Heterocyclic compounds for use in the treatment of cancer - Patents.com

Abstract

The present invention relates to heterocyclic derivatives and their use in the treatment and prevention of cancer, as well as compositions containing said derivatives and processes for their preparation.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to heterocyclic derivatives and their use in the treatment and prevention of cancer, as well as compositions containing said derivatives and processes for their preparation. [Background technology]

[0002] BACKGROUND OF THEINVENTION Robust repair of DNA double-strand breaks (DSBs) is essential for maintaining genomic stability and cell survival. DSBs can be repaired by one of three major pathways: homologous recombination (HR), non-homologous end joining (NHEJ), and alternative NHEJ (alt-NHEJ). Microhomology-mediated end joining (MMEJ) is the best characterized alt-NHEJ mechanism. HR-mediated repair is a high-fidelity mechanism essential for accurate and error-free repair, preventing genomic stability that predisposes to cancer. Conversely, NHEJ and MMEJ are error-prone pathways that can leave mutational scars at the site of repair. MMEJ can function in parallel with both HR and NHEJ pathways (Truong et al., PNAS 2013, 110(19), 7720-7725).

[0003] Unlike normal cells, the survival of cancer cells often depends on misregulation of DNA damage response (DDR) pathways; for example, increased dependency on one pathway (often mutagenic) to cope with either inactivation of another pathway or enhanced replication stress resulting from increased proliferation. Aberrant DDR can also sensitize cancer cells to specific types of DNA damage, and thus defective DDR can be exploited to develop targeted cancer therapies. Crucially, cancer cells with impaired or inactivated HR or NHEJ become highly dependent on MMEJ-mediated DNA repair. Genetic, cell biological, and biochemical data have identified Polθ (UniProtKB-O75417(DPOLQ_HUMAN) as a key protein in MMEJ (Kent et al., Nature Structural & Molecular Biology ((2015), 22(3), 230-237; Mateos-Gomez et al., Nature (2015), 518(7538), 254-257). Polθ is a multifunctional enzyme that contains an N-terminal helicase domain (SF2 HEL308 type) and a C-terminal low-fidelity DNA polymerase domain (A type) (Wood and Doublie, DNA Repair (2016), 44, 22-32). Both domains have been shown to have coordinated mechanistic functions in MMEJ: the helicase domain mediates removal of RPA proteins from the ssDNA ends and stimulates annealing; the polymerase domain extends the ssDNA ends and fills in the remaining gap.

[0004] Thus, therapeutic inactivation of Polθ would abolish the ability of cells to perform MMEJ and provide a novel targeting strategy in many defined tumor contexts. First, Polθ has been shown to be essential for the survival of HR-defective (HRD) cells (e.g., synthetic lethality due to FA / BRCA deficiency) and is upregulated in HRD tumor cell lines (Ceccaldi et al., Nature (2015), 518(7538), 258-262). In vivo studies have also shown that Polθ is significantly overexpressed in a subset of HRD ovarian, uterine, and breast cancers with associated poor prognosis (Higgins et al., Oncotarget (2010), 1, 175-184; Lemee et al., PNAS (2010), 107(30), 13390-13395; Ceccaldi et al., (2015), see above). Importantly, Polθ has been shown to be largely repressed in normal tissues but upregulated in matched cancer samples, thus correlating elevated expression with disease (Kawamura et al., International Journal of Cancer (2004), 109(1), 9-16). Second, its suppression or inhibition confers radiosensitivity in tumor cells. Finally, Polθ inhibition could possibly prevent MMEJ-dependent reversion of function of BRCA2 mutations that underlie the emergence of cisplatin and PARPi resistance in tumors.

[0005] Therefore, there is a need to provide effective Pol θ inhibitors for the treatment of cancer. Summary of the Invention

[0006] (Summary of the invention) According to a first aspect of the present invention, a compound of formula (I): [ka] (In the formula: n represents an integer selected from 0, 1, 2, 3, or 4; R 1 is C1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, hydroxy, halogen, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, C 3-8 Cycloalkyl, cyano, or -NR x R y represents; R 2 is hydrogen, C optionally substituted with one or more amino and / or hydroxy groups; 1-6 Alkyl, C 2-6 Alkenyl, one or more -NR x R y C optionally substituted with a group 1-6 Alkoxy, one or more -NR x R y C optionally substituted with a group 1-6 Alkanols, optionally substituted with one or more hydroxy groups 1-6 Alkyl-NR x R y , -X-aryl, -X-heterocyclyl, or -X-heteroaryl, where the aryl, heterocyclyl, or heteroaryl group is selected from one or more of halogen, hydroxy, oxo, cyano, -NR x R y , C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkanol, C 1-6 Alkoxy, C 1-6 Alkyl-NR x R y , -CO-C 1-6 Alkyl, -CO-C 1-6 Alkanol, -CO-C 1-6 Alkyl-NR x R y , -CONR x R y , -SO2-C 1-6 Alkyl or C 1-6 optionally substituted heterocyclyl groups which are optionally substituted by alkyl groups; X represents a bond or -C(=O)- or one or more of O, OH, C3-8 represents a linker selected from a C1-C4 alkylene group optionally substituted with a cycloalkyl or CO group; R 3 is hydrogen or C 1-6 represents alkyl; R 4 , R 5 , R 6 , and R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, halogen, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, C 3-8 Cycloalkyl, cyano, or -NR x R y represents; and R x and R y are independently hydrogen or C 1-6 (representing alkyl) or a tautomeric or stereochemically isomeric form, a pharma- ceutically acceptable salt, or solvate thereof is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] Detailed Description of the Invention (definition) The term "halo" or "halogen" as used herein refers to fluorine, chlorine, bromine, or iodine.

[0008] The term "cyano" as used herein refers to a group in which a carbon atom is triple bonded to a nitrogen atom.

[0009] As used herein, "C" as a group or part of a group 1-6 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, and the like.

[0010] As used herein, "C" as a group or part of a group 2-6 The term "alkenyl" refers to a straight or branched chain unsaturated hydrocarbon group containing from 2 to 6 carbon atoms and at least one double bond. Examples of such groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

[0011] As used herein, "C" as a group or part of a group 1-6 The term "alkoxy" refers to C alkyl groups containing an oxygen atom. 1-6 The alkyl group is C 1-6 The C alkyl is as defined herein. 1-6 It refers to alkyl. Examples of such groups include methoxy, ethoxy, or propoxy.

[0012] As used herein, "C" as a group or part of a group 1-6 The term "alkanol" refers to C 1-6 The alkyl group is C 1-6 The C alkyl is as defined herein. 1-6 It means an alkyl group.

[0013] As used herein, the term "C1-C4 alkylene" as a group or part of a group means (CH2) 1-4 "alkyl" refers to a group. Examples of such groups include methylene, ethylene, propylene, and butylene.

[0014] As used herein, “haloC” as a group or part of a group 1-6 The term "alkyl" is as defined herein. 1-6 The C alkyl group, in which one or more hydrogen atoms are replaced with halogen. 1-6 It refers to an alkyl group. 1-6 The term "alkyl" refers to monohaloC 1-6 Alkyl and polyhalo C 1-6 There may be one, two, three or more hydrogen atoms replaced with halogen, thus including the haloC1-6 Alkyl can have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, trifluoromethyl, or trifluoroethyl, and the like.

[0015] As used herein, “haloC” as a group or part of a group 1-6 The term "alkoxy" is as defined herein. 1-6 The C is an alkoxy group in which one or more hydrogen atoms are replaced with halogen. 1-6 It means an alkoxy group.

[0016] As used herein, "C 3-8 The term "cycloalkyl" refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0017] The term "oxo" as used herein refers to the group ═O.

[0018] As used herein, the term "hydroxy" refers to the group --OH.

[0019] The term "aryl" as used herein refers to carbocyclyl aromatic groups such as phenyl, naphthyl, indanyl, indenyl, and tetrahydronaphthyl groups. The term "aryl" encompasses polycyclic (e.g., bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. An example of a polycyclic (e.g., bicyclic) aryl group containing an aromatic ring and a non-aromatic ring is the indanyl group. In such polycyclic systems, the group may be bonded at the aromatic ring or the non-aromatic ring. Non-aromatic carbocyclic groups include cycloalkyl groups as defined herein.

[0020] The term "heteroaryl" as used herein refers to, for example, a monocyclic or bicyclic aromatic ring system containing 3 to 12 ring members. Each ring may contain up to 5 heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Particular examples of monocyclic heteroaryls include imidazolyl, pyrazolyl, triazolyl, and pyridinyl. Particular examples of bicyclic heteroaryls include monocyclic carbocyclic, heterocyclic, and monocyclic aromatic heterocycles optionally fused to aromatic heterocycles, such as tetrahydroimidazo[1,2-a]pyrazin-2-yl, tetrahydroisoquinolin-6-yl, isoindolin-5-yl, pyrrolo[2,3-b]pyridin-6-yl, and benzo[d]imidazol-6-yl.

[0021] The term "heterocyclyl" as used herein refers to a mono- or bicyclic non-aromatic, partially saturated, or fully saturated ring system containing, for example, 3 to 12 ring members. Each ring may contain up to five heteroatoms typically selected from nitrogen, sulfur, and oxygen.

[0022] Specific examples of "heterocyclyl" include oxetane, morpholine, thiomorpholine, piperidine (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidinone, pyrrolidine (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl), pyrrolidone, azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g., tetrahydropyran-4-yl), imidazoline, imidazolidinone, oxazoline, thiazoline, pyrazolin-2-yl, pyrazolidine, piperazinone, pipera, hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl, hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl, octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl, tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl, tetrahydroimidazo[1,2-a]pyrazin-2-yl, tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl, tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl, and tetrahydropyrazolo[1,5-a]pyrazin-2-yl.

[0023] It will be appreciated that the term "heterocyclyl" includes reference to spiro and bridged heterocyclic derivatives. Examples of such spiro and bridged heterocyclic derivatives include: hexahydropyrrolo[2,3-c]pyrrolidinyl, diazaspiro[3.3]heptanyl, diazaspiro[3.4]octanyl, diazaspiro[4.4]nonyl, oxa-azaspiro[3.4]octanyl, oxa-azaspiro[4.4]nonyl, tetrahydrofuro[3,4-c]pyrrolidinyl, oxa-azaspiro[ 3.3]heptyl, diazaspiro[3.5]nonanyl, diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl, diazaspiro[3.4]octanyl, diazaspiro[3.5]nonanyl, octahydro-naphthyridinyl, tetrahydropyrazino-oxazinyl, oxadiazaspiro[3.4]octanyl, oxadiazaspiro[3.5]nonanyl, oxadiazaspiro[3.4]octanyl oxa-2,8-diazaspiro[3.5]nonanyl, oxadiazospiro[5.5]undecanyl, triazaspiro[3.5]nonanyl, diazabicyclo[2.2.1]heptan-2-yl, diazaspiro[3.4]octan-6-yl, oxabicyclo[2.2.1]heptanyl, oxa-2,8-diazaspiro[3.5]nonan-8-yl, diazabicyclo[3.2.1]octan-3-yl, oxa -3,7-diazabicyclo[3.3.1]nonan-3-yl, tetrahydro-1′H-spiro[azetidine-3,4′-pyrrolo[1,2-a]pyrazine]-2′(3′H)-yl, tetrahydro-1′H-spiro[azetidine-3,6′-pyrazino[2,1-c][1,4]oxazine]-8′(7′H)-yl, and triazaspiro[3.5]nonan-8-yl.

[0024] The term "optionally substituted," as used herein, refers to a group which may or may not be substituted with substituents as defined herein.

[0025] (Implementation) In one embodiment, n represents 0, 1, 2 or 3. In a further embodiment, n represents 1.

[0026] In one embodiment, R1 is C 1-6 represents alkyl (e.g. methyl) or halogen (e.g. fluorine or chlorine). 1 is C 1-6 It represents alkyl (eg, methyl).

[0027] In a further embodiment, n represents 1. In yet a further embodiment, n represents 1 and R 1 is C 1-6 In yet a further embodiment, n represents 1 and R 1 is C 1-6 It represents alkyl (eg, methyl).

[0028] In another embodiment, n represents 2. In yet a further embodiment, n represents 2 and R 1 represents halogen (e.g., fluorine or chlorine). In still yet further embodiments, n represents 2 and one R 1 The group represents fluorine and the other represents chlorine.

[0029] In another embodiment, n represents 3. In yet a further embodiment, n represents 3 and R 1 In still yet further embodiments, n represents 3 and two R 1 The group represents fluorine and one R 1 The group represents chlorine.

[0030] In one embodiment, R 2 teeth: hydrogen; C optionally substituted with one or more amino and / or hydroxy groups 1-6 alkyl (e.g., -CH2-CH2-N(Et)2, -CH2-CH2-CH2-N(Me)2, -CH2-CH2-NH-CH2-CH2-NH-Me, or -CH2-CH2-N(Me)-CH2-CH2-OH); C2-6 Alkenyl (e.g., -CH2=CH2); One or more -NR x R y C optionally substituted with a group 1-6 Alkoxy (e.g., -CH2-CH2-O-CH2-CH2-N(Me)2); One or more -NR x R y C optionally substituted with a group 1-6 Alkanols (e.g., -CH2-CH2-OH, -CH2-CH2-CH2-OH, -CH2-CH(Me)-OH, -CH2-CH(OH)-Me, or -CH2-CH(OH)-CH2-N(Me)2); -X-aryl (e.g., -phenyl, -CH2-phenyl, or -cyclobutyl-OCH2-phenyl); -X-heterocyclyl (e.g., -CH-pyrrolidinyl, -CH-piperidinyl, -CH-morpholinyl, -CO-piperazinyl, -CH-CH-pyrrolidinyl, -CH-CH-piperidinyl, -CH-CH-piperazinyl, -CH-CH-morpholinyl, -CH-CH-thiomorpholinyl, -CH-CH-1-oxa-6-azaspiro[3.3]heptan-6-yl, -CH-CH-2 ... [3.3]heptan-6-yl, -CH2-CH2-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl, -CH2-CH2-2,5-diazabicyclo[2.2.1]heptan-2-yl, -CH2-CH2-3,8-diazabicyclo[3.2.1]octan-3-yl, -CH2-CH2-CH2-piperazinyl, -CH2-CH2-CH2-morpholinyl, or -CH2-CH(OH)-CH2-morpholinyl); and -X-heteroaryl (e.g., -pyridinyl, -pyrrolo[2,3-b]pyridin-6-yl, benzo[d]imidazol-6-yl, -CH2-pyridinyl, -CH2-tetrahydropyrazolo[1,5-a]pyrazin-2-yl, -CH2-tetrahydroimidazo[1,2-a]pyrazin-2-yl, -CH2-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl, -CH2-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl, -CH2-tetrahydroisoquinolin-6-yl, or -CH2-isoindolin-5-yl) represents; wherein the aryl, heterocyclyl, or heteroaryl group may include one or more halogen (e.g., fluorine), hydroxy, oxo, cyano, -NR x R y (e.g., (-N(Me)2), C 1-6 Alkyl (e.g., methyl), haloC 1-6 Alkyl (e.g., -CH2-CH2-F), -CO-C 1-6 Alkyl (e.g., -CO-methyl), -CO-C 1-6 Alkanols (e.g., -CO-CH(OH)-Me), C 1-6 Alkanols (e.g., -CHOH or -CH-CH-OH), C 1-6 Alkoxy (e.g., -OMe or -CH2-CH2-OMe), -CONR x R y (e.g., -CON(Me)2), -SO2-C 1-6 Alkyl (e.g., -SOMe), or C 1-6 heterocyclyl (e.g., oxetanyl, azetidinyl, pyrrolidinyl) groups optionally substituted with alkyl (e.g., methyl) groups; In one embodiment, R 2 represents hydrogen.

[0031] In another embodiment, R 2 is optionally substituted with one or more amino and / or hydroxy groups; 1-6It represents alkyl (for example, -CH2-CH2-N(Et)2, -CH2-CH2-CH2-N(Me)2, -CH2-CH2-NH-CH2-CH2-NH-Me, or -CH2-CH2-N(Me)-CH2-CH2-OH).

[0032] In another embodiment, R 2 is C 2-6 It represents alkenyl (for example, -CH2=CH2).

[0033] In another embodiment, R 2 is one or more -NR x R y C optionally substituted with a group 1-6 It represents alkoxy (e.g., -CH2-CH2-O-CH2-CH2-N(Me)2).

[0034] In another embodiment, R 2 is one or more -NR x R y C optionally substituted with a group 1-6 It represents an alkanol (e.g., -CH2-CH2-OH, -CH2-CH2-CH2-OH, -CH2-CH(Me)-OH, -CH2-CH(OH)-Me, or -CH2-CH(OH)-CH2-N(Me)2).

[0035] In another embodiment, R 2 is one or more halogen (e.g., fluorine), hydroxy, oxo, cyano, -NR x R y (e.g., (-N(Me)2), C 1-6 Alkyl (e.g., methyl), haloC 1-6 Alkyl (e.g., -CH2-CH2-F), -CO-C 1-6 Alkyl (e.g., -CO-methyl), -CO-C 1-6 Alkanols (e.g., -CO-CH(OH)-Me), C 1-6 Alkanols (e.g., -CHOH or -CH-CH-OH), C 1-6 Alkoxy (e.g., -OMe or -CH2-CH2-OMe), -CONR x Ry (e.g., -CON(Me)2), -SO2-C 1-6 Alkyl (e.g., -SOMe), or C 1-6 It represents -X-aryl (eg, -phenyl, -CH2-phenyl, or -cyclobutyl-OCH2-phenyl) optionally substituted with a heterocyclyl (eg, oxetanyl, azetidinyl, pyrrolidinyl) group which is optionally substituted with an alkyl (eg, methyl) group.

[0036] In another embodiment, R 2 is one or more halogen (e.g., fluorine), hydroxy, oxo, cyano, -NR x R y (e.g., (-N(Me)2), C 1-6 Alkyl (e.g., methyl), haloC 1-6 Alkyl (e.g., -CH2-CH2-F), -CO-C 1-6 Alkyl (e.g., -CO-methyl), -CO-C 1-6 Alkanols (e.g., -CO-CH(OH)-Me), C 1-6 Alkanols (e.g., -CHOH or -CH-CH-OH), C 1-6 Alkoxy (e.g., -OMe or -CH2-CH2-OMe), -CONR x R y (e.g., -CON(Me)2), -SO2-C 1-6 Alkyl (e.g., -SOMe), or C 1-6-X-heterocyclyl (e.g., -CH-pyrrolidinyl, -CH-piperidinyl, -CH-morpholinyl, -CO-piperazinyl, -CH-CH-pyrrolidinyl, -CH-CH-piperidinyl, -CH-CH-piperazinyl, -CH-CH-morpholinyl, -CH-CH-thiomorpholinyl, -CH-CH-1-oxa-6-azaspiro[3 -CH-CH-2-oxa-6-azaspiro[3.3]heptan-6-yl, -CH-CH-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl, -CH-CH-2,5-diazabicyclo[2.2.1]heptan-2-yl, -CH-CH-3,8-diazabicyclo[3.2.1]octan-3-yl, -CH-CH-CH-piperazinyl, -CH-CH-CH-morpholinyl, or -CH-CH(OH)-CH-morpholinyl.

[0037] In another embodiment, R 2 is one or more halogen (e.g., fluorine), hydroxy, oxo, cyano, -NR x R y (e.g., (-N(Me)2), C 1-6 Alkyl (e.g., methyl), haloC 1-6 Alkyl (e.g., -CH2-CH2-F), -CO-C 1-6 Alkyl (e.g., -CO-methyl), -CO-C 1-6 Alkanols (e.g., -CO-CH(OH)-Me), C 1-6 Alkanols (e.g., -CHOH or -CH-CH-OH), C 1-6 Alkoxy (e.g., -OMe or -CH2-CH2-OMe), -CONR x R y (e.g., -CON(Me)2), -SO2-C 1-6 Alkyl (e.g., -SOMe), or C 1-6represents -X-heteroaryl (e.g., -pyridinyl, -pyrrolo[2,3-b]pyridin-6-yl, benzo[d]imidazol-6-yl, -CH-pyridinyl, -CH-tetrahydropyrazolo[1,5-a]pyrazin-2-yl, -CH-tetrahydroimidazo[1,2-a]pyrazin-2-yl, -CH-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl, -CH-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl, -CH-tetrahydroisoquinolin-6-yl, or -CH-isoindolin-5-yl), optionally substituted with a heterocyclyl (e.g., oxetanyl, azetidinyl, pyrrolidinyl) group, which is optionally substituted with an alkyl (e.g., methyl) group.

[0038] In a further embodiment, R 2 teeth: -X-heterocyclyl (e.g., -CH-pyrrolidinyl, -CH-piperidinyl, -CH-morpholinyl, -CO-piperazinyl, -CH-CH-pyrrolidinyl, -CH-CH-piperidinyl, -CH-CH-piperazinyl, -CH-CH-morpholinyl, -CH-CH-thiomorpholinyl, -CH-CH-1-oxa-6-azaspiro[3.3]heptan-6-yl, -CH-CH-2 ... pyrro[3.3]heptan-6-yl, -CH2-CH2-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl, -CH2-CH2-2,5-diazabicyclo[2.2.1]heptan-2-yl, -CH2-CH2-3,8-diazabicyclo[3.2.1]octan-3-yl, -CH2-CH2-CH2-piperazinyl, -CH2-CH2-CH2-morpholinyl, or -CH2-CH(OH)-CH2-morpholinyl) represents; wherein the heterocyclyl group can include one or more halogen (e.g., fluorine), hydroxy, oxo, cyano, -NR x R y (e.g., (-N(Me)2), C 1-6 Alkyl (e.g., methyl), haloC 1-6Alkyl (e.g., -CH2-CH2-F), -CO-C 1-6 Alkyl (e.g., -CO-methyl), -CO-C 1-6 Alkanols (e.g., -CO-CH(OH)-Me), C 1-6 Alkanols (e.g., -CHOH or -CH-CH-OH), C 1-6 Alkoxy (e.g., -OMe or -CH2-CH2-OMe), -CONR x R y (e.g., -CON(Me)2), -SO2-C 1-6 Alkyl (e.g., -SOMe), or C 1-6 It may be optionally substituted with a heterocyclyl (eg, oxetanyl, azetidinyl, pyrrolidinyl) group which is optionally substituted with an alkyl (eg, methyl) group.

[0039] In still further embodiments, R 2 represents -CH-CH-piperazinyl, where the piperazinyl group is selected from one or more C 1-6 It may be optionally substituted with alkyl (eg, methyl) groups.

[0040] In one embodiment, R 3 is hydrogen or C 1-6 In a further embodiment, R 3 is C 1-6 It represents alkyl (eg, methyl).

[0041] In one embodiment, X represents a bond or is -C(=O)- or one or more of O, OH, C 3-8 represents a linker selected from a cycloalkyl, or a C1-C3 alkylene group optionally substituted with a CO group (e.g., -CH2-, -cyclobutyl-OCH2-, -CH2-CH2-, -CH2-CH2-CH2-, or -CH2-CH(OH)-CH2-).

[0042] In one embodiment, R x and R y are independently hydrogen and C1-6 In a further embodiment, R x and R y Both are C 1-6 It represents alkyl (eg methyl or ethyl).

[0043] In one embodiment, R 4 teeth: hydrogen; C 1-6 alkyl (e.g., methyl or ethyl); C 2-6 Alkenyl (e.g., ethenyl); 1-6 Alkoxy (e.g., methoxy); Halogens (e.g., chlorine); or -NR x R y (e.g., -N(Me)2 or -N(Me)(Et)) Represents.

[0044] In a further embodiment, R 4 is C 1-6 It represents alkyl (eg, methyl).

[0045] In one embodiment, R 5 teeth: hydrogen; Halogens (e.g., chlorine); or C 1-6 Alkyl (e.g., methyl) Represents.

[0046] In one embodiment, R 5 represents hydrogen.

[0047] In one embodiment, R 6 teeth: C 1-6 Alkyl (e.g., methyl, ethyl, or isopropyl); C 2-6 Alkenyl (e.g., -C(=CH2)(Me)); halogens (e.g. bromine); HaroC 1-6alkyl (e.g., trifluoromethyl or -C(H)(Me)-CF3); or HaroC 1-6 Alkoxy (e.g., difluoromethoxy) Represents.

[0048] In a further embodiment, R 6 is HaroC 1-6 It represents alkyl (eg, trifluoromethyl).

[0049] In one embodiment, R 7 teeth: Hydrogen; or Cyano Represents.

[0050] In a further embodiment, R 7 represents hydrogen.

[0051] In one embodiment, the compound of formula (I) is a : [ka] (where n, R 1 , R 2 , and R 3 are as defined herein) or a tautomer or stereochemically isomeric form, a pharma- ceutically acceptable salt, or solvate thereof.

[0052] In one embodiment, the present invention provides a compound of formula (I) which is the free base of any of the compounds of Examples 1-149, or a pharma- ceutically acceptable salt or solvate thereof.

[0053] In one embodiment, the compound of formula (I) is a compound other than the compound of Example 12.

[0054] Reference to compounds of formula (I) and subgroups thereof also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, for example as described below; preferably including salts or tautomers or isomers or N-oxides or solvates thereof; more preferably including salts or tautomers or N-oxides or solvates thereof, even more preferably including salts or tautomers or solvates thereof. Hereinafter, compounds as defined in any aspect of the invention (except intermediate compounds in chemical processes), as well as ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, are referred to as "compounds of the invention".

[0055] (salt) Certain compounds of formula (I) can exist in the form of salts, for example acid addition salts and in some cases salts of organic and inorganic bases such as carboxylates, sulfonates, phosphates, etc. All such salts are within the scope of the present invention, and references to compounds of formula (I) include the salt forms of the compounds.

[0056] The salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods such as those described in "Pharmaceutical Salts: Properties, Selection, and Use", P. Heinrich Stahl (ed.), Camille G. Wermuth (ed.), ISBN: 3-90639-026-8, Hardcover, page 388, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of both; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

[0057] Acid addition salts (monosalts or disalts) can be formed with a variety of acids, both inorganic and organic. Examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+) camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric ... Curamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrohalic acids (e.g., hydrobromic acid, hydrochloric acid, acid, hydroiodic acid), isethionic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, Examples of suitable salts include mono- or di-salts formed with acids selected from the group consisting of acetic acid, pamoic acid, phosphoric acid, propionic acid, pyruvic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid, as well as acylated amino acids, and cation exchange resins.

[0058] One particular group of salts consists of salts formed from acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propanoic acid, butanoic acid, malonic acid, glucuronic acid, and lactobionic acid. One particular salt is the hydrochloride salt.

[0059] When a compound of formula (I) has an amine functionality, it may form a quaternary ammonium salt, for example, by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of formula (I).

[0060] The compounds of the present invention have a pK a Depending on the compound, it may exist as a mono- or di-salt.

[0061] It will be appreciated that for use in medicine, the salts of the compounds of formula (I) should be pharma- ceutically acceptable. Suitable pharma- ceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci. 1977, 66, pp. 1-19. Such pharma- ceutically acceptable salts include acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or organic acids, such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid. Other salts, such as oxalates or formates, may be used, for example, in the isolation of the compounds of formula (I), and are included within the scope of the present invention. However, pharma- cetically unacceptable salts may also be prepared as intermediate forms that can be subsequently converted to pharma- cetically acceptable salts. Such non-pharmacologically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

[0062] Some of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0063] (Solvate) Those skilled in the art of organic chemistry will recognize that many organic compounds can form complexes with the solvent in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates." For example, complexes with water are known as "hydrates." Pharmaceutically acceptable solvates of the compounds of the present invention are within the scope of the present invention. In one embodiment, the pharma- ceutically acceptable solvates of the compounds of the present invention include hydrates thereof.

[0064] In one embodiment, the crystalline form of the compound of formula (I) above is a co-crystal or coformer. Such co-crystals or coformers can be prepared with water-soluble molecules such as saccharin, caffeine, nicotinamide, or carboxylic acid. Coformers can be prepared as described in Emami S et al., (2018) BioImpacts 8(4), 305-320, the technique of which is incorporated herein by reference.

[0065] It will be understood that the invention includes pharma- ceutically acceptable derivatives of the compounds of formula (I) and these are included within its scope.

[0066] As used herein, "pharmaceutical acceptable derivative" includes any pharma-ceutically acceptable ester of a compound of formula (I), or a salt of such an ester, which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.

[0067] (N-oxide) Compounds of formula (I) that contain an amine function may also form N-oxides. A reference herein to a compound of formula (I) that contains an amine function also includes said N-oxides.

[0068] If the compound contains several amine functions, one or more of the nitrogen atoms may be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of tertiary amines or the N-oxides of a nitrogen atom of a nitrogen-containing heterocycle.

[0069] N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a percarboxylic acid), see, for example, "Advanced Organic Chemistry," Jerry March, 4th Edition, Wiley Interscience. More specifically, N-oxides can be made by the procedure of LW Deady (Syn. Commun. 1977, 7, 509-514), in which the amine compound is reacted with m-chloroperbenzoic acid (mCPBA) in an inert solvent such as, for example, dichloromethane.

[0070] (Prodrug) Those skilled in the art will recognize that certain protected derivatives of the compounds of formula (I) that may be made before the final deprotection step may not have pharmacological activity themselves, but in some cases may be administered orally or parenterally and then metabolized in the body to form the pharmacologically active compounds of the present invention. Thus, such derivatives may be described as "prodrugs". All such prodrugs of the compounds of the present invention are included within the scope of the present invention. Examples of prodrug functional groups suitable for the compounds of the present invention are described in Drugs of Today, 19, 9, 1983, 499-538 and Topics in Chemistry, Chapter 31, pp. 306-316 and "Design of Prodrugs", H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in these documents are incorporated herein by reference). It will further be recognized by those of skill in the art that, when suitable substituents are present in the compounds of the invention, certain moieties known to those of skill in the art as "pro-moieties," e.g., as described in "Design of Prodrugs" by H. Bundgaard, the disclosure of which is incorporated herein by reference, may be located on such substituents.

[0071] Also included within the scope of the compounds and various salts of the present invention are polymorphs thereof.

[0072] (Enantiomers) When chiral centers are present in the compounds of formula (I), the present invention includes within its scope all possible enantiomers and diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods or any isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. The present invention also extends to any tautomeric forms or mixtures thereof.

[0073] (Isotopes) The present invention also includes all pharma- ceutically acceptable isotopically labeled compounds which are identical to those set forth in formula (I) except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0074] Examples of isotopes suitable for inclusion in the compounds of the present invention include: 2 H(D) and 3 Hydrogen isotopes such as H(T), 11 C. 13 C, and 14 Carbon isotopes such as C, 36 Isotopes of chlorine such as Cl, 18 Fluorine isotopes such as F, 123 I, 125 I, and 131 Iodine isotopes such as I 13 N and 15 Nitrogen isotopes such as N 15 O. 17 O, and 18 Oxygen isotopes such as O 32 Isotopes of phosphorus such as P, 35 Contains isotopes of sulfur such as S.

[0075] Certain isotopically labeled compounds of formula (I), for example those incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. Compounds of formula (I) may also have valuable diagnostic properties in that they may be used to detect or identify the formation of complexes between the labeled compounds and other molecules, peptides, proteins, enzymes, or receptors. Detection or identification methods may employ compounds labeled with labeling agents such as radioisotopes, enzymes, fluorescent substances, luminescent substances (e.g., luminol, luminol derivatives, luciferin, aequorin, and luciferase). The radioisotope tritium, i.e., 3 H(T), and carbon-14, i.e. 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection.

[0076] Deuterium, i.e. 2 Substitution with heavier isotopes, such as H(D), may confer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0077] 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Tissue Distribution (PET) studies for examining target occupancy.

[0078] Isotopically labeled compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples and Preparations below, substituting an appropriate isotopically labeled reagent for the non-labeled reagent previously employed.

[0079] (purity) It will be readily understood that, since the compounds of formula (I) are intended for use in pharmaceutical compositions, each of them is preferably provided in substantially pure form, for example at least 60% pure, more desirably at least 75% pure, preferably at least 85%, especially at least 98% pure (percentages given on a weight to weight basis). Impure preparations of the compounds may be used to prepare the purer forms used in the pharmaceutical compositions.

[0080] (process) According to a further aspect of the present invention, there is provided a process for the preparation of compounds of formula (I) and derivatives thereof. The following schemes are examples of synthetic schemes that can be used to synthesize compounds of the present invention. In the following schemes, reactive groups can be protected and deprotected with protecting groups according to established techniques.

[0081] According to a further aspect of the present invention: (a)R 2represents hydrogen, comprising preparing a compound of formula (I) comprising a compound of formula (II); [ka] (where n, R 1 , R 3 , R 4 , R 5 , R 6 , and R 7 is as previously defined herein, and P 1 represents a suitable protecting group such as Boc) said preparing comprising deprotecting the compound of formula (I); (b) interconversion of a compound of formula (I) or a protected derivative thereof to a further compound of formula (I) or a protected derivative thereof; (c) deprotection of a protected derivative of a compound of formula (I); (e) the optional formation of a pharma- ceutically acceptable salt of a compound of formula (I). There is provided a process for preparing a compound of formula (I) as defined herein comprising:

[0082] Process (a) typically involves a deprotection reaction to prepare a compound of formula (I). For example, P 1 When represents Boc, process (a) typically involves the use of an acid such as TFA.

[0083] Compounds of formula (II) can be prepared according to the procedures described herein. For example, compounds of formula (II) can be prepared according to the experimental procedures described in Example 1.

[0084] A wide range of well-known functional group interconversions for process (b) to convert precursor compounds to compounds of formula (I) are known to those skilled in the art and are described in "Advanced Organic Chemistry", Jerry March, 4th Edition, John Wiley & Sons, 1992. For example, the functionalization possibilities of metal catalysts, such as those using organotin reagents (Stille reaction), Grignard reagents, and reactions with nitrogen nucleophiles, are described in "Palladium Reagents and Catalysts" [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and "Handbook of OrganoPalladium Chemistry for Organic Synthesis" [Vol. 1, Eiichi Negishi, Wiley, ISBN 0-471-31506-0]. It will be appreciated that interconversions form the majority of the experimental procedures detailed herein for preparing compounds of formula (I). For example, R 2 represents hydrogen (i.e., compounds of formula (I) b Compound () [ka] (which may be prepared according to process (a)) can be synthesized by the modification and procedures described herein. 2 represents the remaining radical may be used to prepare any other compound of formula (I).

[0085] Where appropriate, the reactions described herein may be followed or preceded by one or more reactions known to those skilled in the art, carried out in an appropriate order to achieve the necessary substitutions for each of the variables defined herein, to give alternative compounds of formula (I). Non-limiting examples of such reactions, for which conditions are described in the literature, include: Protection of reactive functional groups, Deprotection of reactive functional groups, Halogenation, Dehalogenation, Dealkylation, Alkylation of amines, anilines, alcohols, and phenols; Mitsunobu reaction for hydroxyl groups, Cycloaddition reactions to suitable groups, Reduction of nitro, ester, cyano, and aldehydes, Transition metal catalyzed coupling reactions, Acylation, Sulfonylation / introduction of sulfonyl groups, Saponification / hydrolysis of ester groups, amidation or transesterification of ester groups; Esterification or amidation of carboxyl groups, Halogen exchange, nucleophilic substitution with amines, thiols, or alcohols; Reductive amination, Oxime formation on carbonyl and hydroxylamine groups, S-oxidation, N-oxidation, chloride Examples include:

[0086] It will be appreciated that the order of reactions involving aryl coupling and reduction may be varied. It will also be appreciated that a wide range of palladium-based catalysts are suitable for carrying out the aryl coupling reaction.

[0087] It may also be appreciated that isomer separation may be performed at any suitable stage in the synthetic sequence. It should be emphasized that such chiral separation constitutes an important aspect of the present invention, and that such separation may be performed according to the methods described herein or according to known methods. It is also appreciated that it may be beneficial to temporarily form protected derivatives of intermediates in the synthesis, such as Boc-protected amines or SEM-protected amides, to facilitate chromatographic separation, chiral resolution, or to obtain improved solubility or yield at certain steps.

[0088] In many of the reactions described above, it may be necessary to protect one or more groups to prevent reaction from occurring at undesirable sites on the molecule. Examples of protecting groups and methods for protecting and deprotecting functional groups can be found in "Protective Groups in Organic Synthesis" (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2007).

[0089] Hydroxy groups can be protected, for example, as ethers (-OR) or esters (-OC(=O)R), such as: tert-butyl ethers; tetrahydropyranyl (THP) ethers; benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ethers; trimethylsilyl or tert-butyldimethylsilyl ethers; or acetyl esters (-OC(=O)CH).

[0090] Amine groups can be, for example, as amides (-NRCO-R) or carbamates (-NRCO-OR), such as: methylamide (-NHCO-CH3); benzyl carbamate (-NHCO-OCH2C6H5, -NH-Cbz, or NH-Z); tert-butyl carbamate (-NHCOOC(CH3)3, NH-Boc); 2-biphenyl-2-propyl carbamate (-NHCO-OC(CH3)2C6H4C6H5, NH-Boc ), as 9-fluorenylmethyl carbamate (-NH-Fmoc), as 6-nitroveratryl carbamate (-NH-Nvoc), as 2-trimethylsilylethyl carbamate (-NH-Teoc), as 2,2,2-trichloroethyl carbamate (-NH-Troc), as allyl carbamate (-NH-Alloc), or as 2(-phenylsulfonyl)ethyl carbamate (-NH-Psec).

[0091] Other protecting groups for amines, such as cyclic amines and heterocyclic NH groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups, benzyl groups, such as the para-methoxybenzyl (PMB) group, and the tetrahydropyranyl (THP) group.

[0092] Carboxylic acid groups can be used as esters, e.g. 1-7 Alkyl esters (e.g., methyl esters; tert-butyl esters); C 1-7 Haloalkyl esters (e.g., C 1-7 Trihaloalkyl esters); TriC 1-7 Alkylsilyl-C 1-7 Alkyl ester; or C 5-20 Aryl-C 1-7 It may be protected as an alkyl ester (e.g., benzyl ester; nitrobenzyl ester; para-methoxybenzyl ester).

[0093] It will be appreciated by those skilled in the art that certain compounds of the invention can be converted to other compounds of the invention by standard chemical methods.

[0094] Pharmaceutically acceptable salts may be prepared in a conventional manner by reaction with the appropriate acid or acid derivative.

[0095] (therapeutic utility) The compounds, subgroups and examples of the present invention are inhibitors of Pol θ polymerase activity, which may be useful for preventing or treating disease states or conditions described herein. The compounds and subgroups of the present invention may also be useful for preventing or treating diseases or conditions mediated by Pol θ. Reference to preventing or methods of preventing or treating a disease state or condition, such as cancer, includes within its scope alleviating or reducing the incidence of cancer.

[0096] Thus, for example, it is envisaged that compounds of the invention will be useful in alleviating or reducing the incidence of cancer.

[0097] The compounds of the invention may be useful in the treatment of the adult population.The compounds of the invention may be useful in the treatment of the pediatric population.

[0098] As a result of the compound's inhibition of Polθ, the compound will be useful in providing a means of disabling the ability of cells to perform MMEJ.Therefore, it is expected that the compound will prove useful in treating or preventing proliferation disorders such as cancer.In addition, the compound of the present invention may be useful in treating diseases in which disorders associated with cell accumulation exist.

[0099] Without being bound by theory, it is expected that the Pol θ inhibitors of the present invention will exhibit certain properties that make them particularly useful in the therapeutic treatment of certain cancers.For example, in one embodiment, the Pol θ inhibitors of the present invention are correspondingly lethal in BRCA1 and BRCA2-deficient primary and secondary solid tumors, including breast, ovarian, prostate, and pancreatic.

[0100] In further embodiments, the Polθ inhibitors of the present invention are correspondingly lethal in various primary and secondary solid tumors that are HRD by mechanisms other than BRCA deficiency, such as those involving promoter hypermethylation. In these tumors where DSB repair pathways may not be completely downregulated, Polθi can be administered together with another DDR modulator, such as a PARP inhibitor, a DNA-PK inhibitor, an ATR inhibitor, an ATM inhibitor, a wee1 inhibitor, or a CHK1 inhibitor.

[0101] In further embodiments, the Pol θ inhibitors of the present invention are correspondingly lethal in primary and secondary breast, ovarian, prostate, and pancreatic tumors that have BRCA1 defects but are resistant to PARPi treatment with or without exposure to PARPi drug therapy.

[0102] In further embodiments, the Pol theta inhibitors of the present invention, when given with a PARPi therapeutic program, will correspondingly increase ORR, including CRR, will delay the onset of PARPi resistance, will increase time to recurrence and DFS, and will increase OS in HRD (BRCA1 / 2-deficient and other HRD mechanisms) primary and secondary tumors (breast, ovarian, prostate, and pancreatic).

[0103] In further embodiments, the Pol θ inhibitors of the present invention inhibit ATM activity (ATM), particularly in the context of WT p53. - / - () correspondingly exhibits synthetic sickness and / or synthetic lethality in various tumors. The tumor type would include about 10% of all solid tumors including gastric, lung, breast, and CRC along with CLL. Co-drug treatment with another DDR modifier such as DNA-PK inhibitor, PARP inhibitor, or ATR inhibitor could further enhance such activity. Polθ inhibitor would resensitize CLL to classical chemotherapy and immunochemotherapy where drug resistance has occurred. Thus, according to a further embodiment, the pharmaceutical composition of the present invention further comprises a DNA-PK inhibitor, a PARP inhibitor, or an ATR inhibitor.

[0104] In further embodiments, the Polθ inhibitors of the present invention accordingly exhibit synthetic disease and / or synthetic lethality in various tumors defective in the DNA double strand break repair process of non-homologous end joining (NHEJ-D). The tumor types would comprise about 2-10% of all solid tumors, including prostate, pancreas, cervix, breast, lung, bladder, and esophagus. Co-drug treatment with another DDR modifier, such as a PARP inhibitor, ATM inhibitor, wee1 inhibitor, CHK inhibitor, or ATR inhibitor, may further enhance such activity. Polθ inhibitors would further sensitize NHEJD cancer cells to DNA DSB-inducing chemotherapy and to ionizing radiation-based therapy. Thus, according to further embodiments, the pharmaceutical composition of the present invention further comprises a PARP inhibitor, ATM inhibitor, wee1 inhibitor, CHK inhibitor, or ATR inhibitor.

[0105] In further embodiments, the Pol θ inhibitors of the present invention correspondingly reduce the DNA replication stress response during chemotherapy of HR proficient tumors, such as ovarian, NSCL, and breast tumors, that overexpress Pol θ. This will increase the ORR to treatment and increase OS. Such an effect is particularly likely in the case of cytarabine (Ara-C) and hydroxyurea, which are used in various leukemias, including CML, and in the management of squamous cell carcinoma.

[0106] In further embodiments, the Pol θ inhibitors of the present invention selectively sensitize solid tumors to radiation therapy, including EBRT and brachytherapy, with little or no sensitization of normal tissues. In a fractionated therapeutic setting, this will increase locoregional control leading to increased survival. This will be particularly evident in the management of NSCLC, SCCH&N, rectal cancer, prostate cancer, and pancreatic cancer.

[0107] In further embodiments, the Pol θ inhibitors of the present invention, with or without co-pharmaceutical therapy with PARPi, accordingly exhibit synthetic disease and / or synthetic lethality in PTEN-deficient tumors such as CaP. Moreover, such tumors will be acutely sensitive to radiotherapy due to both PTEN deletion and Pol θ inhibitor-induced radiosensitivity.

[0108] In further embodiments, the Pol θ inhibitors of the present invention correspondingly suppress TLS polymerase activity to sensitize primary and secondary solid tumors (e.g., breast, lung, ovarian, CRC) to drugs (e.g., cisplatin, mitomycin, and cyclophosphamide) and reduce the acquisition of drug-induced mutations implicated in tumor resistance, resulting in prolonged remission and increased TTR.

[0109] In further embodiments, the Pol θ inhibitors of the present invention correspondingly resensitize BCR-ABL positive CML that have developed resistance to imatinib, and other solid tumors with elevated levels of ligase III alpha, decreased levels of ligase IV, and increased dependency on altEJ DSB repair.

[0110] In a further embodiment, the Pol θ inhibitors of the present invention are used to treat aromatase inhibitor-resistant ER - Correspondingly, synthetic disease and / or synthetic lethality in primary and secondary breast cancers is demonstrated, again with elevated levels of ligase IIIα, decreased levels of ligase IV, and increased dependency on altEJ DSB repair.

[0111] According to a further aspect of the invention there is provided a compound of formula (I) as defined herein for use in the treatment of a tumour characterised by a homologous recombination deficiency (HRD).

[0112] It will be appreciated that reference herein to "homologous recombination deficiency (HRD)" refers to any genetic alteration that results in the deficiency or loss of function of a homologous recombination gene. Examples of such genetic alterations include mutations (e.g., point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosomal abnormalities, copy number variations (CNVs), epigenetics, DNA inversions, reduced expression, and mislocalization.

[0113] In one embodiment, the homologous recombination gene is selected from any of ATM, ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), PTEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4, LIG1, RPA1, RPA2, BRIP1, and PTEN.

[0114] It will be appreciated that reference herein to "non-homologous end joining deficiency (NHEJD)" refers to any genetic mutation that results in the deficiency or loss of function of a homologous recombination gene. Examples of such genetic mutations include mutations (e.g., point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosomal abnormalities, copy number variations (CNVs), epigenetics, DNA inversions, reduced expression, and mislocalization.

[0115] In one embodiment, the non-homologous end joining gene is selected from any one or more of: LIG4, NHEJ1, POLL, POLM, PRKDC, XRCC4, XRCC5, XRCC6, and DCLRE1C.

[0116] According to a further aspect of the invention there is provided a compound of formula (I) as defined herein for use in the treatment of tumours overexpressing Pol theta.

[0117] According to a further aspect of the invention there is provided a compound of formula (I) as defined herein for use in the treatment of tumours with elevated levels of ligase IIIα, decreased levels of ligase IV and increased dependency on altEJ DSB repair.

[0118] Examples of cancers (and their benign counterparts) that may be treated (or inhibited) include tumors of epithelial origin (various types of adenomas and carcinomas, including adenocarcinoma, squamous cell carcinoma, transitional cell carcinoma, and other carcinomas), such as tumors of the bladder and urinary tract, breast, gastrointestinal tract (including the esophagus, stomach (gastric), small intestine, colon, rectum, and anus), liver (hepatocellular carcinoma), gallbladder and biliary system, exocrine pancreas, kidney, lung (e.g., adenocarcinoma, small cell lung carcinoma, non-small cell lung carcinoma, bronchoalveolar carcinoma, and mesothelioma), head and neck (e.g., tongue, buccal cavity, larynx, pharynx, nasopharynx, tonsils, salivary glands, nasal cavity, and carcinomas of the ovary, fallopian tubes, peritoneum, vagina, vulva, penis, cervix, myometrium, endometrium, thyroid (e.g., follicular thyroid carcinoma), adrenal gland, prostate, skin, and adnexa (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic nevi); hematologic malignancies and related conditions of the lymphoid system (e.g., acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas, such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt lymphoma, mantle cell lymphoma, M ALT lymphoma, T-cell lymphoma, and leukemia, natural killer [NK] cell lymphoma, Hodgkin's lymphoma, hairy cell leukemia, monoclonal gammopathy of undetermined significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorder), and hematological malignancies and related conditions of the myeloid lineage (e.g., acute myeloid leukemia [AML], chronic myeloid leukemia [CML], chronic myelomonocytic leukemia [CMML], hypereosinophilic syndromes, myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis, myeloproliferative disorders such as myeloproliferative disorders such as myelofibrosis, ... hematological malignancies (i.e., leukemias, lymphomas) and precancerous blood disorders and borderline malignant disorders, including hematologic malignancies (e.g., myeloma, myeloblastic leukemia ...endocrine tumors (e.g., pituitary tumors, adrenal tumors, pancreatic islet cell tumors, parathyroid tumors, carcinoid tumors, and medullary carcinoma of the thyroid); ocular and adnexal tumors (e.g., retinoblastoma); germ cell and trophoblastic tumors (e.g., teratomas, seminomas, dysgerminomas, hydatidiform moles, and choriocarcinomas); and childhood and embryonal tumors (e.g., medulloblastoma, neuroblastoma, Wilms' tumor, and primitive neuroectodermal tumors); or congenital or non-congenital syndromes that predispose a patient to malignancies (e.g., xeroderma pigmentosum);

[0119] Many diseases are characterized by persistent uncontrolled angiogenesis. Chronic proliferative diseases are often accompanied by significant angiogenesis that can contribute to or maintain inflammatory and / or proliferative conditions, or lead to tissue destruction through the infiltrative proliferation of blood vessels. Tumor growth and metastasis are known to be angiogenesis-dependent. Thus, the compounds of the present invention can be useful for preventing and disrupting the initiation of tumor angiogenesis. In particular, the compounds of the present invention can be useful for the treatment of metastasis and metastatic cancer.

[0120] Metastasis or metastatic disease is the spread of disease from one organ or part to another non-adjacent organ or part. Cancers that can be treated by the compounds of the present invention include primary tumors (i.e., cancer cells at the site of origin), local invasion (cancer cells that invade and invade surrounding normal tissues in a localized area), and metastatic (or secondary) tumors, i.e., tumors that arise from malignant cells that have circulated through the bloodstream (hematogenous spread), or through lymphatic vessels, or across body cavities (transcatheterial spread) to other sites and tissues in the body.

[0121] Particular cancers include hepatocellular carcinoma, melanoma, esophageal, renal, colon, colorectal, lung, e.g., mesothelioma or lung adenocarcinoma, breast, bladder, gastrointestinal tract, ovarian, and prostate cancer.

[0122] A further aspect provides the use of a compound for the production of a medicament for the treatment of a disease or condition described herein, in particular cancer.

[0123] The compounds may also be useful in the treatment of tumor growth, pathogenesis, resistance to chemo- and radiotherapy by sensitizing cells to chemotherapy, and as metastasis inhibitors.

[0124] The potency of the compounds of the invention as inhibitors of Pol θ can be measured using the biological and biophysical assays described in the Examples herein, and the level of affinity exhibited by a given compound can be measured using the IC 50 Certain compounds of the invention have an IC value of less than 1 μM, more particularly less than 0.1 μM. 50 It is a compound having a value.

[0125] The role of the loss of Polθ in enhancing the efficacy of CRISPR-mediated gene editing is described in WO2017 / 062754. Thus, Polθ-inhibitory compounds are likely to be useful for enhancing the efficiency of CRISPR-based editing methods and / or CRISPR-based editing treatments. Furthermore, compound-mediated Polθ inhibition is likely to reduce the frequency of random integration events, thus providing a route to improve any safety concerns of CRISPR-mediated technology. Thus, a further aspect of the present invention provides the use of the compound of formula (I) as defined herein in CRISPR-based editing methods and / or CRISPR-based editing treatments, such as enhancing the efficiency of CRISPR-based editing methods and / or CRISPR-based editing treatments.

[0126] Pharmaceutical Composition While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g., a formulation). In one embodiment, this is a sterile pharmaceutical composition.

[0127] Thus, the present invention further provides pharmaceutical compositions as defined above, as well as methods of making (e.g. combining) pharmaceutical compositions comprising at least one compound of formula (I) (and subgroups thereof as defined herein) together with one or more pharma- ceutically acceptable excipients as described herein and, optionally, other therapeutic or prophylactic agents.

[0128] The pharma- ceutically acceptable excipient(s) can be selected, for example, from carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents, fillers or extenders, granulating agents, coating agents, release-controlling agents, binders, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickeners, flavorings, sweeteners, taste-masking agents, stabilizers, or any other excipients conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are described in more detail below.

[0129] The term "pharmaceutical acceptable" as used herein pertains to compounds, materials, compositions, and / or dosage forms suitable for use in contact with the tissues of a subject (e.g., a human) without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0130] Pharmaceutical compositions containing compounds of formula (I) can be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[0131] The pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, intraaural, rectal, intravaginal, or transdermal administration. If the composition is intended for parenteral administration, it may be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration, or for direct delivery into a target organ or tissue by injection, infusion, or other delivery means. Delivery may be by bolus injection, short-term infusion, or longer-term infusion, and may be by passive delivery or by utilizing a suitable infusion pump or syringe-driven device.

[0132] Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain combinations of antioxidants, buffers, bacteriostats, cosolvents, surfactants, organic solvent mixtures, cyclodextrin complexing agents, emulsifiers (to form and stabilize emulsion formulations), liposomal components to form liposomes, gellable polymers to form polymeric gels, lyoprotectants, and agents to stabilize the active ingredient in soluble form and to render the formulation isotonic with the blood of the intended recipient, among others. Pharmaceutical formulations for parenteral administration may also take the form of aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents (RG Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21(2) 2004, pp. 201-230).

[0133] The formulations may be provided in single-dose or multi-dose containers, such as sealed ampoules, vials, and pre-filled syringes, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. In one embodiment, the formulation is provided as an active pharmaceutical ingredient in a bottle for subsequent reconstitution with a suitable diluent.

[0134] Pharmaceutical formulations can be prepared by lyophilisation of a compound of formula (I) or any subgroup thereof. Lyophilisation refers to the procedure of freeze-drying a composition. Thus, freeze-drying and lyophilisation are used synonymously herein.

[0135] Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0136] The pharmaceutical compositions of the present invention for parenteral injection may comprise pharma- ceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and also sterile powders for reconstitution into sterile injectable solutions or dispersions immediately prior to use.

[0137] Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose, and suitable mixtures thereof, vegetable oils (e.g., sunflower oil, safflower oil, corn oil, olive oil, etc.), and injectable organic esters, such as ethyl oleate, etc. Proper fluidity can be maintained, for example, by the use of thickening or coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0138] The compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action may be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include agents for regulating osmotic pressure, such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms may be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0139] In a particular embodiment of the present invention, the pharmaceutical composition is in a form suitable for intravenous administration, for example, by injection or infusion.For intravenous administration, the solution can be administered directly or can be injected into an infusion bag (containing a pharma- ceutical acceptable excipient, for example, 0.9% saline or 5% glucose, etc.) before administration.

[0140] In another particular embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (sc) administration.

[0141] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, liquids, powders, granules, elixirs, and suspensions, sublingual tablets, wafers, or patches, such as buccal patches.

[0142] Thus, the tablet composition may contain a unit dose of the active compound together with an inert diluent or carrier, such as a sugar or sugar alcohol, for example; lactose, sucrose, sorbitol, or mannitol; and / or a non-sugar derived diluent, such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or its derivatives, such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starch, such as corn starch. Tablets may also contain standard ingredients such as binding and granulating agents, such as polyvinylpyrrolidone, disintegrants (e.g., swellable cross-linked polymers, such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and effervescent agents, such as citrate / bicarbonate mixtures. Such excipients are well known and need not be described in detail here.

[0143] Tablets can be designed to release drug either upon contact with gastric fluids or with specific areas of the gastrointestinal tract (immediate release tablets) or to release drug in a controlled manner over an extended period of time (controlled release tablets).

[0144] Capsule formulations may be of the hard or soft gelatin variety and may contain the active ingredient in solid, semi-solid, or liquid form. Gelatin capsules can be made from animal gelatin or its synthetic or vegetable-derived equivalents.

[0145] Solid dosage forms (e.g., tablets, capsules, etc.) can be coated or uncoated. Coatings can act either as protective films (e.g., polymers, waxes, or varnishes) or as mechanisms to control drug release or for aesthetic or identification purposes. Coatings (e.g., Eudragit™ type polymers) can be designed to release the active ingredient at a desired site in the gastrointestinal tract. Thus, coatings can be selected to degrade under certain pH conditions in the gastrointestinal tract, thereby selectively releasing the compound in the stomach or in the ileum, duodenum, jejunum, or colon.

[0146] Instead of or in addition to a coating, the drug may be provided in a solid matrix containing a release control agent, e.g., a release retarding agent, which may be adapted to release the compound in the gastrointestinal tract in a controlled manner. Alternatively, the drug may be provided in a polymer coating, e.g., a polymethacrylate polymer coating, which may be adapted to selectively release the compound in the gastrointestinal tract under conditions of varying acidity or alkalinity. Alternatively, the matrix material or release retarding coating may take the form of a readily degradable polymer (e.g., maleic anhydride polymer) that is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. In another alternative, the coating may be designed to disintegrate under the action of microorganisms in the gastrointestinal tract. As a further alternative, the active compound may be formulated into a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed or sustained release formulations (e.g., ion exchange resin-based formulations) may be prepared according to methods well known to those skilled in the art.

[0147] The compound of formula (I) may be formulated with a carrier and administered in the form of nanoparticles, the increased surface area of ​​which aids in its absorption. In addition, nanoparticles offer the possibility of direct penetration into cells. Nanoparticle drug delivery systems are described in "Nanoparticle Technology for Drug Delivery" (Ram B Gupta and Uday B. Kompella, eds., Informa Healthcare, ISBN 9781574448573, published March 13, 2006). Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91 (1-2), 167-172 and Sinha et al., Mol. Cancer Ther. August 1, (2006) 5, 1909.

[0148] A pharmaceutical composition usually comprises from about 1% (w / w) to about 95% (w / w) of active ingredient and from 99% (w / w) to 5% (w / w) of a pharma- ceutical acceptable excipient or combination of excipients. In particular, the composition comprises from about 20% (w / w) to about 90%,% (w / w) of active ingredient and from 80% (w / w) to 10% of a pharma- ceutical acceptable excipient or combination of excipients. A pharmaceutical composition comprises from about 1% to about 95%, in particular from about 20% to about 90%, of active ingredient. A pharmaceutical composition according to the invention may be in unit dose form, for example in the form of ampoules, vials, suppositories, prefilled syringes, dragees, tablets, or capsules.

[0149] The pharma- ceutically acceptable excipient(s) can be selected according to the desired physical form of the formulation and can be selected, for example, from diluents (e.g., solid diluents, such as fillers or bulking agents; and liquid diluents, such as solvents and cosolvents), disintegrants, buffers, lubricants, flow aids, release-controlling (e.g., release-retarding or delaying polymers or waxes), binders, granulating agents, dyes, plasticizers, antioxidants, preservatives, flavors, taste-masking agents, osmolality adjusting agents, and coating agents.

[0150] Those skilled in the art will have the expertise to select the appropriate amounts of ingredients for use in the formulation. For example, tablets and capsules will typically contain 0-20% disintegrant, 0-5% lubricant, 0-5% flow aid, and / or 0-99% (w / w) filler / or bulking agent (depending on drug dose). They may also contain 0-10% (w / w) polymer binder, 0-5% (w / w) antioxidant, and 0-5% (w / w) pigment. In addition, sustained release tablets will contain 0-99% (w / w) release-controlling (e.g., retarding) polymer (depending on dose). Film coatings for tablets or capsules will typically contain 0-10% (w / w) polymer, 0-3% (w / w) pigment, and / or 0-2% (w / w) plasticizer.

[0151] Parenteral formulations typically contain (depending on the dose and if lyophilized) 0-20% (w / w) buffer, 0-50% (w / w) co-solvent, and / or 0-99% (w / w) water for injection (WFI), and formulations for intramuscular depots also contain 0-99% (w / w) oil.

[0152] Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with a solid carrier, granulating the resulting mixture, if desired, and processing the mixture into tablets, dragee cores, or capsules after adding suitable excipients, if desired or necessary. They can also be incorporated into polymer or wax matrices that allow the active ingredient to diffuse or be released in measured amounts.

[0153] The compounds of the present invention can also be formulated as solid dispersions.Solid dispersions are homogeneous, extremely finely dispersed phases of two or more solids.Solid solutions (molecular dispersions), one type of solid dispersion, are well known for use in pharmaceutical technology (see Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300 (1971)), and are useful for increasing the dissolution rate and bioavailability of poorly water-soluble drugs.

[0154] The present invention also provides solid dosage forms comprising the above-mentioned solid solutions. The solid dosage forms include tablets, capsules, chewable tablets, and dispersible or effervescent tablets. Known excipients can be mixed with the solid solutions to obtain the desired dosage forms. For example, capsules can contain the solid solutions mixed with (a) a disintegrant and a lubricant, or (b) a disintegrant, a lubricant, and a surfactant. In addition, capsules can contain a filler, such as lactose or microcrystalline cellulose. Tablets can contain the solid solutions mixed with at least one disintegrant, a lubricant, a surfactant, a filler, and a flow agent. Chewable tablets can contain the solid solutions mixed with a filler, a lubricant, and additional sweeteners (e.g., artificial sweeteners, etc.) and suitable flavors, if desired. The solid solutions can also be formed by spraying a solution of the drug and a suitable polymer onto the surface of an inert carrier, such as sugar beads ("non-pareils"). These beads can then be filled into capsules or compressed into tablets.

[0155] Pharmaceutical formulations may be provided to patients in "patient packs" that contain the entire course of treatment in a single package, usually a blister pack. Patient packs have the advantage over traditional prescriptions, where a pharmacist dispenses a patient's supply of medicine from a bulk supply, in that the patient always has access to the package insert included in the patient pack, which is not normally included with the patient's prescription. The inclusion of a package insert has been shown to improve patient compliance with physician instructions.

[0156] Compositions for topical and nasal delivery include ointments, creams, sprays, patches, gels, liquid drops, and inserts (e.g., intraocular inserts). Such compositions can be formulated according to known methods.

[0157] Examples of preparations for rectal or vaginal administration include pessaries and suppositories, which may be formed, for example, from a moldable or waxy material in a molded form containing the active compound. Solutions of the active compound may also be used for rectal administration.

[0158] Compositions for administration by inhalation can take the form of inhalable powder compositions or liquid or powder sprays, and can be administered in standard forms using powder inhalation devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, powdered formulations usually contain the active compound together with an inert solid powdered diluent, such as lactose.

[0159] The compounds of formula (I) are generally provided in unit dosage form and therefore will usually contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain 1 ng to 2 g of active ingredient, e.g., 1 ng to 2 mg of active ingredient. Within these ranges, particular subranges of the compounds are 0.1 mg to 2 g of active ingredient (more usually, 10 mg to 1 g, e.g., 50 mg to 500 mg), or 1 μg to 20 mg (e.g., 1 μg to 10 mg, e.g., 0.1 mg to 2 mg of active ingredient).

[0160] For oral compositions, a unit dosage form may contain from 1 mg to 2 g, more typically from 10 mg to 1 g, for example, 50 mg to 1 g, for example, 100 mg to 1 g, of active compound.

[0161] The active compounds will be administered to a patient in need thereof (eg, a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

[0162] (Treatment Methods) The compounds of formula (I) and subgroups as defined herein may be useful in the prevention or treatment of various disease states or conditions mediated by Pol θ. Thus, according to a further aspect of the present invention, there is provided a method of treating a disease state or condition mediated by Pol θ (e.g., cancer), comprising administering to a subject in need thereof a compound of formula (I) as described herein. Examples of such disease states and conditions are mentioned above and include, in particular, cancer.

[0163] The compounds are generally administered to a subject in need of such administration, such as a human or animal patient, particularly a human.

[0164] The compound is usually administered in an amount that is therapeutically or prophylactically useful and generally non-toxic.However, in certain situations (e.g., in the case of life-threatening diseases), the benefits of administering the compound of formula (I) may outweigh the disadvantages of any toxic effects or side effects, and in such cases it may be considered desirable to administer the compound in an amount associated with some degree of toxicity.

[0165] The compound may be administered chronically to maintain beneficial therapeutic effects, or may be administered for only short periods of time, or it may be administered in a continuous or intermittent manner (e.g., in a pulsatile manner) to provide dosing.

[0166] A typical daily dose of a compound of formula (I) per kg of body weight can range from 100 pg to 100 mg per kg of body weight, more typically from 5 ng to 25 mg per kg of body weight, more usually from 10 ng to 15 mg per kg (e.g., 10 ng to 10 mg, more typically from 1 μg per kg to 20 mg per kg, e.g., 1 μg to 10 mg per kg), although higher or lower doses can be administered if required. Compounds of formula (I) can be administered daily or repeatedly, for example, every 2, or 3, or 4, or 5, or 6, or 7, or 10, or 14, or 21, or 28 days.

[0167] The compounds of the present invention may be orally administered in a dosage range of, for example, 1-1500 mg, 2-800 mg, or 5-500 mg, e.g., 2-200 mg or 10-1000 mg, with specific examples of dosages including 10, 20, 50, and 80 mg. The compounds may be administered once or more than once each day. The compounds may be administered continuously (i.e., taken every day without a break throughout the duration of the treatment regimen). Alternatively, the compounds may be administered intermittently (i.e., taken continuously for a given period, such as a week, throughout the duration of the treatment regimen, then discontinued for a period, such as a week, then taken continuously for another period, such as a week, etc.). Examples of treatment regimens involving intermittent administration include regimens in which administration is repeated over one or more cycles, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more cycles, with a cycle of 1 week on, 1 week off; or 2 weeks on, 1 week off; or 3 weeks on, 1 week off; or 2 weeks on, 2 weeks off; or 4 weeks on, 2 weeks off; or 1 week on, 3 weeks off.

[0168] In one particular dosing schedule, a patient receives an infusion of a compound of formula (I) for a period of one hour daily for up to 10 days, particularly up to 5 days, for one week, with treatment repeated at desired intervals, such as every 2 to 4 weeks, particularly every 3 weeks.

[0169] More particularly, patients will receive an infusion of a compound of formula (I) for a period of one hour each day for five days, the treatment being repeated every three weeks.

[0170] In another particular dosing schedule, the patient receives an infusion over 30 minutes to 1 hour, followed by a maintenance infusion of variable duration, eg, 1 to 5 hours, eg, 3 hours.

[0171] In a more particular dosing schedule, the patient receives a continuous infusion for a period of 12 hours to 5 days, and more particularly, a continuous infusion for a period of 24 hours to 72 hours.

[0172] In another particular dosing schedule, the patient is given the compound orally once a week.

[0173] In another particular dosing schedule, the patient is given the compound orally once daily for 7 to 28 days, for example, 7, 14, or 28 days.

[0174] In another particular dosing schedule, patients are given the compound orally once daily for 1, 2, 3, 5, or 1 week, followed by as many days off drug as necessary to complete a 1 or 2 week cycle.

[0175] In another particular dosing schedule, patients are given the compound orally once daily for two weeks, followed by a two-week rest period.

[0176] In another particular dosing schedule, patients are given the compound orally once daily for two weeks, followed by one week of rest.

[0177] In another particular dosing schedule, patients are given the compound orally once daily for one week, followed by one week off drug.

[0178] Ultimately, however, the amount of compound administered and the type of composition used will correspond to the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

[0179] It will be appreciated that Pol theta inhibitors can be used as single agents or in combination with other anticancer agents. Combination studies can be performed, for example, as described in Chou TC, Talalay P., "Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors," Adv Enzyme Regulat 1984;22:27-55.

[0180] The compounds defined herein can be administered as the sole therapeutic agent or they can be administered in combination therapy with one or more other compounds (or therapies) for the treatment of a particular disease state, for example a neoplastic disease such as cancer as already defined herein. For the treatment of the above conditions, advantageously, the compounds of the present invention can be employed in combination with one or more other drugs, more particularly with other anti-cancer drugs or adjuvants in cancer therapy. Examples of other therapeutic drugs or treatments that can be administered together with the compounds of formula (I) (whether simultaneously or at different time intervals) include: Topoisomerase I inhibitors; ·Antimetabolites; ·Tubulin targeting agents; ·DNA binders and topoisomerase II inhibitors; · Alkylating agents; · Monoclonal antibodies; ·Anti-hormones; Signal transduction inhibitors; · Proteasome inhibitors; DNA methyltransferase inhibitors; · Cytokines and retinoids; · Chromatin-targeted therapies; Radiation therapy; and Other therapeutic or preventive agents These include, but are not limited to:

[0181] Specific examples of the anti-cancer agent or adjuvant (or a salt thereof) include the following groups (i) to (xlvi), and optionally group (xlvii): (i) platinum compounds, such as cisplatin (optionally in combination with amifostine), carboplatin, or oxaliplatin; (ii) a taxane compound, such as paclitaxel, paclitaxel protein-bound particles (Abraxane™), docetaxel, cabazitaxel, or larotaxel; (iii) a topoisomerase I inhibitor, such as a camptothecin compound, such as camptothecin, irinotecan (CPT11), SN-38, or topotecan; (iv) topoisomerase II inhibitors, such as antitumor epipodophyllotoxins or podophyllotoxin derivatives, such as etoposide, or teniposide; (v) Vinca alkaloids, such as vinblastine, vincristine, liposomal vincristine (Onco-TCS), vinorelbine, vindesine, vinflunine, or vinvesir; (vi) nucleoside derivatives, such as 5-fluorouracil (5-FU, optionally in combination with leucovorin), gemcitabine, capecitabine, tegafur, UFT, S1, cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine, or nelarabine; (vii) antimetabolites, such as clofarabine, aminopterin, or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine, thiopurine, 6-mercaptopurine, or hydroxyurea (hydroxycarbamide); (viii) alkylating agents, such as nitrogen mustards or nitrosoureas, e.g., cyclophosphamide, chlorambucil, carmustine (BCNU), bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), altretamine, busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil, mechlorethamine, methylcyclohexylchloroethylnitrosurea, or nimustine (ACNU); (ix) anthracyclines, anthracenediones, and related drugs, such as daunorubicin, doxorubicin (optionally in combination with dexrazoxane), liposomal formulations of doxorubicin (e.g., Caelyx™, Myocet™, Doxil™), idarubicin, mitoxantrone, epirubicin, amsacrine, or valrubicin; (x) Epothilones, such as ixabepilone, patupilone, BMS-310705, KOS-862 and ZK-EPO, epothilone A, epothilone B, desoxyepothilone B (also known as epothilone D or KOS-862), azaepothilone B (also known as BMS-247550), aulimalide, isolaulimalide, or luetherobin; (xi) DNA methyltransferase inhibitors, such as temozolomide, azacitidine or decitabine, or SGI-110; (xii) antifolates, such as methotrexate, pemetrexed disodium, or raltitrexed; (xiii) cytotoxic antibiotics, such as antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, or mithramycin; (xiv) tubulin binding agents, such as combrestatin, colchicine, or nocodazole; (xv) Signal transduction inhibitors, such as kinase inhibitors (e.g., EGFR (epidermal growth factor receptor) inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, MTKI (multi-target kinase inhibitors), Raf inhibitors, mTOR inhibitors, such as imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, temsirolimus, everolimus (RAD 001), vemurafenib (PLX4032 / RG7204), dabrafenib, encorafenib, or IκB kinase inhibitors such as SAR-113945, bardoxolone, BMS-066, BMS-345541, IMD-0354, IMD-2560, or IMD-1041, or MEK inhibitors such as selumetinib (AZD6244), and trametinib (GSK121120212); (xvi) Aurora kinase inhibitors, such as AT9283, barasertib (AZD1152), TAK-901, MK0457 (VX680), cenisertib (R-763), danusertib (PHA-739358), alisertib (MLN-8237), or MP-470; (xvii) CDK inhibitors, such as AT7519, roscovitine, seliciclib, alvocidib (flavopiridol), dinaciclib (SCH-727965), 7-hydroxy-staurosporine (UCN-01), JNJ-7706621, BMS-387032 (also known as SNS-032), PHA533533, PD332991, ZK-304709, or AZD-5438; (xviii) PKA / B inhibitors and PKB (akt) pathway inhibitors, such as AKT inhibitors, for example, KRX-0401 (Perifosine / NSC 639966), ipatasertib (GDC-0068; RG-7440), afuresertib (GSK-2110183; 2110183), MK-2206, MK-8156, AT13148, AZD-5363, triciribine phosphate (VQD-002; triciribine phosphate monohydrate (API-2; TCN-P; TCN-PM; VD-0002), RX-0201, NL-71-101, SR-13668, PX-316, AT13148, AZ-5363, Semaphore, SF1126, or Enzastaurin HCl (LY317615), or an MTOR inhibitor, such as a rapamycin analogue, such as RAD 001 (everolimus), CCI 779 (temsirolemus), AP23573 and ridaforolimus, sirolimus (originally known as rapamycin), AP23841 and AP23573, calmodulin inhibitors such as CBP-501 (forkhead translocation inhibitor), enzastaurin HCl (LY317615), or PI3K inhibitors such as dactolisib (BEZ235) , buparlisib (BKM-120; NVP-BKM-120), BYL719, copanlisib (BAY-80-6946), ZSTK-474, CUDC-907, apitolisib (GDC-0980; RG-7422), pictilisib (pictorelisib, GDC-0941, RG-7321), GDC-0032, GDC-0068, GSK-2636771, idelalisib (formerly CAL-101, GS 1101, GS-1101), MLN1117 (INK1117), MLN0128 (INK128), IPI-145 (INK1197), LY-3023414, ipatasertib, afulesertib, MK-2206, MK-8156, LY-3023414, LY294002, SF1126 or PI-103, or sonolisib (PX-866), etc.; (xix) Hsp90 inhibitors, such as AT13387, herbimycin, geldanamycin (GA), 17-allylamino-17-desmethoxygeldanamycin (17-AAG), such as NSC-330507, Kos-953, and CNF-1010, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), such as NSC-707545 and Kos-1022, NVP-AUY922 (VER-52296), NVP-BEP800, CNF-2024 (BIIB-021, oral purine), ganetespib (STA-9090), SNX-5422 (SC-102112), or IPI-504; (xx) Monoclonal antibodies (unconjugated or conjugated to radioisotopes, toxins, or other agents), antibody derivatives and related agents, such as anti-CD, anti-VEGFR, anti-HER2, anti-CTLA4, anti-PD-1, or anti-EGFR antibodies, such as rituximab (CD20), ofatumumab (CD20), ibritumomab tiuxetan (CD20), GA101 (CD20), tositumomab (CD20), epratuzumab (CD22), lintuzumab (CD33), gemtuzumab ozogamicin (CD33), alemtuzumab (CD52), galiximab (CD80), trastuzumab (HER2 antibody), pertuzumab (HER2), trastuzumab-DM1 (HER2), ertumaxomab (HER2 and CD3), cetuximab (EGFR), panitumumab (EGFR), necitumumab (EGFR), nimotuzumab (EGFR), bevacizumab (VEGF), catumaxumab (EpCAM and CD3), abagovomab (CA125), farletuzumab (folate receptor), elotuzumab (CS1), denosumab (RANK ligand), figitumumab (IGF1R), CP751,871 (IGF1R), mapatuzumab (TRAIL receptor), metMAB (met), mitumomab (GD3 ganglioside), naptumomab-Es tafenatox (5T4), siltuximab (IL6), or immunomodulatory agents such as CTLA-4 blocking antibodies and / or antibodies against PD-1 or PD-L1 and / or PD-L2, such as ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly lambrolizumab, anti-PD-1), nivolumab (anti-PD-1), BMS-936559 (anti-PD-L1), MPDL320A, AMP-514 or MEDI4736 (anti-PD-L1), or tremelimumab (formerly ticilimumab, CP-675,206, anti-CTLA-4); (xxi) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or inhibitors of estrogen synthesis, such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, or raloxifene; (xxii) aromatase inhibitors and related drugs, such as exemestane, anastrozole, letrazole, testolactone aminoglutethimide, mitotane, or vorozole; (xxiii) antiandrogens (i.e., androgen receptor antagonists) and related agents, such as bicalutamide, nilutamide, flutamide, cyproterone, or ketoconazole; (xxiv) Hormones and analogs thereof, such as medroxyprogesterone, diethylstilbestrol (also known as diethylstilboestrol) or octreotide; (xxv) steroids, such as dromostanolone propionate, megestrol acetate, nandrolone (decanoate, phenpropionate), fluoxymestrone, or gossypol, (xxvi) steroidal cytochrome P450 17α-hydroxylase-17,20-lyase inhibitors (CYP17), such as abiraterone; (xxvii) gonadotropin-releasing hormone agonists or antagonists (GnRAs), such as abarelix, goserelin acetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin, or deslorelin; (xxviii) Glucocorticoids, such as prednisone, prednisolone, dexamethasone; (xxix) differentiating agents, such as retinoids, rexinoids, vitamin D, or retinoic acid, and retinoic acid metabolism blockers (RAMBAs), such as accutane, alitretinoin, bexarotene, or tretinoin; (xxx) farnesyltransferase inhibitors, such as tipifarnib; (xxxi) chromatin targeted therapy, such as histone deacetylase (HDAC) inhibitors, such as panobinostat, resminostat, abexinostat, vorinostat, romidepsin, belinostat, entinostat, xinostat, pracinostat, tefinostat, mocetinostat, gibinostat, CUDC-907, CUDC-101, ACY-1215, MGCD-290, EVP-0334, RG-2833, 4SC-202, romidepsin, AR-42 (Ohio State University), CG-200745, valproic acid, CKD-581, sodium butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide (FR 901228), dacinostat (NVP-LAQ824), R306465 / JNJ-16241199, JNJ-26481585, trichostatin A, chlamydocin, A-173, JNJ-MGCD-0103, PXD-101, or apicidin; (xxxii) proteasome inhibitors, such as bortezomib, carfilzomib, delanzomib (CEP-18770), ixazomib (MLN-9708), oprozomib (ONX-0912), or marizomib; (xxxiii) photodynamic drugs, such as porfimer sodium or temoporfin; (xxxiv) Anticancer drugs derived from marine organisms, such as trabectidin; (xxxv) Radiolabeled drugs for radioimmunotherapy, for example with beta particle emitting isotopes (e.g., iodine-131, yttrium-90) or alpha particle emitting isotopes (e.g., bismuth-213 or actinium-225), such as ibritumomab or iodine tositumomab; (xxxvi) telomerase inhibitors, for example, telomestatin; (xxxvii) matrix metalloproteinase inhibitors, such as batimastat, marimastat, prinostat, or metastat; (xxxviii) recombinant interferons (such as interferon-gamma and interferon-alpha) and interleukins (such as interleukin-2), such as aldesleukin, denileukin diftitox, interferon-alpha 2a, interferon-alpha 2b, or pegylated interferon-alpha 2b; (xxxix) selective immune response modulators, such as thalidomide, or lenalidomide; (xl) therapeutic vaccines, such as sipuleucel-T (Provenge) or OncoVex; (xli) cytokine activators, such as picibanil, romurtide, sizofiran, virulidin, or thymosin; (xlii) arsenic trioxide; (xliii) inhibitors of G protein-coupled receptors (GPCRs), e.g., atrasentan; (xliv) enzymes, such as L-asparaginase, pegaspargase, rasburicase, or pegademase; (xlv) DNA repair inhibitors, such as PARP inhibitors, for example, olaparib, velaparib, iniparib, rucaparib (AG-014699 or PF-01367338), talazoparib, or AG-014699; (xlvi) DNA damage response inhibitors, such as ATM inhibitors AZD0156 MS3541, ATR inhibitors AZD6738, M4344, M6620, wee1 inhibitors AZD1775, etc.; (xlvii) agonists of death receptors (e.g., TNF-related apoptosis-inducing ligand (TRAIL) receptors), such as mapatuzumab (formerly HGS-ETR1), conatumumab (formerly AMG 655), PRO95780, lexatumumab, dulanermin, CS-1008, apoumab, or recombinant TRAIL ligands, such as recombinant human TRAIL / Apo2 ligand; (xlviii) prophylactic (adjuvant) agents; i.e., agents that reduce or ameliorate some of the side effects associated with chemotherapeutic agents, e.g. -Antiemetics, - agents that prevent or reduce the duration of chemotherapy-associated neutropenia and prevent complications resulting from decreased levels of platelets, red blood cells, or white blood cells, such as interleukin-11 (e.g., oprelvekin), erythropoietin (EPO) and its analogs (e.g., darbepoetin alfa), colony-stimulating factor analogs, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) (e.g., sargramostim), and granulocyte-colony stimulating factor (G-CSF) and its analogs (e.g., filgrastim, pegfilgrastim), - drugs that inhibit bone resorption, such as denosumab or bisphosphonates, for example zoledronate, zoledronic acid, pamidronate, and ibandronate; -Medications that suppress the inflammatory response, such as dexamethasone, prednisone, and prednisolone; - drugs used to reduce blood levels of growth hormone and IGF-I (and other hormones) in patients with acromegaly or other rare hormone-producing tumors, such as synthetic forms of the hormone somatostatin, e.g., octreotide acetate; -Antidotes to drugs that reduce folic acid levels, such as leucovorin or folinic acid, - medicines for pain, such as opiates, e.g. morphine, diamorphine, and fentanyl; nonsteroidal anti-inflammatory drugs (NSAIDs), such as COX-2 inhibitors, for example celecoxib, etoricoxib, and lumiracoxib; - Medications for mucositis, e.g. Palifermin, - Medications for the treatment of side effects including anorexia, cachexia, edema, or thromoembolic episodes, such as megestrol acetate These include, but are not limited to, any of the agents selected from:

[0182] In one embodiment, the anticancer drugs include recombinant interferons (such as interferon-gamma and interferon-alpha) and interleukins (such as interleukin 2), such as aldesleukin, denileukin diftitox, interferon-alpha 2a, interferon-alpha 2b, or pegylated interferon-alpha 2b; interferon-alpha 2 (500 μg / ml), particularly interferon-beta; and signal transduction inhibitors, such as kinase inhibitors (such as EGFR (epidermal growth factor receptor 1 (EGFR)). mTOR inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, MTKI (multi-target kinase inhibitors), Raf inhibitors, mTOR inhibitors, such as imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovotinib, axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib, sunitinib, temsirolimus, everolimus (RAD 001), vemurafenib (PLX4032 / RG7204), dabrafenib, encorafenib, or IκB kinase inhibitors such as SAR-113945, bardoxolone, BMS-066, BMS-345541, IMD-0354, IMD-2560, or IMD-1041, or MEK inhibitors such as selumetinib (AZD6244) and trametinib (GSK121120212), in particular Raf inhibitors (e.g. vemurafenib) or MEK inhibitors (e.g. trametinib).

[0183] Each of the compounds present in the combination of the present invention may be administered by various routes with individually varying dosing schedules. Thus, the dosage of each of the two or more drugs may be different: each may be administered simultaneously or at different times. Those skilled in the art will know by their general knowledge the dosing schedule and combination therapy to be used. For example, the compounds of the present invention may be used in combination with one or more other drugs administered according to their existing combination regimen. Examples of standard combination regimens are shown below.

[0184] The taxane compound is advantageously administered at a dose of 50 to 400 mg per square meter of body surface area (mg / m 2 ), e.g., 75-250 mg / m 2 In particular, for paclitaxel, the dosage is about 175-250 mg / m 2 and for docetaxel, approximately 75-150 mg / m 2 It is administered at .

[0185] The camptothecin compound is advantageously administered at a dose of 0.1 to 400 mg per square meter of body surface area (mg / m) per course of treatment. 2 ) at a dosage of, for example, 1 to 300 mg / m 2 , in particular, about 100 to 350 mg / m for irinotecan 2 For topotecan, the dosage is about 1-2 mg / m 2 It is administered at .

[0186] The antitumor podophyllotoxin derivative is advantageously administered at a dose of 30 to 300 mg per square meter of body surface (mg / m 2 ), e.g., 50-250 mg / m 2 In particular, the dosage for etoposide is about 35-100 mg / m 2 For teniposide, the dosage is about 50-250 mg / m 2 It is administered at .

[0187] The antitumor vinca alkaloids are advantageously administered at a dose of 2 to 30 mg per square meter of body surface area (mg / m 2 ) and, in particular, for vinblastine, about 3-12 mg / m 2 For vincristine, the dosage is about 1-2 mg / m 2 For vinorelbine, the dosage is about 10-30 mg / m 2 is administered at a dosage of

[0188] The antitumor nucleoside derivative is advantageously administered at a dose of 200 to 2500 mg per square meter of body surface area (mg / m 2) dosage, for example, 700-1500 mg / m 2 , especially for 5-FU, 200-500mg / m 2 For gemcitabine, the dosage is about 800-1200 mg / m 2 For capecitabine, the dosage is about 1000-2500 mg / m 2 It is administered at .

[0189] Alkylating agents such as nitrogen mustards or nitrosoureas are advantageously administered at a dose of 100-500 mg per square meter of body surface area (mg / m 2 ), for example, 120-200 mg / m 2 In particular, for cyclophosphamide, the dosage is about 100-500 mg / m 2 For chlorambucil, the dosage is about 0.1-0.2 mg / kg, and for carmustine, the dosage is about 150-200 mg / m 2 For lomustine, the dosage is about 100-150 mg / m 2 is administered at a dosage of

[0190] The antitumor anthracycline derivative is advantageously administered at a dose of 10 to 75 mg per square meter of body surface area (mg / m 2 ), e.g., 15-60 mg / m 2 In particular, for doxorubicin, the dosage is about 40-75 mg / m 2 For daunorubicin, the dosage is about 25-45 mg / m 2 For idarubicin, the dosage is about 10-15 mg / m 2 is administered at a dosage of

[0191] The antiestrogens are advantageously administered in a dosage of about 1 to 100 mg per day depending on the particular agent and the condition being treated. Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, in particular 10 to 20 mg, twice a day, the therapy being continued for a time sufficient to achieve and maintain a therapeutic effect. Toremifene is advantageously administered orally in a dosage of about 60 mg once a day, the therapy being continued for a time sufficient to achieve and maintain a therapeutic effect. Anastrozole is advantageously administered orally in a dosage of about 1 mg once a day. Droloxifene is advantageously administered orally in a dosage of about 20 to 100 mg once a day. Raloxifene is advantageously administered orally in a dosage of about 60 mg once a day. Exemestane is advantageously administered orally in a dosage of about 25 mg once a day.

[0192] The antibody is advantageously administered at a dose of about 1 to 5 mg per square meter of body surface area (mg / m 2 Trastuzumab is advantageously administered at a dosage of 1 to 5 mg per square meter of body surface area (mg / m) per course of treatment. 2 ), especially 2-4 mg / m 2 is administered at a dosage of

[0193] When the compound of formula (I) is administered in combination therapy with one, two, three, four or more other therapeutic agents (particularly one or two, more particularly one), the compounds can be administered simultaneously or sequentially. In the latter case, the two or more compounds are administered within a period and in an amount and manner sufficient to ensure that a beneficial or synergistic effect is achieved. When administered sequentially, they can be administered at short intervals (e.g., 5 to 10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 hours or more, or even longer if necessary), with the exact dosing regimen being commensurate with the nature of the therapeutic agent(s). These doses can be administered, for example, once, twice or more per course of treatment, which can be repeated, for example, every 7, 14, 21 or 28 days.

[0194] In one embodiment, a compound of formula (I) is provided for the manufacture of a medicament for use in therapy, said compound being used in combination with one, two, three, or four other therapeutic agents. In another embodiment, a medicament for treating cancer comprising a compound of formula (I) is provided, said medicament being used in combination with one, two, three, or four other therapeutic agents. The present invention further provides the use of a compound of formula (I) for the manufacture of a medicament for enhancing or increasing response rates in a patient suffering from cancer, said patient being treated with one, two, three, or four other therapeutic agents.

[0195] It will be recognized that the particular method and sequence of administration, as well as the dosage amounts and treatment regimen of each of the components of the combination, will depend on the particular other agents and compounds of the invention being administered, their routes of administration, the particular tumor being treated, and the particular host being treated. The optimal method and sequence of administration, as well as the dosage amounts and treatment regimen, can be readily determined by one of skill in the art using conventional methods and in view of the information set forth herein.

[0196] The weight ratio of the compound according to the invention and said one or more other anticancer drug(s) when administered as a combination can be determined by a person skilled in the art. The ratio and the exact dosage and frequency of administration depend on the particular compound according to the invention and other anticancer drug(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time of administration, and the general health of the particular patient, the mode of administration, and other drugs that the individual may be taking, as is well known to those skilled in the art. Furthermore, it is clear that the effective daily amount can be reduced or increased depending on the response of the subject being treated and / or depending on the evaluation of the physician prescribing the compound of the invention. The particular weight ratio of the compound of formula (I) and another anticancer drug can range from 1 / 10 to 10 / 1, more particularly from 1 / 5 to 5 / 1, and even more particularly from 1 / 3 to 3 / 1.

[0197] The compounds of the invention are also administered in conjunction with non-chemotherapeutic treatments such as radiation therapy, photodynamic therapy, gene therapy; surgery, and restricted diets.

[0198] The compounds of the present invention also have therapeutic applications in sensitizing tumor cells for radiation and chemotherapy. Thus, the compounds of the present invention can be used as "radiosensitizers" and / or "chemosensitizers" or can be administered in combination with another "radiosensitizer" and / or "chemosensitizer". In one embodiment, the compounds of the present invention are for use as chemosensitizers.

[0199] The term "radiosensitizer" is defined as a molecule that is administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to ionizing radiation and / or to facilitate the treatment of a disease treatable with ionizing radiation.

[0200] The term "chemosensitizer" is defined as a molecule that is administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to chemotherapy and / or to facilitate the treatment of a disease treatable with a chemotherapeutic agent.

[0201] In one embodiment, the compound of the invention is administered in combination with a "radiosensitizer" and / or a "chemosensitizer." In one embodiment, the compound of the invention is administered in combination with an "immunosensitizer."

[0202] The term "immunosensitizer" is defined as a molecule that is administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to Pol theta inhibitors.

[0203] Many cancer treatment protocols currently employ radiosensitizers in conjunction with X-ray irradiation. Examples of X-ray activated radiosensitizers include, but are not limited to, metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically active analogs and derivatives thereof.

[0204] Photodynamic therapy (PDT) of cancer employs visible light as the radiation activator of a sensitizer. Examples of photodynamic radiosensitizers include, but are not limited to, the following: hematoporphyrin derivatives, photofrin, benzoporphyrin derivatives, tin etioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanines, and their therapeutically active analogs and derivatives.

[0205] The radiosensitizer may be administered in combination with therapeutically effective amounts of one or more other compounds, such as, but not limited to: a compound of the invention; a compound that promotes incorporation of the radiosensitizer into target cells; a compound that controls the flow of therapeutic substances, nutrients, and / or oxygen to target cells; a chemotherapeutic agent that acts against the tumor with or without additional radiation; or another therapeutically effective compound for treating cancer or other diseases.

[0206] The chemotherapy sensitizer may be administered in combination with one or more therapeutically effective amounts of other compounds, such as, but not limited to: the compounds of the present invention; compounds that promote the incorporation of chemotherapy sensitizers into target cells; compounds that control the flow of therapeutic substances, nutrients, and / or oxygen to target cells; chemotherapy agents acting against tumors, or other therapeutically effective compounds for treating cancer or other diseases. Calcium antagonists, such as verapamil, have been found to be useful in combination with anti-neoplastic agents to establish chemotherapy sensitivity in tumor cells resistant to accepted chemotherapy agents and to enhance the effectiveness of such compounds in drug-sensitive malignancies.

[0207] Examples of immune sensitizers include, but are not limited to, the following: immunomodulators, such as monoclonal antibodies, such as immune checkpoint antibodies (e.g., CTLA-4 blocking antibodies and / or antibodies against PD-1 and PD-L1 and / or PD-L2, such as ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly lambrolizumab, anti-PD-1), nivolumab (anti-PD-1), BMS-936559 (anti-PD-L1), MPDL320A, AMP-514, or MEDI4736 (anti-PD-L1), or tremelimumab (formerly ticilimumab, CP-675,206, anti-CTLA-4)]; or signal transduction inhibitors; or cytokines (such as recombinant interferons); or oncolytic viruses; or immune adjuvants (e.g., BCG).

[0208] The immunosensitizer may be administered in combination with therapeutically effective amounts of one or more other compounds, such as, but not limited to: a compound of the invention; a compound that promotes incorporation of the immunosensitizer into target cells; a compound that controls the flow of therapeutic substances, nutrients, and / or oxygen to target cells; a therapeutic agent acting on a tumor, or other therapeutically effective compound for treating cancer or other diseases.

[0209] For use in combination therapy with another chemotherapeutic agent, the compound of formula (I) and one, two, three, four or more other therapeutic agents can be formulated together, for example, in a dosage form containing two, three, four or more therapeutic agents, i.e., in a single pharmaceutical composition containing all agents. In another embodiment, the individual therapeutic agents can be formulated separately and provided together in the form of a kit, optionally including instructions for their use.

[0210] In one embodiment, a combination of a compound of formula (I) and one or more (e.g., one or two) other therapeutic agents (e.g., anticancer agents as described above) is provided. In a further embodiment, a combination of a Pol θ inhibitor as described herein and a PI3K / AKT pathway inhibitor selected from: apitolisib, buparlisib, copanlisib, pictilisib, ZSTK-474, CUDC-907, GSK-2636771, LY-3023414, ipatasertib, afuresertib, MK-2206, MK-8156, idelalisib, BEZ235 (dactolisib), BYL719, GDC-0980, GDC-0941, GDC-0032, and GDC-0068 is provided.

[0211] In another embodiment, compounds of Formula (I) are provided in combination with one or more (e.g., one or two) other therapeutic agents (e.g., anti-cancer agents) for use in therapy, e.g., in the prevention or treatment of cancer.

[0212] In one embodiment, a pharmaceutical composition comprises a compound of Formula (I) together with a pharma- ceutically acceptable carrier and, optionally, one or more therapeutic agent(s).

[0213] In another embodiment the present invention relates to the use of a combination according to the invention in the manufacture of a pharmaceutical composition for inhibiting the growth of tumour cells.

[0214] In a further embodiment, the present invention relates to a product containing a compound of formula (I) and one or more anti-cancer agents as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer. EXAMPLES

[0215] (Example) The present invention will now be described with reference to specific embodiments described in the following examples, but the invention is not limited thereto. (abbreviation) [Table 1] TIFF2024539132000006.tif80170

[0216] (Typical Preparative HPLC Method) For sample purification by HPLC, the following columns were typically used: SunFire C18, Xtimate C18, Phenomenex Gemini, Phenomenex Synergi C18, Phenomenex Luna, Waters Xbridge C18, Boston Prime C18, and Shim-pack C18. Typical mobile phases used were water and MeCN with either acidic or basic additives such as formic acid (0.1% v / v) or ammonium hydroxide (0.05% v / v). A typical method started with 95% water:5% MeCN and gradually changed the ratio of water to MeCN to become less polar over 5-12 minutes, with a typical flow rate of 25 mL / min. For mass spectrometric HPLC, a typical mass spectrometer used was a Waters 3100 with mass detection from 100 to 700 g / mol.

[0217] (Intermediate 1: 2-(tert-butyl) 3-methyl (2S,3S)-5-oxopyrrolidine-2,3-dicarboxylate) [ka] (Step a.) To a solution of tert-butyl 2-((diphenylmethylene)amino)acetate (CAS: 81477-94-3; 100 g, 339 mmol) and dimethyl fumarate (CAS: 624-49-7; 73.2 g, 508 mmol) in EtOAc (1 L) was added (S)-2-((2,3-bis(dicyclohexylamino)cycloprop-2-en-1-ylidene)amino)propan-1-ol (CAS: 1808186-23-3, prepared as described in J. S. Bander et al., Chem. Sci. 2015, 6, 1537; 18.5 g, 33.9 mmol). The reaction mixture was stirred at room temperature for 48 h. After completion, the reaction mixture was evaporated and the crude product was purified by column chromatography (hexane / EtOAc=4 / 1) to give 1-(tert-butyl) 2,3-dimethyl (1S,2S)-1-((diphenylmethylene)amino)propane-1,2,3-tricarboxylate as a colorless oil (140 g, 94% yield).

[0218] (Step b.) To a solution of 1-(tert-butyl) 2,3-dimethyl (1S,2S)-1-((diphenylmethylene)amino)propane-1,2,3-tricarboxylate (140 g, 318.5 mmol) in THF (1.4 L) was added 15% w / w aqueous citric acid (1.4 L). The reaction mixture was stirred at room temperature for 48 h. After completion, the reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (3 x 1 L). The combined organic layers were dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (hexane / EtOAc = 3 / 7) to give the title compound as a white solid (70 g, 90% yield). [ka]

[0219] (Intermediate 2a: tert-butyl (2-fluoro-6-(methylamino)phenyl)carbamate) [ka] (Step a.) To a solution of 2-fluoro-6-nitroaniline (CAS: 17809-36-8; 100 g, 641 mmol) in DCM (500 mL) was added di-tert-butyl dicarbonate (308 g, 1.41 mol), TEA (130 g, 1.28 mol), and DMAP (7.83 g, 64.1 mmol). The mixture was stirred at 40° C. for 12 h. After completion, the reaction mixture was quenched with saturated aqueous NH4Cl (500 mL) at 25° C., diluted with water (500 mL), and extracted with DCM (3×1 L). The combined organic layers were washed with brine (3×500 mL), dried over Na2SO4, and evaporated. The crude product was triturated (PE / EtOAc=20 / 1, 500 mL) to give tert-butyl (tert-butoxycarbonyl)(2-fluoro-6-nitrophenyl)carbamate (210 g, 92% yield) as a yellow solid. [ka]

[0220] (Step b.) To a solution of tert-butyl (tert-butoxycarbonyl)(2-fluoro-6-nitrophenyl)carbamate (210 g, 589 mmol) in DCM (2.1 L) was added TFA (87.4 g, 766 mmol) and the mixture was stirred at 25° C. for 12 h. After completion, the reaction mixture was quenched with saturated aqueous Na2CO3 (500 mL), diluted with water (500 mL) and extracted with DCM (3×1 L). The combined organic layers were washed with brine (3×500 mL), dried over Na2SO4 and evaporated to give tert-butyl (2-fluoro-6-nitrophenyl)carbamate (145 g, 96% yield) as a yellow solid. [ka]

[0221] (Process c.) To a solution of tert-butyl (2-fluoro-6-nitrophenyl)carbamate (145 g, 567 mmol) in MeOH (2 L) was added 10% Pd / C (15 g) and the mixture was stirred under H2 atmosphere (15 psi (103 kPa)) at 25° C. for 12 h. After completion, the reaction mixture was filtered and evaporated to give tert-butyl (2-amino-6-fluorophenyl)carbamate (128 g, 99% yield) as an off-white solid. [ka]

[0222] (Step d.) To a solution of tert-butyl (2-amino-6-fluorophenyl)carbamate (128 g, 566 mmol) in MeOH (1.5 L) was added paraformaldehyde (25.5 g, 849 mmol) and sodium methoxide (306 g, 5.66 mol). The reaction mixture was stirred at 25° C. for 12 h. Then NaBH3CN (107 g, 2.83 mol) was added slowly and stirred at 25° C. for 12 h. After completion, the reaction mixture was quenched with saturated aqueous NH4Cl (500 mL), diluted with water (500 mL) and extracted with EtOAc (3×1 L). The combined organic layers were washed with brine (3×500 mL), dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (PE / EtOAc=10 / 1) to give the title compound (56 g, 41% yield) as a yellow solid. [ka]

[0223] (Intermediate 2b: tert-butyl (2-chloro-6-(methylamino)phenyl)carbamate) [ka] The title compound was prepared in a similar manner to intermediate 2a using 2-chloro-6-nitroaniline (CAS: 769-11-9) in step a. [ka]

[0224] (Intermediate 3: tert-butyl (2-chloro-4-fluoro-6-(methylamino)phenyl)carbamate) [ka] (Step a.) To a solution of 4-fluoro-2-nitroaniline (16.5 g, 106 mmol) in DMF (330 mL) was added N-chlorosuccinimide (15.5 g, 116 mmol) in DMF (330 mL) and the mixture was stirred at 40° C. for 12 h. After completion, the reaction mixture was quenched with saturated aqueous NH4Cl (100 mL) at 25° C., diluted with water (300 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (3×200 mL), dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (PE / EtOAc=50 / 1) to give 2-chloro-4-fluoro-6-nitroaniline (17 g, 84% yield) as a brown solid. [ka]

[0225] (Process b~e.) These four steps were carried out in a manner similar to steps a-d of intermediate 2a. [ka]

[0226] (Intermediate 4: tert-butyl (6-chloro-3,4-difluoro-2-(methylamino)phenyl)carbamate) [ka] (Step a.) To a solution of 2-chloro-4,5-difluoroaniline (CAS: 2613-32-3; 19.0 g, 116 mmol) in EtOAc (400 mL) was added DIPEA (30.0 g, 232 mmol) and acetic anhydride (17.8 g, 174 mmol) dropwise. The mixture was stirred at 50° C. for 16 h. After completion, the reaction mixture was diluted with water (100 mL) and the layers were separated. The organic layer was washed with water (3×100 mL), dried over Na2SO4, and evaporated to give N-(2-chloro-4,5-difluorophenyl)acetamide (23 g, crude) as a brown solid. [ka]

[0227] (Step b.) To a solution of N-(2-chloro-4,5-difluorophenyl)acetamide (23.0 g, 112 mmol) in concentrated H2SO4 (200 mL) was added 80% HNO3 (32.2 g, 409 mmol) at 0 °C. The mixture was allowed to warm to 25 °C over 1 h. After completion, the reaction mixture was poured into ice water (600 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (PE / EtOAc = 3 / 1) to give N-(6-chloro-3,4-difluoro-2-nitrophenyl)acetamide (26.0 g, 92% yield) as a yellow solid. [ka]

[0228] (Process c.) To a solution of N-(6-chloro-3,4-difluoro-2-nitrophenyl)acetamide (26.0 g, 104 mmol) in 1,4-dioxane (250 mL) was added 12 M aqueous hydrochloric acid (17 mL). The mixture was stirred at 80° C. for 18 h. After completion, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were dried over Na2SO4 and evaporated to give 6-chloro-3,4-difluoro-2-nitroaniline (22 g, crude) as a yellow solid, which was used directly in the next step.

[0229] (Process d~g.) These four steps were carried out in a manner similar to steps a-d of intermediate 2a. [ka]

[0230] (Intermediate 5: (3aR,11aS)-6-chloro-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka]

[0231] (Step a.) A mixture of intermediate 1 (100 g, 411 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (CAS: 451459-17-9; 128 g, 534 mmol), KCO (114 g, 822 mmol), CuI (15.7 g, 82.2 mmol), and N 1 ,N 2A mixture of 2-(tert-butyl) 3-methyl (2S,3S)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2,3-dicarboxylate (108 g, 63% yield) was obtained as a yellow solid. [ka]

[0232] (Step b.) NOTE: The following process was performed in six parallel batches. To a solution of 2-(tert-butyl) 3-methyl (2S,3S)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2,3-dicarboxylate (50 g, 124 mmol) in THF (450 mL) and MeOH (50 mL) was added NaBH4 (7.05 g, 186 mmol) in portions at 0 °C. The mixture was stirred at 0-5 °C for 3 h. After completion, the reaction mixture was quenched with saturated aqueous NH4Cl (3 L) and extracted with EtOAc (2 x 3 L). The organic layers of parallel batches were combined, washed with brine (3 L), dried over Na2SO4 and evaporated to give tert-butyl (2S,3S)-3-(hydroxymethyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxylate (300 g, crude) as a yellow gum. [ka]

[0233] (Process c.) To a solution of tert-butyl (2S,3S)-3-(hydroxymethyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxylate (100 g, 267 mmol) and TEA (54.1 g, 534 mmol) in DCM (1 L) was added MsCl (33.7 g, 294 mmol) dropwise at 0° C. The reaction mixture was stirred at 20° C. for 1 h. After completion, the reaction mixture was diluted with water (1 L). The layers were separated and the organic layer was washed with brine (3×1 L), dried over Na2SO4, filtered through a pad of silica gel (100-200 mesh) and evaporated to give tert-butyl (2S,3S)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(((methylsulfonyl)oxy)methyl)-5-oxopyrrolidine-2-carboxylate (120 g, 99% yield) as a yellow gum. [ka]

[0234] (Step d.) A mixture of tert-butyl (2S,3S)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-3-(((methylsulfonyl)oxy)methyl)-5-oxopyrrolidine-2-carboxylate (50 g, 111 mmol), isoindoline-1,3-dione (16.4 g, 112 mmol), and K2CO3 (25.1 g, 181 mmol) in NMP (400 mL) was stirred at 100° C. for 12 h. After completion, the reaction mixture was diluted with water (1 L) and filtered. The filter cake was dissolved in EtOAc (1 L), washed with brine (3×1 L), dried over Na2SO4, and evaporated. The crude product was triturated (PE / MTBE=1 / 1, 3.0 L) at 25° C. for 12 hours to give tert-butyl (2S,3R)-3-((1,3-dioxoisoindolin-2-yl)methyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxylate (25 g, 44% yield) as a white solid. [ka]

[0235] (Step e.) NOTE: The following process was performed in four parallel batches. To a solution of tert-butyl (2S,3R)-3-((1,3-dioxoisoindolin-2-yl)methyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxylate (25.0 g, 49.7 mmol) in MeOH (250 mL) was added hydrazine monohydrate (85% purity; 4.68 g, 79.5 mmol). The reaction mixture was stirred at 70 °C under N2 atmosphere for 12 h. After completion, the reaction mixture was cooled to room temperature, filtered and the filtrate was evaporated. Residues from parallel batches were combined, diluted with water (1 L), extracted with EtOAc (2×1 L), washed with brine (1 L), dried over Na2SO4 and evaporated to give tert-butyl (2S,3R)-3-(aminomethyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxylate (76 g, crude) as a brown gum. [ka]

[0236] (Process f.) NOTE: The following process was performed in four parallel batches. A mixture of tert-butyl (2S,3R)-3-(aminomethyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxylate (40 g, 107 mmol), 1-chloro-2-fluoro-3-nitrobenzene (CAS: 2106-49-2; 17.8 g, 102 mmol), and NaHCO3 (18.0 g, 214 mmol) in EtOH (380 mL) and water (20 mL) was stirred at 105° C. for 12 h. After completion, the reaction mixture was evaporated, diluted with EtOAc (5 L) and washed with water (2 L). The organic layers of parallel batches were combined, dried over Na2SO4, evaporated and purified by column chromatography (PE / EA=10 / 1) to give tert-butyl (2S,3R)-3-(((2-chloro-6-nitrophenyl)amino)methyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxylate (175 g, 77% yield) as a yellow oil. [ka]

[0237] (Process g.) To a solution of tert-butyl (2S,3R)-3-(((2-chloro-6-nitrophenyl)amino)methyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxylate (110 g, 208 mmol) in THF (1.1 L) was added 3% Pt-V / C (11 g, 1.26 mmol). The reaction mixture was stirred at 25° C. under an atmosphere of H2 (30 psi (207 kPa)) for 16 h. Upon completion, the reaction mixture was filtered and evaporated to give tert-butyl (2S,3R)-3-(((2-amino-6-chlorophenyl)amino)methyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxylate (102 g, 98% yield) as a brown oil. [ka]

[0238] (Process h.) NOTE: The following process was performed in three parallel batches. To a solution of tert-butyl (2S,3R)-3-(((2-amino-6-chlorophenyl)amino)methyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxylate (34.0 g, 68.2 mmol) in DCM (170 mL) was added HCl in 1,4-dioxane (4 M, 170 mL). The reaction mixture was stirred at 25° C. for 12 h. After completion, the reaction mixture was diluted with water (1 L). The pH of the reaction mixture was adjusted to pH 5 with solid NaOH and then evaporated to remove DCM. The residues from parallel batches were combined, extracted with EtOAc (3×1 L), washed with brine (1 L), dried over Na2SO4, and evaporated to give (2S,3R)-3-[(2-amino-6-chloro-anilino)methyl]-1-[6-methyl-4-(trifluoromethyl)-2-pyridyl]-5-oxo-pyrrolidine-2-carboxylic acid (90 g, 99% yield) as a yellow oil. [ka]

[0239] (Process i.) NOTE: The following process was performed in two parallel batches. To a solution of (2S,3R)-3-(((2-amino-6-chlorophenyl)amino)methyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxylic acid (30.0 g, 67.8 mmol) and DIPEA (17.5 g, 136 mmol) in DCM (1800 mL) and EtOAc (600 mL) was added T3P (50% in EtOAc; 43.1 g, 67.8 mmol). The reaction mixture was stirred at 20° C. for 1 h. After completion, the reaction mixture was quenched with water (500 mL) and extracted with EtOAc (3×1 L). The organic layers of the parallel batches were combined, washed with brine (1 L), dried over Na2SO4 and evaporated. Purification by column chromatography (PE / EtOAc / NH4OH=1 / 1 / 0.002) afforded the title compound (40 g, 67% yield) as an off-white solid. [ka]

[0240] (Intermediate A1: 1-oxa-6-azaspiro[3.3]heptane trifluoroacetate) [ka] (Step a.) To a solution of tert-butyl 1-oxa-6-azaspiro[3.3]heptane-6-carboxylate (CAS number: 1223573-41-8; 100 mg, 0.50 mmol) in DCM (4 mL) was added TFA (1.54 g, 13.5 mmol). The reaction mixture was stirred at 20° C. for 30 min. After completion, the reaction mixture was evaporated to give the title compound (105 mg, 98% yield, TFA) as a yellow gum, which was used directly in the subsequent step.

[0241] (Intermediate A2: piperidine-4-carbonitrile) [ka] The title compound was prepared in a similar manner to Intermediate A1 using tert-butyl 4-cyanopiperidine-1-carboxylate (CAS: 91419-52-2). [ka]

[0242] (Intermediate A3: (S)-Pyrrolidine-3-carbonitrile) [ka] The title compound was prepared in a similar manner to Intermediate A1 using tert-butyl (S)-pyrrolidine-3-carbonitrile (CAS: 132945-78-9). [ka]

[0243] (Intermediate A4: (R)-pyrrolidine-3-carbonitrile) [ka] The title compound was prepared in a similar manner to Intermediate A1 using tert-butyl (R)-pyrrolidine-3-carbonitrile (CAS: 132945-76-7).

[0244] (Intermediate A5: (3R,4S)-3-Fluoro-N,N-dimethylpiperidin-4-amine dihydrochloride) [ka] (Step a.) To a mixture of tert-butyl (3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate (CAS number 907544-17-6; 0.2 g, 0.92 mmol), paraformaldehyde (550 mg, 18.3 mmol), and acetic acid (220 mg, 3.67 mmol) in MeOH (2 mL) was added NaBH3CN (173 mg, 2.8 mmol). The reaction mixture was stirred at 25° C. for 12 h. After completion, the reaction mixture was filtered and the filtrate was evaporated. The residue was diluted with saturated aqueous NaHCO3 (20 mL) and the aqueous mixture was extracted with EtOAc (3×20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4 and evaporated to give tert-butyl (3R,4S)-4-(dimethylamino)-3-fluoropiperidine-1-carboxylate (200 mg, 89% yield) as a yellow gum. [ka]

[0245] (Step b.) A mixture of tert-butyl (3R,4S)-4-(dimethylamino)-3-fluoropiperidine-1-carboxylate (90 mg, 0.37 mmol) in HCl in MeOH (4 M, 2 mL) was stirred for 30 min at 20° C. After completion, the reaction mixture was evaporated to give the title compound as the dihydrochloride salt (80 mg, crude) as a white solid, which was used directly in the subsequent step.

[0246] (Intermediate A6: (S)-N,N-Dimethylpyrrolidine-3-carboxamide) [ka] (Step a.) To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (CAS: 140148-70-5; 500 mg, 2.32 mmol), HATU (1.06 g, 2.79 mmol), and DIPEA (900 mg, 6.97 mmol) in DCM (5 mL), dimethylamine hydrochloride (227 mg, 2.79 mmol) was added and stirred for 2 h at 25° C. After completion, the reaction mixture was evaporated and purified by column chromatography (PE / EtOAc=2 / 1) to give tert-butyl (S)-3-(dimethylcarbamoyl)pyrrolidine-1-carboxylate (540 mg, 95% yield) as a colorless oil. [ka]

[0247] (Step b.) This step was carried out in a similar manner to step a of intermediate A1. [ka]

[0248] (Intermediate A7: (R)-N,N-dimethylpyrrolidine-3-carboxamide) [ka] The title compound was prepared in a similar manner to Intermediate A6 using (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (CAS: 72925-16-7).

[0249] (Intermediate A8: (R)-2-hydroxy-1-(piperazin-1-yl)propan-1-one) [ka] The title compound was prepared in a similar manner to intermediate A6 using tert-butyl piperazine-1-carboxylate and (R)-2-hydroxypropanoic acid (CAS: 10326-41-7) in step a. m / z ES+ [M+H]+ 159.1.

[0250] (Intermediate A9: (R)-2-hydroxy-1-(piperazin-1-yl)propan-1-one) [ka] The title compound was prepared in a similar manner to intermediate A6 using tert-butyl piperazine-1-carboxylate and (S)-2-hydroxypropanoic acid (CAS: 79-33-4) in step a. m / z ES+ [M+H] + 159.2.

[0251] (Intermediate A10: (R)-Hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one) [ka] (Step a.) To a solution of tert-butyl (R)-3-(hydroxymethyl)piperazine-1-carboxylate (CAS: 278788-66-2; 5.2 g, 24.0 mmol) in DCM (50 mL) was added TEA (7.30 g, 72.1 mmol) and 2-chloroacetyl chloride (4.07 g, 36.1 mmol) at 0° C. The mixture was stirred at 20° C. for 3 h. After completion, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and evaporated. The residue was purified by column chromatography (PE / EtOAc=1 / 1) to give tert-butyl (R)-4-(2-chloroacetyl)-3-(hydroxymethyl)piperazine-1-carboxylate (5.8 g, 82% yield) as a pale yellow oil. [ka]

[0252] (Step b.) To a solution of tert-butyl (R)-4-(2-chloroacetyl)-3-(hydroxymethyl)piperazine-1-carboxylate (500 mg, 1.71 mmol) in THF (10 mL) was added potassium tert-butoxide (230 mg, 2.05 mmol). The mixture was stirred at 25° C. for 3 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and evaporated to give tert-butyl (R)-4-oxohexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (400 mg, 92% yield) as a pale yellow oil. [ka]

[0253] (Process c.) This step was carried out in a similar manner to step a of intermediate A1. m / z ES+ [M+H] + 157.1.

[0254] (Intermediate B1: 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehyde) [ka] (Step a.) A mixture of dimethyl 1H-pyrazole-3,5-dicarboxylate (5.0 g, 27.2 mmol), tert-butyl (2-bromoethyl)carbamate (7.30 g, 32.6 mmol), and K2CO3 (5.6 g, 40.7 mmol) in DMF (100 mL) was stirred at 0 °C under N2 atmosphere for 2 h. After completion, the reaction mixture was quenched with water (100 mL) and filtered. The filter cake was washed with water (50 mL) to give dimethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-3,5-dicarboxylate (8.50 g, 96% yield) as a yellow solid. [ka]

[0255] (Step b.) A mixture of dimethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-3,5-dicarboxylate (1 g, 3.06 mmol) and TFA (6.97 g, 61.1 mmol) in DCM (10 mL) was stirred at 25° C. for 1 h under N2 atmosphere. After completion, the mixture was evaporated to give dimethyl 1-(2-aminoethyl)-1H-pyrazole-3,5-dicarboxylate (1.0 g, 96% yield) as the TFA salt as a yellow oil. m / z ES+ [M+H] + 228.0.

[0256] (Process c.) A mixture of dimethyl 1-(2-aminoethyl)-1H-pyrazole-3,5-dicarboxylate (TFA salt, 1.0 g, 2.93 mmol) and TEA (2.97 g, 29.3 mmol, 4.08 mL) in MeCN (100 mL) was stirred under N2 atmosphere at 60° C. for 12 h. Upon completion, the reaction mixture was diluted with water (100 mL) and filtered to give methyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (500 mg, 87% yield) as a white solid. [ka]

[0257] (Step d.) A mixture of methyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (500 mg, 2.56 mmol) and a solution of borane dimethylsulfide complex (10 M in THF, 1.28 mL) in THF (5 mL) was stirred at 25° C. for 12 h under N2 atmosphere. After completion, the reaction mixture was quenched with MeOH (10 mL) at 0° C. and stirred for an additional 2 h. The mixture was evaporated to give methyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (0.5 g, crude) as a yellow oil. m / z ES+ [M+H] + 182.1.

[0258] (Step e.) A mixture of methyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (400 mg, 2.21 mmol), formaldehyde (662 mg, 22.1 mmol), and NaBH3CN (138 mg, 2.21 mmol) in MeOH (10 mL) was stirred for 1 h under N2 atmosphere at 25° C. After completion, the reaction mixture was evaporated and purified by column chromatography (DCM / MeOH=10 / 1) to give methyl 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (130 mg, 30% yield) as an off-white solid. [ka]

[0259] (Process f.) To a solution of methyl 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (130 mg, 0.67 mmol) in DCM (2 mL) was added DIBAL-H (1 M in toluene, 2.0 mL) at -78°C and the mixture was stirred at -78°C for 1 h. After completion, the reaction mixture was quenched with MeOH (2 mL) at -78°C and stirred at 25°C for 1 h. The mixture was filtered and evaporated to give the title compound (80 mg, 73% yield) as a yellow oil. [ka]

[0260] (Intermediate B2: tert-Butyl 2-formyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate) [ka] (Step a.) This step was carried out in a manner similar to step f of intermediate B1 using 7-(tert-butyl) 2-ethyl 5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxylate (CAS: 1053656-22-6). [ka]

[0261] (Intermediate B3: tert-Butyl 3-formyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate) [ka] The title compound was prepared in a similar manner to Intermediate B2 using 7-(tert-butyl) 3-ethyl 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-3,7(8H)-dicarboxylate (CAS: 1215852-11-1). [ka]

[0262] (Intermediate B4: tert-butyl 3-fluoro-2-formyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate) [ka] (Step a.) To a solution of 7-(tert-butyl) 2-ethyl 5,6-dihydroimidazo[1,2-a]pyrazine-2,7(8H)-dicarboxylate (CAS: 1053656-22-6; 1.60 g, 5.42 mmol) in THF (16 mL) and MeOH (1.6 mL) was added LiBH4 (354 mg, 16.3 mmol) at 0° C. The reaction mixture was stirred at 20° C. for 12 h. After completion, the reaction mixture was quenched with saturated aqueous NH4Cl (40 mL) and extracted with EtOAc (40 mL). The organic layer was washed with brine (40 mL), dried over Na2SO4, evaporated and purified by column chromatography (EtOAc) to give tert-butyl 2-(hydroxymethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (0.55 g, 40% yield) as a white solid. [ka]

[0263] (Step b.) To a solution of tert-butyl 2-(hydroxymethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (0.55 g, 2.17 mmol) and imidazole (296 mg, 4.34 mmol) in DCM (5 mL) was added TBSCl (491 mg, 3.26 mmol). The reaction mixture was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was diluted with water (30 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4, evaporated and purified by silica gel chromatography (PE / EtOAc=3 / 1) to give tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (0.76 g, 91% yield) as a yellow oil. m / z ES+ [M+H] + 368.6.

[0264] (Process c.) To a solution of tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (0.66 g, 1.80 mmol) in 1,4-dioxane (10 mL) was added NaHCO3 (453 mg, 5.39 mmol) and Selectfluor (1.27 g, 3.59 mmol) at 5-10 °C under N2 atmosphere. The reaction mixture was stirred at 40 °C for 2 h. After completion, the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL). The organic layer was washed with brine (40 mL), dried over Na2SO4, evaporated and purified by column chromatography (PE / EtOAc=5 / 1) to give tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (100 mg, 14% yield) as a yellow gum. m / z ES+ [M+H] + 386.2.

[0265] (Step d.) To a solution of tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (170 mg, 0.44 mmol) in THF (3 mL) was added TBAF (1 M in THF, 0.88 mL). The reaction mixture was stirred at 20° C. for 1 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, evaporated and purified by column chromatography (EtOAc) to give tert-butyl 3-fluoro-2-(hydroxymethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (70 mg, 55% yield) as a yellow oil. m / z ES+ [M+H] + 272.1.

[0266] (Step e.) To a solution of tert-butyl 3-fluoro-2-(hydroxymethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (70 mg, 0.26 mmol) in DCM (2 mL) was added MnO2 (224 mg, 2.58 mmol). The reaction mixture was stirred at 20° C. for 1 h. After completion, the reaction mixture was filtered and evaporated to give the title compound (60 mg, 86% yield) as a yellow gum. m / z ES+ [M+H] + 270.1.

[0267] (Intermediate B5: 2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)acetaldehyde) [ka] (Step a.) To a solution of 2-(2-aminoethoxy)ethanol (CAS: 929-06-6; 10.0 g, 95.1 mmol) in toluene (100 mL) was added isobenzofuran-1,3-dione (14.1 g, 95.1 mmol). The reaction mixture was stirred at 110° C. for 4 h. After completion, the reaction mixture was evaporated. The residue was triturated with PE / EtOAc (5 / 1; 40 mL) and filtered to give 2-(2-(2-hydroxyethoxy)ethyl)isoindoline-1,3-dione (21 g, 92% yield) as a white solid. [ka]

[0268] (Step b.) To a solution of oxalyl chloride (3.24 g, 25.5 mmol) in DCM (30 mL) was added dropwise a solution of DMSO (3.99 g, 51.0 mmol) in DCM (5 mL) at -78 °C. After stirring for 10 min, a solution of 2-(2-(2-hydroxyethoxy)ethyl)isoindoline-1,3-dione (2 g, 8.50 mmol) in DCM (20 mL) was added dropwise. The mixture was stirred at -78 °C for 30 min, after which TEA (7.74 g, 76.5 mmol) was added. The reaction mixture was stirred at -78 °C for an additional 30 min. After completion, the reaction mixture was warmed to 20 °C and water (50 mL) was added. The layers were separated and the organic layer was washed with brine (50 mL), dried over Na2SO4 and evaporated to give the title compound (1.5 g, 76% yield) as a yellow oil. [ka]

[0269] (Intermediate B6: tert-butyl (rac-trans)-3-(benzyloxy)-4-formylpyrrolidine-1-carboxylate) [ka] (Step a.) To a mixture of rac-tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (CAS: 114214-49-2; 5.00 g, 27.0 mmol) and CuI (1.03 g, 5.40 mmol) in THF (50 mL) was added vinylmagnesium bromide (1 M in THF, 108 mL) dropwise at -40°C. The reaction mixture was warmed to -10°C and stirred for 1 h. After completion, the reaction mixture was quenched by slow addition of saturated aqueous NH4Cl (100 mL) at 0°C. The aqueous mixture was extracted with EtOAc (100 mL) and the organic layer was washed with brine (100 mL), dried over Na2SO4, evaporated and purified by column chromatography (PE / EtOAc=5 / 1) to give tert-butyl (rac-trans)-3-hydroxy-4-vinylpyrrolidine-1-carboxylate (4.3 g, 75% yield) as a colorless oil. [ka]

[0270] (Step b.) To a mixture of NaH (375 mg, 9.38 mmol, 60% dispersion in mineral oil) in THF (8 mL) was added a solution of tert-butyl (rac-trans)-3-hydroxy-4-vinylpyrrolidine-1-carboxylate (1 g, 4.69 mmol) in THF (2 mL) at 0° C. The mixture was stirred at 0° C. for 30 min. Then, benzyl bromide (1.20 g, 7.03 mmol) was added and the reaction mixture was stirred at 25° C. for another 12 h. After completion, the reaction mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, evaporated and purified by column chromatography (PE / EtOAc=10 / 1) to give tert-butyl (rac-trans)-3-(benzyloxy)-4-vinylpyrrolidine-1-carboxylate (1.3 g, 88% yield) as a colorless oil. [ka]

[0271] (Process c.) To a solution of tert-butyl (rac-trans)-3-(benzyloxy)-4-vinylpyrrolidine-1-carboxylate (0.95 g, 3.13 mmol) and NaIO4 (2.34 g, 11.0 mmol) in a mixture of THF (10 mL) and water (5 mL), K2OsO4·2H2O (115 mg, 0.31 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After completion, saturated aqueous Na2S2O3 (50 mL) was added and the mixture was stirred at 25 °C for 30 min. The aqueous mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated aqueous Na2S2O3 (50 mL), saturated aqueous NaHCO3 (50 ml), brine (50 mL), dried over Na2SO4, evaporated and purified by column chromatography (PE / EtOAc = 1 / 1) to give the title compound (0.7 g, 69% yield) as a colorless gum. m / z ES+ [M-tBu] + 250.1;

[0272] (Intermediate B7: rac-7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carbaldehyde) [ka] (Step a.) A mixture of 3-methylpyrazin-2-amine (CAS: 19838-08-5; 3.00 g, 27.5 mmol) and ethyl 3-bromo-2-oxopropanoate (6.43 g, 33.0 mmol) in 1,2-dimethoxyethane (30 mL) was stirred at 25° C. for 16 h. After completion, the mixture was cooled to 0° C. and filtered. The filter cake was dissolved in EtOH (40 mL) and stirred at 80° C. for 2 h. After completion, the reaction mixture was cooled to 0° C. and filtered to give ethyl 8-methylimidazo[1,2-a]pyrazine-2-carboxylate (3.2 g, crude) as a white solid. [ka]

[0273] (Step b.) To a solution of ethyl 8-methylimidazo[1,2-a]pyrazine-2-carboxylate (2.00 g, 9.75 mmol) in EtOH (50 mL) was added 10% Pd / C (320 mg). The mixture was stirred at 50° C. under H2 atmosphere (50 Psi (345 kPa)) for 16 h. After completion, the reaction mixture was filtered and evaporated to give ethyl 8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (2 g, crude) as a yellow solid. [ka]

[0274] (Process c.) To a solution of ethyl 8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (2.20 g, 10.5 mmol) and paraformaldehyde (4.27 g, 52.6 mmol) in DCM (22 mL) was added NaBH(OAc)3 (4.46 g, 21.0 mmol). The mixture was stirred at 20° C. for 90 min. After completion, the reaction mixture was evaporated and purified by reverse phase flash chromatography (water (0.1% NH4OH) / MeCN) to give ethyl 7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (1.6 g, 68% yield) as a colorless oil. [ka]

[0275] (Step d.) To a solution of ethyl 7,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (500 mg, 2.24 mmol) in DCM (15 mL) was added DIBAL-H (1 M in toluene, 8.96 mL). The reaction mixture was stirred at -70°C for 20 min. After completion, the mixture was quenched with MeOH (1.8 mL) and stirred at 20°C for 30 min. The reaction mixture was filtered and the filtrate was evaporated. The crude product was purified by column chromatography (EtOAc) to give the title compound (210 mg, 52% yield) as a brown oil. [ka]

[0276] (Intermediate B8: tert-Butyl 2-formyl-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazine-7(8H)-carboxylate) [ka]

[0277] (Step a.) To a solution of NaH (1.59 g, 39.6 mmol, 60% dispersion in mineral oil) in DMF (100 mL) was added methyl (tert-butoxycarbonyl)glycinate (CAS: 31954-27-5; 5 g, 26.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then 3-bromoprop-1-ene (3.20 g, 26.4 mmol) was added. The reaction mixture was stirred at 0° C. for an additional 3 h. After completion, the reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) at 0° C., then diluted with water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, evaporated and purified by column chromatography (PE / EtOAc=5 / 1) to give methyl N-allyl-N-(tert-butoxycarbonyl)glycinate (3.0 g, 50% yield) as a colorless oil. [ka]

[0278] (Step b.) A mixture of methyl N-allyl-N-(tert-butoxycarbonyl)glycinate (500 mg, 2.18 mmol), OsO4 (55.4 mg, 0.22 mmol), NaIO4 (1.40 g, 6.54 mmol) in THF (5 mL) and water (5 mL) was stirred at 0 °C for 3 h under N2 atmosphere. After completion, the mixture was quenched with saturated aqueous Na2S2O3 (5 mL), stirred at 25 °C for an additional 30 min, and then extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated aqueous Na2S2O3 (2 x 15 mL) and brine (20 mL), dried over Na2SO4, filtered, and evaporated to give methyl N-(tert-butoxycarbonyl)-N-(2-oxoethyl)glycinate (350 mg, 1.51 mmol, 69% yield) as a black oil. [ka]

[0279] (Process c.) A mixture of benzyl hydrazinecarboxylate (862 mg, 5.19 mmol), methyl N-(tert-butoxycarbonyl)-N-(2-oxoethyl)glycinate (1.2 g, 5.19 mmol), NaBH3CN (326 mg, 5.19 mmol), 4 Å molecular sieves (300 mg), and acetic acid (1.56 g, 25.9 mmol) in MeOH (30 mL) was stirred at 25 °C under N2 atmosphere for 6 h. After completion, the reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography (PE / EtOAc = 1 / 1) to give benzyl 2-(2-((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)ethyl)hydrazine-1-carboxylate (1.5 g, 76% yield) as a colorless oil. [ka]

[0280] (Step d.) To a solution of benzyl 2-(2-((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)ethyl)hydrazine-1-carboxylate (1.5 g, 3.93 mmol) in MeOH (30 mL) was added 10% Pd / C (150 mg) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 25 °C under H2 atmosphere (15 Psi (103 kPa)) for 5 h. After completion, the reaction mixture was filtered and evaporated to give tert-butyl 4-amino-3-oxopiperazine-1-carboxylate (0.8 g, 95% yield) as a yellow solid. [ka]

[0281] (Step e.) A mixture of tert-butyl 4-amino-3-oxopiperazine-1-carboxylate (0.8 g, 3.72 mmol), ethyl 2-ethoxy-2-iminoacetate (CAS: 816-27-3; 540 mg, 3.72 mmol) in EtOH (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 25 °C under N2 atmosphere for 1 h. After completion, the mixture was evaporated and purified by reverse phase flash chromatography (water (0.1% FA) / MeCN) to give 7-(tert-butyl) 2-ethyl 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazine-2,7(8H)-dicarboxylate (500 mg, 45% yield) as a colorless oil. [ka]

[0282] (Process f.) To a solution of 7-(tert-butyl) 2-ethyl 5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazine-2,7(8H)-dicarboxylate (100 mg, 0.34 mmol) in THF (5 mL) was added DIBAL-H (1M in toluene, 1.01 mL). The mixture was stirred at -78°C for 2 h. After completion, the reaction mixture was quenched with MeOH (1 mL) at -78°C and then stirred for an additional 2 h. The mixture was filtered and evaporated to give the title compound (60 mg, 71% yield) as a white solid. [ka]

[0283] (Intermediate B9: tert-butyl (rac-cis)-3-cyano-4-formylpiperidine-1-carboxylate) [ka] (Step a.) To a solution of 1-(tert-butyl) 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (CAS: 71233-25-5; 10 g, 36.9 mmol) in EtOH (60 mL) was added NaBH4 (697 mg, 18.4 mmol). The reaction mixture was stirred at 20° C. for 2 h. After completion, the reaction mixture was slowly added into saturated aqueous NH4Cl (50 mL) and the aqueous mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, evaporated and purified by column chromatography (PE / EtOAc=5 / 1) to give 1-(tert-butyl) 4-ethyl 3-hydroxypiperidine-1,4-dicarboxylate (7.5 g, 74% yield) as a colorless oil. [ka]

[0284] (Step b.) To a solution of 1-(tert-butyl) 4-ethyl 3-hydroxypiperidine-1,4-dicarboxylate (7.5 g, 27.4 mmol) and TEA (11.1 g, 110 mmol) in DCM (75 mL) was added MsCl (6.29 g, 54.9 mmol) at 0° C. The reaction mixture was stirred at 20° C. for 12 h. After completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and evaporated to give 1-(tert-butyl) 4-ethyl 3-((methylsulfonyl)oxy)piperidine-1,4-dicarboxylate (9.6 g, crude) as a yellow oil. m / z ES+ [M+Na] + 374.0.

[0285] (Process c.) A mixture of 1-(tert-butyl) 4-ethyl 3-((methylsulfonyl)oxy)piperidine-1,4-dicarboxylate (9.6 g, 27.3 mmol), TBAF (1 M in THF, 41.0 mL), and trimethylsilyl cyanide (4.07 g, 41.0 mmol) in MeCN (90 mL) was stirred at 80° C. for 12 h. After completion, the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and evaporated. The residue was purified by column chromatography (PE / EtOAc=5 / 1) to give two isomers.

[0286] The first eluting isomer was confirmed by 2D NMR to be 1-(tert-butyl) 4-ethyl (rac-trans)-3-cyanopiperidine-1,4-dicarboxylate (1.4 g, 18% yield) as a yellow oil. [ka]

[0287] The second eluting isomer was confirmed by 2D NMR to be 1-(tert-butyl) 4-ethyl (rac-cis)-3-cyanopiperidine-1,4-dicarboxylate (5 g, crude) as a yellow oil. [ka]

[0288] (Step d.) To a solution of 1-(tert-butyl) 4-ethyl (rac-cis)-3-cyanopiperidine-1,4-dicarboxylate (0.8 g, 2.83 mmol) in THF (8 mL) and MeOH (1 mL) was added LiBH4 (185 mg, 8.5 mmol) and the mixture was stirred at 10° C. for 12 h. After completion, the mixture was quenched with saturated aqueous NH4Cl (0.2 mL), diluted with EtOAc (30 mL), filtered and evaporated. The residue was purified by column chromatography (PE / EtOAc=1 / 3) to give tert-butyl (rac-cis)-3-cyano-4-(hydroxymethyl)piperidine-1-carboxylate (500 mg, 73% yield) as a colorless oil. [ka]

[0289] (Step e.) To a solution of tert-butyl (rac-cis)-3-cyano-4-(hydroxymethyl)piperidine-1-carboxylate (450 mg, 1.87 mmol) in DCM (10 mL) was added Dess-Martin periodinane (1.59 g, 3.75 mmol) and the mixture was stirred for 1 h at 15° C. After completion, the mixture was filtered, evaporated and purified by column chromatography (PE / EtOAc=1 / 1) to give the title compound (434 mg, crude) as a yellow oil, which was used directly in the subsequent step.

[0290] (Intermediate B10: tert-butyl (R)-3-(2-oxoethyl)pyrrolidine-1-carboxylate) [ka] (Step a.) To a solution of (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid (CAS: 204688-60-8; 1.00 g, 4.36 mmol) in THF (10 mL) was added a solution of borane tetrahydrofuran complex (1 M in THF, 5.23 mL) at 0° C. The reaction mixture was stirred at 20° C. for 1 h. After completion, the reaction mixture was quenched with 10% aqueous NaOH (2 mL). The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL). The organic layer was dried over Na2SO4 and evaporated to give tert-butyl (R)-3-(2-hydroxyethyl)pyrrolidine-1-carboxylate (0.93 g, 99% yield) as a colorless oil. [ka]

[0291] (Step b.) To a solution of tert-butyl (R)-3-(2-hydroxyethyl)pyrrolidine-1-carboxylate (0.3 g, 1.39 mmol) in DCM (3 mL) was added Dess-Martin periodinane (1.18 g, 2.79 mmol). The reaction mixture was stirred at 20 °C for 1 h. After completion, the pH of the reaction mixture was adjusted to pH 9 with saturated aqueous NaHCO3 (20 mL). The layers were separated and the organic layer was washed with brine (20 mL), dried over Na2SO4, evaporated and purified by column chromatography (PE / EtOAc = 3 / 1) to give the title compound (150 mg, 50% yield) as a colorless oil. [ka]

[0292] (Intermediate B11: tert-butyl 6-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate) [ka] (Step a.) A mixture of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (CAS: 893566-74-0; 1.0 g, 3.20 mmol), N-formylsaccharin (CAS: 50978-45-5; 1.35 g, 6.41 mmol), Pd(OAc) (58 mg, 0.26 mmol), 1,4-bis(diphenylphosphino)butane (CAS: 7688-25-7; 163 mg, 0.38 mmol), triethylsilane (819 mg, 7.05 mmol), and NaCO (848 mg, 8.01 mmol) in DMF (20 mL) was stirred at 80 °C under N atmosphere for 16 h. After completion, the reaction mixture was filtered, evaporated and purified by column chromatography (PE / EtOAc=5 / 1) to give the title compound (100 mg, 11% yield) as a colorless oil. [ka]

[0293] (Intermediate B12: tert-Butyl 5-formylisoindoline-2-carboxylate) [ka] The title compound was prepared in a similar manner to Intermediate B11 using tert-butyl 5-bromoisoindoline-2-carboxylate (CAS: 201940-08-1). [ka]

[0294] (Intermediate B13: tert-butyl 3-(3-formylphenyl)azetidine-1-carboxylate) [ka] (Step a.) Methyl 3-bromobenzoate (500 mg, 2.33 mmol), tert-butyl in 1,2-dimethoxyethane (50 mL) A mixture of 3-bromoazetidine-1-carboxylate (714 mg, 3.02 mmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (CAS: 870987-63-6; 26 mg, 0.023 mmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride (CAS: 1034901-50-2; 4.6 mg, 0.012 mmol), tris(trimethylsilyl)silane (CAS: 1873-77-4; 578 mg, 2.33 mmol), and Na2CO3 (493 mg, 4.65 mmol) was degassed and purged with N2 three times, then the mixture was stirred at 25 °C under N2 atmosphere for 14 h. After completion, the reaction mixture was filtered and evaporated. The residue was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4, evaporated and purified by column chromatography (PE / EtOAc=9 / 1) to give tert-butyl 3-(3-(methoxycarbonyl)phenyl)azetidine-1-carboxylate (590 mg, 75% yield) as a pale yellow oil. [ka]

[0295] (Step b.) A mixture of tert-butyl 3-(3-(methoxycarbonyl)phenyl)azetidine-1-carboxylate (100 mg, 0.34 mmol) in DCM (5 mL) was degassed and purged with N2 three times. DIBAL-H (1 M in toluene, 1.03 mL) was added and the reaction mixture was stirred at -60 °C under N2 atmosphere for 1 h. After completion, the reaction mixture was quenched with MeOH (0.5 mL) at -60 °C, filtered and evaporated to give tert-butyl 3-(3-(hydroxymethyl)phenyl)azetidine-1-carboxylate (90 mg, crude) as a pale yellow oil. [ka]

[0296] (Process c.) To a solution of tert-butyl 3-(3-(hydroxymethyl)phenyl)azetidine-1-carboxylate (90 mg, 0.34 mmol) in DCM (1 mL) was added MnO2 (594 mg, 6.84 mmol). The mixture was stirred at 25° C. for 16 h. After completion, the reaction mixture was filtered and evaporated to give the title compound (70 mg, crude) as a pale yellow oil. [ka]

[0297] (Intermediate B14: tert-butyl 2-(4-formylphenyl)pyrrolidine-1-carboxylate) [ka] The title compound was prepared in a similar manner to intermediate B13 using methyl 4-bromobenzoate and (tert-butoxycarbonyl)proline (CAS: 59433-50-0) in step a. [ka]

[0298] (Intermediate B15: tert-butyl 4-formyl-2-methylpiperidine-1-carboxylate) [ka] (Step a.) To a solution of methyl 2-methylisonicotinate (2.00 g, 13.2 mmol) in acetic acid (20 mL) was added PtO2 (451 mg, 1.98 mmol). The mixture was stirred at 40 °C under H2 atmosphere (3 MPa) for 2 days. After completion, the mixture was filtered and evaporated. The residue was dissolved in water (50 mL), then K2CO3 (5.34 g, 38.7 mmol) and di-tert-butyl dicarbonate (5.63 g, 25.8 mmol) were added and the reaction mixture was stirred at 20 °C for 12 h. After completion, the mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL), evaporated and purified by column chromatography (PE / EtOAc=20 / 1) to give 1-(tert-butyl) 4-methyl 2-methylpiperidine-1,4-dicarboxylate (2.4 g, 72% yield) as a colorless oil. m / z ES+ [M-tBu] + 201.9.

[0299] (Step b.) To a solution of 1-(tert-butyl) 4-methyl 2-methylpiperidine-1,4-dicarboxylate (600 mg, 2.33 mmol) in DCM (15 mL) was added DIBAL-H (1M in toluene, 7.0 mL). The reaction mixture was stirred at -70°C for 1 h. After completion, the mixture was quenched with MeOH (2 mL) and stirred at 20°C for an additional 30 min. The mixture was filtered and the filtrate was evaporated to give the title compound (420 mg, 79% yield) as a colorless oil. [ka]

[0300] (Intermediate B16: 2-morpholinoacetaldehyde) [ka] (Step a.) A mixture of 4-(2,2-diethoxyethyl)morpholine (CAS: 3616-59-9; 500 mg, 2.46 mmol) and 12 M HCl (2.05 mL) in water (2 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 80 °C under N2 atmosphere for 1 h. After completion, the reaction mixture was evaporated to give the title compound (317 mg, 100% yield) as a colorless solid. [ka]

[0301] (Intermediate C1: 6-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine) [ka] (Step a.) To a solution of 6-bromo-1H-pyrrolo[2,3-b]pyridine (CAS: 143468-13-7; 0.8 g, 4.06 mmol) in DMF (10 mL) was added NaH (324 mg, 8.12 mmol, 60% dispersion in mineral oil) at 0° C. and the mixture was stirred for 30 min. Then, methyl iodide (1.15 g, 8.12 mmol) was added and the reaction mixture was stirred at 20° C. for 12 h. After completion, the mixture was quenched with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), evaporated and purified by column chromatography (PE / EtOAc=10 / 1) to give the title compound (0.7 g, 81% yield) as a yellow oil. [ka]

[0302] Example 1 (3aR,11aS)-6-Fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione [ka] (Step a.) A mixture of intermediate 1 (40.0 g, 164 mmol) and TFA (250 mL) was stirred at 25° C. under N2 atmosphere for 12 h. After completion, the reaction mixture was evaporated. The residue was triturated (PE / EtOAc=10 / 1) for 60 min. The suspension was filtered to give (2S,3S)-3-(methoxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid (27.0 g, 87% yield) as a white solid. [ka]

[0303] (Step b.) To a solution of (2S,3S)-3-(methoxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid (5 g, 26.7 mmol) in MeCN (50 mL) was added Ghosez reagent (CAS: 26189-59-3; 3.93 g, 29.3 mmol) at 0° C. The mixture was stirred at room temperature for 1 h and then added dropwise to a mixture of intermediate 2a (6.42 g, 26.7 mmol) and N,N-dimethylpyridin-2-amine (6.53 g, 53.4 mmol) in MeCN (50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. After completion, the mixture was quenched with water (6 mL) and then evaporated to remove MeCN. The residue was diluted with additional water (35 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (PE / EtOAc=0 / 1) to give methyl (2S,3S)-2-((2-((tert-butoxycarbonyl)amino)-3-fluorophenyl)(methyl)carbamoyl)-5-oxopyrrolidine-3-carboxylate (8.7 g, 78% yield) as a white solid. [ka]

[0304] (Process c.) A mixture of methyl (2S,3S)-2-((2-((tert-butoxycarbonyl)amino)-3-fluorophenyl)(methyl)carbamoyl)-5-oxopyrrolidine-3-carboxylate (22.0 g, 53.7 mmol), 2-bromo-6-methyl-4-(trifluoromethyl)pyridine (CAS: 451459-17-9; 15.4 g, 64.4 mmol), Pd2(dba)3 (4.92 g, 5.37 mmol), Xantphos (6.22 g, 10.7 mmol), and K2CO3 (18.5 g, 134 mmol) in 1,4-dioxane (220 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 100 °C under N2 atmosphere for 3 h. After completion, the mixture was filtered and evaporated, then water (150 mL) was added and the mixture was extracted with EtOAc (3×170 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (PE / EtOAc=1 / 1) to give methyl (2S,3S)-2-((2-((tert-butoxycarbonyl)amino)-3-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-3-carboxylate (27.7 g, 89% yield) as a yellow solid. [ka]

[0305] (Step d.) To a solution of (2S,3S)-2-((2-((tert-butoxycarbonyl)amino)-3-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-3-carboxylate (53.4 g, 93.9 mmol) in THF (530 mL) and MeOH (53 mL) was added NaBH4 (7.11 g, 187 mmol) in portions at 0° C. The reaction mixture was stirred at 20° C. for 1 h. After completion, the mixture was quenched slowly with saturated aqueous NH4Cl (50 mL). The mixture was stirred for an additional 30 min and then evaporated. Water (200 mL) was added and the mixture was extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (PE / EtOAc=0 / 1) to give tert-butyl (2-fluoro-6-((2S,3S)-3-(hydroxymethyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamide)phenyl)carbamate (47 g, 93% yield) as a yellow solid. [ka]

[0306] (Step e.) To a solution of tert-butyl (2-fluoro-6-((2S,3S)-3-(hydroxymethyl)-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidine-2-carboxamido)phenyl)carbamate (47.0 g, 86.9 mmol) in DCM (500 mL) was added TEA (35.2 g, 347 mmol) at 0° C. Then, MsCl (14.9 g, 130 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at 0° C. for 1 h. After completion, the reaction mixture was quenched with water (400 mL) and extracted with EtOAc (2×400 mL). The combined organic layers were washed with brine (800 mL), dried over Na2SO4 and evaporated to give ((2S,3S)-2-((2-((tert-butoxycarbonyl)amino)-3-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidin-3-yl)methyl methanesulfonate (52.0 g, 98% yield) as a yellow solid. m / z ES+ [M+H] + 619.1.

[0307] (Process f.) To a solution of ((2S,3S)-2-((2-((tert-butoxycarbonyl)amino)-3-fluorophenyl)(methyl)carbamoyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxopyrrolidin-3-yl)methyl methanesulfonate (26.0 g, 42.0 mmol) in NMP (400 mL) was added K3PO4 (26.7 g, 126 mmol). The mixture was stirred at 60° C. for 12 h. After completion, the mixture was diluted with water (1.2 L) and extracted with EtOAc (3×800 mL). The combined organic layers were washed with water (2×1 L), brine (2×1 L), dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (PE / EtOAc=3 / 1) to give tert-butyl (3aR,11aS)-6-fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocine-5-carboxylate (31.0 g, 67% yield) as a yellow solid. m / z ES+ [M+H] + 523.0.

[0308] (Process g.) To a solution of tert-butyl (3aR,11aS)-6-fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocine-5-carboxylate (31.0 g, 59.3 mmol) in DCM (320 mL) was added TFA (123 g, 1.08 mol). The mixture was stirred at 20° C. for 2 h. Upon completion, the pH of the mixture was adjusted to pH 8 with saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was further extracted with EtOAc (3×600 mL). The combined organic layers were washed with brine (2×500 mL), dried over Na 2 SO 4 and evaporated to give the title compound (22.3 g, 90% yield) as a yellow solid. [ka]

[0309] Example 2 (3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione [ka] The title compound was prepared in a similar manner to example 1 using intermediate 2b in step b. [ka]

[0310] Example 3 ((3aR,11aS)-6,10-Dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) A mixture of Example 2 (1.00 g, 2.28 mmol), methylboronic acid (2.73 g, 45.6 mmol), Cs2CO3 (2.23 g, 6.84 mmol), and XPhos-Pd-G2 (CAS: 1310584-14-5; 179 mg, 0.23 mmol) in toluene (15 mL) was stirred at 110 °C under N2 atmosphere for 3 h. After completion, the reaction mixture was filtered and the filtrate was evaporated. The residue was diluted with water (30 mL) and EtOAc (20 mL) and the layers were separated. The aqueous layer was further extracted with EtOAc (2 x 50 mL), dried over Na2SO4, and evaporated. The residue was purified by column chromatography (PE / EtOAc = 1 / 3) to give the title compound (580 mg, 60% yield) as a white solid. [ka]

[0311] Example 4 ((3aR,11aS)-5-Allyl-6-fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) A mixture of Example 1 (7.6 g, 17.9 mmol), Na2CO3 (5.72 g, 53.9 mmol), TBAB (580 mg, 1.80 mmol) in DMF (70 mL) was degassed and purged with N2 three times, then 3-bromoprop-1-ene (8.71 g, 71.9 mmol) was added dropwise at 20 °C. The mixture was stirred at 100 °C under N2 atmosphere for 2 h. After completion, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (3 x 200 mL), brine (2 x 200 mL), dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (PE / EtOAc = 5 / 1) to give the title compound (7 g, 82% yield) as a yellow solid. [ka]

[0312] Example 5 ((3aR,11aS)-5-Allyl-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] The title compound was prepared in a similar manner to Example 4 using Example 2. [ka]

[0313] Example 6 ((3aR,11aS)-5-Allyl-6-chloro-8,9-difluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Process a~g.) These seven steps were carried out in a similar manner to Example 1 using intermediate 4 in step b. m / z ES+ [M+H] + 475.0.

[0314] (Process h.) This step was carried out in a similar manner to Example 4. [ka]

[0315] Example 7 ((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-(4-methylpiperazin-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) This step was carried out in a similar manner to step a of Example 4 using Example 2.

[0316] (Step b.) To a mixture of (3aR,11aS)-5-allyl-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione (4.45 g, 9.29 mmol) and NaIO4 (5.96 g, 27.8 mmol) in THF (50 mL) and water (10 mL) was added OsO4 (236 mg, 0.93 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. After completion, the reaction mixture was quenched with saturated aqueous Na2S2O3 (50 mL) and stirred at 25 °C for another 30 min. The mixture was diluted with water (200 mL) and extracted with EtOAc (3×100 mL). The organic layer was washed with saturated aqueous NaSO (2×100 mL), saturated aqueous NaHCO (2×100 mL) and brine (3×100 mL). The organic layer was dried over NaSO and evaporated to give 2-((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)acetaldehyde (4.4 g, 98% yield) as a yellow solid. [ka]

[0317] (Process c.) To a mixture of 2-((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)acetaldehyde (50 mg, 0.10 mmol), 1-methylpiperazine (11 mg, 0.11 mmol) and 4 Å molecular sieves (10 mg) in MeOH (2 mL) was added acetic acid (31 mg, 0.52 mmol). The mixture was stirred at 20° C. for 30 min, after which NaBH3CN (13 mg, 0.21 mmol) was added. The reaction mixture was stirred at 20° C. for an additional 30 min. After completion, the reaction mixture was quenched with water (0.1 mL) and filtered. The filtrate was evaporated and purified by preparative HPLC to give the title compound (29 mg, 46% yield) as an off-white solid. [ka]

[0318] Example 8 ((3aR,11aS)-6-chloro-8-fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-(4-methylpiperazin-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka]

[0319] (Process a~h.) These eight steps were carried out in a similar manner to Example 1 using intermediate 3 in step b.

[0320] (Process i~j.) These two steps were carried out in a similar manner to Example 7. [ka]

[0321] Example 9 ((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-((R)-3-methylpiperazin-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Process a~c.) These three steps were carried out in a manner similar to steps a to c of Example 7, except that in step c, tert-butyl (R)-2-methylpiperazine-1-carboxylate (CAS: 170033-47-3) was used.

[0322] (Step d.) To a solution of tert-butyl (R)-4-(2-((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)ethyl)-2-methylpiperazine-1-carboxylate (80 mg, 0.12 mmol) in DCM (1 mL) was added TFA (308 mg, 2.70 mmol). The mixture was stirred at 20° C. for 30 min. After completion, the pH of the reaction mixture was adjusted to pH 8 with saturated aqueous NaHCO.sub.3, extracted with EtOAc (3.times.5 mL), evaporated and purified by preparative HPLC to give the title compound (39 mg, 58% yield) as a white solid. [ka]

[0323] Example 10 ((3aR,11aS)-6-chloro-5-(2-((S)-2,4-dimethylpiperazin-1-yl)ethyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione hydrochloride) [ka]

[0324] (Process a~d.) These four steps were carried out in a manner similar to steps a to d of Example 9, except that in step c, tert-butyl (S)-3-methylpiperazine-1-carboxylate (CAS: 147081-29-6) was used.

[0325] (Step e.) A mixture of (3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-((S)-2-methylpiperazin-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione (50 mg, 0.09 mmol), paraformaldehyde (53 mg, 1.77 mmol), 4 Å molecular sieves, NaBH3CN (11 mg, 0.18 mmol), and acetic acid (11 mg, 0.18 mmol) in MeOH (2 mL) was stirred at 40° C. for 16 h. After completion, the reaction mixture was filtered. The filtrate was evaporated and purified by preparative HPLC to give the title compound as an HCl salt (35.0 mg, 64% yield) as a white solid. [ka]

[0326] Example 11 ((3aR,11aS)-5-(2-((S)-4-acetyl-2-methylpiperazin-1-yl)ethyl)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Process a~c.) These three steps were carried out in a manner similar to steps b to d of Example 9, using Example 5 in step a and tert-butyl (S)-3-methylpiperazine-1-carboxylate (CAS: 147081-29-6) in step b.

[0327] (Step d.) To a solution of (3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-((S)-2-methylpiperazin-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione (100 mg, 0.18 mmol) in DCM (2 mL) was added TEA (36 mg, 0.35 mmol) and acetyl chloride (17 mg, 0.21 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 10 min. After completion, the reaction mixture was evaporated and purified by preparative HPLC to give the title compound (60 mg, 55% yield) as a white solid. [ka]

[0328] (Examples 12 and 13) ((3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-(4-methylpiperazin-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione and (3aR,11aS)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-(4-methylpiperazin-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione dihydrochloride) [ka] (Step a.) A mixture of Example 7 (3.5 g, 6.19 mmol), methylboronic acid (11.1 g, 185 mmol), XPhos-Pd-G2 (974 mg, 1.24 mmol), and Cs2CO3 (6.05 g, 18.5 mmol) in toluene (55 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 110 °C under N2 atmosphere for 12 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography (AlO, EtOAc / MeOH=15 / 1) followed by reverse-phase flash chromatography (water (0.1% NHOH) / MeCN) to give (3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-(4-methylpiperazin-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocine-2,11(3H)-dione (5.0 g, 74% yield) as a white solid. Further purification by preparative HPLC afforded (3aR,11aS)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-(4-methylpiperazin-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione as the dihydrochloride salt (120 mg) as a yellow solid.

[0329] Example 12 [ka]

[0330] Example 13 [ka]

[0331] Example 14 ((3aR,11aS)-5-(2-(1-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka]

[0332] (Process a~b.) These two steps were carried out in a manner similar to steps a-b of Example 7, using Example 5 in step a and intermediate A1 in step b.

[0333] (Process c.) This step was carried out in a similar manner to step a of Example 12. [ka]

[0334] Example 15 ((3aR,11aS)-5-(2-((S)-3-(hydroxymethyl)-4-methylpiperazin-1-yl)ethyl)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka]

[0335] (Process a~d.) These four steps were carried out in a manner similar to steps b to e of Example 10, using Example 5 in step a and tert-butyl (S)-2-(hydroxymethyl)piperazine-1-carboxylate (CAS: 1030377-21-9) in step b.

[0336] (Step e.) This step was carried out in a similar manner to step a of Example 12. [ka]

[0337] (Example 16) ((3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-(piperazin-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Process a~c.) These three steps were carried out in a manner similar to steps a-c of Example 7, using tert-butyl piperazine-1-carboxylate in step c.

[0338] (Step d.) This step was carried out in a similar manner to step a of Example 12.

[0339] (Step e.) This step was carried out in a similar manner to step d of Example 9. [ka]

[0340] (Example 17) ((3aR,11aS)-6,10-Dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-((2-(methylamino)ethyl)amino)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka]

[0341] (Process a~c.) These three steps were carried out in a manner similar to steps a to c of Example 7, except that in step c, tert-butyl (2-aminoethyl)(methyl)carbamate (CAS: 121492-06-6) was used.

[0342] (Step d.) To a solution of tert-butyl (2-((2-((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)ethyl)amino)ethyl)(methyl)carbamate (400 mg, 0.63 mmol) and TEA (190 mg, 1.88 mmol) in DCM (4 mL) was added di-tert-butyl dicarbonate (273 mg, 1.25 mmol). The mixture was stirred at 25° C. for 16 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layer was dried over Na2SO4 and evaporated to obtain a residue. The residue was purified by column chromatography (PE / EtOAc=2 / 1) to obtain tert-butyl (2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(2-((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)ethyl)carbamate (180 mg, 33% yield) as a yellow solid. m / z ES+ [M+H] + 739.3.

[0343] (Process e~f.) These two steps were carried out in a manner similar to steps d-e of Example 16. [ka]

[0344] (Example 18) ((3aR,11aS)-6-Fluoro-5-(2-hydroxyethyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) This step was carried out in a similar manner to step b of Example 7 using Example 4.

[0345] (Step b.) A mixture of 2-((3aR,11aS)-6-fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)acetaldehyde (50 mg, 0.11 mmol), NaBH3CN (14 mg, 0.22 mmol), and acetic acid (0.65 mg, 0.01 mmol) in DCM (1 mL) was stirred at 20° C. under N2 atmosphere for 1 h. After completion, the mixture was evaporated and the resulting residue was purified by preparative HPLC to give the title compound (20 mg, 40% yield) as an off-white solid. [ka]

[0346] The examples in Table 1 were prepared using methods similar to those described in the synthesis of Example 7, using the intermediates indicated. (Table 1) [Table 2] TIFF2024539132000144.tif243170TIFF2024539132000145.tif241170TIFF202 4539132000146.tif240170TIFF2024539132000147.tif242170TIFF20245391320 00148.tif242170TIFF2024539132000149.tif241170TIFF2024539132000150.t if241170TIFF2024539132000151.tif242170TIFF2024539132000152.tif241170 TIFF2024539132000153.tif242170TIFF2024539132000154.tif243170TIFF202 4539132000155.tif242170TIFF2024539132000156.tif242170TIFF20245391320 00157.tif241170TIFF2024539132000158.tif242170TIFF2024539132000159.t if242170TIFF2024539132000160.tif241170TIFF2024539132000161.tif241170

[0347] The examples in Table 2 were prepared using methods similar to those described in the synthesis of Example 9, using the intermediates indicated. (Table 2) [Table 3] TIFF2024539132000163.tif241170

[0348] The examples in Table 3 were prepared using methods similar to those described in the synthesis of Example 10, using the intermediates indicated. (Table 3) [Table 4] TIFF2024539132000165.tif242170TIFF2024539132000166.tif241170

[0349] The examples in Table 4 were prepared using methods similar to those described in the synthesis of Example 12, using the intermediates listed. (Table 4) [Table 5] TIFF2024539132000168.tif242170TIFF2024539132000169.tif241170TIFF2024539132000170.tif241170TIFF2024539132000171.tif243170

[0350] (Example 76) ((3aR,11aS)-6-chloro-10-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methyl)-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka]

[0351] (Step a.) To a mixture of Intermediate B1 (80 mg, 0.48 mmol), Example 2 (212 mg, 0.48 mmol) and TMSCl (131 mg, 1.21 mmol) in DMF (1 mL) was added a solution of borane tetrahydrofuran complex (1M in THF, 0.48 mL) in DMF (5 mL). The mixture was stirred at 25° C. under N2 atmosphere for 12 h. After completion, the reaction mixture was quenched with MeOH (1 mL) at 25° C. and evaporated. The residue was purified by reverse phase flash chromatography (water (0.1% FA) / MeCN) to give the title compound (120 mg, 42% yield) as a yellow solid. [ka]

[0352] (Example 77) ((3aR,11aS)-6-Fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(piperidin-4-ylmethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione hydrochloride) [ka] (Step a.) This step was carried out in a manner similar to step a of Example 76 using Example 1 and tert-butyl 4-formylpiperidine-1-carboxylate.

[0353] (Step b.) To a solution of tert-butyl 4-(((3aR,11aS)-6-fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)methyl)piperidine-1-carboxylate (50 mg, 0.081 mmol) in DCM (1 mL) was added TFA (0.2 mL). The mixture was stirred at 20° C. for 1 h. After completion, the reaction mixture was evaporated. The residue was diluted with saturated aqueous NaHCO3 (3 mL) and extracted with EtOAc (3×2 mL). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by preparative HPLC to give the title compound as the HCl salt (25 mg, 54% yield) as a white solid. [ka]

[0354] (Example 78) ((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(piperidin-4-ylmethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) To a solution of Example 2 (150 mg, 0.34 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (365 mg, 1.71 mmol), and 4 Å molecular sieves (100 mg) in DCE (1.5 mL) was added acetic acid (2 mg, 0.03 mmol). The mixture was stirred at 60° C. for 1 h. Then NaBH(OAc)3 (435 mg, 2.05 mmol) was added. The mixture was stirred at 60° C. for another 15 h. After completion, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL) and evaporated. The residue was purified by column chromatography (PE / EtOAc=3 / 1) followed by preparative HPLC to give tert-butyl 4-(((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)methyl)piperidine-1-carboxylate (100 mg, 46% yield) as a yellow solid. [ka]

[0355] (Step b.) This step was carried out in a similar manner to step b of Example 77. [ka]

[0356] (Example 79) ((3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-((1-methylpiperidin-4-yl)methyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) This step was carried out in a manner similar to step a of Example 76 using Example 2 and tert-butyl 4-formylpiperidine-1-carboxylate.

[0357] (Step b.) This step was carried out in a similar manner to step a of Example 12.

[0358] (Process c.) This step was carried out in a similar manner to step b of Example 77.

[0359] (Step d.) This step was carried out in a similar manner to step e of Example 10. [ka]

[0360] (Example 80) ((3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-((5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)methyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) This step was carried out in a manner similar to step a of Example 76 using Example 2 and intermediate B2.

[0361] (Step b.) This step was carried out in a similar manner to step a of Example 12.

[0362] (Process c.) This step was carried out in a similar manner to step b of Example 77. [ka]

[0363] (Example 81) ((3aR,11aS)-6-chloro-5-((3-fluoro-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)methyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione hydrochloride) [ka] (Step a.) This step was carried out in a similar manner to step a of Example 76 using Example 2 and intermediate B4.

[0364] (Step b.) This step was carried out in a similar manner to step b of Example 77.

[0365] (Process c.) This step was carried out in a similar manner to step e of Example 10. [ka]

[0366] (Example 82) ((3aR,11aS)-5-((3,7-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)methyl)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka]

[0367] (Step a.) This step was carried out in a manner similar to step a of Example 76 using Example 2 and intermediate B2.

[0368] (Step b.) A solution of tert-butyl 2-(((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)methyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (280 mg, 0.42 mmol) and NBS (70 mg, 0.39 mmol) in MeCN (20 mL) was stirred at 20 °C for 1 h. After completion, the mixture was evaporated and the residue was purified by reverse phase flash chromatography (water (0.1% FA) / MeCN) to give tert-butyl 3-bromo-2-(((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)methyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (160 mg, 51% yield) as a white solid. m / z ES+ [M+H] + 754.1.

[0369] (Process c.) Methylboronic acid (238 mg, 3.98 mmol), tert-butyl boronic acid in toluene (10 mL) A mixture of 3-bromo-2-(((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)methyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (150 mg, 0.20 mmol), XPhos-Pd-G2 (31 mg, 0.40 mmol), and Cs2CO3 (194 mg, 0.60 mmol) was degassed and purged with N2 three times. The reaction mixture was stirred at 100 °C for 3 h. After completion, the mixture was filtered and the filtrate was evaporated. The residue was purified by reverse-phase flash chromatography (water (0.1% FA) / MeCN) to give tert-butyl 2-(((3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)methyl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (120 mg, 90% yield) as a yellow solid. m / z ES+ [M+H] + 668.3.

[0370] (Step d.) This step was carried out in a similar manner to step b of Example 77.

[0371] (Step e.) This step was carried out in a similar manner to step e of Example 10. [ka]

[0372] (Example 83) ((3aR,11aS)-5-((3-fluoro-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)methyl)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) This step was carried out in a manner similar to step a of Example 76 using Example 2 and intermediate B2.

[0373] (Step b.) This step was carried out in a similar manner to step a of Example 12.

[0374] (Process c.) A solution of tert-butyl 2-(((3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)methyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (100 mg, 0.15 mmol), NaHCO3 (257 mg, 3.06 mmol) and Selectfluor (216 mg, 0.61 mmol) in 1,4-dioxane (3 mL) was stirred at 40° C. for 12 hours. After completion, the mixture was evaporated. The residue was purified by preparative HPLC to give tert-butyl 2-(((3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)methyl)-3-fluoro-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (40 mg, 38% yield) as a white solid. m / z ES+ [M+H] + 672.3.

[0375] (Step d.) This step was carried out in a similar manner to step b of Example 77.

[0376] (Step e.) This step was carried out in a similar manner to step e of Example 10. [ka]

[0377] (Example 84) ((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-((1-methylpiperidin-4-yl)methyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) This step was carried out in a similar manner to step e of Example 10 using Example 78. [ka]

[0378] (Example 85) ((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-((1-(oxetan-3-yl)piperidin-4-yl)methyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) To a solution of Example 78 (50 mg, 0.09 mmol) and 3-oxetanone (20 mg, 0.28 mmol) in THF (1 mL) was added NaBH(OAc)3 (40 mg, 0.19 mmol) at 0° C. The mixture was stirred at 40° C. for 16 h. After completion, the reaction mixture was evaporated and the residue was purified by preparative HPLC to give the title compound (32 mg, 59% yield) as a white solid. [ka]

[0379] (Example 86) ((3aR,11aS)-6-chloro-5-((1-(2-fluoroethyl)piperidin-4-yl)methyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) To a solution of Example 78 (50 mg, 0.09 mmol) and 1-fluoro-2-iodoethane (16 mg, 0.09 mmol) in MeCN (1 mL) was added K2CO3 (26 mg, 0.19 mmol). The mixture was stirred at 60° C. for 6 h. After completion, the reaction mixture was diluted with water (10 mL) and EtOAc (20 mL) was added. The layers were separated and the aqueous layer was further extracted with EtOAc (2×15 mL). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by preparative HPLC to give the title compound (26 mg, 47% yield) as a white solid. [ka]

[0380] (Example 87) ((3aR,11aS)-6-chloro-5-((1-(2-methoxyethyl)piperidin-4-yl)methyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] The title compound was prepared in a similar manner to Example 86 using 1-bromo-2-methoxyethane. [ka]

[0381] (Example 88) ((3aR,11aS)-5-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Process a~b.) These two steps were carried out in a manner analogous to steps a-b of Example 77, using Example 3 and tert-butyl 4-formylpiperidine-1-carboxylate in step a.

[0382] (Process c.) This step was carried out in an analogous manner to step a in example 86, using 2-bromoethan-1-ol in step c. [ka]

[0383] (Example 89) ((3aR,11aS)-6-chloro-5-(2-(2-(dimethylamino)ethoxy)ethyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione hydrochloride) [ka]

[0384] (Step a.) This step was carried out in a manner similar to step a of Example 76 using Example 2 and Intermediate B5.

[0385] (Step b.) To a solution of (3aR,11aS)-6-chloro-5-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione (140 mg, 0.21 mmol) in EtOH (2 mL) was added hydrazine monohydrate (98%; 22 mg, 0.43 mmol). The reaction mixture was stirred at 40 °C for 1 h. After completion, the reaction mixture was filtered and evaporated to give (3aR,11aS)-5-(2-(2-aminoethoxy)ethyl)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocine-2,11(3H)-dione (0.11 g, 98% yield) as a white solid. m / z ES+ [M+H] + 526.4;

[0386] (Process c.) To a solution of (3aR,11aS)-5-(2-(2-aminoethoxy)ethyl)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione (110 mg, 0.21 mmol) in MeOH (2 mL) was added formaldehyde solution (37% in water; 85 mg, 1.05 mmol), and NaBH(OAc)3 (89 mg, 0.42 mmol). The reaction mixture was stirred at 20° C. for 30 min. After completion, the reaction mixture was filtered and the filtrate was evaporated. The residue was purified by preparative HPLC to give the title compound as the HCl salt (55 mg, 44% yield) as a yellow solid. [ka]

[0387] (Example 90) ((3aR,11aS)-5-(2-(2-(dimethylamino)ethoxy)ethyl)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] The title compound was prepared in a similar manner to Example 89 using Example 3 in step a. [ka]

[0388] (Example 91) ((3aR,11aS)-6-fluoro-5-(((rel-trans)-4-hydroxypyrrolidin-3-yl)methyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Process a~b.) These two steps were carried out in a manner similar to steps ab of Example 78, using Example 1 and Intermediate B6 in step a.

[0389] (Process c.) To a solution of (3aR,11aS)-5-(((rel-trans)-4-(benzyloxy)pyrrolidin-3-yl)methyl)-6-fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione (40 mg, 0.07 mmol) in MeOH (3 mL) and HCl in 1,4-dioxane (4 M, 2 uL) was added 10% Pd / C (10 mg). The reaction mixture was stirred at 40° C. under H2 atmosphere (15 psi (103 kPa)) for 1 h. After completion, the reaction mixture was filtered and the filtrate was evaporated. The residue was purified by preparative HPLC and then exchanged with 0.2M HCl solution to give the title compound as the HCl salt (18 mg, 50% yield) as a white solid. [ka]

[0390] (Example 92a and Example 92b) ((3aR,11aS)-5-((rel-trans / cis)-3-(benzyloxy)cyclobutyl)-6-fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione and (3aR,11aS)-5-((rel-trans / cis)-3-(benzyloxy)cyclobutyl)-6-fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] The title compound was prepared in a manner similar to step a of Example 78 using Example 1 and 3-(benzyloxy)cyclobutan-1-one in step a. Step a was followed by an additional chiral SFC step to give two diastereoisomers of arbitrarily assigned and unknown absolute configuration.

[0391] 92a: (3aR,11aS)-5-((rel-cis / trans)-3-(benzyloxy)cyclobutyl)-6-fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione [ka]

[0392] 92b: (3aR,11aS)-5-((rel-trans / cis)-3-(benzyloxy)cyclobutyl)-6-fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione [ka]

[0393] (Example 93) ((3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) A mixture of Example 3 (150 mg, 0.36 mmol), tert-butyl 2-bromoacetate (699 mg, 3.58 mmol), K2CO3 (149 mg, 1.08 mmol), and TBAI (13.2 mg, 0.036 mmol) in NMP (2 mL) was stirred for 12 h at 120° C. After completion, the reaction mixture was filtered and the filtrate was evaporated. The residue was purified by reverse-phase flash chromatography (water (0.1% FA) / MeCN) to give 2-((3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)acetic acid (160 mg, 94% yield) as a grey solid. [ka]

[0394] (Step b.) A mixture of 2-((3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)acetic acid (100 mg, 0.21 mmol), 1-methylpiperazine (42 mg, 0.42 mmol), DIPEA (81 mg, 0.63 mmol), and HATU (96 mg, 0.25 mmol) in DCM (1 mL) was stirred at 20° C. for 1 h. After completion, the reaction mixture was evaporated. The residue was diluted with water (30 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by preparative HPLC to give the title compound (66 mg, 55% yield) as a white solid. [ka]

[0395] The examples in Table 5 were prepared using methods similar to those described in the synthesis of Example 76, using the intermediates listed in step a. For Examples 96a and 96b, an additional chiral SFC step was performed after step a. (Table 5) [Table 6] TIFF2024539132000212.tif242170

[0396] The examples in Table 6 were prepared using methods similar to those described in the synthesis of Example 77, using the intermediates listed in step a. (Table 6) [Table 7] TIFF2024539132000214.tif242170TIFF2024539132000215.tif243170TIFF2024539132000216.tif243170

[0397] The examples in Table 7 were prepared using methods similar to those described in the synthesis of Example 77, using the intermediates listed in step a. For Examples 105a-107a and 105b-107b, an additional chiral SFC step was performed after step a. For Examples 108a-109a and 108b-109b, an additional chiral SFC step was performed after step b. (Table 7) [Table 8] TIFF2024539132000218.tif242170TIFF2024539132000219.tif241170TIFF2024539132000220.tif242170TIFF2024539132000221.tif243170

[0398] The examples in Table 8 were prepared using methods similar to those described in the synthesis of Example 78, using the intermediates listed in step a. (Table 8) [Table 9]

[0399] The examples in Table 9 were prepared using methods similar to those described in the synthesis of Example 80, using the intermediates listed in step a. For Examples 112a and 112b, an additional chiral SFC step was performed after step c. (Table 9) [Table 10]

[0400] The examples in Table 10 were prepared using methods similar to those described in the synthesis of Example 12, using the intermediates listed in step a. (Table 10) [Table 11] TIFF2024539132000225.tif242170TIFF2024539132000226.tif241170

[0401] The examples in Table 11 were prepared using methods similar to those described in the synthesis of Example 84, using the intermediates listed in step a. (Table 11) [Table 12] TIFF2024539132000228.tif242170TIFF2024539132000229.tif240170TIFF2024539132000230.tif242170TIFF2024539132000231.tif241170

[0402] The examples in Table 12 were prepared using methods similar to those described in the synthesis of Example 81, using the intermediates listed in step a. For Examples 125a-b and 126a-d, an additional chiral SFC step was performed after step a. (Table 12) [Table 13] TIFF2024539132000233.tif243170TIFF2024539132000234.tif243170TIFF2024539132000235.tif242170TIFF2024539132000236.tif242170

[0403] (Example 127) ((3aR,11aS)-6-Fluoro-5-(3-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) To a solution of Example 4 (100 mg, 0.22 mmol) in tetrahydrofuran (3 mL) was added a solution of borane dimethylsulfide complex (10 M in THF, 65 μL) in DCM (0.59 mL). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched with methanol (2 mL) and evaporated. The residue was dissolved in THF (4 mL) and 1 M sodium hydroxide (0.65 mL) and 30% hydrogen peroxide (221 mg, 1.95 mmol) were added. The resulting mixture was stirred at 25° C. for 1 h. After completion, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL). The organic layer was washed with water (2×30 mL), 1 M sodium thiosulfate (30 mL), brine (30 mL), dried over Na2SO4 and evaporated. The residue was purified by preparative HPLC to give the title compound (14 mg, 69% yield) as a white solid. [ka]

[0404] (Example 128) ((3aR,11aS)-5-(3-(dimethylamino)propyl)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) This step was carried out in a manner similar to step a of Example 4, using Example 3 in step a.

[0405] (Step b.) This step was carried out in a similar manner to step a of Example 127.

[0406] (Process c.) To a solution of (3aR,11aS)-5-(3-hydroxypropyl)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione (180 mg, 0.38 mmol) and TEA (76 mg, 0.76 mmol) in DCM (1 mL) was added MsCl (52 mg, 0.45 mmol). The reaction mixture was stirred at 25° C. for 1 h. After completion, the reaction was quenched with water (10 mL) and extracted with EtOAc (2×20 mL). The organic layer was washed with brine (2 × 10 mL), dried over NaSO and evaporated to give 3-((3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)propyl methanesulfonate (200 mg, 95% yield) as a yellow oil. m / z ES+ [M+H] + 555.1.

[0407] (Step d.) A mixture of 3-((3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)propyl methanesulfonate (180 mg, 0.32 mmol), dimethylamine (2M in THF, 1.62 mL, 3.24 mmol), and K2CO3 (90 mg, 0.65 mmol) in DMF (4 mL) was stirred at 60 °C for 4 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and evaporated. The residue was purified by preparative HPLC to give the title compound as the HCl salt (55 mg, 30% yield) as a white solid. [ka]

[0408] (Example 129) ((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(3-(4-methylpiperazin-1-yl)propyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) This step was carried out in a similar manner to step a of Example 127 using Example 5.

[0409] (Step b.) A mixture of ((3aR,11aS)-6-chloro-5-(3-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione (20 mg, 0.04 mmol) and Dess-Martin periodinane (26 mg, 0.06 mmol) in DCM (1 mL) was stirred at 25 °C for 30 min. After completion, the reaction mixture was diluted with saturated aqueous NaHCO3 (1 mL) and saturated Na2S2 The mixture was quenched with 03 water (1 mL). The aqueous mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, and evaporated to give 3-((3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)propanal (19 mg, 95% yield) as a white solid. m / z ES+ [M+H] + 495.0.

[0410] (Process c.) This step was carried out in a similar manner to step c of Example 7. [ka]

[0411] Examples 130a and 130b ((3aR,11aS)-6-fluoro-5-((S / R)-2-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione and (3aR,11aS)-6-fluoro-5-((R / S)-2-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) To a solution of Example 4 (500 mg, 1.08 mmol) in THF (8 mL) was added a solution of borane dimethylsulfide complex (10 M in THF, 0.32 mL) in DCM (2.92 mL). The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with MeOH (2 mL) and evaporated. The residue was dissolved in THF (8 mL) and 1 M sodium hydroxide (3.24 mL) and 30% hydrogen peroxide (1.10 g, 9.73 mmol) were added. The resulting mixture was stirred at 25° C. for 1 h. After completion, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (150 mL). The organic layer was washed with water (2×30 mL), 1 M sodium thiosulfate (30 mL), brine (30 mL), dried over Na2SO4 and evaporated. The residue was purified by column chromatography (PE / EtOAc=1 / 2) to give the undesired isomer, Example 127 (370 mg, 71% yield) as a colorless solid, while the desired racemic isomer was obtained, which was further purified by preparative HPLC followed by chiral SFC (column: Daicel ChiralCel OD-H (250×30 mm, 5 μm); mobile phase: A: 0.1% NH4OH / MeOH; B: 50% CO2) to give two products, which were further purified by preparative HPLC to give the title compound of unknown absolute configuration.

[0412] 130a: (3aR,11aS)-6-fluoro-5-((S / R)-2-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione (14 mg) as a white solid. [ka]

[0413] 130b: (3aR,11aS)-6-Fluoro-5-((R / S)-2-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione (17 mg) as a white solid. [ka]

[0414] Examples 131a and 131b ((3aR,11aS)-6-chloro-5-((S / R)-2-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione and (3aR,11aS)-6-chloro-5-((R / S)-2-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] The title compound was prepared in a manner similar to Example 5 in Examples 130a and 130b.

[0415] 131a: (3aR,11aS)-6-chloro-5-((S / R)-2-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione [ka]

[0416] 131b: (3aR,11aS)-6-chloro-5-((R / S)-2-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione [ka]

[0417] Examples 132a and 132b ((3aR,11aS)-6-chloro-5-((S / R)-3-(dimethylamino)-2-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione and (3aR,11aS)-6-chloro-5-((S / R)-3-(dimethylamino)-2-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka]

[0418] (Step a.) To a mixture of Example 5 (100 mg, 0.21 mmol) in DCM (5 mL) was added m-CPBA (144 mg, 0.63 mmol). The reaction mixture was stirred at 30° C. for 20 h. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×30 mL). The organic layers were combined, washed with brine (3×50 mL), dried over Na2SO4 and evaporated. Purification by preparative TLC (PE / EtOAc=1 / 2) afforded (3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(oxiran-2-ylmethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocine-2,11(3H)-dione (90 mg, 87% yield) as a yellow solid. [ka]

[0419] (Step b.) To a mixture of (3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(oxiran-2-ylmethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione (160 mg, 0.32 mmol) in MeOH (5 mL) was added dimethylamine (2M in THF, 1.62 mL). The reaction mixture was stirred at 60° C. for 2 h. After completion, the reaction mixture was evaporated to give a residue which was purified by preparative HPLC to give the racemate (100 mg, 57% yield) as a yellow solid. The racemate was further purified by chiral SFC (column: Daicel ChiralPak IG (250×30 mm, 10 μm); mobile phase: A: 0.1% NH 4 OH / 2-propanol; B: 40% CO 2 ) to give the title compound of unknown absolute configuration.

[0420] 132a: (3aR,11aS)-6-chloro-5-((S / R)-3-(dimethylamino)-2-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocine-2,11(3H)-dione as a white solid (25 mg, 25% yield). [ka]

[0421] 132b: (3aR,11aS)-6-chloro-5-((S / R)-3-(dimethylamino)-2-hydroxypropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocine-2,11(3H)-dione as a white solid (30 mg, 29% yield). [ka]

[0422] Examples 133a and 133b ((3aR,11aS)-6-chloro-5-((S / R)-2-hydroxy-3-morpholinopropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione and (3aR,11aS)-6-chloro-5-((R / S)-2-hydroxy-3-morpholinopropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka]

[0423] The title compound was prepared in a similar manner to Example 132a and Example 132b using morpholine in step b.

[0424] 133a: (3aR,11aS)-6-chloro-5-((S / R)-2-hydroxy-3-morpholinopropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione [ka]

[0425] 133b: (3aR,11aS)-6-chloro-5-((R / S)-2-hydroxy-3-morpholinopropyl)-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione [ka]

[0426] (Example 134) ((3aR,11aS)-6-fluoro-10-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) A mixture of Example 1 (200 mg, 0.47 mmol), 2-bromopyridine (112 mg, 0.71 mmol), RuPhos-Pd-G2 (CAS: 1375325-68-0; 37 mg, 0.047 mmol), and Cs2CO3 (308 mg, 0.95 mmol) in toluene (2 mL) was stirred at 120° C. for 16 h. After completion, the reaction mixture was filtered and evaporated. The residue was purified by preparative HPLC to give the title compound (13 mg, 5% yield) as a yellow solid. [ka]

[0427] The examples in Table 13 were prepared using methods similar to those described in the synthesis of Example 128, using the intermediates listed in steps a and d. (Table 13) [Table 14] TIFF2024539132000259.tif241170

[0428] The examples in Table 14 were prepared using methods similar to those described in the synthesis of Example 134, using the intermediates listed in steps a and d. (Table 14) [Table 15] TIFF2024539132000261.tif243170TIFF2024539132000262.tif242170TIFF2024539132000263.tif241170TIFF2024539132000264.tif242170

[0429] (Example 146) ((3aR,11aS)-6-chloro-10-ethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-(4-methylpiperazin-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) To a solution of intermediate 5 (200 mg, 0.47 mmol) in DMF (2 mL) was added Cs2CO3 (460 mg, 1.41 mmol) and iodoethane (81 mg, 0.52 mmol). The reaction mixture was stirred at 25 °C for 1 h. After completion, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (4 x 15 mL), dried over Na2SO4, and evaporated to give (3aR,11aS)-6-chloro-10-ethyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocine-2,11(3H)-dione (240 mg, crude) as a pale yellow oil. m / z ES+ [M+H] + 453.1.

[0430] (Process b~d.) These three steps were carried out in a manner similar to steps a to c of Example 7. [ka]

[0431] (Example 147) ((3aR,11aS)-6-Methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-morpholinoethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) A mixture of intermediate 5 (1.0 g, 2.35 mmol), methylboronic acid (4.20 g, 70.6 mmol), Cy3P-Pd-G3 (CAS: 1445086-12-3; 153 mg, 0.24 mmol), Cs2CO3 (1.90 g, 5.89 mmol) in 1,4-dioxane (30 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 100 °C under N2 atmosphere for 12 h. After completion, the reaction mixture was filtered. The filtrate was evaporated and purified by column chromatography (PE / EtOAc=1 / 2) to give (3aR,11aS)-6-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocine-2,11(3H)-dione (870 mg, 91% yield) as a white solid. m / z ES+ [M+H] + 404.9.

[0432] (Step b.) A mixture of (3aR,11aS)-6-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione (150 mg, 0.37 mmol), intermediate B16 (240 mg, 1.85 mmol), NaBH3CN (58 mg, 0.93 mmol), acetic acid (111 mg, 1.85 mmol), and 4 Å molecular sieves (150 mg) in MeOH (5 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 25 °C under N2 atmosphere for 12 h. After completion, the mixture was filtered. The filtrate was evaporated and purified by preparative HPLC to give the title compound (69 mg, 35% yield) as a white solid. [ka]

[0433] (Example 148) ((3aR,11aS)-6-Methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-(piperazin-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) To a solution of intermediate 5 (3 g, 7.06 mmol) in DMF (30 mL) was added Cs2CO3 (6.90 g, 21.2 mmol) and SEM-Cl (1.77 g, 10.6 mmol). The reaction mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with HO (60 mL), dried over NaSO, evaporated and purified by column chromatography (PE / EtOAc=3 / 1) to give (3aR,11aS)-6-chloro-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-10-((2-(trimethylsilyl)ethoxy)methyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocine-2,11(3H)-dione (1.5 g, 33% yield) as a pale yellow solid. [ka]

[0434] (Process b~e.) These four steps were carried out in a manner similar to steps a to d of Example 16.

[0435] (Process f.) To a solution of tert-butyl 4-(2-((3aR,11aS)-6-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2,11-dioxo-10-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,3a,4,10,11,11a-octahydro-5H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-5-yl)ethyl)piperazine-1-carboxylate (150 mg, 0.20 mmol) in DCM (3 mL) was added TFA (3 mL). The reaction mixture was stirred at 25° C. for 1 h. After completion, the reaction mixture was evaporated. The resulting residue was dissolved in MeOH (3 mL) and NH4OH (37%, 2.73 g, 28.8 mmol) was added. The mixture was stirred at 25° C. for 1 h. After completion, the reaction mixture was evaporated and purified by preparative HPLC to afford the title compound (11 mg, 22% yield) as an off-white solid. [ka]

[0436] (Example 149) ((3aR,11aS)-6-Methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(2-(4-methylpiperazin-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazocin-2,11(3H)-dione) [ka] (Step a.) This step was carried out in a similar manner to step e of Example 10 using Example 148. [ka]

[0437] (Biological Data) (Polθ polymerase domain WT K I Assay) Using the PicoGreen assay, we determined the K of reversible compounds that inhibit Polθ activity in vitro. I The values ​​were measured.

[0438] Human Pol θ polymerase domain (aa1820-2590) was expressed in E. coli, purified, aliquoted, and stored at -80°C until needed. Pol θ substrate was made from a 1.2:1 mixture of DNA II Short and DNA II Long to give a final concentration of 20 mM substrate in annealing buffer (20 mM Tris pH 7.5, 50 mM NaCl). Substrate was heated in 50 mL aliquots to 95°C for 5 minutes in a heating block, then the heating block was switched off and the reaction was allowed to cool to room temperature and stored at -20°C until needed. [Table 16]

[0439] Assay measurements were performed using 1x buffer containing 25mM Tris pH 7.5, 12.5mM NaCl, 0.5mM NaCl, 5% (v / v) glycerol, 0.01% v / v Triton x-100, 0.1mg / ml BSA, 1mM DTT. Test compounds were prepared by dilution into 100% DMSO to give 12μM intermediate stocks of each (100x final highest concentration). 100nL of 23x 1:1.5-fold serial dilutions and DMSO only controls were dispensed into Greiner 384-well black low volume plates (product code 784076) using a Tecan dispenser. DMSO concentration was maintained at 1% of the final assay volume by replenishing with DMSO.

[0440] 2x working stocks of substrate (200 nM DNA substrate and 100 μM dNTPs) and enzyme (0.312 nM PolΘ) were prepared in assay buffer. 5 μL / well of both enzyme and substrate 2x solutions were dispensed into the assay plate with pre-dispensed compounds using a Tempest dispenser (Formulatrix) to give final assay concentrations of 100 nM DNA substrate, 50 μM dNTPs, and 0.156 nM PolΘ. To stop the reaction, 5 μL of a solution containing 25 mM Tris-HCl pH 7.5 and 20 mM EDTA was added at six time points (t=0, 15, 30, 60, 90, 120, 150, 180 min) using the time delay function of the Tempest instrument. During the time course, the plate was covered to prevent evaporation. Once the assay was completed, 5 μL of detection reagent (25 mM Tris-HCl pH 7.5 and 2.5% (v / v) PicoGreen) was dispensed into the wells using a Tempest liquid handler (Formulatrix) and the plate was subsequently read on a CLARIOstar Plus (BMG Labtech) using default optical and automatic gain / focus settings for fluorescein.

[0441] All data analyses were performed using GraphPad Prism V.8 (GraphPad Software, San Diego, CA). Time series data for each inhibitor concentration were fitted to a linear regression model in GraphPad Prism. Any time points where the control (DMSO alone) response was no longer linear were excluded from the analysis. The initial rates (slope) from the linear regression were then plotted against inhibitor concentration and fitted to a slope (four parameter) model of inhibitor vs. response variables in GraphPad Prism to obtain the K I value was determined.

[0442] The compounds of Examples 1 to 149 were used in combination with the above-mentioned Polθ polymerase domain WT K I The assays were tested and the results are shown in the table below: [Table 17] TIFF2024539132000276.tif188170

Claims

1. Compounds of formula (I), or their tautomers or stereochemical isomers, pharmaceutically acceptable salts, or solvates: 【Chemistry 1】 (In the formula: n represents an integer selected from 0, 1, 2, 3, or 4; R 1 represents C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy, halogen, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, cyano, or -NR x R y ; and R 2 C is optionally substituted with hydrogen, one or more amino and / or hydroxyl groups. 1-6 Alkyl, C 2-6 Alkenyl, one or more -NR x R y C arbitrarily substituted by the group 1-6 Alkoxy, one or more -NR x R y C arbitrarily substituted by the group 1-6 Alkanol, C optionally substituted with one or more hydroxyl groups 1-6 Alkyl-NR x R y -X-aryl, -X-heterocyclyl, or -X-heteroaryl, where the aryl, heterocyclyl, or heteroaryl group is one or more halogens, hydroxy, oxo, cyano, -NR x R y , C 1-6 Alkyl, Halo C 1-6 Alkyl, C 1-6 Alkanol, C 1-6 Alkoxy, C 1-6 Alkyl-NR x R y , -CO-C 1-6 Alkyl, -CO-C 1-6 Alkanol, -CO-C 1-6 Alkyl-NR x R y ,-CONR x R y , -SO 2 -C 1-6 Alkyl, or C 1-6 The heterocyclyl group may be optionally substituted with an alkyl group. X represents a bond, or -C(=O)- or one or more O, OH, C 3-8 C optionally substituted with a cycloalkyl or CO group 1 -C 4 Represents a linker selected from alkylene groups; R 3 is hydrogen or C 1-6 Represents alkyl; R 4 , R 5 , R 6 , and R 7 Independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 1-6 Alkoxy, halogen, halo C 1-6 Alkyl, Halo C 1-6 Alkoxy, C 3-8 Cycloalkyl, cyano, or -NR x R y Represents; and R x and R y These are independently hydrogen or C 1-6 Represents alkyl, However, this compound is not (3aR,11aS)-6,10-dimethyl-1-(6-methyl-4-(trifluoromethyl)pyridine-2-yl)-5-(2-(4-methylpiperazine-1-yl)ethyl)-1,3a,4,5,10,11a-hexahydro-2H-benzo[b]pyrrolo[2,3-f][1,4]diazosin-2,11(3H)-dione (Example 12).

2. The compound according to claim 1, wherein n represents 0, 1, 2, or 3, for example, 1.

3. R 1 However, C 1-6 Alkyl (e.g., methyl) or halogen (e.g., fluorine or chlorine), e.g., C 1-6 A compound according to claim 1 or 2, representing an alkyl group (particularly methyl).

4. n represents 1, and R 1 However, C 1-6 For example, n represents an alkyl (e.g., methyl) or halogen (e.g., fluorine or chlorine), where n represents 1 and R 1 However, C 1-6 Represents alkyl (especially methyl); or n represents 2, and R 1 However, does it represent a halogen (for example, fluorine or chlorine); or n represents 3, and R 1 However, it represents halogens (for example, fluorine or chlorine), The compound according to claim 1 or 2.

5. R 2 but: hydrogen; C optionally substituted with one or more amino and / or hydroxyl groups 1-6 Alkyl (e.g., -CH 2 -CH 2 -N(Et) 2 ,-CH 2 -CH 2 -CH 2 -N(Me) 2 ,-CH 2 -CH 2 -NH-CH 2 -CH 2 -NH-Me, or -CH 2 -CH 2 -N(Me)-CH 2 -CH 2 -OH); C 2-6 Alkenyl (e.g., -CH) 2 =CH 2 ); one or more -NR x R y C optionally substituted by a 1-6 alkoxy (e.g., -CH 2 -CH 2 -O-CH 2 -CH 2 -N(Me) 2 ); One or more -NRs x R y C arbitrarily substituted by the group 1-6 Alkanols (e.g., -CH 2 -CH 2 -OH, -CH 2 -CH 2 -CH 2 -OH, -CH 2 -CH(Me)-OH, -CH 2 -CH(OH)-Me, or -CH 2 -CH(OH)-CH 2 -N(Me) 2 ); -X-aryl (e.g., -phenyl, -CH) 2 -phenyl, or -cyclobutyl-OCH 2 - Pheny); -X-heterocyclyl (e.g., -CH 2 -pyrrolidinil, -CH 2 -Piperidinyl, -CH 2 -morpholinil, -CO-piperazinil, -CH 2 -CH 2 -pyrrolidinil, -CH 2 -CH 2 -Piperidinyl, -CH 2 -CH 2 -piperazinyl, -CH 2 -CH 2 -morpholinyl, -CH 2 -CH 2 -thiomorpholinyl, -CH 2 -CH 2 -1-oxa-6-azaspiro[3.3]heptane-6-yl, -CH 2 -CH 2 -2-oxa-6-azaspiro[3.3]heptane-6-yl, -CH 2 -CH 2 -Hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl, -CH 2 -CH 2 -2,5-diazabicyclo[2.2.1]heptane-2-yl,-CH 2 -CH 2 -3,8-diazabicyclo[3.2.1]octan-3-yl,-CH 2 -CH 2 -CH 2 -piperazinyl, -CH 2 -CH 2 -CH 2 -Molfolinyl, or -CH 2 -CH(OH)-CH 2 -morpholinyl); and -X-heteroaryl (e.g., -pyridinyl, -pyrrolo[2,3-b]pyridin-6-yl, benzo[d]imidazole-6-yl, -CH 2 -pyridinyl, -CH 2 -Tetrahydropyrazolo[1,5-a]pyrazine-2-yl, -CH 2 -Tetrahydroimidazo[1,2-a]pyrazine-2-yl, -CH 2 -Tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-yl,-CH 2 -Tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl,-CH 2 -Tetrahydroisoquinoline-6-yl, or -CH 2 -Isoindoline-5-yl); This represents, Here, the aryl, heterocyclyl, or heteroaryl group is one or more halogens (e.g., fluorine), hydroxyl, oxo, cyano, -NR x R y (For example, -N(Me) 2 ), C 1-6 Alkyl (e.g., methyl), halo C 1-6 Alkyl (e.g., -CH 2 -CH 2 -F), -CO-C 1-6 Alkyl (e.g., -CO-methyl), -CO-C 1-6 Alkanols (e.g., -CO-CH(OH)-Me), C 1-6 Alkanols (e.g., -CH 2 OH or -CH 2 -CH 2 -OH), C 1-6 Alkoxy (e.g., -OMe or -CH) 2 -CH 2 -OMe), -CONR x R y (For example, -CON(Me) 2 ), -SO 2 -C 1-6 Alkyl (e.g., -SO 2 Me), or C 1-6 They may be optionally substituted with heterocyclyl (e.g., oxetanyl, azetidinyl, pyrrolidinyl) groups that are optionally substituted with alkyl (e.g., methyl) groups. For example, R 2 but: -X-heterocyclyl (e.g., -CH 2 -pyrrolidinil, -CH 2 -Piperidinyl, -CH 2 -morpholinil, -CO-piperazinil, -CH 2 -CH 2 -pyrrolidinil, -CH 2 -CH 2 -Piperidinyl, -CH 2 -CH 2 -piperazinyl, -CH 2 -CH 2 -morpholinyl, -CH 2 -CH 2 -thiomorpholinyl, -CH 2 -CH 2 -1-oxa-6-azaspiro[3.3]heptane-6-yl, -CH 2 -CH 2 -2-oxa-6-azaspiro[3.3]heptane-6-yl, -CH 2 -CH 2 -Hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl, -CH 2 -CH 2 -2,5-diazabicyclo[2.2.1]heptane-2-yl,-CH 2 -CH 2 -3,8-diazabicyclo[3.2.1]octan-3-yl,-CH 2 -CH 2 -CH 2 -piperazinyl, -CH 2 -CH 2 -CH 2 -Molfolinyl, or -CH 2 -CH(OH)-CH 2 - Represents morpholinyl; Here, the heterocyclyl group is one or more halogens (e.g., fluorine), hydroxyl, oxo, cyano, -NR x R y (For example, -N(Me) 2 ), C 1-6 Alkyl (e.g., methyl), halo C 1-6 Alkyl (e.g., -CH 2 -CH 2 -F), -CO-C 1-6 Alkyl (e.g., -CO-methyl), -CO-C 1-6 Alkanols (e.g., -CO-CH(OH)-Me), C 1-6 Alkanols (e.g., -CH 2 OH or -CH 2 -CH 2 -OH), C 1-6 Alkoxy (e.g., -OMe or -CH) 2 -CH 2 -OMe), -CONR x R y (For example, -CON(Me) 2 ), -SO 2 -C 1-6 Alkyl (e.g., -SO 2 Me), or C 1-6 They may be optionally substituted with heterocyclyl (e.g., oxetanyl, azetidinyl, pyrrolidinyl) groups that are optionally substituted with alkyl (e.g., methyl) groups. In particular, R 2 However, -CH 2 -CH 2 - Represents piperazinyl, where the piperazinyl group is one or more C 1-6 It may be optionally substituted with an alkyl (e.g., methyl) group. The compound according to claim 1 or 2.

6. R 3 However, hydrogen or C 1-6 Representing alkyl (e.g., methyl or ethyl), for example, R 3 However, C 1-6 A compound according to claim 1 or 2, representing an alkyl group (particularly methyl).

7. X represents a bond, or -C(=O)- or one or more O, OH, C 3-8 C optionally substituted with a cycloalkyl or CO group 1 -C 3 Alkylene group (e.g., -CH 2 -, -cyclobutyl-OCH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, or -CH 2 -CH(OH)-CH 2 A compound according to claim 1 or 2, representing a linker selected from -).

8. R x and R y Independently, hydrogen and C 1-6 Representing alkyl (e.g., methyl or ethyl), for example, R x and R y However, both sides, C 1-6 The compound according to claim 1 or 2, representing an alkyl group (e.g., methyl or ethyl).

9. R 4 but: hydrogen; C 1-6 Alkyl (e.g., methyl or ethyl); C 2-6 alkenyl (for example, etenyl); C 1-6 Alkoxy (e.g., methoxy); Halogens (e.g., chlorine); or -NR x R y (For example, -N(Me) 2 Alternatively, it represents -N(Me)(Et)), For example, R 4 However, C 1-6 A compound according to claim 1 or 2, representing an alkyl group (particularly methyl).

10. R 5 but: hydrogen; Halogens (e.g., chlorine); or C 1-6 Representing alkyl (for example, methyl), For example, R 5 The compound according to claim 1 or 2, wherein hydrogen is represented.

11. R 6 but: C 1-6 Alkyl (e.g., methyl, ethyl, or isopropyl); C 2-6 Alkenyl (for example, -C (=CH) 2 )(Me)); Halogens (e.g., bromine); Hello C 1-6 Alkyl (for example, trifluoromethyl or -C(H)(Me)-CF) 3 ); or Hello C 1-6 Representing alkoxys (e.g., difluoromethoxy), For example, R 6 However, Hello C 1-6 The compound according to claim 1 or 2, representing an alkyl group (e.g., trifluoromethyl).

12. R 7 The compound according to claim 1 or 2, wherein hydrogen or cyano, for example, represents hydrogen.

13. Equation (I) a : 【Chemistry 2】 (where n, R 1 , R 2 , and R 3 (This is as defined in claim 1 or 2.) The compound according to claim 1, which is a compound, or in the form of a tautomer or stereochemical isomer thereof, a pharmaceutically acceptable salt, or a solvate thereof.

14. The compound according to claim 1, which is a free base of the compounds of Examples 1 to 11 and 13 to 149, or a pharmaceutically acceptable salt or solvate thereof.

15. A pharmaceutical composition comprising a compound of formula (I) as described in claim 1 or 14.

16. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or 14 in combination with one or more therapeutic agents.

17. The compound according to claim 1 or 14 for use in therapy.

18. The compound according to claim 1 or 14 for use in the prevention or treatment of cancer.

19. (a)R 2 However, this involves preparing a compound of formula (I) representing hydrogen, and formula (II); 【Transformation 3】 (where n, R 1 , R 3 , R 4 , R 5 , R 6 , and R 7 This is as defined in claim 1, and P 1 (This represents a suitable protecting group (e.g., Boc)) The preparation includes deprotection of the compound; (b) Interconversion of a compound of formula (I) or a protected derivative thereof to a further compound of formula (I) or a protected derivative thereof; (c) Deprotection of protected derivatives of the compound of formula (I); (e) Optionally, the formation of a pharmaceutically acceptable salt of the compound of formula (I). A method for producing a compound of formula (I) according to claim 1, comprising [the specified element].

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