）－ジオン（１０ｍＬ）の０．２ＭのＴＨＦ溶液を加え、この混合物を室温で１６時間撹拌した。揮発性物質を減圧下で除去して残渣を得て、これを逆相クロマトグラフィー（水中の０～１００％アセトニトリル）で精製した。表題化合物を収率４４％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ４３１．０ ［Ｍ＋１］＋。 Step 5: (S)-11-Chloro-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

To a 0° C. solution of triphenylphosphine (3.61 mmol) in THF (5 mL) was added a 0° C. solution of DIAD (3.81 mmol) in THF (5 mL). After 10 min, a 0.2 M THF solution of (S)-7-chloro-8-((3-hydroxy-2-(pyrazin-2-yloxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (10 mL) was added and the mixture was stirred at room temperature for 16 h. The volatiles were removed under reduced pressure to give a residue which was purified by reverse phase chromatography (0-100% acetonitrile in water). The title compound was isolated in 44% yield as a white solid. MS (ESI) m/z: 431.0 [M+1]+.

トルエン（４ｍＬ）中の（Ｓ）－１１－クロロ－３－（ピラジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６，８（７Ｈ）－ジオン（０．７７ｍｍｏｌ）、Ｎ，Ｎ’－ジイソプロピルエチルアミン（７．６６ｍｍｏｌ）及びＰＯＣｌ３（４ｍＬ）の溶液を、１２０℃で９０分間撹拌した。揮発性物質を減圧下で除去し、残渣をジクロロエタン（５ｍＬ）に再溶解した。この溶液をジクロロエタン中のｔｅｒｔ－ブチル（２Ｒ，６Ｓ）－２，６－ジメチルピペラジン－１－カルボキシレート（３．１０ｍｍｏｌ）及びＮ，Ｎ’－ジイソプロピルエチルアミン（７．６６ｍｍｏｌ）の０℃溶液に加えて、この混合物を室温で更に１時間撹拌した。揮発性物質を減圧下で除去して残渣を得て、これをシリカゲルクロマトグラフィーで精製した。表題化合物を収率５１％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６２７．０ ［Ｍ＋１］＋。 Step 6: tert-Butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

A solution of (S)-11-chloro-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione (0.77 mmol), N,N'-diisopropylethylamine (7.66 mmol) and POCl3 (4 mL) in toluene (4 mL) was stirred at 120° C. for 90 min. The volatiles were removed under reduced pressure and the residue was redissolved in dichloroethane (5 mL). This solution was added to a 0° C. solution of tert-butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate (3.10 mmol) and N,N'-diisopropylethylamine (7.66 mmol) in dichloroethane and the mixture was stirred at room temperature for an additional 1 h. The volatiles were removed under reduced pressure to give a residue that was purified by silica gel chromatography. The title compound was isolated in 51% yield as a yellow solid. MS (ESI) m/z: 627.0 [M+1]+.

表題化合物を実施例２３のステップ１と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピラジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率８８％で茶色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ８６５．０ ［Ｍ＋Ｈ］＋。 Step 7: tert-Butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 1 of example 23, substituting tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate for tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 88% yield as a brown solid. MS (ESI) m/z = 865.0 [M+H]+.

表題化合物を実施例２３のステップ３と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロチオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３、４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピラジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率８０％で黄色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ７６５．０ ［Ｍ＋Ｈ］＋。 Step 8: (S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared similarly to step 3 of Example 23 to afford tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The residue was replaced with tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 80% yield as a yellow oil. MS (ESI) m/z=765.0 [M+H]+.

表題化合物を実施例２３のステップ２と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートは（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピラジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンに置き換えた。表題化合物を収率８３％で黄色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ６０９．０ ［Ｍ＋Ｈ］＋。 Step 9: (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared similarly to step 2 of Example 23 to afford tert-butyl(2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dihydro Methyl piperazine-1-carboxylate was replaced with (S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 83% yield as a yellow oil. MS (ESI) m/z= 609.0 [M+H]+.

表題化合物を実施例２３のステップ４と同様に調製し、（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンは（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピラジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンに置き換えた。表題化合物を収率１０％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ６６３．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ８．２７ － ８．２２ （ｍ， １Ｈ）， ８．２０ － ８．１５ （ｍ， １Ｈ）， ８．０９ － ８．０６ （ｍ， ２Ｈ）， ７．３６ － ７．３５ （ｍ， １Ｈ）， ７．００ － ６．８７ （ｍ， １Ｈ）， ６．６７ － ６．５７ （ｍ， １Ｈ）， ６．４５ － ６．３８ （ｍ， １Ｈ）， ５．８２ － ５．５８ （ｍ， ２Ｈ）， ５．０１ － ４．７８ （ｍ， １Ｈ）， ４．７１ － ４．５８ （ｍ， ２Ｈ）， ４．２７ － ４．０９ （ｍ， ２Ｈ）， ３．７０ － ３．２６ （ｍ， ４Ｈ）， ３．１９ － ３．０２ （ｍ， １Ｈ）， １．６４ － １．５０ （ｍ， ６Ｈ）。 Step 10: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to step 4 of example 23, substituting (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one for (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 10% yield as a white solid. MS (ESI) m/z = 663.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.27 - 8.22 (m, 1H), 8.20 - 8.15 (m, 1H), 8.09 - 8.06 (m, 2H), 7.36 - 7.35 (m, 1H), 7.00 - 6.87 (m, 1H), 6.67 - 6.57 (m, 1H), 6.45 - 6.38 (m, 1H), 5.82 - 5.58 (m, 2H), 5.01 - 4.78 (m, 1H), 4.71 - 4.58 (m, 2H), 4.27 - 4.09 (m, 2H), 3.70 - 3.26 (m, 4H), 3.19 - 3.02 (m, 1H), 1.64 - 1.50 (m, 6H).

ステップ１：（Ｓ）－３－（トリチルチオ）プロパン－１，２－ジオール

ＤＭＦ（８００ｍＬ）中のトリフェニルメタンチオール（４５２ｍｍｏｌ）の０℃溶液にカリウムｔｅｒｔ－ブトキシド（４９８ｍｍｏｌ）を加えた。３０分後、ＤＭＦ（２００ｍＬ）中の（２Ｓ）－３－クロロプロパン－１，２－ジオール（４５２ｍｍｏｌ）の溶液を加え、混合物をゆっくりと室温に到達させ、一晩撹拌した。反応混合物を水で希釈し、酢酸エチルで抽出し、組み合わせた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮して残渣を得て、これをシリカゲルクロマトグラフィー（ヘキサン中の１０％酢酸エチル）で精製して、表題化合物を収率９７％で黄色の油として得た。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ３５１．１ ［Ｍ＋Ｈ］＋。 Example 31: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Step 1: (S)-3-(tritylthio)propane-1,2-diol

To a 0° C. solution of triphenylmethanethiol (452 mmol) in DMF (800 mL) was added potassium tert-butoxide (498 mmol). After 30 min, a solution of (2S)-3-chloropropane-1,2-diol (452 mmol) in DMF (200 mL) was added and the mixture was allowed to slowly reach room temperature and stirred overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (10% ethyl acetate in hexanes) to give the title compound in 97% yield as a yellow oil. MS (ESI) m/z=351.1 [M+H]+.

ジクロロメタン（５００ｍＬ）中の（Ｓ）－３－（トリチルチオ）プロパン－１，２－ジオール（１４３ｍｍｏｌ）の０℃溶液にイミダゾール（２２８ｍｍｏｌ）を加えた。３０分後、ｔｅｒｔ－ブチルジフェニルクロロシラン（１７１ｍｍｏｌ）を加え、反応物を室温で一晩撹拌した。反応物を濾過し、揮発性物質を減圧下で除去して残渣を得て、これをシリカゲルクロマトグラフィー（ヘキサン中の０～１０％酢酸エチル）で精製して、表題化合物を収率５８％で無色の油として得た。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ５８９．３ ［Ｍ＋Ｈ］＋。 Step 2: (S)-1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-ol

To a 0° C. solution of (S)-3-(tritylthio)propane-1,2-diol (143 mmol) in dichloromethane (500 mL) was added imidazole (228 mmol). After 30 min, tert-butyldiphenylchlorosilane (171 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was filtered and the volatiles removed under reduced pressure to give a residue which was purified by silica gel chromatography (0-10% ethyl acetate in hexanes) to give the title compound in 58% yield as a colorless oil. MS (ESI) m/z=589.3 [M+H]+.

表題化合物は、実施例２９のステップ１と同様にして調製し、２－フルオロピラジンは２－フルオロピリジンに置き換えた。表題化合物を収率７５％で無色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ６６６．３ ［Ｍ＋Ｈ］＋。 Step 3: (S)-2-((1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)pyridine

The title compound was prepared analogously to step 1 of example 29, substituting 2-fluoropyridine for 2-fluoropyrazine. The title compound was isolated in 75% yield as a colorless oil. MS (ESI) m/z = 666.3 [M+H]+.

表題化合物は実施例２３のステップ２と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートは（Ｓ）－２－（（１－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－３－（トリチルチオ）プロパン－２－イル）オキシ）ピリジンに置き換えた。表題化合物を収率８２％で無色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ４２８．２ ［Ｍ＋Ｈ］＋。 Step 4: (S)-2-(pyridin-2-yloxy)-3-(tritylthio)propag-1-ol

The title compound was prepared analogously to step 2 of example 23, with the exception that tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate was replaced with (S)-2-((1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)pyridine. The title compound was isolated in 82% yield as a colorless oil. MS (ESI) m/z= 428.2 [M+H]+.

表題化合物は実施例２９のステップ２と同様に調製し、（Ｓ）－２－（（１－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－３－（トリチルチオ）プロパン－２－イル）オキシ）ピラジンは（Ｓ）－２－（ピリジン－２－イルオキシ）－３－（トリチルチオ）プロパン－１－オールに置き換えた。表題化合物を定量的収率で白色固体として単離した。 Step 5: (S)-3-mercapto-2-(pyridin-2-yloxy)propan-1-ol

The title compound was prepared analogously to Step 2 of Example 29, substituting (S)-2-((1-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)pyrazine with (S)-2-(pyridin-2-yloxy)-3-(tritylthio)propan-1-ol. The title compound was isolated in quantitative yield as a white solid.

表題化合物は実施例２９のステップ３と同様に調製し、（Ｓ）－３－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－２－（ピラジン－２－イルオキシ）プロパン－１－チオールは（Ｓ）－３－メルカプト－２－（ピリジン－２－イルオキシ）プロパン－１－オールに置き換えた。表題化合物を収率４２％で淡緑色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ４４７．９ ［Ｍ＋Ｈ］＋。 Step 6: (S)-7-Chloro-8-((3-hydroxy-2-(pyridin-2-yloxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared similarly to step 3 of example 29, substituting (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(pyrazin-2-yloxy)propane-1-thiol with (S)-3-mercapto-2-(pyridin-2-yloxy)propan-1-ol. The title compound was isolated in 42% yield as a pale green solid. MS (ESI) m/z= 447.9 [M+H]+.

表題化合物は実施例２９のステップ５と同様に調製し、（Ｓ）－７－クロロ－８－（（３－ヒドロキシ－２－（ピラジン－２－イルオキシ）プロピル）チオ）－６－（トリフルオロメチル）キナゾリン－２，４（１Ｈ，３Ｈ）－ジオンは（Ｓ）－７－クロロ－８－（（３－ヒドロキシ－２－（ピリジン－２－イルオキシ）プロピル）チオ）－６－（トリフルオロメチル）キナゾリン－２，４（１Ｈ，３Ｈ）－ジオンに置き換えた。表題化合物を収率２８％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ４３０．０ ［Ｍ＋Ｈ］＋。 Step 7: (S)-11-Chloro-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to step 5 of example 29, substituting (S)-7-chloro-8-((3-hydroxy-2-(pyrazin-2-yloxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione for (S)-7-chloro-8-((3-hydroxy-2-(pyridin-2-yloxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione. The title compound was isolated in 28% yield as a white solid. MS (ESI) m/z= 430.0 [M+H]+.

表題化合物を実施例２９のステップ６と同様に調製し、（Ｓ）－１１－クロロ－３－（ピラジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６，８（７Ｈ）－ジオンは（Ｓ）－１１－クロロ－３－（ピリジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６，８（７Ｈ）－ジオンに置き換えた。表題化合物を収率７８％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ６２６．２ ［Ｍ＋Ｈ］＋。 Step 8: tert-Butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 6 of example 29, substituting (S)-11-chloro-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione for (S)-11-chloro-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione. The title compound was isolated in 78% yield as a yellow solid. MS (ESI) m/z= 626.2 [M+H]+.

表題化合物を実施例２３のステップ１と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートは、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピリジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率３６％で黄色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ８６５．６ ［Ｍ＋Ｈ］＋。 Step 9: tert-Butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 1 of example 23, except that tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 36% yield as a yellow oil. MS (ESI) m/z = 865.6 [M+H]+.

表題化合物を実施例２３のステップ２と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率８７％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ７０８．２ ［Ｍ＋Ｈ］＋。 Step 10: tert-Butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared similarly to step 2 of Example 23 to afford tert-butyl(2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1 -carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 87% yield as a white solid. MS (ESI) m/z=708.2 [M+H]+.

表題化合物を実施例２３のステップ３と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロチオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３、４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロチオフェン－２－イル）－６－オキソ－３－（ピリジン－２－イルオキシ）－１０－（トリフルオロメチル）－３、４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率８７％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ＝ ６０８．２ ［Ｍ＋Ｈ］＋。 Step 11: (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared similarly to step 3 of Example 23 to afford tert-butyl(2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1 -carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 87% yield as a white solid. MS (ESI) m/z = 608.2 [M+H]+.

Step 12: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared similarly to step 4 of Example 23, except that (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one was replaced with (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated as a white solid in 13% yield. MS (ESI) m/z = 662.2 [M+H]+. 1H NMR (400MHz, CDCl3) δ 8.14 - 8.05 (m, 2H), 7.59 (ddd, J = 2.0, 7.2, 8.4 Hz, 1H), 7.34 (s, 1H), 7.01 - 6.86 (m, 2H), 6.77 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 10.4, 16.8 Hz, 1H), 6.42 (dd, J = 1.6, 16.8 Hz, 1H), 5.84 - 5.70 (m, 2H), 5.00 - 4.57 (m, 4H), 4.20 - 4.10 (m, 2H), 3.52 - 3.33 (m, 4H), 1.55 (br s, 6H).

表題化合物は実施例２９と同様に調製し、ステップ１では、２－フルオロピラジンは２－クロロピリダジンに置き換えた。表題化合物を白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６６３．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ８．９３ （ｄ， Ｊ ＝ ４．０ Ｈｚ， １Ｈ）， ８．０９ （ｓ， １Ｈ）， ７．６６ － ７．５６ （ｍ， １Ｈ）， ７．３５ （ｄ， Ｊ ＝ １．２ Ｈｚ， １Ｈ）， ７．２１ （ｄ， Ｊ ＝ ８．４ Ｈｚ， １Ｈ）， ７．０３ － ６．８７ （ｍ， １Ｈ）， ６．６８ － ６．５８ （ｍ， １Ｈ）， ６．４２ （ｄｄ， Ｊ ＝ ２．０， １６．６ Ｈｚ， １Ｈ）， ５．８９ － ５．７６ （ｍ， ２Ｈ）， ４．９７ － ４．８９ （ｍ， １Ｈ）， ４．８３ （ｓ， ２Ｈ）， ４．７５ － ４．７０ （ｍ， １Ｈ）， ４．２７ － ４．１５ （ｍ， ２Ｈ）， ３．４８ － ３．３９ （ｍ， ２Ｈ）， ３．３８ － ３．３１ （ｍ， １Ｈ）， ３．１７ （ｄｄ， Ｊ ＝ ２．４， １３．６ Ｈｚ， １Ｈ）， １．６１ （ｄ， Ｊ ＝ ７．２ Ｈｚ， ３Ｈ）， １．５０ （ｄ， Ｊ ＝ ７．２ Ｈｚ， ３Ｈ）。 Example 32: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyridazin-3-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared similarly to Example 29, replacing 2-fluoropyrazine with 2-chloropyridazine in step 1. The title compound was isolated as a white solid. MS (ESI) m/z: 663.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J = 4.0 Hz, 1H), 8.09 (s, 1H), 7.66 - 7.56 (m, 1H), 7.35 (d, J = 1.2 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.03 - 6.87 (m, 1H), 6.68 - 6.58 (m, 1H), 6.42 (dd, J = 2.0, 16.6 Hz, 1H), 5.89 - 5.76 (m, 2H), 4.97 - 4.89 (m, 1H), 4.83 (s, 2H), 4.75 - 4.70 (m, 1H), 4.27 - 4.15 (m, 2H), 3.48 - 3.39 (m, 2H), 3.38 - 3.31 (m, 1H), 3.17 (dd, J = 2.4, 13.6 Hz, 1H), 1.61 (d, J = 7.2 Hz, 3H), 1.50 (d, J = 7.2 Hz, 3H).

表題化合物は実施例２９と同様にして調製し、ステップ１では、２－フルオロピラジンは４－クロロピリミジンに置き換えた。表題化合物を黄色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６９０．０ ［Ｍ＋Ｎａ］＋。 Example 33: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyrimidin-4-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared in a similar manner to Example 29, where 2-fluoropyrazine was replaced with 4-chloropyrimidine in step 1. The title compound was isolated as a yellow oil. MS (ESI) m/z: 690.0 [M+Na]+.

ステップ１：２，４，７－トリクロロ－８－ヨード－６－（トリフルオロメチル）キナゾリン

Ｎ，Ｎ－ジイソプロピルエチルアミン（１７．９ｍｍｏｌ）中の７－クロロ－８－ヨード－６－（トリフルオロメチル）キナゾリン－２，４（１Ｈ，３Ｈ）－ジオン（５．１ｍｍｏｌ）の混合物に三塩化ホスホリル（１２ｍＬ）を加えた。混合物を１１０℃で１２時間撹拌し、反応混合物を減圧下で濃縮して残渣を得て、これを冷水に溶解し、酢酸エチルで３回抽出した。組み合わせた有機層をブラインで洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮した。得られた粗物質をシリカゲルクロマトグラフィー（石油エーテル中の０～１５％酢酸エチル）で精製して、表題化合物を収率４４％で白色固体として得た。ＭＳ （ＥＳＩ） ｍ／ｚ： ４２７．０ ［Ｍ＋１］＋。 Example 35: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Step 1: 2,4,7-trichloro-8-iodo-6-(trifluoromethyl)quinazoline

To a mixture of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (5.1 mmol) in N,N-diisopropylethylamine (17.9 mmol) was added phosphoryl trichloride (12 mL). The mixture was stirred at 110° C. for 12 hours and the reaction mixture was concentrated under reduced pressure to give a residue which was dissolved in cold water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude material was purified by silica gel chromatography (0-15% ethyl acetate in petroleum ether) to give the title compound as a white solid in 44% yield. MS (ESI) m/z: 427.0 [M+1]+.

０℃でジクロロメタン（１０ｍＬ）中の２，４，７－トリクロロ－８－ヨード－６－（トリフルオロメチル）キナゾリン（２．０４ｍｍｏｌ）及びトリエチルアミン（６．１１ｍｍｏｌ）の溶液にｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－２，６－ジメチルピペラジン－１－カルボキシラート（１．８３ｍｍｏｌ）を加えた。混合物を室温で１時間撹拌し、揮発性物質を減圧下で除去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン中の５～１５％酢酸エチル）で精製して、表題化合物を収率８２％で白色固体として得た。ＭＳ （ＥＳＩ） ｍ／ｚ： ６０５．２ ［Ｍ＋Ｈ］＋。 Step 2: tert-Butyl (2S,6R)-4-(2,7-dichloro-8-iodo-6-(trifluoromethyl)quinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate

To a solution of 2,4,7-trichloro-8-iodo-6-(trifluoromethyl)quinazoline (2.04 mmol) and triethylamine (6.11 mmol) in dichloromethane (10 mL) at 0° C. was added tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate (1.83 mmol). The mixture was stirred at room temperature for 1 h and the volatiles were removed under reduced pressure. The residue was purified by silica gel column chromatography (5-15% ethyl acetate in hexanes) to give the title compound as a white solid in 82% yield. MS (ESI) m/z: 605.2 [M+H]+.

アセトニトリル（５０ｍＬ）中のｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（２，７－ジクロロ－８－ヨード－６－（トリフルオロメチル）キナゾリン－４－イル）－２，６－ジメチルピペラジン－１－カルボキシラート（１．７３ｍｍｏｌ）の溶液に２－（メチルスルホニル）エタン－１－オール（３．４７ｍｍｏｌ）、炭酸セシウム（３．４７ｍｍｏｌ）及び１，４－ジアザビシクロ［２．２．２］オクタン（０．１７ｍｍｏｌ）を加えた。混合物を８０℃で２時間撹拌し、揮発性物質を減圧下で除去して固体を得て、これをジクロロメタンに再溶解し、水で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮した。得られた残渣をｔｅｒｔ－ブチルメチルエーテルと酢酸エチルの１０：１混合物の６０ｍＬで粉砕して黄色固体を得て、これを濾過し、乾燥させて表題化合物を収率８８％で得た。ＭＳ （ＥＳＩ） ｍ／ｚ： ５８７．２ ［Ｍ＋Ｈ］＋。 Step 3: tert-Butyl (2S,6R)-4-(7-chloro-8-iodo-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate

To a solution of tert-butyl (2S,6R)-4-(2,7-dichloro-8-iodo-6-(trifluoromethyl)quinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (1.73 mmol) in acetonitrile (50 mL) was added 2-(methylsulfonyl)ethan-1-ol (3.47 mmol), cesium carbonate (3.47 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.17 mmol). The mixture was stirred at 80° C. for 2 h and the volatiles were removed under reduced pressure to give a solid which was redissolved in dichloromethane, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was triturated with 60 mL of a 10:1 mixture of tert-butyl methyl ether and ethyl acetate to give a yellow solid which was filtered and dried to give the title compound in 88% yield. MS (ESI) m/z: 587.2 [M+H]+.

３７％ホルムアルデヒド（１．７２ｍｏｌ）中の４－メチルピリジン（４３０ｍｍｏｌ）の混合物を１００℃で１２時間撹拌した。反応混合物を減圧下で濃縮して残渣を得て、これをシリカゲルクロマトグラフィー（酢酸エチル中の１～１０％メタノール）で精製した。表題化合物を収率８８％で無色の油として単離した。１Ｈ ＮＭＲ （４００ ＭＨｚ，メタノール－ｄ４） δ ｐｐｍ ２．９９ （ｑ， Ｊ ＝ ６．４ Ｈｚ， １Ｈ） ３．７７－３．９１ （ｍ， ４Ｈ） ７．２９－７．４７ （ｍ， ２Ｈ） ８．３３－８．５４ （ｍ， ２Ｈ）。 Step 4: 2-(pyridin-4-yl)propane-1,3-diol

A mixture of 4-methylpyridine (430 mmol) in 37% formaldehyde (1.72 mol) was stirred at 100° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (1-10% methanol in ethyl acetate). The title compound was isolated in 88% yield as a colorless oil. 1H NMR (400 MHz, methanol-d4) δ ppm 2.99 (q, J = 6.4 Hz, 1H) 3.77-3.91 (m, 4H) 7.29-7.47 (m, 2H) 8.33-8.54 (m, 2H).

ジクロロメタン（１００ｍＬ）中の２－（ピリジン－４－イル）プロパン－１，３－ジオール（６５．３ｍｍｏｌ）の０℃溶液にｐ－トルエンスルホニルクロリド（６５．３ｍｍｏｌ）、Ｎ，Ｎ’－ジメチルアミノピリジン（６．５３ｍｍｏｌ）及びピリジン（６５．３ｍｍｏｌ）を加えた。混合物を室温で３時間撹拌し、水でクエンチし、酢酸エチルで３回抽出した。有機層を組み合わせ、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮して残渣を得て、これを更に精製することなく以下のステップで使用した。 Step 5: 3-Hydroxy-2-(pyridin-4-yl)propyl-4-methylbenzenesulfonate

To a 0° C. solution of 2-(pyridin-4-yl)propane-1,3-diol (65.3 mmol) in dichloromethane (100 mL) was added p-toluenesulfonyl chloride (65.3 mmol), N,N′-dimethylaminopyridine (6.53 mmol) and pyridine (65.3 mmol). The mixture was stirred at room temperature for 3 hours, quenched with water and extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was used in the following step without further purification.

ジメチルホルムアミド（１５０ｍＬ）中の３－ヒドロキシ－２－（ピリジン－４－イル）プロピル－４－メチルベンゼンスルホネート（５５．３ｍｍｏｌ）の溶液にチオ酢酸カリウム（８１．９ｍｍｏｌ）を加えた。混合物を５０℃で２時間撹拌し、水でクエンチし、酢酸エチルで３回抽出した。組み合わせた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮して残渣を得て、これをシリカゲルクロマトグラフィー（ヘキサン中の５０～１００％酢酸エチル）で精製した。表題化合物を黄色の油として収率１５％で単離した。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ｐｐｍ ２．３５ （ｓ， ３Ｈ） ２．９９ （五重線， Ｊ ＝ ６．４ Ｈｚ， １Ｈ） ３．１５－３．２４ （ｍ， １Ｈ）， ３．３７ （ｄｄ， Ｊ ＝ １４．０， ７．２ Ｈｚ， １Ｈ） ３．７９－３．９０ （ｍ， ２Ｈ） ７．１４－７．２４ （ｍ， ２Ｈ）， ８．４８－８．５９ （ｍ， ２Ｈ）。 Step 6: S-(3-hydroxy-2-(pyridin-4-yl)propyl)ethanethioate

To a solution of 3-hydroxy-2-(pyridin-4-yl)propyl-4-methylbenzenesulfonate (55.3 mmol) in dimethylformamide (150 mL) was added potassium thioacetate (81.9 mmol). The mixture was stirred at 50° C. for 2 h, quenched with water, and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (50-100% ethyl acetate in hexanes). The title compound was isolated as a yellow oil in 15% yield. 1H NMR (400 MHz, CDCl3) δ ppm 2.35 (s, 3H) 2.99 (quintet, J = 6.4 Hz, 1H) 3.15-3.24 (m, 1H), 3.37 (dd, J = 14.0, 7.2 Hz, 1H) 3.79-3.90 (m, 2H) 7.14-7.24 (m, 2H), 8.48-8.59 (m, 2H).

１，２－エタンジオール（２ｍＬ）及びイソプロパノール（２ｍＬ）中のＳ－（３－ヒドロキシ－２－（ピリジン－４－イル）プロピル）エタンチオエート（０．９５ｍｍｏｌ）及びｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（７－クロロ－８－ヨード－２－オキソ－６－（トリフルオロメチル）－１，２－ジヒドロキナゾリン－４－イル）－２，６－ジメチルピペラジン－１－カルボキシラート（１．４２ｍｍｏｌ）の溶液に炭酸カリウム（２．８４ｍｍｏｌ）及びヨウ化第一銅（０．４７ｍｍｏｌ）を加えた。混合物を８５℃で２時間撹拌し、水でクエンチし、酢酸エチルで３回抽出した。組み合わせた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮して残渣を得て、これを分取ＴＬＣで精製した。表題化合物を収率６５％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６２７．９ ［Ｍ＋１］＋。 Step 7: tert-Butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-4-yl)propyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate

To a solution of S-(3-hydroxy-2-(pyridin-4-yl)propyl)ethanethioate (0.95 mmol) and tert-butyl (2S,6R)-4-(7-chloro-8-iodo-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (1.42 mmol) in 1,2-ethanediol (2 mL) and isopropanol (2 mL) was added potassium carbonate (2.84 mmol) and cuprous iodide (0.47 mmol). The mixture was stirred at 85° C. for 2 h, quenched with water, and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative TLC. The title compound was isolated as a yellow solid in 65% yield. MS (ESI) m/z: 627.9 [M+1]+.

テトラヒドロフラン（１００ｍＬ）中のｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（７－クロロ－８－（（３－ヒドロキシ－２－（ピリジン－４－イル）プロピル）チオ）－２－オキソ－６－（トリフルオロメチル）－１，２－ジヒドロキナゾリン－４－イル）－２，６－ジメチルピペラジン－１－カルボキシラート（２．１１ｍｍｏｌ）の０℃溶液にトリフェニルホスフィン（１０．６ｍｍｏｌ）を加えた。混合物を０℃で３０分間撹拌し、アゾジカルボン酸ジエチル（１０．６ｍｍｏｌ）を加えた。１２時間後、揮発性物質を減圧下で除去して残渣を得て、これをシリカゲルクロマトグラフィー（酢酸エチル中の０～１０％メタノール）で精製した。化合物Ｉｎｔ－１ａ及びＩｎｔ－１ｂを、ジアステレオマーの１：１混合物として収率６５％で単離した。純粋なジアステレオマーＩｎｔ－１ａ及びＩｎｔ－１ｂは、セミ分取逆相ＨＰＬＣによるジアステレオマー混合物の精製（カラム＝Ｄａｉｃｅｌ Ｃｈｉｒａｃｅｌ ＯＤ ２５０ｍｍ＊３０ｍｍ、１０ｕｍ、移動相Ｂ＝メタノール、勾配＝５０％、実行時間６．４分）によって得られ、ＳＦＣによって特性評価された（カラム＝Ｃｈｉｒａｃｅｌ ＯＤ－３、５０×４．６ｍｍ Ｉ．Ｄ．、３ｕｍ、３５℃で背圧１００ｂａｒで安定化、移動相Ａ＝ＣＯ２及び移動相Ｂ＝０．０５％ジエチルアミンを含有するメタノール、勾配＝４０％、流量＝３ｍＬ／分、検出器＝フォトダイオードアレイ）。Ｉｎｔ－１ａ： ＳＦＣ Ｒｔ＝ １．０３分；ＭＳ （ＥＳＩ） ｍ／ｚ： ６０９．９ ［Ｍ＋１］＋． Ｉｎｔ－１ｂ： ＳＦＣ Ｒｔ＝ １．４０分；ＭＳ （ＥＳＩ） ｍ／ｚ： ６０９．９ ［Ｍ＋１］＋ Step 8: tert-Butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (Int-1a) and tert-Butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (Int-1b)

To a 0° C. solution of tert-butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-4-yl)propyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (2.11 mmol) in tetrahydrofuran (100 mL) was added triphenylphosphine (10.6 mmol). The mixture was stirred at 0° C. for 30 minutes and diethyl azodicarboxylate (10.6 mmol) was added. After 12 hours, the volatiles were removed under reduced pressure to give a residue which was purified by silica gel chromatography (0-10% methanol in ethyl acetate). Compounds Int-1a and Int-1b were isolated in 65% yield as a 1:1 mixture of diastereomers. Pure diastereomers Int-1a and Int-1b were obtained by purification of the diastereomeric mixture by semi-preparative reversed phase HPLC (column = Daicel Chiracel OD 250mm*30mm, 10um, mobile phase B = methanol, gradient = 50%, run time 6.4min) and characterized by SFC (column = Chiracel OD-3, 50x4.6mm ID, 3um, stabilized at 35°C with 100bar back pressure, mobile phase A = CO2 and mobile phase B = methanol containing 0.05% diethylamine, gradient = 40%, flow rate = 3mL/min, detector = photodiode array). Int-1a: SFC Rt = 1.03min; MS (ESI) m/z: 609.9 [M+1]+. Int-1b: SFC Rt = 1.40 min; MS (ESI) m/z: 609.9 [M+1]+

表題化合物を実施例２３のステップ１と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートは、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピリジン－４－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率３８％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ８４８．１ ［Ｍ＋Ｈ］＋。 Step 9: tert-Butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 1 of example 23, substituting tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate for tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 38% yield as a yellow solid. MS (ESI) m/z: 848.1 [M+H]+.

表題化合物を実施例２３のステップ２と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリジン－４－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率９８％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６９２．２ ［Ｍ＋Ｈ］＋。 Step 10: tert-Butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared similarly to step 2 of example 23 to give tert-butyl(2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine The-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 98% yield as a white solid. MS (ESI) m/z: 692.2 [M+H]+.

表題化合物を実施例２３のステップ３と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロチオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３、４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロチオフェン－２－イル）－６－オキソ－３－（ピリジン－４－イル）－１０－（トリフルオロメチル）－３、４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率９９％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ５９２．２ ［Ｍ＋Ｈ］＋。 Step 11: (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared similarly to step 3 of example 23 to give tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine The 1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 99% yield as a yellow solid. MS (ESI) m/z: 592.2 [M+H]+.

表題化合物を実施例２３のステップ４と同様に調製し、（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンは（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピリジン－４－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンに置き換えた。表題化合物を収率３３％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６４６．２ ［Ｍ＋Ｈ］＋．^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ_３－ｄ） δ ＝ ８．６２ （ｄ， Ｊ ＝ ５．６ Ｈｚ， ２Ｈ）， ８．１３ （ｓ， １Ｈ）， ７．３９ － ７．３２ （ｍ， ３Ｈ）， ７．１２ － ６．８９ （ｍ， １Ｈ）， ６．７０ － ６．６１ （ｍ， １Ｈ）， ６．４４ （ｄｄ， Ｊ ＝ １．６， １６．８ Ｈｚ， １Ｈ）， ５．８３ － ５．７９ （ｍ， １Ｈ）， ４．８８ － ４．６１ （ｍ， ４Ｈ）， ４．１９ （ｂｒ ｄｄ， Ｊ ＝ ９．２， １１．４ Ｈｚ， ２Ｈ）， ３．８３ － ３．６６ （ｍ， ２Ｈ）， ３．４６ － ３．３７ （ｍ， ２Ｈ）， ３．２２ － ３．０９ （ｍ， １Ｈ）， １．６１ （ｂｒ ｄ， Ｊ ＝ ６．８ Ｈｚ， ３Ｈ）， １．５４ （ｂｒ ｄ， Ｊ ＝ ７．２ Ｈｚ， ３Ｈ）。 Step 12: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to step 4 of example 23, substituting (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one for (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 33% yield as a white solid. MS (ESI) m/z: 646.2 [M+H]+. ^1H NMR (400 MHz, _CDCl3 -d) δ = 8.62 (d, J = 5.6 Hz, 2H), 8.13 (s, 1H), 7.39 - 7.32 (m, 3H), 7.12 - 6.89 (m, 1H), 6.70 - 6.61 (m, 1H), 6.44 (dd, J = 1.6, 16.8 Hz, 1H), 5.83 - 5.79 (m, 1H), 4.88 - 4.61 (m, 4H), 4.19 (br dd, J = 9.2, 11.4 Hz, 2H), 3.83 - 3.66 (m, 2H), 3.46 - 3.37 (m, 2H), 3.22 - 3.09 (m, 1H), 1.61 (br d, J = 6.8 Hz, 3H), 1.54 (br d, J = 7.2 Hz, 3H).

ステップ１：ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピリジン－２－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレート（Ｉｎｔ－２ａ）及びｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｒ）－１１－クロロ－６－オキソ－３－（ピリジン－２－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレート（Ｉｎｔ－２ｂ）

Example 37: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Step 1: tert-Butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (Int-2a) and tert-Butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (Int-2b)

The title compound was prepared as a 1:1 mixture of diastereomers as in Example 35, steps 1-8, except that in step 4, 2-(pyridin-4-yl)propane-1,3-diol was replaced with 2-(pyridin-2-yl)propane-1,3-diol. Int-2a and Int-2b were obtained as single diastereomers by purification of the aforementioned mixture by semi-preparative reversed phase HPLC (Column: Daicel Chiralcel OD 250mm x 30mm, 10um, Mobile phase B: Methanol, gradient = 50%, run time 6.4min) and characterized by SFC (Column: Chiracel OD-3, 50 x 4.6mm, ID = 3um, stabilized at 35°C and 100bar back pressure, Mobile phase B = 40% Methanol containing 0.05% diethylamine, gradient = 40%, flow rate = 3mL/min, detector: photodiode array). Int-1a: SFC Rt = 1.39min, MS (ESI) m/z: 610.2 [M+H]+. Int-1b: SFC Rt = 2.25 min; MS (ESI) m/z: 610.2 [M+H]+.

表題化合物を実施例２３のステップ１と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｒ）－１１－クロロ－６－オキソ－３－（ピリジン－２－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率７２％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ８４８．３ ［Ｍ＋Ｈ］＋。 Step 2: tert-Butyl (2S,6R)-4-((R)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 1 of example 23, substituting tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate for tert-butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 72% yield as a yellow solid. MS (ESI) m/z: 848.3 [M+H]+.

表題化合物を実施例２３のステップ２と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｒ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリジン－２－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率９５％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６９２．２ ［Ｍ＋Ｈ］＋。 Step 3: tert-Butyl (2S,6R)-4-((R)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared similarly to step 2 of example 23 to give tert-butyl(2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine The-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((R)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 95% yield as a yellow solid. MS (ESI) m/z: 692.2 [M+H]+.

表題化合物を実施例２３のステップ３と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロチオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３、４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｒ）－１１－（４－クロロチオフェン－２－イル）－６－オキソ－３－（ピリジン－２－イル）－１０－（トリフルオロメチル）－３、４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率９９％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ５９２．２ ［Ｍ＋Ｈ］＋。 Step 4: (R)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared similarly to step 3 of example 23 to give tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine The-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((R)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 99% yield as a yellow solid. MS (ESI) m/z: 592.2 [M+H]+.

表題化合物を実施例２３のステップ４と同様に調製し、（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンは（Ｒ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピリジン－２－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンに置き換えた。表題化合物を収率３３％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６１６．２ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ， ８．５４ － ８．４５ （ｍ， １Ｈ）， ８．０１ （ｓ， １Ｈ）， ７．７０ － ７．５６ （ｍ， １Ｈ）， ７．３０ － ７．２２ （ｍ， ２Ｈ）， ７．１０ （ｓ， １Ｈ）， ６．９８ － ６．７８ （ｍ， １Ｈ）， ６．６２ － ６．５０ （ｍ， １Ｈ）， ６．３５ （ｄｄ， Ｊ ＝ ２．０， １６．８ Ｈｚ， １Ｈ）， ５．７１ （ｄｄ， Ｊ ＝ ２．０， １０．４ Ｈｚ， １Ｈ）， ５．０２ － ４．８５ （ｍ， ２Ｈ）， ４．７２ － ４．４５ （ｍ， ２Ｈ）， ４．２０ － ４．０３ （ｍ， ２Ｈ）， ３．９６ － ３．７４ （ｍ， １Ｈ）， ３．６３ － ３．４１ （ｍ， ２Ｈ）， ３．３４ － ３．１９ （ｍ， ２Ｈ）， １．５１ （ｂｒ ｓ， ３Ｈ）， １．４６ － １．３８ （ｍ， ３Ｈ）。 Step 5: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to step 4 of example 23, substituting (R)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one for (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 33% yield as a yellow solid. MS (ESI) m/z: 616.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ, 8.54 - 8.45 (m, 1H), 8.01 (s, 1H), 7.70 - 7.56 (m, 1H), 7.30 - 7.22 (m, 2H), 7.10 (s, 1H), 6.98 - 6.78 (m, 1H), 6.62 - 6.50 (m, 1H), 6.35 (dd, J = 2.0, 16.8 Hz, 1H), 5.71 (dd, J = 2.0, 10.4 Hz, 1H), 5.02 - 4.85 (m, 2H), 4.72 - 4.45 (m, 2H), 4.20 - 4.03 (m, 2H), 3.96 - 3.74 (m, 1H), 3.63 - 3.41 (m, 2H), 3.34 - 3.19 (m, 2H), 1.51 (br s, 3H), 1.46 - 1.38 (m, 3H).

ステップ１：２－（ピリジン－３－イル）プロパ－２－エン－１－オール

ＴＨＦ（５０ｍＬ）及び水（５０ｍＬ）中のピリジン－３－イルボロン酸（４１ｍｍｏｌ）、２－ブロモプロプ－２－エン－１－オール（４９ｍｍｏｌ）、リン酸カリウム（１２２ｍｍｏｌ）及びＸＰｈｏｓＰｄ Ｇ２（１．０ｍｍｏｌ）の混合物を６０℃で１２時間撹拌した。反応混合物を水で希釈し、酢酸エチルで３回抽出し、組み合わせた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮して残渣を得て、これをシリカゲルクロマトグラフィー（ヘキサン中の３５～８０％酢酸エチル）で精製した。表題化合物を収率５３％で無色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： １３６．１ ［Ｍ＋Ｈ］＋。 Example 43: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Step 1: 2-(pyridin-3-yl)prop-2-en-1-ol

A mixture of pyridin-3-ylboronic acid (41 mmol), 2-bromoprop-2-en-1-ol (49 mmol), potassium phosphate (122 mmol) and XPhosPd G2 (1.0 mmol) in THF (50 mL) and water (50 mL) was stirred at 60° C. for 12 h. The reaction mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (35-80% ethyl acetate in hexanes). The title compound was isolated in 53% yield as a colorless oil. MS (ESI) m/z: 136.1 [M+H]+.

ＴＨＦ（３０ｍＬ）中の２－（ピリジン－３－イル）プロパ－２－エン－１－オール（２２ｍｍｏｌ）の０℃溶液に、ＴＨＦ（８．６ｍＬ）中のボランジメチルスルフィド錯体の１０Ｍ溶液を加えた。５分後、１ＭのＮａＯＨ水溶液（６．５ｍＬ）を滴下し、続いて３５％過酸化水素水溶液（８６ｍｍｏｌ）を滴下した。２時間後、メタノール（５０ｍＬ）を加え、得られた反応物を７０℃で１２時間撹拌した。反応混合物を水で希釈し、酢酸エチルで３回抽出し、組み合わせた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮して残渣を得て、これをシリカゲルクロマトグラフィー（酢酸エチル中の０～２０％メタノール）で精製した。表題化合物を収率７３％で無色の油として単離した。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ８．５８ － ８．４８ （ｍ， ２Ｈ）， ７．６８ － ７．５９ （ｍ， １Ｈ）， ７．３２ － ７．２８ （ｍ， １Ｈ）， ４．１０ － ３．９６ （ｍ， ４Ｈ）， ３．１６ － ３．０７ （ｍ， １Ｈ）。 Step 2: 2-(pyridin-3-yl)propane-1,3-diol

To a 0° C. solution of 2-(pyridin-3-yl)prop-2-en-1-ol (22 mmol) in THF (30 mL) was added a 10 M solution of borane dimethylsulfide complex in THF (8.6 mL). After 5 min, 1 M aqueous NaOH (6.5 mL) was added dropwise, followed by 35% aqueous hydrogen peroxide (86 mmol). After 2 h, methanol (50 mL) was added and the resulting reaction was stirred at 70° C. for 12 h. The reaction mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0-20% methanol in ethyl acetate). The title compound was isolated as a colorless oil in 73% yield. 1H NMR (400 MHz, CDCl3) δ 8.58 - 8.48 (m, 2H), 7.68 - 7.59 (m, 1H), 7.32 - 7.28 (m, 1H), 4.10 - 3.96 (m, 4H), 3.16 - 3.07 (m, 1H).

表題化合物は実施例３１のステップ１と同様に調製し、（Ｓ）－３－（トリチルチオ）プロパン－１，２－ジオールは２－（ピリジン－３－イル）プロパン－１，３－ジオールに置き換えた。表題化合物を収率４７％で無色の油として単離した。１Ｈ ＮＭＲ （４００ ＭＨｚ，ＣＤＣｌ３） δ ８．４９ （ｄ， Ｊ ＝ ４．４ Ｈｚ， １Ｈ）， ８．４５ （ｓ， １Ｈ）， ７．６１ （ｄｄ， Ｊ ＝ ７．６， １１．２ Ｈｚ， ４Ｈ）， ７．５４ （ｄ， Ｊ ＝ ８．０ Ｈｚ，１ Ｈ）， ７．４９ － ７．３３ （ｍ， ６Ｈ）， ７．２１ （ｄｄ， Ｊ ＝ ４．８， ７．６ Ｈｚ， １Ｈ）， ４．１１ － ４．０５ （ｍ， １Ｈ）， ３．９９ － ３．８９ （ｍ， ３Ｈ）， ３．０８ （五重線， Ｊ ＝ ６．０ Ｈｚ， １Ｈ）， ２．１４ （ｓ， １Ｈ）， １．０５ （ｓ， ９Ｈ）。 Step 3: 3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propan-1-ol

The title compound was prepared analogously to Step 1 of Example 31, substituting 2-(pyridin-3-yl)propane-1,3-diol for (S)-3-(tritylthio)propane-1,2-diol. The title compound was isolated in 47% yield as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 4.4 Hz, 1H), 8.45 (s, 1H), 7.61 (dd, J = 7.6, 11.2 Hz, 4H), 7.54 (d, J = 8.0 Hz, 1H), 7.49 - 7.33 (m, 6H), 7.21 (dd, J = 4.8, 7.6 Hz, 1H), 4.11 - 4.05 (m, 1H), 3.99 - 3.89 (m, 3H), 3.08 (quintet, J = 6.0 Hz, 1H), 2.14 (s, 1H), 1.05 (s, 9H).

ＴＨＦ（５０ｍＬ）中のトリフェニルホスフィン（８．２０ｍｍｏｌ）及びＤＩＡＤ（８．１７ｍｍｏｌ）の溶液を０℃で３０分間撹拌した。３－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－２－（ピリジン－３－イル）プロパン－１－オール（４．０９ｍｍｏｌ）及びエタンチオ酸Ｓ－酸（９．８１ｍｍｏｌ）を加え、混合物を室温で１時間撹拌した。揮発性物質を減圧下で蒸発させると、残渣を得て、これをシリカゲルクロマトグラフィー（ヘキサン中の１０～２５％酢酸エチル）で精製した。表題化合物を収率９８％で無色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ４５０．１ ［Ｍ＋Ｈ］＋。 Step 4: S-(3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propyl)ethanethioate

A solution of triphenylphosphine (8.20 mmol) and DIAD (8.17 mmol) in THF (50 mL) was stirred at 0° C. for 30 min. 3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propan-1-ol (4.09 mmol) and ethanethioic S-acid (9.81 mmol) were added and the mixture was stirred at room temperature for 1 h. Evaporation of volatiles under reduced pressure gave a residue which was purified by silica gel chromatography (10-25% ethyl acetate in hexanes). The title compound was isolated in 98% yield as a colorless oil. MS (ESI) m/z: 450.1 [M+H]+.

表題化合物は実施例３５のステップ７と同様に調製し、Ｓ－（３－ヒドロキシ－２－（ピリジン－４－イル）プロピル）エタンチオエートはＳ－（３－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－２－（ピリジン－３－イル）プロピル）エタンチオエートに置き換えた。表題化合物を収率９７％で茶色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ８６６．３ ［Ｍ＋Ｈ］＋。 Step 5: tert-Butyl (2S,6R)-4-(8-((3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propyl)thio)-7-chloro-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 7 of example 35, substituting S-(3-hydroxy-2-(pyridin-4-yl)propyl)ethanethioate with S-(3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propyl)ethanethioate. The title compound was isolated in 97% yield as a brown solid. MS (ESI) m/z: 866.3 [M+H]+.

表題化合物を実施例２３のステップ２と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（８－（（３－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－２－（ピリジン－３－イル）プロピル）チオ）－７－クロロ－２－オキソ－６－（トリフルオロメチル）－１，２－ジヒドロキナゾリン－４－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率８０％で茶色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６２８．２ ［Ｍ＋Ｈ］＋。 Step 6: tert-Butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-3-yl)propyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 2 of example 23, replacing tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate with tert-butyl (2S,6R)-4-(8-((3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propyl)thio)-7-chloro-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 80% yield as a brown solid. MS (ESI) m/z: 628.2 [M+H]+.

表題化合物は実施例２９のステップ５と同様にジアステレオマーの１：１混合物として単離し、（Ｓ）－７－クロロ－８－（（３－ヒドロキシ－２－（ピラジン－２－イルオキシ）プロピル）チオ）－６－（トリフルオロメチル）キナゾリン－２，４（１Ｈ，３Ｈ）－ジオンはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（７－クロロ－８－（（３－ヒドロキシ－２－（ピリジン－３－イル）プロピル）チオ）－２－オキソ－６－（トリフルオロメチル）－１，２－ジヒドロキナゾリン－４－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。Ｉｎｔ－３ａ及びＩｎｔ－３ｂは、セミ分取逆相ＨＰＬＣによる前述の混合物の精製によって単一のジアステレオマーとして得られ（カラム：Ｄａｉｃｅｌ Ｃｈｉｒａｌｃｅｌ ＯＤ ２５０ｍｍ×３０ｍｍ、１０ｕｍ）、移動相Ｂ＝メタノール、勾配＝５０％、実行時間６．４分）、ＳＦＣによって特性評価された（カラム＝Ｃｈｉｒａｃｅｌ ＯＤ－３、５０×４．６ｍｍ、内径＝３ｕｍ、３５℃で背圧１００ｂａｒで安定化、移動相Ｂ＝０．０５％ジエチルアミンを含有するメタノール、勾配＝４０％、流速＝３ｍＬ／分、検出器：フォトダイオードアレイ）。Ｉｎｔ－３ａ： ＳＦＣ Ｒｔ＝ １．９４分；ＭＳ （ＥＳＩ） ｍ／ｚ： ６１０．１ ［Ｍ＋Ｈ］＋． Ｉｎｔ－３ｂ： ＳＦＣ Ｒｔ＝ ２．４２分；ＭＳ （ＥＳＩ） ｍ／ｚ： ６１０．１ ［Ｍ＋Ｈ］＋。 Step 7: tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (int-3a) and tert-butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (int-3b)

The title compound was isolated as a 1:1 mixture of diastereomers as in Step 5 of Example 29, where (S)-7-chloro-8-((3-hydroxy-2-(pyrazin-2-yloxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was replaced with tert-butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-3-yl)propyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate. Int-3a and Int-3b were obtained as single diastereomers by purification of the aforementioned mixture by semi-preparative reversed phase HPLC (column: Daicel Chiralcel OD 250mm x 30mm, 10um), mobile phase B = methanol, gradient = 50%, run time 6.4min) and characterized by SFC (column = Chiracel OD-3, 50 x 4.6mm, ID = 3um, stabilized at 35°C with 100bar back pressure, mobile phase B = methanol containing 0.05% diethylamine, gradient = 40%, flow rate = 3mL/min, detector: photodiode array). Int-3a: SFC Rt = 1.94min; MS (ESI) m/z: 610.1 [M+H]+. Int-3b: SFC Rt = 2.42 min; MS (ESI) m/z: 610.1 [M+H]+.

表題化合物を実施例２３のステップ１と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートは、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピリジン－３－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率７２％で黄色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ８４８．２ ［Ｍ＋Ｈ］＋。 Step 8: tert-Butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 1 of example 23, substituting tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate for tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 72% yield as a yellow oil. MS (ESI) m/z: 848.2 [M+H]+.

表題化合物を実施例２３のステップ２と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリジン－３－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率９２％で白色半固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６９２．２ ［Ｍ＋Ｈ］＋。 Step 9: tert-Butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared similarly to step 2 of example 23 to give tert-butyl(2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine The-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 92% yield as a white semi-solid. MS (ESI) m/z: 692.2 [M+H]+.

表題化合物を実施例２３のステップ３と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロチオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３、４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロチオフェン－２－イル）－６－オキソ－３－（ピリジン－３－イル）－１０－（トリフルオロメチル）－３、４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率９４％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ５９２．３ ［Ｍ＋Ｈ］＋。 Step 10: (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared similarly to step 3 of example 23 to give tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine The 1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 94% yield as a yellow solid. MS (ESI) m/z: 592.3 [M+H]+.

表題化合物を実施例２３のステップ４と同様に調製し、（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンは（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピリジン－３－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンに置き換えた。表題化合物を収率４１％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６４６．１ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ８．５８ （ｓ， １Ｈ）， ８．４８ （ｄ， Ｊ ＝ ４．４ Ｈｚ， １Ｈ）， ８．０６ （ｓ， １Ｈ）， ７．８８ （ｓ， １Ｈ）， ７．８４ － ７．６８ （ｍ， １Ｈ）， ７．３７ （ｓ， １Ｈ）， ７．３３ － ６．９８ （ｍ， １Ｈ）， ６．８２ （ｄｄ， Ｊ ＝ １０．４， １６．４ Ｈｚ， １Ｈ）， ６．２０ （ｄｄ， Ｊ ＝ ２．４， １６．４ Ｈｚ， １Ｈ）， ５．７８ － ５．７１ （ｍ， １Ｈ）， ４．８６ － ４．４７ （ｍ， ４Ｈ）， ４．０８ （ｄ， Ｊ ＝ １３．２ Ｈｚ， ２Ｈ）， ３．９７ － ３．６８ （ｍ， １Ｈ）， ３．６７ － ３．３５ （ｍ， ２Ｈ）， ３．２９ － ３．２２ （ｍ， ２Ｈ）， １．４０ （ｓ， ６Ｈ）。 Step 11: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to step 4 of example 23, substituting (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one for (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 41% yield as a white solid. MS (ESI) m/z: 646.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.48 (d, J = 4.4 Hz, 1H), 8.06 (s, 1H), 7.88 (s, 1H), 7.84 - 7.68 (m, 1H), 7.37 (s, 1H), 7.33 - 6.98 (m, 1H), 6.82 (dd, J = 10.4, 16.4 Hz, 1H), 6.20 (dd, J = 2.4, 16.4 Hz, 1H), 5.78 - 5.71 (m, 1H), 4.86 - 4.47 (m, 4H), 4.08 (d, J = 13.2 Hz, 2H), 3.97 - 3.68 (m, 1H), 3.67 - 3.35 (m, 2H), 3.29 - 3.22 (m, 2H), 1.40 (s, 6H).

ステップ１：２－（ピリミジン－２－イル）マロン酸ジメチル

ジオキサン（３００ｍＬ）中の２－クロロピリミジン（８７．０ｍｍｏｌ）、１，３－プロパン二酸ジエチル（１７５ｍｍｏｌ）、ヨウ化銅（Ｉ）（１７ｍｍｏｌ）、炭酸セシウム（２６２ｍｍｏｌ）、ピコリン酸（３５ｍｍｏｌ）の混合物を１００℃で１６時間撹拌した。反応混合物を水で希釈し、酢酸エチルで３回抽出し、組み合わせた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮して残渣を得て、これをシリカゲルクロマトグラフィー（ヘキサン中の０～３０％酢酸エチル）で精製した。表題化合物を収率２５％で黄色固体として単離した。質量スペクトル（ＥＳＩ） ｍ／ｚ ＝ ２１１．０ （Ｍ＋Ｈ）＋。 Example 45 and Example 46: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one and (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Step 1: Dimethyl 2-(pyrimidin-2-yl)malonate

A mixture of 2-chloropyrimidine (87.0 mmol), diethyl 1,3-propanedioate (175 mmol), copper(I) iodide (17 mmol), cesium carbonate (262 mmol), and picolinic acid (35 mmol) in dioxane (300 mL) was stirred at 100° C. for 16 hours. The reaction mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0-30% ethyl acetate in hexanes). The title compound was isolated in 25% yield as a yellow solid. Mass spectrum (ESI) m/z = 211.0 (M+H)+.

ＴＨＦ（２００ｍＬ）中の１，３－ジメチル２－（ピリミジン－２－イル）プロパンジオエート（９５．２ｍｍｏｌ）の－４０℃溶液にＴＨＦ（３８０ｍＬ）中の１ＭのＤＩＢＡＬＨの溶液を加えた。１時間後、反応を硫酸ナトリウム十水和物でクエンチし、水で希釈し、酢酸エチルで３回抽出した。組み合わせた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮して、表題化合物を黄色の油として得た。ＭＳ （ＥＳＩ） ｍ／ｚ ＝ １５５．１ （Ｍ＋Ｈ）＋。 Step 2: 2-(pyrimidin-2-yl)propane-1,3-diol

To a −40° C. solution of 1,3-dimethyl 2-(pyrimidin-2-yl)propanedioate (95.2 mmol) in THF (200 mL) was added a 1 M solution of DIBALH in THF (380 mL). After 1 h, the reaction was quenched with sodium sulfate decahydrate, diluted with water, and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound as a yellow oil. MS (ESI) m/z = 155.1 (M+H)+.

表題化合物は実施例３１のステップ２と同様に調製し、（Ｓ）－３－（トリチルチオ）プロパン－１，２－ジオールは２－（ピリミジン－２－イル）プロパン－１，３－ジオールに置き換えた。表題化合物を収率５５％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ ＝ ３９３．０ （Ｍ＋Ｈ） ＋。 Step 3: 3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yl)propan-1-ol

The title compound was prepared similarly to step 2 of Example 31, substituting 2-(pyrimidin-2-yl)propane-1,3-diol for (S)-3-(tritylthio)propane-1,2-diol. The title compound was isolated in 55% yield as a yellow solid. MS (ESI) m/z = 393.0 (M+H) +.

表題化合物は実施例４３のステップ４と同様に調製し、３－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－２－（ピリジン－３－イル）プロパン－１－オールは３－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－２－（ピリミジン－２－イル）プロパン－１－オールに置き換えた。表題化合物を収率９９％で黄色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ ＝ ４５１．２ （Ｍ＋Ｈ）＋。 Step 4: S-(3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yl)propyl)ethanethioate

The title compound was prepared analogously to step 4 of example 43, substituting 3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propan-1-ol for 3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yl)propan-1-ol. The title compound was isolated in 99% yield as a yellow oil. MS (ESI) m/z = 451.2 (M+H)+.

ヒドラジン一水和物（６０ｍＬ）、ＴＨＦ（９０ｍＬ）及びメタノール（９０ｍＬ）中のＳ－（３－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－２－（ピリミジン－２－イル）プロピル）エタンチオエート（４８．８ｍｍｏｌ）の溶液を室温で１時間撹拌した。混合物を水で希釈し、ほとんどの揮発性物質を減圧下で除去した。得られた水溶液を酢酸エチルで抽出し、濃縮して残渣を得て、これをシリカゲルクロマトグラフィー（ヘキサン中の０～１５％酢酸エチル）で精製した。表題化合物を収率６７％で無色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ ＝ ４０９．２ ［Ｍ＋Ｈ］＋。 Step 5: 3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yl)propane-1-thiol

A solution of S-(3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yl)propyl)ethanethioate (48.8 mmol) in hydrazine monohydrate (60 mL), THF (90 mL) and methanol (90 mL) was stirred at room temperature for 1 h. The mixture was diluted with water and most of the volatiles were removed under reduced pressure. The resulting aqueous solution was extracted with ethyl acetate and concentrated to give a residue which was purified by silica gel chromatography (0-15% ethyl acetate in hexanes). The title compound was isolated in 67% yield as a colorless oil. MS (ESI) m/z = 409.2 [M+H]+.

表題化合物は実施例２９、ステップ３と同様に調製し、（Ｓ）－３－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－２－（ピラジン－２－イルオキシ）プロパン－１－チオールは３－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－２－（ピリミジン－２－イル）プロパン－１－チオールに置き換えた。表題化合物を収率８６％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ ＝ ６７１．０ ［Ｍ＋Ｈ］＋。 Step 6: 8-((3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yl)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared similarly to Example 29, step 3, substituting 3-((tert-butyldiphenylsilyl)oxy)-2-(pyrazin-2-yloxy)propane-1-thiol for (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yl)propane-1-thiol. The title compound was isolated in 86% yield as a white solid. MS (ESI) m/z = 671.0 [M+H]+.

表題化合物を実施例２３のステップ２と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートは８－（（３－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－２－（ピリミジン－２－イル）プロピル）チオ）－７－クロロ－６－（トリフルオロメチル）キナゾリン－２，４（１Ｈ，３Ｈ）－ジオンに置き換えた。表題化合物を収率９２％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ４３３．０ ［Ｍ＋Ｈ］＋。 Step 7: 7-Chloro-8-((3-hydroxy-2-(pyrimidin-2-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

The title compound was prepared analogously to step 2 of example 23, except that tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate was replaced with 8-((3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yl)propyl)thio)-7-chloro-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione. The title compound was isolated in 92% yield as a white solid. MS (ESI) m/z: 433.0 [M+H]+.

表題化合物は実施例２９のステップ５と同様に調製し、（Ｓ）－７－クロロ－８－（（３－ヒドロキシ－２－（ピラジン－２－イルオキシ）プロピル）チオ）－６－（トリフルオロメチル）キナゾリン－２，４（１Ｈ，３Ｈ）－ジオンは７－クロロ－８－（（３－ヒドロキシ－２－（ピリミジン－２－イル）プロピル）チオ）－６－（トリフルオロメチル）キナゾリン－２，４（１Ｈ，３Ｈ）－ジオンに置き換えた。表題化合物を収率５５％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ４１５．０ ［Ｍ＋Ｈ］＋。 Step 8: 11-Chloro-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione

The title compound was prepared analogously to step 5 of example 29, substituting (S)-7-chloro-8-((3-hydroxy-2-(pyrazin-2-yloxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione with 7-chloro-8-((3-hydroxy-2-(pyrimidin-2-yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione. The title compound was isolated in 55% yield as a yellow solid. MS (ESI) m/z: 415.0 [M+H]+.

表題化合物を実施例２９のステップ６と同様に調製し、（Ｓ）－１１－クロロ－３－（ピラジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６，８（７Ｈ）－ジオンは１１－クロロ－３－（ピリミジン－２－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６，８（７Ｈ）－ジオンに置き換えた。表題化合物を収率６１％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６１１．２ ［Ｍ＋Ｈ］＋。 Step 9: tert-Butyl (2S,6R)-4-(11-chloro-6-oxo-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 6 of example 29, substituting (S)-11-chloro-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione for 11-chloro-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione. The title compound was isolated in 61% yield as a yellow solid. MS (ESI) m/z: 611.2 [M+H]+.

表題化合物を実施例２３のステップ１と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（１１－クロロ－６－オキソ－３－（ピリミジン－２－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率４５％で茶色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ８４９．２ ［Ｍ＋Ｈ］＋。 Step 10: tert-Butyl (2S,6R)-4-(11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 1 of example 23, substituting tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate for tert-butyl (2S,6R)-4-(11-chloro-6-oxo-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 45% yield as a brown solid. MS (ESI) m/z: 849.2 [M+H]+.

Step 11: 11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared in the same manner as in step 3 of Example 23 to obtain tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxamide. The sylate was replaced with tert-butyl (2S,6R)-4-(11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 95% yield as a yellow oil. MS (ESI) m/z: 749.2 [M+H]+.

表題化合物を実施例２３のステップ２と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートは１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピリミジン－２－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンに置き換えた。表題化合物を収率９５％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ５９３．１ ［Ｍ＋Ｈ］＋。 Step 12: 11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared similarly to step 2 of Example 23 to afford tert-butyl(2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2, 6-Dimethylpiperazine-1-carboxylate was replaced with 11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 95% yield as a yellow solid. MS (ESI) m/z: 593.1 [M+H]+.

表題化合物を実施例２３のステップ４と同様に調製し、（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンは１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピリミジン－２－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンに置き換えた。表題化合物を収率３４％でジアステレオマーの１：１混合物として単離した。実施例４５及び実施例４６は、混合物をＳＦＣで精製することによって単一のジアステレオマーとして得られ（カラム＝Ｄａｉｃｅｌ Ｃｈｉｒａｌｐａｋ ＡＳ ２５０ｍｍ×３０ｍｍ、１０ｕｍ、Ａ相：アセトニトリル中の６０％エタノール、Ｂ相：ＣＯ２、勾配：Ｂ中の６０％Ａ、実行時間３分）、ＳＦＣによって特性評価された（カラム：Ｃｈｉｒａｐｐａｋ ＡＳ－３、５０×４．６ｍｍ、内径＝３ｕｍ、３５℃で背圧１００ｂａｒで安定化、移動相Ｂ：０．０５％ジエチルアミンを含有するメタノール、勾配＝Ａ中の５～４０％Ｂ、流速＝３ｍＬ／分、検出器：フォトダイオードアレイ）。 Step 13: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one and (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to step 4 of example 23, substituting 11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one for (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 34% yield as a 1:1 mixture of diastereomers. Examples 45 and 46 were obtained as single diastereomers by purifying the mixture by SFC (column = Daicel Chiralpak AS 250mm x 30mm, 10um, A phase: 60% ethanol in acetonitrile, B phase: CO2, gradient: 60% A in B, run time 3 minutes) and characterized by SFC (column: Chirappak AS-3, 50 x 4.6mm, ID = 3um, stabilized at 35°C and 100 bar back pressure, mobile phase B: methanol containing 0.05% diethylamine, gradient = 5-40% B in A, flow rate = 3mL/min, detector: photodiode array).

Example 45: SFC Rt = 1.95 min, MS (ESI) m/z: 647.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 2H), 8.09 (s, 1H), 7.32 (m, 1H), 7.20 (m, 1H), 6.93 (m, 1H), 6.65 (m, 1H), 6.43 (m, 1H), 5.81 (m, 1H), 5.32 - 4.43 (m, 4H), 4.25 - 3.65 (m, 4H), 3.50 - 3.10 (m, 3H), 1.47 - 1.45 (m, 6H).

Example 46: SFC Rt = 2.36 min, MS (ESI) m/z: 647.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 2H), 8.10 (s, 1H), 7.32 (m, 1H), 7.24 (m, 1H), 6.92 (m, 1H), 6.66 (m, 1H), 6.45 (m, 1H), 5.82 (m, 1H), 5.34 - 4.45 (m, 4H), 4.26 - 3.66 (m, 4H), 3.52 - 3.12 (m, 3H), 1.50 - 1.47 (m, 6H).

ステップ１：ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｒ）－１１－クロロ－３－（５－フルオロピリジン－３－イル）－６－オキソ－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレート（ｉｎｔ－４ａ）及びｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－３－（５－フルオロピリジン－３－イル）－６－オキソ－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレート（ｉｎｔ－４ｂ）

表題化合物は実施例４３のステップ１～７と同様に調製し、ステップ１では、ピリジン－３－イルボロン酸は（５－フルオロピリジン－３－イル）ボロン酸に置き換えた。表題化合物をジアステレオマーの１：１混合物として単離した。Ｉｎｔ－４ａ及びＩｎｔ－４ｂは、ＳＦＣによる混合物の精製によって単一のジアステレオマーとして得られ（カラム＝Ｄａｉｃｅｌ Ｃｈｉｒａｌｐａｋ ＩＣ ２５０ｍｍ×３０ｍｍ、１０ｕｍ、Ａ相：エタノール、Ｂ相：ＣＯ２、勾配：Ｂ中の６５％Ａ、実行時間７．４５分）、ＳＦＣによって特性評価された（カラム：Ｃｈｉｒａｌｐａｋ ＩＣ－３、５０×４．６ｍｍ、内径＝３ｕｍ、３５℃で背圧１００ｂａｒで安定化、移動相：ＣＯ２中の０．０５％ジエチルアミンを含有する６０％エタノール、流速＝３ｍＬ／分、検出器：フォトダイオードアレイ）。Ｉｎｔ－４ａ： ＳＦＣ Ｒｔ＝ １．５８分；ＭＳ （ＥＳＩ） ｍ／ｚ： ６２８．２ ［Ｍ＋Ｈ］＋． Ｉｎｔ－４ｂ： ＳＦＣ Ｒｔ＝ ２．８７分；ＭＳ （ＥＳＩ） ｍ／ｚ： ６２８．２ ［Ｍ＋Ｈ］＋。 Example 49: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Step 1: tert-butyl (2S,6R)-4-((R)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (int-4a) and tert-butyl (2S,6R)-4-((S)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (int-4b)

The title compound was prepared similarly to steps 1-7 of Example 43, except that in step 1, pyridin-3-ylboronic acid was replaced with (5-fluoropyridin-3-yl)boronic acid. The title compound was isolated as a 1:1 mixture of diastereomers. Int-4a and Int-4b were obtained as single diastereomers by purification of the mixture by SFC (column = Daicel Chiralpak IC 250mm x 30mm, 10um, A phase: ethanol, B phase: CO2, gradient: 65% A in B, run time 7.45min) and characterized by SFC (column: Chiralpak IC-3, 50 x 4.6mm, internal diameter = 3um, stabilized at 35°C with 100 bar back pressure, mobile phase: 60% ethanol with 0.05% diethylamine in CO2, flow rate = 3mL/min, detector: photodiode array). Int-4a: SFC Rt = 1.58 min; MS (ESI) m/z: 628.2 [M+H]+. Int-4b: SFC Rt = 2.87 min; MS (ESI) m/z: 628.2 [M+H]+.

表題化合物を実施例２３のステップ１と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－３－（５－フルオロピリジン－３－イル）－６－オキソ－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率７２％で黄色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ８６６．１ ［Ｍ＋Ｈ］＋。 Step 2: tert-Butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 1 of example 23, replacing tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate with tert-butyl (2S,6R)-4-((S)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 72% yield as a yellow oil. MS (ESI) m/z: 866.1 [M+H]+.

表題化合物を実施例２３のステップ２と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－３－（５－フルオロピリジン－３－イル）－６－オキソ－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率７３％で無色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ７１０．０ ［Ｍ＋Ｈ］＋。 Step 3: tert-Butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared similarly to step 2 of Example 23 to afford tert-butyl(2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1- The carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 73% yield as a colorless oil. MS (ESI) m/z: 710.0 [M+H]+.

表題化合物を実施例２３のステップ３と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロチオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３、４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロチオフェン－２－イル）－３－（５－フルオロピリジン－３－イル）－６－オキソ－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシラートに置き換えた。表題化合物を収率９７％で黄色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６０９．９ ［Ｍ＋Ｈ］＋。 Step 4: (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared similarly to step 3 of example 23 to afford tert-butyl(2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1- The carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 97% yield as a yellow oil. MS (ESI) m/z: 609.9 [M+H]+.

表題化合物を実施例２３のステップ４と同様に調製し、（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンは（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（５－フルオロピリジン－３－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンに置き換えた。表題化合物を収率６９％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６６４．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ８．５０ （ｓ， １Ｈ）， ８．４４ （ｄ， Ｊ ＝ ２．４ Ｈｚ， １Ｈ）， ８．１２ （ｓ， １Ｈ）， ７．５４ － ７．４５ （ｍ， １Ｈ）， ７．４３ － ７．３１ （ｍ， １Ｈ）， ７．０８ － ６．８５ （ｍ， １Ｈ）， ６．６９ － ６．５９ （ｍ， １Ｈ）， ６．４３ （ｄｄ， Ｊ ＝ ２．０， １６．８ Ｈｚ， １Ｈ）， ５．８３ － ５．７６ （ｍ， １Ｈ）， ４．９６ － ４．５２ （ｍ， ４Ｈ）， ４．２２ － ４．１５ （ｍ， ２Ｈ）， ３．９７ － ３．６２ （ｍ， ２Ｈ）， ３．４６ － ３．３６ （ｍ， ２Ｈ）， ３．１９ － ３．００ （ｍ， １Ｈ）， １．５８ － １．４９ （ｍ， ６Ｈ）。 Step 5: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to step 4 of example 23, substituting (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one for (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 69% yield as a white solid. MS (ESI) m/z: 664.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 7.54 - 7.45 (m, 1H), 7.43 - 7.31 (m, 1H), 7.08 - 6.85 (m, 1H), 6.69 - 6.59 (m, 1H), 6.43 (dd, J = 2.0, 16.8 Hz, 1H), 5.83 - 5.76 (m, 1H), 4.96 - 4.52 (m, 4H), 4.22 - 4.15 (m, 2H), 3.97 - 3.62 (m, 2H), 3.46 - 3.36 (m, 2H), 3.19 - 3.00 (m, 1H), 1.58 - 1.49 (m, 6H).

ステップ１：３－フルオロ－５－ヨードチオフェン－２－カルボン酸メチル

ＴＨＦ（３０ｍＬ）中の３－フルオロチオフェン－２－カルボン酸メチル（１９ｍｍｏｌ）の－４０℃溶液に１Ｍのクロロ－（２，２，６，６－テトラメチル－１－ピペリジル）マグネシウム－塩化リチウム錯体（１８．７ｍＬ）の溶液を滴下した。３０分後、混合物を－７０℃まで冷却し、ＴＨＦ（１０ｍＬ）中のヨウ素（１９．７ｍｍｏｌ）を加えた。反応物を室温で１時間撹拌し、水でクエンチした。混合物を酢酸エチルで２回抽出し、組み合わせた有機層をブラインで洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮して残渣を得て、これをシリカゲルクロマトグラフィー（ヘキサン中の４％酢酸エチル）で精製した。表題化合物を収率７５％で白色固体として単離した。 Example 53: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(4-fluorothiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

Step 1: Methyl 3-fluoro-5-iodothiophene-2-carboxylate

To a −40° C. solution of methyl 3-fluorothiophene-2-carboxylate (19 mmol) in THF (30 mL) was added dropwise a solution of 1 M chloro-(2,2,6,6-tetramethyl-1-piperidyl)magnesium-lithium chloride complex (18.7 mL). After 30 min, the mixture was cooled to −70° C. and iodine (19.7 mmol) in THF (10 mL) was added. The reaction was stirred at room temperature for 1 h and quenched with water. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (4% ethyl acetate in hexanes). The title compound was isolated as a white solid in 75% yield.

ＴＨＦ（１０ｍＬ）中の３－フルオロ－５－ヨードチオフェン－２－カルボン酸メチル（１４．０ｍｍｏｌ）の溶液に水酸化ナトリウム（４２ｍｍｏｌ）を加え、この混合物を室温で４時間撹拌した。ほとんどの揮発性物質を減圧下で除去し、得られた水溶液を１ＭのＨＣｌ水溶液（１０ｍＬ）で処理して表題化合物の沈殿を誘導し、これを濾過し、乾燥させた。表題化合物を収率７９％で白色固体として単離した。 Step 2: 3-Fluoro-5-iodothiophene-2-carboxylic acid

To a solution of methyl 3-fluoro-5-iodothiophene-2-carboxylate (14.0 mmol) in THF (10 mL) was added sodium hydroxide (42 mmol) and the mixture was stirred at room temperature for 4 h. Most of the volatiles were removed under reduced pressure and the resulting aqueous solution was treated with 1 M aqueous HCl (10 mL) to induce precipitation of the title compound, which was filtered and dried. The title compound was isolated as a white solid in 79% yield.

（メチルスルフィニル）メタン（３０ｍＬ）中の３－フルオロ－５－ヨードチオフェン－２－カルボン酸（１１．０ｍｍｏｌ）の溶液を炭酸銀（１．１０ｍｍｏｌ）及び酢酸（１３．２ｍｍｏｌ）で処理し、この混合物を１２０℃で３時間加熱した。混合物を室温まで冷却し、水で希釈し、酢酸エチルで３回抽出し、組み合わせた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮して、表題化合物を収率９９％で黄色の油として得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ｐｐｍ ６．７２ － ６．７４ （ｍ， １Ｈ） ６．９９ － ７．００ （ｍ， １Ｈ）。 Step 3: 4-Fluoro-2-iodothiophene

A solution of 3-fluoro-5-iodothiophene-2-carboxylic acid (11.0 mmol) in (methylsulfinyl)methane (30 mL) was treated with silver carbonate (1.10 mmol) and acetic acid (13.2 mmol) and the mixture was heated at 120° C. for 3 h. The mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound in 99% yield as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 6.72 - 6.74 (m, 1H) 6.99 - 7.00 (m, 1H).

窒素下で、トルエン（９０ｍＬ）中のｔｅｒｔ－ブチルジメチル（プロプ－２－イン－１－イルオキシ）シラン（５２．８ｍｍｏｌ）、Ｎ，Ｎ’－ビス（２－ベンゾチアゾリル）－２，６－ピリジンジカルボキサミド（５８．１ｍｍｏｌ）、塩化銅（５．２８ｍｍｏｌ）及びナトリウム－ｔｅｒｔ－ブトキシド（７．９３ｍｍｏｌ）の溶液にトリ－ｔｅｒｔ－ブチルホスファン（５．２８ｍｍｏｌ）を加えた。メタノール（４．２８ｍＬ）を加え、混合物を室温で１２時間撹拌した。揮発性物質を減圧下で除去し、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン中の０～５％酢酸エチル）で精製して、表題化合物を収率７６％で無色の油として得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ｐｐｍ ０．９３ （ｓ， ９Ｈ） １．２７ （ｓ， １２Ｈ） ４．２９ － ４．３０ （ｍ， ２Ｈ） ５．８７ － ５．８９ （ｍ， １Ｈ） ５．９７ （ｓ， １Ｈ）。 Step 4: tert-Butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane

Tri-tert-butylphosphane (5.28 mmol) was added to a solution of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (52.8 mmol), N,N'-bis(2-benzothiazolyl)-2,6-pyridinedicarboxamide (58.1 mmol), copper chloride (5.28 mmol) and sodium-tert-butoxide (7.93 mmol) in toluene (90 mL) under nitrogen. Methanol (4.28 mL) was added and the mixture was stirred at room temperature for 12 hours. The volatiles were removed under reduced pressure and the resulting residue was purified by silica gel chromatography (0-5% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 76% yield. 1H NMR (400 MHz, CDCl3) δ ppm 0.93 (s, 9H) 1.27 (s, 12H) 4.29 - 4.30 (m, 2H) 5.87 - 5.89 (m, 1H) 5.97 (s, 1H).

ジオキサン（１０ｍＬ）及び水（５ｍＬ）中の４－フルオロ－２－ヨードチオフェン（１１．０ｍｍｏｌ）及びｔｅｒｔ－ブチルジメチル（（２－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）アリル）オキシ）シラン（１２．１ｍｍｏｌ）の溶液にリン酸カリウム（３２．９ｍｍｏｌ）及びＸＰｈｏｓ Ｐｄ Ｇ３（０．２２ｍｍｏｌ）を加えた。懸濁液を６０℃で２時間撹拌し、揮発性物質を減圧下で除去して残渣を得て、これをシリカゲルクロマトグラフィー（ヘキサン中４％酢酸エチル）で精製した。表題化合物を収率５４％で黄色の油として単離した。 Step 5: tert-butyl((2-(4-fluorothiophen-2-yl)allyl)oxy)dimethylsilane

To a solution of 4-fluoro-2-iodothiophene (11.0 mmol) and tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (12.1 mmol) in dioxane (10 mL) and water (5 mL) was added potassium phosphate (32.9 mmol) and XPhos Pd G3 (0.22 mmol). The suspension was stirred at 60° C. for 2 h and the volatiles were removed under reduced pressure to give a residue which was purified by silica gel chromatography (4% ethyl acetate in hexanes). The title compound was isolated in 54% yield as a yellow oil.

表題化合物は実施例４３のステップ２と同様に調製し、２－（ピリジン－３－イル）プロパ－２－エン－１－オールはｔｅｒｔ－ブチル（（２－（４－フルオロチオフェン－２－イル）アリル）オキシ）ジメチルシランに置き換えた。表題化合物を収率３５％で黄色の油として単離した。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ｐｐｍ ０．０８ （ｓ， ６Ｈ） ０．９１ （ｓ， ９Ｈ） ２．３０ － ２．５２ （ｍ， １Ｈ） ３．２０ （ｔ， Ｊ ＝ ５．６ Ｈｚ， １Ｈ） ３．８５ － ３．９７ （ｍ， ４Ｈ） ６．５５ （ｓ， １Ｈ） ６．６９ （ｓ， １Ｈ）。 Step 6: 3-((tert-butyldimethylsilyl)oxy)-2-(4-fluorothiophen-2-yl)propan-1-ol

The title compound was prepared analogously to step 2 of example 43, substituting tert-butyl((2-(4-fluorothiophen-2-yl)allyl)oxy)dimethylsilane for 2-(pyridin-3-yl)prop-2-en-1-ol. The title compound was isolated in 35% yield as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.08 (s, 6H) 0.91 (s, 9H) 2.30 - 2.52 (m, 1H) 3.20 (t, J = 5.6 Hz, 1H) 3.85 - 3.97 (m, 4H) 6.55 (s, 1H) 6.69 (s, 1H).

表題化合物は実施例４３のステップ４と同様に調製し、３－（（ｔｅｒｔ－ブチルジフェニルシリル）オキシ）－２－（ピリジン－３－イル）プロパン－１－オールは３－（（ｔｅｒｔ－ブチルジメチルシリル）オキシ）－２－（４－フルオロチオフェン－２－イル）プロパン－１－オールに置き換えた。表題化合物を収率９７％で黄色の油として単離した。１Ｈ ＮＭＲ （４００ ＭＨｚ，メタノール－ｄ４） δ ｐｐｍ ０．０５ （ｓ， ６Ｈ） ０．９１ （ｓ， ９Ｈ） ２．３３ （ｓ， ３Ｈ） ３．１２ － ３．１５ （ｍ， ２Ｈ） ３．３１ － ３．３５ （ｍ， １Ｈ） ３．７３ － ３．７７ （ｍ， １Ｈ） ３．８４ － ３．８６ （ｍ， １Ｈ） ６．５３ － ６．５４ （ｍ， １Ｈ） ６．６７ － ６．６８ （ｍ， １Ｈ）。 Step 7: S-(3-((tert-butyldimethylsilyl)oxy)-2-(4-fluorothiophen-2-yl)propyl)ethanethioate

The title compound was prepared analogously to Step 4 of Example 43, substituting 3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propan-1-ol with 3-((tert-butyldimethylsilyl)oxy)-2-(4-fluorothiophen-2-yl)propan-1-ol. The title compound was isolated in 97% yield as a yellow oil. 1H NMR (400 MHz, methanol-d4) δ ppm 0.05 (s, 6H) 0.91 (s, 9H) 2.33 (s, 3H) 3.12 - 3.15 (m, 2H) 3.31 - 3.35 (m, 1H) 3.73 - 3.77 (m, 1H) 3.84 - 3.86 (m, 1H) 6.53 - 6.54 (m, 1H) 6.67 - 6.68 (m, 1H).

表題化合物は実施例３５のステップ７と同様に調製し、Ｓ－（３－ヒドロキシ－２－（ピリジン－４－イル）プロピル）エタンチオエートはＳ－（３－（（ｔｅｒｔ－ブチルジメチルシリル）オキシ）－２－（４－フルオロチオフェン－２－イル）プロピル）エタンチオエートに置き換えた。表題化合物を収率７６％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ７６５．１ ［Ｍ＋Ｈ］＋。 Step 8: tert-Butyl (2S,6R)-4-(8-((3-((tert-butyldimethylsilyl)oxy)-2-(4-fluorothiophen-2-yl)propyl)thio)-7-chloro-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 7 of example 35, substituting S-(3-hydroxy-2-(pyridin-4-yl)propyl)ethanethioate with S-(3-((tert-butyldimethylsilyl)oxy)-2-(4-fluorothiophen-2-yl)propyl)ethanethioate. The title compound was isolated in 76% yield as a yellow solid. MS (ESI) m/z: 765.1 [M+H]+.

表題化合物を実施例２３のステップ２と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（８－（（３－（（ｔｅｒｔ－ブチルジメチルシリル）オキシ）－２－（４－フルオロチオフェン－２－イル）プロピル）チオ）－７－クロロ－２－オキソ－６－（トリフルオロメチル）－１，２－ジヒドロキナゾリン－４－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率４７％で黄色の油として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６５１．１ ［Ｍ＋Ｈ］＋ Step 9: tert-Butyl (2S,6R)-4-(7-chloro-8-((2-(4-fluorothiophen-2-yl)-3-hydroxypropyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 2 of example 23, replacing tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate with tert-butyl (2S,6R)-4-(8-((3-((tert-butyldimethylsilyl)oxy)-2-(4-fluorothiophen-2-yl)propyl)thio)-7-chloro-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 47% yield as a yellow oil. MS (ESI) m/z: 651.1 [M+H]+

表題化合物は実施例２９のステップ５と同様に調製し、（Ｓ）－７－クロロ－８－（（３－ヒドロキシ－２－（ピラジン－２－イルオキシ）プロピル）チオ）－６－（トリフルオロメチル）キナゾリン－２，４（１Ｈ，３Ｈ）－ジオンはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（７－クロロ－８－（（２－（４－フルオロチオフェン－２－イル）－３－ヒドロキシプロピル）チオ）－２－オキソ－６－（トリフルオロメチル）－１，２－ジヒドロキナゾリン－４－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物をジアステレオマーの１：１混合物として単離した。Ｉｎｔ－５ａ及びＩｎｔ－５ｂは、ＳＦＣによる前述の混合物の精製によって単一のジアステレオマーとして得られ（カラム：Ｄａｉｃｅｌ Ｃｈｉｒａｌｐａｋ ＩＣ（２５０ｍｍ＊３０ｍｍ、１０ｕｍ）、Ａ相：アセトニトリル中の５５％メタノール、Ｂ相：ＣＯ２）、ＳＦＣによって特性評価された（カラム：Ｃｈｉｒａｐａｋ ＩＣ－３、５０×４．６ｍｍ、内径＝３ｕｍ、３５℃で背圧１００ｂａｒで安定化、移動相Ａ：ＣＯ２及び移動相Ｂ：０．０５％ジエチルアミンを含有するアセトニトリル中の４０％メタノール、流速＝３ｍＬ／分、検出器：フォトダイオードアレイ）。 Step 10: tert-butyl (2S,6R)-4-((S)-11-chloro-3-(4-fluorothiophen-2-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (int-5a) and tert-butyl (2S,6R)-4-((R)-11-chloro-3-(4-fluorothiophen-2-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (int-5b)

The title compound was prepared analogously to step 5 of example 29, substituting (S)-7-chloro-8-((3-hydroxy-2-(pyrazin-2-yloxy)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione with tert-butyl (2S,6R)-4-(7-chloro-8-((2-(4-fluorothiophen-2-yl)-3-hydroxypropyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated as a 1:1 mixture of diastereomers. Int-5a and Int-5b were obtained as single diastereomers by purification of the aforementioned mixture by SFC (column: Daicel Chiralpak IC (250 mm*30 mm, 10 um), A phase: 55% methanol in acetonitrile, B phase: CO2) and characterized by SFC (column: Chirapak IC-3, 50×4.6 mm, ID=3 um, stabilized at 35° C. and 100 bar back pressure, mobile phase A: CO2 and mobile phase B: 40% methanol in acetonitrile containing 0.05% diethylamine, flow rate=3 mL/min, detector: photodiode array).

Int-5a: SFC Rt = 1.18 min; MS (ESI) m/z: 633.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.51 (s, 9H) 1.37 - 1.50 (m, 6H) 3.18 - 3.36 (m, 3H) 3.68 - 3.83 (m, 1H) 3.98 - 4.18 (m, 3H) 4.31 - 4.45 (m, 2H) 4.53 - 4.72 (m, 1H) 4.83 (dd, J = 13.2, 4.4 Hz, 1H) 6.64 (s, 1H) 6.89 (s, 1H) 8.04 (s, 1H).

Int-5b: SFC Rt = 2.23 min; MS (ESI) m/z: 633.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.51 (s, 9H) 1.55 (s, 6H) 3.16 - 3.34 (m, 3H) 3.68 - 3.80 (m, 1H) 3.97 - 4.17 (m, 3H) 4.31 - 4.44 (m, 2H) 4.53 - 4.71 (m, 1H) 4.83 (dd, J = 13.6, 4.8 Hz, 1H) 6.65 (s, 1H) 6.89 (s, 1H) 8.04 (s, 1H).

表題化合物を実施例２３のステップ１と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－クロロ－３－（４－フルオロチオフェン－２－イル）－６－オキソ－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率９４％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ８７１．１ ［Ｍ＋Ｈ］＋。 Step 11: tert-Butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-3-(4-fluorothiophen-2-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared analogously to step 1 of example 23, replacing tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate with tert-butyl (2S,6R)-4-((S)-11-chloro-3-(4-fluorothiophen-2-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 94% yield as a white solid. MS (ESI) m/z: 871.1 [M+H]+.

表題化合物を実施例２３のステップ２と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロ－５－（トリイソプロピルシリル）チオフェン－２－イル）－３－（４－フルオロチオフェン－２－イル）－６－オキソ－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートに置き換えた。表題化合物を収率６１％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ７１５．０ ［Ｍ＋Ｈ］＋。 Step 12: tert-Butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-3-(4-fluorothiophen-2-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate

The title compound was prepared similarly to step 2 of Example 23 to afford tert-butyl(2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-3-(4-fluorothiophen-2-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 61% yield as a white solid. MS (ESI) m/z: 715.0 [M+H]+.

表題化合物を実施例２３のステップ３と同様に調製し、ｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロチオフェン－２－イル）－６－オキソ－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３、４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシレートはｔｅｒｔ－ブチル（２Ｓ，６Ｒ）－４－（（Ｓ）－１１－（４－クロロチオフェン－２－イル）－３－（４－フルオロチオフェン－２－イル）－６－オキソ－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－８－イル）－２，６－ジメチルピペラジン－１－カルボキシラートに置き換えた。表題化合物を収率８７％で黄色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６１５．０ ［Ｍ＋Ｈ］＋。 Step 13: (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(4-fluorothiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared similarly to step 3 of example 23 to afford tert-butyl(2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-(4-chlorothiophen-2-yl)-3-(4-fluorothiophen-2-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 87% yield as a yellow solid. MS (ESI) m/z: 615.0 [M+H]+.

表題化合物を実施例２３のステップ４と同様に調製し、（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（ピリミジン－２－イルオキシ）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンは（Ｓ）－１１－（４－クロロチオフェン－２－イル）－８－（（３Ｓ，５Ｒ）－３，５－ジメチルピペラジン－１－イル）－３－（４－フルオロチオフェン－２－イル）－１０－（トリフルオロメチル）－３，４－ジヒドロ－２Ｈ，６Ｈ－［１，４］チアゼピノ［２，３，４－ｉｊ］キナゾリン－６－オンに置き換えた。表題化合物を収率４２％で白色固体として単離した。ＭＳ （ＥＳＩ） ｍ／ｚ： ６６９．０ ［Ｍ＋Ｈ］＋． １Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ｐｐｍ １．５１ － １．６１ （ｍ， ６ Ｈ） ２．９９ － ３．２１ （ｍ， １ Ｈ） ３．２９ － ３．４６ （ｍ， ２ Ｈ） ３．５５ － ３．７４ （ｍ， １ Ｈ） ３．８６ － ４．０５ （ｍ， １ Ｈ） ４．１７ （ｔ， Ｊ＝１１．２ Ｈｚ， ２ Ｈ） ４．４３ － ５．００ （ｍ， ４ Ｈ） ５．７６ － ５．８３ （ｍ， １ Ｈ） ６．４３ （ｄｄ， Ｊ＝１６．８， ２．０ Ｈｚ， １ Ｈ） ６．５４ － ６．７３ （ｍ， ２ Ｈ） ６．８２ （ｓ， １ Ｈ） ６．８６ － ７．１０ （ｍ， １ Ｈ） ７．３７ （ｓ， １ Ｈ） ８．０９ （ｓ， １ Ｈ）。 Step 14: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-chlorothiophen-2-yl)-3-(4-fluorothiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one

The title compound was prepared analogously to step 4 of example 23, substituting (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(pyrimidin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one for (S)-11-(4-chlorothiophen-2-yl)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(4-fluorothiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 42% yield as a white solid. MS (ESI) m/z: 669.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.51 - 1.61 (m, 6H) 2.99 - 3.21 (m, 1H) 3.29 - 3.46 (m, 2H) 3.55 - 3.74 (m, 1H) 3.86 - 4.05 (m, 1H) 4.17 (t, J = 11.2 Hz, 2H) 4.43 - 5.00 (m, 4H) 5.76 - 5.83 (m, 1H) 6.43 (dd, J = 16.8, 2.0 Hz, 1H) 6.54 - 6.73 (m, 2H) 6.82 (s, 1H) 6.86 - 7.10 (m, 1H) 7.37 (s, 1H) 8.09 (s, 1H).

Compounds of the present application synthesized according to any one of the above procedures include:

A. Assay and Activity Data The KRAS G12C covalent binding assay is performed as follows.

KRAS G12C Covalent Adduct Formation (CAF) Assay This example provides a protocol for assessing covalent adduct formation (CAF) between compounds of formula (I) and KRAS.

In vitro covalent adduct formation assay: The covalent adduct formation (CAF) reaction between Cys12 of KRAS 4B G12C protein and the compounds disclosed herein is measured in vitro using liquid chromatography mass spectrometry (LC-MS).

Recombinant human KRAS 4B protein containing the G12C mutation is used for compound screening experiments. The protein contains an N-terminal 6-histidine tag followed by a Tobacco Etch Virus (TEV) tag followed by residues 1-169 of the native KRAS 4B sequence for a total of 188 amino acids. The exact mass of the protein as determined by mass spectrometry is 21,310 Da. The complete amino acid sequence is shown below.
MAHHHHHHAG GAENLYFQSM TEYKLVVVGA CGVGKSALTI QLIQNHFVDE YDPTIEDSYR KQVVIDGETC LLDILDTAGQ EEYSAMRDQY MRTGEGFLCV FAINNTKSFE DIHHYREQIK RVKDSEDVPM VLVGNKCDLP SRTVDTKQAQ DLARSYGIPF IETSAKTRQG VDDAFYTLVR EIRKHKEK (SEQ ID NO: 1)

In another screen, the assay can be performed using the KRAS 4b G12C protein, which has 170 amino acids, a mass of 19,336 Da and the following amino acid sequence:
SMTEYKLVVVGA CGVGKSALTI QLIQNHFVDE YDPTIEDSYR KQVVIDGETC LLDILDTAGQ EEYSAMRDQY MRTGEGFLCV FAINNTKSFE DIHHYREQIK RVKDSEDVPM VLVGNKCDLP SRTVDTKQAQ DLARSYGIPF IETSAKTRQG VDDAFYTLVR EIRKHKEK (SEQ ID NO: 2)

Recombinant protein is expressed in E. coli BL21 cells and purified using affinity chromatography over a Ni-NTA column. Protein stocks are nucleotide exchanged to >95% GDP, concentrated to 4 mg/mL, and stored at -80°C in storage buffer (50 mM HEPES pH 7.4, 50 mM NaCl, 5 mM MgCl2, 1 mM DTT). Pure KRAS 4B G12C protein is diluted to a concentration of 5 μM in Tris-buffered saline (pH 7.4). Compounds are dissolved in DMSO and added to the diluted protein to a concentration of 10 μM. The total DMSO concentration in the reaction is 4%. The reaction is mixed by pipette and incubated for 1 hour at 22°C. Aliquots of the reaction are taken over time and diluted 2:1 with 0.1% formic acid. Intact mass of protein samples is measured by LC-MS using a QExactive+ mass spectrometer (Thermo Scientific). 500 ng of total protein is injected onto a C8 reversed-phase column and eluted with a 7 min gradient of 30%-90% acetonitrile/0.1% formic acid, and the intact mass is analyzed by mass spectrometry. Identified adducts were confirmed to be within 1 Dalton of the expected mass, and the relative ratio of free:adducted protein was used to quantify the percentage of protein bound by compound. CAF reactions were performed in duplicate, with typical variation of ±5%.

Examples E1-E4 were evaluated in the CAF assay described above for 60 minutes.

Inhibition of KRAS G12C-mediated phospho-ERK1/2 inhibition by exemplary compounds of formula (I)

This example illustrates that exemplary compounds of the present disclosure inhibit KRAS G12C as measured by downstream inhibition of ERK phosphorylation.

KRAS G12C mutant cell lines, NCI H358 (ATCC, CRL-5807) and Ras Initiative (RI) KRAS G12C, were cultured according to published protocols and maintained at 5% CO ₂ at 37° C. Phospho-ERK HTRF assays were performed according to the provider's protocol (CisBio #64AERPEH). NCI-H358 or RI KRAS G12C cells were seeded at a density of 50,000 cells per well in respective media (RPMI+10% FBS+1% Pen/Strep for NCI-H358 and DMEM+10% FBS+1% Pen/Strep+4ug/ml Blasticidin for RI KRAS G12C) in 96-well plates (Corning #3903) and maintained at 37°C with 5% _CO2 . Cells were allowed to adhere overnight and treated the next day using an 11-point dose response starting with 2,500 nM of exemplary compound followed by serial 1:3 dilutions for 4 or 16 hours using a Tecan D300e digital dispenser (Tecan Group Ltd., Switzerland). After compound treatment, cells were washed once with ice-cold PBS. Cells were lysed by adding 50 μl of lysis buffer (1×) supplemented with 1× Pierce Halt protease and phosphatase inhibitors and incubated at 4° C. for 30 minutes with shaking. After lysis, 16 μL of cell lysate was transferred from the 96-well cell culture plate to a 384-well plate (Perkin Elmer #6007290). A premixed antibody solution was prepared by mixing (volume/volume) Advanced Phospho-ERK1/2 d2 antibody and Advanced Phospho-ERK1/2 Eu Cryptate antibody. The premixed antibody solution (4 μL) was added to the detection plate containing the cell lysate. The detection plate was incubated overnight at 4°C, and the HTRF signal was read the next day using a Spectramax M5 or Spectramax i3 microplate reader (Molecular Devices, San Jose, CA, USA), and the data were processed according to the manufacturer's protocol.

Additional compounds were characterized for inhibition of p-ERK as described below, and the results are summarized in Table 3.

The foregoing embodiments have been described in some detail by way of illustration and example for clarity of understanding, but those skilled in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. In the event of a conflict between this application and a reference provided herein, this application shall control.

Claims (22)

A compound of formula (Ia) or a pharma- ceutically acceptable salt thereof.

(Wherein,
Z is S or O;
m is 1 or 2;
p is 1 or 2;
^L1 is

and
k is an integer from 0 to 4, each R ¹ is independently selected from methyl, cyanomethyl, C ₂ -C ₄ alkyl, cyano, cycloalkyl, halo, haloalkyl, trifluoromethyl, and alkoxy, or any two R ¹ are joined to form a fused ring, said bridge or said spiro ring structure optionally containing a heteroatom selected from S, SO ₂ , O, or N in the bridge or spiro ring, said bridge or spiro ring structure being optionally substituted with oxo;
each R ² is independently selected from the group consisting of alkyl, N-alkylamino, N,N-dialkylamino, alkylamidoalkyl, arylamidoalkyl, -OCH ₂ CONRR', where R and R' are independently selected from hydrogen, alkyl, and cycloalkyl, alkylsulfonamidoalkyl, arylsulfonamidoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halogen, haloalkyl, aryl, aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, and heteroaryloxy, each of which is optionally substituted; or when m is 2, two R ² are joined to form a spirocyclic 3-6 membered ring optionally containing 1-3 heteroatoms selected from N, O, or S;
R ³ , R ⁴ , R ⁵ , and R ⁶ are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino, C-amido (-CONRR'), N-amido (-NHCOR), urea (-NHCONHR), ether (-OR), sulfonamido (-NHSO ₂ R or -SO ₂ NHR), and CF ₃ , where each R and R' is independently hydrogen, alkyl, or cycloalkyl; or any two adjacent R ³ , R ⁴ , R ⁵ , or R ⁶ form an optionally substituted fused 5- or 6-membered ring containing 0-3 heteroatoms selected from N, O, or S;
With the proviso that when one of R ³ , R ⁴ , R ⁵ , or R ⁶ is a bond to the 2-quinazolinone,
^R7 is alkyl, cyano, cycloalkyl, halogen, haloalkyl, trifluoromethyl, and alkoxy. 2. The compound of claim 1 having the formula (IIa) or a pharma- ceutically acceptable salt thereof.

wherein Ar ¹ is a C-linked aryl, heteroaryl, heterocycle, or carbocycle;
n is an integer from 0 to 3, and each R ¹⁰ is independently selected from alkyl, amino, cyanohalogen, trifluoromethyl, and heterocyclyl, or two R ¹⁰ are joined to form a bicyclic fused heterocycle. 2. The compound of claim 1 having the formula (IIb) or a pharma- ceutically acceptable salt thereof.

wherein ^Ar2 is an N-linked heteroaryl or heterocycle;
n is an integer from 0 to 3, and each R ¹⁰ is independently selected from alkyl, amino, cyanohalogen, trifluoromethyl, heterocyclyl, or two R ¹⁰ are joined to form a bicyclic fused heterocycle. 2. The compound of claim 1 having the formula (IIc) or a pharma- ceutically acceptable salt thereof.

wherein ^Ar3 is aryl or heteroaryl;
n is an integer from 0 to 3, and each R ¹⁰ is independently selected from alkyl, amino, cyanohalogen, trifluoromethyl, heterocyclyl, or two R ¹⁰ are joined to form a bicyclic fused heterocycle. The compound according to claims 2 to 4, wherein n is 1. The compound according to claims 2 to 4, wherein n is 2. The compound according to claims 2 to 4, wherein n is 3. The compound according to any one of claims 1 to 7, wherein p is 1. The compound according to any one of claims 1 to 7, wherein p is 2. ^L1 is

is selected from

The compound according to any one of claims 1 to 9, wherein ^L1 is bonded via either of the two nitrogen atoms of L1. ^R2 is methoxy, amino, _MeOCH2- , _EtOCH2- , MeO( _CH2 ) _2NH- ,

The compound according to any one of claims 1 to 10, wherein R is selected from C-linked aryl or heteroaryl, N-linked heteroaryl or heterocyclyl, and R and R' are independently selected from hydrogen, alkyl, and cycloalkyl. R ³ , R ⁴ , R ⁵ and R ⁶ are

defines a fused thiophene selected from
12. The compound of any one of claims 1 to 11, wherein each of W, X, Y, and Z is independently selected from C=O, NH, O, S, CH, C-Q, where Q is amino, halogen, methyl, -O-alkyl, -O-cycloalkyl, or trifluoromethyl. R ³ , R ⁴ , R ⁵ and R ⁶ are

X is hydrogen, chloro, methyl, or CF ₃ ,

The compound according to any one of claims 1 to 11, The compound or a pharma- ceutically acceptable salt thereof is

2. The compound of claim 1, A pharmaceutical composition comprising a pharma- ceutical effective amount of a compound according to any one of claims 1 to 14 or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable excipient. The pharmaceutical composition of claim 15, further comprising an additional therapeutic agent. A method of treating a subject having cancer, the cancer being characterized by the presence of a KRAS G12C mutation, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharma- ceutical composition thereof. The above cancers are cardiac cancer (sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, teratoma), lung cancer (bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma), gastrointestinal cancer (esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, nerve line fibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma)), genitourinary tract cancer (kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testis (spermoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma)), liver cancer (hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma), bile duct cancer (gallbladder cancer, ampullary carcinoma, cholangiocarcinoma), bone cancer (osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumor), nervous system cancer (skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma)), gynecological cancer (uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theatrical cell tumor, Sertoli-Leydig cell 18. The method according to claim 17, wherein the cancer is a tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma)), blood cancer (blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma)), skin cancer (malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, melanocortisone nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis), or adrenal gland cancer (neuroblastoma). The method of claim 17, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, or pancreatic cancer. Use of a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the treatment of cancer in a subject, wherein the cancer is characterized by the presence of a KRAS G12C mutation. The above cancers are cardiac cancer (sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, teratoma), lung cancer (bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma), gastrointestinal cancer (esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, nerve line fibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma)), genitourinary tract cancer (kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testis (spermoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma)), liver cancer (hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma), bile duct cancer (gallbladder cancer, ampullary carcinoma, cholangiocarcinoma), bone cancer (osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumor), nervous system cancer (skull (osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma)), gynecological cancer (uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theatrical cell tumor, Sertoli-Leydig cell 21. The use according to claim 20, which is a cancer of the skin (tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma)), blood cancer (blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma)), skin cancer (malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, melanocortisone nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis), or adrenal gland cancer (neuroblastoma). The method of claim 20, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, or pancreatic cancer.