Antiviral pyridopyrazinedione compounds

Abstract

The present application provides compounds of Formula (I) and pharmaceutically acceptable salts as described herein, pharmaceutical compositions containing the compounds, and methods of using these compounds, salts, and compositions for the treatment of viral infections, particularly infections caused by herpes viruses.

Description

Technical Field

[0001] This invention relates to novel bicyclic pyridone compounds, which are herpesvirus replication inhibitors and are therefore useful for treating herpesvirus infections. The compounds inhibit viral DNA polymerases, including cytomegalovirus (CMV), herpes simplex virus, and various other herpesviruses. This invention provides novel bicyclic pyridone compounds as disclosed herein, pharmaceutical compositions containing such compounds, and methods of treating and preventing herpesvirus diseases using these compounds and compositions. Background Technology

[0002] Human CMV, also known as human herpesvirus 5 (HHV-5), is a beta-herpesvirus that affects all populations worldwide, including adults and children with normal or compromised immune systems. While CMV is usually asymptomatic in healthy individuals, it can be life-threatening in individuals with compromised immune systems. CMV is also a concern during pregnancy because it can be transmitted from mother to fetus and cause serious birth defects. No therapies for the prevention or treatment of congenital CMV infection have been approved. In the context of transplantation, current anti-CMV therapies include nucleoside analogs valganciclovir (valGCV), ganciclovir (GCV), and cidofovir (CDV), as well as the pyrophosphate analog phosphonoformate (FOS). These therapeutic agents all inhibit CMV DNA polymerase (a protein encoded by the UL54 gene), an enzyme essential for viral replication (PNAS 2003, 100(24), 14223-14228; WO 2013 / 152063; WO 2005 / 012545). In solid organ transplant recipients, first-line therapy consists of prophylactic or pre-treatment with GCV or the oral bioavailable prodrug valGCV. GCV significantly reduces disease risk and is effective in treating active CMV infection. However, this drug is poorly tolerated. GCV and valGCV can cause severe myelosuppression, which puts patients at risk of transplant failure in stem cell transplant recipients. Second-line therapies such as CDV and FOS are associated with severe nephrotoxicity. Furthermore, resistance to current anti-CMV nucleoside analogues is a significant cause of treatment failure. Therefore, a new class of CMV therapeutics, particularly non-nucleoside compounds, is needed to provide safer CMV therapies and combat herpesviruses resistant to known classes of antiviral drugs.

[0003] Besides CMV, other herpesviruses that cause widespread human infections include Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and herpes simplex viruses HSV-1 and HSV-2. Other herpesviruses that cause disease in humans include human herpesvirus 6, human herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus.

[0004] Herpesvirus infection is not only widespread, but its incubation period in the host remains lifelong. According to one assessment, over 90% of adults are latently infected with at least one herpesvirus, which can reactivate years later. For example, when varicella-zoster virus (VZV) reactivates from its latent period, it causes shingles, often many years after the original infection (chickenpox) has been controlled. Shingles is a painful condition that primarily affects the elderly and those with weakened immune systems. Complications include postherpetic neuralgia, underlying weakness, and chronic pain syndromes, to which anti-VZV inhibitors (nucleoside analogs) have only marginal effects.

[0005] Immunocompromised individuals (such as transplant recipients) are at high risk of herpesvirus reactivation (e.g., CMV, HSV, or VZV). Therefore, safe and effective viral inhibitors active against a wide range of herpesviruses are highly valuable. This invention provides novel compounds active against a variety of herpesviruses, including CMV, HSV, VZV, and EBV. Summary of the Invention

[0006] This invention provides novel non-nucleoside compounds that inhibit herpesvirus DNA polymerase, exhibiting potent antiviral activity in vitro. The compounds are active against a variety of herpesviruses, including CMV, HSV, VZV, and EBV. These potent non-nucleoside polymerase inhibitors offer significant advantages over current anti-CMV agents. First, unlike nucleoside analogs, these compounds do not incorporate human polymerase, and therefore promise better safety profiles than current anti-CMV drugs. Second, the compounds described herein are active against GCV-resistant viruses, thus offering potential for salvage therapy in patients with cross-resistance to nucleoside analogs. Finally, the compounds are active against a variety of human herpesviruses, providing opportunities for broad-spectrum clinical application. This invention also provides pharmaceutical compositions comprising this novel compound and methods for using the compound and compositions to inhibit herpesvirus recurrence or reactivation and to treat herpesvirus-related or herpesvirus-induced disease conditions. Further objectives of the invention are described in the following description and examples.

[0007] In one aspect, the present invention provides a compound of formula (I):

[0008]

[0009] Or its pharmaceutically acceptable salt, wherein:

[0010] Cy is phenyl, pyridyl, pyrimidinyl, or a 5-8 membered cycloalkyl group, and Cy is optionally substituted by up to 3 groups selected from the following: halogen, CN, hydroxyl, -N(R')2, C 3-6 cycloalkyl, C 1-3 Alkoxy, C1-3 Haloalkyl groups and C groups substituted with Z up to 3 times (0-3 times) 1-3 Alkyl groups, wherein the C-molecules are substituted with Z up to 3 times. 1-3 When two alkyl groups are directly attached to the same carbon atom, they can form a 3-5 membered alkyl ring with the attached carbon atom, which is substituted by Z up to 3 times; R 1 Selected from H and C 1-3 alkyl;

[0011] R 2 Selected from H and C 1-3 alkyl;

[0012] Or R 1 and R 2 Together with the carbon atoms to which it is attached, it can form a 3-6 membered cycloalkyl ring;

[0013] R 3 This indicates at most two (0-2) optional substituents on the ring directly connected to –LW, each independently selected from halogens, CN, C. 1-3 Alkoxy, C 1-3 Alkyl groups, COOR' and C(O)NR'R';

[0014] R 4 Is it H, halogen, or C? 1-3 alkyl;

[0015] R 5 Selected from H, halogens, CN, C 1-3 Alkoxy, -NR'R', and Z 5 Replace C up to 3 times 1-3 Alkyl, Z 5 Replace C up to 3 times 2-4 alkenyl, Z-bonded 5 Replace C up to 3 times 2-4 The alkynyl group and a ring selected from the following: 3-6 membered alkyl rings, 4-6 membered heterocycles containing one or two heteroatoms selected from N, O, and S as ring members, and 5-6 membered heteroaryl rings containing up to four heteroatoms selected from N, O, and S as ring members, wherein the 3-6 membered alkyl ring, 4-6 membered heterocycle, or 5-6 membered heteroaryl ring is optionally separated by 1-2 Z-axis groups. 5 replace;

[0016] L is a C1-C4 straight-chain or branched alkylene linker, or when W is an optionally substituted ring, L can be a C1-C4 straight-chain or branched alkylene linker or bond;

[0017] W is H, -OH, –OR, -C(O)NR'R', -COOR', -NR'R', -NR'COOR, -NR'C(O)R, -SO2R, -SO2NR'R', -NR'SO2R, -P(O)(OR')2, or a ring optionally substituted with the following: 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocyclic group containing one or two N, O, or S heteroatoms as ring members, and 5 membered heteroaryl group containing up to 4 heteroatoms selected from N, O, and S as ring members and optionally fused with a phenyl group.

[0018] The optional substituents for the optionally substituted ring are 1-3 groups selected from the following: C 1-3 Alkyl, oxo, halogen, C 1-3 Halogenated alkyl, –L 2 -OH, –L 2 -OR、–L 2 -OC(O)-NR'R'、–L 2 -SO2R、–L 2 -SO2NR'R'、–L 2 -SO2NR'-C(O)R、–L 2 -C(O)-NR'-SO2R、–L 2 -SOR、–L 2 -S(=O)(=NR')R、–L 2 -NR'SO2NR'R'、–L 2 -NR'SO2R、–L 2 -NR'R'、–L 2 -NR'C(O)R'、–L 2 -NR'COOR、–L 2 -C(O)NR'R' and –L 2 -COOR';

[0019] R is selected from C each time it appears. 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing up to 4 heteroatoms selected from N, O, and S as ring members, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members.

[0020] Each R is optionally substituted by one or two groups selected from the following: C 1-4 Alkyl, C 1-2 Halogenated alkyl, oxo, –L 3 -CN、–L 3 -Halogen, –L 3 -C 1-3 Alkoxy, –L 3 -OH, –L 3-OC(O)-NR'R'、–L 3 -SO2R'、–L 3 -SO2NR'R'、–L 3 -SO2NR'-C(O)R'、–L 3 -C(O)-NR'-SO2R'、–L 3 -SOR'、–L 3 -S(=O)(=NR')R'、–L 3 -NR'SO2NR'R'、–L 3 -NR'SO2R'、–L 3 -NR'R'、–L 3 -NR'C(O)R'、–L 3 -NR'COOR'、–L 3 -C(O)NR'R' and –L 3 -COOR'、-L 3 - (5-6 membered heterocyclic groups containing one or two N, O, or S heteroatoms as ring members), –L 3 -C 3-5 cycloalkyl and –L 3 - (a 5-6 membered heteroaryl ring having up to 4 heteroatoms as ring members, wherein the heteroatoms comprise 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms), wherein the C 1-4 Alkyl, 5-6 membered heterocyclic group, C 3-5 The cycloalkyl and 5-6-membered heteroaryl rings are each optionally substituted by up to three independent groups selected from the following: halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -L 4 -OR'、-L 4 -CN and –L 4 -N(R')2;

[0021] R' is independently selected from H, optionally by a halogen, -OH, amino, or C each time it appears. 1-2 alkoxy-substituted C 1-4 Alkyl groups and optionally halogenated, -OH, amino, or C 1-2 alkoxy-substituted C 3-6 cycloalkyl;

[0022] Alternatively, the two R' atoms together with the nitrogen atom directly attached to them can form a 4-6 membered ring, which optionally contains an additional N, O, or S as a ring member and is optionally substituted by 1 to 3 groups selected from: C 1-2 Alkyl, C 1-2 Alkyl, oxo, and hydroxyl groups;

[0023] Each L2 and L 3 and L 4 Independently, it is a bond or a straight chain or a branch C. 1-3 Alkylene;

[0024] Z and Z 5 Each time it appears, it is independently selected from halogen, hydroxyl, CN, C. 1-3 Alkoxy, C 1-3 Alkyl and C 3-5 cycloalkyl,

[0025] And two Z groups, or two Z 5 The group, together with the carbon atom directly attached to it, can form a 3-5 membered alkyl ring or contain O, N or S as ring members and optionally be selected from at most two oxo and C groups. 1-3 4-6 membered heterocycles substituted with alkyl groups. Attached Figure Description

[0026] Figure 1 XRPD spectra show the two polymorphs (NX-7 and NX-12) of the compound from Example 1 and their properties when they are prepared together as a slurry in ethanol. Detailed Implementation

[0027] For the purposes of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular form will also include the plural form.

[0028] Unless the context clearly indicates otherwise, the terms used in this specification have the following meanings:

[0029] As used herein, the term "subject" refers to an animal. In some respects, the animal is a mammal. A subject also refers to, for example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the subject is a human. As used herein, "patient" refers to a human subject.

[0030] As used herein, the term “inhibition” refers to the reduction or suppression of a given condition, symptom or disorder, or disease, or a significant reduction in baseline activity of a biological activity or process.

[0031] As used herein, in one embodiment, the term "treatment" for any disease or disorder means alleviating the disease or disorder (i.e., slowing or halting or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treatment" means relieving or reducing at least one bodily parameter, including those that cannot be identified by the patient. In yet another embodiment, "treatment" means regulating the disease or disorder physically (e.g., stabilization of identifiable symptoms) or physiologically (e.g., stabilization of bodily parameters) or both. In yet another embodiment, "treatment" means preventing or delaying the onset, development, or progression of a disease or disorder.

[0032] As used herein, the terms “a / an”, “the”, and similar terms used in the context of this invention (particularly in the context of the claims) should be interpreted to cover both the singular and the plural, unless otherwise indicated or clearly contradicted by the context.

[0033] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by the context. The use of any and all instances or exemplary language (e.g., “as”) provided herein is intended only to better illustrate the invention and not to limit the scope of the otherwise claimed invention.

[0034] "Optional substitution" means that the group involved may be substituted at one or more positions by any one or any combination of the groups listed below. The number, position, and selection of substituents should be understood to cover only those substitutions that a skilled chemist would reasonably expect to be stable; therefore, "oxo" will not be a substituent on an aryl or heteroaryl ring, for example, and a single carbon atom will not have three hydroxyl or amino substituents. Unless otherwise stated, optional substituents are generally up to four groups selected from the following: halogen, oxo, CN, amino, hydroxyl, -C 1-3 Alkyl, -OR*, -NR*2, -SR*, -SO2R*, -COOR*, and -CONR*2, wherein each R* is independently H or C. 1-3 alkyl.

[0035] Unless otherwise stated, as used herein, "aryl" refers to a phenyl or naphthyl group. Unless otherwise stated, an aryl group may optionally be substituted by up to four groups selected from the following: halogen, CN, amino, hydroxyl, C. 1-3 Alkyl, -OR*, -NR*2, -SR*, -SO2R*, -COOR*, and -CONR*2, wherein each R* is independently H or C. 1-3 alkyl.

[0036] As used in this article, "halogenated" or "halogen" can refer to fluorine, chlorine, bromine, or iodine.

[0037] As used in this article, "C" 1-6 "Alkyl" or "C1-C6 alkyl" indicates a straight-chain or branched alkyl group having 1-6 carbon atoms. If a different number of carbon atoms is specified, such as C4 or C3, the definition is modified accordingly, for example, "C..." 1-4 "alkyl" will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0038] As used in this article, "C" 1-6 "Alkylene" or "C1-C6 alkylene" refers to a straight-chain or branched alkyl group having 1-6 carbon atoms and two open valences for attaching two other groups. If a different number of carbon atoms is specified, such as C4 or C3, the definition is modified accordingly, for example, "C..." 1-4 "alkylene" will represent methylene (-CH2-), ethylene (-CH2CH2-), straight-chain or branched propylene (-CH2CH2CH2- or -CH2-CHMe-CH2-), etc.

[0039] As used in this article, "C" 1-6 "Alkoxy" refers to a straight-chain or branched alkoxy group (-O-alkyl) having 1-6 carbon atoms. If a different number of carbon atoms is specified, such as C4 or C3, the definition is modified accordingly, for example, "C..." 1-4 "Alkoxy" will represent methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0040] As used in this article, "C" 1-4 "Haloalkyl" or "C1-C4 haloalkyl" refers to a straight-chain or branched alkyl group having 1-4 carbon atoms (where at least one hydrogen atom has been replaced by a halogen). The number of halogen substituents can range from one to the number of hydrogen atoms on the unsubstituted alkyl group. If a different number of carbon atoms is specified, such as C6 or C3, the definition is modified accordingly. Therefore, "C 1-4 "Halogenated alkyl" will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl, wherein at least one hydrogen atom is substituted by a halogen (e.g., where the halogen is fluorine): CF3CF2-, (CF3)2CH-, CH3-CF2-, CF3CF2-, CF3, CF2H-, CF3CF2CH(CF3)-, or CF3CF2CF2CF2-.

[0041] As used in this article, "C" 3-8 "Cycloalkyl" refers to a saturated monocyclic hydrocarbon ring with 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. If a different number of carbon atoms is specified, such as C3-C6, the definition is modified accordingly.

[0042] "4- to 8-membered heterocyclic groups," "5- to 6-membered heterocyclic groups," "3- to 10-membered heterocyclic groups," "3- to 14-membered heterocyclic groups," "4- to 14-membered heterocyclic groups," and "5- to 14-membered heterocyclic groups" refer to 4- to 8-membered heterocycles, 5- to 6-membered heterocycles, 3- to 10-membered heterocycles, 3- to 14-membered heterocycles, 4- to 14-membered heterocycles, and 5- to 14-membered heterocycles, respectively. Unless otherwise specified, such rings contain 1 to 7, 1 to 5, or 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur as ring members, and the rings may be saturated or partially saturated, but are not aromatic. Heterocyclic groups may be attached to another group on a nitrogen or carbon atom. The term "heterocyclic group" includes monocyclic groups, fused-ring groups, and bridging groups. Examples of such heterocyclic groups include, but are not limited to, pyrrolidine, piperidine, piperazine, pyrrolidone, morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiaran, tetrahydropyran, 1,4-dioxane, 1,4-oxothiacyclohexane, 8-aza-bicyclo[3.2.1]octane, 3,8-diaza-bicyclo[3.2.1]octane, 3-oxa-8-aza-bicyclo[3.2.1]octane, 8-oxa-3-aza-bicyclo[3.2.1]octane, 2-oxa-5-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]heptane, acridine, ethylenedioxy, oxacyclobutane, or thiazole. In some embodiments, unless otherwise stated, the heterocyclic group has 1-2 heteroatoms selected from N, O, and S as ring members and 4-7 ring atoms, and is optionally substituted by up to four groups selected from: halogenated, oxo-substituted, CN-substituted, amino-substituted, hydroxyl-substituted, C-substituted. 1-3 Alkyl, -OR*, -NR*2, -SR*, -SO2R*, -COOR*, and -CONR*2, wherein each R* is independently H or C. 1-3 Alkyl groups. In particular, the heterocyclic group containing a sulfur atom is optionally substituted with one or two oxo groups on the sulfur atom.

[0043] "Heteroaryl" is a fully unsaturated (aromatic) ring. The term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic, or tricyclic aromatic ring system having 1 to 8 heteroatoms selected from N, O, or S. Typically, heteroaryl rings are 5-10 membered rings or ring systems (e.g., 5-7 membered monocyclic groups or 8-10 membered bicyclic groups), and the 5-6 membered ring usually contains up to four heteroatoms selected from N, O, and S, although heteroaryl rings typically contain no more than one divalent O or S in the ring. Typical heteroaryl groups include furan; isothiazole; thiadiazole; oxadiazole; indazole; indole; quinoline; 2- or 3-thienyl; 2- or 3-furanyl; 2- or 3-pyrroleyl; 2-, 4-, or 5-imidazolyl; 3-, 4-, or 5-pyrazolyl; 2-, 4-, or 5-thiazolyl; 3-, 4-, or 5-isothiazolyl; 2-, 4-, or 5-oxazolyl; 3-, 4-, or 5-isooxazolyl; 3- or 5-(1,2,4-triazolyl); 4- or 5-(1,2,3-triazolyl); tetrazolyl; triazine; pyrimidine; 2-, 3-, or 4-pyridinyl; 3- or 4-pyridazinyl; 3-, 4-, or 5-pyrazinyl; 2-pyrazinyl; and 2-, 4-, or 5-pyrimidinyl. The heteroaryl group is optionally substituted by up to four groups selected from the following: halogenated, CN, amino, hydroxyl, C 1-3 Alkyl, -OR*, -NR*2, -SR*, -SO2R*, -COOR*, and -CONR*2, wherein each R* is independently H or C. 1-3 alkyl.

[0044] The term "hydroxyl group" refers to the -OH group.

[0045] This document describes various embodiments of the invention. It should be understood that the features specified in each embodiment can be combined with other specified features to provide further embodiments. The following examples are representative of the invention:

[0046] 1. A compound of formula (I)

[0047]

[0048] Or its pharmaceutically acceptable salt, wherein:

[0049] Cy is phenyl, pyridyl, pyrimidinyl, or a 5-8 membered cycloalkyl group, and Cy is optionally substituted by up to 3 groups selected from the following: halogen, CN, hydroxyl, -N(R')2, C 3-6 cycloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl groups and C groups substituted with Z up to 3 times (0-3 times) 1-3 Alkyl groups, wherein the C-molecules are substituted with Z up to 3 times. 1-3When two alkyl groups are directly attached to the same carbon atom, they can form a 3-5 membered cycloalkyl group with the carbon atom to which they are attached, which is substituted by Z up to 3 times.

[0050] R 1 Selected from H and C 1-3 alkyl;

[0051] R 2 Selected from H and C 1-3 alkyl;

[0052] Or R 1 and R 2 Together with the carbon atoms to which it is attached, it can form a 3-6 membered cycloalkyl ring;

[0053] R 3 This indicates that the ring directly connected to –LW has at most two (0-2) optional substituents, each independently selected from halogens, CN, C. 1-3 Alkoxy, C 1-3 Alkyl groups, COOR' and C(O)NR'R';

[0054] R 4 Is it H, halogen, or C? 1-3 alkyl;

[0055] R 5 Selected from H, halogens, CN, C 1-3 Alkoxy, -NR'R', and Z 5 Replace C up to 3 times 1-3 Alkyl, Z 5 Replace C up to 3 times 2-4 alkenyl, Z-bonded 5 Replace C up to 3 times 2-4 The alkynyl group and a ring selected from the following: 3-6 membered alkyl rings, 4-6 membered heterocycles containing one or two heteroatoms selected from N, O, and S as ring members, and 5-6 membered heteroaryl rings containing up to four heteroatoms selected from N, O, and S as ring members, wherein the 3-6 membered alkyl ring, 4-6 membered heterocycle, or 5-6 membered heteroaryl ring is optionally separated by 1-2 Z-axis groups. 5 replace;

[0056] L is a C1-C4 straight-chain or branched alkylene linker, or when W is an optionally substituted ring, L can be a C1-C4 straight-chain or branched alkylene linker or bond;

[0057] W is H, -OH, –OR, -C(O)NR'R', -COOR', -NR'R', -NR'COOR, -NR'C(O)R, -SO2R, -SO2NR'R', -NR'SO2R, -P(O)(OR')2, or a ring optionally substituted with the following: 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocyclic group containing one or two N, O, or S heteroatoms as ring members, and 5 membered heteroaryl group containing up to 4 heteroatoms selected from N, O, and S as ring members and optionally fused with a phenyl group.

[0058] The optional substituents for the optionally substituted ring are 1-3 groups selected from the following: C 1-3 Alkyl, oxo, halogen, C 1-3 Halogenated alkyl, –L 2 -OH, –L 2 -OR、–L 2 -OC(O)-NR'R'、–L 2 -SO2R、–L 2 -SO2NR'R'、–L 2 -SO2NR'-C(O)R、–L 2 -C(O)-NR'-SO2R、–L 2 -SOR、–L 2 -S(=O)(=NR')R、–L 2 -NR'SO2NR'R'、–L 2 -NR'SO2R、–L 2 -NR'R'、–L 2 -NR'C(O)R'、–L 2 -NR'COOR、–L 2 -C(O)NR'R' and –L 2 -COOR';

[0059] R is selected from C each time it appears. 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing up to 4 heteroatoms selected from N, O, and S as ring members, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members.

[0060] Each R is optionally substituted by one or two groups selected from the following: C 1-4 Alkyl, C 1-2 Halogenated alkyl, oxo, –L 3 -CN、–L 3 -Halogen, –L 3 -C 1-3 Alkoxy, –L 3 -OH, –L 3-OC(O)-NR'R'、–L 3 -SO2R'、–L 3 -SO2NR'R'、–L 3 -SO2NR'-C(O)R'、–L 3 -C(O)-NR'-SO2R'、–L 3 -SOR'、–L 3 -S(=O)(=NR')R'、–L 3 -NR'SO2NR'R'、–L 3 -NR'SO2R'、–L 3 -NR'R'、–L 3 -NR'C(O)R'、–L 3 -NR'COOR'、–L 3 -C(O)NR'R' and –L 3 -COOR'、-L 3 - (5-6 membered heterocyclic groups containing one or two N, O, or S heteroatoms as ring members), –L 3 -C 3-5 cycloalkyl and –L 3 - (a 5-6 membered heteroaryl ring having up to 4 heteroatoms as ring members, wherein the heteroatoms comprise 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms), wherein the C 1-4 Alkyl, 5-6 membered heterocyclic group, C 3-5 The cycloalkyl and 5-6-membered heteroaryl rings are each optionally substituted by up to three independent groups selected from the following: halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -L 4 -OR'、-L 4 -CN and –L 4 -N(R')2;

[0061] R' is independently selected from H, optionally by a halogen, -OH, amino, or C each time it appears. 1-2 alkoxy-substituted C 1-4 Alkyl groups and optionally halogenated, -OH, amino, or C 1-2 alkoxy-substituted C 3-6 cycloalkyl;

[0062] Alternatively, the two R' atoms together with the nitrogen atom directly attached to them can form a 4-6 membered ring, which optionally contains an additional N, O, or S as a ring member and optionally is substituted by 1 to 3 groups selected from: C 1-2 Alkyl, C 1-2 Alkyl, oxo, and hydroxyl groups;

[0063] Each L2 and L 3 and L 4 Independently, it is a bond or a straight chain or a branch C. 1-3 Alkylene;

[0064] Z and Z 5 Each time it appears, it is independently selected from halogen, hydroxyl, CN, C. 1-3 Alkoxy, C 1-3 Alkyl and C 3-5 cycloalkyl,

[0065] And two Z groups, or two Z 5 The group, together with the carbon atom directly attached to it, can form a 3-5 membered alkyl ring or contain O, N or S as ring members and optionally be selected from at most two oxo and C groups. 1-3 4-6 membered heterocycles substituted with alkyl groups.

[0066] 2. The compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1 It's H.

[0067] 3. The compound according to Embodiment 1 or Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein R 2 It is H. In an alternative implementation, R 2 It is a methyl group.

[0068] 4. A compound according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from phenyl, pyridin-3-yl, and cyclohexyl, each optionally substituted by one to three groups selected from halogen, CF3, and CN. In some of these embodiments, Cy is a phenyl having one or two substituents selected from Cl, F, Br, and CN. In some of these embodiments, the substituents on the benzene ring Cy are located at the meta and / or para positions on the benzene ring.

[0069] 5. The compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt thereof, wherein R 4 It's H.

[0070] 6. The compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt thereof, wherein R 5 It is H, halogen, methyl, or halomethyl. In some of these embodiments, R 5 It's H.

[0071] 7. The compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt thereof, wherein R 3 Does not exist, or R 3 It represents one or two methyl groups. In some of these embodiments, R3 It does not exist, that is, it represents 0 substituents.

[0072] 8. The compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt thereof, wherein L is –CH2- or –(CH2)2-. In some of these embodiments, L is –CH2-.

[0073] 9. The compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt thereof, wherein W is a cyclopropyl group substituted with a group selected from: C 1-3 Alkyl, oxo, halogen, C 1-3 Alkoxy, OH, -SO2R, -SO2NR'R', -SOR, -S(=O)(=NR')R, -NR'SO2NR'R', -NR'SO2R, -NR'R', -OR, -NR'COOR, -C(O)NR'R' and COOR'.

[0074] 10. The compound according to any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein the W-L portion is selected from:

[0075]

[0076] In some of these embodiments, L is CH2. In these embodiments, R is sometimes selected from methyl, ethyl, isopropyl, and cyclopropyl in each occurrence. In these embodiments, R' is sometimes selected from H and methyl in each occurrence.

[0077] 11. The compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt thereof, wherein Cy is phenyl, and optionally substituted with one or two groups selected from: halogen, CN, OH, C 1-3 Alkyl and C 1-3 Alkyl group.

[0078] 12. The compound according to embodiment 11, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from:

[0079]

[0080] 13. The compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is of formula (II):

[0081]

[0082] in:

[0083] R 1 It is H or methyl;

[0084] Z3 and Z 4 Independently selected from H, halogens, CN, Me, and OMe;

[0085] L is a C1-C4 straight-chain or branched alkylene linker;

[0086] W is -SO2R, -SO2NR'R', -NR'SO2R, or optionally substituted C1-C3 alkyl, or optionally substituted 3-6 membered cycloalkyl;

[0087] The optional substituents for the optionally substituted C1-C3 alkyl and optionally substituted cycloalkyl groups are 1-3 groups independently selected from the following: C 1-3 Alkyl, oxo, halogen, C 1-3 Alkyl groups, OH groups, -SO2R groups, -SO2NR'R' groups, -NR'SO2NR'R' groups, -NR'SO2R groups, -NR'R' groups, -OR groups, -NR'COOR groups, -C(O)NR'R' groups, and COOR' groups.

[0088] R is independently selected from C each time it appears. 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing up to 4 heteroatoms selected from N, O, and S as ring members, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members.

[0089] Each R is optionally substituted by one or two groups selected from the following: C 1-3 Alkyl, oxo, CN, halogen, C 1-3 Alkoxy, OH and C 3-5 cycloalkyl;

[0090] R' is selected from H and optionally replaced by a halogen, -OH, or C in each occurrence. 1-2 alkoxy-substituted C 1-4 alkyl;

[0091] Alternatively, the two R' atoms together with the nitrogen atom directly attached to them can form a 4-6 membered ring, which optionally contains an additional N, O, or S as a ring member and is optionally substituted by one or two groups selected from: C 1-2 Alkyl, C 1-2 Alkyl, oxo, and hydroxyl groups;

[0092] Or its pharmaceutically acceptable salt.

[0093] 14. The compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is of formula (III):

[0094]

[0095] Where R 11 and R 12 Each is independently H or C1-C3 alkyl, or R 11 and R 12 Together with the carbon atoms it is attached to, they form C 3-5 cycloalkyl rings;

[0096] R 10 Selected from C1-C3 alkyl, C3-C5 cycloalkyl and –NR 13 R 14 , where R 13 and R 14 Independently selected from H and C 1-3 Alkyl, or R 13 and R 14 Together with the N group attached thereto, it forms a ring selected from the following: acridine, pyrrolidine, piperidine, piperazine, and morpholine, wherein the acridine, pyrrolidine, piperidine, piperazine, and morpholine are optionally substituted by 1 to 3 independently selected groups from the following: oxo, C 1-3 Alkyl, C 1-3 Alkoxy, CN, and halogens;

[0097] L represents a bond, CH2, or CH2CH2;

[0098] R 1 It is H or Me; and

[0099] Z 3 and Z 4 Selected from H, CN and halogens.

[0100] 15. The compound according to embodiment 14, wherein Z 3 and Z 4 They are not both H.

[0101] 16. The compound according to embodiment 14, wherein R 1 It is H.

[0102] 17. The compound according to embodiment 14, wherein R 10 It is cyclopropyl.

[0103] 18. The compound according to any one of Examples 1-212, or a pharmaceutically acceptable salt thereof. This embodiment includes each example represented in the bioactivity data sheet herein.

[0104] 19. A pharmaceutical composition comprising a compound described in any of the preceding embodiments, which is mixed with at least one pharmaceutically acceptable carrier.

[0105] 20. A method of treating herpes virus infection, comprising administering to a patient with herpes virus infection any of the compounds described in any one of embodiments 1-17, or a pharmaceutical composition comprising any one of the compounds described in any one of embodiments 1-17.

[0106] 21. The method according to embodiment 20, wherein the herpesvirus is selected from cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex virus including HSV-1 and HSV-2, herpesvirus 6, human herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus.

[0107] 22. A compound of formula (IV):

[0108]

[0109] or its salt; wherein:

[0110] R 11 It is a C1-C6 alkyl group that is optionally substituted with Z up to 3 times;

[0111] R 3 This indicates that there are at most two (0-2) optional substituents on the ring directly connected to –LW, each independently selected from halogens, CN, C. 1-3 Alkoxy, C 1-3 Alkyl groups, COOR' and C(O)NR'R';

[0112] R 4 Is it H, halogen, or C? 1-3 alkyl;

[0113] R 5 Selected from H, halogens, CN, C 1-3 Alkoxy, -NR'R', and Z 5 Replace C up to 3 times 1-3 Alkyl, Z 5 Replace C up to 3 times 2-4 alkenyl, Z-bonded 5 Replace C up to 3 times 2-4 The alkynyl group and the ring selected from the following: 3-6 membered alkyl rings, 4-6 membered heterocycles containing one or two heteroatoms selected from N, O, and S as ring members, and 5-6 membered heteroaryl rings containing up to four heteroatoms selected from N, O, and S as ring members, wherein the 3-6 membered alkyl ring, 4-6 membered heterocyclic ring, or 5-6 membered heteroaryl ring is optionally surrounded by 1-2 Z-axis groups. 5 replace;

[0114] L is a C1-C4 straight-chain or branched alkylene linker or bond;

[0115] W is H, -OH, –OR, -C(O)NR'R', -COOR', -NR'R', -NR'COOR, -NR'C(O)R, -SO2R, -SO2NR'R', -NR'SO2R, -P(O)(OR')2, or a ring optionally substituted with the following: 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocyclic group containing one or two N, O, or S heteroatoms as ring members, and 5 membered heteroaryl group containing up to 4 heteroatoms selected from N, O, and S as ring members and optionally fused with a phenyl group, wherein the optional substituents for the optionally substituted ring are 1-3 groups independently selected from: C 1-3 Alkyl, oxo, halogen, C 1-3 Halogenated alkyl, –L 2 -OH, –L 2 -OR、–L 2 -OC(O)-NR'R'、–L 2 -SO2R、–L 2 -SO2NR'R'、–L 2 -SO2NR'-C(O)R、–L 2 -C(O)-NR'-SO2R、–L 2 -SOR、–L 2 -S(=O)(=NR')R、–L 2 -NR'SO2NR'R'、–L 2 -NR'SO2R、–L 2 -NR'R'、–L 2 -NR'C(O)R'、–L 2 -NR'COOR、–L 2 -C(O)NR'R' and –L 2 -COOR';

[0116] R is independently selected from C each time it appears. 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing up to 4 heteroatoms selected from N, O, and S as ring members, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members.

[0117] Each R is optionally substituted by one or two independent groups selected from the following: C 1-4 Alkyl, C 1-2 Halogenated alkyl, oxo, –L 3 -CN、–L 3 -Halogen, –L 3 -C 1-3 Alkoxy, –L 3 -OH, –L 3 -OC(O)-NR'R'、–L3 -SO2R'、–L 3 -SO2NR'R'、–L 3 -SO2NR'-C(O)R'、–L 3 -C(O)-NR'-SO2R'、–L 3 -SOR'、–L 3 -S(=O)(=NR')R'、–L 3 -NR'SO2NR'R'、–L 3 -NR'SO2R'、–L 3 -NR'R'、–L 3 -NR'C(O)R'、–L 3 -NR'COOR'、–L 3 -C(O)NR'R' and –L 3 -COOR'、-L 3 - (5-6 membered heterocyclic groups containing one or two N, O, or S heteroatoms as ring members), –L 3 -C3-5 cycloalkyl and –L 3 - (a 5-6 membered heteroaryl ring having up to 4 heteroatoms as ring members, wherein the heteroatoms comprise 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms), wherein the C 1-4 Alkyl, 5-6-membered heterocyclic, C 3-5 The cycloalkyl and 5-6-membered heteroaryl rings are each optionally substituted by up to three independent groups selected from the following: halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -L 4 -OR'、-L 4 -CN and –L 4 -N(R')2;

[0118] R' is independently selected from H, optionally by a halogen, -OH, amino, or C each time it appears. 1-2 alkoxy-substituted C 1-4 Alkyl groups and optionally halogenated, -OH, amino, or C 1-2 alkoxy-substituted C 3-6 cycloalkyl;

[0119] Alternatively, the two R' atoms together with the nitrogen atom directly attached to them can form a 4-6 membered ring, which optionally contains an additional N, O, or S as a ring member and is optionally substituted by 1 to 3 groups selected from: C 1-2 Alkyl, C 1-2 Alkyl, oxo, and hydroxyl groups;

[0120] Each L 2 and L 3 and L4 Independently, it is a bond, a straight chain, or a branch C. 1-3 Alkylene;

[0121] Z and Z 5 Each time it appears, it is independently selected from halogen, hydroxyl, CN, C. 1-3 Alkoxy, C 1-3 Alkyl and C 3-5 cycloalkyl,

[0122] and two Z groups or two Z 5 The group, together with the carbon atom directly attached to it, can form a 3-5 membered alkyl ring or a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring contains O, N or S as ring members and is optionally selected from at most two groups chosen from oxo and C. 1-3 Alkyl groups are substituted.

[0123] 23. The compound according to embodiment 22, wherein R 11 It is H or C1-C6 alkyl.

[0124] 24. The compound according to embodiment 22 or embodiment 23, wherein R 3 It does not exist.

[0125] 25. The compound according to any one of embodiments 22-24, wherein R 4 and R 5 They represent H respectively.

[0126] 26. The compound according to embodiment 22, wherein:

[0127] L is a C1-C4 straight-chain or branched alkylene linker;

[0128] W is -SO2R, -SO2NR'R', -NR'SO2R, or optionally substituted C1-C3 alkyl, or optionally substituted 3-6 membered cycloalkyl;

[0129] The optional substituents for the optionally substituted C1-C3 alkyl and the optionally substituted cycloalkyl are 1-3 groups independently selected from the following: C 1-3 Alkyl, oxo, halogen, C 1-3 Alkyl groups, OH groups, -SO2R groups, -SO2NR'R' groups, -NR'SO2NR'R' groups, -NR'SO2R groups, -NR'R' groups, -OR groups, -NR'COOR groups, -C(O)NR'R' groups, and COOR' groups.

[0130] R is independently selected from C each time it appears. 1-4Alkyl groups, 3-6 membered cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing up to 4 heteroatoms selected from N, O, and S as ring members, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members.

[0131] Each R is optionally substituted by one or two groups selected from the following: C 1-3 Alkyl, oxo, CN, halogen, C 1-3 Alkoxy, OH and C 3-5 cycloalkyl;

[0132] R' is independently selected from H and optionally converted to halogen, -OH or C each time it appears. 1-2 alkoxy-substituted C 1-4 alkyl;

[0133] Alternatively, the two R' atoms together with the nitrogen atom directly attached to them can form a 4-6 membered ring, which optionally contains an additional N, O, or S as a ring member and is optionally substituted by one or two groups selected from: C 1-2 Alkyl, C 1-2 Alkyl, oxo, and hydroxyl groups.

[0134] 27. The compound according to any one of embodiments 22-26, wherein

[0135] The W-L group is selected from the following:

[0136]

[0137] 28. The compound according to any one of embodiments 22-27, wherein L is CH2.

[0138] 29. The compound according to any one of embodiments 22-28, wherein R is independently selected from methyl, ethyl, isopropyl and cyclopropyl each time it appears.

[0139] 30. The compound according to any one of embodiments 22-29, wherein R' is independently selected from H and methyl each time it appears.

[0140] 31. A method for preparing the compound according to Embodiment 1, comprising:

[0141] Compound of formula (V)

[0142] in

[0143] X represents –OH or a leaving group;

[0144] R 3This indicates at most two (0-2) optional substituents on a ring containing two nitrogen atoms, where each R 3 Independently selected from halogens, CN, C 1-3 Alkoxy, C 1-3 Alkyl groups, COOR', C(O)NH2, and C(O)NRR';

[0145] R 4 Is it H, halogen, or C? 1-3 alkyl;

[0146] R 5 Selected from H, halogens, CN, C 1-3 Alkoxy, -NH2, -NRR', and Z 5 Replace C up to 3 times 1-3 Alkyl, Z 5 Replace C up to 3 times 2-4 alkenyl, Z-bonded 5 Replace C up to 3 times 2-4 The alkynyl group and a ring selected from the following: a 3-6 membered cycloalkyl ring, a 4-6 membered heterocyclic ring containing one or two heteroatoms selected from N, O, and S as ring members, and a 5-6 membered heteroaryl ring containing up to four heteroatoms selected from N, O, and S as ring members, wherein the 3-6 membered cycloalkyl ring, 4-6 membered heterocyclic ring, or 5-6 membered heteroaryl ring is optionally separated by 1-2 Z-axis groups. 5 replace;

[0147] L is a C1-C4 straight-chain or branched alkylene linker;

[0148] W is –OR', -NH2, -NRR', -NR'COOR, -NR'C(O)R', -SO2R, -SO2NH2, -SO2NRR', -NR'SO2R, or an optionally substituted C1-C3 alkyl group, or an optionally substituted ring selected from the following: 3-6 membered cycloalkyl groups, 5-6 membered heterocyclic groups containing one or two N, O, or S heteroatoms as ring members, and 5 membered heteroaryl groups containing up to 4 heteroatoms selected from N, O, and S as ring members.

[0149] The optional substituents for the optionally substituted C1-C3 alkyl group and the optionally substituted ring are 1-3 groups independently selected from the following: C 1-3 Alkyl, oxo, halogen, C 1-3 Alkyl groups, OH groups, -SO2R groups, -SO2NR'R' groups, -SOR groups, -S(=O)(=NR')R groups, -NR'SO2NR'R' groups, -NR'SO2R groups, -NH2 groups, -NR'R' groups, -OR groups, -NR'COOR groups, -C(O)NH2 groups, -C(O)NRR' groups, and COOR' groups.

[0150] R is independently selected from C each time it appears. 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing up to 4 heteroatoms selected from N, O, and S as ring members, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members.

[0151] Each R is optionally substituted by one or two independent groups selected from the following: C 1-3 Alkyl, oxo, CN, halogen, C 1-3 Alkoxy, OH and C 3-5 cycloalkyl;

[0152] R' is independently selected from H and optionally converted to halogen, -OH or C each time it appears. 1-2 alkoxy-substituted C 1-4 alkyl;

[0153] Alternatively, R and R' together with the nitrogen atom directly attached to them can form a 4-6 membered ring, which optionally contains an additional N, O, or S as a ring member and is optionally substituted by one or two groups selected from: C 1-2 Alkyl, C 1-2 Alkyl, oxo, and hydroxyl groups;

[0154] Y is independently selected from halogens and C each time it appears. 1-2 Alkyl, C 1-2 Halogenated alkyl groups and C 1-2 Alkoxy;

[0155] Each Z 5 Each time it appears, it is independently selected from halogen, hydroxyl, CN, C. 1-3 Alkoxy, C 1-3 alkyl,

[0156] And two Zs 5 The group, together with the carbon atom directly attached to it, can form a 3-5 membered alkyl ring or a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring contains O, N, or S as ring members and is optionally selected from at most two oxo and C atoms. 1-3 Alkyl group substitution;

[0157] With compounds of formula (VI):

[0158]

[0159] Contact, wherein Cy is phenyl, pyridyl, pyrimidinyl, or a 5-8 membered cycloalkyl group, and Cy is optionally substituted by up to 3 groups selected from the following: halogen, CN, hydroxyl, -N(R')2, C 3-6 cycloalkyl, C 1-3 Alkoxy, C 1-3Haloalkyl groups and C groups substituted with Z up to 3 times (0-3 times) 1-3 Alkyl groups, wherein the C atoms are substituted with Z up to 3 times 1-3 When two alkyl groups are directly attached to the same carbon atom, they can form a 3-5 membered alkyl ring with the attached carbon atom, which is substituted by Z up to 3 times; R 1 Selected from H and C 1-3 alkyl;

[0160] R 2 Selected from H and C 1-3 alkyl;

[0161] Or R 1 and R 2 Together with the carbon atoms connected thereto, they can form 3-6 membered cycloalkyl rings;

[0162] Z is independently selected from halogen, hydroxyl, CN, and C each time it appears. 1-3 Alkoxy, C 1-3 Alkyl and C 3-5 cycloalkyl,

[0163] The two Z groups, together with the carbon atoms directly attached to them, can form 3-5 membered alkyl rings or 4-6 membered heterocycles, wherein the 4-6 membered heterocycle contains O, N, or S as ring members and is optionally composed of at most two groups selected from oxo and C. 1-3 Alkyl groups are substituted.

[0164] 32. The method according to embodiment 31, wherein the leaving group is selected from halogens and acyl groups.

[0165] 33. The method according to embodiment 31 or embodiment 32, wherein the acyl group is –OC(O)-OR*, where R* represents a C1-C6 alkyl group, and optionally is surrounded by up to 3 halogens or C... 1-3 Alkyl-substituted.

[0166] 34. The method according to any one of embodiments 31-33, wherein the compound of formula (V) is a compound of formula (VB):

[0167]

[0168] Where R 5 H is H or a halogen; L is –CH2-; and W is a cyclopropyl group substituted with –SO2R, where R is as defined in formula (V).

[0169] In some embodiments, the compound of formula (I) is of formula (II):

[0170]

[0171] in:

[0172] R 1 It is H or methyl;

[0173] Z 3 and Z 4 Independently selected from H, halogens, CN, Me, and OMe;

[0174] L is a C1-C4 straight-chain or branched alkylene linker;

[0175] W is -SO2R, -SO2NR'R', -NR'SO2R, or optionally substituted C1-C3 alkyl, or optionally substituted 3-6 membered cycloalkyl;

[0176] The optional substituents for the optionally substituted C1-C3 alkyl and the optionally substituted cycloalkyl are 1-3 groups independently selected from the following: C 1-3 Alkyl, oxo, halogen, C 1-3 Alkyl groups, OH groups, -SO2R groups, -SO2NR'R' groups, -NR'SO2NR'R' groups, -NR'SO2R groups, -NR'R' groups, -OR groups, -NR'COOR groups, -C(O)NR'R' groups, and COOR' groups.

[0177] R is independently selected from C each time it appears. 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing up to 4 heteroatoms selected from N, O, and S as ring members, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members.

[0178] Each R is optionally substituted by one or two groups selected from the following: C 1-3 Alkyl, oxo, CN, halogen, C 1-3 Alkoxy, OH and C 3-5 cycloalkyl;

[0179] R' is selected from H and optionally replaced by a halogen, -OH, or C in each occurrence. 1-2 alkoxy-substituted C 1-4 alkyl;

[0180] Alternatively, the two R' atoms together with the nitrogen atom directly attached to them can form a 4-6 membered ring, which optionally contains an additional N, O, or S as a ring member and optionally is substituted by one or two groups selected from: C 1-2 Alkyl, C 1-2 Alkyl, oxo, and hydroxyl groups;

[0181] Or its pharmaceutically acceptable salt.

[0182] Preferred compounds of formula (I) include compounds of formula (III):

[0183]

[0184] Where R 11 and R 12 Each represents H or C1-C3 alkyl, or R 11 and R 12 Together with the carbon atom it is attached to, they form C 3-5 cycloalkyl rings;

[0185] R 10 Selected from C1-C3 alkyl, C3-C5 cycloalkyl and –NR 13 R 14 , where R 13 and R 14 Independently selected from H and C 1-3 Alkyl, or R 13 and R 14 Together with the N-terminus it is attached to, it forms a ring selected from the following: acridine, pyrrolidine, piperidine, piperazine, and morpholine, wherein the ring is optionally substituted by 1 to 3 groups selected from the following: oxo, C 1-3 Alkyl, C 1-3 Alkyl groups, CN, and halogens; L is a bond or CH2 or CH2CH2; R 1 It can be H or Me; and Z 3 and Z 4 Selected from H, CN, and halogens. Preferably, Z 3 and Z 4 Not both H. Usually, R 1 It is H. In some embodiments of the compound of formula (III), R 10 It is cyclopropyl.

[0186] Another aspect of the invention provides compounds of formula (IV):

[0187]

[0188] or its salt; wherein:

[0189] R 11 It is a C1-C6 alkyl group that is optionally substituted by Z up to 3 times;

[0190] R 3 This indicates up to two (0-2) optional substituents on the ring directly connected to –LW, each independently selected from halogen, CN, C. 1-3 Alkoxy, C 1-3 Alkyl groups, COOR' and C(O)NR'R';

[0191] R 4 Is it H, halogen, or C? 1-3alkyl;

[0192] R 5 Selected from H, halogens, CN, C 1-3 Alkoxy, -NR'R', and Z 5 Replace C up to 3 times 1-3 Alkyl, Z 5 Replace C up to 3 times 2-4 alkenyl, Z-bonded 5 Replace C up to 3 times 2-4 The alkynyl group and the ring selected from the following: 3-6 membered alkyl rings, 4-6 membered heterocycles containing one or two heteroatoms selected from N, O, and S as ring members, and 5-6 membered heteroaryl rings containing up to four heteroatoms selected from N, O, and S as ring members, wherein the 3-6 membered alkyl ring, 4-6 membered heterocycle, or 5-6 membered heteroaryl ring is optionally surrounded by 1-2 Z-axis groups. 5 replace;

[0193] L is a C1-C4 straight-chain or branched alkylene linker or bond;

[0194] W is H, -OH, –OR, -C(O)NR'R', -COOR', -NR'R', -NR'COOR, -NR'C(O)R, -SO2R, -SO2NR'R', -NR'SO2R, -P(O)(OR')2, or a ring optionally substituted from the following: 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocyclic group containing one or two N, O or S heteroatoms as ring members, and 5 membered heteroaryl group containing up to 4 heteroatoms selected from N, O and S as ring members and optionally fused with a phenyl group.

[0195] The optional substituents for the optionally substituted ring are 1-3 groups selected from the following: C 1-3 Alkyl, oxo, halogen, C 1-3 Halogenated alkyl, –L 2 -OH, –L 2 -OR、–L 2 -OC(O)-NR'R'、–L 2 -SO 2 R, –L 2 -SO 2 NR'R', –L 2 -SO2NR'-C(O)R、–L 2 -C(O)-NR'-SO2R、–L 2 -SOR、–L 2 -S(=O)(=NR')R、–L 2 -NR'SO2NR'R'、–L 2 -NR'SO2R、–L 2-NR'R'、–L 2 -NR'C(O)R'、–L 2 -NR'COOR、–L 2 -C(O)NR'R' and –L 2 -COOR';

[0196] R is selected from C each time it appears. 1-4 Alkyl, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl containing up to 4 heteroatoms selected from N, O, and S as ring members, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members, wherein each R is optionally substituted by one or two groups selected from: C 1-4 Alkyl, C 1-2 Halogenated alkyl, oxo, –L 3 -CN、–L 3 -Halogen, –L 3 -C 1-3 Alkoxy, –L 3 -OH, –L 3 -OC(O)-NR'R'、–L 3 -SO2R'、–L 3 -SO2NR'R'、–L 3 -SO2NR'-C(O)R'、–L 3 -C(O)-NR'-SO2R'、–L 3 -SOR'、–L 3 -S(=O)(=NR')R'、–L 3 -NR'SO2NR'R'、–L 3 -NR'SO2R'、–L 3 -NR'R'、–L 3 -NR'C(O)R'、–L 3 -NR'COOR'、–L 3 -C(O)NR'R' and –L 3 -COOR'、-L 3 - (5-6 membered heterocyclic groups containing one or two N, O, or S heteroatoms as ring members), –L 3 -C 3-5 cycloalkyl and –L 3 - (a 5-6 membered heteroaryl ring having up to 4 heteroatoms as ring members, wherein the heteroatoms comprise 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms), wherein the C 1-4 Alkyl, 5-6-membered heterocyclic, C 3-5 The cycloalkyl and 5-6-membered heteroaryl rings are each optionally substituted by up to three independent groups selected from the following: halogen, C 1-3 Alkyl, C1-3 Halogenated alkyl groups, -L 4 -OR'、-L 4 -CN and –L 4 -N(R')2;

[0197] R' is independently selected from H, optionally by a halogen, -OH, amino, or C each time it appears. 1-2 alkoxy-substituted C 1-4 Alkyl groups, and optionally halogenated, -OH, amino, or C 1-2 alkoxy-substituted C 3-6 cycloalkyl;

[0198] Alternatively, the two R' atoms together with the nitrogen atom directly attached to them can form a 4-6 membered ring, which optionally contains an additional N, O, or S as a ring member and is optionally substituted by 1 to 3 groups selected from: C 1-2 Alkyl, C 1-2 Alkyl, oxo, and hydroxyl groups;

[0199] Each L 2 and L 3 and L 4 Independently, it is a bond, a straight chain, or a branch C. 1-3 Alkylene;

[0200] Z and Z 5 Each time it appears, it is independently selected from halogen, hydroxyl, CN, C. 1-3 Alkoxy, C 1-3 Alkyl and C 3-5 cycloalkyl,

[0201] and two Z groups or two Z 5 The group, together with the carbon atom directly attached to it, can form a 3-5 membered alkyl ring or a 4-6 membered heterocycle, wherein the 4-6 membered heterocycle contains O, N or S as a ring member and is optionally composed of at most two groups selected from oxo and C. 1-3 Alkyl groups are substituted.

[0202] In some embodiments of the compound of formula (IV), R 11 It is H or C1-C6 alkyl. In some of these embodiments, R 3 It does not exist. In some of these implementations, R 4 and R 5 They represent H respectively.

[0203] In some embodiments of the compound of formula (IV),

[0204] L is a C1-C4 straight-chain or branched alkylene linker;

[0205] W is -SO2R, -SO2NR'R', -NR'SO2R, or optionally substituted C1-C3 alkyl, or optionally substituted 3-6 membered cycloalkyl;

[0206] The optional substituents for the optionally substituted C1-C3 alkyl and optionally substituted cycloalkyl groups are 1-3 groups independently selected from the following: C 1-3 Alkyl, oxo, halogen, C 1-3 Alkyl groups, OH groups, -SO2R groups, -SO2NR'R' groups, -NR'SO2NR'R' groups, -NR'SO2R groups, -NR'R' groups, -OR groups, -NR'COOR groups, -C(O)NR'R' groups, and COOR' groups.

[0207] R is independently selected from C each time it appears. 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing up to 4 heteroatoms selected from N, O, and S as ring members, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members.

[0208] Each R is optionally substituted by one or two groups selected from the following: C 1-3 Alkyl, oxo, CN, halogen, C 1-3 Alkoxy, OH and C 3-5 cycloalkyl;

[0209] R' is selected from H and optionally replaced by a halogen, -OH, or C in each occurrence. 1-2 alkoxy-substituted C 1-4 alkyl;

[0210] Alternatively, the two R' atoms together with the nitrogen atom directly attached to them can form a 4-6 membered ring, which optionally contains an additional N, O, or S as a ring member and is optionally substituted by one or two groups selected from: C 1-2 Alkyl, C 1-2 Alkyl, oxo, and hydroxyl groups.

[0211] In some such embodiments, the group W-L is selected from the following groups:

[0212]

[0213] In some of these embodiments, L is CH2. In these embodiments, R is sometimes selected from methyl, ethyl, isopropyl, and cyclopropyl in each occurrence. In these embodiments, R' is sometimes selected from H and methyl in each occurrence.

[0214] These compounds are new and can serve as intermediates for the preparation of the compounds of formulas (I)-(III) described herein.

[0215] Another embodiment of the invention provides the compound as described above, or a pharmaceutically acceptable salt thereof, as a drug.

[0216] The use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment or prevention of human herpesvirus diseases and / or infections (including CMV) is also within the scope of this invention.

[0217] Pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are included within the scope of this invention.

[0218] According to another aspect of this embodiment, the pharmaceutical composition according to the invention further comprises a therapeutically effective amount of at least one other antiviral agent.

[0219] The present invention also provides the use of the pharmaceutical composition described above in treating CMV infection or other herpesviruses in humans who have or are at risk of infection. The herpesvirus may be selected from cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex virus including HSV-1 and HSV-2, herpesvirus 6, human herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus.

[0220] The present invention also provides the use of the pharmaceutical composition described above for treating CMV disease or other herpesvirus infections in persons who have or are at risk of the aforementioned disease. The CMV disease or other herpesvirus infections may include, for example, CMV infection in immunocompromised patients (such as transplant recipients); congenital CMV; genital herpes; oral or cold herpes; herpetic keratitis; neonatal herpes; herpetic encephalitis; chickenpox; shingles; infectious mononucleosis; post-transplant lymphoproliferative disorder (PTLD); Kastelman's disease; and hemophagocytic lymphohistiocytosis.

[0221] Another aspect of the invention provides a method for treating a patient’s disease or condition that may be induced, aggravated, and / or accelerated by CMV disease or other herpesvirus infections. These diseases and conditions include Alzheimer’s disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes.

[0222] Another aspect of the invention relates to a method of treating or preventing human herpesvirus diseases and / or infections by administering to humans an antivirally effective amount of the compound of the invention, a pharmaceutically acceptable salt thereof, or the above-mentioned composition (alone or in combination with at least one other antiviral agent, administered together or separately).

[0223] Another aspect of the invention relates to articles comprising compositions effective in treating herpesvirus diseases and / or infections; and packaging material comprising a label indicating that the composition may be used to treat herpesvirus (such as CMV) diseases and / or infections; wherein the composition comprises a compound having formula (I) according to the invention or a pharmaceutically acceptable salt thereof.

[0224] Another aspect of the invention relates to a method for inhibiting the replication of CMV or another herpesvirus, said method comprising exposing the virus to an effective amount of a compound having formula (I) or a salt thereof under conditions that inhibit viral replication. This method can be practiced in vitro or in vivo.

[0225] The scope of this invention further includes the use of compounds having formula (I) or salts thereof to inhibit CMV replication.

[0226] In some embodiments, the compound of formula (I) is co-administered with at least one additional agent selected from: herpesvirus entry inhibitors, herpesvirus early transcription event inhibitors, herpesvirus helicase-primase inhibitors, another herpesvirus DNA polymerase inhibitor, UL97 kinase inhibitors, herpesvirus protease inhibitors, herpesvirus terminal enzyme inhibitors, herpesvirus maturation inhibitors, inhibitors of another target in the herpesvirus life cycle, herpesvirus vaccines, and herpesvirus biological agents. In a preferred embodiment, the herpesvirus is CMV.

[0227] These additional agents can be combined with the compounds of the present invention to produce a single pharmaceutical dosage form. Alternatively, these additional agents can be administered separately to the patient as part of a multi-dosage form, for example using a kit. Such additional agents can be administered to the patient before, simultaneously with, or after administration of the compounds of the present invention or their pharmaceutically acceptable salts.

[0228] The daily dosage range of the compounds of the present invention is typically 0.01 to 100 mg / kg body weight, preferably 0.1 to 50 mg / kg body weight. Each dosage unit conveniently contains 5% to 95% (w / w) of the active compound. Preferably, such formulations contain 20% to 80% of the active compound.

[0229] The actual effective or therapeutic dose of the drug will, of course, depend on factors known to those skilled in the art, such as the patient's age and weight, route of administration, and severity of disease. In any case, the combination will be administered according to the patient's unique condition, in a dosage and manner that allows for the delivery of a pharmaceutically effective dose.

[0230] When the composition of the present invention comprises a combination of the compound of the present invention and one or more other therapeutic or preventive agents, both the compound and the other agent shall be present at a dose level between about 10% and 100%, more preferably between about 10% and 80%, of the dose normally administered in a single therapy regimen.

[0231] Antiviral agents intended for use in such combination therapies include agents (compounds or biologics) that can effectively inhibit viral formation and / or replication in humans, including but not limited to agents that interfere with host or viral mechanisms essential for viral formation and / or replication in humans. Such agents may be selected from: herpesvirus entry inhibitors; herpesvirus early transcription event inhibitors; herpesvirus helicase-primase inhibitors; and herpesvirus DNA polymerase inhibitors, such as ganciclovir. Valganciclovir Sidofovir Phoscarboxylic acid CMX001, cipropavir (MBX-400), and valacyclovir UL97 kinase inhibitors, such as maribavir; herpesvirus protease inhibitors; herpesvirus terminal enzyme inhibitors, such as AIC246 (lemetmovir); herpesvirus maturation inhibitors; other inhibitors, such as artesunate; CMV vaccines, such as TransVax; and herpesvirus biologics, such as Cytogam.

[0232] Many of the compounds of this invention contain one or more chiral centers. These compounds can be prepared and used as a single isomer or a mixture of isomers. Methods for isolating isomers (including diastereomers and enantiomers) are known in the art, and examples of suitable methods are described herein. In some embodiments, the compounds of this invention are used as a single, substantially pure isomer, meaning that at least 90% of a sample of the compound is the specific isomer, while less than 10% of the sample is any other isomer or a mixture of isomers. Preferably, at least 95% of the sample is a single isomer. The selection of suitable isomers is within the realm of ordinary skill, as an isomer is generally more active in the in vitro assay for herpesvirus DNA polymerase described herein and would be the preferred isomer. Where the difference in in vitro activity between isomers is relatively small (e.g., less than about one-quarter), preferred isomers can be selected based on the level of activity against viral replication in cell cultures, for example, those described herein: isomers with lower IC-50 or EC-50 are preferred.

[0233] The compounds of the present invention can be synthesized via the general synthetic route shown below, with specific examples described in more detail in the examples.

[0234] The present invention also provides compounds of formula (I) as described herein and methods for preparing intermediates for preparing compounds of formula (I). Therefore, the present invention further includes a method for preparing a compound of formula (I), comprising making a compound of formula (V)

[0235]

[0236] X represents –OH or a leaving group;

[0237] R 3 This indicates at most two (0-2) optional substituents on a ring containing two nitrogen atoms, where each R 3 Independently selected from halogens, CN, C 1-3 Alkoxy, C 1-3 Alkyl groups, COOR', C(O)NH2, and C(O)NRR';

[0238] R 4 Is it H, halogen, or C? 1-3 alkyl;

[0239] R 5 Selected from H, halogens, CN, C 1-3 Alkoxy, -NH2, -NRR', and Z 5 Replace C up to 3 times 1-3 Alkyl, Z 5 Replace C up to 3 times 2-4 alkenyl, Z-bonded 5Replace C up to 3 times 2-4 The alkynyl group and the ring selected from the following: 3-6 membered alkyl rings, 4-6 membered heterocycles containing one or two heteroatoms selected from N, O, and S as ring members, and 5-6 membered heteroaryl rings containing up to four heteroatoms selected from N, O, and S as ring members, wherein the 3-6 membered alkyl ring, 4-6 membered heterocycle, or 5-6 membered heteroaryl ring is optionally surrounded by 1-2 Z-axis groups. 5 replace;

[0240] L is a C1-C4 straight-chain or branched alkylene linker;

[0241] W is –OR', -NH2, -NRR', -NR'COOR, -NR'C(O)R', -SO2R, -SO2NH2, -SO2NRR', -NR'SO2R, or an optionally substituted C1-C3 alkyl group, or an optionally substituted ring selected from the following: 3-6 membered cycloalkyl groups, 5-6 membered heterocyclic groups containing one or two N, O, or S heteroatoms as ring members, and 5 membered heteroaryl groups containing up to 4 heteroatoms selected from N, O, and S as ring members.

[0242] The optional substituents for the optionally substituted C1-C3 alkyl group and the optionally substituted ring are 1-3 groups selected from the following: C 1-3 Alkyl, oxo, halogen, C 1-3 Alkyl groups, OH groups, -SO2R groups, -SO2NR'R' groups, -SOR groups, -S(=O)(=NR')R groups, -NR'SO2NR'R' groups, -NR'SO2R groups, -NH2 groups, -NR'R' groups, -OR groups, -NR'COOR groups, -C(O)NH2 groups, -C(O)NRR' groups, and COOR' groups.

[0243] R is independently selected from C each time it appears. 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, phenyl groups, 5-6 membered heteroaryl groups containing up to 4 heteroatoms selected from N, O, and S as ring members, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members.

[0244] Each R is optionally substituted by one or two groups selected from the following: C 1-3 Alkyl, oxo, CN, halogen, C 1-3 Alkoxy, OH and C 3-5 cycloalkyl;

[0245] R' is selected from H and optionally replaced by a halogen, -OH, or C in each occurrence. 1-2 alkoxy-substituted C 1-4 alkyl;

[0246] Alternatively, R and R' together with the nitrogen atom directly attached to them can form a 4-6 membered ring, which optionally contains an additional N, O, or S as a ring member and is optionally substituted by one or two groups selected from: C 1-2 Alkyl, C 1-2 Alkyl, oxo, and hydroxyl groups;

[0247] Y is independently selected from halogens and C each time it appears. 1-2 Alkyl, C 1-2 Halogenated alkyl and C 1-2 Alkoxy;

[0248] Each Z 5 Each time it appears, it is independently selected from halogen, hydroxyl, CN, C. 1-3 Alkoxy, C 1-3 alkyl,

[0249] And two Zs 5 The group, together with the carbon atom directly attached to it, can form a 3-5 membered alkyl ring or a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring contains O, N, or S as ring members and is optionally selected from at most two oxo and C atoms. 1-3 Alkyl group substitution;

[0250] With compounds of formula (VI):

[0251]

[0252] Contact; wherein Cy is phenyl, pyridyl, pyrimidinyl, or a 5-8 membered cycloalkyl group, and Cy is optionally substituted by up to 3 groups selected from the following: halogen, CN, hydroxyl, -N(R')2, C 3-6 cycloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl groups and C groups substituted with Z up to 3 times (0-3 times) 1-3 Alkyl groups, wherein the C atoms are substituted with Z up to 3 times 1-3 When two alkyl groups are directly attached to the same carbon atom, they can form a 3-5 membered alkyl ring with the attached carbon atom, which is substituted by Z up to 3 times; R 1 Selected from H and C 1-3 alkyl;

[0253] R 2 Selected from H and C 1-3 alkyl;

[0254] Or R 1 and R 2 Together with the carbon atoms connected thereto, they can form 3-6 membered cycloalkyl rings;

[0255] Z is independently selected from halogen, hydroxyl, CN, and C each time it appears.1-3 Alkoxy, C 1-3 Alkyl and C 3-5 cycloalkyl,

[0256] The two Z groups, together with the carbon atoms directly attached to them, can form 3-5 membered alkyl rings or 4-6 membered heterocycles, wherein the 4-6 membered heterocycle contains O, N, or S as ring members and is optionally composed of at most two groups selected from oxo and C. 1-3 Alkyl groups are substituted.

[0257] Typically, for these methods, compounds of formula (V) and (VI) are combined or mixed together in the presence of an inert solvent under conditions suitable for forming amide bonds (including methods known for peptide synthesis). For example, in the case where X represents –OH, any of a wide range of dehydrating agents known to be suitable for forming amide bonds between amines and carboxylic acids can be used. Some of these are illustrated by examples herein and include carbodiimides (e.g., dicyclohexylcarbodiimide; diisopropylcarbodiimide; EDC, etc.). Optionally, the reaction with carbodiimides can be facilitated in the presence of an activator (such as HOBt, HOAt, N-hydroxysuccinimide, etc.). Alternatively, the acid of formula (V) or a salt thereof can be activated by reacting with an activator (such as HATU, HBTU, BOP, PyBOP, PyBrOP, TBTU, COMU, or TFFH) (optionally in the presence of a base such as triethylamine, DIPEA, DMAP, pyridine, etc.) followed by contact with an amine compound of formula (VI). When X represents a leaving group, it can be a halogen (preferably Cl) or an acyl group, such as –OC(O)-OR*, where R* represents optionally being surrounded by up to 3 halogens or C. 1-3 Alkoxy-substituted C1-C6 alkyl groups.

[0258] In some embodiments, the compound of formula (V) is a compound of formula (VB):

[0259]

[0260] Where R 5 H is H or a halogen; L is –CH2-; and W is a cyclopropyl group substituted with –SO2R, where R is as defined in formula (V).

[0261] The compounds of formulas (V) and (VB) described above, as well as the methods for preparing the compounds of the present invention using them, are also aspects of the present invention.

[0262] The invention further includes any variations of the method, wherein an intermediate product available at any stage is used as a starting material and the remaining steps are carried out, or the starting material is formed in situ under reaction conditions, or wherein the reaction components are used in the form of their salts or optically pure substances.

[0263] The invention also relates to those forms of the method in which a compound obtainable as an intermediate at any stage of the method is used as a starting material and the remaining processing steps are carried out, or in which the starting material is formed under reaction conditions, or in the form of a derivative, for example, in a protected form or in the form of a salt, or in which a compound obtainable by the method according to the invention is produced under the process conditions and further processed in situ.

[0264] The terms "optical isomer" or "stereoisomer" refer to any of the many stereoisomers that can exist for a given compound of the present invention, including geometric isomers. It should be understood that substituents can be attached to the chiral center of a carbon atom. The term "chiral" refers to a molecule that has non-overlapping properties on its mirror-image partner, while the term "chiral" refers to a molecule that is overlappable on its mirror-image partner. Therefore, the present invention includes enantiomers, diastereomers, or racemates of the said compound. An "enantiomer" is a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of enantiomers is a "racemic" mixture. The term is used to denote racemic mixtures where appropriate. A "diastereomer" is a stereoisomer having at least two asymmetric atoms and not being a mirror image of each other. Absolute stereochemistry is defined according to the Cahn-Lngold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be represented by R or S. The resolution of compounds with unknown absolute configuration can be specified as (+) or (-) depending on the direction (right-handed or left-handed) in which they rotate plane-polarized light with wavelengths of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers or axes and can therefore produce enantiomers, diastereomers, and other stereoisomers, which can be defined as (R)- or (S)- in terms of absolute stereochemistry.

[0265] Depending on the choice of starting materials and procedures, the compound may exist in possible isomeric forms or as mixtures thereof (e.g., as a pure optical isomer or as a mixture of isomers, such as racemic and diastereomeric mixtures), depending on the number of asymmetric carbon atoms. This invention aims to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0266] Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers or diastereomers based on the physicochemical differences of the components, for example by chromatography and / or fractional crystallization.

[0267] Racemic derivatives of any resulting end product or intermediate can be resolved into optically active enantiomers by known methods, for example, by separating their diastereomer salts obtained with optically active acids or bases, releasing the optically active acidic or basic compounds. In particular, the compounds of the present invention can therefore be resolved into their optically active enantiomers using a basic moiety, for example, by fractional crystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluamide tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography (e.g., high-performance liquid chromatography (HPLC) using chiral adsorbents).

[0268] Furthermore, the compounds of the present invention (including their salts) can also be obtained in their hydrated form, or include other solvents for their crystallization. The compounds of the present invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention includes both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of the compounds of the present invention (including their pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules (e.g., water, ethanol, etc.) are those commonly used in the pharmaceutical industry and are known to be harmless to the recipient. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0269] The compounds of the present invention (including their salts, hydrates and solvates) can be inherently or by design to form polymorphs.

[0270] As used herein, the term "salt" refers to an acid addition salt or a base addition salt of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt" means a salt that retains the biological efficacy and properties of the compounds of the present invention and is generally not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or similar groups.

[0271] Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromoates, bicarbonates / carbonates, hydrogen sulfates / sulfates, camphor sulfonates, chlorides / hydrochlorides, chlortheophyllonates, citrates, ethanedisulfonates, fumarates, gluconate, gluconate, gluuronates, hippurates, hydroiodates / iodides, hydroxyethyl sulfonates, lactobionates, lacturonates, lauryl sulfates, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, naphthates, naphthalenesulfonates, nicotinates, nitrates, stearates, oleates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propions, stearates, succinates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates.

[0272] Inorganic acids that can form salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0273] Organic acids that can form salts include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid. Pharmaceutically acceptable base addition salts can be formed by inorganic and organic bases.

[0274] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0275] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; and basic ion exchange resins. Some organic amines include isopropylamine, benzylamine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0276] The pharmaceutically acceptable salts of the present invention can be synthesized from the base or acid portion by conventional chemical methods. Typically, such salts are prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (e.g., hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or a mixture of both. Generally, where feasible, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of other suitable salts can be found, for example, in “Remington’s Pharmaceutical Sciences,” 20th edition, Mack Publishing Company, Easton, Pa., (1985); and Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002).

[0277] Any formulas given herein are intended to represent the unlabeled form and isotope-labeled form of compounds of the present invention having up to three atoms with a non-natural isotopic distribution, for example, deuterium-rich or 13 C or 15 The N site. The isotopically labeled compounds have the structure described by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number instead of a natural abundance mass distribution. Examples of isotopes that can be effectively incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl、 125 I. This invention includes various isotope-labeled compounds of this invention, such as those containing a radioactive isotope in a much higher concentration than the normal isotope distribution (e.g., 3 H and 14 Those of type C), or those containing non-radioactive isotopes present in quantities far exceeding the normal isotopic distribution (e.g., [missing information]). 2 H and 13 Those of type C). Compounds labeled with this type of isotope can be used for metabolic studies (e.g., using...). 14C) Reaction kinetic studies (e.g., using...) 2 H or 3 H), detection or imaging techniques (e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or for use in the patient's radiation therapy. Specifically, 18 F-labeled compounds of the present invention may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples and preparations, using a suitable isotopically labeled reagent instead of the typically used unlabeled reagent. Labeled samples may be useful in cases of very low isotopic doping, such as when using radiolabeling to detect trace amounts of compounds.

[0278] In addition, heavier isotopes, especially deuterium (i.e., 2 A wider range of substitutions (H or D) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., prolonged in vivo half-life, reduced dose requirement, or improved therapeutic index). It should be understood that, in this context, deuterium is considered a substituent in the compounds of the present invention, and typically, samples of compounds having deuterium as a substituent have at least 50% deuterium incorporation at one or more labeled sites. The concentration of such heavier isotopes (particularly deuterium) can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a particular isotope and its native abundance. If the substituent in the compound of the present invention refers to deuterium, such a compound has an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping on each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping).

[0279] Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be substituted with an isotope, for example, D₂O, d 6 -Acetone, d 6 -DMSO.

[0280] Compounds of the present invention containing groups capable of acting as donors and / or acceptors of hydrogen bonds can form cocrystals with suitable cocrystal forgings. These cocrystals can be prepared from the compounds of the present invention using known cocrystal formation procedures. Such procedures involve grinding, heating, co-sublimating, co-melting, or contacting and separating the cocrystal formed by the compounds of the present invention with the cocrystal forgings in solution under crystallization conditions. Suitable cocrystal forgings include those described in WO 2004 / 078163. Therefore, the present invention further provides cocrystals comprising the compounds of the present invention.

[0281] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by the context. The use of any and all instances or exemplary language (e.g., “as”) provided herein is intended only to better illustrate the invention and not to limit the scope of the otherwise claimed invention.

[0282] The compounds of the present invention can be administered by known methods, including oral, parenteral, and inhalation methods. In some embodiments, the compounds of the present invention are administered orally as pills, lozenges, trochetes, capsules, solutions, or suspensions. In other embodiments, the compounds of the present invention are administered by injection or infusion. Infusion is usually performed intravenously, typically over a period of about 15 minutes to 4 hours. In other embodiments, the compounds of the present invention are administered intranasally or by inhalation; inhalation is particularly useful for treating respiratory infections. The compounds of the present invention exhibit oral bioavailability, so oral administration is sometimes preferred.

[0283] The compounds of the present invention can also be used in combination with other agents (combination partners), such as other antiviral agents that are or are not of Formula I, to treat viral infections in subjects.

[0284] The term "combination" means a fixed combination in the form of a single dose unit (as separate dosage forms suitable for simultaneous or sequential use), or as part of a kit for combined administration, wherein the compounds and combination partners of the present invention can be administered simultaneously or separately at time intervals, particularly allowing the combination partners to exhibit synergistic (e.g., co-operational) effects, or any combination thereof.

[0285] In some embodiments of the invention, the compounds of the invention are used in combination with a second antiviral agent, such as those named herein.

[0286] The second antiviral agent can be administered in combination with the compounds of the present invention, wherein the second antiviral agent is administered before, simultaneously with, or after one or more compounds of the present invention. When it is desired to administer the compounds of the present invention and the second agent simultaneously and via the same route of administration, the compounds of the present invention and the second agent can be formulated into the same dosage form. Examples of dosage forms containing the compounds of the present invention and the second agent are tablets or capsules.

[0287] In some embodiments, the combination of the compound of the present invention and the second antiviral agent can provide synergistic activity. The compound of the present invention and the second antiviral agent can be administered together, separately, simultaneously, or sequentially.

[0288] The “effective amount” of a compound is an amount necessary or sufficient to treat or prevent the viral infection and / or disease or condition described herein. In one example, the effective amount of a herpesvirus or CMV DNA polymerase inhibitor having Formula I is an amount sufficient to treat the viral infection in a subject. In another example, the effective amount of a DNA polymerase inhibitor is an amount sufficient to treat a viral infection (e.g., but not limited to, CMV, VZV, or EBV) in a subject requiring such treatment. The effective amount can vary depending on factors such as the size and weight of the subject, the type of disease, or the specific compound of the invention. For example, the choice of the compound of the invention affects the composition of the “effective amount.” Those skilled in the art will be able to examine the factors included herein and determine the effective amount of the compounds of the invention without extensive experimentation.

[0289] The administration regimen can affect the composition of the effective dose. The compounds of the present invention can be administered to subjects before or after the onset of a viral infection. Furthermore, several separate doses and intervals can be administered daily or continuously, or the doses can be administered continuously by infusion or by bolus injection. Additionally, the dosage of one or more compounds of the present invention can be increased or decreased proportionally according to the urgency of the treatment or prevention situation.

[0290] The compounds of the present invention can be used to treat the conditions, disorders, or diseases described herein, or to manufacture pharmaceutical compositions for treating these diseases. The present invention provides methods for using the compounds of the present invention in treating these diseases, or methods for preparing pharmaceutical compositions having the compounds of the present invention for treating these diseases.

[0291] The term "pharmaceutical composition" includes formulations suitable for administration to mammals (e.g., humans). When the compounds of the present invention are administered to mammals (e.g., humans) as pharmaceuticals, they may be given alone or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of at least one compound having formula (I) or any subclass thereof as an active ingredient, in combination with, or optionally with, two or more pharmaceutically acceptable carriers.

[0292] The phrase "pharmaceutically acceptable carrier" is recognized in the art and includes pharmaceutically acceptable materials, compositions, or media suitable for administering the compounds of the present invention to mammals. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, said carriers being involved in carrying or transporting the test drug agent from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation and harmlessness to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered astragalus gum; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginate; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical formulations. Generally, pharmaceutically acceptable carriers are sterile and / or substantially pyrogen-free.

[0293] The composition may also contain wetting agents, emulsifiers and lubricants, such as sodium dodecyl sulfate and magnesium stearate, as well as colorants, releasing agents, coating agents, sweeteners, flavoring agents and aroma agents, preservatives and antioxidants.

[0294] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0295] The formulations of the present invention include those suitable for oral, nasal, inhalation, topical, transdermal, oral, sublingual, rectal, vaginal, and / or parenteral administration. The formulations can be conveniently present in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect. Typically, within the range of 100%, the amount ranges from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0296] Methods for preparing these formulations or compositions include the steps of combining the compounds of the present invention with a carrier and optionally one or more auxiliary components. Generally, formulations are prepared by uniformly and tightly combining the compounds of the present invention with a liquid carrier or a finely chopped solid carrier or both, and then, if necessary, shaping the product.

[0297] Formulations of the present invention suitable for oral administration may be in the form of capsules, flat capsules, pills, tablets, lozenges (using a flavoring matrix, such as sucrose and gum arabic or astragalus gum), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as soft lozenges (using an inert matrix, such as gelatin and glycerin, or sucrose and gum arabic), and / or as mouthwashes, etc., each form containing a predetermined amount of the compound of the present invention as an active ingredient. The compounds of the present invention may also be administered in the form of large pills, granules, or pastes.

[0298] In the solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) of this invention for oral administration, the active ingredient is mixed with: one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silica; binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; humectants, such as glycerin; disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; solution blockers, such as paraffin; absorption enhancers, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glyceryl monostearate; absorbents, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain a buffer. Excipients such as lactose and high molecular weight polyethylene glycol may also be used as fillers in soft-filled and hard-filled gelatin capsules.

[0299] Tablets can be prepared by compression or molding (optionally with one or more excipients). Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0300] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention (such as sugar-coated pills, capsules, pellets, and granules) may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may also be formulated using, for example, different proportions of hydroxypropyl methylcellulose to provide a slow or controlled release of the active ingredient therein to deliver the desired release profile, other polymer matrices, liposomes, and / or microspheres. They may be sterilized, for example, by filtering through a bacterial trap filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved immediately in sterile water or some other sterile injectable medium before use. These compositions may also optionally contain a light-blocking agent and may be compositions that release one or more active ingredients, either alone or preferably optionally, in a delayed manner in a portion of the gastrointestinal tract. Examples of usable embedded compositions include polymeric substances and waxes. The active ingredient may also be in a microencapsulated form and, where appropriate, may contain one or more of the excipients described above.

[0301] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents (e.g., water or other solvents), solubilizers, and emulsifiers commonly used in the art, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof.

[0302] In addition to inert diluents, oral compositions may also include excipients such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents, and preservatives.

[0303] In addition to containing active compounds, suspensions may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar and astragalus gum, and mixtures thereof.

[0304] Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration can be presented as suppositories, which can be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylates, and are solid at room temperature but liquid at body temperature, and thus will melt in the rectal or vaginal cavity and release the active compound.

[0305] The formulations of the present invention suitable for vaginal application also include vaginal suppositories, tampons, creams, gels, pastes, foams or sprays containing such carriers known in the art as suitable.

[0306] Dosage forms for topical or transdermal application of the compounds used in this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required.

[0307] In addition to the active compounds of this invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, astragalus gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0308] In addition to the compounds of this invention, powders and aerosols may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures thereof. Aerosols may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0309] Transdermal patches offer the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the transdermal flux of the compounds. The rate of flow can be controlled by providing a rate-controlled membrane or by dispersing the active compounds in a polymer matrix or gel.

[0310] Ophthalmic preparations, ophthalmic ointments, powders, solutions, etc., are also considered within the scope of this invention.

[0311] Pharmaceutical compositions of the present invention suitable for parenteral administration may comprise one or more compounds of the present invention in combination with one or more pharmaceutically acceptable carriers, such as sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders, wherein the sterile powders may be reconstituted in sterile injectable solutions or dispersions immediately prior to use, wherein the sterile injectable solutions or dispersions may contain antioxidants, buffers, antibacterial agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0312] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, glycol ethers, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Appropriate flowability can be maintained, for example, by using a coating material (e.g., lecithin), by maintaining the desired particle size in the case of dispersions, and by using a surfactant.

[0313] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Inhibition of microbial activity can be ensured by including various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol sorbate, etc.). It is also desirable to include isotonic agents such as sugars and sodium chloride in the composition. Furthermore, prolonged absorption of injectable drug forms can be achieved by including agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0314] In some cases, to prolong the action of a drug, it is desirable to slow down its absorption via subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. The absorption rate of the drug then depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, absorption of parenterally administered drug forms can be delayed by dissolving or suspending the drug in an oily medium.

[0315] Injectable reservoir formulations are prepared by forming microcapsule matrices of the subject compound within biodegradable polymers, such as polylactic acid-polyglycolic acid. The drug release rate can be controlled based on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable reservoir formulations are also prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions.

[0316] The formulations of the present invention can be administered orally, parenterally, topically, or rectally. They are, of course, given in a form suitable for each route of administration. For example, they are administered in tablet or capsule form by injection, inhalation, eye wash, ointment, suppository, etc.; by injection, infusion, or inhalation; by topical application as a wash or ointment; and by rectal application as a suppository.

[0317] As used herein, the phrases “parenteral administration” and “via parenteral administration” refer to administration methods other than enteric and local administration, typically by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrasheath, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions. Intravenous infusion is sometimes a preferred method of delivery for the compounds of the present invention. Infusion can be used to deliver a single daily dose or multiple doses. In some embodiments, the compounds of the present invention are administered by infusion over intervals of 15 minutes to 4 hours, typically between 0.5 and 3 hours. Such infusions can be used once daily, twice daily, or up to three times daily.

[0318] As used in this article, the phrases “systemic administration,” “administered via the system,” “administered via the periphery,” and “administered via the periphery” refer to administration of a compound, drug, or other material into the patient’s system, rather than administration directly to the central nervous system, and thereby allowing it to undergo metabolism and other similar processes, such as subcutaneous administration.

[0319] These compounds can be administered to humans and other animals for treatment via any suitable route of administration, including oral, nasal (e.g., by spray), rectal, vaginal, parenteral, intracerebrospinal, and topical (e.g., by powder, ointment, or drops), including buccal and sublingual administration.

[0320] Regardless of the chosen route of administration, the compounds of the present invention (which can be used in a suitable hydrated form) and / or the pharmaceutical compositions of the present invention shall be formulated into pharmaceutically acceptable dosage forms using conventional methods known to those skilled in the art.

[0321] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be changed to obtain a certain amount of active ingredient that effectively achieves the desired therapeutic response for a specific patient, composition and administration method without toxicity to the patient.

[0322] The selected dose level depends on a variety of factors, including the activity of the specific compound of the present invention or its ester, salt or amide; the route of administration; the time of administration; the excretion rate of the specific compound being used; the duration of treatment; other drugs, compounds and / or materials used in combination with the specific compound used; the age, sex, weight, condition, general health and medical history of the patient being treated; and similar factors known in the medical field.

[0323] Physicians or veterinarians with ordinary skills in the art can easily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can begin administering the compound of the present invention used in the pharmaceutical composition at a level below that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0324] Generally, the appropriate daily dose of the compounds of the present invention will be the minimum dose at which the compounds effectively produce a therapeutic effect. This effective dose typically depends on the factors described above. Generally, when used for the indicated effects, the intravenous and subcutaneous doses of the compounds of the present invention to patients range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kilogram of body weight per day, and still more preferably from about 0.1 to about 20 mg per kilogram of body weight per day. An effective dose is an amount for the prevention or treatment of viral infections (e.g., CMV or other herpesviruses).

[0325] If desired, the effective daily dose of the active compound may be administered as a single daily dose at appropriate intervals throughout the day, or as two, three, four, five, six or more sub-dose, optionally in unit dosage form. Compounds delivered orally or by inhalation are typically administered one to four times daily. Compounds delivered by injection are typically administered once daily or every other day. Compounds delivered by infusion are typically administered one to three times daily. When administered multiple times a day, the dose may be given at intervals of approximately 4 hours, 6 hours, 8 hours, or 12 hours.

[0326] Although the compounds of the present invention can be administered alone, it is preferred that they be administered as pharmaceutical compositions, such as those disclosed herein. Therefore, methods of using the compounds of the present invention include administering the compounds as pharmaceutical compositions, wherein at least one compound of the present invention is mixed with a pharmaceutically acceptable carrier prior to administration.

[0327] Use of the compounds of the present invention in combination with immunomodulators

[0328] The compounds and compositions described herein can be used or administered in combination with or as therapeutic agents that act as immunomodulators, such as activators of co-stimulatory molecules, inhibitors of immunosuppressive molecules, or vaccines. Programmed death 1 (PD-1) protein is an inhibitory member of the extended CD28 / CTLA4 family of T-cell regulators (Okazaki et al., (2002) Curr Opin Immunol 14:391779-82; Bennett et al., (2003) J. Immunol. 170:711-8). PD-1 is expressed on activated B cells, T cells, and monocytes. PD-1 is an immunosuppressive protein that negatively regulates TCR signaling (Ishida, Y. et al., (1992) EMBO J. 11:3887-3895; Blank, C. et al., (Epub 2006 Dec. 29) Immunol. Immunother. 56(5):739-745), and is upregulated in chronic infection. The interaction between PD-1 and PD-L1 can act as an immune checkpoint, which can lead to, for example, a reduction in infiltrating lymphocytes, a reduction in T cell receptor-mediated proliferation, and / or immune evasion by cancerous or infected cells (Dong et al., (2003) J. Mol. Med. 81:281-7; Blank et al., (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al., (2004) Clin. Cancer Res. 10:5094-100). Immunosuppression can be reversed by inhibiting the local interaction between PD-1 and PD-L1 or PD-L2; the effect is additive when the interaction between PD-1 and PD-L2 is blocked (Iwai et al., (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al., (2003) J. Immunol. 170:1257-66). Immunomodulation can be achieved by binding to immunosuppressive proteins (e.g., PD-1) or proteins that regulate inhibitory proteins (e.g., PD-L1, PD-L2).

[0329] In one embodiment, the combination therapy of the present invention includes an immunomodulatory agent, which is an inhibitor or antagonist of an immune checkpoint molecule inhibitor. In another embodiment, the immunomodulatory agent binds to a protein that naturally inhibits an immune checkpoint molecule. When used in combination with antiviral compounds, these immunomodulatory agents can enhance the antiviral response, thus improving efficacy compared to treatment with antiviral compounds alone.

[0330] The term "immune checkpoint" refers to a group of molecules on the cell surface of CD4 and CD8 T cells. These molecules can effectively act as "brakes" to downregulate or inhibit adaptive immune responses. Immune checkpoint molecules include, but are not limited to, programmed death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD137, CD40, and LAG3, which directly inhibit immune cells. Immunotherapy agents that can act as immune checkpoint inhibitors in the methods of the present invention include, but are not limited to, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and / or TGFRβ. Inhibition of the inhibitory molecule can be achieved at the DNA, RNA, or protein level. In some embodiments, an inhibitory nucleic acid (e.g., dsRNA, siRNA, or shRNA) can be used to inhibit the expression of the inhibitory molecule. In other embodiments, the inhibitor of the inhibitory signal is a peptide, such as a soluble ligand or an antibody or antigen-binding fragment thereof that binds to the inhibitory molecule.

[0331] The phrase “in combination with” is not intended to imply the necessity of simultaneous administration of the therapy or therapeutic agent and / or formulation for joint delivery, although such delivery methods are also within the scope of this document. Immunomodulators may be administered simultaneously, before, or after one or more compounds of the present invention and optionally one or more additional therapies or therapeutic agents. Therapies in the combination may be administered in any order. Generally, each agent will be administered at a dose and / or schedule determined for that agent. It should also be understood that the therapeutic agents used in the combination may be administered together as a single composition or separately as different compositions. Generally, each therapeutic agent used in the combination is intended to be used at a level not exceeding that of when used alone. In some embodiments, the level used in the combination will be lower than the level used alone.

[0332] In some embodiments, the antiviral compounds described herein are administered in combination with one or more immunomodulators that are inhibitors of PD-1, PD-L1, and / or PD-L2. Each such inhibitor may be an antibody, its antigen-binding fragment, an immunoadhesin, a fusion protein, or an oligopeptide. Examples of such immunomodulators are known in the art.

[0333] In some embodiments, the immunomodulator is an anti-PD-1 antibody selected from MDX-1106, Merck3475, or CT-011.

[0334] In some embodiments, the immunomodulator is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., the Fc region of an immunoglobulin sequence).

[0335] In some embodiments, the immunomodulator is a PD-1 inhibitor, such as AMP-224.

[0336] In some embodiments, the immunomodulator is a PD-L1 inhibitor, such as an anti-PD-L1 antibody.

[0337] In some embodiments, the immunomodulator is an anti-PD-L1 binding antagonist selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105. MDX-1105 (also known as BMS-936559) is an anti-PD-L1 antibody described in WO 2007 / 005874. Antibody YW243.55.S70 is an anti-PD-L1 antibody described in WO 2010 / 077634.

[0338] In some embodiments, the immunomodulator is nivolumab (CAS Registry No.: 946414-94-4). Alternative names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558. Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD-1. Nivolumab (clone 5C4) and other monoclonal antibodies that specifically bind to PD-1 are disclosed in US 8,008,449, EP 2161336, and WO 2006 / 121168.

[0339] In some embodiments, the immunomodulator is the anti-PD-1 antibody pembrolizumab. Pembrolizumab (also known as lambrolizumab, MK-3475, MK03475, SCH-900475, or...) Merck is a humanized IgG4 monoclonal antibody that binds to PD-1. Pembrolizumab and other humanized anti-PD-1 antibodies were disclosed in Hamid, O. et al., (2013) New England Journal of Medicine 369(2):134–44, US 8,354,509, WO2009 / 114335 and WO2013 / 079174.

[0340] In some embodiments, the immunomodulator is pidilimumab (CT-011; Cure Tech), a humanized IgG1k monoclonal antibody that binds to PD1. Pidililimumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO 2009 / 101611.

[0341] Other anti-PD1 antibodies that can be used as immunomodulators in the methods disclosed herein include AMP 514 (Amplimmune), and the anti-PD1 antibodies disclosed in US 8,609,089, US2010028330 and / or US20120114649. In some embodiments, the anti-PD-L1 antibody is MSB0010718C. MSB0010718C (also known as A09-246-2; Merck Serono) is a monoclonal antibody that binds to PD-L1.

[0342] In some embodiments, the immunomodulator is MDPL3280A (Genentech / Roche), a human Fc-optimized IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other monoclonal antibodies against PD-L1 are disclosed in U.S. Patent No. 7,943,743 and U.S. Publication No. 20120039906. Other anti-PD-L1 binders that can be used as immunomodulators in the methods of the present invention include YW243.55.S70 (see WO 2010 / 077634), MDX-1105 (also known as BMS-936559), and an anti-PD-L1 binder disclosed in WO 2007 / 005874.

[0343] In some embodiments, the immunomodulator is AMP-224 (B7-DCIg; Amplimmune; disclosed, for example, in WO2010 / 027827 and WO 2011 / 066342), a PDL2Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1.

[0344] In some embodiments, the immunomodulator is an anti-LAG-3 antibody such as BMS-986016. BMS-986016 (also known as BMS986016) is a monoclonal antibody that binds to LAG-3. BMS-986016 and other humanized anti-LAG-3 antibodies are disclosed in US2011 / 0150892, WO 2010 / 019570, and WO 2014 / 008218.

[0345] In some embodiments, the combination therapies disclosed herein include modulators of co-stimulatory or inhibitory molecules (e.g., co-inhibitory ligands or receptors).

[0346] In one embodiment, the co-stimulatory modulator (e.g., agonist) of the co-stimulatory molecule is selected from OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligands (e.g., agonistic antibodies or their antigen-binding fragments, or soluble fusions).

[0347] In another embodiment, the combination therapy disclosed herein includes an immunomodulatory agent, which is a co-stimulatory molecule, such as an agonist associated with a positive signaling of a co-stimulatory domain including CD28, CD27, ICOS and / or GITR.

[0348] Exemplary GITR agonists include, for example, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as GITR fusion proteins described in U.S. Patent No. 6,111,090, European Patent No. 090505B1, U.S. Patent No. 8,586,023, and PCT Publications WO 2010 / 003118 and 2011 / 090754, or anti-GITR antibodies described in U.S. Patent No. 7,025,962, European Patent No. 1947183B1, U.S. Patent No. 7,812,135, U.S. Patent No. 8,388,967, U.S. Patent No. 8,591,886, European Patent No. EP 1866339, PCT Publications WO 2011 / 028683, PCT Publications WO 2013 / 039954, and PCT Publications WO In the following patents: WO 2005 / 007190, PCT Publication No.: WO 2007 / 133822, PCT Publication No.: WO 2005 / 055808, PCT Publication No.: WO 99 / 40196, PCT Publication No.: WO2001 / 03720, PCT Publication No.: WO 99 / 20758, PCT Publication No.: WO 2006 / 083289, PCT Publication No.: WO2005 / 115451, US Patent No.: 7,618,632, and PCT Publication No.: WO 2011 / 051726.

[0349] In one embodiment, the immunomodulator used is a soluble ligand (e.g., CTLA-4-Ig), or an antibody or antibody fragment that binds to PDL1, PD-L2, or CTLA4. For example, an anti-PD-1 antibody molecule may be administered in combination with an anti-CTLA-4 antibody (e.g., ipilimumab). Exemplary anti-CTLA4 antibodies include tremelimumab (an IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206) and ipilimumab (a CTLA-4 antibody, also known as MDX-010, CAS number 477202-00-9).

[0350] In one embodiment, an anti-PD-1 antibody molecule is administered after treatment with a compound of the present invention as described herein.

[0351] In another embodiment, an anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody or an antigen-binding fragment thereof. In another embodiment, the anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-TIM-3 antibody or an antigen-binding fragment thereof. In other embodiments, the anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody and an anti-TIM-3 antibody, or an antigen-binding fragment thereof. The combinations of antibodies listed herein may be administered separately (e.g., as individual antibodies) or in combination (e.g., as bispecific or trispecific antibody molecules). In one embodiment, a bispecific antibody comprising an anti-PD-1 or PD-L1 antibody molecule and an anti-TIM-3 or anti-LAG-3 antibody, or an antigen-binding fragment thereof, is administered. In some embodiments, the combinations of antibodies listed herein are used to treat cancers, such as those described herein (e.g., solid tumors). The efficacy of the above combinations can be tested in animal models known in the art. For example, an animal model for testing the synergistic effect of anti-PD-1 and anti-LAG-3 is described in, for example, Woo et al. (2012) Cancer Res. 72(4): 917-27.

[0352] Exemplary immunomodulators that can be used in combination therapy include, but are not limited to, atoruzumab (available from...). ); Polyethylene glycol filgrastim Lenalidomide (CC-5013) ); Thalidomide Actimid (CC4047); and cytokines, such as IL-21 or IRX-2 (a mixture of human cytokines including interleukin-1, interleukin-2, and interferon-γ, CAS 951209-71-5, available from IRXTherapeutics).

[0353] Exemplary doses of such immunomodulators that can be used in combination with the antiviral compounds of the present invention include doses of about 1 to 10 mg / kg, such as 3 mg / kg of an anti-PD-1 antibody molecule, and about 3 mg / kg of an anti-CTLA-4 antibody, such as ipilimumab.

[0354] Examples of embodiments of methods for using the antiviral compounds of the present invention in combination with immunomodulators include those that can be used with compounds having Formula I disclosed herein, or any subgenus or species thereof:

[0355] i. A method for treating a viral infection in a subject, the method comprising administering to the subject a compound having formula (I) as described herein and an immunomodulator.

[0356] ii. The method as described in embodiment i, wherein the immunomodulator is an activator of a co-stimulatory molecule or an inhibitor of an immune checkpoint molecule.

[0357] iii. The method as described in embodiments i and ii, wherein the activator of the co-stimulatory molecule is one or more of the following agonists: OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, and CD83 ligands.

[0358] iv. The method of any one of embodiments i-iii above, wherein the inhibitor of the immune checkpoint molecule is selected from PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGFRβ.

[0359] v. The method as described in any one of embodiments i-iii, wherein the inhibitor of the immune checkpoint molecule is selected from inhibitors of PD-1, PD-L1, LAG-3, TIM-3 or CTLA4, or any combination thereof.

[0360] vi. The method as described in any one of embodiments iv, wherein the inhibitor of the immune checkpoint molecule is a soluble ligand or antibody or an antigen-binding fragment thereof that binds to the immune checkpoint molecule.

[0361] vii. The method as described in any one of embodiments i-vi, wherein the antibody or its antigen-binding fragment is derived from IgG1 or IgG4 (e.g., human IgG1 or IgG4).

[0362] viii. The method as described in any one of embodiments i-vii, wherein the antibody or its antigen-binding fragment is altered, for example, mutated, to increase or decrease one or more of the following: Fc receptor binding, antibody glycosylation, number of cysteine ​​residues, effector cell function, or complement function.

[0363] ix. The method of any one of embodiments i-viii, wherein the antibody molecule is a bispecific or multispecific antibody molecule having a first binding specificity to PD-1 or PDL1 and a second binding specificity to TIM-3, LAG-3 or PD-L2.

[0364] x. The method as described in any one of embodiments i-ix, wherein the immunomodulator is an anti-PD-1 antibody selected from nivolumab, pembrolizumab, or pildizumab.

[0365] xi. The method as described in any one of embodiments ix, wherein the immunomodulator is an anti-PD-L1 antibody selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.

[0366] xii. The method as described in any one of embodiments ix, wherein the immunomodulator is an anti-LAG-3 antibody molecule.

[0367] xiii. The method as described in embodiment xii, wherein the anti-LAG-3 antibody molecule is BMS-986016.

[0368] xiv. The method as described in any one of embodiments ix, wherein the immunomodulator is an anti-PD-1 antibody molecule, administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 30 mg / kg, such as about 5 to 25 mg / kg, about 10 to 20 mg / kg, about 1 to 5 mg / kg, or about 3 mg / kg, for example, once a week to every 2, 3, or 4 weeks.

[0369] xv. The method as described in embodiment xiv, wherein the anti-PD-1 antibody molecule is administered every other week at a dose ranging from about 10 to 20 mg / kg.

[0370] xvi. The method as described in embodiment xv, wherein the anti-PD-1 antibody molecule, such as nivolumab, is administered intravenously every two weeks at a dose of about 1 mg / kg to 3 mg / kg, such as about 1 mg / kg, 2 mg / kg or 3 mg / kg.

[0371] xvii. The method as described in embodiment xv, wherein the anti-PD-1 antibody molecule, such as nivolumab, is administered intravenously at a dose of about 2 mg / kg at 3-week intervals.

[0372] General synthesis program

[0373] The compounds described herein can be synthesized via the following general synthetic routes, with specific examples described in more detail in the examples.

[0374] All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents and catalysts used to synthesize the compounds of the present invention are commercially available or can be produced by organic synthesis methods known to those skilled in the art (Houben-Weyl, 4th edition, 1952, Methods of Organic Synthesis, Thieme, Vol. 21).

[0375] List of abbreviations

[0376] Acetyl group

[0377] CAN or MeCN acetonitrile

[0378] AcOEt / EtOAc Ethyl Acetate

[0379] AcOH (acetic acid)

[0380] aq water-based

[0381] Bn benzyl

[0382] Bu butyl (nBu = n-butyl, tBu = tert-butyl)

[0383] CDI carbonyl diimidazole

[0384] CH3CN Acetonitrile

[0385] DBU 1,8-diazabicyclo[5.4.0]-undec-7-ene

[0386] Boc2O ditert-butyl dicarbonate

[0387] DCE 1,2-Dichloroethane

[0388] DCM dichloromethane

[0389] DIAD (Diisopropyl Azodicarbonate)

[0390] DiBAl-H diisobutylaluminum hydride

[0391] DIPEA or DIEA N-ethyldiisopropylamine

[0392] DMA N,N-dimethylacetamide

[0393] DMAP dimethylaminopyridine

[0394] DMF N,N-dimethylformamide

[0395] DMSO (dimethyl sulfoxide)

[0396] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0397] EI electrospray ionization

[0398] Et2O diethyl ether

[0399] Et3N Triethylamine

[0400] Ether diethyl ether

[0401] EtOAc (ethyl acetate)

[0402] EtOH (ethanol)

[0403] FC rapid chromatography

[0404] h hours

[0405] HATU O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethylurea hexafluorophosphate

[0406] HBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0407] HCl hydrochloric acid

[0408] HMPA (Hexamethylphosphoramide)

[0409] HOBt 1-hydroxybenzotriazole

[0410] HPLC (High Performance Liquid Chromatography)

[0411] H2O water

[0412] IPA isopropanol

[0413] L rise

[0414] LC-MS (Liquid Chromatography-Mass Spectrometry)

[0415] LiHMDS bis(trimethylsilyl)aminolithium

[0416] MgSO4 Magnesium sulfate

[0417] Me methyl

[0418] MeI iodomethane

[0419] MeOH (methanol)

[0420] mg

[0421] min minutes

[0422] mL

[0423] MS mass spectrometry

[0424] MsCl methanesulfonyl chloride

[0425] NaHCO3 (Sodium bicarbonate)

[0426] Na2SO4 Sodium sulfate

[0427] NH2OH Hydroxylamine

[0428] Pd / C Palladium / Carbon

[0429] Pd(OH)₂ palladium hydroxide

[0430] PG protection base

[0431] Ph phenyl

[0432] Ph3P Triphenylphosphine

[0433] Prep preparation type

[0434] Rf shift value

[0435] RP inversion

[0436] Rt retention time

[0437] RT room temperature

[0438] SFC Supercritical Fluid Chromatography

[0439] SiO2 silica gel

[0440] SOCl2 thionyl chloride

[0441] Propylphosphonic anhydride

[0442] TBAF Tetrabutylammonium Fluoride

[0443] TBDMS tert-butyldimethylsilyl

[0444] TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate

[0445] TEA Triethylamine

[0446] TFA (trifluoroacetic acid)

[0447] THF Tetrahydrofuran

[0448] TLC (Thin Layer Chromatography)

[0449] TsCl Toluenesulfonyl chloride

[0450] TsOH Toluenesulfonic acid

[0451] In view of the embodiments and schemes provided herein, the compounds of the present invention are prepared from commonly used compounds using methods known to those skilled in the art.

[0452] Within the scope of this document, unless the context otherwise indicates, any easily removable group of a component of a particular desired final product of a compound not of this invention is designated as a “protecting group”. For example, the protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described in the following standard references: Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627pp. (URL: http: / / www.science-of-synthesis.com (electronic version, Vol. 48)); JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; TW Greene and PGM Uts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999, "The Peptides"; Vol. 3 (edited by E. Gross and J. Meienhofer), Academic Press, London and New York 1981, "Methoden der Organicischen Chemie (Methods of Organic Chemistry), Houben Weyl, 4th edition, Vol. 15 / I, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Jeschkeit, Peptide, Protein" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield BeacH and Basel 1982, and Jochen Lehmann, "Chemieder Kohlenhydrate: Monosaccharide und Derivative" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. The protecting group is characterized by its easy removal (i.e., without undesirable side reactions), for example, by solvent decomposition, reduction, photolysis or alternatively under physiological conditions (e.g., by enzymatic cleavage). Salts of the compounds of the invention having at least one salifying group can be prepared in ways known per se. For example, salts can be prepared by using metal compounds, such as alkali metal salts of suitable organic carboxylic acids (e.g., sodium salts of 2-ethylhexanoic acid); or by using organic alkali metal or alkaline earth metal compounds (e.g., the corresponding hydroxides, carbonates or bicarbonates, such as sodium hydroxide or potassium hydroxide, sodium carbonate or...). Potassium carbonate, sodium bicarbonate, or potassium bicarbonate; salts of the compounds of the present invention having acid groups are formed by treating the compound with a corresponding calcium compound or with ammonia or a suitable organic amine; preferably with a stoichiometric amount or only a small excess of a salting agent. Acid addition salts of the compounds of the present invention are obtained in a conventional manner, for example by treating the compound with an acid or a suitable anion exchanger. Inner salts of the compounds of the present invention containing acid and base salting groups (e.g., free carboxyl and free amino groups) can be formed, for example, by neutralizing the salt (e.g., an acid addition salt) to its isoelectric point (e.g., using a weak base or by treatment with an ion exchanger).

[0453] Salts can be converted into free compounds in conventional ways; for example, by treatment with suitable acids and acid addition salts, or by treatment with suitable basic agents, metal and ammonium salts can be converted.

[0454] The mixture of isomers available according to the invention can be separated into individual isomers in a manner known per se; diastereomers can be separated, for example, by partitioning between multiphase solvent mixtures, recrystallization and / or chromatographic separation, such as silica gel chromatography, or by medium-pressure liquid chromatography, for example, using a reversed-phase column; racemic mixtures can be separated, for example, by forming a salt with an optically pure salting agent (e.g., by fractional crystallization) of the diastereomer mixtures thus obtainable, or by chromatographic treatment on an optically active column material.

[0455] Intermediates and final products can be post-processed and / or purified using standard methods, such as chromatography, partitioning, (re)crystallization, etc.

[0456] Example

[0457] The invention is further illustrated by the following examples, which should not be construed as limiting. The assays used throughout the examples are established in the art: effectiveness demonstrated in these assays is generally considered a predictor of effectiveness in subjects.

[0458] The compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art, referring to the following reaction routes and examples. General methods for synthesizing compounds of formula (I) are provided in Routes I through III below.

[0459] Route I: A general method for synthesizing compounds of formula (I).

[0460]

[0461] Route I illustrates a general method for synthesizing many compounds of formula (I) from the intermediates described herein. A bicyclic intermediate (e.g., intermediate I-1) may be N-alkylated to attach the target WL- moiety, particularly where L is linked via –CH2-. WLX represents a suitable alkylating agent for such reactions, where X is a leaving group, such as a halogen (preferably Br or I), or a sulfonate leaving group, such as methanesulfonate, toluenesulfonate, or trifluoromethanesulfonate. The WL- moiety may, of course, contain functional groups, such as hydroxyl or amino groups, that can be further modified in the product of formula (I), preferably in a protected form, which can be deprotected and further derivatized using methods well known in the art.

[0462] R can be a simple alkyl ester, such as methyl, ethyl, propyl, isopropyl, tert-butyl, or n-butyl; and if WL- contains an ester, R can be a different ester, such as benzyl, which is easily distinguishable from the ester in WL-, so R can be selectively hydrolyzed to allow coupling in route I. In some embodiments, R is an ester hydrolyzed under alkylation conditions, possibly due to the presence of foreign water or hydroxide; in other embodiments, a separate hydrolysis step is used, such as the addition of lithium hydroxide, sodium hydroxide, or potassium hydroxide and water. The resulting free formate compound is then readily coupled with a suitable amine containing the desired Cy group, said coupling using standard amide bond formation conditions and reagents well known in the art. This can be a direct amidation of a carboxylic acid ester, or it can be achieved by converting the carboxylic acid into an activated intermediate (acyl chloride, anhydride, etc.) known in the art and illustrated by the appended examples.

[0463] Route II: Substitutional preparation of compound (I).

[0464]

[0465] Route II describes an alternative synthesis of the Formula I compound illustrated in Example 51 below. This synthetic route begins with an intermediate prepared as described herein (see, for example, I-17 below) and uses an amine to introduce the target WL-moment by opening the lactone. The first intermediate shown contains a free primary hydroxyl group, which readily converts to a leaving group (Cl in the examples, but could be replaced with an alkyl sulfonate or aryl sulfonate). Under basic conditions (e.g., NaH), the leaving group readily substitutes to form a new six-membered ring with the desired WL-moment attached. For Route I, the introduced WL-moment may contain a functional group (optionally in a protected form), which can then be modified as needed. For example, the WL-moment in Example 51 contains a thioether, and the sulfur atom is oxidized to provide the desired sulfone.

[0466] Route III: Another synthetic route for compounds of formula I.

[0467]

[0468] Route III provides another method for preparing compounds of formula (I) starting with a carboxypyridone derivative, the synthesis of which is described herein (e.g., Example 91). The initial starting material (e.g., I-17C) is prepared as described herein and coupled to a hydroxyethyl-substituted amine derivative by conventional methods, wherein the amine nitrogen is linked to the desired WL-moment. After coupling, the free hydroxyl group is converted to a leaving group, such as Cl or a methanesulfonate, and then cyclized on the pyridone ring nitrogen under basic conditions; alternatively, coupling can be performed under typical Mitsunobu conditions (e.g., treatment with triphenylphosphine and DIAD). Similarly, the WL-moment may contain functional groups optionally in a protected form, which can then be used for further modification or derivatization of the WL-moment to provide the desired target compound.

[0469] Using these methods, as well as other extensions, modifications, and alterations shown in the following examples, those skilled in the art can readily prepare various Formula I compounds.

[0470] Preparation of key intermediates

[0471] Intermediate 1

[0472] 1,6-Dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylate butyl ester

[0473]

[0474] Butyl 6-(dibutoxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (I-1B). TsOH·H₂O (0.446 g, 2.345 mmol) was added to a slurry of 6-(dimethoxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (I-1A) (5 g, 23.45 mmol) in n-BuOH (100 mL). The resulting mixture was stirred overnight at 110 °C, then cooled to room temperature and concentrated under reduced pressure. I-1B, a deep red oil, was separated as a mixture of Bu / Bu and Me / Bu acetals. LCMS m / z: 312(M+1)OBu / OMe, 354(M+1)OBu / OBu.

[0475] Butyl 6-formyl-2-oxo-1,2-dihydropyridine-3-carboxylate (I-1C). I-1B (8.29 g, 23.45 mmol) was dissolved in TFA (200 mL). H₂O (10 mL) was added to the acidic solution. The resulting solution was stirred at room temperature for 5 h, then concentrated under reduced pressure. The dark residue was dissolved in DCM and washed with H₂O and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give I-1C as a dark brown, foamy substance. LCMS m / z: 224 (M+1). 1 H NMR (400MHz, CDCl3) δppm 0.95-1.03(m,3H)1.48(dq,J=15.01,7.43Hz,2H)1.73-1.84(m,2H)4.42( t,J=6.65Hz,2H)7.44(br.s.,1H)8.35(d,J=7.53Hz,1H)9.90(br.s.,1H).

[0476] 5-(butoxycarbonyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (I-1D). 2-methyl-2-butene (50.3 mL, 474 mmol) was added to a cooled (0 °C) solution of I-1C (3.53 g, 15.81 mmol) in t-BuOH (85 mL) / H₂O (85 mL), followed by the addition of NaH₂PO₄·H₂O (3.27 g, 23.72 mmol) and NaClO₂ (2.145 g, 23.72 mmol). After 2.5 h, the reaction mixture was diluted with CHCl₃ and 2 M HCl. The phases were separated, and the aqueous layer was extracted with CHCl₃. The organic extract was dried over sodium sulfate and concentrated under reduced pressure. The brown solid was ground with Et₂O and heptane. The resulting precipitate was collected by vacuum filtration and dried on a glass frit. I-1D, as a brown solid, was separated. LCMS m / z: 240(M+1). 1H NMR(400MHz,DMSO-d6)δppm 0.91(t,J=7.38Hz,3H)1.40(dq,J=14.91,7.40Hz,2H)1.59-1.68(m,2H)4.20(t,J=6.50Hz,2H)7.00(br.s.,1H)8.06(d,J=7.24Hz,1H).

[0477] 6-((2-chloroethyl)carbamoyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (I-1E). DIEA (2.146 mL, 12.29 mmol) was added to a solution of I-1D (1.47 g, 6.14 mmol) in DCM (75 mL), followed by TMSCl (1.571 mL, 12.29 mmol). The resulting solution was stirred at room temperature for 1.5 h. The reaction mixture was cooled to 0 °C and SOCl2 (0.942 mL, 12.90 mmol) was slowly added. The resulting mixture was heated to room temperature over a period of 2.5 h. The reaction mixture was cooled to 0 °C and 2-chloroethylamine HCl (2.85 g, 24.58 mmol) was added, followed by DIEA (5.37 mL, 30.7 mmol) slowly added. After the addition of the base, the yellow mixture became very dark. After stirring overnight, the reaction mixture was diluted with DCM, washed with 2M HCl and brine, and dried over magnesium sulfate. The dried organic layer was concentrated under reduced pressure. I-1E, a dark oily substance, was separated. LCMS m / z: 301 (M+1).

[0478] Butyl 1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylate (I-1). DIEA (2.227 mL, 12.75 mmol) was added to a solution of I-1E (0.767 g, 2.55 mmol) in ACN (51.0 mL). The mixture was stirred at 90 °C. After the starting material was exhausted, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DCM, washed successively with 2 M HCl and saturated sodium bicarbonate, and dried over sodium sulfate. The dried organic layer was concentrated under reduced pressure. The title compound (I-1) was isolated as a dark solid. LCMS m / z: 265 (M+1). 1 H NMR (400MHz, CDCl3) δppm 0.96(t,J=7.38Hz,3H)1.46(dq,J=15.03,7.43Hz,2H)1.69-1.79(m,2H)3.63-3.73(m ,2H)4.29-4.37(m,4H)6.46(br.s.,1H)7.17(d,J=7.39Hz,1H)8.15(d,J=7.39Hz,1H).

[0479] Intermediate 2

[0480] (1-(cyclopropylsulfonyl)cyclopropyl)methylmethanesulfonate

[0481]

[0482] 2-(cyclopropylsulfonyl)acetic acid benzyl ester (I-2B). 2-Bromobenzyl acetate (5.97 mL, 37.7 mmol) was added to a slurry of sodium cyclopropanesulfinate (5.79 g, 45.2 mmol) in DMF (30 mL). The resulting mixture was stirred overnight at room temperature, followed by dilution with H₂O and Et₂O. The aqueous layer was extracted with Et₂O. The combined Et₂O layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give I-2B (9.37 g, 36.8 mmol, 98% yield) as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δppm 1.02-1.09(m,2H)1.24-1.31(m,2H)2.67-2.76(m,1H)4.03-4.09(m,2H)5.26(s,2H)7.34-7.44(m,5H).

[0483] 1-(cyclopropylsulfonyl)cyclopropanecarboxylic acid benzyl ester (I-2C). K₂CO₃ (10.18 g, 73.7 mmol) was added to a solution of I-2B (9.37 g, 36.8 mmol) in DMF (350 mL), followed by the addition of 1,2-dibromoethane (3.81 mL, 44.2 mmol). The resulting mixture was stirred at 60 °C for 12 h, then cooled to room temperature and diluted with Et₂O. The resulting insoluble matter was filtered off. The filtrate was washed with water. The aqueous layer was extracted with Et₂O. The combined ether extracts were washed with brine and concentrated under reduced pressure. The oil was purified by column chromatography (SiO₂, 0-100% DCM / heptane) to obtain a colorless oil, I-2C. 1 H NMR (400MHz, CDCl3) δppm 0.95-1.01(m,2H)1.20-1.25(m,2H)1.63-1.68(m,2H)1.72-1.78(m,2H)3.00(tt,J=8.09,4.90Hz,1H)5.22-5.26(m,2H)7.32

[0484] -7.41(m,5H).

[0485] (1-(cyclopropylsulfonyl)cyclopropyl)methanol (I-2D). LiBH4 (2M, 11.65mL, 23.29mmol in THF) was added to a solution of I-2C (6.53g, 23.29mmol) in 50mL of THF. The resulting yellow solution was stirred overnight at room temperature. The reaction was quenched by adding the reaction mixture to a 2M HCl / ice mixture. The biphasic mixture was extracted with DCM. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The colorless oil was purified by column chromatography (SiO2, 0-100% EtOAc / heptane) to obtain I-2D as a colorless oil. LCMS m / z: 177 (M+1). 1 H NMR (400MHz, CDCl3) δppm 1.01-1.10 (m, 4H) 1.23-1.29 (m, 2H) 1.47-1.52 (m, 2H) 2.50-2.59 (m, 2H) 3.92 (d, J = 6.11Hz, 2H).

[0486] (1-(cyclopropylsulfonyl)cyclopropyl)methylmethanesulfonate (I-2). DIEA (7.33 mL, 42.0 mmol) and MsCl (1.800 mL, 23.09 mmol) were added to a solution of I-2D (3.7 g, 20.99 mmol) in DCM (40 mL). The color of the reactants changed from colorless to yellow. After 45 min, the reaction mixture was diluted with DCM, washed with 2 M HCl, and dried over sodium sulfate. The dried organic layer was concentrated to obtain the title compound (I-2) as an amber oil. 1 H NMR (400MHz, CDCl3) δppm 1.06-1.13(m,2H)1.18-1.23(m,2H)1.23-1.29(m,2H)1.61-1.67(m,2H)2.50-2.59(m,1H)3.09(s,3H)4.54(s,2H).

[0487] Intermediate 3

[0488] (1-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0489]

[0490] Ethyl 2-((4-oxobut-2-yl)thio)ethyl acetate (I-3B). NET3 (1.160 mL, 8.32 mmol) was added to a solution of I-3A (0.909 mL, 8.32 mmol) in DCM (20 mL), followed by the addition of cis- and trans-crotonaldehyde (0.689 mL, 8.32 mmol). The resulting mixture was stirred at room temperature for approximately 1 h. The reactants were diluted with DCM and washed with 2 M HCl. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. I-3B was separated as a colorless oil. LCMS m / z: 191 (M+1). 1 HNMR(500MHz,CDCl3)δppm 1.29(t,J=7.25Hz,3H)1.38(d,J=6.94Hz,3H)2.63(dt,J=7.25,1.58Hz,1H)2.76(dquin,J=6.46,1.73 ,1.73,1.73,1.73Hz,1H)3.27-3.30(m,2H)3.47(d,J=6.94Hz,1H)4.15-4.25(m,3H)9.75-9.78(m,1H).

[0491] Ethyl 2-((4-hydroxybut-2-yl)thio)ethyl acetate (I-3C). NaBH4 (0.146 g, 3.86 mmol) was added to a cooled (0 °C) solution of I-3B (1.47 g, 7.73 mmol) in THF (25 mL). The resulting mixture was stirred at room temperature for approximately 1.5 h, then cooled to 0 °C and quenched with 2 M HCl. The aqueous mixture was extracted with DCM. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. I-3C was separated as a colorless oil. LCMS m / z: 193 (M+1).

[0492] Ethyl 2-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)thio)ethyl acetate (I-3D). Imidazole (0.956 g, 14.04 mmol) was added to a solution of I-3C (1.35 g, 7.02 mmol) in DCM (25 mL), followed by the addition of TBSCl (1.164 g, 7.72 mmol). The mixture was stirred at room temperature. After the reaction was complete, it was diluted with DCM and washed with 2 M HCl and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. I-3D was separated as a colorless oil. LCMS m / z: 307 (M+1).

[0493] Ethyl 2-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)sulfonyl)ethyl acetate (I-3E). To a solution of I-3D (2 g, 6.52 mmol) in DCM (50 mL), mCPBA (2.92 g, 13.05 mmol) was added. After stirring overnight at room temperature, the reaction mixture was diluted with DCM and filtered through a diatomaceous earth stopper. The filtrate was washed with saturated sodium bicarbonate and brine. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-50% EtOAc / heptane) to give I-3E as a colorless oil. LCMS m / z: 339 (M+1). 1 H NMR (400MHz, CDCl3) δppm 0.07(s,6H)0.90(s,9H)1.33(t,J=7.14Hz,3H)1.45(d,J=6.90Hz,3H)1.70(ddt,J=14.02,9.38,4.76,4.76Hz,1H)2.25-2.36(m,1H)3.59 -3.69(m,1H)3.73(ddd,J=10.42,8.66,4.55Hz,1H)3.83(dt,J=10.48,5.30Hz,1H)3.98(td,J=14.04,5.92Hz,2H)4.28(q,J=7.14Hz,2H).

[0494] 1-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)sulfonyl)cyclopropanecarboxylic acid ethyl ester (I-3F) was prepared from I-3E according to a procedure similar to that described in I-2C. I-3F was isolated as a deep orange oil. LCMS m / z: 365 (M+1).

[0495] (1-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)sulfonyl)cyclopropyl)methanol (I-3G) was prepared from I-3F according to a procedure similar to that described in I-2D. I-3G was isolated as a colorless oil. LCMS m / z: 323 (M+1). 1 HNMR(400MHz, CDCl3)δppm0.08(s,6H)0.90(s,9H)1.05(td,J=5.09,1.47Hz,2H)1.42(d,J=6.85Hz,3H)1.50(td,J=5.28,1.96Hz,2H)1.58 -1.64(m,1H)2.37(dd,J=8.80,5.04Hz,1H)2.63(t,J=5.72Hz,1H)3.62-3.73(m,2H)3.83(dt,J=10.27,5.09Hz,1H)3.88(d,J=5.48Hz,2H).

[0496] (1-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)sulfonyl)cyclopropyl)methylmethanesulfonate (I-3) was prepared from I-3G according to a procedure similar to that described in I-2. I-3 was isolated as an orange oil. LCMS m / z: 401 (M+1).

[0497] Intermediate 4

[0498] (1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0499]

[0500] 1-((benzyloxy)methyl)cyclopropane-1-sulfonate butyl ester (I-4B). I-4A (4.28 mL, 28.1 mmol) was cooled to -78 °C in a solution of THF (200 mL). nBuLi (13.46 mL, 33.7 mmol) was added while maintaining the temperature below -75 °C. After the addition was complete, the yellow solution was stirred for approximately 15 min. Benzyloxymethyl chloride (4.68 mL, 33.7 mmol) was added, and the reaction mixture was heated to room temperature overnight. The reaction mixture was cooled to 0 °C and quenched with H₂O. The aqueous mixture was diluted with EtOAc, and the phases were separated. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (SiO₂ 0-50% EtOAc / heptane) to give the title compound (I-4B) as a colorless oil. LCMS m / z: 299 (M+1). 1 HNMR(400MHz,CDCl3)δppm 0.86-0.92(m,3H)1.08-1.13(m,2H)1.37(dq,J=15.00,7.44Hz,2H)1.46-1.51(m,2H )1.61-1.71(m,2H)3.79(s,2H)4.23(t,J=6.60Hz,2H)4.55(s,2H)7.26-7.38(m,5H).

[0501] 1-((benzyloxy)methyl)cyclopropane-1-sulfonic acid (I-4C). Potassium thiocyanate (2.1 g, 21.61 mmol) was added to a solution of I-4B (6.14 g, 20.58 mmol) in DME (100 mL) / H₂O (100 mL). The resulting mixture was stirred overnight under reflux, then cooled to room temperature and diluted with H₂O and EtOAc. The phases were separated, and the aqueous layer was concentrated under reduced pressure to give I-4C as a yellow solid. LCMS m / z: 243 (M+1). 1H NMR(400MHz, DMSO-d6)δppm 0.57-0.61(m,2H)0.78-0.83(m,2H)3.73(s,2H)4.45(s,2H)7.21-7.36(m,5H).

[0502] 1-((benzyloxy)methyl)cyclopropane-1-sulfonyl chloride (I-4D). SOCl2 (55 mL, 754 mmol) was added to a mixture of I-4C (5.7 g, 20.26 mmol) and DMF (5.5 mL). The mixture was stirred under reflux. After approximately 45 min, the reaction mixture became homogeneous and was concentrated under reduced pressure. The yellow residue was dissolved in EtOAc and washed with brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. I-4D, appearing as an orange oil, was separated. 1 H NMR (400MHz, CDCl3) δppm 1.37-1.43 (m, 2H) 1.76-1.82 (m, 2H) 4.00 (s, 2H) 4.61 (s, 2H) 7.27-7.40 (m, 5H).

[0503] (((1-Hydrosulfonylcyclopropyl)methoxy)methyl)phenyl sodium salt (I-4E). NaHCO3 (4.64 g, 55.2 mmol) was added to a solution of sodium sulfite (3.48 g, 27.6 mmol) in H2O (15 mL). The mixture was stirred at 50 °C for approximately 45 min, followed by the addition of I-4D (7.2 g, 27.6 mmol). The mixture was stirred overnight at 50 °C and then concentrated under reduced pressure. The brown residue was ground with MeOH. The insoluble matter was filtered off and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. I-4E was separated as a brown solid. LCMS m / z: 277 (M+1). 1 H NMR (400MHz, DMSO-d6) δppm 0.22 (d, J = 2.54Hz, 2H) 0.62 (d, J = 2.49Hz, 2H) 3.62 (s, 2H) 4.44 (s, 2H) 7.29 (d, J = 1.91Hz, 5H).

[0504] 2-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)ethyl acetate (I-4F). Ethyl bromoethyl (2.96 mL, 26.6 mmol) was added to a slurry of I-4E (6.6 g, 26.6 mmol) in DMF (25 mL). The resulting mixture was stirred overnight at room temperature and then diluted with Et2O. The insoluble matter was filtered off and the filtrate was washed with brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The orange oily I-4F was separated. LCMS m / z: 313 (M+1). 1H NMR (400MHz, CDCl3) δppm0.98-1.03 (m, 2H) 1.30 (t, J = 1.00Hz, 3H) 1.57-1.63 ( m,2H)3.78(s,2H)4.20-4.27(m,2H)4.28(s,2H)4.57(s,2H)7.27-7.40(m,5H).

[0505] Ethyl 1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropanecarboxylate (I-4G) was prepared from I-4F according to a procedure similar to that described in I-2C. I-4G was isolated as a pale yellow oil. LCMS m / z: 339 (M+1). 1 H NMR (400MHz, CDCl3) δppm 1.05-1.10(m,2H)1.23(t,J=7.19Hz,3H)1.57-1.63(m,2H)1.71-1.77(m,2H)1.7 8-1.84(m,2H)3.71(s,2H)4.13(q,J=7.11Hz,2H)4.48(s,2H)7.26-7.38(m,5H).

[0506] (1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (I-4H) was prepared from I-4G according to a procedure similar to that described in I-2D. I-4H was isolated as a colorless oil and cured overnight in a vacuum. LCMS m / z: 297 (M+1). 1 H NMR (400MHz, CDCl3) δppm 0.95-1.01(m,2H)1.05-1.11(m,2H)1.48-1.55(m,2H)1.62-1.70(m,2H)3.47(t, J=5.65Hz,1H)3.75(s,2H)3.83(d,J=5.67Hz,2H)4.56(s,2H)7.29-7.43(m,5H).

[0507] (1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methylmethane sulfonate (I-4) was prepared from I-4G according to a procedure similar to that described in I-2. I-4 was isolated as an orange oil. 1 H NMR (400MHz, CDCl3) δppm 1.06-1.13(m,4H)1.57-1.66(m,4H)3.00(s,3H)3.75(s,2H)4.51(s,2H)4.53(s,2H)7.27-7.40(m,5H).

[0508] Intermediate 5

[0509] (1-((1-(fluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0510]

[0511] (((1-((1-(fluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (I-5B). CsF (0.192 g, 1.262 mmol) was added to a solution of I-4 (0.315 g, 0.841 mmol) in THF (0.5 mL) / iPrOH (1 mL). The resulting mixture was heated to 100 °C. After 72 h, the reaction mixture was cooled to room temperature and diluted with Et2O. The insoluble matter was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-50% EtOAc / heptane) to give I-5B as a colorless oil. LCMS m / z: 299 (M+1). 1 H NMR (400MHz, CDCl3) δppm 1.01-1.07 (m, 2H) 1.07-1.12 (m, 2H) 1.54-1.63 (m, 4H) 3.79 (s, 2H) 4.53 (s, 2H) 4.58 (d, J = 48.86Hz, 1H) 7.27-7.39 (m, 5H).

[0512] (1-((1-(fluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (I-5C). Pd / C (5.92 mg, 5.56 μmol) was added to a solution of I-5B (0.166 g, 0.556 mmol) in AcOH. The atmosphere was exchanged for H2. After the reaction was complete, the mixture was filtered through an Acros filter. The filtrate was concentrated under reduced pressure to give I-5C as a grayish-white semi-solid. LCMS m / z: 209 (M+1).

[0513] (1-((1-(fluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methylmethanesulfonate (I-5) was prepared from I-5C according to a procedure similar to that described in I-2. I-5 was isolated as a yellow oil. LCMS m / z: 287 (M+1).

[0514] Intermediate 6

[0515] (1-((1-(methoxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0516]

[0517] (((1-((1-(methoxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene(I-6A).

[0518] To a solution of I-4H (0.25 g, 0.844 mmol) in THF (3 mL), NaH (60% suspension in mineral oil, 0.037 g, 0.928 mmol) was added, followed by MeI (0.053 mL, 0.852 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and washed with 2 M HCl and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. I-6A, a yellow oily substance, was separated. LCMS m / z: 311 (M+1). 1 H NMR(500MHz,CDCl3)δppm 0.98-1.02(m,2H)1.06-1.11(m,2H)1.48-1.52(m,2H)1.53-1.57(m,2H)3.32(s,3H)3.72(s,2H)3.83(s,2H)4.55(s,2H)7.30-7.40(m,5H).

[0519] (1-((1-(methoxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (I-6B) was prepared from I-6A according to a procedure similar to that described in I-5C. I-6B was isolated as a yellow oil. LCMS m / z: 211 (M+1).

[0520] (1-((1-(methoxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methylmethanesulfonate (I-6) was prepared from I-6B according to a procedure similar to that described in I-2. I-6 was isolated as a brown oily substance. LCMS m / z: 299, (M+1).

[0521] Intermediate 7

[0522] 3-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)sulfonyl)acetidine-1-carboxylic acid tert-butyl ester

[0523]

[0524] 1-tert-butyl 3-(2-thiopyridin-1(2H)-yl)acetidine-1,3-dicarboxylic acid (I-7B). A solution of I-7A (5 g, 24.85 mmol) in DCM (50 mL) was cooled to 0 °C. Oxaloyl chloride (3.26 mL, 37.3 mmol) and one drop of DMF were added to the cooled solution, which immediately caused vigorous bubbling. The reaction mixture was slowly heated to room temperature. After the reaction was complete, the mixture was cooled to 0 °C and covered with aluminum foil. DMAP (0.304 g, 2.485 mmol) and sodium 2-thiopyridin-1(2H)-ol (5 g, 33.5 mmol) were added sequentially. After 1 h 45 min, the reactants were cooled to 0 °C and extracted with H2O. The phases were separated, and the organic layer was filtered through a diatomaceous earth plug and washed with DCM. The filtrate was concentrated under reduced pressure to obtain the title compound (I-7B) as a dark, viscous oil. LCMS m / z: 311(M+1).

[0525] 3-(pyridin-2-ylsulfonyl)acetidine-1-carboxylic acid tert-butyl ester (I-7C). I-7B (7.71 g, 24.84 mmol) was dissolved in EtOAc (50 mL) and stirred under 150 W lamp irradiation. After 1 h, the reaction mixture was cooled to room temperature and diluted with water (50.0 mL). The flask was cooled to 0 °C and ruthenium trichloride (0.026 g, 0.124 mmol) was added, followed by sodium periodate (31.9 g, 149 mmol). The resulting mixture was stirred overnight at room temperature and then diluted with EtOAc and H2O. The insoluble matter was filtered off and the filter cake was washed with EtOAc. The two-phase filtrate was separated, the organic layer was dried with sodium sulfate, and concentrated under reduced pressure. The residue was dry-loaded onto diatomaceous earth and purified by column chromatography (SiO2, 0-100% EtOAc / heptane) to obtain the title compound (I-7C) as a pale yellow oil. LCMS m / z: 299 (M+1), 243 (M-55). 1 H NMR (400MHz, CDCl3) δppm 1.45(s,9H)4.16-4.23(m,2H)4.39(br.s.,2H)4.41-4.53(m,1H)7.58(ddd,J= 7.65,4.72,1.12Hz,1H)7.96-8.03(m,1H)8.09-8.14(m,1H)8.69-8.76(m,1H).

[0526] Sodium 1-(tert-Butoxycarbonyl)acetidine-3-sulfinate (I-7D). Sodium ethanethiol (2.402 g, 28.6 mmol) was added to a solution of I-7C (2.84 g, 9.52 mmol) in THF (45 mL). After stirring for 24 h, additional sodium ethanethiol (2.402 g, 28.6 mmol) was added at room temperature. After the reaction was complete, the mixture was diluted with heptane and filtered. The viscous filter cake was washed with Et₂O. The semi-solid was dissolved in EtOH and concentrated under vacuum. The title compound (I-7D) was separated as a grayish-white solid and used without further purification. LCMS m / z: 166 (M-55). 1 H NMR (400MHz, D2O) δppm1.40-1.49(m,9H)3.12-3.23(m,1H)4.03(d,J=4.55Hz,2H)4.05-4.14(m,2H).

[0527] 3-((2-ethoxy-2-oxoethyl)sulfonyl)acetidine-1-carboxylic acid tert-butyl ester (I-7E). Ethyl 2-bromoethyl acetate (1.723 mL, 15.57 mmol) was added to a mixture of I-7D (4.54 g, 18.68 mmol) and DMF (100 mL). The reaction mixture was stirred at room temperature for 10 min, followed by dilution with H₂O and Et₂O. The phases were separated, and the aqueous layer was extracted with Et₂O. The combined ether extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, eluting from heptane to DCM to acetone) to obtain the title compound (I-7E) as a yellow oil. LCMS m / z: 252 (M-55). 1 HNMR (400MHz, CDCl3) δppm 1.34 (t, J = 1.00Hz, 3H) 1.45 (s, 9H) 3.95 (s, 2H) 4.13 (q, J = 7.16Hz, 1H) 4.25-4.35 (m, 6H).

[0528] 3-((1-(ethoxycarbonyl)cyclopropyl)sulfonyl)acetidine-1-carboxylic acid tert-butyl ester (I-7F) was prepared from I-7E according to a procedure similar to that described in I-2C. The title compound was isolated as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm1.29 (t, J = 7.14Hz, 3H) 1.44 (s, 9H) 1.63-1.69 (m, 2H) 1.78-1.84 ( m,2H)4.14-4.20(m,2H)4.20-4.26(m,2H)4.38(dd,J=9.44,6.16Hz,2H)4.46-4.55(m,1H).

[0529] 3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)acetidine-1-carboxylic acid tert-butyl ester (I-7G) was prepared from I-7F according to a procedure similar to that described in I-2D. I-7G was isolated as a colorless oil. LCMS m / z: 236 (M-55). 1 H NMR (400MHz, CDCl3) δppm 0.98-1.03 (m, 2H) 1.44 (s, 9H) 1.48-1.54 (m, 2H) 2.43 (t, J = 4.94Hz, 1H) 3.86 (d, J = 4.94Hz, 2H) 4.08 -4.15(m,1H)4.17(d,J=8.46Hz,1H)4.22-4.30(m,1H)4.30-4.36(m,2H).

[0530] 3-((1-((((methylsulfonyl)oxy)methyl)cyclopropyl)sulfonyl)acetidine-1-carboxylic acid tert-butyl ester (I-7) was prepared from I-7G according to a procedure similar to that described in I-2. I-7 was isolated as a yellow oil. LCMS m / z: 392 (M+23), 314 (M-55).

[0531] Intermediate 8

[0532] (1-(cyclopentylsulfonyl)cyclopropyl)methylmethanesulfonate

[0533]

[0534] 2-(cyclopentylthio)ethyl acetate (I-8B). K₂CO₃ (5.29 g, 38.3 mmol) and cyclopentyl iodine (2.95 mL, 25.5 mmol) were added to a solution of I-8A (3.08 mL, 28.1 mmol) in acetone (80 mL). The resulting mixture was stirred overnight at 60 °C. The reaction mixture was cooled to room temperature and filtered to remove excess base. The filtrate was concentrated under reduced pressure, and the residue was dissolved in EtOAc and H₂O. The phases were separated, and the organic layer was washed (3 times) with saturated sodium thiosulfate. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. The title compound (I-8B) was separated from the colorless oil. 1 H NMR (400MHz, CDCl3) δppm 1.25-1.31(m,3H)1.46-1.63(m,4H)1.67-1.89(m,2H)1.96-2.09(m,2H)3.19-3.28(m,3H)4.15 -4.22(m,2H).

[0535] 2-(cyclopentylsulfonyl)ethyl acetate (I-8C). Potassium persulfate (Oxone) (25.9 g, 42.2 mmol) and a catalytic amount of H₂O were added to a solution of I-8B (3.97 g, 21.08 mmol) in EtOH (100 mL). The resulting slurry was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was dissolved in CHCl₃ and H₂O, the phases were separated, and the organic layer was washed with saturated sodium thiosulfate, dried with sodium sulfate, and concentrated under reduced pressure. The resulting yellow residue was purified by column chromatography (SiO₂, 0-100% DCM / heptane) to obtain I-8C as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δppm 1.30-1.36(m,3H)1.64-1.75(m,2H)1.79-1.91(m,2H)2.02-2.17(m,4H)3.78-3.88(m,1H)3.94(s,2H)4.24-4.32(m,2H).

[0536] 1-(cyclopentylsulfonyl)cyclopropanecarboxylate (I-8D) was prepared from I-8B according to a procedure similar to that described in I-2C. LCMS m / z: 247 (M+1).

[0537] (1-(cyclopentylsulfonyl)cyclopropyl)methanol (I-8E) is prepared from I-8D according to a procedure similar to that described in I-2D. 1 H NMR (400MHz, CDCl3) δppm 0.98-1.04(m,2H)1.48-1.53(m,2H)1.63-1.70(m,2H)1.77-1.87(m,2H)2.05-2.1 2(m,4H)2.55(t,J=5.38Hz,1H)3.77(quin,J=8.30Hz,1H)3.88(d,J=4.84Hz,2H).

[0538] (1-(cyclopentylsulfonyl)cyclopropyl)methylmethane sulfonate (I-8) was prepared from I-8E according to a procedure similar to that described in I-2. 1 H NMR (400MHz, CDCl3) δppm 1.15-1.21 (m, 2H) 1.61-1.68 (m, 4H) 1.77-1.84 (m, 2H) 2.05-2.11 (m, 4H) 3.07 (s, 3H) 3.68quin, J = 8.20Hz, 1H) 4.53 (s, 2H).

[0539] Intermediate 9

[0540] (1-((3-((tert-butyldimethylsilyl)oxy)propyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0541]

[0542] Ethyl 2-((3-((tert-butyldimethylsilyl)oxy)propyl)thio)ethyl acetate (I-9B). K₂CO₃ (2.456 g, 17.77 mmol), (3-bromopropoxy)(tert-butyl)dimethylsilane (2.74 mL, 11.85 mmol), and NaI (0.355 g, 2.369 mmol) were added to a solution of I-9A (1.429 mL, 13.03 mmol) in acetone (50 mL). The mixture was stirred at 60 °C. After the reaction was complete, the mixture was cooled to room temperature and filtered to remove insoluble matter. The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc and H₂O. The phases were separated, and the organic layer was washed with an aqueous sodium thiosulfate solution, dried with sodium sulfate, and concentrated under reduced pressure. I-9B, a colorless oily substance, was separated. 1 H NMR (400MHz, CDCl3) δppm 0.06(s,6H)0.90(s,9H)1.29(t,J=7.14Hz,3H)1.82(quin,J=1.00Hz,2H)2.7 2(t,J=7.24Hz,2H)3.22(s,2H)3.70(t,J=6.04Hz,2H)4.20(t,J=7.10Hz,2H).

[0543] 2-((3-((tert-butyldimethylsilyl)oxy)propyl)sulfonyl)ethyl acetate (I-9C). To a solution of I-9B (3.68 g, 12.58 mmol) in DCM (100 mL), add mCPBA (5.64 g, 25.2 mmol). After stirring overnight, dilute the reaction mixture with DCM, wash with saturated sodium bicarbonate, and dry with sodium sulfate. Concentrate the dried organic layer under reduced pressure to obtain the title compound as a colored oil. 1 H NMR (400MHz, CDCl3) δppm 0.07(s,1H)0.91(s,9H)1.34(t,J=7.14Hz,3H)2.08(dd,J=10.10,5.75Hz,2H )3.34-3.41(m,2H)3.76(t,J=5.80Hz,2H)3.97(s,2H)4.29(q,J=7.14Hz,2H).

[0544] 1-((3-((tert-butyldimethylsilyl)oxy)propyl)sulfonyl)cyclopropanecarboxylate (I-9D) was prepared from I-9C according to a procedure similar to that described in I-2C. The title compound was isolated as a colorless oil. 1H NMR (400MHz, CDCl3) δppm 0.06(s,6H)0.89(s,9H)1.31(t,J=6.87Hz,3H)1.60-1.66(m,2H)1.73-1.80(m,2 H)1.99-2.11(m,2H)3.47-3.56(m,2H)3.73(t,J=5.80Hz,2H)4.20-4.31(m,2H).

[0545] (1-((3-((tert-butyldimethylsilyl)oxy)propyl)sulfonyl)cyclopropyl)methanol (I-9E) was prepared from I-9D according to a procedure similar to that described in I-2D. The title compound was isolated as a colorless oil. 1 H NMR (400MHz, CDCl3) δppm 0.06(s,6H)0.89(s,9H)0.99-1.05(m,2H)1.46-1.52(m,2H)2.01-2.12(m,2H)2.48 (t,J=5.77Hz,1H)3.23-3.31(m,2H)3.73(t,J=5.84Hz,2H)3.89(d,J=5.77Hz,2H).

[0546] (1-((3-((tert-butyldimethylsilyl)oxy)propyl)sulfonyl)cyclopropyl)methylmethanesulfonate (I-9) was prepared from I-9E according to a procedure similar to that described in I-2. The title compound was isolated as an orange oil. 1 H NMR (400MHz, CDCl3) δppm 0.04-0.10(m,6H)0.88-0.92(m,9H)1.18-1.24(m,2H)1.62-1.68(m,2H)2.04- 2.13(m,2H)3.08(s,3H)3.22-3.29(m,2H)3.75(t,J=5.82Hz,2H)4.54(s,2H).

[0547] Intermediate 10

[0548] (1-(tert-butylsulfonyl)cyclopropyl)methylmethanesulfonate

[0549]

[0550] Methyl 1-(tert-butylsulfonyl)cyclopropanecarboxylate (I-10B) was prepared from I-10A according to a procedure similar to that described in I-2C. The title compound was isolated as a waxy solid. 1H NMR (400MHz, CDCl3) δppm 1.47 (s, 9H) 1.60-1.65 (m, 2H) 1.78-1.83 (m, 2H) 3.79 (s, 3H).

[0551] (1-(tert-butylsulfonyl)cyclopropyl)methanol (I-10C) was prepared from I-10B according to a procedure similar to that described in I-2D. I-10C was isolated as a white solid. 1 H NMR (400MHz, CDCl3) δppm 1.03-1.07 (m, 2H) 1.49-1.51 (m, 9H) 1.55-1.60 (m, 2H) 2.82-2.87 (m, 1H) 3.88 (d, J = 5.97Hz, 2H).

[0552] (1-(tert-butylsulfonyl)cyclopropyl)methylmethanesulfonate (I-10) was prepared from I-10C according to a procedure similar to that described in I-2. The title compound was isolated as an amber-colored waxy solid. 1 H NMR (400MHz, CDCl3) δppm 1.23-1.28(m,2H)1.50(s,9H)1.71-1.77(m,2H)3.08(s,3H)4.59(s,2H).

[0553] Intermediate 11

[0554] (1-(oxetane-3-ylsulfonyl)cyclopropyl)methylmethanesulfonate

[0555]

[0556] Ethyl 2-(oxetane-3-ylsulfonyl)ethyl acetate (I-11B). K₂CO₃ (2.254 g, 16.31 mmol) and ethyl 2-mercaptoethyl (1.311 mL, 11.96 mmol) were added to a solution of 3-iodooxetane (0.957 mL, 10.87 mmol) in acetone (50 mL). The resulting slurry was stirred overnight at 60 °C, then cooled to room temperature and filtered to remove insoluble matter. The filter cake was washed with acetone. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in EtOH and treated with potassium persulfate (Oxone) (13.37 g, 21.74 mmol) and approximately 0.3 mL of water. After 5 h, the mixture was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The oily residue was dissolved in DCM and washed with an aqueous solution of sodium thiosulfate. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. The title compound was separated from the colorless oily residue. LCMS m / z: 209(M+1). 1H NMR (400MHz, CDCl3) δppm 1.33 (t, J = 7.14Hz, 3H) 3.95 (s, 2H) 4.26 (q, J = 7.16Hz, 2H) 4.73-4.83 (m, 1H) 4.91 (t, J = 7.68Hz, 2H) 4.98-5.06 (m, 2H).

[0557] Ethyl 1-(oxacyclobut-3-ylsulfonyl)cyclopropanecarboxylate (I-11C) was prepared from I-11B according to a procedure similar to that described in I-2C. I-11C was isolated as a pale yellow oil. LCMS m / z: 235 (M+1). 1 H NMR (400MHz, CDCl3) δppm 1.28 (t, J = 7.16Hz, 3H) 1.62-1.69 (m, 2H) 1.77-1.84 (m, 2H) 4.22 (q, = 7.14Hz, 2H) 4.83-4.91 (m, 3H) 5.07-5.15 (m, 2H).

[0558] (1-(oxacyclobut-3-ylsulfonyl)cyclopropyl)methanol (I-11D) was prepared from I-11C according to a procedure similar to that described for I-2D. I-11D was isolated as a colorless oil. LCMS m / z: 193 (M+1). 1 H NMR (400MHz, CDCl3) δppm0.98-1.04(m,2H)1.48-1.55(m,2H)2.02(t,J=4.92Hz,1H )3.86(d,J=4.89Hz,2H)4.68-4.80(m,1H)4.86(t,J=7.60Hz,2H)5.01-5.10(m,2H).

[0559] (1-(oxacyclobut-3-ylsulfonyl)cyclopropyl)methylmethanesulfonate (I-11) was prepared from I-11D according to a procedure similar to that described in I-2. The title compound was isolated as a pale yellow oil. LCMS m / z: 271 (M+1). 1 H NMR (400MHz, CDCl3) δppm 1.20-1.26 (m, 2H) 1.63-1.69 (m, 2H) 3.07 (s, 3H) 4.48 (s, 2H) 4.63-4.71 (m, 1H) 4.89 (t, J = 7.73Hz, 2H) 5.00-5.06 (m, 2H).

[0560] Intermediate 12

[0561] (1-(isopropylsulfonyl)cyclopropyl)methylmethanesulfonate

[0562]

[0563] Methyl 1-(isopropylsulfonyl)cyclopropanecarboxylate (I-12B) was prepared from I-12A according to a procedure similar to that described in I-2C. LCMS m / z: 207 (M+1).

[0564] (1-(isopropylsulfonyl)cyclopropyl)methanol (I-12C) was prepared from I-12B according to a procedure similar to that described in I-2D. I-12C was isolated as a grayish-white solid. LCMS m / z: 179 (M+1). 1 H NMR (400MHz, CDCl3) δppm 0.99-1.04(m,2H)1.40(d,J=6.90Hz,6H)1.47-1.52(m,2H)2.47(t,J=5.62Hz,1H)3.56(dt,J=13.73,6.85Hz,1H)3.87(d,J=5.62Hz,2H).

[0565] (1-(isopropylsulfonyl)cyclopropyl)methylmethanesulfonate (I-12) was prepared from I-12C according to a procedure similar to that described in I-2. The title compound was isolated as a dark, viscous, oily substance. LCMS m / z: 257 (M+1). 1 H NMR (400MHz, CDCl3) δppm 1.17-1.23 (m, 2H) 1.42 (d, J = 6.80Hz, 6H) 1.63-1.68 (m, 2H) 3.08 (s, 3H) 3.46 (dt, J = 13.63, 6.80Hz, 1H) 4.53 (s, 2H).

[0566] Intermediate 13

[0567] (1-(ethylsulfonyl)cyclopropyl)methylmethanesulfonate

[0568]

[0569] 2-(Ethylsulfonyl)ethyl acetate (I-13B). Concentrated H₂SO₄ (1 drop) was added to a solution of I-13A (3.00 mL, 29.1 mmol) in EtOH (50 mL). The resulting solution was refluxed overnight. Then, the reaction mixture was cooled to 0 °C, and potassium persulfate (Oxone) (35.7 g, 58.1 mmol) was added. After the reaction was complete, the mixture was filtered. The filter cake was washed with EtOH, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and washed with brine. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. I-13B, a colorless oil, was separated. LCMS m / z: 181 (M+1). 1H NMR (400MHz, CDCl3) δppm 1.33 (t, J = 7.14Hz, 3H) 1.45 (t, J = 7.48Hz, 3H) 3.29 (q, J = 7.45Hz, 2H) 3.95 (s, 2H) 4.28 (q, J = 7.14Hz, 2H).

[0570] 1-(ethylsulfonyl)cyclopropanecarboxylate (I-13C) was prepared from I-13B according to a procedure similar to that described in I-2C. I-13C was isolated as a colorless oil. LCMS m / z: 207 (M+1). 1 H NMR (400MHz, CDCl3) δppm 1.29-1.34 (m, 3H) 1.41 (t, J = 7.53Hz, 3H) 1.63-1.68 (m, 2H) 1.76-1.81 (m, 2H) 3.47 (q, J = 7.53Hz, 2H) 4.22-4.30 (m, 2H).

[0571] (1-(ethylsulfonyl)cyclopropyl)methanol (I-13D) was prepared from I-13C according to a procedure similar to that described for I-2D. I-13D was isolated as a colorless oil. LCMS m / z: 165 (M+1). 1 H NMR (400MHz, CDCl3) δppm 1.00-1.05(m,2H)1.42(t,J=7.51Hz,3H)1.48-1.53(m,2H)2.45(t,J=5.65Hz,1H)3.22(q,J=7.50Hz,2H)3.90(d,J=5.67Hz,2H).

[0572] (1-(ethylsulfonyl)cyclopropyl)methylmethanesulfonate (I-13) was prepared from I-13D according to a procedure similar to that described in I-2. The title compound was isolated as a dark oily substance. LCMS m / z: 243 (M+1). 1 H NMR (400MHz, CDCl3) δppm 1.18-1.23 (m, 2H) 1.43 (t, J = 7.48Hz, 3H) 1.63-1.67 (m, 2H) 3.09 (s, 3H) 3.19 (q, J = 7.48Hz, 2H) 4.53 (s, 2H).

[0573] Intermediate 14

[0574] (1-(methylsulfonyl)cyclopropyl)methylmethanesulfonate

[0575]

[0576] 1-(methylsulfonyl)cyclopropanecarboxylate (I-14B) was prepared from I-14A according to a procedure similar to that described in I-2C. I-14B was separated from the pale yellow oily substance. 1 H NMR (400MHz, CDCl3) δppm 1.65-1.70 (m, 2H) 1.79-1.84 (m, 2H) 3.20 (s, 3H) 3.81 (s, 3H).

[0577] (1-(methylsulfonyl)cyclopropyl)methanol (I-14C) was prepared from I-14B according to a procedure similar to that described in I-2D. I-14C was separated as a colorless oil. LCMS m / z: 151 (M+1). 1 H NMR (400MHz, CDCl3) δppm 1.01-1.08 (m, 2H) 1.48-1.54 (m, 2H) 2.48 (t, J = 5.45Hz, 1H) 3.04 (s, 3H) 3.92 (d, J = 5.53Hz, 2H).

[0578] (1-(methylsulfonyl)cyclopropyl)methylmethanesulfonate (I-14) was prepared from I-14C according to a procedure similar to that described in I-2. The title compound was isolated as a brown solid. LCMS m / z: 229 (M+1). 1 H NMR (400MHz, CDCl3) δppm1.22 (td, J = 5.97, 1.52Hz, 2H) 1.65 (ddd, J = 5.92, 5.28, 1.47Hz, 2H) 3.03 (s, 3H) 3.06-3.11 (m, 3H) 4.54 (s, 2H).

[0579] Intermediate 15

[0580] (1-(methylsulfonyl)cyclobutyl)methylmethanesulfonate

[0581]

[0582] Ethyl 1-(methylsulfonyl)cyclobutane carboxylate (I-15B). 1,3-Dibromopropane (0.736 mL, 7.22 mmol) was added to a slurry of I-15A (0.794 mL, 6.02 mmol) and K₂CO₃ (1.663 g, 12.03 mmol) in DMF (20 mL). The mixture was stirred at 60 °C. After the reaction was complete, the mixture was diluted with Et₂O and filtered through a diatomaceous earth stopper. The filtrate was diluted with Et₂O and washed with brine. The aqueous layer was extracted with Et₂O. The combined ether extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, 0-50% DCM / heptane) to obtain a colorless oily I-15B. LCMS: m / z: 207 (M+1). 1 H NMR (400MHz, CDCl3) δppm 1.35 (t, J = 7.14Hz, 3H) 1.98-2.21 (m, 2H) 2.60-2.72 (m, 2H) 2.77-2.90 (m, 2H) 2.96 (s, 3H) 4.32 (q, J = 7.14Hz, 2H).

[0583] (1-(methylsulfonyl)cyclobutyl)methanol (I-15C) was prepared from I-15B according to a procedure similar to that described in I-2D. I-15C was isolated as a colorless oil. 1 H NMR (400MHz, CDCl3) δppm 2.01-2.18(m,4H)2.51(br.s.,1H)2.63-2.74(m,2H)2.86(s,3H)4.10(s,2H).

[0584] (1-(methylsulfonyl)cyclobutyl)methylmethanesulfonate (I-15) was prepared from I-15C according to a procedure similar to that described in I-2. I-15 was isolated as a brown solid. 1 H NMR (400MHz, CDCl3) δppm 2.05-2.24(m,4H)2.72-2.84(m,2H)2.87(s,3H)3.11(s,3H)4.66(s,2H).

[0585] Intermediate 16

[0586] 2-(1,1-dioxotetrahydrothiophen-2-yl)ethylmethanesulfonate

[0587]

[0588] 2-(2-(benzyloxy)ethyl)tetrahydrothiophene 1,1-dioxide (I-16B). A solution of I-16A (2.362 mL, 24.96 mmol) in THF (50 mL) was cooled to -78 °C. nBuLi (10.98 mL, 27.5 mmol) was added dropwise to the cooled solution, followed by benzyl-2-bromoethyl ether (3.99 mL, 25.2 mmol). The resulting solution was slowly heated to room temperature. After the reaction was complete, the mixture was cooled to 0 °C and quenched with H₂O. The aqueous mixture was diluted with EtOAc. The phases were separated, and the organic layer was washed with 2 M HCl and brine, dried over sodium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (SiO₂, 0-50% EtOAc / heptane) to obtain a colorless oily I-16B. LCMS m / z: 255 (M+1). 1 H NMR (400MHz, CDCl3) δppm 1.73-1.90(m,2H)2.02-2.13(m,1H)2.14-2.39(m,3H)2.94-3.03(m,1H) 3.11-3.24(m,2H)3.59-3.71(m,2H)4.46-4.59(m,2H)7.27-7.41(m,5H).

[0589] 2-(2-Hydroxyethyl)tetrahydrothiophene 1,1-dioxide (I-16C). Pd / C (0.05 g, 0.047 mmol) was added to a solution of I-16B (2.1 g, 8.26 mmol) in EtOH (10 mL). The resulting mixture was stirred vigorously overnight under H₂. The reaction mixture was filtered through a diatomaceous earth mat using MeOH. The filtrate was concentrated under reduced pressure to obtain a colorless, oily I-16C. LCMS m / z: 165 (M+1). 1 H NMR (400MHz, CDCl3) δppm 1.74-1.92(m,3H)1.97-2.27(m,3H)2.32-2.44(m,1H)2.93-3.05(m,1H)3.11-3.25(m,2H)3.72-3.91(m,2H).

[0590] 2-(1,1-dioxotetrahydrothiophene-2-yl)ethylmethanesulfonate (I-16) was prepared from I-16C according to a procedure similar to that described in I-2. The title compound was isolated as a golden oil. LCMS m / z: 243 (M+1). 1H NMR (400MHz, CDCl3) δppm 1.80(dd,J=13.30,6.26Hz,1H)2.01-2.16(m,2H)2.22(d,J=6.26Hz,1H)2.27- 2.47(m,2H)2.96-3.03(m,1H)3.05(s,3H)3.10-3.23(m,2H)4.36-4.41(m,2H).

[0591] Intermediate 17

[0592] N-(4-chlorobenzyl)-1,6-dioxo-1,3,4,6-tetrahydropyrido[2,1-c][1,4]oxazine-7-carboxamide

[0593]

[0594] N-(4-Chlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (I-17B). A solution of 4-chlorobenzylamine (5.96 mL, 49.0 mmol) in DMF (50 mL) was added to a solution of 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (5 g, 32.7 mmol), HOBt (6.00 g, 39.2 mmol), and EDC.HCl (7.51 g, 39.2 mmol) in DMF (100 mL). The resulting solution was stirred at room temperature. After 72 h, additional 4-chlorobenzylamine (3 mL) was added to induce further conversion. The reaction mixture was cooled to 0 °C, and ice was added directly to the mixture. The turbid mixture was adjusted to pH 1 with 2 M HCl. The resulting white precipitate was collected by vacuum filtration. The filter cake was washed with H2O and heptane and dried overnight on glass frit. I-17B, a white solid, was separated. LCMS m / z: 277 (M+1). 1 H NMR(400MHz,DMSO-d6)δppm 2.29(s,3H)4.50(d,J=6.26Hz,2H)6.31(dd,J=7.43,0.78Hz,1H)7.29-7.35(m,2H) 7.35-7.43(m,2H)8.23(d,J=7.43Hz,1H)10.11(t,J=5.87Hz,1H)12.48(br.s.,1H).

[0595] 5-((4-chlorobenzyl)carbamoyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (I-17C). I-17B (3 g, 10.84 mmol) and dioxane (120 mL) were added to a sealed tube containing SeO2 (20 g, 180 mmol). The resulting mixture was stirred at 120 °C for 72 h, then cooled to room temperature and filtered through a plunger containing diatomaceous earth and Na2SO4. The filtrate was concentrated to a yellow solid. The solid was dissolved in 150 mL of DMF and treated with potassium persulfate (Oxone) (13.33 g, 21.68 mmol). The resulting mixture was stirred overnight at room temperature, then cooled to 0 °C, and ice was added directly to the mixture. The contents were diluted with H2O and adjusted to pH 1 with 2 M HCl. The resulting precipitate was collected by vacuum filtration. The yellow solid I-17C was separated. LCMS m / z: 307 (M+1). 1 H NMR(500MHz,DMSO-d6)δppm 4.49-4.57(m,2H)7.09(d,J=7.25Hz,1H)7.35(d,J=8.51Hz,2H)7.41(d,J=8.20Hz,2H)8.43(d,J=7.25Hz,1H)10.18(br.s.,1H)12.40(br.s.,1H).

[0596] N-(4-chlorobenzyl)-1,6-dioxo-1,3,4,6-tetrahydropyrido[2,1-c][1,4]oxazine-7-carboxamide (I-17). 1,2-Dibromoethane (0.309 mL, 3.59 mmol) was added to a solution of I-17C (1 g, 3.26 mmol) and Cs₂CO₃ (1.594 g, 4.89 mmol) in DMF (50 mL). The resulting mixture was stirred overnight at 60 °C. The reaction mixture was diluted with EtOAc and filtered through a diatomaceous earth stopper. The filtrate was washed with brine (4 times). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. I-17 was separated as a brown solid. LCMS m / z: 333 (M+1). 1 H NMR(500MHz,CD3OD)δppm 4.37(t,J=4.73Hz,2H)4.62(d,J=5.99Hz,3H)4.69-4.74(m,2H)7.36(s,4H)7.43(dd,J=7.57,0.95Hz,1H)8.55-8.58(m,1H)10.40(br.s.,1H).

[0597] Intermediate 18

[0598] 2-(2-aminoethyl)isothiazolidinyl 1,1-dioxide

[0599]

[0600] (2-(3-Chloropropylsulfonamido)ethyl)tert-butyl carbamate (I-18B). 3-Chloropropane-1-sulfonyl chloride (1.670 mL, 13.73 mmol) was added to a solution of I-18A (1.815 mL, 12.48 mmol) and DIEA (2.398 mL, 13.73 mmol) cooled to 0 °C in 100 mL of THF. The reaction was allowed to proceed to room temperature. After the reaction was complete, the mixture was diluted with EtOAc and H₂O. The phases were separated, and the organic layer was washed with H₂O and brine. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. I-18B was separated as an orange solid. LCMS m / z: 245 (M-55). 1 H NMR(400MHz,DMSO-d6)δppm 1.32-1.40(m,9H)2.02-2.11(m,2H)2.94(t,J=5.67Hz,2H)2.96-3.03(m,2H) 3.05-3.13(m,2H)3.70-3.75(m,2H)6.78-6.87(m,1H)7.20(t,J=5.28Hz,1H).

[0601] (2-(1,1-dioxoisothiazolidin-2-yl)ethyl)tert-butyl carbamate (I-18C). NaH (60% suspension in mineral oil, 0.293 g, 7.31 mmol) was added to a solution of I-18B (2 g, 6.65 mmol) cooled to 0 °C in 50 mL of DMF. The resulting mixture was heated to room temperature. After 4 days, the reaction mixture was cooled to 0 °C and diluted with H₂O and EtOAc. The phases were separated, and the aqueous layer was extracted with EtOAc (4 times). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated. I-18C, a pale orange oil, was separated and used without further purification. LCMS m / z: 265 (M+1). 1 H NMR (500MHz, DMSO-d6) δppm 1.37 (s, 9H) 2.20 (quin, J = 7.09Hz, 2H) 3.08 (q, J = 6.52Hz, 2H) 3.12-3.18 (m, 2H) 3.20 (t, J = 6.62Hz, 2H) 6.84 (br.s., 1H).

[0602] 2-(2-Aminoethyl)isothiazolidinyl 1,1-dioxide (I-18). A solution of dioxane (3 mL, 12.00 mmol) containing 4 M HCl was added to a solution of I-18C (1.4 g, 5.30 mmol) in dioxane (5.30 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and ground with Et₂O and heptane to obtain I-18. LCMS m / z: 165 (M+1).

[0603] Intermediate 19

[0604] (1-(methylsulfonyl)acetidin-3-yl)methylamine

[0605]

[0606] ((1-(methylsulfonyl)acetidin-3-yl)methyl)tert-butyl carbamate (I-19B). MsCl (0.138 mL, 1.772 mmol) was added to a solution of I-19A (0.3 g, 1.611 mmol) and DIEA (0.844 mL, 4.83 mmol) in 10 mL of DCM. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and 2 M HCl. The phases were separated, and the organic layer was washed twice with 2 M HCl. The aqueous extract was extracted twice with CHCl3. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain I-19B as a maroon solid. 1 H NMR (400MHz, CDCl3) δppm1.42-1.48 (m, 9H) 2.78 (dt, J = 13.11, 6.75Hz, 1H) 2.86 (s ,3H)3.36(t,J=6.46Hz,2H)3.67(dd,J=8.02,5.67Hz,2H)3.99(t,J=8.22Hz,2H).

[0607] (1-(methylsulfonyl)acetidin-3-yl)methylamine (I-19). TFA (2 mL, 26.0 mmol) was added to a solution of I-19B (0.417 g, 1.578 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to obtain a maroon oily I-19. LCMS m / z: 165 (M+1).

[0608] Intermediate 20

[0609] (1-(methylsulfonyl)acetidin-2-yl)methylamine

[0610]

[0611] ((1-(methylsulfonyl)acetidin-2-yl)methyl)tert-butyl carbamate (I-20B) was prepared from I-20A according to a procedure similar to that described in I-19B. 1 H NMR (400MHz, CDCl3) δppm 1.46(s,8H)1.54-1.60(m,1H)1.83-1.98(m,1H)2.17-2.30(m,1H)2.82-2.91 (m,3H)3.24-3.41(m,2H)3.46-3.59(m,2H)4.26(br.s.,1H)4.69(br.s.,1H).

[0612] (1-(methylsulfonyl)acetidin-2-yl)methylamine (I-20) was prepared by I-20B according to a procedure similar to that described in I-19C. LCMS m / z: 165 (M+1).

[0613] Intermediate 21

[0614] (1-((1-fluorocyclopropyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0615]

[0616] 2-Thiopyridine-1(2H)-yl 1-fluorocyclopropane carboxylate (I-21A) was prepared from 1-fluorocyclopropane carboxylic acid according to a procedure similar to that described in I-7B. I-21A was obtained as a dark, residual substance. MS m / z 214.2 (M+1).

[0617] 2-((1-fluorocyclopropyl)sulfonyl)pyridine (I-21B) was prepared from I-21A according to a procedure similar to that described in I-7C. I-21B was isolated as a white solid. MS m / z 202.2 (M+1).

[0618] Sodium 1-fluorocyclopropane-1-sulfinate (I-21C). At 0 °C, under argon atmosphere, ethanethiol (3.97 mL, 53.7 mmol) was slowly added to a stirred suspension of sodium hydride (1.073 g, 26.8 mmol, a 60% suspension in mineral oil) in THF (29.8 mL). After 5 min, a solution of I-21B (1.8 g, 8.95 mmol) in THF (14.9 mL) was added. The mixture was heated to room temperature, then to 50 °C. After 2 h, the reaction mixture was diluted with DI water and the pH was adjusted to 6 with 2N HCl and saturated NaHCO3. The two-phase mixture was concentrated under vacuum. The crude product was suspended in MeOH and filtered through a diatomaceous earth pad. The filtrate was concentrated and dried under vacuum to obtain I-21C as a grayish-white solid. 1H NMR (400MHz, D2O) δppm 0.85-1.17 (m, 4H).

[0619] 2-((1-fluorocyclopropyl)sulfonyl)benzyl acetate (I-21D). At room temperature, 2-bromoacetic acid benzyl ester (1.084 mL, 6.84 mmol) was added to a mixture of I-21C (1.0 g, 6.84 mmol) and DMF (6.84 mL). After 3 h, the reaction contents were diluted with DI water and DCM, and the layers were separated. The aqueous phase was extracted with DCM (twice), and the combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude residue was purified on SiO2 (0-50% EtOAc / heptane) to obtain a clear, oily I-21D. 1 HNMR (400MHz, CDCl3) δppm 1.33-1.48 (m, 2H) 1.48-1.66 (m, 3H) 4.24 (d, J = 0.64Hz, 2H) 5.25 (s, 2H) 7.27-7.50 (m, 5H). MS m / z 295.1(M+1).

[0620] 1-((1-fluorocyclopropyl)sulfonyl)cyclopropanecarboxylic acid benzyl ester (I-21E) was prepared from I-21D according to a procedure similar to that described in I-2C. The title compound was isolated as a clear oil. 1 HNMR (400MHz, CDCl3) δppm 1.19-1.45(m,2H)1.59-1.71(m,2H)1.71-1.85(m,2H)1.88-2.04(m,2H)5.21(s,2H)7.31-7.55(m,5H). MS m / z299.1(M+1).

[0621] (1-((1-fluorocyclopropyl)sulfonyl)cyclopropyl)methanol (I-21F) was prepared from I-21E according to a procedure similar to that described in I-2D. I-21F was obtained as a clear oil. MS m / z 195.1 (M+1).

[0622] (1-((1-fluorocyclopropyl)sulfonyl)cyclopropyl)methylmethane sulfonate (I-21) was prepared from I-21F according to a procedure similar to that described in I-2. I-21 was obtained as a clear oil. MS m / z 273.1 (M+1).

[0623] Intermediate 22

[0624] (1-(cyclobutylsulfonyl)cyclopropyl)methylmethanesulfonate

[0625]

[0626] Ethyl 2-(cyclobutylthio)ethyl acetate (I-22A). DMF (14.8 mL), ethyl 2-mercaptoethyl (890 mg, 7.41 mmol), K₂CO₃ (1075 mg, 7.78 mmol), 18-crown-6 (196 mg, 0.741 mmol), and bromocyclobutane (500 mg, 3.70 mmol) were placed in a microwave-safe vial. The vial was sealed and the mixture was stirred at 90 °C for 3 days, followed by stirring at 100 °C for 1 hour under microwave irradiation. The reaction mixture was poured into water and extracted with DCM (3 times). The organic layer was dried over Na₂SO₄, filtered, and concentrated to produce an orange oil, I-22A. 1 H NMR (400MHz, CDCl3) δppm 1.26(td,J=7.13,2.62Hz,2H)1.84-2.10(m,4H)2.25-2.42(m,3H)3.16(d,J=2.59Hz,2H)3.50-3.63(m,1H)4.15(qd,J=7.13,2.57Hz,1H). MS m / z 175.1(M+1).

[0627] 2-(Cyclobutylsulfonyl)ethyl acetate (I-22B). Potassium persulfate (Oxone) (3.41 g, 5.55 mmol) was added to a stirred solution of I-22A (0.645 g, 3.7 mmol) in DMF (14.8 mL) at room temperature. The mixture was stirred overnight, during which time it changed from an orange suspension to a pale yellow suspension. The reaction mixture was diluted with water and extracted with DCM (3 times). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to provide the title compound (I-22B) containing residual DMF, ready for use without further purification. MS m / z 207.1 (M+1).

[0628] 1-(cyclobutylsulfonyl)cyclopropanecarboxylate (I-22C) is prepared from I-22B according to a procedure similar to that described in I-2C. 1 H NMR (400MHz, CDCl3) δppm 1.24-1.36(m,3H)1.49-1.63(m,2H)1.70-1.80(m,2H)1.87-2.15(m,2H)2. 18-2.37(m,2H)2.48-2.71(m,2H)4.23(q,J=7.14Hz,2H)4.39-4.59(m,1H). MS m / z 233.2(M+1).

[0629] (1-(cyclobutylsulfonyl)cyclopropyl)methanol (I-22D) was prepared from I-22C according to a procedure similar to that described for I-2D. MS m / z 191.1 (M+1).

[0630] (1-(cyclobutylsulfonyl)cyclopropyl)methylmethanesulfonate (I-22) was prepared from I-22D according to a procedure similar to that described in I-2. MS m / z 269.2 (M+1).

[0631] Intermediate 23

[0632] 3-((1-((((methylsulfonyl)oxy)methyl)cyclopropyl)sulfonyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0633]

[0634] 3-((2-ethoxy-2-oxoethyl)thio)pyrrolidine-1-carboxylic acid tert-butyl ester (I-23A). In two microwave-safe vials, each contained 14.8 mL of DMF, 1.763 mL of ethyl 2-mercaptoacetate (15.99 mmol), 0.553 g of K₂CO₃ (4.00 mmol), and 18-crown-6 (1.057 g, 4.00 mmol). In one vial, add 1.0 g of (S)-3-bromopyrrolidine-1-carboxylic acid tert-butyl ester (4.00 mmol), and in the other vial, add 1.0 g of (R)-3-bromopyrrolidine-1-carboxylic acid tert-butyl ester (4.00 mmol). Seal the vials and microwave at 100 °C for 60 min with stirring. Combine the reaction mixtures, pour into water, and extract with DCM (3 times). The organic layer was dried with Na₂SO₄, filtered, and concentrated to produce I-23A, which was used directly without further purification. MS m / z 290.3 (M+1).

[0635] 3-((2-ethoxy-2-oxoethyl)sulfonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-23B) was prepared from I-23A according to a procedure similar to that described in I-22B. MS m / z 323.3 (M+1).

[0636] 3-((1-(ethoxycarbonyl)cyclopropyl)sulfonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-23C) was prepared from I-23B according to a procedure similar to that described in I-2C. MS m / z 292.1 (M-tBu+1).

[0637] 3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-23D) was prepared from I-23C according to a procedure similar to that described for I-2D. MS m / z 250.1 (M-tBu+1).

[0638] 3-((1-((((methylsulfonyl)oxy)methyl)cyclopropyl)sulfonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-23) was prepared from I-23D according to a procedure similar to that described in I-2. MS m / z 384.2 (M+1), 328.1 (M-tBu+1).

[0639] Intermediate 24

[0640] (1-((3,3-difluorocyclobutyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0641]

[0642] Ethyl 2-((3,3-difluorocyclobutyl)thio)ethyl acetate (I-24A). DMF (14.8 mL), ethyl 2-mercaptoethyl (0.645 mL, 5.85 mmol), K₂CO₃ (849 mg, 6.14 mmol), 18-crown-6 (155 mg, 0.585 mmol), and 3-bromo-1,1-difluorocyclobutane (500 mg, 2.92 mmol) were added to a microwave-safe vial. The vial was sealed and microwaved at 100 °C for 1 h with stirring. The reaction mixture was poured into water and extracted with DCM (3 times). The organic layer was dried over Na₂SO₄, filtered, and concentrated to produce I-24A, which was used directly without further purification.

[0643] 2-((3,3-difluorocyclobutyl)sulfonyl)ethyl acetate (I-24B) was prepared from I-24A according to a procedure similar to that described in I-22B. 1 ¹H NMR (400MHz, CDCl₃) δppm 1.24–1.42 (m, 3H) 2.83–3.04 (m, 2H) 3.04–3.22 (m, 2H) 3.93 (s, 2H) 3.95–4.09 (m, 1H) 4.17–4.39 (m, 3H). According to LCMS, it is unionized.

[0644] 1-((3,3-difluorocyclobutyl)sulfonyl)cyclopropanecarboxylate (I-24C) is prepared from I-24B according to a procedure similar to that described in I-2C. 1 H NMR (400MHz, CDCl3) δppm1.14-1.39(m,5H)1.54-1.70(m,2H)1.70-1.87(m,2H)2.78-2.99(m,2H)3.01-3.27(m,2H)4.11-4.32(m,3H). MS m / z 269.1(M+1).

[0645] (1-((3,3-difluorocyclobutyl)sulfonyl)cyclopropyl)methanol (I-24D) was prepared from I-24C according to a procedure similar to that described for I-2D. MS m / z 227.1 (M+1).

[0646] (1-((3,3-difluorocyclobutyl)sulfonyl)cyclopropyl)methylmethanesulfonate (I-24) was prepared from I-24D according to a procedure similar to that described in I-2. MS m / z 305.1 (M+1).

[0647] Intermediate 25

[0648] (1-((3,3-difluoroacryl-1-yl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0649]

[0650] Methyl 2-((3,3-difluoroacrimidine-1-yl)sulfonyl)acetate (I-25A) was prepared according to the general procedure described in Northup, A. et al., J. Med. Chem. 2013, 56, 2294. At 0 °C and under N2, Huenig base (4.25 mL, 24.32 mmol) was added to a suspension of 3,3-difluoroacrimidine-1-onium chloride (900 mg, 6.95 mmol) in DCM (34.7 mL). After 5 min, methyl 2-(chlorosulfonyl)acetate (1799 mg, 10.42 mmol) was added dropwise to the reaction flask. The reaction mixture was gradually heated to room temperature and stirred for 4 days. The reaction mixture was then partitioned between DCM and water. The aqueous phase was extracted twice with DCM, and the combined organic layers were washed with 1N HCl and brine, dried over Na2SO4, filtered, and concentrated to obtain I-25A. According to LCMS, it was unionized.

[0651] 1-((3,3-difluoroacrylidine-1-yl)sulfonyl)cyclopropanecarboxylate (I-25B) is prepared from I-25A according to a procedure similar to that described in I-2C. 1 H NMR (400MHz, CDCl3) δppm 1.25 (t, J = 7.14Hz, 2H) 1.61-1.68 (m, 2H) 1.70-1.84 (m, 2H) 3.78 (s, 3H) 4.42 (t, J = 12.23Hz, 4H). MS m / z 256.1(M+1).

[0652] (1-((3,3-difluoroacetidin-1-yl)sulfonyl)cyclopropyl)methanol (I-25C) was prepared from I-25B according to a procedure similar to that described in I-2D. MS m / z 228.2 (M+1).

[0653] (1-((3,3-difluoroacetidin-1-yl)sulfonyl)cyclopropyl)methylmethanesulfonate (I-25) was prepared from I-25C according to a procedure similar to that described in I-2. MS m / z 306.1 (M+1).

[0654] Intermediate 26

[0655] (1-(acetidin-1-ylsulfonyl)cyclopropyl)methylmethanesulfonate

[0656]

[0657] Methyl 2-(acetidin-1-ylsulfonyl)acetate (I-26A). A solution of methyl 2-(chlorosulfonyl)acetate (3 g, 17.38 mmol) in DCM (26.1 mL) was added dropwise to a solution of acridine (2.343 mL, 34.8 mmol) in DCM (26.1 mL) at 0 °C. The reaction mixture was allowed to gradually reach room temperature. Brine was added, and the contents were extracted with DCM (3 times). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain a yellow oil, I-26A. This substance was used without further purification. MS m / z 194.0 (M+1).

[0658] Methyl 1-(acidil-1-ylsulfonyl)cyclopropanecarboxylate (I-26B) is prepared from I-26A according to a procedure similar to that described in I-2C. 1 H NMR (400MHz, CDCl3) δppm1.49-1.64(m,2H)1.64-1.77(m,2H)2.12-2.35(m,2H)3.76(s,3H)4.03-4.22(m,4H). MS m / z 220.1(M+1).

[0659] (1-(acetidin-1-ylsulfonyl)cyclopropyl)methanol (I-26C) was prepared from I-26B according to a procedure similar to that described in I-2D. MS m / z 192.1 (M+1).

[0660] (1-(acetidin-1-ylsulfonyl)cyclopropyl)methylmethanesulfonate (I-26) was prepared from I-26C according to a procedure similar to that described in I-2. MS m / z 269.3 (M+1).

[0661] Intermediate 27

[0662] (1-(2-oxooxazolidine-3-yl)cyclopropyl)methylmethanesulfonate

[0663]

[0664] 1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid benzyl ester (I-27A). Benzyl bromide (1.688 mL, 14.19 mmol) was added dropwise to a stirred mixture of 1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (1.19 g, 5.91 mmol) and NEt3 (2.0 mL, 14.19 mmol) in DMF (23.6 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 days, followed by the addition of DI water (80 mL). The resulting suspension was stirred at room temperature for 10 min and collected by vacuum filtration to the title compound (I-27A), a white solid. MS m / z 292.3 (M+1).

[0665] 1-(((2-bromoethoxy)carbonyl)amino)cyclopropanecarboxylic acid benzyl ester (I-27B). TFA (10.3 mL) was added to a solution of I-27A (800 mg, 2.75 mmol) in 10.3 mL of DCM over 2 min at 0 °C and under N2. The reaction was heated to room temperature and stirred for 16 h. TFA and DCM were removed by rotary evaporation, and the resulting clear oil was concentrated twice from heptane.

[0666] The residue was dissolved in DCM (15 mL) and cooled to 0 °C under N2. DMAP (67.1 mg, 0.549 mmol) and NET3 (1.148 mL, 8.24 mmol) were added, followed by dropwise addition of a solution of 2-bromoethyl chloroformate (0.295 mL, 2.75 mmol) in DCM (5 mL). After 3 h, the mixture was diluted with DCM and washed with 1 N Na2CO3. The aqueous layer was extracted with DCM (twice). The combined organic layers were dried over Na2SO4, filtered, and concentrated to produce a grayish-white solid, I-27B. MS m / z 344.2 (M+1).

[0667] 1-(2-oxooxazolidine-3-yl)cyclopropanecarboxylic acid benzyl ester (I-27C). Sodium hydride (60% suspension in mineral oil, 165 mg, 4.13 mmol) was added to a solution of I-27B (941 mg, 2.75 mmol) in THF (27.5 mL) at 0 °C and under N2. The reaction mixture was heated to room temperature and stirred for 16 h, followed by partitioning between EtOAc and DI water. The aqueous layer was extracted twice with DCM, and the combined organic layers were dried with Na2SO4, filtered, and concentrated to obtain a turbid, pale yellow, oily I-27C. MS m / z 262.2 (M+1).

[0668] 3-(1-(hydroxymethyl)cyclopropyl)oxazolidin-2-one (I-27D) was prepared from I-27C according to a procedure similar to that described for I-2D. MS m / z 158.0 (M+1).

[0669] (1-(2-oxooxazolidine-3-yl)cyclopropyl)methylmethanesulfonate (I-27) was prepared from I-27D according to a procedure similar to that described in I-2. MS m / z 236.1 (M+1).

[0670] Intermediate 28

[0671] (1-(N,N-dimethylaminosulfonyl)cyclopropyl)methylmethanesulfonate

[0672]

[0673] Methyl 2-(N,N-dimethylaminosulfonyl)acetate (I-28A) was prepared according to Northup, A. et al., J. Med. Chem. 2013, 56, 2294. At 0 °C, a solution of methyl 2-(chlorosulfonyl)acetate (3.36 g, 19.47 mmol) in DCM (10 mL) was added dropwise to a solution of 2M dimethylamine in THF (19.47 mL, 38.9 mmol) and DCM (10 mL). The reaction mixture was allowed to gradually reach room temperature. Brine was added, and the contents were extracted with DCM (3 times). The organic layer was dried with Na₂SO₄, filtered, and concentrated under vacuum to obtain an orange-yellow oily substance, I-28A. 1 H NMR (500MHz, CDCl3) δppm 2.89-3.00 (m, 6H) 3.83 (s, 3H) 3.95-4.02 (m, 2H). MS m / z 182.2(M+1).

[0674] 1-(N,N-dimethylaminosulfonyl)cyclopropanecarboxylate (I-28B) is prepared from I-28A according to a procedure similar to that described in I-2C. 1 H NMR (500MHz, CDCl3) δppm1.61-1.67(m,2H)1.72-1.83(m,2H)3.00(s,6H)3.80(s,3H). MS m / z 208.1(M+1).

[0675] 1-(hydroxymethyl)-N,N-dimethylcyclopropane-1-sulfonamide (I-28C) was prepared from I-28B according to a procedure similar to that described in I-2D. MS m / z 180.2 (M+1).

[0676] (1-(N,N-dimethylaminosulfonyl)cyclopropyl)methylmethanesulfonate (I-28) was prepared from I-28C according to a procedure similar to that described in I-2. 1H NMR (500MHz, CDCl3) δppm 1.09-1.24(m,2H)1.50-1.68(m,2H)2.97(s,6H)3.10(s,3H)4.46(s,2H). MS m / z 258.2(M+1).

[0677] Intermediate 29

[0678] (1,1-Dioxotetrahydrothiophen-2-yl)methylmethanesulfonate

[0679]

[0680] Tetrahydrothiophene-2-carboxylic acid 1,1-dioxide (I-29A). A solution of 2 M LDA in THF (66.6 mL, 133 mmol) was added dropwise to a stirred solution of tetrahydrothiophene-1,1-dioxide (6.30 mL, 66.6 mmol) in THF (333 mL) at -78 °C and under N2. After 30 min, the yellow suspension was allowed to reach room temperature for 10 min, followed by cooling to -50 °C. The nitrogen inlet was removed, and CO2 was bubbled through the suspension for 1 h. The reaction mixture became a white suspension, which was then gradually heated to room temperature and stirred for 3 days. The reactants were quenched with DI water, and the mixture was partitioned between water and EtOAc. The aqueous layer was washed twice with EtOAc. The aqueous layer was acidified with 1 N and 6 N HCl, followed by extraction with chloroform (3 times). NaCl was added to the aqueous phase, and the mixture was extracted again with chloroform. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain a yellow oily product, I-29A. The crude product also contained unreacted starting materials and residual solvent and was used without further purification. MS m / z 165.0 (M+1).

[0681] 2-(hydroxymethyl)tetrahydrothiophene 1,1-dioxide (I-29B). A solution of 1M boranetetrahydrofuran complex in THF (10.4 mL, 10.40 mmol) was added to a stirred solution of I-29A (680 mg, 4.14 mmol) in THF (41.4 mL) at 0 °C and under N2. The reactants were gradually heated to room temperature and stirred overnight. The reaction was quenched by adding DI water and partitioned between DCM and water. The aqueous layer was extracted with chloroform (twice) and 3:1 chloroform:isopropane (three times). The combined organic layers were washed with 1N HCl, dried over Na2SO4, filtered, and concentrated to produce a clear, oily I-29B. This substance was used without further purification. MS m / z 150.9 (M+1).

[0682] (1,1-Dioxotetrahydrothiophene-2-yl)methylmethanesulfonate (I-29) was prepared from I-28C according to a procedure similar to that described in I-2. The crude product was purified on SiO2 (0-100% EtOAc / heptane) to produce a clear, oily I-29. MS m / z 229.1 (M+1).

[0683] Intermediate 30

[0684] 1-(aminomethyl)-N-(tert-butyl)cyclopropane-1-sulfonamide

[0685]

[0686] N-(tert-butyl)cyclopropanesulfonamide (I-30A) was prepared according to WO 2008137779. Pure cyclopropanesulfonyl chloride (11.55 g, 82 mmol) was added dropwise over 5 min to a stirred solution of tert-butylamine (17.34 mL, 164 mmol) in THF (100 mL) at -20 °C (dry ice / acetone) and N2. The resulting orange solution was gradually heated to room temperature and stirred for 16 h. The resulting suspension was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was dissolved in DCM and washed with 1 N HCl, water, and brine. The organic phase was dried with Na2SO4, filtered, and concentrated. The orange solid was recrystallized from a 5:1 heptane:EtOAc solution to obtain white crystalline I-30A.

[0687] N-(tert-butyl)-1-formylcyclopropane-1-sulfonamide (I-30B) was prepared according to WO 2012151195. Hexane containing 1.6 M n-butyllithium (28.9 mL, 46.3 mmol) was added dropwise over 10 min in a stirred solution of I-30A (4.0 g, 22.57 mmol) in THF (90 mL) at -78 °C and under N2. The reaction mixture was stirred at -78 °C for 30 min, followed by stirring at room temperature for 30 min. The flask was cooled to -78 °C, and DMF (5.24 mL, 67.7 mmol) was added dropwise. The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was quenched with DI water and extracted with EtOAc (twice). The aqueous layer was acidified to pH 2 with 1N HCl, inducing gas generation, and extracted with EtOAc (twice). The organic layers were combined and washed with 1N HCl and brine. The organic phase was dried with Na2SO4, filtered, and concentrated under vacuum to obtain I-30B as a white solid. 1 H NMR (400MHz, CDCl3) δppm 1.35 (s, 9H) 1.56-1.69 (m, 2H) 1.79-1.93 (m, 2H) 9.53 (s, 1H). MS m / z 206.3(M+1).

[0688] N-(tert-butyl)-1-(hydroxymethyl)cyclopropane-1-sulfonamide (I-30C) was prepared according to WO 2012151195. Sodium borohydride (0.854 g, 22.57 mmol) was added in three portions to a stirred solution of I-30B (4.63 g, 22.57 mmol) in THF (56 mL) at 0 °C. After 1.5 h, MeOH (5.60 mL) was added dropwise at 0 °C, resulting in rapid gas generation. After 10 min, brine was added to the flask, and the contents were extracted with EtOAc (twice) and chloroform:isopropane (once) in a 3:1 ratio. The combined organic phases were dried over Na₂SO₄, filtered, and concentrated to obtain I-30C as a white solid. 1 H NMR (400MHz, CDCl3) δppm 0.94-1.07(m,2H)1.31-1.42(m,9H)1.42-1.54(m,2H)2.62-2.84(m,1H)3.85(s,2H)4.27-4.49(m,1H). MS m / z 208.3(M+1).

[0689] (1-(N-(tert-butyl)aminosulfonyl)cyclopropyl)methylmethanesulfonate (I-30D) is prepared from I-30C according to a procedure similar to that described in I-2. 1 H NMR (400MHz, CDCl3) δppm 1.07-1.18(m,2H)1.31-1.42(m,10H)1.54-1.63(m,2H)3.08(s,3H)4.52(s,2H). MS m / z 286.1(M+1).

[0690] 1-(azidomethyl)-N-(tert-butyl)cyclopropane-1-sulfonamide (I-30E). Sodium azide (1.025 g, 15.77 mmol) was added to a solution of I-30D (1.5 g, 5.26 mmol) in DMF (15.0 mL) at room temperature. The flask was immersed in a 60 °C oil bath and stirred under N2. After 1 h, the temperature was increased to 90 °C. After 5 h, the reaction mixture was cooled to room temperature, poured onto crushed ice, and extracted with EtOAc (3 times). The combined organic phases were dried over Na2SO4, filtered, and concentrated to obtain I-30E. MS m / z 233.3 (M+1).

[0691] 1-(aminomethyl)-N-(tert-butyl)cyclopropane-1-sulfonamide (I-30). Under N2, a solution of I-30E (1.222 g, 5.26 mmol) in MeOH (84 mL) was added to a slurry of 10% Pd-C (0.280 g, 0.263 mmol) in THF (3.37 mL). The atmosphere was changed by three vacuum / H2 cycles. The reaction mixture was stirred at 1 atm H2 for 16 h and then filtered through a diatomaceous earth mat. The filtrate was concentrated, and the residue was azeotropically dried twice with toluene to give I-30 as a white solid. 1 H NMR (400MHz, CDCl3) δppm0.80-0.90(m,2H)1.37(s,9H)1.40-1.47(m,3H)3.08(s,2H)4.86-5.05(m,1H). MS m / z 207.1(M+1).

[0692] Intermediate 31

[0693] 1-(aminomethyl)-N-(tert-butyl)-N-methylcyclopropane-1-sulfonamide

[0694]

[0695] 2-(N-(tert-butyl)-N-methylaminosulfonyl)acetic acid methyl ester (I-31A) is prepared from 2-(chlorosulfonyl)acetic acid methyl ester and N,2-dimethylpropyl-2-amine according to a procedure similar to that described in I-26A. 1 H NMR (400MHz, CDCl3) δppm 1.45 (s, 9H) 2.92 (s, 3H) 3.79 (s, 3H) 4.00 (s, 2H). MS m / z 224.3(M+1).

[0696] 1-(N-(tert-butyl)-N-methylaminosulfonyl)cyclopropanecarboxylate (I-31B) is prepared from I-31A according to a procedure similar to that described in I-2C. 1 H NMR (400MHz, CDCl3) δppm 1.40 (s, 9H) 1.60-1.68 (m, 2H) 1.73-1.88 (m, 2H) 3.04 (s, 3H) 3.76 (s, 3H). MS m / z 250.3(M+1),194.2(M-tBu+1).

[0697] N-(tert-butyl)-1-(hydroxymethyl)-N-methylcyclopropane-1-sulfonamide (I-31C) was prepared from I-31B according to a procedure similar to that described in I-2D. MS m / z 222.3 (M+1), 194.2 (M-tBu+1).

[0698] (1-(N-(tert-butyl)-N-methylaminosulfonyl)cyclopropyl)methylmethanesulfonate (I-31D) was prepared from I-31C according to a procedure similar to that described in I-2. MS m / z 244.1 (M-tBu+1).

[0699] 1-(azidomethyl)-N-(tert-butyl)-N-methylcyclopropane-1-sulfonamide (I-31E) was prepared from I-31D according to a procedure similar to that described for I-30E. MS m / z 191.1 (M-tBu+1).

[0700] 1-(aminomethyl)-N-(tert-butyl)-N-methylcyclopropane-1-sulfonamide (I-31) was prepared from I-31E according to a procedure similar to that described in I-30. MS m / z 221.3 (M+1).

[0701] Intermediate 32

[0702] 2-Amino-N,N-Dimethylethanesulfonamide

[0703]

[0704] 2-(1,3-dioxoisoindoline-2-yl)-N,N-dimethylethanesulfonamide (I-32A) was prepared according to WO2012115256. Dimethylamine (40%, aqueous solution) (3.09 mL, 24.44 mmol) was added dropwise to a solution of 2-phthalimide ethanesulfonyl chloride (3.04 g, 11.11 mmol) in THF (40 mL). The flask was capped and the reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated under vacuum, and the resulting white paste was partitioned between a saturated aqueous solution of NaHCO3 and a 10:1 EtOAc:DCM mixture. The aqueous layer was re-extracted twice with DCM. The combined organic layers were dried with Na2SO4, filtered, and concentrated to obtain I-32A as a white solid. MS m / z 283.7 (M+1).

[0705] 2-Amino-N,N-dimethylethanesulfonamide (I-32) was prepared according to WO2012115256. At room temperature, 65% hydrazine hydrate (0.704 mL, 9.44 mmol) was added to a stirred suspension of I-32A (1.3 g, 4.60 mmol) in EtOH (46.0 mL). The mixture was stirred at room temperature for 1 h, during which a white precipitate formed, followed by stirring under reflux (80 °C) for 2 h. After stirring under reflux, the solution first became homogeneous and a white precipitate formed. The flask was cooled to room temperature and the solid was removed by vacuum filtration. The flask and filter cake were rinsed with additional EtOH. The filtrate was concentrated under vacuum, and the resulting residue was dissolved in DCM. The residual precipitate was removed again by vacuum filtration, and the filtrate was concentrated to yield a pale yellow, oily 2-amino-N,N-dimethylethanesulfonamide I-32. 1 H NMR (500MHz, CDCl3) δppm 1.56-1.97 (m, 2H) 2.86-2.96 (m, 6H) 3.02-3.13 (m, 2H) 3.24 (t, J = 6.15Hz, 2H). MS m / z 153.1(M+1).

[0706] Intermediate 33

[0707] (2-((2-hydroxypropyl)amino)ethyl)(methyl)carbamate tert-butyl ester

[0708]

[0709] (2-((2-hydroxypropyl)amino)ethyl)(methyl)carbamate tert-butyl ester (I-33) was prepared according to the general procedure of PCT International Application 2007092435. Under nitrogen, MeOH (80 mL) was added to a suspension of 10% Pd-C (0.614 g, 0.577 mmol) in EtOAc (2 mL). Tert-butyl methyl(2-oxoethyl)carbamate (2 g, 11.55 mmol) and 1-aminoprop-2-ol (1.337 mL, 17.32 mmol) were added to the stirred suspension. The atmosphere was exchanged to H2 by three cycles of vacuum / H2. The reaction mixture was stirred under H2 at room temperature for 3 days, followed by filtration through diatomaceous earth and washing with additional methanol. The crude residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic layer was washed twice with a saturated NaHCO3 aqueous solution, diluted with DCM, dried with Na2SO4, filtered, and concentrated to obtain a clear, oily I-33. MS m / z 233.2 (M+1).

[0710] Intermediate 34

[0711] (2-((1-hydroxypropyl-2-yl)amino)ethyl)(methyl)carbamate tert-butyl ester

[0712]

[0713] (2-((1-hydroxypropyl-2-yl)amino)ethyl)(methyl)carbamate tert-butyl ester (I-34) was prepared from methyl (2-oxoethyl)carbamate tert-butyl ester and 2-aminoprop-1-ol according to a procedure similar to that described in I-33. MS m / z 233.3 (M+1).

[0714] Intermediate 35

[0715] 9-Methyl-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylate butyl ester

[0716]

[0717] Butyl 5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (I-35A). 37% hydrochloric acid (3 mL) was added to a suspension of 5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (5 g, 29.9 mmol) in but-1-ol (120 mL). The resulting suspension was stirred at 115 °C for 6 days. After cooling the reaction mixture to room temperature, unreacted acid was separated from the product by vacuum filtration. The filtrate was concentrated under vacuum, and but-1-ol was removed using an azeotropic reaction with heptane. The resulting residue was suspended in DCM, and the contents were filtered again. The orange filtrate was diluted with DCM and washed once with a saturated aqueous solution of NaHCO3. The organic phase was dried with Na2SO4, filtered, and concentrated to produce an orange oil. Heptane was added, and the contents were further concentrated to produce the title compound (I-35A) as an orange-yellow powder. MS m / z 224.2(M+1).

[0718] Butyl 6-formyl-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (I-35B). Selenium dioxide (1.908 g, 17.20 mmol) was added to a stirred solution of I-35A (1.92 g, 8.60 mmol) in dioxane (86 mL). The reaction mixture was stirred under reflux for 5 h, then cooled to room temperature and filtered through a diatomaceous earth and Na₂SO₄ pad. The filtrate was concentrated under vacuum. The orange-red solid was suspended in DCM and the contents were filtered through a diatomaceous earth pad under vacuum. The filtrate was washed once with DI water, dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain I-35B as an orange-yellow solid. MS m / z 238.2 (M+1).

[0719] 5-(butoxycarbonyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (I-35C). Sodium dihydrogen phosphate (1.449 g, 12.08 mmol) and sodium chlorite (1.365 g, 12.08 mmol) were added sequentially to a suspension of I-35B (1.91 g, 8.05 mmol) in tBuOH (33.3 mL), water (33.3 mL), 2-methyl-2-butene (17.06 mL), and acetone (13.88 mL) at 0 °C. The reaction mixture was gradually heated to room temperature and stirred overnight. The mixture was acidified to pH 2 with 1N HCl and extracted with DCM (3 times). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to produce I-35C. MS m / z 254.2 (M+1).

[0720] 6-((2-chloroethyl)carbamoyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (I-35D) was prepared from I-35C according to a procedure similar to that described in I-1E. The title compound was obtained as a dark brown solid. MS m / z 315.3 (M+1).

[0721] 9-Methyl-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylate (I-35). A mixture of I-35D (433 mg, 1.376 mmol) and K₂CO₃ (951 mg, 6.88 mmol) in DMF (6.9 mL) was stirred in a microwave at 100 °C for 10 min. The reaction mixture was diluted with DI water and extracted with DCM (3 times). The organic layer was dried over Na₂SO₄, filtered, and concentrated. The crude product was purified on SiO₂ to yield I-35 as a brown solid. 1 H NMR (500MHz, CDCl3) δppm0.99 (t, J = 7.41Hz, 3H) 1.41-1.53 ​​(m, 2H) 1.53-1.6 5(m,9H)1.71-1.85(m,2H)2.52(s,3H)3.52-3.70(m,2H)4.24-4.45(m,4H). MS m / z 279.2(M+1).

[0722] Intermediate 36

[0723] (1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0724]

[0725] 1-Methylcyclopropane-1-sulfonate butyl ester (I-36A). Butyllithium (47.1 mL, 75 mmol) was added dropwise to THF (200 mL) containing 11.2 g (62.8 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h, followed by the addition of iodomethane (7.82 mL, 126 mmol). The reaction mixture was stirred at -78 °C for 1 h and then heated to room temperature. The reaction mixture was quenched with water (5 mL) and the resulting mixture was concentrated. EtOAc (200 mL) and water (50 mL) were added to the residue. The organic phase was washed with brine (50 mL), dried (Na₂SO₄), and concentrated. Purification was performed on SiO₂ (0–50% EtOAc / heptane) to obtain I-36A as a white solid. MS m / z 193.2 (M+1).

[0726] Potassium 1-methylcyclopropane-1-sulfonate (I-36B). Potassium thiocyanate (5.52 g, 56.8 mmol) was added to water / DME (150 mL / 150 mL) containing I-36A (10.4 g, 54.1 mmol). The reaction mixture was heated to reflux and stirred for 18 h. The solvent was removed under reduced pressure, and the resulting solid was dried at 50 °C for 5 h under high vacuum. The crude product (I-36B) was used without further purification.

[0727] Methylcyclopropane-1-sulfonyl chloride (I-36C). DMF (1 mL) was added to 150 mL (54.1 mmol) of thionyl chloride containing I-36B (9.43 g, 54.1 mmol). The reaction mixture was heated to reflux and maintained for 16 h. Volatile substances were removed under reduced pressure, and the residue was diluted with DCM (200 mL). The organic phase was washed with water (50 mL), dried (Na₂SO₄), and concentrated to give the crude product (I-36C), which was used without further purification.

[0728] Sodium 1-methylcyclopropane-1-sulfinate (I-36D) was prepared from I-36C according to a procedure similar to that described in I-4E. Ionization was not observed by LCMS.

[0729] 2-((1-methylcyclopropyl)sulfonyl)benzyl acetate (I-36E) was prepared by I-36D according to a procedure similar to that described in I-21D. MS m / z 269.2 (M+1).

[0730] 1-((1-methylcyclopropyl)sulfonyl)cyclopropanecarboxylic acid benzyl ester (I-36F) was prepared from I-36E according to a procedure similar to that described in I-2C. MS m / z 295.3 (M+1).

[0731] (1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methanol (I-36G). Lithium borohydride (0.633 g, 29.0 mmol) was added to a solution of I-36F (5.7 g, 19.36 mmol) in Et₂O (100 mL), followed by dropwise addition of methanol (1.178 mL, 29.0 mmol). The reaction mixture turned milky white and was refluxed at 40 °C for 1 h. The reaction mixture was then cooled to 0 °C and quenched with MeOH (10 mL), followed by pH adjustment to 2 with HCl (4 M, 15 mL). The mixture was concentrated under reduced pressure. The crude product was purified on SiO₂ (0-100% EtOAc / heptane) to obtain a clear, oily I-36G. MS m / z 191.2 (M+1).

[0732] (1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methylmethane sulfonate (I-36) was prepared from I-36G according to a procedure similar to that described in I-2. I-36 was obtained as a white solid. MS m / z 269.2.

[0733] Intermediate 37

[0734] (1-((1-(difluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0735]

[0736] Potassium 1-methylcyclopropane-1-sulfonate (I-37B). The solution of oxaloyl chloride (1.305 mL, 14.91 mmol) in DCM (100 mL) was cooled to -78 °C. A solution of DMSO (1.630 mL, 22.94 mmol) in DCM (10 mL) was added to the cooled solution. The resulting solution was stirred at -78 °C for 20 min, followed by the addition of I-4H (3.40 g, 11.47 mmol) in DCM (10 mL). The resulting mixture was stirred at -78 °C for 1 h. NEt3 (7.99 mL, 57.4 mmol) was added to the reactants. The reactants were heated to 0 °C and stirred for 2 h, followed by quenching with saturated ammonium chloride. The two-phase mixture was extracted with DCM. The organic extract was washed with ammonium chloride and brine, dried over Na2SO4, and concentrated to obtain the yellow oily title product (I-37B). MS m / z 295.2(M+1).

[0737] (((1-((1-(difluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (I-37C). DAST (4.55 mL, 34.4 mmol) was added to chloroform (20 mL) containing I-37B (3.38 g, 11.48 mmol). The reaction mixture was stirred at 60 °C for 3 h, then cooled to room temperature and water (10 mL) was added. The phases were separated, and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic matter was dried (Na₂SO₄) and concentrated. The residue was purified on SiO₂ (0-100% EtOAc / heptane) to obtain I-37C. MS m / z 317.3 (M+1).

[0738] (1-((1-(difluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (I-37D). A flask containing I-37C (700 mg, 2.21 mmol) and 10% Pd / C (706 mg, 0.66 mmol) in HOAc (10 mL) was purified with N2 and filled with H2 (gas bladder). The reaction mixture was stirred for 3 h, followed by the addition of water (15 mL) and extraction of the mixture with DCM (2 x 30 mL). The combined organic matter was dried (Na2SO4) and concentrated to obtain I-37D. MS m / z 227.1 (M+1).

[0739] Ethyl 1-(cyclobutylsulfonyl)cyclopropanecarboxylate (I-37). Methanesulfonyl chloride (174 μL, 2.228 mmol) was added dropwise to 10 mL of DCM containing I-37D (480 mg, 2.122 mmol) and triethylamine (325 μL, 2.334 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then heated to room temperature for 30 min. The mixture was quenched by adding cold water. The phases were separated, and the organic layer was dried (Na₂SO₄) and concentrated to obtain I-37 as a white solid. MS m / z 305.1 (M+1).

[0740] Intermediate 38

[0741] (1-(((3-Methyloxetane-3-yl)methyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0742]

[0743] Ethyl 2-(((3-methyloxetane-3-yl)methyl)thio)ethyl acetate (I-38A). K₂CO₃ (4.19 g, 30.3 mmol) and 3-(bromomethyl)-3-methyloxetane (2.5 g, 15.15 mmol) were added to a solution of ethyl 2-mercaptoethyl (1.827 mL, 16.66 mmol) in acetone (100 mL). NaI (0.454 g, 3.03 mmol) was added to the reactants. The mixture was stirred at 60 °C for 3 days. The reactants were cooled to room temperature and filtered to remove insoluble matter. The filtrate was concentrated to give I-38A, which was used directly without further purification. MS m / z 205.2 (M+1).

[0744] 2-(((3-methyloxetane-3-yl)methyl)sulfonyl)ethyl acetate (I-38B) was prepared from I-38A according to a procedure similar to that described in I-9C. I-38B, a colorless oil, was isolated and solidified into a waxy solid. MS m / z 237.1 (M+1).

[0745] 1-(((3-methyloxetane-3-yl)methyl)sulfonyl)cyclopropane-1-carboxylic acid ethyl ester (I-38C) was prepared from I-38B according to a procedure similar to that described in I-2C. MS m / z 263.2 (M+1).

[0746] (1-(((3-methyloxacyclobut-3-yl)methyl)sulfonyl)cyclopropyl)methanol (I-38D) was prepared from I-38C according to a procedure similar to that described for I-2D. MS m / z 221.2 (M+1).

[0747] (1-(((3-methyloxetane-3-yl)methyl)sulfonyl)cyclopropyl)methylmethane sulfonate (I-38) was prepared from I-38D according to a procedure similar to that described in I-2. MS m / z 299.2 (M+1). 1 H NMR(400MHz, CDCl3)δppm4.66(d,J=6.36Hz,2H)4.55(s,2H)4.44(d,J=6.36Hz ,2H)3.55(s,2H)3.10(s,3H)1.68(s,3H)1.62-1.66(m,2H)1.21-1.26(m,2H).

[0748] Intermediate 39

[0749] (1-(((1-(trifluoromethyl)cyclopropyl)methyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0750]

[0751] (1-(trifluoromethyl)cyclopropyl)methylmethane sulfonate (I-39A) was prepared from (1-(trifluoromethyl)cyclopropyl)methanol according to a procedure similar to that described in I-2. The title compound (I-39A) was isolated as a red, oily substance. 1 H NMR (400MHz, CDCl3) δppm 4.31 (s, 2H) 3.06 (s, 3H) 1.18-1.24 (m, 2H) 0.93-0.99 (m, 2H).

[0752] Ethyl 2-(((1-(trifluoromethyl)cyclopropyl)methyl)thio)ethyl acetate (I-39B). K₂CO₃ (945 mg, 6.84 mmol), NaI (93 mg, 0.621 mmol), 18-crown-6 (164 mg, 0.621 mmol), and I-39A (678 mg, 3.11 mmol) were added sequentially to a solution of ethyl 2-mercaptoethyl acetate (681 μl, 6.21 mmol) in acetone (10 mL). The resulting mixture was stirred in an oil bath at 60 °C for 16 h. The reaction mixture was diluted with ethyl acetate and water. The organic phase was separated and washed with brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The resulting residue was dried under high vacuum to give I-39B as a brown oil. MS m / z 265.3 (M+23). 1 H NMR (400MHz, CDCl3) δppm 4.19-4.22(m,2H)3.23(s,2H)3.00(s,2H)1.28-1.31(m,3H)1.04-1.11(m,2H)0.80-0.86(m,2H).

[0753] 2-(((1-(trifluoromethyl)cyclopropyl)methyl)sulfonyl)ethyl acetate (I-39C) was prepared from I-39B according to a procedure similar to that described in I-9C. MS m / z 275.2 (M+1). 1 HNMR (400MHz, CDCl3) δppm 4.25-4.31(m,2H)4.02(s,2H)3.66(s,2H)1.31-1.34(m,3H)1.24-1.28(m,2H)1.18-1.23(m,2H).

[0754] 1-(((1-(trifluoromethyl)cyclopropyl)methyl)sulfonyl)cyclopropane-1-carboxylic acid ethyl ester (I-39D) was prepared by I-39C according to a procedure similar to that described in I-2C. 1H NMR (400MHz, CDCl3) δppm 4.16-4.31(m,2H)3.77(s,2H)1.79-1.85(m,2H)1.64-1.70(m,2H)1.27-1.34(m,4H)1.24(s,4H).

[0755] (1-(((1-(trifluoromethyl)cyclopropyl)methyl)sulfonyl)cyclopropyl)methanol (I-39E) was prepared from I-39D according to a procedure similar to that described in I-2D. MS m / z 259.2 (M+1).

[0756] (1-(((1-(trifluoromethyl)cyclopropyl)methyl)sulfonyl)cyclopropyl)methylmethanesulfonate (I-39) was prepared from I-39E according to a procedure similar to that described in I-2. MS m / z 337.2 (M+1).

[0757] Intermediate 40

[0758] (1-((tetrahydro-2H-pyran-4-yl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0759]

[0760] 2-((tetrahydro-2H-pyran-4-yl)thio)ethyl acetate (I-40A) was prepared from 2-mercaptoethyl acetate and 4-bromotetrahydro-2H-pyran according to a procedure similar to that described in I-24A. The title product (I-40A) was isolated as an orange oil. MS m / z 205.2 (M+1).

[0761] 2-((tetrahydro-2H-pyran-4-yl)sulfonyl)ethyl acetate (I-40B) was prepared from I-40A according to a procedure similar to that described in I-9C. The colorless oily residue I-40B was separated. MS m / z 237 (M+1).

[0762] 1-((tetrahydro-2H-pyran-4-yl)sulfonyl)cyclopropanecarboxylate (I-40C) was prepared from I-40B according to a procedure similar to that described for I-2C. Compound I-40C was isolated as a pale yellow solid. MS m / z 263 (M+1).

[0763] (1-((tetrahydro-2H-pyran-4-yl)sulfonyl)cyclopropyl)methanol (I-40D) was prepared from I-40C according to a procedure similar to that described for I-2D. I-40D was isolated as a white solid. MS m / z 221 (M+1).

[0764] (1-((tetrahydro-2H-pyran-4-yl)sulfonyl)cyclopropyl)methylmethanesulfonate (I-40) was prepared from I-40D according to a procedure similar to that described in I-2. I-40 was isolated as a brown oil. MS m / z 299 (M+1).

[0765] Intermediate 41

[0766] (1-(tert-butylsulfinyl)cyclopropyl)methylmethanesulfonate

[0767]

[0768] 2-(tert-butylthio)benzyl acetate (I-41A). K₂CO₃ (11.7 g, 85 mmol), NaI (0.39 g, 2.6 mmol), and 2-bromoacetic acid benzyl ester (15 g, 65.5 mmol) were added sequentially to a solution of 2-methylpropane-2-thiol (5.9 mL, 52.4 mmol) in acetone (50 mL). The resulting mixture was stirred at 25 °C for 2 h, followed by dilution with ethyl acetate and water. The organic phase was separated and washed with brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The resulting residue was dried under high vacuum to give I-41A as a yellow oil. MS m / z 239 (M+1).

[0769] 2-(tert-butylsulfinyl)acetic acid benzyl ester (I-41B). Potassium persulfate (Oxone) (17.7 g, 28.8 mmol) was added to a solution of I-41A (12.5 g, 52.4 mmol) in methanol (150 mL) and water (15 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 20 min. The suspension was filtered through diatomaceous earth and the filtrate was concentrated. The resulting residue was partitioned between DI water and DCM. The aqueous phase was extracted twice with DCM, and the combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified on SiO2 (0–50% EtOAc / heptane) to obtain a colorless oily I-41B. MS m / z 255 (M+1).

[0770] 1-(tert-butylsulfinyl)cyclopropanecarboxylate benzyl ester (I-41C). Sodium hydride (0.45 g, 11.3 mmol, a 60% suspension in mineral oil) was added to an ice-cold solution of I-41B (1.6 g, 6.3 mmol) in DMA (20 mL). The resulting mixture was stirred at 25 °C for 30 min. 1,2-Dibromoethane (1.4 g, 7.5 mmol) was added to this suspension, and the mixture was stirred at 25 °C for 3 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified on SiO2 (0-50% EtOAc / heptane) to obtain I-41C. MS m / z 281 (M+1).

[0771] (1-(tert-butylsulfinyl)cyclopropyl)methanol (I-41D) was prepared from I-41C according to a procedure similar to that described for I-2D. I-41D was obtained as a colorless oil. MS m / z 177 (M+1).

[0772] (1-(tert-butylsulfinyl)cyclopropyl)methylmethanesulfonate (I-41) was prepared from I-41D according to a procedure similar to that described in I-2. The title compound I-41 was obtained as a brown solid. MS m / z 255 (M+1).

[0773] Intermediate 42

[0774] (1-((cyclopropylmethyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0775]

[0776] 2-((cyclopropylmethyl)thio)ethyl acetate (I-42A) was prepared from 2-mercaptoethyl acetate and (bromomethyl)cyclopropane according to a procedure similar to that described in I-38A. MS m / z 175 (M+1).

[0777] 2-((cyclopropylmethyl)sulfonyl)ethyl acetate (I-42B) was prepared from I-42A according to a procedure similar to that described in I-9C. MS m / z 207 (M+1).

[0778] 1-((cyclopropylmethyl)sulfonyl)cyclopropanecarboxylate (I-42C) was prepared from I-42B according to a procedure similar to that described in I-2C. The title compound I-42C was isolated as a yellow solid. 1 H NMR (400MHz, CDCl) 3)δ4.24(q,J=7.14Hz,2H),3.37(d,J=7.29Hz,2H),1.79-1.88(m,2H),1.62-1.69(m ,2H),1.24-1.33(m,3H),1.05-1.20(m,1H),0.64-0.74(m,2H),0.32-0.45(m,2H). MS m / z233(M+1).

[0779] (1-((cyclopropylmethyl)sulfonyl)cyclopropyl)methanol (I-42D) was prepared from I-42C according to a procedure similar to that described for I-2D. The title compound I-42D was isolated as a colorless oil. MS m / z 191 (M+1).

[0780] (1-((cyclopropylmethyl)sulfonyl)cyclopropyl)methylmethane sulfonate (I-42) was prepared from I-42D according to a procedure similar to that described in I-2. The title compound I-42 was isolated as a yellow solid. MS m / z 269 (M+1).

[0781] Intermediate 43

[0782] (1-(((1-(cyanomethyl)cyclopropyl)methyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0783]

[0784] Ethyl 2-(((1-(cyanomethyl)cyclopropyl)methyl)thio)ethyl acetate (I-43A) was prepared from ethyl 2-mercaptoethyl acetate and 2-(1-(bromomethyl)cyclopropyl)acetonitrile according to a procedure similar to that described in I-38A. MS m / z 214 (M+1).

[0785] 2-(((1-(cyanomethyl)cyclopropyl)methyl)sulfonyl)ethyl acetate (I-43B) was prepared from I-43A according to a procedure similar to that described in I-9C. The title compound I-43B was isolated as a waxy solid. MS m / z 246 (M+1).

[0786] Ethyl 1-(((1-(cyanomethyl)cyclopropyl)methyl)sulfonyl)cyclopropanecarboxylate (I-43C) was prepared from I-43B according to a procedure similar to that described in I-2C. MS m / z 272 (M+1).

[0787] 2-(1-(((1-(hydroxymethyl)cyclopropyl)sulfonyl)methyl)cyclopropyl)acetonitrile (I-43D) was prepared from I-43C according to a procedure similar to that described for I-2D. The title compound I-43D was isolated as a colorless oil. MS m / z 230 (M+1).

[0788] (1-(((1-(cyanomethyl)cyclopropyl)methyl)sulfonyl)cyclopropyl)methylmethanesulfonate (I-43) was prepared from I-42A according to a procedure similar to that described in I-9C. The title compound I-43 was isolated as a brown solid. 1 H NMR(500MHz, CDCl3)δ4.55(s,2H),3.29(s,2H),3.15(s,3H),2.77(s,2H),1 .63-1.72(m,2H),1.22-1.32(m,2H),0.92-1.02(m,2H),0.78-0.88(m,2H). MS m / z 308(M+1).

[0789] Intermediate 44

[0790] (1-(((1-methylcyclopropyl)methyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0791]

[0792] Ethyl 2-(((1-methylcyclopropyl)methyl)thio)ethyl acetate (I-44A). ZnI₂ (3.29 g, 10.3 mmol) and (1-methylcyclopropyl)methanol (1.0 mL, 10.3 mmol) were added to a solution of ethyl 2-mercaptoethyl (3.39 mL, 30.9 mmol) in DCM (50 mL). The mixture was stirred at 20 °C for 8 days. A saturated aqueous solution of NaHCO₃ was slowly added to the reactants, and the mixture was stirred vigorously at room temperature until gas production ceased. The organic phase was separated and dried over MgSO₄. After concentration, crude I-44A was used for the next step without further purification. MS m / z 189.3 (M+1).

[0793] 2-(((1-methylcyclopropyl)methyl)sulfonyl)ethyl acetate (I-44B) was prepared from I-44A according to a procedure similar to that described in I-9C. The title compound I-44B was obtained as a white solid. MS m / z 221.1 (M+1).

[0794] 1-(((1-methylcyclopropyl)methyl)sulfonyl)cyclopropane-1-carboxylic acid ethyl ester (I-44C) was prepared from I-44B according to a procedure similar to that described in I-2C. MS m / z 247.2 (M+1).

[0795] (1-(((1-methylcyclopropyl)methyl)sulfonyl)cyclopropyl)methanol (I-44D) was prepared from I-44C according to a procedure similar to that described for I-2D. MS m / z 205.1 (M+1).

[0796] (1-(((1-methylcyclopropyl)methyl)sulfonyl)cyclopropyl)methylmethane sulfonate (I-44) was prepared from I-44D according to a procedure similar to that described in I-2. MS m / z 283.2 (M+1).

[0797] Intermediate 45

[0798] (1-(((1-cyanocyclopropyl)methyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0799]

[0800] 2-(((1-cyanocyclopropyl)methyl)thio)ethyl acetate (I-45A) was prepared from ethyl 2-mercaptoethyl and 1-(bromomethyl)cyclopropane-1-carboxynitrile according to a procedure similar to that described in I-38A. The title compound I-45A was isolated as a brown oil. MS m / z 200.1 (M+1).

[0801] 2-(((1-cyanocyclopropyl)methyl)sulfonyl)ethyl acetate (I-45B) was prepared from I-45A according to a procedure similar to that described in I-9C. MS m / z 232.1 (M+1).

[0802] 1-(((1-cyanocyclopropyl)methyl)sulfonyl)cyclopropane-1-carboxylic acid ethyl ester (I-45C) was prepared from I-45B according to a procedure similar to that described in I-2C. MS m / z 258.1 (M+1).

[0803] 1-(((1-(hydroxymethyl)cyclopropyl)sulfonyl)methyl)cyclopropane-1-carboxynitrile (I-45D) was prepared from I-45C according to a procedure similar to that described for I-2D. MS m / z 216.1 (M+1).

[0804] (1-(((1-cyanocyclopropyl)methyl)sulfonyl)cyclopropyl)methylmethane sulfonate (I-45) was prepared from I-45D according to a procedure similar to that described in I-2. MS m / z 294.2 (M+1).

[0805] Intermediate 46

[0806] (1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methylmethane) sulfonates

[0807]

[0808] ((1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methoxy)(tert-butyl)dimethylsilane (I-46A). TBSCl (2.288 g, 15.18 mmol) was added to a solution of I-4H (3 g, 10.12 mmol) and imidazole (2.067 g, 30.4 mmol) in DMF (20 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with Et2O and washed with saturated citric acid, sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. I-46A was separated as a white solid. LCMS m / z: 411 (M+1). 1 H NMR(500MHz,DMSO-d6)δppm 0.00-0.02(m,6H)0.84(s,9H)0.98(td,J=4.73,2.21Hz,2H)1.10(td,J=4.73,2.52Hz,2H)1.23(td,J= 4.41, 2.21Hz, 2H) 1.30 (td, J = 4.73, 2.21Hz, 2H) 3.79 (s, 2H) 3.94 (s, 2H) 4.49 (s, 2H) 7.27-7.39 (m, 5H).

[0809] (1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (I-46B). Pd / C (0.16 g, 0.150 mmol) was added to a solution of I-46A (1.24 g, 3.02 mmol) in EtOH (10 mL) / AcOH (10 mL). The atmosphere was changed to H2. The resulting mixture was stirred at room temperature. After the reaction was complete, the mixture was filtered through a diatomaceous earth plug. The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and washed with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. I-46B was separated as a colorless oil. LCMS m / z: 321 (M+1). 1 H NMR(500MHz,DMSO-d6)δppm 0.04-0.07(m,6H)0.87(s,9H)1.03(ttt,J=5.36,5.36,3.78,3.78,2.52,2.52Hz,4H) 1.17(td,J=4.73,2.52Hz,2H)1.24(td,J=4.41,2.52Hz,2H)3.79(s,2H)3.95(s,2H).

[0810] (1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methylmethanesulfonate (I-46C) was prepared from I-46B according to a procedure similar to that described in I-2. LCMS m / z: 399 (M+1).

[0811] Intermediate 47

[0812] 9-Bromo-N-(4-chlorobenzyl)-1,6-dioxo-1,3,4,6-tetrahydropyrido[2,1-c][1,4]oxazine-7-methyl amide

[0813]

[0814] 5-Bromo-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (I-47A). NaOH (11.8 g, 295.0 mmol, 3.0 equivalents) was dissolved in water (150 mL) and cooled to 0 °C. Bromine (18.7 g, 118.0 mmol, 1.2 equivalents) was added. 6-Methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (15 g, 98.0 mmol, 1.0 equivalents) was dissolved in NaOH (11.7 g, 292.5 mmol, 2.98 equivalents) [in water (45 mL)] at 0 °C. NaOBr (prepared as above) was added and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was acidified to pH 4-5 with 1 N HCl. The precipitated solid was filtered, washed with water and hexane, and co-distilled with toluene to give I-47A. LCMS(m / z): 233.9 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ14.45(s,1H),13.72(s,1H),8.58–8.13(m,1H),2.48–2.42(m,3H).

[0815] 5-Bromo-N-(4-chlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (I-47B) was prepared from I-47A according to a procedure similar to that described in I-17B. LCMS (m / z): 356.0 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ12.95(s,1H),9.98(s,1H),8.28(s,1H),7.39(d,J=8.5Hz,2H),7.33(d,J=8.5Hz,2H),4.51(d,J=6.1Hz,2H),2.38(s,3H).

[0816] 5-Bromo-N-(4-chlorobenzyl)-6-formyl-2-oxo-1,2-dihydropyridine-3-carboxamide (I-47C). Selenium dioxide (70.7 g, 637.0 mmol, 15.0 equivalent) was added to a mixture of I-47B (15 g, 42.0 mmol, 1.0 equivalent) and 1,4-dioxane (525 mL). The reaction mixture was stirred at 130 °C for 24 h, followed by filtration through diatomaceous earth. The filter cake was washed with dichloromethane and the filtrate was concentrated. The crude residue was purified on SiO2 (100% dichloromethane) to obtain I-47C. LCMS (m / z): 369.3 [M+H]. 1 H NMR(400MHz,DMSO-d6)δ10.00(d,J=5.0Hz,1H),9.82(s,1H),8.43(d,J=23.7Hz ,1H),7.39(dd,J=8.5,2.3Hz,2H),7.34(d,J=6.6Hz,2H),4.51(t,J=5.9Hz,2H).

[0817] 3-Bromo-5-((4-chlorobenzyl)carbamoyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (I-47D). I-47C (6 g, 16.2 mmol, 1.0 equivalent) was dissolved in DMF (50 mL). Potassium persulfate (10 g, 32.5 mmol, 2.0 equivalent) was added, and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was quenched with water. The precipitated solid was filtered, washed with water and hexane, and ground with 20% dichloromethane / hexane. The solvent was decanted to give I-47D. LCMS (m / z): 387.0 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ13.14(s,1H),9.85(s,1H),8.32(d,J=28.5Hz,1H),8.37–6.31(m,4H),4.52(d,J=5.9Hz,2H).

[0818] 9-Bromo-N-(4-chlorobenzyl)-1,6-dioxo-1,3,4,6-tetrahydropyrido[2,1-c][1,4]oxazine-7-carboxamide (I-47) was prepared from I-47D according to a procedure similar to that described in I-17. LCMS (m / z): 411.0 [M+H]. 1 H NMR(400MHz,DMSO-d6)δ9.95(t,J=6.1Hz,1H),8.43(s,1H),7.40(d,J=8.5Hz,2H), 7.35(d,J=8.5Hz,2H),4.77–4.63(m,2H),4.55(t,J=5.7Hz,2H),4.42–4.27(m,2H).

[0819] Intermediate 48

[0820] 2-Methyl-2-((1-((((methylsulfonyl)oxy)methyl)cyclopropyl)sulfonyl)tert-butyl propionate

[0821]

[0822] 2-((2-methoxy-2-oxoethyl)thio)-2-methylpropionate tert-butyl ester (I-48A). Methyl 2-mercaptoacetate (4.6 g, 22.0 mmol, 1.0 equivalent) was dissolved in methanol (50 mL), and NaOMe (1.2 g, 22.0 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at room temperature for 2 min, followed by the addition of 2-bromo-2-methylpropionate tert-butyl ester (5 g, 22.0 mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 18 h, followed by quenching with cold water and extraction with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give a crude residue. The crude residue was purified by silica gel column chromatography (0-10% EtOAc / hexane) to obtain the title compound. 1 H NMR (400MHz, DMSO-d6) δ3.63 (s, 2H), 1.41 (s, 9H), 1.38 (s, 6H).

[0823] 2-((2-methoxy-2-oxoethyl)sulfonyl)-2-methylpropionate tert-butyl ester (I-48B) is prepared from I-48A according to a procedure similar to that described in I-8C, with EtOAc replacing EtOH. 1 H NMR (400MHz, DMSO-d6) δ4.54–4.47 (m, 2H), 3.73 (s, 3H), 1.57–1.50 (m, 6H), 1.45 (d, J = 6.0Hz, 9H).

[0824] Methyl 1-((1-(tert-butoxy)-2-methyl-1-oxopropyl-2-yl)sulfonyl)cyclopropane-1-carboxylate (I-48C). A solution of I-48B (2.5 g, 8.0 mmol, 1.0 equivalent) in DMF (5 mL) was degassed for 10 min. 1,2-Dibromoethane (2.5 g, 13.3 mmol, 1.5 equivalent), K₂CO₃ (3.7 g, 26.0 mmol, 3.0 equivalent), and TBAB (0.03 g, 0.08 mmol, 0.01 equivalent) were added, and the reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was quenched with cold water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain a crude residue. The crude residue was purified by silica gel column chromatography (0-10% EtOAc / hexane) to obtain I-48C. 1H NMR (400MHz, CDCl3) δ3.85–3.74(m,3H),1.88–1.81(m,2H),1.72–1.67(m,8H),1.52(d,J=6.5Hz,9H).

[0825] 2-((1-(hydroxymethyl)cyclopropyl)sulfonyl)-2-methylpropionate tert-butyl ester (I-48D). I-48C (0.98 g, 3.2 mmol, 1.0 equivalent) was dissolved in THF (16 mL), and LiAlH[OC(CH3)3]3 (1 M in THF) (16 mL) was added dropwise. The mixture was stirred at 60 °C for 24 h. The reaction mixture was quenched with an aqueous slurry of sodium sulfate. The mixture was filtered through a diatomaceous earth bed and washed with excess EtOAc. The filtrate was concentrated to give the title compound. 1 H NMR (400MHz, DMSO-d6) δ4.05–3.98 (m, 1H), 3.81 (s, 2H), 1.58 (d, J = 14.1Hz, 6H), 1.45 (d, J = 21.7Hz, 9H), 1.21 (d, J = 11.5Hz, 4H).

[0826] 2-Methyl-2-((1-((((methanesulfonyl)oxy)methyl)cyclopropyl)sulfonyl)propionate tert-butyl ester (I-48). THF (4 mL) containing I-48D (0.2 g, 0.72 mmol, 1.0 equivalent) was added, followed by TEA (0.22 g, 2.2 mmol, 3.0 equivalent), and the reaction mixture was cooled to 0 °C. MeSO₂Cl (0.098 g, 0.86 mmol, 1.2 equivalent) was added, and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate, and concentrated to give the title compound.

[0827] Intermediate 49

[0828] (1-((1-methoxy-2-methylpropyl-2-yl)sulfonyl)cyclopropyl)methylamine hydrochloride

[0829]

[0830] 2-Thiopyridine-1(2H)-yl 3-methoxy-2,2-dimethylpropionate (I-49A) is prepared from 3-methoxy-2,2-dimethylpropionic acid according to a procedure similar to that described in I-7B. I-49A is used without purification.

[0831] 2-((1-Methoxy-2-methylpropyl-2-yl)thio)pyridine (I-49B). I-49A (4 g, crude) was dissolved in EtOAc (40 mL), and the solution was irradiated with a tungsten lamp (375 W) for 2 h to produce I-49B. The product was used in the next step without further purification.

[0832] 2-((1-Methoxy-2-methylprop-2-yl)sulfonyl)pyridine (I-49C). I-49B (4 g, 20.3 mmol, 1.0 equivalent) was added to water (40 mL) and cooled to 10 °C. Potassium persulfate (28.7 g, 46.7 mmol, 2.3 equivalent) was added, and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give a crude residue. The crude residue was purified by silica gel column chromatography (30% EtOAc / hexane) to obtain I-49C. LCMS (m / z): 229.8 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ8.80(ddd,J=4.7,1.7,0.8Hz,1H),8.15(td,J=7.8,1.7Hz,1H),8.03(d t, J=7.9, 1.0Hz, 1H), 7.76 (ddd, J=7.6, 4.7, 1.1Hz, 1H), 3.48 (s, 2H), 3.09 (s, 3H), 1.31 (s, 6H).

[0833] Sodium 1-methoxy-2-methylpropane-2-sulfinate (I-49D). I-49C (1.1 g, 4.9 mmol, 1.0 equivalent) was dissolved in THF (12 mL) and cooled to 0 °C. MeSNa (0.85 g, 12.2 mmol, 2.5 equivalent) was added, and the reaction mixture was stirred at 0 °C for 2 h and then at room temperature for 24 h. The reaction mixture was concentrated, and the residue was ground with diethyl ether to remove methylthiopyridine. The crude product was further purified by silica gel column chromatography (20% MeOH / DCM) to obtain I-49D. 1 H NMR (400MHz, D2O) δ3.47(s,2H),3.27(s,3H),1.19(s,6H).

[0834] 2-((1-Methoxy-2-methylprop-2-yl)sulfonyl)acetonitrile (I-49E). 2-Bromoacetonitrile (0.37 g, 3.2 mmol, 1.1 equivalent) was added to a solution of I-49D (0.5 g, 2.9 mmol, 1.0 equivalent) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h, then quenched with cold water and extracted with EtOAc. The organic layer was washed with cold water, dried over sodium sulfate, and concentrated to give a crude residue. The crude residue was purified by silica gel column chromatography (20% EtOAc / hexane) to give I-49E.

[0835] 1-((1-methoxy-2-methylprop-2-yl)sulfonyl)cyclopropane-1-carboxynitrile (I-49F). K₂CO₃ (0.75 g, 5.5 mmol, 5.0 equivalence) and 1,2-dibromoethane (0.62 g, 3.3 mmol, 3.0 equivalence) were added to a solution of I-49E (0.21 g, 1.1 mmol, 1.0 equivalence) in DMF (4 mL). The reaction mixture was stirred at 80 °C for 2 h, then quenched with cold water and extracted with EtOAc. The organic layer was washed with cold water, dried over sodium sulfate, and concentrated to give a crude residue. The residue was purified by silica gel column chromatography (15% EtOAc / hexane) to obtain I-49F. 1 H NMR (400MHz, CDCl3) δ4.23(s,2H),3.60(s,2H),3.45(s,3H),1.51(s,6H). 1 H NMR (400MHz, CDCl3) δ3.62 (s, 2H), 3.43 (d, J = 10.7Hz, 3H), 1.91 (q, J = 5.2Hz, 2H), 1.71 (dd, J = 8.7, 5.3Hz, 2H), 1.56 (s, 6H).

[0836] ((1-((1-methoxy-2-methylprop-2-yl)sulfonyl)cyclopropyl)methyl)tert-butyl carbamate (I-49G). I-49F (0.15 g, 0.7 mmol, 1.0 equivalent) was dissolved in methanol (3 mL) and cooled to 0 °C. NiCl2·6H2O (0.016 g, 0.07 mmol, 0.1 equivalent), (Boc)2O (0.3 g, 1.4 mmol, 2.0 equivalent), and NaBH4 (0.18 g, 4.83 mmol, 7.0 equivalent) were added, and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give a crude residue. The residue was purified by silica gel column chromatography (0-20% EtOAc / hexane) to obtain I-49G. 1H NMR (400MHz, DMSO-d6) δ6.87(s,1H),3.56(s,2H),3.33(s,2H),3.31(s,3H),1.44(s,9H),1.34(s,6H),1.19–1.15(m,2H),0.93(d,J=2.1Hz,2H).

[0837] (1-((1-methoxy-2-methylpropyl-2-yl)sulfonyl)cyclopropyl)methylamine hydrochloride (I-49). HCl (4 M in 1,4-dioxane) (1 mL) was added to a solution of I-49 G (0.08 g, 0.25 mmol, 1.0 equivalence) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and co-distilled with dichloromethane to give I-49. LCMS (m / z): 222.2 [M+H, free amine]. 1 H NMR (400MHz, DMSO-d6) δ7.95 (s, 3H), 3.56 (s, 2H), 3.33 (d, J = 3.6Hz, 5H), 1.91 (dd, J = 8. 9,5.4Hz,1H),1.75(dd,J=8.7,5.2Hz,1H),1.43(s,3H),1.35(s,3H),1.31–1.22(m,2H).

[0838] Intermediate 50

[0839] (1-((1-methoxy-2-methylpropyl-2-yl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0840]

[0841] 2-((1-methoxy-2-methylprop-2-yl)sulfonyl)ethyl acetate (I-50A) was prepared from I-49D according to a procedure similar to that described in I-7E. 1 H NMR (400MHz, DMSO-d6) δ4.15 (s, 2H), 3.30 (d, J = 4.4Hz, 2H), 2.89 (d, J = 8.6Hz, 3H), 2.75–2.71 (m, 3H), 1.30–1.15 (m, 9H).

[0842] 1-((1-methoxy-2-methylprop-2-yl)sulfonyl)cyclopropane-1-carboxylic acid ethyl ester (I-50B) is prepared from I-50A according to a procedure similar to that described in I-2C. 1 H NMR (400MHz, CDCl3) δ4.35–4.10(m,2H), 3.59–3.51(m,2H), 3.42–3.35(m,3H), 1.82–1.09(m,12H).

[0843] 1-((1-methoxy-2-methylprop-2-yl)sulfonyl)cyclopropyl)methanol (I-50C). I-50B (1 g, 3.7 mmol, 1.0 equivalent) was dissolved in THF (10 mL) and cooled to 0 °C. LAH (1.0 M in THF) (4.1 mL, 4.1 mmol, 1.1 equivalent) was added dropwise, and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with an aqueous sodium sulfate slurry, diluted with EtOAc, filtered through a diatomaceous earth bed, and concentrated to give the title compound. 1 H NMR (400MHz, DMSO-d6) δ3.78(s,1H),3.56(s,1H),3.18(s,1H),1.42–1.03(m,4H).

[0844] (1-((1-methoxy-2-methylprop-2-yl)sulfonyl)cyclopropyl)methylmethanesulfonate (I-50) is prepared from I-50C according to a procedure similar to that described in I-2. 1 H NMR (400MHz, CDCl3) δ4.65 (s, 2H), 3.59 (s, 2H), 3.43 (d, J = 4.5Hz, 3H), 3.12 (s, 3H), 1.77–1.66 (m, 2H), 1.51–1.44 (m, 8H).

[0845] Intermediate 51

[0846] 2-(cyclopropylsulfonyl)propylmethanesulfonate

[0847]

[0848] Ethyl 2-(cyclopropylsulfonyl)propionate (I-51A) is prepared from sodium cyclopropanesulfinate and ethyl 2-bromopropionate according to a procedure similar to that described in I-2B. 1 H NMR (400MHz, CDCl3) δ4.33–4.28 (m, 2H), 2.68 (ddd, J = 9.7, 6.4, 4.0Hz, 1H), 1. 69(d,J=7.3Hz,3H),1.44–1.28(m,3H),1.28–1.20(m,2H),1.14–1.06(m,2H).

[0849] 2-(cyclopropylsulfonyl)prop-1-ol (I-51B). Methanol (15 mL) was added dropwise at 0 °C to a flask containing I-51A (3.2 g, 12.9 mmol, 1.0 equivalent) and sodium borohydride (1.96 g, 51.9 mmol, 4.0 equivalent). The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain the title compound. 1 HNMR (400MHz, DMSO-d6) δ 3.83 (dd, J = 11.3, 5.0 Hz, 1H), 3.59 ( dd, J = 10.5, 3.8 Hz, 1H), 3.20 ( d, J = 6.0 Hz, 1H), 1.91 ( s, 3H), 1.29 ( t, J = 7.6 Hz, 4H).

[0850] 2-(cyclopropylsulfonyl)propylmethanesulfonate (I-51) is prepared from I-51B according to a procedure similar to that described in I-2. 1 H NMR (400MHz, DMSO-d6) δ4.48(dd,J=13.3,5.4Hz,2H),3.27(s,3H),2.77–2.73(m,1H),1.37(d,J=7.1Hz,3H),1.14–0.86(m,4H).

[0851] Intermediate 52

[0852] (1-((1-methoxycyclopropyl)sulfonyl)cyclopropyl)methylmethanesulfonate

[0853]

[0854] Methyl 1-methoxycyclopropane-1-carboxylate (I-52A). 1-Hydroxycyclopropane-1-carboxylic acid (5 g, 49.0 mmol, 1.0 equivalent) was dissolved in DMF (10 mL) and cooled to 0 °C. NaH (60% suspension in mineral oil, 2.94 g, 122.5 mmol, 2.5 equivalent) and iodomethane (20.9 g, 147.1 mmol, 3.0 equivalent) were added, and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with cold water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain the title compound. 1 H NMR (400MHz, DMSO-d6) δ3.66(s,2H),3.30(s,2H),1.19–1.13(m,3H).

[0855] 1-Methoxycyclopropane-1-carboxylic acid (I-52B). LiOH·H₂O (2.8 g, 66.2 mmol, 2.0 equivalent) was added to a solution of I-52A (4.3 g, 33.1 mmol, 1.0 equivalent) in THF (40 mL), MeOH (10 mL), and water (10 mL). The reaction mixture was stirred at room temperature for 24 h, then diluted with water and extracted with EtOAc. The aqueous layer was acidified to pH 2–3 with 1.0 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain the title compound. 1 H NMR (400MHz, DMSO-d6) δ12.33(s,1H),3.54–2.97(m,3H),2.00–1.82(m,2H),1.64–0.44(m,4H).

[0856] 2-Thiopyridine-1(2H)-yl-1-methoxycyclopropane-1-carboxylate (I-52C) was prepared by I-52B according to a procedure similar to that described in I-7B. 1 H NMR(400MHz,DMSO-d6)δ8.41(dd,J=7.0,1.3Hz,1H),7.58–7.54(m,1H),7.44(ddd,J=7.2,3 .1,1.4Hz,1H),6.92–6.86(m,1H),3.53–3.46(m,3H),1.63–1.52(m,2H),1.49–1.40(m,2H).

[0857] 2-((1-methoxycyclopropyl)thio)pyridine (I-52D) was prepared from I-52C according to a procedure similar to that described in I-49B.

[0858] 2-((1-methoxycyclopropyl)sulfonyl)pyridine (I-52E) was prepared from I-52D according to a procedure similar to that described in I-49C. 1 H NMR (400MHz, DMSO-d6) δ8.86–8.82(m,1H),8.21–8.13(m,2H),7.79(ddd,J=7.3,4.7 ,1.5Hz,1H),3.43(s,3H),1.58(dd,J=8.5,5.7Hz,2H),1.39(dd,J=8.5,5.8Hz,2H).

[0859] 1-Methoxycyclopropane-1-sodium sulfite (I-52F) is prepared from I-52E according to a procedure similar to that described in I-49D. 1H NMR (400MHz, DMSO-d6) δ3.37 (s, 4H), 0.77 (q, J = 4.2Hz, 3H), 0.42 (q, J = 4.2Hz, 3H).

[0860] 2-((1-methoxycyclopropyl)sulfonyl)ethyl acetate (I-52G) was prepared from I-52F according to a procedure similar to that described in I-7E. 1 H NMR (400MHz, DMSO-d6) δ4.39 (d, J = 8.1Hz, 2H), 4.18 (dd, J = 9.3, 4.9Hz, 2H), 3.52 (s, 3H), 1.39 (d, J = 9.5Hz, 4H), 1.23 (d, J = 7.1Hz, 3H).

[0861] 1-((1-methoxycyclopropyl)sulfonyl)cyclopropane-1-carboxylic acid ethyl ester (I-52H) was prepared by I-52G according to a procedure similar to that described in I-48C. 1 H NMR (400MHz, DMSO-d6) δ4.21–4.15(m,2H),3.45(s,3H),1.68(s,4H),1.49(s,2H),1.41(s,2H),1.24(d,J=7.1Hz,3H).

[0862] (1-((1-methoxycyclopropyl)sulfonyl)cyclopropyl)methanol (I-52I) is prepared from I-52H according to a procedure similar to that described in I-50C. 1 H NMR (400MHz, DMSO-d6) δ5.03(t,J=6.3Hz,1H),3.85(d,J=6.3Hz,2H),3.48(s,3H),1.38–1.26(m,4H),1.23–1.14(m,2H),1.14–1.03(m,2H).

[0863] (1-((1-methoxycyclopropyl)sulfonyl)cyclopropyl)methylmethanesulfonate (I-52) is prepared from I-52I according to a procedure similar to that described in I-2. 1 H NMR (400MHz, DMSO-d6) δ4.54(s,2H),3.48(s,3H),3.21(s,3H),1.48(dd,J=7.5,5.0Hz,2H),1.42–1.34(m,4H),1.19(t,J=7.3Hz,2H).

[0864] Intermediate 53

[0865] (1-(aminomethyl)cyclopropyl)tert-butyl carbamate

[0866]

[0867] Methyl 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylate (I-53A). TEA (18.8 mL, 130.0 mmol, 3.0 equivalents) and (Boc)₂O (14.2 g, 65.0 mmol, 1.5 equivalents) were added to a mixture of methyl 1-aminocyclopropane-1-carboxylate hydrochloride (5 g, 43.0 mmol, 1.0 equivalents) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain I-53A. LCMS (m / z): 216.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ3.61–3.50 (m, 6H), 1.45 (s, 9H), 1.36 (s, 11H), 1.29 (dd, J = 7.7, 4.5Hz, 4H), 1.00 (dd, J = 7.7, 4.4Hz, 4H).

[0868] (1-(hydroxymethyl)cyclopropyl)carbamate tert-butyl ester (I-53B) is prepared from I-53A according to a procedure similar to that described in I-50C. 1 H NMR (400MHz, DMSO-d6) δ7.05 (s, 1H), 4.57 (t, J = 5.8Hz, 1H), 3.37 (d, J = 5.7Hz, 2H), 0.61 (t, J = 3.1Hz, 2H), 0.52 (d, J = 2.1Hz, 2H).

[0869] (1-((tert-butoxycarbonyl)amino)cyclopropyl)methylmethanesulfonate (I-53C) was prepared from I-52B according to a procedure similar to that described in I-2.

[0870] (1-(azidomethyl)cyclopropyl)carbamate tert-butyl ester (I-53D). I-53C (1 g, 3.7 mmol, 1.0 equivalent) and NaN3 (0.74 g, 11.3 mmol, 3.0 equivalent) were added to DMF (10 mL), and the reaction mixture was stirred at 90 °C for 18 h. The reaction mixture was quenched with cold water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain the title product. 1 H NMR (400MHz, DMSO-d6) δ7.40(s,1H),3.34–3.08(m,3H),1.38(s,9H),0.67(s,4H).

[0871] (1-(aminomethyl)cyclopropyl)carbamate tert-butyl ester (I-53). I-53D (0.7 g, 3.3 mmol, 1.0 equivalent) was dissolved in methanol (10 mL). Pd / C (10% water) (0.03 g) was added, and the reaction mixture was stirred for 18 h at room temperature under a H2 (gas) atmosphere. The reaction mixture was filtered through a diatomaceous earth bed, and the filtrate was concentrated to obtain the title product.

[0872] Intermediate 54

[0873] (1-((methylsulfonyl)methyl)cyclopropyl)

[0874]

[0875] Ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (I-54A). LiAlH[OC(CH3)3]3 (1M in THF) (100mL) was added dropwise to a solution of diethyl cyclopropane-1,1-dicarboxylate (10g, 42.9mmol, 1.0 equivalent) in THF (220mL). The reaction mixture was stirred at 66°C for 12h. The reaction mixture was diluted with 10% sodium bisulfite aqueous solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain a crude residue. The crude residue was purified by silica gel column chromatography (40% EtOAc / hexane) to obtain the title product. 1 H NMR (400MHz, CDCl3) δ4.17 (q, J=7.1Hz, 2H), 3.64 (s, 2H), 2.66 (s, 1H), 1.28 (dt, J=9.8, 5.8Hz, 5H), 0.89 (q, J=4.2Hz, 2H).

[0876] 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylic acid ethyl ester (I-54B) is prepared from I-54A according to a procedure similar to that described in I-2. 1 H NMR (400MHz, CDCl3) δ4.18 (q, J = 6.8Hz, 2H), 3.17–3.13 (m, 2H), 3.10 (s, 3H), 1.46–1.40 (m, 5H), 1.07 (dd, J = 7.4, 4.5Hz, 2H).

[0877] Ethyl 1-((methylthio)methyl)cyclopropane-1-carboxylate (I-54C). CH3SNa (4.7 g, 68.0 mmol, 2.0 equivalent) was added to a solution of I-54B (7.5 g, 34.0 mmol, 1.0 equivalent) in DMF (160 mL). The reaction mixture was stirred at room temperature for 24 h, then quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain a crude residue. The crude residue was purified by silica gel column chromatography (5% EtOAc / hexane) to obtain I-54C. 1 H NMR (400MHz, CDCl3) δ4.16 (q, J = 7.1Hz, 2H), 2.85 (s, 2H), 2.18 (s, 3H), 1.36–1.30 (m, 2H), 1.27 (t, J = 7.1Hz, 3H), 0.91 (q, J = 4.2Hz, 2H).

[0878] 1-((methylsulfonyl)methyl)cyclopropane-1-carboxylic acid ethyl ester (I-54D) was prepared from I-54C according to a procedure similar to that described in I-8C. 1 H NMR (400MHz, CDCl3) δ4.18 (q, J = 7.1Hz, 2H), 3.42 (s, 2H), 2.99 (s, 3H), 1.54 (q, J = 4.6Hz, 2H), 1.31–1.23 (m, 5H).

[0879] (1-((methylsulfonyl)methyl)cyclopropyl)methanol (I-54E). I-54D (3.4 g, 16.5 mmol, 1.0 equivalent) was dissolved in THF (34 mL), and LiBH was added dropwise. 4 (2M in THF) (10 mL, 19.8 mmol, 1.2 equivalences), and the reaction mixture was stirred at 66 °C for 4 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain the crude residue. The crude residue was purified by silica gel column chromatography (52% EtOAc / hexane) to obtain I-54E. LCMS (m / z): 165.2 [M+H]. 1 H NMR (400MHz, CDCl3) δ3.63 (s, 2H), 3.19 (s, 2H), 3.03 (s, 3H), 2.68 (s, 1H), 0.80 (t, J = 5.7Hz, 2H), 0.74 (t, J = 5.7Hz, 2H).

[0880] (1-((methylsulfonyl)methyl)cyclopropyl)methylmethanesulfonate (I-54F) is prepared from I-54E according to a procedure similar to that described in I-2. 1H NMR (400MHz, DMSO-d6) δ4.22 (s, 2H), 3.27 (s, 2H), 3.19 (s, 3H), 3.01 (s, 3H), 0.84 (t, J = 5.6Hz, 2H), 0.78 (dd, J = 11.3, 4.0Hz, 2H).

[0881] 1-(azidomethyl)-1-((methylsulfonyl)methyl)cyclopropane (I-54G) was prepared from I-54F according to a procedure similar to that described in I-53D. 1 H NMR (400MHz, DMSO-d6) δ3.45(s,2H),3.24(s,2H),2.99(s,3H),0.78–0.70(m,2H),0.70–0.64(m,2H).

[0882] (1-((methylsulfonyl)methyl)cyclopropyl)methylamine (I-54) was prepared from I-54G (1.2 g, 6.3 mmol, 1.0 equivalent) according to a procedure similar to that described for I-53. 1 H NMR (400MHz, DMSO-d6) δ3.24(d,J=5.2Hz,2H),2.95(s,3H),2.51(dt,J=3.5,1.7Hz,2H),1.78(d,J=30.3Hz,2H),0.60–0.54(m,2H),0.54–0.48(m,2H).

[0883] Intermediate 55

[0884] ethyl 1-(aminomethyl)cyclopropane-1-carboxylate

[0885]

[0886] 1-(azidomethyl)cyclopropane-1-carboxylic acid ethyl ester (I-55A) was prepared by I-54B according to a procedure similar to that described in I-53D. 1 H NMR (400MHz, DMSO-d6) δ4.20–4.02(m,1H),3.68–3.35(m,1H),1.31–1.09(m,3H),1.06–0.89(m,1H).

[0887] Ethyl 1-(aminomethyl)cyclopropane-1-carboxylate (I-55). In an autoclave, Pd / C (0.45 g) was added to a solution of I-55A (4.5 g, 26.6 mmol, 1.0 equivalent) in methanol (45 mL). The reaction mixture was stirred for 24 h at room temperature under H2 (gas) pressure (20 bar). The reaction mixture was filtered through a diatomaceous earth bed and the filtrate was concentrated to obtain the title product.1 H NMR (400MHz, DMSO-d6) δ 4.10–3.96 (m, 2H), 2.67 (d, J = 19.9Hz, 2H), 1.19–1.11 (m, 3H), 1.02–0.94 (m, 2H), 0.86–0.78 (m, 2H).

[0888] Intermediate 56

[0889]

[0890] 2-(1-(methanesulfonyl)cyclopropyl)acetonitrile (I-56A). NaCN (1.9 g, 39.4 mmol, 2.0 equivalent) was added to a solution of I-14D (4.5 g, 19.7 mmol, 1.0 equivalent) in DMSO (45 mL). The reaction mixture was stirred at 60 °C for 3 h, followed by quenching with water and then with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain I-56A. 1 HNMR (400MHz, DMSO-d6) δ3.11(s,2H),2.51(m,3H),1.40–1.33(m,2H),1.16–1.09(m,2H).

[0891] 2-(1-(methylsulfonyl)cyclopropyl)ethyl acetate (I-56B). In a sealed tube, I-56A (2.5 g, 15.7 mmol, 1.0 equivalent) and concentrated H₂SO₄ (2.5 mL) were added to ethanol (20 mL). The reaction mixture was stirred at 120 °C for 12 h. Further concentrated H₂SO₄ (2.5 mL) and ethanol (5 mL) were added, and the reaction mixture was stirred at 120 °C for 12 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain I-56B. 1 HNMR (400MHz, DMSO-d6) δ4.08(q,J=7.1Hz,2H),2.99(s,3H),2.91(s,2H),1.34(q,J=4.6Hz,2H),1.20(t,J=7.1Hz,3H),1.12–1.07(m,2H).

[0892] 2-(1-(methylsulfonyl)cyclopropyl)ethanol-1-ol (I-56C) was prepared from I-56AB according to a procedure similar to that described in I-51B. 1H NMR (400MHz, DMSO-d6) δ3.59–3.50(m,2H),3.00(d,J=1.7Hz,1H),2.99(s,3H),2.01–1.98(m,2H),1.18(t,J=2.9Hz,2H),1.01(t,J=3.1Hz,2H).

[0893] 2-(1-(methylsulfonyl)cyclopropyl)ethylmethanesulfonate (I-56D) is prepared from I-56C according to a procedure similar to that described in I-2. 1 H NMR (400MHz, DMSO-d6) δ4.39(t,J=7.0Hz,2H),3.34(s,2H),3.20(s,3H),3.06(d,J=3.6Hz,3H),2.28(t,J=7.0Hz,2H),1.26–1.23(m,2H),1.06(m,2H).

[0894] 1-(2-Azide-ethyl)-1-(methylsulfonyl)cyclopropane (I-56E) was prepared by I-56D according to a procedure similar to that described in I-53D. 1 H NMR (400MHz, DMSO) δ3.60–3.49(m,2H),3.05(s,3H),2.16–2.04(m,2H),1.26–1.19(m,2H),1.06–0.98(m,2H).

[0895] 2-(1-(methanesulfonyl)cyclopropyl)ethyl-1-amine (I-56) was prepared from I-56E according to a procedure similar to that described in I-53. LCMS (m / z): 164.1 [M+H]. 1 H NMR (400MHz, DMSO) δ3.34 (ddd, J=51.0, 25.2, 8.4Hz, 2H), 3.02–2.94 (m, 3H), 2.73 –2.61(m,2H),1.94–1.82(m,2H),1.21–1.13(m,2H),0.95(td,J=5.5,1.2Hz,2H).

[0896] Intermediate 57

[0897] 2-(1-(aminomethyl)cyclopropyl)isothiazolidinyl 1,1-dioxide

[0898]

[0899] 1-((3-chloropropyl)sulfonamido)cyclopropane-1-carboxylate (I-57A) is prepared from 1-aminocyclopropane-1-carboxylate hydrobromide and 3-chloropropane-1-sulfonyl chloride according to a procedure similar to that described in I-18B. LCMS (m / z): 256.3 [M+H]. 1 H NMR(400MHz, DMSO-d6)δ8.30(s,1H),3.75(dd,J=6.6,4.2Hz,2H),3.64(s,3H),3.21–3.1 5(m,2H),2.14(dt,J=9.7,6.7Hz,2H),1.38(p,J=5.5Hz,2H),1.27(dd,J=7.9,4.7Hz,2H).

[0900] Methyl 1-(1,1-dioxoisothiazolidin-2-yl)cyclopropane-1-carboxylate (I-57B) was prepared from I-57A according to a procedure similar to that described in I-18C. LCMS (m / z): 220.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ3.65(d,J=8.4Hz,3H),3.47(t,J=6.7Hz,2H),3.20(t,J=7.2Hz,2H),2.31–2.22(m,2H),1.38(s,2H),1.32(d,J=2.9Hz,2H).

[0901] 2-(1-(hydroxymethyl)cyclopropyl)isothiazoline 1,1-dioxide (I-57C) was prepared from I-57B according to a procedure similar to that described in I-2D. LCMS (m / z): 192.3 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ4.72(t,J=5.8Hz,1H),3.58(d,J=5.8Hz,2H),3.45(t,J=6.7Hz,2H),3.15(t, J=7.5Hz, 2H), 2.16 (dt, J=13.9, 6.9Hz, 2H), 0.88 (dd, J=6.7, 4.5Hz, 2H), 0.71 (dd, J=6.8, 4.5Hz, 2H).

[0902] 1-(1,1-dioxoisothiazolidin-2-yl)cyclopropyl)methylmethanesulfonate (I-57D) was prepared from I-57C according to a procedure similar to that described in I-2. LCMS (m / z): 287.3 [M+18]. 1H NMR(400MHz,DMSO-d6)δ3.45(dt,J=18.6,6.7Hz,4H),3.20(s,3H),3.18–3.06(m,2H), 2.19 (dd, J = 14.4, 6.9 Hz, 2H), 1.13 (dd, J = 7.2, 5.0 Hz, 2H), 0.93 (dd, J = 7.2, 5.0 Hz, 2H).

[0903] 2-(1-(azidomethyl)cyclopropyl)isothiazoline 1,1-dioxide (I-57E) was prepared by I-57D according to a procedure similar to that described in I-53D. 1 H NMR (400MHz, DMSO-d6) δ3.52(s,1H),3.42(t,J=6.7Hz,1H),3.18(t,J=7.5Hz,1H) ,2.19(dd,J=14.0,6.9Hz,1H), 1.06(q,J=4.9Hz,1H), 0.80(dd,J=7.0,5.0Hz,1H).

[0904] 2-(1-(aminomethyl)cyclopropyl)isothiazoline 1,1-dioxide (I-57) was prepared from I-57E according to a procedure similar to that described in I-53. LCMS (m / z): 191.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ3.37(dd,J=13.3,6.6Hz,2H),3.15(dd,J=14.1,6.8Hz,2H),2.83–2.65( m, 2H), 2.17 (dd, J = 13.8, 6.7Hz, 2H), 1.68 (s, 2H), 0.86 (d, J = 4.7Hz, 2H), 0.70 (d, J = 4.4Hz, 2H).

[0905] Intermediate 58

[0906] 1-(aminomethyl)cyclopropyl dimethylcarbamate

[0907]

[0908] 1-((dibenzylamino)methyl)cycloprop-1-ol (I-58A). Dibenzylglycine ethyl ester (1 g, 3.5 mmol, 1.0 equivalent) was dissolved in diethyl ether (10 mL) and cooled to 0 °C. Ti(OiPr)4 (0.25 g, 0.88 mmol, 0.25 equivalent) and EtMgBr (3.0 M in diethyl ether) (4.7 mL, 14.1 mmol, 4.0 equivalent) were added, and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was cooled to 0 °C, quenched with saturated ammonium chloride aqueous solution, and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give a crude residue. The crude residue was purified by silica gel column chromatography (5% EtOAc / hexane) to obtain I-58A. LCMS (m / z): 268.3 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ7.39(d,J=7.0Hz,4H),7.32(t,J=7.5Hz,4H),7.23(t,J=7.2Hz,2H),5. 06(s,1H),3.64(d,J=20.7Hz,4H),2.53(s,2H),0.57–0.54(m,2H),0.33(dd,J=6.7,4.6Hz,2H).

[0909] 1-((dibenzylamino)methyl)cyclopropyl dimethylcarbamate (I-58B). I-58A (5 g, 18.7 mmol, 1.0 equivalent) was dissolved in THF (50 mL) and cooled to 0 °C. NaH (60% suspension in mineral oil, 0.93 g, 24.3 mmol, 1.3 equivalent) and dimethylcarbamoyl chloride (3 g, 28.1 mmol, 1.5 equivalent) were added, and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to obtain a crude residue. The crude residue was purified by silica gel column chromatography (10% EtOAc / hexane) to obtain I-58B. The product was used without further purification. LCMS (m / z): 339.4 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ7.39–7.25(m,10H),3.64(d,J=15.8Hz,4H),2.83(d,J=28 .9Hz, 6H), 2.71 (d, J = 22.3Hz, 2H), 0.81–0.74 (m, 2H), 0.63 (dd, J = 7.6, 5.7Hz, 2H).

[0910] 1-(aminomethyl)cyclopropyl dimethylcarbamate (I-58). I-58B (0.9 g, 3.78 mmol, 1.0 equivalent) was dissolved in methanol (10 mL), Pd(OH)₂ (0.1 g) was added, and the reaction mixture was stirred for 24 h at room temperature under a H₂ (gas) atmosphere. The reaction mixture was filtered through a diatomaceous earth bed and the filtrate was concentrated to obtain I-58. LCMS (m / z): 159.1 [M+H]. 1 HNMR(400MHz, DMSO-d6)δ2.82(s,1H),2.78(s,3H),0.76–0.67(m,2H).

[0911] Intermediate 59

[0912] (1-Methoxycyclopropyl)methylamine

[0913]

[0914] N,N-Dibenzyl-1-(1-Methoxycyclopropyl)methylamine (I-59A). I-58A (2 g, 7.5 mmol, 1.0 equivalent) was dissolved in THF (20 mL) and cooled to 0 °C. NaH (60% suspension in mineral oil, 0.34 g, 8.98 mmol, 1.2 equivalent) and iodomethane (1.6 g, 11.2 mmol, 1.5 equivalent) were added, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give a crude residue. The crude residue was purified by silica gel column chromatography (3% EtOAc / hexane) to obtain the title compound. LCMS (m / z): 282.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ7.31 (ddd, J = 37.8, 14.1, 7.0Hz, 10H), 3.63 (s, 4H), 3.13 (s, 3H), 2.56 (s, 2H), 0.68 (s, 2H), 0.39 (q, J = 5.1Hz, 2H).

[0915] (1-Methoxycyclopropyl)methylamine (I-59) was prepared from I-59A according to a procedure similar to that described in I-58. LCMS (m / z): 102.0 [M+H]. 1 H NMR (400MHz, DMSO) δ7.56 (s, 2H), 3.21 (s, 3H), 2.97 (s, 2H), 0.79 (dd, J = 7.0, 5.2Hz, 2H), 0.65 (dd, J = 7.2, 5.1Hz, 2H).

[0916] Intermediate 60

[0917] N-(2-aminoethyl)-N-methylmethanesulfonamide

[0918]

[0919] (2-(N-methylmethylsulfonamido)ethyl)carbamate tert-butyl ester (I-60A). DIEA (2.59 mL, 14.84 mmol) was added to a solution of (2-(methylamino)ethyl)carbamate tert-butyl ester (0.9 mL, 4.95 mmol) cooled to 0 °C in 25 mL of DCM, followed by the addition of MsCl (0.424 mL, 5.44 mmol). The resulting mixture was heated to room temperature and stirred overnight. The reaction mixture was diluted with DCM and washed (5 times) with 2 M HCl. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The title compound was isolated as a brown solid. LCMS (m / z): 197.1 [M-tBu+H]. 1 H NMR (400MHz, DMSO-d6) δppm1.37 (s, 9H) 2.76 (s, 3H) 2.85 (s, 3H) 3.08 (d, J = 2.35Hz, 4H) 6.89 (br.s., 1H).

[0920] N-(2-aminoethyl)-N-methylmethanesulfonamide (I-60). A solution of dioxane (6 mL, 24.00 mmol) with 4 M HCl was added to a solution of I-60A (1.17 g, 4.64 mmol) in dioxane (4 mL). The resulting solution was stirred at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure. The title compound was isolated as a brown solid. LCMS (m / z): 153.1. 1 HNMR (400MHz, CD3OD) δppm 2.91 (s, 6H) 3.14 (t, J = 5.67Hz, 2H) 3.39-3.44 (m, 2H).

[0921] Intermediate 61

[0922] N-(4-cyanobenzyl)-1,6-dioxo-1,3,4,6-tetrahydropyrido[2,1-c][1,4]oxazine-7-carboxamide

[0923]

[0924] N-(4-cyanobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (I-61A). N-methylmorpholine (19.8 g, 196.1 mmol, 3.0 equivalence), EDC.HCl (15 g, 78.4 mmol, 1.2 equivalence), HOBT (10.6 g, 78.4 mmol, 1.2 equivalence), and 4-(aminomethyl)benzonitrile hydrochloride (16.6 g, 98.0 mmol, 1.5 equivalence) were added to a solution of 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (10 g, 65.4 mmol, 1.0 equivalence) in THF (250 mL). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water, and the resulting solid was separated by filtration. The filter cake was washed with water and hexane and dried to obtain the title compound. LCMS (m / z): 268.5 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ12.54(s,1H),10.20(t,J=6.0Hz,1H),8.24(d,J=7.4Hz,1H),7.80(d,J =8.3Hz, 2H), 7.48 (d, J = 8.4Hz, 2H), 6.32 (d, J = 7.4Hz, 1H), 4.60 (d, J = 6.1Hz, 2H), 2.30 (s, 3H).

[0925] N-(4-cyanobenzyl)-6-formyl-2-oxo-1,2-dihydropyridine-3-carboxamide (I-61B) was prepared from I-61A according to a procedure similar to that described in I-47C. LCMS (m / z): 282.1 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ12.78(s,1H),10.23(s,1H),9.71(s,1H),8.51(d,J=7.1Hz,1H) ,7.84–7.80(m,2H),7.51(d,J=8.4Hz,2H),7.17(d,J=7.1Hz,1H),4.64(d,J=6.1Hz,2H).

[0926] 5-((4-cyanobenzyl)carbamoyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (I-61C) was prepared by I-61B according to a procedure similar to that described in I-47D. LCMS (m / z): 297.9 [M+H]. 1H NMR (400MHz, DMSO-d6) δ12.42(s,1H),10.25(s,1H),8.41(d,J=7.3Hz,1H),7.81(d ,J=8.3Hz,2H),7.50(d,J=8.1Hz,2H),7.08(d,J=7.2Hz,1H),4.63(d,J=6.1Hz,2H).

[0927] N-(4-cyanobenzyl)-1,6-dioxo-1,3,4,6-tetrahydropyrido[2,1-c][1,4]oxazine-7-carboxamide (I-61). I-61C (3.8 g, 12.8 mmol, 1.0 equivalent) and 1,2-dibromoethane (4.8 g, 25.6 mmol, 2.0 equivalent) were dissolved in DMF (80 mL). TEA (3.9 g, 38.4 mmol, 3.0 equivalent) was added, and the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was quenched with cold water and extracted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated to obtain I-61. LCMS (m / z): 324.4 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ10.14(t,J=6.0Hz,1H),8.46(d,J=7.5Hz,1H),7.82(d,J=8.3Hz,2H),7.50( d,J=8.3Hz,2H),7.32(d,J=7.5Hz,1H),4.76–4.68(m,2H),4.64(d,J=6.1Hz,2H),4.36–4.25(m,2H).

[0928] Intermediate 62

[0929] 2-(cyclopropylsulfonyl)ethyl-1-amine hydrochloride

[0930]

[0931] Sodium cyclopropanesulfinate (I-62A). Add Na₂SO₃ (22.6 g, 178.0 mmol, 1.0 equivalent) to water (250 mL) and stir for 10 min at room temperature. Add Na₂CO₃ (37.7 g, 356.0 mmol, 2.0 equivalent) and stir the reaction mixture at 60 °C for 10 min. Add cyclopropanesulfonyl chloride (25 g, 178.0 mmol, 1.0 equivalent) dropwise and stir the reaction mixture at room temperature for 2 h. Concentrate the reaction mixture to obtain a crude residue. Dissolve the crude residue in ethanol (250 mL) and stir for 20 min at room temperature. Filter the solid and wash with ethanol. Concentrate the filtrate to obtain the title compound. 1H NMR (400MHz, DMSO-d6) δ1.64–1.50(m,1H),0.69–0.32(m,4H).

[0932] 2-(cyclopropylsulfonyl)acetonitrile (I-62B) is prepared from I-62A according to a procedure similar to that described in I-49E. 1 HNMR (400MHz, CDCl3) δ4.11–3.92(m,2H),2.73(tt,J=7.9,4.7Hz,1H),1.53–1.36(m,2H),1.35–1.19(m,2H).

[0933] (2-(cyclopropylsulfonyl)ethyl)tert-butyl carbamate (I-62C). I-62B (5 g, 34.4 mmol, 1.0 equivalent) was added to methanol (50 mL) and cooled to 0 °C. NiCl2·6H2O (0.82 g, 3.44 mmol, 0.1 equivalent) was added, and the reaction mixture was stirred at 0 °C for 5 min. NaBH4 (5.2 g, 138.0 mmol, 4.0 equivalent) was added, and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through a diatomaceous earth bed; the filtrate was concentrated, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The crude residue was purified by silica gel column chromatography (30% EtOAc / hexane) to obtain I-62C. 1 H NMR (400MHz, DMSO-d6) δ7.04(t,J=5.3Hz,1H),3.36(d,J=10.1Hz,2H),3.25(dd,J=7.9,5. 8Hz, 2H), 2.75 (dd, J = 7.8, 2.7Hz, 1H), 1.38 (d, J = 6.2Hz, 9H), 0.99 (dd, J = 6.0, 1.8Hz, 4H).

[0934] 2-(cyclopropylsulfonyl)ethyl-1-amine hydrochloride (I-62) was prepared from I-62C according to a procedure similar to that described in I-49. LCMS (m / z): 150.1 [M+H, free amine]. 1 H NMR (400MHz, DMSO-d6) δ8.30 (s, 2H), 3.60–3.41 (m, 2H), 3.31–3.04 (m, 2H), 2.91 (ddd, J = 12.6, 7.8, 4.8Hz, 1H), 1.18–0.90 (m, 4H).

[0935] Intermediate 63

[0936] N-(1-(aminomethyl)cyclopropyl)-N-methylmethanesulfonamide

[0937]

[0938] (1-(N-methylmethylsulfonamide)cyclopropyl)methylmethanesulfonate (I-63A) is prepared from N-(1-(hydroxymethyl)cyclopropyl)-N-methylmethanesulfonamide according to a procedure similar to that described in I-2. 1 H NMR (400MHz, DMSO-d6) δ4.26 (s, 2H), 3.21 (s, 3H), 2.99 (d, J = 12.7Hz, 3H), 2.88 (d, J = 8.3Hz, 3H), 1.13 (t, J = 6.2Hz, 2H), 0.97 (t, J = 6.2Hz, 2H).

[0939] N-(1-(azidomethyl)cyclopropyl)-N-methylmethanesulfonamide (I-63B) is prepared from I-63A according to a procedure similar to that described in I-53D. 1 H NMR (400MHz, DMSO-d6) δ3.46 (s, 2H), 2.95 (d, J = 7.6Hz, 3H), 2.90–2.83 (m, 3H), 1.03 (q, J = 5.3Hz, 2H), 0.86 (q, J = 5.3Hz, 2H).

[0940] N-(1-(aminomethyl)cyclopropyl)-N-methylmethanesulfonamide (I-63) was prepared by I-63B according to a procedure similar to that described in I-53. LCMS (m / z): 179.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ3.00–2.94(m,3H),2.86(d,J=5.5Hz,3H),2.74–2.65(m,2H),1.68–1.27(m,2H),0.85–0.78(m,2H),0.78–0.71(m,2H).

[0941] Preparation of compound (I)

[0942] Example 1

[0943] N-(4-cyanobenzyl)-2-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetra- Hydrogen-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[0944] 2-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-7-carboxylic acid (Ex-1A). A solution of I-1 (5 g, 18.92 mmol) in DMF (140 mL) was cooled to 0 °C. Add NaH (60% suspension in mineral oil, 1.135 g, 28.4 mmol) to the cooled solution. Stir the resulting mixture at 0 °C until bubbling stops. Add DMF (40 mL) containing I₂ (6.26 g, 24.60 mmol) to the alkaline mixture. Heat the resulting mixture to room temperature. After 72 h, add NaH (60% suspension in mineral oil, 0.378 g, 9.46 mmol). After 2 h, dilute the reactants with H₂O. Stir the reactants at room temperature for 1 h. Separate the precipitate by vacuum filtration to obtain a light brown, foamy sodium salt of Ex-1A. Wash the filtrate with EtOAc. Adjust the pH of the aqueous layer to 1 with 2 M HCl. Extract the acidic aqueous layer with EtOAc. Dry the combined organic extracts with sodium sulfate and concentrate under reduced pressure to obtain a second batch of Ex-1A, a dark brown solid. LCMS m / z: 367 (M+1).

[0945] N-(4-cyanobenzyl)-2-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-1). Oxaloyl chloride (0.594 mL, 6.79 mmol) was added to a slurry of Ex-1A (2.26 g, 6.17 mmol) in DCM (60 mL), followed by one drop of DMF. The reaction immediately released gas and became homogeneous. The reaction mixture was stirred at room temperature for about 1 h, followed by concentration under reduced pressure. The residue was dissolved in DCM (60 mL), and 4-(aminomethyl)benzonitrile HCl (1.248 g, 7.40 mmol) was added. DIEA (2.155 mL, 12.34 mmol) was added to the slurry. The resulting mixture was stirred at room temperature for about 1 h. The reactants were diluted with DCM and washed with 2M HCl and saturated sodium bicarbonate aqueous solution. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. The yellow foam was dissolved in DCM and purified over SiO2 (heptane to acetone) to give the product. The residue was recrystallized by heating in 890 mL of EtOH in a 2 L Erlenmeyer flask under reflux until the solid dissolved (approximately 30–45 min). The solution was slowly cooled to room temperature over 72 h. The resulting crystalline solid was separated by vacuum filtration. The filter cake was washed with heptane and the solid was dried overnight under high vacuum. Ex-1, a pale yellow needle-like substance with a melting point of 186 °C, was separated. Figure 1The XRPD of the product of this reaction (NX-7) is shown compared to that of the second polymorph (NX-12) that dominates when the two crystalline forms are made into a slurry together in ethanol. NX-12 appears to be a more stable polymorph.

[0946] The other compounds in the table below were prepared according to a procedure similar to that described in Ex-1.

[0947]

[0948]

[0949] Example 4

[0950] N-(4-chlorobenzyl)-2-((1-((4-hydroxybut-2-yl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2, 3,4,6-Tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[0951] 2-((1-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-7-carboxylic acid (Ex-4A) was prepared by I-1 and I-3 according to a procedure similar to that described for Ex-1A. Ex-4A was isolated as an orange oil. LCMS m / z: 513 (M+1).

[0952] N-(4-chlorobenzyl)-2-((1-((4-hydroxybut-2-yl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-4). DIEA (0.136 mL, 0.780 mmol) was added to a solution of Ex-4A (0.2 g, 0.390 mmol) in DCM (3 mL). (50% in EtOAc, 0.255 mL, 0.429 mmol). The resulting mixture was stirred for approximately 10 min, followed by the addition of p-chlorobenzylamine (0.057 mL, 0.468 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM, washed with 2 M HCl and saturated sodium bicarbonate, and dried over sodium sulfate. The dried organic layer was concentrated under reduced pressure. The residue was dissolved in DCM (3 mL) and treated with a solution of dioxane (1.5 mL, 6.00 mmol) in 4 M HCl. After 30 min, the reaction mixture was diluted with DCM and washed with H2O. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified using SFC. Ex-4 was separated as a grayish-white solid.

[0953] Compound 5 in the table below was prepared according to a procedure similar to that described in Ex-4.

[0954] (R)&(S)N-(4-chlorobenzyl)-2-((1-((4-hydroxybut-2-yl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-6, Ex-7). Ex-4 was separated by chiral SFC (AD column, 5 mL / min CO2 / EtOH = 70 / 30) to give the enantiomer title compound.

[0955] (R)&(S)N-(4-cyanobenzyl)-2-((1-((4-hydroxybut-2-yl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-8, Ex-9). Ex-5 was separated by chiral HPLC (ADH column, 1 mL / min heptane / IPA = 50 / 50) to give the enantiomer of the title compound.

[0956] The stereochemical classification of Ex-6, Ex-7, Ex-8, and Ex-9 is arbitrary.

[0957]

[0958]

[0959]

[0960] Example 10

[0961] N-(4-chlorobenzyl)-2-((1-((1-(hydroxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1,6-dioxane 2,3,4,6-Tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[0962] 2-((1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-7-carboxylic acid (Ex-10A) was prepared by II and I-4 according to a procedure similar to that described for Ex-1A. Ex-10A was isolated as a yellow solid. LCMS m / z: 487 (M+1).

[0963] 2-((1-((1-(hydroxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-7-carboxylic acid (Ex-10B). Ex-10A (0.528 g, 1.085 mmol) was dissolved in EtOH and treated with 1 drop of H₂SO₄. The resulting solution was stirred under reflux. After complete acid conversion, the reactants were concentrated under reduced pressure. The residue was dissolved in AcOH and treated with Pd / C (0.06 g, 0.056 mmol). The atmosphere was changed to H₂, and the reaction mixture was stirred for approximately 2 h. The reactants were filtered through a diatomaceous earth pad, and the pad was rinsed with EtOH. The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH and treated with 2M NaOH until the pH was alkaline. When the ester was depleted, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in H₂O and washed with EtOAc. The aqueous layer was adjusted to pH 1 with 2M HCl. The acidic aqueous layer was extracted with DCM. The combined DCM extracts were dried with sodium sulfate and concentrated under reduced pressure. Ex-10B was separated as a yellow solid. LCMS m / z: 397 (M+1).

[0964] N-(4-chlorobenzyl)-2-((1-((1-(hydroxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-10). Add to a solution of Ex-10B (0.1 g, 0.252 mmol), DIEA (0.088 mL, 0.505 mmol), and p-chlorobenzylamine (0.031 mL, 0.252 mmol) in DCM (1 mL). (50% in EtOAc, 0.083 mL, 0.277 mmol). The resulting mixture was stirred at room temperature. After complete conversion of the starting material, the reaction mixture was diluted with DCM and washed with 2 M HCl and saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (20–60% (0.1% TFA / H2O) / (0.1% TFA / MeCN)). The purified fraction was extracted with EtOAc, and the EtOAc extract was dried with sodium sulfate and concentrated under reduced pressure. The residue was purified on SiO2 (0–100% acetone / heptane) to obtain Ex-10 as a white solid.

[0965] The other compounds in the table below were prepared according to a procedure similar to that described in Ex-10.

[0966]

[0967]

[0968] The compounds in the table below were prepared by I-1 and I-5 or I-6 according to procedures similar to those described in Ex-10.

[0969]

[0970]

[0971] Example 16 / 17

[0972] 2-((1-((1-(tert-butoxycarbonyl)acetidin-3-yl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-7-carboxylic acid (Ex-16A) was prepared by I-1 and I-7 according to a procedure similar to that described for Ex-1A. Ex-16A was isolated as a brown oil. LCMS m / z: 482 (M+1).

[0973] 3-((1-((7-(((4-cyano-3-fluorobenzyl)carbamoyl)-1,6-dioxo-3,4-dihydro-1H-pyrido[1,2-a]piperazin-2(6H)-yl)methyl)cyclopropyl)sulfonyl)acetidine-1-tert-butyl ester (Ex-16B) was prepared from Ex-16A according to a procedure similar to that described in Ex-10. Ex-16B was isolated as a yellow oil. MS m / z: 614 (M+1).

[0974] 2-((1-(acetidin-3-ylsulfonyl)cyclopropyl)methyl)-N-(4-cyano-3-fluorobenzyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-16). TFA (1 mL) was added to a solution of Ex-16B (0.163 g, 0.266 mmol) in DCM (5.0 mL). The resulting mixture was stirred at room temperature. After 30 min, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with saturated sodium bicarbonate. The aqueous layer was back-extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by SFC (PPU column, CO2 / MeOH 80 mL / min). Ex-16 was separated as a grayish-white solid.

[0975] N-(4-cyano-3-fluorobenzyl)-2-((1-((1-methylacetidin-3-yl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-17). Formaldehyde (0.015 mL, 0.199 mmol) was added to a solution of Ex-16 (0.068 g, 0.132 mmol) in DCE (1 mL), followed by sodium triacetoxyborohydride (0.042 g, 0.199 mmol). The resulting mixture was stirred overnight at room temperature. Additional formaldehyde (0.015 mL, 0.199 mmol) and sodium triacetoxyborohydride (0.042 g, 0.199 mmol) were added until the initial starting material was completely depleted. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. The crude product was purified by HPLC (SunFire column, H2O / ACN 0.1% TFA). Ex-17 was separated as a white solid.

[0976] The other compounds in the table below were prepared according to procedures similar to those described in Ex-16 and Ex-17.

[0977]

[0978]

[0979]

[0980] The compounds in the table below were prepared by I-1 and I-8 according to procedures similar to those described in Ex-1.

[0981]

[0982]

[0983] The compounds in the table below were prepared by I-1 and I-9 according to procedures similar to those described in Ex-4.

[0984]

[0985]

[0986] The compounds in the table below were prepared by I-1 and I-10 according to procedures similar to those described in Ex-1.

[0987]

[0988] The compounds in the table below were prepared by I-1 and I-11 according to procedures similar to those described in Ex-10.

[0989]

[0990]

[0991] The compounds in the table below were prepared by I-1 and I-12 according to procedures similar to those described in Ex-1.

[0992]

[0993]

[0994] The compounds in the table below were prepared by I-1 and I-13 according to procedures similar to those described in Ex-1.

[0995]

[0996]

[0997] The compounds in the table below were prepared by I-1 and I-14 according to procedures similar to those described in Ex-1.

[0998]

[0999]

[1000]

[1001] The compounds in the table below were prepared by I-1 and I-15 according to procedures similar to those described in Ex-1.

[1002]

[1003]

[1004] Example 50-1

[1005] N-(4-chlorobenzyl)-2-(2-(1,1-dioxotetrahydrothiophene-2-yl)ethyl)-1,6-dioxo-2,3,4,6- Tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[1006] N-(4-chlorobenzyl)-2-(2-(1,1-dioxotetrahydrothiophen-2-yl)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-7-carboxamide (Ex-50-1) was prepared by I-1 and I-6 according to a procedure similar to that described in Ex-1, but in which EDC amide coupling was used instead of acyl chloride. EDC·HCl (0.057 g, 0.298 mmol) and HOBt (0.046 g, 0.298 mmol) were added to 1 mL of DMF containing acid (0.088 g, 0.248 mmol). The resulting solution was stirred at room temperature for about 30 min, followed by the addition of p-chlorobenzylamine (0.091 mL, 0.745 mmol). After about 2 h, the reaction mixture was diluted with EtOAc, washed with 2 M HCl and brine, and dried over sodium sulfate. The dried organic layer was concentrated under reduced pressure. The crude product was purified by HPLC (0.1% TFA in H2O / CAN) to obtain the title compound as a grayish-white solid.

[1007]

[1008] Example 50-2

[1009] 2-((1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-7-carboxylic acid (Ex-50-2A). NaH (60% suspension in mineral oil, 0.023 g, 0.568 mmol) was added to a solution of I-1 (0.1 g, 0.378 mmol) in DMF (2 mL). I-46 (0.196 g, 0.492 mmol) in DMF (2 mL) was added to the alkaline reaction mixture. The resulting reaction mixture was stirred at room temperature. After the reaction was complete, it was diluted with EtOAc and H2O. The phases were separated, and the aqueous layer was extracted twice with EtOAc. The aqueous layer was acidified with AcOH and extracted with EtOAc. The EtOAc extract was dried over sodium sulfate and concentrated under reduced pressure. The title compound was isolated as an orange solid. MS m / z: 511 (M+1).

[1010] 2-((1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-N-((6-chloropyridin-3-yl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-50-2B). Add DIEA (0.092 mL, 0.529 mmol) to a solution of Ex-50-2A (0.135 g, 0.264 mmol) in DCM (1 mL). (In EtOAc, 50%, 0.205 mL, 0.344 mmol). The resulting mixture was stirred at room temperature for 10 min. (6-chloropyridin-3-yl)methylamine (0.057 g, 0.397 mmol) was added to the reaction mixture. After the initial starting material was completely depleted, the reaction mixture was diluted with DCM, washed with 2 M HCl and saturated sodium bicarbonate, and dried with sodium sulfate. The dried organic layer was concentrated under reduced pressure. The title compound was isolated as an orange oil. MS m / z: 635 (M+1).

[1011] N-((6-chloropyridin-3-yl)methyl)-2-((1-((1-hydroxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-50-2). TFA (1 mL) was added to a slurry of Ex-50-2B (0.126 g, 0.198 mmol) in DCM. The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The residue was diluted with DCM and washed with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by RP HPLC. Ex-50-2 was isolated as a white solid.

[1012]

[1013]

[1014] Example 51

[1015] N-(4-chlorobenzyl)-2-(2-(methylsulfonyl)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyridyl [1,2-a]pyrazin-7-carboxamide

[1016] N5-(4-chlorobenzyl)-1-(2-hydroxyethyl)-N2-(2-(methylthio)ethyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (Ex-51A). ACN (0.5 mL) and 2-(methylthio)ethylamine (0.252 mL, 2.70 mmol) were added to a microwave-safe vial containing I-17 (0.225 g, 0.676 mmol). The resulting mixture was irradiated with microwaves at 100 °C for 30 min. The reaction mixture was diluted with DCM and 2 M HCl. The phases were separated, and the organic layer was washed three times with 2 M HCl. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. Ex-51A, a yellow foamy substance, was separated. LCMS m / z: 424 (M+1).

[1017] N5-(4-chlorobenzyl)-1-(2-chloroethyl)-N2-(2-(methylthio)ethyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (Ex-51B). NET3 (0.247 mL, 1.769 mmol) and MsCl (0.069 mL, 0.885 mmol) were added to a solution of Ex-51A (0.25 g, 0.590 mmol) in DCM (6 mL). After the initial feedstock was completely converted to the alkyl chloride, the reaction mixture was diluted with DCM, washed successively with saturated sodium bicarbonate (3 times) and 2M HCl (2 times), and dried over sodium sulfate. The dried organic layer was concentrated under reduced pressure. The yellow oil was purified over SiO2 (0–100% EtOAc / heptane) to obtain a yellow residue of Ex-51B. LCMS m / z: 442 (M+1), 444 (M+3). 1 H NMR (400MHz, CDCl3) δppm 2.14(s,3H)2.73-2.78(m,2H)3.62-3.68(m,2H)3.88(t,J=6.26Hz,2H)4.55-4.62(m,4H )6.57(d,J=7.43Hz,1H)7.26-7.32(m,4H)8.53(d,J=7.43Hz,1H)9.98(t,J=5.48Hz,1H).

[1018] N-(4-chlorobenzyl)-2-(2-(methanesulfonyl)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-7-carboxamide (Ex-51). NaH (60% suspension in mineral oil, 0.021 g, 0.519 mmol) was added to a solution of Ex-51B (0.153 g, 0.346 mmol) in THF (4 mL). The resulting mixture was stirred overnight at room temperature, followed by dilution with ice water and EtOAc. The phases were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried with sodium sulfate. The dried organic layers were dissolved in DCM (4 mL) and treated with mCPBA (0.155 g, 0.692 mmol). After complete reaction, the mixture was diluted with DCM and saturated sodium bicarbonate. The phases were separated, and the organic layers were washed with saturated sodium bicarbonate (5 times). The organic layer was dried with sodium sulfate and concentrated under reduced pressure. The yellow residue was purified on SiO2 (0-100% (5% MeOH / EtOAc) / heptane) to obtain Ex-51 as a pale yellow solid.

[1019] The other compounds in the table below were prepared according to procedures similar to those described in Ex-51.

[1020]

[1021]

[1022] Example 54

[1023] (2-(7-((4-chlorobenzyl)carbamoyl)-1,6-dioxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-2 (6H)-yl)ethyl)(methyl)carbamate tert-butyl ester

[1024] (2-(5-((4-chlorobenzyl)carbamoyl)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridin-2-carbamoyl)ethyl)(methyl)carbamate tert-butyl (Ex-54A) was prepared from I-17 and N-Boc-N-methylethylenediamine according to a procedure similar to that described for Ex-51A. LCMS m / z: 507 (M+1).

[1025] (2-(5-((4-chlorobenzyl)carbamoyl)-1-(2-chloroethyl)-6-oxo-1,6-dihydropyridine-2-carbamoyl)ethyl)(methyl)carbamate tert-butyl (Ex-54B) was prepared from Ex-54A according to a procedure similar to that described for Ex-51B. LCMS m / z: 525 (M+1), 527 (M+3).

[1026] (2-(7-((4-chlorobenzyl)carbamoyl)-1,6-dioxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)ethyl)(methyl)carbamate tert-butyl ester (Ex-54): NaH (0.012 g, 0.303 mmol) was added to a solution of Ex-54B (0.106 g, 0.202 mmol) in THF (2.5 mL). The reaction mixture was stirred overnight at room temperature, followed by quenching with H2O. The aqueous mixture was extracted with CHCl3 (3 times). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over SiO2 (0-100% (5% MeOH / EtOAc) / heptane) to obtain Ex-54 as a pale yellow solid.

[1027] The other compounds in the table below were prepared according to procedures similar to those described in Ex-54.

[1028]

[1029]

[1030] Example 58

[1031] N-(4-chlorobenzyl)-2-(2-(N-methylmethylsulfonamido)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro- 1H-pyrido[1,2-a]pyrazine-7-carboxamide

[1032] N-(4-chlorobenzyl)-2-(2-(methylamino)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-7-carboxamide (Ex-58A): A solution of 4M HCl in dioxane (3 mL, 12.00 mmol) was added to a flask containing Ex-54 (0.19 g, 0.389 mmol). The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was co-evaporated with EtOAc / heptane and dried under vacuum to obtain a solid. Ex-58A hydrochloride was separated as a yellow solid. LCMS m / z: 389 (M+1).

[1033] N-(4-chlorobenzyl)-2-(2-(N-methylmethylsulfonamido)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-7-carboxamide (Ex-58): MsCl (7.05 μL, 0.091 mmol) was added to a solution of Ex-58A (0.035 g, 0.082 mmol) and NEt3 (0.029 mL, 0.206 mmol) in DCM (1.5 mL). The resulting mixture was stirred overnight at room temperature and then diluted with DCM and 2 M HCl. The phases were separated, and the organic layer was washed with 2 M HCl (3 times) and brine and dried with sodium sulfate. The dried organic layer was concentrated under reduced pressure, and the residue was purified by rapid chromatography. Ex-58 was separated as a brown solid.

[1034] The other compounds in the table below were prepared according to procedures similar to those described in Ex-58.

[1035]

[1036]

[1037] Example 62

[1038] N-(4-chlorobenzyl)-2-(2-(methylsulfonamido)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyridine [1,2-a]pyrazine-7-carboxamide

[1039] (2-(5-((4-chlorobenzyl)carbamoyl)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-2-carbamoyl)ethyl)tert-butyl carbamate (Ex-62A) was prepared from I-17 and N-Boc-N-ethylenediamine according to a procedure similar to that described for Ex-51A. LCMS m / z: 493 (M+1).

[1040] (2-(5-((4-chlorobenzyl)carbamoyl)-1-(2-chloroethyl)-6-oxo-1,6-dihydropyridine-2-carbamoyl)ethyl)tert-butyl carbamate (Ex-62B) was prepared from Ex-62A according to a procedure similar to that described for Ex-51B. LCMS m / z: 511 (M+1), 513 (M+3).

[1041] (2-(7-((4-chlorobenzyl)carbamoyl)-1,6-dioxo-3,4-dihydro-1H-pyrido[1,2-a]piperazin-2(6H)-yl)ethyl)tert-butyl carbamate (Ex-62C) was prepared from Ex-62B according to a procedure similar to that described in Ex-54. LCMS m / z: 475 (M+1).

[1042] 2-(2-aminoethyl)-N-(4-chlorobenzyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-62D) was prepared from Ex-62C according to a procedure similar to that described in Ex-58A. LCMS m / z: 375 (M+1).

[1043] N-(4-chlorobenzyl)-2-(2-(methylsulfonamido)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-7-carboxamide (Ex-62): MsCl (4.16 μL, 0.053 mmol) was added to a solution of Ex-62D (0.02 g, 0.053 mmol) and NET3 (0.019 mL, 0.133 mmol) in DCM (0.5 mL). The resulting mixture was stirred at room temperature. After Ex-62D was depleted, the reaction mixture was diluted with DCM and washed (twice) with 2 M HCl. The organic layer was purified on SiO2 (0-100% (5% MeOH / EtOAc) / heptane) to obtain Ex-62 as a grayish-white solid.

[1044] The other compounds in the table below were prepared from I-17 and N-Boc-N-methylethylenediamine, (S)-2-(aminomethyl)-1-Boc-pyrrolidine, or (R)-2-(aminomethyl)-1-Boc-pyrrolidine according to procedures similar to those described in Ex-62.

[1045]

[1046]

[1047] Example 64

[1048] N-(4-chlorobenzyl)-2-(2-(1,1-dioxoisothiazolin-2-yl)ethyl)-1,6-dioxo-2,3,4,6- Tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[1049] N5-(4-chlorobenzyl)-N2-(2-(1,1-dioxoisothiazolidin-2-yl)ethyl)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (Ex-64E): DIEA (0.394 mL, 2.254 mmol) was added to a mixture of I-17 (0.15 g, 0.451 mmol) and I-18D (0.362 g, 1.803 mmol) in ACN (1 mL). The mixture was stirred at 90 °C. When the initial feed was exhausted, the reaction mixture was cooled to room temperature, diluted with CHCl3, and washed with 2 M HCl and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The dark orange residue Ex-64E was separated. LCMS m / z: 497 (M+1).

[1050] N5-(4-chlorobenzyl)-1-(2-chloroethyl)-N2-(2-(1,1-dioxoisothiazolidin-2-yl)ethyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (Ex-64F) was prepared from Ex-64E according to a procedure similar to that described in Ex-51B. LCMS m / z: 515 (M+1), 517 (M+3).

[1051] N-(4-chlorobenzyl)-2-(2-(1,1-dioxoisothiazolidin-2-yl)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-7-carboxamide (Ex-64): NaH (60% suspension in mineral oil, 9.43 mg, 0.236 mmol) was added to a solution of Ex-64F (0.081 g, 0.157 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature for 1 h, followed by quenching with H₂O. The aqueous layer was extracted with EtOAc. The organic extract was washed with 2 M HCl and saturated sodium bicarbonate and dried with sodium sulfate. The dried organic layer was concentrated under reduced pressure. The residue was recrystallized from hot EtOH. Yellow needle-like Ex-64 was collected by vacuum filtration.

[1052] The other compounds in the table below were prepared according to procedures similar to those described in Ex-64.

[1053]

[1054]

[1055] Example 67-1

[1056] N-(4-chlorobenzyl)-2-((1-(methylsulfinyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetra- Hydrogen...

Claims

1. A compound of formula (I): Or its pharmaceutically acceptable salt, wherein: Cy is phenyl, pyridyl, pyrimidinyl, or a 5-8 membered cycloalkyl group, and Cy is optionally substituted by up to 3 groups selected from the following: halogen, CN, -N(R')2, C 1-3 Alkoxy groups and C groups substituted with Z up to 3 times 1-3 Alkyl groups, wherein the C-molecules are substituted with Z up to 3 times. 1-3 When two alkyl groups are directly attached to the same carbon atom, they optionally form a 3- to 5-membered cycloalkyl group together with the carbon atom to which they are attached; R 1 Selected from H and C 1-3 alkyl; R 2 It is H; R 3 It does not exist; R 4 It is H; R 5 Selected from H, halogens and Z 5 Replace C up to 3 times 1-3 alkyl; LW is selected from: L is -CH2- or -CH2CH2-; R is selected from C each time it appears. 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members. Each R is optionally substituted by one or two groups selected from the following: C 1-4 Alkyl, C 1-2 Halogenated alkyl, –L 3 -CN、–L 3 -Halogen, –L 3 -C 1-3 Alkoxy, –L 3 -OH, –L 3 -NR'SO2R'、–L 3 -NR'R'、–L 3 -C(O)NR'R'、–L 3 -COOR'、-L 3 - (5-6 membered heterocyclic groups containing one or two N or O heteroatoms as ring members), –L 3 -C 3-5 cycloalkyl and –L 3 -(a 5-6 membered heteroaryl ring containing up to 4 total heteroatoms selected from 1-4 nitrogen atoms and 1 oxygen atom as ring members), wherein the C 1-4 Alkyl, 5-6 membered heterocyclic group, C 3-5 The cycloalkyl and 5-6-membered heteroaryl rings are each optionally substituted by up to three independent groups selected from the following: C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and -CN; R' is independently selected from H or C each time it appears. 1-4 alkyl; Alternatively, the two R' atoms together with the nitrogen atom directly attached to them can form a 4-6 membered ring, which optionally contains another O as a ring member; L 3 Independently, it is either a bond or -CH2-; and Z and Z 5 Each time it appears, it is independently selected from halogen, hydroxyl, CN, and C. 3-5 Cycloalkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 It's H.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from phenyl, pyridin-3-yl, and cyclohexyl, each optionally substituted by one to three groups selected from halogen and CN.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5 It is H, halogen, methyl or halomethyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy is phenyl, and optionally substituted with one or two groups selected from: halogen, CN, and C. 1-3 Alkyl group.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from:

7. A compound of formula (II): Or its pharmaceutically acceptable salt. in: R 1 It is H or methyl; Z 3 and Z 4 Independently selected from H, halogens, CN, and OMe; L is a C1-C4 straight-chain or branched alkylene linker; W is -SO2R, -SO2NR'R', -NR'SO2R, or optionally substituted C1-C3 alkyl, or optionally substituted 3-6 membered cycloalkyl; The optional substituents for the optionally substituted C1-C3 alkyl and optionally substituted 3-6 membered cycloalkyl groups are 1-3 independently selected from the following groups: OH, -SO2R, -NR'SO2R, -NR'R', -OR, -NR'COOR and COOR'. R is independently selected from C each time it appears. 1-4 Alkyl and 3-6 membered cycloalkyl, R' is selected from H and C each time it appears. 1-4 alkyl; Alternatively, the two R' atoms together with the nitrogen atom directly attached to them form a 4-6 membered ring, which optionally contains an additional O as a ring member and is optionally substituted by one or two oxygen atoms.

8. A compound of formula (III): Or its pharmaceutically acceptable salt. Where R 11 and R 12 Each is independently H or C1-C3 alkyl, or R 11 and R 12 Together with the carbon atom it is attached to, they form C 3-5 cycloalkyl ring; R 10 Selected from C1-C3 alkyl, C3-C5 cycloalkyl and –NR 13 R 14 , where R 13 and R 14 Independently selected from H and C 1-3 Alkyl, or R 13 and R 14 Together with the N group attached thereto, it forms a ring selected from the following: acridine, pyrrolidine, piperidine, piperazine, and morpholine, wherein the acridine, pyrrolidine, piperidine, piperazine, and morpholine are optionally substituted by 1 to 3 independently selected groups from the following: oxo, C 1-3 Alkyl, C 1-3 Alkoxy, CN, and halogens; L represents a bond, CH2, or CH2CH2; R 1 It is H or Me; and Z 3 and Z 4 Selected from H, CN and halogens.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein Z 3 and Z 4 They are not both H.

10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R 1 It's H.

11. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein, R 10 It is cyclopropyl.

12. A compound, wherein the compound is selected from: Or its pharmaceutically acceptable salt.

13. A compound, wherein the compound is selected from: Or its pharmaceutically acceptable salt.

14. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, mixed with at least one pharmaceutically acceptable carrier.

15. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of claim 1, in the preparation of a medicament for treating a patient with a herpes virus infection.

16. The use according to claim 15, wherein the herpesvirus is selected from cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, herpes simplex virus including HSV-1 and HSV-2, herpesvirus 6, human herpesvirus 7 and Kaposi's sarcoma-associated herpesvirus.

17. A compound of formula (IV): in: R 11 It is a C1-C6 alkyl group that is optionally substituted with Z up to 3 times; R 3 It does not exist; R 4 It is H; R 5 Selected from H, halogens and Z 5 Replace C up to 3 times 1-3 alkyl; LW is selected from: L is -CH2- or -CH2CH2-; R is independently selected from C each time it appears. 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members. Each R is optionally substituted by one or two independent groups selected from the following: C 1-4 Alkyl, C 1-2 Halogenated alkyl, –L 3 -CN、–L 3 -Halogen, –L 3 -C 1-3 Alkoxy, –L 3 -OH, –L 3 -NR'SO2R'、–L 3 -NR'R'、–L 3 -C(O)NR'R' and –L 3 -COOR'、-L 3 - (5-6 membered heterocyclic groups containing one or two N or O heteroatoms as ring members), –L 3 -C 3-5 cycloalkyl and –L 3 -(a 5-6 membered heteroaryl ring containing up to 4 total heteroatoms selected from 1-4 nitrogen atoms and 1 oxygen atom as ring members), wherein the C 1-4 Alkyl, 5-6-membered heterocyclic, C 3-5 The cycloalkyl and 5-6-membered heteroaryl rings are each optionally substituted by up to three independent groups selected from the following: C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and -CN; R' is independently selected from H or C each time it appears. 1-4 alkyl; Alternatively, the two R' atoms together with the nitrogen atom directly attached to them can form a 4-6 membered ring, which optionally contains another O as a ring member; L 3 Independently, it is a bond or -CH2-; and Z and Z 5 Each time it appears, it is independently selected from halogen, hydroxyl, CN, and C. 3-5 Cycloalkyl.

18. The compound according to claim 17, wherein R 11 It is H or C1-C6 alkyl.

19. The compound according to claim 17, wherein R 4 and R 5 They represent H respectively.

20. The compound according to claim 17, wherein: R is independently selected from C each time it appears. 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members. Each R is optionally substituted by one or two groups selected from the following: C 1-3 Alkyl, CN, Halogen, C 1-3 Alkoxy, OH and C 3-5 Cycloalkyl.

21. The compound according to claim 17, wherein L is CH2.

22. The compound of claim 17, wherein R is independently selected from methyl, ethyl, isopropyl, and cyclopropyl each time it appears.

23. The compound according to claim 17, wherein R' is independently selected from H and methyl each time it appears.

24. A method for preparing the compound according to claim 1, comprising: Compound of formula (V) in X represents –OH or a leaving group; R 3 It does not exist; R 4 It is H; R 5 Selected from H, halogens and Z 5 Replace C up to 3 times 1-3 alkyl; LW is selected from: L is -CH2- or -CH2CH2-; R is independently selected from C each time it appears. 1-4 Alkyl groups, 3-6 membered cycloalkyl groups, and 4-6 membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S as ring members. Each R is optionally substituted by one or two independent groups selected from the following: C 1-3 Alkyl, CN, Halogen, C 1-3 Alkoxy, OH and C 3-5 cycloalkyl; R' is independently selected from H and C each time it appears. 1-4 alkyl; Alternatively, two R' atoms together with the nitrogen atom directly attached to them can form a 4-6 membered ring, which optionally contains an additional O as a ring member; Each Z 5 Each time it appears, it is independently selected from halogens, hydroxyl groups, and CN. With compounds of formula (VI): Contact, wherein Cy is phenyl, pyridyl, pyrimidinyl, or a 5-8 membered cycloalkyl group, and Cy is optionally substituted by up to 3 groups selected from the following: halogen, CN, -N(R')2, and C. 1-3 Alkoxy; R 1 Selected from H and C 1-3 Alkyl; and R 2 It is H.

25. The method of claim 24, wherein the leaving group is selected from halogens and –OC(O)-OR*, wherein R* represents a C1-C6 alkyl group and optionally is surrounded by at most three halogens or C... 1-3 Alkyl-substituted.

26. The method according to claim 24, wherein the compound of formula (V) is a compound of formula (VB): Where R 5 It is H or a halogen; and L is –CH2-.

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