HK1244799A1

HK1244799A1 - 2,4-dioxo-quinazoline-6-sulfonamide derivatives as inhibitors of parg

Info

Publication number: HK1244799A1
Application number: HK18104161.5A
Authority: HK
Inventors: A‧E‧麦格纳格尔; A‧乔丹; B‧瓦尔兹科兹; C‧赫顿; I‧沃德尔; J‧R‧希钦; K‧M‧史密斯; N‧M‧汉密尔顿
Original assignee: 癌症研究科技有限公司
Priority date: 2014-12-12
Filing date: 2015-12-11
Publication date: 2018-08-17

Description

2, 4-dioxo-quinazoline-6-sulfonamide derivatives as inhibitors of PARG

Technical Field

The present invention relates to certain compounds that are useful as inhibitors of PARG (poly ADP-ribose sugar hydrolase) enzyme activity. The invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative diseases such as cancer, and other diseases or conditions in which PARG activity is implicated.

Background

Cancer is caused by uncontrolled and unregulated cell proliferation. The result of this generally rapid proliferation is a high level of oxidative stress within the tumor, which damages DNA and leads to a large increase in mutation rate. Thus, tumor cells are involved in and heavily dependent on DNA damage repair mechanisms.

Single Strand Breaks (SSBs) are the most common type of pathology produced in cells, and PARG (poly ADP-ribose hydrolase) and PARP, along with many other proteins, are involved in Single Strand Break Repair (SSBR) and other repair mechanisms known as Base Excision Repair (BER).

One of the earliest events during single-stranded DNA repair is the cleavage of PARP (poly ADP-ribose polymerase) binding and the rapid synthesis of poly ADP-ribose (PAR) by PARP itself. This molecular structure serves as a signal to recruit other DNA repair proteins (first XRCC1), which then repair the break (Mortusewicz, Fouquerel et al 2011). The signals elicited by these PAR chains are transient in that they are rapidly degraded by PAR glycohydrolase (PARG). When PARP binds to PAR, its catalytic activity decreases and thus PARG activity helps to restore PARP to its catalytically active form (Curtin and Szabo 2013).

PARG exists as a single gene with isoforms found in the nucleus, mitochondria and cytosol. The only other known protein with glycohydrolase activity is ARH3 localized to mitochondria (Mashimo, Kato et al 2014). Although PARG is known to affect PAR signaling in splicing, transcription and epigenetic pathways (Ji and Tulin 2009) (Le May, illis et al 2012) (Dahl, Maturi et al 2014) (Guastafierro, cartizone et al 2013) (Caiafa, Guastafierro et al 2009) primarily due to its direct role in DNA repair.

Cancer cells may depend on a particular DNA repair pathway when other mechanisms of DNA repair do not work. Tumors carrying mutations in proteins involved in double strand break repair are generally more sensitive to PARP inhibitors of SSBR. There has been some evidence that PARG depletion inhibits SSBR and reduces survival of BRCA 2-deficient cells (farthers, Drayton et al 2012). However, other tumor mutations may cause defects in the double-stranded DNA repair mechanism (so-called "BRCA-up"), thereby sensitizing tumor cells to PARG inhibition.

PARG depletion has been studied in a number of murine and human model systems. Murine cells that are ineffective or deficient in PARG have increased sensitivity to experimental and clinical DNA damaging agents. However, since the lack of PARG is insensitive to all drugs (e.g. gemcitabine, camptothecin), this suggests specificity for PARG function with certain DNA damage repair and chemotherapeutic and radiotherapy approaches (Fujihara, Ogino et al 2009) (Shirai, fujimuri et al 2013) (Zhou, Feng et al 2010) (Zhou, Feng et al 2011).

In humans, PARG depletion sensitizes lung, cervix and pancreatic cancer cells to gamma-irradiation or experimental DNA damaging agents (e.g., hydrogen peroxide, methyl mesylate) (Ame, Fouquerel et al 2009) (Nakadate, Kodera et al 2013) (Shirai, Poetsch et al 2013).

PARP inhibitors are currently undergoing a series of clinical trials in which the concept of synthetic lethality or chemosensitization is being explored. Clinical resistance to PARP inhibitors has been described (Drost and Jonkers 2014) (Barber, Sandhu et al 2013) and there is therefore a need for alternative inhibitors aimed at DNA damage repair mechanisms. Since PARG depletion causes the rate of SSBR to decrease to the same extent as PARP1 depletion, PARG inhibition may provide a therapeutic advantage in PARP inhibitor resistant cells (Fisher, Hochegger et al 2007). Furthermore, it has been reported that consumption of PARG results in a gene expression pattern that is significantly different from that of PARP consumption in breast cancer cells (Frizzell, Gamble et al 2009).

Although current models show that PARG depletion leads to PARP-dependent effects on DNA repair, recent studies have shown mechanistic differences from PARP inhibition. Upon genotoxic stimulation of PARG, PARG consumption results in a decrease in NAD levels as opposed to PARP consumption. This leads to lung cancer cell death, which may be the result of energy failure (Erdelyi, Bai et al 2009).

Cell permeable PARG inhibitors are limited to compounds such as tannic acid or gallnut tannins, which have questionable specificity for PARG and limited bioavailability (Sun, Zhang et al 2012) (farthers, Drayton et al 2012) (Blenn, Wyrsch et al 2011).

It is an object of the present invention to provide specific cell-permeable inhibitors of PARG.

Disclosure of Invention

In one aspect, the invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a pharmaceutical composition as defined herein, comprising a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.

In another aspect, the invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

In another aspect, the invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative disorder.

In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer. In a specific embodiment, the cancer is a human cancer.

In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the production of a PARG inhibitory effect.

In another aspect, the invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.

In another aspect, the invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for the treatment of cancer in a human.

In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the production of a PARG inhibitory effect.

In another aspect, the present invention provides a method of inhibiting PARG in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the invention provides a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of treating a proliferative disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of treating cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.

The invention also provides a method of synthesizing a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, obtainable, or obtained, directly, by a synthetic method as defined herein.

In another aspect, the present invention provides novel intermediates as defined herein, suitable for use in any one of the synthetic methods set out herein.

Preferred, suitable and optional features of any one particular aspect of the invention are also preferred, suitable and optional features of any other aspect.

Detailed Description

Definition of

Unless otherwise indicated, the following terms used in the specification and claims have the following meanings set forth below.

It is understood that reference to "treating" or "treatment" includes both prevention and alleviation of established symptoms of a disorder. Thus, "treating" or "treatment" of a state, disorder or condition includes: (1) preventing or delaying the onset of clinical symptoms of a condition, disorder or condition developing in a human who is suffering from or susceptible to the condition, disorder or condition but has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder or condition; (2) inhibiting said state, disorder or condition, i.e. arresting, reducing or delaying the development of said disease or its recurrence (in the case of maintenance therapy) or the development of at least one clinical or subclinical symptom thereof; or (3) alleviating or slowing the disease, i.e., causing regression of the state, disorder or condition, or at least one clinical or subclinical symptom thereof.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a mammal for the treatment of a disease, is sufficient to effect such treatment of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

In this specification, the term "alkyl" includes both straight and branched chain alkyl groups. References to a single alkyl group such as "propyl" are specific only to the straight chain version and references to a single branched alkyl group such as "isopropyl" are specific only to the branched version. For example, "(1-6C) alkyl" includes (1-4C) alkyl, (1-3C) alkyl, propyl, isopropyl, and tert-butyl. Similar convention applies to other groups, for example "phenyl (1-6C) alkyl" includes phenyl (1-4C) alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

The terms "(m-nC)" or "(m-nC) group" used alone or as a prefix, refer to any group having m to n carbon atoms.

An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group that is located between and serves to link two other chemical groups. Thus, "(1-6C) alkylene" means a straight chain saturated divalent hydrocarbon group having one to six carbon atoms or a branched chain saturated divalent hydrocarbon group having three to six carbon atoms, for example, methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.

"(2-6C) alkenylene" means a straight chain divalent hydrocarbon group having two to six carbon atoms or a branched divalent hydrocarbon group having three to six carbon atoms, including at least one double bond, for example, vinylene, 2, 4-pentadienylene, and the like.

"(2-6C) alkynylene" means a straight chain divalent hydrocarbon group having two to six carbon atoms or a branched divalent hydrocarbon group having three to six carbon atoms, containing at least one triple bond, for example, ethynylene, propynyl, butynyl, and the like.

"(3-8C) cycloalkyl" means a hydrocarbon ring containing from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo [2.2.1] heptyl.

"(3-8C) cycloalkenyl" means a hydrocarbon ring containing at least one double bond, such as cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, e.g., 3-cyclohexen-1-yl or cyclooctenyl.

"(3-8C) cycloalkyl- (1-6C) alkylene" means a (3-8C) cycloalkyl group covalently attached to a (1-6C) alkylene group, both of which are defined herein.

The term "halogen (halo)" or "halogen (halogen)" refers to fluorine, chlorine, bromine, and iodine.

The term "heterocyclyl", "heterocyclic" or "heterocycle" means one or more non-aromatic, saturated or partially saturated monocyclic, fused, bridged or spirobicyclic heterocyclic ring systems. The term heterocyclyl includes both monovalent and divalent species. Monocyclic heterocycles contain from about 3 to 12 (suitably from 3 to 7) ring atoms with from 1 to 5 (suitably 1,2 or 3) ring atoms selected from nitrogen, oxygenOr a heteroatom of sulfur. Bicyclic heterocycles contain from 7 to 17, suitably 7 to 12 member atoms in the ring. Bicyclic heterocycles contain from about 7 to about 17 (suitably from 7 to 12) ring atoms. One or more bicyclic heterocycles may be fused, spiro or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as ethylene oxide, oxetane, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1, 3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothioazepine (hexahydrothiopinene). Other heterocycles include dihydro-oxathiolanyl (dihydrooxathiolanyl), tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydro-dioxazolyl, tetrahydro-oxathiazolyl (tetrahydrooxathiolanyl), hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxaquinolinyl (dioxalinyl), octahydrobenzofuranyl, octahydrobenzimidazolyl and octahydrobenzothiazolyl. For sulfur-containing heterocycles, SO or SO-containing compounds are also included₂Oxidized thia-rings of radicals. Examples include sulphoxide and sulphone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothiophene 1, 1-dioxide and thiomorpholinyl 1, 1-dioxide. Suitable values for heterocyclyl radicals having 1 or 2 oxo (═ O) or thio (═ S) substituents are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidinyl, 2, 5-dioxopyrrolidinyl, 2, 5-dioxoimidazolidinyl or 2, 6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyl groups containing 1,2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl 1, 1-dioxide, thiomorpholinyl 1, 1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person will appreciate, any heterocyclic ring may be attached to another group via any suitable atom, such as via a carbon or nitrogen atom. However, in this contextReferences to piperidinyl or morpholinyl refer to the piperidin-1-yl or morpholin-4-yl rings attached through the ring nitrogen.

"bridged ring system" means a ring system in which two rings share more than two atoms, see for example advanced organic Chemistry, Jerry March,4^thEdition, Wiley Interscience, pages 131-]. Examples of bridged heterocyclic ring systems include aza-bicyclo [2.2.1]Heptane, 2-oxa-5-azabicyclo [2.2.1]Heptane, aza-bicyclo [2.2.2]Octane, aza-bicyclo [3.2.1]Octane and quinuclidine.

"Heterocyclyl (1-6C) alkyl" means a heterocyclyl group covalently attached to a (1-6C) alkylene group, both of which are defined herein.

The term "heteroaryl" or "heteroaromatic" means an aromatic mono-, bi-or polycyclic ring incorporating one or more (e.g. 1 to 4, especially 1,2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups comprising from five to twelve ring members, and more typically from 5 to 10 ring members. Heteroaryl groups may be, for example, 5-or 6-membered monocyclic or 9-or 10-membered bicyclic rings, such as bicyclic structures formed by fused five-and six-membered rings or two fused six-membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, e.g. a single heteroatom. In one embodiment, the heteroaryl ring comprises at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogens. Typically, the number of basic nitrogen atoms present in a heteroaryl group (including any amino group substituents of the ring) will be less than five.

Examples of heteroaryl groups include: furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolyl, pyridopyrazinyl, thieno [2,3-b ] furyl, 2H-furo [3,2-b ] -pyranyl, 5H-pyrido [2,3-d ] -oxazolyl-oxazinyl, 1H-pyrazolo [4,3-d ] -oxazolyl, 4H-imidazo [4,5-d ] thiazolyl, pyrazino [2,3-d ] pyridazinyl, imidazo [2,1-b ] thiazolyl, imidazo [1,2-b ] [1,2,4] triazinyl. "heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems wherein at least one ring is aromatic and one or more other rings are non-aromatic, saturated or partially saturated rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1, 2,3, 4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2, 3-dihydro-benzo [1,4] dioxinyl, benzo [1,3] dioxolyl, 2-dioxo-1, 3-dihydro-2-benzothienyl, 4,5,6, 7-tetrahydrobenzofuranyl, indolinyl, 1,2,3, 4-tetrahydro-1, 8-naphthyridinyl, 1,2,3, 4-tetrahydropyrido [2,3-b ] pyrazinyl, and 3, 4-dihydro-2H-pyrido [3,2-b ] [1,4] oxazinyl.

Examples of five-membered heteroaryl groups include, but are not limited to: pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

Examples of six membered heteroaryl groups include, but are not limited to: pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

A bicyclic heteroaryl group may be, for example, a group selected from:

a benzene ring fused with a 5-or 6-membered ring containing 1,2 or 3 ring heteroatoms;

a pyridine ring fused to a 5-or 6-membered ring comprising 1,2 or 3 ring heteroatoms;

a pyrimidine ring fused to a 5-or 6-membered ring containing 1 or 2 ring heteroatoms;

a pyrrole ring fused to a 5 or 6 membered ring comprising 1,2 or 3 ring heteroatoms;

a pyrazole ring fused to a 5-or 6-membered ring containing 1 or 2 ring heteroatoms;

a pyrazine ring fused to a 5-or 6-membered ring containing 1 or 2 ring heteroatoms;

an imidazole ring fused with a 5-or 6-membered ring comprising 1 or 2 ring heteroatoms;

an oxazole ring fused to a 5 or 6 membered ring containing 1 or 2 ring heteroatoms;

an isoxazole ring fused to a 5-or 6-membered ring comprising 1 or 2 ring heteroatoms;

a thiazole ring fused with a 5-or 6-membered ring containing 1 or 2 ring heteroatoms;

an isothiazole ring fused with a 5-or 6-membered ring containing 1 or 2 ring heteroatoms;

a thiophene ring fused to a 5-or 6-membered ring comprising 1,2, or 3 ring heteroatoms;

a furan ring fused to a 5-or 6-membered ring comprising 1,2 or 3 ring heteroatoms;

a cyclohexyl ring fused to a 5-or 6-membered heteroaromatic ring containing 1,2 or 3 ring heteroatoms; and

a cyclopentyl ring fused to a 5-or 6-membered heteroaromatic ring containing 1,2 or 3 ring heteroatoms;

specific examples of bicyclic heteroaryl groups comprising a six-membered ring fused to a five-membered ring include, but are not limited to: benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adenine, guanine), indazolyl, benzodioxolyl (benzodioxolyl), and pyrazolopyridyl groups.

Specific examples of bicyclic heteroaryl groups comprising two fused six-membered rings include, but are not limited to: quinolyl, isoquinolyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

"heteroaryl (1-6C) alkyl" means a heteroaryl group covalently attached to a (1-6C) alkylene group, both of which are defined herein. Examples of heteroaralkyl groups include pyridin-3-ylmethyl, 3- (benzofuran-2-yl) propyl, and the like.

The term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In a particular embodiment, aryl is phenyl.

The term "aryl (1-6C) alkyl" means an aryl group covalently attached to a (1-6C) alkylene group, both of which are defined herein. Examples of aryl- (1-6C) alkyl groups include benzyl, phenylethyl, and the like.

This specification also uses several compound terms to describe groups that include more than one functionality. These terms will be understood by those skilled in the art. For example, heterocyclyl (m-nC) alkyl includes (m-nC) alkyl substituted with heterocyclyl.

The term "optionally substituted" means substitutedAnd unsubstituted groups, structures or molecules. The term "wherein R¹One/any CH, CH of the groups₂、CH₃The group or heteroatom (i.e., NH) is optionally substituted "means R¹(any) hydrogen radical of the group is substituted with the relevant specified group.

When optional substituents are selected from "one or more" groups, it is understood that the definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

The phrase "compounds of the present invention" means those compounds generally and specifically disclosed herein.

Compounds of the invention

In one aspect, the invention relates to a compound of formula (I) -or a pharmaceutically acceptable salt thereof, as shown below:

wherein:

bond c is absent or a single bond;

R_1aselected from hydrogen, fluoro, chloro, cyano, formyl, (1-2C) alkyl, (1-2C) haloalkyl, (2C) alkenyl or (2C) alkynyl;

R_1b、R_1c、R_1dand R_1eEach independently selected from H, fluoro or methyl;

w is selected from-NH-S (O)_y-、-S(O)_y-NH-, -C (O) NH-, -NHC (O) -, -NH-S (O) (NH) -, -S (O) (NH) -NH-, wherein y is 0, 1 or 2;

X₁selected from the group consisting of CR₂Or N; wherein R is₂Is H or fluorine;

X₂selected from the group consisting of CR₃Or N(ii) a Wherein R is₃Is H or fluorine;

X₃selected from the group consisting of CR₄Or N; wherein R is₄Is H, halogen, cyano, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy or (2C) alkynyl; or

R₄Selected from the group having the formula:

-L₄-L_4C-Q_4C

wherein

L₄Absent or is (1-3C) alkylene, (2-4C) alkenylene or (2-4C) alkynylene, each of which is optionally substituted with (1-2C) alkyl or oxo;

L_4Cabsent or selected from O, S, SO₂、N(R_4b)、C(O)、C(O)O、OC(O)、C(O)N(R_4b)、N(R_4b)C(O)、N(R_4b)C(O)O、C(O)N(R_4b)O、N(R_4b)C(O)N(R_4c)、S(O)₂N(R_4b) Or N (R)_4b)SO₂Wherein R is_4bAnd R_4cEach independently selected from hydrogen or (1-2C) alkyl; and

Q_4Cis hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q_6COptionally substituted by one or more groups selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C) alkyl, NR_4dR_4e、OR_4d、C(O)R_4d、C(O)OR_4d、OC(O)R_4d、C(O)N(R_4e)R_4d、N(R_4e)C(O)R_4d、S(O)_yR_4d(wherein y is 0, 1 or 2), SO₂N(R_4e)R_4d、N(R_4e)SO₂R_4dOr (CH)₂)_zNR_4eR_4d(wherein z is 1,2 or 3) wherein R is_4dAnd R_4eEach independently selected from H or (1-4C) alkaneA group;

HET is a fused 6-membered saturated, partially saturated, or fully unsaturated heterocyclic ring having the formula:

wherein

Bond a and bond b are single bonds, or one or both of bond a or bond b is optionally a double bond;

when the bond a is a single bond, X₄Selected from the group consisting of C (═ O), C (═ NH), C (═ S), CHR_5cOr N-R_5NOr X when bond a is a double bond₄Selected from the group consisting of CR_5cOr N;

wherein

R_5cSelected from H, halogen, (1-2C) alkyl, (1-2C) alkoxy, amino, (1-2C) alkylamino, (1-2C) dialkylamino, cyano or (2C) alkynyl, wherein the (1-2C) alkyl is optionally substituted with one or more substituents selected from amino or halogen;

R_5Nselected from H, (1-2C) alkyl or (1-2C) haloalkyl;

when a is a single bond, X₅Selected from the group consisting of C (═ O), C (═ NH), C (═ S), CHR_6cOr N-R_6NOr X when a is a double bond₅Selected from the group consisting of CR_6cOr N;

wherein

R_6cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₆-L_6C-Q_6C

wherein

L₆Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

L_6Cabsent or selected from O, S, SO₂、N(R_b)、C(O)、C(O)O、OC(O)、C(O)N(R_b)、N(R_b)C(O)、N(R_b)C(O)N(R_c)、S(O)₂N(R_b) Or N (R)_b)SO₂Wherein R is_bAnd R_cEach independently selected from hydrogen or (1-2C) alkyl; and

Q_6Cis hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q_6COptionally substituted by one or more groups selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C) alkyl, NR_dR_e、OR_d、C(O)R_d、C(O)OR_d、OC(O)R_d、C(O)N(R_e)R_d、N(R_e)C(O)R_d、S(O)_yR_d(wherein y is 0, 1 or 2), SO₂N(R_e)R_d、N(R_e)SO₂R_dOr (CH)₂)_zNR_eR_d(wherein z is 1,2 or 3) wherein R is_dAnd R_eEach independently selected from H or (1-4C) alkyl;

R_6Nselected from hydrogen or a group having the formula:

-L₆-L_6N-Q_6N

wherein

L₆Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

L_6Nabsent or selected from O, S, SO₂、N(R_f)、C(O)、C(O)O、OC(O)、C(O)N(R_g)、N(R_f)C(O)、N(R_f)C(O)N(R_g)、S(O)₂N(R_f) Or N (R)_f)SO₂Wherein R is_fAnd R_gEach independently selected from hydrogen or (1-2C) alkyl; and

Q_6Nis hydrogen, cyano, (1-6C) alkyl, (2C) alkynyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from: halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, (1-4C) alkyl, NR_hR_i、OR_h、C(O)R_h、C(O)OR_h、OC(O)R_h、C(O)N(R_h)R_i、N(R_h)C(O)R_i、N(R_h)C(O)OR_i、S(O)_yR_h(wherein y is 0, 1 or 2), SO₂N(R_h)R_i、N(R_h)SO₂R_iOr (CH)₂)_zNR_hR_i(wherein z is 1,2 or 3) wherein R_hAnd R_iEach independently selected from H or (1-4C) alkyl; or

Q_6NOptionally substituted with a group having the formula:

-W_6N-Z_6N

wherein

W_6NAbsent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

Z_6Nselected from (3-5C) cycloalkyl, (3-6C) heterocyclyl, (2C) alkynyl, phenyl, 5-or 6-membered heteroaryl, carboxy, carbamoyl or cyano, wherein Z_6NSubstituted with one or more substituents selected from (1-2C) alkyl, (1-2C) alkoxy or halogen;

when the bond b is a single bond, X₆Selected from the group consisting of C (═ O), C (═ NH), C (═ S), CHR_7cOr N-R_7NOr X when bond b is a double bond₆Selected from the group consisting of CR_7cOr N;

wherein

R_7cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₇-L_7C-Q_7C

wherein

L₇Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

L_7Cabsent or selected from O, S, SO₂、N(R_j)、C(O)、C(O)O、OC(O)、C(O)N(R_j)、N(R_j)C(O)、N(R_j)C(O)N(R_k)、S(O)₂N(R_j) Or N (R)_j)SO₂Wherein R is_jAnd R_kEach independently selected from hydrogen or (1-2C) alkyl; and

Q_7Cis hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, aryl (1-2C) alkyl, heterocyclyl- (1-2C) alkyl, heteroaryl or heteroaryl- (1-2C) alkyl; and wherein Q_7COptionally substituted by one or more groups selected from (1-4C) alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, NR_lR_m、OR_l、C(O)R_m、C(O)OR_l、OC(O)R_m、C(O)N(R_l)R_m、N(R_l)C(O)R_m、S(O)_yR_l(wherein y is 0, 1 or 2), SO₂N(R_l)R_m、N(R_l)SO₂R_mOr (CH)₂)_zNR_lR_m(wherein z is 1,2 or 3) wherein R is_lAnd R_mEach independently selected from H or (1-4C) alkyl;

R_7Nselected from hydrogen or a group having the formula:

-L₇-L_7N-Q_7N

wherein

L₇Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

L_7Nselected from O, S, SO₂、N(R_n)、C(O)、C(O)O、OC(O)、C(O)N(R_n)、N(R_n)C(O)、N(R_n)C(O)N(R_o)、S(O)₂N(R_n) Or N (R)_n)SO₂Wherein R is_nAnd R_oEach independently selected from hydrogen or (1-2C) alkyl; and

Q_7Nis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from: halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, (1-4C) alkyl, NR_pR_q、OR_p、C(O)R_p、C(O)OR_p、OC(O)R_p、C(O)N(R_p)R_q、N(R_r)C(O)R_p、S(O)_yR_p(wherein y is 0, 1 or 2), SO₂N(R_p)R_q、N(R_r)SO₂R_pOr (CH)₂)_zNR_pR_q(wherein z is 1,2 or 3) wherein R_pAnd R_qEach independently selected from H or (1-4C) alkyl;

when the bond b is a single bond, X₇Selected from the group consisting of C (═ O), C (═ NH), C (═ S), CHR_8cOr N-R_8NOr X when bond b is a double bond₄Selected from the group consisting of CR_8cOr N;

wherein

R_8cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₈-L_8C-Q_8C

wherein

L₈Absent or (1-3C) alkylene, (3-4C) cycloalkylene, optionally substituted with one or more substituents selected from (1-2C) alkyl, halo or oxo;

L_8Cis absent or selected from O,S、SO、SO₂、N(R_r)、C(O)、C(O)O、OC(O)、C(O)N(R_r)、N(R_r)C(O)、N(R_r)C(O)N(R_s)、S(O)₂N(R_r) Or N (R)_r)SO₂Wherein R is_rAnd R_sEach independently selected from hydrogen or (1-2C) alkyl; and

Q_8Cis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, (2-3C) alkenyl, (2-3C) alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q_8COptionally substituted by one or more groups selected from (1-4C) alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, NR_tR_u、OR_t、C(O)R_t、C(O)OR_t、OC(O)R_t、C(O)N(R_t)R_u、N(R_t)C(O)R_u、S(O)_yR_t(wherein y is 0, 1 or 2), SO₂N(R_t)R_u、N(R_t)SO₂R_uOr (CH)₂)_zNR_tR_u(wherein z is 1,2 or 3) wherein R is_tAnd R_uEach independently selected from H or (1-4C) alkyl; or

Q_6NOptionally substituted with a group having the formula:

-W_8C-L_8’-Z_8C

wherein

W_8CAbsent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

L_8’is absent or selected from C (O), C (O) O, OC (O), C (O) N (R)_v)、N(R_v)C(O)、N(R_v)C(O)N(R_w)、S(O)₂N(R_v) Or N (R)_v)SO₂Wherein R is_vAnd R_wEach independently selected from hydrogen or (1-2C) alkyl; and

Z_8Cis phenyl or 5-6 membered heteroaryl; wherein Z_8COptionally substituted with one or more substituents selected from (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl or sulfamoyl; or Q_8cAnd R₄Are linked such that they form, together with the carbon atom to which they are linked, a group of formula;

wherein R is_zSelected from (1-4C) alkyl, (1-4C) haloalkyl, or a group having the formula:

-L_Rz-Z_Rz

wherein:

L_Rzabsent or is (1-3C) alkylene, optionally substituted with one or more substituents selected from (1-2C) alkyl, halo or oxo; and

Z_Rzis aryl, carbocyclyl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C) alkyl, halogen, trifluoromethyl, trifluoromethoxy, haloalkyl, amino, cyano, hydroxy, carboxy, carbamoyl or sulfamoyl;

R_8Nselected from hydrogen or a group having the formula:

-L₈-L_8N-Q_8N

wherein

L₈Absent or (1-3C) alkylene, (3-4C) cycloalkyl, optionally substituted with one or more substituents selected from (1-2C) alkyl, halo or oxo;

L_8Nabsent or selected from O, S, SO₂、N(R_x)、C(O)、C(O)O、OC(O)、C(O)N(R_x)、N(R_x)C(O)、N(R_x)C(O)N(R_y)、N(R_x)C(O)O、S(O)₂N(R_x) Or N (R)_x)SO₂Wherein R is_xAnd R_yEach independently selected from hydrogen or (1-2C) alkyl;

Q_8Nis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, (2-3C) alkenyl, (2-3C) alkynyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from: (1-4C) alkyl, halogen, trifluoromethyl, trifluoromethoxy, haloalkyl, amino, cyano, aryl, hydroxy, carboxy, carbamoyl, sulfamoyl, NR_zR_a’、OR_z、C(O)R_z、C(O)OR_z、OC(O)R_z、C(O)N(R_z)R_a’、N(R_z)C(O)R_a’、S(O)_yR_z(wherein y is 0, 1 or 2), SO₂N(R_z)R_a’、N(R_z)SO₂R_a’Or (CH)₂)_zNR_zR_a’(wherein z is 1,2 or 3) wherein R_zAnd R_a’Each independently selected from H or (1-4C) alkyl; or Q_8NOptionally substituted with a group having the formula:

-W_8N-L_8’-Z_8N

wherein

W_8NAbsent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

L_8’is absent or selected from C (O), C (O) O, OC (O), C (O) N (R)_b’)、N(R_b’)C(O)、N(R_b’)C(O)N(R_c’)、S(O)₂N(R_b’) Or N (R)_b’)SO₂Wherein R is_b’And R_c’Each independently selected from hydrogen or (1-2C) alkyl; and

Z_8Nis phenyl, (1-4C) alkyl, (4)-6C) heterocyclyl or 5-6 membered heteroaryl; wherein Z_8NOptionally substituted with one or more substituents selected from (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl or sulfamoyl;

the premise is as follows:

R_1b-eone or two of which may be selected from substituents other than H;

X₁、X₂or X₃Only one or two of which may be N;

het may contain up to two ring nitrogen atoms only; and

X₄、X₅、X₆or X₇Only one or two of (a) may be selected from C (═ O), C (═ NH), or C (═ S).

In another aspect, the present invention relates to a compound of formula- (I) -as shown above, or a pharmaceutically acceptable salt thereof, wherein:

bond c, R_1a、R_1b、R_1c、R_1d、R_1e、W、X₁、X₂、X₃Are all as defined above;

R₄selected from the group having the formula:

-L₄-L_4C-Q_4C

wherein

L₄Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

L_4Cabsent or selected from O, S, SO₂、N(R_4b)、C(O)、C(O)O、OC(O)、C(O)N(R_4b)、N(R_4b)C(O)、N(R_4b)C(O)N(R_4c)、S(O)₂N(R_4b) Or N (R)_4b)SO₂Wherein R is_4bAnd R_4cEach independently selected from hydrogen or (1-2C) alkyl; and

Q_4Cis hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q_6COptionally substituted by one or more groups selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C) alkyl, NR_4dR_4e、OR_4d、C(O)R_4d、C(O)OR_4d、OC(O)R_4d、C(O)N(R_4e)R_4d、N(R_4e)C(O)R_4d、S(O)_yR_4d(wherein y is 0, 1 or 2), SO₂N(R_4e)R_4d、N(R_4e)SO₂R_4dOr (CH)₂)_zNR_4eR_4d(wherein z is 1,2 or 3) wherein R is_4dAnd R_4eEach independently selected from H or (1-4C) alkyl;

HET, bond a, bond b, X₄、X₅Is as defined above;

when the bond b is a single bond, X₆Selected from the group consisting of C (═ O), C (═ NH), C (═ S), CHR_7cOr N-R_7NOr X when bond b is a double bond₄Selected from the group consisting of CR_7cOr N;

wherein

R_7cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₇-L_7C-Q_7C

wherein

L₇Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

Q_7Cis hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q_7COptionally substituted by one or more groups selected from (1-4C) alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, NR_lR_m、OR_l、C(O)R_m、C(O)OR_l、OC(O)R_m、C(O)N(R_l)R_m、N(R_l)C(O)R_m、S(O)_yR_l(wherein y is 0, 1 or 2), SO₂N(R_l)R_m、N(R_l)SO₂R_mOr (CH)₂)_zNR_lR_m(wherein z is 1,2 or 3) wherein R is_lAnd R_mEach independently selected from H or (1-4C) alkyl;

R_7Nselected from hydrogen or a group having the formula:

-L₇-L_7N-Q_7N

wherein

L₇Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

Q_7Nis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from: halogenPlain, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C) alkyl, NR_pR_q、OR_p、C(O)R_p、C(O)OR_p、OC(O)R_p、C(O)N(R_p)R_q、N(R_r)C(O)R_p、S(O)_yR_p(wherein y is 0, 1 or 2), SO₂N(R_p)R_q、N(R_r)SO₂R_pOr (CH)₂)_zNR_pR_q(wherein z is 1,2 or 3) wherein R_pAnd R_qEach independently selected from H or (1-4C) alkyl;

wherein

R_8cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₈-L_8C-Q_8C

wherein

L_8Cabsent or selected from O, S, SO₂、N(R_r)、C(O)、C(O)O、OC(O)、C(O)N(R_r)、N(R_r)C(O)、N(R_r)C(O)N(R_s)、S(O)₂N(R_r) Or N (R)_r)SO₂Wherein R is_rAnd R_sEach independently selected from hydrogen or (1-2C) alkyl; and

Q_8Cis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, (2-3C) alkenyl, (2-3C) alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q_8COptionally by one or moreEach selected from (1-4C) alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, NR_tR_u、OR_t、C(O)R_t、C(O)OR_t、OC(O)R_t、C(O)N(R_t)R_u、N(R_t)C(O)R_u、S(O)_yR_t(wherein y is 0, 1 or 2), SO₂N(R_t)R_u、N(R_t)SO₂R_uOr (CH)₂)_zNR_tR_u(wherein z is 1,2 or 3) wherein R is_tAnd R_uEach independently selected from H or (1-4C) alkyl; or

Q_8COptionally substituted with a group having the formula:

-W_8C-L_8’-Z_8C

wherein

W_8CAbsent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

Z_8Cis phenyl or 5-6 membered heteroaryl; wherein Z_8COptionally substituted with one or more substituents selected from (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl or sulfamoyl;

R_8Nselected from hydrogen or a group having the formula:

-L₈-L_8N-Q_8N

wherein

Q_8Nis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, (2-3C) alkenyl, (2-3C) alkynyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from: (1-4C) alkyl, halogen, trifluoromethyl, trifluoromethoxy, haloalkyl, amino, cyano, aryl, hydroxy, carboxy, carbamoyl, sulfamoyl, NR_zR_a’、OR_z、C(O)R_z、C(O)OR_z、OC(O)R_z、C(O)N(R_z)R_a’、N(R_z)C(O)R_a’、S(O)_yR_z(wherein y is 0, 1 or 2), SO₂N(R_z)R_a’、N(R_z)SO₂R_aOr (CH)₂)_zNR_zR_a’(wherein z is 1,2 or 3) wherein R_zAnd R_a’Each independently selected from H or (1-4C) alkyl; or

Q_8NOptionally substituted with a group having the formula:

-W_8N-L_8’-Z_8N

wherein

W_8NAbsent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

Z_8Nis phenyl, (1-4C) alkyl, (4-6C) heterocyclyl or 5-6 membered heteroaryl; wherein Z_8NOptionally substituted with one or more substituents selected from (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, (1-4C) alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl or sulfamoyl;

the premise is as follows:

R_1b-eone or two of which may be selected from substituents other than H;

X₁、X₂or X₃Only one or two of which may be N;

het may contain up to two ring nitrogen atoms only; and

Specific compounds of the invention include, for example, compounds of formula I or pharmaceutically acceptable salts and/or solvates thereof, wherein bond a, bond b, R, unless otherwise specified_1a、R_1b、R_1c、R_1d、R_1e、W、X₁、X₂、X₃、X₄、X₅、X₆、X₇C and any related substituents each have any of the meanings defined above or in any of paragraphs (1) to (53) below: -

(1) Bond a and bond b are single bonds, or one of bond a or bond b is optionally a double bond;

(2) bond a and bond b are single bonds, or bond b is optionally a double bond;

(3)R_1aselected from hydrogen, fluoro, cyano, formyl, (1-2C) alkyl, (1-2C) haloalkyl, or (2C) alkynyl;

(4)R_1aselected from hydrogen, cyano, formyl, (1-2C) alkyl, or (1-2C) haloalkyl;

(5)R_1aselected from hydrogen, cyano, methyl, or (1-2C) haloalkyl;

(6)R_1aselected from hydrogen, cyano, methyl, or fluoromethyl;

(7)R_1aselected from cyano, methyl, or fluoromethyl;

(8)R_1aselected from methyl, or fluoromethyl;

(9)R_1ais methyl;

(10)R_1b、R_1c、R_1dand R_1eIndependently selected from H, or fluorine;

(11)R_1b、R_1c、R_1dand R_1eIs H;

(12) w is selected from-NH-S (O)_y-、-S(O)_y-NH-, -C (O) NH-or-NHC (O) -, wherein y is 0, 1 or 2;

(13) w is selected from-NH-S (O)₂-、-S(O)₂-NH-, -C (O) NH-or-NHC (O) -;

(14) w is selected from-NH-S (O)₂-or-S (O)₂-NH-；

(15) W is-NH-S (O)₂-；

(16)X₁Is N or CR₂Wherein R is₂Is H or fluorine;

(17)X₁is N or CH;

(18)X₁is CH;

(19)X₂is N or CR₃Wherein R is₃Is H or fluorine;

(20)X₂is N or CH;

(21)X₂is CH or CF;

(22)X₂is CH;

(23)X₃selected from the group consisting of CR₄Or N; wherein R is₄Is H, halogen, cyano, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy or (2C) alkynyl; or

R₄Selected from the group having the formula:

-L₄-L_4C-Q_4C

wherein

L₄Absent or is (1-3C) alkylene, (2C) alkenylene or (2C) alkynylene, each of which is optionally substituted with (1-2C) alkyl or oxo;

L_4Cabsent or selected from O, S, SO₂、N(R_4b)、C(O)、C(O)O、OC(O)、C(O)N(R_4b)、N(R_4b)C(O)、C(O)N(R_4b)O、N(R_4b)C(O)N(R_4c)、S(O)₂N(R_4b) Or N (R)_4b)SO₂Wherein R4b and R4C are each independently selected from hydrogen or (1-2C) alkyl; and

(24)X₃selected from the group consisting of CR₄Or N; wherein R is₄Is H, halogen, cyano, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy or (2C) alkynyl; or

R₄Selected from the group having the formula:

-L₄-L_4C-Q_4C

wherein

L_4Cabsent or selected from O, S, SO₂、N(R_4b)、C(O)、C(O)O、OC(O)、C(O)N(R_4b)、N(R_4b)C(O)、C(O)N(R_4b)O、N(R_4b)C(O)N(R_4c)、S(O)₂N(R_4b) Or N (R)_4b)SO₂Wherein R is_4bAnd R_4cEach independently selected from hydrogen or (1-2C) alkyl; and

Q_4Cis hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q_6COptionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, or sulfamoyl;

(25)X₃selected from the group consisting of CR₄Or N; wherein R is₄Is H, halogen, cyano, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy or (2C) alkynyl; or

R₄Selected from the group having the formula:

-L₄-L_4C-Q_4C

wherein

L₄Absent or (1-3C) alkylene or (2C) alkynylene, each optionally substituted with (1-2C) alkyl or oxo;

L_4Cis absent or selected from SO₂、N(R_4b)、C(O)、C(O)O、OC(O)、C(O)N(R_4b)、N(R_4b) C (O) or C (O) N (R)_4b) O, wherein R_4bIndependently selected from hydrogen or (1-2C) alkyl; and

(26)X₃selected from the group consisting of CR₄Or N; wherein R is₄Is H, halogen, cyano, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy or (2C) alkynyl; or

R₄Selected from the group having the formula:

-L₄-L_4C-Q_4C

wherein

(27)X₃selected from the group consisting of CR₄Or N; wherein R is₄Is H, halogen, cyano, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy or (2C) alkynyl; or

R₄Selected from the group having the formula:

-L₄-L_4C-Q_4C

wherein

L₄Absent or (1-2C) alkylene optionally substituted with (1-2C) alkyl or oxo;

L_4Cis absent or selected from C (O) O, OC (O), C (O) N (R)_4b)、N(R_4b) C (O), wherein R_4bSelected from hydrogen or (1-2C) alkyl; and

Q_4Cis hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q_6COptionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, or sulfamoyl;

(28)X₃selected from the group consisting of CR₄Or N; wherein R is₄Is H, halogen, cyano, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy or (2C) alkynyl; or

R₄Selected from the group having the formula:

-L_4C-Q_4C

wherein

L_4CIs absent or selected from C (O) N (R)_4b) Wherein R is_4bSelected from hydrogen or (1-2C) alkyl; and

(29)X₃selected from the group consisting of CR₄Or N; wherein R is₄Is H, halogen, cyano, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy or (2C) alkynyl; or

R₄Selected from the group having the formula:

-L_4C-Q_4C

wherein

Q_4Cis hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, phenyl, 5-or 6-membered heterocyclyl or 5-or 6-membered heteroaryl; and wherein Q_6COptionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, or sulfamoyl;

(30)X₃selected from the group consisting of CR₄Or N; wherein R is₄Is H, halogen, cyano, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy or (2C) alkynyl; or

R₄Selected from the group having the formula:

-L_4C-Q_4C

wherein

Q_4Cis hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, phenyl or 5-membered heteroaryl; and wherein Q_6COptionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy or amino;

(31)X₃selected from the group consisting of CR₄Or N; wherein R is₄Is H, halogen, cyano, (1-2C) alkyl, (1-2C) haloalkyl, or (2C) alkynyl;

(32)X₃selected from the group consisting of CR₄Or N; wherein R is₄Is H, halogen, cyano or (1-2C) alkyl;

(33)X₃selected from the group consisting of CR₄Or N; wherein R is₄Is H, fluoro, cyano or methyl;

(34)X₃selected from the group consisting of CR₄Or N; wherein R is₄Is H or fluorine;

(35)X₃is CH or CF;

(36) when the bond a is a single bond, X₄Selected from the group consisting of C (═ O), C (═ NH), C (═ S), CHR_5cOr N-R_5NOr X when bond a is a double bond₄Selected from the group consisting of CR_5cOr N;

wherein

R_5cSelected from H, fluorine, (1-2C)Alkyl, cyano or (2C) alkynyl;

R_5Nselected from H, (1-2C) alkyl or CF₃；

(37) When the bond a is a single bond, X₄Selected from C (═ O) or N-R_5NOr X when bond a is a double bond₄Selected from the group consisting of CR_5cOr N;

wherein

R_5cSelected from H, halogen, (1-2C) alkyl, cyano or (2C) alkynyl;

R_5Nselected from H, (1-2C) alkyl or CF₃；

(38) When the bond a is a single bond, X₄Selected from C (═ O) or N-R_5NOr X when bond a is a double bond₄Selected from the group consisting of CR_5cOr N;

wherein

R_5cSelected from H, fluoro or (1-2C) alkyl;

R_5Nselected from H, (1-2C) alkyl or CF₃；

(39)X₄Is C (═ O), and bond a is a single bond;

(40) when a is a single bond, X₅Selected from the group consisting of C (═ O), C (═ NH), C (═ S), N-R_6N；

Wherein

R_6NSelected from hydrogen or a group having the formula:

-L₆-L_6N-Q_6N

wherein

L₆Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

Q_6NOptionally substituted with a group having the formula:

-W_6N-Z_6N

wherein

W_6NAbsent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

(41) when a is a single bond, X₅Selected from C (═ O) or N-R_6N；

Wherein

R_6NSelected from hydrogen or a group having the formula:

-L₆-L_6N-Q_6N

wherein

L₆Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

L_6Nabsent or selected from O, S, SO₂、N(R_f)、C(O)、C(O)O、OC(O)、C(O)N(R_g)、N(R_f) C (O) or N (R)_f) SO2, wherein R_fAnd R_gEach independently selected from hydrogen or (1-2C) alkyl; and

Q_6Nis hydrogen, cyano, (1-6C) alkyl, (2C) alkynyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from: halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, (1-4C) alkyl, NR_hR_i、OR_h、C(O)R_h、C(O)OR_h、OC(O)R_h、C(O)N(R_h)R_i、N(R_h)C(O)R_i、N(R_h)C(O)OR_i、S(O)_yR_h(wherein y is 0, 1 or 2) wherein R_hAnd R_iEach independently selected from H or (1-4C) alkyl; or

Q_6NOptionally substituted with a group having the formula:

-W_6N-Z_6N

wherein

W_6NAbsent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

(42)X₅is N-R_6NAnd bond a is a single bond;

wherein

R_6NSelected from the group having the formula:

-L₆-Q_6N

wherein

L₆Is (1-3C) alkylene;

Q_6Nis hydrogen, cyano or 5-or 6-membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, hydroxy, amino, N (R)_h)C(O)OR_iOr (1-4C) alkyl, wherein R_hAnd R_iEach independently selected from H or (1-4C) alkyl; or

Q_6NOptionally substituted with a group having the formula:

-W_6N-Z_6N

wherein

W_6NAbsent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

Z_6Nselected from (3-5C) cycloalkyl, (2C) alkynyl, phenyl, 5-or 6-membered heteroaryl or cyano, wherein Z_6NSubstituted with one or more substituents selected from (1-2C) alkyl, (1-2C) alkoxy or halogen;

(43)X₅is N-R_6NAnd bond a is a single bond;

wherein

R_6NSelected from the group having the formula:

-L₆-Q_6N

wherein

L₆Is (1-2C) alkylene;

Q_6Nis a 5-or 6-membered heteroaryl group, wherein said heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, hydroxy, amino, N (R)_h)C(O)OR_iOr (1-4C) alkyl, wherein R_hAnd R_iEach independently selected from H or (1-4C) alkyl;

(44) when the bond b is a single bond, X₆Selected from the group consisting of C (═ O), C (═ NH), C (═ S), CHR_7cOr N-R_7NOr X when bond b is a double bond₆Selected from the group consisting of CR_7cOr N;

wherein

R_7cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₇-L_7C-Q_7C

wherein

L₇Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

L_7Cabsent or selected from O, S, SO₂、N(R_j)、C(O)、C(O)O、OC(O)、C(O)N(R_j) Or N (R)_j) C (O), wherein R_jIndependently selected from hydrogen or (1-2C) alkyl; and

Q_7Cis hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q_7COptionally substituted with one or more substituents selected from (1-4C) alkyl, halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl or sulfamoyl;

R_7Nselected from hydrogen or a group having the formula:

-L₇-L_7N-Q_7N

wherein

L₇Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

L_7Nabsent or selected from O, S, SO₂、N(R_n)、C(O)、C(O)O、OC(O)、C(O)N(R_n) Or N (R)_n) C (O), wherein R_nIndependently selected from hydrogen or (1-2C) alkyl; and

Q_7Nis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, (1-4C) alkyl;

(45) when the bond b is a single bond, X₆Selected from C (═ O), or when bond b is a double bond, X₆Selected from the group consisting of CR_7cOr N;

wherein

R_7cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₇-Q_7C

wherein

L₇Is (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo; and

Q_7Cis hydrogen or (1-6C) alkyl, (3-6C) cycloalkyl, aryl, (3-6C) heterocyclyl or 5-or 6-membered heteroaryl; and wherein Q_7COptionally substituted with one or more substituents selected from (1-4C) alkyl or halogen;

(46) when the bond b is a single bond, X₆Selected from C (═ O), or when bond b is a double bond, X₆Selected from the group consisting of CR_7cOr N;

wherein

R_7cSelected from hydrogen or a group having the formula:

-L₇-Q_7C

wherein

L₇Is (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo; and

Q_7Cis hydrogen or (1-4C) alkyl, (3-6C) cycloalkyl, aryl, (3-6C) heterocyclyl or 5-or 6-membered heteroaryl; and wherein Q_7COptionally substituted with one or more substituents selected from (1-2C) alkyl or fluoro;

(47)X₆is C (═ O);

(48) when the bond b is a single bond, X₇Selected from C (═ O) or N-R_8NOr X when the bond b is a double bond₇Selected from the group consisting of CR_8cOr N;

wherein

R_8cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₈-L_8C-Q_8C

wherein

L₈(1-3C) alkylene which is absent or optionally substituted by oxo;

L_8Cabsent or selected from O, S, SO₂、N(R_r)、C(O)、C(O)O、OC(O)、C(O)N(R_r) Or N (R)_r) C (O), wherein R_rSelected from hydrogen or (1-2C) alkyl; and

Q_8Cis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, (2-3C) alkenyl, (2-3C) alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q_8COptionally substituted by one or more groups selected from (1-4C) alkyl, halogen, NR_tR_u、OR_t、C(O)R_t、C(O)OR_t、OC(O)R_tSubstituent group(s) takeWherein R is_tAnd R_uEach independently selected from H or (1-2C) alkyl; or

Q_8cAnd R₄Are linked such that they form, together with the carbon atom to which they are linked, a group of formula;

-L_Rz-Z_Rz

wherein:

L_Rzabsent or (1-3C) alkylene; and

Z_Rzis aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C) alkyl, halogen, trifluoromethyl, amino, cyano, or hydroxy;

R_8Nselected from hydrogen or a group having the formula:

-L₈-L_8N-Q_8N

wherein

L₈(1-3C) alkylene which is absent or optionally substituted with one or more substituents selected from (1-2C) alkyl;

L_8Nabsent or selected from O, S, SO₂、N(R_x)、C(O)、C(O)O、OC(O)、C(O)N(R_x)、N(R_x)C(O)、N(R_x) C (O) O, wherein R_xSelected from hydrogen or (1-2C) alkyl;

Q_8Nis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, (2-3C) alkenyl, (2-3C) alkynyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituentsSubstituted with a substituent selected from: (1-4C) alkyl, halogen, trifluoromethyl, trifluoromethoxy, haloalkyl, amino, cyano, aryl, hydroxy, carboxy, carbamoyl, sulfamoyl, NR_zR_a’、OR_z、C(O)R_z、C(O)OR_z、OC(O)R_z、C(O)N(R_z)R_a’、N(R_z)C(O)R_a’Or S (O)_yR_z(wherein y is 0, 1 or 2) wherein R_zAnd R_a’Each independently selected from H or (1-2C) alkyl; or

Q_8NOptionally substituted with a group having the formula:

-L_8’-Z_8N

wherein

L_8’Is absent or selected from C (O), C (O) O, OC (O) or C (O) N (R)_b’) Wherein R is_b’And R_c’Each independently selected from hydrogen or (1-2C) alkyl; and

Z_8Nis phenyl, (1-4C) alkyl, (4-6C) heterocyclyl or 5-6 membered heteroaryl; wherein Z_8NOptionally substituted with one or more substituents selected from (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, (1-2C) alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl or sulfamoyl;

(49) when the bond b is a single bond, X₇Selected from C (═ O) or N-R_8NOr X when the bond b is a double bond₇Selected from the group consisting of CR_8cOr N;

wherein

R_8cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₈-L_8C-Q_8C

wherein

L₈Is absent or is optionally substituted orOxo-substituted (1-3C) alkylene;

Q_8Cis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, (2-3C) alkenyl, (2-3C) alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q_8COptionally substituted by one or more groups selected from (1-4C) alkyl, halogen, NR_tR_u、OR_t、C(O)R_t、C(O)OR_t、OC(O)R_tWherein R is_tAnd R_uEach independently selected from H or (1-2C) alkyl; or

wherein R is_zSelected from (1-4C) alkyl or a group having the formula:

-L_Rz-Z_Rz

wherein:

L_Rzabsent or (1-2C) alkylene; and

Z_Rzis 5-or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from (1-4C) alkyl, halogen, amino, or hydroxy;

R_8Nselected from hydrogen or a group having the formula:

-L₈-L_8N-Q_8N

wherein

Q_8Nis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, (2-3C) alkenyl, (2-3C) alkynyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from: (1-4C) alkyl, halogen, trifluoromethyl, trifluoromethoxy, haloalkyl, amino, cyano, aryl, hydroxy, carboxy, carbamoyl, sulfamoyl, NR_zR_a’、OR_z、C(O)R_z、C(O)OR_z、OC(O)R_z、C(O)N(R_z)R_a’、N(R_z)C(O)R_a’Or S (O)_yR_z(wherein y is 0, 1 or 2) wherein R_zAnd R_a’Each independently selected from H or (1-2C) alkyl; or

Q_8NOptionally substituted with a group having the formula:

-L_8’-Z_8N

wherein

(50) when the bond b is a single bond, X₇Selected from C (═ O) or N-R_8NOr X when the bond b is a double bond₇Selected from the group consisting of CR_8cOr N;

wherein

R_8cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₈-L_8C-Q_8C

wherein

L₈(1-3C) alkylene which is absent or optionally substituted by oxo;

R_8NSelected from hydrogen or a group having the formula:

-L₈-L_8N-Q_8N

wherein

Q_8NOptionally substituted with a group having the formula:

-L_8’-Z_8N

wherein

(51) when the bond b is a single bond, X₇Is selected from N-R_8NOr X when the bond b is a double bond₇Selected from the group consisting of CR_8cOr N;

wherein

R_8cSelected from hydrogen, halogen or a group having the formula:

-L₈-L_8C-Q_8C

wherein

L₈(1-3C) alkylene which is absent or optionally substituted by oxo;

L_8Cis absent or selected from O, N (R)_r) C (O), C (O) O or C (O) N (R)_r) Wherein R is_rSelected from hydrogen or (1-2C) alkyl; and

Q_8Cis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, (2-3C) alkenyl, (2-3C) alkynyl, aryl, heterocyclyl or heteroaryl; and wherein Q_8COptionally substituted by one or more groups selected from (1-4C) alkyl, halogen, NR_tR_u、OR_tWherein R is_tAnd R_uEach independently selected from H or (1-2C) alkyl; or

R_8NSelected from hydrogen or a group having the formula:

-L₈-L_8N-Q_8N

wherein

L_8Nis absent or selected from C (O) N (R)_x) Or N (R)_x) C (O) O, wherein R_xSelected from hydrogen or (1-2C) alkyl;

Q_8Nis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, (2-3C) alkenyl, (2-3C) alkynyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from: (1-4C) alkyl, halogen, trifluoromethyl, trifluoromethoxy, haloalkyl, amino, cyano, aryl, hydroxy, carboxy, carbamoyl, sulfamoyl, NR_zR_a’、OR_z、C(O)N(R_z)R_a’、N(R_z)C(O)R_a’Or S (O)_yR_z(wherein y is 0, 1 or 2) wherein R_zAnd R_a’Each independently selected from H or (1-2C) alkyl; or

Q_8NOptionally substituted with a group having the formula:

-L_8’-Z_8N

wherein

L_8’Is absent or selected from C (O) or C (O) N (R)_b’) Wherein R is_b’And R_c’Each independently selected from hydrogen or (1-2C) alkyl; and is

Z_8NIs phenyl, (1-4C) alkyl, (4-6C) heterocyclyl or 5-6 membered heteroaryl; wherein Z_8NOptionally substituted with one or more substituents selected from (1-2C) alkyl, halogen or hydroxy;

(52) when the bond b is a single bond, X₇Is selected from N-R_8NOr X when the bond b is a double bond₇Selected from the group consisting of CR_8cOr N;

wherein

R_8cSelected from hydrogen, halogen or a group having the formula:

-L₈-L_8C-Q_8C

wherein

L₈(1-3C) alkylene which is absent or optionally substituted by oxo;

Q_8Cis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, (2-3C) alkenyl, (2-3C) alkynyl, phenyl, 5-or 6-membered heterocyclyl or 5-or 6-membered heteroaryl; and wherein Q_8COptionally substituted by one or more groups selected from (1-4C) alkyl, halogen, NR_tR_u、OR_tWherein R is_tAnd R_uEach independently selected from H or (1-2C) alkyl; or

R_8NSelected from hydrogen or a group having the formula:

-L₈-L_8N-Q_8N

wherein

Q_8Nis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, (2-3C) alkenyl, (2-3C) alkynyl, phenyl, 5-or 6-membered heterocyclyl or 5-or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from: (1-4C) alkyl, halogen, trifluoromethyl, trifluoromethoxy, haloalkyl, amino, cyano, aryl, hydroxy, carboxy, carbamoyl, sulfamoyl, NR_zR_a’、OR_z、C(O)N(R_z)R_a’、N(R_z)C(O)R_a’Or S (O)_yR_z(wherein y is 0, 1 or 2) wherein R_zAnd R_a’Each independently selected from H or (1-2C) alkyl;

(53) c is a single bond.

Suitably, a group of heteroaryl or heterocyclyl as defined herein is a group of monocyclic heteroaryl or heterocyclyl comprising one, two or three heteroatoms selected from N, O or S.

Suitably, heteroaryl is a 5-or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

Suitably, the heterocyclyl group is a 4-, 5-or 6-membered heterocyclyl comprising one, two or three heteroatoms selected from N, O or S. Most suitably, a heterocyclyl group is a 5-or 6-membered ring containing one, two or three heteroatoms selected from N, O or S [ e.g. morpholinyl (e.g. 4-morpholinyl), oxetane, methyloxetane (e.g. 3-methyloxetane), pyrrolidone (e.g. pyrrolidin-2-one) ].

The aryl group is suitably phenyl.

Suitably, the keys a and b are as defined in any of paragraphs (1) to (2) above. Suitably, keys a and b are as defined in paragraph (2) above.

Suitably, R_1aIs as defined in any one of paragraphs (3) to (9) above. Most suitably, R_1aIs cyano, methyl or fluoromethyl.

Suitably, R_1b、R_1c、R_1dAnd R_1eAs defined in paragraphs (10) and (11) above. Most suitably, R_1b、R_1c、R_1dAnd R_1eIs H.

Suitably, W is as defined in any of paragraphs (12) to (15) above. Most preferably, W is as defined in paragraph (15), i.e. it is-NH-SO₂-a group in which the NH group is linked to R_1aThe carbon atom to which it is attached.

Suitably, X₁Is as defined in any one of paragraphs (16) to (18) above. Most preferably, X₁As defined in paragraph (18).

Suitably, X₂Is as defined in any one of paragraphs (19) to (22) above. Most preferably, X₂As defined in paragraph (22).

Suitably, X₃Is as defined in any one of paragraphs (23) to (35) above. Most preferably, X₃As defined in paragraph (35).

Suitably, X₄As defined in any of paragraphs (36) to (39) above. Most preferably, X₄As defined in paragraph (39).

Suitably, X₅Is as defined in any one of paragraphs (40) to (43) above. Most preferably, X₅As defined in paragraph (43).

Suitably, X₆As defined in any of paragraphs (44) to (47) above. Most preferably, X₆As defined in paragraph (46).

Suitably, X₇As defined in any of paragraphs (48) to (52) above. Most preferably, X₇As defined in paragraph (52).

In embodiments of compounds of the invention, Het must contain at least one of C (═ O), C (═ NH), or C (═ S). Suitably, Het must contain at least one C (═ O).

In embodiments, the compound of the invention is not one of the following compounds:

(R) -N- (sec-butyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-7-sulfonamide;

(R) -N- (sec-butyl-phenyl) -2- (3, 4-difluorophenyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-7-sulfonamide;

4-chloro-N- (1-methylethyl) -6-quinolinesulfonamide;

4-chloro-N-methyl-N- (1-methylethyl) -6-quinolinesulfonamide;

4-chloro-6- (4- (cyclopropylamino) sulfonyl) -3-quinolinecarboxamide;

2-oxo-4-trifluoromethyl-1, 2-dihydroquinolinesulfonic acid isopropylformamide;

2-oxo-4-trifluoromethyl-1, 2-dihydroquinoline-sulfonic acid isopropylamide;

3- [ [ (2S) -2-cyano-1-pyrrolidinyl ] carbonyl ] -1,2,3, 4-tetrahydro-N- (1-methylethyl) -7-isoquinolinesulfonamide;

2-acetyl-1, 2,3, 4-tetrahydro-7- [ [ (1-methylethyl) amino ] sulfonyl ] - (methyl ester) -3(3S) -isoquinolinecarboxylic acid;

1,2,3, 4-tetrahydro-7- [ [ (1-methylethyl) amino ] sulfonyl ] -3(3S) -isoquinolinecarboxylic acid hydrochloride;

3, 4-dihydro-7- [ [ (1-methylethyl) amino ] sulfonyl ] -2- (1, 1-dimethylethyl) ester- (3S) -2,3- (1H) -isoquinolinedicarboxylic acid;

3- [ [ (2S) -2- (aminocarbonyl) -1-pyrrolidinyl ] carbonyl ] -7- [ [ (1-3-methylethyl) amino ] sulfonyl ] -3, 4-dihydro- (1-1-dimethylethyl) ester- (3S) -2(1H) -isoquinolinecarboxylic acid; or

3- [ [ (2S) -2-cyano-1-pyrrolidinyl ] carbonyl ] -3, 4-dihydro-7- [ [ 1-methylethyl) amino ] sulfonyl ] - (1, 1-dimethylethyl) ester- (3S) -2(1H) -isoquinolinecarboxylic acid.

In a particular group of compounds of the invention, c is a single bond, i.e. the compounds have the structural formula Ia (sub-definition of formula I) shown below:

wherein a, b, X₁、X₂、X₃、X₄、X₅、X₆、X₇、W、R_1a、R_1b、R_1c、R_1dAnd R_1eEach having any one of the meanings defined herein; or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

In an embodiment of the compound of formula Ia:

the bond a and the bond b are as defined in any of the above paragraphs (1) to (2).

R_1aIs as defined in any one of paragraphs (3) to (9) above;

R_1b、R_1c、R_1dand R_1eIs as defined in any of paragraphs (10) and (11) above.

W is as defined in any of paragraphs (12) to (15) above;

X₁is as defined in any one of paragraphs (16) to (18) above;

X₂is as defined in any one of paragraphs (19) to (22) above;

X₃is as defined in any one of paragraphs (23) to (35) above;

X₄is as defined in any one of paragraphs (36) to (39) above;

X₅is as defined in any one of paragraphs (40) to (43) above;

X₆is as defined in any of paragraphs (44) to (47) above; and

X₇as defined in any of paragraphs (48) to (52) above.

In an embodiment of the compound of formula Ia:

keys a and b being as defined in paragraph (2) above

R_1aIs as defined in paragraph (9) above;

R_1b、R_1c、R_1dand R_1eIs as defined in paragraph (11) above;

w is as defined in paragraph (15) above;

X₁is as defined in paragraph (18) above;

X₂is as defined in paragraph (22) above;

X₃is as defined in paragraph (35) above;

X₄is as defined in paragraph (39) above;

X₅is as defined in paragraph (43) above;

X₆is as defined in paragraph (46) above; and

X₇as defined in paragraph (52) above.

In a particular group of compounds of the invention, c is a single bond and W is-NH-S (O)₂-, i.e. the compound has the structural formula IIa (sub-definition of formula I) shown below:

wherein a, b, X₁、X₂、X₃、X₄、X₅、X₆、X₇、R_1a、R_1b、R_1c、R_1dAnd R_1eEach having any one of the meanings defined herein; or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

In the examples of compounds of formula IIa:

R_1aIs as defined in any one of paragraphs (3) to (9) above;

X₁Is as defined in any one of paragraphs (16) to (18) above;

X₂is as defined in any one of paragraphs (19) to (22) above;

X₃is as defined in any one of paragraphs (23) to (35) above;

X₄is as defined in any one of paragraphs (36) to (39) above;

X₅is as defined in any one of paragraphs (40) to (43) above;

X₆is as defined in any of paragraphs (44) to (47) above; and

X₇as defined in any of paragraphs (48) to (52) above.

In the examples of compounds of formula IIa:

keys a and b being as defined in paragraph (2) above

R_1aIs as defined in paragraph (9) above;

R_1b、R_1c、R_1dand R_1eIs as defined in paragraph (11) above;

X₁is as defined in paragraph (18) above;

X₂is as defined in paragraph (22) above;

X₃is as defined in paragraph (35) above;

X₄is as defined in paragraph (39) above;

X₅is as defined in paragraph (43) above;

X₆is as defined in paragraph (46) above; and

X₇as defined in paragraph (52) above.

In a particular group of compounds of the invention, c is a single bond, W is-NH-S (O)₂-and R_1b、R_1c、R_1dAnd R_1eIs H, i.e. the compound has the formulaStructural formula IIb (sub-definition of formula I):

wherein a, b, X₁、X₂、X₃、X₄、X₅、X₆、X₇And R_1aEach having any one of the meanings defined herein; or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

In the examples of compounds of formula IIb:

R_1aIs as defined in any one of paragraphs (3) to (9) above;

X₁is as defined in any one of paragraphs (16) to (18) above;

X₂is as defined in any one of paragraphs (19) to (22) above;

X₃is as defined in any one of paragraphs (23) to (35) above;

X₄is as defined in any one of paragraphs (36) to (39) above;

X₅is as defined in any one of paragraphs (40) to (43) above;

X₆is as defined in any of paragraphs (44) to (47) above; and

X₇as defined in any of paragraphs (48) to (52) above.

In the examples of compounds of formula IIb:

keys a and b are as defined in paragraph (2) above;

R_1ais as defined in paragraph (9) above;

X₁is as defined in paragraph (18) above;

X₂is as defined in paragraph (22) above;

X₃is as defined in paragraph (35) above;

X₄is as defined in paragraph (39) above;

X₅is as defined in paragraph (43) above;

X₆is as defined in paragraph (46) above; and

X₇as defined in paragraph (52) above.

In a particular group of compounds of the invention, c is a single bond, W is-NH-S (O)₂-，R_1b、R_1c、R_1dAnd R_1eIs H, and X₁Is CH, i.e., the compound has structural formula IIc (a sub-definition of formula I) as shown below:

wherein a, b, X₂、X₃、X₄、X₅、X₆、X₇And R_1aEach having any one of the meanings defined herein; or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

In the examples of compounds of formula IIc:

R_1aIs as defined in any one of paragraphs (3) to (9);

X₂is as defined in any of paragraphs (19) to (22) aboveAs defined in a paragraph;

X₃is as defined in any one of paragraphs (23) to (35) above;

X₄is as defined in any one of paragraphs (36) to (39) above;

X₅is as defined in any one of paragraphs (40) to (43) above;

X₆is as defined in any of paragraphs (44) to (47) above; and

X₇as defined in any one of paragraphs (48) to (52).

In the examples of compounds of formula IIc:

keys a and b are as defined in paragraph (2) above;

R_1ais as defined in paragraph (9) above;

X₂is as defined in paragraph (22) above;

X₃is as defined in paragraph (35) above;

X₄is as defined in paragraph (39) above;

X₅is as defined in paragraph (43) above;

X₆is as defined in paragraph (46) above; and

X₇as defined in paragraph (52).

In a particular group of compounds of the invention, W is-NH-S (O)₂-，R_1b、R_1c、R_1dAnd R_1eIs H, X₁Is CH, X₂Is CH, X₄Is C ═ O, and bond a is a single bond, i.e. the compound has structural formula IId (sub-definitions of formula I) as shown below:

wherein b and X₃、X₅、X₆、X₇And R_1aEach having any one of the meanings defined herein; or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

In the examples of compounds of formula IId:

R_1ais as defined in any one of paragraphs (3) to (9);

X₃is as defined in any one of paragraphs (23) to (35) above;

X₅is as defined in any one of paragraphs (40) to (43) above;

X₆is as defined in any of paragraphs (44) to (47) above; and

X₇as defined in any one of paragraphs (48) to (52).

In the examples of compounds of formula IId:

R_1ais as defined in paragraph (9) above;

X₃is as defined in paragraph (35) above;

X₅is as defined in paragraph (43) above;

X₆is as defined in paragraph (46) above; and

X₇as defined in paragraph (52).

In a particular group of compounds of the invention, HET is a compound of formula (III), (IV), (V), (VI), (VII), (VIII) or (IX):

wherein R is_5c、R_6c、R_5N、R_7C、R_6NAnd R_8NAs defined herein.

In another specific group of compounds of the invention, HET is a compound of formula (III), (IV), (V), (VI), (VII) or (VIII):

wherein R is_5N、R_7C、R_6NAnd R_8NAs defined herein.

In another specific group of compounds of the invention, HET is a compound of formula (III) or (V):

wherein R is_7C、R_6NAnd R_8NAs defined herein.

In another specific group of compounds of the invention, HET is a compound of formula (III):

wherein R is_6NAnd R_8NAs defined herein.

Particular compounds of the invention include any of the compounds exemplified herein, or a pharmaceutically acceptable salt or solvate thereof, and in particular any of the following:

n- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

1, 3-dimethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1, 3-dimethyl-2, 4-dioxo-quinazoline-6-sulfonamide;

1, 3-diethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1, 3-diethyl-2, 4-dioxo-quinazoline-6-sulfonamide;

3-ethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

1-benzyl-3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-ethyl-3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-benzyl-3-ethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 6-dichlorophenyl) methyl ] -3-ethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-ethyl-1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyclohexylmethyl) -3-ethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyclopropylmethyl) -3-ethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-ethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- (2-pyrrolidin-1-ylethyl) quinazoline-6-sulfonamide;

3-ethyl-1- (3-methoxypropyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-ethyl-1- (2-methoxyethyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-ethyl-N- (1-methylcyclopropyl) -1- (2-morpholinoethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- (cyclopropylmethyl) -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

4-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-1H-quinoxaline-6-sulfonamide;

1- (cyclopropylmethyl) -4-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-quinoxaline-6-sulfonamide;

1- (cyclopropylmethyl) -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-ethyl-1-isobutyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (2-methoxyethyl) -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [2- (dimethylamino) ethyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-isobutyl-3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-ethyl-2-isobutoxy-N- (1-methylcyclopropyl) -4-oxo-quinazoline-6-sulfonamide;

2-isobutoxy-3-methyl-N- (1-methylcyclopropyl) -4-oxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (3-pyridylmethyl) quinazoline-6-sulfonamide;

3- (cyanomethyl) -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (1-methylcyclopropyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2- [ (1-methylcyclopropyl) methoxy ] -4-oxo-quinazoline-6-sulfonamide;

1- (cyclohexylmethyl) -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (2-methylcyclopropyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 2-difluorocyclopropyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- (tetrahydrofuran-3-ylmethyl) quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- (tetrahydro-pyran-2-ylmethyl) quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1-prop-2-ynyl-quinazoline-6-sulfonamide;

1-benzyl-4-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-quinoxaline-6-sulfonamide;

4-methyl-2- (methylamino) -N- (1-methylcyclopropyl) -3-oxo-quinoxaline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (3-methyloxetan-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (2-cyclopropylethyl) -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

2- (2-cyclopropylethoxy) -3-methyl-N- (1-methylcyclopropyl) -4-oxo-quinazoline-6-sulfonamide;

1-allyl-3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyclopentylmethyl) -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3-prop-2-ynyl-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (1-methylimidazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- (tetrahydrofuran-2-ylmethyl) quinazoline-6-sulfonamide;

3- [ (2, 2-difluorocyclopropyl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

2, 3-dimethyl-N- (1-methylcyclopropyl) -4-oxo-quinazoline-6-sulfonamide;

2-methyl-N- (1-methylcyclopropyl) -4-oxo-3H-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (4-pyridylmethyl) quinazoline-6-sulfonamide;

2-cyclopropyl-N- (1-methylcyclopropyl) -4-oxo-3H-quinazoline-6-sulfonamide;

2-isopropyl-N- (1-methylcyclopropyl) -4-oxo-3H-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- (o-tolylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- (m-tolylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- (p-tolylmethyl) quinazoline-6-sulfonamide;

1- [ (2-methoxyphenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3-methoxyphenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (4-methoxyphenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2-chlorophenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3-chlorophenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (4-chlorophenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2-fluorophenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3-fluorophenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (4-fluorophenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2-cyanophenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3-cyanophenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (4-cyanophenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- [ [2- (trifluoromethyl) phenyl ] methyl ] quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- [ [3- (trifluoromethyl) phenyl ] methyl ] quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- [ [4- (trifluoromethyl) phenyl ] methyl ] quinazoline-6-sulfonamide;

1- [ (2, 6-dichlorophenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 6-difluorophenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3, 5-dichlorophenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3, 5-dimethylphenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3, 5-dimethoxyphenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3, 5-difluorophenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

2-cyclopropyl-3-methyl-N- (1-methylcyclopropyl) -4-oxo-quinazoline-6-sulfonamide;

2-isobutyl-3-methyl-N- (1-methylcyclopropyl) -4-oxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- (2-pyridylmethyl) quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- (3-pyridylmethyl) quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- (4-pyridylmethyl) quinazoline-6-sulfonamide;

2- [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] -N-phenyl-acetamide;

(2S) -1- [2- [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] acetyl ] pyrrolidine-2-carboxamide;

3- [2- (4-aminophenyl) -2-oxo-ethyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] methyl ] -1,2, 4-oxadiazole-5-carboxamide;

4- [ [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] methyl ] benzamide;

2- [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] -N- (1-methylpyrazol-4-yl) acetamide;

3- [2- (4-hydroxyphenyl) -2-oxoethyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

2- [ 3-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-1-yl ] -N-phenyl-acetamide;

3- [ [ 3-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] benzamide;

1- [ [3- (difluoromethyl) phenyl ] methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ [ 3-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] -1,2, 4-oxadiazole-5-carboxamide;

4- [ [ 3-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] benzamide;

3-methyl-N- (1-methylcyclopropyl) -4-oxo-2-phenyl-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -4-oxo-2-pyrrolidin-1-yl-3H-quinazoline-6-sulfonamide;

n-methyl-5- [ [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] methyl ] -1,2, 4-oxadiazole-3-carboxamide;

1- [ (4-cyano-3-fluoro-phenyl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n-methyl-5- [ [ 3-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] -1,2, 4-oxadiazole-3-carboxamide;

3- [2- (4-fluorophenyl) -2-oxoethyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (5-methylisoxazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (4-methylsulfonylphenyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (5-methylisoxazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

2- [ 3-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-1-yl ] -N- (1-methylpyrazol-4-yl) acetamide;

1- [2- (4-hydroxyphenyl) -2-oxoethyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (pyrazin-2-ylmethyl) quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [2- [4- (diethylamino) phenyl ] -2-oxoethyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (5-nitro-2-furyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3- (1H-benzoimidazol-2-ylmethyl) -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (1-methylimidazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- [ 2-oxo-2- (4-pyrrolidin-1-ylphenyl) ethyl ] quinazoline-6-sulfonamide;

3- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (1H-benzoimidazol-2-ylmethyl) -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- [ 2-oxo-2- (4-pyrrolidin-1-ylphenyl) ethyl ] quinazoline-6-sulfonamide;

n- [4- [ [ 3-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] phenyl ] acetamide;

1- [ (5-tert-butyl-1, 2, 4-oxadiazol-3-yl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (5-nitro-2-furyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (2-methylpyrazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- (pyrazin-2-ylmethyl) quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (2-methylpyrazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (4-fluorophenyl) methyl ] -N- (1-methylcyclopropyl) -2, 3-dioxo-4H-quinoxaline-6-sulfonamide;

1, 3-bis [ (3, 5-dimethylisoxazol-4-yl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (4-fluorophenyl) methyl ] -4-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-quinoxaline-6-sulfonamide;

n- (3-hydroxypropyl) -4- [ [ 3-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] benzamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- [ (1S) -1-phenylethyl ] quinazoline-6-sulfonamide;

1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (2-methyl-4-phenyl-thiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2-bromothiazol-5-yl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-but-2-ynyl-3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1-pent-2-ynyl-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- [ [4- (piperazine-1-carbonyl) phenyl ] methyl ] quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (1S) -1-methylpropan-2-ynyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (1R) -1-methylpropan-2-ynyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ (2-bromothiazol-5-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ (2, 4-dimethylthiazol-5-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- (thiazol-5-ylmethyl) quinazoline-6-sulfonamide;

3- [ (2-chlorothiazol-5-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2-chlorothiazol-5-yl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- (thiazol-2-ylmethyl) quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (thiazol-5-ylmethyl) quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- (thiazol-4-ylmethyl) quinazoline-6-sulfonamide;

1- [ (5-tert-butyl-2-methyl-pyrazol-3-yl) methyl ] -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (4-methylthiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (1-methylpyrazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -1- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (thiadiazol-4-ylmethyl) quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylimidazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyclopropylmethyl) -N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

2- (cyclopropylmethoxy) -N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -4-oxo-quinazoline-6-sulfonamide;

1- (cyclopropylmethyl) -3- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-1-prop-2-ynyl-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (5-methyl-1, 3, 4-oxadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1-prop-2-ynyl-quinazoline-6-sulfonamide;

1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

2- [ (2, 5-dimethylpyrazol-3-yl) methoxy ] -N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -4-oxo-quinazoline-6-sulfonamide;

3- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -2- [ (2, 5-dimethylpyrazol-3-yl) methoxy ] -N- (1-methylcyclopropyl) -4-oxo-quinazoline-6-sulfonamide;

3- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -1- [ (4-fluorophenyl) methyl ] -N- (1-methylcyclopropyl) - -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -1- [ (3-methoxyphenyl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (4-fluorophenyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3-methoxyphenyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyclopropylmethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyanomethyl) -3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (4-fluorophenyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3-methoxyphenyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1-prop-2-ynyl-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ [ 2-methyl-4- (trifluoromethyl) thiazol-5-yl ] methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ (1-ethylpyrazol-4-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- (2-morpholino-2-oxoethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (1H-pyrazol-4-ylmethyl) quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- [ [ (2S) -5-oxopyrrolidin-2-yl ] methyl ] quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- [ [ (2R) -5-oxopyrrolidin-2-yl ] methyl ] quinazoline-6-sulfonamide;

3- (cyanomethyl) -1- [ (4-fluorophenyl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- (cyanomethyl) -1- [ (3-methoxyphenyl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (4-methyloxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ (2, 4-dimethyloxazol-5-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methyl-1, 2, 4-oxadiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (4-methylthiodiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3- (cyanomethyl) -1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- (cyanomethyl) -1- (cyclopropylmethyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- (cyanomethyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1-prop-2-ynyl-quinazoline-6-sulfonamide

1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methyl-1H-pyrazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [ [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] methyl ] acetamide

1- (cyclopropylmethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1-prop-2-ynyl-quinazoline-6-sulfonamide;

1- [ (4-fluorophenyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3-methoxyphenyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n-cyclopropyl-1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -3-methyl-2, 4-dioxo-quinazoline-6-sulfonamide;

n-tert-butyl-1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -3-methyl-2, 4-dioxo-quinazoline-6-sulfonamide;

2- [4- [ [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] methyl ] pyrazol-1-yl ] acetamide;

n- (1-cyanocyclopropyl) -1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -3-methyl-2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-pyrido [2,3-d ] pyrimidine-6-sulfonamide;

1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -3-methyl-N- (2-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -1, 3-bis [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

4-chloro-N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxoquinazoline-6-sulfonamide;

7-fluoro-3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

3- [ [1- [ (4-methoxyphenyl) methyl ] pyrazol-4-yl ] methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -7-fluoro-3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

tert-butyl N- [5- [ [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] methyl ] thiazol-2-yl ] carbamate;

3- [ (1-benzylpyrazol-4-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- [ (1-prop-2-ynylpyrazol-4-yl) methyl ] quinazoline-6-sulfonamide;

3- [ [1- (cyanomethyl) pyrazol-4-yl ] methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ [1- (cyclopropylmethyl) pyrazol-4-yl ] methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ [1- [2- (dimethylamino) ethyl ] pyrazol-4-yl ] methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

3- (cyanomethyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

2- [6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-1H-quinazolin-3-yl ] acetamide;

7-fluoro-1, 3-dimethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

8-fluoro-1, 3-dimethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- (isoxazol-5-ylmethyl) -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-chloro-3-methyl-N- (1-methylcyclopropyl) -4-oxo-phthalazine-6-sulfonamide;

n- (1-cyanocyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1-methyl-3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ [ 2-methyl-5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -1- [ [ 2-methyl-5- (trifluoromethyl) pyrazol-3-yl ] methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ (2-aminothiazol-5-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ (3-aminoisoxazol-5-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3-methyl-1- (methylamino) -N- (1-methylcyclopropyl) -4-oxo-phthalazine-6-sulfonamide;

1- [2- (dimethylamino) ethyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -1- [ (1-methyl-3-piperidinyl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [3- (dimethylamino) propyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -1- [ (1-methyl-2-piperidinyl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (3-methoxypropyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3-cyclopropyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

3-cyclopropyl-1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (methylamino) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- [ [3- (trifluoromethyl) isoxazol-5-yl ] methyl ] quinazoline-6-sulfonamide;

1- [2- (dimethylamino) ethyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [3- (dimethylamino) propyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (2-pyrrolidin-1-ylethyl) quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (1-methylpyrrolidin-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [3- (methylamino) propyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (3-methoxypropyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (3-methyl-1, 2, 4-oxadiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [2- (dimethylamino) ethylamino ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

tert-butyl N- [2- [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] ethyl ] carbamate;

4- (4-fluorophenyl) -2-methyl-N- (1-methylcyclopropyl) -1-oxo-isoquinoline-7-sulfonamide;

4-methyl-N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydro-pyran-2-ylmethyl) quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydrofuran-2-ylmethyl) quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydrofuran-3-ylmethyl) quinazoline-6-sulfonamide;

n-cyclopropyl-1-methyl-3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-ethylcyclopropyl) -1-methyl-3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-chloro-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

1- (2-aminoethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- [3- (trifluoromethoxy) propyl ] quinazoline-6-sulfonamide;

n, N-dimethyl-2- [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] acetamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (tetrahydro-pyran-2-ylmethyl) quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (tetrahydrofuran-2-ylmethyl) quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (tetrahydrofuran-3-ylmethyl) quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydro-pyran-4-ylmethyl) quinazoline-6-sulfonamide;

1- (2-methoxyethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (2-morpholinoethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (2-pyrrolidin-1-ylethyl) quinazoline-6-sulfonamide;

3- [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] propionamide;

1- (2-methoxyethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (1-methyl-2-piperidinyl) methyl ] - -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- (2-morpholinoethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] propionamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- [2- (1-piperidinyl) ethyl ] quinazoline-6-sulfonamide;

1- (cyclopentylmethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyclohexylmethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyclobutylmethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (dimethylamino) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

1- [3- (dimethylamino) prop-1-ynyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

3- [ (3-aminoisoxazol-5-yl) methyl ] -1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

4- [3- (dimethylamino) prop-1-ynyl ] -N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide;

4- [3- (dimethylamino) propyl ] -N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide;

1- (cyclobutylmethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyclopentylmethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyclohexylmethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-ethyl-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-isopropyl-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

2-isopropoxy-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -4-oxo-quinazoline-6-sulphonamide;

n- (1-methylcyclopropyl) -1- [ (3-methyloxetan-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-isobutyl-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (2-cyclopropylethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (oxetan-3-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-benzyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- [ (5-oxopyrrolidin-2-yl) methyl ] quinazoline-6-sulfonamide;

6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-1-carboxylic acid methyl ester;

6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-1-carboxylic acid;

n-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-1-carboxamide;

1-ethyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- (oxetan-3-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-1- (tetrahydropyran-4-ylamino) phthalazine-6-sulfonamide;

4-bromo-N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-1- (tetrahydropyran-4-ylmethyl) phthalazine-6-sulfonamide;

1-cyclopentyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

1-isopropyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

4- (cyclopropanecarbonyl) -N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide;

1-methoxy-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

1-cyclopropyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

1- (cyclohexylmethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

1- [ (3-methoxyphenyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

1-ethoxy-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- (oxetan-3-yloxy) -4-oxo-phthalazine-6-sulfonamide;

1- (cyclopropylmethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

1- (cyclobutoxy) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

1- (cyclobutylmethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (tetrahydro-pyran-4-ylmethyl) quinazoline-6-sulfonamide;

4- [ (4-fluorophenyl) methyl ] -N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide;

1-acetonyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (2, 2-difluoroethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (2,2, 2-trifluoroethyl) quinazoline-6-sulfonamide;

n, N-dimethyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-1-carboxamide;

6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -N- (oxetan-3-yl) -4-oxo-phthalazine-1-carboxamide;

n- (1-methylcyclopropyl) -1, 3-bis [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 2-difluoro-1-methyl-cyclopropyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-N- (tetrahydropyran-4-ylmethyl) phthalazine-1-carboxamide;

ethyl 2- [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] acetate;

6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -N- [ (1-methyl-4-piperidinyl) methyl ] -4-oxo-phthalazine-1-carboxamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- [2- (2-oxopyrrolidin-1-yl) ethyl ] quinazoline-6-sulfonamide;

ethyl 2-fluoro-2- [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] acetate;

n- (1-cyanocyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

1- (2-hydroxyethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (2-hydroxypropyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- (oxetan-3-yl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ [3- (hydroxymethyl) oxetan-3-yl ] methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [2- (4-methylpiperazin-1-yl) ethyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [3- (4-methylpiperazin-1-yl) propyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (oxetan-2-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- (cyclopropylmethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1-ethyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3-fluorooxetan-3-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- (oxetan-2-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3-fluorooxetan-3-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (4, 4-dimethyloxetan-2-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (4, 4-dimethyloxetan-2-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-ethyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

n- (1-cyanocyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (oxetan-3-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1-prop-2-ynyl-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- (cyanomethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- (2-methoxyethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- [ (4-fluorophenyl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- [ (3-methylisoxazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (3-hydroxy-3-methyl-butyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (1-methylpyrrolidin-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- (2-methylsulfanylethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3, 3-difluorocyclobutyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 2-difluorocyclopropyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] azetidine-1-carboxylic acid tert-butyl ester;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (2-methylsulfanylethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-acetonyl-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (3-hydroxy-3-methyl-butyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (2-methylsulfinylethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (2-methylsulfonylethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (1-methyl-4-piperidinyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -1- [ (1-methyl-4-piperidinyl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (2-oxo-2-pyrrolidin-1-yl-ethyl) quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] - -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- [ (3-methyloxetan-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydrofuran-3-ylmethyl) quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1, 3-bis [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -1- [ (3-methylisoxazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydrothiopyran-4-ylmethyl) quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (tetrahydrothiopyran-4-ylmethyl) quinazoline-6-sulfonamide;

1- [ (1, 1-dioxothiadin-4-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (1, 1-dioxothiadin-4-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

7-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

7-fluoro-1-methyl-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -7-fluoro-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

1- (cyclopropylmethyl) -7-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-ethyl-7-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

7-fluoro-1- [ (4-fluorophenyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

7-fluoro-N- (1-methylcyclopropyl) -1- [ (3-methylisoxazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -7-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

7-fluoro-N- (1-methylcyclopropyl) -1, 3-bis [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

7-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (oxetan-3-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

7-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydrofuran-3-ylmethyl) quinazoline-6-sulfonamide;

1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -7-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

7-fluoro-N- (1-methylcyclopropyl) -2- [ (3-methyloxetan-3-yl) methoxy ] -3- [ (1-methylpyrazol-4-yl) methyl ] -4-oxo-quinazoline-6-sulfonamide;

7-fluoro-N- (1-methylcyclopropyl) -1- [ (3-methyloxetan-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- (cyclopropylmethyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- [ (3-methylisoxazol-5-yl) methyl ] -3- [ (2-methylthiazol-5-yl) methyl ] - -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -3- [ (2-methylthiazol-5-yl) methyl ] - -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- [ (4-fluorophenyl) methyl ] -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1-prop-2-ynyl-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -7-fluoro-1- [ (3-methylisoxazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (4, 4-difluorocyclohexyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] - -2, 4-dioxo-quinazoline-6-sulfonamide;

n, N-dimethyl-3- [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] propionamide;

1- (3-hydroxypropyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1-methyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] azetidine-1-carboxylic acid tert-butyl ester;

1- (2-fluoroethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (2-fluoroethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- [ (3-oxocyclobutyl) methyl ] quinazoline-6-sulfonamide;

1- (2-methoxy-2-methyl-propyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [2- (azetidin-1-yl) -2-oxoethyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (azetidin-3-ylmethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

1- (cyclopropylmethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (5-methyl-3-pyridyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (4-fluorophenyl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (1-cyanocyclopropyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- [ (4-oxocyclohexyl) methyl ] quinazoline-6-sulfonamide;

8-bromo-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (6-methyl-3-pyridyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxamide;

1- [ (1-formylazetidin-3-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyclopropylmethyl) -3-methyl-N- (1-methylcyclopropyl) -2-oxo-quinoline-6-sulfonamide;

n- (1-ethynylcyclopropyl) -1-methyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [ [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazolin-8-yl ] methyl ] acetamide;

8- [3- (dimethylamino) prop-1-ynyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

n- (1-ethynylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

1- (cyclopropylmethyl) -N- (1-ethynylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (2-methylpyrimidin-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (pyrazolo [1,5- α ] pyridin-3-ylmethyl) quinazoline-6-sulfonamide;

1- [ (2, 2-difluorocyclopropyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3, 3-difluorocyclobutyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-ethyl-N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyanomethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1-prop-2-ynyl-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (3-methylisoxazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydropyran-4-ylmethyl) quinazoline-6-sulfonamide;

1- [ (2, 2-difluorocyclopropyl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3, 3-difluorocyclobutyl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (oxetan-3-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (pyridazin-4-ylmethyl) quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -1, 3-dioxo-benzo [ de ] isoquinoline-5-sulfonamide;

6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxylic acid methyl ester;

n, N-dimethyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxamide;

n-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxamide;

N-methoxy-N-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxamide;

1- (2-cyano-2-methyl-propyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (2-fluoro-2-methyl-propyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -2- [ (1-methylpyrazol-4-yl) methyl ] -1, 3-dioxo-benzo [ de ] isoquinoline-5-sulfonamide;

n- (1-cyanocyclopropyl) -1-ethyl-3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (difluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- [ (1-methylpyrazol-4-yl) methyl ] -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyclopropylmethyl) -N- [1- (difluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (difluoromethyl) cyclopropyl ] -1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (difluoromethyl) cyclopropyl ] -1- [ (4-fluorophenyl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyclobutylmethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- (2-methoxyethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1, 3-dioxo-benzo [ de ] isoquinoline-5-sulfonamide;

1- (2, 2-dimethylpropyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2S) -2-methylbutyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (1-methylcyclobutyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

2- [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] acetic acid ethyl ester

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (2-oxobutyl) quinazoline-6-sulfonamide;

1- (2-ethylbutyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (1-methoxycyclopentyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-isopentyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (1-isopropylpyrazol-4-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxoquinazoline-6-sulfonamide;

1 isohexyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (2-oxo-2-pyrrolidin-1-yl-ethyl) quinazoline-6-sulfonamide;

n, N-dimethyl-2- [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] acetamide;

1- [ (3, 3-dimethylcyclobutyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3, 3-dimethylcyclobutyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-formylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

n-tert-butyl-1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- (oxetan-3-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

8-bromo-1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -8- (1-methylpyrazol-4-yl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-chloro-N- (1-methylcyclopropyl) isoquinoline-7-sulfonamide;

1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-N- [1- (trifluoromethyl) cyclopropyl ] quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxo-1H-quinoline-6-sulfonamide

3-bromo-N- (1-methylcyclopropyl) -2-oxo-1H-quinoline-6-sulfonamide;

3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-N- [1- (trideuteromethyl) cyclopropyl ] -1H-quinazoline-6-sulfonamide;

1-methyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-N- [1- (trideuteromethyl) cyclopropyl ] quinazoline-6-sulfonamide;

1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-N- [1- (trideuteromethyl) cyclopropyl ] quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxoquinoline-6-sulfonamide;

1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxo-quinoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -8- (5-methyl-2-thienyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- (isothiazol-4-ylmethyl) -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -2, 4-dioxo-3- [2- (2-pyridyl) ethyl ] -1H-quinazoline-6-sulfonamide;

3- (2-cyanoethyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

3- (2-cyanoethyl) -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- [2- (2-pyridyl) ethyl ] quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (4-methyl-1, 2, 4-triazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- [ [5- (trifluoromethyl) -1,3, 4-oxadiazol-2-yl ] methyl ] quinazoline-6-sulfonamide;

1- (cyanomethyl) -N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyanomethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3- (3-furylmethyl) -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxoquinazoline-6-sulfonamide;

3- (1H-imidazol-4-ylmethyl) -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (5-methylisoxazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ (1-isopropylpyrazol-4-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (1-methyltetrazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

3- [ (4-isopropylthiadiazol-5-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

3- (isothiazol-5-ylmethyl) -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -3- [ (4-methyl-1, 2, 5-oxadiazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- (isoxazol-5-ylmethyl) -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1-methyl-3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1-methyl-3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

1- (cyclopropylmethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (4-fluorophenyl) methyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-ethyl-N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1, 3-bis [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- (oxetan-3-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyanomethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (tetrahydrofuran-3-ylmethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- (3-methoxypropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (2-fluoroethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- (2-methoxyethyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxoquinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- [ 2-oxo-2- (4-pyridinyl) ethyl ] quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- [ 2-oxo-2- (2-thienyl) ethyl ] quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3-phenacyl-quinazoline-6-sulfonamide;

3- [2- (4-cyanophenyl) -2-oxoethyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1-prop-2-ynyl-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1-methyl-3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-3- (thiazol-5-ylmethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1-propyl-quinazoline-6-sulfonamide;

1-butyl-N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (5-methyl-2-pyridinyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (6-cyano-2-pyridyl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (5-methyl-3-pyridinyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (6-fluoro-2-pyridyl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (2-methyl-4-pyridinyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (3-fluoro-2-pyridyl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (4-cyanophenyl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (2-fluoroethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 5-dimethyl-1, 2, 4-triazol-3-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (2-methyloxazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1-isobutyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (2-methylthiazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (4-methyl-1, 2, 4-triazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (1-methyl-1, 2, 4-triazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 5-dimethyl-1, 2, 4-triazol-3-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (5-methyl-1, 3, 4-oxadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (2-methyl-1, 2, 4-triazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- (oxazol-4-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (2-pyrazol-1-ylethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (3-methyl-1H-pyrazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (2-methyl-1, 2, 4-triazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (thiazol-5-ylmethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (oxazol-5-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (1-methylimidazol-2-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- [2- (2-pyridyl) ethyl ] quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (5-methyl-1, 3, 4-oxadiazol-2-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (2-methyl-1H-imidazol-4-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (5-methylpyrazin-2-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ [1- (hydroxymethyl) cyclopropyl ] methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (4-methyl-2-pyridinyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (4-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (6-methyl-3-pyridinyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (2-cyanoethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- (1H-imidazol-4-ylmethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (3-ethylimidazo-1-4-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- (isothiazol-4-ylmethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- (isothiazol-5-ylmethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (5-methylisoxazol-4-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (2-methyloxazol-4-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (thiazol-4-ylmethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (2-methylthiazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (4-methyl-1, 2, 4-triazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- (isoxazol-5-ylmethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (1H-pyrazol-3-ylmethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (1H-1,2, 4-triazol-3-ylmethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (3-methylimidazol-4-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (1,3, 4-thiadiazol-2-ylmethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (1H-pyrazol-4-ylmethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (3-methylisothiazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (3-methyl-1H-1, 2, 4-triazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (1-methyltriazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1, 3-bis [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (2-methyltriazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1-propyl-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydrofuran-3-ylmethyl) quinazoline-6-sulfonamide;

1- (2, 2-difluoroethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (2, 2-difluoroethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

1-ethyl-N- [1- (fluoromethyl) cyclopropyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (difluoromethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (difluoromethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (difluoromethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (oxazol-4-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (cyclopentylmethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- (3-methylbut-2-enyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (4-pyridylmethyl) quinazoline-6-sulfonamide;

1- [2- (diethylamino) ethyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- (2-ethoxyethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1-isopentyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-ethyl-N- (1-methylcyclopropyl) -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-butyl-N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [2- (2-methoxyethoxy) ethyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydrofuran-2-ylmethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (2-oxobutyl) quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (2,2, 2-trifluoroethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (2,2, 2-trifluoroethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (2,2, 2-trifluoroethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-3- (1,3, 4-thiadiazol-2-ylmethyl) quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1-methyl-3- [ (3-methylisothiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1-methyl-3- [ (2-methyltriazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (1,3, 4-thiadiazol-2-ylmethyl) quinazoline-6-sulfonamide;

3- [ (5-ethyl-1, 3, 4-thiadiazol-2-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide;

1- (2-fluoroethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (1-methylpyrazol-4-yl) methyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- [1- (fluoromethyl) cyclopropyl ] -1- [ (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

or a pharmaceutically acceptable salt or solvate thereof.

The various functional groups and substituents that make up the compound of formula I are generally selected so that the molecular weight of the compound of formula I does not exceed 1000. More typically, the molecular weight of the compound will be less than 900, such as less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, and is, for example, 550 or less.

Suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, acid-addition salts of the compounds of the invention which are sufficiently basic, for example acid-addition salts with, for example, inorganic or organic acids, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, formic, citramethanesulfonic or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of the invention which are sufficiently acidic are alkali metal salts, for example sodium or potassium salts, alkaline earth metal salts, for example calcium or magnesium salts, ammonium salts or salts with organic bases which provide a pharmaceutically acceptable cation, for example salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.

Compounds having the same molecular formula but differing in the nature or order of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers". The term "stereoisomers" is an isomer whose atoms differ in their spatial arrangement. Stereoisomers that are not mirror images of each other are referred to as "diastereomers" and stereoisomers that are not non-superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric centers and are described and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) -isomers, respectively) by the R-and S-sequencing rules of Cahn and Prelog, or by methods in which molecules rotate the plane of polarized light. The chiral compound may exist as a single enantiomer or a mixture thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures".

The compounds of the invention may have one or more asymmetric centers; thus, such compounds may be produced as individual (R) -or (S) -stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers as well as racemic or other mixtures thereof. Methods for stereochemical determination and separation of stereoisomers are well known in the art (see discission in Chapter 4of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York,2001[ "discussion of Chapter 4 in Advanced Organic Chemistry", 4th edition, J. March, John Willi's parent publishing Co., New York,2001 ]) for example by synthesis from optically active starting materials or by resolution of racemic forms. Some of the compounds of the present invention may have geometric isomeric centers (E-and Z-isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof having activity against malignant cell proliferation.

The invention also encompasses compounds of the invention as defined herein comprising one or more isotopic substitutions. For example, H may be in any isotopic form, including¹H、²H, (D) and³h (T); c may be in any isotopic form, including¹²C、¹³C and¹⁴c; and O may be in any isotopic form, including¹⁶O and¹⁸o; and so on.

It will also be appreciated that certain compounds of formula I can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the present invention encompasses all such solvated forms which have activity against proliferation of malignant cells.

It is also understood that certain compounds of formula I may exhibit polymorphism, and that the present invention encompasses all such forms having activity against malignant cell proliferation.

The compounds of formula I can exist in many different tautomeric forms and reference to the compounds of formula I includes all such forms. For the avoidance of doubt, when a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, the compound of formula I still includes all other forms. Examples of tautomeric forms include keto, enol and enolate forms, as in, for example, the following tautomeric pairs: keto/enol (shown below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thione/enethiol, and nitro/acid nitro.

The compounds of formula I containing amine functionality may also form N-oxides. The compounds of formula I comprising amine functional groups mentioned herein also include N-oxides. When a compound contains several amine functional groups, one or more than one nitrogen atom may be oxidized to form an N-oxide. Specific examples of N-oxides are tertiary amines containing nitrogen heterocycles or N-oxides of nitrogen atoms. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, e.g., Advanced Organic Chemistry, Jerry March,4^thEdition, WileyInterscience, pages [ advanced organic chemistry, Jerry March Edition, 4th Edition, Willi International science, Inc. ]]. More specifically, the N-oxide can be obtained by the L.W.Deady program (Syn.Comm.1977,7,509-]) In which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as methylene chloride.

The compounds of formula I can be administered in the form of pro-drugs which break down in the human or animal body to release the compounds of the invention. Prodrugs can be used to alter the physical and/or pharmacokinetic properties of the compounds of the invention. Prodrugs can be formed when the compounds of the invention contain suitable groups or substituents to which a modifying group (property modifying group) can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that may be formed at a carboxyl group or a hydroxyl group in a compound of formula I and in vivo cleavable amide derivatives that may be formed at a carboxyl group or an amino group in a compound of formula I.

The present invention therefore includes those compounds of formula I as defined above when obtainable by organic synthesis and when obtainable in the human or animal body by means of cleavage of a prodrug thereof. The invention therefore includes those compounds of formula I which are produced by organic synthetic means, and also those compounds which are produced in the human or animal body by means of metabolic precursor compounds, i.e. compounds of formula I which may be synthetically produced compounds or metabolically produced compounds.

Suitable pharmaceutically acceptable prodrugs of compounds of formula I are those which are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity, based on sound medical judgment.

For example, various forms of prodrugs have been described in the following documents:

a)Methods in Enzymology,Vol.42p.309-396, edited by K.Widder, et al (Academic Press, 1985); [ methods in enzymology, Vol.42, p.309-396, edited by K.Widder et al, academic Press,1985]

b) Design of Pro drugs, edited by H. Bundgaard, (Elsevier, 1985); [ prodrug design, edited by H.Bundgaard, Escherzel, 1985 ]

c) A Textbook of Drug Design and Development, edited by Krogsgaard Larsen and H.Bundgaard, Chapter 5 "Design and Application of Pro drivers", by H.Bundgaardp.113-191 (1991); [ textbook for drug design and development, edited by Krogsgaard Larsen and H.Bundgaard, Chapter 5, "design and application of prodrug", edited by H.Bundgaard, pp.113-191, 1991 ]

d)H.Bundgaard,Advanced Drug Delivery Reviews,81-38 (1992); [ H. -Bundgaard, reviews on advanced drug delivery, 8, 1-38, 1992]

e)H.Bundgaard,et al.,Journal of Pharmaceutical Sciences,77285 (1988); bundgaard et al, journal of pharmaceutical sciences 77, 285, 1988]

f)N.Kakeya,et al.,Chem.Pharm.Bull.,32692 (1984); kakeya et al, chemical and pharmaceutical bulletin, 32, 692, 1984]

g) T.higuchi and v.stella, "Pro Drugs as Novel Delivery Systems", a.c.s.symposium Series, Volume 14; [ T.Higuchi and V.Stella, "prodrugs as novel delivery System", A.C.S. seminar series, Vol.14 ] and

h) roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press,1987.[ E.Roche editor, "Bioreversible vectors in Drug Design", Pegman Press,1987 ]

Suitable pharmaceutically acceptable prodrugs of compounds of formula I, which prodrugs have a carboxyl group, are, for example, in vivo cleavable esters thereof. In vivo cleavable esters of compounds of formula I comprising a carboxyl group are pharmaceutically acceptable esters which are cleaved, for example in the human or animal body, to yield the parent acid. Suitable pharmaceutically acceptable esters of carboxy include C_1-6Alkyl esters, e.g. methyl, ethyl and tert-butyl, C_1-6Alkoxymethyl esters, e.g. methoxymethyl ester, C_1-6Alkanoyloxymethyl esters, e.g. pivaloyloxymethyl ester, 3-phthalidyl ester, C_3-8Cycloalkyl carbonyloxy-C_1-6Alkyl esters, e.g. cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-1, 3-dioxolan-enyl (dioxolanyl) methyl esters, e.g. 5-methyl-2-oxo-1, 3-dioxolan-4-ylmethyl ester and C_1-6alkoxy-carbonyloxy-C_1-6Alkyl esters such as methoxycarbonyloxymethyl ester and 1-methoxycarbonyloxyethyl ester.

Suitable pharmaceutically acceptable salts of compounds of formula IProdrugs, which have a hydroxyl group, are, for example, esters or ethers thereof which are cleavable in vivo. An in vivo cleavable ester or ether of a compound of formula I comprising a hydroxy group is a pharmaceutically acceptable ester or ether which is cleaved, for example in the human or animal body, to yield the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include inorganic esters such as phosphate esters (including phosphoramide). Other suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include: c_1-10Alkanoyl radicals such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl radicals, C_1-10Alkoxycarbonyl radicals, e.g. ethoxycarbonyl, N- (C)_1-6)₂Carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl include: aminomethyl, N-alkylaminomethyl, N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C)_1-4Alkyl) piperazin-1-ylmethyl suitable pharmaceutically acceptable ether forming groups for the hydroxy group include α -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

Suitable pharmaceutically acceptable prodrugs of compounds of formula I, which prodrugs have a carboxyl group, are, for example, amides which are cleavable in vivo, for example by amines (e.g. ammonia, C)_1-4Alkylamines, e.g. methylamine, (C)_1-4Alkyl radical)₂Amines, e.g. dimethylamine, N-ethyl-N-methylamine or diethylamine, C_1-4alkoxy-C_2-4Alkylamines, e.g. 2-methoxyethylamine, phenyl-C_1-4Amides of alkylamines such as benzylamine and amino acids such as glycine or esters thereof.

Suitable pharmaceutically acceptable prodrugs of compounds of formula I, which prodrugs have an amino group, are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides from amino groups include, for example, with C_1-10Alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Cycloning of phenylacetyl and benzoylExamples of substituents include: aminomethyl, N-alkylaminomethyl, N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C)_1-4Alkyl) piperazin-1-ylmethyl.

The in vivo effect of the compound of formula I may be effected in part by one or more metabolites formed in the human or animal body following administration of the compound of formula I. As mentioned above, the in vivo effect of the compounds of formula I may also be effected by means of metabolism of the precursor compounds (prodrugs).

Although the invention may relate to any compound or specific group of compounds defined by optional, preferred or appropriate features or in other ways with respect to specific embodiments, the invention may also relate to compounds or specific groups of compounds that specifically exclude said optional, preferred or appropriate features or specific embodiments.

Suitably, the present invention excludes any individual compound which does not possess the biological activity defined herein.

Synthesis of

The compounds of the present invention may be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

In the description of the synthetic methods described herein, as well as in any reference synthetic methods for preparing starting materials, it is understood that one skilled in the art may select all proposed reaction conditions, including selection of solvents, reaction atmospheres, reaction temperatures, experimental durations, and work-up procedures.

It will be understood by those skilled in the art of organic synthesis that the functionality present on each moiety of the molecule must be compatible with the reagents and reaction conditions used.

It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups from undesirable reactions. The skilled chemist will understand when such protection is required and how these protecting groups can be put in place and subsequently removed.

For examples of protecting Groups, see one of the many general texts on the subject, e.g., "Protective Groups in Organic Synthesis" (publishers: John Wiley & Sons) [ protecting Groups in Organic Synthesis (publishers: John Wiley International publishing Co.) ] by Theodora-Green. The protecting group may be removed by any convenient method described in the literature or known to the skilled chemist which is suitable for removing the protecting group in question, selected so as to effect removal of the protecting group with minimal perturbation of the group elsewhere in the molecule.

Thus, if a reactant includes, for example, a group, such as an amino, carboxyl, or hydroxyl group, it may be desirable to protect that group in some of the reactions mentioned herein.

Suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, for example alkanoyl groups such as acetyl, alkoxycarbonyl groups, for example methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl groups, arylmethoxycarbonyl groups, for example benzyloxycarbonyl, or aroyl groups, for example benzoyl. The conditions for deprotection of the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or alkoxycarbonyl groups or aroyl groups may be removed by hydrolysis with a suitable base such as an alkali metal hydroxide, e.g. lithium hydroxide or sodium hydroxide and the like. Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-carbon, or by treatment with a lewis acid such as boron tris (trifluoroacetate). Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines, for example dimethylaminopropylamine, or with hydrazine.

Suitable protecting groups for hydroxyl groups are, for example, acyl groups, for example alkanoyl groups such as acetyl, aroyl groups, for example benzoyl, or arylmethyl groups, for example benzyl. The conditions for deprotection of the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or aroyl groups may be removed by hydrolysis with a suitable base such as an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed, for example, by hydrogenation over a catalyst such as palladium-carbon.

Suitable protecting groups for the carboxyl group are, for example, esterification groups, such as methyl or ethyl groups which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or tert-butyl groups which can be removed, for example, by treatment with an acid (such as an organic acid like trifluoroacetic acid), or benzyl groups which can be removed, for example, by hydrogenation over a catalyst such as palladium-carbon.

Resins may also be used as protecting groups.

Methods for synthesizing compounds of formula I will be according to X₁、X₂、X₃、X₄、X₅、X₆、X₇、W、R_1a、R_1b、R_1c、R_1dAnd R_1eAnd the nature of any substituents associated therewith. Suitable methods for their preparation are further described in the accompanying examples.

Once the compound of formula I is synthesized by any of the methods defined herein, the method may then further comprise the additional step of:

(i) removing any protecting groups present;

(ii) converting the compound of formula I into another compound of formula I;

(iii) to form a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or

(iv) Forming a prodrug thereof.

Examples of (ii) above are when a compound of formula I is synthesized, and then X₁、X₂、X₃、X₄、X₅、X₆、X₇、W、R_1a、R_1b、R_1c、R_1dAnd R_1eMay be further reacted to alter the nature of the group and provide alternative compounds of formula I. For example, the compound may be reacted to react R₁To a substituent other than hydrogen.

The resulting compound of formula I can be isolated and purified using techniques well known in the art.

In one aspect of the invention, a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, may be synthesized by any one of the following methods:

a) reacting a compound of formula a:

wherein X₁、X₂、X₃And HET is as defined above, and LG_AIs a suitable leaving group;

reaction with a compound of formula B:

wherein R is_1a、R_1b、R_1c、R_1d、R_1eAnd c is as defined above;

b) reacting a compound of formula C:

wherein X₁、X₂、X₃、X₄、X₅、W、R_1a、R_1b、R_1c、R_1d、R_1eA and c are as defined above;

reaction with a compound of formula D:

R_8N-L

formula D

Wherein R is_8NIs as defined above, and L is a suitable leaving group (e.g., halogen, OMs, hydroxy);

c) reacting a compound of formula E:

wherein X₁、X₂、X₃、X₄、X₅、W、R_1a、R_1b、R_1c、R_1d、R_1eA and c are as defined above, and LG is a suitable leaving group (e.g., halogen, OMs, OTs);

reaction with a compound of formula F:

R_8C-Q

formula F

Wherein R is_8CIs as defined above, and Q is a suitable coupling group (e.g., amino, hydroxy);

d) reacting a compound of formula G:

wherein X₁、X₂、X₃、X₄、X₆、X₇、W、R_1a、R_1b、R_1c、R_1d、R_1eB and c are as described herein;

reaction with a compound of formula H:

R_6N-Z

formula H

Wherein R is_6NIs as defined above, and Z is a suitable leaving group (e.g., halogen, OMs, hydroxy);

e) reacting a compound of formula J:

wherein X₁、X₂、X₃、W、R_1a、R_1b、R_1c、R_1d、R_1eAnd c is as defined herein, H is halogen, and Y is NHR_6NOr OH, and wherein R_6NIs as defined above;

reaction with a compound of formula K:

R_7c-P

formula K

Wherein R is_7cIs as defined in claim 1, and P is H₂NC (NH) -or H₂NC (O) -; and is

Optionally, if desired:

i) removing any protecting groups present;

ii) converting the compound of formula I into another compound of formula I; and/or

iii) forming a pharmaceutically acceptable salt or solvate thereof.

Biological activity

The PARG enzymes and cellular assays described in the accompanying examples section can be used to measure the pharmacological effects of the compounds of the invention.

Although the pharmacological properties of the compounds of formula I vary with structural changes, as expected, the compounds of the present invention were found to be active in these PARG assays.

In general, the compounds of the invention exhibit an IC of 1 μ M or less in the PARG enzyme assay described herein₅₀Preferred compounds of the invention exhibit an IC of 500nM or less₅₀And most preferred compounds of the invention exhibit an IC of 200nM or less₅₀。

In the PARG cell assay described in the examples section, compounds of formula I suitably have an activity of less than 5 μ M, with preferred compounds exhibiting an activity of 1 μ M or less.

Pharmaceutical composition

According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as hereinbefore defined, in association with a pharmaceutically acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for use as: for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), by inhalation (e.g., as a finely divided powder or liquid aerosol), by insufflation (e.g., as a finely divided powder), or for parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration or as a suppository for rectal administration).

The compositions of the invention may be obtained by conventional procedures well known in the art using conventional pharmaceutical excipients. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

An effective amount of a compound of the invention for use in therapy is an amount sufficient to treat or prevent, slow the progression of and/or alleviate the symptoms associated with a proliferative disorder mentioned herein.

The amount of active ingredient combined with one or more excipients to produce a single dosage form will vary depending upon the individual being treated and the particular route of administration. For example, formulations intended for oral administration to humans will generally comprise, for example, from 0.5 to 0.5g (more suitably from 0.5 to 100mg, for example from 1 to 30mg) of the active agent, complexed with a suitable and convenient amount of excipient (which may vary from 5 to 98% by weight of the total composition).

The size of the dose of a compound of formula I for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the condition, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

Where the compounds of the invention are used for therapeutic or prophylactic purposes, they are generally administered such that, if a divided dose is required, a daily dose in the range of, for example, 0.1mg/kg to 75mg/kg body weight is received. Generally, when the parenteral route is used, lower doses will be administered. Thus, for example, for intravenous or intraperitoneal administration, dosages in the range of, for example, 0.1mg/kg to 30mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range of, for example, 0.05mg/kg to 25mg/kg body weight will be used. Oral administration may also be suitable, particularly in the form of tablets. Typically, a unit dosage form will contain from about 0.5mg to 0.5g of a compound of the invention.

Therapeutic uses and applications

The present invention provides compounds useful as PARG inhibitors.

Accordingly, the present invention provides a method of inhibiting PARG enzyme activity in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

The present invention also provides a method of selectively inhibiting PARG enzyme activity over PARP1 or ARH3 enzyme activity in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

The present invention also provides a method of treating a disease or disorder involving PARG activity in a patient in need of such treatment, which method comprises administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition.

The present invention provides a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

The present invention provides a method of treating a proliferative disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, as defined herein.

The present invention provides a method of treating cancer in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, as defined herein.

The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, as defined herein, for use in therapy.

The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, as defined herein, for use in the treatment of a proliferative disorder.

The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, as defined herein, for use in the treatment of cancer. In a specific embodiment, the cancer is a human cancer.

The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in inhibiting PARG enzyme activity.

The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or disorder in which PARG activity is implicated.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for the treatment of cancer in a human.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the inhibition of PARG enzyme activity.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the selective inhibition of PARG enzyme activity over PARP1 or ARH3 enzyme activity.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which PARG activity is implicated.

The term "proliferative disease" is used interchangeably herein and relates to unwanted excess or abnormal cell unwanted or uncontrolled proliferation of cells, for example neoplastic or proliferative growth, whether in vitro or in vivo. Examples of proliferative disorders include, but are not limited to, pre-cancerous and malignant cell proliferation, including, but not limited to, malignancies and tumors, cancer, leukemia, psoriasis, bone disease, fibroproliferative diseases (e.g., connective tissue), and atherosclerosis. Any type of cell can be treated, including but not limited to lung, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.

The antiproliferative effect of the compounds of the invention is particularly useful in the treatment of human cancer (due to their inhibition of PARG enzyme activity).

Anti-cancer effects can result from one or more mechanisms, including but not limited to modulation of cell proliferation, inhibition of angiogenesis (formation of new blood vessels), inhibition of metastasis (spread of tumor from its origin), inhibition of invasion (spread of tumor cells into adjacent normal structures), or promotion of apoptosis (programmed cell death).

In a particular embodiment of the invention, the proliferative disorder to be treated is cancer.

Route of administration

The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemic/peripheral or local (i.e., at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g., by ingestion); a cheek portion; under the tongue; transdermal (including, e.g., via patches, plasters, etc.); transmucosal (including, for example, through patches, plasters, etc.); intranasally (e.g., by nasal spray); eye (e.g., by eye drops); lungs (e.g., by inhalation or insufflation therapy, for example, via aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); the vagina (e.g., through a pessary); parenterally, e.g., by injection, including subcutaneously, intradermally, intramuscularly, intravenously, intraarterially, intracardially, intrathecally, intraspinally, intracapsularly, subcapsular, intraorbitally, intraperitoneally, intratracheally, sub-cuticularly, intraarticularly, subarachnoidally, and intrasternally; by implanting a reservoir or reservoir, e.g., subcutaneously or intramuscularly.

Combination therapy

The anti-proliferative treatment defined above may be administered as the sole therapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following classes of antineoplastic agents:

(i) other antiproliferative/antineoplastic agents and combinations thereof, such as used in surgical oncology, such as alkylating agents (e.g., cis-platinum, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines like doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin D, and mithramycin); antimitotic agents (e.g. vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxanes like paclitaxel and taxotere and polokinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, and camptothecin);

(ii) cytostatic agents, such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and indoxifene (iodoxyfene)), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g. goserelin, leuprolide and buserelin), progestogens (e.g. megestrol acetate), aromatase inhibitors (e.g. as anastrozole, letrozole, vorozole (ravole) and exemestane) and inhibitors of 5 α -reducing agents (e.g. finasteride);

(iii) anti-invasive agents [ e.g. inhibitors of the c-Src kinase family such as 4- (6-chloro-2, 3-methylenedioxyanilino) -7- [2- (4-methylpiperazin-1-yl) ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD 0530; International patent application WO01/94341), N- (2-chloro-6-methylphenyl) -2- {6- [4- (2-hydroxyethyl) piperazin-1-yl]-2-methylpyrimidin-4-ylamino } thiazole-5-carboxamide (dasatinib, BMS-354825;J.Med.Chem.[journal of medical chemistry]2004，476658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors such as marimastat, urokinase plasminogen-activating receptor function inhibitors or heparanase antibodies]；

(iv) Inhibitors of growth factor function: for example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., the anti-erbB 2 antibody trastuzumab [ Herceptin ]^TM]anti-EGFR antibody panitumumab, anti-erbB 1 antibody cetuximab [ erbitux, C225]And Stern et al (Critical reviews in oncology/hematology, 2005, Vol.54, pp11-29) [ oncology/hematology Critical reviews, 2005, Vol.54, pp.11-29](ii) a Such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (e.g. EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, ZD1839), N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) -quinazolin-4-amine (CI-1033)) erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and/or nilotinib (AMN 107); serine/threonine kinase inhibitors (e.g., Ras/Raf signaling inhibitors, e.g., farnesyl transferase inhibitors, e.g., sorafenib (BAY-43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cellular signaling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (e.g. AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor, [ e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin)^TM) And for example VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), vatalinib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4- (4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD 2171; example 240 in WO 00/47212), such as those disclosed in International patent applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds which act by other mechanisms (e.g. linoamine, inhibitors of integrin α v β 3 function and angiostatin)]；

(vi) Vascular damaging agents such as combretastatin a4 and the compounds disclosed in international patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) endothelin receptor antagonists such as zipopotant (ZD4054) or atrasentan;

(viii) antisense therapies, for example those directed against the above-listed targets, such as ISIS-2503, anti-ras antisense therapies;

(ix) gene therapy, including, for example, methods of replacing aberrant genes (such as aberrant p53 or aberrant BRCA1 or BRCA2), GDEPT (gene-directed enzyme pre-drug therapy) methods, such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and methods of increasing a patient's resistance to chemotherapy or radiation therapy, such as multi-drug resistance gene therapy; and

(x) Immunotherapy approaches, including for example ex vivo and in vivo approaches for increasing the immunogenicity of patient tumor cells, such as transfection with cytokines (e.g., interleukin 2, interleukin 4, or granulocyte-macrophage colony stimulating factor), approaches for reducing T-cell disability, approaches using transfected immune cells (e.g., cytokine-transfected dendritic cells), approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies.

In particular embodiments, the anti-proliferative treatment defined above may involve conventional surgery or radiotherapy or chemotherapy in addition to the compounds of the invention.

Such combination therapy may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the therapy. Such combinations employ a compound of the invention within the dosage ranges described above, and other pharmaceutically active agents within their approved dosage ranges.

According to this aspect of the invention there is provided a combination for use in the treatment of cancer (e.g. cancer involving a solid tumour), the combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined above, and another anti-tumour agent.

According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative disorder, for example cancer (e.g. cancer involving a solid tumour), the combination comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined above, and any one of the anti-tumour agents listed above.

In another aspect of the invention there is provided a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of cancer in combination with another anti-neoplastic agent, optionally selected from one of those listed above.

Herein, where the term "combination" is used, it is to be understood that this means simultaneous, separate or sequential administration. In one aspect of the invention, "combination" means administered simultaneously. In another aspect of the invention, "combination" means administered separately. In another aspect of the invention, "combination" refers to sequential administration. Where administration is sequential or separate, delayed administration of the second component should not result in loss of the beneficial effect of the combination.

According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof in combination with an antineoplastic agent (optionally selected from one of those listed above) in association with a pharmaceutically acceptable diluent or carrier.

Examples of the invention

Materials, Equipment and general Experimental details

General experiments

Flash chromatography was performed using pre-loaded silica gel cartridges (KP-Sil SNAP, Biotage, Hengoed UK or RediSepRf, Isco). Merck type 60F for thin layer chromatography₂₅₄Silica gel was coated onto 0.25mm thick plates of 5 × 10 cm. all reagents from commercial sources were used without further purification anhydrous solvents were obtained from Sigma-Aldrich Chemical Company Ltd or Fisher Chemicals Ltd, and were used without further drying.

Unless otherwise statedAll compounds were purified by LC-MS and¹determination of purity by detection of both H-NMR spectra>90 percent. When Cl or Br are present, the expected isotope distribution pattern is observed.

¹H-NMR

Recording protons on a Bruker spectrometer at 300MHz or 400MHz or an ECX 300MHz or ECX 400MHz JEOL spectrometer (¹H) NMR spectrum. The solution is usually deuterated chloroform (CDCl)₃) Or deuterated dimethyl sulfoxide (DMSO-d)₆) Preparation, wherein chemical shifts are referenced to Tetramethylsilane (TMS) or deuterated solvents as internal standard. Report on¹H NMR data indicating chemical shift (), integration (e.g. 1H), multiplicities (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; dd, doublet, etc.) and coupling constants (J) (Hz) (app. means significant coupling in the broad peak signal). Deuterated solvents are available from sigma-aldrich, Goss (Goss), or floro chemicals (Fluorochem).

LC-MS analysis

LC-MS analysis was performed using one of the following methods (shown in table 2):

LC-MS method A

A Watts Acquity UPLC system equipped with a BEH C181.7 μ M chromatography column (2.1X 50mm) and UV diode array detection (210-. Positive and negative ion mass detection was performed using a waters SQD detector. Analysis was performed using buffered acidic or basic solvents and a gradient as described below:

low pH:

solvent A-water +10mM ammonium formate + 0.1% formic acid

Solvent B-acetonitrile + 5% water + 0.1% formic acid

High pH:

solvent A-water +10mM ammonium bicarbonate + 0.1% ammonia solution

Solvent B-acetonitrile + 0.1% ammonia solution

Gradient:

LC-MS method B

Watts Acquity ZQD (ESI) UPLC System equipped with Xbridge C182.1X 50mm, 2.5 μm or equivalent and UV diode array detection (215-

Low pH:

solvent A-MeCN

Solvent B-0.1% formic acid (pH 3)

High pH:

solvent A-MeCN

Solvent B-10mM NH₄HCO₃(pH 10)

Gradient:

time of day	Flow rate (mL/min)	% solvent A	% solvent B
				0	0.8	98	2
0.8	0.8	2	98
				1.2	0.8	2	98
1.25	0.8	98	2

LC-MS method C

Waters X Bridge C18: 50mm 4.6mm, 3.5 μm column, UV diode array detection (214 ion 350nm)

High pH:

solvent A-Water (0.01mol/L NH)₄HCO₃)

Solvent B-MeCN

Gradient:

time of day	Flow rate (mL/min)	% solvent A	% solvent B
				0	2	95	5
1.6	2	5	95
				3	2	95	95

Preparative HPLC

Some compounds were purified by preparative HPLC using the following system. A Watts FractionLynx MS automatic infiltration system with a Watts Xbridge 5 μm C18, 100mm 19mm (inside diameter) column, using UV diode array detection (210-400nm) operating at a flow rate of 20mL/min and using positive and negative ion mass detection for mass directed collection.

Purification is carried out using a suitably buffered acidic or basic solvent system. Compound retention time on the system was routinely assessed using 30-50 μ Ι _ test injections and standard gradients, and then based on the observed retention time, purification was performed using an appropriately selected focused gradient as described below.

Low pH:

solvent A-water +10mM ammonium formate + 0.1% formic acid

Solvent B-acetonitrile + 5% water + 0.1% formic acid

High pH:

solvent A-water +10mM ammonium formate + 0.1% ammonia solution

Solvent B-acetonitrile + 5% water + 0.1% ammonia solution

Standard gradient:

time of day	Flow rate (mL/min)	% solvent A	% solvent B
				0	20	90	10
0.3	20	90	10
				8.5	20	2	98
12	20	2	98
				12.5	0	2	98

Concentration gradient:

a Gilson GX281 automated purification system with Watts Xbridge 5. mu. m C18, 100 mm. times.30 mm (ID) or Watts XSelect 5. mu. m C18, 150 mm. times.19 mm (ID) running at a flow rate of 20mL/min using UV detection (214nm, 254 nm). Purification is carried out using a suitably buffered basic solvent system. Compound retention time on the system was routinely assessed using LC-MS analytical tests as standard gradients, and then based on the observed retention time, purification was performed using an appropriately selected focused gradient as described below.

Column: waters X Bridge C18: 100mm 30mm 5um

Mobile phase: a: water (0.05% ammonia) B₂: methanol

Concentration gradient:

column: watts X-Select 5. mu. m C18, 150mm X19 mm

Mobile phase: a: water (0.05% ammonia) B₂: methanol

Concentration gradient:

column: watts X-Select 5. mu. m C18, 150mm X19 mm

Mobile phase: a: water (10mmol NH)₄HCO₃)B₁: acetonitrile

Concentration gradient:

general reaction scheme

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Scheme 7

Scheme 8

Scheme 9

Scheme 10

Scheme 11

Scheme 12

Scheme 13

Scheme 14

Scheme 15

Scheme 16

Scheme 17

Scheme 18

Scheme 19

Scheme 20

Scheme 21

Scheme 22

Scheme 23

General procedure

1-methylcyclopropylamine hydrochloride

1-methylcyclopropanecarboxylic acid (73.3g, 0.73mol), diphenylphosphoryl azide (221.7g, 0.81mol) and triethylamine (148.1g, 1.46mol) were stirred in t-butanol (330mL) and heated at 75 ℃ overnight, the reaction mixture was cooled to room temperature, poured into a mixture of ethyl acetate (750mL) and water (1500mL) and stirred for 15 minutes, the resulting precipitate was removed by filtration, and the phases were separated, the aqueous layer was extracted with ethyl acetate (2 × 750mL), and the combined organic extracts were washed with water (750mL), dried (MgSO 4), and the resulting precipitate was removed₄) And concentrated to give a light brown solid (88 g.) the solid was suspended in 1, 4-dioxane (295mL) and 4M hydrochloric acid (366mL) was added the reaction mixture was stirred at room temperature for 2 hours diethyl ether was added and the mixture was frozen in a methanol/ice bath for 15 minutes the precipitate was collected by filtration, washed with diethyl ether (2 × 220mL) and the filter cake was then dried for 10 minutes to give 1-methylcyclopropylamine hydrochloride as a shiny white solid (40.5g, 0.38mol, 51%).

¹H NMR(CDCl₃):1.32(s,3H),0.75-0.68(m,2H),0.60-0.51(m,2H)

General procedure for scheme 1:

intermediate S1-A11, 3-dimethylquinazoline-2, 4(1H,3H) -dione

A suspension of benzoyleneurea (2.0g, 12.33mmol) in DMF (24mL) was treated with potassium carbonate (8.5g, 61.67mmol) and placed under nitrogenThe solution was then treated with methyl iodide (2.3mL, 37mmol) and stirred at room temperature for 2 hours the suspension was filtered, and then water (40mL) and EtOAc (40mL) were added, the organic layer was extracted, washed with brine (2 × 20mL), washed with MgSO 20₄Dried and concentrated to give 1, 3-dimethylquinazoline-2, 4-dione (0.96g, 5.05mmol, 41%).

¹H NMR(300MHz,DMSO-d₆)＝8.06(dd,J＝1.7,7.8Hz,1H),7.81-7.75(m,1H),7.47(d,J＝8.5Hz,1H),7.31(app.t,J＝7.5Hz,1H),3.53(s,3H),3.32(s,3H)

The following intermediates were prepared by similar methods:

intermediate S1-A21, 3-diethyl quinazoline-2, 4(1H,3H) -dione

Prepared from benzoyleneurea and iodoethane.

¹H NMR(300MHz,DMSO-d₆)＝8.07(dd,J＝1.6,7.9Hz,1H),7.78(ddd,J＝1.8,7.3,8.5Hz,1H),7.51(d,J＝8.6Hz,1H),7.30(app.t,J＝7.5Hz,1H),4.15(q,J＝7.2Hz,2H),3.99(q,J＝7.2Hz,2H),1.22(t,J＝7.1Hz,3H),1.16(t,J＝7.1Hz,3H)

Intermediate S1-A31, 3-bis [ (3, 5-dimethylisoxazol-4-yl) methyl ] quinazoline-2, 4-dione

Prepared from benzoyleneurea and 4- (bromomethyl) -3, 5-dimethyl-isoxazole.

¹H NMR(300MHz,DMSO-d₆)＝8.13(dd,J＝1.6,7.9Hz,1H),7.77(ddd,J＝1.6,7.1,8.6Hz,1H),7.37(d,J＝8.6Hz,1H),7.33(t,J＝7.7Hz,1H),5.16(s,2H),4.95(s,2H),2.40(s,3H),2.22(s,3H),2.19(s,3H),2.02(s,3H)

Intermediate S1-B11, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride

Chlorosulfonic acid (1.68mL, 25.24mmol) was added portionwise to a stirred 1, 3-dimethylquinazoline-2, 4-dione (960mg, 5.05mmol) cooled to 5-10 ℃. The reaction mixture was heated at 60 ℃ for 4 hours. The reaction mixture was cooled and poured into crushed ice where an off-white precipitate formed. The precipitate was filtered, washed with water and dried in a vacuum oven to give 1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride (0.98g, 3.4mmol, 67%).

¹H NMR(300MHz,DMSO-d₆)＝8.25(d,J＝2.1Hz,1H),7.93(dd,J＝2.2,8.7Hz,1H),7.42(d,J＝8.8Hz,1H),3.52(s,3H),3.31(s,3H)

The following intermediates were prepared by similar methods:

intermediate S1-B22, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride

Prepared from benzoyleneurea and chlorosulfonic acid.

¹H NMR(300MHz,DMSO-d₆)＝11.31(s,1H),11.22(s,1H),8.10(d,J＝2.1Hz,1H),7.82(dd,J＝2.0,8.4Hz,1H),7.11(d,J＝8.4Hz,1H)

Intermediate S1-B31, 3-diethyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride

Prepared from 1, 3-diethyl quinazoline-2, 4(1H,3H) -diketone and chlorosulfonic acid.

¹H NMR(300MHz,DMSO-d₆)＝8.26(d,J＝2.5Hz,1H),7.92(dd,J＝2.1,8.7Hz,1H),7.46(d,J＝8.9Hz,1H),4.14(q,J＝6.8Hz,2H),3.99(q,J＝7.0Hz,2H),1.25-1.13(m,6H)

Intermediate S1-B41, 3-bis [ (3, 5-dimethylisoxazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonyl chloride

Prepared from 1, 3-bis [ (3, 5-dimethylisoxazol-4-yl) methyl ] quinazoline-2, 4-dione and chlorosulfonic acid in DCM.

¹H NMR(300MHz,CDCl₃)＝8.93(d,J＝2.4Hz,1H),8.23(dd,J＝2.4,9.0Hz,1H),7.22(d,J＝9.0Hz,1H),5.18(s,2H),5.08(s,2H),2.53(s,3H),2.32(s,6H),2.13(s,3H)

General procedure for scheme 2:

intermediate S2-A13-methyl-1H-quinazoline-2, 4-dione

A solution of 2-amino-N-methylbenzamide (15g, 0.10mol) and 1, 1-carbonyldiimidazole (21g, 0.13mol) in N, N-dimethylformamide (150mL) was heated at 135-145 ℃ overnight. The reaction showed 30% starting material by LC, so 1, 1-carbonyldiimidazole (14g, 0.086mol) was added further and the reaction mixture was heated at 140 ℃ overnight. The reaction showed complete conversion, which was cooled and poured into ice/water (300mL) and stirred for 10 minutes. The suspension was filtered and the product was washed with water. The solid was dried in a vacuum oven at 50 ℃ overnight to give 3-methylquinazoline-2, 4(1H,3H) -dione (15.8g, 0.090mol, 90%).

¹H NMR(300MHz,DMSO-d₆)＝11.44(br.s,1H),7.93(dd,J＝1.5,7.8Hz,1H),7.65(app.t,J＝7.7Hz,1H),7.23-7.15(m,2H),3.33(s,3H)

Intermediate S2-A23-ethyl-1H-quinazoline-2, 4-dione

Ethyl isocyanate (1.27mL, 16.04mmol) was added to a solution of anthranilic acid (2.0g, 14.58mmol) in THF (20mL) and the reaction mixture was heated at 70 ℃ for 2.5 h. The reaction mixture was evaporated to dryness, then EtOH (20mL) and concentrated HCl (4mL, 2mL/g) were added and the mixture was heated at 70 ℃ for 30 minutes. The reaction mixture was cooled in an ice bath, water (40mL) was added and a white precipitate formed. The solid was filtered and dried in a vacuum oven to give 3-ethyl-1H-quinazoline-2, 4-dione (2.22g, 11.67mmol, 80%).

¹H NMR(300MHz,DMSO-d₆)＝11.41(s,1H),7.93(dd,J＝1.6,7.9Hz,1H),7.65(app.t,J＝7.6Hz,1H),7.23-7.14(m,2H),3.93(q,J＝7.0Hz,2H),1.15(t,J＝7.1Hz,3H)

Intermediate S2-B13-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride

3-methyl-quinazoline-2, 4(1H,3H) -dione (15g, 0.085mol) was added portionwise to chlorosulfonic acid (60mL, 0.9mol) with cooling, maintaining the temperature <20 ℃. The reaction mixture was heated to 60 ℃ and stirred for 2 hours, then allowed to cool. The reaction mixture was carefully added to ice (500mL) over 30 minutes. The resulting precipitate was stirred for 30 minutes, collected by filtration and washed with water. The solid was dried in a vacuum oven to give 3-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride (23g, 0.084mol, 99%).

¹H NMR(300MHz,DMSO-d₆)＝11.54(s,1H),8.15(d,J＝2.1Hz,1H),7.83(dd,J＝2.0,8.4Hz,1H),7.13(d,J＝8.5Hz,1H),3.25(s,3H)

The following intermediates were prepared by similar methods:

intermediate S2-B23-ethyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride

Prepared from 3-ethyl-1H-quinazoline-2, 4-diketone and chlorosulfonic acid.

¹H NMR(300MHz,DMSO-d₆)＝11.50(s,1H),8.15(d,J＝2.0Hz,1H),7.83(dd,J＝2.0,8.4Hz,1H),7.12(d,J＝8.5Hz,1H),3.93(q,J＝7.1Hz,2H),1.15(t,J＝7.0Hz,3H)

Example 73-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide

3-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride (12g, 43.7mmol) and 1-methylcyclopropylamine hydrochloride (5.16g, 48mmol) were slurried in dichloromethane (120mL) at 20 ℃. Triethylamine (13.4mL, 96mmol) was added over 15 minutes: this was exothermic and the temperature was raised to 34 ℃. As the reaction cooled, a precipitate formed. After stirring for 2 hours, the reaction was complete by HPLC. 1M hydrochloric acid (100mL) was added and stirred for 25 minutes. The product was filtered from the biphasic mixture and washed with water (100 mL). The solid was dried in a vacuum oven to give 3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (12.03g, 0.039mol, 89%).

¹H NMR(300MHz,DMSO-d₆)＝11.83(br.s,1H),8.32(d,J＝2.2Hz,1H),8.13(s,1H),7.99(dd,J＝2.2,8.6Hz,1H),7.32(d,J＝8.6Hz,1H),1.06(s,3H),0.62-0.55(m,2H),0.42-0.35(m,2H)

The following intermediates were prepared by similar methods:

example 63-Ethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide

Prepared from 3-ethyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride and 1-methylcyclopropylamine hydrochloride.

¹H NMR(300MHz,DMSO-d₆)＝14.48(br.s,2H),11.54(s,1H),8.15(d,J＝2.1Hz,1H),7.83(dd,J＝2.0,8.4Hz,1H),7.13(d,J＝8.5Hz,2H),3.25(s,3H)

Intermediate S2-C31-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-pyrido [2,3-d ] pyrimidine-6-sulfonamide

From 1-methyl-2, 4-dioxo-1H, 2H,3H, 4H-pyrido [2,3-d ] pyrimidine-6-sulfonyl chloride (enamine) and 1-methylcyclopropylamine hydrochloride.

¹H NMR(300MHz,DMSO-d₆)＝12.00(s,1H),8.98(d,J＝2.4Hz,1H),8.54(d,J＝2.4Hz,1H),8.35(s,1H),3.50-3.42(m,3H),1.12(s,3H),0.71-0.54(m,2H),0.52-0.37(m,2H)

Intermediate S2-D1N- ((3-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -N- (1-methylcyclopropyl) acetamide

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (11g, 35.6mmol) was slurried in pyridine (30mL) and 4-dimethylaminopyridine (430mg, 3.5mmol) was added. Acetic anhydride (33.6mL, 356mmol) was added over 10 minutes and the resulting concentrated slurry was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (25mL) and filtered. The solid was washed with ethyl acetate. The solid was transferred to a conical flask and slurried in water (40mL) at 60 ℃ for 2 hours. The slurry was cooled to 35 ℃ and filtered, washing with water (20 mL). The solid was dried in a vacuum oven to give N- ((3-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -N- (1-methylcyclopropyl) acetamide (10.4g, 0.030mol, 83%).

¹H NMR(300MHz,DMSO-d₆)＝11.91(br.s,1H),8.39(d,J＝2.3Hz,1H),8.09(dd,J＝2.3,8.7Hz,1H),7.33(d,J＝8.8Hz,1H),3.26(s,3H),2.23(s,3H),1.54(s,3H),1.25-1.16(m,2H),1.10-0.97(m,2H)

The following intermediates were prepared by similar methods:

intermediate S2-D2N- ((3-ethyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -N- (1-methylcyclopropyl) acetamide

Prepared from 3-ethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide and acetic anhydride.

¹H NMR(300MHz,CDCl₃)＝10.47(s,1H),8.65(d,J＝2.3Hz,1H),8.29(dd,J＝2.3,8.7Hz,1H),7.23(d,J＝8.8Hz,1H),4.15(q,J＝7.1Hz,2H),2.29(s,3H),1.65(s,3H),1.40-1.27(m,4H),1.21-1.10(m,2H)

Intermediate S2-D3N- (1-cyanocyclopropyl) -N- [ [3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] acetamide

Preparation from N- (1-cyanocyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (intermediate S4-C6) and acetic anhydride

¹H NMR(300MHz,DMSO-d₆)＝12.17(s,1H),8.47(d,J＝2.3Hz,1H),8.18(dd,J＝2.3,8.7Hz,1H),7.41(d,J＝8.7Hz,1H),6.33(s,1H),5.16(s,2H),2.31(s,3H),2.18(s,3H),2.12-2.03(m,1H),2.01-1.92(m,2H),1.82-1.71(m,1H)

General procedure for scheme 3:

intermediate S3-A1-methyl quinazoline-2, 4(1H,3H) -dione

Sodium cyanate (30.15g, 0.46mol) was added to a slurry of N-anthranilic acid (50.0g, 0.33mol) in water (1.75L) and acetic acid (3.3 mL). The reaction mixture was heated to 50 ℃ for 1 hour. The solution was slowly basified by addition of sodium hydroxide (exothermic). The resulting solution was heated to 80 ℃ and stirred overnight. The reaction mixture was cooled to 0 ℃, and the resulting precipitate was collected by filtration. The solid was dissolved in boiling water (200mL) and acidified to pH2 with concentrated sulfuric acid. The slurry was cooled to room temperature and filtered. The solid was dried in a vacuum oven to give 1-methyl quinazoline-2, 4(1H,3H) -dione (53g, 0.30mol, 77%).

¹H NMR(300MHz,DMSO-d₆)＝11.54(br.s.,1H),8.00(d,J＝7.7Hz,1H),7.77(t,J＝7.9Hz,1H),7.43(d,J＝8.6Hz,1H),7.28(t,J＝7.5Hz,1H),3.33(s,3H)

Intermediate S3-B1-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride

1-Methylquinazoline-2, 4(1H,3H) -dione (25g, 0.142mol) was added portionwise to chlorosulfonic acid (125mL, 1.88mol) at 50 ℃. The reaction mixture was heated to 50 ℃ and stirred overnight, then allowed to cool. The reaction mixture was carefully added to ice/water (1.5L) maintaining a temperature <20 ℃. The resulting precipitate was collected by filtration and dried in an open atmosphere to give 1-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride as a white powder (44g, 0.16mol, 113% water).

¹H NMR(300MHz,DMSO-d₆)＝11.57(s,1H),8.19(d,J＝2.1Hz,1H),7.91(dd,J＝2.2,8.7Hz,1H),7.38(d,J＝8.7Hz,1H)

Example 191-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide

Triethylamine (8.1g, 80.1mmol) was added to a stirred solution of 1-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride (11.3g, 36.4mmol) in dichloromethane (250 mL). 1-methylcyclopropylamine hydrochloride (4.3g, 40.0mmol) was added portionwise over 10 minutes, and the reaction mixture was stirred at room temperature for 3 hours. TLC showed the reaction was complete. The reaction mixture was poured into water (250mL) and filtered to give the desired product 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (10.5g, 0.034mol, 93%).

¹H NMR(300MHz,DMSO-d₆)＝11.83(br.s,1H),8.35(d,J＝2.4Hz,1H),8.17(s,1H),8.06(dd,J＝2.3,8.8Hz,1H),7.61(d,J＝8.9Hz,1H),3.48(s,3H),1.07(s,3H),0.64-0.55(m,2H),0.44-0.35(m,2H)

General procedure for scheme 4:

intermediate S4-A2, 4-dioxo-1H-3, 1-benzoxazine-6-sulfonyl chloride

To stirred chlorosulfonic acid (100mL, 1.51mol) was added in portions at room temperature, lotto acid (60g, 0.368mol), and the mixture was heated at 50 ℃ for 3 hours. After cooling to room temperature, the reaction mixture was added dropwise to ice/water. The precipitated solid was filtered and dried to give 2, 4-dioxo-1H-3, 1-benzoxazine-6-sulfonyl chloride (74g, 0.283mol, 77%).

¹H NMR(300MHz,DMSO-d₆)＝11.82(s,1H),8.06(d,J＝2.0Hz,1H),7.91(dd,J＝2.0,8.5Hz,1H),7.11(d,J＝8.5Hz,1H)

Intermediate S4-B12-amino-5- [ (1-methylcyclopropyl) sulfamoyl ] -N- [ (1-methylpyrazol-4-yl) methyl ] benzamide

A suspension of the compound 2, 4-dioxo-1H-3, 1-benzoxazine-6-sulfonyl chloride (10g, 38.3mmol) in DMF (100mL) was treated with 1-methylcyclopropylamine hydrochloride (4.1g, 38.3mmol) and cooled to 10 deg.C in an ice/MeOH bath Triethylamine (8.51g, 87.5mmol) was added to the mixture and the resulting solution was stirred at 10 deg.C for 1 hour (1-methyl-1H-pyrazol-4-yl) methylamine (8.45g, 57.5mmol) in DMF (10mL) was added to the mixture at 0 deg.C, then Triethylamine (11.6g, 115mmol) was added and the reaction mixture was stirred at room temperature for 3 hours Water (200mL) was added to the reaction mixture, then extracted with EtOAc (2 × 100mL), the combined organic phases were washed with brine (100mL), dried over sodium sulfate, filtered and evaporated, the crude product was purified by autoplumn₂(Biotage, 120g, eluent:0-80% EtOAc in petroleum ether) to give 2-amino-5- [ (1-methylcyclopropyl) sulfamoyl]-N- [ (1-methylpyrazol-4-yl) methyl]Benzamide (4.7g, 12.9mmol, 34%).

¹H NMR(300MHz,DMSO-d₆)＝8.83(t,J＝5.7Hz,1H),7.87(d,J＝2.3Hz,1H),7.58(s,1H),7.55(s,1H),7.46(dd,J＝2.2,8.7Hz,1H),7.35(s,1H),7.09(br.s,2H),6.79(d,J＝8.8Hz,1H),4.22(d,J＝5.7Hz,2H),3.78(s,3H),1.04(s,3H),0.65-0.51(m,2H),0.36-0.29(m,2H)

The following intermediates were prepared by similar methods:

intermediate S4-B22-amino-5- [ (1-methylcyclopropyl) sulfamoyl ] -N- [ (3-methylisoxazol-5-yl) methyl ] benzamide

Prepared from 2, 4-dioxo-1H-3, 1-benzoxazine-6-sulfonyl chloride, 1-methylcyclopropylamine hydrochloride and (3-methylisoxazol-5-ylmethyl) amine.

¹H NMR(300MHz,CDCl₃)＝7.95(d,J＝2.1Hz,1H),7.65(dd,J＝2.2,9.1Hz,1H),6.99(br.s,1H),6.72(d,J＝8.6Hz,1H),6.10(s,1H),4.68(d,J＝5.7Hz,2H),2.29(s,3H),1.22(s,3H),0.79-0.75(m,2H),0.49-0.44(m,2H)

Intermediate S4-B32-amino-N- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -5- [ (1-ethylcyclopropyl) sulfamoyl ] benzamide

From 2, 4-dioxo-1H-3, 1-benzoxazine-6-sulfonyl chloride, 1-methylcyclopropylamine hydrochloride and (3, 5-dimethyl-1, 2-oxa-4-yl) methanamine.

¹H NMR(300MHz,CDCl₃)＝7.82(d,J＝2.2Hz,1H),7.61(dd,J＝2.2,8.8Hz,1H),6.70(d,J＝8.8Hz,1H),6.58(br.s,1H),4.98(br.s,1H),4.35(d,J＝5.4Hz,2H),2.45(s,3H),2.27(s,3H),1.21(s,3H),0.79-0.73(m,2H),0.48-0.43(m,2H)

Intermediate S4-B42-amino-5- [ (1-methylcyclopropyl) sulfamoyl ] -N- [ (2-methylthiazol-5-yl) methyl ] benzamide

Prepared from 2, 4-dioxo-1H-3, 1-benzoxazine-6-sulfonyl chloride, 1-methylcyclopropylamine hydrochloride and (2-methyl-1, 3-thiazol-5-yl) methanamine.

¹H NMR(300MHz,CDCl₃)＝7.90(d,J＝2.2Hz,1H),7.62(dd,J＝2.2,8.8Hz,1H),7.53(br.s,1H),7.12(t,J＝6.0Hz,1H),6.70(d,J＝8.8Hz,1H),6.24(br.s,2H),5.11(s,1H),4.71(d,J＝5.7Hz,2H),3.08(s,1H),2.68(s,3H),1.18(s,3H),0.80-0.72(m,2H),0.47-0.42(m,2H)

Intermediate S4-B52-amino-N- (cyanomethyl) -5- [ (1-methylcyclopropyl) sulfamoyl ] benzamide

Prepared from 2, 4-dioxo-1H-3, 1-benzoxazine-6-sulfonyl chloride, 1-methylcyclopropylamine hydrochloride and aminoacetonitrile bisulfate.

¹H NMR(300MHz,CDCl₃)＝7.19(s,1H),7.99(d,J＝2.2Hz,1H),7.67(dd,J＝2.1,8.8Hz,1H),7.22-7.16(m,1H),6.73(d,J＝8.8Hz,1H),5.06(br.s,1H),4.32(d,J＝5.7Hz,2H),1.23(s,2H),0.81-0.76(m,2H),0.50-0.45(m,2H)

Intermediate S4-B62-amino-5- [ (1-cyanocyclopropyl) sulfamoyl ] -N- [ (3-methylisoxazol-5-yl) methyl ] benzamide

Prepared from 2, 4-dioxo-1H-3, 1-benzoxazine-6-sulfonyl chloride, 1-amino-1-cyclopropanecarbonitrile hydrochloride and (3-methylisoxazol-5-ylmethyl) amine.

¹H NMR(300MHz,DMSO-d₆)＝9.21(t,J＝5.7Hz,1H),8.68(s,1H),8.03(d,J＝2.3Hz,1H),7.53(dd,J＝2.2,8.9Hz,1H),7.31(s,2H),6.85(d,J＝8.9Hz,1H),6.20(s,1H),4.50(d,J＝5.5Hz,2H),2.20(s,3H),1.42-1.32(m,2H),1.23-1.16(m,2H)

Intermediate S4-B72-amino-N-cyclopropyl-5- [ (1-methylcyclopropyl) sulfamoyl ] benzamide

Prepared from 2, 4-dioxo-1H-3, 1-benzoxazine-6-sulfonyl chloride, 1-methylcyclopropylamine hydrochloride and cyclopropylamine.

¹H NMR(300MHz,DMSO-d₆)＝8.50(d,J＝4.0Hz,1H),7.83(d,J＝2.3Hz,1H),7.55(s,1H),7.46(dd,J＝2.2,8.7Hz,1H),7.05(br.s,2H),6.78(d,J＝8.8Hz,1H),2.87-2.77(m,1H),1.04(s,3H),0.71-0.63(m,2H),0.61-0.51(m,4H),0.37-0.28(m,2H)

Intermediate S4-B82-amino-4-fluoro-N-methyl-5- [ (1-methylcyclopropyl) sulfamoyl ] benzamide

Prepared from 7-fluoro-2, 4-dioxo-1H-3, 1-benzoxazine-6-sulfonyl chloride, 1-amino-1-cyclopropanenitrile hydrochloride, and methylamine.

¹H NMR(300MHz,DMSO-d₆)＝8.53-8.46(m,1H),7.91(s,1H),7.35(br.s,2H),6.55(d,J＝13.0Hz,1H),2.72(d,J＝4.4Hz,3H),1.10(s,3H),0.67-0.60(m,2H),0.39-0.32(m,2H)

Intermediate S4-C1N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

Triphosgene (1.9g, 6.5mmol) was added to the compound 2-amino-5- [ (1-methylcyclopropyl) sulfamoyl ] -N- [ (1-methylpyrazol-4-yl) methyl ] benzamide (4.7g, 12.9mmol) in THF (50mL) at 0 ℃ and the resulting mixture was warmed to room temperature over 1.5 hours. The reaction mixture was quenched with 2M NaOH (10mL) and stirred overnight. EtOAc (50mL) was added to the mixture, which was then cooled and acidified (to pH 3) with 2M HCl. The organic phase was separated, dried and evaporated to give N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (5.2g, 10.6mmol, 82%).

¹H NMR(400MHz,CD₃OD):8.51(d,J＝2.0Hz,1H),8.03 8.05(m,1H),7.68(s,1H),7.54(s,1H),7.29(d,J＝8.8Hz,1H),5.05(s,2H),3.84(s,3H),1.16(s,3H),0.7-0.71(m,2H),0.43-0.46(m,2H)

The following intermediates were prepared by similar methods:

example 221N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

Prepared from 2-amino-5- [ (1-methylcyclopropyl) sulfamoyl ] -N- [ (3-methylisoxazol-5-yl) methyl ] benzamide and triphosgene.

¹H NMR(400MHz,DMSO-d₆):12.03(s,1H),8.31(d,J＝8.3Hz,1H),8.17(s,1H),8.02-8.04(m,1H),7.36(d,J＝8.8Hz,1H),6.33(s,1H),5.16(s,2H),2.17(s,3H),1.07(s,3H),0.58(m,2H),0.37-0.40(m,2H)。

Intermediate S4-C33- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide

From 2-amino-N- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -5- [ (1-methylcyclopropyl) sulfamoyl ] benzamide and triphosgene.

¹H NMR(300MHz,DMSO-d₆)＝11.88(s,1H),8.32(d,J＝2.2Hz,1H),8.11(s,1H),7.99(dd,J＝2.2,8.6Hz,1H),7.32(d,J＝8.6Hz,1H),4.85(s,2H),2.42(s,3H),2.23(s,3H),1.07(s,3H),0.63-0.55(m,2H),0.38(d,J＝2.3Hz,2H)

Example 220N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

Prepared from 2-amino-5- [ (1-methylcyclopropyl) sulfamoyl ] -N- [ (2-methylthiazol-5-yl) methyl ] benzamide and triphosgene.

¹H NMR(300MHz,DMSO-d₆)＝11.98(s,1H),8.32(d,J＝2.2Hz,1H),8.14(s,1H),8.01(dd,J＝2.2,8.6Hz,1H),7.61(s,1H),7.33(d,J＝8.6Hz,1H),5.19(s,2H),1.06(s,3H),0.65-0.51(m,2H),0.45-0.31(m,2H)

Example 2223- (cyanomethyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide

From 2-ammoniaYl-N- (cyanomethyl) -5- [ (1-methylcyclopropyl) sulfamoyl]Benzamide and triphosgene. The reaction mixture was cooled in an ice bath and then NaHCO was added dropwise over 15 min₃The aqueous phase was extracted with EtOAc (2 × mL), and the combined organic phases were passed through a hydrophobic frit and evaporated to dryness to yield the desired product.

¹H NMR(300MHz,DMSO-d₆)＝12.13(s,1H),8.33(d,J＝2.2Hz,1H),8.17(s,1H),8.04(dd,J＝2.2,8.6Hz,1H),7.36(d,J＝8.7Hz,1H),4.91(s,2H),1.07(s,3H),0.68-0.51(m,2H),0.42-0.35(m,2H)

Example 228N- (1-Cyanocyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

Prepared from 2-amino-5- [ (1-cyanocyclopropyl) sulfamoyl ] -N- [ (3-methylisoxazol-5-yl) methyl ] benzamide and triphosgene.

¹H NMR(300MHz,DMSO-d₆)＝12.11(s,1H),9.23(s,1H),8.37(d,J＝2.3Hz,1H),8.09(dd,J＝2.3,8.7Hz,1H),7.41(d,J＝8.7Hz,1H),6.32(s,1H),5.18(s,2H),2.18(s,3H),1.49-1.40(m,2H),1.30-1.23(m,2H)

Example 2403-cyclopropyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide

From 2-amino-N-cyclopropyl-5- [ (1-methylcyclopropyl) sulfamoyl ] benzamide and triphosgene.

¹H NMR(300MHz,DMSO-d₆)＝11.63(br.s.,1H),8.28(d,J＝2.1Hz,1H),8.10(s,1H),7.96(dd,J＝2.2,8.6Hz,1H),7.27(d,J＝8.6Hz,1H),2.69-2.62(m,1H),1.09-1.04(m,3H),1.04-0.98(m,2H),0.80-0.72(m,2H),0.62-0.55(m,2H),0.41-0.35(m,2H)

Example 2117-fluoro-3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide

From 2-amino-4-fluoro-N-methyl-5- [ (1-methylcyclopropyl) sulfamoyl ] benzamide and triphosgene.

Example 2232- [6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-1H-quinazolin-3-yl ] acetamide

From 2-amino-N- (cyanomethyl) -5- [ (1-methylcyclopropyl) sulfamoyl ] benzamide and triphosgene. Hydrolysis of the nitrile occurred during the work-up procedure used as described for intermediates S4-C1.

Intermediate S4-D12-amino-4-fluoro-N- [ (1-methylpyrazol-4-yl) methyl ] benzamide

C- (1-methyl-1H-pyrazol-4-yl) -methylamine (1.29g, 11.59mmol) was added to a solution of 7-fluoro-isatoic anhydride (2.00g, 11.04mmol) in DMF (20mL) at 0 ℃ and the resulting mixture was stirred at ambient temperature for 3 hours and then heated at 40 ℃ for 1 hour. The solvent was removed in vacuo and the crude product was suspended in diethyl ether (40mL) with stirring for 30 minutes. The solid was then filtered and the filter cake was washed with diethyl ether (2 × 20mL) to yield 2-amino-4-fluoro-N- [ (1-methylpyrazol-4-yl) methyl ] benzamide (2.37g, 9.56mmol, 87%).

¹H NMR(300MHz,DMSO-d₆)＝8.55(t,J＝6.0Hz,1H),7.57(s,1H),7.54(dd,J＝6.6,8.9Hz,1H),7.33(s,1H),6.76(br.s,2H),6.44(dd,J＝2.6,11.9Hz,1H),6.29(app.td,J＝2.6,8.6Hz,1H),4.21(d,J＝5.7Hz,2H),3.78(s,3H)

The following intermediates were prepared in a similar manner:

intermediate S4-D22-amino-4-fluoro-N-methyl-benzamide

Prepared from 7-fluoro-isatoic anhydride and methylamine (2M in THF) in DCM, stirred at ambient temperature for 2 hours.

¹H NMR(300MHz,DMSO-d₆)＝8.16(br.s,1H),7.50(dd,J＝6.6,8.8Hz,1H),6.75(br.s,2H),6.44(dd,J＝2.6,11.9Hz,1H),6.30(app.td,J＝2.6,8.6Hz,1H),2.71(d,J＝4.5Hz,3H)

Intermediate S4-D32-amino-N- [ (1-methylpyrazol-4-yl) methyl ] benzamide

Prepared from itotic acid and C- (1-methyl-1H-pyrazol-4-yl) -methylamine, and heated at 50 ℃ for 3 hours.

¹H NMR(300MHz,DMSO-d₆)＝8.54(t,J＝5.8Hz,1H),7.57(s,1H),7.46(dd,J＝1.6,7.9Hz,1H),7.33(s,1H),7.12(ddd,J＝1.6,7.0,8.3Hz,1H),6.68(dd,J＝1.3,8.2Hz,1H),6.48(ddd,J＝1.2,6.9,8.0Hz,1H),6.41(s,2H),4.22(d,J＝5.7Hz,2H),3.78(s,3H)

Intermediate S4-D42-amino-N- [ (2-methylthiazol-5-yl) methyl ] benzamide

Prepared from itolmic acid and (2-methyl-1, 3-thiazol-5-yl) methylamine, stirred at 50 ℃ for 3 hours.

LCMS (high pH): RT 0.81min, [ M-H ]]^-246.1, 100% purity

Intermediate S4-D52-amino-N- [ (3-methylisoxazol-5-yl) methyl ] benzamide

Prepared from etoxic acid and (3-methylisoxazol-5-ylmethyl) amine and stirred at ambient temperature overnight.

¹H NMR(300MHz,DMSO-d₆)＝8.84(t,J＝5.9Hz,1H),7.53(dd,J＝1.6,8.0Hz,1H),7.16(ddd,J＝1.5,7.0,8.4Hz,1H),6.70(dd,J＝1.2,8.3Hz,1H),6.52(ddd,J＝1.3,7.0,8.1Hz,1H),6.46(s,2H),6.18(s,1H),4.48(dd,J＝0.9,5.9Hz,2H),2.22-2.18(m,3H)

Intermediate S4-E17-fluoro-3-methyl-1H-quinazoline-2, 4-dione

Triphosgene (564.67mg, 1.9mmol) was added to a solution of 2-amino-4-fluoro-N-methyl-benzamide (800mg, 4.76mmol) in 1, 4-dioxane (10mL) and the resulting solution was stirred at ambient temperature for 2 hours. The reaction was quenched by the addition of 1N NaOH (10mL) and allowed to stir at ambient temperature overnight. Volatiles were removed in vacuo and the resulting suspension was diluted with water (20mL) and filtered. The filter cake was washed with water (2X 10mL) and dried to give the desired product 7-fluoro-3-methyl-1H-quinazoline-2, 4-dione (512.1mg, 2.63mmol, 55%).

¹H NMR(300MHz,DMSO-d₆)＝11.56(br.s,1H),7.99(dd,J＝6.2,8.9Hz,1H),7.05(app.td,J＝2.5,8.8Hz,1H),6.90(dd,J＝2.4,9.9Hz,1H),3.24(s,3H),1.23(s,1H)

The following intermediates were prepared in a similar manner:

intermediate S4-E27-fluoro-3- [ (1-methylpyrazol-4-yl) methyl ] -1H-quinazoline-2, 4-dione

Prepared from 2-amino-4-fluoro-N- [ (1-methylpyrazol-4-yl) methyl ] benzamide and triphosgene in THF, after 1 hour at ambient temperature triethylamine (1 equivalent) was added and the reaction mixture was stirred at ambient temperature for an additional 1 hour.

¹H NMR(300MHz,DMSO-d₆)＝11.56(br.s,1H),8.00(dd,J＝6.1,8.9Hz,1H),7.64(s,1H),7.36(s,1H),7.06(app.td,J＝2.4,8.8Hz,1H),6.90(dd,J＝2.4,9.9Hz,1H),4.87(s,2H),3.33(s,3H)

Intermediate S4-E33- [ (1-methylpyrazol-4-yl) methyl ] -1H-quinazoline-2, 4-dione

Prepared from 2-amino-N- [ (1-methylpyrazol-4-yl) methyl ] benzamide and triphosgene in THF and stirred at ambient temperature overnight.

¹H NMR(300MHz,DMSO-d₆)＝11.43(br.s,1H),7.94(dd,J＝1.6,8.0Hz,1H),7.68-7.62(m,2H),7.36(s,1H),7.23-7.15(m,2H),4.89(s,2H),3.75(s,3H)

Intermediate S4-E43- [ (2-methylthiazol-5-yl) methyl ] -1H-quinazoline-2, 4-dione

Prepared from a solution of 2-amino-N- [ (2-methylthiazol-5-yl) methyl ] benzamide and triphosgene in THF and stirred at ambient temperature overnight.

LCMS (high pH): RT 0.83min, [ M + H ]]⁺274.1, 87% purity

Intermediate S4-E53- [ (3-methylisoxazol-5-yl) methyl ] -1H-quinazoline-2, 4-dione

Prepared from a solution of 2-amino-N- [ (3-methylisoxazol-5-yl) methyl ] benzamide and triphosgene in THF and stirred at ambient temperature overnight.

¹H NMR(300MHz,DMSO-d₆)＝11.63(br.s.,1H),7.95(ddd,J＝0.8,1.6,7.9Hz,1H),7.70(ddd,J＝1.5,7.3,8.2Hz,1H),7.27-7.20(m,2H),6.26(s,1H),5.17(s,2H),2.17(s,3H)

Intermediate S4-E67-fluoro-1, 3-dimethyl-quinazoline-2, 4-dione

Sodium hydride (60% w/w) (113.31mg, 2.83mmol) was added to a solution of 7-fluoro-3-methyl-1H-quinazoline-2, 4-dione (500.mg, 2.58mmol) in DMF (10mL) and the reaction mixture was stirred at ambient temperature for 1H. Methyl iodide (0.18mL, 2.83mmol) was then added and the resulting mixture was stirred at ambient temperature for 4 hours. After water treatment, the desired product 7-fluoro-1, 3-dimethyl-quinazoline-2, 4-dione was isolated (470mg, 2.26mmol, 88%).

¹H NMR(300MHz,DMSO-d₆)＝8.10(dd,J＝6.5,8.8Hz,1H),7.37(dd,J＝2.4,11.2Hz,1H),7.14(app.td,J＝2.4,8.6Hz,1H),3.49(s,3H),3.29(s,3H)

The following intermediates were prepared in a similar manner:

intermediate S4-E71-methyl-3- [ (3-methylisoxazol-5-yl) methyl ] quinazoline-2, 4-dione

Prepared from 3- [ (3-methylisoxazol-5-yl) methyl ] -1H-quinazoline-2, 4-dione/sodium hydride (60% w/w) and methyl iodide.

¹H NMR(300MHz,DMSO-d₆)＝8.07(dd,J＝1.6,7.8Hz,1H),7.82(ddd,J＝1.6,7.3,8.5Hz,1H),7.50(d,J＝8.3Hz,1H),7.34(ddd,J＝0.8,7.3,7.9Hz,1H),6.27(s,1H),5.22(s,2H),3.54(s,3H),2.17(s,3H)

Intermediate S4-F1

A solution of 7-fluoro-1, 3-dimethyl-quinazoline-2, 4-dione (400mg, 1.92mmol) in chlorosulfonic acid (3.mL, 1.92mmol) was heated at 60 ℃ for 24 hours. The reaction mixture was poured into ice (40mL) and the resulting suspension was filtered. The filter cake was washed with water (2X 10mL) to give the desired product 7-fluoro-1, 3-dimethyl-2, 4-dioxo-quinazoline-6-sulfonyl chloride (570mg, 1.86mmol, 97%).

¹H NMR(300MHz,DMSO-d₆)＝8.24(d,J＝7.9Hz,1H),7.21(d,J＝11.7Hz,1H),3.21(s,3H)

The following intermediates were prepared in a similar manner:

intermediate S4-F27-fluoro-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonyl chloride

Prepared from 7-fluoro-3- [ (1-methylpyrazole-4-yl) methyl ] -1H-quinazoline-2, 4-dione and chlorosulfonic acid.

LCMS (high pH): RT 0.84 min, [ M + H ]]⁺373.0, 90% purity

Intermediate 1A 1- [ (2, 4-Dimethylthiazol-5-yl) methyl ] -3-methyl-2, 4-dioxo-quinazoline-6-sulfonyl chloride

Step 1

To a stirred solution of 3-methyl-1H-quinazoline-2, 4-dione (846.75mg, 4.81mmol) and potassium carbonate (1.4g, 10.12mmol) in DMF (10mL) at 0 deg.C was added 5- (chloromethyl) -2, 4-dimethyl-1, 3-thiazole hydrochloride (1.0g, 5.06mmol) portionwise. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was poured into ice/water (50mL), and the resulting precipitate was collected by vacuum filtration to give 1- [ (2, 4-dimethylthiazol-5-yl) methyl ] ethyl ester]-3-methyl-quinazoline-2, 4-dione (1.3g, 4.17mmol, 82%).¹H NMR(300MHz,DMSO-d₆)＝8.09(dd,J＝1.5,7.7Hz,1H),7.80(ddd,J＝1.6,7.2,8.6Hz,1H),7.46(d,J＝8.2Hz,1H),7.32(ddd,J＝0.9,7.2,7.9Hz,1H),5.43(s,2H),3.34(s,3H),2.48(s,3H),2.47(s,3H)

Step 2

1- [ (2, 4-dimethylthiazol-5-yl) methyl]-3-methyl-quinazoline-2, 4-dione (1.2g, 4.00mmol) was added portionwise to chlorosulfonic acid (3.98mL, 59.7mmol), the reaction mixture was heated to 60 ℃ overnight, DCM (20mL) was added to the reaction mixture, which was then added dropwise to a stirred 1:1v/v mixture of ice/water and DCM, the organic layer was separated and the aqueous layer was washed with DCM (2 × 30mL), the organic layers were combined, washed with brine, passed through a hydrophobic frit, and concentrated to dryness, the product was dried in a vacuum oven at 40 ℃ for 1 hour, and was used without further purification, 1- [ (2, 4-dimethylthia-ne)Oxazol-5-yl) methyl]-3-methyl-2, 4-dioxo-quinazoline-6-sulfonyl chloride (1.5g, 3.83mmol, 96%).¹H NMR(300MHz,CDCl₃)＝8.91(d,J＝2.4Hz,1H),8.26(dd,J＝2.4,8.9Hz,1H),7.39(d,J＝9.0Hz,1H),5.44(s,2H),3.55(s,3H),2.61(s,3H),2.58(s,3H)

The method comprises the following steps: sulfonamide formation

The quinazolinedione sulfonyl chloride derivative (1 equivalent), amine (2-3 equivalents) and triethylamine (2-3 equivalents) in DCM were stirred at room temperature and monitored by LCMS; the reaction time may vary from 1 hour to overnight. The reaction mixture was diluted with 2m hcl (5mL) and DCM (5mL) and stirred vigorously for 10 min, then filtered through a hydrophobic frit and the organic layer was concentrated to dryness. Alternatively, the reaction mixture was evaporated to dryness. The crude product is formed by automatic column chromatography or preparative. HPLC, high pH purification to yield the desired product. For examples 5 and 204, pyridine was used without addition of triethylamine.

The following intermediates were prepared by method 1:

example 3847-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

Prepared from 7-fluoro-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonyl chloride, 1-methylcyclopropylamine hydrochloride and diisopropylamine in place of triethylamine.

Intermediate S4-G2N- (1-cyanocyclopropyl) -7-fluoro-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

Prepared from 7-fluoro-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonyl chloride, -1-amino-1-cyclopropanenitrile hydrochloride and pyridine (5mL) in place of DCM and triethylamine.

LCMS (high pH): RT 0.60 min, [ M + H ]]⁺419.1，>95% purity

The method 2 comprises the following steps: one-pot sulfonyl chloride formation/sulfonamide synthesis

Step 1

A mixture of the quinazolinedione intermediate (1 equivalent) in chlorosulfonic acid (20 equivalents) was heated at 60 ℃ for 3 hours. The cooled reaction mixture was added to crushed ice (about 50mL) with stirring and once the addition was complete DCM (30mL) was added and the mixture was stirred for 5 minutes. The DCM layer was separated by passage through a hydrophobic frit and the aqueous layer was washed with DCM. The combined DCM extracts were concentrated under reduced pressure.

Step 2

The crude sulfonyl chloride was dissolved in DMF (5mL) and the solution was added dropwise to a stirred solution of amine (1.5-3 equivalents), 4-dimethylaminopyridine (0.02 equivalents) and N, N-diisopropylethylamine (3 equivalents) in DMF (5mL) and heated at 60 ℃ overnight. The reaction mixture was cooled and concentrated under reduced pressure. DCM (20mL) and 1M HCl (15mL) were added and the mixture was stirred for 5 min. The DCM layer was separated by passage through a hydrophobic frit and the aqueous layer was washed with DCM. The combined DCM extracts were concentrated under reduced pressure and purified by automatic column chromatography to yield the desired product. Used to prepare examples 260 and 261.

The following intermediates were prepared by method 2:

example 336N- (1-Cyanocyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulphonamide

Prepared from 3- [ (1-methylpyrazole-4-yl) methyl ] -1H-quinazoline-2, 4-dione and chlorosulfonic acid. Then, the intermediates sulfonyl chloride, 1-amino-1-cyclopropanecarbonitrile hydrochloride, and pyridine (5mL) were used instead of 4-dimethylaminopyridine, N-diisopropylethylamine, and DMF.

Intermediate S4-G4N- (1-cyanocyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

Prepared from 3- [ (2-methylthiazol-5-yl) methyl ] -1H-quinazoline-2, 4-dione and chlorosulfonic acid. Then, the intermediates sulfonyl chloride, 1-amino-1-cyclopropanecarbonitrile hydrochloride, and pyridine (5mL) were used instead of 4-dimethylaminopyridine, N-diisopropylethylamine, and DMF.

LCMS (high pH): RT 0.68min, [ M + H ]]⁺418.1，>95% purity

Intermediate S4-H1N- (1-cyanocyclopropyl) -N- [ [3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] acetamide

Acetyl chloride (0.36mL, 4.99mmol) was added to N- (1-cyanocyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl]-2, 4-dioxo-1H-quinazoline-6-sulphonamide (1.g, 2.5mmol) and potassium carbonate (1.73g, 12.49mmol) in solution in DMF (20mL) and the reaction mixture was stirred at ambient temperature for 2 hours. EtOAc (100mL) and saturated NaHCO were added₃Aqueous solution (A), (B) and (C)100mL), the mixture was stirred for 5 minutes. The organic layer was separated and the aqueous layer was washed with EtOAc. The combined organic extracts were passed through a hydrophobic frit and concentrated under reduced pressure to give the crude product as a minimum volume of DMF. Water was added, causing a precipitate to form. The precipitate was filtered, washed with water and dried to give N- (1-cyanocyclopropyl) -N- [ [3- [ (1-methylpyrazol-4-yl) methyl ] N]-2, 4-dioxo-1H-quinazolin-6-yl]Sulfonyl radical]Acetamide (0.720g, 1.59mmol, 64%).

¹H NMR(300MHz,DMSO-d₆)＝11.99(br.s,1H),11.99(br.s,1H),8.13(dd,J＝2.5,8.8Hz,1H),7.67(s,1H),7.43-7.32(m,2H),4.89(s,2H),3.76(s,3H),2.30(s,3H),2.14-2.02(m,1H),1.98-1.85(m,2H),1.83-1.68(m,1H)

The following intermediates were prepared in a similar manner:

intermediate S4-H2N- (1-cyanocyclopropyl) -N- [ [3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] acetamide

Prepared from N- (1-cyanocyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, acetyl chloride and potassium carbonate.

¹H NMR(300MHz,DMSO-d₆)＝12.12(br.s.,1H),8.46(d,J＝2.3Hz,1H),8.15(dd,J＝2.4,8.7Hz,1H),7.61(s,1H),7.37(d,J＝8.9Hz,1H),5.19(s,2H),2.57(s,3H),2.30(s,3H),2.14-2.03(m,1H),2.01-1.88(m,2H),1.82-1.69(m,1H)

Intermediate S4-H3N- (1-cyanocyclopropyl) -N- [ [ 7-fluoro-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] acetamide

Prepared from N- (1-cyanocyclopropyl) -7-fluoro-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, acetyl chloride and potassium carbonate.

¹H NMR(300MHz,DMSO-d₆)＝12.09(br.s.,1H),8.42(d,J＝7.8Hz,1H),7.67(s,1H),7.38(s,1H),7.09(d,J＝11.2Hz,1H),4.88(s,2H),3.76(s,3H),2.36(s,3H),2.11-1.82(m,4H)

The method 3 comprises the following steps: pyrazole alkylation

A solution of 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (1H-pyrazol-4-ylmethyl) quinazoline-6-sulfonamide (example 183) (1 eq) and sodium hydride (60% w/w) (2.2 eq) in DMF was stirred at ambient temperature for 0.5H. Alkyl bromide (1 eq) was added to the reaction mixture and the reaction mixture was stirred at ambient temperature for 1-2 hours. Carefully add water (1mL) to the reaction mixture followed by 2M HCl (1 mL). DCM (10mL) was added and the mixture was stirred vigorously for 10 minutes, then passed through a hydrophobic frit. The aqueous layer was washed with DCM (5mL) and the combined organic phases were concentrated to dryness in vacuo. The crude product was purified by preparative HPLC at high pH to yield the desired product.

Alkylation of quinazolinediones

Method A1

The quinazolinedione intermediate (intermediates S2-D1-S2-D3, S4-C1, S4-C4, S4-C7 and S4-H1) (1 equivalent), potassium carbonate (1.2 equivalents), alkyl halide or mesylate (1.2-1.5 equivalents) were stirred in DMF at ambient temperature for 16 hours (shorter if LCMS indicated that the reaction was complete) (NaI (0.2 equivalent) was added if mesylate was used).

Examples 344-347, 355-359, 378 and 379 were prepared using potassium carbonate (4 equivalents).

When an N-acyl sulfonamide intermediate is used; once alkylation was complete, potassium carbonate (1 eq) and MeOH were added and the reaction mixture was stirred at ambient temperature for 3 hours. Alternatively, 500 μ L of concentrated ammonia was added and the reaction mixture was stirred for 2 hours. DCM (10mL) and saturated NH were added₄Aqueous Cl (10mL) and the mixture was stirred for 5 min. The DCM layer was separated by passage through a hydrophobic frit and the aqueous layer was washed with DCM.

Method A2

Quinazolinedione intermediates (intermediates S2-D1, S2-D2, S3-C, S4-C1-S4-C5 and S4-H1) (1 equivalent), diisopropyl azodicarboxylate (2 equivalents), alkyl alcohol (2 equivalents) PS-PPh₃(2 equivalents) and DMF are stirred at room temperature or 50 ℃ for 16 h (or less if LCMS indicates completion of the reaction).

For examples 341 and 342, the reaction was heated to 100 ℃.

When an N-acyl sulfonamide intermediate is used; once alkylation was complete, the reaction mixture was filtered through a frit and then potassium carbonate (1 eq) and MeOH were added to the filtrate and the mixture was stirred at ambient temperature for 3 hours. Alternatively, 500 μ L of concentrated ammonia was added and the reaction mixture was stirred for 2 hours. DCM (10mL) and NH were added₄Aqueous solution (10mL) was saturated with Cl, and the mixture was stirred for 5 minutes. The DCM layer was separated by passage through a hydrophobic frit and the aqueous layer was washed with DCM.

Method A3

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (intermediate S3-C) (1 equivalent), sodium hydride (60% w/w) (1.1 equivalents), alkyl halide or mesylate (1.1 equivalents) in DMF (if mesylate is used, NaI (0.2 equivalents) is added) and stirred at room temperature for 16 hours (or less if LCMS indicates completion of the reaction).

Method A4

Methanesulfonyl chloride (1.5 eq) and triethylamine (1.5 eq) were added to a solution of alcohol (1.5 eq) in THF and the reaction mixture was stirred for 2 hours. Cesium carbonate (1.5 equivalents) and the quinazolinedione intermediate (intermediate S2-D1) (1 equivalent) were added sequentially to the mesylate THF solution, DMF was added to aid solubility, and then potassium iodide (0.14 equivalents) was added. The reaction mixture was stirred at ambient temperature for 64 hours. DCM and saturated NaHCO were added₃The organic phase was separated from the aqueous solution and evaporated to dryness in Genevac. The crude product was purified by preparative HPLC at high pH. The resulting N-acyl product was dissolved in DCM, and potassium carbonate (10mg) was added while stirring the mixture for 2 hours. Water was added, the organic phase was separated with a hydrophobic frit and evaporated to dryness in Genevac to give the desired product.

Method A5

A solution of the quinazolinedione intermediates (intermediates S3-C, S4-C1-S4-C5 and S4-C8) (1 equivalent), cesium carbonate (1.1 equivalents), an alkyl halide or mesylate (1.1 equivalents) in DMF was stirred at ambient temperature for 1-16 hours (until LCMS indicated that the reaction was complete).

Method A6

The quinazolinedione intermediates (intermediates S4-C1 and S4-C2) (1 equivalent), cesium carbonate (3 equivalents), alkyl methanesulfonate (1.1 equivalents), potassium iodide (1.2 equivalents) in DMF were heated by microwave irradiation at 100 ℃ for 1 hour.

Method A7

The quinazolinedione intermediate (intermediate S4-C2) (1 equivalent), cesium carbonate (3 equivalents), an alkyl halide or mesylate (1.1 equivalents), potassium iodide (1.2 equivalents) in DMF was heated by microwave irradiation at 70 ℃ for 1 hour.

Method A8

The quinazolinedione intermediates (intermediates S3-C, S4-C1 and S4-C2) (1 equivalent), potassium carbonate (3 equivalents), alkyl halide or mesylate (1 equivalent), potassium iodide (1 equivalent) in DMF was stirred at ambient temperature for 48 hours.

Method A9

A solution of the quinazolinedione intermediates (intermediates S3-C, S4-C1 and S4-C2) (1 equivalent), potassium carbonate (2.2 equivalents), an alkyl halide or mesylate (1.2 equivalents), potassium iodide (1 equivalent) in DMF was heated by microwave irradiation at 80 ℃ for 15 minutes.

Method A10

The quinazolinedione intermediates (intermediates S4-C1 and S4-C2) (1 equivalent), potassium carbonate (1.2 equivalents), alkyl halide, mesylate or tosylate (1.2 equivalents) in DMF were heated by microwave irradiation at 80 deg.C for 10-20 minutes. The reaction mixture was monitored by LCMS and if < 10% product conversion, further heated by microwave irradiation at 100 ℃ for 1-2 hours. In some cases, sodium iodide (1.2 equivalents) was added to the reaction mixture as indicated.

For example 324, additional alkyl halide (1.2 equivalents) was added and the reaction mixture was heated by microwave irradiation at 120 ℃ for 1 hour.

For examples 337 and 338, potassium carbonate (2 equiv.) and alkyl bromide (2 equiv.) were used. These reactions were further heated by microwave irradiation at 100 ℃ for 2 hours.

Method A11

The quinazolinedione intermediate (intermediate S4-C1), tert-BuOK (3 equivalents), alkyl halide (1.2 equivalents) and potassium iodide (1.2 equivalents) in DMF was heated at 100 ℃ for 24 h.

Method A12

The quinazolinedione intermediate (intermediate S4-C2) (1 equivalent), potassium carbonate (1.2 equivalents), alkyl halide, mesylate or tosylate (1.2 equivalents) and sodium iodide (1.2 equivalents) in DMF were heated by microwave irradiation at 120 ℃ for 30 minutes.

Examples 332 and 339 were further heated by microwave irradiation at 130 ℃ for 1-2 hours.

Method A13

The quinazolinedione intermediate (intermediates S4-C1, S4-C2) (1 equivalent), potassium carbonate (1.2 equivalents), alkyl halide, mesylate or tosylate (1.2 equivalents) in DMF was irradiated by microwave irradiation at 100 ℃ for 30 minutes.

Examples 321, 361 and 340 were further heated by microwave irradiation at 100 ℃ or 120 ℃ for 30 minutes and then for 1 hour, respectively.

In example 368, additional alkyl bromide (0.6 eq) and sodium iodide (0.1 eq) were added and the reaction mixture was further heated by microwave irradiation at 100 ℃ for 30 minutes and then at 120 ℃ for 5 hours.

Method A14

The quinazolinedione intermediate (intermediates S4-C1, S4-C2) (1 equivalent), potassium carbonate (1.2 equivalents), alkyl halide, mesylate or tosylate (1.2 equivalents) and sodium iodide (1.2 equivalents) in DMF were heated by microwave irradiation at 130 ℃ for 1 hour and then heated for an additional 1 hour.

Examples 343 and 348 were heated for only 1 hour.

Example 330 uses potassium carbonate (3 equivalents) and alkyl chloride (3 equivalents).

Examples 371 and 372 used potassium carbonate (3 equivalents) and the reaction mixture was further heated by microwave irradiation at 135 ℃ for 5 hours.

Post-treatment of method A1-A14; the mixture was concentrated in vacuo and purified directly or after the following work-up, water and ethyl acetate were added and the layers were separated. The organic layer was washed with water and concentrated under reduced pressure. Purification by mass directed preparative HPLC or automatic column chromatography gave the desired product.

Deprotection of amines

Example 2323- [ (2-Aminothiazol-5-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide

Step 1

3- [ [2- (2, 5-dimethylpyrrol-1-yl) thiazol-5-yl ] methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide prepared from intermediate S3-C and [2- (2, 5-dimethylpyrrol-1-yl) thiazol-5-yl ] methanol using method a 2.

Step 2

3- [ [2- (2, 5-dimethylpyrrol-1-yl) thiazol-5-yl ] group]Methyl radical]-1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide (100.mg, 0.16mmol), hydroxylamine hydrochloride (171.08mg, 2.46mmol), and 2M NaOH (0.82mL, 1.64 mmol). The reaction mixture was concentrated and the residue was taken up in DCM and saturated NaHCO was added₃Aqueous solution and water, stirred for 5 minutes, and then passed through a hydrophobic frit and washed with DCM. The combined organics were concentrated and the residue was purified by preparative HPLC to give 3- [ (2-aminothiazol-5-yl) methyl]-1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide (8mg, 0.019mmol, 12%).

Example 2333- [ (3-Aminoisoxazol-5-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide

Step 1

Tert-butyl N- [5- [ [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] methyl ] isoxazol-3-yl ] carbamate was prepared according to method A3 from intermediate S3-C and tert-butyl N- [5- (bromomethyl) isoxazol-3-yl ] carbamate.

Step 2

A solution of tert-butyl N- [5- [ [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] methyl ] isoxazol-3-yl ] carbamate (130.74mg, 0.26mmol) in 1, 4-dioxane (2mL) was treated with a 4N HCl solution in 1, 4-dioxane (0.5mL, 2mmol) and stirred at ambient temperature for 2 hours, then heated at 45 ℃ for 27 hours. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to yield 3- [ (3-aminoisoxazol-5-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide (24mg, 0.059mmol, 23%).

Example 2631- (2-aminoethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide hydrochloride

Step 1

N- [2- [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] ethyl ] carbamic acid tert-butyl ester was prepared from intermediates S4-C1 and N-Boc-bromoethylamine using method A9.

Step 2

N- [2- [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1-yl ] ethyl ] carbamic acid tert-butyl ester (38.5mg, 0.070mmol) in 4M HCl in dioxane (2.mL, 8mmol) was stirred at ambient temperature for 2.5 hours. The reaction mixture was evaporated to dryness in vacuo and dried in a vacuum oven to yield 1- (2-aminoethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) -methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide hydrochloride (26mg, 0.060mmol, 83%).

Example 2853- [ (3-Aminoisoxazol-5-yl) methyl ] -1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulphonamide

Step 1

Tert-butyl N- [5- [ [ [ 2-amino-5- [ (1-methylcyclopropyl) sulfamoyl ] benzoyl ] amino ] methyl ] isoxazol-3-yl ] carbamate was prepared from 2, 4-dioxo-1H-3, 1-benzoxazine-6-sulfonyl chloride, 1-amino-1-cyclopropanenitrile hydrochloride and tert-butyl N- [5- (aminomethyl) isoxazol-3-yl ] carbamate using the route in scheme 4 for intermediate S4-B, and was then used directly in step 2 without purification.

Step 2

Tert-butyl N- [5- [ [6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-1H-quinazolin-3-yl ] methyl ] isoxazol-3-yl ] carbamate was prepared from tert-butyl N- [5- [ [ [ 2-amino-5- [ (1-methylcyclopropyl) sulfamoyl ] benzoyl ] amino ] methyl ] isoxazol-3-yl ] carbamate and triphosgene using the route in scheme 4 for intermediate S4-C, and then used directly in step 3 without purification.

Step 3

Tert-butyl N- [5- [ [1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] methyl ] isoxazol-3-yl ] carbamate was prepared from tert-butyl N- [5- [ [6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-1H-quinazolin-3-yl ] methyl ] isoxazol-3-yl ] carbamate and 5- (chloromethyl) -1, 3-dimethyl-pyrazole using method a 10.

Step 4

A solution of tert-butyl N- [5- [ [1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] methyl ] isoxazol-3-yl ] carbamate (20.Mg, 0.030mmol) and 4M HCl in 1, 4-dioxane (1mL) in dioxane (0.05mL, 0.20mmol) was stirred at ambient temperature for 2 hours, then heated at 50 ℃ for 5 hours, then at 35 ℃ for 16 hours for 2 days. The reaction mixture was evaporated to dryness and purified by preparative HPLC to give 3- [ (3-aminoisoxazol-5-yl) methyl ] -1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide (4mg, 0.008mmol, 30%).

Amide formation

Intermediate 1B 4- [ [6- [ acetyl- (1-methylcyclopropyl) sulfamoyl ] -3-methyl-2, 4-dioxo-quinazolin-1-yl ] methyl ] benzoic acid methyl ester

Prepared from N- ((3-methyl-2, 4-dioxo-1, 2,3, 4-tetrahydroquinazolin-6-yl) sulfonyl) -N- (1-methylcyclopropyl) acetamide (intermediate S2-D1) and methyl 4- (bromomethyl) benzoate using method a 1.

¹H NMR(300MHz,CDCl₃)＝8.75(d,J＝2.4Hz,1H),8.20(dd,J＝2.4,8.9Hz,1H),8.03(d,J＝8.6Hz,2H),7.32(d,J＝8.3Hz,2H),7.14(d,J＝8.9Hz,1H),5.45(br.s,2H),3.92(s,3H),3.57(s,3H),2.25(s,3H),1.58-1.37(m,1H),1.29-1.11(m,1H),1.08-0.85(m,2H)

Example 131N- (3-hydroxypropyl) -4- [ [ 3-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] benzamide;

a suspension of methyl 4- [ [6- [ acetyl- (1-methylcyclopropyl) sulfamoyl ] -3-methyl-2, 4-dioxo-quinazolin-1-yl ] methyl ] benzoate (intermediate 1B) (75.mg, 0.15mmol) and 3-amino-1-propanol (0.5mL, 6.54mmol) was heated by microwave irradiation at 120 ℃ for 30 minutes. LCMS indicated formation of carboxylic acid and desired product, and the reaction mixture was heated by microwave irradiation at 120 ℃ for an additional 30 minutes to see if the carboxylic acid would react. LCMS indicated reduction of the desired product with little change in carboxylic acid. EtOAc (10mL) and water (10mL) were added to the reaction mixture and the organic phase was separated, passed through a hydrophobic frit and evaporated to dryness. The crude product was purified by preparative HPLC at high pH to yield N- (3-hydroxypropyl) -4- [ [ 3-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] benzamide (9.5mg, 0.0190mmol, 13%).

Example 1383-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- [ [4- (piperazine-1-carbonyl) phenyl ] methyl ] quinazoline-6-sulfonamide;

step 1

Methyl 4- [ [6- [ acetyl- (1-methylcyclopropyl) sulfamoyl ] -3-methyl-2, 4-dioxo-quinazolin-1-yl ] methyl ] benzoate (intermediate 1B) (160.mg, 0.32mmol) in THF (5mL) and lithium hydroxide (15.3mg, 0.64mmol) and water (2mL) were heated at reflux for 4.5 h. The reaction mixture was removed by heating, cooled and treated with 2M HCl until acidic and a white precipitate formed. The white solid was filtered and dried in a vacuum oven to give 4- [ [ 3-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] benzoic acid (115mg, 0.26mmol, 81%) which was used without further purification.

Step 2

A solution of 4- [ [ 3-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] benzoic acid (55.0mg, 0.12mmol) and 1, 1' -carbonyldiimidazole (20.1mg, 0.12mmol) in DMF (2mL) was stirred at ambient temperature for 1 hour. Piperazine (12.8mg, 0.15mmol) was added and the reaction mixture was heated at 60 ℃ overnight. Water (10mL) and EtOAc (10mL) were added to the reaction mixture, the organic phase was separated, passed through a hydrophobic frit and evaporated to dryness. The crude product was purified by preparative HPLC at high pH to yield 3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1- [ [4- (piperazine-1-carbonyl) phenyl ] methyl ] quinazoline-6-sulfonamide (20mg, 0.039mmol, 32%).

Example 373N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (2-oxo-2-pyrrolidin-1-yl-ethyl) quinazoline-6-sulfonamide

A mixture of ethyl 2- [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] acetate (30.mg, 0.060mmol) and pyrrolidine (0.05mL, 0.63mmol) in DMF (1mL) was heated by microwave irradiation at 150 ℃ for 1 hour and then at 150 ℃ for 2 hours. The reaction mixture was diluted with water (10mL), acidified to pH 4 and extracted with EtOAc (2 × 20mL), the combined organic phases washed with brine (10mL), passed through a hydrophobic frit and evaporated to dryness. The crude product was purified by preparative HPLC at low pH to yield N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (2-oxo-2-pyrrolidin-1-yl-ethyl) quinazoline-6-sulfonamide (1mg, 0.002mmol, 3%).

Oxidation of mercaptans

Example 370N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (2-methylsulfonylethyl) -2, 4-dioxo-quinazoline-6-sulfonamide

Example 369N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (2-methylsulfinylethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

a solution of N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (2-methylsulfanylethyl) -2, 4-dioxo-quinazoline-6-sulfonamide (76.mg, 0.12mmol) in acetic acid (2mL) was treated with hydrogen peroxide (0.1mL, 3.26mmol) and stirred at ambient temperature for 4.5 h, then at 45 ℃ for 30 min. LCMS indicated the presence of sulfoxide and sulfone at about 1: 1. Saturated aqueous sodium sulfite (5mL) was added to the reaction mixture, then extracted with EtOAc (2 × 10mL), and the combined organics were washed with water (20mL), passed through a hydrophobic frit and concentrated to dryness. The crude product was purified by preparative HPLC at high pH to yield N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (2-methylsulfinylethyl) -2, 4-dioxo-quinazoline-6-sulfonamide (7mg, 0.015mmol, 12%) and N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (2-methylsulfonylethyl) -2, 4-dioxo-quinazoline-6-sulfonamide (23mg, 0.046mmol, 37%).

Example 3821- [ (1, 1-dioxothiadin-4-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

hydrogen peroxide (30% w/w) (0.93mL, 30.23mmol) was added at ambient temperature to a solution of N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (tetrahydrothiopyran-4-ylmethyl) quinazoline-6-sulfonamide (45.mg, 0.090mmol) in 1, 4-dioxane (2 mL). The reaction mixture was stirred at ambient temperature overnight. LCMS indicated 100% conversion to sulfoxide, but not to sulfone. 3-Chloroperbenzoic acid (15.39mg, 0.090mmol) was added and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water (20mL) and extracted with EtOAc (2X 20mL), and the combined organic phases were washed with aqueous sodium metabisulphite solution (10mL), passed through a hydrophobic frit and evaporated to dryness. The crude product was purified by preparative HPLC at high pH to yield 1- [ (1, 1-dioxothiadin-4-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazole) 5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide (23.0mg, 0.043mmol, 48%).

The following examples were prepared in a similar manner:

example 3831- [ (1, 1-dioxothian-4-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

prepared from N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (tetrahydrothiopyran-4-ylmethyl) ylquinazoline-6-sulfonamide, hydrogen peroxide (30% w/w) and 3-chloroperbenzoic acid.

General procedure for scheme 5:

intermediate S5-A6-bromo-2, 3-dihydrophthalazine-1, 4-dione

A stirred solution of 4-bromophthalic anhydride (50.g, 0.22mol) in acetic acid (150mL) was heated at 125 ℃ for 1 hour. The mixture was then cooled to ambient temperature and hydrazine hydrate (11.25mL, 0.23mol) was added dropwise over 5 minutes to form a thick white solid, acetic acid (50mL) was added and the mixture was heated at 125 ℃ for 30 minutes. The mixture was cooled and diluted with acetic acid (200mL) and then filtered. The filter cake was washed with acetic acid (3X 100mL) and dried under vacuum. The filter cake was then dissolved in 5% (w/w) NaOH solution (250mL) and the suspension was acidified with acetic acid (30mL) to give a thick white precipitate. The mixture was filtered and the filter cake was washed successively with water (2X 200mL) and methanol (2X 200mL) and then dried under vacuum at 40 ℃ to give a white solid, 6-bromo-2, 3-dihydrophthalazine-1, 4-dione (55g, 0.23mol, quantitative).

¹H NMR(300MHz,DMSO-d₆)＝8.16(dd,J＝0.7,2.0Hz,1H),7.98(dd,J＝0.7,8.4Hz,1H),7.93(d,J＝8.4Hz,1H),1.84(s,2H)

Intermediate S5-B-7-bromo-4-chlorophthalazin-1 (2H) -one

6-bromo-2, 3-dihydrophthalazine-1, 4-dione (25.g, 0.10mol) was added to a mixture of phosphorus oxychloride (100.mL, 1.06mol) and thionyl chloride (100.mL, 1.37mol) under nitrogen, cooled to 0 ℃. Once the initial exotherm had subsided, the reaction mixture was warmed to ambient temperature and then heated at 100 ℃ for 4 hours. The mixture was then cooled to ambient temperature and then concentrated under vacuum. The residue was dissolved in iPrOAc (350mL), washed with saturated sodium carbonate solution (addition until effervescence ceased), a precipitate formed, and the two layers were filtered to isolate the first intermediate. The organic layer was collected and distilled to dryness to give a second crop of intermediate. The solids were combined and partitioned between 1, 4-dioxane (200mL) and 2N NaOH (100 mL). The resulting mixture was heated at 40 ℃ overnight, and then cooled to ambient temperature and left to stand. The solid precipitate (first product) was filtered and the resulting solution was partitioned between EtOAc (250mL) and water (200 mL). Additional precipitate formed, which was filtered and mixed with the first batch of product, the organic phase was separated and evaporated to dryness to give a second batch of product. The isolated product was a mixture of two positional isomers, 7-bromo-4-chloro-2H-phthalazin-1-one and 6-bromo-4-chloro-2H-phthalazin-1-one, for a total of isolated products (17.6g, 68.0mmol, 66%).

¹H NMR(300MHz,DMSO-d₆) 13.02(s,1H),12.98(s,1H),8.36(d, J ═ 2.1Hz,1H),8.22(dd, J ═ 2.1,8.6Hz,1H),8.17-8.11(m,3H),7.93(d, J ═ 8.7Hz, 1H). 1:1, a mixture of two positional isomers.

Intermediate S5-C1-7- (benzylsulfanyl) -4-chlorophthalazin-1 (2H) -one

The reaction was carried out in two flasks containing the reagents described below, and then combined for work-up.

A stirred solution of 7-bromo-4-chloro-2H-phthalazin-1-one and 6-bromo-4-chloro-2H-phthalazin-1-one (8.82g, 33.99mmol) (mixture of regioisomers at about 1: 1), a solution of tris (dibenzylideneacetone) dipalladium (0) (1.56g, 1.7mmol) and Xantphos (1.97g, 3.4mmol) in 1, 4-dioxane (200mL) was degassed with nitrogen. N, N-diisopropylethylamine (12.1mL, 68.0mmol) and benzylthiol (7.98mL, 68.0mmol) were then added to the flask in that order, and the resulting mixture was heated at 60 ℃ for 18 hours.

The two flasks were combined and distilled to dryness, and the residue was suspended in DCM (200 mL). The mixture was stirred for 30 minutes and filtered to give the desired product as a mixture of the regioisomers of about 1:1, 7-benzylsulfanyl-4-chloro-2H-phthalazin-1-one and 6-benzylsulfanyl-4-chloro-2H-phthalazin-1-one. The isomer mixture was recrystallized from acetic acid (200mL) and hot filtered to remove inorganic impurities. The resulting crystalline solid was filtered and washed with AcOH and a minimal amount of diethyl ether to yield 7-benzylsulfanyl-4-chloro-2H-phthalazin-1-one (5.35g, 17.7mmol, 26%) as a white solid, which was dried in a vacuum oven at 40 ℃.

¹H NMR(300MHz,DMSO-d₆)＝12.86(s,1H),8.07(d,J＝2.1Hz,1H),7.95(dd,J＝2.1,8.6Hz,1H),7.87(d,J＝8.6Hz,1H),7.49-7.44(m,2H),7.37-7.24(m,3H),4.49(s,2H)

The following compounds were prepared by a similar method:

intermediate S5-C2-7-benzylsulfanyl-4-chloro-2-methyl-2, 3-phthalazin-1-one

Prepared from a mixture of the 1:1 positional isomers of 7-bromo-4-chloro-2-methyl-phthalazin-1-one and 6-bromo-4-chloro-2-methyl-phthalazin-1-one, benzylmercaptan, tris (dibenzylideneacetone) dipalladium (0), Xantphos and N, N-diisopropylethylamine.

LCMS (high pH): RT 1.34 min, [ M ] +317.2, 93% purity

Intermediate S5-D17-benzylsulfanyl-4-chloro-2- [ (3-methylisoxazol-5-yl) methyl ] phthalazin-1-one

A solution of 7-benzylsulfanyl-4-chloro-2H-phthalazin-1-one (500.Mg, 1.65mmol) in DMF (15mL) was cooled in an ice bath, treated with sodium hydride (60% w/w) (69.35Mg, 1.73mmol) and the resulting mixture stirred at ambient temperature for 1H. To the reaction was added 5- (bromomethyl) -3-methyl-1, 2-oxazole (0.22mL, 1.73mmol) and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with water (50mL) and extracted with DCM (2X 50 mL). The organic layer was passed through a hydrophobic frit and concentrated to dryness and the crude product was purified by automatic column chromatography eluting with 0-40% EtOAc in isopropanol to yield the desired product 7-benzylsulfanyl-4-chloro-2- [ (3-methylisoxazol-5-yl) methyl ] phthalazin-1-one (554mg, 1.37mmol, 83%).

¹H NMR(300MHz,CDCl₃)＝8.26(d,J＝2.0Hz,1H),7.84(d,J＝8.6Hz,1H),7.69(dd,J＝2.0,8.6Hz,1H),7.44-7.28(m,5H),6.14(s,1H),5.43(s,2H),4.33(s,2H),2.28(s,3H)

The following compounds were prepared by a similar method:

intermediate S5-D27-bromo-4-chloro-2-methyl-phthalazin-1-one

Prepared from a mixture of 7-bromo-4-chloro-2H-phthalazin-1-one and 6-bromo-4-chloro-2H-phthalazin-1-one and methyl iodide.

¹H NMR(300MHz,DMSO-d₆) 8.38(d, J ═ 2.0Hz,1H),8.23-8.17(m,2H),8.16-8.12(m,2H),7.94(d, J ═ 8.6Hz,1H),3.70(s,3H),3.69(s, 3H). 1:1 mixture of two positional isomers.

Intermediate S5-E1(2,3,4,5, 6-pentafluorophenyl) 1-chloro-3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonate

To 7-benzylsulfanyl-4-chloro-2- [ (3-methylisoxazol-5-yl) methyl at 0 deg.C]To a solution of phthalazin-1-one (1.80g, 4.52mmol) in a mixture of MeCN (50mL) acetic acid (5mL) and water (3mL) was added 1, 3-dichloro-5, 5-dimethylhydantoin (1.78g, 9.05mmol) and the resulting mixture was stirred at 0 ℃ for 1 hour. Pentafluorophenol (0.95mL, 9.05mmol) was added, and the resulting mixture was stirred at 0 ℃ for 15 minutes, triethylamine (1.77mL, 12.7mmol) was added, and the resulting mixture was stirred at 0 ℃ for 30 minutes. The reaction mixture was evaporated to dryness and the crude product was purified by automatic column chromatography (SiO)₂RediSep, 12g) 0-80% EtOAc in isohexane purification to yield (2,3,4,5, 6-pentafluorophenyl) 1-chloro-3- [ (3-methylisoxazol-5-yl) methyl]-4-oxo-phthalazine-6-sulfonate (1.90g, 3.64mmol, 80%).

¹H NMR(300MHz,CDCl₃)＝9.04(d,J＝2.4Hz,1H),8.45(dd,J＝2.0,8.6Hz,1H),8.27(d,J＝8.6Hz,1H),6.22(s,1H),5.48(s,2H),2.30(s,3H)

The following compounds were prepared by a similar method:

intermediate S5-E2- (2,3,4,5, 6-pentafluorophenyl) 1-chloro-3-methyl-4-oxo-phthalazine-6-sulfonate

From a 1:1 mixture of the positional isomers 7-benzylsulfanyl-4-chloro-2-methyl-phthalazin-1-one and 6-benzylsulfanyl-4-chloro-2-methyl-phthalazin-1-one, 1, 3-dichloro-5, 5-dimethylhydantoin, pentafluorophenol and triethylamine. Purification by automatic column chromatography allows isolation of the product desired isomer.

¹H NMR(300MHz,CDCl₃)＝9.04(d,J＝1.9Hz,1H),8.42(dd,J＝2.0,8.6Hz,1H),8.25(d,J＝8.6Hz,1H),3.89(s,3H)

Example 2621-chloro-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

to (2,3,4,5, 6-pentafluorophenyl) -1-chloro-3- [ (3-methylisoxazol-5-yl) methyl under a nitrogen atmosphere at ambient temperature]To a stirred solution of-4-oxo-phthalazine-6-sulfonate (900.mg, 1.72mmol) and 1-methylcyclopropylamine hydrochloride (204.09mg, 1.9mmol) in DCM (20mL) was added triethylamine (0.53mL, 3.79 mmol). The reaction mixture was heated at 40 ℃ for 2 hours. The reaction mixture was evaporated to dryness and partitioned between DCM (10mL) and water (10 mL). The organic phase was collected and evaporated to dryness and the crude product was purified by automatic column chromatography (SiO)₂RediSep, 12g) eluent was purified in isohexane with 0-70% EtOAc to give 1-chloro-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl]-4-oxo-phthalazine-6-sulfonamide (400.0mg, 0.98mmol, 57%).

¹H NMR(300MHz,DMSO-d₆)＝8.65(d,J＝8.0Hz,1H),8.57(s,1H),8.37(dd,J＝2.1,8.6Hz,1H),8.26(d,J＝8.5Hz,1H),6.43(s,1H),5.45(s,2H),2.20(s,3H),1.08(s,3H),0.64-0.57(m,2H),0.47-0.39(m,2H)

The following compounds were prepared by a similar method:

example 2271-chloro-3-methyl-N- (1-methylcyclopropyl) -4-oxo-phthalazine-6-sulfonamide;

from (2,3,4,5, 6-pentafluorophenyl) 1-chloro-3-methyl-4-oxo-phthalazine-6-sulfonate, 1-methylcyclopropylamine hydrochloride and triethylamine.

¹H NMR(300MHz,CDCl₃)＝8.95(d,J＝1.9Hz,1H),8.35(dd,J＝2.0,8.5Hz,1H),8.13(d,J＝8.5Hz,1H),5.21(s,1H),3.87(s,3H),1.25(s,3H),0.81-0.74(m,2H),0.59-0.51(m,2H)

N-substituted phthalazinones

The method 4 comprises the following steps: substituted by amines

A mixture of 1-chloro-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide (intermediate S5-F1) (1 eq) and amine (20 eq) in ethanol (1mL) was heated by microwave irradiation at 180 ℃ for 30 minutes. LCMS analysis incomplete reaction. The reaction mixture was further heated by microwave irradiation at 180 ℃ for 1 hour, twice.

The reaction mixture was evaporated to dryness and the crude product was purified by preparative HPLC, high pH, to give the desired product.

Example 2343-methyl-1- (methylamino) -N- (1-methylcyclopropyl) -4-oxo-phthalazine-6-sulfonamide;

a mixture of 1-chloro-3-methyl-N- (1-methylcyclopropyl) -4-oxo-phthalazine-6-sulfonamide (80.Mg, 0.2400mmol) and methylamine (2M in THF) (1.mL, 24.34mmol) was heated by microwave irradiation at 180 ℃ for 1 hour. The reaction mixture was partitioned between EtOAc (4mL) and water (4 mL). The EtOAc layer was collected and washed with water (4mL) then distilled to dryness. The crude product was purified by preparative HPLC, low pH, to give the desired product 3-methyl-1- (methylamino) -N- (1-methylcyclopropyl) -4-oxo-phthalazine-6-sulfonamide (20mg, 0.062mmol, 25%).

The following compounds were prepared by a similar method:

example 244-1- (methylamino) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide

Prepared from 1-chloro-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide and methylamine (2M solution in THF).

Example 299N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

prepared from 1-chloro-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide and cyclopropylamine as a by-product after heating by microwave irradiation at 180 ℃ for 30 minutes under the conditions of method 4.

O-substituted phthalazinones

The method 5 comprises the following steps: alcohol substitution

1-chloro-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide (intermediate S5-F1) (1 eq) was added to a suspension of alcohol (3 eq) and potassium tert-butoxide (4 eq) in MeCN (1 mL). The reaction mixture was heated to reflux in a sealed Wheaton vial for 30 minutes and then stirred at ambient temperature overnight. To the reaction mixture was added water (20mL) and EtOAc (20mL), and the aqueous phase was acidified to pH2 with 2M HCl. The organic phase was separated, further extracted with EtOAc (20mL), the organic phases combined, passed through a hydrophobic frit and evaporated to dryness. The crude product was purified by automatic column chromatography eluting with EtOAc in isohexane.

Example 3121-methoxy-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

sodium methoxide (0.5N in methanol) (22.65uL, 0.12mmol) was added dropwise to 1-chloro-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol) -5-yl) methyl]-suspension of 4-oxo-phthalazine-6-sulfonamide (50.Mg, 0.12mmol) in MeCN (1 mL). The reaction mixture was stirred at ambient temperature for 4.5 hours, then additional sodium methoxide (0.5N in methanol) (45.2uL, 0.24mmol) was added and the reaction mixture heated to reflux in a sealed Wheaton vial for 24 hours. Water (20mL) and EtOAc (20mL) were added to the reaction mixture, the aqueous phase was acidified to pH2 with 2M HCl, and the organic phase was separated. The aqueous phase was further extracted with EtOAc (20mL) and the combined organic phases were passed through a hydrophobic frit and evaporated to dryness. The crude product was passed through automated column chromatography on wet SiO in DCM₂(RediSep, 4g) purification eluting with 0-50% EtOAc in isohexane to yield 1-methoxy-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl]-4-oxo-phthalazine-6-sulfonamide (25.2mg, 0.062mmol, 51%).

Example 3161-ethoxy-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

a suspension of 1-chloro-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide (40.Mg, 0.10mmol), cyclohexylamine (0.22mL, 1.96mmol), and cesium fluoride (14.86Mg, 0.10mmol) in ethanol (1mL) was heated to reflux in a sealed Wheaton vial for 7 days (LCMS indicated the ethoxy product formed, no amine substituted product). Water (10mL) and EtOAc (20mL) were added to the reaction mixture, the aqueous phase was acidified to pH2 with 2M HCl, and the reaction mixture was extracted with EtOAc (20 mL). The organic phase was separated, passed through a hydrophobic frit and evaporated to dryness. The crude product was purified by preparative HPLC, high pH, to yield 1-ethoxy-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide (13.1mg, 0.031mmol, 32%).

C-substituted phthalazinones

Example 2831- [3- (dimethylamino) prop-1-ynyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide;

1-chloro-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl in THF (1mL)]A mixture of-4-oxo-phthalazine-6-sulfonamide (intermediate S5-F1) (50.mg, 0.12mmol), 3-dimethylamide-1-propyne (19.75uL, 0.18mmol), isopropylamine (15.76uL, 0.18mmol), tetra-N-butylammonium iodide (45.17mg, 0.12mmol), tetrakis (triphenylphosphine) palladium (0) (8.49mg, 0.01mmol) and copper (I) iodide (2.79mg, 0.01mmol) was placed in a reactor vial. The tube was sealed and the mixture was heated in the absence of light for 16 hours. The solvent and volatiles escaped from the flask, leaving a residue. THF (2mL) was added to dissolve the residue. The flask was refilled with diisopropylamine (25.71. mu.l, 0.18mmol), tetrakis (triphenylphosphine) palladium (0) (8.49mg, 0.01mmol), copper (I) iodide (2.79mg, 0.01mmol) and 3-dimethylamino-1-propyne (19.75uL, 0.18 mmol). The flask was sealed and heated at 80 ℃ overnight. The mixture was distilled to dryness, and the residue was between DCM (10mL) and water (10mL)And (6) distributing. The DCM layer was collected and distilled to dryness to give a residue which was purified by preparative HPLC, high pH, to give the desired product, accompanied by the presence of triphenylphosphine oxide and tetra-N-butylammonium iodide. Passing the material through an automatic column chromatography, SiO₂(RediSep, 4g), purification in 0-10.0% MeOH eluent in DCM to give the desired product 1- [3- (dimethylamino) prop-1-ynyl]-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl]-4-oxo-phthalazine-6-sulfonamide (20mg, 0.044mmol, 36%).

Example 2841-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide

Nitrogen was bubbled through a stirred solution of 1-chloro-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide (intermediate S5-F1) (40.mg, 0.10mmol) and iron (III) acetylacetonate (1.3mg, 0.04mmol) in THF (2mL) at 0 ℃ for 5 minutes. Methyl magnesium bromide (104.82uL, 0.15mmol) was added to the solution in a dropwise addition and the resulting mixture was stirred at 0 ℃ for 30 minutes. The reaction mixture was quenched with water (2mL), acidified with 2N HCl (2mL), and extracted with EtOAc (2X 10 mL). The combined organics were distilled to dryness to give the crude product as a residue which was purified by preparative HPLC, high pH, to give the desired product 1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-6-sulfonamide (10.1mg, 0.026mmol, 26%).

General procedure for scheme 6:

the method 6 comprises the following steps: general procedure for the Synthesis of 7-bromo-4-substituted-phthalazin-1 (2H) -ones

A2.0M solution of isopropyl magnesium chloride in THF (1.65mmol) was added to a magnetically stirred solution of 5-bromo-2-iodobenzoate (1.50mmol) in THF (10mL) at-78 deg.C, and the resulting mixture was stirred at 0 deg.C for 30 minutes. To this orange solution was added zinc bromide (1.65mmol dried under vacuum with a hot air gun) to give a thick yellow precipitate which was stirred at 0 ℃ for 15 min. The acid chloride (1.80mmol) and tetrakis (triphenylphosphine) palladium (0) (0.070mmol) were then added to the reaction and the resulting mixture was heated at 60 ℃ for 2 hours. The mixture was cooled to ambient temperature and saturated NH was added₄The resulting solution was extracted with diethyl ether (2 × 20mL), and the combined extracts were MgSO₄And (5) drying. The solvent was removed in vacuo to give the crude acylate as a residue, which was dissolved in ethanol (10 mL). Hydrazine (1.50mmol) was added to the ethanol solution and the resulting mixture was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo to give the crude phthalazinone product as a residue which was purified by silica gel column chromatography eluting with a gradient of 0 to 80% EtOAc in hexanes to give the desired product.

The following intermediates were prepared by similar methods:

intermediate S6-A17-bromo-4-ethylphthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7-bromo-4-substituted-phthalazin-1 (2H) -one using propionyl chloride as the acid chloride component. The desired product was isolated as a white solid in 52% yield.

¹H NMR(300MHz,CDCl₃)＝10.11(br.s.,1H),8.63(d,J＝2.0Hz,1H),7.96(dd,J＝2.1,8.6Hz,1H),7.72(d,J＝8.6Hz,1H),2.98(q,J＝7.4Hz,2H),1.37(t,J＝7.4Hz,4H)

Intermediate S6-A27-bromo-4-isopropylphthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7-bromo-4-substituted-phthalazin-1 (2H) -one using isopropanoyl chloride as the acid chloride component. The desired product was isolated as a white solid in 40% yield.

¹H NMR(300MHz,DMSO-d₆)＝12.66(s,1H),8.36(d,J＝2.0Hz,1H),8.12(dd,J＝2.2,8.7Hz,1H),8.02(d,J＝8.7Hz,1H),3.54(quin,J＝6.8Hz,1H),1.26(d,J＝6.8Hz,6H)

Intermediate S6-A37-bromo-4-cyclopropylphthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7-bromo-4-substituted-phthalazin-1 (2H) -one using cyclopropanecarbonyl chloride as the acid chloride component. The desired product was isolated as a white solid in 46% yield.

¹H NMR(300MHz,DMSO-d₆)＝12.55(s,1H),8.33(d,J＝1.7Hz,1H),8.20(d,J＝8.5Hz,1H),8.17(dd,J＝2.1,8.7Hz,1H),2.47-2.36(m,1H),1.02-0.84(m,4H)

Intermediate S6-A47-bromo-4-cyclopentylphthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7-bromo-4-substituted-phthalazin-1 (2H) -one using cyclopentanecarbonyl chloride as the acid chloride component. The desired product was isolated as a white solid in 39% yield.

¹H NMR(300MHz,DMSO-d₆)＝12.61(s,1H),8.34(d,J＝2.1Hz,1H),8.10(dd,J＝2.2,8.7Hz,1H),8.03(d,J＝8.7Hz,1H),3.63(quin,J＝7.7Hz,1H),2.10-1.94(m,2H),1.89-1.60(m,6H)

Intermediate S6-A57-bromo-4- (cyclopropylmethyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7-bromo-4-substituted-phthalazin-1 (2H) -one using 2-cyclopropylacetyl chloride as the acid chloride component. The desired product was isolated as a white solid in 46% yield.

¹H NMR(300MHz,DMSO-d₆)＝12.64(s,1H),8.35(d,J＝2.2Hz,1H),8.11(t,J＝4.9Hz,1H),7.98(d,J＝8.7Hz,1H),2.83(d,J＝6.8Hz,2H),1.14-1.03(m,1H),0.54-0.43(m,2H),0.27-0.20(m,2H)

Intermediate S6-A67-bromo-4- (cyclobutylmethyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7-bromo-4-substituted-phthalazin-1 (2H) -one using 2-cyclobutylacetyl chloride as the acid chloride component. The desired product was isolated as a white solid in 47% yield.

¹H NMR(300MHz,DMSO-d₆)＝12.62(s,1H),8.33(d,J＝2.0Hz,1H),8.10(dd,J＝2.2,8.6Hz,1H),7.95(d,J＝8.7Hz,1H),3.01(d,J＝7.4Hz,2H),2.81-2.65(m,1H),2.11-1.95(m,2H),1.89-1.65(m,4H)

Intermediate S6-A77-bromo-4- (cyclohexylmethyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7-bromo-4-substituted-phthalazin-1 (2H) -one using cyclohexanecarbonyl chloride as the acid chloride component. The desired product was isolated as a white solid in 48% yield.

¹H NMR(300MHz,CDCl₃)＝9.93(br.s.,1H),8.63(d,J＝2.1Hz,1H),7.96(dd,J＝2.1,8.6Hz,1H),7.70(d,J＝8.6Hz,1H),2.79(d,J＝6.7Hz,2H),1.75(d,J＝12.2Hz,5H),1.29-1.01(m,6H)

Intermediate S6-A87-bromo-4- ((tetrahydro-2H-pyran-4-yl) methyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7-bromo-4-substituted-phthalazin-1 (2H) -one using 2- (tetrahydro-2H-pyran-4-yl) acetyl chloride as the acid chloride component. The desired product was isolated as a white solid in 41% yield.

¹H NMR(300MHz,DMSO-d₆)＝12.78-12.53(m,1H),8.35(d,J＝2.2Hz,1H),8.10(dd,J＝2.2,8.6Hz,1H),8.00(d,J＝8.5Hz,1H),3.88-3.72(m,2H),3.30-3.17(m,2H),2.84(d,J＝7.2Hz,2H),2.05-1.88(m,1H),1.58(m,2H),1.39-1.19(m,2H)

Intermediate S6-A94-benzyl-7-bromophthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7-bromo-4-substituted-phthalazin-1 (2H) -one using 2-phenylacetyl chloride as the acid chloride component. The desired product was isolated as a white solid in 48% yield.

¹H NMR(300MHz,DMSO-d₆)＝12.76(s,1H),8.34(d,J＝2.1Hz,1H),8.05(dd,J＝2.2,8.7Hz,1H),7.88(d,J＝8.7Hz,1H),7.33-7.14(m,5H),4.29(s,2H)

Intermediate S6-A107-bromo-4- (3-methoxybenzyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7-bromo-4-substituted-phthalazin-1 (2H) -one using 2- (3-methoxyphenyl) acetyl chloride as the acid chloride component. The desired product was isolated as a white solid in 45% yield.

¹H NMR(300MHz,CDCl₃)＝10.01(br.s.,1H),8.60(d,J＝2.1Hz,1H),7.84(dd,J＝2.1,8.6Hz,1H),7.63(d,J＝8.7Hz,1H),7.27-7.20(m,1H),6.89-6.76(m,3H),4.26(s,2H),3.79(s,3H)

Intermediate S6-A116-bromo-4-oxo-3, 4-dihydrophthalazine-1-carboxylic acid methyl ester

This compound was prepared according to the general procedure described above for the synthesis of 7-bromo-4-substituted-phthalazin-1 (2H) -one using methyl 2-chloro-2-oxoacetate as the acid chloride component. The desired product was isolated as a white solid in 50% yield.

¹H NMR(300MHz,DMSO-d₆)＝13.36(s,1H),8.51(d,J＝8.9Hz,1H),8.38(d,J＝2.0Hz,1H),8.19(dd,J＝2.2,8.8Hz,1H),3.92(s,3H)

The method 7 comprises the following steps: general procedure for the Synthesis of 7- (benzylsulfanyl) -4-substituted-phthalazin-1 (2H) -ones

To a magnetically stirred solution of 7-bromo-4-substituted-phthalazin-1 (2H) -one (0.65mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.030mmol) in 1, 4-dioxane (10mL) was added Xantphos (0.060mmol) under a nitrogen atmosphere at 20 ℃, and the resulting mixture was stirred at ambient temperature for 5 minutes. N, N-diisopropylethylamine (0.68mmol) was then added to the reaction, followed by benzyl mercaptan (81.58uL, 0.6800mmol), and the resulting mixture was heated at 60 ℃ for 1 hour. The mixture was cooled to ambient temperature and distilled to dryness to give a residue which was solid supported on silica and purified by automatic column chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in hexane to give the desired product.

Intermediate S6-B17- (benzylsulfanyl) -4-ethylphthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-phthalazin-1 (2H) -one using 7-bromo-4-ethylphthalazin-1 (2H) -one. The desired product was isolated as a yellow solid in 95% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.08(d,J＝1.7Hz,1H),7.87(d,J＝8.3Hz,1H),7.85(dd,J＝2.0,8.6Hz,1H),7.48-7.41(m,2H),7.37-7.22(m,3H),4.45(s,2H),2.91(q,J＝7.4Hz,2H),1.23(d,J＝7.4Hz,4H)

Intermediate S6-B27- (benzylsulfanyl) -4-isopropylphthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-phthalazin-1 (2H) -one using 7-bromo-4-isopropyl-phthalazin-1 (2H) -one. The desired product was isolated as a yellow solid in 79% yield.

¹H NMR(300MHz,DMSO-d₆)＝12.48(s,1H),8.09(d,J＝2.1Hz,1H),7.95(d,J＝8.7Hz,1H),7.83(dd,J＝2.2,8.6Hz,1H),7.52-7.41(m,2H),7.37-7.25(m,3H),4.45(s,2H),3.58-3.44(m,1H),1.24(d,J＝6.8Hz,6H)。

Intermediate S6-B37- (benzylthio) -4-cyclopropylphthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-phthalazin-1 (2H) -one using 7-bromo-4-cyclopropyl-phthalazin-1 (2H) -one. The desired product was isolated as an orange solid in 92% yield.

¹H NMR(300MHz,DMSO-d₆)＝12.37(s,1H),8.14(d,J＝8.6Hz,1H),8.07(d,J＝1.9Hz,1H),7.88(dd,J＝2.2,8.6Hz,1H),7.48-7.42(m,2H),7.37-7.23(m,3H),4.46(s,2H),2.44-2.33(m,1H),0.96-0.83(m,4H)。

Intermediate S6-B47- (benzylsulfanyl) -4-cyclopentylphthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-phthalazin-1 (2H) -one using 7-bromo-4-cyclopentylphthalazin-1 (2H) -one. The desired product was isolated as a brown solid in 88% yield.

¹H NMR(300MHz,DMSO-d₆)＝12.44(s,1H),8.08(d,J＝2.1Hz,1H),7.95(d,J＝8.7Hz,1H),7.82(dd,J＝2.1,8.6Hz,1H),7.47-7.42(m,2H),7.36-7.23(m,3H),4.45(s,2H),3.59(t,J＝7.7Hz,1H),2.08-1.90(m,2H),1.86-1.60(m,6H)。

Intermediate S6-B57- (benzylsulfanyl) -4- (cyclopropylmethyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-phthalazin-1 (2H) -one using 7-bromo-4- (cyclopropylmethyl) phthalazin-1 (2H) -one. The desired product was isolated as a yellow solid in 87% yield.

¹H NMR(300MHz,DMSO-d₆)＝12.46(s,1H),8.08(d,J＝2.1Hz,1H),7.93-7.87(m,1H),7.87-7.81(m,1H),7.51-7.39(m,2H),7.38-7.22(m,3H),4.45(s,2H),2.80(d,J＝6.9Hz,2H),1.13-1.03(m,1H),0.51-0.43(m,2H),0.25-0.19(m,2H)

Intermediate S6-B67- (benzylthio) -4- (cyclobutylmethyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-phthalazin-1 (2H) -one using 7-bromo-4- (cyclobutylmethyl) phthalazin-1 (2H) -one. The desired product was isolated as a white solid in 95% yield.

¹H NMR(300MHz,DMSO-d₆)＝12.44(s,1H),8.06(d,J＝2.0Hz,1H),7.88(d,J＝8.6Hz,1H),7.82(dd,J＝2.1,8.5Hz,1H),7.47-7.42(m,2H),7.37-7.24(m,3H),4.45(s,2H),2.97(d,J＝7.4Hz,2H),2.10-1.95(m,2H),1.89-1.68(m,5H)

Intermediate S6-B77- (benzylsulfanyl) -4- (cyclohexylmethyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-phthalazin-1 (2H) -one using 7-bromo-4- (cyclohexylmethyl) phthalazin-1 (2H) -one. The desired product was isolated as a white solid in 95% yield.

¹H NMR(300MHz,CDCl₃)＝9.78(br.s.,1H),8.35-8.31(m,1H),7.68-7.63(m,2H),7.45-7.40(m,1H),7.37-7.28(m,3H),4.33(s,2H),2.75(d,J＝6.6Hz,2H),1.81-1.66(m,6H),1.26-1.02(m,5H)

Intermediate S6-B87- (benzylsulfanyl) -4- ((tetrahydro-2H-pyran-4-yl) methyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-phthalazin-1 (2H) -one using 7-bromo-4- ((tetrahydro-2H-pyran-4-yl) methyl) phthalazin-1 (2H) -one. The desired product was isolated as a yellow solid in 79% yield.

¹H NMR(300MHz,DMSO-d₆)＝12.49(s,1H),8.08(d,J＝2.1Hz,1H),7.93(d,J＝8.7Hz,1H),7.82(dd,J＝2.1,8.5Hz,1H),7.46(d,J＝7.5Hz,2H),7.37-7.23(m,3H),4.46(s,2H),3.81(dd,J＝2.7,11.8Hz,2H),3.28-3.16(m,2H),2.80(d,J＝7.1Hz,2H),2.02-1.87(m,1H),1.57(d,J＝12.2Hz,2H),1.33-1.21(m,2H)。

Intermediate S6-B94-benzyl-7- (benzylthio) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-phthalazin-1 (2H) -one using 4-benzyl-7-bromophthalazin-1 (2H) -one. The desired product was isolated as a white solid in 95% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.06(d,J＝1.8Hz,1H),7.82(d,J＝8.6Hz,1H),7.76(dd,J＝2.0,8.6Hz,1H),7.47-7.39(m,2H),7.36-7.15(m,8H),4.43(s,2H),4.25(s,2H)

Intermediate S6-B107- (benzylthio) -4- (3-methoxybenzyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-phthalazin-1 (2H) -one using 7-bromo-4- (3-methoxybenzyl) phthalazin-1 (2H) -one. The desired product was isolated as a white solid in 89% yield.

¹H NMR(300MHz,CDCl₃)＝9.89(s,1H),8.30(d,J＝1.9Hz,1H),7.61(d,J＝8.6Hz,1H),7.55(dd,J＝2.1,8.6Hz,1H),7.45-7.19(m,11H),6.89-6.75(m,3H),4.30(s,2H),4.23(s,2H),3.78(s,3H)

Intermediate S6-B116- (benzylthio) -4-oxo-3, 4-dihydrophthalazine-1-carboxylic acid methyl ester

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-phthalazin-1 (2H) -one using methyl 6-bromo-4-oxo-3, 4-dihydrophthalazin-1-carboxylate. The desired product was isolated as a white solid in 95% yield.

¹H NMR(300MHz,DMSO-d₆)＝13.17(br.s.,1H),8.08(d,J＝2.1Hz,1H),7.91(dd,J＝2.2,8.8Hz,1H),7.49-7.42(m,2H),7.37-7.22(m,3H),4.47(s,2H),3.90(s,3H)

The method 8 comprises the following steps: synthesis of 7- (benzylthio) -4-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one By means of programs

To a magnetically stirred solution of 7- (benzylthio) -4-substituted-phthalazin-1 (2H) -one (0.40mmol) in DMF (8mL) at 20 ℃ was added sodium hydride (0.44mmol, 60% w/w) under nitrogen and the resulting mixture was stirred at ambient temperature for 1H. 5- (bromomethyl) -3-methyl-1, 2-oxazole (0.44mmol) was then added to the reaction and the resulting mixture was stirred at ambient temperature for 1 hour. Methanol (100uL) was added to quench the reaction and the solvent was removed under vacuum to give the crude product as a residue. The residue was adsorbed onto silica and purified by automatic column chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in hexanes to give the desired product.

Intermediate S6-C17- (benzylthio) -4-ethyl-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one using 7- (benzylsulfanyl) -4-ethyl-phthalazin-1 (2H) -one. The desired product was isolated as an off-white solid in 90% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.11(d,J＝1.7Hz,1H),7.93(d,J＝8.6Hz,1H),7.87(dd,J＝2.0,8.6Hz,1H),7.49-7.42(m,2H),7.37-7.22(m,3H),6.25(s,1H),5.76(s,1H),5.38(s,2H),4.47(s,2H),2.18(s,3H)

Intermediate S6-C27- (benzylthio) -4-isopropyl-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one using 7- (benzylsulfanyl) -4-isopropyl-phthalazin-1 (2H) -one. The desired product was isolated as a pale yellow oil in 34% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.12(d,J＝2.1Hz,1H),7.99(d,J＝8.8Hz,1H),7.87(dd,J＝2.1,8.6Hz,1H),7.49-7.42(m,2H),7.37-7.25(m,3H),6.24(s,1H),5.38(s,2H),4.46(s,2H),3.59-3.48(m,1H),2.18(s,3H),1.24(d,J＝6.8Hz,6H)。

Intermediate S6-C37- (benzylthio) -4-cyclopropyl-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one using 7- (benzylsulfanyl) -4-cyclopropyl-phthalazin-1 (2H) -one. The desired product was isolated as a thick amber oil in 75% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.17(d,J＝8.6Hz,1H),8.09(d,J＝2.1Hz,1H),7.91(dd,J＝2.1,8.6Hz,1H),7.55-7.40(m,2H),7.40-7.22(m,3H),6.22(s,1H),5.33(s,2H),4.47(s,2H),2.46-2.37(m,1H),2.18(s,3H),1.01-0.91(m,2H),0.90-0.82(m,2H)。

Intermediate S6-C47- (benzylthio) -4-cyclopentyl-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one using 7- (benzylsulfanyl) -4-cyclopentylphthalazin-1 (2H) -one. The desired product was isolated as an orange oil in 90% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.10(d,J＝2.1Hz,1H),7.99(d,J＝8.7Hz,1H),7.85(dd,J＝2.2,8.6Hz,1H),7.46(d,J＝7.6Hz,2H),7.37-7.23(m,3H),6.24(s,1H),5.37(s,2H),4.46(s,2H),3.71-3.55(m,1H),2.18(s,3H),1.98(q,J＝5.9Hz,2H),1.86-1.57(m,6H)。

Intermediate S6-C57- (benzylthio) -4-cyclopropylmethyl-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one using 7- (benzylsulfanyl) -4-cyclopropylmethyl-phthalazin-1 (2H) -one. The desired product was isolated as an off-white solid in 90% yield.

¹H NMR(300MHz,CDCl₃)＝8.09(d,J＝2.0Hz,1H),7.47(d,J＝8.5Hz,1H),7.40(dd,J＝2.0,8.6Hz,1H),7.21-7.14(m,2H),7.14-7.04(m,3H),5.85(s,1H),5.21(s,2H),4.08(s,2H),2.57(d,J＝6.8Hz,2H),1.58(s,3H),0.95-0.85(m,1H),0.35-0.25(m,2H),0.08--0.01(m,2H)

Intermediate S6-C67- (benzylthio) -4-cyclobutylmethyl-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylthio) -4-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one using 7- (benzylthio) -4-cyclobutylmethyl-phthalazin-1 (2H) -one. The desired product was isolated as an off-white solid in 90% yield.

¹H NMR(300MHz,CDCl₃)＝8.32(m,1H),7.69-7.59(m,2H),7.46-7.24(m,5H),6.08(s,1H),5.44(s,2H),4.32(s,2H),2.99(d,J＝7.4Hz,2H),2.84-2.71(m,1H),2.27(s,3H),2.15-2.02(m,2H),1.97-1.73(m,4H)

Intermediate S6-C77- (benzylthio) -4-cyclohexylmethyl-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one using 7- (benzylsulfanyl) -4-cyclohexylmethyl-phthalazin-1 (2H) -one. The desired product was isolated as an off-white solid in 88% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.10(dd,J＝2.0,9.4Hz,1H),7.92(d,J＝8.7Hz,1H),7.88-7.82(m,1H),7.50-7.41(m,2H),7.39-7.22(m,3H),5.76(s,1H),5.38(s,2H),4.51-4.43(m,2H),2.81-2.70(m,2H),2.17(s,3H),1.64(d,J＝11.3Hz,7H),1.22-0.88(m,6H)

Intermediate S6-C87- (benzylthio) -2- ((3-methylisoxazol-5-yl) methyl) -4- ((tetrahydro-2H-pyran-4-yl) methyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one using 7- (benzylsulfanyl) -4- ((tetrahydro-2H-pyran-4-yl) methyl) phthalazin-1 (2H) -one. The desired product was isolated as a yellow oil in 84% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.11(d,J＝2.0Hz,1H),7.96(d,J＝8.6Hz,1H),7.87(d,J＝8.3Hz,1H),7.49-7.43(m,2H),7.37-7.23(m,3H),6.25(s,1H),5.38(s,2H),4.47(s,2H),3.79(dd,J＝2.7,11.5Hz,2H),3.27-3.15(m,2H),2.82(d,J＝7.1Hz,2H),2.17(s,3H),1.96-1.83(m,1H),1.62-1.47(m,2H),1.34-1.20(m,2H)。

Intermediate S6-C94-benzyl-7-benzylthio-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 4- (benzylthio) -7-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one using 4-benzyl-7- (benzylthio) phthalazin-1 (2H) -one. The desired product was isolated as an off-white solid in 86% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.08(d,J＝1.9Hz,1H),7.84(d,J＝8.4Hz,1H),7.78(dd,J＝2.1,8.5Hz,1H),7.46-7.39(m,2H),7.35-7.18(m,8H),6.28(s,1H),5.44(s,2H),4.44(s,2H),4.27(s,2H),2.20(s,3H)

Intermediate S6-C107- (benzylthio) -4- (3-methoxybenzyl) -2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one using 7- (benzylsulfanyl) -4- (3-methoxybenzyl) phthalazin-1 (2H) -one. The desired product was isolated as an off-white solid in 74% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.08(d,J＝1.9Hz,1H),7.86(d,J＝8.4Hz,1H),7.80(dd,J＝2.0,8.6Hz,1H),7.48-7.39(m,2H),7.36-7.13(m,4H),6.89-6.82(m,2H),6.78-6.71(m,1H),6.28(s,1H),5.44(s,2H),4.43(s,2H),4.23(s,2H),3.68(s,3H),2.20(s,3H)

Intermediate S6-C116- (benzylsulfanyl) -3- ((3-methylisoxazol-5-yl) methyl) -4-oxo-3, 4-dihydrophthalazine-1-carboxylic acid methyl ester

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one using methyl 6- (benzylsulfanyl) -4-oxo-3, 4-dihydrophthalazin-1-carboxylate. The desired product was isolated as an off-white solid in 81% yield.

¹H NMR(300MHz,CDCl₃)＝8.50(d,J＝8.8Hz,1H),8.29(d,J＝2.1Hz,1H),7.69(dd,J＝2.1,8.8Hz,1H),7.47-7.39(m,2H),7.39-7.29(m,3H),6.14(s,1H),5.54(s,2H),4.33(s,2H),4.02(s,3H),2.28(s,3H)

The method 9: synthesis of perfluorophenyl 1-substituted-3 ((3-methylisoxazol-5-yl) methyl) -4-oxo-3, 4-dihydrophthalazine- General procedure for 6-sulfonate

To a magnetically stirred solution of 7- (benzylthio) -4-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one (1.0mmol) in a mixture of MeCN (10mL), water (0.6mL) and acetic acid (1.0mL) at 0 ℃ was added 1, 3-dichloro-5, 5-dimethylhydantoin (2.0mmol) and the resulting mixture was stirred at 0 ℃ for 2 hours. Pentafluorophenol (2.0mmol) was then added to the reaction followed by triethylamine (2.8mmol) and the resulting mixture stirred at ambient temperature for 2 hours. The solvent was removed under vacuum to give the crude product as a residue, which was suspended in EtOAc (10mL) and filtered. The filtrate was collected and distilled to dryness to give a residue which was purified by automatic column chromatography on silica gel eluting with a gradient of 0 to 80% (v/v) EtOAc in hexanes to give the desired product as a solid.

Intermediate S6-D1 perfluorophenyl 1-ethyl-3- ((3-methylisoxazol-5-yl) methyl) -4-oxo-3, 4-dihydrophthalazine-6-sulfonate

This compound was prepared according to the general procedure described above for the synthesis of perfluorophenyl 1-substituted-3- ((3-methylisoxazol-5-yl) methyl) -4-oxo-3, 4-dihydrophthalazin-6-sulfonate using 7- (benzylthio) -4-ethyl-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one. The desired product was isolated as an off-white solid in 61% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.74(d,J＝1.9Hz,1H),8.54(dd,J＝2.1,8.6Hz,1H),8.38(d,J＝8.7Hz,1H),6.35(s,1H),5.75(s,3H),5.45(s,2H),3.06(q,J＝7.3Hz,2H),2.19(s,3H),1.34(s,2H),1.26(t,J＝7.4Hz,4H)

Intermediate S6-D2 perfluorophenyl 1- (cyclopropylmethyl) -3- ((3-methylisoxazol-5-yl) methyl) -4-oxo-3, 4-dihydrophthalazine-6-sulfonate

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- (isoxazol-3-ylmethyl) phthalazin-1 (2H) -one using 7-benzylsulfanyl-4- (cyclopropylmethyl) -2- [ (3-methylisoxazol-5-yl) methyl ] phthalazin-1-one. The desired product was isolated as an off-white solid in 92% yield.

¹H NMR(300MHz,CDCl₃)＝9.09-9.04(m,1H),8.37(dd,J＝2.1,8.6Hz,1H),8.10(d,J＝8.7Hz,1H),6.17(s,1H),5.49(s,2H),2.96-2.88(m,2H),2.29(s,3H),0.99-0.77(m,1H),0.67-0.56(m,2H),0.32(d,J＝5.8Hz,2H)

Intermediate S6-D3 perfluorophenyl 1- (cyclobutylmethyl) -3- ((3-methylisoxazol-5-yl) methyl) -4-oxo-3, 4-dihydrophthalazine-6-sulfonate

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- (isoxazol-3-ylmethyl) phthalazin-1 (2H) -one using 7-benzylsulfanyl-4- (cyclobutylmethyl) -2- [ (3-methylisoxazol-5-yl) methyl ] phthalazin-1-one. The desired product was isolated as an off-white solid in 78% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.74(d,J＝2.0Hz,1H),8.53(dd,J＝2.2,8.6Hz,1H),8.38(d,J＝8.7Hz,1H),6.33(s,1H),5.45(s,2H),3.13(d,J＝7.3Hz,2H),2.81-2.66(m,1H),2.19(s,3H),1.99(s,3H),1.80(d,J＝5.1Hz,5H)

Intermediate S6-D4 perfluorophenyl 1- (cyclohexylmethyl) -3- ((3-methylisoxazol-5-yl) methyl) -4-oxo-3, 4-dihydrophthalazine-6-sulfonate

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- (isoxazol-3-ylmethyl) phthalazin-1 (2H) -one using 7-benzylsulfanyl-4- (cyclohexylmethyl) -2- [ (3-methylisoxazol-5-yl) methyl ] phthalazin-1-one. The desired product was isolated as an off-white solid in 78% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.76(d,J＝2.1Hz,1H),8.55-8.48(dd,J＝2.1,8.6Hz,1H),8.43-8.37(m,1H),6.34(s,1H),5.46(s,2H),2.89(d,J＝6.5Hz,2H),2.19(s,3H),1.83-1.53(m,5H),1.30-0.93(m,6H)

Intermediate S6-D5 perfluorophenyl 1-benzyl-3- ((3-methylisoxazol-5-yl) methyl) -4-oxo-3, 4-dihydrophthalazine-6-sulfonate

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- (isoxazol-3-ylmethyl) phthalazin-1 (2H) -one using 4-benzyl-7-benzylsulfanyl-2- [ (3-methylisoxazol-5-yl) methyl ] phthalazin-1-one. The desired product was isolated as an off-white solid in 78% yield.

¹H NMR(300MHz,DMSO-d₆)＝8.74(d,J＝1.9Hz,1H),8.48(dd,J＝2.1,8.6Hz,1H),8.29(s,1H),7.36-7.18(m,5H),6.36(s,1H),5.50(s,2H),4.42(s,2H),2.21(s,3H),1.35(s,3H)

Intermediate S6-D6 perfluorophenyl 1- (3-methoxybenzyl) -3- ((3-methylisoxazol-5-yl) methyl) -4-oxo-3, 4-dihydrophthalazine-6-sulfonate

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- (isoxazol-3-ylmethyl) phthalazin-1 (2H) -one using 7-benzylsulfanyl-4- [ (3-methoxybenzyl) methyl ] -2- [ (3-methylisoxazol-5-yl) methyl ] phthalazin-1-one. The desired product was isolated as an off-white solid in 78% yield.

¹H NMR(300MHz,CDCl₃)＝9.04(d,J＝2.0Hz,1H),8.24(dd,J＝2.1,8.6Hz,1H),7.96(d,J＝8.6Hz,1H),6.88-6.76(m,3H),6.19(s,1H),5.53(s,2H),4.33(s,2H),3.82-3.75(m,3H),2.30-2.26(m,3H)

Intermediate S6-D73- ((3-methylisoxazol-5-yl) methyl) -4-oxo-6- ((perfluorophenoxy) sulfonyl) -3, 4-dihydrophthalazine-1-carboxylic acid methyl ester

This compound was prepared according to the general procedure described above for the synthesis of 7- (benzylsulfanyl) -4-substituted-2- (isoxazol-3-ylmethyl) phthalazin-1 (2H) -one using methyl 6- (benzylsulfanyl) -3- ((3-methylisoxazol-5-yl) methyl) -4-oxo-3, 4-dihydrophthalazin-1-carboxylate. The desired product was isolated as an off-white solid in 90% yield.

¹H NMR(300MHz,CDCl₃)＝9.13-8.97(m,2H),8.40(dd,J＝2.4,6.7Hz,1H),6.22(s,1H),5.58(s,2H),4.09-4.03(m,3H),2.33-2.26(m,3H)

The method 10 comprises the following steps: synthesizing 1-substituted-N- (1-methylcyclopropyl) -3- ((3-methyl isoxazol-5-yl) methyl) -4-oxo-3, general procedure for 4-dihydrophthalazine-6-sulfonamide

To a magnetically stirred solution of perfluorophenyl 1-substituted-3- (isoxazol-3-ylmethyl) -4-oxo-3, 4-dihydrophthalazine-6-sulfonate (1.0mmol) in DMF solution (8.0mL) at 20 deg.C was added 1-methylcyclopropylamine hydrochloride (1.2mmol) followed by triethylamine (2.4mmol) and the resulting mixture was stirred at 60 deg.C for 2 hours. The solvent was removed under vacuum to give the crude product as a residue, which was purified by automatic column chromatography on silica gel eluting with a gradient of 0 to 80% (v/v) EtOAc in hexane to give the desired product as a solid.

Example 3026- (N- (1-methylcyclopropyl) sulfamoyl) -3- ((3-methylisoxazol-5-yl) methyl) -4-oxo-3, 4-dihydrophthalazine-1-carboxylic acid

Lithium hydroxide (5mmol) was added to a solution of methyl 6- (N- (1-methylcyclopropyl) sulfamoyl) -3- ((5-methylisoxazol-3-yl) methyl) -4-oxo-3, 4-dihydrophthalazine-1-carboxylate in a mixture of 1:1(v/v) THF and water (10mL) and the resulting mixture was stirred at ambient temperature for 1 hour. The solvent was removed in vacuo and the residue partitioned between DCM (10mL) and 1N HCl (10 mL). The organic phase was collected and distilled to dryness to give the desired product as a white solid in 98% yield.

The method 11 comprises the following steps: amide formation

To a magnetically stirred solution of 6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -4-oxo-phthalazine-1-carboxylic acid (0.060mmol) and HATU (0.060mmol) in DMF (4mL) at 20 ℃ under a nitrogen atmosphere was added the desired amine (0.12mmol) and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction was distilled to dryness to give a residue which was adsorbed onto silica and purified by automatic column chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in hexane to give the desired product.

The method 12 comprises the following steps: synthesizing 1-substituted-N- (1-methylcyclopropyl) -3- ((3-methyl isoxazol-5-yl) methyl) -4-oxo-3, general procedure for 4-dihydrophthalazine-6-sulfonamide

The following examples were prepared by bringing the intermediate to the final product (telescope):

a solution of 7- (benzylthio) -4-substituted-2- ((3-methylisoxazol-5-yl) methyl) phthalazin-1 (2H) -one (0.36mmol) in a mixture of acetonitrile (3mL), water (0.1mL) and acetic acid (0.2mL) was treated with 1, 3-dichloro-5, 5-dimethylhydantoin (0.72mmol) at 0 ℃ and the resulting mixture was stirred at 0 ℃ for 2 hours. Pentafluorophenol (0.72mmol) was then added to the reaction followed by triethylamine (1.07mmol) and the resulting mixture was stirred at ambient temperature for 2 hours. The solvent was removed under vacuum to give the crude product as a residue, which was suspended in EtOAc (10mL) and filtered. The filtrate was collected and distilled to dryness to give the crude sulfonate.

It was taken up in acetonitrile (2mL), treated with 1-methylcyclopropylamine hydrochloride (0.54mmol) and diisopropylethylamine (1.44mmol), and stirred at 60 ℃ for 2 hours. The cooled reaction mixture was then diluted with EtOAc (10mL) and water (5mL) and partitioned. The aqueous layer was re-extracted with EtOAc, and the combined organics were passed through a hydrophobic frit and concentrated. Purification by preparative HPLC, high pH, gave the desired product.

General procedure for scheme 7:

intermediate S7-A2-bromo-5-chlorosulfonyl-benzoic acid

Following the procedure of WO 2011072174. 2-Bromobenzoic acid (2.g, 9.95mmol) was added portionwise to stirred chlorosulfonic acid (6.62mL, 99.5mmol) at 0 deg.C under nitrogen. The reaction mixture was heated at 110 ℃ for 6 hours. The reaction mixture was cooled and then added dropwise to stirred ice to form a white precipitate which was filtered and dried in a vacuum oven to yield 2-bromo-5-chlorosulfonyl-benzoic acid (2.5g, 8.35mmol, 84%).

¹H NMR(300MHz,DMSO-d₆)＝7.92(d,J＝2.2Hz,1H),7.68(d,J＝8.1Hz,1H),7.59(dd,J＝2.1,8.2Hz,1H)

Intermediate S7-B2-bromo-5-chlorosulfonyl-benzoic acid methyl ester

Following the procedure of WO 2009005998. Thionyl chloride (2.44mL, 33.4mmol) was added to a stirred suspension of 2-bromo-5-chlorosulfonyl-benzoic acid (1.g, 3.34mmol) in DCE (5mL) and the reaction mixture was heated at reflux for 1 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo, to the resulting brown liquid was added toluene (10m L) and then removed in vacuo to give crude 2-bromo-5-chlorosulfonyl-benzoyl chloride as a brown liquid. Crude 2-bromo-5-chlorosulfonyl-benzoyl chloride was cooled in an ice bath, cold methanol (8mL) was added, and the reaction mixture was stirred in the ice bath for 10 minutes and then at room temperature for 15 minutes. The reaction mixture was added to ice-cold water (8mL), and the resulting white precipitate was filtered, washed with cold water (10mL), and dried in a vacuum oven to yield 2-bromo-5-chlorosulfonyl-benzoic acid methyl ester (854mg,2.72mmol, 82%).

¹H NMR(300MHz,DMSO-d₆)＝7.96(d,J＝1.8Hz,1H),7.73(d,J＝8.3Hz,1H),7.64(dd,J＝2.2,8.3Hz,1H),3.87(s,3H)

Intermediate S7-C2-bromo-5- [ (1-methylcyclopropyl) sulfamoyl ] benzoic acid methyl ester

1-methylcyclopropylamine hydrochloride (281.1mg, 2.61mmol) and triethylamine (726.6uL, 5.23mmol) were added successively to a stirred solution of methyl 2-bromo-5-chlorosulfonyl-benzoate (745.mg, 2.38mmol) in DCM (15 mL). The reaction mixture was stirred for 1 hour, then 2M HCl (10mL) was added and the reaction mixture was stirred vigorously for 15 minutes. The organic phase was separated using a hydrophobic frit and evaporated to dryness. The crude product was purified by automatic column chromatography, SiO₂(RediSep, 24g) eluent was purified 30% EtOAc in isohexane to yield 2-bromo-5- [ (1-methylcyclopropyl) sulfamoyl]Methyl benzoate (630.2mg, 1.81mmol, 76%).

¹H NMR(300MHz,CDCl₃)＝8.32-8.30(m,1H),7.86-7.79(m,2H),4.99(s,1H),3.99(s,3H),1.25(s,3H),0.82-0.75(m,2H),0.57-0.50(m,2H)

Intermediate S7-D2-bromo-5- [ (1-methylcyclopropyl) sulfamoyl ] benzoic acid

Methyl 2-bromo-5- [ (1-methylcyclopropyl) sulfamoyl ] benzoate (95.mg, 0.27mmol) and lithium hydroxide (13.1mg, 0.55mmol) in THF (2mL) were stirred at room temperature overnight. Water (10mL) was added and the aqueous phase was washed with DCM (10mL), the organic phase was separated and the resulting aqueous phase was cooled in an ice bath and acidified with 2M HCl (to pH 1). The resulting precipitate was filtered and dried in a vacuum oven to yield 2-bromo-5- [ (1-methylcyclopropyl) sulfamoyl ] benzoic acid (68.5mg, 0.21mmol, 75%).

¹H NMR(300MHz,DMSO-d₆)＝13.91(s,1H),8.30(s,1H),8.12(d,J＝2.4Hz,1H),7.98(d,J＝8.4Hz,1H),7.80(dd,J＝2.4,8.4Hz,1H),1.07(s,3H),0.67-0.57(m,2H),0.49-0.38(m,2H)

Method 13: synthesis of 4-oxo-3H-quinazoline-6-sulfonamide

According to Angew. chem. int.Ed. [ journal of applied chemistry ]]2009, 48, 348-. Reacting 2-bromo-5- [ (1-methylcyclopropyl) sulfamoyl]Benzoic acid methyl ester (examples 52 and 55) or 2-bromo-5- [ (1-methylcyclopropyl) sulfamoyl]A solution of benzoic acid (examples 54 and 98) (1 eq) and formamidine (2 eq) in DMF was stirred at ambient temperature for 10 min. Cesium carbonate (2 eq) was added and after a further 15 minutes copper (I) iodide (0.2 eq) was added to the reaction mixture. The mixture was stirred under nitrogen and heated at 80 ℃ for 16 hours (for example 98, the reaction mixture was heated at 110 ℃ for 16 hours). The reaction mixture was cooled and filtered through celite, which was washed with MeOH and the organic phase was evaporated to dryness. Alternatively, NH is added₄A saturated aqueous solution of Cl (10mL) was added to the reaction mixture, which was then extracted with EtOAc (2 × 20mL), the organic phase was separated, passed through a hydrophobic frit and evaporated to dryness the crude product was purified by preparative HPLC, high pH, to yield the desired product.

General procedure for scheme 8:

intermediate S8-A2-bromo-N-methyl-benzamide

Commun]2011, 47, 2074. sup. 12076 the procedure was followed 2-bromobenzoic acid (1.g, 4.97mmol) and thionyl chloride (5.mL, 68.6mmol) were stirred at reflux for 2 hours, the solvent was removed under vacuum to give the crude acid chloride, potassium carbonate (1.72g, 12.4mmol) and THF (3mL) were added to the crude acid chloride, the reaction mixture was cooled in an ice bath, methylamine (2M in THF) (3.73mL, 7.46mmol) was slowly added to the reaction mixture, which was stirred at ambient temperature overnight, the reaction mixture was slowly quenched with 2M HCl (10mL) while cooling in an ice bath and extracted with EtOAc (3 × 30mL), the organic phase was extracted with NaHCO₃The saturated aqueous solution and brine were washed, and then dried over sodium sulfate. The organic phase was evaporated to dryness to yield 2-bromo-N-methyl-benzamide (941.8mg, 4.40mmol, 88%).

¹H NMR(300MHz,CDCl₃)＝7.58(dd,J＝1.2,8.0Hz,1H),7.53(dd,J＝1.9,7.5Hz,1H),7.35(dt,J＝1.3,7.5Hz,1H),7.27(dt,J＝1.8,7.6Hz,1H),6.03(br.s,1H),3.02(d,J＝4.9Hz,3H)

Intermediate S8-B4-bromo-3- (methylcarbamoyl) benzenesulfonyl chloride

Chlorosulfonic acid (1.45mL, 21.7mmol) was added dropwise to a stirred solution of 2-bromo-N-methyl-benzamide (465mg, 2.17mmol) in DCM (1mL) at 0 deg.C under nitrogen. The reaction mixture was heated at 110 ℃ for 7 hours. The reaction mixture was cooled and then added dropwise to stirred ice to form a beige precipitate, which was filtered and dried in a vacuum oven to yield 4-bromo-3- (methylcarbamoyl) benzenesulfonyl chloride (528.6mg, 1.69mmol, 78%).

¹H NMR(300MHz,DMSO-d₆)＝8.46-8.36(m,1H),7.59(d,J＝8.6Hz,1H),7.54-7.49(m,2H),2.74(d,J＝4.6Hz,3H)

Intermediate S8-C2-bromo-N-methyl-5- [ (1-methylcyclopropyl) sulfamoyl ] benzamide

1-methylcyclopropylamine hydrochloride (386.2mg, 3.59mmol) and triethylamine (997.9uL, 7.18mmol) were added successively to a stirred solution of 4-bromo-3- (methylcarbamoyl) benzenesulfonyl chloride (1.02g, 3.26mmol) in DCM (20mL) at ambient temperature. The reaction mixture was stirred for 1 hour, then 2M HCl (10mL) was added, and the mixture was stirred for 10 minutes. The mixture was passed through a hydrophobic frit and the resulting organic phase was collected. Saturated NaHCO for acidic aqueous phase₃The aqueous solution was neutralized to pH7, extracted with EtOAc (25mL), the organic phase was separated and passed through a hydrophobic frit. The combined organic phases were evaporated to dryness. The crude product obtained is passed through an automatic column chromatography SiO₂(Biotage, 24g) eluent was purified 0-75% EtOAc in isohexane to yield 2-bromo-N-methyl-5- [ (1-methylcyclopropyl) sulfamoyl]Benzamide (510mg, 1.47mmol, 45%).

¹H NMR(300MHz,CDCl₃)＝8.00(dd,J＝0.8,2.0Hz,1H),7.78-7.75(m,2H),6.06(br.s,1H),5.06(br.s.,1H),3.05(d,J＝4.9Hz,3H),1.26(s,3H),0.81-0.76(m,2H),0.56-0.49(m,2H)

The method 14 comprises the following steps: synthesis of 4-oxo-3H-quinazoline-6-sulfonamide

Reacting 2-bromo-N-methyl-5- [ (1-methylcyclopropyl) sulfamoylAcyl radical]A suspension of benzamide (1 equivalent), amide (2 equivalents), trans-4-hydroxy-L-proline (0.07 equivalents), copper (I) iodide (0.07 equivalents) and cesium carbonate (2 equivalents) in DMF was heated at 80 ℃ for 2 hours. The reaction mixture is removed from heating and NH is added₄The aqueous phase was extracted with EtOAc (2 × 10mL), and the combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness to give the crude uncyclized intermediate.

The crude intermediate was dissolved in DMF, then zinc chloride (0.5 eq) and hexamethyldisilazane (3 eq) were added and the reaction mixture was heated at 110 ℃ for 16 h. The reaction mixture was cooled and NH was added₄The aqueous solution was saturated with Cl and the reaction mixture was extracted with EtOAc (2 × 20mL), the combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness.

General procedure for scheme 9:

intermediate S9-A7-bromo-4-chloro-2H-isoquinolin-1-one

Following the procedure of WO 2009060209. A suspension of 7-bromo-1-hydroxyisoquinoline (2.73g, 12.2mmol) and N-chlorosuccinimide (1.95g, 14.6mmol) in MeCN (50mL) was heated at 90 ℃ for 2 hours. The reaction mixture was cooled to room temperature and the resulting precipitate was collected and washed with MeOH to yield 7-bromo-4-chloro-2H-isoquinolin-1-one (2.24g, 8.67mmol, 71%).

¹H NMR(300MHz,DMSO-d₆)＝11.77(br.s.,1H),8.31(d,J＝2.2Hz,1H),8.02(dd,J＝2.2,8.7Hz,1H),7.75(d,J＝8.7Hz,1H),7.54(s,1H)

Intermediate S9-B7-benzylsulfanyl-2H-isoquinolin-1-one

A solution of 7-bromo-1-hydroxyisoquinoline (2.0g, 8.93mmol), tris (dibenzylideneacetone) dipalladium (0) (408.7mg, 0.45mmol) and Xantphos (516.51mg, 0.89mmol) in 1, 4-dioxane (250mL) was degassed with nitrogen. N, N-diisopropylethylamine (1.67mL, 9.37mmol) and benzylthiol (1.1mL, 9.37mmol) were then added sequentially to the flask and the resulting mixture was heated at 80 ℃ for 5 hours. The reaction mixture was evaporated to dryness and the residue was suspended in DCM (80mL) and the resulting mixture was stirred for 15 min. The mixture was filtered to give a solid which was air dried to give the desired product 7-benzylsulfanyl-2H-isoquinolin-1-one (1.4g, 5.24mmol, 59%).

¹H NMR(300MHz,DMSO-d₆)＝11.28(br.s,1H),8.05(d,J＝2.1Hz,1H),7.65(dd,J＝2.0,8.3Hz,1H),7.58(d,J＝8.3Hz,1H),7.39-7.20(m,5H),7.13(dd,J＝5.8,7.1Hz,1H),6.51(d,J＝6.8Hz,1H),4.33(s,2H)

Intermediate S9-C17-benzylsulfanyl-4-chloro-2H-isoquinolin-1-one

A solution of 7-bromo-4-chloro-2H-isoquinolin-1-one (1.94g, 7.5mmol), tris (dibenzylideneacetone) dipalladium (0) (171.81mg, 0.19mmol) and Xantphos (217.12mg, 0.38mmol) in 1, 4-dioxane (50mL) was degassed with nitrogen for 10 minutes and N, N-diisopropylethylamine (2.48mL, 15.01mmol) and benzyl mercaptan (0.99mL, 8.26mmol) were added to the mixture in that order. The reaction mixture was heated by microwave irradiation at 80 ℃ for 20 minutes. The reaction mixture was diluted with EtOAc (100mL) and the organic phase was washed with water (100 mL). The organic phase was filtered and the solid was washed with water and diethyl ether and then dried in a vacuum oven to yield the desired product. The aqueous phase was further extracted with EtOAc (2X 50mL) and the combined organic phases were washed with water (100 mL). The organic phase was separated and evaporated to dryness. The crude product was recrystallized from EtOAc (50mL), the precipitate formed was filtered, washed with water and ether, dried in a vacuum oven and combined with the first crop of product to yield 7-benzylsulfanyl-4-chloro-2H-isoquinolin-1-one (2.38g, 7.89mmol, 105%) containing inorganic impurities without further purification.

¹H NMR(300MHz,DMSO-d₆)＝11.61(br.s.,1H),8.09(d,J＝2.1Hz,1H),7.82(dd,J＝2.1,8.5Hz,1H),7.72(d,J＝8.6Hz,1H),7.44(s,1H),7.42-7.37(m,2H),7.34-7.21(m,3H),4.38(s,2H)

Intermediate S9-C27-benzylsulfanyl-4-bromo-2H-isoquinolin-1-one

N-bromosuccinimide (1.76g, 9.87mmol) was added to a stirred suspension of 7-benzylsulfanyl-2H-isoquinolin-1-one (2.4g, 8.98mmol) in MeCN (100mL) under nitrogen and the resulting mixture was stirred at ambient temperature for 2H. The reaction mixture was filtered and the filter cake was washed with MeCN (2X 20mL) to give the desired product 7-benzylsulfanyl-4-bromo-2H-isoquinolin-1-one (2.3mg, 6.64mmol, 74%).

¹H NMR(300MHz,DMSO-d₆)＝11.63(d,J＝5.9Hz,1H),8.08(d,J＝1.8Hz,1H),7.81(dd,J＝2.1,8.5Hz,1H),7.67(d,J＝8.5Hz,1H),7.51(d,J＝6.0Hz,1H),7.42-7.35(m,2H),7.35-7.20(m,3H),4.38(s,2H)

Intermediate S9-D17-benzylsulfanyl-4-bromo-2- [ (3-methylisoxazol-5-yl) methyl ] isoquinolin-1-one

Sodium hydride (60% w/w) (0.46g, 11.4mmol) was added portionwise to a solution of 7-benzylsulfanyl-4-bromo-2H-isoquinolin-1-one (2.82g, 8.14mmol) in DMF (40mL) at 0 ℃. After 1 hour, 5- (bromomethyl) was addedYl) -3-methyl-1, 2-oxazole (1.72g, 9.77mmol) and the mixture was stirred at ambient temperature overnight. EtOAc (150mL) and NaHCO were added₃The aqueous solution was saturated (150mL), and the mixture was stirred for 5 minutes. The EtOAc layer was separated and the aqueous layer was washed with EtOAc (100 mL). The combined organic extracts were passed through a hydrophobic frit, concentrated under reduced pressure, and purified by automatic column chromatography eluting with 0-100% EtOAc in isohexane to yield 7-benzylsulfanyl-4-bromo-2- [ (3-methylisoxazol-5-yl) methyl]Isoquinolin-1-one (1.78g, 4.03mmol, 49%).

LCMS (high pH): RT 1.40min, [ M + H ] +441.0, 94% purity

The following intermediates were prepared by similar methods:

intermediate S9-D27-benzylsulfanyl-4-chloro-2- [ (3-methylisoxazol-5-yl) methyl ] isoquinolin-1-one

Prepared from 7-benzylsulfanyl-4-chloro-2H-isoquinolin-1-one and 5- (bromomethyl) -3-methyl-1, 2-oxazole.

¹H NMR(300MHz,DMSO-d₆)＝8.12(d,J＝1.6Hz,1H),7.96(s,1H),7.86(d,J＝8.7Hz,1H),7.75(d,J＝8.5Hz,1H),7.44-7.38(m,2H),7.38-7.19(m,3H),6.29(s,1H),5.29(s,2H),4.39(s,2H),2.18(s,3H)

Intermediate S9-D37-benzylsulfanyl-4-bromo-2-methyl-isoquinolin-1-one

Prepared from 7-benzylsulfanyl-4-bromo-2H-isoquinolin-1-one and iodomethane.

¹H NMR(300MHz,DMSO-d₆)＝8.11(d,J＝2.2Hz,1H),7.92(s,1H),7.81(dd,J＝2.1,8.6Hz,1H),7.66(d,J＝9.0Hz,1H),7.42-7.37(m,2H),7.34-7.21(m,3H),4.38(s,2H),3.50(s,3H)

Intermediate S9-E1(2,3,4,5, 6-pentafluorophenyl) 4-chloro-2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonate

Reacting 7-benzylsulfanyl-4-chloro-2- [ (3-methylisoxazol-5-yl) methyl]A suspension of isoquinolin-1-one (150.Mg, 0.38mmol), acetic acid (2.4mL), water (1.6mL) and MeCN (20mL) was cooled to 0 ℃. After stirring for 5 minutes, 1, 3-dichloro-5, 5-dimethylhydantoin (148.92mg, 0.76mmol) was added portionwise and stirring was continued for 40 minutes at 0-5 ℃. A solution of pentafluorophenol (139.13mg, 0.76mmol) in MeCN (2mL) and triethylamine (147.09uL, 1.06mmol) were added to the reaction mixture in that order. The mixture was stirred at 0 ℃ for 20 minutes, then removed from the cooling bath and stirred at ambient temperature overnight. Water (20mL) and EtOAc (20mL) were added, the organic phase was separated and washed with water (10mL), the organic phase was passed through a hydrophobic frit and evaporated to dryness. Subjecting the crude product to automatic column chromatography, SiO₂(Biotage, 10g) eluent of 0-50% EtOAc in isohexane was purified to yield (2,3,4,5, 6-pentafluorophenyl) 4-chloro-2- [ (3-methylisoxazol-5-yl) methyl]-1-oxo-isoquinoline-7-sulfonate (110.8mg, 0.21mmol, 56%).

¹H NMR(300MHz,CDCl₃)＝9.03(d,J＝2.0Hz,1H),8.29(dd,J＝2.0,8.7Hz,1H),8.11(d,J＝8.6Hz,1H),7.62(s,1H),6.25(s,1H),5.27(s,2H),2.30(s,3H)

The following intermediates were prepared by similar methods:

intermediate S9-E2(2,3,4,5, 6-pentafluorophenyl) 4-bromo-2- [ (1-methylpyrazol-4-yl) methyl ] -1-oxo-isoquinoline-7-sulfonate

Prepared from 7-benzylsulfanyl-4-bromo-2- [ (3-methylisoxazol-5-yl) methyl ] isoquinolin-1-one, 1, 3-dichloro-5, 5-dimethylhydantoin, pentafluorophenol and triethylamine.

LCMS (high pH): RT 1.31min, [ M + H ] +522.0, 100% purity

Example 2094-chloro-N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide

1-methylcyclopropylamine hydrochloride (193.65mg, 1.8mmol) and triethylamine (417.01uL, 3mmol) were added at ambient temperature to a solution of (2,3,4,5, 6-pentafluorophenyl) 4-chloro-2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonate (625mg, 1.2mmol) in DMF (10mL) and the reaction mixture was heated at 60 ℃ for 1.5 h. The reaction mixture was cooled, then water (50mL) and EtOAc (50mL) were added, the organic phase was separated, and the aqueous phase was further extracted with EtOAc (50 mL). The combined organic phases were washed with water (50mL), separated, passed through a hydrophobic frit and evaporated to dryness. The crude product was triturated with a minimum volume of EtOAc to afford 4-chloro-N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide (442mg, 1.08mmol, 90%).

¹H NMR(300MHz,DMSO-d₆)＝8.67(d,J＝2.4Hz,1H),8.35(s,1H),8.23(dd,J＝2.0,8.6Hz,1H),8.21(s,1H),8.06(d,J＝8.5Hz,1H),6.36(s,1H),5.34(s,2H),2.19(s,3H),1.06(s,3H),0.67-0.51(m,2H),0.44-0.36(m,2H)

The following intermediates were prepared by similar methods:

example 3074-bromo-N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide

Prepared from (2,3,4,5, 6-pentafluorophenyl) 4-bromo-2- [ (1-methylpyrazol-4-yl) methyl ] -1-oxo-isoquinoline-7-sulfonate, 1-methylcyclopropylamine hydrochloride and triethylamine.

¹H NMR(300MHz,DMSO-d₆)＝8.66(d,J＝2.1Hz,1H),8.34(s,1H),8.28(s,1H),8.22(dd,J＝2.0,8.5Hz,1H),8.00(d,J＝9.0Hz,1H),6.36(s,1H),5.34(s,2H),2.19(s,3H),1.06(s,3H),0.66-0.51(m,2H),0.47-0.33(m,2H)

Examples of 1-oxo-isoquinoline-7-sulfonamides

Example 242N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide

4-bromo-N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl at-20 deg.C under nitrogen]-1-oxo-isoquinoline-7-sulfonamide (intermediate S9-F2) (90.Mg, 0.20mmol) and lithium chloride (8.44Mg, 0.20mmol) in THF (10mL) was added methylmagnesium chloride (66.33uL, 0.20mmol) and the resulting mixture was stirred at-20 ℃ for 45 min. Then a solution of isopropyl magnesium chloride lithium chloride complex (33.43uL, 0.22mmol) was added and the resulting mixture was stirred at 20-20 ℃ for 45 minutes. Allyl bromide (17.22. mu.L, 0.20mmol) was added and the mixture was allowed to warm to ambient temperature. LCMS indicated that debromination facilitated the desired reaction. By addition of NH₄The reaction was quenched with saturated aqueous Cl (10mL) and extracted with ether (20 mL). The ether layer was collected and distilled to dryness. The crude product was purified by preparative HPLC, low pH to yield N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl]-1-oxo-isoquinoline-7-sulfonamide (10mg, 0.0268mmol, 13%).

Example 2864- [3- (dimethylamino) prop-1-ynyl ] -N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide;

4-bromo-N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl]A mixture of-1-oxo-isoquinoline-sulfonamide (intermediate S9-F2) (100.mg, 0.22mmol), 3-dimethylamino-1-propyne (35.71uL, 0.33mmol), tetra-N-butylammonium iodide (81.66mg, 0.22mmol), tetrakis (triphenylphosphine) palladium (0) (15.36mg, 0.010mmol), copper (I) iodide (5.05mg, 0.03mmol) and isopropylamine (46.48uL, 0.33mmol) in THF (2mL) was heated in a sealed tube in the absence of light for 48 hours. The mixture was evaporated to dryness and the residue partitioned between DCM (10mL) and water (10 mL). The DCM layer was collected and distilled to dryness to give a residue which was purified by automatic column chromatography SiO₂(RediSep, 4g) eluent in DCM solution 0 to 10% MeOH purification to yield 4- [3- (dimethylamino) prop-1-ynyl]-N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl]-1-oxo-isoquinoline-7-sulfonamide (40mg, 0.088mmol, 40%).

Example 2874- [3- (dimethylamino) propyl ] -N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide;

4- [3- (dimethylamino) prop-1-ynyl]-N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl]-1-oxo-isoquinoline-7-sulfonamide (30.mg, 0.070mmol) is dissolved in EtOH (2mL) at ambient temperature with stirring and the solution is purged 3 times with nitrogen under vacuum. Palladium activated charcoal (20.75mg, 0.070mmol) was then added to the reaction mixture and the resulting suspension was purged 3 times under vacuum with nitrogen. The reaction mixture was then purged 3 times with hydrogen under vacuum and stirred under a positive pressure of hydrogen for 2 hours. Subjecting the mixture to nitrogenThe filter cake was washed with EtOH (2 × 4mL) and the combined filtrates were distilled to dryness under vacuum to give the crude product as a residue which was purified by automatic column chromatography, SiO₂(RediSep, 4g) eluent for 0-10.0% MeOH in DCM to give the desired product 4- [3- (dimethylamino) propyl]-N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl]-1-oxo-isoquinoline-7-sulfonamide (10mg, 0.0218mmol, 33%).

General procedure for scheme 10:

intermediate S10-A7-benzylsulfanyl-4- (cyclopropanecarbonyl) -2H-isoquinolin-1-one

Methyllithium (1.6M in diethyl ether) (1.29mL, 2.07mmol) was added to a solution of 7-benzylsulfanyl-4-bromo-2H-isoquinolin-1-one (intermediate S9-C2) (650mg, 1.88mmol) in THF (10 mL). After 10 min, the reaction mixture was cooled to-78 deg.C and n-butyllithium (1.6M in hexanes) (1.41mL, 2.25mmol) was added dropwise. After 10 min, cyclopropanecarbonyl chloride (0.19mL, 2.07mmol) was added and the reaction mixture was stirred at-78 ℃ for 10 min and then warmed to ambient temperature. After 1h at ambient temperature, DCM (30mL) and NaHCO were added₃The aqueous solution was saturated (20mL), and the mixture was stirred for 5 minutes. The DCM layer was separated by passage through a hydrophobic frit and the aqueous layer was washed with DCM. The combined DCM extracts were concentrated under reduced pressure and purified by automatic column chromatography, SiO₂The eluent was purified as 0-100% EtOAc in isohexane to yield 7-benzylsulfanyl-4- (cyclopropanecarbonyl) -2H-isoquinolin-1-one (320mg, 0.954mmol, 51%).

LCMS (high pH): RT 1.22min, [ M + H ]]⁺336.2, 82% purity

Intermediate S10-B17-benzylsulfanyl-4- (cyclopropanecarbonyl) -2- [ (3-methylisoxazol-5-yl) methyl ] isoquinolin-1-one

Sodium hydride (60% w/w) (34.1mg, 0.85mmol) was added to a solution of 7-benzylsulfanyl-4- (cyclopropanecarbonyl) -2H-isoquinolin-1-one (220.mg, 0.66mmol) in DMF (8 mL). After 15 min, 5- (bromomethyl) -3-methyl-1, 2-oxazole (0.15mL, 0.85mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. DCM (25mL) and NaHCO were added₃Saturated aqueous solution (25mL) and the mixture was stirred for 5 min. The DCM layer was separated by passage through a hydrophobic frit and the aqueous layer was washed with DCM. The combined DCM extracts were concentrated under reduced pressure and purified by automatic column chromatography, SiO₂The eluent was purified as 0-100% EtOAc in isohexane to yield 7-benzylsulfanyl-4- (cyclopropanecarbonyl) -2- [ (3-methylisoxazol-5-yl) methyl]Isoquinolin-1-one (263mg, 0.61mmol, 93%). Directly used for synthesizing an intermediate S10-C1.

Intermediate S10-B27-benzylsulfanyl-4- [ (4-fluorophenyl) methyl ] -2- [ (3-methylisoxazol-5-yl) methyl ] isoquinolin-1-one

Step 1

7-benzylsulfanyl-4-bromo-2- [ (3-methylisoxazol-5-yl) methyl]A mixture of isoquinolin-1-one (intermediate S9-D1) (2.g, 4.53mmol), bis (pinacol) diboron (3.45g, 13.59mmol) and potassium acetate (1.33g, 13.59mmol) in 1, 4-dioxane (40mL) was degassed with nitrogen. 1, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane adduct (370.07mg, 0.45mmol) was added and the reaction mixture was heated by microwave irradiation at 80 ℃ for 45 minutes. DCM (80mL) and NaHCO were added₃Saturated aqueous solution (80mL) and the mixture was stirred for 5 minutes. The DCM layer was separated by passage through a hydrophobic frit and the aqueous layer was washed with DCM. The combined DCM extracts were concentrated under reduced pressureAnd by automatic column chromatography, SiO₂The eluate was purified with 0-100% EtOAc in isohexane to yield 7-benzylsulfanyl-2- [ (3-methylisoxazol-5-yl) methyl]-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoquinolin-1-one (1.1g, 2.25mmol, 50%).

LCMS (high pH): RT 1.52min [ M-H]^-489.3, 80% purity

Step 2

7-benzylsulfanyl-2- [ (3-methylisoxazol-5-yl) methyl]A solution of-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoquinolin-1-one (100.mg, 0.20mmol) and sodium carbonate (54.25mg, 0.51mmol) in DME (1mL) and water (0.5mL) was degassed with nitrogen. Tetrakis (triphenylphosphine) palladium (0) (11.85mg, 0.010mmol) was added followed by 4-fluorobenzyl bromide (0.04mL, 0.31mmol) and the reaction mixture was heated by microwave irradiation at 50 ℃ for 40 min. DCM (8mL) and NaHCO were added₃Saturated aqueous solution (8mL) and the mixture was stirred for 5 minutes. The DCM layer was separated by passage through a hydrophobic frit and the aqueous layer was washed with DCM. The combined DCM extracts were concentrated under reduced pressure and purified by automatic column chromatography with 0-100% EtOAc in isohexane to yield 7-benzylsulfanyl-4- [ (4-fluorophenyl) methyl]-2- [ (3-methylisoxazol-5-yl) methyl]Isoquinolin-1-one (78mg, 0.17mmol, 81%) as a yellow oil, several impurities of which could be removed in the subsequent steps.

LCMS (high pH): RT 1.42min, [ M + H ]]⁺471.2, 87% purity

Intermediate S10-B37-benzylsulfanyl-4- (4-fluorophenyl) -2-methyl-isoquinolin-1-one

7-Benzylsulfanyl-4-bromo-2-methyl-isoquinolin-1-one (intermediate S9-D3) (100.mg, 0.2800mmol), potassium carbonate (28.09mg, 0.28mmol) and 1, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane adduct (16.33mg, 0.020mmol) were suspendedIn a mixture of 1, 4-dioxane (4mL) and water (0.40mL) and the resulting mixture was purged with nitrogen under vacuum. 4-Fluorophenylboronic acid (38.84mg, 0.28mmol) was added and the resulting mixture was heated at 140 ℃ for 30 minutes by microwave irradiation. The reaction was partitioned between DCM (10mL) and water (10mL) and the organic phase was collected. The mixture was evaporated to dryness and the crude product was purified by automatic column chromatography, SiO₂(RediSep 12g) the eluate was purified as 0-80% EtOAc in isohexane to yield 7-benzylsulfanyl-4- (4-fluorophenyl) -2-methyl-isoquinolin-1-one (100mg, 0.27mmol, 96%).

¹H NMR(300MHz,DMSO-d₆)＝8.19(d,J＝1.9Hz,1H),7.66(dd,J＝2.2,8.6Hz,1H),7.51-7.43(m,3H),7.42-7.20(m,8H),4.35(s,2H),3.33(s,3H)

Intermediate S10-B47-benzylsulfanyl-4-methyl-2- [ (3-methylisoxazol-5-yl) methyl ] isoquinolin-1-one

Reacting 7-benzylsulfanyl-4-bromo-2- [ (3-methylisoxazol-5-yl) methyl]A mixture of isoquinolin-1-one (intermediate S9-D1) (300mg, 0.68mmol), potassium carbonate (206.35mg, 2.04mmol) and trimethylcyclotriboroxane (95.02uL, 0.68mmol) in 1, 4-dioxane (8mL) and water (0.80mL) was purged in vacuo with nitrogen three times. Tetrakis (triphenylphosphine) palladium (0) (78.55mg, 0.070mmol) was added and the resulting mixture was heated at 100 ℃ for 48 h. The reaction mixture was cooled and evaporated to dryness to give a residue, and the crude product was purified by automatic column chromatography, SiO₂(Biotage 12g) eluent was purified as 0-80% EtOAc in isohexane to yield 7-benzylsulfanyl-4-methyl-2- [ (3-methylisoxazol-5-yl) methyl]Isoquinolin-1-one (160mg, 0.43mmol, 63%).

LCMS (high pH): RT 1.29min, [ M + H]⁺377.3，>88% purity

Intermediate S10-C1(2,3,4,5, 6-pentafluorophenyl) 4- (cyclopropanecarbonyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonate

Prepared from 7-benzylsulfanyl-4- (cyclopropanecarbonyl) -2- [ (3-methylisoxazol-5-yl) methyl ] isoquinolin-1-one (intermediate S10-B1), 1, 3-dichloro-5, 5-dimethylhydantoin, pentafluorophenol and triethylamine using the method detailed in intermediate S9-E1.

LCMS (high pH): RT 1.36min, [ M + H ]]⁺553.1, 70% purity

Intermediate S10-C2(2,3,4,5, 6-pentafluorophenyl) 4- [ (4-fluorophenyl) methyl ] -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonate

Prepared from 7-benzylsulfanyl-4- [ (4-fluorophenyl) methyl ] -2- [ (3-methylisoxazol-5-yl) methyl ] isoquinolin-1-one (intermediate S10-B2), 1, 3-dichloro-5, 5-dimethylhydantoin, pentafluorophenol and triethylamine using the method detailed in intermediate S9-E1.

LCMS (high pH): RT 1.36min, [ M + H ]]⁺595.2, 70% purity

Intermediate S10-C3(2,3,4,5, 6-pentafluorophenyl) 4- (4-fluorophenyl) -2-methyl-1-oxo-isoquinoline-7-sulfonate

Prepared from 7-benzylsulfanyl-4- (4-fluorophenyl) -2-methyl-isoquinolin-1-one (intermediate S10-B2), 1, 3-dichloro-5, 5-dimethylhydantoin, pentafluorophenol and triethylamine using the method detailed for intermediates S9-E1.

¹H NMR(300MHz,DMSO-d₆)＝8.80(d,J＝1.9Hz,1H),8.23(dd,J＝2.3,8.8Hz,1H),7.90(s,1H),7.77(d,J＝8.8Hz,1H),7.58-7.50(m,2H),7.44-7.35(m,2H),3.62(s,3H)

Intermediate S10-C4(2,3,4,5, 6-pentafluorophenyl) 4-methyl-2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonate

Prepared from 7-benzylsulfanyl-4-methyl-2- [ (3-methylisoxazol-5-yl) methyl ] isoquinolin-1-one (intermediate S10-B4), 1, 3-dichloro-5, 5-dimethylhydantoin, pentafluorophenol and triethylamine using the method detailed in intermediate S9-E1.

LCMS (high pH): RT 1.29min, [ M + H]⁺501.3, 70% pure Material to the next step (example 256)

Example 3114- (cyclopropanecarbonyl) -N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide;

prepared from (2,3,4,5, 6-pentafluorophenyl) 4- (cyclopropanecarbonyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonate, 1-methylcyclopropylamine hydrochloride and triethylamine using the procedures detailed in example 209.

Example 3224- [ (4-fluorophenyl) methyl ] -N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide;

prepared from (2,3,4,5, 6-pentafluorophenyl) 4- [ (4-fluorophenyl) methyl ] -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonate, 1-methylcyclopropylamine hydrochloride and triethylamine using the methods detailed in example 209.

Example 2554- (4-fluorophenyl) -2-methyl-N- (1-methylcyclopropyl) -1-oxo-isoquinoline-7-sulfonamide;

prepared from (2,3,4,5, 6-pentafluorophenyl) 4- (4-fluorophenyl) -2-methyl-1-oxo-isoquinoline-7-sulfonate, 1-methylcyclopropylamine hydrochloride and triethylamine using the procedure detailed in example 209.

Example 2564-methyl-N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonamide;

prepared from (2,3,4,5, 6-pentafluorophenyl) 4-methyl-2- [ (3-methylisoxazol-5-yl) methyl ] -1-oxo-isoquinoline-7-sulfonate, 1-methylcyclopropylamine hydrochloride and triethylamine using the procedure detailed in example 209.

General procedure for scheme 11 and scheme 12:

intermediate S11-A3-fluoro-N- (1-methylcyclopropyl) -4-nitro-benzenesulfonamide

Triethylamine (1.18mL, 8.47mmol) was added to a solution of 3-fluoro-4-nitrobenzenesulfonyl chloride (2.03g, 8.47mmol) and 1-methylcyclopropylamine hydrochloride (911.43mg, 8.47mmol) in DCM (40mL) at 0 deg.C. After 5 min, pyridine (0.68mL, 8.47mmol) was added dropwise and the reaction mixture was allowed to warm to ambient temperature with stirring Stir overnight, add water (50mL), separate the organic layer, and the aqueous layer was extracted with DCM (2 × 10mL), the organics were combined, passed through a hydrophobic frit and evaporated to dryness, the crude product was purified by automatic column chromatography, SiO₂The eluate was purified in 0-50% EtOAc in isohexane to yield 3-fluoro-N- (1-methylcyclopropyl) -4-nitro-benzenesulfonamide (1.44g, 5.26mmol, 62%).

¹H NMR(300MHz,CDCl₃)＝8.19(t,J＝7.7Hz,1H),7.88-7.79(m,2H),5.10(s,1H),1.30(s,3H),0.83-0.72(m,2H),0.69-0.49(m,2H)

The following intermediates were prepared in a similar manner:

intermediate S12-A4-chloro-N- (1-methylcyclopropyl) -3-nitro-benzenesulfonamide

From 4-chloro-3-nitro-benzenesulfonyl chloride, 1-methylcyclopropylamine hydrochloride and triethylamine.

¹H NMR(300MHz,CDCl₃)＝8.38(d,J＝3.6Hz,1H),8.02(dd,J＝2.2,8.4Hz,1H),7.73(t,J＝6.1Hz,1H),5.09(s,1H),1.30(s,3H),0.83-0.72(m,2H),0.66-0.50(m,2H)

Intermediate S11-B3- (methylamino) -N- (1-methylcyclopropyl) -4-nitro-benzenesulfonamide

Methylamine solution (2M in THF) (8.26mL, 16.53mmol) was added dropwise to a solution of 3-fluoro-N- (1-methylcyclopropyl) -4-nitro-benzenesulfonamide (1.51g, 5.51mmol) and triethylamine (1.15mL, 8.26mmol) in DMF (15mL) with stirring the reaction mixture was heated at 50 ℃ for 2h, water (15mL) and EtOAc (20mL) were added and the organic layer was separated, the aqueous layer was extracted with DCM (2 × 15mL), the combined organics were passed through a hydrophobic frit and under vacuumConcentrate under air. The crude product is passed through an automatic column chromatography, SiO₂The eluate was purified with 0-50% EtOAc in isohexane to yield 3- (methylamino) -N- (1-methylcyclopropyl) -4-nitro-benzenesulfonamide (1.378g, 4.83mmol, 88%).

¹H NMR(300MHz,CDCl₃)＝8.30(d,J＝8.9Hz,1H),8.14(br.s,1H),7.43(d,J＝2.0Hz,1H),7.05(dd,J＝1.9,8.9Hz,1H),5.00(s,1H),3.11(d,J＝4.2Hz,3H),1.29(s,3H),0.92-0.77(m,2H),0.60-0.52(m,2H)

The following intermediates were prepared in a similar manner:

intermediate S12-B4- [ (4-fluorophenyl) methylamino ] -N- (1-methylcyclopropyl) -3-nitro-benzenesulfonamide

From 4-chloro-N- (1-methylcyclopropyl) -3-nitro-benzenesulfonamide, 4-fluorobenzylamine and triethylamine.

¹H NMR(300MHz,CDCl₃)＝8.75(d,J＝2.3Hz,1H),8.68(t,J＝5.6Hz,1H),7.82(dd,J＝2.3,9.0Hz,1H),7.36-7.29(m,2H),7.15-7.04(m,2H),6.90(d,J＝9.1Hz,1H),4.58(d,J＝5.8Hz,2H),1.27(s,3H),0.88-0.70(m,2H),0.60-0.42(m,2H)

Intermediate S11-C4-amino-3- (methylamino) -N- (1-methylcyclopropyl) benzenesulfonamide

To a stirred suspension of 3- (methylamino) -N- (1-methylcyclopropyl) -4-nitrobenzenesulfonamide (4.97g, 17.42mmol) in EtOH (75mL) were added iron (4.86g, 87.1mmol), ammonium chloride (4.66g, 87.1mmol) and water (75 mL). The mixture was stirred at 80 ℃ for 2 hours, then filtered through celite, washing with hot EtOH. The filtrate was concentrated to a slurry under vacuum and addedWater (80mL) and DCM (80 mL.) the organic layer was separated and the aqueous layer was extracted with DCM (2 × 30 mL.) the combined organics were passed through a hydrophobic frit and concentrated to dryness₂The eluent was purified in 0-10% MeOH in DCM to yield 4-amino-3- (methylamino) -N- (1-methylcyclopropyl) benzenesulfonamide (3.83g, 15.0mmol, 86%).

¹H NMR(300MHz,CDCl₃)＝7.25(dd,J＝2.1,8.1Hz,1H),7.13(d,J＝2.1Hz,1H),6.72(d,J＝8.1Hz,1H),5.01(s,1H),3.73(br.s.,2H),2.89(s,3H),1.18(s,3H),0.89-0.71(m,2H),0.51-0.34(m,2H)

The following intermediates were prepared in a similar manner:

intermediate S12-C3-amino-4- [ (4-fluorophenyl) methylamino ] -N- (1-methylcyclopropyl) benzenesulfonamide

Prepared from 4- [ (4-fluorophenyl) methylamino ] -N- (1-methylcyclopropyl) -3-nitro-benzenesulfonamide, iron and ammonium chloride.

¹H NMR(300MHz,CDCl₃)＝7.42-7.30(m,4H),7.09-6.98(m,2H),6.60(d,J＝8.3Hz,1H),5.08(br.s.,1H),4.36(s,2H),1.17(s,3H),0.81-0.72(m,2H),0.46-0.37(m,2H)

Example 214-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-1H-quinoxaline-6-sulfonamide;

oxalyl chloride (0.05mL, 0.56mmol) was added to a stirred solution of 4-amino-3- (methylamino) -N- (1-methylcyclopropyl) benzenesulfonamide (120.mg, 0.47mmol) and triethylamine (0.33mL, 2.35mmol) in DCM (2mL) under nitrogen. The reaction mixture was stirred at ambient temperature for 1 hour. Water (5mL) and DCM (5mL)) And the mixture was stirred for 5 min the DCM layer was separated by passage through a hydrophobic frit and the aqueous layer was washed with DCM (2 × 2mL), the combined DCM extracts evaporated to dryness and the crude product passed through an automatic column chromatography, SiO₂The eluent was purified with 0-10% MeOH in DCM to yield 4-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-1H-quinoxaline-6-sulfonamide (29mg, 0.0937mmol, 20%).

¹H NMR(300MHz,DMSO-d₆)＝12.31(br.s.,1H),8.05(s,1H),7.64(d,J＝1.8Hz,1H),7.59(dd,J＝1.9,8.3Hz,1H),7.29(d,J＝8.3Hz,1H),3.53(s,3H),1.06(s,3H),0.65-0.59(m,2H),0.42-0.35(m,2H)

The following intermediates were prepared in a similar manner:

example 1281- [ (4-fluorophenyl) methyl ] -N- (1-methylcyclopropyl) -2, 3-dioxo-4H-quinoxaline-6-sulfonamide;

prepared from 3-amino-4- [ (4-fluorophenyl) methylamino ] -N- (1-methylcyclopropyl) benzenesulfonamide, oxalyl chloride and triethylamine.

LCMS (high pH): RT 0.89min, [ M-H ] -402.5, > 95% purity

Example 221- (cyclopropylmethyl) -4-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-quinoxaline-6-sulfonamide

Sodium hydride (60% w/w) (3.27Mg, 0.0800mmol) was added to a stirred solution of 4-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-1H-quinoxaline-6-sulfonamide (23.Mg, 0.070mmol) in DMF (1 mL). After 5 min, 1- (bromomethyl) cyclopropane (0.01mL, 0.080mmol) was added and the reaction mixture was stirred under nitrogen overnight. DCM (5mL) and NaHCO were added₃The combined DCM extracts were concentrated to dryness, and the crude product was purified by automatic column chromatography with 0-100% EtOAc in isohexane to yield 1- (cyclopropylmethyl) -4-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-quinoxaline-6-sulfonamide (17.6mg, 0.048mmol, 65%).

The following examples were prepared in a similar manner:

example 401-benzyl-4-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-quinoxaline-6-sulfonamide

From 4-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-1H-quinoxaline-6-sulfonamide (intermediate S11-D), benzyl bromide and sodium hydride (60% w/w).

Example 1301- [ (4-fluorophenyl) methyl ] -4-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-quinoxaline-6-sulfonamide

From 1- [ (4-fluorophenyl) methyl ] -N- (1-methylcyclopropyl) -2, 3-dioxo-4H-quinoxaline-6-sulfonamide (intermediate S12-D), iodomethane and potassium carbonate.

Example 414-methyl-2- (methylamino) -N- (1-methylcyclopropyl) -3-oxo-quinoxaline-6-sulfonamide

Step 1

A solution of 4-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-1H-quinoxaline-6-sulfonamide (intermediate S11-D) (300.mg, 0.9700mmol) in phosphorus oxychloride (3.mL, 32.19mmol) was added and heated at reflux for 4 hours. The reaction mixture was cooled and excess phosphorus oxychloride was removed under reduced pressure. The residue was dissolved in anhydrous DMF (10mL), which was used as the starting solution without further purification.

Step 2

Methylamine solution (2M in THF) (0.11mL, 3.05mmol) was added to a solution of 2-chloro-4-methyl-N- (1-methylcyclopropyl) -3-oxo-quinoxaline-6-sulfonamide (100.mg, 0.31mmol) in anhydrous DMF (2 mL). The reaction mixture was stirred at ambient temperature overnight under nitrogen. The reaction mixture was evaporated to dryness and the residue was purified by preparative HPLC, low pH, to yield 4-methyl-2- (methylamino) -N- (1-methylcyclopropyl) -3-oxo-quinoxaline-6-sulfonamide (26mg, 0.081mmol, 26%).

General procedure for scheme 13:

S13-A17-fluoro-1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide

A mixture of 7-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (0.20mmol), alkylating agent (0.20mmol) and potassium carbonate (0.40mmol) in DMF (2mL) was heated with stirring under microwave irradiation at 80 ℃ for 30 minutes. The solvent was removed in vacuo to give the crude product as a residue, which was purified by preparative HPLC (high pH) to give the desired product.

The following intermediates were prepared by similar methods:

S13-A2N- (1- (fluoromethyl) cyclopropyl) -1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide

General procedure for scheme 14:

S14-A1 Mitsunobu strategy for the synthesis of 7-fluoro-1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide

To a magnetically stirred solution of 7-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (0.20mmol) and ethanol (0.40mmol) in DMF (4mL) at 20 ℃ under nitrogen was added polymer-supported triphenylphosphine (0.60mmol) and the resulting mixture was stirred at room temperature for 15 min. Diisopropyl azodicarboxylate (0.40mmol) was added and the resulting mixture was stirred for 12 hours. The mixture was then filtered and the solvent removed in vacuo to give a residue which was purified by preparative HPLC (high pH) to give the desired product.

General procedure for scheme 23:

2-amino-N- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] benzamide

(5-methyl-1, 3, 4-thiadiazol-2-yl) methylamine (2.4g, 17.28mmol) was added to a magnetically stirred solution of etoposide (2.7g, 16.55mmol) in DMF (20mL) at 0 ℃. After addition, the resulting mixture was heated to 60 ℃ for 5 hours and then stirred at room temperature for 16 hours. The solvent was removed in vacuo to give a light brown solid, which was pre-adsorbed onto silica and column chromatographed, eluting with 0-5% MeOH/DCM to give the desired product in 89% purity (3.0g, 10.753mmol, 65%) as a light brown solid.

¹H NMR(300MHz,DMSO-d₆)＝9.12(t,J＝5.8Hz,1H),7.51(dd,J＝1.4,8.0Hz,1H),7.16(ddd,J＝1.5,7.0,8.3Hz,1H),6.71(dd,J＝1.1,8.2Hz,1H),6.59-6.43(m,3H),4.72(d,J＝5.9Hz,2H),2.67(s,3H)。

3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -1H-quinazoline-2, 4-dione

2-amino-N- [ (5-methyl-1, 3, 4-thiadiazole-2-yl) methyl]A solution of benzamide (3.0g, 10.75mmol) in THF (100mL) was cooled to 0 deg.C and treated with triphosgene (1.6g, 5.38mmol) to cause a precipitate to form. The mixture was stirred in the cooling bath for 15 minutes and then at room temperature for 18 hoursThen (c) is performed. For mixtures K₂CO₃Saturated brine (50mL) was quenched and stirred at room temperature for 24 h. The resulting precipitate was collected by filtration, washed with water and dried to give the desired product (1.7g, 6.1976mmol, 58%) as an off-white solid.

¹H NMR(300MHz,DMSO-d₆)＝11.80(br s,1H),7.96(d,J＝7.8Hz,1H),7.69(dt,J＝1.5,7.7Hz,1H),7.28-7.16(m,2H),5.44(s,2H),2.67(s,3H)。

3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonyl chloride

A solution of 3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -1H-quinazoline-2, 4-dione (1.7g, 6.2mmol) in chlorosulfonic acid (5mL, 6.2mmol) was heated to 50 ℃. LCMS showed absence of SM after 2 hours, the mixture was left to stand at room temperature for 3 days, then added dropwise to crushed ice (about 20mL) at-10 ℃ and stirred for 20 minutes. The precipitated solid was collected by filtration, washed with water and oven dried to give a sticky solid. It was azeotroped with PhMe (× 3) to give the desired product (1.6g, 4.2917mmol, 69%) as a pale yellow solid.

¹H NMR(300MHz,DMSO-d₆)＝11.76(s,1H),8.16(d,J＝2.0Hz,1H),7.88(dd,J＝2.0,8.4Hz,1H),7.17(d,J＝8.5Hz,1H),5.44(s,2H),2.67(s,3H)。

Example 3857-fluoro-1-methyl-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to the general procedure for the synthesis of 7-fluoro-1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (scheme 13) using iodomethane to give the desired product (20mg, 0.047mmol, 24%) as a white powder.

Example 386N- (1-Cyanocyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

A solution of 3- [ (2-methylthiazol-5-yl) methyl ] -1H-quinazoline-2, 4-dione (1.25g, 4.57mmol) in chlorosulfonic acid (4.0mL, 4.57mmol) was heated to 60 ℃ with stirring for 3 hours. The mixture was allowed to cool and added dropwise to crushed ice (300 mL). 5% MeOH/DCM (300mL) was added and the mixture was stirred for 5 min. The DCM layer was separated and the aqueous layer was extracted with 5% MeOH/DCM (100 mL). The combined extracts were passed through a hydrophobic frit and concentrated under reduced pressure. The crude product was added to a solution of 1-amino-1-cyclopropanecarbonitrile hydrochloride (1.08g, 9.15mmol) in pyridine (5mL) with stirring. After 1 hour, the reaction mixture was added to EtOAc (300mL) and saturated aqueous ammonium chloride (300mL) and stirred for 5 minutes. The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined extracts were passed through a hydrophobic frit and concentrated under reduced pressure. The solid residue was sonicated in water, filtered and dried to give the desired product (358mg, 0.858mmol, 18.7%) as a white solid.

Example 387N- (1-cyanocyclopropyl) -7-fluoro-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

7-fluoro-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonyl chloride (0.44g, 1.18mmol) was added to 1-amino-1-cyclopropanenitrile hydrochloride (0.28g, 2.36mmol) and pyridine (5mL) with stirring. The mixture was added to EtOAc (300mL) and saturated aqueous sodium bicarbonate (300mL) and the mixture was stirred for 5 minutes. The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined extracts were passed through a hydrophobic frit and concentrated under reduced pressure and purified by column chromatography (DCM- > 10% MeOH/DCM) to yield the desired product (150mg, 0.359mmol, 30.4%) as a white solid.

Example 388N- (1-Cyanocyclopropyl) -7-fluoro-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

This compound was prepared according to the general procedure for the synthesis of 7-fluoro-1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (scheme 13) using iodomethylcyclopropane to afford the desired product (20mg, 0.043mmol, 22%) as a white powder.

Example 3891-Ethyl-7-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to the general procedure for the synthesis of 7-fluoro-1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (scheme 13) using iodoethane to afford the desired product (20mg, 0.046mmol, 23%) as a white powder.

Example 3907-fluoro-1- [ (4-fluorophenyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to the general procedure for the synthesis of 7-fluoro-1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (scheme 13) using 4-fluorobromobenzyl to give the desired product (25mg, 0.048mmol, 25%) as a white powder.

Example 3917-fluoro-N- (1-methylcyclopropyl) -1- [ (3-methylisoxazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to the general procedure for the synthesis of 7-fluoro-1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (scheme 13) using 5- (bromomethyl) -3-methyl-1, 2-oxazole to give the desired product (20mg, 0.040mmol, 20%) as a white powder.

Example 3921- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -7-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to the general procedure for the synthesis of 7-fluoro-1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (scheme 13) using 5- (chloromethyl) -1, 3-dimethyl-1H-pyrazole to give the desired product (25mg, 0.048mmol, 25%) as a white powder.

Example 3937-fluoro-N- (1-methylcyclopropyl) -1, 3-bis [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to the general procedure for the synthesis of 7-fluoro-1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (scheme 13) using 4- (chloromethyl) -1-methyl-1H-pyrazole hydrochloride to give the desired product (24mg, 0.048mmol, 24%) as a white powder.

Example 3947-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (oxetan-3-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to the Mitsunobu strategy for the synthesis of 7-fluoro-1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (scheme 14) using oxetane-3-methanol to give the desired product (20mg, 0.042mmol, 21%) as a white powder.

Example 3957-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydrofuran-3-ylmethyl) quinazoline-6-sulfonamide

This compound was prepared according to the Mitsunobu strategy for the synthesis of 7-fluoro-1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (scheme 14) using 3-tetrahydrofuryl alcohol to give the desired product (20mg, 0.041mmol, 21%) as a white powder.

Example 3961- [ (2, 4-dimethylthiazol-5-yl) methyl ] -7-fluoro-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to the Mitsunobu strategy for the synthesis of 7-fluoro-1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (scheme 14) using (2, 4-dimethyl-1, 3-thiazol-5-yl) methanol to give the desired product (20mg, 0.038mmol, 19%) as a white powder.

Example 3977-fluoro-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2- ((3-methyloxetan-3-yl) methoxy) -4-oxo-3, 4-dihydroquinazoline-6-sulfonamide

This compound was prepared according to the Mitsunobu strategy for the synthesis of 7-fluoro-1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (scheme 14) using 3-methyl-3-oxetanemethanol to give the desired product (20mg, 0.031mmol, 16%) as a white powder.

Example 3987-fluoro-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -1- ((3-methyloxetan-3-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide

Example 399N- (1-Cyanocyclopropyl) -1- (cyclopropylmethyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Iodomethylcyclopropane (0.03mL, 0.20mmol) was added to a stirred mixture of N- (1-cyanocyclopropyl) -N- [ [3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] acetamide (76mg, 0.170mmol) and potassium carbonate (92mg, 0.66mmol) in DMF (3mL) and stirred at room temperature for 16H. Concentrated aqueous ammonia (100 μ L) was added and the mixture was heated to 40 ℃ for 10 minutes. The mixture was allowed to cool and DCM (8mL) and saturated aqueous ammonium chloride (8mL) were added and the mixture was stirred for 5 min. The DCM layer was separated by passage through a hydrophobic frit and the aqueous layer was washed with DCM (10 mL). The combined DCM extracts were concentrated under reduced pressure and purified by preparative HPLC (low pH) to yield the desired product (8mg, 0.017mmol, 10%) as a white powder.

Example 400N- (1-Cyanocyclopropyl) -1- [ (3-methylisoxazol-5-yl) methyl ] -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to the method described in example 399 from 5- (bromomethyl) -3-methyl-1, 2-oxazole (0.02mL, 0.20mmol) and N- (1-cyanocyclopropyl) -N- [ [3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] acetamide (76mg, 0.170 mmol). This gave the desired product (10mg, 0.020mmol, 12%) as a white powder.

Example 401N- (1-Cyanocyclopropyl) -1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Diisopropyl azodicarboxylate (0.07mL, 0.330mmol) was added to a stirred mixture of N- (1-cyanocyclopropyl) -N- [ [3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] acetamide (76mg, 0.170mmol), (2, 4-dimethyl-1, 3-thiazol-5-yl) methanol (0.04mL, 0.33mmol), and triphenylphosphine, with a polymer linkage of about 1.6mmol/g (310mg, 0.500mmol) in DMF (5 mL). After stirring at room temperature for 3 hours, concentrated aqueous ammonia (500 μ L) was added, and the mixture was stirred for 2 hours. DCM (10mL) and saturated aqueous ammonium chloride (10mL) were added and the mixture was stirred for 5 min. The DCM layer was separated by passage through a hydrophobic frit and the aqueous layer was extracted with DCM. The combined DCM extracts were concentrated under reduced pressure and purified by preparative HPLC (low pH) to yield the desired product (15mg, 0.028mmol, 17%) as a white powder.

Example 402N- (1-Cyanocyclopropyl) -1- [ (4-fluorophenyl) methyl ] -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to the method described in example 399 from 4-fluorobenzyl bromide (0.02mL, 0.20mmol) and N- (1-cyanocyclopropyl) -N- [ [3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] acetamide (76mg, 0.170 mmol). This gave the desired product (10mg, 0.019mmol, 12%) as a white powder.

Example 403N- (1-Cyanocyclopropyl) -3- (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1-prop-2-ynyl-quinazoline-6-sulfonamide

This compound was prepared from 3-bromopropyne (0.03mL, 0.270mmol) and N- (1-cyanocyclopropyl) -N- [ [3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] acetamide (104mg, 0.230mmol) according to the method described in example 399. This gave the desired product (18mg, 0.04mmol, 17%) as a white powder.

Example 404N- (1-Cyanocyclopropyl) -7-fluoro-1- [ (3-methylisoxazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to the method described in example 399 from 5- (bromomethyl) -3-methyl-1, 2-oxazole (0.02mL, 0.170mmol) and N- (1-cyanocyclopropyl) -N- [ [ 7-fluoro-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] acetamide (65mg, 0.140 mmol). This gave the desired product (6mg, 0.012mmol, 8.3%) as a white powder.

Example 4051- [ (4, 4-Difluorocyclohexyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Using method a2, prepared from N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide and (4, 4-difluorocyclohexyl) methanol. This gave the desired product (48mg, 0.092mmol, 8.3%) as a white powder.

Example 406N, N-dimethyl-3- [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] propionamide

Using method a2, prepared from N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide and 3-hydroxy-N, N-dimethylpropionamide. This gave the desired product (12mg, 0.025mmol, 12%) as a white powder.

Example 4071- (3-hydroxypropyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a1, prepared from N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide and 3-bromopropane-1-propanol. This gave the desired product (6mg, 0.013mmol, 6.5%) as a white powder.

Example 408N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

This compound was prepared according to the general procedure for the synthesis of N- (1- (fluoromethyl) cyclopropyl) -1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (scheme 13) using iodomethane to afford the desired product (20mg, 0.047mmol, 35%) as a white powder.

Example 4093- [ [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] azetidine-1-carboxylic acid tert-butyl ester

Prepared using method a14 from N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (300mg, 0.770mmol) and 1-boc-3- (bromomethyl) azetidine (231mg, 0.920mmol) by heating for only 1 hour. The desired product (190mg, 0.34mmol, 44.2%) was given as an off-white powder.

Example 4101- (2-fluoroethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a14 from 3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (80mg, 0.20mmol) and 1-bromo-2-fluoroethane (0.02mL, 0.25mmol) by heating for only 1 hour. The desired product (15mg, 0.034mmol, 17%) was given as a white powder.

Example 4111- (2-fluoroethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a14 from N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (80mg, 0.20mmol) and 1-bromo-2-fluoroethane (0.02mL, 0.25mmol) by heating for only 1 hour. The desired product (22mg, 0.05mmol, 25%) was given as a white powder.

Example 412N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- [ (3-oxocyclobutyl) methyl ] quinazoline-6-sulfonamide

Using method a14, from N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (80mg, 0.20mmol) and 1-3- (bromomethyl) cyclobutanone (0.02mL, 0.25mmol), heat to 130 ℃ by microblog irradiation for 1 hour. More potassium carbonate (34mg, 0.25mmol) and 3- (bromomethyl) cyclobutanone (0.02mL, 0.25mmol) were added, and then the mixture was heated to 135 ℃ by microwave irradiation for 2 hours. Work-up to give the desired product (7mg, 0.015mmol, 7%) as a brown powder.

Example 4131- (2-methoxy-2-methyl-propyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (80mg, 0.20mmol), potassium carbonate (68mg, 0.25mmol) and 1-bromo-2-methoxy-2-methyl-propane (0.04mL, 0.50mmol) in DMF (2mL) were heated to 150 ℃ by microwave irradiation for 2 hours. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2X 20 mL). The organic phases were combined, washed with brine (10mL), passed through a hydrophobic frit and evaporated to dryness. The crude product mixture was purified by preparative HPLC (high pH) to give the desired product (4mg, 0.008mmol, 4%) as a white powder.

Example 4141- [2- (azetidin-1-yl) -2-oxoethyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a14 from N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (80mg, 0.20mmol) and 1- (chloroacetyl) azetidine (0.02mL, 0.250mmol) by heating for only 1 hour. The desired product (24mg, 0.049mmol, 24%) was given as a white powder.

Example 4151- (azetidin-3-ylmethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

A mixture of 3- [ [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazolin-1-yl ] methyl ] azetidine-1-carboxylic acid tert-butyl ester (160mg, 0.29mmol), trifluoroacetic acid (1.0mL, 13.5mmol) and DCM (10mL) was stirred at ambient temperature. After 2 hours, the reaction mixture was concentrated to dryness under reduced pressure. The crude product mixture was purified by preparative HPLC (high pH) to give the desired product (50mg, 0.109mmol, 38%) as a white powder.

Example 416N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulphonamide

Reacting 3- [ (1-methylpyrazol-4-yl) methyl]-2, 4-dioxo-1H-quinazoline-6-sulfonyl chloride (200mg, 0.56mmol) was added to a stirred solution of 1- (fluoromethyl) cyclopropane-1-amine hydrochloride (34mg, 0.27mmol), N-diisopropylethylamine (301uL, 1.69mmol) and 4-dimethylaminopyridine (69mg, 0.56mmol) in DMF (8mL) and the resulting mixture was mixedThe material was stirred at 60 ℃ for 30 minutes. The mixture was cooled to ambient temperature and distilled to dryness to give the crude product as residue, which was passed through automatic column chromatography (SiO)₂(ii) a RediSep-12 g; DCM in DCM 0 to 10% MeOH) to give the desired product (150mg, 0.368mmol, 65%) as a white solid.

Example 4171- (Cyclopropylmethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

This compound was prepared according to the general procedure for the synthesis of N- (1- (fluoromethyl) cyclopropyl) -1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide using iodomethylcyclopropane to afford the desired product (20mg, 0.043mmol, 22%) as a white powder.

Example 4181-methyl-N- (1-methylcyclopropyl) -3- [ (5-methyl-3-pyridyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

3- (bromomethyl) -5-methylpyridine hydrobromide (1:1) (45mg, 0.17mmol) was added to a solution of 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (50mg, 0.160mmol) and potassium carbonate (47mg, 0.34mmol) in DMF (1 mL). The reaction mixture was stirred at ambient temperature overnight. LCMS confirmed conversion to the desired product. The reaction mixture was carefully poured into dilute aqueous sodium bicarbonate (50mL) and extracted with EtOAc (2X 20 mL). The organic liquids were combined, washed with brine (10mL), passed through a hydrophobic frit and evaporated to dryness. The crude product mixture was purified by preparative HPLC (high pH) to give the desired product (16mg, 0.039mmol, 24%) as a white powder.

Example 419N- [1- (fluoromethyl) cyclopropyl ] -1- [ (4-fluorophenyl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to the general procedure for the synthesis of N- (1- (fluoromethyl) cyclopropyl) -1-substituted-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide using 4-fluorobenzyl bromide to afford the desired product (20mg, 0.039mmol, 23%) as a white powder.

Example 4201- [ (1-Cyanocyclopropyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a10 (tosylate), prepared from N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide and (1-cyanocyclopropyl) methyl 4-methylbenzenesulfonic acid. This gave the desired product (12mg, 0.026mmol, 13%) as a white powder.

Example 421N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- [ (4-oxocyclohexyl) methyl ] quinazoline-6-sulfonamide

Using method a10 (tosylate), prepared from N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide and (4-oxocyclohexyl) methyl 4-methylbenzenesulfonic acid. This gave the desired product (8mg, 0.016mmol, 8%) as a white powder.

Example 4228-bromo-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-sulfonamide

Intermediate S15-A2-amino-3-bromo-N- [ (1-methylpyrazol-4-yl) methyl ] benzamide

C- (1-methyl-1H-pyrazol-4-yl) -methylamine (506mg, 4.56mmol) was added to a magnetically stirred solution of 8-bromoisatoic anhydride (1050mg, 4.34mmol) in DMF (20mL) at 0 ℃ and the resulting mixture was heated at 40 ℃ for 4 hours. The solvent was removed under vacuum to give a light brown solid, which was suspended in ether (40mL) and stirred for 30 minutes. The solid was then filtered and the filter cake was washed with diethyl ether (2 × 20mL) to give the desired product (1300mg, 97%) as an off-white solid.

¹H NMR(300MHz,DMSO-d₆)＝8.77(s,1H),7.59(s,1H),7.52(d,J＝7.8Hz,2H),7.34(s,1H),6.58-6.44(m,3H),4.24(d,J＝5.7Hz,2H),3.78(s,3H)

Intermediate S15-B8-bromo-3- ((1-methyl-1H-pyrazol-4-yl) methyl) quinazoline-2, 4(1H,3H) -dione

To 2-amino-3-bromo-N- [ (1-methylpyrazol-4-yl) methyl at 0 deg.C]To a magnetically stirred solution of benzamide (1300mg, 4.2mmol) in THF (100mL) was added triphosgene (624mg, 2.1mmol) and the resulting mixture was stirred at ambient temperature for 1 hour. Addition of triethylamine (0.59mL, 4.2mmol), and the resulting suspension is stirred for 12 hours. The reaction was quenched by the addition of saturated potassium carbonate (150mL) and the resulting suspension was stirred for 12 hours. The mixture was partitioned between EtOAc (200mL) and water (100mL) and the organic phase was collected. The aqueous solution was extracted with EtOAc (100mL) and the combined organics were washed with brine (100mL) and dried (Na)₂SO₄). The solvent was removed to give the crude product, which was suspended in ether and stirred for 30 minutes. The mixture was then filtered to give the desired product (970mg, 69%) as a white solid.

¹H NMR(300MHz,DMSO-d₆)＝10.61(br.s.,1H),7.97(ddd,J＝1.4,7.9,9.2Hz,2H),7.65(s,1H),7.37(s,1H),7.16(t,J＝7.9Hz,1H),4.90(s,2H),3.76(s,3H)

Intermediate S15-C8-bromo-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride

At 20 ℃, 8-bromo-3- [ (1-methylpyrazol-4-yl) methyl]-1H-quinazoline-2, 4-dione (970mg, 2.89mmol) was added to stirred chlorosulfonic acid (10mL, 2.89mmol) and the resulting mixture was heated at 60 ℃ for 12H, the mixture was cooled to ambient temperature, carefully poured into ice (100mL), the milky suspension was then extracted with 5% MeOH in DCM (4 × 50mL), and the combined extracts were dried (Na)₂SO₄) And evaporated to dryness to give the desired product (1170mg, 93%) as a white solid.

¹H NMR (300MHz, chloroform-d) 8.79(d, J2.2 Hz,1H),8.41(d, J2.1 Hz,1H),8.33(s,1H),7.65(s,1H),7.57(s,1H),5.09(s,2H),3.90(s,3H)

S15-D8-bromo-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

Reacting 8-bromo-3- [ (1-methylpyrazol-4-yl) methyl]-2, 4-dioxo-1H-quinazoline-6-sulfonyl chloride (1.0g, 2.31mmol) was added to a stirred solution of 1-methylcyclopropylamine hydrochloride (372mg, 3.46mmol), N-diisopropylethylamine (1.23mL, 6.92mmol) and 4-dimethylaminopyridine (282mg, 2.31mmol) in DMF (8mL) and the resulting mixture was stirred at 60 ℃ for 60 minutes. LCMS showed TM (rt ═ 0.79 min, 94%) and several smaller impurities. The mixture was cooled to ambient temperature and evaporated to dryness to give a residue which was purified by automatic column chromatography (SiO)₂(ii) a RediSep-24 g; 0 to 10% MeOH in DCM) to give the desired product (850mg, 1.82mmol, 78.7%) as a white solid.

Example 4231-methyl-N- (1-methylcyclopropyl) -3- [ (6-methyl-3-pyridyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to example 418 using 5- (bromomethyl) -2-methylpyridine hydrobromide (1:1) (45mg, 0.170mmol) and 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (50mg, 0.16 mmol). The desired product (5mg, 0.012mmol, 7.5%) was obtained as a white powder.

Example 4246- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxamide

Reacting 8-bromo-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl]-2, 4-dioxo-1H-quinazoline-6-sulfonamide (80mg, 0.17mmol) and tetrakis (triphenylphosphine) palladium (0) (19.77mg, 0)02mmol) in DMF (2mL) was purged three times in vacuo with nitrogen. Zinc cyanide (24mg, 0.20mmol) was added to the reaction and the resulting mixture was heated at 80 ℃ for 16 hours with stirring. The mixture was cooled to ambient temperature and filtered through celite. The filtrate was distilled to dryness to give a residue, which was subjected to automatic column chromatography (SiO)₂(ii) a RediSep-4 g; 0 to 10% MeOH in DCM) to give 8-cyano-3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (50mg, 71%) as a white solid.

¹H NMR(300MHz,DMSO-d₆)＝8.50(d,J＝2.2Hz,1H),8.35(d,J＝2.2Hz,1H),8.29(s,1H),7.67(s,1H),7.39(s,1H),4.90(s,2H),3.78-3.75(m,3H),1.09(s,3H),0.65-0.55(m,2H),0.49-0.36(m,2H)。

To a solution of 8-cyano-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (20mg, 0.05mmol) and potassium carbonate (0.67mg, 0.05mmol) in water (2mL) at 20 ℃ under nitrogen was added hydrogen peroxide (1.64mg, 0.05mmol) and the resulting mixture was stirred at ambient temperature for 16H. The mixture was concentrated and a white solid precipitated, which was collected by filtration. The solid was washed with water (2X 2mL) and dried under vacuum at 40 ℃ to give the desired product 6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxamide (10mg, 0.023mmol, 48%) as a white solid.

Example 4251- [ (1-Formylazetidin-3-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

A mixture of 1- (azetidin-3-ylmethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide (40mg, 0.090mmol), potassium carbonate (14mg, 0.10mmol) and iodomethane (0.01mL, 0.090mmol) in DMF (2mL) was heated to 100 ℃ by microwave irradiation for 20 min. LCMS showed good conversion to product. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2X 20 mL). The organic phases were combined, washed with brine (10mL), passed through a hydrophobic frit and evaporated to dryness. The crude product mixture was purified by preparative HPLC (high pH) to give the desired product (3mg, 0.006mmol, 7%) as a white powder.

Example 4261- (cyclopropylmethyl) -3-methyl-N- (1-methylcyclopropyl) -2-oxo-quinoline-6-sulfonamide

Intermediate S16-B N- (2-formylphenyl) propionamide

According to heterocyclic compounds]65, (9) p, 2095-2105A solution of 2-nitrobenzaldehyde (2.0g, 13.2mmol) in ethanol (32mL), acetic acid (32mL) and water (16mL) was treated with iron (5.2g, 92.7mmol), heated to 100 ℃ for 10 minutes and then stirred at room temperature for 10 minutes. The cooled reaction mixture was filtered through celite and refiltered through filter paper into a separatory funnel. The mixture was diluted with water and EtOAc and separated. The aqueous layer was re-extracted with EtOAc and the combined organic layers were re-extracted with saturated NaHCO₃The aqueous solution was washed (3 × 75 mL-to pH8), dried (hydrophobic frit) and concentrated to give crude aniline intermediate S16-a as a yellow oil (1.25g), which was used without further purification.

The yellow oil was dissolved in THF (80mL), treated with pyridine (1.6mL, 19.85mmol), then propionyl chloride (1.7mL, 19.9mmol) was added slowly, and a cloudy precipitate formed midway through the addition. After stirring at room temperature for 30 min, the reaction mixture was quenched with 1M HCl (40mL), then THF was removed under vacuum. The aqueous residue was extracted with EtOAc (2 × 60mL), and the organic layer was washed with water, dried (hydrophobic frit) and concentrated to give 2.0g of a yellow oil. Purification by flash column chromatography eluting with isohexane-1: 1 isohexane: EtOAc provided intermediate S16-B N- (2-formylphenyl) propionamide (717mg, 4.0mmol, 31%) as a light yellow oil.

¹H NMR (300MHz, chloroform-d) ═ 11.17(br.s.,1H),9.94(s,1H),8.78(d, J ═ 8.5Hz,1H),7.69(dd, J ═ 1.6,7.7Hz,1H),7.66-7.59(m,1H),7.24(dt, J ═ 0.9,7.5Hz,1H),2.52(q, J ═ 7.6Hz,2H),1.30(t, J ═ 7.6Hz,3H)

LCMS (high pH) found 176.1[ M-H ] T ═ 0.96min, UV purity 92%.

Intermediate S16-C3-methyl-1H-quinolin-2-one

A mixture of N- (2-formylphenyl) propionamide (200mg, 1.13mmol) and cesium carbonate (1.84g, 5.64mmol) in DMF (5mL) was heated to 60 ℃ for 5h following the procedure described for the heterocyclic compound, 65, (9), 2005, p.2095-2105. The reaction mixture was then cooled, diluted with DCM (20mL) and saturated NH₄Aqueous Cl and water, and the organic layer (hydrophobic frit) was dried and concentrated. Purification by flash column chromatography eluting with isohexane-80% EtOAc/isohexane gave 3-methyl-1H-quinolin-2-one (84mg, 0.53mmol, 47%) as an off-white solid.

¹H NMR (300MHz, chloroform-d) ═ 11.24(br.s.,1H),7.70-7.65(m,1H),7.52(d, J ═ 7.8Hz,1H),7.50-7.44(m,1H),7.39-7.33(m,1H),7.25-7.18(m,1H),2.32(d, J ═ 1.1Hz,3H)

LCMS (high pH) found 160.1[ M + H ] + T ═ 0.81min, UV purity 100%.

Intermediate S16-D3-methyl-2-oxo-1H-quinoline-6-sulfonyl chloride

A solution of 3-methyl-1H-quinolin-2-one (92mg, 0.58mmol) in chlorosulfonic acid (1.0mL, 0.5800mmol) was heated to 60 ℃ for 2 hours after the light shield in a sealed reaction-visual, and then the temperature was raised to 80 ℃ for 2 hours. The reaction mixture was allowed to stand overnight and then carefully pipetted into stirred ice/water and the precipitate was collected by filtration and dried to give 3-methyl-2-oxo-1H-quinoline-6-sulfonyl chloride (115mg, 0.45mmol, 77%) as a white powder. This material was used in the next step without purification.

¹H NMR(300MHz,DMSO-d₆)＝11.80(br.s.,1H),7.85-7.78(m,2H),7.63(dd,J＝1.8,8.4Hz,1H),7.21(d,J＝8.5Hz,1H),2.08(d,J＝1.0Hz,3H)

Intermediate S16-E3-methyl-N- (1-methylcyclopropyl) -2-oxo-1H-quinoline-6-sulfonamide

A solution of 3-methyl-2-oxo-1H-quinoline-6-sulfonyl chloride (40mg, 0.12mmol) and 1-methylcyclopropylamine hydrochloride (20mg, 0.19mmol) in DCM (1mL) was treated with triethylamine (0.05mL, 0.37mmol) and stirred at room temperature. After 1 hour, 1mL of DMF was added to completely dissolve the reaction, and after 3 hours an additional portion of triethylamine (0.05mL, 0.37mmol) was added and the mixture was stirred for 18 hours and then diluted with water (2mL) and DCM (10 mL). The aqueous layer was re-extracted with DCM and the combined organic extracts were washed with water, dried (hydrophobic frit) and concentrated. Purification by flash column chromatography eluting with EtOAc-5% MeOH/EtOAc provided 3-methyl-N- (1-methylcyclopropyl) -2-oxo-1H-quinoline-6-sulfonamide (20mg, 0.068mmol, 55%) as a white solid.

¹H NMR(300MHz,DMSO-d₆)＝12.10(br.s.,1H),8.05(d,J＝2.1Hz,1H),8.00(br.s.,1H),7.96-7.92(m,1H),7.78(dd,J＝2.0,8.6Hz,1H),7.41(d,J＝8.7Hz,1H),2.11(d,J＝1.0Hz,3H),1.04(s,3H),0.64-0.53(m,2H),0.40-0.30(m,2H)

LCMS: high pH-found 293.1[ M + H ] + T ═ 0.86min, UV purity 100%; low pH-found 293.1[ M + H ] + T ═ 0.85 min, UV purity 100%.

S16-F1- (cyclopropylmethyl) -3-methyl-N- (1-methylcyclopropyl) -2-oxo-quinoline-6-sulfonamide

A solution of 3-methyl-N- (1-methylcyclopropyl) -2-oxo-1H-quinoline-6-sulfonamide (17mg, 0.06mmol) and iodomethylcyclopropane (16mg, 0.09mmol) in DMF (1mL) was treated with potassium carbonate (16mg, 0.12mmol) and stirred at 80 ℃ under microwave irradiation for 20 min. The reaction mixture was diluted with water (2mL) and DCM (5mL) and stirred vigorously for 10 minutes, then passed through a hydrophobic frit. The aqueous layer was re-extracted with DCM and the organic layer was dried (hydrophobic frit), concentrated and purified by preparative HPLC (high pH) to give the desired product 1- (cyclopropylmethyl) -3-methyl-N- (1-methylcyclopropyl) -2-oxo-quinoline-6-sulfonamide (4mg, 0.012mmol, 20%) as a white powder.

Example 427N- (1-ethynylcyclopropyl) -1-methyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Intermediate S17-A (cyclopropylethynyl) trimethylsilane

A magnetically stirred solution of ethynylcyclopropane (8.8mL, 104mmol) in dry ether (50mL) was cooled to-78 deg.C and treated with methyllithium (65.mL, 104mmol) over a period of 10 minutes. After stirring for 2 hours, TMS-chloride (13.2mL, 104mmol) was added over a period of 5 minutes, stirred for an additional 2 hours, and then warmed to ambient temperature. After stirring for another 1 hour, the mixture was poured into ice-cooled water (100mL) and extracted with EtOAc (3X 100 mL). The combined organic extracts were passed through a hydrophobic frit and concentrated to dryness to give crude 2-cyclopropylethynyl (trimethyl) silane (13.5g, 92.6mmol, 89.0%) which was used without further purification.

¹H NMR (300MHz, chloroform-d) ═ 1.08(s,1H),0.68-0.55(m,4H), 0.04-0.04 (m,9H)

Intermediate S17-B1- (2-trimethylsilylethynyl) cyclopropanecarboxylic acid

To a solution of 2-cyclopropylethynyl (trimethyl) silane (7.14g, 51.6mmol) in diethyl ether (70mL) was added a 1.6M solution of n-butyllithium in hexane (30.7mL, 49.1 mmol). After 6 hours, the mixture was cooled to-78 ℃ and the CO was stirred vigorously₂The mixture was warmed to room temperature with bubbling through for 2 hours and poured into a stirred mixture of ice-water (300mL) and ether (300 mL.) the ether layer was separated, the aqueous layer was extracted with ether (3 × 100 mL.) then the aqueous layer was acidified with 1 molar equivalent of concentrated HCl and then extracted with ether (3 × 100 mL.) the combined ether extracts were dried over magnesium sulfate and concentrated under reduced pressure to yield crude 1- (2-trimethylsilylethynyl) cyclopropanecarboxylic acid (4.6g, 25.2mmol, 48.9%) as a white solid.

¹H NMR (300MHz, chloroform-d) ═ 11.71-9.06(m,1H),1.62(q, J ═ 3.9Hz,2H),1.45-1.36(m,2H),0.26-0.02(m,7H), 0.39-0.18 (m,1H)

Intermediate S17-C N- [1- (2-trimethylsilylethynyl) cyclopropyl ] carboxylic acid tert-butyl ester

A solution of 1- (2-trimethylsilylethynyl) cyclopropanecarboxylic acid (3.0g, 16.5mmol), diphenylphosphoryl azide (3.37mL, 15.63mmol) and triethylamine (4.58mL, 32.9mmol) in butanol (10mL) was heated at 75 deg.C. After 16 h, the reaction mixture was cooled to ambient temperature and poured into a biphasic mixture of water (200mL) and EtOAc (100 mL). The biphasic mixture was stirred for 15 min, and then the organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined extracts were then washed with water (100mL) and then dried over magnesium sulfate, then distilled to dryness to give the desired product, tert-butyl N- [1- (2-trimethylsilylethynyl) cyclopropyl ] carboxylate (3.1g, 12.2mmol, 74.3%) as a white solid, which was used without further purification.

¹H NMR (300MHz, chloroform-d) ═ 5.15-4.83(m,1H),1.47(s,9H),1.17(br s,4H),0.13(s,9H)

Intermediate S17-D1-ethynylcyclopropylamine hydrochloride

A mixture of tert-butyl N- [1- (2-trimethylsilylethynyl) cyclopropyl ] carboxylate (1.31g, 5.17mmol) and potassium fluoride (901.Mg, 15.51mmol) in DMF (75mL) and water (75mL) was stirred for 16 h. EtOAc (200mL) and saturated aqueous sodium bicarbonate solution (200mL) were added and the mixture was stirred for 5 min. The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined EtOAc layers were passed through a hydrophobic frit and concentrated to dryness. The crude mixture was purified by column chromatography (hexanol >50:50 EtOAc: Hex) to give an oil. It was taken up in 4M HCl in dioxane (50mL) and stirred for 16 hours. The resulting white precipitate was filtered, washed with ether and dried to yield 1-ethynylcyclopropylamine hydrochloride (830mg, 7.06mmol, 136%) as a white solid.

¹H NMR(300MHz,DMSO-d₆)＝9.13-8.79(m,1H),8.96(br s,2H),3.60(s,1H),1.38-1.28(m,2H),1.16(d,J＝2.6Hz,2H)

S17-E N- (1-ethynylcyclopropyl) -1-methyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

A solution of 1-methyl-3- [ (1-methylpyrazol-4-yl) methyl ] quinazoline-2, 4-dione (120mg, 0.440mmol) in chlorosulfonic acid (1.0mL, 0.440mmol) was stirred at room temperature for 16 hours. The mixture was added dropwise to stirred EtOAc (20mL) and ice (ca. 20 mL). After addition was complete, the mixture was stirred for 5 min, the EtOAc layer was separated and the aqueous layer was extracted with EtOAc (20 mL). The combined extracts were passed through a hydrophobic frit and concentrated under reduced pressure. The resulting white solid was added to a stirred solution of 1-ethynylcyclopropylamine hydrochloride (52mg, 0.44mmol) in pyridine (3mL) and stirred for 16 h. EtOAc (10mL) and 1M HCl (aq) (10mL) were added and the mixture was stirred for 5 min. The EtOAc layer was separated and the aqueous phase was extracted with EtOAc. The combined EtOAc layers were passed through a hydrophobic frit, concentrated under reduced pressure, and purified by preparative HPLC (high pH) to yield N- (1-ethynylcyclopropyl) -1-methyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide (20mg, 0.05mmol, 11%) as a white powder.

Example 428N- [ [6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazolin-8-yl ] methyl ] acetamide

Reacting 8-cyano-N- (1-methylcyclopropyl) -3- [ (1-methyl)Pyrazol-4-yl) methyl]A suspension of-2, 4-dioxo-1H-quinazoline-6-sulfonamide (80mg, 0.19mmol), acetic anhydride (36.5. mu.L, 0.39mmol) and nickel (II) chloride hexahydrate (46mg, 0.19mmol) in methanol (4mL) was cooled to 0 ℃ and treated with sodium borohydride (51mg, 1.35 mmol). The resulting mixture was stirred at ambient temperature overnight. The solvent was removed under vacuum to give a residue which was taken up in EtOAc (10mL) and saturated NaHCO₃(10 mL). The EtOAc layer was collected and evaporated to dryness to give a residue which was purified by preparative HPLC (high pH) to give the desired product (10mg, 0.022mmol, 11%) as a white powder.

Example 4298- [3- (dimethylamino) prop-1-ynyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

A mixture of 8-bromo-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (50mg, 0.11mmol), tetrakis (triphenylphosphine) palladium (0) (12.3mg, 0.01mmol), triethylamine (60uL, 0.43mmol) and 3-dimethylamino-1-propyne (23 uL, 0.21mmol) in THF (2mL) was degassed with nitrogen for 5 minutes. Copper iodide (2.03mg, 0.010mmol) was added to the reaction, and the resulting mixture was heated at 80 ℃ overnight. The mixture was cooled to ambient temperature and filtered through celite. The solvent was then removed in vacuo to give a residue which was purified by preparative HPLC (high pH) to give the desired product (20mg, 0.043mmol, 40%) as a white powder.

Example 430N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Prepared using process intermediates S4-C1. The desired product (2mg) was given as a white powder.

Example 431N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Prepared from 3- [ (1-methylpyrazol-4-yl) methyl ] -1H-quinazoline-2, 4-dione (90mg, 0.350mmol) in a similar manner to N- (1-ethynylcyclopropyl) -1-methyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide (scheme 17). The desired product (42mg, 0.105mmol, 30%) was obtained as a white powder.

Example 4321- (cyclopropylmethyl) -N- (1-ethynylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulphonamide

A mixture of N- (1-ethynylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (42mg, 0.110mmol), iodomethylcyclopropane (9.2. mu.L, 0.120mmol) and potassium carbonate (29mg, 0.210mmol) in DMF (2mL) was heated with stirring in a microwave at 80 ℃ for 45 minutes. The solvent was removed in vacuo leaving a residue which was purified by preparative HPLC (high pH) to give the desired product (10mg, 0.022mmol, 21%) as a white powder.

Example 4331-methyl-N- (1-methylcyclopropyl) -3- [ (2-methylpyrimidin-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

To a solution of (2-methyl-5-pyrimidinyl) methanol (26mg, 0.21mmol) in THF (2.5mL) were added triethylamine (21mg, 0.21mmol) and methanesulfonyl chloride (0.08mL, 1mmol), and the mixture was stirred at room temperature for 2 hours. After 2h 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (65mg, 0.21mmol) and a solution of sodium hydride in mineral oil in 60% dispersion (13mg, 0.53mmol) in DMF were added by syringe and the mixture was stirred at ambient temperature overnight. LCMS confirmed conversion to the desired product. The reaction mixture was diluted with water (25mL) and extracted with EtOAc (2X 25 mL). The organic phases were combined, washed with brine (10mL), passed through a hydrophobic frit and evaporated to dryness. The crude product mixture was purified by preparative HPLC (high pH) to give the desired product (23mg, 0.055mmol, 26.4%) as a colourless gum.

Example 4341-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (pyrazolo [1, 5-. alpha. -pyridin-3-ylmethyl) quinazoline-6-sulfonamide

This compound was prepared according to example 433 using pyrazolo [1,5-a ] pyridin-3-ylmethanol (31mg, 0.21 mmol). This gave the desired product (3mg, 0.007mmol, 3.2%) as a yellow powder.

Example 4351- [ (2, 2-Difluorocyclopropyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Prepared from 3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide and 1- (bromomethyl) -2, 2-difluorocyclopropane using method a12(100 ℃). This gave the desired product (28mg, 0.058mmol, 28%) as a white powder.

Example 4361- [ (3, 3-Difluorocyclobutyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Prepared from 3- ((1-methyl-1H-pyrazol-4-yl) methyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide and 3- (bromomethyl) -1, 1-difluorocyclobutane using method a12(100 ℃). This gave the desired product (20mg, 0.041mmol, 20%) as a white powder.

Example 4371- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a10, prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 5- (chloromethyl) -1, 3-dimethyl-1H-pyrazole. This gave the desired product (16mg, 0.031mmol, 21%) as a white powder.

Example 4381- (Ethyl-N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a10, prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and iodoethane. This gave the desired product (14mg, 0.032mmol, 22%) as a white powder.

Example 4391- (cyanomethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a10, prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and bromoacetonitrile. This gave the desired product (5mg, 0.011mmol, 8%) as a white powder.

Example 440N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1-prop-2-ynyl-quinazoline-6-sulfonamide

Prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 3-bromopropyne using method A10. This gave the desired product (8mg, 0.018mmol, 12%) as a white powder.

Example 441N- [1- (fluoromethyl) cyclopropyl ] -1- [ (3-methylisoxazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 5- (bromomethyl) -3-methyl-1, 2-oxazole using method a 10. This gave the desired product (10mg, 0.02mmol, 14%) as a white powder.

Example 442N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydropyran-4-ylmethyl) quinazoline-6-sulfonamide

Using method a10, prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 4- (bromomethyl) tetrahydropyran. This gave the desired product (8mg, 0.016mmol, 11%) as a white powder.

Example 4431- [ (2, 2-Difluorocyclopropyl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 1- (bromomethyl) -2, 2-difluorocyclopropane using method a 10. This gave the desired product (14mg, 0.028mmol, 19%) as a white powder.

Example 4441- [ (3, 3-Difluorocyclobutyl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 3- (bromomethyl) -1, 1-difluorocyclobutane using method a 10. This gave the desired product (8mg, 0.016mmol, 11%) as a white powder.

Example 445N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (oxetan-3-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

using method a10 (tosylate), prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and oxetan-3-ylmethyl 4-methylbenzenesulfonate. This gave the desired product (12mg, 0.025mmol, 17%) as a white powder.

Example 4461-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (pyridazin-4-ylmethyl) quinazoline-6-sulfonamide

This compound was prepared according to example 433 using pyridin-4-ylmethanol (23mg, 0.21 mmol). This gave the desired product (8mg, 0.02mmol, 9.5%) as a pink powder.

Example 447N- (1-methylcyclopropyl) -1, 3-dioxo-benzo [ de ] isoquinoline-5-sulfonamide

Chlorosulfonic acid (2.0mL) was added to 1, 8-naphthalimide (200mg, 0.690mmol) and the resulting solution was stirred under nitrogen at 80 ℃ for 5 hours. The reaction mixture was allowed to stand overnight and then added dropwise to a stirred ice/water slurry (about 30 mL). After addition was complete, EtOAc (40mL) was added and the mixture was stirred for 5 minutes. The EtOAc layer was separated by passage through a hydrophobic frit and the aqueous phase was washed with EtOAc (2 × 40 mL). The EtOAc extracts were combined and dried over anhydrous MgSO 4. The solution was filtered and a mixture of 1-methylcyclopropylamine hydrochloride (148mg, 1.37mmol) and triethylamine (348mg, 3.43mmol) in EtOAc/DCM (10mL) was added dropwise with stirring. After 1 hour at ambient temperature, water (30mL) was added and the mixture was stirred for 5 minutes. The organic layer was separated and the aqueous layer was washed with EtOAc (2X 40 mL). The combined EtOAc extracts were concentrated under reduced pressure and the crude residue flash chromatographed on silica gel then purified by preparative HPLC (high pH) to give the desired product (38mg, 0.115mmol, 17%) as a white powder.

Example 4486- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxylic acid methyl ester

Reacting 6-chlorosulfonyl-3- [ (1-methylpyrazol-4-yl) methyl]-methyl 2, 4-dioxo-1H-quinazoline-8-carboxylate (550mg, 1.33mmol) was added to a stirred solution of 1-methylcyclopropane hydrochloride (143mg, 1.33mmol) and N, N-diisopropylethylamine (0.52mL, 2.93mmol) in DMF (10mL), and the resulting mixture was stirred at ambient temperature for 12 hours. The solvent was removed under vacuum and the resulting residue was purified by automatic column chromatography (SiO)₂(ii) a RediSep-4 g; 0 to 80% EtOAc in hexanes) to give the desired product (350mg, 0.782mmol, 59%) as a white foam.

Example 449N, N-dimethyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxamide

3- ((1-methyl-1H-pyrazol-4-yl) methyl) -6- (N- (1-methylcyclopropyl) sulfamoyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-8-carboxylic acid

To a magnetically stirred suspension of methyl 6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxylate (250mg, 0.56mmol) in a 1:1(v/v) mixture of THF (2mL) and water (2mL) was added lithium hydroxide (66.9mg, 2.79mmol), and the resulting mixture was stirred at ambient temperature for 1 hour. The solvent was removed under vacuum to give a gum, which was partitioned between EtOAc (10mL) and water (10 mL). The aqueous phase was collected and acidified (pH 1.0) with 1N HCl to give a cloudy suspension. EtOAc (30mL) and water (10mL) were added and the resulting mixture was stirred for 5 min. The organic phase was collected and dried and evaporated in vacuo to afford 3- ((1-methyl-1H-pyrazol-4-yl) methyl) -6- (N- (1-methylcyclopropyl) sulfamoyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-8-carboxylic acid as a white solid (220mg, 91%).

¹H NMR(300MHz,DMSO-d₆)＝11.37(br.s.,1H),8.57(d,J＝2.2Hz,1H),8.51(d,J＝2.2Hz,1H),8.31(s,1H),7.69(s,1H),7.40(s,1H),4.92(s,2H),3.76(s,3H),1.08(s,3H),0.59(s,2H),0.44-0.38(m,2H)

N, N-dimethyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxamide

HATU (48mg, 0.13mmol) was added to a stirred solution of 6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxylic acid (50mg, 0.12mmol) in DMF (2mL) and the resulting mixture was stirred for 30 minutes. Dimethylamine solution (63 μ L, 0.13mmol) was then added to the reaction and the resulting mixture was stirred for 16 hours. The solvent was removed in vacuo to give a residue which was purified by preparative HPLC (low pH) to give the desired product (20mg, 0.043mmol, 39%) as a white powder.

Example 450N-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxamide

HATU (48mg, 0.13mmol) was added to a stirred solution of 6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxylic acid (50mg, 0.12mmol) in DMF (2mL) and the resulting mixture was stirred for 30 minutes. Methylamine solution (63 μ L, 0.13mmol) was then added to the reaction and the resulting mixture was stirred for 16 hours. The solvent was removed in vacuo to give a residue which was purified by preparative HPLC (low pH) to give the desired product (20mg, 0.045mmol, 39%) as a white powder.

Example 451N-methoxy-N-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxamide

HATU (96.5mg, 0.250mmol) was added to a stirred solution of 6- [ (1-methylcyclopropyl) sulfamoyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-8-carboxylic acid (100mg, 0.2300mmol) in DMF (4mL) and the resulting mixture was stirred for 30 min. N, O-dimethylhydroxyamine hydrochloride (127. mu.L, 0.25mmol) and triethylamine (0.07mL, 0.5100mmol) were then added to the reaction and the resulting mixture was stirred for 12 hours. The solvent was removed in vacuo to give a residue which was purified by automatic column chromatography (SiO 2; SNAP-10 g; 0 to 10% MeOH in DCM) to give the desired product (100mg, 0.21mmol, 91%) as a white solid.

Example 4521- (2-cyano-2-methyl-propyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared from N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide and (2-cyano-2-methyl-propyl) -4-methylbenzenesulfonate using method a12 (6 hours at 120 ℃). This gave the desired product (11mg, 0.023mmol, 11%) as a white powder.

Example 4531- (2-fluoro-2-methyl-propyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared from N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide and 1-bromo-2-fluoro-2-methyl-propane using method a12 (6 hours at 120 ℃). This gave the desired product (3mg, 0.006mmol, 3%) as a white powder.

Example 454N- (1-methylcyclopropyl) -2- [ (1-methylpyrazol-4-yl) methyl ] -1, 3-dioxo-benzo [ de ] isoquinoline-5-sulfonamide

S18

To a solution of 1, 8-naphthalimide (395mg, 2.0mmol) in DMF (10mL) was added sodium iodide (60mg, 0.40mmol), cesium carbonate (1371mg, 4.21mmol) and 4- (chloromethyl) -1-methyl-1H-pyrazole hydrochloride (0.24mL, 2.2 mmol). The resulting mixture was heated in a microwave at 120 ℃ for 14 hours. The reaction mixture was diluted with water (100mL) and extracted with EtOAc (2X 100 mL). The combined extracts were washed with brine and the solution was passed through a hydrophobic frit and concentrated under reduced pressure to give the residue crude 2- [ (1-methylpyrazol-4-yl) methyl ] benzo [ de ] isoquinoline-1, 3-dione (ca. 200mg), which was used without characterization or purification.

Chlorosulfonic acid (2.0mL) was added to 2- [ (1-methylpyrazol-4-yl) methyl ] benzo [ de ] isoquinoline-1, 3-dione (200mg, 0.69mmol), and the resulting solution was stirred at 80 ℃ for 5 hours under nitrogen. The reaction mixture was allowed to stand overnight and then added dropwise to a stirred ice/water slurry (about 30 mL). After addition was complete, EtOAc (40mL) was added and the mixture was stirred for 5 minutes. The EtOAc layer was separated by passage through a hydrophobic frit and the aqueous phase was washed with EtOAc (2 × 40 mL). The EtOAc extracts were combined and dried over anhydrous MgSO 4. The solution was filtered and a mixture of 1-methylcyclopropylamine hydrochloride (148mg, 1.37mmol) and triethylamine (348mg, 3.43mmol) in EtOAc/DCM (10mL) was added dropwise with stirring. After 1 hour at ambient temperature, water (30mL) was added and the mixture was stirred for 5 minutes. The organic layer was separated and the aqueous layer was washed with EtOAc (2X 40 mL). The combined EtOAc extracts were concentrated under reduced pressure and the crude residue was flash chromatographed on silica gel then purified by preparative HPLC (high pH) to give the desired product (11mg, 0.026mmol, 3.8%) as a white powder.

Example 455N- (1-Cyanocyclopropyl) -1-ethyl-3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Iodothane (0.02mL, 0.2600mmol) was added to a stirred mixture of N- (1-cyanocyclopropyl) -N- [ [3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] acetamide (100mg, 0.220mmol) and potassium carbonate (120mg, 0.870mmol) in DMF (3mL) and stirred at room temperature for 16H. Concentrated aqueous ammonia (100 μ L) was added and the mixture was heated to 40 ℃ for 10 minutes. The mixture was allowed to cool and DCM (8mL) and saturated aqueous ammonium chloride (8mL) were added and the mixture was stirred for 5 min. The DCM layer was separated by passage through a hydrophobic frit and the aqueous layer was washed with DCM (8 mL). The combined DCM extracts were concentrated under reduced pressure and purified by preparative HPLC (low pH) to give N- (1-cyanocyclopropyl) -1-ethyl-3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide (12mg, 0.027mmol, 12%) as a white solid.

Example 456N- [1- (difluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulphonamide

Prepared from 3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonyl chloride and 1- (difluoromethyl) cyclopropane-1-amine hydrochloride using method a1 (sulfonamide formation). This gave the desired product (187mg, 0.440mmol, 47.3%) as a white powder.

Example 457N- (1-Cyanocyclopropyl) -1- [ (1-methylpyrazol-4-yl) methyl ] -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

This compound was prepared according to example 455 using N- (1-cyanocyclopropyl) -N- [ [3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] acetamide (100mg, 0.2200mmol) and 4- (chloromethyl) -1-methyl-1H-pyrazole hydrochloride (0.02mL, 0.2600 mmol). The desired product (5mg, 0.010mmol, 4.5%) was obtained as a white solid.

Example 4581- (cyclopropylmethyl) -N- [1- (difluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a10, prepared from N- [1- (difluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and iodomethylcyclopropane. This gave the desired product (11mg, 0.023mmol, 22%) as a white powder.

Example 459N- [1- (difluoromethyl) cyclopropyl ] -1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a10, prepared from N- [1- (difluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 5- (chloromethyl) -1, 3-dimethyl-1H-pyrazole. This gave the desired product (12mg, 0.022mmol, 21%) as a white powder.

Example 460N- [1- (difluoromethyl) cyclopropyl ] -1- [ (4-fluorophenyl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a10, prepared from N- [1- (difluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 4-fluorobenzyl bromide. This gave the desired product (10mg, 0.019mmol, 18%) as a white powder.

Example 4611- (cyclobutylmethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and (bromomethyl) cyclobutane using method a 10. This gave the desired product (10mg, 0.021mmol, 18%) as a white powder.

Example 462N- [1- (fluoromethyl) cyclopropyl ] -1- [ (2-methoxyethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Using method a10, prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 2-bromoethyl methyl ether. This gave the desired product (7mg, 0.015mmol, 13%) as a white powder.

Example 4631- [ (2, 4-Dimethylthiazol-5-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a2, prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and (2, 4-dimethyl-1, 3-thiazol-5-yl) methanol. This gave the desired product (8mg, 0.015mmol, 13%) as a white powder.

Example 464N- (1-methylcyclopropyl) -2- [ (3-methylisoxazol-5-yl) methyl ] -1, 3-dioxo-benzo [ de ] isoquinoline-5-sulfonamide

To a solution of 1, 8-naphthalimide (395mg, 2mmol) in DMF (10mL) was added sodium iodide (60mg, 0.40mmol), cesium carbonate (718mg, 2.2mmol) and 5- (bromomethyl) -3-methyl-1, 2-oxazole (0.24mL, 2.2 mmol). The resulting mixture was heated in a microwave at 70 ℃ for 50 minutes. The reaction mixture was diluted with water (100mL) and extracted with EtOAc (2X 100 mL). The combined extracts were washed with brine and the solution was passed through a hydrophobic frit and concentrated under reduced pressure. The residue (604mg) was triturated from diethyl ether to give 2- [ (3-methylisoxazol-5-yl) methyl ] benzo [ de ] isoquinoline-1, 3-dione (516mg, 88.1% yield).

1H NMR(300MHz,DMSO-d6)＝8.53(dt,J＝1.1,7.4Hz,4H),7.92(d,J＝7.3Hz,1H),7.89(d,J＝7.3Hz,1H),6.32(s,1H),5.33(s,2H),2.16(s,3H)

Chlorosulfonic acid (4.0mL) was added to 2- [ (3-methylisoxazol-5-yl) methyl ] benzo [ de ] isoquinoline-1, 3-dione (466mg, 1.59mmol), and the resulting solution was stirred at 80 ℃ for 3 hours under nitrogen. The reaction mixture was added dropwise to a stirred ice/water slurry (about 30 mL). After addition was complete, EtOAc (40mL) was added and the mixture was stirred for 5 minutes. The EtOAc layer was separated by passage through a hydrophobic frit and the aqueous phase was washed with EtOAc (2 × 40 mL). The EtOAc extracts were combined and dried over anhydrous MgSO 4. The solution was filtered and a mixture of 1-methylcyclopropylamine hydrochloride (343mg, 3.19mmol) and triethylamine (1.11mL, 7.97mmol) in EtOAc/DCM (10mL) was added dropwise with stirring. After 1 hour at ambient temperature, water (30mL) was added and the mixture was stirred for 5 minutes. The organic layer was separated and the aqueous layer was washed with EtOAc (2X 40 mL). The combined EtOAc extracts were concentrated under reduced pressure and the residue triturated with MeOH/diethyl ether to give the desired product (254mg, 0.697mmol, 37.5%) as an off-white powder.

Example 4651- (2, 2-dimethylpropyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (100mg, 0.260mmol), cesium carbonate (100mg, 0.3100mmol), sodium iodide (8mg,0.05mmol), and 1-bromo-2, 2-dimethylpropane (426mg,2.8mmol) in DMF (2mL) were heated to 130 ℃ by microwave irradiation for 1.5 h. The reaction mixture was diluted with water (10mL) and extracted with EtOAc (2X 20 mL). The organic phases were combined, washed with brine (10mL), passed through a hydrophobic frit and evaporated to dryness. The crude product mixture was purified by preparative HPLC (high pH) to give the desired product (14mg, 0.03mmol, 12%) as an off-white powder.

Example 4661- [ (2S) -2-methylbutyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

This compound was prepared according to example 465 using N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (100mg, 0.260mmol) and (S) -1-bromo-2-methylbutane (43mg, 0.28 mmol). The reaction mixture was heated to 100 ℃ for 1 hour by microwave irradiation. The desired product (25mg, 0.054mmol, 21%) was obtained as a white powder.

Example 4671- [ (1-methylcyclobutyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to example 465 using N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (100mg, 0.260mmol) and 1- (bromomethyl) -1-methylbutane (251mg, 1.54 mmol). The reaction mixture was heated to 130 ℃ for 1 hour by microwave irradiation. The desired product (24mg, 0.051mmol, 20%) was obtained as a white powder.

Example 4682- [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] acetic acid ethyl ester

Using method a3, prepared from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide and ethyl bromoacetate. This gave the desired product (23mg, 0.058mmol, 30%) as a white powder.

Example 4691-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (2-oxobutyl) quinazoline-6-sulfonamide

Using method a3, prepared from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide and 1-bromobutan-2-one. This gave the desired product (20mg, 0.053mmol, 27%) as a white powder.

Example 4701- (2-ethylbutyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to example 465 using N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (100mg, 0.260mmol) and 1-bromo-2-ethylbutane (46mg, 0.28 mmol). The reaction mixture was heated to 100 ℃ for 1 hour by microwave irradiation. The desired product (37mg, 0.078mmol, 30%) was obtained as a white powder.

Example 4711- [ (1-Methoxycyclopentyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

This compound was prepared according to example 465 using N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (100mg, 0.260mmol) and 1- (bromomethyl) -1-methoxycyclopentane (247mg, 1.28 mmol). The reaction mixture was heated to 130 ℃ for 1 hour by microwave irradiation. The desired product (17mg, 0.034mmol, 13%) was obtained as a colorless gum.

Example 4721-Isopentyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

This compound was prepared according to example 465 using N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (100mg, 0.260mmol) and 1-bromo-3-methylbutane (43mg, 0.28 mmol). The reaction mixture was heated to 100 ℃ for 1 hour by microwave irradiation. The desired product (22mg, 0.048mmol, 19%) was obtained as an off-white powder.

Example 4731- [ (1-Isopropylpyrazol-4-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to example 465 using N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (100mg, 0.260mmol) and 4- (bromomethyl) -1-isopropylpyrazole (57mg, 0.28 mmol). The reaction mixture was heated to 100 ℃ for 1 hour by microwave irradiation. The desired product (62mg, 0.121mmol, 47%) was obtained as a white powder.

Example 4741-isohexyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to example 465 using N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (100mg, 0.260mmol) and 1-bromo-4-methylpentane (0.04mL, 0.2800 mmol). The reaction mixture was heated to 100 ℃ for 1 hour by microwave irradiation. The desired product (13mg, 0.027mmol, 11%) was obtained as a white powder.

Example 4751-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (2-oxo-2-pyrrolidin-1-yl-ethyl) quinazoline-6-sulfonamide

Using method a3, prepared from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide and 2-bromo-1-pyrrolidin-1-yl-ethanone. This gave the desired product (21mg, 0.05mmol, 26%) as a white powder.

Example 476N, N-dimethyl-2- [ 1-methyl-6- [ (1-methylcyclopropyl) sulfamoyl ] -2, 4-dioxo-quinazolin-3-yl ] acetamide

Using method a3, prepared from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide and 2-chloro-N, N-dimethylacetamide. This gave the desired product (39mg, 0.099mmol, 51%) as a white powder.

Example 4771- [ (3, 3-dimethylcyclobutyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to example 465 using N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (100mg, 0.260mmol) and 3- (bromomethyl) -1, 1-dimethylcyclobutane (50mg, 0.280 mmol). The reaction mixture was heated to 120 ℃ for 1 hour by microwave irradiation. The desired product (5mg, 0.01mmol, 4%) was obtained as a white powder.

Example 4781- [ (3, 3-dimethylcyclobutyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

This compound was prepared according to example 465 using N- (1-methylcyclopropyl) -3- ((2-methylthiazol-5-yl) methyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide (104mg, 0.260mmol) and 3- (bromomethyl) -1, 1-dimethyl-cyclobutane (50mg, 0.280 mmol). The reaction mixture was heated to 120 ℃ for 1 hour by microwave irradiation. The desired product (3mg, 0.006mmol, 2%) was obtained as an off-white powder.

Example 479N- (1-formylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulphonamide

Reacting N- [1- (hydroxymethyl) cyclopropyl]-3- [ (1-methylpyrazol-4-yl) methyl]A suspension of-2, 4-dioxo-1H-quinazoline-6-sulfonamide (53mg, 0.13mmol) in DCM (2mL) was treated with dessimutan's oxidant in a 15 wt% solution of DCM (0.41mL, 0.14mmol) and stirred at room temperature. After 20 minutes, DMF (0.5mL) was added to dissolve the reagents sufficiently. After a further 1 hour, the reaction mixture was taken up with saturated Na₂S₂O₃Aqueous solution (2mL) and saturated NaHCO₃The aqueous solution (2mL) was quenched, diluted with DCM (5mL) and stirred vigorously until the mixture became clear (about 20 min). The mixture was passed through a hydrophobic frit and the aqueous layer was re-extracted with DCM (5 mL). The combined organic extracts were dried, concentrated and purified by flash column chromatography, eluting with DCM-10% MeOH/DCM to give N- (1-formylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl]-2, 4-dioxo-1H-quinazoline-6-sulfonamide (46mg, 0.11mmol, 87%) as a white powder.

Example 480N-tert-butyl-1- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a10, prepared from N-tert-butyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 5- (chloromethyl) -1, 3-dimethyl-1H-pyrazole. This gave the desired product (17mg, 0.034mmol, 38%) as a white powder.

Example 4811-methyl-N- (1-methylcyclopropyl) -3- (oxetan-3-ylmethyl) -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a3 (tosylate), from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide and oxetan-3-ylmethyl 4-toluenesulfonic acid. This gave the desired product (31mg, 0.082mmol, 42%) as a white powder.

Example 4828-bromo-1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Intermediate S19-A3-bromo-2- (methylamino) benzoic acid methyl ester

To a magnetically stirred solution of methyl 3-bromo-2-fluorobenzoate (5.20g, 22.31mmol) and potassium carbonate (6.17g, 44.63mmol) in 1, 4-dioxane (20mL) was added a methylamine solution (22.31mL, 44.63mmol) under nitrogen at 20 ℃ and the resulting mixture was heated at 40 ℃ for 12 hours. The solvent was removed in vacuo, and the resulting residue was partitioned between DCM (100mL) and water (100 mL). The DCM layer was collected and washed with brine (50mL), then dried (Na)₂SO₄) And distilled to dryness to give methyl 3-bromo-2- (methylamino) benzoate (5.40g, 99%) as a yellow oil.

¹H NMR(300MHz,DMSO-d₆)ppm 2.84(d,J＝5.37Hz,3H)3.83(s,3H)6.32(d,J＝5.27Hz,1H)6.68(t,J＝7.82Hz,1H)7.63(ddd,J＝15.40,7.86,1.60Hz,2H)。

Intermediate S19-B3-bromo-2- (methylamino) benzoic acid

To a magnetically stirred solution of methyl 3-bromo-2- (methylamino) benzoate (1.0g, 4.1mmol) in THF (10mL) and water (10mL) was added lithium hydroxide (490mg, 20.48mmol) at 20 deg.C, and the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between DCM (50mL) and water (40mL), and the aqueous phase was collected and acidified to pH 1-2 with 2N HCl. The solution was then extracted with DCM (3 × 50mL) and the combined organics were distilled to dryness to give 3-bromo-2- (methylamino) benzoic acid (700mg, 74%) as a colorless oil.

¹H NMR(300MHz,DMSO-d₆)ppm 2.91(s,3H)5.76(s,1H)6.71(t,J＝7.82Hz,1H)7.66(dd,J＝7.82,1.60Hz,1H)7.73(dd,J＝7.77,1.55Hz,1H)

Intermediate S19-C3-bromo-N- ((1-methyl-1H-pyrazol-4-yl) methyl) -2- (methylamino) benzamide

To a magnetically stirred solution of 3-bromo-2- (methylamino) benzoic acid (750mg, 3.26mmol) in DMF (10mL) was added 1, 1' -carbonyldiimidazole (581mg, 3.59mmol) and the resulting mixture was stirred at ambient temperature for 30 min. (3-methylisoxazol-5-ylmethyl) amine (365mg, 3.26mmol) was added and the resulting mixture was stirred at 40 ℃ for 12 h. The solvent was removed in vacuo, and the residue was partitioned between DCM (20mL) and water (20 mL). The organic layer was collected and dried (MgSO₄) And evaporated to dryness to give a residue which was purified by automatic column chromatography (SiO 2; RediSep-24 g; 0-40% EtOAc in hexanes) to give 3-bromo-N- ((1-methyl-1H-pyrazol-4-yl) methyl) -2- (methylamino) benzamide (570mg, 54%) as a white solid.

¹H NMR(300MHz,DMSO-d₆)ppm 2.21(s,3H)2.73(d,J＝5.37Hz,3H)3.32(s,2H)5.52(q,J＝5.53Hz,1H)6.24(s,1H)6.64(t,J＝7.72Hz,1H)7.26(dd,J＝7.68,1.46Hz,1H)7.53(dd,J＝7.82,1.51Hz,1H)9.07(t,J＝5.79Hz,1H)

Intermediate S19-D8-bromo-1-methyl-3- ((3-methylisoxazol-5-yl) methyl) quinazoline-2, 4(1H,3H) -dione

To 3-bromo-2- (methylamino) -N- [ (3-methylisoxazol-5-yl) methyl at 20 ℃ under nitrogen]To a magnetically stirred solution of benzamide (500mg, 1.54mmol) in THF (50mL) was added triphosgene (229mg, 0.77mmol), and the resulting mixture was stirred at ambient temperature for 1 hour. Triethylamine (0.21mL, 1.54mmol) was added to the reaction and the resulting mixture was stirred for 12 hours. By addition of saturated NaHCO₃The reaction was quenched with aqueous solution (50mL) and the resulting mixture was stirred for 30 minutes (pH 8.0). The mixture was partitioned between EtOAc (100mL) and water (50 mL). The EtOAc layer was collected and dried (Na)₂SO₄) The solvent was removed in vacuo to give 8-bromo-1-methyl-3- ((3-methylisoxazol-5-yl) methyl) quinazoline-2, 4(1H,3H) -dione (540mg, 100%) as a white solid.

¹H NMR(300MHz,DMSO-d₆)ppm 2.17(s,3H)3.70(s,3H)5.17(s,2H)6.32(s,1H)7.26(t,J＝7.82Hz,1H)8.07(q,J＝1.57Hz,1H)8.09(q,J＝1.60Hz,1H)

Intermediate S19-E8-bromo-1-methyl-3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride

8-bromo-1-methyl-3- [ (3-methylisoxazol-5-yl) methyl ] quinazoline-2, 4-dione (550mg, 1.57mmol) was treated with chlorosulphonic acid (183mg, 1.57mmol) at 20 ℃ and the resulting brown solution was heated at 40 ℃ for 16 h. The reaction was then poured into ice and the resulting precipitate was extracted with EtOAc (2 × 20 mL). The combined extracts were dried and evaporated to dryness to give 8-bromo-1-methyl-3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonyl chloride (690mg, 98%) as a pale yellow solid.

¹H NMR(300MHz,DMSO-d₆)ppm 2.17(s,3H)3.70(s,3H)5.17(s,2H)6.32(s,1H)8.09(d,J＝1.98Hz,1H)8.22(d,J＝1.98Hz,1H)

S19-F8-bromo-1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

To 8-bromo-1-methyl-3- [ (3-methylisoxazol-5-yl) methyl at 20 ℃ under nitrogen]To a magnetically stirred solution of-2, 4-dioxo-quinazoline-6-sulfonyl chloride (700mg, 1.56mmol) and 1-methylcyclopropylamine hydrochloride (185mg, 1.72mmol) in DMF (20mL) was added triethylamine (0.73mL, 3.43mmol), and the resulting mixture was stirred at 20 ℃ for 2 hours. The solvent was removed under vacuum and the resulting residue was purified by automatic column chromatography (SiO)₂(ii) a RediSep-24 g; 0 to 5% MeOH in DCM) to give the desired product (560mg, 1.16mmol, 74%) as a white foam.

Example 4831-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -8- [ (1-methylpyrazol-4-yl) ] -2, 4-dioxo-quinazoline-6-sulphonamide

8-bromo-1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide (80mg, 0.17mmol), (1-methyl-1H-pyrazol-4-yl) boronic acid (43.77mg, 0.35mmol), cesium carbonate (173mg, 0.53mmol), and 1, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane adduct (20.3mg, 0.02mmol) were placed in a 7mL microwave vial, followed by the addition of THF (2.5mL) and water (0.5mL), and the resulting mixture was degassed with nitrogen for 5 minutes. The vial was then sealed and heated under microwave irradiation at 80 ℃ for 20 minutes. The mixture was filtered through celite and evaporated to dryness to give a residue which was purified by preparative HPLC (high pH) to give the desired product (20mg, 0.041mmol, 25%) as a white powder.

Example 4841-chloro-N- (1-methylcyclopropyl) isoquinoline-7-sulfonamide

To a solution of N, N-diisopropylethylamine (0.14mL, 0.81mmol) in THF (5mL) cooled in an ice bath was added a mixture of 1-methylcyclopropylamine hydrochloride (0.05mL, 0.40mmol) and 1-chloroisoquinoline-7-sulfonyl chloride (100mg, 0.38mmol) in DCM (3mL) and the mixture was stirred at room temperature overnight. The mixture was diluted with water (30mL) and extracted with DCM (2X 30 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product mixture was purified by preparative HPLC (high pH) to give the desired product (48mg, 0.16mmol, 42%) as a white powder.

Example 4851- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-N- [1- (trifluoromethyl) cyclopropyl ] quinazoline-6-sulphonamide

Prepared from N- [ [3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] -N- [1- (trifluoromethyl) cyclopropyl ] acetamide and 5- (chloromethyl) -1, 3-dimethyl-1H-pyrazole using method a 1. The reaction mixture was stirred at room temperature for 2h, and the crude product was chromatographed on silica gel, eluting with EtOAc-5% MeOH/EtOAc, and triturated from diethyl ether to give the desired product (15mg, 0.027mmol, 49%) as a white powder.

Example 486N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxo-1H-quinoline-6-sulphonamide

Intermediate S20-A3- (1-methylpyrazol-4-yl) propionyl chloride

A suspension of 3- (1-methylpyrazol-4-yl) propionic acid (0.5g, 3.2mmol) in DCM (5mL) was treated with 5 drops of DMF (0.0500mL) and thionyl chloride (0.24mL, 3.2mmol) following the procedure of WO2010/66829A 1. The resulting solution was heated to reflux for 30 minutes, and then cooled to room temperature and concentrated. The oily residue 3- (1-methylpyrazol-4-yl) propionyl chloride (560mg, 3.26mmol, 100%) was used without purification.

¹H NMR (300MHz, chloroform-d) ═ 7.87(s,1H),7.67(s,1H),4.30(s,3H),3.30-3.20(m,2H),2.98-2.91(m,2H)

Intermediate S20-B N- (2-formylphenyl) -3- (1-methylpyrazol-4-yl) propionamide

Crude 2-aminobenzaldehyde (about 7mmol) (a yellow oil prepared as described in scheme 16) was taken up in THF (40mL) and added to 3- (1-methylpyrazol-4-yl) propionyl chloride (1.5g, 8.9mmol) followed by pyridine (0.9mL, 11.2 mmol). Triethylamine (1.6mL, 11.2mmol) was added to try to dissolve the thick viscous oil at the bottom of the flask. The mixture was stirred at room temperature for 90 minutes, and then diluted with water (20mL) and extracted with EtOAc (2X 50 mL). The combined organic extracts were washed with water, passed through a hydrophobic frit and concentrated. Purification by flash column chromatography eluting with 1:1 isohexane: EtOAc-EtOAc provided N- (2-formylphenyl) -3- (1-methylpyrazol-4-yl) propionamide (640mg, 2.5mmol, 33%) as a light yellow oil.

¹H NMR (300MHz, chloroform-d) 11.15(br.s.,1H),9.92(s,1H),8.76(d, J ═ 8.5Hz,1H),7.68(dd, J ═ 1.6,7.6Hz,1H),7.66-7.59(m,1H),7.39(s,1H),7.27-7.21(m,2H),3.86(s,3H),2.99-2.88(m,2H),2.77-2.67(m,2H)

LCMS (high pH) found 256.1[ M-H ] -T ═ 0.89min, UV purity 62%. At 1.35 minutes, the impurity was 18% (566 mass).

Intermediate S20-C3- [ (1-methylpyrazol-4-yl) methyl ] -1H-quinolin-2-one

A solution of N- (2-formylphenyl) -3- (1-methylpyrazol-4-yl) propionamide (640mg, 2.5mmol) in DMF (15mL) was treated with cesium carbonate (4.1g, 12.4mmol) and heated to 70 ℃ for 4 hours following the procedure for the heterocyclic compound, 2005,65,9, 2095-2105. The reaction mixture was then washed with DCM (50mL) and saturated NH₄Aqueous Cl (25 mL). The aqueous layer was re-extracted with DCM and the combined organic extracts were re-extracted with saturated NH₄Washed with aqueous Cl, dried (hydrophobic frit) and concentrated. Purify the crude material by flash column chromatography, eluting with EtOAc-10% MeOH/EtOAc to give 3- [ (1-methylpyrazol-4-yl) methyl]-1H-quinolin-2-one (274mg, 1.15mmol, 45%) as a pale yellow solid.

¹H NMR(300MHz,DMSO-d₆)＝11.78(s,1H),7.61(s,1H),7.57(d,J＝7.8Hz,1H),7.52(s,1H),7.42(dd,J＝1.3,7.1Hz,1H),7.32-7.26(m,2H),7.17-7.09(m,1H),3.78(s,3H),3.62(s,2H)

LCMS: high pH-found 238.0[ M-H ] -T ═ 0.83min, UV purity 100%; low pH-found 240.1[ M + H ] + T ═ 0.79 min, UV purity 100%.

Intermediate S20-D3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxo-1H-quinoline-6-sulfonyl chloride

3- [ (1-methylpyrazol-4-yl) methyl ] -1H-quinolin-2-one (400mg, 1.67mmol) was added to stirred chlorosulfonic acid (4mL, 1.67mmol) and the resulting mixture was stirred at 50 ℃ for 16H. The reaction was then cooled to room temperature and added dropwise to ice (10g, cooled in an acetone/ice bath at-10 ℃) with stirring. The resulting precipitate was stirred at 0 ℃ for 15 minutes and then filtered. The filter cake was washed with cold water (2X 4mL) and dried under vacuum at 40 ℃ for 16H to give 3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxo-1H-quinoline-6-sulfonyl chloride (400mg, 1.18mmol, 71%) as a brown solid.

¹H NMR(300MHz,DMSO-d₆)ppm 3.63(s,2H)3.80(s,3H)7.22(d,J＝8.48Hz,1H)7.41(s,1H)7.59(s,1H)7.65(dd,J＝8.48,1.88Hz,1H)7.74(s,1H)7.80(d,J＝1.79Hz,1H)11.85(br.s.,1H)

S20-E N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxo-1H-quinoline-6-sulfonamide

A solution of 3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxo-1H-quinoline-6-sulfonyl chloride (43mg, 0.13mmol), 1-methylcyclopropylamine hydrochloride (21mg, 0.19mmol), N-diisopropylethylamine (0.07mL, 0.38mmol) and 4-dimethylaminopyridine (16mg, 0.13mmol) in DMF (1mL) was stirred at room temperature for 10 minutes. The reaction mixture was concentrated to dryness and purified by automatic column chromatography eluting with DCM-10% MeOH/DCM to give the desired product N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxo-1H-quinoline-6-sulfonamide (30mg, 0.081mmol, 63%) as a white powder.

Example 4873-bromo-N- (1-methylcyclopropyl) -2-oxo-1H-quinoline-6-sulfonamide

Intermediate S21-A3-bromo-1-oxy-quinolin-1-ium

A solution of 3-bromoquinoline (0.65mL, 4.8mmol) in chloroform (8mL) was treated in portions with 3-chloroperbenzoic acid (1.2g, 5.3mmol) at room temperature and the mixture was stirred under nitrogen for 20 hours after the light shield following the procedure described in Synth. Comm.30, (3), 427-432. The reaction mixture was washed with saturated NaHCO₃Aqueous solution (6mL) and 1M NaOH (2 mL). The layers were separated and the aqueous phase was taken up in CHCl₃(15mL) was re-extracted and the combined organics were extracted with 5% wt. aqueous sodium sulfite (10mL), saturated NaHCO₃Aqueous solution (10mL), water (10mL) and brine (10mL) were washed, passed through a hydrophobic frit and concentrated to give 3-bromo-1-oxo-quinolin-1-ium (1.1g, 4.7mmol, 98%) as an off-white solid.

¹H NMR (300MHz, chloroform-d) ═ 8.74-8.58(m,2H),7.91(s,1H),7.85-7.65(m,3H)

LCMS (high pH) found 224/226[ M + H ] +, T ═ 0.80min, UV purity 98%.

Intermediate S21-B3-bromo-1H-quinolin-2-one

A mixture of 3-bromo-1-oxo-quinolin-1-ium (1.1g, 4.7mmol) and sodium hydroxide (431mg, 10.8mmol) in water (14mL) and DCM (7mL) was stirred vigorously and treated slowly with benzoyl chloride (0.65mL, 5.6mmol) at room temperature. The mixture was stirred vigorously at room temperature for 2 hours. The reaction mixture was then filtered, the solid washed thoroughly with water and DCM and oven dried to give 3-bromo-1H-quinolin-2-one (637mg, 2.8mmol, 61%) as a white solid.

¹H NMR(300MHz,DMSO-d₆)＝12.27(br.s.,1H),8.51(s,1H),7.68(d,J＝7.8Hz,1H),7.55(t,J＝7.8Hz,1H),7.33(d,J＝8.2Hz,1H),7.22(t,J＝7.6Hz,1H)

LCMS (high pH) found 223.9/225.9[ M + H ] + T ═ 0.87min, UV purity 100%.

Intermediate S21-C3-bromo-2-oxo-1H-quinoline-6-sulfonyl chloride

A solution of 3-bromo-1H-quinolin-2-one (637mg, 2.84mmol) in chlorosulfonic acid (2mL, 30mmol) was stirred at room temperature for 1 hour and then heated to 65 deg.C (sealed tube) for 20 hours. The reaction mixture was cooled, carefully transferred into stirred water (ca. 5mL), and the resulting precipitate was collected by filtration, washed with water (2 x 5mL) and dried to give a white powder (333mg) which was used without further purification.

LCMS (high pH) showed a mixture of 47% SM (0.86min) and 49% product (0.98 min). For the product peak, 321.9,323.9[ M + H ] +.

S21-D3-bromo-N- (1-methylcyclopropyl) -2-oxo-1H-quinoline-6-sulfonamide

A solution of 3-bromo-2-oxo-1H-quinoline-6-sulfonyl chloride (150mg, 0.23mmol), 1-methylcyclopropylamine hydrochloride (38mg, 0.35mmol), N-diisopropylethylamine (0.12mL, 0.7mmol) and 4-dimethylaminopyridine (28mg, 0.23mmol) in DMF (2mL) was stirred at room temperature for 20 minutes. The reaction mixture was concentrated to dryness to give an oily residue which was purified by automatic column chromatography (DCM-10% MeOH/DCM-weak chromophore) to give 3-bromo-N- (1-methylcyclopropyl) -2-oxo-1H-quinoline-6-sulfonamide (46mg, 0.13mmol, 55%) as a white powder.

Example 4883- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-N- [1- (trideuteromethyl) cyclopropyl ] -1H-quinazoline-6-sulphonamide

Intermediate S22-A2, 6-di-tert-butyl-4-methylphenylcyclopropane carboxylate

A2.0M solution of n-butyllithium (36.3mL, 90.8mmol) in hexane was added to a magnetically stirred solution of 2, 6-di-tert-butyl-4-methylphenol (20g, 90.8mmol) in THF (100mL) at 0 deg.C under nitrogen, and the resulting mixture was stirred at that temperature for 15 minutes. Cyclopropanecarbonyl chloride (8.65mL, 95.3mmol) was then added to the reaction over 5 minutes and the resulting cloudy suspension was stirred at ambient temperature overnight. The mixture was poured into saturated NH₄Aqueous Cl (100mL) and the resulting mixture was stirred for 5 minutes the organic phases were collected and the aqueous solution was extracted with diethyl ether (2 × 100mL) the organic phases were combined and successively saturated NaHCO₃The aqueous solution (100mL) and brine (100mL) were washed and dried (Na)₂SO₄) The solvent was removed in vacuo to give the crude product as an oil (23.4 g.) the oil was taken up in methanol (50mL), the resulting solution was stirred for 30 minutes the white precipitate formed, which was collected by filtration the filter cake was washed with methanol (3 × 15mL) and dried under vacuum at 40 ℃ for 2 hours to give the desired product (24g, 94%) as a white solid.

¹H NMR(300MHz,DMSO-d₆)＝7.08(s,2H),2.27(s,3H),2.08-1.93(m,1H),1.28(s,18H),1.15-1.03(m,2H),0.99-0.89(m,2H)

Intermediate S22-B2, 6-di-tert-butyl-4-methylphenyl 1- (methyl-d)₃) Cyclopropane-1-carboxylic acid esters

To a magnetically stirred solution of (2, 6-di-tert-butyl-4-methyl-phenyl) cyclopropanecarboxylate (7.8g, 27.0mmol) in THF (50mL) under nitrogen at-78 deg.C was added a 1.6M solution of tert-butyllithium in hexane (21.3mL, 29.8mmol) over 10 minutes and the resulting mixture was stirred at-78 deg.C for 30 minutes. Then the iodomethane-d is added₃A solution of (2.02mL, 32.45mmol) in THF (5mL) was added to the reaction and the resulting mixture was warmed to ambient temperature with stirring for 4 hours. The mixture was diluted with diethyl ether (60mL) and, in turn, saturated NH₄Aqueous Cl (50mL) and brine (50mL) were washed, then dried (Na)₂SO₄). The solvent was then removed under vacuum to give the crude product, which was passed through automatic column chromatography (SiO)₂(ii) a RediSep-100 g; EtOAc in hexanes 0 to 40%) to give the desired product (6.8g, 82%) as a white solid.

¹H NMR(300MHz,DMSO-d₆)＝7.08(s,2H),2.27(s,3H),1.28(s,18H),1.20-1.15(m,2H),0.98-0.92(m,2H)

Intermediate S22-C1- (methyl-d)₃) Cyclopropane-1-carboxylic acid

To a solution of (2, 6-di-tert-butyl-4-methyl-phenyl) 1- (trideuteromethyl) cyclopropanecarboxylate (6.4g, 20.9mmol) and potassium tert-butoxide (14.1g, 126mmol) in THF (150mL) at 20 deg.C under nitrogen was added water (0.75mL, 41.9mmol) and the resulting mixture was stirred at reflux for 36 h. Cooling the mixture to ambient temperatureAnd extracted with 2N KOH (2 × 20mL), the combined extracts were cooled on ice and acidified to pH 1 with 6N HCl, the mixture was extracted with diethyl ether (2 × 40mL), and the combined extracts were extracted with Na₂SO₄And (5) drying. The solvent was removed in vacuo to give the desired product (2.0g, 93%) as a yellow oil.

¹H NMR(300MHz,DMSO-d₆)＝12.01(br.s.,1H),1.03(q,J＝3.4Hz,2H),0.65(q,J＝3.6Hz,2H)

Intermediate S22-D1- (methyl-D)₃) Cyclopropane-1-amine hydrochloride

A solution of 1- (Trideuteromethyl) cyclopropanecarboxylic acid (2.0g, 19.39mmol), diphenylphosphorylazide (3.76mL, 17.45mmol) and triethylamine (5.39mL, 38.79mmol) in t-butanol (10mL) was heated at 75 deg.C overnight. The reaction mixture was cooled and poured into a biphasic mixture of water (40mL) and EtOAc (30 mL). The biphasic mixture was allowed to stir for 15 minutes and the solids formed during this time were removed by filtration. The aqueous layer was collected and extracted with EtOAc (2X 30 mL). The combined extracts were then washed with water (20mL) and then dried over magnesium sulphate and then distilled to dryness to give an off-white solid (1.6 g). The solid material was suspended in 1, 4-dioxane (10mL) and treated with a solution of 4N hydrogen chloride in dioxane (10 mL). The reaction mixture was then stirred at room temperature for 2 hours, during which time a precipitate formed. Diethyl ether (100mL) was added to the mixture in portions over 5 minutes, and the resulting mixture was stirred for an additional 15 minutes. The mixture was then filtered and the filter cake was washed with diethyl ether (2 × 30mL) and air dried for 5 minutes to give the desired product (0.5g, 23%) as a white solid.

¹H NMR(300MHz,DMSO-d₆)＝8.38(br.s.,3H),0.93-0.86(m,2H),0.63-0.56(m,2H)

S22-E3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-N- [1- (trideuteromethyl) cyclopropyl ] -1H-quinazoline-6-sulfonamide

To a magnetically stirred solution of 1- (Trideuteromethyl) cyclopropylamine hydrochloride (200mg, 1.81mmol) and N, N-diisopropylethylamine (1.08mL, 6.51mmol) in DMF (5mL) under nitrogen at 20 deg.C was added 3- [ (1-methylpyrazol-4-yl) methyl ] methyl]-2, 4-dioxo-1H-quinazoline-6-sulfonyl chloride (770mg, 2.17mmol) and the resulting mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under vacuum to give a residue, which was partitioned between DCM (50mL) and water (50 mL). The organic phase was collected and MgSO₄Drying and then distillation to dryness gave a crude product which was purified by automatic column chromatography (SiO 2; RediSep-24 g; 0 to 10% MeOH in DCM) to give the desired product (430mg, 1.096mmol, 60.6%) as a white solid.

Example 4891-methyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-N- [1- (trideuteromethyl) cyclopropyl ] quinazoline-6-sulphonamide

1-methyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonyl chloride (240mg, 0.65mmol) was added to a stirred solution of 1- (trideuteromethyl) cyclopropylamine hydrochloride (60mg, 0.54mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.43mL, 2.44mmol) in DMF (4mL) and the resulting mixture was stirred overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC (high pH) to give the desired product (50mg, 0.12mmol, 23%) as a white powder.

Example 4901- [ (2, 5-Dimethylpyrazol-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-N- [1- (Trideuteromethyl) cyclopropyl ] quinazoline-6-sulfonamide

A mixture of 3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-N- [1- (trideuteriomethyl) cyclopropyl ] -1H-quinazoline-6-sulphonamide (100mg, 0.25mmol), 5- (chloromethyl) -1, 3-dimethyl-1H-pyrazole (37mg, 0.25mmol), potassium carbonate (70mg, 0.51mmol) and potassium iodide (42mg, 0.25mmol) in DMF (2mL) was heated with stirring in a microwave at 80 ℃ for 30 minutes. The solvent was removed in vacuo and the residue was purified by preparative HPLC (high pH) to give the desired product (68mg, 0.136mmol, 53%) as a white powder.

Example 4911-methyl-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxo-quinoline-6-sulphonamide

A solution of N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxo-1H-quinoline-6-sulphonamide (30mg, 0.08mmol) and iodomethane (0.01mL, 0.1mmol) in DMF (2mL) was treated with potassium carbonate (13mg, 0.1mmol) and heated to 80 ℃ for 20 min under microwave irradiation. The reaction mixture was diluted with water (2mL) and DCM (5mL) and stirred vigorously for 10 min. The aqueous layer was re-extracted with DCM and the combined organic extracts were passed through a hydrophobic frit, concentrated and purified by preparative HPLC (high pH) to give 1-methyl-N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxo-quinoline-6-sulfonamide (8mg, 0.021mmol, 26%) as a white powder.

Example 4921- [ (2, 5-Dimethylpyrazol-3-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxo-quinoline-6-sulphonamide

A mixture of N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2-oxo-1H-quinoline-6-sulphonamide (60mg, 0.16mmol), 5- (chloromethyl) -1, 3-dimethyl-1H-pyrazole (23mg, 0.16mmol), potassium carbonate (45mg, 0.32mmol) and potassium iodide (27mg, 0.16mmol) in DMF (2mL) was heated with stirring in a microwave at 80 ℃ for 30 min. The solvent was removed in vacuo and the residue was purified by preparative HPLC (high pH) to give the desired product (20mg, 0.042mmol, 26%) as a white powder.

Example 4931-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -8- (5-methyl-2-thienyl) -2, 4-dioxo-quinazoline-6-sulfonamide

8-bromo-1-methyl-N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide (80mg, 0.17mmol), (1-methyl-1H-pyrazol-4-yl) boronic acid (44mg, 0.35mmol), cesium carbonate (173mg, 0.53mmol), and 1, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane adduct (20mg, 0.02mmol) were placed in a 7mL microwave vial, followed by the addition of THF (2.5mL) and water (0.5mL), and the resulting mixture was degassed with nitrogen for 5 minutes. The vial was then sealed and heated under microwave irradiation at 80 ℃ for 20 minutes. The mixture was filtered through celite and evaporated to dryness to give a residue which was purified by preparative HPLC (high pH) to give the desired product (20mg, 0.04mmol, 32%) as a white powder.

EXAMPLE 494N- [1- (fluoromethyl) cyclopropyl ] -3- (isothiazol-4-ylmethyl) -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide

A mixture of N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide (74mg, 0.23mmol), isothiazol-4-ylmethyl methanesulfonate (43.7mg, 0.23mmol), potassium carbonate (62.5mg, 0.45mmol) and potassium iodide (37.53mg, 0.23mmol) in DMF (4mL) was heated with stirring in a microwave at 80 ℃ for 45 minutes. The mixture was partitioned between DCM (10mL) and water (10mL), the organic phase was collected and distilled to dryness to give a residue. The residue was purified by preparative HPLC (high pH) to give the desired product N- [1- (fluoromethyl) cyclopropyl ] -3- (isothiazol-4-ylmethyl) -1-methyl-2, 4-dioxo-quinazoline 6-sulfonamide as a white solid (20mg, 0.0471mmol, 21%).

Example 495N- (1-methylcyclopropyl) -2, 4-dioxo-3- [2- (2-pyridyl) ethyl ] -1H-quinazoline-6-sulfonamide

A suspension of 2, 4-dioxo-1H-3, 1-benzoxazine-6-sulfonyl chloride (261mg, 1mmol) in DMF (2mL) was treated with 1-methylcyclopropylamine hydrochloride (0.11g, 1mmol) and cooled to-10 ℃ in an ice/MeOH bath. The solution was treated with triethylamine (0.31mL, 2.2mmol) for 5 min. To the reaction mixture was added a solution of 2- (2-pyridyl) ethylamine (0.16mL, 1.3mmol) in DMF (2mL) at 0 ℃. Additional triethylamine (0.31mL, 2.2mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (40mL) and extracted with EtOAc (3X 30 mL). The combined extracts were washed with water, passed through a hydrophobic frit and evaporated to dryness. The residue was purified by flash chromatography on silica (CH2Cl 2/ether/MeOH/Et 3N eluent) to give 2-amino-5- [ (1-methylcyclopropyl) sulfamoyl ] -N- [2- (2-pyridyl) ethyl ] benzamide (257mg, 0.686mmol, 69%).

¹H NMR (300MHz, chloroform-d) ppm 8.73-8.69(m,1H),8.14-8.08(m,2H),7.86-7.78(m,1H),7.68-7.62(m,1H),7.39-7.32(m,1H),7.33(d, J ═ 8.2Hz,1H),6.68(d, J ═ 8.7Hz,1H),6.14(br s,2H),5.32(br s,1H),3.89-3.81(m,2H), 3.28-3.22 (m,2H),1.23, (s,3H),0.86-0.78(m,2H),0.48-0.42(m,2H)

Triphosgene (99mg, 0.33mmol) was added to a solution of 2-amino-5- [ (1-methylcyclopropyl) sulfamoyl ] -N- [2- (2-pyridyl) ethyl ] benzamide (250mg, 0.668mmol) in THF (10mL) at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 15 minutes and then at ambient temperature overnight. 2M aqueous sodium hydroxide (2mL, 2M) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. The mixture was cooled and acidified to pH2 with 2M HCl. The product was extracted with EtOAc. The combined extracts were washed with water, evaporated and purified by preparative hplc to give the desired product (160mg, 0.40mmol, 60%) as a white powder.

Example 4963- (2-cyanoethyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide

A suspension of 2, 4-dioxo-1H-3, 1-benzoxazine-6-sulfonyl chloride (261mg, 1mmol) in DMF (2mL) was treated with 1-methylcyclopropylamine hydrochloride (0.11g, 1mmol) and cooled to-10 ℃ in an ice/MeOH bath. The solution was treated with triethylamine (0.31mL, 2.2mmol) for 5 min. To the reaction mixture was added 3-aminopropionitrile (0.1mL, 1.3mmol) in DMF (2mL) at 0 ℃. Additional triethylamine (0.31mL, 2.2mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (40mL) and extracted with EtOAc (3X 30 mL). The combined extracts were washed with water, passed through a hydrophobic frit and evaporated to dryness. The residue was purified by flash chromatography on silica (CH2Cl 2/ether/MeOH/Et 3N eluent) to give 2-amino-N- (2-cyanoethyl) -5- [ (1-methylcyclopropyl) sulfamoyl ] benzamide (87mg, 0.27mmol, 27%).

¹H NMR (300MHz, chloroform-d) ppm 7.86-7.84(m,1H),7.80-7.76(m,2H),7.61-7.56(m,1H),6.66(d, J ═ 8.7Hz,1H),3.68-3.58(m,2H),2.72-2.66(m,2H),1.19,1.16, (s,3H),0.75-0.68(m,2H),0.46-0.38(m,2H)

Triphosgene (40mg, 0.13mmol) was added to a solution of 2-amino-N- (2-cyanoethyl) -5- [ (1-methylcyclopropyl) sulfamoyl ] benzamide (87mg, 0.27mmol) in THF (10mL) at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 15 minutes and then at ambient temperature overnight. 2M aqueous sodium hydroxide (2mL, 2M) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. The mixture was cooled and acidified to pH2 with 2M HCl. The product was extracted with EtOAc. The combined extracts were washed with water, evaporated and purified by preparative hplc to give the desired product (67mg, 0.192mmol, 71%) as a white powder.

Example 4973- (2-cyanoethyl) -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method A10 using 3- (2-cyanoethyl) -N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide (50mg, 0.144mmol), potassium carbonate (24mg, 0.172mmol), and iodomethane (20 μ L, 0.34 mmol). The reaction mixture was heated to 80 ℃ for 1 hour in a microwave. The desired product (25mg, 0.069mmol, 48%) was obtained as a white powder.

Example 4981-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- [2- (2-pyridinyl) ethyl ] quinazoline-6-sulfonamide

Prepared using method A10 using N- (1-methylcyclopropyl) -2, 4-dioxo-3- [2- (2-pyridyl) ethyl ] -1H-quinazoline-6-sulfonamide (145mg, 0.362mmol), potassium carbonate (60mg, 0.435mmol), and iodomethane (27 μ L, 0.435 mmol). The reaction mixture was heated to 80 ℃ for 30 minutes in a microwave. The desired product (52mg, 0.126mmol, 35%) was obtained as a white powder.

Example 4991-methyl-N- (1-methylcyclopropyl) -3- [ (4-methyl-1, 2, 4-triazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a3 (with 2 equivalents NaH) from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide, 3- (chloromethyl) -4-methyl-4H-1, 2, 4-triazole hydrochloride, and 1 equivalent NaI. This gave the desired product (5mg, 0.0124mmol, 6%) as a white powder.

Example 5001-methyl-N- (1-methylcyclopropyl) -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Using method a3, prepared from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide, 2- (chloromethyl) -5-methyl-1, 3, 4-thiadiazole and 1 equivalent of NaI. This gave the desired product (28mg, 0.0664mmol, 34%) as a white powder.

Example 5011-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- [ [5- (trifluoromethyl) -1,3, 4-oxadiazol-2-yl ] methyl ] quinazoline-6-sulfonamide

Prepared using method a3 from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide, 2- (chloromethyl) -5- (trifluoromethyl) -1,3, 4-oxadiazole and 1 equivalent of NaI. This gave the desired product (12mg, 0.0261mmol, 13%) as a white powder.

Example 5021- (cyanomethyl) -N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method A10 using N- (1-methylcyclopropyl) -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (60mg, 0.148mmol), potassium carbonate (25mg, 0.177mmol), and bromoacetonitrile (11 μ L, 0.155 mmol). The reaction mixture was heated to 100 ℃ for 30 minutes in a microwave. The desired product (17mg, 0.038mmol, 26%) was obtained as a white powder.

Example 5031- (cyanomethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a10 using N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (58mg, 0.148mmol), potassium carbonate (25mg, 0.177mmol), and bromoacetonitrile (11 μ L, 0.155 mmol). The reaction mixture was heated to 100 ℃ for 30 minutes in a microwave. The desired product (16mg, 0.037mmol, 25%) was obtained as an off-white powder.

Example 5043- (Furanylmethyl) -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxoquinazoline-6-sulfonamide

Using method a2, prepared from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide and furan-3-methanol. This gave the desired product (10mg, 0.0257mmol, 10%) as a white powder.

Example 5053- (1H-imidazol-4-ylmethyl) -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a2, prepared from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide and 4-imidazolemethanol. This gave the desired product (4mg, 0.0103mmol, 5%) as a white powder.

Example 5061-methyl-N- (1-methylcyclopropyl) -3- [ (5-methylisoxazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Using method a2, from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide and (5-methyl-1, 2-oxazol-4-yl) methanol. This gave the desired product (18mg, 0.0445mmol, 23%) as a white powder.

Example 5073- [ (1-Isopropylpyrazol-4-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method A2 with 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide (160mg, 0.517mmol) and (1-isopropyl-1H-pyrazol-4-yl) methanol (127 μ L, 1.034 mmol). The desired product (15mg, 0.035mmol, 6.7%) was obtained as a colorless gum.

Example 5081-methyl-N- (1-methylcyclopropyl) -3- [ (1-methyltetrazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Prepared using method A3 with 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide (100mg, 0.323mmol) and 5- (chloromethyl) -1-methyl-1H, 1,2,3, 4-tetrazole (43mg, 0.323 mmol). The desired product (39mg, 0.096mmol, 30%) was obtained as a white powder.

Example 5093- [ (4-Isopropylthiadiazol-5-yl) methyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method A3 with 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide (100mg, 0.323mmol) and 5- (chloromethyl) -4-isopropyl-1, 2, 3-thiadiazole (57mg, 0.323 mmol). The desired product (26mg, 0.058mmol, 18%) was obtained as an off-white powder.

Example 5103- (Isothiazol-5-ylmethyl) -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method A2 with 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide (160mg, 0.517mmol) and isothiazol-5-ylmethanol (119mg, 1.034 mmol). The desired product (9mg, 0.022mmol, 4.3%) was obtained as a white powder.

Example 5111-methyl-N- (1-methylcyclopropyl) -3- [ (4-methyl-1, 2, 5-oxadiazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Prepared using method A2 with 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide (135mg, 0.436mmol) and (4-methyl-1, 2, 5-oxadiazol-3-yl) -methanol (100mg, 0.873 mmol). The desired product (21mg, 0.052mmol, 12%) was obtained as a white powder.

Example 512N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide

To a stirred solution of N, N-diisopropylethylamine (3.9mL, 22.4mmol) in THF (50mL) and DCM (30mL) was added 1- (fluoromethyl) cyclopropane-1-amine hydrochloride (1.07g, 8.51mmol) and then 1-methyl-2, 4-dioxo-quinazoline-6-sulfonyl chloride (2.46g, 8.96mmol) at 0 ℃ and the mixture was stirred at ambient temperature overnight. The solvent was evaporated and the resulting white solid was triturated from MeOH, filtered and dried in vacuo to give the desired product (1.43g, 4.37mmol, 49%) as a white powder.

Example 513N- [1- (fluoromethyl) cyclopropyl ] -3- (isoxazol-5-ylmethyl) -1-methyl-2, 4-dioxo-quinazoline-6-sulphonamide

Using method A3, N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide (200mg, 0.611mmol) and 5- (bromomethyl) -1, 2-oxazole (99mg, 0.611mmol) were used. The desired product (77mg, 0.189mmol, 31%) was obtained as a white powder.

Example 514N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a3 using N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide (100mg, 0.323mmol) and 5- (bromomethyl) -3-methyl-1, 2-oxazole (57mg, 0.323 mmol). The desired product (64mg, 0.152mmol, 47%) was obtained as a white powder.

Example 515N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method A3 using N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide (120mg, 0.367mmol) and 2- (chloromethyl) -5-methyl-1, 3, 4-thiadiazole (54mg, 0.367 mmol). The desired product (15mg, 0.034mmol, 9.3%) was obtained as a white powder.

Example 516N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

A suspension of 1, 4-dihydro-2, 4-dioxo-2H-3, 1-benzoxazine-6-sulfonyl chloride (14g, 53.5mmol), prepared by chlorosulfonation of isatoic anhydride chlorosulfonic acid in DMF (200mL) at 60 deg.C, was treated with 1-fluoromethylcyclopropylamine hydrochloride (8.0g, 64mmol) and cooled to-10 deg.C in an ice/MeOH bath. The solution was slowly treated with triethylamine (16.3mL, 96.7mmol) and the resulting solution was stirred at-10 ℃ for 1 hour. (3-methylisoxazol-5-ylmethyl) amine (8.97g, 80.0mmol) in DMF (40mL) was added to the reaction mixture at 0 ℃ and then triethylamine (14.8mL, 107mmol) was added and the reaction mixture was stirred at ambient temperature for 3 hours. Water (450mL) was added to the reaction mixture, which was then extracted with EtOAc (2 × 900mL), and the organic phase was washed with brine (450mL), dried over sodium sulfate, filtered and evaporated to dryness. The crude product was chromatographed on silica gel and dried to give 2-amino-5- [ (1-fluoromethylcyclopropyl) sulfamoyl ] -N- [ (3-methylisoxazol-5-yl) methyl ] benzamide (6.0g, 16.4mmol, 31%) as a white solid.

Triphosgene (2.31g, 7.73mmol) was added to a solution of 2-amino-5- [ (1-fluoromethylcyclopropyl) sulfamoyl ] -N- [ (3-methylisoxazol-5-yl) methyl ] benzamide (6.0g, 16.4mmol) in THF (120mL) cooled in an ice bath. A white precipitate formed, and triethylamine (2.35mL, 17mmol) was added. The reaction mixture was removed from cooling and stirred at ambient temperature for 1.5 hours. The reaction mixture was quenched with 2M NaOH (120mL) and stirred overnight. The next morning, EtOAc (240mL) was added to the reaction mixture, which was then cooled and acidified (to pH 3) with 2M HCl. The organic phase was separated and evaporated to dryness to give the desired product (5.1g, 12.5mmol, 76%) as a white powder.

Example 5171- (Cyclopropylmethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Using method a10, prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and iodomethylcyclopropane. This gave the desired product (22mg, 0.0476mmol, 32%) as a white powder.

Example 518N- [1- (fluoromethyl) cyclopropyl ] -1- [ (4-fluorophenyl) methyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Using method a10, prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 4-fluorobenzyl bromide. This gave the desired product (24mg, 0.0465mmol, 32%) as a white powder.

Example 5191- [ (2, 5-Dimethylpyrazol-3-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a10, prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, 5- (chloromethyl) -1, 3-dimethyl-1H-pyrazole, and 0.2 eq sodium iodide. This gave the desired product (30mg, 0.0581mmol, 40%) as a white powder.

Example 5201-Ethyl-N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Using method a10, prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and iodoethane. This gave the desired product (20mg, 0.0458mmol, 31%) as a white powder.

Example 521N- [1- (fluoromethyl) cyclopropyl ] -1, 3-bis [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 5- (bromomethyl) -3-methyl-1, 2-oxazole using method a 10. This gave the desired product (20mg, 0.0397mmol, 27%) as a white powder.

Example 522N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- (oxetan-3-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a10 from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, oxetan-3-ylmethyl 4-methylbenzenesulfonate and 0.2 equivalent of NaI. This gave the desired product (22mg, 0.0460mmol, 31%) as a white powder.

Example 5231- (cyanomethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to example 465 using N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.245mmol) and bromoacetonitrile (19. mu.L, 0.269 mmol). The reaction mixture was heated to 120 ℃ for 1 hour by microwave irradiation. The desired product (17mg, 0.038mmol, 16%) was obtained as a beige powder.

Example 524N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (tetrahydrofuran-3-ylmethyl) quinazoline-6-sulfonamide

This compound was prepared according to example 465 using N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.245mmol) and 3- (bromomethyl) tetrahydrofuran (60 μ L, 0.538 mmol). The reaction mixture was heated to 120 ℃ for 2 hours by microwave irradiation. The desired product (21mg, 0.042mmol, 25%) was obtained as a beige powder.

Example 525N- [1- (fluoromethyl) cyclopropyl ] -1- (3-methoxypropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to example 465 using N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (105mg, 0.256mmol) and 1-bromo-3-methoxypropane (62. mu.L, 0.564 mmol). The reaction mixture was heated to 120 ℃ for 2 hours by microwave irradiation. The desired product (34mg, 0.071mmol, 28%) was obtained as a white powder.

Example 5261- (2-fluoroethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a2 using N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (306mg, 0.749mmol) and 1-bromo-2-fluoroethane (61 μ L, 0.824 mmol). After stirring overnight at ambient temperature, 1-bromo-2-fluoroethane (61 μ L, 0.824mmol) was added and the reaction mixture was heated to 80 ℃ by microwave irradiation. The desired product (16mg, 0.035mmol, 4.7%) was obtained as a white powder.

Example 527N- [1- (fluoromethyl) cyclopropyl ] -1- (2-methoxyethyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

This compound was prepared according to example 465 using N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.245mmol) and 2-bromoethyl methyl ether (22. mu.L, 0.269 mmol). The reaction mixture was heated to 120 ℃ for 1 hour by microwave irradiation. The desired product (5mg, 0.01mmol, 4.4%) was obtained as an off-white powder.

Example 5281-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- [ 2-oxo-2- (4-pyridinyl) ethyl ] quinazoline-6-sulfonamide

Prepared from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide and 4- (bromoacetyl) pyridine hydrobromide using method a3 (with 2 equivalents NaH). This gave the desired product (5mg, 0.0117mmol, 6%) as a white powder.

Example 5291-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- [ 2-oxo-2- (2-thienyl) ethyl ] quinazoline-6-sulfonamide

Using method a3, prepared from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide and 2-bromo-1- (2-thiophene) ethanone. This gave the desired product (34mg, 0.0784mmol, 40%) as a white powder.

Example 5301-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3-benzoylmethyl-quinazoline-6-sulfonamide

Using method a3, prepared from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide and 2-bromoacetophenone. This gave the desired product (31mg, 0.0725mmol, 37%) as a white powder.

Example 5313- [2- (4-cyanophenyl) -2-oxoethyl ] -1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide

Using method a3, prepared from 1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide and 4- (bromoacetyl) benzonitrile. This gave the desired product (29mg, 0.0641mmol, 33%) as a white powder.

Example 532N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1-prop-2-ynyl-quinazoline-6-sulfonamide

This compound was prepared according to example 465 using N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.245mmol) and 3-bromopropyne (19. mu.L, 0.269 mmol). The reaction mixture was heated to 120 ℃ for 1 hour by microwave irradiation. The desired product (6mg, 0.054mmol, 5.5%) was obtained as a white powder.

Example 533N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Using method a2, prepared from N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide and (2-methyl-1, 3-thiazol-5-yl) methanol. This gave the desired product (19mg, 0.043mmol, 8.4%) as a white powder.

Example 534N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-3- (thiazol-5-ylmethyl) quinazoline-6-sulfonamide

Using method a2, prepared from N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide and 5- (hydroxymethyl) -1, 3-thiazole. This gave the desired product (8mg, 0.019mmol, 3.6%) as a white powder.

Example 535N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1-propyl-quinazoline-6-sulfonamide

Prepared using method A10 using N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (200mg, 0.49mmol), potassium carbonate (136mg, 0.979mmol), and 1-bromopropane (53 μ L, 0.59 mmol). The desired product (13mg, 0.029mmol, 5.9%) was obtained as an off-white powder.

Example 5361-butyl-N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method A10 using N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (200mg, 0.49mmol), potassium carbonate (136mg, 0.979mmol), and 1-bromobutane (63. mu.L, 0.59 mmol). The desired product (66mg, 0.142mmol, 29%) was obtained as a white powder.

General experiments for examples 537-

Flash chromatography was performed using a pre-packed silica gel column (YMC 4g, 40 to 60 μm silica particles) with a maximum operating pressure of 200psi/14 bar. Merck type 60F for thin layer chromatography₂₅₄Silica gel was coated onto a 0.25mm thick 5 × 10cm plate, all reagents obtained from commercial sources were used without further purification.

All compounds were prepared by LC-MS and¹detection of both H NMR spectra confirmed purity>95 percent. When Cl or Br are present, the expected isotope distribution pattern is observed.

¹H NMR

Recording protons on a 400MHz Varian spectrometer: (¹H) And carbon (C)¹³C) NMR spectrum. The solution is typically deuterated methanol (CD)₃OD) or deuterated dimethylsulfoxide (d)⁶-DMSO), chemical shifts referenced to Tetramethylsilane (TMS) or deuterated solvents as internal standards.¹H NMR data reports indicate chemical shift (), integral (e.g., 1H), multiplicities (s, singlet; d, doublet; t, triplet)(ii) a q, quartet; m, multiplet; br, broad peak; dd, doublet, etc.) and a coupling constant (J) (Hz) (app. means significant coupling on a broad peak signal). Deuterated solvents were obtained from sigma-aldrich, inc.

Analytical LC-MS (method D).

LC-MS analysis was performed on a Shimadzu LCMS system equipped with YMC triat C18 or YMC ODS C18, 3.0. mu.M column (4.6X 50mm) and UV diode array detection (210-400 nm). Positive and negative ion mass detection was performed using a Shimadzu SQD detector. Analysis was performed using buffered acidic or basic solvents, or a gradient as described below:

low pH:

solvent A-water +5mM ammonium formate + 0.1% formic acid

Solvent B-5% solvent A + 0.1% formic acid in acetonitrile

High pH:

solvent A-Water +5mM ammonium formate + 0.1% Ammonia solution

Solvent B-acetonitrile + 5% solvent A + 0.1% ammonia solution

Gradient:

time of day	Flow rate (mL/min)	% solvent A	% solvent B
				0	1.20mL/min	80	20
2.5	1.20mL/min	05	95
				3.0	1.20mL/min	05	95
4.0	1.20mL/min	80	20
				4.5	1.20mL/min	80	20

Preparative HPLC

Some compounds were purified by preparative HPLC using YMC-ODS 10. mu. m C18, a 500mm X30 mm inner diameter column, running at a flow rate of 40mL/min using UV diode array detection (210-400nm), and mass directed collection using positive and negative ion mass detection.

Purification is carried out using a suitably buffered acidic or basic solvent system. Compound retention times on the system were routinely assessed using 30-50 μ L test injections and standard gradients, and then based on observed retention times, purification was performed using appropriately selected focused gradients as described below.

Low pH:

solvent A-water +10mM ammonium bicarbonate + 0.1% formic acid

Solvent B-acetonitrile + 5% water + 0.1% formic acid

Standard gradient:

time of day	Flow rate (mL/min)	% solvent A	% solvent B
				0.01	40mL/min	95	5
2	40mL/min	95	5
				30	40mL/min	70	30
40	40mL/min	60	40

Example 537N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (5-methyl-2-pyridinyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of (2-methylpyridin-2-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (5 eq) in DCM at 0 deg.C with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (58mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (14mg, 0.027mmol, 11%) as a white powder.

Example 5381- [ (6-cyano-2-pyridyl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 6- (chloromethyl) cyanopyridine (picolininotrile) (65mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were heated conventionally to 70 ℃ for 4 hours. Usual work-up gave the desired product (15mg, 0.029mmol, 7.3%) as a white powder.

Example 539N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (5-methyl-3-pyridinyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of (2-methylpyridin-3-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (5 eq) in DCM at 0 deg.C with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (57mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (11mg, 0.021mmol, 8.3%) as a white powder.

Example 540N- [1- (fluoromethyl) cyclopropyl ] -1- [ (6-fluoro-2-pyridyl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of (6-fluoropyridin-2-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 deg.C with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (55mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (26mg, 0.050mmol, 19%) as a white powder.

Example 541N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (2-methyl-4-pyridinyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of (2-methylpyridin-4-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 deg.C with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (57mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (46mg, 0.090mmol, 35%) as a white powder.

Example 542N- [1- (fluoromethyl) cyclopropyl ] -1- [ (3-fluoro-2-pyridyl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of (3-fluoropyridin-2-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 deg.C with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (55mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (15mg, 0.030mmol, 11%) as a white powder.

Example 5431- [ (4-cyanophenyl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 4- (bromomethyl) benzonitrile (84mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (60mg, 0.115mmol, 29%) as a white powder.

Example 5441- (2-fluoroethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 1-fluoro-2-iodoethane (75mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (14mg, 0.031mmol, 7.9%) as a white powder.

Example 5451- [ (3, 5-Dimethylisoxazol-4-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of (3, 5-dimethylisoxazol-4-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (55mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (25mg, 0.048mmol, 19%) as a white powder.

Example 546N- [1- (fluoromethyl) cyclopropyl ] -1- [ (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 3- (bromomethyl) -5-methyl-1, 2, 4-oxadiazole (76mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (21mg, 0.042mmol, 11%) as a white powder.

Example 5471- [ (2, 5-dimethyl-1, 2, 4-triazol-3-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 5- (chloromethyl) -1, 3-dimethyl-1H-1, 2, 4-triazole (62mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were heated conventionally to 70 ℃ for 4 hours. General work-up gave the desired product (10mg, 0.019mmol, 5.0%) as a white powder.

Example 548N- [1- (fluoromethyl) cyclopropyl ] -1- [ (2-methyloxazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of (2-methyloxazol-5-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (51mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (25mg, 0.050mmol, 19%) as a white powder.

Example 549N- [1- (fluoromethyl) cyclopropyl ] -1-isobutyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 1-bromo-2-methylpropane (59mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (37mg, 0.080mmol, 20%) as a white powder.

Example 550N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (2-methylthiazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a10 from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, 4- (chloromethyl) -2-methyl-1, 3-thiazole and 0.2 equivalent of NaI. This gave the desired product (28mg, 0.0539mmol, 37%) as a white powder.

Example 551N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (4-methyl-1, 2, 4-triazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Using method A10 (with 2.2 eq K)₂CO₃) From N- [1- (fluoromethyl) cyclopropyl]-3- [ (3-methylisoxazol-5-yl) methyl]-2, 4-dioxo-1H-quinazoline-6-sulfonamide, 3- (chloromethyl) -4-methyl-4H-1, 2, 4-triazole hydrochloride and 0.2 equivalent of NaI. This gave the desired product (17mg, 0.0338mmol, 23%) as a white powder.

Example 552N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a10 from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, 2- (chloromethyl) -5-methyl-1, 3, 4-thiadiazole and 0.2 equivalent of NaI. This gave the desired product (12mg, 0.0231mmol, 16%) as a white powder.

Example 553N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (1-methyl-1, 2, 4-triazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a10 from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole and 0.2 equivalent of NaI. This gave the desired product (30mg, 0.0596mmol, 41%) as a white powder.

Example 5541- [ (2, 5-dimethyl-1, 2, 4-triazol-3-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a10 from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, 5- (chloromethyl) -1, 3-dimethyl-1H-1, 2, 4-triazole and 0.2 equivalent of NaI. This gave the desired product (29mg, 0.0560mmol, 38%) as a white powder.

Example 555N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Using method A10 (with 2.2 eq K)₂CO₃) From N- [1- (fluoromethyl) cyclopropyl]-3- [ (3-methylisoxazol-5-yl) methyl]-2, 4-dioxo-1H-quinazoline-6-sulfonamide, 4- (chloromethyl) -1-methyl-1H-pyrazole hydrochloride and 0.2 equivalent of NaI. This gave the desired product (28mg, 0.0557mmol, 38%) as a white powder.

Example 556N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (5-methyl-1, 3, 4-oxadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, 2- (chloromethyl) -5-methyl-1, 3, 4-oxadiazole and 0.2 equivalent of sodium iodide using method a 10. This gave the desired product (8mg, 0.0159mmol, 11%) as a white powder.

Example 557N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (2-methyl-1, 2, 4-triazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Using method A10 (with 2.2 eq K)₂CO₃) From N- [1- (fluoromethyl) cyclopropyl]-3- [ (3-methylisoxazol-5-yl) methyl]-2, 4-dioxo-1H-quinazoline-6-sulfonamide, 5- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole hydrochloride and 0.2 equivalent of NaI. This gave the desired product (28mg, 0.0556mmol, 38%) as a white powder.

Example 558N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, (5-methyl-1, 2, 4-oxadiazol-3-yl) methylmethanesulfonate and 0.2 equivalent NaI using method a 10. This gave the desired product (30mg, 0.0595mmol, 17%) as a white powder.

Example 559N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -1- (oxazol-4-ylmethyl) - -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 1, 3-oxazol-4-ylmethanol using method a 2. Bis (4-chlorobenzyl) azodicarboxylate was used instead of DIAD and the crude product was triturated with DCM to remove hydrazine by-product. This gave the desired product (8mg, 0.0163mmol, 7%) as a white powder.

Example 560N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (2-pyrazol-1-ylethyl) quinazoline-6-sulfonamide

1- (2-chloroethyl) -1H-pyrazole was prepared by reacting pyrazole with 1-bromo-2-chloroethane. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), 1- (2-chloroethyl) -1H-pyrazole (37mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were heated conventionally to 70 ℃ for 4 hours. Usual work-up gave the desired product (7mg, 0.014mmol, 5.4%) as a white powder.

Example 561N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (3-methyl-1H-pyrazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

(3-methyl-1H-pyrazol-5-yl) methanol was Boc-protected by reaction with Boc-anhydride (1.2 eq) and triethylamine (2.5 eq) in DCM at 0 ℃ with warming to ambient temperature. The alcohol of the Boc-protected amine was then converted to the mesylate by reaction with methanesulfonyl chloride (1.5 eq) and triethylamine (2.5 eq) in DCM at 0 ℃ while warming to ambient temperature for 2 hours. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), methanesulfonate (83mg, 0.286mmol) and potassium carbonate (54mg, 0.39mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. After Boc-deprotection with HCl in dioxane, general work-up yielded the desired product (6mg, 0.012mmol, 4.6%) as a white powder.

Example 562N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (2-methyl-1, 2, 4-triazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of (1-methyl-1H-1, 2, 4-triazol-5-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (55mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (30mg, 0.060mmol, 23%) as a white powder.

Example 563N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (thiazol-5-ylmethyl) quinazoline-6-sulfonamide

The mesylate of thiazol-5-ylmethanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (55mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (15mg, 0.030mmol, 11%) as a white powder.

Example 564N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (oxazol-5-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of oxazol-5-ylcarbinol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (51mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (20mg, 0.041mmol, 16%) as a white powder.

Example 565N- [1- (fluoromethyl) cyclopropyl ] -1- [ (1-methylimidazol-2-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

(1-methyl-1H-imidazol-2-yl) methanol was converted to the corresponding alkyl chloride by reaction with thionyl chloride in DCM. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude alkyl chloride (37mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (66mg, 0.132mmol, 51%) as a white powder.

Example 566N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- [2- (2-pyridyl) ethyl ] quinazoline-6-sulfonamide

The mesylate of 2- (2-pyridine) ethanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (57mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (11mg, 0.021mmol, 8.2%) as a white powder.

Example 567N- [1- (fluoromethyl) cyclopropyl ] -1- [ (5-methyl-1, 3, 4-oxadiazol-2-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of (5-methyl-1, 3, 4-oxadiazol-2-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (55mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (28mg, 0.056mmol, 21%) as a white powder.

EXAMPLE 568N- [1- (fluoromethyl) cyclopropyl ] -1- [ (2-methyl-1H-imidazol-4-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

2-methyl-1H-imidazole-5-methanol was Boc-protected by reaction with Boc-anhydride (1.2 equiv.) and triethylamine (2.5 equiv.) in DCM at 0 deg.C with warming to ambient temperature. The alcohol of the Boc-protected amine was then converted to the mesylate by reaction with methanesulfonyl chloride (1.5 eq) and triethylamine (2.5 eq) in DCM at 0 ℃ while warming to ambient temperature for 2 hours. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), methanesulfonate (83mg, 0.286mmol) and potassium carbonate (54mg, 0.39mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. After Boc-deprotection with HCl in dioxane, general work-up yielded the desired product (11mg, 0.022mmol, 8.4%) as a white powder.

Example 569N- [1- (fluoromethyl) cyclopropyl ] -1- [ (5-methylpyrazin-2-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of (5-methylpyrazin-2-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (54mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (35mg, 0.068mmol, 26%) as a white powder.

Example 570N- [1- (fluoromethyl) cyclopropyl ] -1- [ [1- (hydroxymethyl) cyclopropyl ] methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Cyclopropane-1, 1-diyidimethanol as TBDMS ether, was mono-protected with TBDMS chloride and triethylamine in DCM. The free alcohol was then converted to the mesylate using a solution of methanesulfonyl chloride and triethylamine in DCM. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), methanesulfonate (84mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. After deprotection of the TBDMS group. General work-up gave the desired product (13mg, 0.026mmol, 10%) as a white powder.

Example 571N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (4-methyl-2-pyridinyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of (2-methylpyridin-2-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (4 eq) in DCM at 0 deg.C with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (57mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (14mg, 0.027mmol, 11%) as a white powder.

Example 572N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (4-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of (4-methylthiazol-5-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (56mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (15mg, 0.029mmol, 11%) as a white powder.

Example 573N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (6-methyl-3-pyridinyl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of (2-methylpyridin-3-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (6 eq) in DCM at 0 deg.C with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (57mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (11mg, 0.021mmol, 8.2%) as a white powder.

Example 5741- (2-cyanoethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

3-hydroxypropionitrile was converted to the corresponding mesylate by reaction with methanesulfonyl chloride and triethylamine in DCM. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), m (26mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (10mg, 0.022mmol, 8.4%) as a white powder.

Example 575N- [1- (fluoromethyl) cyclopropyl ] -1- (1H-imidazol-4-ylmethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

1H-imidazole-5-methanol was Boc-protected by reaction with Boc-anhydride (1.2 eq) and triethylamine (2.5 eq) in DCM at 0 ℃ with warming to ambient temperature. The alcohol of the Boc-protected amine was then converted to the mesylate by reaction with methanesulfonyl chloride (1.5 eq) and triethylamine (2.5 eq) in DCM at 0 ℃ while warming to ambient temperature for 2 hours. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), methanesulfonate (79mg, 0.286mmol) and potassium carbonate (54mg, 0.39mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. After Boc-deprotection with HCl in dioxane, the usual work-up yielded the desired product (31mg, 0.064mmol, 24%) as an off-white powder.

Example 5761- [ (3-ethylimidazol-4-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

(1-ethyl-1H-imidazol-5-yl) methanol was converted to the corresponding alkyl chloride by reaction with thionyl chloride in DCM. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude alkyl chloride (41mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (12mg, 0.023mmol, 9%) as a white powder.

Example 577N- [1- (fluoromethyl) cyclopropyl ] -1- (isothiazol-4-ylmethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of isothiazol-4-ylmethanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (55mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (33mg, 0.065mmol, 25%) as a white powder.

Example 578N- [1- (fluoromethyl) cyclopropyl ] -1- (isothiazol-5-ylmethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of isothiazol-5-ylcarbinol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 deg.C with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (52mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (21mg, 0.042mmol, 16%) as a white powder.

Example 579N- [1- (fluoromethyl) cyclopropyl ] -1- [ (5-methylisoxazol-4-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of (5-methylisoxazol-4-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (55mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (17mg, 0.034mmol, 13%) as a white powder.

Example 580N- [1- (fluoromethyl) cyclopropyl ] -1- [ (2-methyloxazol-4-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of (2-methyloxazol-4-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (54mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (16mg, 0.032mmol, 12%) as a white powder.

Example 581N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (thiazol-4-ylmethyl) quinazoline-6-sulfonamide

The mesylate of thiazol-4-ylmethanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (52mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (11mg, 0.022mmol, 8.4%) as a white powder.

Example 582N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (2-methylthiazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of (2-methylthiazol-4-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (59mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (13mg, 0.025mmol, 10%) as a white powder.

Example 583N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of (5-methyl-1, 3, 4-thiadiazol-2-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (60mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (19mg, 0.037mmol, 14%) as a white powder.

Example 584N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (4-methyl-1, 2, 4-triazol-3-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 3- (chloromethyl) -4-methyl-4H-1, 2, 4-triazole (66mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (19mg, 0.038mmol, 9.7%) as a white powder.

Example 585N- [1- (fluoromethyl) cyclopropyl ] -1- (isoxazol-5-ylmethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of isoxazol-5-ylcarbinol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (51mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (13mg, 0.027mmol, 10%) as a white powder.

EXAMPLE 586N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (1H-pyrazol-3-ylmethyl) quinazoline-6-sulfonamide

(1H-pyrazol-3-yl) methanol was Boc-protected by reaction with Boc-anhydride (1.2 eq) and triethylamine (2.5 eq) in DCM at 0 ℃ with warming to ambient temperature. The alcohol of the Boc-protected amine was then converted to the mesylate by reaction with methanesulfonyl chloride (1.5 eq) and triethylamine (2.5 eq) in DCM at 0 ℃ while warming to ambient temperature for 2 hours. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), methanesulfonate (79mg, 0.286mmol) and potassium carbonate (54mg, 0.39mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. After Boc-deprotection with HCl in dioxane, general work-up yielded the desired product (6mg, 0.012mmol, 4.7%) as a white powder.

Example 587N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (1H-1,2, 4-triazol-3-ylmethyl) quinazoline-6-sulfonamide

1H-1,2, 4-triazole-5-methanol was Boc-protected by reaction with Boc-anhydride (1.2 equiv.) and triethylamine (2.5 equiv.) in DCM at 0 deg.C with warming to ambient temperature. The alcohol of the Boc-protected amine was then converted to the mesylate by reaction with methanesulfonyl chloride (1.5 eq) and triethylamine (2.5 eq) in DCM at 0 ℃ while warming to ambient temperature for 2 hours. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), methanesulfonate (79mg, 0.286mmol) and potassium carbonate (54mg, 0.39mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. After Boc-deprotection with HCl in dioxane, usual work-up gave the desired product (8mg, 0.016mmol, 6.3%) as a white powder.

Example 588N- [1- (fluoromethyl) cyclopropyl ] -1- [ (3-methylimidazol-4-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

(1-methyl-1H-imidazol-5-yl) methanol was converted to the corresponding alkyl chloride by reaction with thionyl chloride in DCM. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude alkyl chloride (37mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (37mg, 0.074mmol, 28%) as an off-white powder.

Example 589N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (1,3, 4-thiadiazol-2-ylmethyl) quinazoline-6-sulfonamide

The mesylate of (1,3, 4-thiadiazol-2-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (56mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (24mg, 0.047mmol, 18%) as a white powder.

Example 590N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (1H-pyrazol-4-ylmethyl) quinazoline-6-sulfonamide

(1H-pyrazol-4-yl) methanol was Boc-protected by reaction with Boc-anhydride (1.2 eq) and triethylamine (2.5 eq) in DCM at 0 ℃ with warming to ambient temperature. The alcohol of the Boc-protected amine was then converted to the mesylate by reaction with methanesulfonyl chloride (1.5 eq) and triethylamine (2.5 eq) in DCM at 0 ℃ while warming to ambient temperature for 2 hours. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), methanesulfonate (79mg, 0.286mmol) and potassium carbonate (54mg, 0.39mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. After Boc-deprotection with HCl in dioxane, usual work-up gave the desired product (14mg, 0.029mmol, 11%) as a white powder.

Example 591N- [1- (fluoromethyl) cyclopropyl ] -1- [ (3-methylisothiazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of (3-methylisothiazol-5-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (59mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (7mg, 0.013mmol, 5.2%) as a white powder.

Example 592N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (3-methyl-1H-1, 2, 4-triazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

(3-methyl-1H-1, 2, 4-triazol-5-yl) methanol was Boc-protected by reaction with Boc-anhydride (1.2 equiv.) and triethylamine (2.5 equiv.) in DCM at 0 deg.C with warming to ambient temperature. The alcohol of the Boc-protected amine was then converted to the mesylate by reaction with methanesulfonyl chloride (1.5 eq) and triethylamine (2.5 eq) in DCM at 0 ℃ while warming to ambient temperature for 2 hours. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), methanesulfonate (83mg, 0.286mmol) and potassium carbonate (54mg, 0.39mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. After Boc-deprotection with HCl in dioxane, usual work-up gave the desired product (12mg, 0.030mmol, 11%) as a white powder.

EXAMPLE 593N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (1-methyltriazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of (1-methyl-1H-1, 2, 3-triazol-4-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (55mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (29mg, 0.058mmol, 22%) as a white powder.

Example 594N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of (2-methylthiazol-5-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (56mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (12mg, 0.023mmol, 8.9%) as a white powder.

Example 595N- [1- (fluoromethyl) cyclopropyl ] -1, 3-bis [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of (1-methyl-1H-pyrazol-4-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (54mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (12mg, 0.024mmol, 9.2%) as a white powder.

Example 596N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- [ (2-methyltriazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

The mesylate of (2-methyl-2H-1, 2, 3-triazol-4-yl) methanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (55mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (22mg, 0.044mmol, 17%) as a white powder.

EXAMPLE 597N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1-propyl-quinazoline-6-sulphonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 1-bromopropane (52mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (6mg, 0.013mmol, 3.4%) as a white powder.

EXAMPLE 598N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydrofuran-3-ylmethyl) quinazoline-6-sulfonamide

The tosylate of (tetrahydrofuran-3-yl) methanol was prepared by reaction with p-toluenesulfonyl chloride and triethylamine in DCM at 0 deg.C with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude tosylate ester (73mg, 0.286mmol) and potassium carbonate (43mg, 0.312mmol) in DMF were heated conventionally to 70 ℃ for 4 hours. Usual work-up gave the desired product (17mg, 0.035mmol, 13%) as a white powder.

Example 5991- (2, 2-Difluoroethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

A stirred solution of 3- [ (1-methylpyrazol-4-yl) methyl ] -1H-quinazoline-2, 4-dione (800mg, 3.12mmol) in DMF (10mL) was treated with 2-iodo-1, 1-difluoroethane (330. mu.L, 3.75mmol) and potassium carbonate (863mg, 6.24mmol), and the mixture was stirred at room temperature over the weekend. Additional 2-iodo-1, 1-difluoroethane (1.5mmol) was added and the mixture was heated in a microwave at 80 ℃ for 2 hours. The reaction mixture was diluted with water (100mL) and extracted with EtOAc (2 × 200mL), the organic phases combined, washed with brine (10mL), passed through a hydrophobic frit and evaporated to dryness to give 1- (2, 2-difluoroethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] quinazoline-2, 4-dione (602mg, 1.88mmol, 60%) which was used in the next step without further purification.

¹H NMR(300MHz,DMSO-d₆)＝8.09(dd,J＝7.9,1.6Hz,1H),7.81-7.74(m,1H),7.66(s,1H),7.60(d,J＝8.5Hz,1H),7.38(m,1H),7.33(d,J＝7.6Hz,1H),6.35(tt,J＝55,3.9Hz,1H),4.96(s,2H),4.70-4.57(m,2H),3.76(s,3H)。

Chlorosulfonic acid (6mL) was added to 1- (2, 2-difluoroethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] quinazoline-2, 4-dione (600mg, 1.87mmol) at 5 ℃. The mixture was heated at 50 ℃ for 4 hours, and then allowed to cool. The reaction mixture was added dropwise to stirred ice/water and extracted rapidly with DCM and 5% MeOH/DCM. The combined extracts were evaporated to dryness to yield 1- (2, 2-difluoroethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonyl chloride (765mg, 1.83mmol, 97%) which was used in the next step without purification.

To a solution of N, N-diisopropylethylamine (0.49mL, 2.79mmol) in THF (10mL) and DCM (6mL) cooled in an ice bath was added a mixture of 1-methylcyclopropylamine hydrochloride (0.2g, 1.87mmol) followed by the addition of 1- (2, 2-difluoroethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonyl chloride (0.39g, 0.93mmol) in portions. After stirring overnight, the solvent was evaporated and the residue was purified by preparative hplc to give the desired product (58mg, 0.128mmol, 14%) as a white powder.

Example 6001- (2, 2-Difluoroethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

To a solution of N, N-diisopropylethylamine (0.49mL, 2.79mmol) in THF (10mL) and DCM (6mL) cooled in an ice bath was added a mixture of 1- (fluoromethyl) cyclopropane-1-amine hydrochloride (0.23g, 1.86mmol) followed by the addition of 1- (2, 2-difluoroethyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonyl chloride (0.39g, 0.93mmol) prepared as described in example 599 in portions. After stirring overnight, the solvent was evaporated and the residue was purified by preparative hplc to give the desired product (50mg, 0.12mmol, 13%) as an off-white powder.

Example 601N- [1- (fluoromethyl) cyclopropyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide

Prepared from 3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonyl chloride and 1- (fluoromethyl) cyclopropane-1-amine hydrochloride using general procedure 1. This gave the desired product (222mg, 0.5218mmol, 48%) as a white powder.

Example 6021-Ethyl-N- [1- (fluoromethyl) cyclopropyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and iodoethane using method A10. This gave the desired product (12mg, 0.0265mmol, 19%) as a white powder.

Example 6031- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a10 from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, 5- (chloromethyl) -1, 3-dimethyl-1H-pyrazole, and 0.2 equivalent of NaI. This gave the desired product (17mg, 0.0319mmol, 23%) as a white powder.

Example 6041- (difluoromethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a10 using N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.245mmol), potassium carbonate (102mg, 0.74mmol), and difluoro (iodo) methane (218mg, 1.2 mmol). The reaction mixture was heated to 120 ℃ for 2 hours in a microwave. The desired product (4mg, 0.009mmol, 3.6%) was obtained as an off-white powder.

Example 6051- (difluoromethyl) -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a10 using N- (1-methylcyclopropyl) -3- ((3-methylisoxazol-5-yl) methyl) -2, 4-dioxo-1, 2,3, 4-tetrahydroquinazoline-6-sulfonamide (96mg, 0.245mmol), potassium carbonate (102mg, 0.74mmol), and difluoro (iodo) methane (109mg, 0.61 mmol). The reaction mixture was heated to 120 ℃ for 2 hours in a microwave. The desired product (12mg, 0.027mmol, 11%) was obtained as a white powder.

Example 6061- (difluoromethyl) -N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Prepared using method a10 using N- (1-methylcyclopropyl) -N- [ [3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazolin-6-yl ] sulfonyl ] acetamide (106mg, 0.245mmol), potassium carbonate (102mg, 0.74mmol) and difluoro (iodo) methane (109mg, 0.61 mmol). The reaction mixture was heated to 120 ℃ for 1 hour in a microwave. The desired product (55mg, 0.125mmol, 51%) was obtained as a white powder.

Example 607N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -1- (oxazol-4-ylmethyl) -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of oxazol-4-ylcarbinol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (51mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (31mg, 0.063mmol, 24%) as a white powder.

Example 6081- (Cyclopentylmethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), (bromomethyl) cyclopentane (70mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (26mg, 0.053mmol, 14%) as a white powder.

Example 609N- [1- (fluoromethyl) cyclopropyl ] -1- (3-methylbut-2-enyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 1-bromo-3-methyl-2-butene (64mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were heated conventionally to 70 ℃ for 4 hours. General work-up gave the desired product (52mg, 0.109mmol, 28%) as a white powder.

Example 610N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (4-pyridylmethyl) quinazoline-6-sulfonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 4- (bromomethyl) pyridine (74mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (37mg, 0.074mmol, 19%) as a white powder.

Example 6111- [2- (diethylamino) ethyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 2-chloro-N, N-diethylethanamine hydrochloride (74mg, 0.429mmol) and potassium carbonate (130mg, 0.936mmol) in DMF were heated conventionally to 70 ℃ for 4 hours. Usual work-up gave the desired product (40mg, 0.079mmol, 20%) as a white powder.

Example 6121- (2-ethoxyethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

The mesylate of 2-ethoxyethanol (100mg) was prepared by reaction with methanesulfonyl chloride (1.1 eq) and triethylamine (2 eq) in DCM at 0 ℃ with warming to ambient temperature. N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), crude methanesulfonate ester (58mg, 0.286mmol), and potassium carbonate (43mg, 0.312mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (31mg, 0.066mmol, 25%) as a white powder.

Example 613N- [1- (fluoromethyl) cyclopropyl ] -1-isopentyl-3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 1-bromo-3-methylbutane (65mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. Usual work-up gave the desired product (17mg, 0.035mmol, 9.1%) as a white powder.

Example 6141-Ethyl-N- (1-methylcyclopropyl) -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Using method a10, prepared from N- (1-methylcyclopropyl) -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and iodoethane. The desired product (6mg, 0.0138mmol, 20%) was given as a white powder.

Example 6151- [ (2, 5-dimethylpyrazol-3-yl) methyl ] -N- (1-methylcyclopropyl) -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared using method a10 from N- (1-methylcyclopropyl) -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, 5- (chloromethyl) -1, 3-dimethyl-1H-pyrazole, and 0.2 equivalent of sodium iodide. This gave the desired product (28mg, 0.0543mmol, 44%) as a white powder.

Example 6161- [ (2, 4-Dimethylthiazol-5-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, (2, 4-dimethylthiazol-5-yl) methylmethanesulfonate and 0.2 eq NaI using method a 10. This gave the desired product (50mg, 0.0937mmol, 38%) as a white powder.

Example 6171-butyl-N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 1-bromobutane (59mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (8mg, 0.017mmol, 4.4%) as a white powder.

Example 618N- [1- (fluoromethyl) cyclopropyl ] -1- [2- (2-methoxyethoxy) ethyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 1-bromo-2- (2-methoxyethoxy) ethane (79mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were heated conventionally to 70 ℃ for 4 hours. General work-up gave the desired product (13mg, 0.026mmol, 6.5%) as a white powder.

Example 619N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (tetrahydrofuran-2-ylmethyl) quinazoline-6-sulfonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 2- (bromomethyl) tetrahydrofuran (71mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were heated conventionally to 70 ℃ for 4 hours. Usual work-up gave the desired product (6mg, 0.012mmol, 3.1%) as a white powder.

Example 620N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (2-oxobutyl) quinazoline-6-sulphonamide

N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (150mg, 0.390mmol), 1-bromo-2-butanone (65mg, 0.429mmol) and potassium carbonate (65mg, 0.468mmol) in DMF were conventionally heated to 70 ℃ for 4 hours. General work-up gave the desired product (38mg, 0.080mmol, 20%) as a white powder.

Example 621N- (1-methylcyclopropyl) -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (2,2, 2-trifluoroethyl) quinazoline-6-sulfonamide

Prepared using method A10 using N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (200mg, 0.46mmol), potassium carbonate (160mg, 1.16mmol), and 1,1, 1-trifluoro-2-iodoethane (0.11mL, 1.1 mmol). The reaction mixture is typically heated to 120 ℃ for 18 hours. The desired product (20mg, 0.04mmol, 9%) was obtained as a white powder.

Example 622N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (2,2, 2-trifluoroethyl) quinazoline-6-sulfonamide

Prepared using method a10 using N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), potassium carbonate (85mg, 0.61mmol), and 1,1, 1-trifluoro-2-iodoethane (0.06mL, 0.59 mmol). The reaction mixture is typically heated to 120 ℃ for 18 hours. The desired product (5mg, 0.01mmol, 4.2%) was obtained as a beige powder.

Example 623N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1- (2,2, 2-trifluoroethyl) quinazoline-6-sulphonamide

Prepared using method A10 using N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide (100mg, 0.260mmol), potassium carbonate (85mg, 0.61mmol), and 1,1, 1-trifluoro-2-iodoethane (0.06mL, 0.59 mmol). The reaction mixture is typically heated to 120 ℃ for 18 hours. The desired product (2mg, 0.004mmol, 1.7%) was obtained as a beige powder.

Example 624N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-3- (1,3, 4-thiadiazol-2-ylmethyl) quinazoline-6-sulfonamide

Prepared as described in example 494, using N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide (80mg, 0.24mmol), 1,3, 4-thiadiazol-2-ylmethyl methanesulfonate (47.5mg, 0.24mmol), potassium carbonate (67.6mg, 0.49mmol), and potassium iodide (40.6mg, 0.24mmol) in DMF (4mL) to give the desired product N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-3- (1,3, 4-thiadiazol-2-ylmethyl) quinazoline-6-sulfonamide as a white solid (30mg, 0.071mmol, 29%).

Example 625N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-3- [ (3-methylisothiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared as described in example 494, from N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide (70mg, 0.21mmol), (3-methylisothiazol-5-yl) methylmethanesulfonate (44.3mg, 0.21mmol), potassium carbonate (59.1mg, 0.43mmol), and potassium iodide (35.5mg, 0.21mmol) in DMF (4mL) to give the desired product N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-N, 3-bis [ (3-methylisothiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide as a white solid (31mg, 0.070mmol, 28%).

Example 626N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-3- [ (2-methyltriazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared as described in example 494, from N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide (70mg, 0.21mmol), (2-methyltriazol-4-yl) methylmethanesulfonate (40.9mg, 0.21mmol), potassium carbonate (59.1mg, 0.43mmol), and potassium iodide (35.5mg, 0.21mmol) in DMF (4mL) to give the desired product N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-3- [ (2-methylthiazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide as a white solid (20mg, 0.047mmol, 22%).

Example 627N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1- (1,3, 4-thiadiazol-2-ylmethyl) quinazoline-6-sulfonamide

Prepared using method a10 from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide, 1,3, 4-thiadiazol-2-ylmethyl methanesulfonate, and 0.2 equivalent of NaI. This gave the desired product (12mg, 0.0237mmol, 16%) as a white powder.

Example 6283- [ (5-Ethyl-1, 3, 4-thiadiazol-2-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide

Prepared as described in example 494, from N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide (70mg, 0.21mmol), 2- (chloromethyl) -5-ethyl-1, 3, 4-thiadiazole (34.8mg, 0.21mmol), potassium carbonate (59.1mg, 0.43mmol), and potassium iodide (35.5mg, 0.21mmol) in DMF (4mL) to give the desired product 3- [ 5-ethyl-1, 3, 4-thiadiazol-2-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -1-methyl-2, 4-dioxo-quinazoline-6-sulfonamide as a tan solid (10mg, 0.022mmol, 10%).

Example 6291- (2-fluoroethyl) -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 1-fluoro-2-bromoiodoethane using method a 10. This gave the desired product (5mg, 0.0106mmol, 11%) as a white powder.

Example 630N- [1- (fluoromethyl) cyclopropyl ] -1- [ (1-methylpyrazol-4-yl) methyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide

Using method A10 (with 2.2 eq K)₂CO₃) From N- [1- (fluoromethyl) cyclopropyl]-3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl]-2, 4-dioxo-1H-quinazoline-6-sulfonamide, 4- (chloromethyl) -1-methyl-1H-pyrazole hydrochloride and 0.2 equivalent of sodium iodide. This gave the desired product (7mg, 0.0135mmol, 14%) as a white powder.

Example 631N- [1- (fluoromethyl) cyclopropyl ] -1- [ (5-methyl-1, 2, 4-oxadiazol-3-yl) methyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulphonamide

Prepared from N- [1- (fluoromethyl) cyclopropyl ] -3- [ (5-methyl-1, 3, 4-thiadiazol-2-yl) methyl ] -2, 4-dioxo-1H-quinazoline-6-sulfonamide and 3- (bromomethyl) -5-methyl-1, 2, 4-oxadiazole using method A10. This gave the desired product (8mg, 0.0153mmol, 20%) as a white powder.

PARG assay (biological Activity)

PARG assay

PARG in vitro assays were performed in a standard 384 well plate format with a total volume of 15 ul. Mu.l of human full-length PARG (manufactured internally by the manufacturer ASTRICON pharmacia) used at a final reaction concentration of 80pM in assay buffer (50mM Tris pH7.4, 0.1mg/ml BSA, 3mM EDTA, 0.4mM EGTA, 1mM DTT, 0.01% Tween 20, 50mM KCl) was added to 5ul of Ribosylated PARP substrate (also manufactured internally by the manufacturer ASTRICON pharmacia) at a final reaction concentration of 4.5 nM. The reaction was incubated at room temperature for 10 minutes and then 5 μ l of detection reagent was added. The detection reagent consisted of 42nM MAb anti-6 HIS XL665 (CisBio: 61HISXLB) and 2.25nM streptavidin europium Cryptate (Cryptate) (CisBio: 610SAKLB) in 50mM Tris pH7.4, 0.1mg/ml BSA, 100mM KF assay buffer, both at 3 working stock concentrations (14 nM and 0.75nM final concentrations, respectively). After incubation in the dark for 60 minutes at room temperature, TR-FRET signals were measured at Ex 340 and Em665 and Em 620. The ratio of each well was calculated as Em665/Em620x104 and used to calculate the percent inhibition of the test compound.

PARG cell assay

The method is based on the detection of endogenous levels of poly (ADP) ribose chains present in the nucleus of the HeLa cell line using indirect immunofluorescence. MMS stimulation increased PAR chain length for up to 25 minutes. Thereafter, PARG activates and breaks down PAR chains until 1 hour after stimulation, no PAR chains are detected. Inhibition of PARG maintains the PAR chain.

Briefly, after complexing and treatment with the DNA damaging agent Methyl Mesylate (MMS), cell monolayers were fixed, then permeabilized and incubated with mouse monoclonal antibodies against poly (ADP) ribose multimers. After overnight incubation, excess antibody was removed by washing and Alexafluor 488-linked secondary antibody that recognizes mouse monoclonal antibody was added along with nuclear stain (Hoechst 33342). Images of the cells were then captured and analyzed on a high-content screening platform and the total intensity of nuclear fluorescence signal at 488nM was quantified. The increase in fluorescence indicates the presence of more PAR chains and thus the intensity of PARG inhibition.

HeLa cells seeded at 4000/well in 384-well plates in 30. mu.L RPMI 1640 medium supplemented with 10% FBS and 2mM Glutamax were incubated overnight at 37 ℃ under 5% CO 2.

The following day, cells were dosed in quadruplicate with compound (10-point dose response) and incubated at 37 ℃ for 1 hour at 5% CO 2.

At the end of the 1 hour dosing period, the MMS was added in duplicate at a final concentration of 50 μ g/mL for another 1 hour.

The medium was decanted and the cells were fixed with 50 μ L of ice-cold 95% MetOH/PBS for 15 min at-20 ℃. After PBS wash, 50 μ L PBS/0.1% Triton was added to the cells for 20 minutes. After another PBS wash, the anti-PAR antibody (Calbiochem AM80) was diluted 1:4000 in buffer (PBS + 0.5% FBS + 0.05% tween 20) and added to the cells and incubated overnight at 4 ℃.

The following day, cells were washed three times with PBS, and then with a 1:1000 dilution of secondary antibody (Alexa)488 goat anti-mouse IgG (H + L)) and Hoechst diluted 1:5000 in buffer (5% FBS + 0.05% Tween 20 in PBS) were incubated for 1 hour.

Cells were washed three times with PBS and plates were sealed with a light tight seal.

Images of cells were captured on celllnight, siemer fly and the average total intensity of fluorescent spots at 485nm in the nucleus is reported.

TABLE 1 Synthesis methods and PARG Activity (Biochemical and cellular Activity)

TABLE 2 LC-MS data

TABLE 3-¹H NMR data

ARH3 and PARP1 assays (Selectivity data)

ARH3 determination

ARH3 in vitro selectivity assays were performed in a standard 384 well plate format with a total volume of 15 ul. Mu.l of human full-length ARH3 (Enzor biosciences: ALX-201-292) used at a final reaction concentration of 17.5nM was added to 5ul Ribosylated PARP substrate (also manufactured internally by the manufacturer ASTERISIKAN pharmaceuticals) at a final reaction concentration of 4.5nM (50mM Tris pH7.4, 0.1mg/ml BSA, 3mM EDTA, 0.4mM EGTA, 1mM DTT, 0.01% Tween 20, 50mM KCl) in assay buffer. The reaction was incubated at room temperature for 30 minutes, then 5. mu.l of detection reagent was added. The detection reagent consisted of 42nM MAb anti-6 HISXL665 (CisBio: 61HISXL LB) and 2.25nM europium streptavidin Cryptate (Cryptate) in 50mM Tris pH7.4, 0.1mg/ml BSA, 100mM KF assay buffer, both at 3 working stock concentrations (final concentrations 14nM and 0.75nM, respectively). After incubation in the dark for 60 minutes at room temperature, TR-FRET signals were measured at Ex 340 and Em665 and Em 620. The ratio of each well was calculated as Em665/EM620X104 and used to calculate the percent inhibition of the test compound.

PARP1 determination

The PARP1 in vitro selectivity assay was performed as a10 ul reaction volume in a NUNC Maxisorp 384 well assay plate with internal pre-coating of histones. 5. mu.l of human highly specific active PARP1 (Trevigen: 4668-01) were used at a final reaction concentration of 0.02 units/ml in 1 XPARP buffer (Trevigen: 4671-096-02) and 5. mu.l of 1 XPARP mixture, the 1 XPARP mixture being a mixture of 10 XPARP mixture (Trevigen: 4671-096-03), 10 Xactive DNA (Trevigen: 4671-096-06) and 20 XPARP buffer (as described above). The reaction was incubated at room temperature for 60 minutes to allow the histones on the coated plate to become PAR-ized. The wells were then washed with PBS/0.1% Triton X100. PARP1 activity was then detected by measuring the extent of PAR. First, 10ul of streptavidin-HRP (Trevigen: 4800-30-06) in 1:250 diluted 1 XPARG assay buffer (Trevigen: 4680-096-02) was added to each well and incubated at room temperature for 60 minutes. Next, after another wash with PBS/0.1% Triton X100, equal amounts of the peroxygenated fluorescent reagents A and B (Trevigen: 4675-. The luminescence signal is then measured immediately.

TABLE 4 ARH3 and PARP1 Activity data (Selectivity data)

Reference to the literature

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Claims

1. A compound having the structural formula (I) shown below or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof:

wherein:

bond c is absent or a single bond;

R_1aselected from hydrogen, fluorine, chlorine, cyano, formyl, (1-2C) alkyl, (1-2C)) Haloalkyl, (2C) alkenyl, or (2C) alkynyl;

R_1b、R_1c、R_1dand R_1eEach independently selected from H, fluoro or methyl;

X₂selected from the group consisting of CR₃Or N; wherein R is₃Is H or fluorine;

R₄Selected from the group having the formula:

-L₄-L_4C-Q_4C

wherein

R_5Nselected from H, (1-2C) alkyl or (1-2C) haloalkyl;

wherein

R_6cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₆-L_6C-Q_6C

wherein

L₆Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

L_6Cis absent or selected fromO、S、SO、SO₂、N(R_b)、C(O)、C(O)O、OC(O)、C(O)N(R_b)、N(R_b)C(O)、N(R_b)C(O)N(R_c)、S(O)₂N(R_b) Or N (R)_b)SO₂Wherein R is_bAnd R_cEach independently selected from hydrogen or (1-2C) alkyl; and

R_6Nselected from hydrogen or a group having the formula:

-L₆-L_6N-Q_6N

wherein

L₆Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

Q_6Nis hydrogen, cyano, (1-6C) alkyl, (2C) alkynyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from: halogen, trifluoromethylYl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C) alkyl, NR_hR_i、OR_h、C(O)R_h、C(O)OR_h、OC(O)R_h、C(O)N(R_h)R_i、N(R_h)C(O)R_i、N(R_h)C(O)OR_i、S(O)_yR_h(wherein y is 0, 1 or 2), SO₂N(R_h)R_i、N(R_h)SO₂R_iOr (CH)₂)_zNR_hR_i(wherein z is 1,2 or 3) wherein R_hAnd R_iEach independently selected from H or (1-4C) alkyl; or

Q_6NOptionally substituted with a group having the formula:

-W_6N-Z_6N

wherein

W_6NAbsent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

wherein

R_7cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₇-L_7C-Q_7C

wherein

L₇Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

R_7Nselected from hydrogen or a group having the formula:

-L₇-L_7N-Q_7N

wherein

L₇Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

Q_7Nis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from: halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, (1-4C) alkyl、NR_pR_q、OR_p、C(O)R_p、C(O)OR_p、OC(O)R_p、C(O)N(R_p)R_q、N(R_r)C(O)R_p、S(O)_yR_p(wherein y is 0, 1 or 2), SO₂N(R_p)R_q、N(R_r)SO₂R_pOr (CH)₂)_zNR_pR_q(wherein z is 1,2 or 3) wherein R_pAnd R_qEach independently selected from H or (1-4C) alkyl;

when the bond b is a single bond, X₇Selected from the group consisting of C (═ O), C (═ NH), C (═ S), CHR_8cOr N-R_8NOr X when bond b is a double bond₇Selected from the group consisting of CR_8cOr N;

wherein

R_8cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₈-L_8C-Q_8C

wherein

Q_8COptionally substituted with a group having the formula:

-W_8C-L_8’-Z_8C

wherein

W_8CAbsent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

-L_Rz-Z_Rz

wherein:

R_8Nselected from hydrogen or a group having the formula:

-L₈-L_8N-Q_8N

wherein

Q_8Nis hydrogen, cyano, (1-6C) alkyl, (3-6C) cycloalkyl, (2-3C) alkenyl, (2-3C) alkynyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from: (1-4C) alkyl, halogen, trifluoromethyl, trifluoromethoxy, haloalkyl, amino, cyano, aryl, hydroxy, carboxy, carbamoyl, sulfamoyl, NR_zR_a’、OR_z、C(O)R_z、C(O)OR_z、OC(O)R_z、C(O)N(R_z)R_a’、N(R_z)C(O)R_a’、S(O)_yR_z(wherein y is 0, 1 or 2), SO₂N(R_z)R_a’、N(R_z)SO₂R_a’Or (CH)₂)_zNR_zR_a’(wherein z is 1,2 or 3) wherein R_zAnd R_a’Each independently selected from H or (1-4C) alkyl; or

Q_8NOptionally substituted with a group of the formulaAnd (3) substitution:

-W_8N-L_8’-Z_8N

wherein

W_8NAbsent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

the premise is as follows:

(i)R_1b-eonly one or two of which may be selected from any substituent other than H;

(ii)X₁、X₂or X₃Only one or two of which may be N;

(iii) het may contain up to two ring nitrogen atoms only;

(iv)X₄、X₅、X₆or X₇Only one or two of may be selected from C (═ O), C (═ NH), or C (═ S); and

(v) the compound is not one of the following compounds:

(R) -N- (sec-butyl) -1-oxo-1, 2,3, 4-tetrahydroisoquinoline-7-sulfonamide;

4-chloro-N- (1-methylethyl) -6-quinolinesulfonamide;

4-chloro-N-methyl-N- (1-methylethyl) -6-quinolinesulfonamide;

4-chloro-6- (4- (cyclopropylamino) sulfonyl) -3-quinolinecarboxamide;

2-oxo-4-trifluoromethyl-1, 2-dihydroquinolinesulfonic acid isopropylformamide;

2-oxo-4-trifluoromethyl-1, 2-dihydroquinoline-sulfonic acid isopropylamide;

2. The compound of claim 1, wherein bond c is a single bond.

3. The compound of claims 1-2, wherein W is selected from-NH-S (O)₂-、-S(O)₂-NH-, -C (O) NH-or-NHC (O) -.

4. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure (II) shown below:

and wherein X₁、X₂、X₃、HET、R_1a、R_1b、R_1c、R_1dAnd R_1eIs as defined in claim 1.

5. The compound of claims 1-4, wherein R_1aSelected from hydrogen, fluoro, cyano, formyl, (1-2C) alkyl, (1-2C) haloalkyl, or (2C) alkynyl.

6. The compound of claim 5, wherein R_1aSelected from hydrogen, cyano, formyl, (1-2C) alkyl or (1-2C) haloalkyl.

7. The compound of claims 1-6, wherein X₁Is CR₂Wherein R is₂Is H or fluorine.

8. The compound of claim 7, wherein X₁Is C-H.

9. A compound according to any preceding claim, wherein X₂Is CR₃Wherein R is₃Is H or fluorine.

10. A compound according to any preceding claim, wherein X₃Selected from the group consisting of CR₄Or N; wherein R is₄Is H or halo.

11. The compound of claim 10, wherein X₃Is C-H, C-F or C-C (O) NH₂。

12. A compound according to any preceding claim, wherein R_1b、R_1c、R_1dAnd R_1eIs H.

13. A compound according to any one of the preceding claims,wherein when the bond a is a single bond, X₄Selected from the group consisting of C (═ O), C (═ NH), C (═ S), CHR_5cOr N-R_5NOr X when bond a is a double bond₄Selected from the group consisting of CR_5cOr N;

wherein

R_5cSelected from H, fluoro, (1-2C) alkyl, cyano or (2C) alkynyl;

R_5Nselected from H, (1-2C) alkyl or CF₃。

14. A compound according to any preceding claim, wherein X₄Is C (═ O) and bond a is a single bond.

15. A compound according to any preceding claim, wherein when a is a single bond, X₅Selected from the group consisting of C (═ O), C (═ NH), C (═ S), N-R_6N；

Wherein

R_6NSelected from hydrogen or a group having the formula:

-L₆-L_6N-Q_6N

wherein

L₆Absent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

Q_6NOptionally substituted with a group having the formula:

-W_6N-Z_6N

wherein

W_6NAbsent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

Z_6Nselected from (3-5C) cycloalkyl, (3-6C) heterocyclyl, (2C) alkynyl, phenyl, 5-or 6-membered heteroaryl, carboxy, carbamoyl or cyano, wherein Z_6NSubstituted with one or more substituents selected from (1-2C) alkyl, (1-2C) alkoxy or halogen.

16. A compound according to any preceding claim, wherein X₅Is N-R_6NAnd bond a is a single bond;

wherein

R_6NSelected from the group having the formula:

-L₆-Q_6N

wherein

L₆Is (1-3C) alkylene;

Q_6NOptionally substituted with a group having the formula:

-W_6N-Z_6N

wherein

W_6NAbsent or (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo;

Z_6Nselected from (3-5C) cycloalkyl, (2C) alkynyl, phenyl, 5-or 6-membered heteroaryl or cyano, wherein Z_6NSubstituted with one or more substituents selected from (1-2C) alkyl, (1-2C) alkoxy or halogen.

17. A compound according to any preceding claim, wherein when bond b is a single bond, X₆Selected from C (═ O), or when bond b is a double bond, X₆Selected from the group consisting of CR_7cOr N;

wherein

R_7cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₇-Q_7C

wherein

L₇Is (1-3C) alkylene optionally substituted with (1-2C) alkyl or oxo; and

Q_7Cis hydrogen or (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl or heteroaryl; and wherein Q_7COptionally substituted with one or more substituents selected from (1-4C) alkyl or halogen.

18. A compound according to any preceding claim, wherein when bond b is a single bond, X₇Selected from C (═ O) or N-R_8NOr X when the bond b is a double bond₇Selected from the group consisting of CR_8cOr N;

wherein

R_8cSelected from hydrogen, cyano, halogen or a group having the formula:

-L₈-L_8C-Q_8C

wherein

L₈(1-3C) alkylene which is absent or optionally substituted by oxo;

L_8Cabsent or selected from O, S, SO₂、N(R_r)、C(O)、C(O)O、OC(O)、C(O)N(R_r) Or N (R)_r)C(O) Wherein R is_rSelected from hydrogen or (1-2C) alkyl; and

R_8NSelected from hydrogen or a group having the formula:

-L₈-L_8N-Q_8N

wherein

Q_8NOptionally substituted with a group having the formula:

-L_8’-Z_8N

wherein

Z_8Nis phenyl, (1-4C) alkyl, (4-6C) heterocyclyl or 5-6 membered heteroaryl; wherein Z_8NOptionally substituted with one or more substituents selected from (1-2C) alkyl, halogen, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, (1-2C) alkylamino, amino, cyano, hydroxy, carboxy, carbamoyl or sulfamoyl.

19. A compound according to any preceding claim, wherein when bond b is a single bond, X₇Is selected from N-R_8NOr X when the bond b is a double bond₇Selected from the group consisting of CR_8cOr N;

wherein

R_8cSelected from hydrogen, halogen or a group having the formula:

-L₈-L_8C-Q_8C

wherein

L₈(1-3C) alkylene which is absent or optionally substituted by oxo;

R_8NSelected from hydrogen or a group having the formula:

-L₈-L_8N-Q_8N

wherein

L₈Is absent or is optionally selected from (1-2C)(1-3C) alkylene substituted with a substituent for alkyl;

Q_8NOptionally substituted with a group having the formula:

-L_8’-Z_8N

wherein

Z_8NIs phenyl, (1-4C) alkyl, (4-6C) heterocyclyl or 5-6 membered heteroaryl; wherein Z_8NOptionally substituted with one or more substituents selected from (1-2C) alkyl, halogen or hydroxy.

20. The compound of claims 1-12, wherein HET is a compound of formula (III), (IV), (V), (VI), (VII), (VIII), or (IX):

wherein R is_5c、R_6c、R_5N、R_7C、R_6NAnd R_8NAs defined in claim 1.

21. A compound selected from any one of:

n- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

1, 3-dimethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1, 3-dimethyl-2, 4-dioxo-quinazoline-6-sulfonamide;

1, 3-diethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1, 3-diethyl-2, 4-dioxo-quinazoline-6-sulfonamide;

3-ethyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-1H-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

4-methyl-N- (1-methylcyclopropyl) -2, 3-dioxo-1H-quinoxaline-6-sulfonamide;

3-ethyl-2-isobutoxy-N- (1-methylcyclopropyl) -4-oxo-quinazoline-6-sulfonamide;

2-isobutoxy-3-methyl-N- (1-methylcyclopropyl) -4-oxo-quinazoline-6-sulfonamide;

2, 3-dimethyl-N- (1-methylcyclopropyl) -4-oxo-quinazoline-6-sulfonamide;

2-methyl-N- (1-methylcyclopropyl) -4-oxo-3H-quinazoline-6-sulfonamide;

2-cyclopropyl-N- (1-methylcyclopropyl) -4-oxo-3H-quinazoline-6-sulfonamide;

2-isopropyl-N- (1-methylcyclopropyl) -4-oxo-3H-quinazoline-6-sulfonamide;

2-isobutyl-3-methyl-N- (1-methylcyclopropyl) -4-oxo-quinazoline-6-sulfonamide;

3-methyl-N- (1-methylcyclopropyl) -4-oxo-2-phenyl-quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -4-oxo-2-pyrrolidin-1-yl-3H-quinazoline-6-sulfonamide;

3- [ (3, 5-dimethylisoxazol-4-yl) methyl ] -1- [ (4-fluorophenyl) methyl ] -N- (1-methylcyclopropyl) -2, 4-dioxo-quinazoline-6-sulfonamide;

1-chloro-3-methyl-N- (1-methylcyclopropyl) -4-oxo-phthalazine-6-sulfonamide;

n- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -1- [ (1-methyl-2-piperidinyl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- [ (3-methylisoxazol-5-yl) methyl ] -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

n- (1-cyanocyclopropyl) -1- [ (2, 4-dimethylthiazol-5-yl) methyl ] -3- [ (2-methylthiazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1- [ (4, 4-difluorocyclohexyl) methyl ] -N- (1-methylcyclopropyl) -3- [ (3-methylisoxazol-5-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

1-methyl-N- (1-methylcyclopropyl) -2, 4-dioxo-3- (pyrazolo [1,5-a ] pyridin-3-ylmethyl) quinazoline-6-sulfonamide;

n- (1-methylcyclopropyl) -1, 3-dioxo-benzo [ de ] isoquinoline-5-sulfonamide;

1-chloro-N- (1-methylcyclopropyl) isoquinoline-7-sulfonamide;

3-bromo-N- (1-methylcyclopropyl) -2-oxo-1H-quinoline-6-sulfonamide;

1- [ (3-ethylimidazo-4-yl) methyl ] -N- [1- (fluoromethyl) cyclopropyl ] -3- [ (1-methylpyrazol-4-yl) methyl ] -2, 4-dioxo-quinazoline-6-sulfonamide;

or a pharmaceutically acceptable salt or solvate thereof.

22. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

23. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer.

24. A pharmaceutical composition comprising a compound according to claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

25. A method of treating a proliferative disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound according to claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof.

26. The method according to claim 25, wherein the proliferative disorder is cancer.