TW201307358A - Heterocyclic compounds - Google Patents

Abstract

Provided is a compound useful for the prophylaxis or treatment of cancer. The present invention relates to a compound represented by formula (I): wherein each symbol in the formula is as defined in the specification, or a salt thereof or a prodrug thereof, which is useful for the prophylaxis or treatment of cancer.

Description

Heterocyclic compound

This invention relates to heterocyclic compounds and their use. More specifically, the present invention relates to a fused heterocyclic compound having a strong cell division cycle 7 (Cdc7) inhibitory activity and a use thereof, which is suitable for the prevention or treatment of cancer and the like.

Cancer is characterized by abnormal cell proliferation with a damage control mechanism. Most cancer cells grow faster than normal tissue cells. In the cell division cycle, chromosomal repeats are necessary, and the DNA replication system in the S phase is strictly regulated. Inhibition of DNA replication has been identified as an effective treatment for cancer. For example, DNA replication inhibitors such as hydroxyurea (HU), gemcitabine and active metabolite 5-fluorouracil are widely used as clinical practice cancers. Therapeutic agent.

The Cdc7 line evolves well-preserved serine/threonine kinase and plays an important role in the initiation of DNA replication (Non-Patent Document 1). The kinase activity of Cdc7 is controlled by binding to its activation partner. From the late G1 to the S phase, Cdc7 forms a complex with Dbf4 (also known as ASK) and phosphorylates the Cdc7 substrate to control the transfer from the G1 phase to the S phase (Non-Patent Document 2). Furthermore, recent studies have reported that Cdc7 plays an important role in both DNA replication and DNA damage signaling pathways (Non-Patent Document 3).

In recent years, Cdc7 has received much attention as an attractive target for cancer treatment. Excessive expression of Cdc7 was observed in clinical tumors such as breast cancer, colorectal cancer, lung cancer, and many cancer cell lines (Non-Patent Document 4). In some cancer cell lines, an increase in the chromosome copy number of the activating factor Dbf4 was found. Interestingly, cancer cell lines and untransformed fibroblast strains showed different responses to the use of siRNA to suppress Cdc7 expression. The use of siRNA to suppress the expression of Cdc7 causes S phase arrest in cancer cell lines and leads to apoptosis, whereas in normal cells, it leads to G1 arrest of the mechanism involved in p53 activity (Non-Patent Document 5). Furthermore, the Cdc7 kinase system is activated in cells under replication stress, and apoptosis induced by hydroxyurea and etoposide is increased in Cdc7 down-regulated cells (Non-Patent Document 6) ). Therefore, Cdc7 inhibitors, as a single agent or in combination with other chemotherapeutic agents, are suitable for selective cancer therapy.

Patent Document 1 describes a compound represented by the following formula, which is a compound having Pim kinase inhibitory activity.

Wherein A ¹ and A ² are each independently a hydrogen atom, R ¹ , R ² , R ³ , R ⁴ or a hydroxyl group; A ³ is a hydrogen atom, R ¹² , R ¹³ , R ¹⁴ or R ¹⁵ or the like; and R ¹ is benzene. R ² is a heteroaromatic group or the like; R ³ is a cycloalkyl group; R ⁴ and R ¹⁵ are an alkyl group; R ¹² is a phenyl group; R ¹³ is a heteroaryl group; and R ¹⁴ is a cycloalkyl group; And R ¹⁵ is an alkyl group or the like.

Patent Document 2 describes a compound represented by the following formula, which is a compound suitable for the treatment of diseases related to the Src family tyrosine kinase.

Wherein R ₁ is a hydrogen atom or an alkyl group; R ₂ is a hydrogen atom or an alkyl group; and R ₃ is a hydrogen atom, an alkyl group, or a hydrogen bond donor or hydrazine crosslinked to a hydrogen bond acceptor.

Patent Document 3 describes a compound represented by the following formula, which is a protein kinase inhibitor

Wherein X is an oxygen atom or a sulfur atom; Y is an oxygen atom, a sulfur atom or -NR ¹ -; R ¹ is R, CO ₂ R or the like; R is a hydrogen atom or a C _1-6 aliphatic group; and R ² is R And N(R) ₂ or the like; R ³ is R or CN; and R ⁴ is R, N(R) ₂ or the like.

Patent Document 4 describes a compound represented by the following formula, which is a compound having B-Raf kinase inhibitory activity and suitable for treating cancer.

Wherein R ¹ is a phenyl group or a heterocyclic ring; R ² is a hydrogen atom or a heteroaryl group; R ⁴ is a hydrogen atom or a C _1-8 alkyl group; R ⁵ is a hydrogen atom or a nitro group; R ⁷ is C _1-8 alkyl or the like; X is a nitrogen atom or the like; X' is a sulfur atom or =C(R ³ )-, etc., and Z is a sulfur atom or =C(R ³ )-, and only one of X' and Z is =C(R ³ )-; and a single bond or a double bond, and another compound represented by the following formula

The codes are as defined above.

Patent Document 5 describes a compound represented by the following formula, which is a compound having an IKB kinase β inhibitory activity and is suitable for treating diseases such as cancer.

Wherein X is a sulfur atom or the like; R ₁ is a hydrogen atom or a C _1-10 alkyl group; R ₂ is a hydrogen atom or a C _5-20 heteroaryl group; and R ₃ is a hydrogen atom or a C _1-10 alkyl group; R ₄ and R _{6 are} each a hydrogen atom or a C _1-5 alkyl group; R ₆ is a hydrogen atom or a C _1-5 alkyl group; For single or double bonds, the compounds represented by the following formula are also described

The codes are as defined above.

Patent Document 6 describes a compound represented by the following formula, which is a compound having a Tie2 receptor tyrosine kinase inhibitory activity and is suitable for treating a disease state such as cancer.

Wherein A together with its bonded carbon atom form a fused 5-membered heteroaryl ring wherein the heteroaryl ring contains 1 or 2 heteroatoms selected from O, N and S; a 5-membered ring containing G a ring formed by bonding A to the bridgehead carbon labeled with # in the formula; G is selected from O, S and NR ⁵ ; Z is N; etc.; Q ¹ is an aryl group, a heteroaryl group or the like; R ¹ is a hydrogen atom or a halogen atom or the like; R ² is a hydrogen atom or an amine group; and R ³ is independently as defined for R ⁴ and R ⁶ , with the proviso that when R ^{3 is} not hydrogen and is bonded to the nitrogen of the A ring; In the case of an atom, R ^{3 is} not a halogen group; R ⁵ is independently as defined for R ⁴ and R ⁶ , with the proviso that R ^{5 is} not a halogen group; and R ⁴ and R ⁶ are the same or different and each is hydrogen, a halogen group, Trifluoromethyl, trifluoromethoxy, cyano, and the like.

Patent Document 7 describes a compound represented by the following formula, which is effective for treating a compound which is at least partially affected by CDC7, PKA and/or Akt-mediated cell proliferative diseases.

Wherein ring A is a nitrogen-containing heteroaryl group having 5 or 6 ring atoms, and 1 to 4 ring atoms are nitrogen atoms; n is an integer selected from 0 or 1, and m is an integer equal to 0, 1 or 2; R is a hydrogen atom, a hydroxyl group or the like; R ¹ is a halogen group or a cyano group; R ² and R ⁴ are each independently hydrogen, a cycloalkyl group or the like; R ³ is a hydrogen atom or a C ₁ - C ₅ alkyl group; -C(X')NR ⁶ -etc, wherein X' is selected from the group consisting of oxygen and sulfur, and R ⁶ is hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ substituted alkyl, etc., or R ⁶ forms a heterocyclic group or a substituted heterocyclic group with a carbon atom to which Q and Q are bonded, or a carbon atom to which R ⁴ or R ⁴ is bonded.

Patent Document 8 describes a compound represented by the following formula, which is a compound effective for preventing and/or treating an inflammatory disease.

Wherein A ¹ is a nitrogen-containing heteroaryl group which may have a substituent; A ² is an optionally substituted aryl group or optionally a cycloalkyl group; and R ¹ and R ² are each independently A lower alkyl group which may have a substituent, a fluorenyl group which may have a substituent, a decyloxy group which may have a substituent, etc. as needed; m and n each an integer of 0-2; Q ¹ , Q ² , Q ³ and Q ⁴ are respectively selected from C, CH, CH ₂ , C=O, O, N and NH, and one or both of Q ¹ to Q ⁴ are N or NH; It is a double key or a single key.

Patent Document 9 describes a compound represented by the following formula, which is a drug having cGMP-specific phosphodiesterase inhibitory activity and the like.

Wherein R ₁ is a hydrogen atom or a C _1-6 alkyl group; R ₂ is a C _3-8 cycloalkyl group which may be optionally substituted, a phenyl group which may be optionally substituted, and the like; R ₃ is 1 to 4 views. A saturated or unsaturated heterocyclic group such as N, O or S which may be substituted; R ₄ is a hydrogen atom, a C _1-6 alkyl group, a hydroxyl group, a C _1-6 alkoxy group, a halogen, a C _1-6 halogen An alkyl group, a nitro group or a cyano group; and R ₅ is a cyano group, optionally substituted phenyl group, containing 1 to 4 optionally substituted N, O or S saturated or unsaturated heterocyclic groups, etc. .

[document list] [Patent Document]

Patent Document 1: US2009/0030196

Patent Document 2: WO02/057271

Patent Document 3: US2003/0096813

Patent Document 4: WO2009/059272

Patent Document 5: WO2007/102679

Patent Document 6: WO2004/013141

Patent Document 7: WO2005/095386

Patent Document 8: JP-A-2002-105081

Patent Document 9: WO02/026745

[Non-patent document]

Non-Patent Document 1: EMBO J. 1999, 18(20), p.5703-5713

Non-Patent Document 2: J Cell Physiol. 2002, 190(3), p.287-296

Non-Patent Document 3: Oncogene. 2008, 27(24), p. 3475-3482

Non-Patent Document 4: Neoplasia. 2008, 10(9), p.920-931

Non-Patent Document 5: Cancer Res. 2004, 64(19), p.7110-7116

Non-Patent Document 6: J Biol Chem. 2007, 282(1), p.208-215

Cdc7 inhibitors, which are excellent in efficacy, pharmacokinetics, solubility, interaction with other pharmaceutical products, safety and stability, are expected to exhibit superior therapeutic effects. Accordingly, it is an object of the present invention to provide a low toxicity compound which has Cdc7 inhibitory activity and is sufficiently satisfactory as a pharmaceutical product.

The present inventors have found that the following compounds represented by the formula (I) have excellent Cdc7 inhibitory effects, have been studied and completed the present invention. Accordingly, the present invention is directed to the following.

[1] A compound represented by the following formula or a salt thereof:

Wherein one of X and Y is a sulfur atom, and the other is CH, R ₁ is a C _1-6 alkyl group which may be optionally substituted by a halogen atom, and R ₂ is a substituent.

[2] The compound of the above [1] or a salt thereof, wherein X is a sulfur atom; and Y is CH.

[3] The compound of the above [1], wherein R ₂ is a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or a non-aromatic heterocyclic ring which may have a substituent, if necessary, or a salt thereof Alkylcarbonyl.

[4] The compound of the above [1] or a salt thereof, wherein R ₂ is (1) a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the following (a) may optionally be subjected to 1 to 3 substituents selected from the substituents of the non-aromatic heterocyclic group (i) a halogen atom, (ii) hydroxyl, (iii) can be optionally substituted with 1-3 substituents selected from the group of C _{1- a 6} alkyl (aa) halogen atom, a (bb) hydroxyl group, a (cc) C _1-6 alkoxy group, and (dd) a C _6-14 aryl group which may be substituted with 1 to 3 C _1-6 alkyl groups as needed. a (C)C _1-6 alkoxy group, (v) a C _6-14 aryl group which may be substituted with 1 to 3 halogen atoms, (vi) a C _6-14 aryloxy group, (vii) C _{1 -6} alkoxy-carbonyl, (viii) C _1-6 alkyl-carbonyl, (ix) cyano, (x) C _6-14 aryl sulfonyl, (xi) carboxy, (xii) optionally a C _1-6 alkyl mono- or di-substituted amine group, (xiii) a non-aromatic heterocyclic group optionally substituted by a keto group (oxo), and (xiv) a ketone group, (b) C _{1 -6} alkoxy, (c) optionally substituents may be selected from the following group of mono - or di - substituted amino group of (i) may be optionally substituted with 1-3 substituents selected from the group of C _{1- 6} alkyl (aa) may be optionally substituted with 1 to 3 C _1-6 alkoxy groups a C _6-14 aryl group, (bb) C _1-6 alkoxy-carbonyl, (cc) aromatic heterocyclic group, (dd) C _3-8 cycloalkyl group which may be substituted with an aromatic heterocyclic group, and (ee) hydroxyl group, (ii) A non-aromatic heterocyclic group which may be substituted with 1 to 3 C _7-13 aralkyl groups, (iii) a C _6-14 aryl group which may be optionally substituted with 1 to 3 C _1-6 alkoxy groups, And (iv) a C _3-8 cycloalkyl group, (d) a 5- or 6-membered aromatic heterocyclic group, (e) a C _6-14 aryl group, and (f) an optionally substituted amino group C _{a 3-8} cycloalkyl group; (2) a C _6-14 aryl group which may be substituted with 1 to 3 halogen atoms, if necessary; (3) a non-aromatic group which may be substituted with 1 to 3 substituents selected from the group consisting of: a heterocyclic group (a) a halogen atom, (b) a C _1-6 alkyl (i) hydroxy group optionally substituted with 1 to 3 substituents selected from the group consisting of (ii) a C _1-6 alkoxy group a carbonyl group, and (iii) an amine carbenyl group, (c) a C _6-14 aryloxy group, (d) a C _1-6 alkoxy-carbonyl group, (e) a C _1-6 alkyl-carbonyl group, (f a C _6-14 aryl group which may be optionally substituted by a C _1-6 alkylsulfonyl group, (g) a C _7-13 aralkyl group which may be substituted with 1 to 3 halogen atoms, (h) a hydroxyl group, if necessary , (i) an amine carbenyl group, and (j) a non-aromatic heterocyclic group; (4) a C _{2 - which} may be substituted with 1 to 3 C _6-14 aryl groups as needed ₆ alkenyl; (5) 5- or 6-membered aromatic heterocyclic group; (6) non-aromatic heterocyclic group-carbonyl; or (7) C _3-8 cycloalkyl group optionally substituted with an amine group .

[5] The compound of the above [1] or a salt thereof, wherein R ₂ is (1) a 4 to 6-membered non-aromatic heterocyclic group-C _1-6 alkyl group which may be optionally substituted with 1 to 3 halogen atoms. (2) a C _6-14 aryl group which may be substituted with 1 to 3 halogen atoms as needed; or (3) a non-aromatic heterocyclic group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of a) a halogen atom, and (b) a C _1-6 alkyl group or a salt thereof.

[6] The compound of the above [4] or a salt thereof, wherein X is a sulfur atom; Y is CH; and R ₁ is a C _1-6 alkyl group.

[7] The compound of the above [1], wherein R ₁ is a C _1-6 alkyl group, or a salt thereof.

[8] 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-pyrrolidin-2-yl]thieno[3,2-d]pyrimidine-4(3H) a ketone, or a salt thereof.

[9] 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]thieno[3,2-d]pyrimidine-4(3H) a ketone, or a salt thereof.

[10] 2-(7-Indylbicyclo[2.2.1]hept-1-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- 4(3H)-one, or a salt thereof.

[11]6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-1,2,3,6-tetrahydropyridin-2-yl]thieno[3,2 -d]pyrimidine-4(3H)-one, or a salt thereof.

[12] 2-[(2S)-Piperidin-2-yl]-6-[5-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidine- 4(3H)-one, or a salt thereof.

[13] 2-[(2S)-1-Indoxedo[2.2.2]oct-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2- d] pyrimidine-4(3H)-one, or a salt thereof.

[14] A medicament comprising the compound of the above [1] or a salt thereof.

[15] The medicament according to [14] above, which is a cell division cycle inhibitor.

[16] The medicament according to [14] above, which is an agent for preventing or treating cancer.

[17] A method of inhibiting a cell division cycle 7 of a mammal, which comprises administering to a mammal an effective amount of the compound of the above [1] or a salt thereof.

[18] A method for preventing or treating cancer in a mammal, which comprises administering to a mammal an effective amount of the compound of the above [1] or a salt thereof.

[19] The use of the compound of the above [1] or a salt thereof for the production of a cell division cycle inhibitor.

[20] The use of the compound of the above [1] or a salt thereof for the manufacture of a medicament for preventing or treating cancer.

The compound of the present invention is low in toxicity and exhibits potent Cdc7 inhibitory action, and is useful as an agent for preventing or treating cancer, a cancer growth inhibitor or a cancer metastasis suppressor.

The definition of each code in the formula (I) is described below.

Unless otherwise specifically stated, "halogen atom" in the specification means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Examples of the "C _1-6 alkyl group" in the present specification include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a secondary butyl group, a tertiary butyl group, a pentyl group, and an isopentyl group. , neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethyl Butyl butyl.

Examples of the "C _6-14 aryl group" in the present specification include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group, an anthracenyl group, and a biphenyl group.

Examples of the "C _2-6 alkenyl group" in the present specification include a vinyl group, a 1-propenyl group, a 2-propenyl group, a 2-methyl-1-propenyl group, a 1-butenyl group, a 2-butenyl group, and 3 -butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl , 1-hexenyl, 3-hexenyl and 5-hexenyl.

Examples of the "C _2-6 alkynyl group" in the present specification include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, and a 1-pentyl group. Alkynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1,1-dimethylprop-2-yn-1-yl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.

Examples of the "C _1-6 alkoxy group" in the present specification include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a bis-butoxy group, and a tertiary butyl group. Oxyl, pentyloxy, isopentyloxy, and hexyloxy.

Examples of the "C _1-6 alkyl-carbonyl group" in the present specification include an ethyl carbonyl group, an ethyl carbonyl group, a propylcarbonyl group, an isopropylcarbonyl group, a butylcarbonyl group, an isobutylcarbonyl group, a secondary butylcarbonyl group, and a tertiary stage. Butylcarbonyl, pentylcarbonyl, and hexylcarbonyl.

Examples of the "C _1-6 alkoxy-carbonyl group" in the present specification include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, and a tertiary butoxycarbonyl group.

Examples of the "C _3-8 cycloalkyl group" in the present specification include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

Examples of the "C _3-8 cycloalkane" in the present specification include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

Examples of the "C _3-6 cycloalkane" in the present specification include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

Examples of the "C _3-8 cycloalkenyl group" in the present specification include a cyclopropenyl group (e.g., 2-cyclopropen-1-yl group), a cyclobutenyl group (e.g., 2-cyclobuten-1-yl group), a ring. Pentenyl (eg, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl) and cyclohexenyl (eg, 2-cyclohexen-1-yl, 3-cyclohexene- 1-base).

Examples of the "C _7-13 aralkyl group" in the present specification include benzyl, phenethyl and naphthylmethyl.

Examples of the "C _4-10 cyclodienyl group" in the present specification include a cyclopentadienyl group.

Examples of the "heterocyclic group" in the present specification include an aromatic heterocyclic group and a non-aromatic heterocyclic group.

Examples of the "aromatic heterocyclic group" in the present specification include 4- to 7-members (preferably 5- or 6-members) containing 1 to 4 selected from an oxygen atom and a sulfur atom (the sulfur atom may be optionally used A monocyclic aromatic heterocyclic group having a hetero atom of a nitrogen atom and a nitrogen atom as a constituent atom of a ring other than a carbon atom, and a fused aromatic heterocyclic group. Examples of the fused aromatic heterocyclic group include a group derived from a condensed ring in which a ring corresponding to a 4- to 7-membered monocyclic aromatic heterocyclic group is selected from 1 or 2 selected from 1 or 2 a 5- or 6-membered aromatic heterocyclic ring of a nitrogen atom (eg, pyrrole, imidazole, pyrazole, pyridinium) , pyridine, pyrimidine), a 5-membered aromatic heterocyclic ring containing a sulfur atom (eg, thiophene), and a benzene ring ring fused.

Preferred examples of the aromatic heterocyclic group include a monocyclic aromatic heterocyclic group such as a furyl group (e.g., 2-furyl group, 3-furyl group), a thienyl group (e.g., 2-thienyl group, 3-thienyl group). , pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), anthracene Base (eg, 3-嗒 Base, 4-嗒 Base Base (eg, 2-pyridyl , pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), Pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl ( For example, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), Azolyl (eg, 2- Azolyl, 4- Azolyl, 5- Zozolyl) Azolyl (eg, 3-iso) Azolyl, 4-iso Azolyl, 5-iso Azolyl), Diazolyl (eg, 1, 2, 4- Diazol-5-yl, 1,3,4- Diazol-2-yl), thiadiazolyl (eg, 1,3,4-thiadiazol-2-yl), triazolyl (eg, 1,2,4-triazol-1-yl, 1 , 2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl ), tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl), three Base (eg, 1, 2, 4-three -1-base, 1,2,4-three -3-yl) and the like; and a fused aromatic heterocyclic group such as quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolinyl), isoquinoline Base (eg, 3-isoquinolinyl), quinazolinyl (eg, 2-quinazolinyl, 4-quinazolinyl), quin Olinyl (eg, 2-quine Lolinyl, 6-quinoline Phenyl), benzofuranyl (eg, 2-benzofuranyl, 3-benzofuranyl), benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzo Azolyl (eg, 2-benzo) Zozolyl) Azolyl (eg, 7-benzazole) Azolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzimidazolyl (eg, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl) , benzotriazolyl (eg, 1H-1,2,3-benzotriazol-5-yl), fluorenyl (eg, indol-1-yl, indol-2-yl, anthracene) 3-yl, indol-5-yl), oxazolyl (eg, 1H-carbazol-3-yl), pyrrolopypene Base (eg, 1H-pyrrolo[2,3-b]pyridyl -2-yl, 1H-pyrrolo[2,3-b]pyridyl -6-yl), imidazopyridyl (eg, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, 2H-imidazole And [1,2-a]pyridin-3-yl), imidazopyridine Base (eg, 1H-imidazo[4,5-b]pyridinyl -2-yl), pyrazolopyridyl (eg, 1H-pyrazolo[4,3-c]pyridin-3-yl), pyrazolothiophenyl (eg, 2H-pyrazolo[3,4 -b]thiophen-2-yl), pyrazolo Base (eg, pyrazolo[5,1-c][1,2,4] -3-yl) and so on.

Examples of the "non-aromatic heterocyclic group" in the present specification include 4- to 7-members (preferably 4- or 6-members) containing 1 to 4 selected from oxygen atoms and sulfur atoms (the sulfur atom is optionally required A monocyclic non-aromatic heterocyclic group which may be an oxidized atom and a hetero atom of a nitrogen atom as a constituent atom of a ring other than a carbon atom, and a fused non-aromatic heterocyclic group. Examples of the fused non-aromatic heterocyclic group include a group derived from a condensed ring, wherein a ring system corresponding to a 4- to 7-membered monocyclic non-aromatic heterocyclic group is selected from 1 or 2 selected from 1 or 5- or 6-membered aromatic heterocyclic ring of two nitrogen atoms (eg, pyrrole, imidazole, pyrazole, pyridyl) , pyridine, pyrimidine), a 5-membered aromatic heterocyclic ring containing a sulfur atom (e.g., thiophene), and a benzene ring ring fused, and a group in which the above group is partially saturated.

Preferred examples of the non-aromatic heterocyclic group include a monocyclic non-aromatic heterocyclic group such as oxetanyl group (e.g., 2-oxetanyl group, 3-oxetanyl group), pyrrolidinyl group (e.g. , pyrrolidin-1-yl, pyrrolidin-2-yl), piperidinyl (eg, N-piperidinyl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), Morpholinyl (eg, N-morpholinyl), thiomorpholinyl (eg, N-thiomorpholinyl), piperidine Base -1-yl, piperazine -2-yl, piperidine 3-yl), cyclohexamethyleneimine (eg, cyclohexamethyleneimine-1-yl), Azolidinyl (eg, Azolidin-2-yl, Iazolidine-5-yl), tetrahydrothiazolyl (eg, tetrahydrothiazol-2-yl), imidazolidinyl (eg, imidazolidin-2-yl, imidazolidin-3-yl), Oxazoline group (eg, Oxazolin-2-yl), thiazolinyl (eg, thiazolin-2-yl), imidazolinyl (eg, imidazolin-2-yl, imidazolin-3-yl), dioxolyl (eg, 1,3-dioxol-4-yl), dioxolane (eg, 1,3-dioxol-4-yl), dihydrogen Diazolyl (eg, 4,5-dihydro-1,2,4- Diazol-3-yl), 2-thioketo-1,3- Azolidin-5-yl, piperidyl (e.g., 4-piperidyl), tetrahydropyranyl (e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyran Thiopiperidyl (eg, 4-thiopiperidyl), tetrahydrothiopiperidyl (eg, 2-tetrahydrothiopiperidyl, 3-tetrahydrothiopiperidyl, 4-tetrahydrothiopiperidinyl), 1-oxidized tetrahydrothiopiperidyl (eg, 1-oxytetrahydrothiopyran-4-yl), 1,1-dihydrotetrathiothiophene A thiol group (eg, 1,1-dihydrotetrahydrothiopyran-4-yl), a tetrahydrofuranyl group (eg, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), a pyrazolidine group (eg, pyrazole) Pyridin-1-yl, pyrazolidine-3-yl), pyrazolinyl (eg, pyrazolin-1-yl), tetrahydropyrimidinyl (eg, tetrahydropyrimidin-1-yl), dihydrogen Azolyl (eg, 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (eg, 2,3,4,5-tetrahydro-1H-1) , 2,3-triazol-1-yl), azepanyl (eg, azepan-3-yl, azepan-2-yl), azetidinyl ( For example, azetidin-1-yl, azetidin-2-yl), dihydropyridyl (eg, 3,6-dihydropyridin-1-yl, 3,6-dihydropyridine) 2-yl), tetrahydropyridyl (eg, 1 , 2,3,6-tetrahydropyridin-2-yl), pendant oxytetrahydropyrimidinyl (e.g., pendant oxytetrahydropyrimidin-1-yl), and the like; fused non-aromatic heterocyclic group such as indoline Base (eg, 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (eg, 1,3-dihydro-2H-isoindol-2-yl), dihydrogen Benzofuranyl (eg, 2,3-dihydro-1-benzofuran-5-yl), dihydrobenzodioxinyl (eg, 2,3-dihydro- 1,4-benzodioxanyl), dihydrobenzodioxanylene (for example, 3,4-dihydro-2H-1,5-benzodioxole) Heptatrienyl), tetrahydrobenzofuranyl (eg, 4,5,6,7-tetrahydro-1-benzofuran-3-yl), chromenyl (eg, 4H-) Benzopyran-2-yl, 2H-benzopiperan-3-yl), dihydroquinolinyl (eg, 1,2-dihydroquinolin-4-yl), tetrahydroquinolinyl (eg , 1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolinyl (eg, 1,2-dihydroisoquinolin-4-yl, 3,4-dihydroisoquine Benzan-2-yl), tetrahydroisoquinolinyl (eg, 1,2,3,4-tetrahydroisoquinolin-4-yl), indoline Base (eg, 1,4-dihydroanthracene -4-yl), octahydroquinone Octahydropurine -3-yl, octahydroquinone -5-yl), octahydroquine Base (eg, octahydro-2H-quine -4-yl), octahydropyrrolopyrr Base (eg, octahydropyrrolo[1,2-a]pyridyl 3-yl), octahydroindenyl (eg, hydrogen-1H-indol-2-yl), octahydrocyclopenta[b]pyrrolyl, decahydroisoquinolinyl (eg, decahydroquinoline) Polin-1-yl) and the like.

Further, the "non-aromatic heterocyclic group" in the present specification may be bridged with a non-aromatic heterocyclic group or a spirocyclic non-aromatic heterocyclic group.

Examples of the bridged non-aromatic heterocyclic group include an anthracene bicyclo[2.1.1]hexane group (e.g., 2-indolebicyclo[2.1.1]hex-1-yl), anthracene bicyclo[3.1.0]hexane group. (eg, 3-indole bicyclo[3.1.0]hex-2-yl, 3-indolylbicyclo[3.1.0]hex-3-yl, 2-indolylbicyclo[3.1.0]hex-3-yl, 2-吖Bicyclo[3.1.0]hex-1-yl), anthracene bicyclo[2.2.1]heptyl (eg, 2-indolebicyclo[2.2.1]heptan-3-yl, 7-fluorenebicyclo[2.2.1 Hept-1-yl), anthracene bicyclo[2.2.2]octyl (eg, 2-indolyl[2.2.2]oct-3-yl, 1-indolyl[2.2.2]oct-2-yl , 吖bicyclo[2.2.1] hexane group (eg, 2-indolebicyclo[2.2.1]hex-1-yl), indole bicyclo[4.1.0]heptyl (eg, 3-indole bicyclo [4.1] .0] hept-4-yl) and the like.

Examples of the spirocyclic non-aromatic heterocyclic group include 1,4-dioxa-7-azaspiro[4.4]indol-7-yl, tetrahydro-5H-spiro[1,3- Oxazo[3,4-a]pyridyl -1,4'-piperidinyl-1'-yl, 4-azaspiro[2.4]hept-5-yl and the like.

When the compound (I) has a tautomer, each isomer is also contained in the compound (I).

For example, the partial structure of the compound (I) is as follows

The code numbers are as defined above and are the following.

Each of the symbols is as defined above and is also included in the compound (I).

Further, for example, a partial structure of the following formula in the compound (I)

The code numbers are as defined above and are the following.

Each of the symbols is as defined above and is also included in the compound (I).

One of X and Y is a sulfur atom, and the other is CH.

Preferably, X is a sulfur atom and Y is CH.

R ₁ is a C _1-6 alkyl group which may be optionally substituted by a halogen atom.

R _{1 is} preferably a methyl group, an ethyl group, a trifluoromethyl group or the like.

More preferably, R ₁ is a methyl group, a trifluoromethyl group or the like.

Further, R _{1 is} more preferably a methyl group or the like.

R ₂ is a substituent.

Examples of the R ₂ "substituent" include a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent as necessary, and a group (5) to (30) in the following substituent group A.

Examples of the "hydrocarbyl group" of the above-mentioned "hydrocarbon group which may have a substituent" include a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _{3 - 8-} cycloalkenyl, C _4-10 cyclodienyl and C _6-14 aryl.

The above C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group and C _4-10 cyclodienyl group may each be condensed with a benzene ring. Examples of fused ring groups include indanyl, dihydronaphthyl, tetrahydronaphthyl and anthracenyl. Further, a bridged hydrocarbon group such as a raw spinachyl group, an adamantyl group or the like is also contained in the above hydrocarbon group.

The hydrocarbon group of the above-mentioned "hydrocarbon group which may have a substituent" is preferably a C _1-6 alkyl group (e.g., methyl group, ethyl group), a C _3-8 cycloalkyl group (particularly, a cyclopentyl group, a cyclohexyl group). , C _2-6 alkenyl (eg, vinyl), or C _6-14 aryl (eg, phenyl). Particularly preferred are C _1-6 alkyl groups (e.g., methyl, ethyl) and C _6-14 aryl groups (e.g., phenyl).

The C _1-6 alkyl group, the C _2-6 alkenyl group and the C _2-6 alkynyl group as examples of the above "hydrocarbon group" may have 1 to 5 (preferably 1 to 3) substitutions based on the substitutable positions.

Examples of the substituent include the following substituent group A. When the number of substituents is not less than 2, the respective substituents may be the same or different.

(Substituent group A)

(1) A C _3-8 cycloalkyl group which may be substituted with an amine group (for example, a cyclopropyl group, a cyclopentyl group or a cyclohexyl group); (2) may have 1 to 3 substituents selected from the group consisting of the following: Substituted C _6-14 aryl (eg, phenyl, naphthyl) (a) optionally substituted with 1 to 3 halogen atoms, C _1-6 alkyl, (b) hydroxy, (c) optionally a C _1-6 alkoxy group substituted by 1 to 3 halogen atoms, (d) a halogen atom (e.g., a fluorine atom), and (e) a C _1-6 alkyl sulfonyl group (e.g., methyl sulfonyl group) (3) an aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the following (e.g., thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, Azyl, thiazolyl, (oxadiazolyl, thiadiazolyl, pyrrolyl) (a) optionally substituted by 1 to 3 halogen atoms, C _1-6 alkyl, (b) hydroxy, (c) 1 to 3 as needed a C _1-6 alkoxy group substituted with a halogen atom, and (d) a halogen atom; (4) a non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the group consisting of, for example, tetrahydrofuranyl group, Morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperidine , azetidinyl, 3,4-dihydroisoquinolinyl, tetrahydroisoquinolinyl, dihydropyridyl, tetrahydropyridyl, 1,3-dihydro-2H-isoindolyl 1,4-Dioxa-7-azaspiro[4.4]壬-7-yl, tetrahydro-5H-spiro[1,3- Oxazo[3,4-a]pyridyl 1,4'-piperidin] -1'-yl, acridine bicyclo [3.1.0] hex-3-yl) (a) may be optionally substituted with 1 to 3 substituents selected from the substituents of C _{1- a 6} alkyl group (e.g., a methyl group) (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxyl group, and (iii) a C _6-14 aryl group (e.g., a phenyl group) which may be optionally substituted by (aa) a halogen atom (e.g., a fluorine atom), (bb) a hydroxyl group, (cc) a C _1-6 alkoxy group (e.g., a methoxy group), and (dd) 1 to 3 C _1-6 alkyl groups ( For example, methyl), (b) hydroxy, (c) a C _1-6 alkoxy group (eg, methoxy) which may be substituted with 1 to 3 halogen atoms, (d) a halogen atom (eg, fluorine) Atom), (e) a keto group, (f) a C _6-14 aryl group (e.g., phenyl) which may be substituted with 1 to 3 halogen atoms (e.g., a fluorine atom), (g) C _6-14 An aryloxy group (e.g., phenoxy), (h) C _1-6 alkoxy-carbonyl (e.g., ethoxycarbonyl) or a C _1-6 alkyl-carbonyl (e.g., ethyl fluorenyl), (i) Cyano, (j) C _6-14 arylsulfonyl (eg, phenylsulfonyl), (k) carboxyl, (l) optionally C _1-6 alkyl (eg, methyl), single a - or a di-substituted amine group, and (m) a non-aromatic heterocyclic group (e.g., pyrrolidinyl, tetrahydropyrimidinyl) which may be optionally substituted by a keto group; (5) optionally selected The following substituents mono - or di - amine (a) may be optionally substituted with the 1 to 3 substituents selected from a substituent of the C _1-6 alkyl (e.g., methyl, ethyl, isopropyl, (i) a halogen atom, (ii) a C _6-14 aryl group (e.g., phenyl) which may be substituted with 1 to 3 C _1-6 alkoxy groups (e.g., methoxy group), (iii) a C _1-6 alkoxy-carbonyl group (e.g., ethoxycarbonyl), (iv) an aromatic heterocyclic group (e.g., pyridyl), (v) optionally 1 to 3 aromatic heterocyclic groups (e.g., , thienyl) substituted C _3-8 cycloalkyl (eg, cyclopropyl), and (vi) hydroxy, (b) optionally substituted with 1 to 3 halogen atoms, C _1-6 alkyl-carbonyl , (c) may be optionally substituted with 1 to 3 of halogen atoms, C _1-6 alkoxy - carbonyl group, (d) may be optionally substituted with 1 to 3 halogen atoms of C _1-6 alkylsulfonyl group (e.g., methanesulfonamide acyl), (E) may be optionally by C _1-6 alkyl mono - or di - substituted carbamoyl of acyl, C _1-6 alkyl which may be optionally 1-3 Substituted by a halogen atom, (f) an aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, Azyl, thiazolyl, a oxadiazolyl, thiadiazolyl), (g) a non-aromatic heterocyclic group (eg, pyrrolidinyl) which may be substituted with 1 to 3 C _7-13 aralkyl groups (eg, benzyl), if desired) , (h) a C _6-14 aryl group (eg, phenyl) substituted with 1 to 3 C _1-6 alkoxy groups (eg, methoxy), and (i) a C _3-8 ring An alkyl group (e.g., cyclopentyl); (6) a C _1-6 alkyl-carbonyl group which may be optionally substituted with 1 to 3 halogen atoms; (7) optionally 1 to 3 substituents selected from the group consisting of a C _1-6 alkoxy-carbonyl group (for example, a tertiary butyloxycarbonyl group) (a) a halogen atom, (b) a C _1-6 alkoxy group, and (c) a C _6-14 aryl group (eg, Phenyl), and (d) a heterocyclic group (eg, tetrahydrofuranyl); (8) a C _1-6 alkylsulfonyl group which may be substituted with 1 to 3 halogen atoms as required (eg, methylsulfonyl, Ethylsulfonyl, isopropylsulfonyl); (9) optionally substituted with a C _1-6 alkyl mono- or di-substituted amine carbenyl group, and the C _1-6 alkyl group may be subjected to 1 substituted to 3 halogen atoms; (10) optionally C _1-6 alkyl may be mono - or di - substituted carbamoyl of thio acyl, C _1-6 alkyl which may be optionally substituted with 1 to 3 a halogen atom; (11) C _1-6 alkyl may be optionally mono over - or di - substituted amine sulfonamide of acyl C _1-6 alkyl which may be optionally substituted with 1 to 3 halogen atoms; (12) a carboxyl group; (13) hydroxy; (14) may be optionally substituted with 1 to 3 substituents selected from the substituents of C _1-6 alkoxy (eg, ethoxy) (a) halogen atom, (b) carboxyl group, (c) C _1-6 alkoxy group, (d) 1 to 3 C _6-14 as needed An aryl group (e.g., phenyl) substituted with a C _1-6 alkoxy-carbonyl group, (e) optionally selected from a C _1-6 alkyl group and a C _1-6 alkoxy-carbonyl group mono- or di- a substituted amino group, (f) a heterocyclic group (e.g., tetrahydrofuranyl), and (g) a C _3-8 cycloalkyl group; (15) a C _2-6 alkene which may be substituted with 1 to 3 halogen atoms as needed An oxy group (e.g., a vinyloxy group); (16) a C _7-13 aralkyloxy group (e.g., benzyloxy); (17) a C _6-14 aryloxy group (e.g., a phenoxy group, a naphthyloxy group) (18) C _1-6 alkyl-carbonyloxy (eg, ethoxycarbonyl, tert-butylcarbonyloxy); (19) optionally substituted with 1 to 3 substituents selected from the group consisting of a C _6-14 aryl-carbonyl group (e.g., benzhydryl) (a) a halogen atom, and (b) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms as desired; (20) An aromatic heterocyclic carbonyl group (eg, pyrazole) which may be substituted with 1 to 3 substituents selected from a C _1-6 alkyl group is required Carbonyl, pyridyl Carbonyl, different An oxazocarbonyl group, a pyridinecarbonyl group, a thiazolecarbonyl group, and the C _1-6 alkyl group may be substituted with 1 to 3 halogen atoms as needed; (21) may optionally be 1 to 3 selected from a C _1-6 alkyl group. a substituent-substituted non-aromatic heterocyclic carbonyl group (eg, pyrrolidinylcarbonyl, morpholinecarbonyl), and the C _1-6 alkyl group may be substituted with 1 to 3 halogen atoms as needed; (22) C _7-13 An aralkoxy-carbonyl group (e.g., benzyloxycarbonyl); (23) a fluorenyl group; (24) a C _1-6 alkylthio group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of Methylthio, ethylthio) (a) halogen atom, and (b) C _1-6 alkoxy-carbonyl; (25) C _7-13 aralkylthio (eg, phenylthio); C _6-14 arylthio (eg, phenylthio, naphthylthio); (27) cyano; (28) nitro; (29) halogen atom (eg, chlorine atom); (30) as needed a C _3-10 cycloalkoxy group (for example, a cyclopropoxy group, a cyclopentyloxy group) (a) a halogen atom (for example, a fluorine atom) substituted with 1 to 3 substituents selected from the group consisting of: (b) C _1-6 alkoxy (e.g., methoxy); and (31) keto.

The above C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _4-10 cyclodienyl group and C _6-14 aryl group as examples of the above "hydrocarbon group" may have 1 to 5 each as needed ( Preferably 1 to 3) substitutions are based on substitutable positions.

Examples of the substituent include the following substituent group B. When the number of substituents is not less than 2, the respective substituents may be the same or different.

(Substituent Group B)

(1) a group as an example of the above substituent group A; (2) a C _1-6 alkyl group (a) halogen atom which may be substituted with 1 to 3 substituents selected from the following, (b) Carboxyl group, (c) hydroxy group, (d) C _1-6 alkoxy-carbonyl group, (e) C _1-6 alkoxy group, (f) optionally substituted by C _1-6 alkyl group An amine group, and (g) an amine carbenyl group; (3) a C _2-6 alkenyl group (e.g., a vinyl group, a 1-propenyl group) which may be optionally substituted with 1 to 3 substituents selected from the group consisting of a) a halogen atom, (b) a carboxyl group, (c) a hydroxyl group, (d) a C _1-6 alkoxy-carbonyl group, (e) a C _1-6 alkoxy group, and (f) may be subjected to C _{1- a 6-} alkyl mono- or di-substituted amine group; and (4) a C _7-13 aralkyl group (e.g., benzyl) which may be substituted with 1 to 3 substituents selected from the group consisting of (a) A C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxyl group, (c) a C _1-6 alkoxy group, and (d) a halogen atom, as needed.

Preferable examples of the substituent of the above-mentioned "hydrocarbon group which may have a substituent" may include (1) a halogen atom (e.g., a chlorine atom), and (2) a _C1-6 alkoxy group (e.g., methoxy group, ethoxy group). And (3) a non-aromatic heterocyclic group which may be substituted with 1 to 4 substituents selected from the group consisting of pyridinyl, piperidinyl, morpholinyl, thiomorpholinyl, or , azetidinyl, tetrahydroisoquinolyl, dihydropyridyl, tetrahydropyridyl, tetrahydrofuranyl, 1,3-dihydro-2H-isoindolyl, 1,4-dioxan -7-azaspiro[4.4]壬-7-yl, tetrahydro-5H-spiro[1,3- Oxazo[3,4-a]pyridyl -1,4'-piperidine]-1'-yl, anthracene bicyclo[3.1.0]hex-3-yl) (a) a halogen atom (eg, a fluorine atom), (b) a hydroxyl group, (c) as needed a C _1-6 alkyl group (e.g., methyl) substituted with 1 to 3 substituents selected from a halogen atom (e.g., a fluorine atom) and a hydroxyl group, (d) a C _1-6 alkoxy group (e.g., A Oxy), (e) a C _6-14 aryl group (e.g., phenyl) substituted with 1 to 3 halogen atoms (e.g., a fluorine atom), (f) a C _6-14 aryloxy group (e.g. , phenoxy), (g) C _1-6 alkoxy-carbonyl (eg, ethoxycarbonyl), (h) C _1-6 alkyl-carbonyl (eg, ethyl hydrazino), (i) cyano , (j) C _6-14 arylsulfonyl (eg, phenylsulfonyl), (k) carboxyl, (l) optionally _C1-6 alkyl (eg, methyl) mono- or di a substituted amino group, (m) a non-aromatic heterocyclic group (e.g., pyrrolidinyl, tetrahydropyrimidinyl) which may be substituted by a keto group, and (n) a ketone group, if desired, (4) a mono- or di-substituted amine group (a) selected from the group consisting of a C _1-6 alkyl group (e.g., methyl, ethyl, isopropyl) substituted with a substituent selected from the group consisting of (i) may be optionally C _1-6 alkoxy (e.g., methoxy) substituent of a C _6-14 aryl group (e.g., phenyl), (II) C _1-6 alkoxy group - Group (e.g., ethoxycarbonyl), (III) an aromatic heterocyclic group (e.g., pyridyl), and (iv) may be optionally substituted with 1 to 3 of the aromatic heterocyclic group (e.g., thienyl) C _{a 3-8} cycloalkyl group (e.g., cyclopropyl), (b) a non-aromatic heterocyclic group optionally substituted with 1 to 3 C _7-13 aralkyl groups (e.g., benzyl) (e.g., Pyrrolidinyl), and (c) a C _6-14 aryl (eg, phenyl), (5) ketone, optionally substituted with 1 to 3 C _1-6 alkoxy groups (eg, methoxy) a group, and (6) a 5- or 6-membered aromatic heterocyclic group (e.g., imidazolyl).

More preferable examples of the substituent of the above-mentioned "hydrocarbon group which may have a substituent" include (1) a halogen atom (e.g., a chlorine atom), and (2) may be optionally substituted with 1 to 3 substituents selected from the group consisting of 4- to 6-membered non-aromatic heterocyclic group (eg, pyrrolidinyl, piperidinyl, morpholinyl, piperidine) a group, azetidinyl group, tetrahydrofuranyl group, dihydropyridyl group) (a) a halogen atom (e.g., a fluorine atom), (b) a hydroxyl group, (c) optionally 1 to 3 selected from a halogen atom ( For example, a fluorine atom) and a substituent of a hydroxyl group are substituted by a C _1-6 alkyl group (e.g., methyl), (d) a C _1-6 alkoxy group (e.g., a methoxy group), and (e) a C _{6- group. 14} aryl (e.g., phenyl), and (3) C _1-6 alkoxy (e.g., ethoxy).

Particularly preferred examples of the substituent of the above-mentioned "hydrocarbon group which may have a substituent" include (1) a halogen atom (e.g., a chlorine atom), and (2) may optionally have 1 to 3 halogen atoms (e.g., a fluorine atom). a 4- to 6-membered non-aromatic heterocyclic group substituted with a chlorine atom (eg, pyrrolidinyl, dihydropyridyl).

Preferred examples of the above heterocyclic group of "heterocyclic group which may have a substituent" may include a non-aromatic heterocyclic group. The non-aromatic heterocyclic group may be a monocyclic non-aromatic heterocyclic group or a fused non-aromatic heterocyclic group.

Preferred examples of the above monocyclic non-aromatic heterocyclic group include a 4- to 7-membered monocyclic non-aromatic heterocyclic group (e.g., pyrrolidinyl, morpholinyl, piperidinyl, piperidine). Base, tetrahydrofuranyl, tetrahydropyridyl, azetidinyl, azepanyl, thiazolidinyl).

The above monocyclic non-aromatic heterocyclic group is preferably a 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g., pyrrolidinyl, piperidinyl, piperidine). Base, morpholinyl). The 5- or 6-membered monocyclic non-aromatic heterocyclic group is more preferably a pyrrolidinyl group, a piperidinyl group, a morpholinyl group or the like. Preferred examples of other 5- or 6-membered monocyclic non-aromatic heterocyclic groups include pyrrolidinyl, piperidinyl and tetrahydropyridyl.

Preferred examples of the above condensed non-aromatic heterocyclic group include 8- to 10-membered fused non-aromatic heterocyclic groups (e.g., octahydroquinone) Octahydroquine Octahydropyrrolopyrene Base, octahydrofluorenyl, octahydrocyclopenta[b]pyrrolyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl).

The above non-aromatic heterocyclic group may be a bridged non-aromatic heterocyclic group or a spirocyclic non-aromatic heterocyclic group.

A preferred example of bridging a non-aromatic heterocyclic group includes an anthracene bicyclo[3.1.0]hexane group (e.g., 3-indolyl[3.1.0]hex-2-yl, 2-indolyl[3.1.0] -3-yl), anthracene bicyclo [2.2.2] octyl (eg, 2-indolyl [2.2.2] oct-3-yl), indole bicyclo [2.2.1] heptyl (eg, 2- Bicyclo[2.2.1]heptan-3-yl, 7-fluorenebicyclo[2.2.1]heptan-1-yl), indole bicyclo[2.2.1]hexaneyl (eg, 2-indole bicyclo [2.2.1] ]hex-1-yl), anthracene bicyclo [2.2.2]octyl (eg, 1-indolyl [2.2.2]oct-2-yl) and indole bicyclo [2.1.1] hexane (eg, 2-吖bicyclo[2.1.1]hex-1-yl). A more preferred example of bridging a non-aromatic heterocyclic group includes an anthracene bicyclo[2.2.2]octyl group (e.g., 2-indolyl[2.2.2]oct-3-yl, 2-indolyl[2.2.2]octyl -2-yl), anthracene bicyclo [2.2.1] heptyl (eg, 2-indolebicyclo[2.2.1]heptan-3-yl, 2-indolebicyclo[2.2.1]hept-1-yl), etc. .

Preferred examples of the spirocyclic non-aromatic heterocyclic group include a nitrogen snail [2.4] heptyl group (4-azaspiro[2.4]hept-5-yl) and the like.

The above heterocyclic group of "heterocyclic group which may have a substituent" is preferably a 4- to 7-membered monocyclic non-aromatic heterocyclic group (e.g., pyrrolidinyl, piperidinyl, morpholinyl, nitrogen). Heterocyclobutane, azepanyl), 8- to 10-membered fused non-aromatic heterocyclic group (eg, octahydroindolyl) or bridged non-aromatic heterocyclic group (eg, hydrazine) Bicyclo[3.1.0]hexaneyl, indolobicyclo[2.2.1]heptyl, anthracene bicyclo[2.2.2]octyl.

The heterocyclic group of "heterocyclic group which may have a substituent as required" of R ₂ may have 1 to 5 (preferably 1 to 3) substitutions based on the substitutable position.

Examples of such a substituent include a group as an example of the above-mentioned substituent group B. When the number of substituents is two or more, the respective substituents may be the same or different.

Preferable examples of the substituent of the above "heterocyclic group which may have a substituent" may include (1) a halogen atom (e.g., a fluorine atom), and (2) may have 1 to 3 substituents selected from the group consisting of the following: Substituted C _1-6 alkyl (eg, methyl, ethyl) (a) hydroxy, (b) C _1-6 alkoxy-carbonyl (eg, ethoxycarbonyl, tertiary butoxycarbonyl), and c) Aminomethyl thiol, (3) C _1-6 alkoxy (eg, methoxy), (4) C _6-14 aryl (eg, phenyl), (5) C _6-14 aryloxy a group (e.g., phenoxy), (6) C _7-13 aralkoxy (e.g., benzyloxy), (7) C _1-6 alkoxy-carbonyl (e.g., tert-butoxycarbonyl) (8) a C _6-14 aryl group (e.g., phenyl) substituted with a C _1-6 alkylsulfonyl group (e.g., methylsulfonyl), (9) C _1-6 alkyl, if desired a carbonyl group (e.g., an ethylidene group), (10) a C _7-13 aralkyl group (e.g., benzyl group) substituted with 1 to 3 halogen atoms (e.g., a fluorine atom), (11) a hydroxyl group, if necessary And (12) an amine carbenyl group, and (13) a non-aromatic heterocyclic group (e.g., piperidinyl group).

More preferable examples of the substituent of the above "heterocyclic group which may have a substituent" may include (1) a halogen atom (e.g., a fluorine atom), and (2) a C _6-14 aryloxy group (e.g., a phenoxy group). And (3) C _1-6 alkyl (eg, methyl).

R _{2 is} preferably a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or a non-aromatic heterocyclic group-carbonyl group which may have a substituent, if necessary. Among them, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent as needed is preferable. Examples of the above-mentioned "non-aromatic heterocyclic group-carbonyl group which may have a substituent" include the group (21) in the above substituent group A.

R _{2 is more} preferably a C _1-6 alkyl group (particularly, methyl group, ethyl group, isopropyl group, isobutyl group) which may have a substituent, and optionally a C _6-14 aryl group which may have a substituent. (particularly, phenyl), or a 5- or 6-membered non-aromatic heterocyclic group (particularly, pyrrolidinyl, morpholinyl) which may have a substituent. Preferably, (1) a 4- to 6-membered non-aromatic heterocyclic group-C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms as needed; (2) 1 to 3 as needed a C _6-14 aryl group substituted by a halogen atom; or (3) a non-aromatic heterocyclic group (a) halogen atom which may be substituted with 1 to 3 substituents selected from the group consisting of, and (b) C ₁ Specific preferred examples of the _-6 alkyl group R ₂ include (1) a C _1-6 alkyl group which may have a substituent as desired (particularly, methyl, ethyl, isopropyl, isobutyl), (2) A C _6-14 aryl group (particularly, a phenyl group) which may have a substituent, and (3) a non-aromatic heterocyclic group which may have a substituent as needed (particularly, pyrrolidinyl, morpholinyl, piperidine) Base, piperidinyl, tetrahydrofuranyl, tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, azetidinyl, azepanyl, octahydro Pyrrolopypene , octahydroindenyl, octahydrocyclopenta[b]pyrrolidinyl, tetrahydrothiazolyl, indolobicyclo[3.1.0]hexane, indole bicyclo[2.1.1]hexane, indole bicyclo[2.2 .1] heptyl, indolobicyclo[4.1.0]heptyl, anthracene bicyclo[2.2.2]octyl, azaspiro[2.4]heptyl), (4) optionally having a substituent C _{2 -6} alkenyl (particularly, vinyl), (5) 5- or 6-membered aromatic heterocyclic group (particularly, pyridyl, pyrazolyl, thiazolyl) which may have a substituent, (6) a non-aromatic heterocyclic group-carbonyl group (particularly, pyrrolidinylcarbonyl group) which may have a substituent, and (7) a C _3-8 cycloalkyl group which may have a substituent as needed (particularly, cyclopentane) Base, cyclohexyl).

More specific preferred examples of R ₂ include (1) a C _1-6 alkyl group which may be optionally substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, isopropyl, and isobutyl a (a) a non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the group consisting of pyrididyl, piperidinyl, morpholinyl, thiomorpholinyl, Piper , azetidinyl, tetrahydroisoquinolinyl, tetrahydropyridyl, 1,3-dihydro-2H-isoindolyl, 1,4-dioxa-7-azaspiro[4.4]壬-7-based, tetrahydro-5H-spiro[1,3- Oxazo[3,4-a]pyridyl -1,4'-piperidine]-1'-yl, anthracene bicyclo[3.1.0]hexane group) (i) a halogen atom (particularly, a fluorine atom), (ii) a hydroxyl group, (iii) optionally C _1-6 alkyl (especially methyl) (aa) halogen atom (particularly, fluorine atom), (bb) hydroxy group, (cc) C ₁ -substituted by 1 to 3 substituents selected from the group consisting of _{a 6} alkoxy group (particularly, a methoxy group), and (dd) a C _6-14 aryl group which may be optionally substituted with 1 to 3 C _1-6 alkyl groups (particularly, methyl group) (in particular, Phenyl) (iv) C _1-6 alkoxy (particularly, methoxy), (v) C _6-14 aryl which may be substituted with 1 to 3 halogen atoms (particularly, fluorine atom) as needed (in particular, phenyl), (vi) C _6-14 aryloxy (especially, phenoxy), (vii) C _1-6 alkoxy-carbonyl (particularly, ethoxycarbonyl), (viii C _1-6 alkyl-carbonyl (especially, ethyl fluorenyl), (ix) cyano, (x) C _6-14 aryl sulfonyl (especially, phenylsulfonyl), (xi) carboxyl , (xii) optionally substituted by a C _1-6 alkyl (especially methyl) mono- or di-substituted amine group, (xiii) optionally substituted by a keto group (specific Yes, pyrrolidinyl, tetrahydropyrimidinyl, and (xiv) keto, (b) C _1-6 alkoxy (especially , ethoxy), (c) an optionally substituted mono- or di-substituted amine group, (i) optionally substituted with 1 to 3 substituents selected from the group consisting of _{: -6} alkyl (especially methyl, ethyl, isopropyl) (aa) C _{6-14 which may be} substituted with 1 to 3 C _1-6 alkoxy groups (especially, methoxy groups), if desired Aryl (particularly, phenyl), (bb) C _1-6 alkoxy-carbonyl (particularly, ethoxycarbonyl), (cc) aromatic heterocyclic (particularly, pyridyl), (dd) a C _3-8 cycloalkyl group (particularly, a cyclopropyl group) and an (ee) hydroxyl group which may be substituted with an aromatic heterocyclic group (particularly, a thienyl group), and (ii) may be subjected to 1 to 3 as needed a C _7-13 aralkyl (in particular, benzyl) substituted non-aromatic heterocyclic group (in particular, pyrrolidinyl), (iii) optionally 1 to 3 C _1-6 alkoxy Substituted (particularly, methoxy) substituted C _6-14 aryl (particularly phenyl), and (iv) C _3-8 cycloalkyl (especially, cyclopentyl), (d) 5- Or a 6-membered aromatic heterocyclic group (particularly, imidazolyl, pyrrolyl), (e) a C _6-14 aryl group (particularly, a phenyl group), and (f) an optionally substituted amino group C _3-8 cycloalkyl (especially, cyclopropyl, Group, a cyclohexyl group), (2) may be optionally substituted with 1 to 3 halogen atoms (particularly, chlorine atom) of the substituted C _6-14 aryl group (especially, phenyl), (3) may be optionally 1 a non-aromatic heterocyclic group substituted with three substituents selected from the group consisting of pyrididyl, morpholinyl, and piperidin Base, piperidinyl, tetrahydrofuranyl, tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, azetidinyl, azepanyl, octahydro Pyrrolopypene , octahydroindenyl, octahydrocyclopenta[b]pyrrolidinyl, tetrahydrothiazolyl, indolobicyclo[3.1.0]hexane, indole bicyclo[2.1.1]hexane, indole bicyclo[2.2 .1]heptyl, anthracene bicyclo[4.1.0]heptanyl, anthracene bicyclo[2.2.2]octyl, azaspiro[2.4]heptyl) (a) a halogen atom (in particular, a fluorine atom), (b) a C _1-6 alkyl group (in particular, a methyl group, a propyl group) (i) a hydroxyl group substituted with 1 to 3 substituents selected from the group consisting of, and (ii) a C _1-6 alkoxy group. a carbonyl group (in particular, an ethoxycarbonyl group, a tertiary butyloxycarbonyl group), and (iii) an amine carbaryl group, (c) a C _6-14 aryloxy group (particularly, a phenoxy group), (d) C _{1 -6} alkoxy-carbonyl (particularly, tertiary butoxycarbonyl), (e) C _1-6 alkyl-carbonyl (especially, ethyl fluorenyl), (f) optionally C _1-6 alkane a sulfonyl group (in particular, a methylsulfonyl group) substituted with a C _6-14 aryl group (particularly, a phenyl group), (g) optionally having 1 to 3 halogen atoms (particularly, a fluorine atom) Substituting a C _7-13 aralkyl group (particularly, benzyl), (h) a hydroxyl group, (i) an amine carbenium group, and (j) a non-aromatic heterocyclic group (in particular, a piperidinyl group), (4) optionally may be from 1 to 3 C _6-14 aryl group (especially, phenyl) substituted with C _2-6 alkenyl group (particularly, vinyl), (5) a 5- or 6-membered aromatic heterocyclic group (in particular, pyridyl, pyrazolyl, thiazolyl), (6) a non-aromatic heterocyclic a cyclo-carbonyl group (particularly, pyrrolidinylcarbonyl), and (7) a C _3-8 cycloalkyl group (particularly, a cyclopentyl group, a cyclohexyl group) which may be optionally substituted with an amine group.

More specific preferred examples of R ₂ include (1) an amine methyl group which may be substituted with 1 or 2 C _1-6 alkyl groups (particularly, methyl group), and (2) may be subjected to C _1-6 as needed. Alkyl (particularly, methyl) substituted 5- or 6-membered non-aromatic heterocyclic-methyl (especially pyrrolidinylmethyl, dihydropyridylmethyl), or (3) as needed a non-aromatic heterocyclic group which may be substituted by 1 to 3 halogen atoms (particularly, a fluorine atom) (particularly, pyrrolidinyl, morpholinyl, piperidinyl, 1,2,3,6-tetrahydropyridine , azacycloheptyl, 3-indolebicyclo[3.1.0]hexane, 7-fluorenebicyclo[2.2.1]heptyl, 2-indolyl[2.2.1]heptyl, 1- Bicyclo[2.2.2]octyl, 2-indolyl[2.2.2]octyl.

Other specific preferred examples of R ₂ include (1) 5- or 6-membered non-aromatic heterocyclic-methyl groups (particularly, pyrrolidinylmethyl), or (2) 1 to 3 as needed a non-aromatic heterocyclic group substituted with a halogen atom (particularly, a fluorine atom) (particularly, pyrrolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, 7-fluorenebicyclo[2.2.1 Heptylalkyl, 2-indolylbicyclo[2.2.1]heptyl, 1-indolylbicyclo[2.2.2]octyl.

Other more specific preferred examples of R ₂ include a non-aromatic heterocyclic group which may be optionally substituted with 1 to 3 halogen atoms (particularly, a fluorine atom) (in particular, pyrrolidinyl, morpholinyl, piperidine) 1,1,2,3,6-tetrahydropyridyl, azepanyl, 3-indolyl[3.1.0]hexane, 7-fluorenebicyclo[2.2.1]heptanyl, 2- Bicyclo[2.2.1]heptyl, 1-indolylbicyclo[2.2.2]octyl, 2-indolyl[2.2.2]octyl). Among them, pyrrolidin-2-yl, piperidin-2-yl, 1,2,3,6-tetrahydropyridin-2-yl, 7-fluorenebicyclo[2.2.1]hept-1-yl, 2-吖Bicyclo[2.2.1]heptan-3-yl or 1-indolyl[2.2.2]oct-2-yl is preferred, and may have 1 to 3 halogen atoms (particularly, fluorine atom) as needed. Replace.

Preferred examples of the compound (I) include the following compounds.

[Compound A-2]

A compound or a salt thereof, wherein X is a sulfur atom; Y is CH; and R ₁ is a C _1-6 alkyl group optionally substituted by a halogen atom (particularly, methyl, ethyl, Isopropyl, isobutyl); and R ₂ is (1) a C _1-6 alkyl group (particularly, methyl, ethyl) which may have a substituent, and (2) may have a substituent as needed a C _6-14 aryl group (particularly, a phenyl group), (3) a non-aromatic heterocyclic group which may have a substituent as needed (particularly, pyrrolidinyl, morpholinyl, piperidine Base, piperidinyl, tetrahydrofuranyl, tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, azetidinyl, azepanyl, octahydro Pyrrolopypene , octahydroindenyl, octahydrocyclopenta[b]pyrrolidinyl, tetrahydrothiazolyl, indolobicyclo[3.1.0]hexane, indene bicyclo[3.1.0]hexane, indole ring [2.1 .1] hexane group, anthracene bicyclo[2.2.1]heptyl, anthracene bicyclo[4.1.0]heptanyl, anthracene bicyclo[2.2.2]octyl, azaspiro[2.4]heptyl), 4) a C _2-6 alkenyl group (particularly, a vinyl group) which may have a substituent, and (5) a 5- or 6-membered aromatic heterocyclic group which may have a substituent as needed (particularly, a pyridyl group) , pyrazolyl, thiazolyl), (6) a non-aromatic heterocyclic group-carbonyl group (in particular, pyrrolidinylcarbonyl) which may have a substituent, or (7) a C which may have a substituent as needed _3-8 cycloalkyl (especially, cyclopentyl, cyclohexyl).

[Compound A-1]

A compound or a salt thereof, wherein X is a sulfur atom; Y is CH; R ₁ is a C _1-6 alkyl group (particularly, methyl); and R ₂ is (1) optionally a C _1-6 alkyl group having a substituent (particularly, a methyl group, an ethyl group), (2) a C _6-14 aryl group (particularly, a phenyl group) which may have a substituent, and (3) as needed Non-aromatic heterocyclic group which may have a substituent (particularly, pyrrolidinyl, morpholinyl, piperidinyl, tetrahydrofuranyl, azetidinyl, azepanyl, octahydropyrrolopyrene , octahydroindenyl, tetrahydrothiazolyl, indolobicyclo[3.1.0]hexan-2-yl, indolobicyclo[2.2.1]heptan-3-yl, anthracene bicyclo[2.2.2]oct-3- And (4) a C _2-6 alkenyl group (particularly, a vinyl group) which may have a substituent, or (5) a 5- or 6-membered aromatic heterocyclic group which may have a substituent as needed ( In particular, pyridyl).

[Compound A]

A compound or a salt thereof, wherein X is a sulfur atom; Y is CH; R ₁ is a C _1-6 alkyl group (particularly, methyl); and R ₂ may have a substituent as needed a C _1-6 alkyl group (particularly, a methyl group, an ethyl group), a C _6-14 aryl group (particularly, a phenyl group) which may have a substituent, or a 5- group which may have a substituent as needed A 6-membered non-aromatic heterocyclic group (particularly, pyrrolidinyl, morpholinyl).

[Compound B-2]

A compound or a salt thereof, wherein X is a sulfur atom; Y is CH; and R ₁ is a C _1-6 alkyl group optionally substituted by a halogen atom (particularly, a fluorine atom) (especially , methyl, ethyl); and R ₂ is (1) optionally substituted by 1 to 3 C _1-6 alkyl groups (in particular, methyl, ethyl, isopropyl) (isobutyl) (a) a non-aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from the group consisting of pyrididyl, piperidinyl, morpholinyl, thiomorpholine, if necessary Base , azetidinyl, tetrahydroisoquinolinyl, tetrahydropyridyl, 1,3-dihydro-2H-isoindolyl, 1,4-dioxa-7-azaspiro[4.4]壬-7-based, tetrahydro-5H-spiro[1,3- Oxazo[3,4-a]pyridyl -1,4'-piperidine]-1'-yl, anthracene bicyclo[3.1.0]hexane group) (i) a halogen atom (particularly, a fluorine atom), (ii) a hydroxyl group, (iii) optionally C _1-6 alkyl (especially methyl) (aa) halogen atom (particularly, fluorine atom), (bb) hydroxy group, (cc) C ₁ -substituted by 1 to 3 substituents selected from the group consisting of _{a 6} alkoxy group (particularly, a methoxy group), and (dd) a C _6-14 aryl group which may be optionally substituted with 1 to 3 C _1-6 alkyl groups (particularly, methyl group) (in particular, Phenyl), (iv) C _1-6 alkoxy (especially, methoxy), (v) C _6-14 aryl which may be substituted by 1 to 3 halogen atoms (particularly, fluorine atom) as needed a base (particularly, phenyl), (vi) a C _6-14 aryloxy group (particularly, a phenoxy group), (vii) a C _1-6 alkoxy-carbonyl group (particularly, an ethoxycarbonyl group), Viii) C _1-6 alkyl-carbonyl (especially, ethyl fluorenyl), (ix) cyano, (x) C _6-14 aryl sulfonyl (especially, phenylsulfonyl), (xi) a carboxyl group, (xii) optionally a mono- or di-substituted amino group via a C _1-6 alkyl group (especially a methyl group), (xiii) a non-aromatic heterocyclic group which may be optionally substituted by a ketone group ( In particular, pyrrolidinyl, tetrahydropyrimidinyl) and (xiv) a ketone group, (b) C _1-6 alkoxy (Laid Is ethoxy), (c) optionally substituents may be selected from the following group of mono - or di - substituted amine group of, (i) may be optionally substituted with 1 to 3 substituents selected from the substituents of C _1-6 alkyl (especially, methyl, ethyl, isopropyl) (aa) may be optionally substituted with 1 to 3 C _1-6 alkoxy (particularly, methoxy group) substituted with the C _{6- 14} aryl (particularly, phenyl), (bb) C _1-6 alkoxy-carbonyl (particularly, ethoxycarbonyl), (cc) aromatic heterocyclic group (in particular, pyridyl), (dd a C _3-8 cycloalkyl group (particularly, a cyclopropyl group) substituted with an aromatic heterocyclic group (particularly, a thienyl group), and (ee) a hydroxyl group, (ii) optionally 1 through 3 C _7-13 aralkyl (especially, benzyl) substituted non-aromatic heterocyclic groups (in particular, pyrrolidinyl) (iii) optionally 1 to 3 C _1-6 alkoxy groups Substituted (particularly, methoxy) substituted C _6-14 aryl (particularly phenyl), and (iv) C _3-8 cycloalkyl (especially, cyclopentyl), (d) 5- Or a 6-membered aromatic heterocyclic group (particularly, imidazolyl, pyrrolyl), (e) a C _6-14 aryl group (particularly, a phenyl group), and (f) an optionally substituted amino group C _3-8 cycloalkyl (especially, cyclopropyl, cyclo a pentyl group, a cyclohexyl group, (2) a C _6-14 aryl group (particularly, a phenyl group) which may be substituted with 1 to 3 halogen atoms (particularly, a chlorine atom), if desired, (3) 1 to 3 non-aromatic heterocyclic groups substituted with a substituent selected from the group consisting of pyrididyl, morpholinyl, and piperidin Base, piperidinyl, tetrahydrofuranyl, tetrahydropyridyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, azetidinyl, azepanyl, octahydro Pyrrolopypene , octahydroindenyl, octahydrocyclopenta[b]pyrrolidinyl, tetrahydrothiazolyl, indolobicyclo[3.1.0]hexane, indole bicyclo[2.1.1]hexane, indole bicyclo[2.2 .1]heptyl, anthracene bicyclo[4.1.0]heptanyl, anthracene bicyclo[2.2.2]octyl, azaspiro[2.4]heptyl) (a) a halogen atom (in particular, a fluorine atom), (b) a C _1-6 alkyl group (in particular, a methyl group, a propyl group) (i) a hydroxyl group substituted with 1 to 3 substituents selected from the group consisting of, and (ii) a C _1-6 alkoxy group. a carbonyl group (in particular, an ethoxycarbonyl group, a tertiary butyloxycarbonyl group), and (iii) an amine carbaryl group, (c) a C _6-14 aryloxy group (particularly, a phenoxy group), (d) C _{1 -6} alkoxy-carbonyl (particularly, tertiary butoxycarbonyl), (e) C _1-6 alkyl-carbonyl (especially, ethyl fluorenyl), (f) optionally C _1-6 alkane a sulfonyl group (in particular, a methylsulfonyl group) substituted with a C _6-14 aryl group (particularly, a phenyl group), (g) optionally having 1 to 3 halogen atoms (particularly, a fluorine atom) Substituting a C _7-13 aralkyl group (particularly, benzyl), (h) a hydroxyl group, (i) an amine carbenium group, and (j) a non-aromatic heterocyclic group (in particular, a piperidinyl group), (4) optionally may be from 1 to 3 C _6-14 aryl group (especially, phenyl) substituted with C _2-6 alkenyl group (particularly, vinyl), (5) a 5- or 6-membered aromatic heterocyclic group (in particular, pyridyl, pyrazolyl, thiazolyl), (6) a non-aromatic heterocyclic A cyclo-carbonyl group (particularly, a pyrrolidinylcarbonyl group), or (7) a C _3-8 cycloalkyl group (particularly, a cyclopentyl group or a cyclohexyl group) which may be optionally substituted with an amine group.

[Compound B-1]

A compound or a salt thereof, wherein the compound (I) is a sulfur atom; Y is CH; R ₁ is a C _1-6 alkyl group (particularly, methyl); and R ₂ is (1) optionally 1 to 3 C _1-6 alkyl groups (in particular, methyl, ethyl) substituted with a substituent selected from the group consisting of a non-aromatic group optionally substituted with 1 to 3 substituents selected from the group consisting of Heterocyclic group (in particular, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperidine Base, azetidinyl, 3,4-dihydroisoquinolinyl, dihydropyridyl, 1,3-dihydro-2H-isoindolyl, 1,4-dioxa-7-nitrogen Snail [4.4]壬-7-based, tetrahydro-5H-spiro[1,3- Oxazo[3,4-a]pyridyl -1,4'-piperidine]-1'-yl, anthracene bicyclo[3.1.0]hex-3-yl) (i) a halogen atom (particularly, a fluorine atom), (ii) a hydroxyl group, (iii) There is a need for a C _1-6 alkyl (especially methyl) (aa) halogen atom (particularly, a fluorine atom), (bb) hydroxy, (cc) C which may be substituted with 1 to 3 substituents selected from the group consisting of _{a 1-6} alkoxy group (particularly, a methoxy group), and (dd) a C _6-14 aryl group optionally substituted with 1 to 3 C _1-6 alkyl groups (particularly, a methyl group) Yes, phenyl), (iv) C _1-6 alkoxy (especially, methoxy), (v) C _{6- which} may be substituted with 1 to 3 halogen atoms (particularly, fluorine atom) as needed ₁₄ aryl (particularly, phenyl), (vi) C _6-14 aryloxy (particularly, phenoxy), (vii) C _1-6 alkoxy-carbonyl (particularly, ethoxycarbonyl) Or C _1-6 alkyl-carbonyl (especially, ethyl fluorenyl), (viii) cyano, (ix) C _6-14 aryl sulfonyl (especially, phenylsulfonyl), (x) carboxyl , (xi) optionally substituted by a C _1-6 alkyl (especially methyl) mono- or di-substituted amine group, (xii) optionally substituted by a keto group (special Yes, pyrrolidinyl, tetrahydropyrimidinyl, and (xiii) keto, (b) C _1-6 alkoxy (especially , ethoxy), (c) an optionally substituted mono- or di-substituted amine group, (i) optionally substituted with 1 to 3 substituents selected from the group consisting of _{: -6} alkyl (especially methyl, ethyl, isopropyl) (aa) C _{6-14 which may be} substituted with 1 to 3 C _1-6 alkoxy groups (especially, methoxy groups), if desired An aryl group (particularly, phenyl), (bb) C _1-6 alkoxy-carbonyl (particularly, ethoxycarbonyl), (cc) an aromatic heterocyclic group (particularly, pyridyl), and (dd a C _3-8 cycloalkyl group (particularly, a cyclopropyl group) which may be substituted with an aromatic heterocyclic group (particularly, a thienyl group), and (ii) may have 1 to 3 C _7-13 as needed. An aralkyl group (particularly, a benzyl group) substituted with a non-aromatic heterocyclic group (particularly, pyrrolidinyl group), and (iii) optionally 1 to 3 C _1-6 alkoxy groups (especially , methoxy) substituted C _6-14 aryl (particularly, phenyl), (d) 5- or 6-membered aromatic heterocyclic group (particularly, imidazolyl), and (e) C _{6- a 14} aryl group (particularly, a phenyl group); (2) a C _6-14 aryl group (particularly, a phenyl group) which may be optionally substituted with 1 to 3 halogen atoms (particularly, a chlorine atom); (3) 1 to 3 may be selected from the following as needed Substituent substituted non-aromatic heterocyclic group (in particular, pyrrolidinyl, morpholinyl, piperidinyl, tetrahydrofuranyl, azetidinyl, azepanyl, octahydropyrrolopyrene , octahydroindenyl, tetrahydrothiazolyl, indolobicyclo[3.1.0]hex-2-yl, indolobicyclo[2.2.1]heptan-3-yl, anthracene bicyclo[2.2.2]oct-3- (a) a halogen atom (particularly, a fluorine atom), (b) a C _1-6 alkyl group (particularly, a methyl group), (c) a C _6-14 aryloxy group (particularly, a phenoxy group) , (d) C _1-6 alkoxy-carbonyl (particularly, tertiary butoxycarbonyl), (e) optionally C _1-6 alkylsulfonyl (especially, methylsulfonyl) a substituted C _6-14 aryl group (particularly, a phenyl group), and (f) a C _7-13 aralkyl group which may be optionally substituted with 1 to 3 halogen atoms (particularly, a fluorine atom) (in particular, Benzyl); (4) C _2-6 alkenyl (especially vinyl) substituted with 1 to 3 C _6-14 aryl groups (especially phenyl), if desired; or (5) 5 Or a 6-membered aromatic heterocyclic group (particularly, pyridyl).

[Compound B]

A compound or a salt thereof, wherein X is a sulfur atom; Y is CH; R ₁ is a C _1-6 alkyl group (particularly, methyl); and R ₂ is (1) optionally a C _1-6 alkyl group (particularly, methyl, ethyl) substituted with 1 to 3 substituents selected from the group consisting of 4 to 4 optionally substituted with a substituent selected from the group consisting of To a 6-membered non-aromatic heterocyclic group (in particular, pyrrolidinyl, piperidinyl, morpholinyl, piperidine) (i) a halogen atom (particularly, a fluorine atom), (ii) a hydroxyl group, (iii) optionally 1 to 3 selected from a halogen atom (particularly, fluorine) Substituted by a substituent of a hydroxy group, a C _1-6 alkyl group (eg, methyl), (iv) a C _1-6 alkoxy group (particularly, a methoxy group), and (v) a C _6-14 aryl group a base (particularly, a phenyl group), and (b) a C _1-6 alkoxy group (particularly, an ethoxy group), and (2) may be optionally substituted with 1 to 3 halogen atoms (particularly, a chlorine atom) a C _6-14 aryl group (particularly, a phenyl group), or (3) a 5- or 6-membered non-aromatic heterocyclic ring which may be optionally substituted with 1 to 3 substituents selected from the group consisting of (in particular, Pyrrolidinyl, morpholinyl) (a) a halogen atom (particularly, a fluorine atom), and (b) a C _6-14 aryloxy group (particularly, a phenoxy group).

[Compound C-1]

A compound or a salt thereof, wherein X is a sulfur atom; Y is CH; R ₁ is a C _1-6 alkyl group (particularly, methyl); and R ₂ is (1) optionally a 4- to 6-membered non-aromatic heterocyclic group-C _1-6 alkyl group substituted with 1 to 3 halogen atoms (particularly, a fluorine atom) (particularly, pyrrolidinylmethyl, dihydropyridyl group) (2) a C _6-14 aryl group (particularly, a phenyl group) which may be substituted with 1 to 3 halogen atoms (particularly, a chlorine atom), or (3) may be subjected to 1 to 3 as needed a non-aromatic heterocyclic group substituted with a substituent selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl, azetidinyl, azepanyl, octahydroindenyl , bisbicyclo[3.1.0]hex-2-yl, anthracene bicyclo[2.2.1]heptan-3-yl, anthracene bicyclo[2.2.2]oct-3-yl) (a) halogen atom (especially, fluorine Atom), and (b) C _1-6 alkyl (especially, methyl).

[Compound D-2]

A compound or a salt thereof, wherein X is a sulfur atom; Y is CH; and R ₁ is a C _1-6 alkane which may be substituted with 1 to 3 halogen atoms (particularly, a fluorine atom) as needed. a base (particularly, methyl); and R ₂ is (1) an aminomethyl group which may be substituted by 1 or 2 C _1-6 alkyl groups (particularly, methyl group) as desired, and (2) optionally a 5- or 6-membered non-aromatic heterocyclic-methyl group substituted by a C _1-6 alkyl group (in particular, a methyl group) (in particular, pyrrolidinylmethyl, dihydropyridylmethyl), or (3) a non-aromatic heterocyclic group which may be substituted with 1 to 3 halogen atoms (particularly, a fluorine atom) as needed (particularly, pyrrolidinyl, morpholinyl, piperidinyl, 1, 2, 3, 6-tetrahydropyridyl, azepanyl, 3-indolyl[3.1.0]hexane, 7-fluorenebicyclo[2.2.1]heptyl, 2-indolyl[2.2.1]g Alkyl, 1-indolylbicyclo[2.2.2]octyl, 2-indolylbicyclo[2.2.2]octyl).

[Compound E-2]

A compound or a salt thereof, wherein X is a sulfur atom; Y is CH; and R ₁ is a C _1-6 alkane which may be substituted with 1 to 3 halogen atoms (particularly, a fluorine atom) as needed. a group (in particular, methyl); and R ₂ is a (1) 5- or 6-membered non-aromatic heterocyclic group-methyl group (in particular, pyrrolidinylmethyl), or (2) optionally a non-aromatic heterocyclic group substituted with 1 to 3 halogen atoms (particularly, a fluorine atom) (particularly, pyrrolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, 7-fluorene double ring [2.2.1] Heptanyl, 2-indolylbicyclo[2.2.1]heptyl, 1-indolylbicyclo[2.2.2]octyl), or a salt thereof.

[Compound F-2]

A compound or a salt thereof, which is the compound: 6-(5-methyl-1H-pyrazol-4-yl)-2-[(2S)-pyrrolidin-2-yl]thieno[3,2 -d]pyrimidin-4(3H)-one (Example 11); 6-(5-methyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]thiophene And [3,2-d]pyrimidin-4(3H)-one (Example 83); 2-(7-fluorenebicyclo[2.2.1]hept-1-yl)-6-(5-methyl-1H -pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one (Example 116); 6-(5-methyl-1H-pyrazol-4-yl)-2 -[(2S)-1,2,3,6-tetrahydropyridin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one (Example 145); 2-[(2S -piperidin-2-yl]-6-[5-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidin-4(3H)-one (implementation) Example 161); 2-[(2S)-1-indenylbicyclo[2.2.2]oct-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2 -d]pyrimidine-4(3H)-one (Example 170).

The salt of the compound (I) is preferably a pharmaceutically acceptable salt, and examples thereof include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a salt with an alkaline or acidic amino acid.

Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salts, potassium salts and the like; alkaline earth metal salts such as calcium salts, magnesium salts and the like; aluminum salts and ammonium salts.

Preferred examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, methyridine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], and tertiary A salt of butylamine, cyclohexylamine, benzylamine, dicyclohexylamine or N,N-diphenylmethylethylenediamine.

Preferred examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid.

Preferred examples of the salt with an organic acid include with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid. a salt of methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.

Preferred examples of the salt with a basic amino acid include salts with arginine, lysine or ornithine.

Preferred examples of the salt with an acidic amino acid include a salt with aspartic acid or glutamic acid.

Among the above salts, a salt with a mineral acid (preferably hydrochloric acid) or an organic acid (preferably trifluoroacetic acid) is preferred.

The method for producing the compound (I) is explained below.

The compound or the like in the following reaction scheme may form a salt, and examples of such a salt include the salts similar to the compound (I).

Although the compound obtained by the respective steps can be used as a crude product in the form of a reaction mixture for the next reaction, it can be isolated from the reaction mixture by a conventional separation method such as recrystallization, distillation, chromatography or the like.

For example, the compound (I) can be obtained according to the method shown in the following reaction scheme, or the like.

(Reaction Figure 1)

Wherein Pg is a protecting group for pyrazole nitrogen. Examples of the protecting group include a tertiary butoxycarbonyl group and an N,N-dimethylaminosulfonyl group. R ₃ is a halogen atom (for example, a bromine atom, a chlorine atom or an iodine atom), and R ₄ is a boric acid or a boric acid ester (e.g., 4,4,5,5-tetramethyl-1,3,2-dioxa Borapentan-2-yl), trifluoromethanesulfonyl, or a substituted tin alkyl (e.g., tributylstannyl), and other code numbers are as defined above.

In this reaction, the compound (II) is subjected to a reaction generally called Suzuki reaction or Stille reaction or a method similar thereto, and if necessary, the compound is deprotected to remove the protective group, thereby producing a compound. (I).

This reaction is preferably carried out in the presence of a palladium catalyst.

The compound (III) is used in an amount of about 1 to 3 equivalents based on the compound (II).

This reaction can be carried out in the presence of a base.

Examples of the base include sodium carbonate, potassium carbonate, and cesium carbonate. The base is used in an amount of about 2 to 20 equivalents based on the compound (II).

Examples of the palladium catalyst include [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride methylene complex and tetrakis(triphenylphosphine)palladium(0). The palladium catalyst is used in an amount of about 0.01 to 1 equivalent based on the compound (II). This reaction is preferably carried out in a solvent. Examples of the solvent include aromatic hydrocarbons (e.g., benzene, toluene, xylene), ethers (e.g., tetrahydrofuran, dioxane, 1,2-dimethoxyethane), acetone, acetonitrile, acetic acid. a mixture of ethyl ester, N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl hydrazine, water, and the like Solvent.

This reaction can be carried out at room temperature (about 15 to 30 ° C) or under heating (about 40 to 150 ° C). The reaction time is usually from about 1 to 50 hours, preferably from about 1 to 20 hours.

The compound (III) may be a commercially available product or may be produced according to a method known per se.

The compound (II) is obtained, for example, according to the method shown in the following reaction scheme or the like.

(Reaction Figure 2)

Wherein R ₅ is a carbonyl chloride or a carboxyl group, and the other code numbers are as defined above.

(Method A)

In this reaction, the compound (VI) can be produced by reacting the compound (IV) with the compound (V).

In the reaction, the compound (V) is used in an amount of usually 1 to 10 equivalents, preferably 1 to 5 equivalents based on the compound (IV).

This reaction is preferably carried out in a solvent. Examples of the solvent include ethers (e.g., tetrahydrofuran, dioxane, 2-dimethoxyethane), acetonitrile, decylamines (e.g., N,N-dimethylformamide, N,N). a mixed solvent of dimethylacetamide, N-methylpyrrolidone, and the like.

When the compound (V) wherein R ₅ is a carbonyl chloride group is used, the reaction is preferably carried out in the presence of a base. Examples of the base include pyridine, N,N-dimethylpyridin-4-amine, triethylamine, and N-methyl-N-(1-methylethyl)propan-2-amine. The amount of the base to be used is from 1 to 100 equivalents, preferably from 1 to 10 equivalents based on the compound (IV). When a compound (V) wherein R ₅ is a carboxyl group is used, the reaction can be carried out under conventional condensation reaction conditions. Examples of conventional condensation reaction conditions include N,N-dimethylformamide and 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea Conditions for the simultaneous presence of hexafluorophosphate and N-ethyl-N-(1-methylethyl)propan-2-amine, and conditions generally referred to as mixed acid anhydride methods, for example, 2-methyl propyl chlorocarbonate The conditions in which the ester, triethylamine and tetrahydrofuran coexist.

This reaction can be carried out at room temperature (about 15-30 ° C) or under heating (about 40-150 ° C). The reaction time is usually from about 1 to 50 hours, preferably from about 1 to 5 hours.

The compound (IV) and the compound (V) may be commercially available or may be produced by a method known per se.

(Method B)

In this reaction, the compound (II) is obtained by cyclizing the compound (VI) in the presence of a base.

An example of a base in this reaction contains sodium hydroxide. The amount of the base to be used is from 1 to 100 equivalents, preferably from 1 to 10 equivalents based on the compound (VI).

This reaction is preferably carried out in a solvent. Examples of the solvent include organic solvents such as alcohols (methanol, ethanol, etc.); ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.); and the like, water, and the like. Solvent.

This reaction can be carried out at room temperature (about 15-30 ° C) or under heating (about 40-120 ° C). The reaction time is usually about 1 to 20 hours, preferably about 1 to 4 hours.

Compound (II) wherein R ₂ is an amino group-substituted methyl group which may optionally be mono- or di-substituted with a substituent selected from the group consisting of the following. (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, if necessary, (b) a C _1-6 alkyl-carbonyl group which may be substituted with 1 to 3 halogen atoms, if necessary, (c) as needed may be substituted with 1 to 3 halogen atoms of C _1-6 alkoxy - carbonyl group, (d) may be optionally substituted with 1 to 3 halogen atoms of C _1-6 alkylsulfonyl group (e.g., methyl sulfonamide acyl), (E) may be optionally by C _1-6 alkyl mono - or di - substituted carbamoyl of acyl, C _1-6 alkyl which may be optionally substituted with 1 to 3 halogen atoms, and (f) an aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, Azyl, thiazolyl, The oxadiazolyl, thiadiazolyl) can be produced, for example, according to the method shown in the following reaction scheme or a method similar thereto.

(Reaction Figure 3)

Wherein R ₆ is a C _1-6 alkyl group, R ₇ is a halogen atom (for example, a chlorine atom), and the other code numbers are each as defined above.

(Method C)

In this reaction, the compound (IX) can be produced by reacting the compound (VII) in the presence of an acid to produce the compound (IX).

The compound (III) is used in an amount of usually 1 to 10 equivalents, preferably 1 to 5 equivalents based on the compound (VII). An example of the acid in this reaction comprises a solution of HCl/cyclopentyl methyl ether cyclopentyl methyl ether. The acid is used in an amount of usually 1 to 100 equivalents, preferably 1 to 10 equivalents based on the compound (VII).

This reaction is preferably carried out in a solvent. Examples of the solvent include ethers (e.g., diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane).

This reaction can be carried out at room temperature (about 15-30 ° C) or under heating (about 40-120 ° C). The reaction time is usually about 1 to 20 hours, preferably about 1 to 4 hours.

(Method D)

In this reaction, the compound (X) can be produced by heating the compound (IX) under reduced pressure.

This reaction can be carried out under heating (about 40-100 ° C). The reaction time is usually from about 1 to 8 hours, preferably from about 1 to 4 hours. This reaction was carried out under reduced pressure (about 4-10 Torr). The compound (VII) and the compound (VIII) may be commercially available or may be produced by a method known per se.

(Method E)

In this reaction, a monoamine, a secondary amine, a guanamine, a carbamate, a sulfonamide or a sulfonamide may be used, which may be mono- or di-substituted with a substituent selected from the group consisting of: The urea is substituted for R _{7 of the} compound (X) to produce the compound (II) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, and (b) 1 to 3 halogen atoms may be optionally used. Substituted C _1-6 alkyl-carbonyl, (c) C _1-6 alkoxy-carbonyl optionally substituted with 1 to 3 halogen atoms, (d) optionally substituted with 1 to 3 halogen atoms a C _1-6 alkylsulfonyl group (e.g., methylsulfonyl), (e) optionally a mono- or di-substituted amine carbenyl group via a C _1-6 alkyl group, and the C _{1- The 6} alkyl group may be optionally substituted with 1 to 3 halogen atoms, and (f) an aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, Azyl, thiazolyl, Diazolyl, thiadiazolyl).

The primary amine, the secondary amine, the decylamine, the carbamate, the sulfonamide or the urea is used in an amount of usually 1 to 10 equivalents, preferably 1 to 3 equivalents based on the compound (X).

This reaction can be carried out in the presence of a base.

An example of a base contains potassium carbonate. The amount of the base to be used is usually from 1 to 10 equivalents, preferably from 1 to 5 equivalents based on the compound (X).

This reaction is preferably carried out in a solvent. Examples of the solvent include ethers (e.g., tetrahydrofuran, dioxane, 1,2-dimethoxyethane), acetonitrile, ethyl acetate, N,N-dimethylformamide, N,N a mixed solvent of dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl hydrazine, and the like.

This reaction can be carried out at room temperature (about 15-30 ° C) or under heating (about 40-120 ° C). The reaction time is usually from about 0.5 to 20 hours, preferably from about 0.5 to 4 hours.

The compound (II) can also be produced, for example, according to the method shown in the following reaction scheme or a method similar thereto.

(Reaction Figure 4)

The codes are as defined above.

In this reaction, the compound (II) can be produced by reacting the compound (VII) with the compound (XI) in the presence of an acid.

The compound (XI) is used in an amount of usually 1 to 10 equivalents, preferably 1 to 5 equivalents based on the compound (VII). An example of the acid in this reaction comprises a solution of HCl/cyclopentyl methyl ether. The acid is used in an amount of usually 1 to 100 equivalents, preferably 1 to 10 equivalents based on the compound (VII). This reaction is preferably carried out in a solvent. Examples of the solvent in this reaction include ethers (e.g., diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane).

This reaction can be carried out at room temperature (about 15-30 ° C) or under heating (about 40-120 ° C). The reaction time is usually about 1 to 20 hours, preferably about 1 to 4 hours.

The compound (XI) may be a commercially available product or may be produced by a method known per se.

The compound (I) can be produced, for example, according to the method shown in the following reaction scheme or a method similar thereto.

(Reaction Figure 5)

Wherein R ₈ is a C _1-6 alkyl group (e.g., methyl, ethyl) which may be substituted with 1 to 3 substituents selected from the group consisting of (i) optionally 1 to 3 C _1-6 as needed Alkoxy (eg, methoxy) substituted C _6-14 aryl (eg, phenyl), (ii) aromatic heterocyclic (eg, pyridyl), and (iii) aromatic as desired A C _3-8 cycloalkyl group (e.g., cyclopropyl) substituted with a heterocyclic group (e.g., thienyl), and other code numbers are as defined above.

(Method F)

In this reaction, the compound (XII) can be produced by substituting the primary amine for the R _{7 of the} compound (X) in the same manner as shown in the method E of Reaction Scheme 3. An example of a primary amine comprises benzylamine.

(method G)

In this reaction, the compound (XIII) can be produced by reacting the compound (XII) with, for example, formaldehyde. An example of formaldehyde contains 37% aqueous formaldehyde solution.

The amount of formaldehyde used in this reaction is usually from 10 to 1,000 equivalents based on the compound (XII).

This reaction is more desirable to carry out in a solvent. Examples of the solvent in the reaction include aromatic hydrocarbons (e.g., benzene, toluene, xylene), ethers (e.g., tetrahydrofuran, dioxane, 1,2-dimethoxyethane), and Mix the solvent.

This reaction can be carried out at room temperature (about 15-30 ° C) or under heating (about 40-150 ° C). The reaction time is usually about 1 to 50 hours, preferably about 1 to 20 hours.

(Method H)

In this reaction, the compound (XIV) can be produced from the compound (XIII) and the compound (III) in the same manner as shown in the reaction scheme of Figure 1.

(Method I)

In this reaction, the compound (I') can be produced by heating the compound (XIV) in trifluoroacetic acid in the presence of an alcohol. Examples of the alcohol include a mixed solvent of methanol, ethanol, and the like.

The amount of trifluoroacetic acid used in this reaction is usually from 10 to 1,000 equivalents based on the compound (XIV).

This reaction can be carried out under heating (about 40-80 ° C). The reaction time is usually about 1 to 20 hours, preferably about 1 to 10 hours.

The compound (I) can be produced, for example, according to the method shown in the following reaction scheme or a method similar thereto.

(Reaction Figure 6)

Wherein Pg' is a protecting group for the indoleamine group. Examples of the protecting group include [2-(trimethylmethyl)ethoxy]methyl and 2,4-dimethoxybenzyl. Other codenames are as defined above.

(Method J)

In this reaction, the compound (XV), the compound (XVI), or a mixture of the compound (XV) and the compound (XVI) can be produced by introducing a protecting group into the indoleamine group of the compound (II).

In one example of Process J, that is, when [2-(trimethylsulfonyl)ethoxy]methyl is introduced into the indoleamine group, compound (II) can be reacted with, for example, in the presence of a base. The compound (XV), the compound (XVI), or a mixture of the compound (XV) and the compound (XVI) is produced by reacting 2-(chloromethoxy)ethyl](trimethyl)decane.

An example of a base in this reaction contains sodium hydride. The amount of the base to be used is usually 1 to 5 equivalents, preferably 1 to 2 equivalents based on the compound (II).

The amount of [2-(chloromethoxy)ethyl](trimethyl)decane used in the reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents based on the compound (II). This reaction can be carried out under cooling (about 0-10 ° C), at room temperature (about 15-30 ° C) or under heating (about 40-80 ° C). The reaction time is usually about 1 to 20 hours, preferably about 1 to 3 hours. This reaction is more desirable to carry out in a solvent. Examples of the solvent in this reaction include ethers (e.g., tetrahydrofuran, dioxane, 1,2-dimethoxyethane).

In another example of Method J, ie, when a 2,4-dimethoxybenzyl group is introduced into an indoleamine group, the compound (XV), the compound (XVI), or the compound (XV) and the compound ( A mixture of XVI) can be produced, for example, by reacting a compound (II) and (2,4-dimethoxyphenyl)methanol with a reaction generally referred to as a Mitsunobu reaction, for example, in a solvent with triphenylphosphine. And (E)-diazenedicarboxylate reaction.

The amount of triphenylphosphine used in this reaction is about 1 to 5 equivalents based on the compound (II).

The diethyl (E)-diazoenedicarboxylate is used in an amount of about 1 to 5 equivalents based on the compound (II).

(2,4-Dimethoxyphenyl)methanol is used in an amount of about 1 to 5 equivalents based on the compound (II).

Examples of the solvent in this reaction include ethers (e.g., tetrahydrofuran, dioxane, 1,2-dimethoxyethane).

This reaction can be carried out under cooling (about 0-10 ° C), at room temperature (about 15-30 ° C) or under heating (about 40-80 ° C). The reaction time is usually about 1 to 20 hours, preferably about 1 to 8 hours.

(method K)

In this reaction, the compound (XVII) can be produced from the compound (XV) and the compound (III) in the same manner as shown in the reaction scheme of Figure 1. Further, the compound (XVII) can be produced from the compound (XVI) and the compound (III) in the same manner. Further, a compound (XVII), a compound (XVIII), or a mixture of the compound (XVII) and the compound (XVIII) can be produced in the same manner from a mixture of the compound (XV) and the compound (XVI), and the compound (III). The protecting group on the pyrazole nitrogen of the compound (XVII) and the compound (XVIII) is sometimes removed during this reaction.

(method L)

In this reaction, the compound (I) can be produced by a conventional method by removing the protective group of the compound (XVII), the compound (XVIII), or a mixture of the compound (XVII) and the compound (XVIII).

In one example of the method L, that is, when the protecting group on the pyrazole nitrogen is a tertiary butoxycarbonyl group, the tertiary butoxycarbonyl group may be an acid with the compound (XVII), the compound (XVIII), or a compound ( XVII) is deprotected with a mixture of compounds (XVIII).

Examples of the acid in this reaction include trifluoroacetic acid, 10% HCl/methanol solution, and 4M HCl/ethyl acetate solution. The acid is used in an amount of about 10 to 5000 equivalents based on the compound (XVII), the compound (XVIII), or a mixture of the compound (XVII) and the compound (XVIII).

A solvent can be used for this reaction. Examples of the solvent include alcohols (e.g., methanol, ethanol). This reaction can be carried out at room temperature or under heating (about 40-80 ° C). The reaction time is usually from about 0.5 to 20 hours, preferably from about 0.5 to about 3 hours.

In another example of method L, that is, when the protecting group of the indoleamine group is [2-(trimethylsulfonyl)ethoxy]methyl, the [2-(trimethylsulfonyl)ethoxy] The methyl group can be deprotected by contacting the compound (XVII), the compound (XVIII) or a mixture of the compound (XVII) and the compound (XVIII) with a fluoride-containing solvent, or with an acid.

An example of the fluoride containing solvent in this reaction comprises a 1 M N,N,N-tributylbutane-1-ammonium fluoride/tetrahydrofuran solution. The fluoride is used in an amount of about 5 to 50 equivalents based on the compound (XVII), the compound (XVIII), or a mixture of the compound (XVII) and the compound (XVIII). This reaction is more desirably carried out under heating (about 40-80 ° C). The reaction time is usually about 1 to 20 hours, preferably about 1 to 8 hours. Examples of the acid in this reaction include trifluoroacetic acid, 10% HCl/methanol solution, and 4M HCl/ethyl acetate solution. The acid is used in an amount of about 10 to 5000 equivalents based on the compound (XVII), the compound (XVIII), or a mixture of the compound (XVII) and the compound (XVIII). This reaction can be carried out at room temperature or under heating (about 40-80 ° C). The reaction time is usually about 1 to 20 hours, preferably about 1 to 3 hours.

In still another example of method L, that is, when the protecting group of the indoleamine group is 2,4-dimethoxybenzyl, the 2,4-dimethoxybenzyl group can be Acid to protect. An example of the acid in this reaction comprises trifluoroacetic acid. The acid is used in an amount of about 10 to 5000 equivalents based on the compound (XVII), the compound (XVIII), or a mixture of the compound (XVII) and the compound (XVIII). A solvent can be used for this reaction. Examples of the solvent include dichloromethane and water. This reaction can be carried out under heating (about 40-100 ° C). The reaction time is usually about 1 to 20 hours, preferably about 1 to 8 hours.

The compound (I) can be produced, for example, according to the method shown in the following reaction scheme or a method similar thereto.

(Reaction Figure 7)

Wherein Pg" is a protecting group on the pyrazole nitrogen. Examples of the protecting group include benzyl, tert-butyl and 4-methoxybenzyl. The other symbols are as defined above.

(method M)

In this reaction, the compound (XIX) is reacted with 1,1-dimethoxy-N,N-dimethylmethylamine (method M-1), followed by a hydrazine having a Pg" group or a salt thereof. The reaction (method M-2) gives the compound (XX). The compound (XIX), 1,1-dimethoxy-N,N-dimethylmethylamine and the hydrazine having a Pg" group or a salt thereof may be Commercially available products can be made by methods known per se.

(method M-1)

The amount of 1,1-dimethoxy-N,N-dimethylmethylamine used in the reaction is usually from 1 to 10 equivalents, preferably from 1 to 2 equivalents based on the compound (XIX). This reaction can be carried out under heating (about 60-100 ° C). The reaction time is usually about 1 to 50 hours, preferably about 1 to 5 hours.

(method M-2)

The amount of the hydrazine having a Pg" group or a salt thereof used in the reaction is usually 1 to 5 equivalents, preferably 1 to 2 equivalents based on the compound (XIX). The reaction is preferably carried out in a solvent. Examples include ethers (eg, tetrahydrofuran, dioxane, 1,2-dimethoxyethane). This reaction can be cooled (about 0-10 ° C), room temperature (about 15-30 ° C) It is carried out under heating (about 40-100 ° C). The reaction time is usually about 30 minutes to 5 hours, preferably about 30 minutes to 1 hour.

(method N)

In this reaction, the compound (XX) is reacted with a Vilsmeier reagent (Method N-1), followed by reaction with hydroxylamine hydrochloride (Method N-2) to give the compound (XXI). The protecting group on the pyrazole nitrogen can be removed during the reaction of Method N-2. In this case, the compound (XXI) (Method N-3) can be produced by reacting with a halide having a Pg" group in the presence of a base.

(method N-1)

The amount of the Vilsmeier reagent used in this reaction is usually from 1 to 10 equivalents, preferably from 1 to 5 equivalents based on the compound (XX). The Vilsmeier reagent can be produced from N,N-dimethylformamide and phosphorus oxychloride under generally accepted conditions. For example, phosphorus oxychloride is added to N,N-dimethylformamide under ice cooling and the mixture is stirred at room temperature for 30 minutes to 1 hour.

This reaction can be carried out at room temperature or under heating (about 40-60 ° C). The reaction time is usually about 30 minutes to 2 hours, preferably about 30 minutes to 1 hour.

(Method N-2)

The amount of hydroxylamine hydrochloride used in this reaction is usually 5 to 20 equivalents, preferably 5 to 10 equivalents based on the compound (XX). The protecting group on the pyrazole nitrogen can be removed during this reaction. This reaction can be carried out under heating (about 50-80 ° C). The reaction time is usually about 0.5 to 8 hours, preferably about 0.5 to 2 hours.

(Method N-3)

Examples of the halide having a Pg" group in this reaction include (bromomethyl)benzene and 1-(chloromethyl)-4-methoxybenzene. The halide having a Pg" group is used in an amount relative to the compound (XX). It is generally from 1 to 3 equivalents, preferably from 1 to 2 equivalents. An example of the base in this reaction contains potassium carbonate. The potassium carbonate is usually used in an amount of from 1 to 5 equivalents, preferably from 1 to 3 equivalents. This reaction is preferably carried out in a solvent. Examples of the solvent include N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, and the like. This reaction can be carried out at room temperature (about 15-30 ° C) or under heating (about 40-120 ° C). The reaction time is usually from about 2 to 48 hours, preferably from about 6 to 24 hours.

(method O)

In this reaction, the compound (XXII) is obtained by reacting the compound (XXI) with a sulfonyl acetate having an R ₆ group in the presence of a base.

The sulbanylacetate having an R ₆ group is used in an amount of usually 1 to 3 equivalents, preferably 1 to 2 equivalents based on the compound (XXI). The thioacetate having an R ₆ group may be a commercially available product or may be produced by a method known per se. Examples of the base in this reaction include an inorganic base (e.g., sodium hydride, potassium carbonate, cesium carbonate) and an organic base (e.g., triethylamine, N-ethyl-N-(1-methylethyl)propane-2 -amine). This reaction is preferably carried out in a solvent. An example of a solvent contains N,N-dimethylformamide. This reaction can be carried out under cooling (about 0-10 ° C), at room temperature (about 15-30 ° C) or under heating (about 40-100 ° C). The reaction time is usually from about 30 minutes to 5 hours, preferably from about 30 minutes to 2 hours.

(Method P)

In this reaction, the compound (XXIII) can be produced from the compound (XXII) and the compound (V) in the same manner as shown in the method A of the reaction scheme 2.

(method Q)

In this reaction, the compound (XXIV) can be produced from the compound (XXIII) in the same manner as shown in the method B of the reaction scheme 2.

(method R)

In this reaction, the compound (I") can be produced by subjecting the compound (XXIV) to deprotection of the Pg" group. For example, a compound (I") having a benzyl group as a Pg" group (XXIV) and a palladium hydroxide-carbon are reacted in a formic acid under a hydrogen atmosphere to obtain a compound (I"). The amount of palladium hydroxide-carbon used in this reaction is from 1 to 2 equivalents based on the amount of the catalyst (XXIV). The hydrogen atmosphere in this reaction is 1-3 atmospheres. This reaction can be carried out at room temperature (about 15-30 ° C) or under heating (about 40-100 ° C). The reaction time is usually about 2 to 120 hours, preferably about 8 to 24 hours.

Further, for example, the compound (I") is obtained by heating a compound (XXIV) having a 4-methoxybenzyl group as a Pg" group in trifluoroacetic acid in the presence of methoxybenzene to give a compound (I"). The amount of methoxybenzene used in this reaction is 1-5 equivalents. This reaction can be carried out under heating (about 40-100 ° C). The reaction time is usually from about 8 to 48 hours, preferably from about 8 to 24 hours.

The compound (I) can be produced, for example, according to the method shown in the following reaction scheme or a method similar thereto.

(Reaction Figure 8)

Wherein Pg''' is a protecting group on a sulfur atom. An example of a protecting group includes an ethenyl group. Other codenames are as defined above.

(method S)

In this reaction, the compound (XXV) is reacted with chloroethion chloride (method S-1), and then reacted with a thiol having a Pg'' group in the presence of a base (method S-2) to obtain a compound ( XXVI).

(Method S-1)

The amount of chloroacetic chloride used in the reaction is usually 2 to 10 equivalents, preferably 2 to 4 equivalents based on the compound (XXV). This reaction can be carried out at room temperature (about 15-30 ° C) or under heating (about 40-120 ° C). The reaction time is usually about 3 to 24 hours, preferably about 12 to 18 hours.

(Method S-2)

The thiol having a Pg''' group is used in the reaction in an amount of usually 1 to 2 equivalents, preferably 1 to 1.1 equivalents based on the compound (XXV). The base (e.g., potassium carbonate, triethylamine) is used in an amount of usually 1 to 2 equivalents, preferably 1 to 1.1 equivalents based on the compound (XXV). This reaction is preferably carried out in a solvent. An example of a solvent contains tetrahydrofuran. This reaction can be carried out under ice cooling (about -5 to 5 ° C) or at room temperature (about 15 to 30 ° C). The reaction time is usually about 0.1 to 1 hour, preferably about 0.1 to 0.5 hour.

The compound (XXV) and chloroacetic acid chloride may be commercially available or may be produced by a method known per se.

(method T)

In this reaction, the compound (XIX) is reacted with 1,1-dimethoxy-N,N-dimethylmethylamine (Method T-1), followed by reaction with a tertiary butylamine or a salt thereof (method) Compound (XXVII) is obtained by T-2). The compound (XIX) and the tertiary butyl conjugated amine or a salt thereof may be a commercially available product.

(Method T-1)

The amount of 1,1-dimethoxy-N,N-dimethylmethylamine used in the reaction is usually 1 to 10 equivalents, preferably 1 to 2 equivalents based on the compound (XIX). This reaction can be carried out under heating (about 60-100 ° C). The reaction time is usually about 1 to 50 hours, preferably about 1 to 5 hours.

(Method T-2)

The tertiary butyl conjugated amine or a salt thereof is used in an amount of usually 1 to 5 equivalents, preferably 1 to 2 equivalents based on the compound (XIX). This reaction is preferably carried out in a solvent. Examples of the solvent include ethers (e.g., tetrahydrofuran, dioxane, 1,2-dimethoxyethane). This reaction can be carried out under cooling (about 0-10 ° C), at room temperature (about 15-30 ° C) or under heating (about 40-100 ° C). The reaction time is usually from about 30 minutes to 5 hours, preferably from about 30 minutes to 1 hour.

(Method U)

In this reaction, the compound (XXVII) is reacted with a Vilsmeier reagent (Method U-1), followed by reaction with hydroxylamine hydrochloride (Method U-2) to give the compound (XXVIII).

(Method U-1)

The Vilsmeier reagent is used in an amount of usually 1 to 10 equivalents, preferably 1 to 5 equivalents based on the compound (XXVII). The Vilsmeier reagent can be prepared from N,N-dimethylformamide and phosphorus oxychloride under generally accepted conditions. (For example, phosphorus oxychloride is added to N,N-dimethylformamide under ice cooling, and the mixture is stirred at room temperature for 30 minutes to 1 hour).

This reaction can be carried out at room temperature (about 15-30 ° C) or under heating (about 40-60 ° C). The reaction time is usually about 30 minutes to 2 hours, preferably about 30 minutes to 1 hour.

(Method U-2)

The hydroxylamine hydrochloride is used in an amount of usually 5 to 20 equivalents, preferably 5 to 10 equivalents based on the compound (XXVII). This reaction can be carried out under heating (about 40-60 ° C). The reaction time is usually about 30 minutes to 2 hours, preferably about 30 minutes to 1 hour.

(method V)

In this reaction, the compound (XXIX) can be produced by reacting the compound (XXVIII) with the compound (XXVI) in the presence of a base.

The compound (XXVI) is used in this reaction in an amount of usually 1 to 1.5 equivalents, preferably 1 to 1.1 equivalents based on the compound (XXVIII). The base (e.g., potassium carbonate, cesium carbonate) is used in an amount of usually 1 to 2 equivalents, preferably 1 to 1.2 equivalents based on the compound (XXVIII). This reaction is preferably carried out in a solvent. Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, and the like. This reaction can be carried out under ice cooling (about -5 to 5 ° C) or at room temperature (about 15 to 30 ° C). The reaction time is usually from about 0.5 to 5 hours, preferably from about 0.5 to 2 hours.

(method W)

In this reaction, the compound (I") can be produced by reacting an acid or a base with the compound (XXIX).

Examples of the acid in this reaction include diluted hydrochloric acid and trifluoroacetic acid. The acid is used in an amount of usually 2 to 20 equivalents, preferably 5 to 10 equivalents based on the compound (XXIX). Examples of the base in this reaction include an aqueous sodium hydroxide solution, potassium carbonate, and sodium hydride. The amount of the base to be used is usually from 1 to 10 equivalents, preferably from 2 to 5 equivalents based on the compound (XXIX). This reaction is preferably carried out in a solvent. Examples of the solvent include a mixed solvent of methanol, N,N-dimethylformamide, and the like. This reaction can be carried out at room temperature (about 15-30 ° C) or under heating (about 40-120 ° C). The reaction time is usually from about 0.2 to 72 hours, preferably from about 0.2 to 5 hours.

The compound (I) can also be subjected to conversion of a substituent by a method known per se to produce a compound within the scope of the invention (e.g., introduction of a substituent and conversion of a functional group).

A conventionally used method can be used to convert a substituent. Examples thereof include conversion to a carboxyl group by hydrolysis of an ester, conversion to an aminomethyl group by amidation of a carboxyl group, conversion to a methylol group by reduction of a carboxyl group, reduction or alkylation by a carbonyl group, and carbonyl group Reductive amination, deuteration of carbonyl group, deuteration of amine group, ureaification of amine group, sulfonation of amine group, alkylation of amine group, substitution or amination of active halogen atom by amine, alkylation of hydroxyl group The substitution or hydroxylation of a hydroxyl group is converted into an alcohol compound.

When a reactive group which causes a non-target reaction occurs during the introduction of the substituent and the conversion of the functional group, the protecting group may be introduced into the reactive group in advance by a method known per se, and the target itself may be used after the target reaction. The protecting group is known to be removed, whereby compounds within the scope of the invention can also be produced.

For example, when the starting compound or intermediate has an amine group, a carboxyl group or a hydroxyl group as a substituent, these groups can be protected by a protecting group generally used for peptide chemistry or the like. In this case, the protective group may be removed after the reaction as needed to obtain the target compound.

Examples of the amine-protecting group include an aldehyde group; a C _1-6 alkyl-carbonyl group, a C _1-6 alkoxy-carbonyl group, a benzhydryl group, a C _7-10 aralkyl-carbonyl group (e.g., a benzocarbonyl group) , C _7-14 aralkoxy-carbonyl (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl, fluorenyl, N,N-dimethylamine methylene, substituted Sulfhydryl groups (eg, trimethyl decyl, triethyl decyl, dimethylphenyl fluorenyl, tert-butyl dimethyl fluorenyl, tert-butyl butyl diethyl decyl) and C _{2 6} alkenyl (eg, 1-allyl). These groups may be optionally substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkoxy group and a nitro group.

Examples of the carboxy-protecting group include a C _1-6 alkyl group, a C _7-11 aralkyl group (e.g., benzyl), a phenyl group, a trityl group, a substituted fluorenyl group (e.g., a trimethyl fluorenyl group, Triethyl decyl, dimethylphenyl fluorenyl, tert-butyl dimethyl dimethyl decyl, tert-butyl butyl diethyl fluorenyl) and C _2-6 alkenyl (eg 1-allyl) . These groups may be optionally substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkoxy group and a nitro group.

Examples of the hydroxy-protecting group include a C _1-6 alkyl group, a phenyl group, a triphenylmethyl group, a C _7-10 aralkyl group (e.g., a benzyl group), an aldehyde group, a C _1-6 alkyl-carbonyl group, and a benzene group. Mercapto, C _7-10 aralkyl-carbonyl (eg, benzylcarbonyl), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, substituted fluorenyl (eg, trimethyl decyl, triethyl) Anthracenyl, dimethylphenylindenyl, tert-butyldimethylmercapto, tert- _{butyldiethyldecyl} ) and C _2-6 alkenyl (eg, 1-allyl). These groups may be optionally substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group and a nitro group. The above protecting group can be removed by a method known per se, for example, "Protective Groups in Organic Synthesis" (John Wiley and Sons (1980)). For example, the use of acid, alkali, ultraviolet, hydrazine, phenyl bisamine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkyl sulfonium halide (eg, three A method such as reduction of an iodide, trimethyl sulfonium bromide, or the like.

Depending on the kind of the substituent of the starting compound, the starting compound having different substituents can be obtained by the above-described substituent conversion method using the compound produced by the above production method as a raw material compound.

The product (I) of the above reaction can be prepared as a single compound or a mixture.

The compound (I) obtained as described above can be isolated and purified according to a separation method known per se, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

When the obtained compound (I) is in a free form, it can be converted into a desired salt according to a method known per se or the like; in contrast, when the obtained compound (I) is a salt, it can be known per se or A similar method is converted to free form or other desired salt form.

When the compound (I) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotamer or the like, such an isomer and a mixture thereof are also contained in the compound (I). For example, when the compound (I) has an optical isomer, the optical isomer from which the racemate is isolated is also contained in the compound (I). A single product of such isomers can be obtained according to synthetic techniques and separation techniques known per se (eg, concentration, solvent extraction, column chromatography, recrystallization).

The compound (I) may be in a crystalline form, and the crystal form of the crystal may be singly or plurally, both of which are contained in the compound (I). The crystals can be produced by a crystallization method known per se.

Further, the compound (I) may be a pharmaceutically acceptable co-crystal or eutectic salt. Herein, the eutectic or eutectic salt means a crystalline substance composed of two or more specific solids each having different physical properties at room temperature (eg, structure, melting point, heat of fusion, absorption). Wetness and stability). The eutectic or eutectic salt can be produced by a co-crystallizing method known per se.

The compound (I) may be a hydrate, a non-hydrate, a solvate or an unsolvate, and is contained in the compound (I).

A compound or the like labeled with an isotope (e.g., ² H, ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I) is also included in the compound (I).

The compound (I) of the present invention refers to a compound which can be converted into a compound (I) by an action of an enzyme, a gastric acid or the like under physiological conditions, that is, can be converted into a compound via oxidation, reduction, hydrolysis, or the like. a compound of (I); a compound which is converted into a compound (I) by a hydrolysis reaction such as gastric acid or the like. The compound (I) is a compound obtained by subjecting an amine group of the compound (I) to thiolation, alkylation or phosphorylation (for example, oxime formation, alanine thiolation from the amine group of the compound (I) , pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidinyl methylation a compound obtained by trimethylacetoxymethylation or tertiary butylation; a compound obtained by deuteration, alkylation, phosphorylation or boronation of a hydroxyl group of the compound (I) (eg, The hydroxyl group of the compound (I) is subjected to acetylation, palmitoylation, propylation, trimethylacetylation, amber thiolation, fumarate, alanine or dimethylamine methylcarbonylation. a compound obtained by esterification or guanidation of a carboxyl group of the compound (I) (for example, ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethyl ester from a carboxyl group of the compound (I); Aminomethyl esterification, trimethylacetoxymethyl esterification, ethoxycarbonyloxyethyl esterification, mercaptoesterification, (5-methyl-2-oxo-1,3-di Olecyclopent-4-yl)methyl ester , Cyclohexyl oxycarbonyl ethyl esterification or amination methyl acyl) and the like. Any of these compounds can be produced from the compound (I) by a method known per se.

The prodrug of Compound (I) can also be converted to a compound of Compound (I) under physiological conditions, such as described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design of Molecules, pp 163-198, published by HIROKAWA SHOTEN (1990).

The compound (I) or a prodrug thereof (in the specification, sometimes simply referred to as "the compound of the present invention") has Cdc7 inhibitory activity, and is a cancer preventive or therapeutic agent, a cancer growth inhibitor, and a cancer metastasis suppressor.

Because the compounds of the present invention exhibit potent Cdc7 inhibitory activity, and exhibit efficacy, pharmacokinetics (eg, absorption, distribution, metabolism, secretion), solubility (eg, water solubility), interaction with other pharmaceutical products (eg, drugs) Excellent for metabolic enzyme inhibition), safety (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and stability (eg, chemical stability, enzyme stability, etc.) As a drug.

The compound of the present invention exhibits low inhibitory activity against protein kinases other than Cdc7, and thus is suitable as a cancer preventive or therapeutic agent having reduced toxicity to normal cells.

Accordingly, the compounds of the present invention can be used to inhibit excessive (abnormal) Cdc7 effects in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans).

The compound of the present invention is used as a drug, such as a drug for preventing or treating a disease which may be affected by Cdc7, a cancer cell growth inhibitor, a cancer metastasis suppressor, an apoptosis promoter, etc., and a disease which may be affected by Cdc7, for example, cancer. [For example, colorectal cancer (eg, colorectal cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary non-caries colorectal cancer (hereditary) Nonpolyposis colorectal cancer), gastrointestinal stromal tumor, lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer Pancreatic cancer) (eg, pancreatic duct cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophagus cancer, gastric cancer (eg, Papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma, Gastrointestinal cancer, small intestine cancer, breast cancer (eg, infiltrating intraductal carcinoma, noninfiltrating intraductal carcinoma, inflammatory breast cancer), ovarian cancer (eg, ovarian epithelial carcinoma, extragonad germ cell tumor, ovarian germ cell tumor, ovarian low malignant potential tumor), Testis tumor, prostate cancer (eg, hormone-dependent prostate cancer, non-hormone dependent prostate cancer), liver cancer (eg, liver) Hepatocellular cancer, primary liver cancer, extrahepatic biliary cancer (Extrahepatic Bile Duct Cancer), thyroid cancer (eg, medullary thyroid carcinoma), Renal cancer (eg, renal cell carcinoma, renal pelvis, and transitional cell carcinoma) Arcinoma of renal pelvis and urinary duct), uterine cancer (eg, cervical cancer, cancer of uterine body, uterus sarcoma), brain tumors (eg, Medulloblastoma, glioma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, regression Anaplastic astrocytoma, pituitary adenoma, retinoblastoma, skin cancer (eg, basal cell tumor, malignant melanoma) Sarcoma (eg, rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma), malignant bone tumor, urinary bladder cancer, blood cancer Hematologic cancer) (eg, multiple myeloma, leukemia, malignant lymphoma, Hodgkin's diseas) e), chronic bone marrow proliferative disease, unknown primary cancer.

Specifically, the compound of the present invention is effective for hematological cancer, breast cancer, colorectal cancer, lung cancer, pancreatic cancer and the like.

The compound of the present invention can be administered to the above mammal as a medicament in the form of a mixture of itself or a pharmaceutically acceptable carrier, either orally or parenterally.

The drug comprising the compound of the present invention (sometimes abbreviated as "the drug of the present invention") is described in detail below.

Examples of the pharmaceutical dosage form of the present invention for orally administered to the compound of the present invention include oral preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, oral tablets, orally rapidly disintegrating tablets), pills, and granules. Agents, powders, capsules (including soft capsules, microcapsules), syrups, emulsions, suspensions and filming agents (eg, oral mucoadhesive film agents). Examples of the pharmaceutical dosage form of the present invention for parenteral administration include injections, infusions, dripping agents, tablets (e.g., iontophoretic patches), and suppositories. It is also possible to combine a compound of the invention with a suitable base (eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, a mixture of butyric acid polymer and glycolic acid polymer, polyglycerol fatty acid). Ester) Effective preparation of sustained release preparations.

The medicament of the present invention can be produced by a conventional method generally used in the field of pharmaceutical preparation technology (e.g., the method described in Japanese Pharmacopoeia). Further, the medicament of the present invention may, if necessary, suitably contain appropriate additives generally used in the field of pharmacy, such as excipients, binders, disintegrators, lubricants, sweeteners, surfactants, suspending agents, Emulsifiers, colorants, preservatives, fragrances, flavoring agents, stabilizers, thickeners, and the like.

Examples of such pharmaceutically acceptable carriers include such additives.

For example, the tablet can be produced using an excipient, a binder, a disintegrant, a lubricant, or the like, and the pellet and the granule can be produced using an excipient, a binder, and a disintegrating agent. Further, the powder and the capsule can be produced using an excipient or the like, the syrup can be produced using a sweetener or the like, and the emulsion and the suspending agent can be produced using a suspending agent, a surfactant, an emulsifier or the like.

Examples of the excipient include lactose, refined sugar, glucose, starch, sucrose, crystalline cellulose, licorice powder, mannitol, sodium hydrogencarbonate, calcium phosphate, and calcium sulfate.

Examples of the binder include 5 to 10% by weight of a starch paste, 10 to 20% by weight of a gum arabic solution or gelatin solution, 1 to 5% by weight of a tragacanth solution, a carboxymethylcellulose solution, a sodium alginate solution, and glycerin.

Examples of the disintegrant include starch and calcium carbonate.

Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, and refined talc.

Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and common syrup.

Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan mono-fatty acid ester, and polyoxyl 40 stearate.

Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, and bentonite.

Examples of the emulsifier include gum arabic, tragacanth, gelatin, and polysorbate 80.

For example, when the medicament of the present invention is in the form of a tablet, the tablet can be produced by a method known per se, for example, by adding an excipient (e.g., lactose, refined sugar, starch) to a compound of the present invention, a disintegrating agent. (eg, starch, calcium carbonate), binders (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose) or lubricants (eg, talc, magnesium stearate, polyethylidene) Glycol 6000), compression molding the mixture, and then, if necessary, applying a coating in a manner known per se for the purpose of odor, casing coating or persistence. Examples of the coating agent used for coating include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, pluronic F68, cellulose. Acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, methacrylic acid-acrylic acid copolymer) and dyes (eg, Hematite oxide, titanium dioxide). The resulting lozenge can be any immediate release formulation and sustained release formulation.

Examples of the above injection include intravenous injection as well as subcutaneous injection, intradermal injection, intramuscular injection, drip, and the like.

Such injections are prepared by methods known per se or by dissolving, suspending or emulsifying the compound of the invention in a sterile aqueous or oily liquid. Examples of the aqueous liquid include an isotonic solution containing physiological saline, glucose, and other adjuvants (e.g., D-sorbitol, D-mannitol, sodium chloride) and the like. The aqueous liquid may contain suitable co-solvents such as alcohols (eg, ethanol), polyols (eg, propylene glycol, polyethylene glycol), and nonionic surfactants (eg, polysorbate 80, HCO). -50). Examples of the oily liquid include sesame oil, soybean oil, and the like. The oily liquid may contain a suitable cosolvent. Examples of the cosolvent include benzyl benzoate, benzyl alcohol and the like. In addition, the injection may contain a buffer (eg, phosphate buffer, sodium acetate buffer), a soothing agent (eg, benzalkonium chloride, procaine hydrochloride), a stabilizer (eg, human serum albumin) , polyethylene glycol), preservatives (eg, benzyl alcohol, phenol). The prepared injections are generally filled in ampoules.

Although the amount of the compound of the present invention in the agent of the present invention varies depending on the form of the pharmaceutical preparation, it is usually about 0.01 to 100% by weight, preferably about 2 to 85% by weight, more preferably about the total amount of the preparation. 5 to 70% by weight.

Although the amount of the additive in the medicament of the present invention varies depending on the form of the pharmaceutical preparation, it is usually about 1 to 99.9% by weight, preferably about 10 to 90% by weight based on the total amount of the preparation.

The compound of the present invention is stable and low in toxicity and can be used safely. Although the daily dose will vary with the patient's condition and weight, the type of compound, the route of administration, etc., in this case, for example, when the patient is orally administered to treat cancer, the daily dose to an adult (weight about 60 kg) is about From 1 to 1000 mg, preferably from about 3 to 300 mg, more preferably from about 10 to 200 mg, of the compound of the present invention can be administered once a day or in two to three divided doses.

When the compound of the invention is administered parenterally, it is generally administered in liquid form (e.g., by injection). Although the dosage may vary depending on the administration target, the target organ, the symptoms, the administration method, and the like, it is, for example, about 0.01 mg to about 100 mg, preferably about 0.01 to about 50 mg, per 1 kg of body weight, more preferably It is preferably from about 0.01 to about 20 mg, preferably intravenously.

The compounds of the invention can be used simultaneously with other drugs. Specifically, the compound of the present invention may be used in combination with a drug, such as a hormonal therapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, a drug which inhibits the action of a cell growth factor or a receptor thereof, and the like. Hereinafter, a drug which can be used in combination with the compound of the present invention is simply referred to as a concomitant drug.

Examples of "hormone therapeutics" include fosfestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate Megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone Gestrinone), mepartricin, raloxifene, Ormeloxifene, levomeloxifene, antiestrogens (eg, tamoxifen citrate, special) Toremifene citrate, pellet preparation, mepitiostane, testrolactone, aminoglutethimide, LH-RH agonist (eg, Gosher Goserelin acetate, buserelin, leuprorelin, droloxifene, epitiostanol, ethinyllestradiol sulfonate Aromatase inhibitors (eg, fadrozole hydrochloride, ampoules) An azole (anastrozole), retrozole, exemestane, vorozole, formestane, antiandrogen (eg, flutamide, bika) Bicaramide, nilutamide, 5α-reductase inhibitors (eg, finasteride, epristeride), adrenocortical drugs (eg, dexamethasone) Dexamethasone, prednisolone, betamethasone, triamcinolone, androgen synthesis inhibitors (eg, abiraterone), Retinoids and drugs that delay the metabolism of retinoids (eg, lariozole), thyroid hormones, and the like, drug delivery system (DDS) preparations.

Examples of "chemotherapeutic agents" include alkylating agents, antimetabolites, anticancer antibiotics, and anticancer agents derived from plants.

Examples of "alkylating agents" include nitrogen mustard, nitrogen mustard N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa , carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, levo- amphetamine (melphalan), Dhakaba (dacarbazine), ramimustine, estramustine sodium phosphate, tri-ethyl melamine, carmustine, lomustine, streptozotocin Streptozocin), pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, hexamethylene honey Alkretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, lopus Ribosumtin, temozolomide, treosulphan, trophosphamide, zinostatin stimalamer, adozelesin, cystemustine ), bizelesin, and the like DDS preparations.

Examples of "anti-metabolites" include hydroxythioguanidine, 6-hydroxythioguanidine riboside, sulpho-inosine, methotrexate, pemetrexed, enocitabine, cytarabine ( Cytarabine), cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, doxivudine) Doxifluridine), carmofur, gallocitabine, emitefur, capecitabine, amine pterin, nelzarabine, formazan tetrahydrogen Leucovorin calcium salt, tabloid, butocine, calcium leucovorin, calcium levulinate, cladribine, emitefur, fludarabine ), gemcitabine, hydroxyurea, pentostatin, piritrexim, idoxuridine, mitoguazone, thiazoplirine, amoxicillin (ambamustine), bendamustine, and the like DDS preparations.

Examples of "anticancer antibiotics" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, and peplomycin. Sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, Epirubicin hydrochloride, neocarzinostatin, mithramycin, sarcomycin, carzinophilin, mitotane, Zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and the like DDS preparation.

Examples of "plant-derived anticancer agents" include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide , paclitaxel, docetaxel, vinorelbine, and the like DDS preparations.

Examples of "immunotherapy agents" include picibanil, krestin, sizofiran, lentinan, ubenimex, interferon, interleukin , macrophage community stimulating factor, granulocyte community stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole ) and anti-CTLA4 antibodies.

Examples of "cell growth factors" in "agents that inhibit the action of cell growth factors or their receptors" include any substance that promotes cell proliferation, usually a peptide having a molecular weight of not more than 20,000 and can be used at low concentrations. The body is combined to exhibit its activity, and specific examples thereof include (1) EGF (epidermal growth factor) or a substance having substantially the same activity as EGF [eg, TGF-α], (2) insulin or substantially having the same activity as insulin. Substance [eg, insulin, IGF (Insulin-like Growth Factor)-1, IGF-2], (3) FGF (fibroblast growth factor) or a substance that has substantially the same activity as FGF [eg, acidic FGF, alkali FGF, KGF (keratinocyte growth factor), FGF-10], (4) other cell growth factors [eg, CSF (community stimulating factor), EPO (erythropoietin), IL-2 (interleukin - 2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transformation growth factor β), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), growth factor ligand (heregulin ), angiopoietin (angiopoietin)].

Examples of the "cell growth factor receptor" include any receptor which binds to the above cell growth factor, and examples thereof include an EGF receptor, a growth factor ligand (heregulin) receptor (HER3, etc.), an insulin receptor, and an IGF receptor. Body-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (Tie2, etc.), PDGF receptor and the like.

Examples of "agents that inhibit the action of cell growth factors or their receptors" include EGF inhibitors, TGFa inhibitors, growth factor ligand inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors , EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGFβ inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor Insulin receptor inhibitor, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor -4 inhibitor, VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor, Src inhibitor, PKC inhibitor, Trk Inhibitors, Ret inhibitors, mTOR inhibitors, Aurora inhibitors, PLK inhibitors, MEK (MEK1/2) inhibitors, MET inhibitors, CDK inhibitors, Akt inhibitors, ERK inhibitors, and the like. More specific examples thereof include an anti-VEGF antibody (e.g., Bevacizumab), an anti-HER2 antibody (e.g., Trastuzumab, Pertuzumab), an anti-EGFR antibody (e.g., Cetuximab, Panitumumab, Matuzumab, Nimotuzumab, anti-VEGFR antibody, anti-HGF antibody, Imatinib, inhibitor Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatinib (Vatalanib), 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy] Quinazoline (AZD-2171), Lestaurtinib, Pazopanib, Cantintinib, Tandutinib, 3-(4-bromo-2, 6-Difluorobenzyloxy)-5-[3-[4-(1-pyrrolidinyl)butyl]ureido]isothiazole-4-carboxamide (CP-547632), eptinib (Axitinib), N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-(pyridin-4-ylmethylamino)pyridine-3-methyl Indoleamine (AMG-706), Nitininib, 6-[4-(4-B Piperazine -1-ylmethyl)phenyl]-N-[1(R)-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE-788), fentanyl Vandetanib, Temsirolimus, Everolimus, Enzastaurin, N-[4-[4-(4-methylperazine) -1-yl)-6-(3-methyl-1H-pyrazol-5-ylamino)pyrimidin-2-ylthio]phenyl]cyclopropanecarboxamide (VX-680), phosphoric acid 2- [N-[3-[4-[5-[N-(3-Fluorophenyl)amine-methylmethyl)-1H-pyrazol-3-ylamino]quinazoline-7-yloxy ]propyl]-N-ethylamino]ethyl ester (AZD-1152), 4-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimidine[5,4-d ][2]benzoxan-2-ylamino]benzoic acid (MLN-8054), N-[2-methoxy-5-[(E)-2-(2,4,6-trimethoxy) Phenyl)vinylsulfonylmethyl]phenyl]glycinate (ON-1910Na), 4-[8-cyclopentyl-7(R)-ethyl-5-methyl-6-side Oxy-5,6,7,8-tetrahydropteridin-2-ylamino]-3-methoxy-N-(1-methylpiperidin-4-yl)phenylguanamine (BI-2536 , 5-(4-bromo-2-chlorophenylamino)-4-fluoro-1-methyl-1H-benzimidazole-6-methoxypropanoic acid 2-hydroxyethyl ester (AZD-6244), N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide (PD-O325901), Ivey Everyone (RAD001) and so on.

In addition to the above drugs, the following drugs may also be used as a concomitant drug: L-aspartate, aceglatone, procarbazine hydrochloride, pre-blood-cobalt Salt, blood purple mercury-sodium, topoisomerase I inhibitors (eg, irinotecan, topotecan), topoisomerase II inhibitors (eg, Sorbozon ( Sobuzoxane)), differentiation inducers (eg, retinoids, vitamin D), other vascular distribution inhibitors (eg, fumagillin, shark extract, COX-2 inhibitor), alpha-resistance Broken agents (eg, tamsulosin hydrochloride), bisphosphonates (eg, pamidronate, zoledronate), thalidomide , 5-azacytidine nucleoside, decitabine, proteasome inhibitor (e.g., bortezomib), anti-tumor antibody such as anti-CD20 antibody, antibody labeled with toxin, and the like.

By combining the compound of the present invention and a concomitant drug, the following excellent effects can be obtained, such as (1) the dose can be lower than when the compound of the present invention is used alone or in combination, and (2) the drug combined with the compound of the present invention can be used according to the patient. The condition of the disease (moderate, severe, etc.), (3) can extend the treatment period, (4) can design a continuous medical effect, (5) the combination of the compound of the present invention and the concomitant drug can achieve synergistic effects, etc. .

Hereinafter, the compound of the present invention and the combined use drug are collectively referred to as "combination agent of the present invention".

When the combination agent of the present invention is used, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug can be administered to a subject at the same time or at different times. When administered in a staggered manner, the time difference will vary depending on the active ingredient to be administered, the form of the agent, and the method of administration. For example, when the drug is administered in combination, the compound of the present invention can be administered within 1 minute to 3 days, preferably 10 minutes to 1 day, more preferably 15 minutes to 1 hour, after administration of the drug. When the compound of the present invention is administered first, the concomitant drug can be administered within 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hour, after administration of the compound of the present invention. The dosage of the combined drug can be adjusted according to the clinical dosage, and can be appropriately selected according to the administration object, the administration route, the disease, the combination, and the like.

Examples of the administration mode of the compound of the present invention and a concomitant drug include the following methods: (1) simultaneous administration of a compound of the present invention together with a concomitant drug, and (2) preparation of two preparations from the compound of the present invention and a concomitant drug, respectively. Simultaneous administration according to the same administration route, (3) two preparations are prepared from the compound of the present invention and the concomitant drug, and are administered in a staggered manner according to the same administration route, and (4) two preparations are prepared from the compound of the present invention and the concomitant drug respectively. Different administration routes are simultaneously administered, (5) two preparations are prepared from the compound of the present invention and the concomitant drug, and are administered in a staggered manner according to different administration routes (for example, according to the order of the compound of the present invention and the concomitant drug, or the reverse order), etc. .

The dose of the combined drug can be appropriately adjusted according to the clinical dose, and the ratio of the compound of the present invention to the concomitant drug can be appropriately determined depending on the administration target, the administration route, the target disease, the symptom, the combination, and the like. For example, when the administration target is a human, the concomitant drug is used in an amount of from 0.01 to 100 parts by weight based on 1 part by weight of the compound of the present invention.

The combination of the present invention is low in toxicity and, for example, the compound of the present invention and/or the above-mentioned concomitant drug can be mixed with a pharmaceutically acceptable carrier according to a method known per se, and a pharmaceutical composition such as a tablet (including a dragee and the like) can be obtained. Membrane tablets, powders, granules, capsules (including soft capsules), liquids, injections, suppositories, and sustained release agents, administered orally or parenterally (eg, topical, rectal, intravenous) Mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans). The injection can be administered intravenously, intramuscularly, subcutaneously or intra-tissue or directly to the lesion.

Examples of pharmaceutically acceptable carriers for use in the preparation of the combination agents of the present invention comprise such pharmaceutically acceptable carriers as those described above for the preparation of the agents of the present invention.

In the combination agent of the present invention, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately determined depending on the administration target, the administration route, the disease, and the like.

For example, the content of the compound of the present invention in the combination agent of the present invention may vary depending on the formulation form, and is usually from about 0.01% by weight to 100% by weight, preferably from about 0.1% by weight to 50% by weight, based on the total weight of the preparation, more preferably About 0.5% by weight to 20% by weight.

The amount of the concomitant drug in the combination agent of the present invention may vary depending on the formulation form, and is usually from about 0.01% by weight to 90% by weight, preferably from about 0.1% by weight to 50% by weight, more preferably about 0.5% by weight based on the total weight of the preparation. % to 20% by weight.

The content of the additive in the combination agent of the present invention may vary depending on the formulation form, and is usually from about 1% by weight to 99.99% by weight, preferably from about 10% by weight to 90% by weight based on the total weight of the preparation.

When the compound of the present invention is prepared separately from the concomitant drug, the same amount can also be employed.

The combination agent of the present invention can be produced by a method known per se which is generally used in the field of pharmaceutical preparation technology.

The compound of the present invention is preferably molded into an oral preparation such as a solid preparation (e.g., powder, granule, lozenge, capsule) or the like, or molded into a rectal administration preparation such as a suppository. In particular, oral preparations are preferred.

The drug can be prepared according to the drug type as the above dosage form.

The dose of the combination agent of the present invention varies depending on the kind of the compound of the present invention; the age, body weight, condition of the patient; the pharmaceutical dosage form, the administration method, the administration period, and the like, for example, for a cancer patient (adult, weight: about 60 kg), combination The medicament is administered intravenously at a dose of from about 0.01 to about 1000 mg/kg/day, preferably from about 0.01 to about 100 mg/kg/day, more preferably from about 0.1 to about 100 mg/kg/day, in particular. Preferably, from about 0.1 to about 50 mg/kg/day, especially from about 1.5 to about 30 mg/kg/day, the compound of the invention or a combination of drugs is administered, administered once a day or in divided doses. Of course, since the above dosages may vary depending on various conditions, sometimes a dose lower than the above dose may be sufficient, and further, or sometimes it may be necessary to administer a dose higher than the above.

The amount of the drug can be set to any value as long as there is no side effect. The daily dose of the combined drug varies depending on the severity of the symptom, the age, sex, weight and sensitivity of the patient, the time of administration and the interval of administration, the characteristics of the drug preparation, the prescription and the type, the type of the active ingredient, and the like, and is not particularly limited; For example, when administered orally, the dosage of the drug is usually from about 0.001 mg to 2000 mg, preferably from about 0.01 mg to 500 mg, more preferably from about 0.1 mg to 100 mg per kg of body weight of the mammal. This dose is usually divided into 1 to 4 per day. Sub-dosing.

Furthermore, the compounds of the invention or the combination agents of the invention may be used concurrently with non-pharmacological therapies. It is to be correctly stated that the compound of the present invention or the combination agent of the present invention can be treated with, for example, (1) surgery, (2) use of angiotensin II, etc., (3) gene therapy, (4) heat therapy, (5) Cryotherapy, (6) laser ablation and (7) non-drug therapy for radiation therapy.

For example, the use of a compound of the present invention or a combination of the present invention before or after the above-mentioned surgery or the like, or before or after combining two or three treatments, can provide preventive resistance, prolong disease-free survival, suppress cancer metastasis or Recurrence, prolong life and other benefits.

Furthermore, the therapeutic and supportive therapies of the compounds of the invention or the combination agents of the invention may be used in combination [(i) administration of antibiotics (e.g., beta-endamines such as pansporin, etc., macrolides such as Carnamycin (clarithromycin), etc., to treat a variety of different infection complications, (ii) to give high calorie infusion, amino acid preparations or general vitamin preparations to improve malnutrition, (iii) to morphine for pain relief, (iv) administering drugs that improve side effects such as nausea, vomiting, anorexia, diarrhea, leukopenia, thrombocytopenia, decreased blood cell concentration, hair loss, liver disease, nephropathy, DIC, fever, etc., and (v) administration of suppressed cancer Drugs with multiple drug resistance, etc. ].

Preferably, the compound of the present invention or the combination agent of the present invention is administered orally (including a sustained release preparation), intravenously (including a bolus, a drip, and an inclusion compound), subcutaneously, and before or after the above-mentioned supportive therapy. Intramuscular administration (including bolus injection, instillation and sustained release preparations), transdermal, intratumoral or near tumor administration.

In the case where the compound of the present invention or the combination agent of the present invention is administered prior to surgery or the like, for example, the compound of the present invention or the combination agent of the present invention can be administered once every 30 minutes to 24 hours before surgery or the like, or about 3 to 3 before surgery or the like. 6 months divided into 1 to 3 doses. In this manner, surgery or the like can be easily performed, for example, because the cancer tissue can be administered by the administration of the compound of the present invention or the combination of the present invention by surgery or the like.

In the case where the compound of the present invention or the combination agent of the present invention is administered after surgery or the like, for example, administration is performed about 30 minutes to 24 hours after surgery or the like, and repeated administration is performed every few weeks to 3 months. In this manner, the effect of surgery or the like can be enhanced by administering the compound of the present invention or the combination of the present invention after surgery or the like.

Example

The invention is described in more detail below with reference to the examples, the test examples and the examples of the invention, but these should not be construed as limiting the invention, and the invention may be varied within the scope of the invention.

In the examples below, "room temperature" generally means from about 10 ° C to about 35 ° C. The ratio of the mixed solvent indicates the volume mixing ratio unless otherwise stated. % indicates % by weight unless otherwise stated.

In the rubber column chromatography, alkaline tantalum rubber column chromatography means the use of a silicone gel combined with aminopropyl decane. ¹ H-NMR (proton nuclear magnetic resonance spectroscopy) was measured by Fourier transform NMR. Very weak proton peaks such as hydroxyl groups and amine groups are not recorded.

The abbreviations in the examples and test examples are based on the general examples which are now used in the technical field and are intended as follows.

s: single peak

d: double peak

t: triple peak

q: Quadruple peak

Dd: double doublet

m: multiple peak

Brs: wide single peak

J: coupling constant

DMSO: dimethyl hydrazine

Hz: Hertz

CDCl ₃ : chloroform

¹ H-NMR: proton nuclear magnetic resonance

SDS: sodium dodecyl sulfate

PAGE: Polyacrylamide gel electrophoresis

PVDF: Polyvinylidene fluoride

HRP: Wasabi Peroxidase

The SEQ ID NOs of the Sequence Listing of the present specification show the following sequences.

(SEQ ID NO: 1) Base sequence of the primer used in Test Example 1.

(SEQ ID NO: 2) Base sequence of the primer used in Test Example 1.

(SEQ ID NO: 3) Base sequence of the primer used in Test Example 1.

(SEQ ID NO: 4) Base sequence of the primer used in Test Example 1.

Example 1 Manufacture of 2-(2-chlorophenyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one A) Preparation of methyl 3-[(trifluoroethenyl)amino]thiophene-2-carboxylate

Pyridine (31 mL) and trifluoroacetic anhydride (58.6 mL) were added to a solution of methyl 3-aminothiophene-2-carboxylate (50 g) in acetonitrile (650 mL). Stir at 0 ° C for 5 minutes. After stirring, the reaction was allowed to warm to room temperature and after 10 min, poured into ice water (6L). After stirring for 20 minutes, the title compound was obtainedjjjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 3.86 (3H, s), 7.72 (1H, d, J = 5.4 Hz), 8.03 (1H, d, J = 5.4 Hz), 11.17 (1H, brs).

B) Manufacture of methyl 5-bromo-3-[(trifluoroethenyl)amino]thiophene-2-carboxylate

A 1.6 M solution of n-butyllithium in hexane (82.4 mL) was added to a solution of diisopropylamine (20 mL) in tetrahydrofuran (200 mL), and the mixture was stirred at 0 ° C for 15 min. After stirring, the reaction was cooled to -78 ° C, and a solution of methyl 3-[(trifluoroethyl)amino]thiophene-2-carboxylate (10 g) in tetrahydrofuran (50 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour, and then 1,2-dibromoethane (20.6 mL) was added. After stirring at the same temperature for 30 minutes, the reaction was allowed to warm to room temperature and stirred for additional 30 min. The reaction was poured into aq. EtOAc EtOAc. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj ¹ H-NMR (CDCl ₃ ) δ 3.94 (3H, s), 8.11 (1H, s), 11.15 (1H, brs).

C) Manufacture of methyl 3-amino-5-bromothiophene-2-carboxylate

A mixture of methyl 5-bromo-3-[(trifluoroethenyl)amino]thiophene-2-carboxylate (5.3 g), potassium carbonate (10 g), methanol (100 mL) and water (25 mL) Stir for 2 hours. The reaction was concentrated under reduced pressure and ethyl acetate and water were poured. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjd ¹ H-NMR (DMSO-d ₆ ) δ 3.70 (3H, s), 6.68 (2H, brs), 6.75 (1H, s).

D) Manufacture of 3-amino-5-bromothiophene-2-carboxamide

A mixture of methyl 3-amino-5-bromothiophene-2-carboxylate (5.76 g), sodium hydroxide (2.94 g), water (25 mL) and methanol (100 mL) was stirred at 70 ° C overnight. The reaction system was ice-cooled, and then 6M hydrochloric acid (8.17 mL) was added, and the mixture was concentrated under reduced pressure. Ammonium chloride (26.3 g), triethylamine (49.7 g) and N,N-dimethylformamide (230 mL) were added to the residue, and the mixture was stirred at room temperature for 5 min. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.2 g) and 1-hydroxybenzotriazole (19.9 g) were added to the reaction system to form a mixture Stir at room temperature for 5 days. The reaction was poured into EtOAc EtOAc (EtOAc) The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj ^{1 H-NMR (300MHz, DMSO} -d 6) δ6.56 (2H, brs), 6.70 (1H, s), 6.91 (2H, brs).

E) Manufacture of 6-bromo-2-(2-chlorophenyl)thieno[3,2-d]pyrimidin-4(3H)-one

3-Amino-5-bromothiophene-2-carboxamide (100 mg), 2-chlorobenzidine chloride (57 μL), N,N-dimethylpyridin-4-amine (55 mg), pyridine (1.0) A mixture of mL) and N,N-dimethylformamide (2.0 mL) was stirred at 70 ° C for 1.5 hours. The reaction system was concentrated under reduced pressure, and a 2M aqueous sodium hydroxide solution was added to the residue and the mixture was heated to 120 °C. After 1 hour, the insoluble material was filtered off and the filtrate was neutralized with 1M hydrochloric acid. The precipitate was collected by EtOAc (EtOAc m. ¹ H-NMR (DMSO-d ₆ ) δ 7.44-7.67 (4H, m), 7.69 (1H, s), 13.04 (1H, brs).

F) Manufacture of 2-(2-chlorophenyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(2-chlorophenyl)thieno[3,2-d]pyrimidin-4(3H)-one (157 mg), 3-methyl-4-(4,4,5,5 - tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (425 mg), sodium carbonate (138 mg), 1,2- Dimethoxyethane (4.0 mL) and water (2.0 mL) were placed in a flask and the air in the flask was purged with argon. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (38 mg) was added, and the air in the flask was again purged with hydrogen. The reaction was stirred at 100 ° C for 1 hour, 8M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at 100 ° C for 30 minutes. After stirring, the mixture was extracted with a mixture of ethyl acetate / tetrahydrofuran, and the extract was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 2.43 (3H, brs), 7.43-7.69 (5H, m), 7.92 (0.6H, brs), 8.30 (0.4H, brs), 12.78 (1H, brs), 13.03 (1H, brs).

Example 2 Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one A) Manufacture of 6-bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one

Methyl 3-amino-5-bromothiophene-2-carboxylate (15 g), chloroacetonitrile (12 mL) and 4M HCl/cyclopentyl methyl ether solution (100 mL) manufactured in Example 1, Step C, at room temperature Stir for 2 hours and then at 70 ° C for 1 hour. The reaction was concentrated under reduced pressure and a saturated aqueous solution of sodium bicarbonate was added to the residue. The precipitate was collected by filtration and washed with water. The obtained solid was dried under reduced pressure of EtOAc. ¹ H-NMR (DMSO-d ₆ ) δ 4.51 (2H, s), 7.56 (1H, s), 13.00 (1H, brs).

B) Manufacture of 6-bromo-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one

Add 6-bromo-2-(chloromethyl) to a mixture of pyrrolidine (2.2 mL), potassium carbonate (2.5 g), sodium iodide (134 mg) and N,N-dimethylformamide (40 mL) Thieno[3,2-d]pyrimidin-4(3H)-one (2.5 g), and the mixture was stirred at 70 ° C for 30 min. The insoluble material was filtered, and the residue was evaporated. The filtrate was purified with EtOAc EtOAc m. The total yield of the title compound was 2.37 g. ¹ H-NMR (DMSO-d ₆ ) δ 1.65-1.77 (4H, m), 2.52-2.60 (4H, m), 3.57 (2H, s), 7.60 (1H, s), 12.24 (1H, brs).

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacturing

6-Bromo-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one (100 mg), 3-methyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (294 mg), sodium carbonate (95 mg), 1 2-Dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the air in the flask was purged with argon. Add [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride complex (1:1) (26 mg), again purge the air in the flask with argon . The reaction was stirred at 100 ° C for 3 hours, then aqueous 8M sodium hydroxide (1 mL) was added and the mixture was stirred at 100 ° C for 30 min. After stirring, the mixture was extracted with a mixture of ethyl acetate / tetrahydrofuran, and the extract was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.65-1.78 (4H, m), 2.45 (3H, s), 2.53-2.59 (4H, m), 3.57 (2H, s), 7.37 (1H, s), 8.00 (1H, brs), 11.84-13.16 (2H, m).

MS (ESI+): [M+H] ⁺ 316.

MS (ESI+), found: 316.

Example 3 Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-phenylthieno[3,2-d]pyrimidin-4(3H)-one A) Manufacture of 6-bromo-2-phenylthieno[3,2-d]pyrimidin-4(3H)-one

In the same manner as in Example 1, Step E, from 3-amino-5-bromothiophene-2-carboxamide (120 mg) and benzamidine chloride (0.063 mL), N,N-dimethylpyridine-4 -Amine (66 mg), EtOAc (m. ¹ H-NMR (DMSO-d ₆ ) δ 7.50-7.61 (3H, m), 7.70 (1H, s), 8.07-8.14 (2H, m), 12.87 (1H, brs).

B) Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-phenylthieno[3,2-d]pyrimidin-4(3H)-one

In the same manner as in Example 1, Step F, from 6-bromo-2-phenylthieno[3,2-d]pyrimidin-4(3H)-one (110 mg) and 3-methyl-4-(4) , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (331 mg), sodium carbonate (107 mg ), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloride Methane complex (1:1) (29 mg) gave ¹ H-NMR (DMSO-d ₆ ) δ 2.49 (3H, brs), 7.49 (1H, s), 7.51-7.65 (3H, m), 7.94 (0.6H, brs), 8.10-8.20 (2H, m ), 8.29 (0.4H, brs), 12.65 (1H, brs), 13.02 (1H, brs).

Example 4 2-{[(3S)-3-fluoropyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone A) Manufacture of 6-bromo-2-{[(3S)-3-fluoropyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 200 mg), (3S)-3-fluoropyrrolidine hydrochloride (270 mg), potassium carbonate (494 mg), sodium iodide (10 mg) and N,N-dimethylformamide (4.0 mL) The title compound (197 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.75-2.28 (2H, m), 2.44-2.54 (1H, m), 2.67-2.98 (3H, m), 3.61 (2H, s), 4.96-5.48 (1H , m), 7.62 (1H, s), 12.42 (1H, brs).

B) 2-{[(3S)-3-fluoropyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-{[(3S)-3-fluoropyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine-4 ( 3H)-ketone (192mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1-carboxylic acid tert-butyl butyl ester (392 mg), sodium carbonate (139 mg), 1,2-dimethoxyethane (4,0 mL) and water (2.0 mL) and [1,1'-bis(diphenyl) The phosphinyl)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (47 mg) ¹ H-NMR (DMSO-d ₆ ) δ 1.75-2.30 (2H, m), 2.45 (3H, brs), 2.48-2.55 (1H, m), 2.69-3.04 (3H, m), 3.61 (2H, s ), 4.97-5.45 (1H, m), 7.38 (1H, s), 7.89 (1H, brs), 12.19 (1H, brs), 12.99 (1H, brs).

Example 5 2-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone A) Manufacture of 6-bromo-2-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 200 mg), (3R)-3-fluoropyrrolidine hydrochloride (270 mg), potassium carbonate (494 mg), sodium iodide (10 mg) and N,N-dimethylformamide (4.0 mL) The title compound (192 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.75-2.26 (2H, m), 2.41-2.51 (1H, m), 2.67-2.97 (3H, m), 3.60 (2H, s), 5.03-5.37 (1H , m), 7.61 (1H, s), 12.44 (1H, brs).

B) 2-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine-4 ( 3H)-ketone (192mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1-carboxylic acid tert-butyl butyl ester (392 mg), sodium carbonate (139 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) and [1,1'-bis(diphenyl) The phosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (47 mg) gave ¹ H-NMR (DMSO-d ₆ ) δ 1.75-2.27 (2H, m), 2.45 (3H, brs), 2.48-2.57 (1H, m), 2, 69-3.01 (3H, m), 3.61 (2H) , s), 5.03-5.38 (1H, m), 7.38 (1H, s), 7.97 (1H, brs), 12.17 (1H, brs), 12.98 (1H, brs).

Example 6 2-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone A) Manufacture of 6-bromo-2-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), (3R)-pyrrolidin-3-ol (0.16 mL), potassium carbonate (178 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) were obtained as pale yellow The title compound (129 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.40-1.67 (1H, m), 1.88-2.11 (1H, m), 2.39-2.49 (2H, m), 2.65-2.80 (2H, m), 3.58 ( 2H, s), 4.1-4.22 (1H, m), 4.85 (1H, brs), 7.60 (1H, s), 12.27 (1H, brs).

B) 2-{[(3R)-3-Hydroxypyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine-4 ( 3H)-ketone (125mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1-carboxylic acid tert-butyl butyl ester (257 mg), sodium carbonate (91 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and [1,1'-bis(diphenyl) The phosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (31 mg) gave ¹ H-NMR (DMSO-d ₆ ) δ 1.48-1.65 (1H, m), 1.92-2.12 (1H, m), 2.41-2.49 (5H, m), 2.68-2.82 (2H, m), 3.58 ( 2H, s), 4.11-4.25 (1H, m), 7.35 (1H, s), 8.02 (1H, brs), 12.22-13.36 (2H, m).

Example 7 2-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone A) Manufacture of 6-bromo-2-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), (3S)-pyrrolidin-3-ol (0.16 mL), potassium carbonate (178 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) The title compound (99 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.49-1.66 (1H, m), 1.90-2.11 (1H, m), 2.39-2.49 (2H, m), 2.65-2.82 (2H, m), 3.59 (2H) , s), 4.10-4.24 (1H, m), 4.85 (1H, brs), 7.60 (1H, s), 12.11 (1H, brs).

B) 2-{[(3S)-3-Hydroxypyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine-4 ( 3H)-ketone (95mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1-carboxylic acid tertiary butyl ester (195 mg), sodium carbonate (69 mg), 1,2-dimethoxyethane (2.0 mL) and water (1.0 mL) and [1,1'-bis(diphenyl) The phosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (24 mg) gave ¹ H-NMR (DMSO-d ₆ ) δ 1.46-1.67 (1H, m), 1.92-2.09 (1H, m), 2.40-2.48 (5H, m), 2.69-2.83 (2H, m), 3.57 (2H) , s), 4.11-4.25 (1H, m), 7.33 (1H, s), 8.00 (1H, brs), 12.49-13.20 (2H, m).

Example 8 2-[(3,3-difluoropyrrolidin-1-yl)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 (3H)-ketone manufacture A) Manufacture of 6-bromo-2-[(3,3-difluoropyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), 3,3-difluoropyrrolidine hydrochloride (277 mg), potassium carbonate (445 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) to give a pale yellow The title compound (162 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 2.13-2.36 (2H, m), 2.83 (2H, t, J = 7.0 Hz), 3.04 (2H, t, J = 13.5 Hz), 3.62 (2H, s) , 7.62 (1H, s), 12.51 (1H, brs).

B) 2-[(3,3-d-difluoropyrrolidin-1-yl)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-[(3,3-difluoropyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidine-4 (3H )-ketone (162 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole- 1-carboxylic acid tertiary butyl ester (314 mg), sodium carbonate (111 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and [1,1'-bis(diphenylphosphine) The title compound (103 mg) was obtained as a pale yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 2.18-2.35 (2H, m), 2.46 (3H, brs), 2.85 (2H, t, J = 6.9 Hz), 3.06 (2H, t, J = 13.4 Hz) , 3.63 (2H, s), 7.39 (1H, s), 7.90 (0.6H, brs), 8.26 (0.4H, brs), 12.25 (1H, brs), 12.98 (1H, brs).

Example 9 Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-(piperidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one A) Manufacture of 6-bromo-2-(piperidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), piperidine (0.19 mL), potassium carbonate (178 mg), sodium iodide (9.7 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.31-1.42 (2H, m), 1.45-1.56 (4H, m), 2.35-2.46 (4H, m), 3.40 (2H, s), 7.61 (1H, s ), 12.20 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(piperidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacturing

In the same manner as in Example 2, Step C, from 6-bromo-2-(piperidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one (175 mg) and 3 -Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (361 mg), sodium carbonate (128 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium(II)-dichloromethane complex (1:1) (44 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.30-1.44 (2H, m), 1.44-1.60 (4H, m), 2.40-2.48 (7H, m), 3.42 (2H, s), 7.38 (1H, s ), 8.04 (1H, brs), 12.61 (2H, brs).

Example 10 Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-(morpholin-4-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one A) Manufacture of 6-bromo-2-(morpholin-4-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), morpholine (0.17 mL), potassium carbonate (178 mg), sodium iodide (9.7 mg), and N,N-dimethylformamide (3.0 mL) ¹ H-NMR (DMSO-d ₆ ) δ 2.44-2.49 (4H, m), 3.44 (2H, s), 3.54-3.64 (4H, m), 7.61 (1H, s), 12.40 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(morpholin-4-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacturing

In the same manner as in Example 2, Step C, from 6-bromo-2-(morpholin-4-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one (110 mg) and 3 -Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (226 mg), sodium carbonate (80 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium(II)-dichloromethane complex (1:1) (27 mg) gave m. ¹ H-NMR (DMSO-d ₆ ) δ 2.39-2.48 (7H, m), 3.45 (2H, s), 3.54-3.64 (4H, m), 7.38 (1H, s), 7.88 (0.6H, brs) , 8.23 (0.4H, brs), 12.11 (1H, brs), 12.96 (1H, brs).

Example 11 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-pyrrolidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one Production of trifluoroacetate A) (2S)-2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)pyrrolidine-1-carboxylic acid tert-butyl Ester manufacture

3-Amino-5-bromothiophene-2-carboxamide (300 mg), 1-(tertiary butoxycarbonyl)-L-proline (700 mg), O-, which was produced in Example 1, Step D. (7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.55g) and N-ethyl-N-(1-A A solution of chloroethylamine-2-amine (0.713 mL) in N,N-dimethylformamide (8 mL) was stirred at <RTI ID=0.0> Ethyl acetate (40 mL) and aqueous sodium bicarbonate (20 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL). The collected organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate /hexane) to afford (2S)-2-[(5-bromo-2-amine-carbamoylthiophen-3-yl)aminecarbazyl]pyrrole An inseparable mixture (starting material) in the form of a yellow oil of pyridine-1-carboxylic acid tert-butyl ester and 3-amino-5-bromothiophene-2-carboxamide. 2M aqueous sodium hydroxide solution (2.04 mL) was added to the above-produced (2S)-2-[(5-bromo-2-aminomethylthiophenyl-3-yl)aminecarboxylidene]pyrrolidine-1-carboxylic acid. A mixture of the tertiary butyl ester and 3-amino-5-bromothiophene-2-carboxamide was dissolved in ethanol (6 mL), and the mixture was stirred at 70 ° C for 4 hours. 6M Hydrochloric acid (1 mL), ethyl acetate (20 mL), and aqueous sodium hydrogen carbonate (10 mL) were added to the mixture, and the aqueous layer was separated with ethyl acetate (5 mL×2). The collected organic layer was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.12 (9H, s, major), 1.37 (9H, s, minor), 1.73-2.04 (3H, m), 2.18-2.36 (1H, m), 3.32-3.43 (1H, m), 3.48-3.59 (1H, m), 4.56 (1H, dd, J=7.6, 4.8 Hz, major), 4.60-4.66 (1H, m, minor), 7.60 (1H, s, minor) , 7.63 (1H, s, major), 12.63 (1H, brs, minor), 12.72 (1H, brs, major). The observed isomer ratio was 2:1.

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-pyrrolidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)- Manufacture of ketone monotrifluoroacetate

(2S)-2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)pyrrolidine-1-carboxylic acid tert-butyl butyl ester (173 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate Tributyl citrate (266 mg), cesium carbonate (282 mg), 1,2-dimethoxyethane (5 mL) and water (0.5 mL) were placed in a flask, and the air in the flask was purged with argon. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride complex (1:1) (71 mg) was added, and the air in the flask was again purged with argon. The mixture was stirred at 80 ° C for 2 hours. Ethyl acetate (20 mL) and water (5 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5mL×2). The collected organic layer was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and concentrated to give 4-{2-[(2S)-1-(tris-butoxycarbonyl)pyrrolidine- 2-yl]-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl}-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl Ester and (2S)-2-[6-(5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidine- A mixture of 2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester. The above-prepared 4-{2-[(2S)-1-(tertiarybutoxycarbonyl)pyrrolidin-2-yl]-4-yloxy-3,4-dihydrothieno[3,2- d]pyrimidin-6-yl}-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester and (2S)-2-[6-(5-methyl-1H-pyrazole-4- a mixture of 4-tert-oxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester in trifluoroacetic acid (10 mL) The solution was stirred at room temperature for 1 hour, and the mixture was concentrated under reduced pressure. The residue was crystallized from EtOAcqqqqqqqq ¹ H-NMR (DMSO-d ₆ ) δ 1.93-2.15 (3H, m), 2.38-2.44 (1H, m), 2.46 (3H, brs), 3.35-3.50 (2H, m), 4.66 (1H, t , J = 7.2 Hz), 7.37 (1H, s), 7.85-8.48 (1H, m), 8.99 (1H, brs), 9.52 (1H, brs), 12.80 (1H, brs), 13.06 (1H, brs) </RTI>^<RTIID=0.0></RTI>^<RTIID=0.0>

Example 12 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2R)-pyrrolidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one Production of trifluoroacetate A) (2R)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)pyrrolidine-1-carboxylic acid tert-butyl Ester manufacture

3-Amino-5-bromothiophene-2-carboxamide (300 mg) and 1-(tertiary butoxycarbonyl)-as produced in Example 1, Step D, as in Example 11, Step A. D-proline (878 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.06 g) and N-Ethyl-N-(1-methylethyl)propan-2-amine (0.95 mL), ield. ¹ H-NMR (DMSO-d ₆ ) δ 1.12 (9H, s, major), 1.37 (9H, s, minor), 1.77-2.02 (3H, m), 2.19-2.34 (1H, m), 3.34-3.43 (1H, m), 3.47-3.59 (1H, m), 4.56 (1H, dd, J = 7.6, 4.8 Hz, major), 4.62 (1H, dd, J = 7.7, 3.4 Hz, minor), 7.59 (1H) , s, minor), 7.62 (1H, s, major), 12.70 (1H, brs). The observed isomer ratio was 2:1.

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2R)-pyrrolidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)- Manufacture of ketone monotrifluoroacetate

In the same manner as in Example 11, Step B, from (2R)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) Pyrrolidine-1-carboxylic acid tert-butyl butyl ester (173 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Base)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (266 mg) and cesium carbonate (282 mg) and 1,2-dimethoxyethane (5 mL) and water (0.5 mL) and [1,1' - bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (71 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.94-2.15 (3H, m), 2.39-2.47 (1H, m), 2.46 (3H, s), 3.27-3.43 (2H, m), 4.66 (1H, t , J = 7.1 Hz), 7.37 (1H, s), 8.09 (1H, brs), 8.98 (1H, brs), 9.55 (1H, brs), 12.80 (1H, brs).

Example 13 6-(5-Methyl-1H-pyrazol-4-yl)-2-(2-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacturing A) Manufacture of 6-bromo-2-(2-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)-one

3-Acryl chloride (0.057 mL) was added to 3-amino-5-bromothiophene-2-carboxamide (120 mg), triethylamine, manufactured in Example 1, Step D, with stirring at room temperature. (0.083 mL) and a mixture of tetrahydrofuran (3.0 mL). After 10 minutes, pyrrolidine (0.23 mL) was added and the mixture was stirred at room temperature for 10 min. The reaction system was concentrated under reduced pressure, and a 2M aqueous sodium hydroxide solution (1.0 mL) was added to the residue, and the mixture was stirred at 120 ° C for 1 hour under heating. The mixture was extracted with EtOAc, washed with brine and dried over anhydrous sodium sulfate. The title compound (131 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.63-1.70 (4H, m), 2.43-2.49 (4H, m), 2.78-2.82 (4H, m), 7.57 (1H, s), 12.61 (1H, Brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(2-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)- Ketone manufacturing

In the same manner as in Example 1, Step F, from 6-bromo-2-(2-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)-one (125 mg) And 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tertiary Butyl ester (352 mg), sodium carbonate (114 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and [1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) chloride-dichloromethane complex (1:1) (31 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.51-1.78 (4H, m), 2.40-2.49 (7H, m), 2.75-2.89 (4H, m), 7.34 (1H, s), 8.02 (1H, brs ), 11.93-13.36 (2H, m).

Example 14 6-(5-methyl-1H-pyrazol-4-yl)-2-[(4-phenylpiperidine) Manufacture of -1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one A) 6-bromo-2-[(4-phenylperidine) Manufacture of -1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), 1-phenylperidine (0.29 mL), potassium carbonate (178 mg), EtOAc (EtOAc) ¹ H-NMR (DMSO-d ₆ ) δ 2.60-2.70 (4H, m), 3.05-3.19 (4H, m), 3.52 (2H, s), 6.72-6.81 (1H, m), 6.92 (2H, d , J = 7.9 Hz), 7.13 - 7.26 (2H, m), 7.63 (1H, s), 12.36 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(4-phenylperidine) Manufacture of -1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-[(4-phenylpiperidine) -1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one (180 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (410 mg), sodium carbonate (133 mg), 1,2-dimethoxyethane ( 3.0 mL) and water (1.5 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (36 mg) The title compound (86 mg) was obtained as white crystal. ¹ H-NMR (DMSO-d ₆ ) δ 2.39-2.48 (3H, m), 2.60-2.70 (4H, m), 3.08-3.23 (4H, m), 3.53 (2H, s), 6.77 (1H, t , J = 7.2 Hz), 6.92 (2H, d, J = 7.2 Hz), 7.12 - 7.26 (2H, m), 7.40 (1H, s), 7.89 (0.6H, brs), 8.26 (0.4H, brs) , 12.18 (1H, brs), 13.00 (1H, brs).

Example 15 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(4-phenylpiperidin-1-yl)methyl]thieno[3,2-d]pyrimidine-4 (3H )--Manufacture of ketone A) Manufacture of 6-bromo-2-[(4-phenylpiperidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 240 mg), 4-phenylpiperidine (415 mg), potassium carbonate (237 mg), sodium i. ). ¹ H-NMR (DMSO-d ₆ ) δ 1.53-1.82 (4H, m), 2.14-2.32 (2H, m), 2.43-2.48 (1H, m), 2.93-3.03 (2H, m), 3.50 (2H) , s), 7.10-7.35 (5H, m), 7.62 (1H, s), 12.24 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(4-phenylpiperidin-1-yl)methyl]thieno[3,2-d]pyrimidine-4 (3H)-ketone manufacture

In the same manner as in Example 2, Step C, from 6-bromo-2-[(4-phenylpiperidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)- Ketone (240mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1- Tributyl carboxylic acid ester (549 mg), sodium carbonate (178 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) and [1,1'-bis(diphenylphosphino) The ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (49 mg) gave the title compound (138 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.61-1.83 (4H, m), 2.14-2.33 (2H, m), 2.40-2.50 (4H, m), 2.90-3.08 (2H, m), 3.50 ( 2H, s), 7.10-7.34 (5H, m), 7.39 (1H, s), 7.96 (1H, brs), 12.08 (1H, brs), 12.97 (1H, brs).

Example 16 2-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2- Manufacture of d]pyrimidin-4(3H)-one dihydrochloride A) Manufacture of 6-bromo-2-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), (2S)-pyrrolidin-2-ylmethanol (0.19 mL), potassium carbonate (178 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) The title compound (112 mg) was obtained as a yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.49-1.92 (4H, m), 2.21-2.41 (1H, m), 2.59-2.72 (1H, m), 2.82-3.00 (1H, m), 3.19- 3.54 (3H, m), 4.01 (1H, d, J = 14.7 Hz), 4.74 (1H, brs), 7.60 (1H, s), 12.04 (1H, brs).

B) 2-{[(2S)-2-(Hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3, Manufacture of 2-d]pyrimidin-4(3H)-one dihydrochloride

In the same manner as in Example 2, Step C, from 6-bromo-2-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d] Pyrimidine-4(3H)-one (112 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole-1-carboxylic acid tertiary butyl ester (300 mg), sodium carbonate (78 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and [1,1'-double (Diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (27 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.67-2.22 (4H, m), 2.47 (3H, s), 3.33-3.50 (1H, m), 3.63-3.91 (4H, m), 4.37-4.51 (1H , m), 4.65-4.78 (1H, m), 7.41 (1H, s), 8.10 (1H, s), 10.27 (1H, brs), 12.77 (1H, brs).

Example 17 2-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2- Manufacture of d]pyrimidin-4(3H)-one dihydrochloride A) Manufacture of 6-bromo-2-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), (2R)-pyrrolidin-2-ylmethanol (0.19 mL), potassium carbonate (178 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) afforded colorless The title compound (122 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.53-1.91 (4H, m), 2.23-2.38 (1H, m), 2.61-2.71 (1H, m), 2.83-2.98 (1H, m), 3.20-3.55 (3H, m), 4.01 (1H, d, J = 14.7 Hz), 4.33-5.67 (1H, m), 7.60 (1H, s), 11.13-12.68 (1H, m).

B) 2-{[(5R)-2-(Hydroxymethyl)pyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3, Manufacture of 2-d]pyrimidin-4(3H)-one dihydrochloride

In the same manner as in Example 2, Step C, from 6-bromo-2-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d] Pyrimidine-4(3H)-one (122 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole-1-carboxylic acid tertiary butyl ester (327 mg), sodium carbonate (85 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and [1,1'-double (Diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (29 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.69-2.23 (4H, m), 2.47 (3H, s), 3.31-3.52 (1H, m), 3.63-3.94 (4H, m), 4.35-4.54 (1H , m), 4.62-4.82 (1H, m), 7.40 (1H, s), 8.09 (1H, s), 10.29 (1H, brs), 12.76 (1H, brs).

Example 18 2-{[(3S)-3-methoxypyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one A) Manufacture of 6-bromo-2-{[(3S)-3-methoxypyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), (3S)-3-methoxypyrrolidine hydrochloride (265 mg), potassium carbonate (445 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) The title compound (152 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.59-1.76 (1H, m), 1.90-2.07 (1H, m), 2.52-2.59 (2H, m), 2.60-2.71 (1H, m), 2.75-2.85 (1H, m), 3.15 (3H, s), 3.55 (2H, s), 3.82-3.95 (1H, m), 7.61 (1H, s), 12.36 (1H, brs).

B) 2-{[(3S)-3-Methoxypyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2- Manufacture of d]pyrimidin-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-{[(3S)-3-methoxypyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine- 4(3H)-one (150mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Pyrazole-1-carboxylic acid tertiary butyl ester (403 mg), sodium carbonate (105 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) and [1,1'-bis (two Phenylphosphino)ferrocene]palladium(II)-dichloromethane complex (1:1) (36 mg) ¹ H-NMR (DMSO-d ₆ ) δ 1.60-1.74 (1H, m), 1.92-2.07 (1H, m), 2.45 (3H, s), 2.52-2.61 (2H, m), 2.63-2.73 (1H) , m), 2.77-2.87 (1H, m), 3.16 (3H, s), 3.56 (2H, s), 3.81-4.02 (1H, m), 7.38 (1H, s), 7.97 (1H, brs), 12.10 (1H, brs), 12.96 (1H, brs).

Example 19 2-{[(3R)-3-methoxypyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one A) Manufacture of 6-bromo-2-{[(3R)-3-methoxypyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), (3R)-3-methoxypyrrolidine hydrochloride (265 mg), potassium carbonate (445 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL). The title compound (150 mg) was obtained as a pale yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.57-1.74 (1H, m), 1, 91-2.07 (1H, m), 2.52-2.59 (2H, m), 2.61-2.71 (1H, m), 2.75-2.85 (1H, m), 3.15 (3H, s), 3.55 (2H, s), 3.81-3.96 (1H, m), 7.61 (1H, s), 12.36 (1H, brs).

B) 2-{[(3R)-3-Methoxypyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2- Manufacture of d]pyrimidin-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-{[(3R)-3-methoxypyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine- 4(3H)-one (150mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Pyrazole-1-carboxylic acid tertiary butyl ester (403 mg), sodium carbonate (105 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) and [1,1'-bis (two Phenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (36 mg) ¹ H-NMR (DMSO-d ₆ ) δ 1.60-1.74 (1H, m), 1.92-2.07 (1H, m), 2.45 (3H, s), 2.52-2.61 (2H, m), 2.62-2.72 ( 1H, m), 2.77-2.86 (1H, m), 3.16 (3H, s), 3.56 (2H, s), 3.81-3.97 (1H, m), 7.38 (1H, s), 8.00 (1H, brs) , 12.21 (1H, brs), 12.92 (1H, brs).

Example 20 6-(5-Methyl-1H-pyrazol-4-yl)-2-(1-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacturing A) Manufacture of 6-bromo-2-(1-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)-one

2-Bromopropionyl chloride (0.11 mL) was added to 3-amino-5-bromothiophene-2-carboxamide (221 mg), triethylamine (Step 1), which was stirred at room temperature. A mixture of 0.15 mL) and tetrahydrofuran (5.0 mL). After 10 minutes, pyrrolidine (0.42 mL) was added and the mixture was stirred at 70 ° C for 1 hour. The reaction was concentrated under reduced pressure and a 2M aqueous solution of sodium hydroxide (1.OmL) was added to the residue, and the mixture was heated to 120 ° C and stirred for 2 hours. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.38 (3H, d, J = 6.8 Hz), 1.69 (4H, brs), 2.40-2.48 (2H, m), 2.55-2.66 (2H, m), 3.49 ( 1H, q, J = 6.8 Hz), 7.59 (1H, s), 12.14 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(1-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)- Ketone manufacturing

In the same manner as in Example 2, Step C, from 6-bromo-2-(1-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)-one (270 mg) And 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tertiary Butyl ester (761 mg), sodium carbonate (198 mg), 1,2-dimethoxyethane (6.0 mL) and water (3.0 mL) and [1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) chloride-dichloromethane complex (1:1) (67 mg) gave m. ¹ H-NMR (DMSO-d ₆ ) δ 1.39 (3H, d, J = 6.8 Hz), 1.64-1.75 (4H, m), 2.40-2.48 (5H, m), 2.55-2.65 (2H, m), 3.49 (1H, q, J = 6.8 Hz), 7.37 (1H, s), 8.02 (1H, brs), 12.00-13.09 (2H, m).

Example 21 6-(5-ethyl-1H-pyrazol-4-yl)-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride Salt manufacturing A) Manufacture of N,N-dimethyl-1H-pyrazole-1-sulfonamide

Sodium hydride (50%, 8.46 g) was added to a solution of pyrazole (12 g) in tetrahydrofuran (200 mL). After 20 minutes, dimethylamine sulfonium chloride (17 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour and then warmed to room temperature over 1 hour. The reaction mixture was poured into aq. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj ¹ H-NMR (300 MHz, CDCl ₃ ) δ 2.95 (6H, s), 6.40 (1H, m), 7.75 (1H, m), 7.99 (1H, d, J = 2.7 Hz).

B) Manufacture of 5-ethyl-N,N-dimethyl-1H-pyrazole-1-sulfonamide

1.6 M n-butyllithium/hexane solution (99 mL) was added dropwise to a stirred solution of N,N-dimethyl-1H-pyrazole-1-sulfonamide (25.3 g) in tetrahydrofuran at -78 °C. In solution (200 mL). 30 minutes after the completion of the dropwise addition, ethyl iodide (12.8 mL) was added dropwise. The mixture was stirred at the same temperature for 30 minutes and the reaction was allowed to warm to room temperature. After 1 hour, tetrahydrofuran (200 mL) was added to facilitate stirring of the reaction mixture, and the mixture was stirred for 2 hours. The reaction was poured into aq. EtOAc (EtOAc) The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to EtOAc EtOAc EtOAcjjjjjjj ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.30 (3H, t, J = 7.8 Hz), 2.94 (2H, dd, J = 15.0, 7.5 Hz), 3.03 (6H, s), 6.13 (1H, brs) , 7.55 (1H, brs).

C) Manufacture of 4-bromo-5-ethyl-N,N-dimethyl-1H-pyrazole-1-sulfonamide

1-Bromopyrrolidine-2,5-dione (20.8 g) was added to 5-ethyl-N,N-dimethyl-1H-pyrazole-1-sulfonamide at room temperature (19.8) g) In tetrahydrofuran (300 mL). The reaction was heated to 50 ° C, stirred for 2 h and concentrated under reduced pressure. The residue was poured into aq. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAcjjjjj elut elut ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.24 (3H, t, J = 7.5 Hz), 2.97 (2H, dd, J = 15.0 Hz, 7.8 Hz), 3.06 (6H, s), 7.54 (1H, s ).

D) 5-Ethyl-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Manufacture of pyrazole-1-sulfonamide

4-Bromo-5-ethyl-N,N-dimethyl-1H-pyrazole-1-sulfonamide (13.0 g), 4,4,4',4',5,5,5', 5'-octamethyl-2,2'-linked-1,3,2-dioxaborolane (12.3g), potassium acetate (13.6g) and 1,2-dimethoxyethane (300mL) Place in the flask and purge the air in the flask with argon. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride complex (1:1) (3.76 g) was added, and the flask was again purged with argon. Air and the mixture was stirred at 90 ° C overnight. The reaction was allowed to cool to room temperature. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. A mixture of ethyl acetate and hexane (1:1) was added to the residue, and the insoluble material was filtered again, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjj ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.25 (3H, t, J = 7.5 Hz), 1.31 (12H, s), 3.03 (6H, s), 3.17 (2H, dd, J = 15.0, 7.5 Hz) , 7.75 (1H, s).

E) 6-(5-Ethyl-1H-pyrazol-4-yl)-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacture of hydrochloride

6-Bromo-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one (100 mg), 5-ethyl-N,N-dimethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-sulfonamide (210 mg), cesium carbonate (311 mg), 1,2-dimethoxyethane (5 mL) and water (1 mL) were placed in a flask, and the air in the flask was purged with argon. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride complex (1:1) (26.0 mg) was added, and the flask was again purged with argon. Air, and the mixture was stirred at 90 ° C for 3 hours. The reaction was allowed to cool to room temperature and sodium carbonate (169 mg), 5-ethyl-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-1H-pyrazole-1-sulfonamide (210 mg), water (1 mL) and [1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) chloride-dichloromethane complex (1:1) (26.0 mg). The air in the flask was again purged with argon, and the mixture was stirred at 90 ° C overnight. The reaction mixture was poured into brine, and the mixture was extracted with ethyl acetate and tetrahydrofuran (3:1) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic hydrazine column chromatography (methanol / ethyl acetate). A 1 M HCl/diethyl ether solution (5 mL) and methanol (5 mL) were added to the residue, and the mixture was stirred at 60 ° C for 2 hr. The reaction was cooled to rt. ¹ H-NMR (DMSO-d ₆ ) δ 1.26 (3H, t, J = 7.5 Hz), 1.99 (4H, m), 2.84 - 2.92 (2H, m), 3.17 - 3.25 (2H, m), 3.64 3.77 (2H, m), 4.51 (2H, s), 7.38 (1H, s), 8.09 (1H, s), 10.61 (1H, brs), 12.80 (1H, brs).

Example 22 2-[(2S)-4,4-difluoropyrrolidin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone dihydrochloride A) (2S)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-4,4-difluoropyrrolidine- Manufacture of 1-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (250 mg) and 1-(tertiary butoxycarbonyl)-as produced in Example 1, Step D, as in Example 11, Step A. 4,4-Difluoro-L-proline (568 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro Phosphate (1.29g) and N-ethyl-N-(1-methylethyl)propan-2-amine (0.592mL) and N,N-dimethylformamide (5mL) gave a pale yellow solid The title compound (286 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.14 (9H, s, major), 1.39 (9H, s, minor), 2.55-2.71 (1H, m), 2.86-2.97 (1H, m), 3.80-4.03 (2H, m), 4.74-4.90 (1H, m), 7.60 (1H, s, minor), 7.63 (1H, s, major), 12.84 (1H, brs). The observed isomer ratio is 3. :2.

B) 2-[(2S)-4,4-Difluoropyrrolidin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketone dihydrochloride

In the same manner as in Example 11, Step B, from (2S)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) -4,4-difluoropyrrolidine-1-carboxylic acid tert-butyl butyl ester (286 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Tertiary borolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (404 mg) and cesium carbonate (427 mg) and 1,2-dimethoxyethane (7 mL) and water (0.7 mL) And [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (107 mg) afforded the title compound 163mg). ¹ H-NMR (DMSO-d ₆ ) δ 2.46 (3H, s), 2.75-2.95 (1H, m), 3.01-3.21 (1H, m), 3.89 (2H, t, J = 12.3 Hz), 5.05 ( 1H, t, J = 8.5 Hz), 7.41 (1H, s), 8.11 (1H, s), 10.32 (1H, brs), 12.87 (1H, brs).

Example 23 2-[(2S,4R)-4-fluoropyrrolidin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 ( Manufacture of 3H)-ketone dihydrochloride A) (2S,4R)-2-(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-4-fluoropyrrolidin-1 -Manufacture of carboxylic acid tertiary butyl ester

3-Amino-5-bromothiophene-2-carboxamide (250 mg) and (4R)-1-(Tri-tertene) were prepared in the same manner as in Example 11, Step A, from Example 1, Step D. Oxycarbonyl)-4-fluoro-L-proline (568mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Fluorophosphate (1.29g) and N-ethyl-N-(1-methylethyl)propan-2-amine (0.592mL) and N,N-dimethylformamide (5mL) gave a pale yellow The title compound (239 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.11 (9H, s, major), 1.37 (9H, s, minor), 2.09-2.35 (1H, m), 2.54-2.67 (1H, m), 3.63-3.86 (2H, m), 4.64 - 4.76 (1H, m), 5.38 (1H, d, J = 53.4 Hz), 7.58 (1H, s, minor), 7.61 (1H, s, major), 12.79 (1H, brs The observed isomer ratio was 2:1.

B) 2-[(2S,4R)-4-fluoropyrrolidin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone dihydrochloride

In the same manner as in Example 11, Step B, from (2S,4R)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2- Tert-butyl 4-fluoropyrrolidine-1-carboxylate (237 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Tert-butyl butyl bromide-2-yl)-1H-pyrazole-1-carboxylate (348 mg) and cesium carbonate (368 mg) and 1,2-dimethoxyethane (5 mL) and water (0.5 mL) And [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (92.3 mg) afforded the title compound 139mg). ¹ H-NMR (DMSO-d ₆ ) δ 2.29-2.45 (1H, m), 2.46 (3H, s), 2.76-2.93 (1H, m), 3.50-3.70 (2H, m), 4.80-4.96 (1H) , m), 5.45-5.69 (1H, m), 7.37 (1H, s), 8.10 (1H, s), 9.38 (1H, brs), 10.44 (1H, brs), 12.85 (1H, brs).

Example 24 2-[(2S,4S)-4-fluoropyrrolidin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 ( Manufacture of 3H)-ketone dihydrochloride A) (2S,4S)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-4-fluoropyrrolidin-1 -Manufacture of carboxylic acid tertiary butyl ester

3-Amino-5-bromothiophene-2-carboxamide (250 mg) and (4S)-1-(tri-butyl) manufactured in Example 1, Step D, as in Example 11, Step A. Oxycarbonyl)-4-fluoro-L-proline (568mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Fluorophosphate (1.29g) and N-ethyl-N-(1-methylethyl)propan-2-amine (0.592mL) and N,N-dimethylformamide (5mL) afforded as a colorless solid The title compound (106 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.18 (9H, s, major), 1.42 (9H, s, minor), 2.19-2.38 (1H, m), 2.55-2.82 (1H, m), 3.57-3.83 (2H, m), 4.71-4.86 (1H, m), 5.16-5.41 (1H, m), 7.59 (1H, s, minor), 7.62 (1H, s, major), 12.61 (1H, brs). The observed isomer ratio was 2:1.

B) 2-[(2S,4S)-4-Fluoropyridin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone dihydrochloride

In the same manner as in Example 11, Step B, from (2S,4S)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2- Tert-butyl 4-fluoropyrrolidine-1-carboxylate (180 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Tert-butyl butyl bromide-2-yl)-1H-pyrazole-1-carboxylate (265 mg) and cesium carbonate (281 mg) and 1,2-dimethoxyethane (5 mL) and water (0.5 mL) And [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (70.3 mg) afforded the title compound 102mg). ¹ H-NMR (DMSO-d ₆ ) δ 2.46 (3H, s), 2.71-2.96 (1H, m), 3.47-3.77 (3H, m), 4.87 (1H, brs), 5.37-5.61 (1H, m), 7.37 (1H, s), 8.10 (1H, s), 9.40 (1H, brs), 10.34 (1H, brs), 12.87 (1H, brs).

Example 25 2-[(3,3-Difluoroazetidin-1-yl)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one

6-bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H) as in Example 2, Step A, as in Example 2, Step B and Step C. -ketone (160 mg) and 3,3-difluoroazetidine hydrochloride (200 mg) and potassium carbonate (158 mg) and sodium iodide (8.6 mg) and N,N-dimethylacetamide (4.0 mL) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid Tertiary butyl ester (353 mg) and cesium carbonate (373 mg) and 1,2-dimethoxyethane (4.0 mL) and water (1 mL) and [1,1'-bis(diphenylphosphino)ferrocene Palladium(II) chloride-dichloromethane complex (1:1) (26 mg) gave the title compound (93 mg). ¹ H-NMR (DMSO-d ₆ ) δ 2.42-2.47 (3H, m), 3.71-3.82 (6H, m), 7.36-7.38 (1H, m), 7.88 (0.6H, brs), 8.25 (0.4) H, brs), 12.28 (1H, brs), 12.97 (1H, brs).

Example 26 6-(5-Methyl-1H-pyrazol-4-yl)-2-{[(3R)-3-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine -4(3H)-one manufacture A) Manufacture of 6-bromo-2-{[(3R)-3-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), (3R)-3-methylpyrrolidine hydrochloride (235 mg), potassium carbonate (445 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) The title compound (171 mg) was obtained as a pale yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 0.98 (3H, d, J = 6.6 Hz), 1.17-1.37 (1H, m), 1.85-2.02 (1H, m), 2.03-2.26 (2H, m), 2.53-2.61 (1H, m), 2.62-2.71 (1H, m), 2.77-2.86 (1H, m), 3.55 (2H, s), 7.59 (1H, s), 12.30 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-{[(3R)-3-methylpyrrolidin-1-yl]methyl}thieno[3,2-d Manufacture of pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-{[(3R)-3-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine-4 (3H)-ketone (170 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridyl Zirconium-1-carboxylic acid tert-butyl butyl ester (479 mg), sodium carbonate (124 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) and [1,1'-bis(diphenyl) The phosphinyl) ferrocene]palladium(II)-dichloromethane complex (1:1) (42 mg) gave the title compound (m. ¹ H-NMR (DMSO-d ₆ ) δ 0.98 (3H, d, J = 6.6 Hz), 1.21-1.37 (1H, m), 1.87-2.02 (1H, m), 2.06-2.26 (2H, m), 2.45 (3H, brs), 2.53-2.61 (1H, m), 2.62-2.73 (1H, m), 2.77-2.89 (1H, m), 3.55 (2H, s), 7.37 (1H, s), 8.03 ( 1H, brs), 12.13-12.91 (2H, m).

Example 27 6-(5-Methyl-1H-pyrazol-4-yl)-2-{[(3S)-3-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine -4(3H)-one manufacture A) Manufacture of 6-bromo-2-{[(3S)-3-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), (3S)-3-methylpyrrolidine hydrochloride (235 mg), potassium carbonate (445 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) The title compound (186 mg), m. ¹ H-NMR (DMSO-d ₆ ) δ 0.98 (3H, d, J = 6.6 Hz), 1.21-1.36 (1H, m), 1.86-2.03 (1H, m), 2.05-2.25 (2H, m), 2.53-2.61 (1H, m), 2.61-2.74 (1H, m), 2.76-2.88 (1H, m), 3.55 (2H, s), 7.59 (1H, s), 12.19 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-{[(3S)-3-methylpyrrolidin-1-yl]methyl}thieno[3,2-d Manufacture of pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-{[(3S)-3-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine-4 (3H)-ketone (180 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridyl Triazole carboxylic acid tert-butyl ester (507 mg), sodium carbonate (132 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) and [1,1'-bis(diphenyl) The phosphinyl)ferrocene]palladium(II)-dichloromethane complex (1:1) (45 mg) gave the title compound (37 mg). ¹ H-NMR (DMSO-d ₆ ) δ 0.98 (3H, d, J = 6.6 Hz), 1.20-1.37 (1H, m), 1.88-2.03 (1H, m), 2.05-2.25 (2H, m) , 2.45 (3H, s), 2.53-2.62 (1H, m), 2.62-2.72 (1H, m), 2.78-2.86 (1H, m), 3.55 (2H, s), 7.37 (1H, s), 8.02 (1H, brs), 11.97-13.06 (2H, m).

Example 28 6-(5-Methyl-1H-pyrazol-4-yl)-2-{[3-(trifluoromethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine -4(3H)-one manufacture A) Manufacture of 6-bromo-2-{[3-(trifluoromethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 200 mg) and 3-trifluoromethylpyrrolidine hydrochloride (377 mg) and triethylamine (0.595 mL) and sodium iodide (10.7 mg) and N,N-dimethylformamide (4.0 mL) The title compound (220 mg) was obtained as a brown solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.70-1.84 (1H, m), 1.95-2.10 (1H, m), 2.55-2.72 (3H, m), 2.91 (1H, t, J = 9.3 Hz) , 3.02-3.19 (1H, m), 3.58 (2H, s), 7.58 (1H, s), 12.37 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-{[3-(trifluoromethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d Manufacture of pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-{[3-(trifluoromethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine-4 (3H)-ketone (218 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridyl Triazole 1,3-carboxylic acid (351 mg), cesium carbonate (371 mg), 1,2-dimethoxyethane (5.0 mL) and water (0.5 mL) and [1,1'-bis(diphenyl) The phosphinyl) ferrocene]palladium(II)-dichloromethane complex (1:1) (93 mg) gave the title compound (57.3 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.71-1.86 (1H, m), 1.96-2.12 (1H, m), 2.45 (3H, s), 2.57-2.78 (3H, m), 2.93 (1H, t , J=9.2 Hz), 3.01-3.21 (1H, m), 3.60 (2H, s), 7.38 (1H, s), 7.70-8.39 (1H, m), 12.16 (1H, brs), 12.97 (1H, Brs).

Example 29 6-(5-Methyl-1H-pyrazol-4-yl)-2-{[2-(trifluoromethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine -4(3H)-one manufacture A) Preparation of 6-bromo-2-{[2-(trifluoromethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 200 mg) and 2-trifluoromethylpyrrolidine (0.247 mL) and triethylamine (0.298 mL) and sodium iodide (10.7 mg) and N,N-dimethylformamide (4.0 mL) gave a pale yellow The title compound (35.8 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.68-1.89 (3H, m), 2.02-2.17 (1H, m), 2.75-2.86 (1H, m), 3.03-3.13 (1H, m), 3.78-3.85 (1H, m), 3.87 (2H, d, J = 3.8 Hz), 7.57 (1H, s), 12.42 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-{[2-(trifluoromethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d Manufacture of pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-{[2-(trifluoromethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine-4 (3H)-ketone (34 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridyl Zirconium-1-carboxylic acid tertiary butyl ester (54.8 mg), cesium carbonate (58.0 mg), 1,2-dimethoxyethane (3.0 mL) and water (0.3 mL) and [1,1'-double ( Diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (14.5 mg) gave the title compound (l. ¹ H-NMR (DMSO-d ₆ ) δ 1.66-1.92 (3H, m), 2.06-2.23 (1H, m), 2.46 (3H, s), 2.75-2.87 (1H, m), 3.06-3.16 (1H , m), 3.80-3.89 (1H, m), 3.90 (2H, s), 7.39 (1H, s), 7.85-8.32 (1H, m), 12.16 (1H, brs), 12.99 (1H, brs).

Example 30 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,4R)-4-phenoxypyrrolidin-2-yl]thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone dihydrochloride A) (2S,4R)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-4-phenoxypyrrolidine Manufacture of 1-carboxylic acid tert-butyl butyl ester

(4R)-1-(tertiary butoxycarbonyl)-4-phenoxy-L-proline (1.04 g), O-(7-azabenzotriazol-1-yl)-N, N,N',N'-tetramethyluronium hexafluorophosphate (1.29g) and N-ethyl-N-(1-methylethyl)propan-2-amine (0.692mL) in N,N A solution of dimethylformamide (5 mL) was stirred at room temperature for 30 minutes. 3-Amino-5-bromothiophene-2-carboxamide (250 mg), which was produced in Example 1, Step D, was added to the reaction mixture, and the mixture was stirred at 90 ° C for 1.5 hours. The reaction mixture was concentrated under reduced pressure. ethyl acetate (EtOAc) The collected organic layer was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate /hexane) to afford (2S,4R)-2-[(5-bromo-2-amine-carbamoylthiophen-3-yl)amine A mixture of tert-butyl 4-phenyloxypyrrolidine-1-carboxylate and an impurity having an undefined structure as a pale yellow solid. 2M aqueous sodium hydroxide solution (1.70 mL) was added to the above-obtained insoluble (2S,4R)-2-[(5-bromo-2-aminomethylsulfenyl-3-yl)aminecarbamyl]-4 A mixture of phenoxypyrrolidine-1-carboxylic acid tert-butyl butyl ester and an impurity having an undefined structure in ethanol (5 mL), and the mixture was stirred at 70 ° C for 2 hours. 6M Hydrochloric acid (0.60 mL) was added to the reaction mixture, and the title compound was obtained from EtOAc (EtOAc) ). ¹ H-NMR (DMSO-d ₆ ) δ 1.11 (9H, s, major), 1.34 (9H, s, minor), 2.24-2.37 (1H, m), 2.43-3.58 (1H, m), 3.56-3.67 (1H, m), 3.79-3.91 (1H, m), 4.67-4.81 (1H, m), 5.07-5.15 (1H, m), 6.93-7.02 (3H, m), 7.27-7.37 (2H, m) , 7.60 (1H, s, minor), 7.63 (1H, s, major), 12.77 (1H, brs). The observed isomer ratio was 2:1.

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,4R)-4-phenoxypyrrolidin-2-yl]thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one dihydrochloride

In the same manner as in Example 11, Step B, from (2S,4R)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2- 3-phenyloxypyrrolidine-1-carboxylic acid tert-butyl butyl ester (450 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-di Tert-butyl borolan-2-yl)-1H-pyrazole-1-carboxylic acid (564 mg), cesium carbonate (596 mg), 1,2-dimethoxyethane (10 mL) and water (1.0 </ RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; (310 mg). ¹ H-NMR (DMSO-d ₆ ) δ 2.36-2.46 (1H, m), 2.47 (3H, s), 2.79 (1H, dd, J = 14.0, 6.8 Hz), 3.42-3.54 (1H, m) , 3.78-3.92 (1H, m), 4.84-4.97 (1H, m), 5.28 (1H, t, J = 4.5 Hz), 6.99-7.08 (3H, m), 7.32-7.38 (2H, m), 7.39 (1H, s), 8.11 (1H, s), 9.42 (1H, brs), 10.67 (1H, brs), 12.83 (1H, brs).

Example 31 Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-morpholin-4-ylthieno[3,2-d]pyrimidin-4(3H)-one A) Manufacture of 6-bromo-2-morpholin-4-ylthieno[3,2-d]pyrimidin-4(3H)-one

3-Amino-5-bromothiophene-2-carboxylic acid methyl ester (200 mg), morpholine-4-carbonitrile (0.17 mL) and 4M HCl/cyclopentyl methyl ether, which were produced in Example 1, Step C. The solution (3.0 mL) was stirred at 110 ° C for 4 hours. The reaction was concentrated under reduced pressure and a saturated aqueous solution of sodium bicarbonate was added to the residue. The precipitate was collected by filtration and washed with water. The obtained pale brown solid was washed with ethyl acetate / hexane (1:1). ¹ H-NMR (DMSO-d ₆ ) δ 3.51-3.60 (4H, m), 3.61-3.71 (4H, m), 7.29 (1H, s), 11.50 (1H, brs).

B) Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-morpholin-4-ylthieno[3,2-d]pyrimidin-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-morpholin-4-ylthieno[3,2-d]pyrimidin-4(3H)-one (140 mg) and 3-methyl-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (410 mg), carbonic acid Sodium (106 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride - dichloromethane complex (1:1) (36 mg). ¹ H-NMR (DMSO-d ₆ ) δ 2.33-2.47 (3H, m), 3.50-3.61 (4H, m), 3.61-3.72 (4H, m), 7.11 (1H, s), 7.83 (0.6H, Brs), 8.19 (0.4H, brs), 11.35 (1H, brs), 12.79-13.07 (1H, m).

Example 32 Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-(tetrahydrofuran-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one A) Manufacture of tetrahydrofuran-2-carbonyl chloride

A mixture of tetrahydrofuran-2-carboxylic acid (0.19 mL) and hexanedichlorodichloride (0.42 mL) was stirred at room temperature for 18 hr. The title compound (241 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ 2.14-2.46 (2H, m), 3.50-3.63 (1H, m), 3.77-4.06 (3H, m), 4.06-4.16 (1H, m).

B) Manufacture of 6-bromo-2-(tetrahydrofuran-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one

Tetrahydrofuran-2-carbonyl chloride (80 mg) was added to the 3-amino-5-bromothiophene-2-carboxamide (120 mg) and triethylamine (0.083 mL) obtained in Example 1, Step D, with stirring at room temperature. And a mixture of tetrahydrofuran (3.0 mL). The reaction was stirred for 10 minutes and the reaction was concentrated under reduced pressure. A 2 M aqueous sodium hydroxide solution (1.0 mL) was added to the residue, and the mixture was stirred for 2 hr. The mixture was extracted with EtOAc, washed with brine and dried over anhydrous sodium sulfate. The title compound (160 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 2.04-2.33 (2H, m), 3.22-3.34 (1H, m), 3.67-3.89 (3H, m), 3.93-4.01 (1H, m), 7.32 (1H) , s).

C) Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-(tetrahydrofuran-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-(tetrahydrofuran-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one (160 mg) and 3-methyl -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (491 mg) Sodium carbonate (128 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( II)-Dichloromethane complex (1:1) (43 mg). ¹ H-NMR (DMSO-d ₆ ) δ 2.18-2.31 (2H, m), 2.38-2.48 (3H, m), 3.38-3.52 (1H, m), 3.72-3.94 (3H, m), 3.99-4.06 (1H, m), 7.38 (1H, s), 7.89 (0.6H, brs), 8.25 (0.4H, brs), 12.38 (1H, brs), 12.87-13.06 (1H, m).

Example 33 6-(5-Methyl-1H-pyrazol-4-yl)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine -4(3H)-one manufacture A) Manufacture of 6-bromo-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]midine-4(3H)-one as produced in Example 2, Step A, as in Example 2, Step B. (180 mg), (2R)-2-methylpyrrolidine hydrochloride (235 mg), potassium carbonate (445 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL). The title compound (205 mg) was obtained as a yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.04 (3H, d, J = 6.0 Hz), 1.28-1.42 (1H, m), 1.56-1.74 (2H, m), 1.80-1.97 (1H, m), 2.21-2.35(1H,m), 2.52-2.57(1H,m),2.88-3.04(1H,m), 3.32(1H,d,J=14.2Hz),3.81(1H,d,J=14.2Hz) , 7.61 (1H, s), 12.18 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}thieno[3,2-d Manufacture of pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine-4 (3H)-ketone (200mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridyl Triazole carboxylic acid tert-butyl ester (564 mg), sodium carbonate (146 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) and [1,1'-bis(diphenyl) The phosphinyl)ferrocene]palladium(II)-dichloromethane complex (1:1) (50 mg) gave the title compound (m. ¹ H-NMR (DMSO-d ₆ ) δ 1.06 (3H, d, J = 6.0 Hz), 1.27-1.47 (1H, m), 1.57-1.76 (2H, m), 1.85-2.00 (1H, m), 2.24-2.37 (1H, m), 2.45 (3H, s), 2.52-2.60 (1H, m), 2.93-3.04 (1H, m), 3.33 (1H, d, J = 14.0 Hz), 3.81 (1H, d, J = 14.0 Hz), 7.37 (1H, s), 8.03 (1H, brs), 11.92-13.20 (2H, m).

Example 34 Manufacture of 2-(ethoxymethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one A) Manufacture of ethoxylated ethyl chlorochloride

A mixture of ethoxyacetic acid (0.19 mL) and hexanedichlorodichloride (0.42 mL) was stirred at room temperature for 18 hr. The title compound (220 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ 1.26 (3H, t, J = 7.0 Hz), 3.65 (2H, q, J = 7.0 Hz), 4.41 (2H, s).

B) Manufacture of 6-bromo-2-(ethoxymethyl)thieno[3,2-d]pyrimidin-4(3H)-one

3-Amino-5-bromothiophene-2-carboxamide (120 mg), and triethylamine (0.083 mL) and tetrahydrofuran, as in Example 32, Step B, from Example 1, Step D. (3.0 mL) and ethoxyethyl chlorobenzene (74 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.14 (3H, t, J = 7.0 Hz), 3.53 (2H, q, J = 7.0 Hz), 4.30 (2H, s), 7.48 (1H, s), 12.60 (1H, brs).

C) 2-(ethoxymethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-(ethoxymethyl)thieno[3,2-d]pyrimidin-4(3H)-one (140 mg) and 3-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (448 mg), Sodium carbonate (116 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II) The title compound (59 mg) was obtained as a pale brown solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.17 (3H, t, J = 7.0 Hz), 2.38-2.50 (3H, m), 3.56 (2H, q, J = 7.0 Hz), 4.38 (2H, s) , 7.39 (1H, s), 7.89 (0.6H, brs), 8.26 (0.4H, brs), 12.34 (1H, brs), 12.77-13.18 (1H, m).

Example 35 6-(5-Methyl-1H-pyrazol-4-yl)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketone dihydrochloride

6-bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H) as in Example 2, Step A, as in Example 2, Step B and Step C. -ketone (140 mg) and (S)-2-methylpyrrolidine hydrochloride (182 mg) and potassium carbonate (276 mg) and sodium iodide (7.5 mg) and N,N-dimethylformamide (4.0 mL) And 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid III Butyl butyl ester (308 mg) and sodium carbonate (265 mg) and 1,2-dimethoxyethane (4.0 mL) and water (1 mL) and [1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) chloride-dichloromethane complex (1:1) (26 mg) gave the title compound (104 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.41-1.43 (3H, m), 1.62-1.74 (1H, m), 1.93-2.03 (2H, m), 2.17-2.27 (1H, m), 2.46 (3H) , s), 3.28-3.38 (3H, m), 4.25-4.64 (2H, m), 7.40 (1H, s), 8.10 (1H, s), 10.24 (1H, brs), 12.80 (1H, brs).

Example 36 Optics of 6-(5-methyl-1H-pyrazol-4-yl)-2-(1-pyrrolidinyl-1-ylethyl)thieno[3,2-d]pyrimidin-4(3H)-one isolation

High performance liquid chromatography (column: CHIRALPAK AD (50 mm id × 500 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol/diethylamine (500/500/1), flow rate : 60 mL / min, column temperature: 30 ° C) distinguish 6-(5-methyl-1H-pyrazol-4-yl)-2-(1-pyrrolidinyl-1)ethyl thiophene [3, 2 -d]pyrimidine-4(3H)-one (106 mg). Under the above high performance liquid chromatography conditions, the optically active type distinguishing solution containing a shorter residence time is concentrated to obtain 6-(5-methyl-1H-pyrazol-4-yl)-2-(1-pyrrole Optically active form of pyridine-1 -ethyl)thieno[3,2-d]pyrimidin-4(3H)-one (53 mg, retention time 10.6 min, 99.3% ee). ¹ H-NMR (DMSO-d ₆ ) δ 1.39 (3H, d, J = 6.6 Hz), 1.63-1.77 (4H, m), 2.38-2.48 (5H, m), 2.55-2.65 (2H, m), 3.49 (1H, q, J = 6.6 Hz), 7.37 (1H, s), 8.02 (1H, brs), 12.09-12.93 (2H, m).

Further, a solution containing an optically active type having a longer residence time is concentrated to obtain 6-(5-methyl-1H-pyrazol-4-yl)-2-(1-pyrrolidinyl-1)ethylthiophene. And optically active form of [3,2-d]pyrimidin-4(3H)-one (39 mg, retention time 12.1 minutes, >99.9% ee). ¹ H-NMR (DMSO-d ₆ ) δ 1.39 (3H, d , J = 6.8 Hz), 1.60-1.75 (4H, m), 2.37-2.48 (5H, m), 2.54-2.66 (2H, m), 3.49 (1H, q, J = 6.8 Hz), 7.37 (1H, s), 8.02 (1H, brs), 12.12-13.00 (2H, m).

The system was subjected to high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm id × 250 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol/diethylamine (500/500/1), flow rate: The analysis was carried out at 0.5 mL/min, column temperature: 30 ° C, and detection at 220 nm.

Example 37 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-pyrrolidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one Manufacture of hydrochloride

(2S)-2-(6-Bromo-4-yloxy-3,4-dihydrothieno[3, as in Example 11, Step A, as described in Example 83, Step C below. 2-d]pyrimidin-2-yl)pyrrolidine-1-carboxylic acid tert-butyl butyl ester (2.27 g), 3-methyl-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (2.94 g), cesium carbonate (3.11 g), [1,1'-bis(diphenyl) Phosphino)ferrocene]palladium(II)-dichloromethane complex (1:1) (779 mg), 1,2-dimethoxyethane (50 mL), water (5 mL), 4M HCl The title compound (1.39 g) was obtained as a white crystal. ¹ H-NMR (DMSO-d ₆ ) δ 1.93-2.16 (3H, m), 2.37-2.47 (1H, m), 2.46 (3H, s), 3.23 - 3.48 (2H, m), 4.61-4.74 (1H , m), 7.37 (1H, s), 8.10 (1H, s), 8.98 (1H, brs), 10.05 (1H, brs), 12.85 (1H, brs).

Example 38 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(3-phenoxypyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidine-4 ( 3H)-ketone manufacture A) Manufacture of 6-bromo-2-[(3-phenoxypyrrolidin-1yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), 3-phenoxypyrrolidine hydrochloride (385 mg), potassium carbonate (445 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) afforded as colorless solid. The title compound (212 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.72-1.88 (1H, m), 2.20-2.37 (1H, m), 2.54-2.64 (1H, m), 2.69-2.77 (1H, m), 2.77-2.87 (1H, m), 2.96-3.06 (1H, m), 3.54-3.67 (2H, m), 4.83-4.93 (1H, m), 6.82-6.95 (3H, m), 7.19-7.33 (2H, m) , 7.61 (1H, s), 12.45 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(3-phenoxypyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone

In the same manner as in Example 2, Step C, from 6-bromo-2-[(3-phenoxypyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H) -ketone (210 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1 - carboxylic acid tertiary butyl ester (478 mg), sodium carbonate (124 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and [1,1'-bis(diphenylphosphino) The ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (42 mg) gave the title compound (46 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.73-1.88 (1H, m), 2.22-2.37 (1H, m), 2.45 (3H, brs), 2.55-2.67 (1H, m), 2.70-2.79 (1H , m), 2.79-2.90 (1H, m), 2, 96-3.11 (1H, m), 3.53-3.69 (2H, m), 4.81-4.98 (1H, m), 6.80-6.97 (3H, m) , 7.20-7.33 (2H, m), 7.38 (1H, s), 7.90 (0.6H, brs), 8.22 (0.4H, brs), 12.20 (1H, brs), 12.97 (1H, brs).

Example 39 2-(1,4-Dioxa-7-azaspiro[4.4]dec-7-ylmethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2 -d]Production of pyrimidine-4(3H)-one A) Manufacture of 1,4-dioxa-7-aziro[4.4]indole-7-carboxylic acid benzyl ester

a mixture of 3-oxopyrrolidine-1-carboxylic acid benzyl ester (2.00 g), ethyl-1,2-diol (2.85 mL), p-toluenesulfonic acid monohydrate (10 mg) and toluene (20 mL) The mixture was stirred under heating at 120 ° C for 6 hours in a Dean-Stark apparatus. The mixture was cooled to room temperature, diluted with EtOAc (EtOAc) (EtOAc) The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc ¹ H-NMR (CDCl ₃ ) δ 2.00-2.13 (2H, m), 3.42-3.49 (2H, m), 3.51-3.62 (2H, m), 3.93-4.02 (4H, m), 5.13 (2H, s ), 7.28-7.41 (5H, m).

B) Manufacture of 1,4-dioxa-7-azaspiro[4.4]decane

Palladium(II) hydroxide (100 mg) was added to a solution of 1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylic acid benzyl ester (1.1 g) in methanol (30 mL) at room temperature. in. The mixture was stirred under a hydrogen atmosphere (0.4 MPa) for 2.5 hours. The insoluble material was filtered, and the filtrate was evaporated. ¹ H-NMR (DMSO-d ₆ ) δ 1.76 (2H, t, J = 7.1 Hz), 2.71 (2H, s), 2.81 (2H, t, J = 7.1 Hz), 3.81 (4H, s).

C) 6-bromo-2-(1,4-dioxa-7-azaspiro[4.4]dec-7-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacturing

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 390 mg), 1,4-dioxa-7-azaspiro[4.4]decane (540 mg), potassium carbonate (384 mg), sodium iodide (21 mg) and N,N-dimethylformamide (3.0 mL) The title compound (422 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.87-1.97 (2H, m), 2.63-2.71 (4H, m), 3.53 (2H, s), 3.73-3.87 (4H, m), 7.61 (1H, s), 11.63 (1H, brs).

D) 2-(1,4-Dioxa-7-azaspiro[4.4]dec-7-ylmethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3 , 2-d] pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-(1,4-dioxa-7-azaspiro[4.4]fluoren-7-ylmethyl)thieno[3,2-d Pyrimidine-4(3H)-one (422mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (1.05 g), sodium carbonate (271 mg), 1,2-dimethoxyethane (5.0 mL) and water (2.5 mL) and [1,1' - bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (92 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.94 (2H, t, J = 6.9 Hz), 2.45 (3H, brs), 2.63-2.75 (4H, m), 3.54 (2H, s), 3.74-3.88 (4H, m), 7.38 (1H, s), 7.89 (0.6H, brs), 8.19 (0.4H, brs), 12.17 (1H, brs), 12.98 (1H, brs).

Example 40 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,5R)-5-phenylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone monohydrochloride A) (2S,5R)-2-[(5-bromo-2-aminomethylsulfonylthiophen-3-yl)amine-carbamoyl]-5-phenylpyrrolidine-1-carboxylic acid tert-butyl acrylate Manufacturing

3-Amino-5-bromothiophene-2-carboxamide (250 mg) and (5R)-1-(Tri-tertidine) were prepared in the same manner as in Example 11, Step A, from Example 1, Step D. Oxycarbonyl)-5-phenoxy-L-proline (988 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate (1.28g) and N-ethyl-N-(1-methylethyl)propan-2-amine (0.692mL) and N,N-dimethylformamide (5mL) were obtained. The title compound (434 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.11 (9/2H, brs), 1.24 (9/2H, brs), 1.69-1.86 (1H, m), 2.01 (1H, brs), 2.13-2.42 (2H , m), 4.28-4.45 (1H, m), 4.64 - 4.96 (1H, m), 7.16-7.25 (1H, m), 7.25-7.34 (2H, m), 7.56 (2H, d, J = 7.4 Hz ), 7.74 (2H, brs), 8.13 (1H, s), 11.51 (1H, brs). * observed as a mixture of rotamers 1:1.

B) (2S,5R)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5-phenylpyrrolidine- Manufacture of 1-carboxylic acid tert-butyl butyl ester

2M sodium hydroxide aqueous solution (1.31 mL) was added to the above-produced (2S,5R)-2-[(5-bromo-2-aminomethylsulfenyl-3-yl)aminecarbamyl]-5-phenyl Pyrrolidine-1-carboxylic acid tert-butyl butyl ester (430 mg) was dissolved in ethanol (5 mL), and the mixture was stirred at 70 ° C for 2.5 hr. The reaction mixture was neutralized with 6M hydrochloric acid (0.45 mL), and water (4 mL) was added dropwise at room temperature. The precipitated solid was collected to give the title compound (342mg) ¹ H-NMR (DMSO-d ₆ ) δ 0.94-1.22 (9H, m), 1.78-2.12 (2H, m), 2.17-2.41 (2H, m), 4.62-4.98 (2H, m), 7.17-7.27 (1H, m), 7.37 (2H, t, J = 7.6 Hz), 7.68 (1H, brs), 7.74-7.86 (2H, m), 12.76 (1H, brs).

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,5R)-5-phenylpyrrolidin-2-yl]thieno[3,2-d]thiazide Manufacture of pyridine-4(3H)-one monohydrochloride

In the same manner as in Example 83, Step C below, from (2S,5R)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d] Pyrimidin-2-yl)-5-phenylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (340 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (440 mg), cesium carbonate (466 mg), [1,1'-bis(diphenylphosphine) Base) ferrocene] palladium(II) chloride-dichloromethane complex (1:1) (117 mg), 1,2-dimethoxyethane (5 mL) and water (0.5 mL) afforded white Solid 4-{2-[(2S,5R)-1-(tertiarybutoxycarbonyl)-5-phenylpyrrolidin-2-yl]-4-yloxy-3,4-dihydrothiophene [3,2-d]pyrimidin-6-yl}-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester. 4M HCl/ethyl acetate solution (2 mL) was added to the above-mentioned 4-{2-[(2S,5R)-1-(tertiarybutoxycarbonyl)-5-phenylpyrrolidin-2-yl]- 4-tert-oxy-3,4-dihydrothieno[3,2-d]thiaridin-6yl}-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester in methanol (10 mL The solution was stirred at 50 ° C for 1.5 hours. The reaction mixture was concentrated under reduced EtOAc. ¹ H-NMR (DMSO-d ₆ ) δ 2.20-2.47 (3H, m), 2.47 (3H, brs), 2.53-2.62 (1H, m), 4.79 (1H, dd, J = 10.8, 6.6 Hz), 4.88 (1H, dd, J = 8.5, 4.2 Hz), 7.42 (1H, s), 7.43-7.56 (3H, m), 7.62-7.70 (2H, m), 7.86-8.44 (1H, m), 8.80 ( 1/2H, brs), 10.91 (1/2H, brs), 12.46-13.35 (2H, m).

Example 41 2-[(Dimethylamino)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one di-salt Manufacture of acid salt

6-bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H) as in Example 2, Step A, as in Example 2, Step B and Step C. -ketone (140 mg) and N-methylmethylamine hydrochloride (203 mg) and N,N-dimethylformamide (3.0 mL) and 3-methyl-4-(4,4,5,5- Tertiary butyl tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (380 mg) and sodium carbonate (265 mg) and 1,2-di Methoxyethane (4.0 mL) and water (2 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane complex (1:1) The title compound (66 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 2.47 (3H, s), 2.95 (6H, s), 4.40 (2H, s), 7.40 (1H, s), 8.10 (1H, s), 10.40 (1H, Brs), 12.82 (1H, brs).

Example 42 Manufacture of 2-[(diethylamino)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one

0.57M diethylamine/N,N-dimethylacetamide solution (0.7 mL), 0.15 M sodium iodide/N,N-dimethylacetamide solution (0.2 mL), 0.12 M 6-bromo 2-(Chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one/N,N-dimethylacetamide solution (1.0 mL) was added sequentially to potassium carbonate (33.2 mg) The mixture was stirred at 70 ° C for 2.5 hours. The insoluble material was filtered off, and the filtrate was purified by high performance liquid chromatography (column: YMC CombiPrep Pro C18 RS (20 mm id × 50 mmL), mobile phase: acetonitrile/10% aqueous ammonium formate}. The obtained compound was dissolved in 1,2-dimethoxyethane (0.5 mL), and 0.48 M 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-diox was added. Trifluorobutyl-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl acrylate/DME solution (0.5 mL), 0.96 M aqueous calcium carbonate solution (0.5 mL) and [1,1'-double (two Phenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (10 mg), and the mixture was stirred at 100 ° C for 4 hours under nitrogen. The insoluble material was filtered, and the title compound ( 8.5 mg) was obtained from ethylamine. MS (ESI+): [M+H] ⁺ 318.

Example 43 2-[(4-Hydroxypiperidin-1-yl)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H) - manufacture of ketones

In addition to using 0.57 M piperidin-4-ol/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide solution (0.7 mL) The title compound (12 mg) was obtained. MS (ESI +): [M + H] + 346.MS (ESI +), Found: 346.

Example 44 2-[(3-Hydroxypiperidin-1-yl)methyl]-6-(5-methyl-IH-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4(3H) - manufacture of ketones

In addition to using 0.57 M piperidin-3-ol/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide solution (0.7 mL) The title compound (20.5 mg) was obtained. MS (ESI +): [M + H] + 346.MS (ESI +), Found: 346.

Example 45 Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-(thiomorpholin-4-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one

In addition to using 0.57 M thiomorpholine/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide solution (0.7 mL), The title compound (9.7 mg) was obtained. MS (ESI +): [M + H] + 348.MS (ESI +), Found: 348.

Example 46 2-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2 -d]Production of pyrimidine-4(3H)-one

Instead of using 0.57M (2R)-2-(methoxymethyl)pyrrolidine/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamidine The title compound (17.6 mg) was obtained. MS (ESI+): [M+H] ⁺ 360.

Example 47 2-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2 -d]Production of pyrimidine-4(3H)-one

Instead of using 0.57M (2S)-2-(methoxymethyl)pyrrolidine/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamidine The title compound (17.6 mg) was obtained. MS (ESI+): [M+H] ⁺ 360.

Example 48 2-(1,3-Dihydro-2H-isoindol-2-ylmethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone

Instead of using 0.57M 2,3-dihydro-1H-isoindole/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide solution The title compound (12.5 mg) was obtained. MS (ESI +): [M + H] + 364.MS (ESI +), Found: 364.

Example 49 2-{[Benzylmethyl(methyl)amino]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H) - manufacture of ketones

Instead of using 0.57M N-methyl-1-benzylamine/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide solution (0.7 The title compound (14.1 mg) was obtained in the same manner as in Example 42. MS (ESI +): [M + H] + 366.MS (ESI +), Found: 366.

Example 50 2-(3,4-Dihydroisoquinolin-2(1H)-methyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone

Instead of using 0.57M 1,2,3,4-tetrahydroisoquinoline/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide The title compound (3.6 mg) was obtained. MS (ESI +): [M + H] + 378.MS (ESI +), Found: 378.

Example 51 1-([6-(5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]- Manufacture of ethyl p-piperidine-3-carboxylate

Instead of using 0.57M piperidine-3-carboxylic acid ethyl ester/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide solution (0.7 mL) The title compound (23.8 mg) was obtained. MS (ESI +): [M + H] + 402.MS (ESI +), Found: 402.

Example 52 1-{[6-(5-Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]- Manufacture of keto-4-phenylpiperidine-4-carbonitrile

Instead of using 0.57M 4-phenylpiperidine-4-carbonitrile monohydrochloride/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethyl B The title compound (1.4 mg) was obtained. MS (ESI +): [M + H] + 431.MS (ESI +), Found: 431.

Example 53 2-[(4-Ethyl-4-phenylpiperidin-1-yl)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d Manufacture of pyrimidine-4(3H)-one

Instead of using 0.57M 1-(4-phenylpiperidin-4-yl)ethanone monohydrochloride/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N The title compound (13.1 mg) was obtained from m. MS (ESI +): [M + H] + 448.MS (ESI +), Found: 448.

Example 54 1-{[6-(5-Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]- Manufacture of }--L-proline

In addition to using 0.57 M L-valeric acid benzyl ester monohydrochloride / N, N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine / N, N-dimethylacetamide solution The title compound (20.6 mg) was obtained. MS (ESI+): [M+H] ⁺ 360.

Example 55 2-{[3-(Dimethylamino)pyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one

In addition to using 0.57 MN, N-dimethylpyrrolidine-3-amine/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide solution The title compound (10.3 mg) was obtained. MS (ESI +): [M + H] + 359.MS (ESI +), Found: 359.

Example 56 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(4-(pyrrolidin-1-yl)piperidin-1-yl)methyl]thieno[3,2-d Manufacture of pyrimidine-4(3H)-one

In addition to using 0.57M 4-(pyrrolidin-1-yl)piperidine/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide solution The title compound (22.2 mg) was obtained. MS (ESI+): [M+H] ⁺ 399.

Example 57 2-{[(1-phenylmethylpyrrolidin-3-yl)(methyl)amino]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3, Manufacture of 2-d]pyrimidin-4(3H)-one

Instead of using 0.57M 1-benzyl-N-methylpyrrolidine-3-amine/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethyl The title compound (16.2 mg) was obtained. MS (ESI +): [M + H] + 435.MS (ESI +), Found: 435.

Example 58 2-{[4-(2-fluorophenyl)piperidin Manufacture of -1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one

In addition to using 0.57M 1-(2-fluorophenyl) piperidine The title was obtained in the same manner as in Example 42 except that a solution of /N,N-dimethylacetamide (0.7 mL) was used instead of 0.57 M diethylamine/N,N-dimethylacetamide solution (0.7 mL). Compound (1 mg). MS (ESI +): [M + H] + 425.MS (ESI +), Found: 425.

Example 59 N-{[6-(5-Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]- Manufacture of ethyl}-N-(pyridin-2-ylmethyl)glycine ethyl ester

Instead of using 0.57 MN-(pyridin-2-ylmethyl)glycolic acid/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamidine The title compound (1.1 mg) was obtained. MS (ESI +): [M + H] + 439.MS (ESI +), Found: 439.

Example 60 2-{[bis(pyridin-3-ylmethyl)amino]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 ( 3H)-ketone manufacture

Instead of using 0.57M 1-(pyridin-3-yl)-N-(pyridin-3-ylmethyl)methylamine/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N, The title compound (4.5 mg) was obtained from m. MS (ESI +): [M + H] + 444.MS (ESI +), Found: 444.

Example 61 2-{[4-(diphenylmethyl)perazine Manufacture of -1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one

In addition to using 0.57M 1-(diphenylmethyl)perazine The title was obtained in the same manner as in Example 42 except that a solution of /N,N-dimethylacetamide (0.7 mL) was used instead of 0.57 M diethylamine/N,N-dimethylacetamide solution (0.7 mL). Compound (7.3 mg). MS (ESI +): [M + H] + 497.MS (ESI +), Found: 497.

Example 62 2-{[(3,5-Dimethoxyphenyl)amino]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone

Instead of using 0.57M 3,5-dimethoxyaniline/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide solution (0.7 mL) The title compound (1.4 mg) was obtained. MS (ESI+): [M+H] ⁺ 398.

Example 63 2-{[(2,4-Dimethoxyphenyl)amino]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone

Instead of using 0.57M 2,4-dimethoxyaniline/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide solution (0.7 mL) The title compound (2.1 mg) was obtained. MS (ESI+): [M+H] ⁺ 398.

Example 64 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2-phenylthiomorpholin-4-yl)methyl]thieno[3,2-d]pyrimidine-4 (3H)-ketone manufacture

Instead of using 0.57 M 2-phenylthiomorpholine/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide solution (0.7 mL) The title compound (10.8 mg) was obtained. MS (ESI +): [M + H] + 424.MS (ESI +), Found: 424.

Example 65 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2-phenylpyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidine-4 (3H )--Manufacture of ketone

In addition to using 0.57 M 2-phenylpyrrolidine/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide solution (0.7 mL) The title compound (10.8 mg) was obtained. MS (ESI +): [M + H] + 392.MS (ESI +), Found: 392.

Example 66 2-{[3-(4-methylbenzyl)pyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2- Manufacture of d]pyrimidin-4(3H)-one

In addition to using 0.57M 3-(4-methylbenzyl)pyrrolidine monohydrochloride/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethyl The title compound (3.5 mg) was obtained from m. MS (ESI+): [M+H] ⁺ 420.

Example B7 6-(5-Methyl-1H-pyrazol-4-yl)-2-{[4-(2-oxo-tetrahydropyrimidin-1(2H)-yl)piperidin-1-yl]methyl} Manufacture of thieno[3,2-d]pyrimidin-4(3H)-one

Instead of using 0.57M 1-(piperidin-4-yl)tetrahydropyrimidin-2(1H)-one/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N The title compound (10.6 mg) was obtained from m. MS (ESI +): [M + H] + 428.MS (ESI +), Found: 428.

Example 68 6-(5-Methyl-1H-pyrazol-4-yl)-2-({[(1-(thiophen-2-yl)cyclopropyl)methyl]amino}methyl)thiophene[3 , 2-d] pyrimidine-4(3H)-one A) Manufacture of 1-(thiophen-2-yl)cyclopropylcarbonitrile

A solution of thiophen-2-ylacetonitrile (25 g) in DMSO (20 mL) was added dropwise to a suspension of sodium hydride (19.1 g) in DMSO (200 mL), and the mixture was stirred for 0.5 hr. A solution of 1-bromo-2-chloroethane (25 mL) in DMSO (20 mL) was added dropwise to the obtained mixture, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified with EtOAc EtOAc EtOAc EtOAc ¹ H-NMR (CDCl ₃ ) δ 1.39-1.46 (2H, m), 1.71-1.78 (2H, m), 6.94 (1H, dd, J = 5.1, 3.6 Hz), 7.06 (1H, dd, J = 3.6 , 1.1Hz), 7.19 (1H, dd, J = 5.2, 1.2Hz).

B) 1-[1-(Thien-2-yl)cyclopropyl]methylamine monohydrochloride

Add 1.1 M borane ‧ tetrahydrofuran complex (100 mL) to a solution of 1-(thiophen-2-yl)cyclopropylcarbonitrile (14.9 g) in tetrahydrofuran (100 mL). Stir at °C overnight. A 6 M aqueous hydrochloric acid solution (20 mL) was carefully added to the reaction mixture, and the mixture was stirred at 60 ° C for 0.5 hour. The reaction mixture was allowed to cool to room temperature and then evaporated to dryness. The resulting residue was diluted with water and washed with ethyl acetate. The aqueous layer was basified with aq. EtOAc (EtOAc). The residue was dissolved in ethyl acetate. EtOAc (EtOAc) The obtained solid was recrystallized from ethanol-ethyl acetate toiel ¹ H-NMR (DMSO-d ₆ ) δ 0.92-1.00 (2H, m), 1.11-1.22 (2H, m), 3.08 (2H, s), 6.98 (1H, dd, J = 5.1, 3.4 Hz), 7.08 (1H, dd, J = 3.5, 1.2 Hz), 7.40 (1H, dd, J = 5.1, 1.3 Hz), 8.05 (3H, s).

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[({[1-(thiophen-2-yl)cyclopropyl)methyl}amino)methyl]thiophene Manufacture of [3,2-d]pyrimidin-4(3H)-one

Instead of using 0.57M 1-[1-(thiophen-2-yl)cyclopropyl]methylamine monohydrochloride/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N The title compound (1.9 mg) was obtained from m. MS (ESI +): [M + H] + 397.MS (ESI +), Found: 397.

Example 69 7-Methyl-1'-{[6-(5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidine -2-yl]methyl}tetrahydro-5H-spiro[1,3- Oxazo[3,4-a]pyridyl Manufacture of -1,4'-piperidin-3-one A) 4-methylper pipe Manufacture of 1-carboxylic acid tert-butyl butyl ester

1-methylperidazole A mixture of (15 g), triethylamine (22.7 mL) and tetrahydrofuran (300 mL) was cooled to 0 ° C, and then di-di-butyl-dicarbonate (22 g) was added with stirring. After that, the reaction was stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure. EtOAc (EtOAc) The extract was washed with water (200 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc ¹ H-NMR (CDCl ₃ ) δ 1.40 (9H, s), 2.25 (3H, s), 2.31 (4H, t, J = 4.8 Hz), 3.40 (4H, t, J = 4.8 Hz).

B) 1'-Benzyl-7-methyltetrahydro-5H-spiro[1,3- Oxazo[3,4-a]pyridyl Manufacture of -1,4'-piperidin-3-one

4-methylper pipe a mixture of 1-carboxylic acid tert-butyl ketone (24.2 g), N,N,N',N'-tetramethylethane-1,2-diamine (21 g) and tetrahydrofuran (500 mL) under nitrogen Cool to -78 ° C and add dropwise butyl lithium (184 mL, 1.3 M solution in cyclohexane) dropwise over 1.5 hours with stirring. Further, the mixture was stirred at the same temperature for 2 hours, the reaction system was heated to 30 ° C, and the mixture was stirred for 1.5 hours. Thereafter, the reaction was cooled to -78 ° C, and a solution of 1-phenylmethylpiperidin-4-one (28.3 g) in tetrahydrofuran (50 mL) was added dropwise over 1 hour. The reaction was stirred at room temperature overnight and the mixture was cooled to 0 °C. Saturated aqueous ammonium chloride (100 mL) was added and the mixture was stirred at room temperature for 30 min. The mixture was extracted with ethyl acetate (300 mL). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjd ¹ H-NMR (CDCl ₃ ) δ 1.62-1.89 (6H, m), 2.21 (3H, s), 2.31-2.40 (2H, m), 2.62 (1H, m), 2.96 (1H, m), 3.31 ( 1H, m), 3.42 (2H, m), 3.67 (1H, m), 7.20-7.28 (5H, m).

C) 7-methyltetrahydro-5H-spiro[1,3- Oxazo[3,4-a]pyridyl Manufacture of -1,4'-piperidin-3-one monohydrochloride

1'-Benzyl-7-methyltetrahydro-5H-spiro[1,3- Oxazo[3,4-a]pyridyl A mixture of -1,4'-piperidin-3-one (14.6 g), 10% palladium on carbon (Pd/C) (2 g) and ethanol (100 mL) was stirred at room temperature under a hydrogen atmosphere for 72 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (75 mL) and 4M EtOAc /EtOAc The title compound (10.45 g) was obtained as a white solid. ¹ H-NMR (CD ₃ OD) δ 2.14-2.18 (2H, m), 2.19-2.31 (2H, m), 3.03 (3H, s), 3.19-3.37 (4H, m), 3.48-3.59 (4H, m), 3.75 (1H, m), 4.03-4.13 (2H, m).

D) 7-Methyl-1 '-{[6-(5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d Pyrimidin-2-yl]methyl}tetrahydro-5H-spiro[1,3- Oxazo[3,4-a]pyridyl Manufacture of -1,4'-piperidin-3-one

In addition to using 0.57M 7-methyltetrahydro-5H-spiro[1,3- Oxazo[3,4-a]pyridyl -1,4'-piperidin-3-one monohydrochloride/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide The title compound (4.1 mg) was obtained. MS (ESI +): [M + H] + 470.MS (ESI +), Found: 470.

Example 70 6-(5-Methyl-1H-pyrazol-4-yl)-2-{[3-(phenylsulfonyl)pyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidine -4(3H)-one manufacture

In addition to using 0.57M 3-(phenylsulfonyl)pyrrolidine/N,N-dimethylacetamide solution (0.7 mL) instead of 0.57 M diethylamine/N,N-dimethylacetamide solution (0.7 The title compound (11.8 mg) was obtained in the same manner as in Example 42. MS (ESI+): [M+H] ⁺ 495.

Example 71 6-(5-Methyl-1H-pyrazol-4-yl)-2-(piperidin-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride Manufacturing A) Manufacture of 2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylic acid tert-butyl butyl ester

2-Methyl chlorocarbonate (0.309 mL) was added to (2S)-1-(tertiary butoxycarbonyl)piperidine-2-carboxylic acid (518 mg) and triethylamine (0.392 mL) at 0 °C In a solution of tetrahydrofuran (5 mL), the mixture was stirred at room temperature for 30 min. A solution of the 3-amino-5-bromothiophene-2-carboxamide (250 mg) in Example 1, Step D, in tetrahydrofuran (5 mL) was added to the reaction mixture, and the mixture was stirred at 60 ° C for 15 hours. . Ethyl acetate (20 mL) and aqueous sodium bicarbonate (10 mL) were added toEtOAc. The collected organic layer was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered out, and the filtrate was evaporated to dryness crystals crystalssssssssssssssssssssssss Tributyl carboxylic acid ester. A 2 M aqueous sodium hydroxide solution (1.70 mL) was added to the above-prepared 2-[(5-bromo-2-aminomethylsulfonylthiophen-3-yl)amine-carbamoyl]piperidine-1-carboxylic acid tert-butyl ester. The mixture was stirred at 70 ° C for 4 hours in a solution of ethanol (5 mL). The reaction mixture was neutralized with 6M hydrochloric acid (0.6 mL) under ice-cooling, and water (5mL) was added dropwise at room temperature. The precipitated solid was collected to give the title compound (240 mg). * Optical purity is 2.9% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm id × 250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/2-propanol/diethylamine (700) /300/1), flow rate: 1 mL/min, column temperature: 30 ° C, detection 220 nm). ¹ H-NMR (DMSO-d ₆ ) δ 1.16-1.58 (3H, m), 1.30 (9H, brs), 1.59-1.86 (2H, m), 1.98-2.13 (1H, m), 3.36-3.53 (1H , m), 3.76-3.88 (1H, m), 4.90-5.07 (1H, m), 7.57 (1H, s), 12.64 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(piperidin-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride Salt manufacturing

2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) was prepared from the same manner as in Example 83, Step C below. Piperidine-1-carboxylic acid tert-butyl butyl ester (232 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (345 mg), cesium carbonate (395 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II) - dichloromethane complex (1:1) (91.5 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL), 4M HCl / ethyl acetate (1 mL) and methanol ( The title compound (97.4 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.47-1.94 (5H, m), 2.23 - 2.35 (1H, m), 2.46 (3H, s), 2.96-3.12 (1H, m), 3.28-3.41 (1H , m), 4.16-4.28 (1H, m), 7.34 (1H, s), 8.12 (1H, s), 9.07-9.26 (1H, m), 9.34-9.46 (1H, m), 12.82 (1H, brs ).

Example 72 6-(5-Methyl-1H-pyrazol-4-yl)-2-(morpholin-3-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride Manufacturing A) Manufacture of 3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)morpholine-4-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (250 mg), (3S)-4-(tri-butyl), as in Example 71, in the same manner as in Step A, from Example 1, Step D. Oxycarbonyl)morpholine-3-carboxylic acid (548 mg), 2-methylpropyl chlorocarbonate (0.309 mL), triethylamine (0.392 mL) and tetrahydrofuran (5 mL), 2M aqueous sodium hydroxide (1. Ethyl alcohol (5 mL) gave ¹ H-NMR (DMSO-d ₆ ) δ 1.12-1.55 (9H, m), 3.39-3.52 (1H, m), 3.53-3.95 (3H, m), 3.76 (1H, dd, J = 12.3, 4.2 Hz), 4.09-4.29 (1H, m), 4.72 (1H, brs), 7.58 (1H, s), 12.74 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(morpholin-3-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride Salt manufacturing

3-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) was prepared from the same manner as in Example 83, Step C below. Morpholine-4-carboxylic acid tert-butyl butyl ester (268 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (397 mg), cesium carbonate (420 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II) - dichloromethane complex (1:1) (105 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL), 4M HCl/EtOAc (1 mL) and methanol (3 mL) The title compound (103 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 2.46 (3H, s), 3.17-3.42 (2H, m), 3.68 (1H, dd, J = 12.1, 10.2 Hz), 3.72-3.85 (1H, m) , 3.93-4.04(1H,m), 4.33(1H,dd,J=12.4,3.3Hz),4.44-4.56(1H,m),7.37(1H,s),8.12(1H,s),9.69(1H , brs), 10.00 (1H, brs), 12.92 (1H, brs).

Example 73 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(3-o-oxypyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidine-4 (3H )--Manufacture of ketone

2-1,4-Dioxa-7-azaspiro[4.4]dec-7-ylmethyl)-6-(5-methyl-1H-pyrazole-4), which was produced in Example 39, Step D A mixture of thieno[3,2-d]pyrimidin-4(3H)-one (150 mg), 6M hydrochloric acid (3 mL) and propan-2-ol (3 mL) was stirred at 90 ° C for 5 hours. A saturated aqueous solution of sodium hydrogencarbonate (20 mL) was added to the mixture, and the precipitated solid was collected and washed with ethyl acetate (3mL) and water (3mL). The obtained pale brown solid was crystalljjjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 2.37 (2H, t, J = 6.9 Hz), 2.46 (3H, brs), 3.01 (2H, t, J = 6.9 Hz), 3.08 (2H, s), 3.71 (2H, s), 7.39 (1H, s), 7.89 (0.6H, brs), 8.26 (0.4H, brs), 12.22 (1H, brs), 12.99 (1H, brs).

Example 74 6-(5-Methyl-1H-pyrazol-4-yl)-2-[phenyl(pyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)- Ketone manufacturing A) Manufacture of 5-bromo-3-{[phenyl(pyrrolidin-1-yl)ethenyl]amino}thiophene-2-carboxamide Chloro(phenyl)acetamidine chloride (0.174 mL) was added to 3-amino-5-bromothiophene-2-carboxamide (221 mg), which was produced in Example 1, Step D, at room temperature with stirring. A mixture of ethylamine (0.153 mL) and tetrahydrofuran (5.0 mL). The reaction mixture was stirred for 10 min and pyrrolidine (0.42 mL) was added. The reaction mixture was stirred with heating at 70 ° C for 1 hour, and the reaction was concentrated under reduced pressure. A 2 M aqueous sodium hydroxide solution (1.5 mL) was added to the residue, and the mixture was stirred and stirred at 120 ° C for 2 hr. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic EtOAc (EtOAc/hexane). The obtained yellow solid was washed with EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.67-1.80 (4H, m), 2.32-2.44 (2H, m), 2.44-2.49 (2H, m), 3.96 (1H, s), 7.26-7.45 (5H , m), 7.70 (2H, brs), 7.99 (1H, s), 12.24 (1H, s). B) Manufacture of 6-bromo-2-[phenyl(pyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one

5-Bromo-3-{[phenyl(pyrrolidin-1-yl)ethenyl]amino}thiophene-2-carboxamide (320 mg), 2M aqueous sodium hydroxide (3 mL) and 1,2- A mixture of dimethoxyethane (1 mL) was heated and stirred at 150 ° C for 30 minutes in a microwave reactor. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.65-1.85 (4H, m), 2.34 - 2.47 (4H, m), 4.35 (1H, s), 7.22-7.40 (3H, m), 7.55-7.65 (3H , m), 12.47 (.1H, brs).

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[phenyl(pyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidine-4 (3H )--Manufacture of ketone

In the same manner as in Example 2, Step C, from 6-bromo-2-[phenyl(pyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one ( 320 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid Tertiary butyl ester (758mg), sodium carbonate (197mg), 1,2-dimethoxyethane (4.0mL), water (2.0mL) and [1,1'-bis(diphenylphosphino) ferrocene Iron] palladium(II) chloride-dichloromethane complex (1:1) (67 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.65-1.85 (4H, m), 2.34-2.48 (7H, m), 4.34 (1H, s), 7.20-7.46 (4H, m), 7.62 (2H, d , J = 7.2 Hz), 7.78-8.26 (1H, m), 12.26 (1H, brs), 12.94 (1H, brs).

Example 75 2-(3,6-dihydropyridine-1(2H)-ylmethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 (3H)-ketone manufacture A) Manufacture of 6-bromo-2-(3,6-dihydropyridine-1(2H)-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), 1,2,3,6-tetrahydropyridine (0.18 mL), potassium carbonate (178 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) The title compound (169 mg) was obtained as a yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 2.04-2.16 (2H, m), 2.57-2.65 (2H, m), 2.96-3.04 (2H, m), 3.51 (2H, s), 5.54-5.78 (2H , m), 7.61 (1H, s), 12.36 (1H, brs).

B) 2-(3,6-Dihydropyridine-1(2H)-ylmethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine -4(3H)-one manufacture

In the same manner as in Example 2, Step C, from 6-bromo-2-(3,6-dihydropyridine-1(2H)-ylmethyl)thieno[3,2-d]pyrimidine-4 (3H )-ketone (169 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole- 1-carboxylic acid tertiary butyl ester (479 mg), sodium carbonate (124 mg), 1,2-dimethoxyethane (3.0 mL), water (1.5 mL), and [1,1'-bis(diphenylphosphine) The title compound (81 mg) was obtained as a pale brown solid. ¹ H-NMR (DMSO-d ₆ ) δ 2.03-2.18 (2H, m), 2.45 (3H, brs), 2.63 (2H, t, J = 5.7 Hz), 2.97-3.09 (2H, m), 3.52 (2H, s), 5.47-5.90 (2H, m), 7.38 (1H, s), 8.02 (1H, brs), 12.18 (1H, brs), 12.91 (1H, brs).

Example 76 2-[(2S)-5,5-dimethylpyrrolidin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone A) (5S)-5-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2,2-dimethylpyrrolidine Manufacture of 1-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (250 mg), 1-(tertiary butoxycarbonyl)-, as in Example 71, Step A, from Example 1, Step D. 5,5-Dimethyl-L-proline (577 mg), 2-methylpropyl chlorocarbonate (0.324 mL), triethylamine (0.392 mL), tetrahydrofuran (5 mL), 2M aqueous sodium hydroxide (2.83) The title compound (431 mg) was obtained as a white crystal. ¹ H-NMR (DMSO-d ₆ ) δ 1.11 (9H, s, major), 1.30-1.43 (6H, m), 1.57 (9H, s, minor), 1.66-1.88 (2H, m), 1.90-2.25 (2H,m), 4.67 (1H, dd, J=8.3, 3.6 Hz, major), 4.70-4.77 (1H, m, minor), 7.54 (1H, s, minor), 7.57 (1H, s, major) , 12.68 (1H, brs).* observed as a 7:4 mixture of rotamers. ** Only a single peak was observed under chiral analysis conditions. By high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm id × 250 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/2-propanol/diethylamine (800/200/ 1), flow rate: 1 mL/min, column temperature: 30 ° C, detection of 220 nm).

B) 2-[(2S)-5,5-Dimethylpyrrolidin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one

(5S)-5-(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidine-2, as prepared in the same manner as in Example 83, Step C -yl)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (423 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (610 mg), cesium carbonate (644 mg), [1,1'-bis(diphenylphosphino) ) ferrocene] palladium(II) chloride-dichloromethane complex (1:1) (162 mg), 1,2-dimethoxyethane (5 mL) and water (0.5 mL) were obtained as pale yellow 4-{2-[(2S)-1-(tertiary butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl]-4- oxo-3,4-di as an amorphous solid Hydrogen thieno[3,2-d]pyrimidin-6yl}-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester. 4M HCl/ethyl acetate solution (1 mL) was added to the above-prepared 4-{2-[(2S)-1-(tertiarybutoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl]- 4-tert-oxy-3,4-dihydrothieno[3,2-d]pyrimidin-6yl}-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester in methanol (4 mL) In the solution, the mixture was stirred at 50 ° C for 2 hours. Ethyl acetate (50 mL) and aqueous sodium bicarbonate (10 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL). The collected organic layer was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the residue was evaporated. ¹ H-NMR (DMSO-d ₆ ) δ 1.17 (3H, s), 1.19 (3H, s), 1.60 (2H, t, J = 7.4 Hz), 1.92-2.05 (1H, m), 2.23-2.38 ( 1H, m), 2.45 (3H, s), 4.24 (1H, dd, J = 8.6, 6.3 Hz), 7.37 (1H, s), 8.02 (1H, brs).

Example 77 2-[(2S)-azetidin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H) - manufacture of ketones A) (2S)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-1-carboxylic acid Manufacture of tertiary butyl ester

3-Amino-5-bromothiophene-2-carboxamide (267 mg), (2S)-1-(tri-butyl), as in Example 71, Step A, from Example 1, Step D. Oxycarbonyl)azetidine-2-carboxylic acid (510 mg), 2-methylpropyl chlorocarbonate (0.346 mL), triethylamine (0.419 mL), tetrahydrofuran (5 mL), 2M aqueous sodium hydroxide (2.83) The title compound (335 mg) was obtained as a colourless solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.04-1.51 (9H, m), 2.20-2.35 (1H, m), 2.44-2.57 (1H, m), 3.84 (1H, brs), 3.91-4.02 (1H , m), 5.01 (1H, dd, J = 8.6, 5.6 Hz), 7.64 (1H, s), 12.74 (1H, brs). * Only a single peak was observed under chiral analysis conditions. By high performance liquid chromatography (column: CHIRALPAK AD-3 (4.6 mm id × 250 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol/diethylamine (700/300/1), The analysis was carried out at a flow rate of 1 mL/min, column temperature: 30 ° C, and detection of 220 nm.

B) 2-[(2S)-azetidin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 ( 3H)-ketone manufacture

(2S)-2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2, as prepared in the same manner as in Example 76, Step B -Based azetidine-1-carboxylic acid tert-butyl butyl ester (328 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Boratopentan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (523 mg), cesium carbonate (554 mg), [1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) chloride-dichloromethane complex (1:1) (139 mg), 1,2-dimethoxyethane (10 mL), water (1 mL), 4M HCl/EtOAc (1 mL) The title compound (42.1 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 2.41-2.61 (2H, m), 2.45 (3H, s), 3.30-3.38 (1H, m), 3.61 (1H, q, J = 7.9 Hz), 4.73 ( 1H, t, J = 7.8 Hz), 7.38 (1H, s), 8.03 (1H, brs).

Example 78 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,3aS,7aS)-octahydro-1H-indol-2-yl]thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one A) (2S, 3aS, 7aS)-2-[(5-bromo-2-aminomethylsulfonylthiophen-3-yl)aminecarboxylidene] octahydro-1H-indole-1-carboxylic acid tert-butyl Ester manufacture

Add 2-methylpropyl chlorocarbonate (0.324 mL) to (2S,3aS,7aS)-1-(tertiary butoxycarbonyl) octahydro-1H-indole-2-carboxylic acid (638 mg) at 0 °C. And a solution of triethylamine (0.392 mL) in tetrahydrofuran (5 mL). Then, a solution of 3-amino-5-bromothiophene-2-carboxamide (250 mg) in tetrahydrofuran (5 mL), which was produced in Example 1, step D, was added to the reaction system, and the mixture was stirred at 60 ° C. 26 hours. Ethyl acetate (20 mL) and aqueous sodium bicarbonate (10 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (5mL). The collected organic layer was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc ¹ H-NMR (DMSO-d ₆ ) δ 1.07-1.49 (13H, m), 1.53-1.67 (3H, m), 1.85-2.06 (2H, m), 2.07-2.20 (1H, m), 2.22-2.36 (1H, m), 3.70-3.81 (1H, m), 4.14 (1H, dd, J = 9.7, 7.5 Hz), 7.72 (2H, brs), 8.11 (1H, s), 11.61 (1H, brs).

B) (2S, 3aS, 7aS)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)octahydro-1H-indole Manufacture of 哚-1-carboxylic acid tertiary butyl ester

(2S,3aS,7aS)-2-[(5-bromo-2-aminomethylsulfonylthiophen-3-yl)aminecarbenyl]octahydrogen as described above in the same manner as in Example 40, Step B -1H-indole-1-carboxylic acid tert-butyl butyl ester (340 mg), EtOAc (EtOAc m. ¹ H-NMR (DMSO-d ₆ ) δ 1.06-1.48 (3H, m), 1.09 (9H, s, major), 1.34 (9H, s, minor), 1.53-1.78 (4H, m), 1.92-2.18 (2H, m), 2.29-2.41 (1H, m), 3.40-3.49 (1H, m, major), 3.67-3.79 (1H, m), 4.35 (1H, t, J = 5.0 Hz, minor), 4.50 -4.62 (1H, m), 7.55 (1H, s, minor), 7.60 (1H, s, major), 12.71 (1H, brs).* observed as a 2:1 mixture of rotamers.

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,3aS,7aS)-octahydro-1H-indol-2-yl]thieno[3,2- Manufacture of d]pyrimidin-4(3H)-one

(2S, 3aS, 7aS)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d], as described in Example 76, Step B, Pyrimidin-2-yl) octahydro-1H-indole-1-carboxylic acid tert-butyl butyl ester (263 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (357 mg), cesium carbonate (377 mg), [1,1'-bis(diphenylphosphine) Base ferrocene] palladium(II) chloride-dichloromethane complex (1:1) (94.7 mg), 1,2-dimethoxyethane (10 mL), water (1 mL), 4M HCl / ethyl acetate solution (1 mL) and MeOH (5 mL) ¹ H-NMR (DMSO-d ₆ ) δ 1.10-1.66 (8H, m), 1.76-1.88 (1H, m), 1.95-2.10 (1H, m), 2.25-2.39 (1H, m), 2.45 ( 3H, s), 3.23 (1H, q, J = 5.2 Hz), 4.19 (1H, dd, J = 10.0, 5.5 Hz), 7.38 (1H, s), 7.89-8.29 (1H, m).

Example 79 Manufacture of 2-(azepane-2-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one A) 2-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)azepane-1-carboxylic acid tert-butyl acrylate Manufacturing

3-Amino-5-bromothiophene-2-carboxamide (237 mg), 1-(tertiary butoxycarbonyl) nitrogen, as in Example 71, Step A, from Example 1, Step D. Heterocyclic heptane-2-carboxylic acid (547 mg), 2-methylpropyl chlorocarbonate (0.306 mL), triethylamine (0.371 mL) and tetrahydrofuran (5 mL) afforded 2-[(5- Bromo-2-amine-methylthiophen-3-yl)amine-carbamoyl]azetidin-1-carboxylic acid tert-butyl ester. 2M aqueous sodium hydroxide solution (2.68 mL) was added to the above 2-[(5-bromo-2-aminomethylthiothiophen-3-yl)aminecarboxylidene]azepane-1-carboxylic acid The butyl ester was dissolved in ethanol (5 mL) and the mixture was stirred at 70 ° C for 3 hours. Ethyl acetate (20 mL), 6M hydrochloric acid (1 mL) and water (5 mL) was added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (5mL). The collected organic layer was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc ¹ H-NMR (DMSO-d ₆ ) δ 1.12-1.46 (12H, m), 1.58-1.99 (4H, m), 2.11-2.35 (1H, m), 3.16-3.29 (1H, m), 3.77-3.88 (1H, m, minor), 3.97 (1H, dd, J = 14.8, 5.2 Hz, major), 4.65 (1H, dd, J = 12.0, 4.8 Hz, major), 4.83 (1H, dd, J = 12.1, 5.9 Hz, minor), 7.58 (1H, s, minor), 7.60 (1H, s, major), 12.61 (1H, brs). * Observed as a 5:4 mixture of rotamers.

B) 2-(azepane-2-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacturing

2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)nitrogen produced above, in the same manner as in Example 76, Step B Heterocyclic heptane-1-carboxylic acid tert-butyl butyl ester (150 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-based)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (215 mg), cesium carbonate (228 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II)-dichloromethane complex (1:1) (57.2 mg), 1,2-dimethoxyethane (50 mL), water (0.5 mL), 4M HCl/EtOAc (1 mL) The title compound (21.8 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.41-1.89 (7H, m), 2.07-2.20 (1H, m), 2.45 (3H, s), 2.75-2.97 (2H, m), 3.74-3.87 (1H , m), 7.34 (1H, s), 8.00 (1H, brs).

Example 80 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(3-phenylpyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidine-4 (3H )--Manufacture of ketone A) Manufacture of 6-bromo-2-[(3-phenylpyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), 3-phenylpyrrolidine hydrochloride (355 mg), potassium carbonate (445 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) Compound (182 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.71-1.85 (1H, m), 2.18-2.32 (1H, m), 2.55-2.63 (1H, m), 2.75-2.85 (2H, m), 3.04 (1H) , t, J = 8.4 Hz), 3.26-3.40 (1H, m), 3.65 (2H, s), 7.14 - 7.22 (1H, m), 7.24 - 7.34 (4H, m), 7.61 (1H, s), 12.39 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(3-phenylpyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidine-4 (3H)-ketone manufacture

In the same manner as in Example 2, Step C, from 6-bromo-2-[(3-phenylpyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)- Ketone (182 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1- Tributyl carboxylic acid ester (431 mg), sodium carbonate (112 mg), 1,2-dimethoxyethane (4.0 mL), water (2.0 mL), and [1,1'-bis(diphenylphosphino) The ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (38 mg) gave the title compound (m. ¹ H-NMR (DMSO-d ₆ ) δ 1.72-1.87 (1H, m), 2.19-2.33 (1H, m), 2.45 (3H, brs), 2.55-2.64 (1H, m), 2.76-2.87 (2H , m), 3.02-3.11 (1H, m), 3.27-3.41 (1H, m), 3.65 (2H, s), 7.13-7.22 (1H, m), 7.25-7.34 (4H, m), 7.38 (1H , s), 8.03 (1H, brs), 11.92-13.34 (2H, m).

Example 81 2-{[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2 -d]Production of pyrimidine-4(3H)-one A) Manufacture of 3-(trifluoromethyl)pyrrolidin-3-ol

3-tert-butylpyrrolidine-1-carboxylic acid tert-butyl ester (600 mg), trimethyl(trifluoromethyl)decane (0.57 mL), 1 M N,N,N-tributylbutane-1- A mixture of the ammonium fluoride/tetrahydrofuran solution (0.50 mL) and tetrahydrofuran (6 mL) was stirred at room temperature for 30 min. A saturated aqueous solution of ammonium chloride (2 mL) and 1M EtOAc, EtOAc (EtOAc) The mixture was extracted with ethyl acetate, washed sequentially with water and brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAcEtOAc The resulting solid was dissolved in MeOH (1 mL) and EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 4 hr. EtOAc EtOAc m. The title compound (260 mg) was obtained eluted elute ¹ H-NMR (CDCl ₃ ) δ 1.80-1.91 (1H, m), 2.14 - 2.25 (1H, m), 2.93-3.10 (2H, m), 3.12-3.29 (2H, m).

B) 6-Bromo-2-{[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d]pyrimidin-4(3H)-one Manufacturing

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), 3-(trifluoromethyl)pyrrolidin-3-ol (260 mg), potassium carbonate (356 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL). The title compound (163 mg) was obtained as a brown solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.77-1.93 (1H, m), 2.04-2.17 (1H, m), 2.59-2.69 (1H, m), 2.71-2.80 (1H, m), 2.81-2.99 (2H,m), 3.62 (2H, s), 6.28 (1H, brs), 7.61 (1H, s), 12.35 (1H, brs).

C) 2-{[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3 , 2-d] pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-{[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]methyl}thieno[3,2-d Pyrimidine-4(3H)-one (160 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (371 mg), sodium carbonate (96 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) and [1,1'- Bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (33 mg) gave the title compound (m. ¹ H-NMR (DMSO-d ₆ ) δ 1.79-1.93 (1H, m), 2.05-2.20 (1H, m), 2.46 (3H, brs), 2.60-2.71 (1H, m), 2.72-2.83 ( 1H, m), 2.83-3.00 (2H, m), 3.63 (2H, s), 6.28 (1H, brs), 7.38 (1H, s), 7.90 (0.6H, brs), 8.26 (0.4H, brs) , 12.16 (1H, brs), 12.99 (1H, brs).

Example 82 6-(5-Methyl-1H-pyrazol-4-yl)-2-(2-methylpyrrolidin-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacture of hydrochloride A) 2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidin-1-carboxylic acid Manufacture of butyl ester

2-methylpropyl chlorocarbonate (0.2 mL) was added to 1-(tertiary butoxycarbonyl)-2-methylproline (425 mg) and triethylamine (0.425 mL) at room temperature with stirring. In a mixture of tetrahydrofuran (10 mL). After 1 hour, 3-amino-5-bromothiophene-2-carboxamide (337 mg), which was obtained in Example 1, Step D, was added and the mixture was stirred at 60 ° C overnight. Thereafter, the mixture was stirred in a microwave reactor at 120 ° C for 4 hours. The reaction mixture was allowed to cool to room temperature and poured into saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the extract was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (5 mL), and then 2M aqueous sodium hydroxide (2.04mL) was added, and the mixture was stirred at 60 ° C for 1 hour and at 80 ° C for 1 hour. Ethanol (4 mL) was added to the reaction mixture, and the mixture was stirred at 100 ° C for 4 hr. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of sodium hydrogen sulfate. The extract was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjj MS (ESI +): [M + H] + 414.MS (ESI +), Found: 414.

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(2-methylpyrrolidin-2-yl)thieno[3,2-d]pyrimidin-4(3H)- Manufacture of ketone dihydrochloride

In the same manner as in Example 11, Step B, from 2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-yl Pyryryryl-1-tertiary butyl ester (109 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (162 mg), cesium carbonate (400 mg), 1,2-dimethoxyethane (4 mL), water (0.5 mL), and [1,1'- Bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (21 mg) ¹ H-NMR (DMSO-d ₆ ) δ 1.75 (3H, s), 1.84-2.40 (4H, m), 2.46 (3H, s), 3.30-3.42 (2H, m), 7.37 (1H, s) , 8.10 (1H, brs), 9.21 (1H, brs), 9.75 (1H, brs), 12.82 (1H, brs).

Example 83 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one Manufacture of hydrochloride A) (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylic acid tert-butyl Ester manufacture

2-Methyl chlorocarbonate (2.84 mL) was added to (2S)-1-(tertiary butoxycarbonyl)piperidine-2-carboxylic acid (5.00 g) and triethylamine (3.16 mL) at 10 °C. The mixture was stirred at room temperature for 1 hour in tetrahydrofuran (45 mL). Thereafter, a solution of 3-amino-5-bromothiophene-2-carboxamide (2.19 g) manufactured in Example 1, Step D, in tetrahydrofuran (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature. 7 days. Ethyl acetate (50 mL) and aqueous sodium bicarbonate (50 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (20mL). The collected organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered out, and the filtrate was evaporated to dryness crystals crystals crystals crystalssssssssssssssssssssss Butyl-1-carboxylic acid tertiary butyl ester. 2M aqueous sodium hydroxide solution (24.8 mL) was added to the above-produced (2S)-2-[(5-bromo-2-aminomethylsulfonylthiophen-3-yl)aminecarbenyl]piperidine-1-carboxylic acid The mixture of the tertiary butyl ester in ethanol (50 mL) was stirred at 70 ° C for 3 hours. The reaction mixture was neutralized with 6M hydrochloric acid (EtOAc) (EtOAc). The precipitated solid was collectedjjjjjjjjjjjjj The optical purity was 73.8% ee. By high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm id × 250 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/2-propanol/diethylamine (700/300/ 1), flow rate: 1 mL/min, column temperature: 30 ° C, detection 220 nm). ¹ H-NMR (DMSO-d ₆ ) δ 1.09-1.45 (11H, m), 1.46-1.58 (1H, m), 1.60-1.86 (2H, m), 1.98-2.14 (1H, m), 3.38-3.53 (1H, m), 3.75-3.89 (1H, m), 4.89-5.10 (1H, m), 7.58 (1H, s), 12.64 (1H, brs).

B) (2S)-2-(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylic acid tert-butyl Optical separation of ester

By high performance liquid chromatography (column: CHIRALPAK AD (50 mm id × 500 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/2-propanol/diethylamine (700/300/1), flow rate :80 mL/min, column temperature: 30 ° C) separation of (2S)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl Piperidine-1-carboxylic acid tert-butyl butyl ester (3.03 g, 75.5% ee). (2S)-2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine was obtained under the above high performance liquid chromatography conditions. 3-carboxylic acid tert-butyl ester (2.55 g, >99.9% ee, retention time 6.1 minutes) and (2R)-2-(6-bromo-4-oxo-3,4-dihydrothieno[ 3,2-d]pyrimidin-2-yl)piperidine-1-carboxylic acid tert-butyl butyl ester (330 mg, 99.2% ee, retention time 8.1 min). By high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm id × 250 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/2-propanol/diethylamine (700/300/ 1), flow rate: 1 mL/min, column temperature: 30 ° C, detection 220 nm).

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)- Manufacture of ketone dihydrochloride

(2S)-2-(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylic acid III Butyl ester (2.55g), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1-carboxylic acid tert-butyl butyl ester (3.79 g), sodium carbonate (4.01 g), 1,2-dimethoxyethane (50 mL) and water (5 mL) were placed in a flask, and the air in the flask was purged with argon. . [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride complex (1:1) (502 mg) was added, and the air in the flask was again purged with argon. The mixture was stirred at 80 ° C for 1.5 hours. Ethyl acetate (75 mL) and water (50 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (20mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the title compound was concentrated under reduced pressure to give (2S)-2-{6-[1-( Oxycarbonyl)-3-methyl-1H-pyrazol-4-yl]-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine-1 - Tributyl carboxylic acid ester. 4M HCl/ethyl acetate solution (10 mL) was added to (2S)-2-{6-[1-(tertiary butoxycarbonyl)-3-methyl-1H-pyrazol-4-yl]- 4-tert-oxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine-1-carboxylic acid tert-butyl butyl ester in methanol (50 mL), the mixture Stir at 50 ° C for 4 hours and at room temperature for 1 hour. The precipitated solid was collected to give the title compound (l. ¹ H-NMR (DMSO-d ₆ ) δ 1.48-1.92 (5H, m), 2.23-2.35 (1H, m), 2.46 (3H, s), 2.94-3.12 (1H, m), 3.29-3.41 (1H , m), 4.16-4.29 (1H, m), 7.34 (1H, s), 8.12 (1H, s), 9.07-9.25 (1H, m), 9.46-9.60 (1H, m), 12.84 (1H, brs MS (ESI+): [M+H] ⁺ 316. MS (ESI+), found: 316.

D) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)- Manufacture of ketone dihydrochloride

(2S)-2-(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) was prepared from the following Example 172, Step B. Piperidine-1-carboxylic acid tert-butyl butyl ester (3.25 g), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Based -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (4.83 g), cesium carbonate (5.11 g), 1,2-dimethoxyethane (88 mL) and water (8.8 mL) were placed in a flask The air in the flask was purged with argon. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride complex (1:1) (574 mg) was added, and the air in the flask was again purged with argon. The mixture was stirred at 80 ° C for 1 hour. Ethyl acetate (100 mL) and water (100 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (20mL×2). The collected organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the title compound was concentrated under reduced pressure to afford (2S)-2-{6-[ Carbonyl)-3-methyl-1H-pyrazol-4-yl]-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidin-1- Tributyl carboxylic acid ester. Methanol (50 mL) and 4M HCl/ethyl acetate solution (17 mL) were added to (2S)-2-{6-[1-(tris-butoxycarbonyl)-3-methyl-1H-pyrazole as above. 3-yl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine-1-carboxylic acid tert-butyl ester, the mixture was at 50 ° C Stir for 1 hour. Methanol (17 mL) and ethyl acetate (85 mL) were added, and the mixture was stirred at 50 ° C for 1 hour and then at room temperature for 2 hours. The mixture was concentrated under reduced pressure. Methanol (50 mL) was added to the residue, and the mixture was stirred at 50 ° C for 1 hour and then at room temperature for 1 hour. The precipitated solid was collected to give the title compound (l. ¹ H-NMR (DMSO-d ₆ ) δ 1.48-1.91 (5H, m), 2.24-2.32 (1H, m), 2.46 (3H, s), 2.97-3.12 (1H, m), 3.29-3.41 (1H , m), 4.14-4, 29 (1H, m), 7.34 (1H, s), 8.11 (1H, s), 9.07-9.23 (1H, m), 9, 36-9.48 (1H, m), 12.81 (1H, brs).

The mother liquid was concentrated under reduced pressure, and methanol (20 mL) was added to the residue, and the mixture was stirred at 50 ° C for 1 hour and then at room temperature for 1 hour. Ethyl acetate (20 mL) was evaporated. ¹ H-NMR (DMSO-d ₆ ) δ 1.51-1.91 (5H, m), 2.25-2.33 (1H, m), 2.46 (3H, s), 2.97-3.10 (1H, m), 3.29-3.40 (1H , m), 4.16-4.28 (1H, m), 7.34 (1H, s), 8.11 (1H, s), 9, 07-9.22 (1H, m), 9.45-9.56 (1H, m), 12.83 (1H , brs).

Example 84 6-(5-Methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-3-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride Manufacturing A) Manufacture of 3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)pyrrolidine-1-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (250 mg), 1-(tertiary butoxycarbonyl)pyrrole, as in Example 71, Step A, from Example 1, Step D. Pyridine-3-carboxylic acid (511 mg), 2-methylpropyl chlorocarbonate (0.323 mL), triethylamine (0.392 mL), tetrahydrofuran (5 mL), 2M aqueous sodium hydroxide (2.83 mL) and ethanol (5 mL) The title compound (396 mg) was obtained as crystals. ¹ H-NMR (DMSO-d ₆ ) δ 1.40 (9H, s), 2.12-2.30 (2H, m), 3.39-3.56 (4H, m), 3.59-3.69 (1H, m), 7.60 (1H, s ).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-3-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride Salt manufacturing

3-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)pyrrole produced as above, in the same manner as in Example 83, Step C Acridine-1-carboxylic acid tert-butyl butyl ester (390 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (601 mg), cesium carbonate (635 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II) - dichloromethane complex (1:1) (159 mg), 1,2-dimethoxyethane (10 mL), water (1 mL), 4M HCl/EtOAc (1 mL) and methanol (5 mL) The title compound (228 mg) was obtained as a pale yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 2.09-2.24 (1H, m), 2.29-2.43 (1H, m), 2.45 (3H, s), 3.20-3.40 (2H, m), 3.47-3.66 (3H , m), 7.36 (1H, s), 8.05 (1H, s), 9.18 (1H, brs), 9.30 (1H, brs), 12.54 (1H, brs).

Example 85 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2R)-piperidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one Manufacture of hydrochloride

(2R)-2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2], as in Example 81, Step C, from Example 81, Step B. -d]pyrimidin-2-yl)piperidine-1-carboxylic acid tert-butyl butyl ester (120 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (179 mg), cesium carbonate (189 mg), [1,1'-bis(diphenylphosphino)di Ferrocene] palladium(II) chloride-dichloromethane complex (1:1) (47.3 mg), 1,2-dimethoxyethane (50 mL), water (0.5 mL), 4M HCl/acetic acid Ethyl ester solution (1 mL) and MeOH (3 mL) ¹ H-NMR (DMSO-d ₆ ) δ 1.48-1.94 (5H, m), 2.24-2.35 (1H, m), 2.46 (3H, s), 2.96-3.13 (1H, m), 3.29-3.41 (1H , m), 4.16-4.27 (1H, m), 7.34 (1H, s), 8.12 (1H, s), 9.07-9.25 (1H, m), 9.35-9.50 (1H, m), 12.82 (1H, brs ).

Example 86 6-(5-Methyl-1H-pyrazol-4-yl)-2-{1-[4-(methylsulfonyl)phenyl]pyrrolidin-2-yl}thieno[3,2- Manufacture of d]pyrimidin-4(3H)-one A) Manufacture of 6-bromo-2-{1-[4-(methylsulfonyl)phenyl]pyrrolidin-2-yl}thieno[3,2-d]pyrimidin-4(3H)-one

2-Methyl chlorocarbonate (0.259 mL) was added to 1-[4-(methylsulfonyl)phenyl]proline (512 mg) and triethylamine (0.314 mL) in tetrahydrofuran at 0 °C. In a solution of 10 mL), the mixture was stirred at room temperature for 30 minutes. Thereafter, 3-amino-5-bromothiophene-2-carboxamide (200 mg) manufactured in Example 1, Step D was added to the reaction system, and the mixture was stirred at 60 ° C for 19 hours. Ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) was added to the mixture, and the separated organic layer was washed with brine (5mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). 3-yl)-1-[4-(methylsulfonyl)phenyl]decylamine. 2M sodium hydroxide aqueous solution (2.83 mL) was added to the above-produced N-(5-bromo-2-aminomethylthiophenyl-3-yl)-1-[4-(methylsulfonyl)phenyl]anthracene The solution of the amine amide in ethanol (5 mL) was stirred at 70 ° C for 10 hours. The reaction mixture was neutralized with 6M hydrochloric acid (0.6 mL), and evaporated. The precipitated solid was collectedjjjjjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.96-2.19 (3H, m), 2.35-2.48 (1H, m), 3.03 (3H, s), 3.36-3.47 (1H, m), 3.73-3.83 ( 1H, m), 4.76 (1H, dd, J = 8.4, 2.0 Hz), 6.60 (2H, d, J = 8.9 Hz), 7.59 (1H, s), 7.62 (2H, d, J = 8.9 Hz), 12.69 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-{1-[4-(methylsulfonyl)phenyl]pyrrolidin-2-yl}thieno[3, Manufacture of 2-d]pyrimidin-4(3H)-one

6-Bromo-2-{1-[4-(methylsulfonyl)phenyl]pyrrolidin-2-yl}thieno[3,2-d]pyrimidin-4(3H)-one prepared above (203 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate Tributyl citrate (275 mg), cesium carbonate (291 mg), 1,2-dimethoxyethane (5 mL) and water (0.5 mL) were placed in a flask, and the air in the flask was purged with argon. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethanechloride complex (1:1) (73.0 mg) was added, and the flask was again purged with argon. The mixture was stirred at 80 ° C for 1.5 hours. A 2 M aqueous sodium hydroxide solution (1 mL) was added to the reaction mixture, and the mixture was further stirred at 80 ° C for 2 hr. Ethyl acetate (20 mL) and 1M hydrochloric acid (3 mL) were added toEtOAc. The collected organic layer was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (methanol / ethyl acetate). The residue was purified with EtOAcqqqqqqqq ¹ H-NMR (DMSO-d ₆ ) δ 1.96-2.22 (3H, m), 2.33-2.47 (4H, m), 3.03 (3H, s), 3.37-3.48 (1H, m), 3.73-3.85 (1H , m), 4.77 (1H, dd, J = 8.4, 1.6 Hz), 6.61 (2H, d, J = 8.9 Hz), 7.34 (1H, s), 7.63 (2H, d, J = 8.9 Hz), 7.80 -8.34(1H,m),12.47(1H,brs),12.83-13.09(1H,m).

Example 87 2-[(1R ^* ,2S ^* ,5S ^* )-3-indolyl[3.1.0]hex-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[ Manufacture of 3,2-d]pyrimidin-4(3H)-one dihydrochloride A) (1R ^* , 2S ^* , 5S ^* )-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3- Manufacture of bisbicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (450 mg), (1R ^* , 2S ^* , 5S ^* ), manufactured in Example 1, Step D, in the same manner as in Example 86, Step A. -3-(tertiary butoxycarbonyl)-3-indole bicyclo[3.1.0]hexane-2-carboxylic acid (974 mg), 2-methylpropyl chlorocarbonate (0.584 mL), triethylamine (0.707 mL) The title compound (354 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 0.47-0.62 (1H, m), 0.76-0.92 (1H, m), 1.07 (9H, s, major), 1.35 (9H, s, minor), 1.62-1.76 (1H,m),1.86-1.99(1H,m), 3.47-3.59(2H,m), 4.27(1H,d,J=5.1Hz,minor),4.77(1H,d,J=5.1Hz,major ), 7.61 (1H, s, minor), 7.65 (1H, s, major), 12.44-12.80 (1H, m).* observed as a 3:2 mixture of rotamers.

B) 2-[(1R*,2S*,5S*)-3-indenylbicyclo[3.1.0]hex-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thiophene And [3,2-d]pyrimidine-4(3H)-one dihydrochloride

(1R*, 2S*, 5S*)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3, as described above, in the same manner as in Example 83, Step C. 2-d]pyrimidin-2-yl)-3-indole bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl butyl ester (200 mg), 3-methyl-4-(4,4,5,5 - tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (299 mg), cesium carbonate (316 mg), [1,1 '-Bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane complex (1:1) (79.2 mg), 1,2-dimethoxyethane (8 mL) The title compound (36.5 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 0.57-0.73 (2H, m), 1.83-1.93 (1H, m), 2.25-2.36 (1H, m), 2.46 (3H, s), 3.38-3.47 (2H , m), 4.92 (1H, brs), 7.32 (1H, s), 8.10 (1H, s), 8.74 (1H, brs), 10.25 (1H, brs), 13.03 (1H, brs).

Example 88 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-1-methylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine-4 (3H )-Manufacture of ketone dihydrochloride A) Preparation of (2S)-2-[(5-bromo-2-aminomethylsulfonylthiophen-3-yl)amine-carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (1.00 g), 1-(tertiary butoxycarbonyl), as in Example 78, Step A, from Example 1, Step D. -L-Proline (2.04 g), 2-methylpropyl chloroformate (1.29 mL), triethylamine (1. ¹ H-NMR (DMSO-d ₆ ) δ 1.25 (9H, s, major), 1.40 (9H, s, minor), 1.79-1.97 (3H, m), 2.12-2.30 (1H, m), 3.35-3.55 (2H, m), 4.09-4.21 (1H, m), 7.72 (2H, brs), 8.05 (1H, s), 11.66 (1H, s, major), 11.68 (1H, s, minor). * Observed as A 8:7 mixture of rotamers.

B) Manufacture of N-(5-bromo-2-amine-mercaptothiophen-3-yl)-L-nonylamine decylamine hydrochloride

4M HCl/ethyl acetate (10 mL) was added to the above-produced (2S)-2-[(5-bromo-2-amine-mercaptothiophen-3-yl)aminecarboxylidene]pyrrolidine-1-carboxylic acid A solution of tributyl butyl ester (1.66 g) in methanol / tetrahydrofuran (20 mL / 10 mL) was stirred at 50 ° C for one hour. Ethyl acetate (10 mL) was added toEtOAc. ¹ H-NMR (DMSO-d ₆ ) δ 1.86-2.07 (3H, m), 2.28-2.41 (1H, m), 3.17-3.29 (2H, m), 4.52 (1H, t, J = 7.5 Hz) , 7.84 (2H, brs), 7.88 (1H, s), 9.15 (2H, brs), 11.46 (1H, brs).

C) Manufacture of 6-bromo-2-[(2S)-1-methylpyrrolidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one

Fumarline (1.10 mL) and sodium cyanoborohydride (558 mg) were added to the above-produced N-(5-bromo-2-aminomethylthiophenyl-3-yl)-L-indoleamine hydrochloride (1.05). g) The mixture was stirred at room temperature for 1 hour in methanol (25 mL). A 2 M aqueous sodium hydroxide solution (7.40 mL) was added to the reaction mixture, and the mixture was stirred at 50 ° C for further 5 hours. The reaction mixture was neutralized with 6M hydrochloric acid (2.5 mL) under ice cooling and concentrated to a half volume under reduced pressure. Ethyl acetate (50 mL) and brine (10 mL) were evaporated. The collected organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc / EtOAc) elute The obtained residue was purified tojjjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.68-1.99 (3H, m), 2.10-2.39 (2H, m), 2.24 (3H, s), 3.08-3.18 (1H, m), 3.25-3.32 ( 1H, m), 7.57 (1H, s), 11.90 (1H, brs).

D) 6-Bromo-2-[(2S)-1-methylpyrrolidin-2-yl]-3-{[2-(trimethyldecyl)ethoxy]methyl}thiophene [3, Manufacture of 2-d]pyrimidin-4(3H)-one

Sodium hydride (60% in oil, 38.2 mg) was added to the above-produced 6-bromo-2-[(2S)-1-methylpyrrolidin-2-yl]thiophene [3,2- under ice cooling. d] Pyrimidine-4(3H)-one (250 mg) in tetrahydrofuran (5 mL). [2-(Chloromethoxy)ethyl](trimethyl)decane (0.169 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (15 mL) and aqueous ammonium chloride (5 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (5mL). The collected organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAcjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ -0.03 (9H, s), 0.82-0.91 (2H, m), 1.73-2.06 (3H, m), 2.17-2.29 (1H, m), 2.21. s), 2.35 (1H, q, J = 8.4 Hz), 3.05-3.15 (1H, m), 3.64 (2H, t, J = 8.1 Hz), 3.72 (1H, dd, J = 8.4, 7.1 Hz), 5.62 (1H, d, J = 10.5 Hz), 5.72 (1H, d, J = 10.5 Hz), 7.65 (1H, s).

E) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-1-methylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone dihydrochloride

6-Bromo-2-[(2S)-1-methylpyrrolidin-2-yl]-3-{[2-(trimethyldecyl) was prepared from the same manner as in Example 83, Step C. Ethoxy]methyl}thieno[3,2-d]pyrimidin-4(3H)-one (160 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (222 mg), cesium carbonate (234 mg), [1,1'-bis(diphenyl) Phenylphosphino)ferrocene]palladium(II)-dichloromethane complex (1:1) (58.8 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL) 3-methyl-4-(2-[(2S)-1-methylpyrrolidin-2-yl]-4- oxo-3-{[2-(trimethyl) as a pale yellow oil Mercapto)Ethoxy]methyl}-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester. 1 M tetrabutylammonium fluoride/tetrahydrofuran solution (1.44 mL) was added to the above-prepared 3-methyl-4-(2-[(2S)-1-methylpyrrolidin-2-yl]-4-side oxygen 3-{[2-(trimethylindolyl)ethoxy]methyl}-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl)-1H-pyrazole- A solution of 1-carboxylic acid tert-butyl ester in N,N-dimethylformamide (2 mL) was stirred at 90 ° C for 4 hours. Ethyl acetate (20 mL) and brine (10 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (2×10 mL). The collected organic layer was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic EtOAc EtOAc (EtOAc/EtOAc). A solution of the title compound (15.6 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.92-2.21 (3H, m), 2.46 (3H, s), 2.60-2.71 (1H, m), 2.96 (3H, s), 3.24-3.38 (1H, m ), 3.67-3.75 (1H, m), 4.45-4.57 (1H, m), 7.37 (1H, s), 8.10 (1H, brs), 10.08 (1H, brs), 12.92 (1H, brs).

Example 89 2-[2-(4-Fluorobenzyl)pyrrolidin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone dihydrochloride A) 2-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-(4-fluorobenzyl)pyrrolidine- Manufacture of 1-carboxylic acid tert-butyl butyl ester

In the same manner as in Example 82, Step A, from 1-(tris-butoxycarbonyl)-2-(4-fluorobenzyl)proline (466 mg), triethylamine (0.335 mL), THF (10 mL) 2-methylpropyl chlorocarbonate (0.158 mL), 3-amino-5-bromothiophene-2-carboxamide (265 mg) manufactured in Example 1, Step D, 2M aqueous sodium hydroxide solution (3 mL) The title compound (53 mg) was obtained as a pale yellow solid. MS (ESI +): [M + H] + 508.MS (ESI +), Found: 508.

B) 2-[2-(4-Fluorobenzyl)pyrrolidin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketone dihydrochloride

In the same manner as in Example 11, Step B, from 2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-( 4-fluorobenzyl)pyrrolidine-1-carboxylic acid tert-butyl butyl ester (53 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Tertiary borolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (64 mg), cesium carbonate (200 mg), 1,2-dimethoxyethane (3 mL), water (0.25 mL) And [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (8 mg) afforded the title compound 13mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.75-2.73 (7H, m), 3.36-3.79 (4H, m), 7.09-7.12 (4H, m), 7.19 (1H, s), 8.07 (1H, brs ), 9.26 (1H, brs), 9.70 (1H, brs), 13.05 (1H, brs).

Example 90 2-[(Benzylamino)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one mono-three Manufacture of fluoroacetate A) Manufacture of 2-[(benzylamino)methyl]-6-bromothieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 500 mg), 1-phenylmethylamine (0.58 mL), potassium carbonate (495 mg), sodium iodide (27 mg) and N,N-dimethylformamide (5.0 mL) Product (234 mg).

B) Manufacture of 6-benzyl-2-bromo-6,7-dihydroimidazo[1,5-a]thieno[3,2-d]pyrimidin-9(5H)-one

a crude product of 2-[(benzylamino)methyl]-6-bromothieno[3,2-d]pyrimidin-4(3H)-one (185 mg), 37% aqueous formaldehyde (1 mL) A mixture of tetrahydrofuran (2 mL) was stirred at room temperature for 1 hour. The precipitate was collected by EtOAc (EtOAc m.

C) 6-Benzyl-2-(5-methyl-1H-pyrazol-4-yl)-6,7-dihydroimidazo[1,5-a]thieno[3,2-d] Manufacture of pyrimidine-9(5H)-one

In the same manner as in Example 2, Step C, from 6-benzyl-2-bromo-6,7-dihydroimidazo[1,5-a]thieno[3,2-d]pyrimidine-9 ( 5H)-ketone crude product (100 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H Pyrazole-1-carboxylic acid tert-butyl butyl ester (255 mg), sodium carbonate (66 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and [1,1'-bis ( Diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (23 mg) gave the title compound (m.

D) 2-[(Benzylamino)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacture of monotrifluoroacetate

6-Benzyl-2-(5-methyl-1H-pyrazol-4-yl)-6,7-dihydroimidazo[1,5-a]thieno[3,2-d]pyrimidine A mixture of the crude product of -9(5H)-one (80 mg), methanol (2mL) and trifluoroacetic acid (2mL) was stirred and stirred at 70 ° C for 5 hours. The reaction was concentrated under reduced pressure. ¹ H-NMR (DMSO-d ₆ ) δ 2.46 (3H, brs), 4.20 (2H, s), 4.31 (2H, s), 7.40 (1H, s), 7.42-7.58 (5H, m), 8.05 ( 1H, brs), 9.15- 1.12 (2H, m), 13.04 (1H, brs).

Example 91 2-[(1R,3S,4S)-2-indolyl[2.2.1]heptan-3-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2 -d]Production of pyrimidine-4(3H)-one A) (1R, 3S, 4S)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-indole bicyclo[ 2.2.1] Manufacture of heptane-2-carboxylic acid tert-butyl butyl ester

Isobutyl chloroformate (0.487 mL) was added to (1R,3S,4S)-2-(tertiary butoxycarbonyl)-2-indolebicyclo[2.2.1]heptane-3-carboxyl under ice-cooling stirring. A solution of acid (0.894 g) and triethylamine (0.541 mL) in tetrahydrofurane (15 mL). After stirring at room temperature for 30 minutes, a solution of 3-amino-5-bromothiophene-2-carboxamide (0.78 g) in tetrahydrofuran (3 mL). The reaction was heated and stirred at 60 ° C for 40 hours. Water was poured into the reaction system, the mixture was extracted with ethyl acetate, brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. 2M aqueous sodium hydroxide solution (7.06 mL) and ethanol (14 mL) were added to the residue, and the mixture was stirred and stirred at 70 ° C for 5 hours. The reaction was neutralized with 1 M hydrochloric acid (4 mL) with stirring with ice. Insoluble matter was filtered off. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.07-1.83 (14H, m), 2.00-2.12 (1H, m), 2.58-2.67 (1H, m), 4.14 (1H, brs), 4.17-4.25 (1H , m), 7.56-7.81 (1H, m), 12.45-12.79 (1H, m).

B) (1R, 3S, 4S)-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2- Manufacture of d]pyrimidin-2-yl]-2-indole bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester

(1R,3S,4S)-3-(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-indole bicyclo[2.2 .1] heptane-2-carboxylic acid tertiary butyl ester (1.03g) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborate Cyclo-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (1.49 g), sodium carbonate (768 mg), 1,2-dimethoxyethane (8.0 mL), and water (4.0 mL) Place in the flask and purge the air in the flask with argon. Add [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (197 mg), and again purge the air in the flask with argon. . The reaction was stirred at 100 ° C for 3 hr. The insoluble material was filtered off, and the extract was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.04-1.86 (14H, m), 2.04-2.20 (1H, m), 2.33-2.48 (3H, m), 2.60-2.67 (1H, m), 4.11-4.17 (1H,m), 4.18-4.26(1H,m),7.34-7.54(1H,m),7.88(0.6H,brs),8.23(0.4H,brs),12.23-12.48(1H,m),12.82 -13.09(1H,m).

C) 2-[(1R,3S,4S)-2-indolyl[2.2.1]heptan-3-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3 , 2-d] pyrimidine-4(3H)-one

4M HCl/ethyl acetate solution (2.0 mL) was added to (1R,3S,4S)-3-[6-(5-methyl-1H-pyrazol-4-yl)-4- 3-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-indolebicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (690 mg) In a solution of methanol (10 mL). The reaction was stirred with heating at 50 ° C for 30 minutes, and the mixture was concentrated under reduced pressure. The residue was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. Insoluble matter was filtered off. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjjj The optical purity is 86% ee. The system was subjected to high performance liquid chromatography (column: CHIRALPAK OD-H (4.6 mm id × 250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: methanol, flow rate: 0.5 mL/min, column temperature: 30 °C, detection 254 nm) was performed for this analysis. ¹ H-NMR (DMSO-d ₆ ) δ 1.17 (1H, s), 1.27-1.38 (1H, m), 1.45-1.73 (4H, m), 2.45 (3H, s), 2.66-2.72 (1H, m), 3.57 (1H, s), 3.73 (1H, s), 7.35 (1H, s), 8.01 (1H, brs). MS (ESI+): [M+H] ⁺ 328.MS (ESI+), measured Value: 328.

Example 92 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,4S)-4-methylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone dihydrochloride A) (2S,4S)-2-[(5-bromo-2-aminomethylsulfonylthiophen-3-yl)amine-carbamoyl]-4-methylpyrrolidine-1-carboxylic acid tert-butyl acrylate Manufacturing

2-Methyl chlorocarbonate (0.292 mL) was added to (4S)-1-(tertiary butoxycarbonyl)-4-methyl-L-proline (491 mg) and triethylamine at 0 °C. 0.353 mL) In a solution of tetrahydrofuran (5 mL), the mixture was stirred at room temperature for 1 hour. Thereafter, 3-amino-5-bromothiophene-2-carboxamide (225 mg) manufactured in Example 1, Step D was added to the reaction system, and the mixture was stirred at 60 ° C for 24 hours. Ethyl acetate (20 mL) and aqueous sodium bicarbonate (10 mL) were added toEtOAc. The collected organic layer was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was crystallised from ethanol (5mL). The obtained colorless solid was subjected to high performance liquid chromatography (column: CHIRALPAK AD (50 mm id × 500 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (850/150), flow rate: 80 mL/ Min, column temperature: 30 ° C) to give the title compound (302 mg). ¹ H-NMR (DMSO-d ₆ ) δ 0.94-1.03 (3H, m), 1.22 (9H, s, major), 1.39 (9H, s, minor), 1.41-1.56 (1H, m), 2.13-2.33 (1H, m), 2.35-2.48 (1H, m), 2.82-3.00 (1H, m), 3.70 (1H, dd, J = 10.1, 7.5 Hz), 4.13 (1H, t, J = 8.1 Hz), 7.71 (2H, brs), 8.03 (1H, s, minor), 8.05 (1H, s, major), 11.65 (1H, s). * observed as a 3:2 mixture of rotamers.

B) (2S, 4S)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-4-methylpyrrolidinium- Manufacture of 1-carboxylic acid tert-butyl butyl ester

(2S,4S)-2-[(5-Bromo-2-aminomethylsulfonylthiophen-3-yl)aminecarbenyl]-4-A was prepared in the same manner as in Example 40, Step B. The title compound (240 mg) was obtained as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ 0.98-1.05 (3H, m), 1.08 (9H, s, major), 1.35 (9H, s, minor), 1.45-1.66 (1H, m), 2.18-2.33 (1H,m),2.34-2.46(1H,m),2.97-3.13(1H,m),3.57-3.71(1H,m),4.49-4.60(1H,m),7.61(1H,s,minor) , 7.64 (1H, s, major), 12.73 (1H, brs). * Observed as a 2:1 mixture of rotamers.

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,4S)-4-methylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketone dihydrochloride

(2S,4S)-2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine as described above in the same manner as in Example 83, Step C 4-yl)-4-methylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (238 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (354 mg), cesium carbonate (374 mg), 1,1'-bis(diphenylphosphino)di Ferrocene] palladium(II) chloride-dichloromethane complex (1:1) (93.9 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL), 4M HCl/acetic acid Ethyl ester solution (1 mL) and MeOH (4 mL) ¹ H-NMR (DMSO-d ₆ ) δ 1.07 (3H, d, J = 6.6 Hz), 1.59-1.75 (1H, m), 2.34 - 2.50 (1H, m), 2.46 (3H, s), 2.60- 2.76 (1H, m), 2.82-2.99 (1H, m), 3.40-3.53 (1H, m), 4.59-4.76 (1H, m), 7.37 (1H, s), 8.10 (1H, s), 9.04 ( 1H, brs), 10.02 (1H, brs), 12.85 (1H, brs).

Example 93 Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-pyridin-2-ylthieno[3,2-d]pyrimidin-4(3H)-one A) Manufacture of 6-bromo-2-pyridin-2-ylthieno[3,2-d]pyrimidin-4(3H)-one

Pyridine-2-carbonyl chloride hydrochloride (214 mg) was added to the 3-amino-5-bromothiophene-2-carboxamide (221 mg), triethyl b, which was produced in Example 1, Step D, with stirring at room temperature. A mixture of amine (0.42 mL) and tetrahydrofuran (15 mL). The mixture was stirred at room temperature for 30 minutes and at 50 ° C overnight. Triethylamine (0.42 mL) and pyridine-2-carbonyl chloride hydrochloride (214 mg) were added to the reaction mixture. After 2 hours, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with water and brine (5 mL) and evaporated The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethanol (10 mL) and a 2M aqueous sodium hydroxide solution (3.0 mL) were added to the residue, and the mixture was stirred at 80 ° C for one hour. The reaction mixture was neutralized with 6 M hydrochloric acid under ice cooling. The mixture was extracted with ethyl acetate. The organic layer was washed with brine (10 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the filtrate was evaporated. MS (ESI+): </RTI>^</RTI> ESI.

B) 6-Bromo-2-pyridin-2-yl-3-{[2-(trimethyldecyl)ethoxy]methyl}thieno[3,2-d]pyrimidin-4(3H)- Ketone manufacturing

6-Bromo-2-pyridin-2-ylthieno[3,2-d]pyrimidin-4(3H)-one (223 mg), tetrahydrofuran (10 mL) prepared in the same manner as in Example 88, Step D , sodium hydride (60% in oil, 70 mg), and [2-(chloromethoxy)ethyl](trimethyl)decane (0.31 mL). ). MS (ESI +): [M + H] + 439.MS (ESI +), found: 438,410.

C) Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-pyridin-2-ylthieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-pyridin-2-yl-3-{[2-(trimethyldecyl)ethoxy]methyl}thiophene [from the above], in the same manner as in Example 83, Step C. 3,2-d]pyrimidin-4(3H)-one (302 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (425 mg), cesium carbonate (1.35 g), 1,1'-bis(diphenylphosphino)ferrocene] dichlorination Palladium(II)-dichloromethane complex (1:1) (25.2 mg), 1,2-dimethoxyethane (6 mL) and water (2 mL) gave 3-methyl as a pale orange oil. -4-(4-Sideoxy-2-pyridin-2-yl-3-{[2-(trimethyldecyl)ethoxy]methyl}-3,4-dihydrothieno[3, 2-d]pyrimidin-6-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester. 1 M tetrabutylammonium fluoride/tetrahydrofuran solution (3.0 mL) was added to 3-methyl-4-(4-o-oxy-2-pyridin-2-yl-3-{[2-(tri-) Ethyl methoxy)methyl}-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester The mixture was stirred at 50 ° C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate / tetrahydrofuran (3:1). The organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Trifluoroacetic acid (3 mL) was added to the residue and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. aqueous sodium hydrogen sulfate was added to the residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran (3:1). The organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjjjli ¹ H-NMR (DMSO-d ₆ ) δ 2.41-2.47 (3H, m), 7.54 (1H, s), 7.66 (1H, ddd, J = 7.6, 4.7, 1.1 Hz), 7.95 (0.67H, brs) , 8.08 (1H, td, J = 7.7, 1.5 Hz), 8.29-8.35 (0.33H, m), 8.40 (1H, d, J = 7.9 Hz), 8.77 (1H, d, J = 4.2 Hz), 11.94 (1H, brs), 13.05 (1H, brs).

Example 94 6-(5-Methyl-1H-pyrazol-4-yl)-2-(2-phenyl-1-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidine-4 ( 3H)-ketone manufacture A) Manufacture of 2-chloro-3-phenylpropionyl chloride

Thionium chloride (1.3 mL) was added in small portions to a mixture of 2-hydroxy-3-phenylpropionic acid (1.0 g) and toluene (10 mL). The reaction was stirred with heating at 40 ° C for 2 hours, and then N,N-dimethylformamide (0.093 mL) was added. The reaction was stirred with heating at 40 ° C for 20 hr. The mixture was concentrated under reduced pressure and toluene (20 mL). The mixture was concentrated under reduced pressure to give the title compound (l. ¹ H-NMR (氘-chloroform) δ 3.19-3.31 (1H, m), 3.39-3.57 (1H, m), 4.65-4.80 (1H, m), 7.04-7.46 (5H, m).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(2-phenyl-1-pyrrolidin-1-ylethyl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone

2-Chloro-3-phenylpropionyl chloride (305 mg) was added to 3-amino-5-bromothiophene-2-carboxamide (221 mg) prepared in Example 1, Step D, with stirring at room temperature. A mixture of triethylamine (0.21 mL) and tetrahydrofuran (5.0 mL). The reaction mixture was stirred for 10 min and pyrrolidine (0.42 mL) was added. The reaction mixture was stirred with heating at 70 ° C for 2 hours, sodium iodide (2.0 mg) was added, and the mixture was stirred and stirred at 70 ° C for 18 hours. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc The obtained pale yellow solid (285 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridyl Triazole carboxylic acid azole (435 mg), sodium carbonate (126 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) were placed in a flask to remove air from the flask with hydrogen . 1,1 '-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (57 mg) was added, and the air in the flask was again purged with argon. The reaction was stirred at 100 ° C for 30 min, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the extract was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) The solids which were prepared earlier were purified by silica gel column chromatography (ethyl acetate / hexane) to give 3-methyl-4-{4-s. The crude product (5.0 mg) of benzyl]-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl}-1H-pyrazole-1-carboxylic acid tert-butyl ester. The title compound (18 mg) was obtained as a colorless solid (yield: EtOAc) . ¹ H-NMR (DMSO-d ₆ ) δ 1.54-1.72 (4H, m), 2.24-2.49 (7H, m), 2.85-3.03 (1H, m), 3.33-3.40 (1H, m), 3.91-4.00 (1H, m), 7.14-7.30 (5H, m), 7.32 (1H, s), 7.77-8.38 (1H, m), 12.21 (1H, brs), 12.96 (1H, brs).

Example 95 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(E)-2-phenylvinyl]thieno[3,2-d]pyrimidin-4(3H)-one Manufacture of hydrochloride

4M HCl/ethyl acetate solution (0.50 mL) was added to the methyl 3-methyl-4-{4-trioxy-2-[(E)-2-phenylethene]. -3,4-Dihydrothieno[3,2-d]pyrimidin-6-yl}-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (5.0 mg) in methanol (1.0 mL) In solution. The reaction was stirred at room temperature for 30 min and the mixture was concentrated under reduced pressure. The residue was crystallized from EtOAc (EtOAc) ¹ H-NMR (DMSO-d ₆ ) δ 2.47 (3H, s), 7.04 (1H, d, J = 16.1 Hz), 7.41 (1H, s), 7.42-7.51 (3H, m), 7.63-7.70 ( 2H, m), 7.93 (1H, d, J = 16.1 Hz), 8.06 (1H, s).

Example 96 Manufacture of 2-(1H-imidazol-1-ylmethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one A) Manufacture of 6-bromo-2-(1H-imidazol-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), 1H-imidazole (131 mg), potassium carbonate (178 mg), sodium iodide (9.7 mg), and N,N-dimethylformamide (3.0 mL) ¹ H-NMR (DMSO-d ₆ ) δ 5.19 (2H, s), 6.91 (1H, brs), 7.21. (1H, brs), 7.59 (1H, s), 7.71 (1H, brs), 12.92 (1H, Brs).

B) 2-(1H-imidazol-1-ylmethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacturing

In the same manner as in Example 2, Step C, from 6-bromo-2-(1H-imidazol-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one (88 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl Ester (174 mg), sodium carbonate (51 mg), 1,2-dimethoxyethane (2.0 mL) and water (1.0 mL) and 1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium(II)-dichloromethane complex (1:1) (23 mg) gave m. ¹ H-NMR (DMSO-d ₆ ) δ 2.37-2.47 (3H, m), 5.19 (2H, s), 6.92 (1H, s), 7.23 (1H, s), 7.36 (1H, s), 7.73 ( 1H, s), 7.88 (0, 6H, brs), 8.25 (0.4H, brs), 12.68 (1H, brs), 12.88-13.04 (1H, m).

Example 97 2-[(2,2-Dimethylpyrrolidin-1-yl)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone A) Manufacture of 6-bromo-2-[(2,2-dimethylpyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), 2,2-dimethylpyrrolidine monohydrochloride (261 mg), potassium carbonate (445 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) The title compound (109 mg) was obtained as a pale yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.02 (6H, s), 1.56-1.76 (4H, m), 2.65-2.72 (2H, m), 3.52 (2H, s), 7.60 (1H, s) , 11.91 (1H, brs).

B) 2-[(2,2-Dimethylpyrrolidin-1-yl)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-[(2,2-dimethylpyrrolidin-1-yl)methyl]thieno[3,2-d]pyrimidine-4 ( 3H)-ketone (109mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1-carboxylic acid tert-butyl butyl ester (196 mg), sodium carbonate (57 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and 1,1'-bis(diphenylphosphine) The title compound (22 mg) was obtained as a brown crystal. ¹ H-NMR (DMSO-d ₆ ) δ 1.03 (6H, s), 1.65 (4H, s), 2.45 (3H, s), 2.71 (2H, brs), 3.53 (2H, s), 7.37 (1H, s), 8.02 (1H, brs), 11.52-13.00 (2H, m).

Example 98 6-(5-Methyl-1H-pyrazol-4-yl)-2-(2-propylpyrrolidin-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacture of hydrochloride A) 2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-propylpyrrolidine-1-carboxylic acid Manufacture of butyl ester

In the same manner as in Example 82, Step A, from 1-(tertiary butoxycarbonyl)-2-propylproline (503 mg) and triethylamine (0.454 mL) and tetrahydrofuran (10 mL) Methyl propyl ester (0.211 mL) and 3-amino-5-bromothiophene-2-carboxamide (360 mg) manufactured in Example 1, step D, and 2M aqueous sodium hydroxide (4 mL) and ethanol (10 mL) The title compound (33 mg) was obtained. MS (ESI +): [M + H] + 442.MS (ESI +), Found: 442.

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(2-propylpyrrolidin-2-yl)thieno[3,2-d]pyrimidin-4(3H)- Manufacture of ketone dihydrochloride

In the same manner as in Example 11, Step B, from 2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-propane Pyridyl-1-carboxylic acid tert-butyl butyl ester (33 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (46 mg) and cesium carbonate (146 mg) and 1,2-dimethoxyethane (3 mL) and water (0.2 mL) and 1,1' - bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (3 mg). ¹ H-NMR (DMSO-d ₆ ) δ 0.77-0.89 (3H, m), 0.90-1.02 (1H, m), 1.23-1.38 (1H, m), 1.74-1.89 (1H, m), 1.93-2.43 (5H, m), 2.46 (3H, s), 3.25-3.44 (2H, m), 7.34 (1H, s), 8.09 (1H, brs), 9.32 (1H, brs), 9.55 (1H, brs), 12.83 (1H, brs).

Example 99 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(8aR)-octahydropyrrolo[1,2-a]pyridyl Manufacture of -3-yl]thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride A) Manufacture of N-benzyl-5-sideoxy-D-guanamine amide

5-sided oxy-D-proline (5.0 g), benzylamine (4.65 mL), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide salt under ice cooling The acid salt (8.5 g) and 1-hydroxybenzotriazole (6.3 g) were combined in acetonitrile (100 mL) and the mixture was warmed to room temperature and stirred for 3 hr. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The precipitated solid was collected by EtOAcjjjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.82-1.96 (1H, m), 2.02-2.36 (3H, m), 3.99-4.09 (1H, m), 4, 29 (2H, d, J = 5.9 Hz ), 7.18-7.38 (5H, m), 7.85 (1H, s), 8.50 (1H, t, J = 5.9 Hz).

B) Manufacture of 1-phenyl-N-[(2R)-pyrrolidin-2-ylmethyl]methylamine

A suspension of N-benzyl-5-oxo-D-decylamine (11.0 g) in tetrahydrofuran (350 mL) was added dropwise to a solution of lithium aluminum hydride (5.40 g) in tetrahydrofuran (150 mL). In the suspension, the mixture was heated and stirred at 60 ° C for 14 hours. The reaction mixture was cooled to 0 ° C, and water (10.8 mL), 1M aqueous sodium hydroxide (5.4 mL) and water (5.4 mL) were added, and the obtained insoluble material was filtered out. The title compound (8.95 g) was obtained. This compound was used in the next step without further purification. ¹ H-NMR (DMSO-d ₆ ) δ 1.18-1.33 (1H, m), 1.48-1.81 (3H, m), 2.09 (2H, m), 2.30-2.44 (2H, m), 2.63-2.80 (2H , m), 3.00-3.12 (1H, m), 3.68 (2H, s), 7.13 - 7.37 (5H, m).

C) (3S,8aR)-2-benzyl octahydropyrrolo[1,2-a]pyridin Manufacture of methyl-3-carboxylate

Triethylamine (22.9 mL) and methyl 2,3-di-bromopropionate (13.4 g) were added to 1-phenyl-N-[(2R)-pyrrolidin-2-ylmethyl under ice cooling. The suspension of methylamine (13.6 g) in toluene (120 mL) was stirred and stirred at 90 ° C for 5 hours. The reaction mixture was cooled to room rt and diluted with diethyl ether (200 mL) and brine. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble material was filtered. The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.14-1.28 (1H, m), 1.53-1.77 (3H, m), 1.83-2.00 (2H, m), 2.31 (1H, dd, J = 10.7, 3.9 Hz ), 2.61-2.95 (3H, m), 3.29 (1H, dd, J = 10.7, 2.0 Hz), 3.53 (1H, dd, J = 3.7, 1.8 Hz), 3.62 (3H, s), 3.89 (2H, s), 7.17-7.37 (5H, m).

D) (3S, 8aR)-hexahydropyrrolo[1,2-a]pyridin Manufacture of 2-,3(1H)-dicarboxylic acid 2-tris-butyl 3-methyl ester

Add 10% palladium-carbon (680 mg, 50% by weight) to (3S,8aR)-2-benzylmethyloctahydropyrrolo[1,2-a]pyridin Methyl 3-carboxylate (6.80 g) was added to a solution of 5-10% hydrogen chloride-methanol, and the mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 10 hr. The insoluble material was filtered off through a pad of Celite, and the filtrate was concentrated to give a pale yellow oil. The resulting (3S,8aR)-octahydropyrrolo[1,2-a]pyridyl The methyl 3-carboxylic acid salt dihydrochloride was dissolved in saturated aqueous sodium hydrogencarbonate (25 mL), and tetrahydrofuran (50 mL) and di-tert-butyl dicarbonate (5.68 g) were added, and the mixture was stirred at room temperature. 1 hour. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL) and brine The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjj ¹ H-NMR (氘-chloroform) δ 1.18-1.39 (1H, m), 1.42-1.51 (9H, m), 1.61-1.94 (4H, m), 1.97-2.12 (1H, m), 1.99-2.11 ( 1H, m), 2.22-2.33 (1H, m), 2.69-2.91 (1H, m), 2.99-3.09 (1H, m), 3.48-3.58 (1H, m), 3.72-3.78 (2H, m), 3.93-4.13(1H,m), 4.56-4.82(1H,m).

E) (8aR)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[1,2-a Pyridine Manufacture of -2(1H)-carboxylic acid tertiary butyl ester

Add 2-methylpropyl chlorocarbonate (0.13 mL) to (8aR)-2-(tertiary butoxycarbonyl) octahydropyrrolo[1,2-a]pyridine with stirring at room temperature A mixture of 3-carboxylic acid (270 mg), triethylamine (0.18 mL) and tetrahydrofuran (10 mL). After 2 hours, 3-amino-5-bromothiophene-2-carboxamide (221 mg), which was obtained in Example 1, Step D, was added and the mixture was stirred at 50 ° C for 2 hours. The reaction mixture was poured into a saturated aqueous The extract was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (10 mL), EtOAc (EtOAc) The reaction mixture was allowed to cool to room temperature and poured into saturated aqueous sodium hydrogen sulfate. It was extracted with a mixture of ethyl acetate / tetrahydrofuran, and the extract was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc MS (ESI +): [M + H] + 455.MS (ESI +), Found: 455.

F) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(8aR)-octahydropyrrolo[1,2-a]pyridin Manufacture of -3-yl]thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride

In the same manner as in Example 11, Step B, from (8aR)-3-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) Hexahydropyrrolo[1,2-a]pyridyl -2(1H)-carboxylic acid tertiary butyl ester (65 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (88 mg) and cesium carbonate (279 mg) and 1,2-dimethoxyethane (10 mL) and water (1 mL) and 1,1'- Bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (5 mg) gave the title compound (36 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.55-4.06 (14H, m), 4.57-4.85 (1H, m), 7.40 (1H, s), 8.11 (1H, s), 12.01 (1H, brs) .

Example 100 (2S)-2-[6-(5-Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2- Manufacture of benzylidene piperidine-1-carboxylic acid tert-butyl butyl ester

Triethylamine (1.87 mL) and di-tertiary butyl dicarbonate (0.932 mL) were added to the compound of Example 83, Step 6-(5-Methyl-1H-pyrazol-4-yl)-2 a suspension of [[2S)-piperidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride (1.05 g) in tetrahydrofuran (35 mL) The mixture was stirred at 50 ° C for 1.5 hours. Ethyl acetate (50 mL) and aqueous ammonium chloride (30 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL). The collected organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAcjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.15-1.60 (12H, m), 1.60-1.89 (2H, m), 1.99-2.16 (1H, m), 2.37-2.48 (3H, m), 3.41-3.59 (1H, m), 3.80-3.91 (1H, m), 5.01 (1H, brs), 7.37 (1H, s), 7.84-8.37 (1H, m), 12.36 (1H, brs), 12.97 (1H, brs ).

Example 101 2-[(2R)-azepane-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4(3H) - manufacture of ketones A) 2-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)azepane-1-carboxylic acid tert-butyl acrylate Optical separation

2-(6-Bromo-4-o-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)azepane, which was produced in Example 79, Step A - 1-carboxylic acid tert-butyl butyl ester (772 mg) by high performance liquid chromatography (column: CHIRALPAK AD (50 mm id × 500 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (500/500) ), flow rate: 60 mL / min, column temperature: 30 ° C). (2R)-2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)aza was obtained under the above high performance liquid chromatography conditions. Cycloheptane-1-carboxylic acid tert-butyl butyl ester (325 mg, >99.9% ee, retention time 11.2 minutes) and (2S)-2-(6-bromo-4-oxooxy-3,4-dihydrothiophene And [3,2-d]pyrimidin-2-yl)azetidin-1-carboxylic acid tert-butyl ester (326 mg, >99.9% ee, retention time 13.7 min). High performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm id × 250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (500/500), flow rate: 0.5 mL /min, column temperature: 30 ° C, detection 220 nm) was performed for this analysis. The absolute spatial configuration after optical resolution is determined by X-ray crystal structure analysis with a retention time of 13.7 minutes.

B) 2-[(2R)-azepane-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 ( 3H)-ketone manufacture

(2R)-2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2 was prepared as above in the same manner as in Example 76, Step B. -yl)azetane-1-carboxylic acid tert-butyl butyl ester (325 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Tert-butyl butyl bromide-2-yl)-1H-pyrazole-1-carboxylate (468 mg), cesium carbonate (495 mg), 1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) chloride-dichloromethane complex (1:1) (31.0 mg), 1,2-dimethoxyethane (8 mL), water (0.8 mL), 4M HCl/ethyl acetate solution ( 1 mL) and MeOH (5 mL) ¹ H-NMR (DMSO-d ₆ ) δ 1.42-1.89 (7H, m), 2.07-2.21 (1H, m), 2.45 (3H, s), 2.74-2.96 (2H, m), 3.82 (1H, dd , J = 9.5, 4.4 Hz), 7.34 (1H, s), 8.01 (1H, brs).

Example 102 2-[(2S)-azepane-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4(3H) - manufacture of ketones

In the same manner as in Example 76, Step B, self-produced in Example 101, Step 2, (2S)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2 -d]pyrimidin-2-yl)azetidin-1-carboxylic acid tert-butyl butyl ester (310 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (446 mg), cesium carbonate (472 mg), 1,1'-bis(diphenylphosphino) ) ferrocene] palladium(II) chloride-dichloromethane complex (1:1) (29.6 mg), 1,2-dimethoxyethane (8 mL), water (0.8 mL), 4M HCl The title compound (92.7 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.40-1.89 (7H, m), 2.05-2.21 (1H, m), 2.45 (3H, s), 2.74-2.97 (2H, m), 3.76-3.86 (1H , m), 7.34 (1H, s), 8.01 (1H, brs).

Example 103 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-2-methylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine-4 (3H )-Manufacture of ketone dihydrochloride A) (2S)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidin-1- Manufacture of carboxylic acid tertiary butyl ester

In the same manner as in Example 82, Step A, from 1-(tris-butoxycarbonyl)-2-methyl-L-proline (1.2 g) and triethylamine (1.21 mL) and tetrahydrofuran (20 mL) 2-methylpropyl chlorocarbonate (0.566 mL) and 3-amino-5-bromothiophene-2-carboxamide (964 mg) and the 2M aqueous sodium hydroxide solution (10.9 mL). The crude product (244 mg) was obtained from m. MS (ESI+): </RTI>^<RTIID=0.0></RTI></RTI><RTIgt; By high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm id × 250 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 1.0 mL/min, tube The analysis was carried out at a column temperature of 30 ° C and a detection of 220 nm.

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-2-methylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone dihydrochloride

In the same manner as in Example 11, Step B, from (2S)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) 3-methylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (239 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Butyl-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (356 mg) and cesium carbonate (1.13 g) and 1,2-dimethoxyethane (6 mL) and water (1.5 mL) And 1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (21 mg). . ¹ H-NMR (DMSO-d ₆ ) δ 1.74 (3H, s), 1.83-2, 40 (4H, m), 2.46 (3H, brs), 3.27-3.44 (2H, m), 7.37 (1H, s ), 8.10 (1H, brs), 9.18 (1H, brs), 9.62 (1H, brs), 12.81 (1H, brs).

Example 104 2-(3-indolebicyclo[3.1.0]hex-3-ylmethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 (3H)-ketone manufacture A) Manufacture of 2-(3-indolebicyclo[3.1.0]hex-3-ylmethyl)-6-bromothieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), 3-indole bicyclo[3.1.0]hexane monohydrochloride (231 mg), potassium carbonate (445 mg), sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) The title compound (90 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 0.24-0.38 (1H, m), 0.66-0.75 (1H, m), 1.31-1.41 (2H, m), 2.43-2.48 (2H, m), 2.90 (2H) , d, J = 8.5 Hz), 3.55 (2H, s), 7.60 (1H, s), 12.27 (1H, brs).

B) 2-(3-吖Bicyclo[3.1.0]hex-3-ylmethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine -4(3H)-one manufacture

In the same manner as in Example 2, Step C, from 2-(3-indolebicyclo[3.1.0]hex-3-ylmethyl)-6-bromothieno[3,2-d]pyrimidine-4 (3H )-ketone (90 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole- 1-carboxylic acid tertiary butyl ester (170 mg), sodium carbonate (50 mg), 1,2-dimethoxyethane (2.0 mL) and water (1.0 mL) and 1,1'-bis(diphenylphosphino) The ferrocene]palladium(II)-dichloromethane complex (1:1) (23 mg) gave the title compound (16 mg). ¹ H-NMR (DMSO-d ₆ ) δ 0.26-0.41 (1H, m), 0.65-0.78 (1H, m), 1.31-1.46 (2H, m), 2.38-2.49 (5H, m), 2.92 ( 2H,d,J=8.5Hz), 3.56(2H,s), 7.37(1H,s), 7.80-8.42(1H,m),12.01(1H,brs),12.99(1H,brs).

Example 105 2-{[(4-methoxybenzyl)(1-methylethyl)amino]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3, Manufacture of 2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 180 mg), N-(4-methoxybenzyl)propan-2-amine monohydrochloride (416 mg), potassium carbonate (445 mg), sodium iodide (9.7 mg) and N,N-dimethylformamidine Amine (3.0 mL) gave 6-bromo-2-{[(4-methoxybenzyl)(1-methylethyl)amino]methyl}thieno[3,2-d] as a yellow solid. Pyrimidine-4(3H)-one (120 mg). In the same manner as in Example 2, Step C, from the obtained 6-bromo-2-{[(4-methoxybenzyl)(1-methylethyl)amino]methyl}thiophene [3, 2-d]pyrimidin-4(3H)-one (120 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (175 mg), sodium carbonate (51 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and 1,1 '-Bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (23 mg) ¹ H-NMR (DMSO-d ₆ ) δ 1.05 (6H, d, J = 6.6 Hz), 2.44 (3H, brs), 2.91-3.03 (1H, m), 3.55-3.64 (4H, m), 3.66 (3H, s), 6.79 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.32 (1H, s), 7.73 - 8.42 (1H, m), 11.42 (1H, Brs), 12.96 (1H, brs).

Example 106 (3S)-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2- Manufacture of tert-butyl 2-cyclobis[2.2.2]octane-2-carboxylic acid tert-butyl butyl ester A) (3S)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-indole bicyclo[2.2.2] Manufacture of octane-2-carboxylic acid tert-butyl butyl ester

Isobutyl chloroformate (0.26 mL) was added to (3S)-2-(tertiary butoxycarbonyl)-2-indolebicyclo[2.2.2]octane-3-carboxylic acid (0.511 g) with stirring under ice cooling. And a solution of triethylamine (0.348 mL) in tetrahydrofuran (5 mL). After stirring at room temperature for 30 minutes, a solution of 3-amino-5-bromothiophene-2-carboxamide (0.221 g) in THF (1 mL). The reaction was heated and stirred at 60 ° C for 4 days. Water was poured into the reaction system, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. 2M aqueous sodium hydroxide solution (3.0 mL) and 1,2-dimethoxyethane (6.0 mL) were added to the residue, and the mixture was stirred at 150 ° C for one hour in a microwave reactor. The insoluble material was filtered off and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc The optical purity is 70% ee. High performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm id × 250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (800/200), flow rate: 1.0 mL /min, column temperature: 30 ° C, detection 220 nm) was performed for this analysis. ¹ H-NMR (DMSO-d ₆ ) δ 1.07-1.83 (16H, m), 2.03-2.23 (2H, m), 3.95-4.08 (1H, m), 4.51-4.56 (1H, m), 7.63 (1H) , s), 12.50-12.77 (1H, m).

B) (3S)-3-[6-(5-Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidine- Manufacture of 2-yl]-2-indole bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl butyl ester

(3S)-3-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-indolebicyclo[2.2.2] octyl Alkyl butyl carboxylic acid (190 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (266 mg), sodium carbonate (78 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask to Argon purged the air from the flask. 1,1 '-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (35 mg) was added, and the air in the flask was again purged with hydrogen. The reaction was stirred at 100 ° C for 3 hr. The insoluble material was filtered off, and the extract was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.08-1.85 (16H, m), 2.06-2.22 (2H, m), 2.39-2.48 (3H, m), 3.97-4.09 (1H, m), 4.52-4.56 (1H, m), 7.39 (0.4H, s), 7.42 (0.6H, s), 7.92 (0, 6H, brs), 8.27 (0.4H, brs), 12.24-12.46 (1H, m), 12.96 ( 1H, brs).

Example 107 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S*,5R*)-5-phenylpiperidin-2-yl]thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketone monohydrochloride

3-Amino-5-bromothiophene-2-carboxamide (323 mg), 1-(tertiary butoxycarbonyl)-, as in Example 86, Step A, from Example 1, Step D. 5-Phenylpiperidine-2-carboxylic acid (511 mg, available from ChemImpex, non-image isomer ratio unknown), 2-methylpropyl chlorocarbonate (0.418 mL), triethylamine (0.506 mL), and tetrahydrofuran ( 8 mL), 2M aqueous sodium hydroxide solution (2 mL) and ethanol (5 mL) afforded (2S ^* ,5R ^* )-2-(6-bromo-4- oxo-3,4-di) as a pale yellow amorphous solid. Hydrogen thieno[3,2-d]pyrimidin-2-yl)-5-phenylpiperidine-1-carboxylic acid tert-butyl ester. (2S ^* ,5R ^* )-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d], as prepared in the same manner as in Example 76, Step B Pyrimidin-2-yl)-5-phenylpiperidine-1-carboxylic acid tert-butyl butyl ester, 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (321 mg), cesium carbonate (339 mg), 1,1'-bis(diphenylphosphino) ferrocene Iron] palladium(II) chloride-dichloromethane complex (1:1) (21.2 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL), 4M HCl/ethyl acetate The title compound (119 mg) was obtained eluted eluted elute ¹ H-NMR (DMSO-d ₆ ) δ 1.66-1.89 (2H, m), 2.15-2.32 (1H, m), 2.47 (3H, s), 2.99-3.13 (1H, m), 3.34-3.44 (2H , m), 3.85-4.01 (1H, m), 4.72 (1H, brs), 7.23-7.31 (3H, m), 7.31-7.40 (2H, m), 7.49 (1H, s), 8.11 (1H, brs ), 9.29-9.43 (1H, m), 9.78-9.93 (1H, m), 12.67 (1H, brs).

Example 108 2-[(3S)-2-indolyl[2.2.2]oct-3-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketone dihydrochloride

4M HCl/ethyl acetate solution (1.0 mL) was added to the (3S)-3-[6-(5-methyl-1H-pyrazole-4-). 4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-indole bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl The ester (143 mg) was taken in a solution of methanol (3.0 mL). The reaction was stirred with EtOAc (EtOAc)EtOAc. ¹ H-NMR (DMSO-d ₆ ) δ 1.31-2.16 (8H, m), 2.31-2.38 (1H, m), 2.47 (3H, s), 3.51-3.64 (1H, m), 4.39-4.58 (1H , m), 7.38 (1H, s), 8.12 (1H, s), 8.19-8.40 (1H, m), 10.08-10.32 (1H, m), 12.87 (1H, brs).

Example 109 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2R)-2-methylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine-4 (3H )-Manufacture of ketone dihydrochloride A) 2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidin-1-carboxylic acid Manufacture of butyl ester

In the same manner as in Example 82, Step A, from 1-(tert-butoxycarbonyl)-2-methyl-L-proline (1.5 g) and triethylamine (3.0 mL) and tetrahydrofuran (20 mL) 2-methylpropyl chlorocarbonate (0.707 mL) and 3-amino-5-bromothiophene-2-carboxamide (1.21 g), which was obtained in Example 1, step D, and 2M aqueous sodium hydroxide (13.6 mL) The title compound (199 mg) was obtained as a pale brown oil. MS (ESI +): [M + H] + 414.MS (ESI +), Found: 414.

B) 2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylic acid tertiary Optical Separation of Butyl Ester

High performance liquid chromatography (column: CHIRALPAK AD (50 mm id × 500 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 80 mL/min, tube Column temperature: 30 ° C) Distinguish between 2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidin-1 - Tributyl carboxylic acid ester (180 mg). The optically active type differential solution having a shorter residence time is concentrated under the above high performance liquid chromatography conditions to obtain (2R)-2-(6-bromo-4-oxo-3,4-dihydrothiophene. And [3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (88 mg, 9.25 min, >99.9% ee). Further, the optically active type discrimination solution containing a longer residence time is concentrated to obtain (2S)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d] Pyrimidin-2-yl)-2-methylpyrrolidin-1-carboxylic acid tert-butyl ester (85 mg, 19.3 min, >99.9% ee). High performance liquid chromatography (column: CHIRALPAK AD (4.6 mm id × 250 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 1.0 mL/min, tube Column analysis: 30 ° C, detection of 220 nm). The absolute configuration is the (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2 produced in Example 103, Step A. -Based on 2-methylpyrrolidine-1-carboxylic acid tert-butyl ketone.

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2R)-2-methylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone dihydrochloride

In the same manner as in Example 11, Step B, from (2R)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) 3-methylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (88 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Tert-butyl pentyl-2-yl)-1H-pyrazole-1-carboxylate (131 mg) and cesium carbonate (415 mg) and 1,2-dimethoxyethane (2 mL) and water (0.5 mL) 1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (7.8 mg) . ¹ H-NMR (DMSO-d ₆ ) δ 1.75 (3H, s), 1.81-2.40 (4H, m), 2.46 (3H, s), 3.30-3.43 (2H, m), 7.37 (1H, s) , 8.10 (1H, brs), 9.23 (1H, brs), 9.77 (1H, brs), 12.81 (1H, brs).

Example 110 2-[(1S ^* ,2S ^* ,5R ^* )-3-indolyl[3.1.0]hex-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[ Manufacture of 3,2-d]pyrimidin-4(3H)-one dihydrochloride A) (1S ^* , 2S ^* , 5R ^* )-2-[(5-bromo-2-aminomethylsulfonylthiophen-3-yl)amine-carbamoyl]-3-indolebicyclo[3.1.0]hexane Manufacture of 3-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (338 mg), (1S ^* , 2S ^* , 5R ^* ), manufactured in Example 1, Step D, in the same manner as in Example 78, Step A. -3-(tertiary butoxycarbonyl)-3-indolebicyclo[3.1.0]hexane-2-carboxylic acid (695 mg), 2-methylpropyl chlorocarbonate (0.398 mL), triethylamine (0.424 mL) The title compound (400 mg) was obtained as a pale yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 0.46-0.60 (1H, m), 0.60-0.72 (1H, m), 1.11-1.48 (9H, m), 1.63-1.73 (1H, m), 1.86- 1.97 (1H, m), 3.40-3.47 (1H, m), 3.48-3.57 (1H, m), 4.27 (1H, d, J = 4.9 Hz), 7.69 (2H, brs), 8.05 (1H, s) , 11.51 (1H, brs).

B) 2-[(1S ^* ,2S ^* ,5R ^* )-3-indolyl[3.1.0]hex-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thiophene And [3,2-d]pyrimidine-4(3H)-one dihydrochloride

2M aqueous sodium hydroxide solution (4.62 mL) was added to the above-made (1S ^* , 2S ^* , 5R ^* )-2-[(5-bromo-2-aminomethylsulfonylthiophen-3-yl)amine mercapto group] To a solution of -3-indole bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (400 mg) in ethanol (4 mL). The reaction mixture was neutralized with 6M hydrochloric acid (1. 5 mL) and evaporated. The separated organic layer was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give (1S,2S,5R)-2-(6-bromo-4-oxooxy-3,4-dihydrothiophene [3] as a pale yellow solid. , 2-d]pyrimidin-2-yl)-3-indole bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester. (1S ^* , 2S ^* , 5R ^* )-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3, as described above, in the same manner as in Example 83, Step C. 2-d]pyrimidin-2-yl)-3-indole bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl butyl ester, 3-methyl-4-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (572 mg), cesium carbonate (605 mg), 1,1'-double ( Diphenylphosphino)ferrocene]palladium(II)-dichloromethane complex (1:1) (38.0 mg), 1,2-dimethoxyethane (7 mL), water (0.7 The title compound (130 mg) was obtained eluted eluted eluted ¹ H-NMR (DMSO-d ₆ ) δ 0.56-0.73 (2H, m), 1.82-1.93 (1H, m), 2.25-2.36 (1H, m), 2.46 (3H, s), 3.38-3.54 (2H , m), 4.91 (1H, brs), 7.33 (1H, s), 8.11 (1H, s), 8.73 (1H, brs), 10.50 (1H, brs), 13.06 (1H, brs).

Example 111 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(4R)-1,3-tetrahydrothiazol-4-yl]thieno[3,2-d]pyrimidine-4 ( 3H)-ketone manufacture A) (4R)-4-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-1,3-tetrahydrothiazole-3 -Manufacture of carboxylic acid tertiary butyl ester

3-Amino-5-bromothiophene-2-carboxamide (500 mg), (4R)-3-(Terminal D), as in Example 71, Step A, from Example 1, Step D Oxycarbonyl)-1,3-tetrahydrothiazole-4-carboxylic acid (1.16g), 2-methylpropyl chlorocarbonate (0.647mL), triethylamine (0.694mL) and tetrahydrofuran (10mL), 2M sodium oxide Aqueous <RTI ID=0.0>(</RTI></RTI><RTIgt; ¹ H-NMR (DMSO-d ₆ ) δ 1.17 (9H, brs, major), 1.41 (9H, brs, minor), 3.18 (1H, brs), 3.51 (1H, brs), 4.60 (2H, q, J) = 8.7 Hz), 4.90 (1H, brs, major), 5.05 (1H, brs, minor), 7.61 (1H, brs), 12.77 (1H, brs). * observed as a 3:2 mixture of rotamers.

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(4R)-1,3-tetrahydrothiazol-4-yl]thieno[3,2-d]pyrimidine- 4(3H)-ketone

(4R)-4-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2 was prepared as above in the same manner as in Example 76, Step B. -yl)-1,3-tetrahydrothiazole-3-carboxylic acid tert-butyl butyl ester (250 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (369 mg), cesium carbonate (389 mg), 1,1'-bis(diphenylphosphino) ferrocene Iron] palladium(II) chloride-dichloromethane complex (1:1) (24.4 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL), 4M HCl/ethyl acetate The ester solution (1 mL) and EtOAc (3 mL) ¹ H-NMR (DMSO-d ₆ ) δ 2.47 (3H, brs), 3.03 (1H, dd, J = 10.0, 7.0 Hz), 3.21. (1H, dd, J = 10.0, 6.6 Hz), 3.58 (1H, Brs), 4.11 (1H, d, J = 8.7 Hz), 4.19 - 4.33 (2H, m), 7.37 (1H, s), 7.90 (1H, brs, major), 8.26 (1H, brs, minor), 12.28 (1H, brs), 13.01 (1H, brs).* observed as a 3:2 mixture of rotamers.

Example 112 2-[(1S,2R,5R)-3-indolyl[3.1.0]hex-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2 -d]Production of pyrimidine-4(3H)-one dihydrochloride A) (1R ^* , 2S ^* , 5S ^* )-2-[6-(5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3 Manufacture of 2-d-pyrimidin-2-yl]-3-indolebicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl butyl ester

(1R ^* , 2S ^* , 5S ^* )-2-(6-bromo-4-yloxy-3,4-di, as described in Example 83, Step C, as in Example 87, Step A Hydrothieno[3,2-d]pyrimidin-2-yl)-3-indole bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (293 mg), 3-methyl-4-(4) , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (437 mg), cesium carbonate (463 mg) , 1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane complex (1:1) (29.0 mg), 1,2-dimethoxy Ethyl (7 mL) and water (0.7 mL) gave (1R ^* ,2S ^* ,5S ^* )-2-{6-[1-(tris-butoxycarbonyl)-3-methyl as a pale yellow amorphous solid. -1H-pyrazol-4-yl]-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}-3-indolebicyclo[3.1.0]hexane 3-carboxylic acid tertiary butyl ester. 2M aqueous sodium hydroxide solution (1 mL) was added to the above-made (1R ^* , 2S ^* , 5S ^* )-2-{6-[1-(tertiary butoxycarbonyl)-3-methyl-IH-pyrazole- 4-yl]-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}-3-indolebicyclo[3.1.0]hexane-3-carboxylic acid III The butyl ester was dissolved in tetrahydrofuran (5 mL) and the mixture was stirred at 60 ° C for 2 hr. Ethyl acetate (20 mL) and 1M hydrochloric acid (2 mL) was evaporated. The insoluble material was filtered, and the filtrate was evaporated. ¹ H-NMR (DMSO-d ₆ ) δ 0.50-0.63 (1H, m), 0.79-0.96 (1H, m), 1.07 (9H, s, major), 1.36 (9H, s, minor), 1.63-1.76 (1H, m), 1.89-2.02 (1H, m), 2.45 (3H, s), 3.47-3.63 (2H, m), 4.77 (1H, d, J = 5.1 Hz), 7.38 (1H, brs, minor) ), 7.42 (1H, s, major), 7.77-8.43 (1H, m), 12.36 (1H, brs), 12.96 (1H, brs). * observed as a 5:2 mixture of rotamers.

B) (1R ^* , 2S ^* , 5S ^* )-2-[6-(5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3 Optical isolation of 2-d-pyrimidin-2-yl]-3-indole bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

High performance liquid chromatography (column: CHIRALPAK AD (50 mm id × 500 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 80 mL/min, column temperature :30 ° C) Distinguish (1R*, 2S*, 5S*)-2-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothiophene And [3,2-d]pyrimidin-2-yl]-3-indolebicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (205 mg). (1S,2R,5R)-2-[6-(5-Methyl-1H-pyrazol-4-yl)-4-oxooxy-3,4-dihydrol was obtained via the above high performance liquid chromatography conditions. Thio[3,2-d]pyrimidin-2-yl]-3-indolebicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl butyl ester (80 mg, >99.9% ee, retention time 20.2 min) (1R,2S,5S)-2-[6-(5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d] Pyrimidin-2-yl]-3-indole bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (77 mg, 99.8% ee, retention time 30.2 min). High performance liquid chromatography (column: CHIRALPAK AD-3 (4.6 mm id × 250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (850/150), flow rate: 1 mL/ Min, column temperature: 30 ° C, detection 220 nm) was performed for this analysis. The absolute spatial configuration after optical resolution is determined by X-ray crystallography which is distinguished by a residence time of 20.2 minutes.

C) 2-[(1S,2R,5R)-3-indenylbicyclo[3.1.0]hex-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3 ,2-d]pyrimidine-4(3H)-one dihydrochloride

4M HCl/ethyl acetate solution (1 mL) was added to (1S,2R,5R)-2-[6-(5-methyl-1H-pyrazol-4-yl)-4- oxo- 3,4-Dihydrothieno[3,2-d]pyrimidin-2-yl]-3-indolebicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (75.0 mg) in methanol (5 mL The solution was stirred at 50 ° C for 2 hours. Ethyl acetate (4 mL) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 0.55-0.74 (2H, m), 1.82-1.94 (1H, m), 2.25-2.36 (1H, m), 2.46 (3H, s), 3.37-3.56 (2H , m), 4.91 (1H, brs), 7.33 (1H, s), 8.10 (1H, s), 8.73 (1H, brs), 10.43 (1H, brs), 13.04 (1H, brs).

Example 113 2-[(1R,2S,5S)-3-indenylbicyclo[3.1.0]hex-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2 -d]Production of pyrimidine-4(3H)-one dihydrochloride

(1R, 2S, 5S)-2-[6-(5-methyl-1H-pyrazol-4-yl)-, as in Example 112, Step B, in the same manner as in Example 110, Step C 4-tertiary oxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-3-indole bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl butyl ester (75.0 The title compound (56.9 mg) was obtained as a white crystal. ¹ H-NMR (DMSO-d ₆ ) δ 0.57-0.73 (2H, m), 1.82-1.93 (1H, m), 2.25-2.36 (1H, m), 2.46 (3H, s), 3.36-3.56 (2H , m), 4.91 (1H, brs), 7.32 (1H, s), 8.10 (1H, s), 8.73 (1H, brs), 10.40 (1H, brs), 13.04 (1H, brs).

Example 114 2-[(2,5-Dimethylpyrrolidin-1-yl)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone

6-bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H) as in Example 2, Step A, as in Example 2, Step B and Step C. -ketone (180 mg), 2,5-dimethylpyrrolidine (0.170 mL) and potassium carbonate (178 mg) and sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) and -Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (252 mg) and sodium carbonate (130 mg) and 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and 1,1'-bis(diphenylphosphino)ferrocene] dichloride Palladium(II)-dichloromethane complex (1:1) (33 mg). ¹ H-NMR (DMSO-d ₆ ) δ 0.96-1.06 (6H, m), 1.28-1.43 (2H, m), 1.75-1.91 (2H, m), 2.45 (3H, s), 2.72-2.85 (2H , m), 3.67 (2H, s), 7.37 (1H, s), 7.84 - 8.19 (1H, m), 11.48-12.21 (1H, m), 12.58-13.18 (1H, m).

Example 115 6-(5-Methyl-1H-pyrazol-4-yl)-2-(1,2,3,4-tetrahydroisoquinolin-3-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone dihydrochloride A) 3-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3,4-dihydroisoquinoline-2 (1H Manufacture of -carboxylic acid tertiary butyl ester

3-Amino-5-bromothiophene-2-carboxamide (265 mg), (3S)-2-(tertiary), as in Example 71, in the same manner as in Step A, from Example 1, Step D. Oxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (699 mg), 2-methylpropyl chlorocarbonate (0.327 mL), triethylamine (0.416 mL), and tetrahydrofuran (5 mL) The title compound (182 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.07-1.53 (9H, m), 2.97-3.28 (2H, m), 4.43-5.18 (3H, m), 7.06-7.32 (4H, m), 7.43-7.66 (1H, m), 12.77 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(1,2,3,4-tetrahydroisoquinolin-3-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one dihydrochloride

3-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-produced above, in the same manner as in Example 83, Step C 3,4-Dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl butyl ester (150 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (200 mg), cesium carbonate (211 mg), 1,1'-bis(diphenylphosphino)di Ferrocene] palladium(II) chloride-dichloromethane complex (1:1) (13.3 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL), 4M HCl/acetic acid Ethyl ester solution (1 mL) and MeOH (4 mL) ¹ H-NMR (DMSO-d ₆ ) δ 2.48 (3H, s), 3.20 (1H, dd, J = 16.8, 11.9 Hz), 3.48-3.62 (1H, m), 4.35-4.52 (2H, m) , 4.62-4.78 (1H, m), 5.95-7.55 (7H, m), 8.14 (1H, s), 9.92-10.17 (1H, m), 10.40 (1H, brs), 13.02 (1H, brs).

Example 116 2-(7-Indylbicyclo[2.2.1]hept-1-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 (3H )-Manufacture of ketone monohydrochloride A) Manufacture of methyl 2-[(phenylcarbonyl)amino]prop-2-enoate

The serine acid methyl hydrochloride (45.0 g) and triethylamine (132 mL) were added to dichloromethane (400 mL), and then········· After stirring overnight at room temperature, the reaction was washed twice with saturated aqueous sodium hydrogen sulfate and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure by filtration of insoluble material. The residue was dissolved in dichloromethane (300 mL) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]indole (52.0 g) was added. The mixture was stirred at room temperature for 4 hours, then the mixture was washed twice with water and sat. The insoluble material was filtered, and the filtrate was evaporated. ¹ H-NMR (氘-chloroform) δ 3.88 (3H, s), 5.99 (1H, s), 6.79 (1H, s), 7.45-7.56 (3H, m), 7.83 (2H, d, J = 7.2 Hz ), 8.53 (1H, s).

B) Manufacture of methyl 4-iodo-1-[(phenylcarbonyl)amino]cyclohexanecarboxylate

Zinc iodide (104 g) was added to a solution of the crude product (67.0 g) of 2-[(phenylcarbonyl)amino]prop-2-enoate as described above in dichloromethane (300 mL). Trimethyl[(1-methyleneprop-2-en-1-yl)oxy]decane (173 mL) was added to the mixture, and the mixture was heated under reflux for 24 hr. The reaction was allowed to cool to room temperature, washed with water and dried over anhydrous sodium sulfate. A mixture of 1 M hydrochloric acid and tetrahydrofuran (1:4, 40 mL) was added to the filtrate, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was washed with EtOAcq. The residue was purified by EtOAcjjjjjj elut elut ¹ H-NMR (氘-chloroform) δ 2.49-2.57 (8H, m), 3.79 (3H, s), 6.43 (1H, s), 7.44-7.48 (2H, m), 7.53-7.57 (1H, m) , 7.78-7.80 (2H, m).

C) Manufacture of N-(3-oxo-2-oxabicyclo[2.2.2]oct-4-yl)benzamide

A solution of methyl 4-oxo-1-[(phenylcarbonyl)amino]cyclohexanecarboxylate (56.0 g) obtained above in tetrahydrofuran (300 mL) was cooled to -78 ° C, which was added dropwise. A 1M solution of tris(di-butyl)borohydride/tetrahydrofuran was added and the mixture was stirred at room temperature for 15 hours and allowed to warm to room temperature overnight. The reaction was quenched with aqueous ammonium chloride and most of the tetrahydrofuran was evaporated under reduced pressure. The organic product was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by EtOAcjjjjj elut elut ¹ H-NMR (氘-chloroform) δ 1.72-1.81 (2H, m), 1.93-2.00 (2H, m), 2.14-2.20 (2H, m), 3.25-3.33 (2H, m), 4.80 (1H, t, J = 4.0 Hz), 7.43 - 7.54 (4H, m), 7.80 - 7.82 (2H, m).

D) Manufacture of methyl trans-4-hydroxy-1-[(phenylcarbonyl)amino]cyclohexanecarboxylate

4-methylbenzenesulfonic acid (1.90 g) was added to the above-produced N-(3-oxo-2-oxabicyclo[2.2.2]oct-4-yl)benzamide (26.0 g) The solution was heated under reflux overnight in a solution of methanol (200 mL). The reaction mixture was concentrated to give the title compound (2. Without further purification, the resulting compound was used in the next step of reaction. ¹ H-NMR (氘-chloroform) δ 1.73-1.85 (4H, m), 1.94-2.00 (2H, m), 2.39-2.47 (2H, m), 3.76 (3H, s), 3.98 (1H, d, J = 2.8 Hz), 6.30 (1H, s), 7.42 - 7.54 (4H, m), 7.72 - 7.80 (2H, m).

E) Manufacture of methyl 7-(phenylcarbonyl)-7-indole bicyclo[2.2.1]heptane-1-carboxylate

N-ethyl-N-(1-methylethyl)propan-2-amine (33.8 mL) was added to the above-produced trans-4-hydroxy-1-[(phenylcarbonyl)amino]cyclohexane A solution of methyl carboxylate (27.0 g) in dichloromethane (200 mL). Methylsulfonium chloride (15.2 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction was washed with aq. The residue was dissolved in tetrahydrofuran (300 mL) and cooled to -78. A 1 M solution of 2-methylpropan-2-ol/tetrahydrofuran (150 mL) was added dropwise, and the mixture was stirred at room temperature for one hour, and then allowed to warm to room temperature. After stirring overnight, the mixture was acidified with 1M hydrochloric acid and ethyl acetate was evaporated. The extract was washed with brine and dried over anhydrous sodium sulfate The residue was purified with EtOAc EtOAc EtOAc EtOAc ¹ H-NMR (氘-chloroform) δ 1.53-1.62 (2H, m), 1.78-1.85 (2H, m), 1.89-1.96 (2H, m), 2.32-2.39 (2H, m), 3.81 (3H, s), 4.27 (1H, t, J = 4.8 Hz), 7.38-7.50 (3H, m), 7.02-7.23 (2H, m).

F) Manufacture of 7-[(benzyloxy)carbonyl]-7-fluorenebicyclo[2.2.1]heptane-1-carboxylic acid

A mixture of the above-produced methyl 7-(phenylcarbonyl)-7-indolebicyclo[2.2.1]heptane-1-carboxylate (8.0 g) and concentrated hydrochloric acid (100 mL) was heated under reflux for 24 hours. Concentrate under reduced pressure. Water (50 mL) was added to the residue and the mixture was washed twice with ethyl acetate. The obtained aqueous layer was alkalized with sodium carbonate, and sodium carbonate (9.80 g) and benzyl chlorocarbonate (5.40 mL) were added to 1,4-di A solution of the alkane (30 mL) was stirred at room temperature overnight. The reaction mixture was washed twice with ethyl acetate and the aqueous layer was adjusted to pH 3 with 2M hydrochloric acid. The organic layer was extracted with EtOAc (EtOAc) (EtOAc) ¹ H-NMR (氘-chloroform) δ 1.49-1.56 (2H, m), 1.85-1.95 (4H, m), 2.16-2.20 (2H, m), 4.47 (1H, t, J = 4.4 Hz), 5.14 (2H, s), 7.32-7.37 (5H, m).

G) Manufacture of 1-(chlorocarbonyl)-7-indole bicyclo[2.2.1]heptane-7-carboxylic acid benzyl ester

Ethylene dichloride dichloride (0.80 mL) was added dropwise to 7-[(benzyloxy)carbonyl]-7-indole bicyclo[2.2.1]heptane-1-carboxylic acid (550 mg) prepared above at room temperature. , a mixture of N,N-dimethylformamide (0.02 mL) and tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 30 minutes and the reaction was concentrated under reduced pressure. A small amount of tetrahydrofuran was added to the residue. The crude product of the title compound obtained was used in the next step without further purification.

H) 1-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-7-indolebicyclo[2.2.1]heptane-7 -Manufacture of carboxylic acid benzyl ester

N-Ethyl-N-(1-methylethyl)propan-2-amine (0.70 mL) was added to the 3-amino-5-bromothiophene-2- which was produced in Example 1, Step D, at room temperature. Methionamine (221 mg), the crude product (2.0 mmol) of 1-(chlorocarbonyl)-7-indole bicyclo[2.2.1]heptane-7-carboxylic acid benzyl ester manufactured above, and tetrahydrofuran (10 mL). After stirring for 1 hour, the reaction was poured into a saturated aqueous solution of sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethanol (10 mL) and 2M sodium hydroxide (2.5 mL) were added to the residue, and the mixture was stirred at 100 ° C overnight. The reaction was cooled to room temperature and poured into a saturated aqueous The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.50-1.64 (2H, m), 1.78-1.93 (4H, m), 2.16-2.29 (2H, m), 4.37-4.42 (1H, m), 4.90 (2H) , s), 7.06-7.27 (5H, m), 7.57 (1H, s), 12.52 (1H, s).

I) 2-(7-Indylbicyclo[2.2.1]hept-1-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone monohydrochloride

1-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-7-indolebicyclo[2.2.1]heptane manufactured above Benzene -7-carboxylate (313 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (419 mg), cesium carbonate (1.33 g), 1,2-dimethoxyethane (8 mL) and water (2.0 mL) were placed in a flask and purged with hydrogen Air in the flask. 1,1 '-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (25 mg) was added, and the air in the flask was again purged with argon. The mixture was stirred at 100 ° C for 1 hour. The reaction mixture was poured into aq. aq. The resulting organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and concentrated to give 1-{6-[1-(tris-butoxycarbonyl)-3-methyl- 1H-pyrazol-4-yl]-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}-7-indolebicyclo[2.2.1]heptane- 7-carboxylate benzyl ester (240 mg). The above-prepared 1-{6-[1-(tertiary butoxycarbonyl)-3-methyl-1H-pyrazol-4-yl]-4-yloxy-3,4-dihydrothieno[ 3,2-d]pyrimidin-2-yl}-7-indole bicyclo[2.2.1]heptane-7-carboxylic acid benzyl ester (240 mg) dissolved in methanol (10 mL), 10% palladium-carbon (100 mg) 50% by weight), the mixture was stirred under a hydrogen atmosphere (1 atm) for 2 hours. The reaction system was filtered through a celite pad, and the formic acid was passed through the celite pad to the compound to sufficiently elute. The filtrate was concentrated under reduced pressure and a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with 3:1 ethyl acetate/tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. A 10% HCl/methanol solution (5.0 mL) was added to the residue, and the mixture was stirred at 50 ° C for one hour. The mixture was concentrated under reduced pressure and a mixture of &lt;RTI ID=0.0&gt;&gt; The filtrate was allowed to stand at room temperature for 1 hour, and the title compound (103 mg) ¹ H-NMR (DMSO-d ₆ ) δ 1.79-2.14 (6H, m), 2.37-2.47 (5H, m), 4.16-4.25 (1H, m), 7.38 (1H, s), 7.91-8.40 (1H , m), 9.71 (2H, brs), 12.66-13.15 (2H, m). MS (ESI+): [M+H] ⁺ 328. MS (ESI+), found: 328.

Example 117 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,4S)-4-phenylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone dihydrochloride A) (2S,4S)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-4-phenylpyrrolidine- Manufacture of 1-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (361 mg), (4S)-1-(Terminal D), as in Example 71, Step A, from Example 1, Step D. Oxycarbonyl)-4-phenyl-L-proline (500mg) and 2-methylpropyl chlorocarbonate (0.225mL) and triethylamine (0.239mL) and tetrahydrofuran (10mL) and ethanol (5mL) and 2M Aqueous sodium hydroxide (3.27 mL) gave ¹ H-NMR (DMSO-d ₆ ) δ 1.15 (5.5H, s), 1.39 (3.5H, s), 2.22-2.48 (2H, m), 3.33-3.39 (1H, m), 3.54-3.74 (1H , m), 3.89-4.08 (1H, m), 4.71-4.87 (1H, m), 7.18-7.38 (5H, m), 7.56-7.65 (1H, m), 12.72 (1H, brs).

B) (2S,4S)-2-[6-(5-Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d] Manufacture of pyridyl-2-yl]-4-phenylpyrrolidine-1-carboxylic acid tert-butyl butyl ester

In the same manner as in Example 2, Step C, from (2S,4S)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2- 3-phenylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (250 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Tertiary borolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (323 mg), sodium carbonate (167 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 </ RTI></RTI><RTIgt;</RTI><RTIgt;</RTI></RTI><RTIgt;</RTI></RTI><RTIgt; (231 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.17 (6H, s), 1.40 (3H, s), 2.21-2.48 (5H, m), 3.33-3.41 (1H, m), 3.62-3.79 (1H, m ), 3.93-4.06 (1H, m), 4.76-4.91 (1H, m), 7.18-7.38 (5H, m), 7.43-7.53 (1H, m), 7.79-8.45 (1H, m), 12.32-12.59 (1H, m), 12.84-13.09 (1H, m).

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,4S)-4-phenylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketone dihydrochloride

In the same manner as in Example 108, from (2S,4S)-2-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxooxy-3,4-dihydrothiophene [3,2-d]pyrimidin-2-yl]-4-phenylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (230 mg) and methanol (3.0 mL), 4M HCl / ethyl acetate solution (1.0 mL) The title compound (186 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 2.42-2.57 (4H, m), 2.58-2.70 (1H, m), 3.26-3.44 (1H, m), 3.55-3.71 (1H, m), 3.83-3.97 (1H, m), 4.93-5.05 (1H, m), 7.24-7.45 (6H, m), 8.11 (1H, s), 9.21 (1H, brs), 10.59 (1H, brs), 12.66-13.09 (1H , m).

Example 118 2-(6,6-Dimethylmorpholin-3-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4(3H) -Manufacture of ketone dihydrochloride A) 5-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2,2-dimethylmorpholine-4-carboxylate Manufacture of tertiary butyl acid

2-Methyl chlorocarbonate (0.50 mL) was added to 4-(tertiary butoxycarbonyl)-6,6-dimethylmorpholine-3-carboxylic acid (1.00 g) and three under ice-cooling stirring. A solution of ethylamine (1.08 mL) in tetrahydrofuran (20 mL). After stirring at room temperature for 30 minutes, a solution of 3-amino-5-bromothiophene-2-carboxamide (568 mg) in tetrahydrofuran (3 mL) was obtained. The reaction was heated and stirred at 60 ° C for 3 hours. Water was poured into the reaction system, and the mixture was extracted with EtOAc. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. 2M aqueous sodium hydroxide solution (7.7 mL) and ethanol (20 mL) were added to the residue, and the mixture was stirred and stirred at 80 ° C for 5 hours. The brine was poured into the reaction system, the mixture was extracted with a 3:1 ethyl acetate / tetrahydrofuran mixture, and the extract was washed with brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.05-1.50 (15H, m), 3.30-3.59 (2H, m), 3.86-4.03 (2H, m), 4.68-4.87 (1H, m), 7.61 (1H) , brs), 12.72 (1H, brs).

B) 2-(6,6-Dimethylmorpholin-3-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 ( Manufacture of 3H)-ketone dihydrochloride

5-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-produced above, in the same manner as in Example 83, Step C 2,2-Dimethylmorpholine-4-carboxylic acid tert-butyl butyl ester (111 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Tertiary borolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (154 mg), cesium carbonate (489 mg), 1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) chloride-dichloromethane complex (1:1) (9.1 mg), 1,2-dimethoxyethane (3 mL), water (0.75 mL), 10% HCl/methanol solution ( 2 mL) and MeOH (2 mL) ¹ H-NMR (DMSO-d ₆ ) δ 1.28 (3H, s), 1.34 (3H, s), 2.46 (3H, s), 2.96-3.08 (1H, m), 3.25-3.36 (1H, m), 3.87 (1H, dd, J = 12.8, 9.4 Hz), 4.12-4.24 (1H, m), 4.32-4.44 (1H, m), 7.38 (1H, s), 8.11 (1H, s), 9.42 (1H, Brs), 10.43 (1H, brs), 12.88 (1H, brs).

Example 119 2-[(1S,3S,5S)-2-indolyl[3.1.0]hex-3-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2 -d]Production of pyrimidine-4(3H)-one dihydrochloride A) (1S, 3S, 5S)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-indole bicyclo[ 3.1.0] Manufacture of hexane-2-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (255 mg), (1S, 3S, 5S)-2-, as produced in Example 1, Step D, in the same manner as in Example 71, Step A. (tertiary butoxycarbonyl)-2-indole bicyclo[3.1.0]hexane-3-carboxylic acid (550 mg), 2-methylpropyl chlorocarbonate (0.315 mL), triethylamine (0.399 mL) and tetrahydrofuran (5 mL), 2M aq. ¹ H-NMR (DMSO-d ₆ ) δ 0.64-0.92 (2H, m), 1.06-1.43 (9H, m), 1.49-1.63 (1H, m), 1.92-2.04 (1H, m), 2.55- 2.77 (1H, m), 3.37-3.52 (1H, m), 4.88-5.08 (1H, m), 7.54-7.67 (1H, m), 12.63 (1H, brs).

B) 2-[(1S,3S,5S)-2-indolyl[3.1.0]hex-3-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3 ,2-d]pyrimidine-4(3H)-one dihydrochloride

(1S,3S,5S)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d], as prepared in the same manner as in Example 83, Step C Pyrimidin-2-yl)-2-indole bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl butyl ester (200 mg), 3-methyl-4-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (149 mg), cesium carbonate (316 mg), 1,1'-double ( Diphenylphosphino)ferrocene]palladium(II)-dichloromethane complex (1:1) (20.0 mg), 1,2-dimethoxyethane (5 mL), water (0.5 The title compound (56 mg) was obtained eluted eluted eluted eluted ¹ H-NMR (DMSO-d ₆ ) δ 0.83-1.13 (2H, m), 1.77-1.90 (1H, m), 2.34 (1H, dd, J = 13.6, 3.8 Hz), 2.47 (3H, s), 2.61-2.76(1H,m), 3.35-3.44(1H,m),4.97-5.16(1H,m),7.30-7.46(1H,m),8.11(1H,s),9.22(1H,brs), 10.64-11.11(1H,m), 12.86(1H,brs).

Example 120 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,4R)-4-phenylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone dihydrochloride A) (2S,4R)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-4-phenylpyrrolidine- Manufacture of 1-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (361 mg) and (4R)-1-(tertiary) were prepared in the same manner as in Example 71, Step A, from Example 1, Step D. Oxycarbonyl)-4-phenyl-L-proline (500mg) and 2-methylpropyl chlorocarbonate (0.225mL) and triethylamine (0.239mL) and tetrahydrofuran (10mL) and ethanol (5mL) and 2M Aqueous sodium hydroxide (3.27 mL) gave ¹ H-NMR (DMSO-d ₆ ) δ 1.15 (6H, s), 1.37 (3H, s), 2.01-2.21 (1H, m), 2.58-2.71 (1H, m), 3.41-3.61 (2H, m ), 3.85-3.98 (1H, m), 4.64 - 4.75 (1H, m), 7.19-7.40 (5H, m), 7.60-7.67 (1H, m), 12.81 (1H, brs).

B) (2S,4R)-2-[6-(5-Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d] Manufacture of pyridyl-2-yl]-4-phenylpyrrolidine-1-carboxylic acid tert-butyl butyl ester

In the same manner as in Example 2, Step C, from (2S,4R)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2- 3-phenylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (250 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Tertiary borolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (323 mg), sodium carbonate (167 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 </ RTI></RTI><RTIgt;</RTI><RTIgt;</RTI></RTI><RTIgt;</RTI></RTI><RTIgt; (218 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.12 (6H, s), 1.38 (3H, s), 2.06-2.23 (1H, m), 2.38-2.48 (3H, m), 2.60-2.77 (1H, m), 3.42-3.62 (2H, m), 3.87-3.98 (1H, m), 4.64-4.79 (1H, m), 7.18-7.47 (6H, m), 7.79-8.33 (1H, m), 12.40- 12.65 (1H, m), 12.83-13.09 (1H, m).

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,4R)-4-phenylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketone dihydrochloride

In the same manner as in Example 108, from (2S,4R)-2-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxooxy-3,4-dihydrothiophene [3,2-d]pyrimidin-2-yl]-4-phenylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (210 mg) and methanol (3.0 mL) and 4M HCl / ethyl acetate solution (1.0 mL) The title compound (172 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 2.16-2.30 (1H, m), 2.47 (3H, s), 2.89-3.04 (1H, m), 3.28-3.45 (1H, m), 3.59-3.86 (2H , m), 4.78-4.93 (1H, m), 7.24-7.44 (6H, m), 8.11 (1H, s), 9.36 (1H, brs), 10.48 (1H, brs), 12.90 (1H, brs).

Example 121 2-[Amino(cyclohexyl)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride Salt manufacturing A) Preparation of [(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)(cyclohexyl)methyl]aminecarboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (265 mg), (2S)-[(tri-tertoxy) as described in Example 71, Step A, from Example 1, Step D Carbonyl)amino](cyclohexyl)acetic acid (648 mg), 2-methylpropyl chlorocarbonate (0.327 mL), triethylamine (0.416 mL) and tetrahydrofuran (5 mL), 2M aqueous sodium hydroxide (3.00 mL) Ethyl alcohol (5 mL) gave ¹ H-NMR (DMSO-d ₆ ) δ 0.73-1.88 (21H, m), 3.71-4.34 (1H, m), 6.80-7.16 (1H, m), 12.49 (1H, brs).

B) 2-[Amino(cyclohexyl)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacture of hydrochloride

[(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) (cyclo), as prepared in the same manner as in Example 83, Step C Hexyl)methyl] carbamic acid tert-butyl butyl ester (499 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (697 mg), cesium carbonate (737 mg), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II) - dichloromethane complex (1:1) (46.5 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL), 4M HCl/EtOAc (1 mL) and methanol (4 mL) The title compound (125 mg) was obtained as a colourless solid. ¹ H-NMR (DMSO-d ₆ ) δ 0.91-2.03 (11H, m), 2.47 (3H, s), 3.98-4.18 (1H, m), 5.99 (2H, brs), 7.31-7.39 (1H, m ), 8.11 (1H, s), 8.71 (3H, s), 12.80 (1H, brs).

Example 122 6-(5-Methyl-1H-pyrazol-4-yl)-2-(1,2,3,4-tetrahydroquinolin-2-yl)thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone dihydrochloride A) 2-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3,4-dihydroquinolin-1 (2H) -Manufacture of carboxylic acid tertiary butyl ester

3-Amino-5-bromothiophene-2-carboxamide (265 mg), (2S)-1-(tri-butyl), as in Example 71, Step A, from Example 1, Step D Oxycarbonyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid (699 mg), 2-methylpropyl chlorocarbonate (0.327 mL), triethylamine (0.416 mL) and tetrahydrofuran (5 mL) The title compound (245 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.22-1.33 (9H, m), 1.73-1.90 (1H, m), 2.24-2.40 (1H, m), 2.55-2.77 (2H, m), 5.10 (1H) , t, J = 7.3 Hz), 6.92-7.03 (1H, m), 7.08-7.24 (2H, m), 7.56 (1H, s), 7.79 (1H, d, J = 8.1 Hz), 12.85 (1H, Brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(1,2,3,4-tetrahydroquinolin-2-yl)thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketone dihydrochloride

2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-produced above, in the same manner as in Example 83, Step C 3,4-Dihydroquinoline-1(2H)-carboxylic acid tert-butyl butyl ester (200 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (267 mg), cesium carbonate (282 mg), 1,1'-bis(diphenylphosphino) ferrocene Iron] palladium(II) chloride-dichloromethane complex (1:1) (17.8 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL), 4M HCl/ethyl acetate The ester solution (1 mL) and EtOAc (EtOAc) ¹ H-NMR (DMSO-d ₆ ) δ 2.09-2.24 (2H, m), 2.46 (3H, s), 2.63 - 2.86 (2H, m), 4.54 (1H, t, J = 5.8 Hz), 6.48- 7.83 (10H, m), 8.09 (1H, s).

Example 123 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl]thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one A) Manufacture of 1-(1-benzylmethyl-3-methyl-1H-pyrazol-4-yl)ethanone

A mixture of pentane-2,4-dione (10.01 g) and 1,1-dimethoxy-N,N-dimethylmethylamine (12.51 g) was stirred at 80 ° C for 1 hour. Tetrahydrofuran (20 mL) was added to the reaction mixture, and hydrazine hydrate (7.51 g) was added in small portions under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was warmed to room temperature and ethyl acetate (100 mL) and water (100 mL). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered out, and the filtrate was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1-(5-Methyl-1H-pyrazol-4-yl)ethanone was dissolved in N,N-dimethylformamide (10 mL), and bromotoluene (18.80 g) and potassium carbonate (15.20) were added thereto. g) The mixture was stirred at 60 ° C for 18 hours. The reaction mixture was warmed to room temperature and ethyl acetate (100 mL) and water (100 mL). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 2.36 (3H, s), 2.49 (3H, s), 5.24 (2H, s), 7.04-7.44 (5H, m), 7.73 (1H, s).

B) Manufacture of (2Z)-3-(1-benzyl-3-methyl-1H-pyrazol-4-yl)-3-chloroprop-2-enenitrile

Phosphorus oxychloride (28.1 g) was added to N,N-dimethylformamide (13.4 g) in small portions under ice cooling, and the mixture was stirred at room temperature for 15 min. The above-prepared 1-(1-benzylmethyl-3-methyl-1H-pyrazol-4-yl)ethanone (9.80 g) was added in small portions under ice cooling, and the reaction mixture was stirred at 50 ° C. minute. The powdered hydroxylamine hydrochloride (25.4 g) was added in small portions at 50 ° C, and the reaction mixture was stirred at 50 ° C for 30 minutes. Ice water (200 mL) was added to the reaction mixture, and the mixture was evaporated to ethyl ether (100 mL). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAcjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 2.39 (3H, s), 5.22 (2H, s), 5.65 (1H, s), 7.02-7.48 (5H, m), 7.64 (1H, s).

C) Manufacture of methyl 3-amino-5-(1-benzyl-3-methyl-1H-pyrazol-4-yl)thiophene-2-carboxylate

(2Z)-3-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-3-chloroprop-2-enenitrile (5.73 g), thioacetate A A mixture of the ester (2.95 g), sodium hydride (0.80 g) and N,N-dimethylformamide (10 mL) was stirred at 60 ° C for 2 hours. Ethyl acetate (20 mL) and water (10 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the residue was evaporated. ¹ H-NMR (DMSO-d ₆ ) δ 2.33 (3H, s), 3.65 (3H, s), 5.23 (2H, s), 7.04-7.44 (6H, m), 7.49 (1H, s).

D) Manufacture of 2-benzylmethyl 1-tributyl (2S, 3aS, 6aS)-hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate

(2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid benzyl ester hydrochloride (1.00g), di-tertiary butyl dicarbonate (1.16g), triethylamine A mixture of (0.72 g) and tetrahydrofuran (10 mL) was stirred at room temperature for 18 h. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (10mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The title compound (1.23 g) was obtained eluted eluted elute ¹ H-NMR (DMSO-d ₆ ) δ 1.20-1.57 (11H, m), 1.57-2.05 (5H, m), 2.30-2.50 (1H, m), 2.58-2.73 (1H, m), 4.08-4.53 (2H, m), 5.00-5.30 (2H, m), 7.25-7.45 (5H, m).

E) (2S, 3aS, 6aS)-1-(tertiary butoxycarbonyl) octahydrocyclopenta[b]pyrrole-2-carboxylic acid

2-Benzyl 1-tertiary butyl (2S,3aS,6aS)-hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylic acid prepared above under a hydrogen atmosphere at room temperature The ester (1.23 g), 20% palladium hydroxide-carbon (200 mg) and methanol (5 mL) were stirred for 1 hour. The insoluble material was filtered, and the filtrate was evaporated to dryness, ethyl acetate (50mL) and water (50mL) was added to the residue, and the separated aqueous layer was extracted with ethyl acetate (10mL × 2). The collected organic layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. The title compound (0.91 g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.40-1.65 (13H, m), 1.65-2.00 (3H, m), 2.15-2.25 (1H, m), 2.35-2.45 (1H, m), 2.60-2.75 (1H, m), 4.12-4.23 (1H, m), 4.37-4.48 (1H, m).

F) (3aS, 6aS)-2-{[5-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2-(methoxycarbonyl)thiophen-3-yl]amine Manufacture of dimethyl hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylic acid tert-butyl butyl ester

(2S, 3aS, 6aS)-1-(tertiary butoxycarbonyl) octahydrocyclopenta[b]pyrrole-2-carboxylic acid (766 mg), 2-methylpropyl chlorocarbonate (410 mg) manufactured above A mixture of triethylamine (304 mg) and tetrahydrofuran (10 mL) was stirred for 1 hour under ice-cooling to afford 3-amino-5-(1-phenylmethyl-3-methyl). Methyl-1H-pyrazol-4-yl)thiophene-2-carboxylate (327 mg) was added to the obtained reaction mixture under ice cooling, and the mixture was stirred at 60 ° C for 18 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (10mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the filtrate was evaporated,jjjjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.20-1.65 (12H, m), 1.65-1.85 (2H, m), 1.90-2.20 (4H, m), 2.48 (3H, s), 2.60-3.80 (1H , m), 3.85 (3H, s), 4.20-4.35 (1H, m), 5.24 (2H, s), 7.10-7.40 (6H, m), 7.60 (1H, s), 8.10 (1H, s).

G) (3aS, 6aS)-2-[6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[ Manufacture of 3,2-d]pyrimidin-2-yl]hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylic acid tert-butyl butyl ester

(3aS,6aS)-2-{[5-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2-(methoxycarbonyl)thiophen-3-yl a mixture of carbamoyl}hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylic acid tert-butyl butyl ester (340 mg), 2M aqueous sodium hydroxide (2 mL) and methanol (10 mL) was stirred at 60 ° C 1 hour. The reaction mixture was neutralized with EtOAc (2 mL). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (2 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.15 g), 1 Hydroxybenzotriazole (810 mg), ammonium chloride (1.28 g) and triethylamine (0.705 mL), and the mixture was stirred at 80 ° C for 18 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (10 mL). The reaction mixture was neutralized with EtOAc (EtOAc) (EtOAc) The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the residue was evaporated,jjjjjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.35-1.55 (12H, m), 1.60-1.80 (4H, m), 2.00-2.10 (2H, m), 2.50 (3H, s), 2.70-2.85 (1H) , m), 4.20-4.85 (1H, m), 5.27 (2H, s), 7.17 (1H, s), 7.23-7.47 (5H, m), 7.38 (1H, s).

H) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl]thieno[3,2- Manufacture of d]pyrimidin-4(3H)-one

The above-produced (3aS,6aS)-2-[6-(1-benzylmethyl-3-methyl-1H-pyrazol-4-yl)-4-yloxy group was produced under a hydrogen atmosphere at 60 ° C. 3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylic acid tert-butyl butyl ester (220 mg), formic acid (5 mL) And 20% palladium hydroxide-carbon (20 mg) was stirred for 18 hours. The insoluble material was filtered, and the filtrate was evaporated,jjjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.45-1.80 (6H, m), 1.95-2.05 (1H, m), 2.46 (3H, s), 2.62-2.78 (1H, m), 2.80-2.95 (1H) , m), 4.02 (1H, brs), 4.41-4.58 (1H, m), 7.39 (1H, s), 8.08 (1H, brs).

Example 124 2-(1-Ethylpyrrolidin-2-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacturing A) 2-[5-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2-(methoxycarbonyl)thiophen-3-ylaminecarboxylidene]pyrrolidine-1 -Manufacture of carboxylic acid tertiary butyl ester

3-Amino-5-(1-benzyl-3-methyl-1H-pyrazol-4-yl)thiophene was prepared in the same manner as in Example 123, Step F from Example 123, Step C. Methyl 2-carboxylate (1.00 g), 1-(tertiary butoxycarbonyl)proline (1.97 g), 2-methylpropyl chlorocarbonate (1.25 g), triethylamine (0.93 g) and The title compound (1.20 g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.25-1.55 (10H, m), 1.85-2.05 (2H, m), 2.10-2.35 (2H, m), 2.48 (3H, s), 3.55-3.70 (1H , m), 3, 87 (3H, s), 4.25-4, 35 (1H, m), 5.24 (2H, s), 7.10-7.40 (6H, m), 7.59 (1H, s), 8.08 (1H , s).

B) 2-[6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d] Manufacture of pyridin-2-yl]pyrrolidine-1-carboxylic acid tert-butyl butyl ester

2-[5-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2-(methoxycarbonyl)thiophene was prepared from the same manner as in Example 123, Step G. -3-ylaminocarbamimidyl]pyrrolidine-1-carboxylic acid tert-butyl butyl ester (1.20 g), 2M aqueous sodium hydroxide solution (2 mL), methanol (10 mL), and 1-ethyl-3-(3- Dimethylaminopropyl)carbodiimide hydrochloride (4.39g), 1-hydroxybenzotriazole (3.10g), ammonium chloride (4.90g), triethylamine (9.27g), N,N- Dimethylformamide (10 mL), EtOAc (EtOAc m. ¹ H-NMR (DMSO-d ₆ ) δ 1.30-1.55 (13H, m), 1.90-2.10 (2H, m), 2.50 (3H, s), 3.15-3.25 (1H, m), 5.27 (1H, s), 5.32-5.38 (1H, m), 7.18 (1H, s), 7.26-7.38 (5H, m), 7.61 (1H, s).

C) 6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-2-yl)thieno[3,2-d]pyrimidine-4 (3H )--Manufacture of ketone

2-[6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-4-oxooxy-3,4-dihydrothieno[3,2- A mixture of d]pyrimidin-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (0.85 g) and trifluoroacetic acid (5 mL) was stirred for 1 hour under ice cooling. The reaction mixture was concentrated under reduced pressure. ethyl acetate (20 mL) and water (20mL) The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The title compound (0.67 g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.45-1.90 (4H, m), 2.49 (3H, s), 3.05-3.20 (2H, m), 4.30-4.40 (1H, m), 5.27 (2H, s), 5.35-5.40 (1H, m), 7.10-7.20 (1H, m), 7.17 (1H, s), 7.26-7.38 (5H, m), 7.61 (1H, s).

D) 2-(1-Ethylpyrrolidin-2-yl)-6-(1-benzyl-3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine -4(3H)-one manufacture

6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-2-yl)thieno[3,2-d]pyrimidine-4 A mixture of (3H)-one (196 mg), acetic anhydride (255 mg) and pyridine (5 mL) was stirred at 60 ° C for 18 hours. Ethyl acetate (50 mL) and water (50 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the filtrate was evaporated, mjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.90-2.20 (4H, m), 2.17 (3H, s), 2.50 (3H, s), 2.75-2.90 (1H, m), 3.50-3.70 (2H, m ), 5.15-5.40 (2H, m), 7.17 (1H, s), 7.26-7.40 (5H, m), 7.60 (1H, s).

E) 2-(1-Ethylpyrrolidin-2-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)- Ketone manufacturing

2-(1-Ethylpyrrolidin-2-yl)-6-(1-benzylmethyl-3-methyl-1H-pyrazole-4) was prepared from the same procedure as in Example 123, Step H - yl) thieno[3,2-d]pyrimidin-4(3H)-one (216 mg), EtOAc (5 mL), m. . ¹ H-NMR (DMSO-d ₆ ) δ 1.90-2.10 (4H, m), 2.20 (3H, brs), 2.45 (3H, brs), 3.50-3.65 (1H, m), 3.65-3.80 (1H, m ), 4.77 (1H, dd, J = 8.3, 3.6 Hz), 7.34 (1H, s), 7.89 (1H, brs).

Example 125 2-[(1R ^* ,2S ^* )-2-Aminocyclohexyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 (3H )-Manufacture of ketone dihydrochloride A) [(1R ^* ,25 ^* )-2-(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)cyclohexyl]aminecarboxylic acid Manufacture of tertiary butyl ester

In the same manner as in Example 82, Step A, from (1R*, 2S*)-2-[(tris-butoxycarbonyl)amino]cyclohexanecarboxylic acid (365 mg) and triethylamine (0.418 mL) Tetrahydrofuran (10 mL) and 2-methylpropyl chlorocarbonate (0.195 mL) and 3-amino-5-bromothiophene-2-carboxamide (221 mg) and 2M sodium hydroxide produced in Example 1, Step D Aqueous (3 mL) and EtOAc (3 mL) MS (ESI +): [M + H] + 428.MS (ESI +), Found: 428.

B) 2-[(1R ^* , 2S ^* )-2-Aminocyclohexyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone dihydrochloride

[(1R ^* ,2S ^* )-2-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-], as prepared in the same manner as in Example 83, Step C d]pyrimidin-2-yl)cyclohexyl]carbamic acid tert-butyl butyl ester (63 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (91 mg), cesium carbonate (288 mg), 1,1'-bis(diphenylphosphino) ferrocene Iron] palladium(II) chloride-dichloromethane complex (1:1) (5.4 mg), 1,2-dimethoxyethane (3 mL), water (0.50 mL), 10% HCl/methanol The title compound (20 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.28-1.88 (6H, m), 1.93-2.19 (2H, m), 2.46 (3H, s), 3.04-3.14 (1H, m), 3.72 (1H, brs ), 7.38 (1H, s), 7.99 (3H, brs), 8.04 (1H, brs), 12.40 (1H, brs).

Example 126 2-(6-(5-Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)pyrrolidine Manufacture of -1-carbamamine A) 2-(6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d] Manufacture of pyrimidin-2-yl)pyrrolidine-1-carboxamide

6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-2-yl)thiophene [3,2] will be prepared in Example 124, Step C A mixture of -d-pyrimidine-4(3H)-one (196 mg), N,N'-carbonyldiimidazole (162 mg) and pyridine (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 8MNH ₃ / methanol solution, and the mixture was stirred at room temperature for 18 hours. Ethyl acetate (50 mL) and water (50 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (10mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the filtrate was evaporated, mjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.80-2.25 (4H, m), 2.25-2.35 (1H, m), 2.38 (3H, s), 3.45-3.55 (1H, m), 4.73 (1H, dd , J = 7.9, 3.2 Hz), 5.28 (2H, s), 5.98 (2H, s), 7.15-7.48 (6H, m), 8.37 (1H, s).

B) 2-(6-(5-Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) Manufacture of pyrrolidine-1-carboxamide

2-(6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-4- oxo-3, as prepared from the above, in the same manner as in Example 123, Step H 4-Dihydrothieno[3,2-d]pyrimidin-2-yl)pyrrolidine-1-carboxamide (60 mg), formic acid (5 mL), and 20% palladium hydroxide-carbon (20 mg) afforded colorless The title compound (23 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.90-2.10 (3H, m), 2.15-2.30 (1H, m), 2.45 (3H, brs), 3.50-3.65 (1H, m), 3.65-3.80 (1H , m), 4.77 (1H, dd, J = 8.3, 3.6 Hz), 7.34 (1H, s), 7.89 (1H, brs).

Example 127 Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-1-ylcarbonyl)thieno[3,2-d]pyrimidin-4(3H)-one

3-Amino-5-bromothiophene-2-carboxamide (100 mg), and side oxygen (pyrrolidin-1-yl), as in Example 11, Step A, from Example 1, Step D. Acetic acid (68 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (206 mg) and N-ethyl -N-(1-methylethyl)propan-2-amine (0.158 mL) and N,N-dimethylformamide (2 mL) and ethanol (1 mL) and 2M aqueous sodium hydroxide (0.91 mL) 6-Bromo-2-(pyrrolidin-1-ylcarbonyl)thieno[3,2-d]pyrimidin-4(3H)-one as a yellow solid. 6-Bromo-2-(pyrrolidin-1-ylcarbonyl)thieno[3,2-d]pyrimidin-4(3H)-one and 3-produced therefrom, in the same manner as in Example 2, Step C Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester ( 263 mg), sodium carbonate (136 mg), 1,2-dimethoxyethane (2.0 mL) and water (1.0 mL) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II)-Dichloromethane complex (1:1) (35 mg) ¹ H-NMR (DMSO-d ₆ ) δ 1.82-1.95 (4H, m), 2.39-2.48 (3H, m), 3.44-3, 57 (2H, m), 3.64-3.78 (2H, m), 7.43 (1H, s), 7.85-8.45 (1H, m), 12.47-12.67 (1H, m), 12, 87-13.11 (1H, m).

Example 128 2-[(1R ^* ,3S,4R ^* ,5S)-5-fluoro-2-indenylbicyclo[2.2.1]heptan-3-yl]-6-(5-methyl-1H-pyrazole-4- Manufacture of thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride A) (1R ^* , 3S, 4R ^* , 5S)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5 -Production of fluoro-2-indolyl [2.2.1] heptane-2-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (200 mg) and (1R ^* , 3S, 4R ^* , 5S) were prepared in the same manner as in Example 71, Step A, from Example 1, Step D. -2-(tertiary butoxycarbonyl)-5-fluoro-2-indenylbicyclo[2.2.1]heptane-3-carboxylic acid (352 mg) and 2-methylpropyl chlorocarbonate (0.178 mL) and Ethylamine (0.190 mL), EtOAc (EtOAc m. ¹ H-NMR (DMSO-d ₆ ) δ 1.07-1.67 (11H, m), 2.00-2.33 (2H, m), 2.93-3.06 (1H, m), 4.05-4.24 (1H, m), 4.63-4.77 (1H, m), 5.18-5.51 (1H, m), 7.54-7.79 (1H, m), 12.59-12.98 (1H, m).

B) (1R ^* , 3S, 4R ^* , 5S)-5-fluoro-3-[6-(5-methyl-1H-pyrazol-4-yl)-4- oxo-3,4-di Manufacture of tert-butyl butyl thiothieno[3,2-d]pyrimidin-2-yl]-2-indolebicyclo[2.2.1]heptane-2-carboxylate

(1R ^* ,3S,4R ^* ,5S)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5- Fluor-2-indole bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester (300 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (416 mg), sodium carbonate (215 mg), 1,2-dimethoxyethane (3.0 mL) Water (1.5 mL) was placed in the flask and the air in the flask was purged with argon. 1,1 '-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (55 mg) was added, and the air in the flask was again purged with argon. The reaction was stirred at 100 ° C for 3 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) for high-performance liquid chromatography (column: L-column 2 ODS (20 mm id x 50 mmL), mobile phase: 0.1% trifluoroacetic acid The resulting pale yellow solid was purified using aqueous solution / 0.1% trifluoroacetic acid - EtOAc. The target was distinguished by a saturated aqueous sodium hydrogencarbonate solution, and the mixture was concentrated under reduced pressure. The residue was collected by EtOAcjjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.12-1.61 (11H, m), 2.05-2.34 (2H, m), 2.36-2.48 (3H, m), 2.93-3.07 (1H, m), 4.04-4.28 (1H, m), 4.58-4.83 (1H, m), 5.17-5.53 (1H, m), 7.33-7.54 (1H, m), 7.81-8.34 (1H, m), 12.31-12.61 (1H, m) , 12.82-13.13 (1H, m).

C) 2-[(1R ^* ,3S,4R ^* ,5S)-5-fluoro-2-indolyl[2.2.1]heptan-3-yl]-6-(5-methyl-1H-pyrazole- Manufacture of 4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride

In the same manner as in Example 108, from (1R ^* , 3S, 4R ^* , 5S)-5-fluoro-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-side oxygen 3-,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-indolebicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (80 mg) and methanol ( The title compound (71 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.66-1.77 (1H, m), 1.81-2.02 (2H, m), 2.16-2.34 (1H, m), 2.46 (3H, s), 3.25-3.31 (1H , m), 4.3-4.25 (1H, m), 4.77-4.87 (1H, m), 5.23-5.54 (1H, m), 7.37 (1H, s), 8.10 (1H, s), 8.79 (1H, brs ), 10.23 (1H, brs), 13.09 (1H, brs).

Example 129 2-[(1R*,2R*)-2-aminocyclohexyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 (3H )-Manufacture of ketone dihydrochloride A) [(1R*, 2R*)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)cyclohexyl]aminecarboxylic acid Manufacture of tertiary butyl ester

In the same manner as in Example 82, Step A, from (1R*, 2R*)-2-[(tris-butoxycarbonyl)amino]cyclohexanecarboxylic acid (365 mg) and triethylamine (0.418 mL) Tetrahydrofuran (10 mL) and 2-methylpropyl chlorocarbonate (0.195 mL) and 3-amino-5-bromothiophene-2-carboxamide (221 mg) and 2M sodium hydroxide produced in Example 1, Step D Aqueous (3 mL) and EtOAc (EtOAc) MS (ESI +): [M + H] + 428.MS (ESI +), Found: 428.

B) 2-[(1R*,2R*)-2-Aminocyclohexyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone dihydrochloride

[(1R*, 2R*)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-], as prepared in the same manner as in Example 83, Step C d]pyrimidin-2-yl)cyclohexyl]carbamic acid tert-butyl butyl ester (61 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (87 mg), cesium carbonate (277 mg), 1,1'-bis(diphenylphosphino) ferrocene Iron] palladium(II) chloride-dichloromethane complex (1:1) (5.2 mg), 1,2-dimethoxyethane (3 mL), water (0.50 mL), 10% HCl/methanol The title compound (27 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.16-1.55 (4H, m), 1.69-1.84 (2H, m), 2.01-2.15 (2H, m), 2.45 (3H, s), 2.75-2.87 (1H , m), 3.50-3.64 (1H, m), 7.36 (1H, s), 7.94 (3H, brs), 8.05 (1H, s), 12.45 (1H, brs).

Example 130 Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-(1H-pyrrol-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one

6-bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H) as in Example 2, Step A, as in Example 2, Step B and Step C. a ketone (180 mg) and 2,5-dihydro-1H-pyrrole (0.150 mL) and potassium carbonate (178 mg) and sodium iodide (9.7 mg) and N,N-dimethylformamide (3.0 mL) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl Ester (248 mg) and sodium carbonate (128 mg) and 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and 1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium(II)-dichloromethane complex (1:1) (33 mg) gave ¹ H-NMR (DMSO-d ₆ ) δ 2.37-2.48 (3H, m), 5.03 (2H, s), 6.02 (2H, t, J = 2.1 Hz), 6.87 (2H, t, J = 2.1 Hz) , 7.38 (1H, s), 7.79-8.31 (1H, m), 12.63 (1H, brs), 12.87-13.06 (1H, m).

Example 131 Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-morpholin-2-ylthieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride A) Manufacture of 2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)morpholine-4-carboxylic acid tert-butyl butyl ester

In the same manner as in Example 118, Step A, from 3-amino-5-bromothiophene-2-carboxamide (221 mg), 4-(tertiary butoxycarbonyl) manufactured in Example 1, Step D? Benzene-2-carboxylic acid (347 mg), 2-methylpropyl chlorocarbonate (0.195 mL), triethylamine (0.418 mL) and tetrahydrofuran (10 mL), 2M aqueous sodium hydroxide (3.0 mL) and ethanol (10 mL) The title compound (290 mg) was obtained as white crystal. ¹ H-NMR (DMSO-d ₆ ) δ 1.42 (9H, s), 2.91-3.06 (1H, m), 3.09-3.25 (1H, m), 3.53 (1H, td, J = 11.4, 2.7 Hz) , 3.72-3.80 (1H, m), 3.92-4.00 (1H, m), 4.00-4.13 (1H, m), 4.38 (1H, dd, J = 10.2, 3.0 Hz), 7.65 (1H, s), 12.57 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-morpholin-2-ylthieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride Manufacturing

Is 2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) produced as above in the same manner as in Example 83, Step C? Tertiary butyl 4-carboxylic acid (290 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (429 mg), cesium carbonate (1.34 g), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II) - dichloromethane complex (1:1) (26 mg), 1,2-dimethoxyethane (6 mL), water (2 mL), 10% HCl/methanol (4 mL) and methanol (4 mL) The title compound (102 mg) was obtained as white crystal. ¹ H-NMR (DMSO-d ₆ ) δ 2.46 (3H, s), 3.04-3.60 (4H, m), 3.83-4.13 (2H, m), 4.81 (1H, dd, J = 10.1, 2.7 Hz), 7.43 (1H, s), 8.05 (1H, s), 9.29-9.53 (2H, m), 12.55 (1H, brs).

Example 132 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2R ^* ,3R ^* )-3-phenylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketone dihydrochloride A) (2R ^* ,3R ^* )-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3-phenylpyrrole Manufacture of pyridine-1-carboxylic acid tert-butyl butyl ester

In the same manner as in Example 82, Step A, from ((2R ^* ,3R ^* )-1-(tertiarybutoxycarbonyl)-3-phenylproline (437 mg) and triethylamine (0.418 mL) Tetrahydrofuran (10 mL) and 2-methylpropyl chlorocarbonate (0.195 mL) and 3-amino-5-bromothiophene-2-carboxamide (221 mg) and 2M sodium hydroxide produced in Example 1, Step D aqueous solution (3mL) and ethanol (10 mL) to give the title compound as a white solid (27mg) .MS (ESI +) : [M + H] + 476.MS (ESI +), Found: 476.

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2R ^* ,3R ^* )-3-phenylpyrrolidin-2-yl]thieno[3,2-d Manufacture of pyrimidine-4(3H)-one dihydrochloride

(2R ^* ,3R ^* )-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d], as prepared in the same manner as in Example 83, Step C Pyrimidin-2-yl)-3-phenylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (27 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (35 mg), cesium carbonate (111 mg), 1,1'-bis(diphenylphosphino) ) ferrocene] palladium(II) chloride-dichloromethane complex (1:1) (2.1 mg), 1,2-dimethoxyethane (2 mL), water (0.17 mL), 10% The title compound (11 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 2.41-2.56 (5H, m), 3.36-3.52 (1H, m), 3.71-3.83 (1H, m), 3.95-4.08 (1H, m), 4.88-4.98 (1H, m), 7.07-7.23 (5H, m), 7.36 (1H, s), 8.09 (1H, s), 9.20 (1H, brs), 10.34 (1H, brs), 12.39 (1H, brs).

Example 133 2-[(Methylamino)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride Manufacturing A) Preparation of [(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)methyl]methylaminecarboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (473 mg), N-(tertiary butoxycarbonyl)-, as in Example 71, Step A, from Example 1, Step D. N-methylglycine (850 mg), 2-methylpropyl chlorocarbonate (0.583 mL), triethylamine (0.741 mL) and tetrahydrofuran (5 mL), 2M aqueous sodium hydroxide (5.35 mL) and ethanol (10 mL) The title compound (780 mg) was obtained as a colourless solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.31-1.49 (9H, m), 2.77-2.87 (3H, m), 3.79-3.90 (2H, m), 7.60 (1H, s), 12.63 (1H, brs ).

B) 2-[(Methylamino)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one di-salt Manufacture of acid salt

[(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)methyl) was prepared from the same manner as in Example 83, Step C ] Methylaminocarbamic acid tert-butyl ester (400 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylic acid tert-butyl 659mg), cesium carbonate (696mg), 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloride Methane complex (1:1) (44.0 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL), 4M HCl/EtOAc (1 mL) and methanol (5 mL) The title compound (50 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 2.47 (3H, s), 2.69 (3H, brs), 4.23 (2H, brs), 7.31-8.30 (5H, m), 9.54 (2H, brs).

Example 134 2-(2-Amino-2-methylpropyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacture of dihydrochloride A) [2-(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-1,1-dimethylethyl]aminecarboxylic acid Manufacture of tertiary butyl ester

3-Amino-5-bromothiophene-2-carboxamide (412 mg), 3-[(tertiary-butoxycarbonyl), as in Example 71, Step A, from Example 1, Step D. Amino]-3-methylbutyric acid (850 mg), 2-methylpropyl chlorocarbonate (0.507 mL), triethylamine (0.646 mL), and tetrahydrofuran (5 mL), 2M aqueous sodium hydroxide (4.66 mL) The title compound (780 mg) was obtained from EtOAc. ¹ H-NMR (DMSO-d ₆ ) δ 1.24-1.43 (15H, m), 2.92 (2H, s), 7.51 (1H, s), 11.77-12.47 (2H, m).

B) 2-(2-Amino-2-methylpropyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4(3H) -Manufacture of ketone dihydrochloride

[2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) was prepared from the same manner as in Example 83, Step C. -1,1-Dimethylethyl]carbamic acid tert-butyl butyl ester (700 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Tert-butyl butyl bromide-2-yl)-1H-pyrazole-1-carboxylate (1072 mg), cesium carbonate (1134 mg), 1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) chloride-dichloromethane complex (1:1) (71.6 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL), 4M HCl/EtOAc ( 1 mL) and MeOH (4 mL) ¹ H-NMR (DMSO-d ₆ ) δ 1.39 (6H, s), 2.48 (3H, s), 3.02 (2H, s), 6.95 (3H, brs), 7.39-7.44 (1H, m), 8.09 ( 1H, s), 8.37 (3H, brs).

Example 135 2-(1-Amino-1-methylethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacture of dihydrochloride

Thionine dichloride (0.673 mL) was added to a solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-methylalanine (3.00 g) in toluene (20 mL). The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then 3-amino-5-bromothiophene-2-carbamide (1.70 g), pyridine (729 mg), and tetrahydrofuran (5 mL) The residue was stirred at 100 ° C for 15 hours. Ethyl acetate (20 mL) and water (10 mL) were added toEtOAc. The collected organic layer was washed with brine (5 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered out, and the filtrate was concentrated to give crystals (yield: (2-[(5-bromo-2-amine-carbamoylthiophen-3-yl)amino)-1, 1- Methyl-2-oxoethyl}aminecarboxylic acid 9H-inden-9-ylmethyl ester.

A 2 M aqueous sodium hydroxide solution (19.2 mL) was added to the {2-[(5-bromo-2-aminomethylsulfonylthiophen-3-yl)amino]-1,1-dimethyl-2- side prepared above. To a solution of 9H-inden-9-ylmethyl oxoacetate in ethanol (50 mL), the mixture was stirred at 70 ° C for 15 hr. The reaction mixture was neutralized with 1M hydrochloric acid (38.4 mL) and evaporated. The residue was dissolved in tetrahydrofuran (20 mL). Ethyl acetate (20 mL) and water (10 mL) were added toEtOAc. The collected organic layer was washed with brine (5 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give [1-(6-bromo-4- </RTI><RTIgt;</RTI><RTIgt; 3-tert-butyl-1-methylethyl]aminecarboxylic acid. [1-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) was prepared from the same manner as in Example 83, Step C. 3-tert-butyl -1-methylethyl]aminecarboxylic acid, 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (1.03 g), cesium carbonate (1.09 g), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( II)-Dichloromethane complex (1:1) (68.9 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL), 4M HCl/EtOAc (1 mL) and methanol The title compound (240 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.74 (6H, s), 2.49 (3H, s), 7.41 (1H, s), 7.59-8.99 (7H, m).

Example 136 6-(5-Methyl-1H-pyrazol-4-yl)-2-(1,2,3,6-tetrahydropyridin-2-yl)thieno[3,2-d]pyrimidine-4 ( Manufacture of 3H)-ketone dihydrochloride A) 2-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)- Manufacture of carboxylic acid tertiary butyl ester

3-Amino-5-bromothiophene-2-carboxamide (636 mg), (2S)-1-(Terminal D), as in Example 82, Step A, from Example 1, Step D. Oxycarbonyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid (980 mg), 2-methylpropyl chlorocarbonate (0.559 mL), triethylamine (1.20 mL), and tetrahydrofuran (30 mL), The title compound (663 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.19-1.48 (9H, m), 2.53-2.68 (2H, m), 3.93-4.18 (2H, m), 5.06-5.32 (1H, m), 5. 5.83 (2H, m), 7.54 (1H, s), 12.65 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(1,2,3,6-tetrahydropyridin-2-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone dihydrochloride

2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-produced above, in the same manner as in Example 83, Step C 3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl butyl ester (100 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-di Tert-butyl borolan-2-yl)-1H-pyrazole-1-carboxylic acid (149 mg), cesium carbonate (474 mg), 1,1'-bis(diphenylphosphino)ferrocene Palladium(II) chloride-dichloromethane complex (1:1) (8.9 mg), 1,2-dimethoxyethane (3 mL), water (0.5 mL), 10% HCl/methanol solution (2 mL) and MeOH (3 mL) ¹ H-NMR (DMSO-d ₆ ) δ 2.35-2.47 (4H, m), 2.70-2.86 (1H, m), 3.62-3.84 (2H, m), 4.35-6.05 (3H, m), 7.37 ( 1H, s), 8.12 (1H, s), 9.71 (2H, brs), 12.86 (1H, brs).

Example 137 2-(2-Aminocyclopentyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride Manufacturing A) Manufacture of [2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)cyclopentyl]aminecarboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (116 mg), (1R ^* , 2S ^* )-2-, as produced in Example 1, Step D, in the same manner as in Example 82, Step A. [(Tri-tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (180 mg), 2-methylpropyl chlorocarbonate (0.102 mL), triethylamine (0.219 mL), and tetrahydrofuran (6 mL), 2M sodium hydroxide Aqueous (1.57 mL) and EtOAc (EtOAc) MS (ESI +): [M + H] + 414.MS (ESI +), Found: 414.

B) 2-(2-Aminocyclopentyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one di-salt Manufacture of acid salt

[2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) was prepared from the same manner as in Example 83, Step C. Cyclopentyl]amino acid tert-butyl butyl ester (51 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (76 mg), cesium carbonate (241 mg), 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride- Methylene chloride complex (1:1) (4.5 mg), 1,2-dimethoxyethane (3 mL), water (0.3 mL), 10% HCl/methanol (2mL) and methanol (2mL) The title compound (21 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.61-2.34 (6H of major, 6H of minor, m), 2.45 (3H of major, 3H of minor, s), 3.13 - 3.26 (1H of major, m), 3.26-3.37 (1H of minor, m), 3.82-3.92 (1H of minor, m), 4.02-4.15 (1H of major, m), 7.35 (1H of minor, s), 7.38 (1H of major, s) , 7.93 (3H of minor, brs), 8.04 (1H of major, 1H of minor, brs), 8.13 (3H of major, brs), 12.47 (1H of major, 1H of minor, brs).* observed The isomer ratio was 2.5:1.

Example 138 Manufacture of 6-(5-methyl-1H-pyrazol-4-yl)-2-(1,3-thiazol-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one A) Manufacture of 6-bromo-2-(1,3-thiazol-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one

Add 1,3-thiazole-2-methylhydrazine chloride (0.22 g) to 3-amino-5-bromothiophene-2-carboxamide (200 mg), manufactured in Example 1, Step D, at 0 ° C. In a mixture of ethylamine (0.19 mL) and tetrahydrofuran (4.0 mL), the mixture was stirred at room temperature for 2 hr. Water was added to the reaction system, and the precipitate was collected by filtration to give N-(5-bromo-2-amine-carbamoylthiophen-3-yl)-1,3-thiazole-2-carboxamide as a pale yellow solid. 290mg). 2M aqueous sodium hydroxide solution (1.75 mL) and 1,2-dimethoxyethane (4.0 mL) were added to the above-produced N-(5-bromo-2-aminomethylthiophenyl-3-yl)-1, 3-thiazole-2-carboxamide, the mixture was stirred at 100 ° C for 18 hours. The reaction was neutralized with 1 M hydrochloric acid at 0 °C. The title compound (236 mg) was obtained eluted eluted ¹ H-NMR (DMSO-d ₆ ) δ 7.73 (1H, s), 8.03-8.18 (2H, m), 13.01 (1H, brs).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-(1,3-thiazol-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacturing

In the same manner as in Example 2, Step C, from 6-bromo-2-(1,3-thiazol-2-yl)thieno[3,2-d]pyrimidin-4(3H)-one (230 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl Ester (451 mg), sodium carbonate (233 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and 1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium(II)-dichloromethane complex (1 : 1) (60 mg) ¹ H-NMR (DMSO-d ₆ ) δ 2.43-2.49 (3H, m), 7.53 (1H, s), 7.81-8.52 (3H, m), 12.61-13.20 (2H, m).

Example 139 2-(2-Aminocyclopentyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride Manufacturing A) Manufacture of [2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)cyclopentyl]aminecarboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (663 mg), (1R ^* , 2R ^* )-2-, as produced in Example 1, Step D, as in Example 82, Step A. [(Tri-tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (1.03 g), 2-methylpropyl chlorocarbonate (0.584 mL), triethylamine (1.25 mL), and tetrahydrofuran (30 mL) Aqueous sodium hydroxide (9.0 mL) and EtOAc (30 mL) MS (ESI +): [M + H] + 414.MS (ESI +), Found: 414.

B) 2-(2-Aminocyclopentyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one di-salt Manufacture of acid salt

[2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) was prepared from the same manner as in Example 83, Step C. Cyclopentyl]amino acid tert-butyl butyl ester (610 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (907 mg), cesium carbonate (2.88 g), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II) - dichloromethane complex (1:1) (54 mg), 1,2-dimethoxyethane (7 mL), water (3 mL), 10% HCl/methanol (6 mL) and methanol (6 mL) The title compound (242 mg) was obtained as white crystal. ¹ H-NMR (DMSO-d ₆ ) δ 1.66-1.89 (4H, m), 2.07-2.32 (2H, m), 2.46 (3H, s), 3.20-3.30 (1H, m), 4.03-4.15 (1H , m), 7.39 (1H, s), 8.05 (1H, s), 8.28 (3H, brs).

Example 140 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,3S)-3-methylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone dihydrochloride A) Manufacture of (3S)-1-(tertiary butoxycarbonyl)-3-methyl-L-proline

Di-tert-butyl dicarbonate (0.67 mL) was added to (3S)-3-methyl-L-proline (250 mg), tetrahydrofuran (10 mL) and 1 M aqueous sodium hydroxide (2.9). In a mixture of mL). After stirring overnight, the reaction mixture was ice-cooled, and then 1M hydrochloric acid (2.9mL) was added dropwise to pH 4. The organic product was extracted with EtOAc (EtOAc)EtOAc. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate/hexane was added to the residue. ¹ H-NMR (DMSO-d ₆ ) δ 1.06-1.11 (3H, m), 1.33 (9H of major, s), 1.39 (9H of minor, s), 1.41-1.56 (1H, m), 1.87-2.01 (1H, m), 2.13-2.25 (1H, m), 3.20-3.29 (1H, m), 3.37-3.47 (1H, m), 3.55-3.62 (1H, m), 12.49 (1H, brs). The observed ratio of rotamers was 2:1.

B) (2S,3S)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3-methylpyrrolidinium- Manufacture of 1-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (208 mg) manufactured in Example 1, Step D, in the same manner as in Example 82, Step A, (3S)-1-( Tertiary butoxycarbonyl)-3-methyl-L-proline (323 mg), 2-methylpropyl chlorocarbonate (0.183 mL), triethylamine (0.393 mL) and tetrahydrofuran (10 mL), 2M EtOAc Aqueous sodium hydroxide (2.8 mL) and EtOAc (EtOAc) MS (ESI +): [M + H] + 414.MS (ESI +), ^{Found:. 414 1 H-NMR (} DMSO-d 6) δ 1.03-1.07 (3H, m), 1.09 (9H of major, s ), 1.33-1.38 (9H of minor, m), 1.47-1.62 (1H, m), 1.99-2.11 (1H, m), 2.24-2.38 (1H, m), 3.42-3.57 (2H, m), 4.05 -4.15 (1H, m), 7.61 (1Hofminor, s), 7.63 (1H of major, s), 12.77 (1H, brs). The observed ratio of rotamers was 5:2.

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S,3S)-3-methylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketone dihydrochloride

(2S,3S)-2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine as described above in the same manner as in Example 83, Step C 3-yl)-3-methylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (272 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (405 mg), cesium carbonate (1.28 g), 1,1'-bis(diphenylphosphino) Ferrocene] palladium(II) chloride-dichloromethane complex (1:1) (24 mg), 1,2-dimethoxyethane (5 mL), water (2 mL), 10% HCl/methanol The title compound (127 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.17 (3H, d, J = 6.8 Hz), 1.60-1.75 (1H, m), 2.14-2.28 (1H, m), 2.46 (3H, s), 2.50-2.59 (1H, m), 3.36-3.48 (2H, m), 4.17-4.25 (1H, m), 7.37 (1H, s), 8.09 (1H, s), 9.00 (1H, brs), 10.25 ( 1H, brs), 12.94 (1H, brs).

Example 141 2-(4-Hydroxy-4-phenylpyrrolidin-2-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 (3H )-Manufacture of ketone dihydrochloride A) 2-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-4-hydroxy-4-phenylpyrrolidin-1- Manufacture of carboxylic acid tertiary butyl ester

A 1 M solution of lithium hexamethyldiamine amide in tetrahydrofuran (4.84 mL) was added at 0 ° C to methyl 3-amino-5-bromothiophene-2-carboxylate (1.14 g, manufactured in Example 1, Step C). The mixture was stirred for 30 minutes in tetrahydrofuran (20 mL). (1S,4R)-3-Sideoxy-1-phenyl-2-oxa-5-indolebicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl butyl ester (700 mg) in tetrahydrofuran (5 mL The solution was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was neutralized with EtOAc (EtOAc)EtOAc. The organic layer was washed with brine (5 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered out, and the filtrate was evaporated to dryness crystals crystals crystalsssssssssssssssssssssss 4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester. A 2M aqueous solution of sodium hydroxide (5.00 mL) was added to the above-prepared 2-{[5-bromo-2-(methoxycarbonyl)thiophen-3-yl]aminecarbenyl}-4-hydroxy-4-phenylpyrrole A solution of pyridine-1-carboxylic acid tert-butyl ester in ethanol (15 mL) was stirred at 60 ° C for 2 hr. The reaction mixture was neutralized with 6M hydrochloric acid (1. Ammonium chloride (137 mg), triethylamine (0.520 mL) and N,N-dimethylformamide (5 mL) were added to the residue, and the mixture was stirred at room temperature for 5 min. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (399 mg) and 1-hydroxybenzotriazole (278 mg) were added to the reaction system, and the mixture was allowed to stand at room temperature. Stir for 15 hours. The reaction was poured into water (10 mL). The organic layer was washed with a saturated aqueous The insoluble material was filtered out, and the filtrate was evaporated to dryness crystals crystals crystals 4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester. 2M aqueous sodium hydroxide solution (1.71 mL) was added to the above 2-[(5-bromo-2-aminomethylsulfonylthiophen-3-yl)aminemethylmercapto]-4-hydroxy-4-phenylpyrrolidine A solution of 1-carboxylic acid tert-butyl ester in ethanol (5 mL) was stirred at 70 ° C for 3 hours. The reaction mixture was neutralized with EtOAc (EtOAc) The organic layer was washed with water and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the residue was evaporated,jjjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.11-1.43 (9H, m), 2.25-2.41 (1H, m), 2.76-2.91 (1H, m), 3.70-3.85 (2H, m), 4.72-4.89 (1H, m), 6.18-6.44 (1H, m), 7.21-7.43 (3H, m), 7.49-7.58 (2H, m), 7.62-7.70 (1H, m), 12.28-12.52 (1H, m) .

B) 2-(4-Hydroxy-4-phenylpyrrolidin-2-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 Manufacture of (3H)-ketone dihydrochloride

2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-produced above, in the same manner as in Example 83, Step C 4-Hydroxy-4-phenylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (58 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-di Tert-butyl butyl bromide-2-yl)-1H-pyrazole-1-carboxylate (72.6 mg), cesium carbonate (77.0 mg), 1,1'-bis(diphenylphosphino) Ferrocene] palladium(II) chloride-dichloromethane complex (1:1) (4.85 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL), 4M HCl/acetic acid Ethyl ester solution (1 mL) and MeOH (4 mL) ¹ H-NMR (DMSO-d ₆ ) δ 2.48 (3H, s), 2.56-5.15 (6H, m), 7.27-7.60 (7H, m), 8.12 (1H, s), 9.12 (1H, brs), 10.66 (1H, brs), 12.90 (1H, brs).

Example 142 2-[(1R,3S,4R,5S) or (1S,3S,4S,5S)-5-hydroxy-2-indolyl[2.2.1]heptan-3-yl]-6-(5-methyl Manufacture of -1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride A) (1R ^* , 3S, 4R ^* , 5S)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5 -Hydroxy-2-indolebicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester

Add 2-methylpropyl chlorocarbonate (0.178 mL) to (1R ^* ,3S,4R ^* ,5S)-2-(tertiarybutoxycarbonyl)-5-hydroxy-2-indole bicyclo[2.2] at 0 °C A solution of heptane-3-carboxylic acid (349 mg) and triethylamine (0.190 mL) in THF (4 mL). A solution of the 3-amino-5-bromothiophene-2-carboxamide (200 mg) in Example 1, Step D, in tetrahydrofuran (2 mL) was added to the reaction system, and the mixture was stirred at 60 ° C for 18 hours. . Water was added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. 2M aqueous sodium hydroxide solution (1.81 mL) and ethanol (4.0 mL) were added to the obtained pale yellow amorphous solid (307 mg), and the mixture was stirred at 70 ° C for 5 hours. The reaction was neutralized with 1 M hydrochloric acid at 0 °C. Water (2 mL) was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with EtOAc (EtOAc) ¹ H-NMR (DMSO-d ₆ ) δ 1.13-1.47 (11H, m), 1.88-2.15 (2H, m), 2.56-2.63 (1H, m), 3.97-4.10 (1H, m), 4.23-4.34 (1H, m), 4.79-4.88 (1H, m), 5.05-5.14 (1H, m), 7.47-7.74 (1H, m), 12.25-12.70 (1H, m).

B) (1R ^* , 3S, 4R ^* , 5S)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5 Optical Segregation of 3-Hydroxy-2-indolyl[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester

High performance liquid chromatography (column: CHIRALPAK AD (50 mm id × 500 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (800/200) and hexane/ethanol (200/800) ), flow rate: 80 mL/min, column temperature: 30 ° C) Distinguish (1R ^* , 3S, 4R ^* , 5S) -3- (6-bromo-4-yloxy-3,4-dihydrothieno[ 3,2-d]pyrimidin-2-yl)-5-hydroxy-2-indolyl[2.2.1]heptane-2-carboxylic acid tert-butyl ester (211 mg). Obtaining (1R, 3S, 4R, 5S) or (1S, 3S, 4S, 5S)-3-(6-bromo-4-oxo-3,4-dihydrothiophene under the above high performance liquid chromatography conditions And [3,2-d]pyrimidin-2-yl)-5-hydroxy-2-indolebicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester (101 mg, >99.9% ee, in hexane / ethanol (800/200) rushed to distinguish, retention time 6.3 minutes) and (1R, 3S, 4R, 5S) or (1S, 3S, 4S, 5S) -3- (6-bromo-4- oxo -3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5-hydroxy-2-indolebicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (100 mg, >99.9% ee, distinguished by hexane/ethanol (200/800), with a residence time of 8.9 minutes). High performance liquid chromatography (column: CHIRALPAK AS-H (4.6 mm id × 250 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (850/150), flow rate: 1 mL/min The column temperature was 30 ° C and the detection was 220 nm).

C) (1R, 3S, 4R, 5S) or (1S, 3S, 4S, 5S)-5-hydroxy-3-[6-(5-methyl-1H-pyrazol-4-yl)-4- side Manufacture of oxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-indole bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester

In the same manner as in Example 2, Step C, from (1R, 3S, 4R, 5S) or (1S, 3S, 4S, 5S)-3-(6-bromo-4-yloxy-3,4-di Hydrothieno[3,2-d]pyrimidin-2-yl)-5-hydroxy-2-indolyl[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester (100 mg, >99.9% ee, Separation by hexane/ethanol (800/200), retention time 6.3 minutes) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Butyl-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (139 mg), sodium carbonate (72 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) And 1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (18 mg). . ¹ H-NMR (氘-chloroform) δ 1.32-2.01 (11H, m), 2.05-2.23 (2H, m), 2.42-2.64 (3H, m), 2.95-3.20 (1H, m), 4.14-4.39 ( 1H, m), 4.51-4.63 (1H, m), 5.08-5.25 (1H, m), 7.11-7.23 (1H, m), 7.73-7.89 (1H, m).

D) 2-[(1R,3S,4R,5S) or (1S,3S,4S,5S)-5-hydroxy-2-indenylbicyclo[2.2.1]heptan-3-yl]-6-(5- Manufacture of methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride

In the same manner as in Example 108, from (1R, 3S, 4R, 5S) or (1S, 3S, 4S, 5S)-5-hydroxy-3-[6-(5-), which was produced in Example 142, Step C. Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-indole bicyclo[2.2.1] The title compound (59 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.41-1.52 (1H, m), 1.62-1.72 (1H, m), 1.77-1.86 (1H, m), 2.01-2.15 (1H, m), 2.46 (3H) , s), 2.91-3.01 (1H, m), 4.01-4.14 (1H, m), 4.28-4.42 (1H, m), 4.92-5.02 (1H, m), 7.35 (1H, s), 8.08 (1H , s), 8.57-8.68 (1H, m), 9.60-9.72 (1H, m), 12.97 (1H, brs).

Example 143 2-(pyrrolidin-1-ylmethyl)-6-[5-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidin-4(3H)- Ketone manufacturing

6-Bromo-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one (372 mg), [3- (Trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]boronic acid (600 mg), sodium carbonate (314 mg), ethanol (10 mL) and water (1.5 mL) were placed in a flask to Hydrogen purges the air from the flask. Tetrakis(triphenylphosphine)palladium(0) (68.4 mg) was added, and the air in the flask was again purged with argon, and the mixture was stirred at 80 ° C for 5 hours. Ethyl acetate (20 mL) and water (10 mL) were added to the mixture. The separated aqueous layer was extracted with ethyl acetate (10 mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 3-(Trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidin-4(3H)-one. HCl/methanol solution (5 mL) was added to 2-(pyrrolidin-1-ylmethyl)-6-[3-(trifluoromethyl)-1-trityl-1H-pyrazole-4 as above. -yl]thieno[3,2-d]pyrimidin-4(3H)-one, the mixture was stirred at 60 ° C for 6 hours. Ethyl acetate (20 mL) and a saturated aqueous solution of sodium hydrogen carbonate (10 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.66-1.78 (4H, m), 2.54-2.60 (4H, m), 3.58 (2H, s), 7.37 (1H, s), 8.53 (1H, s).

Example 144 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2R ^* ,3S ^* )-3-phenylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketohydrochloride A) (2R ^* , 3S ^* )-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3-phenylpyrrole Manufacture of pyridine-1-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (221 mg), (2R ^* , 3S ^* )-1-, as produced in Example 1, Step D, as in Example 82, Step A. (tertiary butoxycarbonyl)-3-phenylproline (437 mg), 2-methylpropyl chlorocarbonate (0.195 mL), triethylamine (0.418 mL) and tetrahydrofuran (10 mL), 2M aqueous sodium hydroxide (3 mL) and EtOAc (10 mL) ¹ H-NMR (DMSO-d ₆ ) δ 1.09 (9H of major, s), 1.38 (9H of minor, s), 2.03-2.35 (2H of major, 2H of minor, m), 3.46-3.70 (3H of Major, 2H of minor, m), 4.00-4.13 (1H of minor, m), 4.54-4.67 (1H of major, 1H of minor, m), 7.19-7.36 (5H of major, 5H of minor, m), 7.59-7.65 (1H of major, 1H of minor, m), 12.78 (1H of major, 1H of minor, brs). The observed ratio of rotamers was 5:2.

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2 ^* ,3S ^* )-3-phenylpyrrolidin-2-yl]thieno[3,2-d Manufacture of pyrimidine-4(3H)-one hydrochloride

(2R ^* ,3S ^* )-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d], as prepared in the same manner as in Example 83, Step C Pyrimidin-2-yl)-3-phenylpyrrolidine-1-carboxylic acid tert-butyl butyl ester (345 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (446 mg), cesium carbonate (1.42 g), 1,1'-bis(diphenylphosphine) Base ferrocene] palladium(II) chloride-dichloromethane complex (1:1) (27 mg), 1,2-dimethoxyethane (6 mL), water (2 mL), 10% HCl The title compound (185 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 2.15-2.29 (1H, m), 2.43-2.60 (4H, m), 3.45-3.66 (2H, m), 3.76-3.90 (1H, m), 4.62 (1H) , d, J = 8.9 Hz), 7.28-7.38 (5H, m), 7.43 (1H, s), 7.86-8.39 (1H, m), 9.12-10.47 (1H, m), 13.05 (1H, brs).

Example 145 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-1,2,3,6-tetrahydropyridin-2-yl]thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one dihydrochloride A) (2S)-2-(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3,6-dihydropyridine-1 Manufacture of (2H)-carboxylic acid tertiary butyl ester

2-methylpropyl chlorocarbonate (0.662 mL) was added to (2S)-1-(tertiary butoxycarbonyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid with stirring at room temperature. (1.16 g), a mixture of triethylamine (1.42 mL) and tetrahydrofuran (12 mL). After 1 hour, 3-amino-5-bromothiophene-2-carboxamide (752 mg), which was obtained in Example 1, Step D, was added, and the mixture was stirred at 100 ° C for 2 hours in a microwave reactor. The reaction mixture was allowed to cool to room temperature and poured into saturated aqueous sodium hydrogen sulfate. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (10 mL), EtOAc (EtOAc) The reaction mixture was ice-cooled, and 6M hydrochloric acid (3.33 mL) was added dropwise. The reaction mixture was poured into brine and extracted with a 3: 1 ethyl acetate / THF mixture. The extract was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjj The optical purity was 51.1% ee. High performance liquid chromatography (column: CHIRALPAK IC (4.6 mm id × 250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 1 mL/min, The column temperature was 30 ° C and the detection was 220 nm). ¹ H-NMR (DMSO-d ₆ ) δ 1.21-1.47 (9H, m), 2.53-2.65 (2H, m), 3.92-4.19 (2H, m), 5.09-5.31 (1H, m), 5.62-5.81 (2H,m), 7.54 (1H, s), 12.65 (1H, brs).

B) (2S)-2-(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3,6-dihydropyridine-1 Optical Segregation of (2H)-Dicarboxylic Acid Tert-Butyl Ester

High performance liquid chromatography (column: CHIRALPAK IC (50 mm id × 500 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 80 mL/min, tube Column temperature: 30 ° C) Distinguish between (2S)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3,6- Dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (0.86 g, 51.1% ee). (2S)-2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine was obtained under the above high performance liquid chromatography conditions. 1-carboxylic acid tert-butyl ketone (0.54 g, 99.8% ee, residence time 10.16 min) and (2R)-2-(6-bromo-4-o-oxo-3,4-dihydrothieno[3] , 2-d]pyrimidin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (0.20 g, >99.9% ee, retention time 7.31 min). High performance liquid chromatography (column: CHIRALPAK IC (4.6 mm id × 250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 1 mL/min, The column temperature was 30 ° C and the detection was 220 nm).

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-1,2,3,6-tetrahydropyridin-2-yl]thieno[3,2- Manufacture of d]pyrimidin-4(3H)-one dihydrochloride

(2S)-2-(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3,6-dihydropyridine -1(2H)-carboxylic acid tert-butyl butyl ester (900 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Based -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (1.35 g), cesium carbonate (4.27 g), 1,2-dimethoxyethane (12 mL) and water (4 mL) were placed in a flask The air in the flask was purged with hydrogen. 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (80 mg) was added, and the air in the flask was again purged with argon gas. The mixture was stirred at 90 ° C for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with a 3:1 ethyl acetate/tetrahydrofuran mixture. The resulting organic layer was washed with EtOAcq. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the title compound was concentrated under reduced pressure to give (2S)-2-{6-[ Carbonyl)-3-methyl-1H-pyrazol-4-yl]-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}-3,6- Dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester. Add 10% HCl/methanol solution (14 mL) to (2S)-2-{6-[1-(tertiary butoxycarbonyl)-3-methyl-1H-pyrazol-4-yl]-4 -Sideoxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester in methanol (15 mL The solution was stirred at 50 ° C for 1 hour. The title compound (620 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 2.37-2.53 (4H, m), 2.71-2.86 (1H, m), 3.61-3.83 (2H, m), 4.34-4.51 (1H, m), 5.74-6.02 (2H, m), 7.36 (1H, s), 8.13 (1H, brs), 9.74 (1H, brs), 9.85-9.96 (1H, m), 12.89 (1H, brs). MS (ESI+): [M +H] ⁺ 314.MS (ESI+), found: 314.

Example 146 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2R)-1,2,3,6-tetrahydropyridin-2-yl]thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one dihydrochloride

(2R)-2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2], as in Example 145, Step C, from Example 145, Step B. -d]pyrimidin-2-yl)piperidine-1-carboxylic acid tert-butyl butyl ester (117 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (175 mg), cesium carbonate (555 mg), 1,1'-bis(diphenylphosphino) ferrocene Iron] palladium(II) chloride-dichloromethane complex (1:1) (10 mg), 1,2-dimethoxyethane (3 mL), water (1 mL), 10% HCl/methanol solution ( 2 mL) and MeOH (3 mL) ¹ H-NMR (DMSO-d ₆ ) δ 2.38-2.48 (4H, m), 2.72-2.87 (1H, m), 3.61-3.85 (2H, m), 4.36-4.49 (1H, m), 5.76-6.02 (2H, m), 7.37 (1H, s), 8.12 (1H, s), 9.62-9.94 (2H, m), 12.88 (1H, brs).

Example 147 6-(5-methyl-1H-pyrazol-4-yl)-2-(piperidin Manufacture of -2-yl)thieno[3,2-d]pyrimidin-4(3H)-one di-trifluoroacetate A) 2-{[5-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2-(methoxycarbonyl)thiophen-3-yl]aminecarbenyl}piperider Manufacture of -1,4-dicarboxylic acid di-tertiary butyl ester

3-Amino-5-(1-benzyl-3-methyl-1H-pyrazol-4-yl)thiophene was prepared in the same manner as in Example 123, Step F from Example 123, Step C. Methyl 2-carboxylate (327 mg), 1,4-bis(tertiary butoxycarbonyl)per 2-carboxylic acid (496 mg), 2-methylpropyl chlorocarbonate (205 mg), triethylamine (304 mg) ¹ H-NMR (DMSO-d ₆ ) δ 1.41 (9H, s), 1.57 (9H, s), 2.47 (3H, s), 2.92-3.10 (2H, m), 3.30-3.45 (4H, m), 3.80-3.90 (1H, m), 3.85 (3H, s), 5.24 (2H, s), 7.10-7.20 (1H, m), 7.26-7.40 (4H, m), 7.59 (1H, s), 8.07 ( 1H, s), 10.76 (1H, brs).

B) 2-[6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d] Pyrimidin-2-yl]peri Manufacture of -1,4-dicarboxylic acid di-tertiary butyl ester

2-{[5-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2-(methoxycarbonyl) was prepared from the same manner as in Example 123, Step G. Thiophen-3-yl]aminemethanyl}peri -1,4-dicarboxylic acid di-tertiary butyl ester (250 mg), 2 M aqueous sodium hydroxide solution (1 mL), methanol (5 mL), and 1-ethyl-3-(3-dimethylaminopropyl) carbon Diimine hydrochloride (1.92 g), 1-hydroxybenzotriazole (1.35 g), ammonium chloride (2.14 g), triethylamine (4.05 g), N,N-dimethylformamide ( The title compound (150 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.41 (9H, s), 1.58 (9H, s), 2.49 (3H, s), 3.20-3.50 (4H, m), 3.85-4.00 (2H, m) , 5.07-5.17 (1H, m), 5.27 (2H, s), 7.12-7.20 (2H, m), 7.25-7.40 (4H, m), 7.61 (1H, s), 10.00 (1H, brs).

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-piperider Manufacture of 2-ylthieno[3,2-d]pyrimidin-4(3H)-one di-trifluoroacetate

2-[6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-4-oxo-oxy-3, as prepared in the same manner as in Example 123, Step H, 4-dihydrothieno[3,2-d]pyrimidin-2-yl]peri -1,4-dicarboxylic acid di-tertiary butyl ester (150 mg), formic acid (5 mL), and 20% palladium hydroxide-carbon (20 mg) afforded 6-(5-methyl-1H-pyridin as a colorless solid. Zin-4-yl)-2-(piperidin -2-yl) thieno[3,2-d]pyrimidin-4(3H)-one (90 mg). This was dissolved in trifluoroacetic acid (5 mL). ¹ H-NMR (DMSO-d ₆ ) δ 2.47 (3H, s), 3.05-3.12 (1H, m), 3.90-4.01 (4H, m), 4, 22-4.32 (1H, m), 5.20-5.25 (1H,m), 7.44 (1H, s), 8.26 (1H, s).

Example 148 2-(2-吖Bicyclo[2.1.1]hex-1-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 (3H )-Manufacture of ketone hydrochloride A) 1-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-indolebicyclo[2.1.1]hexane-2 -Manufacture of carboxylic acid tertiary butyl ester

3-Amino-5-bromothiophene-2-carboxamide (327 mg), 2-(tertiary butoxycarbonyl)-, as in Example 71, Step A, from Example 1, Step D. 2-indole bicyclo[2.1.1]hexane-1-carboxylic acid (455 mg), 2-methylpropyl chlorocarbonate (273 mg), triethylamine (202 mg) and tetrahydrofuran (10 mL), and 2M aqueous sodium hydroxide (1 mL) and MeOH (5 mL) ¹ H-NMR (DMSO-d ₆ ) δ 1.02 (9H, brs), 1.70 (2H, dd, J = 4.5, 1.7 Hz), 1.97 (2H, brs), 2.64 (1H, t, J = 2.9 Hz) , 3.34 - 3.38 (2H, m), 7.19 (1H, s).

B) 2-(2-吖Bicyclo[2.1.1]hex-1-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 Production of (3H)-ketohydrochloride

1-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-produced from the same manner as in Example 83, Step C 2-indole bicyclo [2.1.1] hexane-2-carboxylic acid tert-butyl butyl ester (150 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (270 mg), cesium carbonate (290 mg), 1,1'-bis(diphenylphosphino) ferrocene Iron] palladium(II) chloride-dichloromethane complex (1:1) (18 mg), 1,2-dimethoxyethane (10 mL), water (1 mL), and 4M HCl/ethyl acetate The title compound (98 mg) was obtained eluted eluted eluted ¹ H-NMR (DMSO-d ₆ ) δ 1.80-1.92 (2H, m), 2.47 (3H, s), 2.68-2.82 (2H, m), 2.92-3.02 (1H, m), 3.28-3.40 (2H , m), 7.42 (1H, s), 8.12 (1H, s), 9.95 (2H, brs).

Example 149 2-[(cyclopentylamino)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride Salt manufacturing A) Preparation of [(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)methyl]cyclopentylaminecarboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (431 mg), N-(tertiary butoxycarbonyl)-, as described in Example 71, Step A, from Example 1, Step D. N-cyclopentylglycine (996 mg), 2-methylpropyl chlorocarbonate (0.531 mL), triethylamine (0.676 mL) and tetrahydrofuran (5 mL), 2M aqueous sodium hydroxide (4.88 mL) and ethanol ( The title compound (620 mg) was obtained as a white crystal. ¹ H-NMR (DMSO-d ₆ ) δ 1.05-2.00 (17H, m), 3.63-4.52 (3H, m), 7.57 (1H, s), 12.42 (1H, brs).

B) 2-[(Cyclopentylamino)methyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one Manufacture of hydrochloride

[(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)methyl) was prepared from the same manner as in Example 83, Step C Tricyclobutyl cyclopentylamine (700 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (1.01 g), cesium carbonate (1.07 g), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II) - dichloromethane complex (1:1) (67.2 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL), 4M HCl / ethyl acetate (1 mL) and methanol ( The title compound (242 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.46-1.61 (2H, m), 1.66-1.82 (4H, m), 1.91-2.06 (2H, m), 2.47 (3H, s), 3.56-3.73 (1H , m), 4.24 (2H, qd), 7.39 (1H, s), 8.11 (1H, s), 9.63 (2H, brs).

Example 150 2-[(1R,3S,4R,5S) or (1S,3S,4S,5S)-5-hydroxy-2-indolyl[2.2.1]heptan-3-yl]-6-(5-methyl Manufacture of -1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride A) (1R, 3S, 4R, 5S) or (1S, 3S, 4S, 5S)-5-hydroxy-3-[6-(5-methyl-1H-pyrazol-4-yl)-4- side Manufacture of oxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-indole bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester

In the same manner as in Example 2, Step C, from (142, B, 4S, 5S) 3-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5-hydroxy-2-indolyl[2.2.1]heptane-2-carboxylic acid tert-butyl ester (100mg, >99.9% ee, distinguished by hexane/ethanol (200/800), retention time 8.9 minutes) and 3-methyl-4-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (139 mg), sodium carbonate (72 mg), 1,2-dimethoxyethane ( 3.0 mL) and water (1.5 mL) and 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (18 mg) were obtained. The title compound (87 mg) was obtained as white crystal. ¹ H-NMR (DMSO-d ₆ ) δ 1.10-1.49 (11H, m), 1.88-2.23 (2H, m), 2.37-2.48 (3H, m), 2.57-2.67 (1H, m), 4.00-4.12 (1H, m), 4.24-4.40 (1H, m), 4.78-4.93 (1H, m), 5.01-5.17 (1H, m), 7.32-7.55 (1H, m), 7.77-8.36 (1H, m) , 11.98-12.43 (1H, m), 12.80-13.12 (1H, m).

B) 2-[(1R,3S,4R,5S) or (1S,3S,4S,5S)-5-hydroxy-2-indolebicyclo[2.2.1]heptan-3-yl]-6-(5- Manufacture of methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride

In the same manner as in Example 108, from (1R, 3S, 4R, 5S) or (1S, 3S, 4S, 5S)-5-hydroxy-3-[6-(5-) produced in Example 150, Step A Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-indole bicyclo[2.2.1] The title compound (50 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.39-1.51 (1H, m), 1.62-1.72 (1H, m), 1.78-1.88 (1H, m), 2.01-2.15 (1H, m), 2.46 (3H) , s), 2.89-2.99 (1H, m), 4.00-4.13 (1H, m), 4.29-4.42 (1H, m), 4.93-5.01 (1H, m), 7.35 (1H, s), 8.08 (1H , s), 8.53-8.71 (1H, m), 9.46-9.65 (1H, m), 12.91-13.04 (1H, m).

Example 151 Manufacture of 2-(cyclopentylmethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one A) Manufacture of 5-bromo-3-[(cyclopentylethyl)amino]thiophene-2-carboxamide

3-Amino-5-bromothiophene-2-carboxamide (200 mg) and cyclopentyl acetic acid (0.113 mL) and O, as in Example 1, Step A, from Example 1, Step D. -(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (413 mg) and N-ethyl-N-(1-A The title compound (290 mg) was obtained as a yellow oil. ¹ H-NMR (氘-chloroform) δ 1.13-1.30 (2H, m), 1.60 (4H, s), 1.81-1.94 (2H, m), 2.24-2.38 (1H, m), 2.39-2.45 (2H, m), 5.42 (2H, brs), 8.28 (1H, s), 10.86 (1H, brs).

B) Manufacture of 6-bromo-2-(cyclopentylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one

2M sodium hydroxide aqueous solution (1.75 mL) and ethanol (3.0 mL) were added to 5-bromo-3-[(cyclopentylethyl)amino]thiophene-2-carboxamide (290 mg). Stir at 70 ° C for 2 hours. The reaction was neutralized with 1 M hydrochloric acid at 0 °C. Water (2 mL) was added. ¹ H-NMR (DMSO-d ₆ ) δ 1.12-1.28 (2H, m), 1.42-1.75 (6H, m), 2.24 - 2.35 (1H, m), 2.60 (2H, d, J = 7.6 Hz), 7.57 (1H, s), 12.52 (1H, brs).

C) Manufacture of 2-(cyclopentylmethyl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-(cyclopentylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one (160 mg) and 3-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (315 mg) Sodium carbonate (162 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II) The title compound (57 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.09-1.32 (2H, m), 1.40-1.78 (6H, m), 2.25-2.40 (1H, m), 2.45 (3H, brs), 2.61 (2H, d , J = 7.4 Hz), 7.34 (1H, s), 7.73 - 8.37 (1H, m), 12.26 (1H, brs), 12.95 (1H, brs).

Example 152 {2-[6-(5-Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]pyrrole Manufacture of ethyl pyridine-1-yl}acetate A) {2-[6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d Manufacture of ethylpyrimidin-2-pyrimidin-1-yl}acetate

6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2-(pyrrolidin-2-yl)thiophene [3,2] will be prepared in Example 124, Step C -d]pyrimidine-4(3H)-one (391 mg), ethyl 2-bromoacetate (184 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (258 mg), and N A mixture of N-dimethylformamide (5 mL) was stirred at 60 ° C for 2 hours. Ethyl acetate (50 mL) and water (50 mL) were added, and the separated aqueous layer was extracted with ethyl acetate (10mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the filtrate was evaporated,jjjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.26 (3H, t, J = 7.2 Hz), 1.73-2.12 (3H, m), 2.35-2.57 (1H, m), 2.49 (3H, s), 2.84 ( 1H, td, J = 9.2, 6.6 Hz), 3.28-3.41 (1H, m), 3.41-3.64 (2H, m), 4.04 (1H, dd, J = 9.5, 4.1 Hz), 4.18 (2H, q, J = 7.2 Hz), 5.27 (2H, s), 7.16 (1H, s), 7.24-7.47 (5H, m), 7.62 (1H, s), 10.52 (1H, brs).

B) {2-[6-(5-Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl Manufacture of ethyl pyrrolidin-1-yl}acetate

{2-[6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-4-oxooxy-3 was prepared as above in the same manner as in Example 123, Step H , 4-dihydrothieno[3,2-d]pyrimidin-2-yl]pyrrolidin-1-yl}acetate (40 mg), palladium hydroxide (10 mg), and formic acid (5mL) The title compound (13 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.27 (3H, t, J = 6.9 Hz), 1.73-2.14 (3H, m), 2.39-2.54 (1H, m), 2.55 (3H, s), 2.84 ( 1H, td, J = 9.2, 6.6 Hz), 3.36 (1H, ddd, J = 8.9, 6.7, 2.5 Hz), 3.42-3.64 (2H, m), 4.05 (1H, dd, J = 9.4, 4.1 Hz) , 4.19 (2H, q, J = 7.1 Hz), 7.22 (1H, s), 7.83 (1H, s).

Example 153 Manufacture of 2-(decahydroisoquinolin-1-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one

3-Amino-5-bromothiophene-2-carboxamide (0.22 g), 2-(tertiary butoxycarbonyl), as in Example 71, in the same manner as in Step A, from Example 1, Step D. -2-indole bicyclo[2.1.1]hexane-1-carboxylic acid (0.57 g), 2-methylpropyl chlorocarbonate (0.27 g), triethylamine (0.20 g) and tetrahydrofuran (10 mL), and 2M Aqueous sodium hydroxide (1 mL) and methanol (5 mL) gave 1-(6-bromo-4- </RTI></RTI><RTIgt;</RTI><RTIgt; Octahydroisoquinoline-2(1H)-carboxylic acid tert-butyl butyl ester (180 mg). In the same manner as in Example 83, Step C, the compound of the above, 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (270 mg), cesium carbonate (290 mg), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II)-Dichloromethane complex (1:1) (18 mg), 1,2-dimethoxyethane (10 mL), water (1 mL), and 4M HCl/EtOAc (2 mL) and methanol (10 mL) gave 2-(decahydroisoquinolin-1-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 (3H) - Ketone hydrochloride. The title compound (36 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.21-1.46 (8H, m), 1.48-1.70 (2H, m), 1.83-1.93 (1H, m), 2.13 - 2.23 (1H, m), 2.45 (3H) , s), 2.65-2.85 (2H, m), 3.80-3.90 (1H, m), 7.36 (1H, s), 8.02 (1H, s).

Example 154 2-[2-(1-Aminocyclopropyl)ethyl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4(3H) -Manufacture of ketone dihydrochloride

{1-[2-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,], as in Example 155, in the same manner as in Step 155 below, from Example 155, Step F. 2-()pyrimidin-2-yl)ethyl]cyclopropyl}carbamic acid 2-(trimethyldecyl)ethyl ester (57 mg), 3-methyl-4-(4,4,5,5- Tertiary butyl tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (77 mg), cesium carbonate (243 mg), 1,1'- Bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane complex (1:1) (4.6 mg), 1,2-dimethoxyethane (3 mL), water The title compound (18 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 0.71-0.79 (2H, m), 0.88-0.96 (2H, m), 2.00-2.11 (2H, m), 2.45 (3H, s), 2.77-2.87 (2H , m), 7.33 (1H, s), 8.03 (1H, brs), 8.34 (3H, brs), 12.34 (1H, brs),

Example 155 2-(4-Azaspiro[2.4]hept-5-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)- Manufacture of ketone dihydrochloride A) Manufacture of ethyl 2-(diethoxyphosphonyl)hex-5-enoate

Sodium hydride (60% in oil, 65.0 g) was suspended in tetrahydrofuran (800 mL) under nitrogen atmosphere, and ethyl (diethoxyphosphonyl)acetate (200 g) was added dropwise at room temperature over 30 minutes. . After the dropwise addition was completed, the mixture was further stirred with a mechanical stirrer for 30 minutes. 4-Bromobut-1-ene (217 g) was added dropwise to the reaction mixture over a period of 30 minutes. The reaction mixture was heated under reflux for 5 hours, cooled to room temperature and then quenched by addition of 1M aqueous ammonium chloride (300 mL). The mixture was concentrated under reduced pressure, and water (500 mL) and diethyl ether (500 mL) was added to the residue, and the mixture was partitioned. The aqueous layer was saturated with sodium chloride and the mixture was extracted with diethyl ether (500 mL×2). The collected extract was washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was evaporated. This compound was used in the next step without further purification. ¹ H-NMR (氘-chloroform) δ 1.21-1.30 (9H, m), 1.80-2.15 (4H, m), 2.88-2.97 (1H, m), 4.05-4.20 (6H, m), 4.91-5.01 ( 2H, m), 5.65-5.73 (1H, m).

B) Manufacture of 1-but-3-en-1-ylcyclopropanecarboxylic acid

Sodium hydride (60% in oil, 42 g) was suspended in toluene (500 mL) under nitrogen to give ethyl 2-(diethoxyphosphonyl)hex-5-enoate (241.6 g). A solution of toluene (200 mL) was added dropwise at room temperature over a period of 1 hour. A catalytic amount of ethanol (0.6 mL) was added and the reaction mixture was cooled to 0 ° C in an ice bath. Ethylene oxide (176.6 g) was added to the reaction mixture in a flask cooled with dry ice/ethanol. The ice bath was removed and the reaction mixture was gently heated under reflux for 6 h. The reaction mixture was quenched by careful addition of 1M aqueous ammonium chloride (500 mL), and the mixture was extracted three times with diethyl ether (600 mL). The collected extract was washed with a saturated aqueous solution of sodium bicarbonate (400 mL), water (400 mL) and brine (400 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained oil was dissolved in ethanol (500 mL), and aqueous sodium sulfate (90.3 g) (500 mL) was added. The mixture was stirred and heated under reflux for 12 hours. After cooling to room temperature, the ethanol was evaporated under reduced pressure. The residue was cooled and kept at 0 ° C, and concentrated hydrochloric acid was added dropwise to pH 1 . The resulting suspension was extracted three times with ethyl acetate (400 mL). The insoluble material was filtered, and the filtrate was evaporated. This compound was used in the next step without further purification. ¹ H-NMR (氘-chloroform) δ 1.92-2.37 (4H, m), 3.53-4.22 (4H, m), 5.02-5.06 (2H, m), 5.75-5.87 (1H, m), 7.81 (1H, Brs).

C) Preparation of 2-(trimethyldecyl)ethyl (1-but-3-en-1-ylcyclopropyl)carbamate

The crude product (130.5 g) of 1-but-3-en-1-ylcyclopropanecarboxylic acid obtained above was dissolved in tetrahydrofuran (1300 mL), and the mixture was cooled to 0 ° C under nitrogen atmosphere. Triethylamine (263 mL) and ethyl chlorocarbonate (152.0 g) were added sequentially, and the mixture was stirred at 0 ° C for one hour. An aqueous solution of sodium azide (152 g) (500 mL) was added to the reaction mixture, and the mixture was stirred at 0 ° C for 2 hr. Ethyl acetate (500 mL) and water (300 mL) were added to the mixture. The mixture is dispensed. The organic layer was separated and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene (1000 mL) and the mixture was evaporated. 2-(Trimethyldecyl)ethanol (118 g) was added to the reaction mixture, and the mixture was further heated under reflux for 6 hr. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj ¹ H-NMR (氘-chloroform) δ 0.09 (9H, m), 0.65-1.00 (6H, m), 1.66-1.68 (2H, m), 2.18-2.24 (2H, m), 4.14 (2H, t, J = 7.2 Hz), 4.96-5.07 (3H, m), 5.83-5.87 (1H, m).

D) Manufacture of 2-(trimethylmethyl)ethyl 5-(hydroxymethyl)-4-aspiro[2.4]heptane-4-carboxylic acid

3-Chloroperbenzoic acid (122.0 g) was added to 2-(trimethylsulfonyl)ethyl ester of (1-but-3-en-1-ylcyclopropyl)carbamate (120.0 g) In a solution of methyl chloride (1000 mL), the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in acetic acid, and the mixture was stirred at room temperature for 24 hr. The solvent was evaporated under reduced pressure. mjjjjjjjjj ¹ H-NMR (氘-chloroform) δ 0.01 (9H, s), 0.46-1.71 (11H, m), 3.64 - 3.69 (1H, m), 4.06 - 4.10 (3H, m).

E) Manufacture of 4-{[2-(trimethylsulfonyl)ethoxy]carbonyl}-4-aziro[2.4]heptane-5-carboxylic acid

Jones reagent (257 mL) was added to the above-produced 5-(hydroxymethyl)-4-aspiro[2.4]heptane-4-carboxylic acid 2-(trimethyldecyl)ethyl ester (42.0 g) ) in a solution of acetone (600 mL). The resulting suspension was stirred at room temperature for 30 minutes and 2-propanol (30 mL) was added to aq. Insoluble matter was filtered off. The organic layer was separated from EtOAc (EtOAc)EtOAc. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj ¹ H-NMR (氘-chloroform) δ 0.01-0.05 (9H, m), 0.47-0.96 (4H, m), 1.74-1.87 (2H, m), 2.03-2.51 (4H, m), 4.06-4.50 ( 3H, m), 9.60 (1H, s).

F) 5-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-4-azaspiro[2.4]heptane-4-carboxylate Manufacture of 2-(trimethylindenyl)ethyl acid

3-Amino-5-bromothiophene-2-carboxamide (221 mg) manufactured in Example 1, Step D, in the same manner as in Example 82, Step A, 4-{[2-( Crude product of trimethylsulfonyl)ethoxy]carbonyl}-4-aspiro[2.4]heptane-5-carboxylic acid (571 mg), 2-methylpropyl chlorocarbonate (0.259 mL), triethylamine The title compound (133 mg) was obtained as a white solid. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m ¹ H-NMR (DMSO-d ₆ ) δ-0.15 (9H, s), 0.44-0.68 (4H, m), 1.20-2.37 (6H, m), 3.79-3.95 (2H, m), 4.84 (1H, Dd, J = 8.3 Hz, 3.6 Hz), 7.61 (1H, s), 12.70 (1H, brs).

Further, {1-[2-(6-bromo-4-ylidene-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)ethyl]cyclopropyl}aminecarboxylic acid is obtained. 2-(Trimethyldecyl)ethyl ester (57 mg). The crude product of 4-{[2-(trimethyldecyl)ethoxy]carbonyl}-4-azaspiro[2.4]heptane-5-carboxylic acid as described above contains 3-[1- ({[2-(Trimethyldecyl)ethoxy)carbonyl}amino)cyclopropyl]propanoic acid. ¹ H-NMR (DMSO-d ₆ ) δ-0.01 (9H, s), 0.58 (4H, d, J = 14.4 Hz), 0.80-0.92 (2H, m), 1.79-1.91 (2H, m), 2.62 -2.75 (2H, m), 3.91-4.02 (2H, m), 7.33 (1H, brs), 7.53 (1H, s), 12.52 (1H, brs).

G) 2-(4-Azaspiro[2.4]hept-5-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 (3H )-Manufacture of ketone dihydrochloride

5-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-4-azaspiro[2.4]heptane-4 manufactured above 2-carboxylic acid 2-(trimethyldecyl)ethyl ester (133 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (174 mg), cesium carbonate (553 mg), 1,2-dimethoxyethane (5 mL) and water (0.8 mL) were placed in a flask The air in the flask was purged with argon. 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (10 mg) was added, and the air in the flask was again purged with argon gas. The mixture was stirred at 90 ° C for 30 minutes. The reaction mixture was poured into a saturated aqueous The resulting organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). 3-methyl-1H-pyrazol-4-yl]-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}-4-azaspiro[2.4 ]Heptane-4-carboxylic acid 2-(trimethyldecyl)ethyl ester. A 10% HCl/methanol solution (5 mL) was added to the 5-{6-[1-(tertiary butoxycarbonyl)-3-methyl-1H-pyrazol-4-yl]-4-yloxy group prepared above. -3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}-4-azaspiro[2.4]heptane-4-carboxylic acid 2-(trimethyldecyl)ethyl ester in methanol In a solution of (5 mL), the mixture was stirred at 60 ° C overnight. The reaction mixture was concentrated under reduced pressure and 2-propanol (5 mL) was added to the residue, and the mixture was stirred at 80 ° C for 30 min. The title compound (55 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 0.82-0.95 (2H, m), 1.19-1.36 (2H, m), 1.98-2.32 (3H, m), 2.46-4.89 (5H, m), 7.38 (1H) , s), 8.10 (1H, s), 9.22 (1H, brs), 10.22 (1H, brs), 12.86 (1H, brs).

Example 156 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-4-piperidin-1-ylpyrrolidin-2-yl]thieno[3,2-d]pyrimidine -4(3H)-one manufacture A) (2S)-2-(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-4-piperidin-1-ylpyrrole Manufacture of pyridine-1-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (200 mg) and 1-(tertiary butoxycarbonyl)-as produced in Example 1, Step D, as in Example 11, Step A. 4-piperidin-1-yl-L-proline (270 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Hexafluorophosphate (413 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (0.316 mL) and N,N-dimethylformamide (5.0 mL) (2S)-2-[(5-Bromo-2-amine-mercaptothiophen-3-yl)amine-methylmethyl]-4-piperidin-1-ylpyrrolidin-1-carboxylic acid as a brown amorphous solid Tert-butyl butyl ester (132 mg). 2M sodium hydroxide aqueous solution (0.52 mL) and ethanol (1.0 mL) were added to the above-made (2S)-2-[(5-bromo-2-aminomethylsulfonylthiophen-3-yl)aminecarbamyl]- 4-piperidin-1-ylpyrrolidin-1-carboxylic acid tert-butyl ester, the mixture was stirred at 70 ° C for 2 hours. The reaction was neutralized with 1 M hydrochloric acid at 0 °C. The mixture was extracted with ethyl acetate, and the mixture was washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The title compound (63 mg) was obtained eluted elute ¹ H-NMR (氘-chloroform) δ 1.23-2.01 (16H, m), 2.21-2.43 (1H, m), 2.49-2.74 (4H, m), 3.18-3.32 (1H, m), 3.88-4.25 ( 3H, m), 7.27 (1H, s).

B) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-4-piperidin-1-ylpyrrolidin-2-yl]thieno[3,2-d Manufacture of pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from (2S)-2-(6-bromo-4-oxooxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl) 4-piperidin-1-ylpyrrolidin-1-carboxylic acid tert-butyl butyl ester (60 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (76 mg), sodium carbonate (40 mg), 1,2-dimethoxyethane (1.5 mL) and water (0.75 mL) and 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (10 mg) gave a pale brown solid. (2S)-2-[6-(5-Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2- Tertiary 4-butyl piperidin-1-ylpyrrolidin-1-carboxylate (57 mg). 4M HCl/ethyl acetate solution (0.26 mL) was added to the (2S)-2-[6-(5-methyl-1H-pyrazol-4-yl)-4- side prepared above under stirring at room temperature. Oxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-4-piperidin-1-ylpyrrolidin-1-carboxylic acid tert-butyl ester in methanol (1.0 mL) In the solution. After the reaction mixture was stirred with heating at 50 ° C for 3 hr, the mixture was concentrated under reduced pressure and ethyl acetate (1 mL) and saturated aqueous sodium hydrogen carbonate (0.5 mL) was added to the residue. The insoluble material was filtered out, and the filtrate was concentrated, evaporated, mjjjjj The obtained pale yellow solid was crystalljjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.02-1.37 (2H, m), 1.51-1.64 (1H, m), 1.66-1.91 (4H, m), 2.09-2.25 (1H, m), 2.25-2.48 (6H, m), 2.53-2.64 (1H, m), 2.78-2.98 (2H, m), 3.16-3.25 (1H, m), 3.79-3.91 (1H, m), 7.34 (1H, s), 8.01 (1H, s).

Example 157 2-[(1S,5R)-2-indolyl[3.1.0]hex-1-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d Manufacture of pyrimidine-4(3H)-one dihydrochloride A) Manufacture of (4S)-4-(2-chloroethyl)-1,3,2-dioxathiolane 2,2-dioxide

Add thioxanthene chloride (34.4 mL) to a solution of (2S)-but-1,2,4-triol (10.0 g) and pyridine (15.2 mL) in acetonitrile (100 mL) at 0 ° C Stir at room temperature for 15 hours. Ethyl acetate (20 mL) and 0.1 M hydrochloric acid (10 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAcHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 3,2-Dioxathiolane 2-oxide. (4S)-4-(2-chloroethyl)-1,3,2-dioxathiolane 2-oxide, sodium periodate (19.6 g), ruthenium chloride monohydrate A mixture of (172 mg), acetonitrile (200 mL) and water (40 mL) was stirred at room temperature for 15 hr. The acetonitrile was evaporated under reduced pressure. The separated aqueous layer was extracted with ethyl acetate (10 mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAcjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.87-2.43 (2H, m), 3.62-3.87 (2H, m), 4.26-5.40 (3H, m).

B) Manufacture of (1S,5R)-2-indole bicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester hydrochloride

(4S)-4-(2-chloroethyl)-1,3,2-dioxathiolan 2,2-dioxide (7.50 g) and N-(di) manufactured above at 0 °C Phenyl methine ethylglycolate (10.7 g) was added to a suspension of sodium hydride (3.21 g) in 1,2-dimethoxyethane (100 mL), and the mixture was stirred under reflux for 15 hours. . Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in diethyl ether (100 mL). The separated aqueous layer was washed with ethyl acetate (100 mL) and evaporated. The residue was dissolved in ethanol (50 mL). Insoluble material was filtered off, and a 4M HCl/ethyl acetate solution (10 mL) was added to the filtrate. The solvent was evaporated under reduced pressure. Ethyl acetate (8 mL) and EtOAc (2 mL) was evaporated. ¹ H-NMR (DMSO-d ₆ ) δ 1.23 (3H, t, J = 7.1 Hz), 1.48-1.73 (2H, m), 1.90-2.37 (3H, m), 2.87-3.02 (1H, m), 3.26-3.40 (1H, m), 4.13-4.26 (2H, m), 10.22 (2H, brs).

C) Manufacture of (1S,5R)-2-(tertiary butoxycarbonyl)-2-indolebicyclo[3.1.0]hexane-1-carboxylic acid

(1S,5R)-2-indolebicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester hydrochloride (1.50 g), di-tertiary butyl dicarbonate (1.91 mL) and triethylamine ( 2.18 mL) A solution of tetrahydrofuran (15 mL) was stirred at room temperature for 15 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (EtOAc) (EtOAc) The reaction mixture was acidified with EtOAc EtOAc m. ¹ H-NMR (DMSO-d ₆ ) δ 0.99 (1H, t, J = 5.3 Hz), 1.40 (9H, s), 1.72 (1H, dd, J = 8.9, 4.7 Hz), 1.77-1.90 (1H, m), 1.95-2.06 (1H, m), 2.10-2.24 (1H, m), 3.22-3.46 (1H, m), 3.60 (1H, ddd, J = 11.0, 9.4, 6.2 Hz), 12.35 (1H, Brs).

D) (1S,5R)-1-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-indole bicyclo[3.1. 0] Manufacture of hexane-2-carboxylic acid tert-butyl butyl ester

3-Amino-5-bromothiophene-2-carboxamide (321 mg) manufactured in Example 1, Step D, in the same manner as in Example 71, Step A, (1S, 5R)-2 -(tertiary butoxycarbonyl)-2-indole bicyclo[3.1.0]hexane-1-carboxylic acid (495 mg), 2-methylpropyl chlorocarbonate (0.283 mL), triethylamine (0.503 mL) and Tetrahydrofuran (10 mL), 8M aq. ¹ H-NMR (DMSO-d ₆ ) δ 1.00-1.51 (10H, m), 1.87-2.05 (3H, m), 2.17-2.35 (1H, m), 3.22-3.31 (1H, m), 3.77 (1H) , td, J = 10.4, 4.0 Hz), 7.54 (1H, s), 12.65 (1H, brs).

E) 2-[(1S,5R)-2-indolyl[3.1.0]hex-1-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2 -d]Production of pyrimidine-4(3H)-one dihydrochloride

(1S,5R)-1-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine as described above in the same manner as in Example 83, Step C 2-yl)-2-indole bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (301 mg), 3-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (448 mg), cesium carbonate (474 mg), 1,1'-bis(diphenyl Phenylphosphino)ferrocene]palladium(II)-dichloromethane complex (1:1) (29.9 mg), 1,2-dimethoxyethane (5 mL), water (0.5 mL) The title compound (145 mg) was obtained eluted eluted eluting ¹ H-NMR (DMSO-d ₆ ) δ 1.77 (2H, d, J = 7.7 Hz), 2.05-2.30 (2H, m), 2.46 (3H, s), 2.64 - 2.76 (1H, m), 2.94 3.14 (1H, m), 3.33-3.48 (1H, m), 7.38 (1H, s), 8.12 (1H, s), 9.82 (1H, brs), 10.53 (1H, brs).

Example 158 2-[1-(2-hydroxyethyl)pyrrolidin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 ( 3H)-ketone manufacture A) 6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-2-[1-(2-hydroxyethyl)pyrrolidin-2-yl]thieno[3, Manufacture of 2-d]pyrimidin-4(3H)-one

{2-[6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-4-oxooxy-3,4-dihydrogen of Example 152, Step A Ethyl thieno[3,2-d]pyrimidin-2-yl]pyrrolidin-1-yl}acetate (80 mg), sodium borohydride (63 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) hour. 1M Hydrochloric acid (2 mL) was added to the reaction mixture, and the mixture was evaporated to mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ) extracting the separated aqueous layer. The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The mixture was crystallized from EtOAc (EtOAc m. ¹ H-NMR (DMSO-d ₆ ) δ 1.55-1.74 (2H, m), 1.82-2.06 (1H, m), 2.07-2.26 (1H, m), 2.27-2.47 (5H, m), 2.74-2.90 (1H, m), 3.17-3.35 (1H, m), 3.39-3.59 (3H, m), 5.20 (2H, s), 7.08 (1H, s), 7.18-7.39 (5H, m), 7.49 (1H) , s).

B) 2-[1-(2-Hydroxyethyl)pyrrolidin-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone

6-[1-Benzyl-3-methyl-1H-pyrazol-4-yl]-2-[1-(2-hydroxyethyl) was prepared in the same manner as in Example 123, Step H Pyrrolidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one (73 mg), 20% palladium hydroxide-carbon (20 mg), and formic acid (5 mL) The title compound (40 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.69-1.98 (3H, m), 2.15-2.33 (1H, m), 2.58 (3H, s), 3.41 (1H, brs), 3.45-3.59 (1H, m ), 3.65 (1H, dd, J = 9.2, 5.1 Hz), 3.98-4.17 (4H, m), 4.75 (1H, brs), 7.34 (2H, s).

Example 159 2-[(1R,3S,4R,5R) or (1S,3S,4S,5R)-5-fluoro-2-indenylbicyclo[2.2.1]heptan-3-yl]-6-(5-methyl Manufacture of -1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride A) (1R*, 3S, 4R*, 5R)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5 -Production of fluoro-2-indolyl [2.2.1] heptane-2-carboxylic acid tert-butyl butyl ester

Add 2-methylpropyl chlorocarbonate (0.178 mL) to (1R ^* ,3S,4R ^* ,5R)-2-(tertiarybutoxycarbonyl)-5-fluoro-2-indole bicyclo[2.2] at 0 °C A solution of heptane-3-carboxylic acid (352 mg) and triethylamine (0.190 mL) in THF (4 mL). A solution of the 3-amino-5-bromothiophene-2-carboxamide (200 mg) in Example 1, Step D, in tetrahydrofuran (2 mL) was added to the reaction system, and the mixture was stirred at 60 ° C for 18 hours. . Water was added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. 2M aqueous sodium hydroxide solution (1.81 mL) and ethanol (4.0 mL) were added to the obtained pale yellow solid (328 mg), and the mixture was stirred at 70 ° C for 5 hours. The reaction was neutralized with 1 M hydrochloric acid at 0 °C. Water (2 mL) was added to the titled crystals. ¹ H-NMR (DMSO-d ₆ ) δ 1.13 (5H, s), 1.39 (4H, s), 1.47-1.90 (2H, m), 2.01-2.21 (2H, m), 2.84-2.94 (1H, m ), 4.02-4.11 (1H, m), 4.16-4.30 (1H, m), 4.91-5.20 (1H, m), 7.64-7.71 (1H, m), 12.67 (1H, brs).

B) (1R ^* , 3S, 4R ^* , 5R)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5 Optical Separation of -Fluoro-2-indolebicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester

High performance liquid chromatography (column: CHIRALPAK AD (50 mm id × 500 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (800/200), flow rate: 80 mL/min, column temperature :30 ° C) Distinguish (1R*, 3S, 4R*, 5R)-3-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl 5-fluoro-2-indenylbicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (274 mg). Obtaining (1R, 3S, 4R, 5R) or (1S, 3S, 4S, 5R)-3-(6-bromo-4-oxo-3,4-dihydrothiophene under the above high performance liquid chromatography conditions And [3,2-d]pyrimidin-2-yl)-5-fluoro-2-indolyl[2.2.1]heptane-2-carboxylic acid tert-butyl ester (130 mg, >99.9% ee, retention time 5.4 Minutes) and (1R, 3S, 4R, 5R) or (1S, 3S, 4S, 5R)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d Pyrimidin-2-yl)-5-fluoro-2-indolyl [2.2.1] heptane-2-carboxylic acid tert-butyl ester (127 mg, >99.9% ee, retention time 7.5 min). High performance liquid chromatography (column: CHIRALPAK AS-H (4.6 mm id × 250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (850/150), flow rate: 1 mL/ Min, column temperature: 30 ° C, detection 220 nm) was performed for this analysis.

C) (1R, 3S, 4R, 5R) or (1S, 3S, 4S, 5R)-5-fluoro-3-[6-(5-methyl-1H-pyrazol-4-yl)-4- side Manufacture of oxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-indole bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester

In the same manner as in Example 2, Step C, from (1R, 3S, 4R, 5R) or (1S, 3S, 4S, 5R)-3-(6-bromo-4-) produced in Example 159, Step B 3-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5-fluoro-2-indolyl[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester (125 mg, >99.9% ee, retention time 5.4 minutes) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (173 mg), sodium carbonate (89 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) and 1,1'- Bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride (1:1) (23 mg) gave the title compound (116 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.14 (5H, s), 1.40 (4H, s), 1.48-1.87 (2H, m), 2.04-2.23 (2H, m), 2.46 (3H, brs), 2.83-2.95 (1H, m), 4.02-4.14 (1H, m), 4.16-4.32 (1H, m), 4.89-5.21 (1H, m), 7.39-7.51 (1H, m), 7.77-8.37 (1H , m), 12.38 (1H, brs), 12.96 (1H, brs).

D) 2-[(1R,3S,4R,5R) or (1S,3S,4S,5R)-5-fluoro-2-indenylbicyclo[2.2.1]heptan-3-yl]-6-(5- Manufacture of methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride

In the same manner as in Example 108, from (1R, 3S, 4R, 5R) or (1S, 3S, 4S, 5R)-5-fluoro-3-[6-(5-), which was produced in Example 159, Step C. Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-indole bicyclo[2.2.1] The title compound (66 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.75-1.98 (3H, m), 2.46 (3H, s), 2.53-2.64 (1H, m), 3.18-3.25 (1H, m), 4.20-4.33 (2H , m), 4.93-5.19 (1H, m), 7.35 (1H, s), 8.09 (1H, s), 8.62 (1H, brs), 10.04 (1H, brs), 12.95 (1H, brs).

Example 160 2-[(1R,3S,4R,5R) or (1S,3S,4S,5R)-5-fluoro-2-indenylbicyclo[2.2.1]heptan-3-yl]-6-(5-methyl Manufacture of -1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride A) (1R, 3S, 4R, 5R) or (1S, 3S, 4S, 5R)-5-fluoro-3-[6-(5-methyl-1H-pyrazol-4-yl)-4- side Manufacture of oxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-indole bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester

(1R, 3S, 4R, 5R) or (1S, 3S, 4S, 5R)-3-(6-bromo-4-oxo-3,4-dihydrothiophene) will be prepared in Example 159, Step B. And [3,2-d]pyrimidin-2-yl)-5-fluoro-2-indolyl[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester (125 mg, >99.9% ee, residence time 7.5 Minutes) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid A tertiary butyl ester (173 mg), sodium carbonate (89 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the air in the flask was purged with argon. 1,1 '-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (23 mg) was added, and the air in the flask was again purged with argon. The reaction was stirred at 100 ° C for 3 hours and water was added. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.14 (5H, s), 1.40 (4H, s), 1.50-1.87 (2H, m), 2.04-2.23 (2H, m), 2.39-2.48 (3H, m ), 2.86-2.95 (1H, m), 4.03-4.12 (1H, m), 4.18-4.32 (1H, m), 4.92-5.18 (1H, m), 7.37-7.49 (1H, m), 7.82-8.33 (1H, m), 12.29-12.47 (1H, m), 12.88-13.02 (1H, m).

B) 2-[(1R,3S,4R,5R) or (1S,3S,4S,5R)-5-fluoro-2-indenylbicyclo[2.2.1]heptan-3-yl]-6-(5- Manufacture of methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride

4M HCl/ethyl acetate solution (0.53 mL) was added to the solution of Example 160, Step A (1R, 3S, 4R, 5R) or (1S, 3S, 4S, 5R)-5- with stirring at room temperature. Fluor-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl] -2-Indolyl [2.2.1] heptane-2-carboxylic acid tert-butyl ester (105 mg) in methanol (2.0 mL). The reaction was heated and stirred at 50 ° C for 30 min. ¹ H-NMR (DMSO-d ₆ ) δ 1.71-2.00 (3H, m), 2.46 (3H, s), 2.51-2.61 (1H, m), 3.18-3.27 (1H, m), 4.17-4.33 (2H , m), 4.93-5.19 (1H, m), 7.35 (1H, s), 8, 09 (1H, s), 8.63 (1H, brs), 9.88 (1H, brs), 12.92 (1H, brs). MS (ESI +): [M + H] + 346.MS (ESI +), Found: 346.

Example 161 2-[(2S)-piperidin-2-yl]-6-[5-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidine-4 (3H )-Manufacture of ketone hydrochloride

(2S)-2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine, which was prepared in Example 83, Step B 1-carboxylic acid tert-butyl butyl ester (1.41 g), [3-(trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]boronic acid (1.72 g), sodium carbonate (902 mg) Ethanol (15 mL) and water (3 mL) were placed in a flask, and the air in the flask was purged with hydrogen. Tetrakis(triphenylphosphine)palladium(0) (197 mg) was added, and the air in the flask was again purged with argon, and the mixture was stirred at 80 ° C for 15 hours. Ethyl acetate (20 mL) and water (10 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) elute -[3-(Trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidin Butyl-1-carboxylic acid tertiary butyl ester. 4M HCl/ethyl acetate solution (1 mL) was added to the above-produced (2S)-2-{4-Sideoxy-6-[3-(trifluoromethyl)-1-trityl-1H-pyridyl a solution of azole-4-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine-1-carboxylic acid tert-butyl ester in methanol (4 mL), The mixture was stirred at 60 ° C for 15 hours. The precipitated solid was collected to give the title compound (530 mg). ¹ H-NMR (DMSO-d ₆ ) δ 1.47-1.93 (5H, m), 2.23 - 2.36 (1H, m), 2.95-3.11 (1H, m), 3.28-3.34 (1H, m), 4.22-4.34 (1H, m), 7.39 (1H, s), 8.64 (1H, s), 9.13 (1H, brs), 9.78 (1H, brs), 13.04 (1H, brs), 14.30 (1H, brs). MS ( ESI+): [M+H] ⁺ 370. MS (ESI+), found: 370.

Example 162 6-(5-ethyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one Manufacture of hydrochloride [0667] A) Manufacture of N,N-dimethyl-1H-pyrazole-1-sulfonamide

The pyrazole (12 g) was dissolved in tetrahydrofuran (200 mL). EtOAc (EtOAc:EtOAc: After 20 minutes, dimethylamine sulfonium chloride (17 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour and stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen sulfate (400 mL). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAcjjjjjj ¹ H-NMR (氘-chloroform) δ 2.95 (6H, s), 6.40 (1H, m), 7.75 (1H, m), 7.99 (1H, d, J = 2.7 Hz).

B) Manufacture of 5-ethyl-N,N-dimethyl-1H-pyrazole-1-sulfonamide

The N,N-dimethyl-1H-pyrazole-1-sulfonamide (25.3 g) produced above was dissolved in tetrahydrofuran (200 mL), and the mixture was cooled to -78 °C. A 1.6 M n-butyllithium/hexane solution (99 mL) was added dropwise with stirring. After the dropwise addition was completed, the mixture was stirred for 30 minutes and ethyl iodide (12.8 mL) was added dropwise. The reaction mixture was stirred for a further 30 minutes and allowed to warm to room temperature. After 1 hour, stirring became difficult due to the precipitate, and tetrahydrofuran (200 mL) was added to dissolve the precipitate. After stirring for 2 hours, the reaction mixture was poured into EtOAc EtOAc. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjjj ¹ H-NMR (氘-chloroform) δ 1.30 (3H, t, J = 7.8 Hz), 2.94 (2H, dd, J = 15.0 Hz, 7.5 Hz), 3.03 (6H, s), 6.13 (1H, brs) , 7.55 (1H, brs).

C) Manufacture of 4-bromo-5-ethyl-N,N-dimethyl-1H-pyrazole-1-sulfonamide

The above-produced 5-ethyl-N,N-dimethyl-1H-pyrazole-1-sulfonamide (19.8 g) was dissolved in tetrahydrofuran (300 mL), and 1-bromopyrrolidine-2,5- Dione (20.8 g). The mixture was stirred at 50 ° C for 2 hours. The reaction mixture was concentrated under reduced EtOAc. The extract was washed with brine (10 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjjjjj ¹ H-NMR (氘-chloroform) δ 1.24 (3H, t, J = 7.5 Hz), 2.97 (2H, dd, J = 15.0 Hz, 7.8 Hz), 3.06 (6H, s), 7.54 (1H, s) .

D) 5-Ethyl-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Manufacture of pyrazole-1-sulfonamide

The above-prepared 4-bromo-5-ethyl-N,N-dimethyl-1H-pyrazole-1-sulfonamide (13.0 g), 4,4,4',4',5,5, 5',5'-octamethyl-2,2'-linked 1,3,2-dioxaborolan (12.3g), potassium acetate (13.6g) and 1,2-dimethoxyethane ( 300 mL) was placed in a flask, and the air in the flask was purged with argon. Add 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (3.76 g), and again purge the air in the flask with argon. The mixture was stirred at 90 ° C overnight. The reaction mixture was allowed to cool to room temperature and the insoluble material was filtered. The filtrate was concentrated under reduced pressure, and a 1:1 ethyl acetate/hexane solution was added to the residue, and the insoluble material was filtered. The filtrate was concentrated under reduced pressure and the residue was purified mjjjjjjjjj The target fraction was concentrated under reduced pressure and the obtained residue was stood at room temperature overnight. The precipitate was collected by EtOAc EtOAcjjjjjjj ¹ H-NMR (氘-chloroform) δ 1.25 (3H, t, J = 7.5 Hz), 1.31 (12H, s), 3.03 (6H, s), 3.17 (2H, dd, J = 15.0, 7.5 Hz), 7.75 (1H, s).

E) 6-(5-Ethyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)- Manufacture of ketone dihydrochloride

The above-produced 5-ethyl-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole-1-sulfonamide (658 mg), (2S)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3], produced in Example 83, Step B , 2-d]pyrimidin-2-yl)piperidine-1-carboxylic acid tert-butyl butyl ester (414 mg), cesium carbonate (1.96 g), 1,2-dimethoxyethane (6 mL), and water (2 mL) Place in the flask and purge the air in the flask with argon. 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (37 mg) was added, and the air in the flask was again purged with argon gas. The mixture was stirred at 90 ° C for 1 hour. The reaction mixture was poured into aq. aq. The organic layer was washed with a saturated aqueous The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Aminesulfonyl)-5-ethyl-1H-pyrazol-4-yl]-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine 3-carboxylic acid tertiary butyl ester. A 10% HCl/methanol solution (8 mL) was added to the above-produced (2S)-2-{6-[1-(dimethylaminesulfonyl)-5-ethyl-1H-pyrazol-4-yl] a 4-tert-butyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl}piperidine-1-carboxylic acid tert-butyl ester in methanol (10 mL), The mixture was stirred at 50 ° C for 1 hour. The reaction mixture was allowed to cool to rt then ethyl acetate (10 mL). The precipitated solid was collected to give the title compound ( 136 g ¹ H-NMR (DMSO-d ₆ ) δ 1.25 (3H, t, J = 7.6 Hz), 1.50-1.92 (5H, m), 2.24 - 2.33 (1H, m), 2.87 (2H, q, J = 7.6 Hz), 2.96-3.11 (1H, m), 3.29-3.40 (1H, m), 4.15-4.29 (1H, m), 7.32 (1H, s), 8.09 (1H, s), 9.06-9.22 (1H, m), 9.40-9.52 (1H, m), 12.82 (1H, brs).

Example 163 2-{2-[6-(5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl Manufacture of pyrrolidin-1-yl}acetamide A) 2-{2-[6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2 -d]Pyridine-2-yl]pyrrolidin-1-yl}acetamide

{2-[6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-4-oxooxy-3,4-dihydrogen of Example 152, Step A A mixture of thieno[3,2-d]pyrimidin-2-yl]pyrrolidin-1-yl}acetate (80 mg), 2M aqueous sodium hydroxide (1 mL) and methanol (5 mL) . 1M Hydrochloric acid (2 mL) was added to the reaction mixture, and ethyl acetate (20 mL) and water (20 mL) was evaporated. The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (2 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (675 mg), 1-hydroxyl. Benzotriazole (397 mg), ammonium chloride (628 mg) and triethylamine (1.19 g) were stirred at 80 ° C for 18 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (10mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.81-2.04 (2H, m), 2.26-2.69 (2H, m), 2.50 (3H, s), 2.91-3.04 (1H, m), 3.19 (1H, d , J = 16.4 Hz), 3.48 (1H, d, J = 16.4 Hz), 3.62 (1H, brs), 3.84 (1H, dd, J = 9.0, 6.2 Hz), 5.28 (2H, s), 5.58 (2H , brs), 7.12-7.24 (2H, m), 7.24-7.47 (4H, m), 7.65 (1H, s), 8.13 (1H, brs),

B) 2-{2-[6-(5-Methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidine-2 Manufacture of pyridyl-1-yl}acetamido

2-{2-[6-(1-Benzyl-3-methyl-1H-pyrazol-4-yl)-4-yloxy group produced above, in the same manner as in Example 123, Step H -3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]pyrrolidin-1-yl}acetamide (60 mg), 20% palladium hydroxide-carbon (20 mg), and formic acid ( The title compound (22 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.75-2.07 (4H, m), 2.43 (3H, s), 2.56-2.70 (1H, m), 2.88-3.05 (1H, m), 3.15-3.25 (2H , m), 3.72 (1H, brs), 7.19 (1H, brs), 7.32-7.41 (2H, m), 7.84 (1H, brs).

Example 164 2-[(2R)-1-indenylbicyclo[2.2.2]oct-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketotrifluoroacetate A) Manufacture of 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl butyl ester

Add sodium hydroxide (1.6 g) to a mixed solution of 2-piperidin-4-ylethanol (5.0 g), water (12 mL) and 2-methylpropan-2-ol (9 mL) at 0 ° C. The reaction was stirred for 30 minutes. Di-tert-butyl dicarbonate (8.5 g) was added in small portions each time and the reaction was stirred at room temperature overnight. The reaction was poured into water (100 mL). The extract was washed with water and brine and evaporated ¹ H-NMR (氘-chloroform) δ 1.19-1.23 (2H, m), 1.50 (9H, s), 1.59-1.61 (6H, m), 2.68-2.72 (2H, m), 3.68-3.73 (2H, m), 4.08 (2H, s).

B) Manufacture of 4-(2-oxoethyl)piperidine-1-carboxylic acid tert-butyl butyl ester

Pyridyl chlorochromate (125.0 g) and acetic acid were added to a solution of 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl butyl ester (89.0 g) in dichloromethane (150 mL). Sodium (48.0 g) was dissolved in dichloromethane (300 mL). The reaction was stirred at 25 ° C for 3 hrs, then diethyl ether (300 mL) was added and filtered and filtered and evaporated. The filtrate was concentrated to give the title compound (60.0 g). ¹ H-NMR (氘-chloroform) δ 1.18-1.22 (2H, m), 1.46 (9H, s), 1.68-1.72 (2H, m), 2.08-2.10 (1H, m), 2.38-2.42 (2H, m), 2.73-2.77 (2H, m), 4.06-4.10 (2H, m), 9.78 (1H, s).

C) Manufacture of 4-(2-cyano-2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl butyl ester

Add a small amount of sodium cyanide (32.4g) in water (100mL) and concentrated hydrochloric acid (55mL) to a solution of 4-(2-oxoethyl)piperidine-1-carboxylic acid tert-butylate at 0 ° C (60 g) in a solution of diethyl ether (150 mL). The reaction was stirred for 4 hr. ¹ H-NMR (氘-chloroform) δ 1.20-1.24 (2H, m), 1.50 (9H, s), 1.79-1.83 (5H, m), 2.70-2.74 (2H, m), 3.50-3.54 (1H, m), 4.11-4.15 (2H, m), 4.56-4.60 (1H, m).

D) Manufacture of 4-{2-cyano-2-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylic acid tert-butyl butyl ester

A solution of methanesulfonium chloride (36.3 g) in dichloromethane (200 mL) was slowly added to 4-(2-cyano-2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (67.0 g). A solution of triethylamine (35.0 g) in dichloromethane (500 mL). The reaction was stirred at room temperature for 2 hr and added to ice water (300 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4). ¹ H-NMR (氘-chloroform) δ 1.18-1.22 (2H, m), 1.48 (9H, s), 1.73-1.77 (3H, m), 1.93-1.97 (1H, m), 2.03-2.07 (1H, m), 2.72-2.76 (2H, m), 3.23 (3H, s), 4.13-4.15 (2H, m), 5.27-5.29 (1H, m).

E) Manufacture of 1-indole bicyclo [2.2.2] octane-2-carbonitrile

Add a solution of trifluoroacetic acid (137.0 g) in dichloromethane (200 mL) to 4-{2-cyano-2-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylic acid The butyl ester (80.0 g) was dissolved in dichloromethane (200 mL), and the mixture was stirred at room temperature overnight. The reaction was concentrated, acetonitrile (200 mL) was added to the residue, and the mixture was slowly added at 0 ° C. Amine (98.0 g). The mixture was concentrated, the residue was diluted with methylene chloride. The insoluble material was filtered off, and the filtrate was concentrated. The title compound (13.0 g) was obtained eluted eluting ¹ H-NMR (氘-chloroform) δ 1.58-1.62 (3H, m), 1.80-1.84 (3H, m), 2.00-2.02 (1H, m), 2.88-2.92 (3H, m), 3.23 - 3.27 ( 1H, m), 3.86-3.90 (1H, m).

F) Manufacture of (2R)-1-indenylbicyclo[2.2.2]octane-2-carboxylic acid hydrochloride

The title compound was synthesized by optical resolution by the non-image isomer salt method in the same manner as in the literature (Mi, Y.; Corey, EJ Tetrahedron Communication 2006, 47, 2515-2516). That is, a solution of (+)-tartaric acid (22.0 g) in methanol (100 mL) was slowly added to 1-indane bicyclo[2.2.2]octane-2-carbonitrile (20.0 g) in methanol (100 mL). ) in the solution. The reaction was stirred for 90 minutes, concentrated and the solid was crystallised from methanol four times. The precipitate was filtered off and the filtrate was concentrated. Water (150 mL) was added to the residue and sodium bicarbonate was added to pH 8. The mixture was extracted with dichloromethane (200 mL x 3), and the extract was washed with brine, dried and concentrated. The obtained white solid (15.0 g) was dissolved in methanol (100 mL), and a solution of (-)- tartaric acid (16.5 g) in methanol (100 mL) was slowly added at 0 °C. The reaction was stirred for 90 minutes and concentrated, and the obtained solid was crystallised from methanol four times to give (2,1,1,2-bibicyclo[2.2.2]octane-2-carbonitrile (-)-tartrate (4.0 g) , >90% ee). Water (50 mL) was added to the obtained solid, and sodium hydrogen carbonate was added to pH 8. The mixture was extracted with dichloromethane (100 mL x 3), and the extract was washed with brine, dried and concentrated. The resulting white solid (1.75 g) was dissolved in EtOAc (EtOAc) After concentration, a solution of sodium hydroxide (1.04 g) in water (10 mL) was slowly added to the residue at 0 °C. The mixture was concentrated, concentrated hydrochloric acid (5 mL) was added and the mixture was concentrated again. The resulting white solid was extracted with MeOH (10 mL). The insoluble material was filtered out, and the filtrate was evaporated to ethylamine. ¹ H-NMR (氘-chloroform) δ 1.68-1.72 (4H, m), 1.88-1.92 (1H, m), 2.13-2.17 (2H, m), 3.32-3.36 (4H, m), 4.43 (1H, t, J = 9.6 Hz), 9.89 (1H, s), 14.15 (1H, brs).

G) Manufacture of 2-[(2R)-1-indenylbicyclo[2.2.2]oct-2-yl]-6-bromothieno[3,2-d]pyrimidin-4(3H)-one

O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (413 mg) was added at 0 ° C to manufacture in Example 1. Step 3-D 3-Amino-5-bromothiophene-2-carboxamide (200 mg), (2R)-1-indolylbicyclo[2.2.2]octane-2-carboxylic acid hydrochloride (173 mg), And a solution of N-ethyl-N-(1-methylethyl)propan-2-amine (0.395 mL) in N,N-dimethylformamide (4.0 mL). Stir at °C for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give (2R)-N-(5-bromo-2-amine-carbamoylthiophen-3-yl)-1-indanebicyclo[2.2.2]octane- A mixture of 2-mercaptoamine and the title compound. Mixture of (2R)-N-(5-bromo-2-aminomethylsulfonylthiophen-3-yl)-1-indolylbicyclo[2.2.2]octane-2-carboxamide and the title compound prepared above The solution, and ethanol (2.0 mL) and 2M aqueous sodium hydroxide (1.8 mL) were stirred at 70 ° C for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid at 0 ° C, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.39-1.52 (2H, m), 1.52-1.66 (2H, m), 1.73-1.85 (1H, m), 1.85-1.94 (1H, m), 2.19-2.32 (1H, m), 2.59-2.77 (2H, m), 2.83-2.97 (1H, m), 3.03-3.16 (1H, m), 3.93-4.01 (1H, m), 7.60 (1H, s).

H) 2-[(2R)-1-indenylbicyclo[2.2.2]oct-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d Manufacture of pyrimidine-4(3H)-one trifluoroacetate

2-[(2R)-1-indenylbicyclo[2.2.2]oct-2-yl]-6-bromothieno[3,2-d]pyrimidin-4(3H)-one (110 mg) and 3- Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester ( 199 mg), sodium carbonate (103 mg), 1,2-dimethoxyethane (2.0 mL) and water (1.0 mL) were placed in a flask, and the air in the flask was purged with argon. 1,1 '-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (26 mg) was added, and the air in the flask was again purged with argon. The reaction was stirred at 100 ° C for 2 hours, brine was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAcEtOAcEtOAc [(2R)-1-indenylbicyclo[2.2.2]oct-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 (3H)-The crude product of ketone (50 mg). Triethylamine (0.020 mL) and di-tertiary butyl dicarbonate (0.034 mL) were added to the above-produced 2-[(2R)-1-indenylbicyclo[2.2.2]oct-2-yl]-6- The crude product (50 mg) of (5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one in N,N-dimethylformamide 1.0 mL) in suspension. The reaction mixture was stirred at room temperature for 18 hr. water was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to afford 4-{2-[(2R)-1- bisbicyclo[2.2.2] oct-2-yl] -4-Sideoxy-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl}-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (pyrazole) The Boc position on the ring is undetermined) (22 mg). Water (0.50 mL) and trifluoroacetic acid (51.6 mg) were added to the above-prepared 4-{2-[(2R)-1-indenylbicyclo[2.2.2]oct-2-yl]-4-oneoxy- 3,4-Dihydrothieno[3,2-d]pyrimidin-6-yl}-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester, the reaction is stirred at 90 ° C 30 minute. The reaction was concentrated with EtOAc (EtOAc m. ¹ H-NMR (DMSO-d ₆ ) δ 1.74-1.97 (4H, m), 2.06-2.29 (2H, m), 2.36-2.48 (4H, m), 3.22-3.29 (2H, m), 3.42-3.79 (2H, m), 4.67-4.81 (1H, m), 7.44 (1H, s), 7.86-8.29 (1H, m), 9.83 (1H, brs), 12.68 (1H, brs).

Example 165 2-(2-吖Bicyclo[2.1.1]hex-1-yl)-6-[5-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketone dihydrochloride

1-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-, as in Example 148, Step A, as in Example 161. 2-oxobicyclo[2.1.1]hexane-3-carboxylic acid tert-butyl butyl ester (35.0 mg), [3-(trifluoromethyl)-1-trityl-1H-pyrazole- 4-yl]boronic acid (71.7 mg), sodium carbonate (22.5 mg), ethanol (5 mL), water (0.5 mL), tetrakis(triphenylphosphine)palladium(0) (4.90 mg), methanol (4 mL) and 4M HCl / EtOAc (1 mL) ¹ H-NMR (DMSO-d ₆ ) δ 1.84-1.90 (2H, m), 2.72-2.81 (2H, m), 2.94-2.99 (1H, m), 3.30-3.38 (2H, m), 7.43 (1H) , s), 8.63 (1H, s), 9.88-10.26 (3H, m), 13.03 (1H, brs), 14.26 (1H, brs).

Example 166 Manufacture of 2-cyclohexyl-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one A) Manufacture of 6-bromo-2-cyclohexylthieno[3,2-d]pyrimidin-4(3H)-one

Cyclohexanecarbonyl chloride (0.18 mL) was added at 0 ° C to 3-amino-5-bromothiophene-2-carboxamide (200 mg), triethylamine (0.19 mL). In a mixed solution of tetrahydrofuran (4.0 mL), the mixture was stirred at room temperature for 30 minutes. Water was poured into the reaction system, the mixture was extracted with ethyl acetate, and the mixture was washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give 5-bromo-3-[(cyclohexylcarbonyl)amino]thiophene-2-carbamide. 2M aqueous sodium hydroxide solution (0.90 mL) and ethanol (2.0 mL) were added to 5-bromo-3-[(cyclohexylcarbonyl)amino]thiophene-2-carboxamide prepared above, and the mixture was stirred at 70 ° C. 2 hours. The reaction was neutralized with 1 M hydrochloric acid at 0 °C. Water (2 mL) was added. ¹ H-NMR (DMSO-d ₆ ) δ 1.14-1.38 (3H, m), 1.44-1.62 (2H, m), 1.63-1.95 (5H, m), 2.55-2.67 (1H, m), 7.57 (1H) , s), 12.45 (1H, brs).

B) Manufacture of 2-cyclohexyl-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-cyclohexylthieno[3,2-d]pyrimidin-4(3H)-one (250 mg) and 3-methyl-4-(4) , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (492 mg), sodium carbonate (254 mg ), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) and 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane The title compound (158 mg) was obtained as a pale yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.11-1.97 (10H, m), 2.45 (3H, s), 2.54-2.68 (1H, m), 7.35 (1H, s), 7.95 (1H, brs), 12.20 (1H, brs), 12.96 (1H, brs).

Example 167 Manufacture of 2-methyl-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one A) Manufacture of 6-bromo-2-methylthieno[3,2-d]pyrimidin-4(3H)-one

3-Amino-5-bromothiophene-2-carboxamide (200 mg), triethylamine (0.19 mL), tetrahydrofuran (Prepared from Example 166, Step A, from Example 1, Step D). The title compound (131 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 2.36 (3H, s), 7.54 (1H, s), 12.55 (1H, brs).

B) Manufacture of 2-methyl-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-methylthieno[3,2-d]pyrimidin-4(3H)-one (130 mg) and 3-methyl-4-(4) , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (327 mg), sodium carbonate (169 mg , 1,2-Dimethoxyethane (3.0 mL) and water (1.5 mL) and 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane The title compound (74 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 2.36 (3H, s), 2.44 (3H, s), 7.31 (1H, s), 7.98 (1H, brs), 12.30 (1H, brs), 12.96 (1H, Brs).

Example 168 2-{[(2-hydroxy-2-methylpropyl)amino]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine -4(3H)-one manufacture

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 300 mg), and 1-amino-2-methylpropan-2-ol (191 mg) and potassium carbonate (445 mg) and sodium iodide (16 mg) and N,N-dimethylformamide (5.0 mL). 6-Bromo-2-{[(2-hydroxy-2-methylpropyl)amino]methyl}thieno[3,2-d]pyrimidin-4(3H)-one (160 mg) as a white solid . 6-Bromo-2-{[(2-hydroxy-2-methylpropyl)amino]methyl}thieno[3,2-d]pyrimidin-4(3H)-one (130 mg) manufactured above , triethylamine (0.060 mL), di-tertiary butyl dicarbonate (0.100 mL), N,N-dimethylpyridin-4-amine (4.78 mg) and N,N-dimethylformamide ( The mixture of 2.0 mL) was stirred at 50 ° C for 2 hours. The mixture was purified by basic EtOAc (EtOAc/EtOAcEtOAcEtOAcEtOAc And [3,2-d]pyrimidin-2-yl)methyl](2-hydroxy-2-methylpropyl)aminecarboxylic acid tert-butyl butyl ester (the Boc position on the pyrazole ring is undetermined) (96 mg). [(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)methyl, as prepared above, in the same manner as in Example 2, Step C (2-hydroxy-2-methylpropyl)aminecarboxylic acid tert-butyl butyl ester (95 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-di Tert-butyl borolan-2-yl)-1H-pyrazole-1-carboxylic acid (135 mg), sodium carbonate (70 mg), 1,2-dimethoxyethane (2.0 mL) and water ( 1.0 mL) and 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (18 mg) gave a pale yellow solid ( 2-hydroxy-2-methylpropyl){[6-(5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2- d]Pyryl pyridin-2-yl]methyl}aminocarboxylic acid tert-butyl ester (30 mg). 4M HCl/ethyl acetate solution (1.0 mL) was added to the above-produced (2-hydroxy-2-methylpropyl){[6-(5-methyl-1H-pyrazole-4) under stirring at room temperature. 4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]methyl}aminecarboxylic acid tert-butyl butyl ester (30 mg) in methanol (3.0 mL) In solution. The reaction was stirred with heating at 50 ° C for 5 hr and concentrated under reduced pressure. The title compound (13 mg) was obtained from m. . ¹ H-NMR (DMSO-d ₆ ) δ 1.09 (6H, s), 2.41 (2H, s), 2.45 (3H, s), 3.70 (2H, s), 4.38 (1H, brs), 7.36 (1H, s), 8.01 (1H, brs).

Example 169 2-{[(2-hydroxyethyl)(methyl)amino]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine- Manufacture of 4(3H)-ketone A) Manufacture of 6-bromo-2-{[(2-hydroxyethyl)(methyl)amino]methyl}thieno[3,2-d]pyrimidin-4(3H)-one

6-Bromo-2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 6) was prepared in the same manner as in Example 2, Step B. 300 mg), and 2-(methylamino)ethanol (0.172 mL) and potassium carbonate (445 mg) and sodium iodide (16 mg) and N,N-dimethylformamide (5.0 mL) The title compound (128 mg). ¹ H-NMR (DMSO-d ₆ ) δ 2.22 (3H, s), 2.52-2.57 (2H, m), 3.50 (2H, t, J = 5.5 Hz), 3.55 (2H, s), 4.63 (1H, s), 7.60 (1H, s), 12.10 (1H, brs).

B) 2-{[(2-Hydroxyethyl)(methyl)amino]methyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one

In the same manner as in Example 2, Step C, from 6-bromo-2-{[(2-hydroxyethyl)(methyl)amino]methyl}thieno[3,2-d]pyrimidine-4 ( 3H)-ketone (28mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1-carboxylic acid tert-butyl butyl ester (54 mg), sodium carbonate (28 mg), 1,2-dimethoxyethane (1.0 mL) and water (0.5 mL) and 1,1'-bis(diphenylphosphine) The title compound (10 mg) was obtained as a pale brown solid. ¹ H-NMR (DMSO-d ₆ ) δ 2.24 (3H, s), 2.45 (3H, s) 2.55 (2H, t, J = 5.6 Hz), 3.51 (2H, t, J = 5.6 Hz), 3.55 ( 2H, s), 7.36 (1H, s), 7.92 (1H, brs), 12.98 (1H, brs).

Example 170 2-[(2S)-1-indenylbicyclo[2.2.2]oct-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketotrifluoroacetate A) Production of (2S)-1-indenylbicyclo[2.2.2]octane-2-carboxylic acid hydrochloride

The title compound was synthesized by optical resolution by the method of the non-mirogram isomer salt in the same manner as in the literature (Mi, Y.; Corey, EJ Tetrahedron Communication 2006, 47, 2515-2516). That is, a solution of (+)-tartaric acid (22.0 g) in methanol (100 mL) was slowly added at 0&lt;~&gt;&gt; A solution of the nitrile (20.0 g) in methanol (100 mL). The reaction was stirred for 90 minutes, concentrated, and the obtained solid was crystallised from methanol four times to give (2S)-1-yt-bicyclo[2.2.2]octane-2-carbonitrile (+)-tartrate (3.0 g) , >90% ee). Water (50 mL) was added to the obtained solid, and sodium hydrogen carbonate was added to pH 8. The mixture was extracted with dichloromethane (100 mL x 3), and the extract was washed with brine, dried and concentrated. The resulting white solid (1.4 g) was dissolved in EtOAc (EtOAc)EtOAc. After concentration, a solution of sodium hydroxide (0.83 g) in water (10 mL) was slowly added to the residue at 0 °C. The mixture was concentrated, concentrated hydrochloric acid (5 mL) was added and the mixture was concentrated again. The resulting white solid was extracted with MeOH (10 mL). The insoluble material was filtered out, and the filtrate was evaporated to ethylamine. ¹ H-NMR (DMSO-d ₆ ) δ 1.88-1.92 (5H, m), 2.13-2.17 (2H, m), 3.32-3.36 (4H, m), 4.43 (1H, t, J = 9.6 Hz), 10.01 (1H, s), 14.10 (1H, brs).

B) Manufacture of 2-[(2S)-1-indenylbicyclo[2.2.2]oct-2-yl]-6-bromothieno[3,2-d]pyrimidin-4(3H)-one

O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.24 g) was added at 0 ° C to manufacture in the examples. 1, 3-D-amino-5-bromothiophene-2-carboxamide (600 mg), (2S)-1-indolylbicyclo[2.2.2]octane-2-carboxylic acid hydrochloride (520 mg) And N-ethyl-N-(1-methylethyl)propan-2-amine (1.19 mL) in a solution of N,N-dimethylformamide (10 mL). Stir at °C for 20 hours. Water was added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give (2S)-N-(5-bromo-2-amine-mercaptothiophen-3-yl)-1-indanebicyclo[2.2.2]octane- A mixture of 2-mercaptoamine and the title compound. (2S)-N-(5-Bromo-2-aminomethylsulfonylthiophen-3-yl)-1-indolylbicyclo[2.2.2]octane-2-carboxamide and the title compound in ethanol A mixed solution of (4.0 mL) and a 2M aqueous sodium hydroxide solution (2.7 mL) were stirred at 70 ° C for 2 hours. The reaction mixture was neutralized with 1 M hydrochloric acid at 0 ° C, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.40-1.63 (4H, m), 1.73-1.94 (2H, m), 2.18-2.30 (1H, m), 2.60-2.71 (2H, m), 2.83-2.97 (1H, m), 3.04-3.17 (1H, m), 3.89-4.01 (1H, m), 7.60 (1H, s).

C) 2-[(2S)-1-indenyl[2.2.2]oct-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d Manufacture of pyrimidine-4(3H)-one trifluoroacetate

2-[(2S)-1-indenylbicyclo[2.2.2]oct-2-yl]-6-bromothieno[3,2-d]pyrimidin-4(3H)-one (210 mg) and 3- Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester ( 571 mg), sodium carbonate (196 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) were placed in a flask, and the air in the flask was purged with argon. 1,1 '-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (252 mg) was added, and the air in the flask was again purged with hydrogen. The reaction was stirred at 100 ° C for 2 hours, brine was added and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexanesssssssssssssssssss The crude product (96 mg) of -6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one. Triethylamine (0.039 mL) and di-tertiary butyl dicarbonate (0.065 mL) were added to the above-produced 2-[(2S)-1-indolyl[2.2.2]oct-2-yl]-6- The crude product (96 mg) of (5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one in N,N-dimethylformamide 1.0 mL) in suspension. The reaction mixture was stirred at 50 ° C for 18 hours, water was added and the mixture was extracted with ethyl acetate. It was dried over anhydrous sodium sulfate, and the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to afford 4-{2-[(2S)-1- bisbicyclo[2.2.2] oct-2-yl] -4-Sideoxy-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl}-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (pyrazole) The Boc position on the ring was undetermined) (49 mg). Water (0.50 mL) and trifluoroacetic acid (50.6 mg) were added to the above-prepared 4-{2-[(2S)-1-indenylbicyclo[2.2.2]oct-2-yl]-4-oneoxy- 3,4-Dihydrothieno[3,2-d]pyrimidin-6-yl}-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester, the reaction is stirred at 90 ° C 30 minute. The reaction was concentrated under reduced pressure. EtOAc m. The obtained pale yellow solid was purified by high performance liquid chromatography (column: L-column 2 ODS (20 mm id × 50 mmL), mobile phase: 0.1% aqueous trifluoroacetic acid / 0.1% trifluoroacetic acid in acetonitrile). The title compound (6 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.70-1.95 (4H, m), 2.05-2.25 (2H, m), 2.36-2.48 (4H, m), 3.21-3.31 (2H, m), 3.42-3.56 (1H, m), 3.59-3.78 (1H, m), 4.57-4.84 (1H, m), 7.44 (1H, s), 7.81-8.44 (1H, m), 9.81 (1H, brs), 12.43-13.20 (2H, m) .MS (ESI +): [m + H] + 342.MS (ESI +), Found: 342.

Example 171 2-[(1R ^* ,6R ^* )-3-indolyl[4.1.0]hept-4-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2 -d]Production of pyrimidine-4(3H)-one dihydrochloride A) Manufacture of methyl 2-[(tri-butyloxycarbonyl)amino]pent-4-enoate

2-[(Tertiary butoxycarbonyl)amino]pent-4-enoic acid (20.0 g), potassium carbonate (13.2 g) and N,N-dimethylformamide (100 mL) were stirred for 15 min. The mixture was cooled to 0 ° C, iodomethane (9.2 g) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered and the residue washed with ethyl acetate. The filtrate was washed with 5% hydrochloric acid and brine and dried over anhydrous sodium sulfate. Insolubles were filtered off, the filtrate was concentrated under reduced pressure to give the title compound ^{(21.0g) 1 H-NMR.} ( Deuterium - chloroform) δ1.45 (9H, s), 2.47-2.58 (2H, m), 3.75 ( 3H, s), 4.40 (1H, q, J = 6.4 Hz), 5.07 (1H, d, J = 5.6 Hz), 5.13-5.16 (2H, m), 5.66-5.74 (1H, m).

B) Manufacture of methyl 2-((tertiary butoxycarbonyl)(prop-2-en-1-yl)amino]pent-4-enoate

A solution of the above-produced methyl 2-[(tris-butoxycarbonyl)amino]pent-4-enoate (10.5 g) in ethanol (50 mL) was cooled to -20 ° C, then 3-bromopropan-1- The olefin (6.1 g) and sodium hydride (60% in oil, 2.0 g) were stirred at -20 ° C for 1.5 hr and quenched by the addition of saturated aqueous ammonium chloride (20 mL). The organic product was extracted with diethyl ether and the extract was dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was evaporated. ¹ H-NMR (氘-chloroform) δ 1.47 (9H, s), 2.59-2.75 (2H, m), 3.72 (3H, s), 3.79-4.15 (3H, m), 5.08-5.36 (4H, m ), 5.74-5.84 (2H, m).

C) Manufacture of [1-(hydroxymethyl)but-3-en-1-yl]prop-2-en-1-ylaminecarboxylic acid tert-butyl butyl ester

1 M hydrogenated diisobutylaluminum/toluene solution (60 mL) was added to 2-[(tri-n-butoxycarbonyl)(prop-2-en-1-yl)amino]pent-4- as prepared above at 0 °C In a mixture of methyl enoate (5.0 g) and tetrahydrofuran (100 mL), the mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with an aqueous solution of sodium potassium tartrate and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The insoluble material was filtered. ¹ H-NMR (氘-chloroform) δ 1.45 (9H, s), 2.35-2.37 (2H, m), 3.49-3.84 (5H, m), 5.01-5.18 (4H, m), 5.69-5.87 (2H, m).

D) Manufacture of 2-[(tertiary butoxycarbonyl)(prop-2-en-1-yl)amino]pent-4-en-1-yl 4-nitrobenzoate

N,N-dimethylpyridin-4-amine (0.7 g) was added to the above-prepared [1-(hydroxymethyl)but-3-en-1-yl]prop-2-en-1-ylaminecarboxylic acid A mixture of tertiary butyl ester (15.0 g), triethylamine (19.0 g) and dichloromethane (150 mL). A solution of 4-benzylidene chloride (14.2 g) in dichloromethane (30 mL) was added dropwise to the mixture, and the mixture was stirred at 0 ° C for 30 min. The reaction mixture was diluted with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with dichloromethane, and the mixture was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified to silicagel elut elut elut elut elut ¹ H-NMR (氘-chloroform) δ 1.45 (9H, s) 2.33-2.38 (1H, m) 2.42-2.47 (1H, m), 3.73 (1H, s), 3.84 (1H, s), 4.38-4.52 (3H, m), 5.01-5.16 (4H, m), 5.72-5.79 (2H, m), 8.19 (2H, d, J = 8.0 Hz), 8.26-8.28 (2H, m).

E) Manufacture of 2-({[(4-nitrophenyl)carbonyl]oxy}methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl butyl ester

2-[(Tributylbutoxycarbonyl)(prop-2-en-1-yl)amino]pent-4-en-1-yl 4-nitrobenzoate prepared above under nitrogen atmosphere (14.0 g) A solution of benzene (300 mL) was heated under reflux for 15 min and cooled to 10 °C. Grubbs reagent (1.9 g) was added at 10 ° C, and the reaction mixture was stirred for 3 hours. Dimethyl hydrazine (8.6 mL) was added, and the mixture was evaporated. ¹ H-NMR (氘-chloroform) δ 1.25-1.33 (9H, m), 2.01-2.09 (1H, m), 2.51-2.56 (1H, m), 3.60-3.64 (1H, m), 4.14-4.44 ( 3H, m), 4.75-4.79 (1H, m), 5.69-5.77 (2H, m), 8.20 (2H, d, J = 8.4 Hz), 8.25 (2H, s).

F) (1R ^* , 4S ^* , 6R ^* )-4-({[(4-nitrophenyl)carbonyl)oxy}methyl)-3-indolebicyclo[4.1.0]heptane-3-carboxylate Manufacture of tertiary butyl acid

The above-prepared 2-({[(4-nitrophenyl)carbonyl]oxy}methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (10.0 g) was dissolved. Palladium acetate (689 mg) was added at 10 ° C in 5% diazomethane / diethyl ether (1.4 L), and the mixture was stirred at the same temperature for 40 min. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 2-({[(4-nitrophenyl)carbonyloxy]methyl}-3,6-dihydropyridine-1 A mixture of the (2H)-carboxylic acid tert-butyl ester and the title compound. The title compound ( 8.4 g) was obtained from the title compound ( ¹ g). , m), 0.69-0.74 (1H, m), 0.95-1.02 (2H, m), 1, 40 (9H, s), 1.80-1.97 (2H, m), 3.39-3.43 (1H, m), 3.82 -3.91 (1H, m), 4.24 - 4.48 (3H, m), 8.16-8.20 (2H, m), 8.27-8.29 (2H, m).

G) Manufacture of (1R ^* ,4S ^* ,6R ^* )-4-(hydroxymethyl)-3-indolylbicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl butyl ester

Lithium hydroxide monohydrate (2.7 g) was added to the above-made (1R ^* ,4S ^* ,6R ^* )-4-({[(4-nitrophenyl)carbonyl)oxy}methyl)-3- A mixture of bisbicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (8.2 g), tetrahydrofuran (70 mL), methanol (70 mL) and water (35 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with brine and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj ¹ H-NMR (氘-chloroform) δ 0.24 (1H, brs), 0.61-0.64 (1H, m), 0.88-0.92 (2H, m), 1.24-1.29 (1H, m), 1.45 (9H, m) , 1.73 (2H, brs), 1.88 (1H, brs), 3.47 (1H, brs), 3.58-3.61 (1H, m), 3.67-3.72 (1H, m), 4.00-4.13 (1H, m).

H) Manufacture of (1R ^* ,4S ^* ,6R ^* )-4-carboxylidene-3-indolyl[4.1.0]heptane-3-carboxylic acid tert-butyl butyl ester

(1R ^* ,4S ^* ,6R ^* )-4-(hydroxymethyl)-3-indolyl[4.1.0]heptane-3-carboxylic acid tert-butyl ester (200 mg) and Dess-Martin A solution of the oxidizing agent (450 mg) in dichloromethane (10 mL) was stirred at 0 ° C for 3 hr. Water (10 mL) was added and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj ¹ H-NMR (氘-chloroform) δ 0.17-0.27 (1H, m), 0.67-0.72 (1H, m), 0.85-1.14 (2H, m), 1.42-1.48 (9H, m), 1.66-1.77 ( 1H, m), 2.27-2.39 (1H, m), 3.49-3.89 (2H, m), 3.97-4.25 (1H, m), 9.52 (1H, s).

I) (1R*, 4S*, 6R*)-3-(tertiary butoxycarbonyl)-3-indolebicyclo[4.1.0]heptane-4-carboxylic acid

2-methylbut-2-ene (0.5 mL), sodium chloride (367 mg), and 1.67 M aqueous sodium dihydrogen phosphate solution (1.67 mL) were added to the above-made (1R*, 4S*, 6R*)-4- Methylmercapto-3-indole bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl butyl ester (700 mg) in a solution of tert-butanol (20 mL). The oxidation reaction was carried out at room temperature for 2 hours and quenched with water. The mixture was adjusted to pH 4 with 5% hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAcjjjjj elut elut ¹ H-NMR (氘-chloroform) δ 0.07-0.17 (1H, m), 0.56-0.62 (1H, m), 0.88-0.97 (1H, m), 1.31-1.39 (9H, m), 1.72-1.76 ( 1H, m), 2.16-2.31 (1H, m), 3.33-3.38 (2H, m), 3.52-3.63 (1H, m), 4.02-4.21 (1H, m).

J) (1R*,6R*)-4-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3-indole bicyclo[ 4.1.0] Manufacture of heptane-3-carboxylic acid tertiary butyl ester

3-Amino-5-bromothiophene-2-carboxamide (663 mg) manufactured in Example 1, Step D, in the same manner as in Example 82, Step A, (1R ^* , 4S ^* , 6R ^* )-3-(tertiary butoxycarbonyl)-3-indenylbicyclo[4.1.0]heptane-4-carboxylic acid (1.09g), 2-methylpropyl chlorocarbonate (0.584mL), triethyl The title compound (310 mg) was obtained as a white crystal. ¹ H-NMR (DMSO-d ₆ ) δ 0.18-1.37 (13H, m), 1.87-2.39 (2H, m), 3.52-4.59 (3H, m), 7.57-7.63 (1H, m), 12.63 (1H) , brs).

K) 2-[(1R ^* ,6R ^* )-3-indenylbicyclo[4.1.0]hept-4-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3 ,2-d]pyrimidine-4(3H)-one dihydrochloride

(1R ^* ,6R ^* )-4-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d], as prepared in the same manner as in Example 83, Step C Pyrimidin-2-yl)-3-indole bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl butyl ester (310 mg), 3-methyl-4-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (448 mg), cesium carbonate (711 mg), 1,1'-double ( Diphenylphosphino)ferrocene]palladium(II)-dichloromethane complex (1:1) (53 mg), 1,2-dimethoxyethane (7.5 mL), water (0.75 </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI> ¹ H-NMR (DMSO-d ₆ ) δ 0.51-2.27 (6H of major, 6H of minor, m), 2.42 - 2.47 (3H of major, 3H of minor, m), 3.02-4.03 (3H of major, 3H Of minor, m), 7.32 (1H of minor, s), 7.34 (1H of major, s), 8.11-8.12 (1H of major, 1H of minor, m), 8.99-9.72 (2H of major, 2H of minor , m), 12.71-12.91 (1H of major, 1H of minor, m). The ratio of non-image isomers observed was 3:2.

Example 172 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one salt Manufacture of acid salt A) (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylic acid tert-butyl Ester manufacture

A solution of (2S)-1-(tertiary butoxycarbonyl)piperidine-2-carboxylic acid (37.8 g) in tetrahydrofuran (375 mL) was cooled in an ice bath to an internal temperature of 10 °C. Triethylamine (23.0 mL) was added and the mixture was stirred at room temperature for 10 min. 2-Methyl chlorocarbonate (21.4 mL) was added dropwise to the mixture over a period of 30 minutes (internal temperature 8 to 13 ° C). The ice bath was removed and the mixture was stirred at room temperature for 1 hour. Then, 3-amino-5-bromothiophene-2-carboxamide (16.6 g), which was produced in Example 1, Step D, was added to the reaction mixture, and the mixture was stirred at 60 ° C for 12 hours. The reaction mixture was stirred at room temperature for 8 hr then ethyl acetate (EtOAc) The precipitate was collected by filtration and washed with water to give (2S)-2-[(5-bromo-2-amine-carbamoylthiophen-3-yl)aminecarbazyl]piperidine-1-carboxylic acid as a white solid. The crude product of butyl ester (18.6 g). The organic layer was separated from the mother liquid and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained yellow oily residue (38 g) and the above-produced (2S)-2-[(5-bromo-2-aminomethylsulfonylthiophen-3-yl)aminemethanyl]piperidine-1-carboxylate The crude product of the tertiary butyl acid ester (18.6 g) was added to ethanol (375 mL) and 2M aqueous sodium hydroxide (188 mL). The mixture was stirred at 75 &lt;0&gt;C for 2 h, cooled in an ice-bath and water (EtOAc) The mixture was adjusted to pH 7 with 6M hydrochloric acid ( 117 mL), with the internal temperature maintained at 4 to 8 °C. The reaction mixture was stirred in an ice bath for 30 min. The title compound (24.8 g) was obtained. The optical purity was 38.7% ee. High performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm id × 250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/2-propanol/diethylamine (700/ 300/1), flow rate: 1 mL/min, column temperature: 30 ° C, detection 220 nm). ¹ H-NMR (DMSO-d ₆ ) δ 1.09-1.45 (11H, m), 1.46-1.58 (1H, m), 1.60-1.86 (2H, m), 1.98-2.14 (1H, m), 3.38-3.53 (1H, m), 3.75-3.89 (1H, m), 4.89-5.10 (1H, m), 7.58 (1H, s), 12.64 (1H, brs).

B) (2S)-2-(6-Bromo-4-indolyl-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylic acid tert-butyl Optical separation of ester

High performance liquid chromatography (column: CHIRALPAK AD (50 mm id × 500 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/2-propanol/diethylamine (700/300/1), Flow rate: 80 mL/min, column temperature: 30 ° C) Distinguish (2S)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2- Base piperidine-1-carboxylic acid tert-butyl butyl ester (10.1 g, 38.7% ee). (2S)-2-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine was obtained under the above high performance liquid chromatography conditions. 1-carboxylic acid tert-butyl butyl ester (6.59 g, >99.9% ee, retention time 6.32 minutes) and (2R)-2-(6-bromo-4-yloxy-3,4-dihydrothieno[ 3,2-d]pyrimidin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (2.71 g, >99.9% ee, retention time 8.6 min). High performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm id × 250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/2-propanol/diethylamine (700/ 300/1), flow rate: 1 mL/min, column temperature: 30 ° C, detection 220 nm).

C) 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)- Manufacture of ketone hydrochloride

The mother liquor obtained in the final step of the crystallization step of Example 83, Step D was concentrated under reduced pressure. Ethanol (7 mL) was added to the residue, and the mixture was stirred with heating at 80 °C. Water (0.5 mL) was added and the resulting solution was gradually cooled to room temperature with stirring. The title compound (75 mg) was obtained as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 1.51-1.92 (5H, m), 2.25-2.33 (1H, m), 2.46 (3H, s), 2.97-3.10 (1H, m), 3.35-3.39 (1H , m), 4.16-4.25 (1H, m), 7.34 (1H, s), 8.00 (1H, brs), 9.23 (1H, brs), 13.02 (1H, brs). MS (ESI+): [M+H ] ⁺ 316. MS (ESI+), found: 316.

Example 173 2-{2-[(2-hydroxyethyl)(methyl)amino]ethyl}-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one

3-chloropropionyl chloride (0.143 mL) was added to 3-amino-5-bromothiophene-2-carboxamide (300 mg), triethylamine (Step 3), which was stirred at 0 ° C. A mixture of 0.208 mL) and tetrahydrofuran (7.0 mL). The reaction mixture was stirred at room temperature for 30 min and then added &lt;RTI ID=0.0&gt;&gt; The reaction mixture was stirred with heating at 70 ° C for 18 hours. The reaction mixture was neutralized with a 1M aqueous solution of hydrochloric acid. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) (Methyl)amino]ethyl}thieno[3,2-d]pyrimidin-4(3H)-one (405 mg). 6-Bromo-2-{2-[(2-hydroxyethyl)(methyl)amino]ethyl}thiophene [3,2-d] prepared as above in the same manner as in Example 2, Step C Pyrimidine-4(3H)-one (50mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylic acid tert-butyl butyl ester (93 mg), sodium carbonate (48 mg), 1,2-dimethoxyethane (1.0 mL) and water (0.5 mL) and 1,1'-double (Diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (12 mg). ¹ H-NMR (DMSO-d ₆ ) δ 2.24 (3H, s), 2.39-2.48 (5H, m), 2.70-2.84 (4H, m), 3.46 (2H, t, J = 6.2 Hz), 4.42 ( 1H, brs), 7.33 (1H, s), 7.67-8.32 (1H, m), 12.15-13.16 (2H, m).

Example 174 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]thieno[3,2-d]pyrimidin-4(3H)-one Manufacturing

6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]thieno[3,2-d, mp. Pyrimidine-4(3H)-one dihydrochloride (255 mg) was suspended in methanol (7 mL) and triethylamine (0.28 mL) was added to give a solution. Alkaline tannin (5 g) was added to the mixture and mixed. The solvent was evaporated under reduced pressure. The residue was purified by basic column chromatography (methanol / ethyl acetate). The target was concentrated under reduced pressure and ethyl acetate (10 mL) was then evaporated. The title compound (183 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.36-1.62 (4H, m), 1.77-1.94 (2H, m), 2.44 (3H, s), 2.59-2.69 (1H, m), 2.98-3.08 (1H , m), 3.60-3.68 (1H, m), 7.31 (1H, s), 8.00 (1H, brs). MS (ESI+): [M+H] ⁺ 316. MS (ESI+), found: 316.

Example 175 2-[(1R,3S,4R,5R) or (1S,3S,4S,5R)-5-fluoro-2-indenylbicyclo[2.2.1]heptan-3-yl]-6-(5-methyl Manufacture of -1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one hydrochloride A) (1R ^* , 3S, 4R ^* , 5R)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5 -Production of fluoro-2-indolyl [2.2.1] heptane-2-carboxylic acid tert-butyl butyl ester

Add 2-methylpropyl chlorocarbonate (1.34 mL) to (1R ^* ,3S,4R ^* ,5R)-2-(tertiarybutoxycarbonyl)-5-fluoro-2-indole bicyclo[2.2] at 0 °C. A solution of heptane-3-carboxylic acid (2.65 g) and triethylamine (1.42 mL) in THF (35 mL). A solution of 3-amino-5-bromothiophene-2-carboxamide (1.88 g) in Example 1, Step D, in tetrahydrofuran (10 mL) was added to the reaction system, and the mixture was stirred at 60 ° C for 18 hours. . Water was added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. A 2 M aqueous sodium hydroxide solution (34 mL) and ethanol (200 mL) were added to the obtained pale yellow solid, and the mixture was stirred at 80 ° C for 8 hours. The reaction mixture was neutralized with 1 M hydrochloric acid at 0 °C. The title compound (2.82 g) was obtained eluted eluted elute ¹ H-NMR (DMSO-d ₆ ) δ 1.06-1.45 (9H, m), 1.50-1.86 (2H, m), 2.01-2.22 (2H, m), 2.83-2.95 (1H, m), 4.03-4.13 (1H, m), 4.15-4.32 (1H, m), 4.91-5.20 (1H, m), 7.57-7.75 (1H, m), 12.58-12.76 (1H, m).

B) (1R ^* , 3S, 4R ^* , 5R)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-5 Optical Separation of -Fluoro-2-indolebicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester

High performance liquid chromatography (column: CHIRALPAK AD (50 mm id × 500 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (800/200), flow rate: 80 mL/min, column temperature :30 ° C) Distinguish (1R ^* , 3S, 4R ^* , 5R)-3-(6-Bromo-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl 5-fluoro-2-indenylbicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (274 mg). Obtaining (1R, 3S, 4R, 5R) or (1S, 3S, 4S, 5R)-3-(6-bromo-4-oxo-3,4-dihydrothiophene under the above high performance liquid chromatography conditions And [3,2-d]pyrimidin-2-yl)-5-fluoro-2-indolyl[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester (1.39 g, >99.9% ee, residence time 7.1 min) and (1R, 3S, 4R, 5R) or (1S, 3S, 4S, 5R)-3-(6-bromo-4-yloxy-3,4-dihydrothieno[3,2- d]pyrimidin-2-yl)-5-fluoro-2-indolyl[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.40 g, 99.8% ee, retention time 14.2 min). High performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm id × 250 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (800/200), flow rate: 1 mL/min, The column temperature was 30 ° C and the detection was 220 nm).

C) 2-[(1R,3S,4R,5R) or (1S,3S,4S,5R)-5-fluoro-2-indenylbicyclo[2.2.1]heptan-3-yl]-6-(5- Manufacture of methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one hydrochloride

(1R, 3S, 4R, 5R) or (1S, 3S, 4S, 5R)-3-(6-bromo-4-oxo-3,4-dihydrothiophene) will be prepared in Example 175, Step B. And [3,2-d]pyrimidin-2-yl)-5-fluoro-2-indolyl[2.2.1]heptane-2-carboxylic acid tert-butyl butyl ester (1.40 g, 99.8% ee, retention time 14.2) Minutes) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid A tertiary butyl ester (1.94 g), sodium carbonate (1.00 g), 1,2-dimethoxyethane (30 mL) and water (15 mL) were placed in a flask, and the air in the flask was purged with hydrogen. 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (257 mg) was added, and the air in the flask was again purged with argon. The reaction was stirred at 100 ° C for 1 hour and water was added. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) toield (1R,3S,4R,5R) or (1S,3S,4S,5R)-5-fluoro-3 as a pale yellow solid. -[6-(5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2- Bicyclo[2.2.1] heptane-2-carboxylic acid tert-butyl ester (1.39 g). Add 5% HCl/methanol solution (15 mL) to the above-made (1R, 3S, 4R, 5R) or (1S, 3S, 4S, 5R)-5-fluoro-3-[6-( 5-methyl-1H-pyrazol-4-yl)-4-yloxy-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-indole bicyclo[2.2. 1] A solution of heptane-2-carboxylic acid tert-butyl ester (1.39 g) in methanol (15 mL). The reaction was stirred with heating at 50 ° C for 3 hours and the reaction mixture was concentrated under reduced pressure. Ethanol (15 mL) was added to the residue and water (2 mL) was slowly added at 100 °C. The solution was cooled to rt. ¹ H-NMR (DMSO-d ₆ ) δ 1.75-1.96 (3H, m), 2.46 (3H, s), 2.53-2.62 (1H, m), 3.18-3.26 (1H, m), 4.19-4.31 (2H , m), 4.93-5.18 (1H, m), 7.35 (1H, s), 8.09 (1H, s), 8.64 (1H, brs), 9.98 (1H, brs), 12.94 (1H, brs). ESI+): [M+H] ⁺ 346. MS (ESI+), found: 346.

Example 176 2-(1-indolebicyclo[2.2.2]oct-2-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 (3H )--Manufacture of ketone A) Manufacture of 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)ethanone

A mixture of pentane-2,4-dione (5.01 g) and 1,1-dimethoxy-N,N-dimethylmethylamine (6.26 g) was stirred at 80 ° C for one hour. Tetrahydrofuran (10 mL) was added to the reaction mixture, and tributyl sulfonium hydrochloride was added in small portions under ice cooling, and the mixture was stirred at 60 ° C for 30 minutes. The reaction mixture was cooled to rt. EtOAc (EtOAc) (EtOAc) The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The title compound (7.47 g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.67 (9H, s), 2.42 (3H, s), 2.77 (3H, s), 7.76 (1H, s).

B) Manufacture of (2Z)-3-chloro-3-(5-methyl-1H-pyrazol-4-yl)prop-2-enenitrile

Phosphorus oxychloride (25.4 g) was added in small portions to N,N-dimethylformamide (12.1 g), and the mixture was stirred at room temperature for 15 min. The above-prepared 1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)ethanone (7.47 g) was added thereto in small portions under ice cooling to give the reaction mixture. Stir at 50 ° C for 30 minutes. A powder of hydroxylamine hydrochloride (11.5 g) was added thereto in small portions at 50 ° C, and the reaction mixture was stirred at 50 ° C for 30 minutes. Ice water (200 mL) was added to the reaction mixture, and the mixture was evaporated to ethyl acetate (100 mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the residue was evaporated,jjjjjjjjjjjjjjj . ¹ H-NMR (DMSO-d ₆ ) δ 2.48 (3H, s), 5.68 (1H, s), 7.82 (1H, s).

C) Manufacture of methyl 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene-2-carboxylate

(2Z)-3-chloro-3-(5-methyl-1H-pyrazol-4-yl)prop-2-enenitrile (3.08 g), methyl thioacetate (2.15 g), A mixture of sodium hydride (1.47 g) and N,N-dimethylacetamide (10 mL) was stirred at 60 ° C for 2 hours. Ethyl acetate (20 mL) and water (10 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The title compound (3.57 g) was obtained eluted eluted eluted eluted ¹ H-NMR (DMSO-d ₆ ) δ 2.39 (3H, s), 3.68 (3H, s), 6.53 (2H, s), 6.65 (1H, s), 7.46-8.26 (1H, m), 12.83 ( 1H, brs).

D) 3-Amino-5-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl]thiophene-2-carboxylic acid methyl ester and 3-amino group- Manufacture of methyl 5-[1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-4-yl]thiophene-2-carboxylate

Methyl 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene-2-carboxylate (3.50 g), potassium carbonate (2.45 g), 1-(chlorine) A mixture of methyl)-4-methoxybenzene (2.43 g) and N,N-dimethylformamide (30 mL) was stirred at 100 ° C for 15 hours. Ethyl acetate (20 mL) and water (10 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the filtrate was evaporated. ¹ H-NMR (DMSO-d ₆ ) δ 2.29 (2H, s), 2.39 (1H, s), 3.68-3.75 (6H, m), 5.16 (1.33H, s), 5.29 (0.67H, s), 6.54 (2H, s), 6.61-6.67 (1H, m), 6.86-6.94 (2H, m), 7.10-7.17 (0.67H, m), 7.21-7.29 (1.33H, m), 7.72 (0.33H, s), 8.15 (0.67H, s).

E) 3-[(1-吖Bicyclo[2.2.2]oct-2-ylcarbonyl)amino]-5-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazole Methyl 4-methyl]thiophene-2-carboxylate and 3-[(1-indenylbicyclo[2.2.2]oct-2-ylcarbonyl)amino]-5-[1-(4-methoxybenzoate) Manufacture of methyl 5-methyl-1H-pyrazol-4-yl]thiophene-2-carboxylate

A mixture of 1-indolebicyclo[2.2.2]octane-2-carboxylic acid (488 mg), sulfinium chloride (5 mL) and N,N-dimethylformamide (23 mg) was stirred at room temperature for 15 hours. . The reaction mixture was concentrated under reduced pressure and dichloromethane was evaporated. Addition of methyl 3-amino-5-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl]thiophene-2-carboxylate and 3-amine prepared above Methyl 5-[1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-4-yl]thiophene-2-carboxylate (750 mg), and N-ethyl-N A mixture of -(1-methylethyl)propan-2-amine (0.916 mL) was stirred at 60 ° C for 2 h. Ethyl acetate (20 mL) and water (10 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the filtrate was evaporated. ¹ H-NMR (DMSO-d ₆ ) δ 1.31-1.59 (4H, m), 1.73-1.87 (3H, m), 2.33 (2H, s), 2.43 (1H, s), 2.55-3.11 (4H, m ), 3.54-3.66 (1H, m), 3.70-3.85 (6H, m), 5.18 (1.33H, s), 5.31 (0.67H, s), 6.84-6.95 (2H, m), 7.10-7.32 (2H , m), 7.82 (0.33H, s), 8.09-8.15 (1H, m), 8.32 (0.67H, s), 11.24 (1H, s).

F) N-{2-Aminomethylindolyl-5-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl]thiophen-3-yl}-1- Bis-cyclo[2.2.2]octane-2-carboxamide and N-{2-aminocarbamido-5-[1-(4-methoxybenzyl)-5-methyl-1H-pyrazole Manufacture of -4-yl]thiophen-3-yl}-1-indenylbicyclo[2.2.2]octane-2-carboxamide

3-[(1-Indoxyl[2.2.2]oct-2-ylcarbonyl)amino]-5-[1-(4-methoxybenzyl)-3-methyl-1H- Methyl pyrazol-4-yl]thiophene-2-carboxylate and 3-[(1-indenylbicyclo[2.2.2]oct-2-ylcarbonyl)amino]-5-[1-(4-methoxy Mixture of methyl benzyl)-5-methyl-1H-pyrazol-4-yl]thiophene-2-carboxylate (500 mg), 8 M aqueous sodium hydroxide (1 mL), and ethanol (7 mL) at 60 ° C Stir for 2 hours. The reaction mixture was neutralized with 6M hydrochloric acid (1. 4 mL) and evaporated. Ammonium chloride (162 mg), triethylamine (0.705 mL) and N,N-dimethylformamide (5 mL) were added to the residue, and the mixture was stirred at room temperature for 5 min. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (235 mg) and 1-hydroxybenzotriazole (205 mg) were added to the reaction system, and the mixture was stirred at room temperature. 15 hours. The reaction was poured into water (10 mL). The organic layer was washed with a saturated aqueous The title compound (316 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.31-1.55 (4H, m), 1.71-1.86 (3H, m), 2.33 (1H, s), 2.41-2.45 (2H, m), 2.55-3.05 (4H , m), 3.50-3.59 (1H, m), 3, 70-3.76 (3H, m), 5.18 (0.67H, s), 5.30 (1.33H, s), 6.87-6.96 (2H, m), 7.10 -7.50 (4H, m), 7.72 (0.67H, s), 8.06-8.11 (1H, m), 8.17 (0.33H, s), 11.85 (1H, s).

G) 2-(1-indolebicyclo[2.2.2]oct-2-yl)-6-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl] Thieno[3,2-d]pyrimidin-4(3H)-one and 2-(1-indolebicyclo[2.2.2]oct-2-yl)-6-[1-(4-methoxybenzyl) Manufacture of 5-methyl-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidin-4(3H)-one

The above-produced N-{2-aminoformamido-5-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl]thiophen-3-yl}- 1-indole bicyclo[2.2.2]octane-2-carboxamide and N-{2-aminoformamido-5-[1-(4-methoxybenzyl)-5-methyl-1H- Pyrazol-4-yl]thiophen-3-yl}-1-indole bicyclo[2.2.2]octane-2-carboxamide (200 mg), 2M aqueous sodium hydroxide (1 mL), and ethanol (3 mL) The mixture was stirred at 80 ° C for 3 hours. The reaction mixture was neutralized with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate (20mL). The organic layer was washed with brine (5 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the filtrate was evaporated. ¹ H-NMR (DMSO-d ₆ ) δ 1.38-3.14 (14H, m), 3.72-3.75 (3H, m), 3.92 (1H, t, J = 8.9 Hz), 5.19 (1.8H, s), 5.32 (0.2H, s), 6.88-6.96 (1.8H, m), 7.17 (0.2H, d, J = 8.5 Hz), 7.27 (2H, d, J = 8.5 Hz), 7.38 (0.9H, s), 7.45 (0.1H, s), 7.92 (0.1H, s), 8.32 (0.9H, s).

H) 2-(1-indolebicyclo[2.2.2]oct-2-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-4 (3H)-ketone manufacture

The above-produced 2-(1-indolebicyclo[2.2.2]oct-2-yl)-6-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4- Thio[3,2-d]pyrimidin-4(3H)-one and 2-(1-indolebicyclo[2.2.2]oct-2-yl)-6-[1-(4-methoxybenzene Methyl)-5-methyl-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidin-4(3H)-one (120 mg), trifluoroacetic acid (3 mL), and methoxybenzene A mixture of (0.3 mL) was stirred at 70 ° C for 24 hours. The reaction mixture was concentrated under reduced pressure and dried over NaH. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the residue was evaporated,jjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.35-1.63 (4H, m), 1.69-1.81 (1H, m), 1.83-1.92 (1H, m), 2.22-2.34 (1H, m), 2.46 (3H) , s), 2.55-2.67 (2H, m), 2.79-2.93 (1H, m), 3.01-3.15 (1H, m), 3.86-3.97 (1H, m), 7.44 (1H, s), 8.04 (1H , s), 12.21 (1H, brs). MS (ESI+): [M+H] ⁺ 342.

Example 177 6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-1,2,3,6-tetrahydropyridin-2-yl]thieno[3,2-d] Manufacture of pyrimidine-4(3H)-one hydrochloride

6-(5-Methyl-1H-pyrazol-4-yl)-2-[(2S)-1,2,3,6-tetrahydropyridin-2-yl, which was produced in Example 145, Step C Thio[3,2-d]pyrimidin-4(3H)-one dihydrochloride (350 mg) was suspended in ethanol (12 mL), and the mixture was stirred and stirred at 90 °C. Water (1.6 mL) was added to give a solution which was allowed to cool to room temperature. The mixture was concentrated under reduced pressure, and methanol (8 mL) was added to the residue, and the mixture was stirred and stirred at 65 °C. Water (0.8 mL) was added and the mixture was cooled to room temperature. The title compound (169 mg) was obtained eluted eluted ¹ H-NMR (DMSO-d ₆ ) δ 2.37-2.53 (4H, m), 2.71-2.86 (1H, m), 3.62-3.84 (2H, m), 4.41 (1H, dd, J = 11.1, 4.5 Hz ), 5.77-5.85 (1H, m), 5.92-6.01 (1H, m), 7.37 (1H, s), 7.98 (0.6H, brs), 8.31 (0.4H, brs), 9.75 (1H, brs), </ RTI>^</RTI>^</RTI>^</RTI>^<RTIgt;

Example 178 2-[(2S)-1-indenylbicyclo[2.2.2]oct-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine Manufacture of -4(3H)-ketone dihydrochloride A) Manufacture of 1-(1-benzyl-5-methyl-1H-pyrazol-4-yl)ethanone

A mixture of pentane-2,4-dione (10.01 g) and 1,1-dimethoxy-N,N-dimethylmethylamine (12.51 g) was stirred at 80 ° C for 1 hour. Tetrahydrofuran (20 mL) was added to the reaction mixture, and benzamidine dihydrochloride (21.46 g) was added in small portions under ice cooling, and the mixture was stirred at 60 ° C for 30 minutes. The reaction mixture was cooled to room temperature, then ethyl acetate (100 mL) and water (100 mL). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The title compound (13.53 g) was obtained eluted eluted elute ¹ H-NMR (DMSO-d ₆ ) δ 2.44 (3H, s), 2.51 (3H, s), 5.31 (2H, s), 7.05-7.15 (2H, m), 7.18-7.40 (3H, m), 7.89 (1H, s).

B) Manufacture of (2Z)-3-(1-benzyl-5-methyl-1H-pyrazol-4-yl)-3-chloroprop-2-enenitrile

Phosphorus oxychloride (36.8 g) was added in small portions to N,N-dimethylformamide (17.55 g), and the mixture was stirred at room temperature for 15 min. 1-(1-Benzyl-5-methyl-1H-pyrazol-4-yl)ethanone (12.86 g) prepared above was added thereto in small portions under ice cooling, and the reaction mixture was Stir at 50 ° C for 30 minutes. A powder of hydroxylamine hydrochloride (33.40 g) was added thereto at a small amount at 50 ° C, and the reaction mixture was stirred at 50 ° C for 30 minutes. Ice water (200 mL) was added to the reaction mixture, and the mixture was evaporated to ethyl acetate (100 mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the residue was evaporated,jjjjjjjjjj . ¹ H-NMR (DMSO-d ₆ ) δ 2.37 (3H, s), 5.33 (2H, s), 5.57 (1H, s), 7.03-7.19 (5H, m), 7.73 (1H, s).

C) Manufacture of methyl 3-amino-5-(1-phenylmethyl-5-methyl-1H-pyrazol-4-yl)thiophene-2-carboxylate

(2Z)-3-(1-Benzyl-5-methyl-1H-pyrazol-4-yl)-3-chloroprop-2-enenitrile (5.73 g), thioacetate A The ester (2.95 g), sodium hydride (0.80 g) and N,N-dimethylformamide (10 mL) were stirred at 60 ° C for 2 h. Ethyl acetate (20 mL) and water (10 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered, and the residue was evaporated. ¹ H-NMR (DMSO-d ₆ ) δ 2.33 (3H, s), 3.65 (3H, s), 5.23 (2H, s), 7.04-7.44 (6H, m), 7.49 (1H, s).

D) 3-{[(2S)-1-indenylbicyclo[2.2.2]oct-2-ylcarbonyl]amino}-5-(1-benzyl-5-methyl-1H-pyrazole-4 -Based on the manufacture of methyl thiophene-2-carboxylate

N,N-Dimethylformamide (0.038 mL) was added to the (2S)-1-indolebicyclo[2.2.2]octane-2-carboxylic acid hydrochloride salt (0.62). g) In a solution of sulfoxide (4.93 mL), the mixture was stirred at room temperature for 24 hours. The reaction was concentrated under reduced pressure to give 3-amino-5-(1-phenylmethyl-5-methyl-1H-pyrazol-4-yl)thiophene-2 as in Example 178, Step C. Methyl carboxylate (704 mg) and tetrahydrofuran (7.0 mL) were added to the residue. N-Ethyl-N-(1-methylethyl)propan-2-amine (0.939 mL) was added to the reaction mixture at 0 ° C, and the mixture was stirred at 80 ° C for one day, and water was added. The mixture was extracted with EtOAc. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj ¹ H-NMR (氘-chloroform) δ 1.43-1.61 (4H, m), 1.86-1.99 (3H, m), 2.42 (3H, s), 2.71-3.18 (4H, m), 3.47-3.58 (1H, m), 3.88 (3H, s), 5.34 (2H, s), 7.09-7.16 (2H, m), 7.27-7.38 (3H, m), 7.75 (1H, s), 8.18 (1H, s), 11.35 (1H, brs).

E) 2-[(2S)-1-indenylbicyclo[2.2.2]oct-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d Manufacture of pyrimidine-4(3H)-one dihydrochloride

3-{[(2S)-1-indenylbicyclo[2.2.2]oct-2-ylcarbonyl]amino}-5-(1-benzyl-5-methyl-1H-pyrazole-4- A mixed solvent of methyl thiophene-2-carboxylate (480 mg), methanol (15 mL) and a 2M aqueous sodium hydroxide solution (3.1 mL) was stirred at 60 ° C for 4 hours. The reaction mixture was neutralized with 1 M hydrochloric acid and evaporated. Ammonium chloride (2.2 g), triethylamine (5.74 mL) and N,N-dimethylformamide (15 mL) were added to the residue, and the mixture was stirred at room temperature for 5 min. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.98 g) and 1-hydroxybenzotriazole (1.39 g) were added to the reaction system, and the mixture was placed in the chamber. Stir for 18 hours. Pour water into the reaction system. The mixture was extracted with EtOAc. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to afford (2S)-N-[5-(1-phenylmethyl-3-methyl-1H-pyrazole) as a yellow solid. The crude product (226 mg) of 4-yl)-2-amine-carbamoylthiophen-3-yl]-1-indolebicyclo[2.2.2]octane-2-carbamide. Formic acid (10 mL) and 20% palladium hydroxide-carbon (50 mg) were added to (2S)-N-[5-(1-benzyl-3-methyl-1H-pyrazol-4-yl)-2- In the crude product of the amidomethylthiophen-3-yl]-1-indenylbicyclo[2.2.2]octane-2-carboxamide, the mixture was stirred at 80 ° C for 3 hours under a hydrogen atmosphere. Under a hydrogen atmosphere, 20% palladium hydroxide-carbon (50 mg) was added 8 times and the mixture was stirred at 80 ° C for 3 hours (total reaction time: 27 hours, palladium hydroxide-carbon total amount: 450 mg) . The palladium hydroxide-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAcEtOAcEtOAc The obtained pale yellow solid was purified by high performance liquid chromatography (column: L-column 2 ODS (20 mm id × 50 mmL), mobile phase: 0.1% aqueous trifluoroacetic acid / 0.1% trifluoroacetic acid-acetonitrile solution). Depress the target to distinguish it. Ethanol (1.0 mL) and a 2M aqueous sodium hydroxide solution (0.38 mL) were added to the residue (91 mg), and the mixture was stirred at 70 ° C for 30 minutes. The reaction mixture was concentrated under reduced EtOAcqqqqm Methanol (2 mL) and 4M HCl /EtOAc (2 mL) was then evaporated. The title compound (57 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 1.73-1.92 (4H, m), 2.09-2.29 (2H, m), 2.37-2.47 (4H, m), 3.23-3.39 (2H, m), 3.44-3.56 (1H, m), 3.61-3.76 (1H, m), 4.70-4.81 (1H, m), 7.44 (1H, s), 8.10 (1H, brs), 9.99 (1H, brs), 12.72 (1H, brs MS (ESI+): [M+H] ⁺ 342. MS (ESI+), Found: 342.

Example 179 2-(1-indolebicyclo[2.2.2]oct-2-yl)-6-[5-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidine -4(3H)-one manufacture A) 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1-tritylmethyl -1H-pyrazole manufacturing

4-Bromo-3-(trifluoromethyl)-1-trityl-1H-pyrazole (3.45 g), 4,4,4',4',5,5,5',5'- Octamethyl-2,2'-linked 1,3,2-dioxaborolane (5.75 g), potassium acetate (3.70 g) and N,N-dimethylformamide (30 mL) were placed in a flask The air in the flask was purged with argon. 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride-dichloromethane complex (1:1) (621 mg) was added, and the air in the flask was again purged with argon. The mixture was stirred at 80 ° C for 15 hours. Ethyl acetate (50 mL) and water (50 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (30mL×2). The collected organic layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjj ¹ H-NMR (DMSO-d ₆ ) δ 1.23 (12H, s), 6.99-7.07 (6H, m), 7.36-7.46 (9H, m), 7.60 (1H, d, J = 0.9 Hz).

B) Manufacture of 2-(1-indolebicyclo[2.2.2]oct-2-yl)-6-bromothieno[3,2-d]pyrimidin-4(3H)-one

A mixture of 1-indolylbicyclo[2.2.2]octane-2-carboxylic acid hydrochloride (2.57 g), sulfinium chloride (10 mL) and N,N-dimethylformamide (100 mg) in a chamber Stir for 15 hours. The reaction mixture was concentrated under reduced pressure and the residue was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj And N-ethyl-N-(1-methylethyl)propan-2-amine (4.74 mL), and the mixture was stirred at 60 ° C for 2 hr. Ethyl acetate (50 mL) and water (50 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (30mL). The collected organic layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered out, and the filtrate was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (ethyl acetate/hexane) to afford N-(5-bromo-2-amine-methylthiophene-3- Base)-1-indenylbicyclo[2.2.2]octane-2-carboxamide. The above-produced N-(5-bromo-2-aminomethylsulfonylthiophen-3-yl)-1-indolylbicyclo[2.2.2]octane-2-carboxamide was dissolved in ethanol (10 mL) and 8 M hydroxide. A mixture of aqueous sodium (3 mL) was stirred at 80 ° C for 3 hours. The reaction mixture was neutralized with 1 M hydrochloric acid at 0 ° C and concentrated. Methanol (5 mL) was added to the residue. EtOAc m. ¹ H-NMR (DMSO-d ₆ ) δ 1.40-1.65 (4H, m), 1.73-1.94 (2H, m), 2.24 (1H, dd, J = 12.9, 7.8 Hz), 2.56-2.74 (2H, m ), 2.83 - 2.97 (1H, m), 3.05-3.17 (1H, m), 3.97 (1H, t, J = 8.8 Hz), 7.60 (1H, s).

C) 2-(1-indolebicyclo[2.2.2]oct-2-yl)-6-[5-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[3,2-d Manufacture of pyrimidine-4(3H)-one

The above-produced 2-(1-indolebicyclo[2.2.2]oct-2-yl)-6-bromothieno[3,2-d]pyrimidin-4(3H)-one (400 mg), 4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1-trityl-1H-pyrazole (889 mg), cesium carbonate (766 mg), 1,2-dimethoxyethane (10 mL) and water (1 mL) were placed in a flask, and the air in the flask was purged with argon. Add 1,1'-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane chloride complex (1:1) (48.4 mg), and again purge the air in the flask with argon. The mixture was stirred at 80 ° C for 15 hours. Ethyl acetate (20 mL) and water (10 mL) were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The collected organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) -yl)-6-[3-(trifluoromethyl)-1-trityl-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidin-4(3H)-one. 4M HCl/ethyl acetate solution (4 mL) was added to the above-produced 2-(1-indolebicyclo[2.2.2]oct-2-yl)-6-[3-(trifluoromethyl)-1-triphenyl To a solution of methyl-1H-pyrazol-4-yl]thieno[3,2-d]pyrimidin-4(3H)-one in methanol (4 mL), this mixture was stirred at 60 ° C for 15 hr. The reaction mixture was concentrated under reduced pressure. ethyl acetate (10 mL) The resulting aqueous layer was basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (10 mL×2). The collected organic layer was washed with brine (10 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjjjjjj ¹ H-NMR (氘-chloroform) δ 0.72-2.20 (7H, m), 2.46-2.64 (1H, m), 2.74-3.18 (3H, m), 3.80-3.92 (1H, m), 7.42-7.48 ( 1H, m), 7.92 (1H, s).

The structural formulae of the compounds described in Examples 1-179 are listed below.

Test Example 1: Preparation of microchromosomal maintenance protein 2 (MCM2 protein) taken from human body

The genetic engineering methods described below are described in the method described in (Maniatis et al., Molecular Colonization, Cold Spring Harbor Laboratory, 1989) or in the procedures attached to the reagents.

The N-terminal histidine-recombinant human MCM 2 protein corresponding to the 10th to 294th amino acid from the N-terminus was selected to the expression vector pET-21 of Escherichia coli (E. coli). This vector was inserted into pET-21a(+) by the following 6×Histag synthetic DNA 5'-TATGCATCATCATCATCATCACGGATCCCATCATCATCATCATCACTGAGC-3' (SEQ ID NO: 1); and 5'-GGCCGCTCAGTGATGATGATGATGATGGGATCCGTGATGATGATGATGATGCA-3' (SEQ ID NO: 2) Prepared by the Nde I-Not I site of Novagen).

The Mcm2 (10-294 a.a.) gene encoding the 10th to 294th amino acid of the N-terminal side of the human minichromosome maintenance protein 2 was cloned by PCR. The PCR was carried out using the synthetic DNA 5'-CGCGGATCCATGGCATCCAGCCCGGCCCA-3' (SEQ ID NO: 3) prepared by the nucleotide sequence of GenBank accession No.: NM_004526; and 5'-ATTCTTATGCGGCCGCTCACAGCTCCTCCACCAGAGGCA-3 '(SEQ ID NO: 4) was used as a template for the primer set and the human testis cDNA gene library (TAKARA BIO INC.). The PCR reaction was carried out in accordance with the procedure attached to Pyrobest (TAKARA BIO INC.).

The 883 bp fragment obtained by restriction enzyme BamHI and NotI was inserted into the BamHI-NotI site of pET21-HH, and it was confirmed that the inserted base sequence produced pET21-HHhMcm2(10-294) plastid. This pET21-HHhMcm2(10-294) plastid was introduced into E. coli BL21 (DE3) cell strain (American Type Culture Collection).

The Escherichia coli cells introduced with the above plastids were cultured in LB medium (1% trypsin, 0.5% yeast extract, 0.5% sodium chloride) containing 50 mg/L of ampicillin, and induced by adding 1 mM IPTG for 6 hours. The performance of MCM 2. E. coli cells expressing MCM 2 were recovered by centrifugation (6000 rpm, 10 minutes), washed with phosphate buffered saline, and cryopreserved at -80 °C. The cryopreserved E. coli cells were thawed on ice and suspended in Buffer A (25 mM tris-HCl (pH 7.4), 2.7 mM potassium chloride, supplemented with Complete EDTA (Roche Diagnostics GmbH, Mannheim, Germany). 137 mM sodium chloride). The above-mentioned suspended Escherichia coli cells were decomposed with 1 mg/mL lysozyme, and subjected to ultrasonication under ice-water cooling using an ultrasonic cell disrupter 201M (Kubota) for 4 times at 170 W for 30 seconds. The extract was ultracentrifuged at 15,000 rpm for 20 minutes at 4 ° C, and the resulting suspension was passed through a 0.22 μm filter paper to obtain a cell extract free of E. coli cells. The cell extract without E. coli cells was passed through a nickel-NTA (Ni-NTA) super flow resin, and the obtained resin was washed with buffer A to buffer B (25 mM tris-HCl (pH 7.4), 2.7 mM potassium chloride). , 137 mM sodium chloride, 10% glycerol, 200 mM imidazole). The extract was concentrated using Amicon Ultra 4 (5K MWCO, Millipore, MA, USA) and used as buffer C (25 mM tris-HCl (pH 7.4), 2.7 mM potassium chloride, 137 mM sodium chloride, 10%). GEL, 200 mM imidazole) was purified by gel filtration of HiLoad 16/60 Superdex 200 pg (GE healthcare, Chalfont St. Giles, UK). The fraction containing the MCM 2 protein was concentrated as a purified sample and cryopreserved at -80 °C.

Test Example 2: Measurement of Cdc7 kinase inhibitory activity

Full length Cdc7 was demonstrated from Carna Biosciences (Kobe) in combination with full length Dbf4. The enzyme activity of the Cdc7/Dbf4 complex was measured by the Transcreener ADP assay (Cisbio Inc., MA, USA) of the homogenous time difference fluorescence method. The enzyme reaction was carried out by adding 1.0 μm ATP, and 10 μg/ml MCM 2 (prepared in Test Example 1) in kinase buffer (20 mM HEPES pH 7.5, 10 mM magnesium acetate, 1 mM dithiothreitol) 0.1 μg. In /ml. Free ADP produced by hydrolysis of ATP was detected by (铕³⁺ )-cryptate-labeled anti-ADP monoclonal antibody competing with d2-labeled ADP, and the amount of production was measured. The resulting time-lapse fluorescence resonance energy transfer signal was measured by EnVision (Perkin Elmer Inc., MA, USA). The inhibition rate (%) of the test compound against Cdc7 was calculated by the following formula.

Inhibition rate (%) = (1 - count of test compound - count of blank group) ÷ (count of control group - count of blank group) × 100

The count of the Cdc7/Dbf4 reaction mixture in the absence of the compound was used as a control group, and the counts in the absence of the compound and the Cdc7/Dbf4-free condition were blank.

The Cdc7 kinase inhibition rate of the compounds of the present invention is shown in Table 2.

This test example shows that the compound of the present invention has excellent Cdc7 inhibitory activity.

Test Example 3: Measurement of growth inhibitory activity against human colorectal cancer cell Colo205

The growth inhibition of human colorectal cancer cells by the compounds of the present invention can be measured by the following method.

A cell suspension (100 μl) of human colorectal cancer cell Colo 205 (purchased from ATCC) (3,000 cells/well) was seeded in a 96-well plate and cultured at 37 ° C for 1 day in a 5% carbon dioxide gas incubator. 100 μl of various 2 μM test compound solutions were added and the cells were cultured for 3 days. CellTiter-GloTM Luminescent Cell Viability Assay Reagent (50 μl, Promega) was added to the 96-well plate, and the luminescence level was measured with an illuminometer and the amount of residual ATP was used as the cell amount. The luminosity of the small holes of the uninoculated cells was set to a blank group. The cell proliferation inhibition rate (%) of the test compound was calculated by the following formula.

Inhibition rate (%) = (1 - (test compound - degree of luminescence of blank group) ÷ (luminance of control group - blank group)) × 100

The inhibition rates of the various compounds are shown in Table 3.

This test example shows that the compound of the present invention has an excellent cancer (colorectal cancer) cell proliferation suppressing action.

Test Example 4: Measurement of MCM 2 phosphorylation inhibitory activity in human colorectal cancer cell Colo205

The MCM 2 phosphorylation suppression of the compound of the present invention in human colorectal cancer cell Colo205 can be measured by the method described.

A cell suspension (500 μl) of human colorectal cancer cell Colo 205 (purchased from ATCC) (50,000 cells/well) was seeded in a 24-well plate and cultured at 37 ° C for 1 day in a 5% carbon dioxide gas incubator. 500 μl of each 2 μM test compound solution was added and the cells were cultured for 8 hours. The well plate was washed with PBS, and the cells were decomposed in Laemmli (Sample Buffer) sample buffer (BioRad), and the cell fraction was treated at 95 ° C for 5 minutes. Then, colloidal SDS- polyacrylamide electrophoresis (SDS-PAGE) and transferred by using iBlot ^TM gel system (Invitrogen) The proteins were transferred to polyvinylidene difluoride (PVDF) membrane. The membrane was blocked with StartingBlock T20 (PBS) blocking buffer (Thermo Scientific) and anti-phosphorylated MCM 2 (Ser40/Ser41) diluted with Can Get Signal immune response promoting solution 1 (TOYOBO) (Bethyl Laboratories, A300) -788A) role. The membrane was washed with tris-buffered saline (BioRad) containing 0.05% Tween 20 (Bio-Rad) and labeled with a 1000-fold diluted wasabi peroxidase at room temperature with Can Get Signal immunoreactive solution 2 (TOYOBO). HRP-labeled rabbit IgG complex antibody (Amersham Biosciences, NA9340) was used for 1 hour. The membrane was washed in the same manner as above, and the chemiluminescence of the phosphorylated MCM 2 protein labeled with the antibody of SuperSignal West Femto highest sensitivity matrix (Pierce Biotechnology) was detected by a luminescence image analyzer LAS-1000 (Fuji Film).

MCM 2 protein was detected in the same manner as above using an anti-MCM 2 antibody (Santa Cruzu Biotechnology, sc-9839) and a wasabi peroxidase-labeled goat IgG complex antibody (Santa Cruzu Biotechnology, sc-2020).

The specific activity of the phosphorylated MCM 2 protein of each sample was calculated by the following formula.

Specific activity of phosphorylated MCM 2 protein = (phosphorylated MCM 2 luminosity - background value) ÷ (MCM 2 luminosity - background value)

The phosphorylated MCM 2 protein inhibition rate (%) of the test compound was calculated by the following formula and is shown in the table.

Inhibition rate (%) = (1 - specific activity of phosphorylated MCM 2 of test compound / specific activity of phosphorylated MCM 2 of control group) × 100

The inhibition rates of various test compounds are shown in Table 4.

This test example shows that the compound of the present invention has an excellent MCM 2 phosphorylation inhibitory effect on cancer (colorectal cancer) cells, that is, the compound of the present invention has an excellent Cdc7 inhibitory effect on cancer (colorectal cancer) cells.

Test Example 5: Measurement of MCM 2 phosphorylation inhibitory activity in tumors of mice bearing human colorectal cancer cell Colo205 cancer

The MCM 2 phosphorylation inhibitory activity of the compound of the present invention in a tumor of a mouse bearing human colorectal cancer cell Colo205 cancer can be measured by the following method.

Human colorectal cancer cell Colo205 was suspended in 50% Matrigel solution, and 5.0×10 ⁶ cells were transplanted by subcutaneous injection into 6- to 7-week-old female BALB/c mice (CLEA Japan, Inc.). The tumor diameter was measured from 7 to 14 days after transplantation, and the tumor volume was calculated by the following formula.

Tumor volume = long diameter × short diameter × short diameter × (1/2)

A suspension of the test compound in a 0.5% methylcellulose solution (Wako Pure Chemical Industries, LTD.) was orally administered to a mouse having a tumor volume of 150-600 mm ³ at a dose shown in the table. Four hours after administration of the test compound, the tumor was removed under ether anesthesia and homogenized in Cell Signaling. The protein in the tumor decomposing fluid was quantified using a BCA protein assay kit (Thermo Scientific) and the amount of protein was corrected. The above protein solution was treated with Laemmli sample buffer (BioRad) at 95 ° C for 5 minutes.

Then, SDS polyacrylamide electrophoresis colloid (SDS-PAGE) and transferred by using iBlot ^TM gel system (Invitrogen) The proteins were transferred to polyvinylidene difluoride (PVDF) membrane. The membrane was blocked with StartingBlock T20 (PBS) blocking buffer (Thermo Scientific) and anti-phosphorylated MCM 2 (Ser40/Ser41) diluted with Can Get Signal immune response promoting solution 1 (TOYOBO) (Bethyl Laboratories, A300) -788A) role. The membrane was washed with tris-buffered saline (BioRad) containing 0.05% Tween 20 (Bio-Rad) and labeled with 10,000-fold wasabi peroxidase at room temperature with Can Get Signal immunoreactive solution 2 (TOYOBO) ( HRP-labeled rabbit IgG complex antibody (Amersham Biosciences, NA9340) was used for 1 hour. The membrane was washed in the same manner as above, and the chemiluminescence of the phosphorylated MCM 2 protein labeled with the antibody of SuperSignal West Femto highest sensitivity matrix (Pierce Biotechnology) was detected by a luminescence image analyzer LAS-1000 (Fuji Film).

MCM 2 protein was detected in the same manner as above using an anti-MCM 2 antibody (Santa Cruzu Biotechnology, sc-9839) and a wasabi peroxidase-labeled goat IgG complex antibody (Santa Cruzu Biotechnology, sc-2020).

The specific activity of phosphorylated MCM 2 of each sample was calculated by the following formula.

Specific activity of phosphorylated MCM 2 = (phosphorylated MCM 2 luminosity - background value) ÷ (MCM 2 luminosity - background value)

The phosphorylated MCM 2 protein inhibition rate (%) of the test compound was calculated by the following formula and is shown in the table.

Inhibition rate (%) = (1 - specific activity of phosphorylated MCM 2 of test compound / specific activity of phosphorylated MCM 2 of control group) × 100

The inhibition rates of various test compounds are shown in Table 5.

This test example shows that the compound of the present invention has an excellent MCM 2 phosphorylation inhibitory effect on mice bearing cancerous (colorectal cancer) cell carcinoma, that is, the compound of the present invention is excellent for mice bearing cancerous (colorectal cancer) cell carcinoma. Cdc7 inhibition.

Test Example 6: Measurement of antitumor activity in mice bearing human colorectal cancer cell Colo205 cancer

The antitumor activity of the compound of the present invention against a mouse bearing human colorectal cancer cell Colo205 cancer can be measured by the following method.

Human colorectal cancer cell Colo205 was suspended in 50% Matrigel solution, and 5.0×10 ⁶ cells were transplanted by subcutaneous injection into 6- to 7-week-old female BALB/c mice (CLEA Japan, Inc.). The tumor diameter was measured from 7 to 14 days after transplantation, and the tumor volume was calculated by the following formula.

Tumor volume = long diameter × short diameter × short diameter × (1/2)

Mice with a transplanted tumor volume of approximately 200 mm ³ were selected and tested in groups of five. A suspension of the test compound in a 0.5% methylcellulose solution (Wako Pure Chemical Industries, LTD.) was orally administered twice a day for 14 days at the doses listed in Table 1. Tumor diameters were measured and the tumor volume was calculated one day before the start of administration and the second day after the completion of administration.

The ratio of the tumor growth rate of the test compound administration group to the tumor growth rate of the control administration group was T/C (%), and was calculated by the following formula.

T/C (%) = (the tumor volume of the test compound administration group after completion of administration - the tumor volume of the test compound administration group one day before the start of administration) / (the tumor volume of the control administration group after completion of administration - the control administration group one day before the start of administration) Tumor volume) × 100

The T/C values of the various test compounds are shown in Table 6.

This test example shows that the compound of the present invention has an excellent antitumor effect.

Matching example 1

The following formula can be used, for example, to manufacture a medicament containing the compound of the present invention as an active ingredient.

Capsule

(1) Compound obtained in Example 1 40 mg

(2) Lactose 70 mg

(3) Microcrystalline cellulose 9 mg

(4) Magnesium stearate 1 mg

1 capsule 120 mg

Mix (1), (2), (3), and 1/2 (4) and granulate. The remainder of (4) was added here and the whole amount was filled in a gelatin capsule.

2. Lozenges

(1) Compound obtained in Example 1 40 mg

(2) Lactose 58 mg

(3) Corn Starch 18 mg

(4) Microcrystalline cellulose 3.5 mg

(5) Magnesium stearate 0.5 mg

1 lozenge 120 mg

Mix (1), (2), (3), 2/3 (4), and 1/2 (5) and granulate. The remainder of (4) and (5) is added to the granules and the mixture is molded into a tablet.

Matching example 2

The compound obtained in Example 1 (50 mg) was dissolved in Japanese Pharmacopoeia distilled water for injection (50 ml), and the Japanese Pharmacopoeia distilled water for injection was added thereto to make a volume of 100 ml. The resulting solution was filtered under sterile conditions. This solution (1 ml) was taken, filled in a small flask for injection under aseptic conditions, and lyophilized, and the flask was sealed.

Industrial applicability

Since the compound of the present invention has excellent cdc7 inhibitory action, it is suitable for use as an agent for preventing or treating a disease associated with cdc7 (e.g., cancer, etc.). In addition, the compounds of the present invention are suitable for use as pharmaceutical products because of their excellent efficacy, pharmacokinetics, solubility, interaction with other pharmaceutical products, safety and stability.

Although some embodiments of the present invention have been described in detail hereinabove, it is obvious to those skilled in the art that various modifications and changes can be made to the particular implementations shown. . Such modifications and variations are included within the spirit and scope of the invention as indicated by the appended claims.

<110> Takeda Pharmaceutical Industry Co., Ltd.

<120> Heterocyclic compound

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<170> PatentIn version 3.3

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Claims (20)

A compound represented by the formula: or a salt thereof: Wherein one of X and Y is a sulfur atom, and the other is CH, R ₁ is a C _1-6 alkyl group which may be optionally substituted by a halogen atom, and R ₂ is a substituent. The compound or a salt thereof according to claim 1, wherein X is a sulfur atom; and Y is CH. The compound or a salt thereof according to claim 1, wherein R ₂ is a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or a non-aromatic group which may have a substituent, if necessary A heterocyclic carbonyl group. The compound or a salt thereof according to claim 1, wherein R ₂ is (1) a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the group as required (a) as needed a non-aromatic heterocyclic group (i) halogen atom substituted with 1 to 3 substituents selected from the group consisting of: (ii) a hydroxyl group, (iii) optionally substituted with 1 to 3 substituents selected from the group consisting of C _1-6 alkyl (aa) a halogen atom, (BB) hydroxy, (CC) C _1-6 alkoxy, and (dd) may be optionally substituted by from 1 to 3 of C _1-6 alkyl C _{6 -14} aryl (iv) C _1-6 alkoxy, (v) C _6-14 aryl which may be substituted with 1 to 3 halogen atoms, (vi) C _6-14 aryloxy, (vii C _1-6 alkoxy-carbonyl, (viii) C _1-6 alkyl-carbonyl, (ix) cyano, (x) C _6-14 aryl sulfonyl, (xi) carboxy, (xii) a non-aromatic heterocyclic group which may be substituted by a keto group (oxo), and a (xiv) ketone group, if necessary, may be a C _1-6 alkyl mono- or di-substituted amine group, (xiii) optionally substituted with a keto group (oxo) a C _1-6 alkoxy group, (c) an optionally substituted mono- or di-substituted amine group (i) may be optionally substituted with 1 to 3 substituents selected from the group consisting of: C _1-6 alkyl (aa) may be optionally substituted with 1 to 3 C _1-6 alkoxy taken The C _6-14 aryl group, (bb) C _1-6 alkoxy - carbonyl group, (cc) an aromatic heterocyclic group, (dd) may be optionally substituted aromatic heterocyclic group of C _3-8 cycloalkyl a base, and (ee) a hydroxyl group, (ii) a non-aromatic heterocyclic group which may be substituted with 1 to 3 C _7-13 aralkyl groups as desired, and (iii) 1 to 3 C _1-6 as needed An alkoxy-substituted C _6-14 aryl group, and (iv) a C _3-8 cycloalkyl group, (d) a 5- or 6-membered aromatic heterocyclic group, (e) a C _6-14 aryl group, and (f) a C _3-8 cycloalkyl group which may be optionally substituted with an amine group; (2) a C _6-14 aryl group which may be substituted with 1 to 3 halogen atoms as needed; (3) may be subjected to 1 to 1 3 non-aromatic heterocyclic groups (a) halogen atoms substituted with a substituent selected from the group consisting of: (b) optionally substituted by 1 to 3 C _1-6 alkyl groups (i) substituted with the following substituents Hydroxy, (ii) C _1-6 alkoxy-carbonyl, and (iii) amine carbenyl, (c) C _6-14 aryloxy, (d) C _1-6 alkoxy-carbonyl, (e a C _1-6 alkyl-carbonyl group, (f) a C _6-14 aryl group optionally substituted by a C _1-6 alkylsulfonyl group, (g) optionally substituted with 1 to 3 halogen atoms a C _7-13 aralkyl group, (h) a hydroxyl group, (i) an amine carbenyl group, and (j) a non-aromatic heterocyclic group; (4) 1 to 3 as needed a C _6-14 aryl-substituted C _2-6 alkenyl group; (5) a 5- or 6-membered aromatic heterocyclic group; (6) a non-aromatic heterocyclic group-carbonyl group; or (7) optionally Amine substituted C _3-8 cycloalkyl. The compound or a salt thereof according to the first aspect of the invention, wherein R ₂ is (1) a 4 to 6-membered non-aromatic heterocyclic group-C _{1- which} may be substituted with 1 to 3 halogen atoms as needed. _{a 6} alkyl group; (2) a C _6-14 aryl group which may be substituted with 1 to 3 halogen atoms as needed; or (3) a non-aromatic impurity which may be substituted with 1 to 3 substituents selected from the group consisting of: a ring group (a) a halogen atom, and (b) a C _1-6 alkyl group. The compound of claim 4 or a salt thereof, wherein X is a sulfur atom; Y is CH; and R ₁ is a C _1-6 alkyl group. The compound or a salt thereof according to claim 1, wherein R ₁ is a C _1-6 alkyl group. A compound or a salt thereof, which is 6-(5-methyl-1H-pyrazol-4-yl)-2-[(2S)-pyrrolidin-2-yl]thieno[3,2-d] Pyrimidine-4(3H)-one. A compound or a salt thereof, which is 6-(5-methyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]thieno[3,2-d] Pyrimidine-4(3H)-one. A compound or a salt thereof, which is 2-(7-fluorenebicyclo[2.2.1]hept-1-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3, 2-d]pyrimidin-4(3H)-one. A compound or a salt thereof, which is 6-(5-methyl-1H-pyrazol-4-yl)-2-[(2S)-1,2,3,6-tetrahydropyridin-2-yl] Thieno[3,2-d]pyrimidin-4(3H)-one. A compound or a salt thereof, which is 2-[(2S)-piperidin-2-yl]-6-[5-(trifluoromethyl)-1H-pyrazol-4-yl]thieno[3, 2-d]pyrimidin-4(3H)-one. A compound or a salt thereof, which is 2-[(2S)-1-indenyl[2.2.2]oct-2-yl]-6-(5-methyl-1H-pyrazol-4-yl)thiophene And [3,2-d]pyrimidine-4(3H)-one. A medicament comprising the compound according to item 1 of the patent application or a salt thereof. The drug of claim 14, which is a cell division cycle inhibitor. The pharmaceutical agent according to claim 14, which is an agent for preventing or treating cancer. A method of inhibiting the cell division cycle 7 of a mammal, comprising administering a compound effective as described in claim 1 or a salt thereof. A method for preventing or treating cancer in a mammal comprising administering a compound or a salt thereof according to claim 1 in an effective amount to a mammal. A use of the compound of claim 1 or a salt thereof for the manufacture of a cell division cycle 7 inhibitor. The use of a compound according to claim 1 or a salt thereof for the manufacture of a medicament for preventing or treating cancer.