Antiviral pyridopyrazinedione compounds

Abstract

To provide a compound for the treatment and prevention of disease.SOLUTION: The invention provides compounds of Formula (I) as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods to use these compounds, salts and compositions for treating viral infections, particularly infections caused by herpesviruses. The present invention relates to novel bicyclic pyridone compounds that are inhibitors of herpesvirus replication, and are thus useful to treat herpesvirus infections. The compounds inhibit viral DNA polymerases of various herpesviruses, including cytomegalovirus (CMV), herpes simplex viruses, and the like. The invention provides novel bicyclic pyridone compounds as disclosed herein, pharmaceutical compositions containing such compounds, and methods of using these compounds and compositions in the treatment and prevention of herpesvirus disease.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to novel bicyclic pyridone compounds that are inhibitors of herpesvirus replication and are therefore useful for treating herpesvirus infections. The compounds inhibit the viral DNA polymerase of various herpesviruses, including cytomegalovirus (CMV), herpes simplex virus, and others. The present invention provides the novel bicyclic pyridone compounds disclosed herein, pharmaceutical compositions containing such compounds, and methods of using these compounds and compositions for the treatment and prevention of herpesvirus diseases. [Background technology]

[0002] Human CMV, also known as human herpesvirus 5 (HHV-5), is a β-herpesvirus that affects all populations worldwide, including adults and children with normal or compromised immune systems. While CMV is often asymptomatic in healthy individuals, it can become life-threatening in immunocompromised individuals. CMV is also a concern during pregnancy because it can be transmitted from mother to fetus and cause serious congenital anomalies. There are no approved treatments for preventing or treating congenital CMV infection. In transplant settings, current anti-CMV therapies include the nucleoside analogs valganciclovir (valGCV), ganciclovir (GCV), and cidofovir (CDV), as well as the pyrophosphate analog foscarnet (FOS). Each of these therapeutic agents inhibits CMV DNA polymerase, a protein encoded by the UL54 gene, an enzyme essential for viral replication (PNAS 2003, 100(24), 14223-14228; WO2013 / 152063; WO2005 / 012545). In solid organ transplant recipients, first-line treatment consists of either prophylactic or preemptive treatment with GCV or the orally bioavailable prodrug valGCV. GCV can significantly reduce the risk of disease and effectively treat active CMV infection. However, this drug is poorly tolerated. GCV and valGCV can cause severe bone marrow suppression, which places patients at risk of engraftment failure in stem cell transplant recipients. Second-line treatments, such as CDV and FOS, are associated with severe nephrotoxicity. Furthermore, resistance to current anti-CMV nucleoside analogs is a significant cause of treatment failure. Thus, new classes of CMV therapeutics, particularly non-nucleoside compounds, are needed to provide safer CMV treatments and to combat herpes viruses that are resistant to known classes of antiviral drugs.

[0003] In addition to CMV, herpesviruses that cause a wide range of human viral 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. Herpesvirus infections are not only widespread, but they also persist in their hosts in a latent state throughout their lives. According to one estimate, over 90% of human adults are latently infected with at least one herpesvirus, which can reactivate many years later. Shingles (shingles), for example, occurs when the varicella-zoster virus (VZV) reactivates from latency, typically many years after the initial infection (chickenpox) has been controlled. Shingles is a painful condition that primarily affects older adults and immunocompromised individuals. Complications include postherpetic neuralgia, potentially debilitating, and chronic pain syndromes, whereas anti-VZV inhibitors (nucleosides) have only minor effects. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2013 / 152063 [Patent Document 2] International Publication No. 2005 / 012545 Summary of the Invention [Means for solving the problem]

[0005] Immunocompromised individuals, such as transplant patients, are at high risk for reactivation of herpes viruses, such as CMV, HSV, or VZV. Therefore, safe and potent virus inhibitors with broad anti-herpes virus activity would be highly valuable. The present invention provides novel compounds that are active against several herpes viruses, including CMV, HSV, VZV, and EBV.

[0006] The present invention provides novel non-nucleoside compounds that inhibit herpesvirus DNA polymerase and have potent antiviral activity in vitro. The compounds are active against several herpesviruses, including CMV, HSV, VZV, and EBV. Potent non-nucleoside polymerase inhibitors offer significant advantages over current anti-CMV agents. First, unlike nucleoside analogs, the compounds are not incorporated by human polymerases and are therefore expected to have a better safety profile than current anti-CMV drugs. Second, the compounds described herein are active against GCV-resistant viruses, thus potentially aiding in the treatment of patients with cross-resistance to nucleoside analogs. Finally, the compounds are active against several human herpesviruses, providing opportunities for broad clinical use. The present invention also provides pharmaceutical compositions, compounds, and compositions containing the novel compounds for inhibiting herpesvirus replication or reactivation and for treating disease states associated with or caused by herpesviruses. Further objects of the present invention are described in the following description and examples.

[0007] In one embodiment, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein:

[0008] Cy is phenyl, pyridinyl, pyrimidinyl or 5-8 membered cycloalkyl, Cy is halo, CN, hydroxy, -N(R')2, C 3~6Cycloalkyl, C 1~3 Alkoxy, C 1~3 C substituted up to 3 times (0-3) with haloalkyl and Z 1~3 alkyl, and C optionally substituted up to three times with Z. 1~3 When two of the alkyls are directly bonded to the same carbon atom, they may be joined together with the carbon to which they are bonded to form a 3- to 5-membered cycloalkyl ring substituted up to three times with Z; R 1 is H and C 1~3 alkyl;

[0009] R 2 is H and C 1~3 alkyl;

[0010] or R 1 and R 2 may be taken together with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring;

[0011] R 3 represents up to two (0-2) optional substituents on the ring to which -LW is directly attached, each of which independently represents halo, CN, C 1~3 Alkoxy, C 1~3 alkyl, COOR′ and C(O)NR′R′;

[0012] R 4 is H, halo or C 1~3 is alkyl;

[0013] R 5 H, halo, CN, C 1~3 Alkoxy, -NR'R', Z 5 C substituted up to three times with 1~3 Alkyl, Z 5 C substituted up to three times with 2~4 Alkenyl, Z 5 C substituted up to three times with 2~4alkynyl, and a ring selected from a 3- to 6-membered cycloalkyl ring, a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, and a 5- to 6-membered heteroaryl ring containing up to 4 heteroatoms selected from N, O and S as ring members, wherein the 3- to 6-membered cycloalkyl ring, the 4- to 6-membered heterocyclic ring or the 5- to 6-membered heteroaryl ring is selected from one to two Z 5 with substitution as necessary;

[0014] L is a C1-C4 straight or branched alkylene linker, or when W is an optionally substituted ring, L may be a C1-C4 straight or branched alkylene linker or a bond;

[0015] W is H, -OH, -OR, -C(O)NR'R', -COOR', -NR'R', -NR'COOR, -NR'C(O)R, -S02R, -S02NR'R', -NR'S02R, -P(O)(OR')2, or an optionally substituted ring selected from 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocyclyl containing 1 or 2 N, O or S heteroatoms as ring members, and 5 membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, optionally fused to phenyl;

[0016] The optional substituents on the optionally substituted ring are C 1~3 Alkyl, oxo, halo, C 1~3 Haloalkyl, -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';

[0017] R, in each occurrence, 1~4 selected from alkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, and 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S as ring members;

[0018] Each R is C 1~4 Alkyl, C 1~2 Haloalkyl, oxo, -L 3 -CN, -L 3 -Halo, -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 - (one or two N, O or or S heteroatom-containing 5- to 6-membered heterocyclyl), -L 3 -C 3~5 Cycloalkyl, and -L3 -(a 5- to 6-membered heteroaryl ring having up to 4 heteroatoms, including 1 to 4 nitrogen atoms, 0 to 1 oxygen atom, and 0 to 1 sulfur atom as ring members), and 1~4 Alkyl, 5-6 membered heterocyclyl, C 3~5 The cycloalkyl and 5- to 6-membered heteroaryl rings are each selected from halo, C 1~3 Alkyl, C 1~3 Haloalkyl, -L 4 -OR', -L 4 -CN and -L 4 -N(R')2;

[0019] R', independently in each occurrence, is H, C 1~4 Alkyl, halo, —OH, amino or C 1~2 C optionally substituted with alkoxy 1~4 Alkyl, and C 3~6 Cycloalkyl is halo, —OH, amino or C 1~2 C optionally substituted with alkoxy 3~6 cycloalkyl;

[0020] or two R', together with the nitrogen atom to which they are both directly attached, optionally contain additional N, O or S as ring members, C 1~2 Alkyl, C 1~2 may form a 4- to 6-membered ring optionally substituted with 1 to 3 groups selected from alkoxy, oxo, and hydroxy;

[0021] Each L 2 and L 3 and L 4 are independently a bond or a linear or branched C 1~3 is alkylene;

[0022] Z and Z 5 is independently, in each occurrence, halo, hydroxy, CN, C 1~3 Alkoxy, C1~3 Alkyl and C 3~5 cycloalkyl;

[0023] Two Z groups or two Z 5 The group, together with the carbon atoms to which both are directly attached, is a 3- to 5-membered cycloalkyl ring or ring containing O, N, or S as a ring member, and is also suitable for oxo and C 1~3 It may form a 4- to 6-membered heterocyclic ring optionally substituted with up to two groups selected from alkyl. [Brief explanation of the drawings]

[0024] [Figure 1] FIG. 1 shows XRPD spectra illustrating the two polymorphs (NX-7 and NX-12) of the compound of Example 1 and their behavior when slurried together in ethanol. DETAILED DESCRIPTION OF THE INVENTION

[0025] For the purposes of interpreting this specification, the following definitions will apply and, whenever appropriate, terms used in the singular will also include the plural.

[0026] As used herein, terms have the following meanings unless the context clearly indicates otherwise.

[0027] As used herein, the term "subject" refers to an animal. In certain aspects, an animal is a mammal. A subject also refers to, for example, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, a subject is a human. As used herein, a "patient" refers to a human subject.

[0028] As used herein, the term "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder or disease, or biological activity or process. refers to a significant decrease in baseline activity.

[0029] As used herein, the term "treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., delaying or halting or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to alleviating or improving at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.

[0030] As used herein, the terms "a," "an," "the," and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed as encompassing both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0031] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better clarify the invention and does not pose a limitation on the scope of the invention as otherwise claimed.

[0032] "Optionally substituted" means that the referenced group may be substituted at one or more positions with any one or any combination of the radicals listed thereafter. The number, arrangement, and selection of substituents are understood to encompass only those substituents that a chemical engineer would reasonably expect to be stable; thus, for example, "oxo" would not be considered a substituent on an aryl or heteroaryl ring, and a single carbon atom would not be considered to have three hydroxy or amino substituents. Unless otherwise specified, optional substituents are typically halo, oxo, CN, amino, hydroxy, -C 1~3 Alkyl, -OR * , -NR * 2, -SR * , -SO2R * , -COOR * and -CONR * 2, and each R * are independently H or C 1~3 It is alkyl.

[0033] As used herein, unless otherwise specified, "aryl" refers to a phenyl or naphthyl group. Unless otherwise specified, an aryl group includes halo, CN, amino, hydroxy, C 1~3 Alkyl, -OR * , -NR * 2, -SR * , -SO2R * , -COOR * and -CONR * 2, and each R * are independently H or C 1~3 It is alkyl.

[0034] As used herein, "halo" or "halogen" may be fluorine, chlorine, bromine or iodine.

[0035] As used herein, "C 1~6"C alkyl" or "C1-C6 alkyl" refers to a straight or branched chain alkyl having from 1 to 6 carbon atoms. When a different number of carbon atoms is specified, such as C4 or C3, the definition is modified accordingly, e.g., "C 1~4 "Alkyl" refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0036] As used herein, "C 1~6 Alkylene" or "C1-C6 alkylene" denotes a straight or branched alkyl having 1 to 6 carbon atoms and two valences open for bonding to two other groups. When a different number of carbon atoms, such as C4 or C3, is specified, this definition is modified accordingly, e.g., "C 1~4 "Alkylene" refers to methylene (-CH2-), ethylene (-CH2CH2-), straight or branched chain propylene (-CH2CH2CH2- or -CH2-CHMe-CH2-), and the like.

[0037] As used herein, "C 1~6 "Alkoxy" refers to a straight or branched chain alkoxy (-O-alkyl) having 1 to 6 carbon atoms. When a different number of carbon atoms is specified, such as C4 or C3, the definition is modified accordingly, e.g., "C 1~4 "Alkoxy" refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

[0038] As used herein, "C 1~4 "Haloalkyl" or "C1-C4 haloalkyl" refers to a straight or branched alkyl having from 1 to 4 carbon atoms, in which at least one hydrogen is replaced with a halogen. The number of hydrogen substitutions can be from 1 to the number of hydrogen atoms in the unsubstituted alkyl group. When a different number of carbon atoms is specified, such as C6 or C3, this definition is modified accordingly. Thus, "C 1~4"Haloalkyl" refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl having at least one hydrogen replaced with a halogen, for example, where the halogen is fluorine: CFCF-, (CF)CH-, CH-CF-, CFCF-, CF, CFH-, CFCFCH(CF)-, or CFCFCFCFCF-.

[0039] As used herein, "C 3~8 "Cycloalkyl" refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When a different number of carbon atoms, such as C3-C6, is specified, the definition is modified accordingly.

[0040] "4- to 8-membered heterocyclyl," "5- to 6-membered heterocyclyl," "3- to 10-membered heterocyclyl," "3- to 14-membered heterocyclyl," "4- to 14-membered heterocyclyl," and "5- to 14-membered heterocyclyl" refer to 4- to 8-membered, 5- to 6-membered, 3- to 10-membered, 3- to 14-membered, 4- to 14-membered, and 5- to 14-membered heterocyclic rings, respectively; unless otherwise specified, such rings contain 1-7, 1-5, or 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur as ring members, and the ring may be saturated or partially saturated, but is not aromatic. A heterocyclic group may be attached to another group at a nitrogen or carbon atom. The term "heterocyclyl" includes single-ring groups, fused-ring groups, and bridging groups. Examples of such heterocyclyls include, but are not limited to, pyrrolidine, piperidine, piperazine, pyrrolidinone, morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4-dioxane, 1,4-oxathiane, 8-aza-bicyclo[3.2.1]octane, 3,8-diazabicyclo[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, azetidine, ethylenedioxo, oxetane, or thiazole. In certain embodiments, unless otherwise specified, heterocyclic groups have 1-2 heteroatoms selected from N, O, and S as ring members, and 4-7 ring atoms, and are not limited to halo, oxo, CN, amino, hydroxy, C 1~3 Alkyl, -OR * , -NR * 2, -SR * , -SO2R * , -COOR * and -CONR * 2, and each R * are independently H or C 1~3 In particular, heterocyclic groups containing sulfur atoms are The sulfur is optionally substituted with one or two oxo groups.

[0041] A "heteroaryl" is a fully unsaturated (aromatic) ring. The term "heteroaryl" refers to a 5- to 14-membered monocyclic, bicyclic, or tricyclic aromatic ring system having 1 to 8 heteroatoms selected from N, O, or S. Typically, a heteroaryl is a 5- to 10-membered ring or ring system (e.g., a 5- to 7-membered monocyclic group or an 8- to 10-membered bicyclic group), often a 5- to 6-membered ring containing up to four heteroatoms selected from N, O, and S, although often a heteroaryl ring contains 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-furyl, 2- or 3-pyrrolyl, 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-isoxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2,3-triazolyl), tetrazolyl, triazine, pyrimidine, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl. Heteroaryl groups include halo, CN, amino, hydroxy, C 1~3 Alkyl, -OR * , -NR * 2, -SR * , -SO2R * , -COOR * and -CONR * 2, and each R * are independently H or C 1~3 It is alkyl.

[0042] The term "hydroxy" or "hydroxyl" refers to the group --OH.

[0043] Various embodiments of the present invention are described herein. It is recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments. The following numbered embodiments are representative of the present invention:

[0044] 1. A compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, Cy is phenyl, pyridinyl, pyrimidinyl or 5-8 membered cycloalkyl, Cy is halo, CN, hydroxy, -N(R')2, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 C substituted up to 3 times (0-3) with haloalkyl and Z 1~3 alkyl, and C optionally substituted up to three times with Z. 1~3 When two of the alkyls are directly bonded to the same carbon atom, they may be taken together with the carbon to which they are attached to form a 3- to 5-membered cycloalkyl ring substituted up to three times by Z; R 1 is H and C 1~3 alkyl; R 2 is H and C 1~3 alkyl; or R 1 and R 2 may be taken together with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl ring; R 3 -LW may optionally have up to two (0-2) substituents on the ring to which it is directly attached. each of which independently represents halo, CN, C 1~3 Alkoxy, C 1~3 alkyl, COOR′ and C(O)NR′R′; R 4 is H, halo or C 1~3 is alkyl; R5 H, halo, CN, C 1~3 Alkoxy, -NR'R', Z 5 C substituted up to three times with 1~3 Alkyl, Z 5 C substituted up to three times with 2~4 Alkenyl, Z 5 C substituted up to three times with 2~4 alkynyl, and a ring selected from a 3- to 6-membered cycloalkyl ring, a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, and a 5- to 6-membered heteroaryl ring containing up to 4 heteroatoms selected from N, O and S as ring members, wherein the 3- to 6-membered cycloalkyl ring, the 4- to 6-membered heterocyclic ring or the 5- to 6-membered heteroaryl ring is selected from one to two Z 5 with substitution as necessary; L is a C1-C4 straight or branched alkylene linker, or when W is an optionally substituted ring, L may be a C1-C4 straight or branched alkylene linker or a bond; W is H, -OH, -OR, -C(O)NR'R', -COOR', -NR'R', -NR'COOR, -NR'C(O)R, -S02R, -S02NR'R', -NR'S02R, -P(O)(OR')2, or an optionally substituted ring selected from 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocyclyl containing 1 or 2 N, O or S heteroatoms as ring members, and 5 membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, optionally fused to phenyl; The optional substituents on the optionally substituted ring are C 1~3 Alkyl, oxo, halo, C 1~3 Haloalkyl, -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'; R, in each occurrence, 1~4 selected from alkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, and 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S as ring members; Each R is C 1~4 Alkyl, C 1~2 Haloalkyl, oxo, -L 3 -CN, -L 3 -Halo, -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 heterocyclyl containing 1 or 2 N, O or S heteroatoms as ring members), -L3 -C 3~5 Cycloalkyl, and -L 3 -(a 5- to 6-membered heteroaryl ring having up to 4 heteroatoms, including 1 to 4 nitrogen atoms, 0 to 1 oxygen atom, and 0 to 1 sulfur atom as ring members), and 1~4 Alkyl, 5-6 membered heterocyclyl, C 3~5 The cycloalkyl and 5- to 6-membered heteroaryl rings are each selected from halo, C 1~3 Alkyl, C 1~3 Haloalkyl, -L 4 -OR', -L 4 -CN and -L 4 -N(R')2; R', independently in each occurrence, is H, C 1~4 Alkyl, halo, —OH, amino or C 1~2 C optionally substituted with alkoxy 1~4 Alkyl, and C 3~6 Cycloalkyl is halo, —OH, amino or C 1~2 Required for alkoxy C substituted according to 3~6 cycloalkyl; or two R', together with the nitrogen atom to which they are both directly attached, optionally contain additional N, O or S as ring members, C 1~2 Alkyl, C 1~2 may form a 4- to 6-membered ring optionally substituted with 1 to 3 groups selected from alkoxy, oxo, and hydroxy; Each L 2 and L 3 and L 4 are independently a bond or a linear or branched C 1~3 is alkylene; Z and Z 5 is independently, in each occurrence, halo, hydroxy, CN, C 1~3 Alkoxy, C 1~3 Alkyl and C 3~5 cycloalkyl; Two Z groups or two Z 5 The group, together with the carbon atoms to which both are directly attached, is a 3- to 5-membered cycloalkyl ring or ring containing O, N, or S as a ring member, and is also suitable for oxo and C 1~3 and alkyl, optionally forming a 4- to 6-membered heterocyclic ring substituted with up to two groups selected from the group consisting of aryl, aryl, aryloxy ...

[0045] 2. R 1 is H, or a pharmaceutically acceptable salt thereof.

[0046] 3. R 2 is H. In an alternative embodiment, R 2 is methyl.

[0047] 4. The compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein Cy is selected from phenyl, pyridin-3-yl, and cyclohexyl, each of which is optionally substituted with 1-3 groups selected from halo, CF3, and CN. In some of these embodiments, Cy is phenyl with 1 or 2 substituents selected from Cl, F, Br, and CN. In some of these embodiments, the substituents on the phenyl ring Cy are in the meta and / or para positions of the phenyl ring.

[0048] 5. R 4 is H, or a pharmaceutically acceptable salt thereof.

[0049] 6. R 5 is H, halo, methyl, or halomethyl, or a pharmaceutically acceptable salt thereof. 5 is H.

[0050] 7. R 3 does not exist or R 3represents one or two methyl groups, or a pharmaceutically acceptable salt thereof. 3 does not exist, i.e., R 3 represents 0 substituents.

[0051] 8. The compound of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein L is -CH2- or -(CH2)2-. In some of these embodiments, L is -CH2-.

[0052] 9. W is C 1~3 Alkyl, oxo, halo, C 1~3 The compound of any preceding embodiment is cyclopropyl substituted with a group selected from alkoxy, OH, -S0R, -S0NR'R', -SOR, -S(=O)(=NR')R, -NR'S0NR'R', -NR'S0R, -NR'R', -OR, -NR'COOR, -C(O)NR'R' and COOR', or a pharmaceutically acceptable salt thereof.

[0053] 10. Part WL-- is [ka] 9. The compound of any of embodiments 1 to 8, selected from the group consisting of:

[0054] In some of these embodiments, L is CH. R in these embodiments, at each occurrence, is optionally selected from methyl, ethyl, isopropyl, and cyclopropyl. R' in these embodiments, at each occurrence, is optionally selected from H and methyl.

[0055] 11. Cy is phenyl and halo, CN, OH, C 1~3 Alkyl and C 1~3 The compound of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two groups selected from alkoxy.

[0056] 12. Cy, [ka] 12. The compound of embodiment 11, selected from:

[0057] 13. The compound of formula (I) is of formula (II): [ka] (In the formula, R 1 is H or methyl; Z 3 and Z 4 are independently selected from H, halo, CN, Me, and OMe; L is a C1-C4 straight or branched alkylene linker; W is -SO2R, -SO2NR'R', -NR'S02R, or optionally substituted C1-C3 alkyl, or optionally substituted 3-6 membered cycloalkyl; The optionally substituted C1-C3 alkyl and optionally substituted cyclo The optional substituents on alkyl are C 1~3 Alkyl, oxo, halo, C 1~3 1 to 3 groups independently selected from alkoxy, OH, —S0R, —S0NR′R′, —NR′S0NR′R′, —NR′S0R, —NR′R′, —OR, —NR′COOR, —C(O)NR′R′, and COOR′; R, independently in each occurrence, is C 1~4 selected from alkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, and 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S as ring members; Each R is C 1~3 Alkyl, oxo, CN, halo, C 1~3Alkoxy, OH and C 3~5 optionally substituted with 1 or 2 groups independently selected from cycloalkyl; R' in each occurrence is independently H, and halo, -OH or C 1~2 C optionally substituted with alkoxy 1~4 alkyl; or two R', together with the nitrogen atom to which they are both directly attached, optionally contain additional N, O or S as ring members, C 1~2 Alkyl, C 1~2 It may form a 4- to 6-membered ring optionally substituted with one or two groups selected from alkoxy, oxo and hydroxy. or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof.

[0058] 14. The compound of formula (I) is of formula (III): [ka] (In the formula, R 11 and R 12 are each independently H or C1-C3 alkyl, or R 11 and R 12 together with the carbon atoms to which they are attached, C 3~5 forming a cycloalkyl ring; R 10 is C1-C3 alkyl, C3-C5 cycloalkyl and -NR 13 R 14 Selected from R 13 and R 14 are independently H and C 1~3 alkyl, or R 13 and R 14 are both joined together with the N to which they are attached to form a ring selected from azetidine, pyrrolidine, piperidine, piperazine and morpholine, and said azetidine, pyrrolidine, piperidine, piperazine or morpholine is selected from the group consisting of oxo, C1~3 Alkyl, C 1~3 optionally substituted with 1 to 3 groups independently selected from alkoxy, CN, and halo; L is a bond, CH2 or CH2CH2; R 1 is H or Me; Z 3 and Z 4 is selected from H, CN and halo or a pharmaceutically acceptable salt thereof.

[0059] 15. Z 3 and Z 4 but not both are H.

[0060] 16. R 1 The compound of embodiment 14, wherein is H.

[0061] 17. R 10 The compound of embodiment 14, wherein is cyclopropyl.

[0062] 18. A compound of any of Examples 1-212, or a pharmaceutically acceptable salt thereof. This embodiment includes each of the Examples set forth in the Bioactivity Data Tables herein.

[0063] 19. A pharmaceutical composition comprising a compound according to any of the preceding embodiments in admixture with at least one pharmaceutically acceptable carrier.

[0064] 20. A method for treating a herpes virus infection, comprising administering to a patient having a herpes virus infection a compound of any of embodiments 1 to 17, or a pharmaceutical composition comprising a compound of any of embodiments 1 to 17.

[0065] 21. The method of embodiment 20, wherein the herpesvirus is selected from cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex viruses including HSV-1 and HSV-2, herpesvirus 6, human herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus.

[0066] 22. Compound of formula (IV): [ka] (In the formula, R 11 is H or C1-C6 alkyl optionally substituted up to three times with Z; R 3 represents up to two (0-2) optional substituents on the ring to which -LW is directly attached, each of which independently represents halo, CN, C 1~3 Alkoxy, C 1~3 alkyl, COOR′ and C(O)NR′R′; R 4 is H, halo or C 1~3 is alkyl; R 5 H, halo, CN, C 1~3 Alkoxy, -NR'R', Z 5 C substituted up to three times with 1~3 Alkyl, Z 5 C substituted up to three times with 2~4 Alkenyl, Z 5 C substituted up to three times with 2~4 alkynyl, and a ring selected from a 3- to 6-membered cycloalkyl ring, a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, and a 5- to 6-membered heteroaryl ring containing up to 4 heteroatoms selected from N, O and S as ring members, wherein the 3- to 6-membered cycloalkyl ring, the 4- to 6-membered heterocyclic ring or the 5- to 6-membered heteroaryl ring is selected from one to two Z 5 with substitution as necessary; L is a C1-C4 straight or branched alkylene linker or a bond; W is H, -OH, -OR, -C(O)NR'R', -COOR', -NR'R', -NR'COOR, -NR'C(O)R, -S02R, -S02NR'R', -NR'S02R, -P(O)(OR')2, or an optionally substituted ring selected from 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heterocyclyl containing 1 or 2 N, O, or S heteroatoms as ring members, and 5-membered heteroaryl containing up to 4 heteroatoms selected from N, O, and S as ring members, optionally fused to phenyl. and; The optional substituents on the optionally substituted ring are C 1~3 Alkyl, oxo, halo, C 1~3 Haloalkyl, -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'; R, independently in each occurrence, is C 1~4 selected from alkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, and 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S as ring members; Each R is C 1~4 Alkyl, C 1~2 Haloalkyl, oxo, -L3 -CN, -L 3 -Halo, -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 heterocyclyl containing 1 or 2 N, O or S heteroatoms as ring members), -L 3 -C 3~5 Cycloalkyl, and -L 3 -(a 5- to 6-membered heteroaryl ring having up to 4 heteroatoms, including 1 to 4 nitrogen atoms, 0 to 1 oxygen atoms, and 0 to 1 sulfur atom as ring members), and 1~4 Alkyl, 5-6 membered heterocyclyl, C 3~5 The cycloalkyl and 5- to 6-membered heteroaryl rings are each selected from halo, C 1~3 Alkyl, C 1~3 Haloalkyl, -L 4 -OR', -L 4 -CN and -L 4 -N(R')2; R', independently in each occurrence, is H, C 1~4 Alkyl, halo, —OH, amino or C 1~2 C optionally substituted with alkoxy 1~4Alkyl, and C 3~6 Cycloalkyl is halo, —OH, amino or C 1~2 C optionally substituted with alkoxy 3~6 cycloalkyl; or two R', together with the nitrogen atom to which they are both directly attached, optionally contain additional N, O or S as ring members, C 1~2 Alkyl, C 1~2 may form a 4- to 6-membered ring optionally substituted with 1 to 3 groups selected from alkoxy, oxo, and hydroxy; Each L 2 and L 3 and L 4 are independently a bond or a linear or branched C 1~3 is alkylene; Z and Z 5 is independently, in each occurrence, halo, hydroxy, CN, C 1~3 Alkoxy, C 1~3 Alkyl and C 3~5 cycloalkyl; Two Z groups or two Z 5 The group, together with the carbon atoms to which both are directly attached, is a 3- to 5-membered cycloalkyl ring or ring containing O, N, or S as a ring member, and is also suitable for oxo and C 1~3 and alkyl, optionally forming a 4- to 6-membered heterocyclic ring substituted with up to two groups selected from Or its salt.

[0067] 23. R 11 is H or C1-C6 alkyl.

[0068] 24. R 3 24. The compound of embodiment 22 or 23, wherein is absent.

[0069] 25. R 4 and R 5 and each represent H.

[0070] 26. L is a C1-C4 straight or branched alkylene linker; W is -SO2R, -SO2NR'R', -NR'S02R, or optionally substituted C1-C3 alkyl, or optionally substituted 3-6 membered cycloalkyl; The optional substituents of the optionally substituted C1-C3 alkyl and optionally substituted cycloalkyl are 1~3 Alkyl, oxo, halo, C 1~3 1 to 3 groups independently selected from alkoxy, OH, —S0R, —S0NR′R′, —NR′S0NR′R′, —NR′S0R, —NR′R′, —OR, —NR′COOR, —C(O)NR′R′, and COOR′; R, independently in each occurrence, 1~4 selected from alkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, and 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S as ring members; Each R is C 1~3 Alkyl, oxo, CN, halo, C 1~3 Alkoxy, OH and C 3~5 optionally substituted with 1 or 2 groups selected from cycloalkyl; R' is independently in each occurrence H, and halo, -OH or C 1~2 C optionally substituted with alkoxy 1~4 cycloalkyl; or two R', together with the nitrogen atom to which they are both directly attached, optionally contain an additional N, O or S as a ring member, C 1~2 Alkyl, C 1~2 optionally forming a 4- to 6-membered ring optionally substituted with one or two groups selected from alkoxy, oxo, and hydroxy; The compound of embodiment 22.

[0071] 27. Base WL-- is [ka] 27. The compound of any of embodiments 22 to 26, selected from the group consisting of:

[0072] 28. The compound of any of embodiments 22 to 27, wherein L is CH2.

[0073] 29. The compound of any of embodiments 22 to 28, wherein R is independently at each occurrence selected from methyl, ethyl, isopropyl, and cyclopropyl.

[0074] 30. The compound of any of embodiments 22 to 29, wherein R', at each occurrence, is selected from H and methyl.

[0075] 31. A method of making a compound according to embodiment 1, comprising: Compound of formula (V) [ka] (In the formula, X represents —OH or a leaving group; R 3 represents up to two (0-2) optional substituents on the ring containing the two nitrogen atoms, and each R 3 are independently halo, CN, C 1~3 Alkoxy, C 1~3 alkyl, COOR′, C(O)NH2 and C(O)NRR′; R 4 is H, halo or C 1~3 is alkyl; R 5 H, halo, CN, C 1~3 Alkoxy, -NH2, -NRR', Z 5 C substituted up to three times with 1~3 Alkyl, Z 5 C substituted up to three times with 2~4 Alkenyl, Z 5 C substituted up to three times with 2~4alkynyl, and a ring selected from a 3- to 6-membered cycloalkyl ring, a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, and a 5- to 6-membered heteroaryl ring containing up to 4 heteroatoms selected from N, O and S as ring members, wherein the 3- to 6-membered cycloalkyl ring, the 4- to 6-membered heterocyclic ring or the 5- to 6-membered heteroaryl ring is selected from one to two Z 5 with substitution as necessary; L is a C1-C4 straight or branched alkylene linker; W is -OR', -NH2, -NRR', -NR'COOR, -NR'C(O)R', -S02R, -SON2NH2, -SON2NRR', -NR'S02R, or an optionally substituted C1-C3 alkyl, or an optionally substituted ring selected from 3-6 membered cycloalkyl, 5-6 membered heterocyclyl containing 1 or 2 N, O or S heteroatoms as ring members, and 5 membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members; The optionally substituted C1-C3 alkyl and optionally substituted ring optional substituents are C 1~3 Alkyl, oxo, halo, C 1~3 1 to 3 groups independently selected from alkoxy, OH, —SOR, —S0NR′R′, —SOR, —S(═O)(═NR′)R, —NR′S0NR′R′, —NR′S0R, —NH, —NR′R′, —OR, —NR′COOR, —C(O)NH, —C(O)NRR′, and COOR′; R, independently in each occurrence, is C 1~4 selected from alkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, and 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S as ring members; Each R is C 1~3 Alkyl, oxo, CN, halo, C 1~3 Alkoxy, OH and C 3~5optionally substituted with 1 or 2 groups independently selected from cycloalkyl; R', independently in each occurrence, is H, and halo, -OH or C 1~2 C optionally substituted with alkoxy 1~4 alkyl; or R and R′, together with the nitrogen atom to which they are both directly attached, optionally contain additional N, O or S as ring members, C 1~2 Alkyl, C 1~2 may form a 4- to 6-membered ring optionally substituted with one or two groups selected from alkoxy, oxo, and hydroxy; Y, in each occurrence, independently represents a halo, C 1~2 Alkyl, C 1~2 Haloalkyl and and C 1~2 selected from alkoxy; each Z 5 is independently, in each occurrence, halo, hydroxy, CN, C 1~3 Alkoxy, C 1~3 alkyl, Two Zs 5 The group, together with the carbon atoms to which both are directly attached, is a 3- to 5-membered cycloalkyl ring or ring containing O, N, or S as a ring member, and is also suitable for oxo and C 1~3 and alkyl, optionally forming a 4- to 6-membered heterocyclic ring substituted with up to two groups selected from with a compound of formula (VI): [ka] wherein Cy is phenyl, pyridinyl, pyrimidinyl, or 5- to 8-membered cycloalkyl; Cy is halo, CN, hydroxy, —N(R′), C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 C substituted up to 3 times (0-3) with haloalkyl and Z 1~3 alkyl, and C optionally substituted up to three times with Z. 1~3When two of the alkyls are directly bonded to the same carbon atom, they may be taken together with the carbon to which they are attached to form a 3- to 5-membered cycloalkyl ring substituted up to three times by Z; R 1 is H and C 1~3 alkyl; R 2 is H and C 1~3 alkyl; or R 1 and R 2 together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl ring; Z, independently at each occurrence, is selected from halo, hydroxy, CN, C 1~3 Alkoxy, C 1~3 Alkyl and C 3~5 cycloalkyl; The two Z groups, together with the carbon atoms to which they are both directly attached, form a 3- to 5-membered cycloalkyl ring or ring containing O, N, or S as ring members, and are substituted with oxo and C 1~3 and alkyl, optionally forming a 4- to 6-membered heterocyclic ring substituted with up to two groups selected from The method comprises contacting the

[0076] 32. The method of embodiment 31, wherein the leaving group is selected from the group consisting of halo and acyl groups.

[0077] 33. The acyl group is -OC(O)-OR * and R * can have up to three halos or C 1~3 The method of embodiment 31 or embodiment 32, wherein the alkoxy group represents C1-C6 alkyl optionally substituted.

[0078] 34. The compound of formula (V) is a compound of formula (VB): [ka] (In the formula, R 5is H or halo; L is -CH-; W is cyclopropyl substituted with -SOR, and R is as defined for formula (V). 34. The method of any one of embodiments 31 to 33, wherein

[0079] In certain embodiments, the compound of formula (I) is of formula (II): [ka] (In the formula, R 1 is H or methyl; Z 3 and Z 4 are independently selected from H, halo, CN, Me, and OMe; L is a C1-C4 straight or branched alkylene linker; W is -SO2R, -SO2NR'R', -NR'S02R, or optionally substituted C1-C3 alkyl, or optionally substituted 3-6 membered cycloalkyl; The optional substituents of the optionally substituted C1-C3 alkyl and optionally substituted cycloalkyl are C 1~3 Alkyl, oxo, halo, C 1~3 1 to 3 groups independently selected from alkoxy, OH, —S0R, —S0NR′R′, —NR′S0NR′R′, —NR′S0R, —NR′R′, —OR, —NR′COOR, —C(O)NR′R′, and COOR′; R, independently in each occurrence, is C 1~4 selected from alkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, and 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S as ring members; Each R is C 1~3 Alkyl, oxo, CN, halo, C 1~3 Alkoxy, OH and C 3~5optionally substituted with 1 or 2 groups selected from cycloalkyl; R' in each occurrence is H, and halo, -OH or C 1~2 C optionally substituted with alkoxy 1~4 alkyl; or two R', together with the nitrogen atom to which they are both directly attached, optionally contain additional N, O or S as ring members, C 1~2 Alkyl, C 1~2 It may form a 4- to 6-membered ring optionally substituted with one or two groups selected from alkoxy, oxo and hydroxy. or a pharmaceutically acceptable salt thereof is.

[0080] Preferred compounds of formula (I) are those of formula (III): [ka] (In the formula, R 11 and R 12 each represents H or C1-C3 alkyl, or R 11 and R 12 together with the carbon atoms to which they are attached, C 3~5 forming a cycloalkyl ring; R 10 is C1-C3 alkyl, C3-C5 cycloalkyl and -NR 13 R 14 Selected from R 13 and R 14 are independently H and C 1~3 alkyl, or R 13 and R 14 are both taken together with the N to which they are attached to form a ring selected from azetidine, pyrrolidine, piperidine, piperazine and morpholine, and are oxo, C 1~3 Alkyl, C 1~3 optionally substituted with 1 to 3 groups selected from alkoxy, CN, and halo; L is a bond, CH, or CHCH; R 1can be H or Me; Z 3 and Z 4 is selected from H, CN, and halo. Preferably, neither Z3 nor Z4 is H. Often, R1 is H. In certain embodiments of compounds of formula (III), R 10 is cyclopropyl.

[0081] Another aspect of the present invention is a compound of formula (IV): [ka] or a salt thereof, wherein: R 11 is H or C1-C6 alkyl optionally substituted up to three times with Z; R 3 represents up to two (0-2) optional substituents on the ring to which -LW is directly attached, each of which independently represents halo, CN, C 1~3 Alkoxy, C 1~3 alkyl, COOR′ and C(O)NR′R′; R 4 is H, halo or C 1~3 is alkyl; R 5 H, halo, CN, C 1~3 Alkoxy, -NR'R', Z 5 C substituted up to three times with 1~3 Alkyl, Z 5 C substituted up to three times with 2~4 Alkenyl, Z 5 C substituted up to three times with 2~4 alkynyl, and a ring selected from a 3- to 6-membered cycloalkyl ring, a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, and a 5- to 6-membered heteroaryl ring containing up to 4 heteroatoms selected from N, O and S as ring members, wherein the 3- to 6-membered cycloalkyl ring, the 4- to 6-membered heterocyclic ring or the 5- to 6-membered heteroaryl ring is selected from one to two Z 5 with substitution as necessary; L is a C1-C4 straight or branched alkylene linker or a bond; W is H, -OH, -OR, -C(O)NR'R', -COOR', -NR'R', -NR'COOR, -NR'C(O)R, -S02R, -S02NR'R', -NR'S02R, -P(O)(OR')2, or an optionally substituted ring selected from 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocyclyl containing 1 or 2 N, O or S heteroatoms as ring members, and 5 membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, optionally fused to phenyl; The optional substituents on the optionally substituted ring are C 1~3 Alkyl, oxo, halo, C 1~3 Haloalkyl, -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'; R, in each occurrence, 1~4 selected from alkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, and 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S as ring members; Each R is C 1~4 Alkyl, C 1~2Haloalkyl, oxo, -L 3 -CN, -L 3 -Halo, -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 heterocyclyl containing 1 or 2 N, O or S heteroatoms as ring members), -L 3 -C 3~5 Cycloalkyl, and -L 3 -(a 5- to 6-membered heteroaryl ring having up to 4 heteroatoms, including 1 to 4 nitrogen atoms, 0 to 1 oxygen atom, and 0 to 1 sulfur atom as ring members), and 1~4 Alkyl, 5-6 membered heterocyclyl, C 3~5 The cycloalkyl and 5- to 6-membered heteroaryl rings are each selected from halo, C 1~3 Alkyl, C 1~3 Haloalkyl, -L 4 -OR', -L 4 -CN and -L 4 -N(R')2; R', independently in each occurrence, is H, C 1~4 Alkyl, halo, —OH, amino or C 1~2 C optionally substituted with alkoxy1~4 Alkyl, and C 3~6 Alkyl, halo, —OH, amino or C 1~2 C optionally substituted with alkoxy 3~6 alkyl; or two R', together with the nitrogen atom to which they are both directly attached, optionally contain additional N, O or S as ring members, C 1~2 Alkyl, C 1~2 may form a 4- to 6-membered ring optionally substituted with 1 to 3 groups selected from alkoxy, oxo, and hydroxy; Each L 2 and L 3 and L 4 are independently a bond or a linear or branched C 1~3 is alkylene; Z and Z 5 is independently, in each occurrence, halo, hydroxy, CN, C 1~3 Alkoxy, C 1~3 Alkyl and C 3~5 cycloalkyl; Two Z groups or two Z 5 The group, together with the carbon atoms to which both are directly attached, is a 3- to 5-membered cycloalkyl ring or ring containing O, N, or S as a ring member, and is also suitable for oxo and C 1~3 It may form a 4- to 6-membered heterocyclic ring optionally substituted with up to two groups selected from alkyl.

[0082] In some embodiments of the compound of Formula (IV), R11 is H or C1-C6 alkyl. In some of these embodiments, R3 is absent. In some of these embodiments, R4 and R5 each represent H.

[0083] In some embodiments of the compound of formula (IV), L is a C1-C4 straight or branched alkylene linker; W is -SO2R, -SO2NR'R', -NR'S02R, or optionally substituted C1-C3 alkyl, or optionally substituted 3-6 membered cycloalkyl; The optional substituents of the optionally substituted C1-C3 alkyl and optionally substituted cycloalkyl are 1~3 Alkyl, oxo, halo, C 1~3 1 to 3 groups independently selected from alkoxy, OH, —S0R, —S0NR′R′, —NR′S0NR′R′, —NR′S0R, —NR′R′, —OR, —NR′COOR, —C(O)NR′R′, and COOR′; R, independently in each occurrence, 1~4 selected from alkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, and 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S as ring members; Each R is C 1~3 Alkyl, oxo, CN, halo, C 1~3 Alkoxy, OH and C 3~5 optionally substituted with 1 or 2 groups selected from cycloalkyl; R', in each occurrence, is H, and halo, -OH or C 1~2 C optionally substituted with alkoxy 1~4 alkyl; or two R', together with the nitrogen atom to which they are both directly attached, optionally contain an additional N, O or S as a ring member, C 1~2 Alkyl, C 1~2 It may form a 4- to 6-membered ring optionally substituted with one or two groups selected from alkoxy, oxo and hydroxy.

[0084] In some such embodiments, the group WL-- is [ka] is selected from the group consisting of:

[0085] In some of these embodiments, L is CH. R in these embodiments, at each occurrence, is selected from methyl, ethyl, isopropyl, and cyclopropyl. R' in these embodiments, at each occurrence, is selected from H and methyl.

[0086] These compounds are novel and useful as intermediates for the preparation of compounds of formulae (I)-(III) described herein.

[0087] Another embodiment of the present invention provides a compound as described above, or a pharmaceutically acceptable salt thereof, as a medicament.

[0088] Also within the scope of the invention is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of herpes virus disease and / or infection, including CMV, in humans.

[0089] Within the scope of the present invention is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0090] According to a further aspect of this embodiment, the pharmaceutical composition according to the invention further comprises a therapeutically effective amount of at least one other antiviral agent.

[0091] The present invention also provides the use of the pharmaceutical composition described hereinabove for the treatment of CMV infection or other herpesviruses in humans with or at risk of infection. The herpesvirus may be selected from cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex viruses including HSV-1 and HSV-2, herpesvirus 6, human herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus.

[0092] The present invention also provides the use of the pharmaceutical composition described herein above for treating CMV disease or other herpesvirus infection in people who have or are at risk of having the disease.CMV disease or other herpesvirus infection can include CMV infection in immunocompromised patients such as transplant recipients; congenital CMV; genital herpes; oral herpes or cold sores; herpes keratitis; neonatal herpes; herpes encephalitis; varicella (chickenpox); herpes zoster (herpes zoster); infectious mononucleosis; post-transplant lymphoproliferative disease (PTLD); Castleman's disease; and hemophagocytic lymphohistiocytosis.

[0093] Another aspect of the present invention provides methods of treating diseases or disorders in a patient that can be induced, exacerbated, and / or accelerated by CMV disease or other herpesvirus infection, including 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.

[0094] Another aspect of the invention involves a method of treating or preventing herpes virus disease and / or infection in a human by administering to the human an antivirally effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a composition as described above, either alone or in combination with at least one other antiviral agent administered together or separately.

[0095] A further aspect of the present invention refers to an article of manufacture comprising a composition effective for treating herpes virus disease and / or infection; and packaging material comprising a label indicating that the composition can be used to treat disease and / or infection by a herpes virus, such as CMV, wherein the composition comprises a compound of formula (I) according to the present invention, or a pharmaceutically acceptable salt thereof.

[0096] Yet another aspect of the present invention relates to a method for inhibiting the replication of CMV or another herpes virus, comprising exposing the virus to an effective amount of a compound of formula (I) or a salt thereof under conditions such that replication of the virus is inhibited. The method can be carried out in vitro or in vivo.

[0097] Further included within the scope of the present invention is the use of a compound of formula (I) or a salt thereof to inhibit the replication of CMV.

[0098] In some embodiments, the compound of formula (I) is co-administered with at least one additional agent selected from a herpesvirus entry inhibitor, a herpesvirus early transcription event inhibitor, a herpesvirus helicase-primase inhibitor, another herpesvirus DNA polymerase inhibitor, an inhibitor of UL97 kinase, a herpesvirus protease inhibitor, a herpesvirus terminase inhibitor, a herpesvirus maturation inhibitor, an inhibitor of another target in the herpesvirus life cycle, a herpesvirus vaccine, and a herpesvirus biological agent. In a preferred embodiment, the herpesvirus is CMV.

[0099] These additional agents can be combined with a compound of the invention to create a single pharmaceutical dosage form. Alternatively, these additional agents can be administered to the patient separately, as part of a multiple dosage form, for example, using a kit. Such additional agents can be administered to the patient prior to, concurrently with, or following administration of a compound of the invention or a pharmaceutically acceptable salt thereof.

[0100] The daily applicable dose range of the compound of the present invention is usually 0.01-100 mg / kg body weight, preferably 0.1-50 mg / kg body weight. Each dosage unit may conveniently contain 5%-95% active compound (w / w). Preferably, such preparations contain 20%-80% active compound.

[0101] The actual pharmaceutically effective amount or therapeutic dosage will, of course, depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease, etc. In any case, the combination will be administered in a dosage based on the patient's specific condition and in a manner that allows a pharmaceutically effective amount to be delivered.

[0102] When a composition of the invention comprises a combination of a compound of the invention and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent(s) should be present at dosage levels that are about 10-100%, more preferably about 10-80%, of the dosage normally administered in a monotherapy regimen.

[0103] Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologics) that are effective in inhibiting virus formation and / or replication in humans, including, but not limited to, agents that interfere with either the host or viral machinery necessary for virus formation and / or replication in humans. Such agents include herpesvirus entry inhibitors; herpesvirus early transcription event inhibitors; herpesvirus helicase-primase inhibitors; herpesvirus DNA polymerase inhibitors, such as ganciclovir (Cytovene®);

[0104] The inhibitors may be selected from valganciclovir (Valcyte®; Cymeval®), cidofovir (Vistide®), foscarnet (Foscavir®), CMX001, cyclopropavir (MBX-400) and valacyclovir (Valtrex®; Zelitrex®); inhibitors of UL97 kinase such as maribavir; herpesvirus protease inhibitors; herpesvirus terminase inhibitors such as AIC246 (Letermovir); herpesvirus maturation inhibitors; other inhibitors such as artesunate; CMV vaccines such as TransVax and herpesvirus biologics such as Cytogam (Cytotect®).

[0105] Many compounds of the present invention contain one or more chiral centers. These compounds can be prepared and used as single isomers or mixtures of isomers. Methods for separating isomers, including diastereomers and enantiomers, are known in the art, and examples of suitable methods are described herein. In certain embodiments, the compounds of the present invention are used as a single, substantially pure isomer, meaning that at least 90% of a sample of the compound is a specific isomer and less than 10% of the sample is any other isomer or mixture of isomers. Preferably, at least 95% of the sample is a single isomer. Since one isomer is typically more active in herpesvirus DNA polymerase in the in vitro assays described herein and is the preferred isomer, selecting a suitable isomer is within the level of ordinary skill. When the difference in in vitro activity between isomers is relatively small, e.g., less than about four-fold, a preferred isomer can be selected based on its activity level against viral replication in cell culture using methods such as those described herein, with the isomer having a lower IC-50 or EC-50 being preferred.

[0106] The compounds of the present invention can be synthesized by the following general synthetic routes, specific examples of which are described in more detail in the Examples.

[0107] The present invention also provides methods for making the compounds of formula I described herein and intermediates useful for preparing compounds of formula (I). Accordingly, the present invention also includes methods for making compounds of formula (I), which include the steps of: [ka]

[0108] (X represents —OH or a leaving group;

[0109] R 3 represents up to two (0-2) optional substituents on the ring containing the two nitrogen atoms, and each R 3 are independently halo, CN, C1~3 Alkoxy, C 1~3 alkyl, COOR′, C(O)NH2 and C(O)NRR′;

[0110] R 4 is H, halo or C 1~3 is alkyl;

[0111] R 5 H, halo, CN, C 1~3 Alkoxy, -NH2, -NRR', Z 5 C substituted up to three times with 1~3 Alkyl, Z 5 C substituted up to three times with 2~4 Alkenyl, Z 5 C substituted up to three times with 2~4 alkynyl, and a ring selected from a 3- to 6-membered cycloalkyl ring, a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, and a 5- to 6-membered heteroaryl ring containing up to 4 heteroatoms selected from N, O and S as ring members, wherein the 3- to 6-membered cycloalkyl ring, the 4- to 6-membered heterocyclic ring or the 5- to 6-membered heteroaryl ring is selected from one to two Z 5 with substitution as necessary;

[0112] L is a C1-C4 straight or branched alkylene linker;

[0113] W is -OR', -NH2, -NRR', -NR'COOR, -NR'C(O)R', -S02R, -SON2NH2, -SON2NRR', -NR'S02R, or an optionally substituted C1-C3 alkyl, or an optionally substituted ring selected from 3-6 membered cycloalkyl, 5-6 membered heterocyclyl containing 1 or 2 N, O or S heteroatoms as ring members, and 5 membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members;

[0114] The optionally substituted C1-C3 alkyl and optionally substituted ring optional substituents are C1~3 Alkyl, oxo, halo, C 1~3 1 to 3 groups selected from alkoxy, OH, -SOR, -S0NR'R', -SOR, -S(=O)(=NR')R, -NR'S0NR'R', -NR'S0R, -NH, -NR'R', -OR, -NR'COOR, -C(O)NH, -C(O)NRR' and COOR';

[0115] R, in each occurrence, 1~4 selected from alkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, and 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S as ring members;

[0116] Each R is C 1~3 Alkyl, oxo, CN, halo, C 1~3 Alkoxy, OH and C 3~5 optionally substituted with 1 or 2 groups selected from cycloalkyl;

[0117] R', in each occurrence, is H, and halo, -OH or C 1~2 C optionally substituted with alkoxy 1~4 alkyl;

[0118] or R and R′, together with the nitrogen atom to which they are both directly attached, optionally contain additional N, O or S as ring members, C 1~2 Alkyl, C 1~2 may form a 4- to 6-membered ring optionally substituted with one or two groups selected from alkoxy, oxo, and hydroxy;

[0119] Y, in each occurrence, independently represents a halo, C 1~2 Alkyl, C 1~2 Haloalkyl and C 1~2 selected from alkoxy;

[0120] each Z 5is independently, in each occurrence, halo, hydroxy, CN, C 1~3 Alkoxy, C 1~3 alkyl,

[0121] Two Zs 5 The group, together with the carbon atoms to which both are directly attached, is a 3- to 5-membered cycloalkyl ring or ring containing O, N, or S as a ring member, and is also suitable for oxo and C 1~3 and alkyl, optionally forming a 4- to 6-membered heterocyclic ring substituted with up to two groups selected from of,

[0122] Compounds of formula (VI): [ka]

[0123] (Wherein, Cy is phenyl, pyridinyl, pyrimidinyl or 5- to 8-membered cycloalkyl.) Cy is halo, CN, hydroxy, -N(R')2, C 3~6 Cycloalkyl, C 1~3 Alkoxy, C 1~3 C substituted up to 3 times (0-3) with haloalkyl and Z 1~3 alkyl, and C optionally substituted up to three times with Z. 1~3 When two of the alkyls are directly bonded to the same carbon atom, they may be joined together with the carbon to which they are bonded to form a 3- to 5-membered cycloalkyl ring substituted up to three times with Z; R 1 is H and C 1~3 alkyl;

[0124] R 2 is H and C 1~3 alkyl;

[0125] or R 1 and R 2 together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl ring;

[0126] Z, independently at each occurrence, is selected from halo, hydroxy, CN, C 1~3 Alkoxy, C 1~3 Alkyl and C 3~5 cycloalkyl;

[0127] The two Z groups, together with the carbon atoms to which they are both directly attached, form a 3- to 5-membered cycloalkyl ring or ring containing O, N, or S as ring members, and are substituted with oxo and C 1~3 and alkyl, optionally forming a 4- to 6-membered heterocyclic ring substituted with up to two groups selected from The method includes contacting the

[0128] Typically, for these methods, compounds of formula (V) and formula (VI) are combined or mixed in the presence of an inert solvent under conditions suitable for amide bond formation, including known methods used in peptide synthesis. For example, when X represents -OH, any of a wide range of known dehydrating agents suitable for forming amide bonds from amines and carboxylic acids can be used. Some of these are illustrated by the examples herein and include carbodiimides (e.g., dicyclohexylcarbodiimide; diisopropylcarbodiimide; EDC; and the like). If necessary, reaction with the carbodiimide can be facilitated by the presence of an activating agent such as HOBt, HOAt, N-hydroxysuccinimide, or the like. Alternatively, the acid of formula (V) or its salt can be activated by reaction with an activating agent such as HATU, HBTU, BOP, PyBOP, PyBrOP, TBTU, COMU, or TFFH, optionally in the presence of a base such as triethylamine, DIPEA, DMAP, pyridine, and the like, prior to contact with the amine compound of formula (VI). When X represents a leaving group, the leaving group is halo (preferably Cl), or —OC(O)—OR * and R * represents a C1-C6 alkyl optionally substituted with up to three halo or C1-3 alkoxy groups.

[0129] In certain embodiments, the compound of formula (V) is a compound of formula (VB): [ka] (In the formula, R 5 is H or halo; L is -CH-; W is cyclopropyl substituted with -SOR, and R is as defined for formula (V). is.

[0130] Compounds of formula (V) and (VB) described above, and methods of using them to make compounds of the invention, are also aspects of the invention.

[0131] The present invention further includes any variant of the process in which intermediate products obtainable at any stage thereof are used as starting materials to carry out the remaining steps, or in which starting materials are formed in situ under the reaction conditions, or in which reaction components are used in the form of their salts or optically pure substances.

[0132] The present invention also relates to processes in which compounds obtainable as intermediates at any stage of the process are used as starting materials and the remaining process steps are carried out, or starting materials are formed under the reaction conditions or are used in the form of derivatives, for example in protected form or in the form of salts, or compounds obtainable by the process according to the invention are produced under the process conditions and further treated in situ.

[0133] The terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that may exist in a given compound of the present invention, including geometric isomers. It is understood that substituents may be attached at a carbon atom at a chiral center. The term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner. Thus, the present invention includes enantiomers, diastereomers, or racemates of a compound. "Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to refer to a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated as either R or S. Resolved compounds of unknown absolute configuration can be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and can therefore occur as enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry.

[0134] Depending on the selection of starting materials and procedures, the compounds may exist in one form of possible isomers or mixtures thereof, for example, as pure optical isomers, or as isomeric mixtures, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. The present invention is meant 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. When the compounds contain double bonds, the substituents may be in the E- or Z-configuration. When the compounds contain disubstituted cycloalkyl, the cycloalkyl substituents may have cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0135] Any resulting mixture of isomers can be separated on the basis of the physical chemical differences of the components into pure or substantially pure geometric or optical isomers or diastereomers, for example, by chromatography and / or fractional crystallization.

[0136] Any racemic final products or intermediates obtained can be resolved into their optical antipodes by known methods, for example, by separation of their diastereomeric salts, obtained with optically active acids or bases, and liberating the optically active acidic or basic compounds. In particular, basic moieties can thus be used to resolve the compounds of this invention into their optical antipodes by fractional crystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0137] Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or contain other solvents used in their crystallization.The compounds of the present invention naturally or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to encompass both solvated and non-solvated forms.The term "solvate" refers to a molecular complex of the compounds of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules.Such solvent molecules are those commonly used in the pharmaceutical field, known to be harmless to recipients, such as water, ethanol, and the like.The term "hydrate" refers to a complex in which the solvent molecule is water.

[0138] The compounds of the present invention, including their salts, hydrates and solvates, may by nature or design form polymorphs.

[0139] As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention, and typically are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of analogous amino and / or carboxyl groups therein.

[0140] Pharmaceutically acceptable acid addition salts include those of inorganic and organic acids, such as acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, hydrogen sulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorotheophylonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate. , lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

[0141] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0142] Organic acids from which salts can be derived 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, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0143] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly preferred Suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

[0144] 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, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0145] The pharmaceutically acceptable salts of the present invention can be synthesized from basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stereostoichiometric amount of an appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting the free base form of these compounds with a stereostoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, if applicable. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0146] Any formula provided herein is intended to represent unlabeled forms of the compounds of the present invention, with up to three atoms of non-natural isotopic distribution, as well as isotopically labeled forms, such as sites enriched with deuterium, C, or N. Isotopically labeled compounds have the structure shown in the formula provided herein, except that one or more atoms are replaced by atoms with a selected atomic mass or mass number outside the natural abundance mass distribution. Examples of isotopes that can be usefully incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as H, H, C, C, C, N, F, P, P, S, Cl, and I, respectively. The present invention includes various isotopically labeled compounds of the present invention, such as those in which radioactive isotopes such as H and C, or non-radioactive isotopes such as H and C, are present at levels substantially above the normal isotopic distribution. Such isotope-labeled compounds are useful for metabolic studies (e.g., by C), reaction kinetic studies (e.g., by H or H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or for radioactive treatment of patients. In particular, the F-labeled compounds of the present invention may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying examples and preparations, using appropriate isotope-labeled reagents instead of typically used non-labeled reagents. Labeled samples can be useful with very low isotope incorporation, such as when radiolabeling is used to detect trace amounts of compounds.

[0147] Furthermore, more extensive substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), may confer certain therapeutic benefits resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements or improved therapeutic index. In this context, deuterium is considered a substituent of the compounds of the invention, and typically, samples of compounds having deuterium as a substituent have at least 50% deuterium incorporation at the labeled positions. It is understood that the concentration of such a heavier isotope, specifically deuterium, can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope. When a substituent of a compound of the invention denotes deuterium, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0148] Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, eg D2O, d6-acetone, d6-DMSO.

[0149] Compounds of the present invention containing groups capable of acting as hydrogen bond donors and / or acceptors may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of the present invention by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimating, co-melting, or contacting a compound of the present invention with a co-crystal former in solution under crystallization conditions and isolating the co-crystal thereby formed. Suitable co-crystal formers include those described in WO 2004 / 078163. Accordingly, the present invention further provides co-crystals comprising compounds of the present invention.

[0150] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better clarify the invention and does not pose a limitation on the scope of the invention as otherwise claimed.

[0151] The compounds of the present invention can be administered by known methods, including orally, parenterally, inhalation, and the like. In certain embodiments, the compounds of the present invention are administered orally as a pill, lozenge, troche, capsule, solution, or suspension. In other embodiments, the compounds of the present invention are administered by injection or infusion. Infusion is typically administered intravenously, often 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 methods are particularly useful for treating respiratory infections. The compounds of the present invention exhibit oral bioavailability, and therefore, oral administration is sometimes preferred.

[0152] The compounds of the invention can also be used in combination with other agents (combination partners), for example, additional antiviral agents, whether of Formula I or not, for the treatment of viral infections in a subject.

[0153] The term "combination" means either a compound of the present invention and a combination partner independently, simultaneously, or, especially when they can be administered separately within a time interval which allows the combination partners to exhibit a joint action, e.g., a synergistic effect, as separate dosage forms suitable for use together, simultaneously or sequentially, or as a kit-of-parts for combined administration, in a fixed combination in one dosage unit form, or any combination thereof.

[0154] In certain embodiments of the invention, the compounds of the invention are used in combination with a second antiviral agent, such as those named herein.

[0155] The second antiviral agent can be administered in combination with the compound of the present invention, and the second antiviral agent can be administered before, simultaneously or after one or more compounds of the present invention.When simultaneous administration of the compound of the present invention and the second drug is desired and the administration route is the same, the compound of the present invention can be formulated into the same dosage form as the second drug.Examples of dosage forms containing the compound of the present invention and the second drug are tablets or capsules.

[0156] In some embodiments, the combination of a compound of the invention and a second antiviral agent may result in synergistic activity. The compound of the invention and the second antiviral agent may be administered together, separately but simultaneously, or sequentially.

[0157] An "effective amount" of a compound is an amount necessary or sufficient to treat or prevent a viral infection and / or a disease or condition described herein. In one example, an effective amount of a herpesvirus or CMV DNA polymerase inhibitor of Formula I is an amount sufficient to treat a viral infection in a subject. In another example, an effective amount of a DNA polymerase inhibitor is an amount sufficient to treat a viral infection, such as, but not limited to, CMV, VZV, or EBV, in a subject in need of such treatment. The effective amount may vary depending on factors such as the size and weight of the subject, the type of illness, or the particular compound of the present invention. For example, the selection of the compound of the present invention may affect what constitutes an "effective amount." One of ordinary skill in the art would be able to study the factors contained herein and make a determination regarding the effective amount of a compound of the present invention without undue experimentation.

[0158] The dosage regimen can affect what constitutes an effective amount. The compound of the present invention can be administered to a subject either before or after the onset of viral infection. In addition, several divided doses and staggered doses can be administered daily or sequentially, or the dose can be administered by continuous infusion or bolus injection. Furthermore, the dosage of the compound of the present invention can be increased or decreased proportionally as indicated by the exigencies of the treatment or prophylactic situation.

[0159] The compounds of the present invention can be used in the treatment of the conditions, disorders, or diseases described herein, or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases. The present invention provides methods of using the compounds of the present invention in the treatment of these diseases, or for the preparation of pharmaceutical compositions having the compounds of the present invention for the treatment of these diseases.

[0160] The term "pharmaceutical composition" includes preparations suitable for administration to mammals, e.g., humans. When the compounds of the present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given as is or as a pharmaceutical composition containing, as an active ingredient, e.g., 0.1 to 99.5% (more preferably, 0.5 to 90%) of at least one compound of formula (I) or any subgenus thereof in combination with a pharmaceutically acceptable carrier, or optionally two or more pharmaceutically acceptable carriers.

[0161] The phrase "pharmaceutically acceptable carrier" is art-recognized and includes pharmaceutically acceptable materials, compositions, or vehicles suitable for administering the compounds of the present invention to a mammal. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that are involved in carrying or transporting the subject agent from one organ or body part to another. Each carrier should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can serve 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 carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; Pharmaceutically acceptable carriers include 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 glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic compatible substances used in pharmaceutical formulations. Typically, pharmaceutically acceptable carriers are sterile and / or substantially pyrogen-free.

[0162] Wetting agents, emulsifying and lubricating agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents, and preservatives and antioxidants can also be present in the composition.

[0163] Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfite, sodium disulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0164] The formulations of the present invention include those suitable for oral, nasal, inhalation, topical, transdermal, buccal, sublingual, rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical arts. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0165] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with a carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0166] Formulations of the present invention suitable for oral administration may be in the form of capsules, sachets, pills, tablets, lozenges (using a flavored base, for example, usually sucrose and acacia or tragacanth), powder, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as mouthwash and the like, each containing a predetermined amount of a compound of the present invention as the active ingredient. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0167] In the solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; humectants, such as glycerol; agar, calcium carbonate, potato or tapioca starch, alginate, or the like. It is mixed with any of the following disintegrating agents: acids, certain silicates, and sodium carbonate; solution retarders: paraffin; absorption accelerators: quaternary ammonium compounds; wetting agents: cetyl alcohol and glycerol monostearate; absorbents: kaolin and bentonite clay; lubricants: talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and coloring agents.For capsules, tablets, and pills, pharmaceutical compositions may also contain buffering agents.Similar solid compositions can also be used as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol and the like.

[0168] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of moistened powdered compound with an inert liquid diluent in a suitable machine.

[0169] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical arts. They may also be formulated to provide delayed or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to produce the desired release profile. They may be stabilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents, and may be composed to release the active ingredient only, or preferentially, in a delayed manner in a certain part of the gastrointestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be microencapsulated, if appropriate, with one or more of the above-mentioned excipients.

[0170] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form may contain inert diluent commonly used in the art, such as water or other solvent, solubilizer, and emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol and fatty acid ester of sorbitan, and their mixtures.

[0171] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0172] In addition to the active compound, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0173] Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration may be presented as suppositories. These can be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or salicylic acid, which are solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound.

[0174] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0175] The dosage forms for topical or transdermal administration of the compound of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers or propellants that may be required.

[0176] The ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0177] Powders and sprays can contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0178] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the active compound in a polymer matrix or gel.

[0179] Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated as being within the scope of this invention.

[0180] Pharmaceutical compositions of the invention suitable for parenteral administration may contain one or more compounds of the 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 that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0181] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, glycol ether, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0182] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the composition. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0183] In some cases, in order to prolong the effect of drugs, it is desirable to delay the absorption of drugs from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility.The absorption rate of drugs then depends on their dissolution rate, which in turn depends on crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending drugs in oil vehicles.

[0184] Injectable depot forms are prepared by forming microencapsulated matrices of the target compound in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of drug to polymer and the properties of the specific polymer used, the drug release rate can be controlled.Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations can also be prepared by embedding the drug in liposomes or microemulsions that are compatible with body tissues.

[0185] The preparations of the present invention can be administered orally, parenterally, topically or rectally.They are naturally administered in a form suitable for each administration route.For example, they are administered in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc., by injection, infusion or inhalation; topically by lotions or ointments; and rectally by suppositories.

[0186] As used herein, the phrases "parenteral administration" and "parenterally administered" refer to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, epidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Intravenous infusion is sometimes the preferred delivery method 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 an interval of 15 minutes to 4 hours, typically 0.5 to 3 hours. Such infusions may be used once daily, twice daily, or up to three times daily.

[0187] As used herein, the phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" refer to the administration of a compound, drug, or other material other than directly into the central nervous system, e.g., subcutaneous administration, so that it enters the patient's system and is therefore subject to metabolism and other similar processes.

[0188] These compounds may be administered to humans and other animals for treatment by any suitable route of administration, including orally, nasally, e.g., by spray, rectally, vaginally, parenterally, intracisternally, and topically, including buccal and sublingually, by powder, ointment, or drops.

[0189] Regardless of the route of administration selected, the compounds of the present invention and / or pharmaceutical compositions of the present invention, which may be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0190] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0191] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the invention, or ester, salt, or amide thereof, being employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound being employed, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0192] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start with a compound of the present invention used in a pharmaceutical composition at a dose below the level required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0193] In general, a suitable daily dose of a compound of the present invention is that amount of compound that is the lowest effective dose to produce a therapeutic effect. Such an effective dose generally depends on the factors described above. In general, when used for the indicated effects, intravenous and subcutaneous doses of a compound of the present invention to a patient 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 even more preferably from about 0.1 to about 20 mg per kilogram of body weight per day. An effective amount is an amount that prevents or treats a viral infection, such as CMV or another herpes virus.

[0194] If desired, the effective daily dose of the active compound may be administered as a single dose per day, or as two, three, four, five, six, or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. Compounds delivered orally or by inhalation are generally administered in one to four doses per day. Compounds delivered by injection are typically administered once daily or once every other day. Compounds delivered by infusion are typically administered in one to three doses per day. When multiple doses are administered within a single day, the doses may be administered at intervals of about 4 hours, about 6 hours, about 8 hours, or about 12 hours.

[0195] Although the compounds of the present invention can be administered alone, it is preferable to administer the compounds as a pharmaceutical composition, such as those described herein. Thus, methods of using the compounds of the present invention include administering the compounds as a pharmaceutical composition, in which at least one compound of the present invention is mixed with a pharmaceutically acceptable carrier prior to administration.

[0196] Use of Compounds of the Invention in Combination with Immunomodulators

[0197] The compounds and compositions described herein can be used or administered in combination with one or more therapeutic agents that act as immunomodulators, e.g., activators of costimulatory molecules, or inhibitors of immunosuppressive molecules, or vaccines. The 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 signals (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 infections. The interaction between PD-1 and PD-L1 acts 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). Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; this effect is additive when the interaction of PD-1 with PD-L2 is similarly blocked (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66). Immune modulation can be achieved by binding to immunosuppressive proteins (e.g., PD-1) or to proteins that modulate inhibitory proteins (e.g., PD-L1, PD-L2).

[0198] In one embodiment, the combination therapy of the invention includes an immunomodulator that is an inhibitor or antagonist of an inhibitory molecule of an immune checkpoint molecule. In another embodiment, the immunomodulator binds to a protein that normally inhibits an immune checkpoint molecule. When used in combination with an antiviral compound, these immunomodulators can enhance the antiviral response, thus enhancing efficacy compared to treatment with the antiviral compound alone.

[0199] The term "immune checkpoint" refers to a group of molecules on the cell surface of CD4 and CD8 T cells. These molecules can effectively serve as "brakes" that 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. Immunotherapeutic agents that can act as immune checkpoint inhibitors useful in the methods of the present invention include, but are not limited to, inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and / or TGFR beta. Inhibition of inhibitory molecules can be achieved by inhibition at the DNA, RNA, or protein level. In some embodiments, inhibitory nucleic acids (e.g., dsRNA, siRNA, or shRNA) can be used to inhibit the expression of inhibitory molecules. In other embodiments, the inhibitor of an inhibitory signal is a polypeptide, such as a soluble ligand, or an antibody or antigen-binding fragment thereof that binds to the inhibitory molecule.

[0200] "In combination with" is not intended to imply that the therapies or therapeutic agents must be administered simultaneously and / or formulated to be delivered together, although these delivery methods are within the scope described herein. An immunomodulator can be administered simultaneously with, prior to, or subsequent to one or more compounds of the invention, and optionally one or more additional therapies or therapeutic agents. The therapeutic agents in the combination can be administered in any order. Generally, each agent will be administered at a dose and / or time schedule determined for that agent. It will be further recognized that the therapeutic agents utilized in the combination may be administered together in a single composition or separately in different compositions. Generally, it is expected that each of the therapeutic agents utilized in the combination will be utilized at levels that do not exceed the levels utilized individually. In some embodiments, the levels utilized in the combination will be lower than the levels utilized individually.

[0201] In certain 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 can be an antibody, antigen-binding fragment thereof, immunoadhesin, fusion protein, or oligopeptide. Examples of such immunomodulators are known in the art.

[0202] In some embodiments, the immunomodulator is an anti-PD-1 antibody selected from MDX-1106, Merck3475, or CT-011.

[0203] In some embodiments, the immunomodulator is an immunoadhesin (e.g., an immunoadhesin comprising the PD-1-binding portion of PD-L1 or PD-L2 fused to an extracellular or constant region (e.g., an Fc region of an immunoglobulin sequence).

[0204] In some embodiments, the immunomodulator is a PD-1 inhibitor, such as AMP-224.

[0205] In some embodiments, the immunomodulatory agent is a PD-Ll inhibitor, such as an anti-PD-Ll antibody.

[0206] In some embodiments, the immunomodulatory agent is an anti-PD-Ll 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-Ll antibody described in WO2007 / 005874. Antibody YW243.55.S70 is an anti-PD-Ll antibody described in WO2010 / 077634.

[0207] In some embodiments, the immunomodulator is nivolumab (CAS Registry Number: 946414-94-4). Other 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 human monoclonal antibodies that specifically bind to PD-1 are disclosed in US8,008,449, EP2161336, and WO2006 / 121168.

[0208] In some embodiments, the immunomodulator is the anti-PD-1 antibody pembrolizumab. Pembrolizumab (also known as lambrolizumab, MK-3475, MK03475, SCH-900475, or KEYTRUDA®; Merck) is a humanized IgG4 monoclonal antibody that binds to PD-1. Pembrolizumab and other humanized anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, US8,354,509, WO2009 / 114335, and WO2013 / 079174.

[0209] In some embodiments, the immunomodulator is pidilizumab (CT-011; Cure Tech), a humanized IgG1k monoclonal antibody that binds to PD1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO2009 / 101611.

[0210] Other anti-PD1 antibodies useful as immunomodulators for use in the methods disclosed herein include AMP514 (Amplimmune) and the anti-PD1 antibodies disclosed in US8,609,089, 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.

[0211] In some embodiments, the immunomodulator is MDPL3280A (Genentech / Roche), a human Fc-optimized IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies to PD-L1 are disclosed in U.S. Patent No. 7,943,743 and U.S. Patent Publication No. 20120039906. Other anti-PD-L1 binding agents useful as immunomodulators for the methods of the invention include YW243.55.S70 (see WO2010 / 077634), MDX-1105 (also known as BMS-936559), and the anti-PD-L1 binding agents disclosed in WO2007 / 005874.

[0212] In some embodiments, the immunomodulator is AMP-224 (B7-DCIg; Amplimmune; disclosed, for example, in WO2010 / 027827 and WO2011 / 066342), a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1.

[0213] In some embodiments, the immunomodulator is an anti-LAG-3 antibody, such as BMS-986016. BMS-986016 (also referred to 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, WO2010 / 019570, and WO2014 / 008218.

[0214] In certain embodiments, the combination therapies disclosed herein include modulators of costimulatory or inhibitory molecules, e.g., co-inhibitory ligands or receptors.

[0215] In one embodiment, the costimulatory modulator, e.g., agonist, of a costimulatory molecule is selected from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion) of 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 ligand.

[0216] In another embodiment, the combination therapy disclosed herein includes an immunomodulatory agent that is an agonist associated with a positive signal involving a costimulatory domain of a costimulatory molecule, e.g., CD28, CD27, ICOS, and / or GITR.

[0217] Exemplary GITR agonists include, for example, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Pat. No. 6,111,090, European Patent No. 090505B1, U.S. Pat. No. 8,586,023, PCT Publication Nos. WO 2010 / 003118 and 2011 / 090754, or those described in, for example, U.S. Pat. No. 7,025,962, European Patent No. 1947183B1, U.S. Pat. No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat. No. 8,591,886, European Patent No. EP 186633. 9, PCT Publication No. WO2011 / 028683, PCT Publication No. WO2013 / 039954, PCT Publication No. WO2005 / 007190, PCT Publication No. WO2007 / 133822, PCT Publication No. WO2005 / 055808, PCT Publication No. WO99 / 40196, PCT Publication No. WO2001 / 03720, PCT Publication No. WO99 / 20758, PCT Publication No. WO2006 / 083289, PCT Publication No. WO2005 / 115451, U.S. Patent No. 7,618,632, and PCT Publication No. WO2011 / 051726.

[0218] In one embodiment, the immunomodulator used is a soluble ligand (e.g., CTLA-4-Ig), or an antibody or antibody fragment that binds to PD-L1, PD-L2, or CTLA4. For example, an anti-PD-1 antibody molecule can be used, e.g., an anti-CTLA-4 antibody, e.g., It can be administered in combination with ipilimumab. Exemplary anti-CTLA4 antibodies include tremelimumab (formerly known as ticilimumab, an IgG2 monoclonal antibody available from Pfizer, CP-675,206); and ipilimumab (a CTLA-4 antibody, also known as MDX-010, CAS number 477202-00-9).

[0219] In one embodiment, the anti-PD-1 antibody molecule is administered after treatment with a compound of the invention described herein.

[0220] In another embodiment, the anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody, or 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 antigen-binding fragment thereof. In yet 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 antigen-binding fragment thereof. The antibody combinations referred to herein can be administered separately, e.g., as separate antibodies, or linked, e.g., as a bispecific or trispecific antibody molecule. In one embodiment, a bispecific antibody, or antigen-binding fragment thereof, comprising an anti-PD-1 or PD-L1 antibody molecule and an anti-TIM-3 or anti-LAG-3 antibody is administered. In certain embodiments, the antibody combinations referred to herein are used to treat cancer, such as a cancer described herein (e.g., a solid tumor). The efficacy of the aforementioned combinations can be tested in animal models known in the art. For example, animal models for testing the synergistic effects of anti-PD-1 and anti-LAG-3 are described, for example, in Woo et al. (2012) Cancer Res. 72(4):917-27).

[0221] Exemplary immunomodulators that may be used in combination therapy include, but are not limited to, afutuzumab (available from Roche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimid (CC4047); and cytokines, such as IL-21 or IRX-2 (a mixture of human cytokines including interleukin-1, interleukin-2, and interferon-gamma, CAS951209-71-5, available from IRX Therapeutics).

[0222] Exemplary doses of such immunomodulators that may be used in combination with the antiviral compounds of the invention include a dose of about 1-10 mg / kg, e.g., 3 mg / kg, of the anti-PD-1 antibody molecule, and a dose of about 3 mg / kg of the anti-CTLA-4 antibody, e.g., ipilimumab.

[0223] Examples of embodiments of methods of using the antiviral compounds of the invention in combination with immunomodulators include the following, which may be used with the compounds of Formula I, or any subgenus or species thereof, disclosed herein:

[0224] i. A method of treating a viral infection in a subject, comprising administering to the subject a compound of formula (I) described herein and an immunomodulatory agent.

[0225] ii. The method of embodiment i, wherein the immunomodulatory agent is an activator of a costimulatory molecule or an inhibitor of an immune checkpoint molecule.

[0226] iii. Activators of costimulatory molecules include OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, The method of either embodiment i or ii, wherein the antibody is an agonist of one or more of NKG2C, SLAMF7, NKp80, CD160, B7-H3 and CD83 ligand.

[0227] iv. The method of any of embodiments i-iii above, wherein the inhibitor of an immune checkpoint molecule is selected from PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and TGFR beta.

[0228] v. The method of any of embodiments i-iii, wherein the inhibitor of an immune checkpoint molecule is selected from an inhibitor of PD-1, PD-L1, LAG-3, TIM-3 or CTLA4, or any combination thereof.

[0229] vi. The method of any of embodiments i-v, wherein the inhibitor of the immune checkpoint molecule is a soluble ligand, or an antibody or antigen-binding fragment thereof that binds to the immune checkpoint molecule.

[0230] vii. The method of any of embodiments i-vi, wherein the antibody or antigen-binding fragment thereof is from IgG1 or IgG4 (e.g., human IgG1 or IgG4).

[0231] viii. The method of any of embodiments i-vii, wherein the antibody or antigen-binding fragment thereof has been altered, e.g., mutated, to increase or decrease one or more of Fc receptor binding, antibody glycosylation, the number of cysteine ​​residues, effector cell function, or complement function.

[0232] ix. The method of any of embodiments i-viii, wherein the antibody molecule is a bispecific or multispecific antibody molecule having a first binding specificity to PD-1 or PD-L1, and a second binding specificity to TIM-3, LAG-3, or PD-L2.

[0233] x. The method of any of embodiments i-ix, wherein the immunomodulator is an anti-PD-1 antibody selected from nivolumab, pembrolizumab, or pidilizumab.

[0234] xi. The method of any of embodiments i-x, wherein the immunomodulator is an anti-PD-L1 antibody selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.

[0235] xii. The method of any of embodiments i-x, wherein the immunomodulator is an anti-LAG-3 antibody molecule.

[0236] xiii. The method of embodiment xii, wherein the anti-LAG-3 antibody molecule is BMS-986016.

[0237] xiv. The method of any of embodiments i-x, wherein the immunomodulatory agent is an anti-PD-1 antibody molecule administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1-30 mg / kg, e.g., about 5-25 mg / kg, about 10-20 mg / kg, about 1-5 mg / kg, or about 3 mg / kg, e.g., once weekly to once every 2, 3, or 4 weeks.

[0238] xv. The method of embodiment xiv, wherein the anti-PD-1 antibody molecule is administered at a dose of about 10-20 mg / kg every other week.

[0239] xvi. The method of embodiment xv, wherein the anti-PD-1 antibody molecule, e.g., nivolumab, is administered intravenously every two weeks at a dose of about 1 mg / kg to 3 mg / kg, e.g., about 1 mg / kg, 2 mg / kg, or 3 mg / kg.

[0240] xvii. The method of embodiment xv, wherein the anti-PD-1 antibody molecule, e.g., nivolumab, is administered intravenously at a dose of about 2 mg / kg every 3 weeks.

[0241] General synthetic procedure

[0242] The compounds described herein can be synthesized by the following general synthetic routes, specific examples of which are described in more detail in the Examples.

[0243] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to those skilled in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). List of abbreviations Ac Acetyl ACN or MeCN acetonitrile AcOEt / EtOAc ethyl acetate AcOH acetic acid aq water-based Bn Benzyl Bu butyl (nBu = n-butyl, tBu = tert-butyl) CDI Carbonyldiimidazole CH3CN Acetonitrile DBU 1,8-diazabicyclo[5.4.0]undec-7-ene Boc2O di-tert-butyl dicarbonate DCE 1,2-dichloroethane DCM dichloromethane DIAD Diisopropyl azodicarboxylate DiBAl-H Diisobutylaluminum hydride DIPEA or DIEA N-Ethyldiisopropylamine DMA N,N-dimethylacetamide DMAP dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EI electrospray ionization Et2O diethyl ether Et3N Triethylamine Ether diethyl ether EtOAc ethyl acetate EtOH ethanol FC flash chromatography h time HATU O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate HBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl Thiuronium Hexafluorophosphate HCl Hydrochloric acid HMPA Hexamethylphosphoramide HOBt 1-hydroxybenzotriazole HPLC High Performance Liquid Chromatography H2O Water IPA Isopropanol L liters LC-MS Liquid Chromatography Mass Spectrometry LiHMDS Lithium bis(trimethylsilyl)amide MgSO4 Magnesium Sulfate Me methyl MeI iodomethane MeOH Methanol mg milligram min mL milliliter MS mass spectrometry MsCl methanesulfonyl chloride NaHCO3 Sodium bicarbonate Na2SO4 Sodium Sulfate NH2OH Hydroxyamine Pd / C Palladium on carbon Pd(OH)2 palladium hydroxide PG protecting group Ph Phenyl Ph3P Triphenylphosphine Prep Rf Front Ratio RP reverse phase Rt retention time RT room temperature SFC Supercritical Fluid Chromatography SiO2 Silica Gel SOCl2 Thionyl chloride T3P® Propylphosphonic Anhydride TBAF Tetrabutylammonium Fluoride TBDMS t-butyldimethylsilyl TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TsCl Toluenesulfonyl chloride TsOH Toluenesulfonic acid

[0244] The compounds of the present invention are prepared from generally available compounds using procedures known to those skilled in the art in light of the examples and schemes provided herein.

[0245] Within the scope of this document, unless the context indicates otherwise, only easily removable groups that are not constituents of a particular desired end product of the compound of the present invention are designated as "protecting groups". The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions can be found in standard reference texts such as, for example, Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp. (URL: http: / / www.science-of-synthesis.com (Electronic Version, 48 Volumes)); JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999, “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, “Methoden der Organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be easily removed (i.e., without undesired secondary reactions), for example, by solvolysis, reduction, photolysis, or alternatively under physiological conditions (e.g., by enzymatic cleavage).

[0246] Salts of the compounds of the present invention having at least one salt-forming group can be prepared by methods known per se. For example, salts of the compounds of the present invention having an acid group can be formed by treating the compounds with metal compounds such as alkali metal salts of suitable organic carboxylic acids, for example, sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates, or bicarbonates, for example, sodium or potassium hydroxide, sodium or potassium carbonate, or sodium or potassium bicarbonate, with the corresponding calcium compounds, or with ammonia or a suitable organic amine, preferably using a stoichiometric amount or only a slight excess of the salt-forming agent. Acid addition salts of the compounds of the present invention can be obtained by conventional methods, for example, by treating the compounds with an acid or a suitable anion exchange reagent. Internal salts of the compounds of the present invention containing acidic and basic salt-forming groups, for example, free carboxy groups and free amino groups, can be formed, for example, by neutralizing salts such as acid addition salts to the isoelectric point, for example, with a weak base or by treatment with an ion exchanger.

[0247] Salts can be converted into the free compounds in the conventional manner; metal and ammonium salts can be converted, for example, by treatment with a suitable acid, and acid addition salts, for example, by treatment with a suitable basic agent.

[0248] The mixtures of isomers obtainable according to the present invention can be separated into the individual isomers in a manner known per se; diastereomers can be separated, for example, by partition between polyphasic solvent mixtures, recrystallization and / or chromatographic separation, for example on silica gel or by medium pressure liquid chromatography, for example on reversed-phase columns, and racemates can be separated, for example, by salt formation with an optically pure salt-forming reagent and separation of the diastereomeric mixtures thus obtainable, for example, by fractional crystallization or by chromatography on optically active column materials.

[0249] Intermediates and final products can be worked up and / or purified according to standard methods, for example using chromatographic methods, distribution methods, (re-)crystallization and the like. [Example]

[0250] The present invention is further illustrated by the following examples, which should not be construed as limiting. The assays used throughout the examples are well established in the art, and demonstration of efficacy of these assays is generally considered predictive of efficacy in subjects.

[0251] The compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art with reference to the following reaction schemes and examples: General methods for the synthesis of compounds of formula (I) are provided below in Schemes I-III.

[0252] Scheme I. General Method for the Synthesis of Compounds of Formula (I) [ka]

[0253] Scheme I shows a general method for synthesizing many compounds of Formula (I) from intermediates described herein. Bicyclic intermediates (e.g., intermediate I-1), especially when L is attached through -CH2-, can be N-alkylated and attached to the desired WL-moiety. WLX represents an alkylating agent suitable for such a reaction, where X is a leaving group such as halo (preferably Br or I), or a sulfonate leaving group such as mesylate, tosylate, or triflate. The WL-moiety may, of course, contain functional groups such as hydroxyl or amine groups, preferably in protected form, which may be further modified in the product of Formula (I), and which may be deprotected and further derivatized using methods well known in the art.

[0254] R can be a simple alkyl ester such as methyl, ethyl, propyl, isopropyl, t-butyl, or n-butyl; if WL- contains an ester, R can be a different ester that can be easily distinguished from that of WL-, such as benzyl, so that R can be selectively hydrolyzed for the coupling reaction of Scheme I. In some of these examples, R is an ester that hydrolyzes under the alkylation reaction conditions, perhaps due to the adventitious presence of moisture or hydroxide; in other examples, a separate hydrolysis step is used, such as the addition of lithium, sodium, or potassium hydroxide and water. The resulting free carboxylate compound is then readily coupled to a suitable amine containing the desired Cy group using standard amide bond forming conditions and reagents well known in the art. This can be direct amidation of the carboxylate, as known in the art and exemplified by the accompanying examples, or can be accomplished by converting the carboxylic acid to an activated intermediate (acyl chloride, acyl anhydride, etc.).

[0255] Scheme II. Alternative Preparation of Compounds of Formula (I) [ka]

[0256] Scheme II shows an alternative synthesis of compounds of Formula I, exemplified by Example 51 below. This synthetic scheme begins with an intermediate prepared as described herein (see, e.g., I-17 below) and uses an amine to introduce the desired WL-moiety by ring-opening the lactone. The first intermediate shown contains a free primary hydroxyl group, which is easily converted to a leaving group (Cl in the example, but an alkylsulfonate or arylsulfonate can be used instead). Under basic conditions (e.g., NaH), the leaving group easily shifts position to form a new six-membered ring to which the desired WL-moiety is attached. As with Scheme I, the introduced WL-moiety may optionally contain a protected functional group, which may be subsequently modified if desired. For example, Example 51 has a thioether at the WL-group, and the sulfur atom is oxidized to provide the desired sulfone.

[0257] Scheme III. Further synthetic routes to compounds of formula I. [ka]

[0258] Scheme III illustrates the synthesis of carboxy- Another method for preparing compounds of formula (I) is provided, starting with a pyridone derivative. The starting material is prepared as described herein (e.g., I-17C) and coupled to a hydroxyethyl-substituted amine derivative by conventional methods, and the amine nitrogen is attached to the desired WL-moiety. After coupling, the free hydroxyl is converted to a leaving group such as Cl or mesylate, and then cyclized onto the pyridone ring nitrogen under basic conditions; alternatively, coupling can be achieved under typical Mitsunobu conditions (e.g., treatment with triphenylphosphine and DIAD). Again, the WL-moiety may contain functional groups, optionally in protected form, which can then be used to further modify or derivatize the WL-moiety to provide the desired target compound.

[0259] Those skilled in the art can readily prepare a variety of compounds of Formula I using these methods, along with further extensions, modifications and variations as illustrated by the following examples. Preparation of key intermediates Intermediate 1 Butyl 1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylate [ka]

[0260] Butyl 6-(dibutoxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (I-1B). 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) was added TsOH·HO (0.446 g, 2.345 mmol). The resulting mixture was stirred at 110 °C overnight, after which it was cooled to RT and concentrated under reduced pressure. I-1B was isolated as a dark red oil and as a mixture of Bu / Bu and Me / Bu acetals. LCMS m / z: 312 (M+1) OBu / OMe, 354 (M+1) OBu / OBu.

[0261] 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). To the acidic solution, HO (10 mL) was added. The resulting solution was stirred at RT for 5 h, after which it was concentrated under reduced pressure. The dark residue was dissolved in DCM and washed with HO 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 foam. LCMS m / z: 224 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 0.95 - 1.03 (m, 3 H) 1.48 (dq, J=15.01, 7.43 Hz, 2 H) 1.73 - 1.84 (m, 2 H) 4.42 (t, J=6. 65 Hz, 2 H) 7.44 (br. s.,1 H) 8.35 (d, J=7.53 Hz, 1 H) 9.90 (br. s., 1 H).

[0262] 5-(Butoxycarbonyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (I-1D). To a cooled (0 °C) solution of I-1C (3.53 g, 15.81 mmol) in t-BuOH (85 mL) / HO (85 mL) was added 2-methyl-2-butene (50.3 mL, 474 mmol), followed by NaHPO·HO (3.27 g, 23.72 mmol) and NaClO (2.145 g, 23.72 mmol). After 2.5 h, the reaction mixture was diluted with CHCl and 2 M HCl. The phases were separated, and the aqueous layer was extracted with CHCl. ​​The organic extract was dried over sodium sulfate and concentrated under reduced pressure. The tan solid was triturated with EtO and heptane. The resulting precipitate was collected by vacuum filtration and dried on a frit. I-1D was isolated as a tan solid. LCMS m / z: 240 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.38 Hz, 3 H) 1.40 (dq, J=14.91, 7.40 Hz, 2 H) 1.59 - 1.68 (m, 2 H) 4.20 (t, J=6.50 Hz, 2 H) 7.00(br. s., 1 H) 8.06 (d, J=7.24 Hz, 1 H).

[0263] Butyl 6-((2-chloroethyl)carbamoyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (I-1E). To a solution of I-1D (1.47 g, 6.14 mmol) in DCM (75 mL) was added DIEA (2.146 mL, 12.29 mmol), followed by TMSCl (1.571 mL, 12.29 mmol). The resulting solution was stirred at RT for 1.5 h. The reaction mixture was cooled to 0 °C, and SOCl (0.942 mL, 12.90 mmol) was added slowly. The resulting mixture was allowed to warm to RT over the course of 2.5 h. The reaction was cooled to 0 °C, and 2-chloroethanamine HCl (2.85 g, 24.58 mmol) was added, followed by the slow addition of DIEA (5.37 mL, 30.7 mmol). Upon addition of the base, the yellow mixture became extremely 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 was isolated as a dark oil. LCMS m / z: 301 (M+1).

[0264] Butyl 1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylate (I-1). To a solution of I-1E (0.767 g, 2.55 mmol) in ACN (51.0 mL) was added DIEA (2.227 mL, 12.75 mmol). The resulting mixture was stirred at 90 °C. After consumption of the starting material, the reaction mixture was cooled to RT 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 (400 MHz, CDCl3) δ ppm 0.96 (t, J=7.38 Hz, 3 H) 1.46 (dq, J=15.03, 7.43 Hz, 2 H) 1.69 - 1.79 (m, 2 H) 3.63 - 3.73 (m, 2 H) 4.29 - 4.37 (m, 4H) 6.46 (br. s., 1 H) 7.17 (d, J=7.39 Hz, 1 H) 8.15 (d, J=7.39 Hz, 1 H). Intermediate 2 (1-(cyclopropylsulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0265] Benzyl 2-(cyclopropylsulfonyl)acetate (I-2B). To a slurry of sodium cyclopropanesulfinate (5.79 g, 45.2 mmol) in DMF (30 mL) was added benzyl 2-bromoacetate (5.97 mL, 37.7 mmol). The resulting mixture was stirred at RT overnight and then diluted with HO and EtO. The aqueous layer was extracted with EtO. The combined EtO 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 light yellow oil. 1 H NMR (400 MHz, CDCl3) δ ppm 1.02 - 1.09 (m, 2 H) 1.24 - 1.31 (m, 2 H) 2.67 - 2.76 (m, 1 H) 4.03 - 4.09 (m, 2 H) 5.26 (s, 2 H) 7.34 - 7.44 (m, 5 H).

[0266] Benzyl 1-(cyclopropylsulfonyl)cyclopropanecarboxylate (I-2C). To a solution of I-2B (9.37 g, 36.8 mmol) in DMF (350 mL) was added KCO (10.18 g, 73.7 mmol), followed by 1,2-dibromoethane (3.81 mL, 44.2 mmol). The resulting mixture was stirred at 60 °C for 12 h, after which it was cooled to RT and diluted with EtO. The resulting insoluble material was filtered off. The filtrate was washed with water. The aqueous layer was extracted with EtO. The combined ether extracts were washed with brine and concentrated under reduced pressure. The oil was purified by column chromatography (SiO, 0–100% DCM / heptane) to afford I-2C as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 0.95 - 1.01 (m, 2 H) 1.20 - 1.25 (m, 2 H) 1.63 - 1.68 (m, 2 H) 1.72 - 1.78 (m, 2 H) 3.00 (tt, J=8.09, 4.90 Hz, 1 H) 5.22 - 5.26 (m, 2 H) 7.32 - 7.41 (m, 5 H).

[0267] (1-(Cyclopropylsulfonyl)cyclopropyl)methanol (I-2D). To a solution of I-2C (6.53 g, 23.29 mmol) in THF (50 mL) was added LiBH (2 M in THF, 11.65 mL, 23.29 mmol). The resulting yellow solution was stirred at RT overnight. The reaction was quenched by adding the reaction mixture to a 2 M 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 (SiO, 0–100% EtOAc / heptane) to afford I-2D as a colorless oil. LCMS m / z: 177 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.01 - 1.10 (m, 4 H) 1.23 - 1.29 (m, 2 H) 1.47 - 1.52 (m, 2 H) 2.50 - 2.59 (m, 2 H) 3.92 (d, J=6.11 Hz, 2 H).

[0268] (1-(Cyclopropylsulfonyl)cyclopropyl)methyl methanesulfonate (I-2). To a solution of I-2D (3.7 g, 20.99 mmol) in DCM (40 mL) was added DIEA (7.33 mL, 42.0 mmol) and MsCl (1.800 mL, 23.09 mmol). The reaction color 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 give the title compound (I-2) as an amber oil. 1 H NMR (400 MHz, CDCl3) δ ppm 1.06 - 1.13 (m, 2 H) 1.18 - 1.23 (m, 2 H) 1.23 - 1.29 (m, 2 H) 1.61 - 1.67 (m, 2 H) 2.50 - 2.59 (m, 1 H) 3.09 (s, 3 H) 4.54 (s, 2 H). Intermediate 3 (1-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0269] Ethyl 2-((4-oxobutan-2-yl)thio)acetate (I-3B). To a solution of I-3A (0.909 mL, 8.32 mmol) in DCM (20 mL) was added NEt3 (1.160 mL, 8.32 mmol), followed by crotonaldehyde cis & trans (0.689 mL, 8.32 mmol). The resulting mixture was stirred at RT for approximately 1 h. The reaction was 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 isolated as a colorless oil. LCMS m / z: 191 (M+1). 1H NMR (500 MHz, CDCl3) δ ppm 1.29 (t, J=7.25 Hz, 3 H) 1.38 (d, J=6.94 Hz, 3 H) 2.63 (dt, J=7.25, 1.58 Hz, 1 H) 2.76 (dquin, J=6.46, 1.73, 1.73, 1.73, 1.73 Hz, 1 H) 3.27 - 3.30 (m, 2 H) 3.47 (d, J=6.94 Hz, 1 H) 4.15 - 4.25 (m, 3 H) 9.75 - 9.78 (m, 1 H).

[0270] Ethyl 2-((4-hydroxybutan-2-yl)thio)acetate (I-3C). To a cooled (0 °C) solution of I-3B (1.47 g, 7.73 mmol) in THF (25 mL) was added NaBH4 (0.146 g, 3.86 mmol). The resulting mixture was stirred at RT for about 1.5 h, after which it was 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 isolated as a colorless oil. LCMS m / z: 193 (M+1).

[0271] Ethyl 2-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl )thio)acetate (I-3D). To a solution of I-3C (1.35 g, 7.02 mmol) in DCM (25 mL) was added imidazole (0.956 g, 14.04 mmol), followed by TBSCl (1.164 g, 7.72 mmol). The resulting mixture was stirred at RT. Upon completion of the reaction, 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 isolated as a colorless oil. LCMS m / z: 307 (M+1).

[0272] Ethyl 2-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)sulfonyl)acetate (I-3E). To a solution of I-3D (2 g, 6.52 mmol) in DCM (50 mL) was added mCPBA (2.92 g, 13.05 mmol). After stirring at RT overnight, the reaction mixture was diluted with DCM and filtered through a plug of Celite. 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 (SiO, 0–50% EtOAc / heptane) to afford I-3E as a colorless oil. LCMS m / z: 339 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 0.07 (s, 6 H) 0.90 (s, 9 H) 1.33 (t, J=7.14 Hz, 3 H) 1.45 (d, J=6.90 Hz, 3 H) 1.70 (ddt, J=14.02, 9.38, 4.76, 4.76 Hz, 1 H) 2.25 - 2.36 (m, 1 H) 3.59 - 3.69 (m, 1 H) 3.73 (ddd, J=10.42, 8.66, 4.55 Hz, 1H) 3.83 (dt, J=10.48, 5.30 Hz, 1 H) 3.98 (td, J=14.04, 5.92 Hz, 2 H) 4.28 (q, J=7.14 Hz, 2 H).

[0273] Ethyl 1-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)sulfonyl)cyclopropanecarboxylate (I-3F) was prepared from I-3E following a procedure similar to that described for I-2C. I-3F was isolated as a dark orange oil. LCMS m / z: 365 (M+1).

[0274] (1-((4-((tert-Butyldimethylsilyl)oxy)butan-2-yl)sulfonyl)cyclopropyl)methanol (I-3G) was prepared from I-3F following a procedure similar to that described for I-2D. I-3G was isolated as a colorless oil. LCMS m / z: 323 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 0.08 (s, 6 H) 0.90 (s, 9 H) 1.05 (td, J=5.09, 1.47 Hz, 2 H) 1.42 (d, J=6.85 Hz, 3 H) 1.50 (td, J=5.28, 1.96 Hz, 2 H) 1.58 - 1.64 (m, 1 H) 2.37 (dd, J=8.80, 5.04 Hz, 1 H) 2.63 (t, J=5.72 Hz, 1 H) 3.62 - 3.73 (m, 2 H) 3.83 (dt, J=10.27, 5.09 Hz, 1 H) 3.88 (d, J=5.48 Hz, 2 H).

[0275] (1-((4-((tert-Butyldimethylsilyl)oxy)butan-2-yl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-3) was prepared from I-3G following a procedure similar to that described for I-2. I-3 was isolated as an orange oil. LCMS m / z: 401 (M+1). Intermediate 4 (1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0276] Butyl 1-((benzyloxy)methyl)cyclopropane-1-sulfonate (I-4B). A solution of I-4A (4.28 mL, 28.1 mmol) in THF (200 mL) was cooled to -78 °C. 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 allowed to warm to RT overnight. The reaction mixture was cooled to 0 °C and quenched with HO. 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 afford the title compound (I-4B) as a colorless oil. LCMS m / z: 299 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 0.86 - 0.92 (m, 3 H) 1.08 - 1.13 (m, 2 H) 1.37 (dq, J=15.00, 7.44 Hz, 2 H) 1.46 - 1.51 (m, 2 H) 1.61 - 1.71 (m,2 H) 3.79 (s, 2 H) 4.23 (t, J=6.60 Hz, 2 H) 4.55 (s, 2 H) 7.26 - 7.38 (m, 5 H).

[0277] 1-((benzyloxy)methyl)cyclopropane-1-sulfonic acid (I-4C). To a solution of I-4B (6.14 g, 20.58 mmol) in DME (100 mL) / HO (100 mL) was added potassium thiocyanate (2.1 g, 21.61 mmol). The resulting mixture was stirred at reflux overnight, after which it was cooled to RT and diluted with HO 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 (400 MHz, DMSO-d6) δ ppm 0.57 - 0.61 (m, 2 H) 0.78 - 0.83 (m, 2 H) 3.73 (s, 2 H) 4.45 (s, 2 H) 7.21 - 7.36 (m, 5 H).

[0278] 1-((benzyloxy)methyl)cyclopropane-1-sulfonyl chloride (I-4D). To a mixture of I-4C (5.7 g, 20.26 mmol) in DMF (5.5 mL) was added SOCl2 (55 mL, 754 mmol). The resulting mixture was stirred at 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 was isolated as an orange oil. 1 H NMR (400 MHz, CDCl3) δ ppm 1.37 - 1.43 (m, 2 H) 1.76 - 1.82 (m, 2 H) 4.00 (s, 2 H) 4.61 (s, 2 H) 7. 27 - 7.40 (m, 5 H).

[0279] (((1-hydrosulfonylcyclopropyl)methoxy)methyl)benzene sodium salt (I-4E). To a solution of sodium sulfite (3.48 g, 27.6 mmol) in H2O (15 mL) was added NaHCO3 (4.64 g, 55.2 mmol). The resulting mixture was stirred at 50 °C for about 45 minutes, after which I-4D (7.2 g, 27.6 mmol) was added. The resulting mixture was stirred at 50 °C overnight and then concentrated under reduced pressure. The tan residue was triturated with MeOH. The insoluble material was filtered off and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. I-4E was isolated as a tan solid. LCMS m / z: 277 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.22 (d, J=2.54 Hz, 2 H) 0.62 (d, J=2.49 Hz, 2 H) 3.62 (s, 2 H) 4.44 (s, 2 H) 7.29 (d, J=1.91 Hz, 5 H).

[0280] Ethyl 2-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)acetate (I-4F). To a slurry of I-4E (6.6 g, 26.6 mmol) in DMF (25 mL) was added ethyl bromoacetate (2.96 mL, 26.6 mmol). The resulting mixture was stirred at RT overnight and then diluted with EtO. The insoluble material was filtered off and the filtrate was washed with brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. I-4F was isolated as an orange oil. LCMS m / z: 313 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 0.98 - 1.03 (m, 2 H) 1.30 (t, J=1.00 Hz, 3 H) 1.57 - 1.63 (m, 2 H) 3.78 (s, 2 H) 4.20 - 4.27 (m, 2 H) 4.28 (s, 2H) 4.57 (s, 2H) 7.27 - 7.40 (m, 5H)

[0281] Ethyl 1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropanecarboxylate (I-4G) was prepared from I-4F following a procedure similar to that described for I-2C. I-4G was isolated as a light yellow oil. LCMS m / z: 339 (M+1). 1 H NMR (400 MHz, CDCl3) δppm 1.05 - 1.10 (m, 2 H) 1.23 (t, J=7.19 Hz, 3 H) 1.57 - 1.63 (m, 2 H) 1.71 - 1.77 (m, 2 H) 1.78 - 1.84 (m, 2 H)3.71 (s, 2 H) 4.13 (q, J=7.11 Hz, 2 H) 4.48 (s, 2 H) 7.26 - 7.38 (m, 5 H).

[0282] (1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (I-4H) was prepared from I-4G following a procedure similar to that described for I-2D. I-4H was isolated as a colorless oil that solidified in vacuo overnight. LCMS m / z: 297 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 0.95 - 1.01 (m, 2 H) 1.05 - 1.11 (m, 2 H) 1.48 - 1.55 (m, 2 H) 1.62 - 1.70 (m, 2 H) 3.47 (t, J=5.65 Hz, 1 H)3.75 (s, 2 H) 3.83 (d, J=5.67 Hz, 2 H) 4.56 (s, 2 H) 7.29 - 7.43 (m, 5 H).

[0283] (1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-4) was prepared from I-4G following a procedure similar to that described for I-2. I-4 was isolated as an orange oil. 1 H NMR (400 MHz, CDCl3) δ ppm 1.06 - 1.13 (m, 4 H) 1.57 - 1.66 (m, 4 H) 3.00 (s, 3 H) 3.75 (s, 2 H) 4.51 (s, 2 H) 4.53 (s, 2 H) 7.27 - 7.40 (m, 5H). Intermediate 5 (1-((1-(fluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0284] (((1-((1-(fluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (I-5B). To a solution of I-4 (0.315 g, 0.841 mmol) in THF (0.5 mL) / iPrOH (1 mL) was added CsF (0.192 g, 1.262 mmol). The resulting mixture was heated to 100 °C. After 72 h, the reaction mixture was cooled to RT and diluted with EtO. The insoluble material was filtered off through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO, 0–50% EtOAc / heptane) to afford I-5B as a colorless oil. LCMS m / z: 299 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.01 - 1.07 (m, 2 H) 1.07 - 1.12 (m, 2 H) 1.54 - 1.63 (m, 4 H) 3.79 (s, 2 H) 4.53 (s, 2 H) 4.58 (d, J=48.86 Hz, 1H) 7.27 - 7.39 (m, 5H).

[0285] (1-((1-(fluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (I-5C). To a solution of I-5B (0.166 g, 0.556 mmol) in AcOH was added Pd / C (5.92 mg, 5.56 μmol). The atmosphere was exchanged for H. After completion of the reaction, the mixture was filtered through an Acros filter disc. The filtrate was concentrated under reduced pressure to give I-5C as an off-white semi-solid. LCMS m / z: 209 (M+1).

[0286] (1-((1-(fluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-5) was prepared from I-5C following a procedure similar to that described for I-2. I-5 was isolated as a yellow oil. LCMS m / z: 287 (M+1). Intermediate 6 (1-((1-(methoxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0287] (((1-((1-(methoxymethyl)cyclopropyl)sulfonyl)cyclopropyl )Methoxy)methyl)benzene (I-6A). To a solution of I-4H (0.25 g, 0.844 mmol) in THF (3 mL) was added NaH (60% suspension in mineral oil, 0.037 g, 0.928 mmol), followed by MeI (0.053 mL, 0.852 mmol). The resulting mixture was stirred at RT overnight. 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 was isolated as a yellow oil. LCMS m / z: 311 (M+1). 1 H NMR (500 MHz, CDCl3) δ ppm 0.98 - 1.02 (m, 2 H) 1.06 - 1.11 (m, 2 H) 1.48 - 1.52 (m, 2 H) 1.53 - 1.57 (m, 2 H) 3.32 (s, 3 H) 3.72 (s, 2 H) 3.83 (s, 2 H) 4.55 (s, 2 H) 7.30 - 7.40 (m, 5 H).

[0288] (1-((1-(methoxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (I-6B) was prepared from I-6A following a procedure similar to that described for I-5C. I-6B was isolated as a yellow oil. LCMS m / z: 211 (M+1).

[0289] (1-((1-(methoxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-6) was prepared from I-6B following a procedure similar to that described for I-2. I-6 was isolated as a brown oil. LCMS m / z: 299, (M+1). Intermediate 7 tert-Butyl 3-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)sulfonyl)azetidine-1-carboxylate [ka]

[0290] 1-tert-Butyl 3-(2-thioxopyridine-1(2H)-yl)azetidine-1,3-dicarboxylate (I-7B). A solution of I-7A (5 g, 24.85 mmol) in DCM (50 mL) was cooled to 0 °C. To the cooled solution was added oxalyl chloride (3.26 mL, 37.3 mmol) and a drop of DMF, which immediately resulted in vigorous bubbling. The reaction mixture was allowed to warm slowly to RT. Upon completion of the reaction, the mixture was cooled to 0 °C and covered with aluminum foil. DMAP (0.304 g, 2.485 mmol) was added, followed by sodium 2-thioxopyridine-1(2H)-oleate (5 g, 33.5 mmol). After 1 h 45 min, the reaction was cooled to 0 °C and quenched with HO. The phases were separated, and the organic layer was quenched with HCl. The mixture was filtered through a plug of silica gel and rinsed with DCM. The filtrate was concentrated under reduced pressure to give the title compound (I-7B) as a dark viscous oil. LCMS m / z: 311 (M+1).

[0291] tert-Butyl 3-(pyridin-2-ylsulfonyl)azetidine-1-carboxylate (I-7C). I-7B (7.71 g, 24.84 mmol) was dissolved in EtOAc (50 mL), and the solution was stirred under irradiation from a 150 W lamp. After 1 h, the reaction mixture was cooled to RT 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 RT and then diluted with EtOAc and HO. The insoluble material was filtered off, and the filter cake was rinsed with EtOAc. The biphasic filtrate was separated, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was dry-loaded onto Celite and purified by column chromatography (SiO, 0-100% EtOAc / heptane) to afford the title compound (I-7C) as a light yellow oil. LCMS m / z: 299 (M+1), 243 (M-55). 1 H NMR (400 MHz, CDCl3) δ ppm 1.45 (s, 9 H) 4.16 - 4.23 (m, 2 H) 4.39 (br. s., 2 H) 4.41 - 4.53 (m, 1 H) 7.58 (ddd, J=7.65, 4.72, 1.12 Hz, 1 H)7.96 - 8.03 (m, 1 H) 8.09 - 8.14 (m, 1 H) 8.69 - 8.76 (m, 1 H).

[0292] Sodium 1-(tert-butoxycarbonyl)azetidine-3-sulfinate (I-7D). To a solution of I-7C (2.84 g, 9.52 mmol) in THF (45 mL) was added sodium ethanethiol (2.402 g, 28.6 mmol). After stirring for 24 h, additional sodium ethanethiol (2.402 g, 28.6 mmol) was added at RT. Upon completion of the reaction, the mixture was diluted with heptane, and the resulting mixture was filtered. The sticky filter cake was washed with EtO. The semi-solid was dissolved in EtOH and concentrated in vacuo. The title compound (I-7D) was isolated as an off-white solid and used without further purification. LCMS m / z: 166 (M-55).1 H NMR (400 MHz, D2O) δ ppm 1.40 - 1.49 (m, 9 H) 3.12 - 3.23 (m, 1 H) 4.03 (d, J=4.55 Hz, 2 H) 4.05 - 4.14 (m, 2 H).

[0293] tert-Butyl 3-((2-ethoxy-2-oxoethyl)sulfonyl)azetidine-1-carboxylate (I-7E). To a mixture of I-7D (4.54 g, 18.68 mmol) in DMF (100 mL) was added ethyl 2-bromoacetate (1.723 mL, 15.57 mmol). The reaction mixture was stirred at RT for 10 min, after which it was diluted with HO and EtO. The phases were separated, and the aqueous layer was extracted with EtO. The combined ether extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, elution from heptane to DCM to acetone) to give the title compound (I-7E) as a yellow oil. LCMS m / z: 252 (M-55). 1 H NMR (400 MHz, CDCl3) δ ppm 1.34 (t, J=1.00 Hz, 3 H) 1.45 (s, 9 H) 3.95 (s, 2 H) 4.13 (q, J=7.16 Hz, 1 H) 4.25 - 4.35 (m, 6 H).

[0294] tert-Butyl 3-((1-(ethoxycarbonyl)cyclopropyl)sulfonyl)azetidine-1-carboxylate (I-7F) was prepared from I-7E following a procedure similar to that described for I-2C. The title compound was isolated as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ ppm 1.29 (t, J= 7.14 Hz, 3 H) 1.44 (s, 9 H) 1.63 - 1.69 (m, 2 H) 1.78 - 1.84 (m, 2 H) 4.14 - 4.20 (m, 2 H) 4.20 - 4.26(m, 2 H) 4.38 (dd, J=9.44, 6.16 Hz, 2 H) 4.46 - 4.55 (m, 1 H).

[0295] tert-Butyl 3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)azetidine-1-carboxylate (I-7G) was prepared from I-7F following a procedure similar to that described for I-2D. I-7G was isolated as a colorless oil. LCMS m / z: 236 (M-55). 1 H NMR (400 MHz, CDCl3) δ ppm 0.98 - 1.03 (m, 2 H) 1.44 (s, 9 H) 1.48 - 1.54 (m, 2 H) 2.43 (t, J=4.94 Hz, 1 H) 3.86 (d, J=4.94 Hz, 2 H) 4.08 -4.15 (m, 1 H) 4.17 (d, J=8.46 Hz, 1 H) 4.22 - 4.30 (m, 1 H) 4.30 - 4.36 (m, 2 H).

[0296] tert-Butyl 3-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)sulfonyl)azetidine-1-carboxylate (I-7) was prepared from I-7G according to a procedure similar to that described for I-2. I-7 was isolated as a yellow oil. LCMS m / z: 392 (M+23), 314 (M-55). Intermediate 8 (1-(Cyclopentylsulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0297] Ethyl 2-(cyclopentylthio)acetate (I-8B). To a solution of I-8A (3.08 mL, 28.1 mmol) in acetone (80 mL) was added KCO (5.29 g, 38.3 mmol) and cyclopentyl iodide (2.95 mL, 25.5 mmol). The resulting mixture was stirred at 60 °C overnight. The reaction was cooled to RT and filtered to remove excess base. The filtrate was concentrated under reduced pressure, and the residue was dissolved in EtOAc and HO. The phases were separated, and the organic layer was washed with saturated sodium thiosulfate (3x). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The title compound (I-8B) was isolated as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 1.25 - 1.31 (m, 3 H) 1.46 - 1.63 (m, 4 H) 1.67 - 1.89 (m, 2 H) 1.96 - 2.09 (m, 2 H) 3.19 - 3.28 (m, 3 H) 4.15 -4.22 (m, 2 H).

[0298] Ethyl 2-(cyclopentylsulfonyl)acetate (I-8C). To a solution of I-8B (3.97 g, 21.08 mmol) in EtOH (100 mL) was added oxone (25.9 g, 42.2 mmol) and a catalytic amount of HO. The resulting slurry was stirred at RT overnight, after which it was concentrated under reduced pressure. The residue was dissolved in CHCl and HO. The phases were separated, and the organic layer was washed with saturated sodium thiosulfate, dried over sodium sulfate, and concentrated under reduced pressure. The resulting yellow residue was purified by column chromatography (SiO, 0-100% DCM / heptane) to afford I-8C as a light yellow oil. 1 H NMR (400 MHz, CDCl3) δ ppm 1.30 - 1.36 (m, 3 H) 1.64 - 1.75 (m, 2 H) 1.79 - 1.91 (m, 2 H) 2.02 - 2.17 (m, 4 H) 3.78 - 3.88 (m, 1 H) 3.94 (s, 2 H) 4.24- 4.32 (m, 2 H).

[0299] Ethyl 1-(cyclopentylsulfonyl)cyclopropanecarboxylate (I-8D) was prepared from I-8B following a procedure similar to that described for I-2C. LCMS m / z: 247 (M+1).

[0300] (1-(Cyclopentylsulfonyl)cyclopropyl)methanol (I-8E) was prepared from I-8D following a procedure similar to that described for I-2D. 1 H NMR (400 MHz, CDCl3) δ ppm 0.98 - 1.04 (m, 2 H) 1.48 - 1.53 (m, 2 H) 1.63 - 1.70 (m, 2 H) 1.77 - 1.87 (m, 2 H) 2.05 - 2.12 (m, 4 H) 2.55 (t, J=5.38 Hz, 1 H) 3.77 (quin, J=8.30 Hz, 1 H) 3.88 (d, J=4.84 Hz, 2 H).

[0301] (1-(Cyclopentylsulfonyl)cyclopropyl)methyl methanesulfonate (I-8) was prepared from I-8E following a procedure similar to that described for I-2. 1 H NMR (400 MHz, CDCl3) δ ppm 1.15 - 1.21 (m, 2 H) 1.61 - 1.68 (m, 4 H) 1.77 - 1.84 (m, 2 H) 2.05 - 2.11 (m, 4 H) 3.07 (s, 3 H) 3.68 quin, J=8.20 Hz, 1 H) 4.53 (s, 2 H). Intermediate 9 (1-((3-((tert-butyldimethylsilyl)oxy)propyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0302] Ethyl 2-((3-((tert-butyldimethylsilyl)oxy)propyl)thio)acetate (I-9B). To a solution of I-9A (1.429 mL, 13.03 mmol) in acetone (50 mL) was added KCO (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). The resulting mixture was The mixture was stirred at 60 °C. Upon completion of the reaction, the mixture was cooled to RT and filtered to remove insoluble material. 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 aqueous sodium thiosulfate, dried over sodium sulfate, and concentrated under reduced pressure. I-9B was isolated as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 0.06 (s, 6 H) 0.90 (s, 9 H) 1.29 (t, J=7.14 Hz, 3 H) 1.82 (quin, J=1.00 Hz, 2 H) 2.72 (t, J=7.24 Hz, 2 H) 3.22(s, 2 H) 3.70 (t, J=6.04 Hz, 2 H) 4.20 (t, J=7.10 Hz, 2 H).

[0303] Ethyl 2-((3-((tert-butyldimethylsilyl)oxy)propyl)sulfonyl)acetate (I-9C). To a solution of I-9B (3.68 g, 12.58 mmol) in DCM (100 mL) was added mCPBA (5.64 g, 25.2 mmol). After stirring overnight, the reaction mixture was diluted with DCM, washed with saturated sodium bicarbonate, and dried over sodium sulfate. The dried organic layer was concentrated under reduced pressure to give the title compound as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 0.07 (s, 1 H) 0.91 (s, 9 H) 1.34 (t, J=7.14 Hz, 3 H) 2.08 (dd, J=10.10, 5.75 Hz, 2 H) 3.34 - 3.41 (m, 2 H) 3.76(t, J=5.80 Hz, 2 H) 3.97 (s, 2 H) 4.29 (q, J=7.14 Hz, 2 H).

[0304] Ethyl 1-((3-((tert-butyldimethylsilyl)oxy)propyl)sulfonyl)cyclopropanecarboxylate (I-9D) was prepared from I-9C following a procedure similar to that described for I-2C. The title compound was isolated as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 0.06 (s, 6 H) 0.89 (s, 9 H) 1.31 (t, J=6.87 Hz, 3 H) 1.60 - 1.66 (m, 2 H) 1.73 - 1.80 (m, 2 H) 1.99 - 2.11 (m, 2H) 3.47 - 3.56 (m, 2 H) 3.73 (t, J=5.80 Hz, 2 H) 4.20 - 4.31 (m, 2 H).

[0305] (1-((3-((tert-butyldimethylsilyl)oxy)propyl)sulfonyl)cyclopropyl)methanol (I-9E) was prepared from I-9D following a procedure similar to that described for I-2D. The title compound was isolated as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 0.06 (s, 6 H) 0.89 (s, 9 H) 0.99 - 1.05 (m, 2 H) 1.46 - 1.52 (m, 2 H) 2.01 - 2.12 (m, 2 H) 2.48 (t, J=5.77 Hz, 1 H) 3.23 - 3.31 (m, 2 H) 3.73 (t, J=5.84 Hz, 2 H) 3.89 (d, J=5.77 Hz, 2 H).

[0306] (1-((3-((tert-butyldimethylsilyl)oxy)propyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-9) was prepared from I-9E following a procedure similar to that described for I-2. The title compound was isolated as an orange oil. 1 H NMR (400 MHz, CDCl3) δ ppm 0.04 - 0.10 (m, 6 H) 0.88 - 0.92 (m, 9 H) 1.18 - 1.24 (m, 2 H) 1.62 - 1.68 (m, 2 H) 2.04 - 2.13 (m, 2 H) 3.08 (s,3 H) 3.22 - 3.29 (m, 2 H) 3.75 (t, J=5.82 Hz, 2 H) 4.5 4 (s, 2 H). Intermediate 10 (1-(tert-butylsulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0307] Methyl 1-(tert-butylsulfonyl)cyclopropanecarboxylate (I-10B) was prepared from I-10A following a procedure similar to that described for I-2C. The title compound was isolated as a waxy solid. 1 H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 9 H) 1.60 - 1.65 (m, 2 H) 1.78 - 1.83 (m, 2 H) 3.79 (s, 3 H).

[0308] (1-(tert-Butylsulfonyl)cyclopropyl)methanol (I-10C) was prepared from I-10B following a procedure similar to that described for I-2D. I-10C was isolated as a white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 1.03 - 1.07 (m, 2 H) 1.49 - 1.51 (m, 9 H) 1.55 - 1.60 (m, 2 H) 2.82 - 2.87 (m, 1 H) 3.88 (d, J=5.97 Hz, 2 H).

[0309] (1-(tert-Butylsulfonyl)cyclopropyl)methyl methanesulfonate (I-10) was prepared from I-10C following a procedure similar to that described for I-2. The title compound was isolated as an amber waxy solid. 1 H NMR (400 MHz, CDCl3) δ ppm 1.23 - 1.28 (m, 2 H) 1.50 (s, 9 H) 1.71 - 1.77 (m, 2 H) 3.08 (s, 3 H) 4.59 (s, 2 H). Intermediate 11 (1-(oxetan-3-ylsulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0310] Ethyl 2-(oxetan-3-ylsulfonyl)acetate (I-11B). To a solution of 3-iodooxetane (0.957 mL, 10.87 mmol) in acetone (50 mL) was added K2CO3 (2.254 g, 16.31 mmol) and ethyl 2-mercaptoacetate (1.311 mL, 11.96 mmol). The resulting slurry was stirred at 60 °C overnight, after which it was cooled to RT and filtered to remove insoluble material. The filter cake was rinsed with acetone. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in EtOH and treated with oxone (13.37 g, 21.74 mmol) and approximately 0.3 mL of water. 5 h After a while, the mixture was filtered to remove insoluble material, and the filtrate was concentrated under reduced pressure. The oily residue was dissolved in DCM and washed with aqueous sodium thiosulfate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The title compound was isolated as a colorless oil. LCMS m / z: 209 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.33 (t, J=7.14 Hz, 3 H) 3.95 (s, 2 H) 4.26 (q, J=7.16 Hz, 2 H) 4.73 - 4.83 (m, 1 H) 4.91 (t, J=7.68 Hz, 2 H) 4.98 - 5.06 (m, 2 H).

[0311] Ethyl 1-(oxetan-3-ylsulfonyl)cyclopropanecarboxylate (I-11C) was prepared from I-11B following a procedure similar to that described for I-2C. I-11C was isolated as a light yellow oil. LCMS m / z: 235, (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.28 (t, J=7.16 Hz, 3 H) 1.62 - 1.69 (m, 2 H) 1.77 - 1.84 (m, 2 H) 4.22 (q, =7.14 Hz, 2 H) 4.83 - 4.91 (m, 3 H)5.07 - 5.15 (m, 2 H).

[0312] (1-(Oxetan-3-ylsulfonyl)cyclopropyl)methanol (I-11D) was prepared from I-11C following 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 (400 MHz, CDCl3) δ ppm 0.98 - 1.04 (m, 2 H) 1.48 - 1.55 (m, 2 H) 2.02 (t, J=4.92 Hz, 1 H) 3.86 (d, J=4.89 Hz, 2 H) 4.68 - 4.80 (m, 1 H) 4.86 (t, J=7.60 Hz, 2 H) 5.01 - 5.10 (m, 2 H).

[0313] (1-(Oxetan-3-ylsulfonyl)cyclopropyl)methyl methanesulfonate (I-11) was prepared from I-11D following a procedure similar to that described for I-2. The title compound was isolated as a light yellow oil. LCMS m / z: 271 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.20 - 1.26 (m, 2 H) 1.63 - 1.69 (m, 2 H) 3.07 (s, 3 H) 4.48 (s, 2 H) 4.63 - 4.71 (m, 1 H) 4.89 (t, J=7.73 Hz, 2H) 5.00 - 5.06 (m, 2 H). Intermediate 12 (1-(Isopropylsulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0314] Methyl 1-(isopropylsulfonyl)cyclopropanecarboxylate (I-12B) was prepared from I-12A following a procedure similar to that described for I-2C. LCMS m / z: 207 (M+1).

[0315] (1-(isopropylsulfonyl)cyclopropyl)methanol (I-12C) was prepared from I-12B following a procedure similar to that described for I-2D. C was isolated as an off-white solid. LCMS m / z: 179 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 0.99 - 1.04 (m, 2 H) 1.40 (d, J=6.90 Hz, 6 H) 1.47 - 1.52 (m, 2 H) 2.47 (t, J=5.62 Hz, 1 H) 3.56 (dt, J=13.73,6.85 Hz, 1 H) 3.87 (d, J=5.62 Hz, 2 H).

[0316] (1-(Isopropylsulfonyl)cyclopropyl)methyl methanesulfonate (I-12) was prepared from I-12C following a procedure similar to that described for I-2. The title compound was isolated as a dark viscous oil. LCMS m / z: 257 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.17 - 1.23 (m, 2 H) 1.42 (d, J=6.80 Hz, 6 H) 1.63 - 1.68 (m, 2 H) 3.08 (s, 3 H) 3.46 (dt, J=13.63, 6.80 Hz, 1H) 4.53 (s, 2H). Intermediate 13 (1-(ethylsulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0317] Ethyl 2-(ethylsulfonyl)acetate (I-13B). To a solution of I-13A (3.00 mL, 29.1 mmol) in EtOH (50 mL) was added concentrated HSO (1 drop). The resulting solution was refluxed overnight. The reaction mixture was then cooled to 0 °C, and Oxone (35.7 g, 58.1 mmol) was added. Upon completion of the reaction, the mixture was filtered. The filter cake was rinsed 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 over sodium sulfate and concentrated under reduced pressure. I-13B was isolated as a colorless oil. LCMS m / z: 181 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.33 (t, J=7.14 Hz, 3 H) 1.45 (t, J=7.48 Hz, 3 H) 3.29 (q, J=7.45 Hz, 2 H) 3.95 (s, 2 H) 4.28 (q, J=7.14 Hz, 2H).

[0318] Ethyl 1-(ethylsulfonyl)cyclopropanecarboxylate (I-13C) was prepared from I-13B following a procedure similar to that described for I-2C. I-13C was isolated as a colorless oil. LCMS m / z: 207 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.29 - 1.34 (m, 3 H) 1.41 (t, J=7.53 Hz, 3 H) 1.63 - 1.68 (m, 2 H) 1.76 - 1.81 (m, 2 H) 3.47 (q, J=7.53 Hz, 2 H) 4.22 - 4.30 (m, 2 H).

[0319] (1-(ethylsulfonyl)cyclopropyl)methanol (I-13D) was prepared from I-13C following a procedure similar to that described for I-2D. Isolated as a colored oil. LCMS m / z: 165 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.00 - 1.05 (m, 2 H) 1.42 (t, J=7.51 Hz, 3 H) 1.48 - 1.53 (m, 2 H) 2.45 (t, J=5.65 Hz, 1 H) 3.22 (q, J=7.50 Hz,2 H) 3.90 (d, J=5.67 Hz, 2 H).

[0320] (1-(Ethylsulfonyl)cyclopropyl)methyl methanesulfonate (I-13) was prepared from I-13D following a procedure similar to that described for I-2. The title compound was isolated as a dark oil. LCMS m / z: 243 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.18 - 1.23 (m, 2 H) 1.43 (t, J=7.48 Hz, 3 H) 1.63 - 1.67 (m, 2 H) 3.09 (s, 3 H) 3.19 (q, J=7.48 Hz, 2 H) 4.53(s, 2 H). Intermediate 14 (1-(methylsulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0321] Methyl 1-(methylsulfonyl)cyclopropanecarboxylate (I-14B) was prepared from I-14A following a procedure similar to that described for I-2C. I-14B was isolated as a light yellow oil. 1 H NMR (400 MHz, CDCl3) δ ppm 1.65 - 1.70 (m, 2 H) 1.79 - 1.84 (m, 2 H) 3.20 (s, 3 H) 3.81 (s, 3 H).

[0322] (1-(Methylsulfonyl)cyclopropyl)methanol (I-14C) was prepared from I-14B following a procedure similar to that described for I-2D. I-14C was isolated as a colorless oil. LCMS m / z: 151 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.01 - 1.08 (m, 2 H) 1.48 - 1.54 (m, 2 H) 2.48 (t, J=5.45 Hz, 1 H) 3.04 (s, 3 H) 3.92 (d, J=5.53 Hz, 2 H).

[0323] (1-(Methylsulfonyl)cyclopropyl)methyl methanesulfonate (I-14) was prepared from I-14C following a procedure similar to that described for I-2. The title compound was isolated as a tan solid. LCMS m / z: 229 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (td, J=5.97, 1.52 Hz, 2 H) 1.65 (ddd, J=5.92, 5.28, 1.47 Hz, 2 H) 3.03 (s, 3 H) 3.06 - 3.11 (m, 3 H) 4.54(s, 2H). Intermediate 15 (1-(methylsulfonyl)cyclobutyl)methyl methanesulfonate [ka]

[0324] Ethyl 1-(methylsulfonyl)cyclobutanecarboxylate (I-15B). To a slurry of I-15A (0.794 mL, 6.02 mmol) and K2CO3 (1.663 g, 12.03 mmol) in DMF (20 mL) was added 1,3-dibromopropane (0.736 mL, 7.22 mmol). The resulting mixture was stirred at 60 °C. Upon completion of the reaction, the mixture was diluted with Et2O and filtered through a plug of Celite. 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 afford I-15B as a colorless oil. LCMS: m / z: 207 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.35 (t, J=7.14 Hz, 3 H) 1.98 - 2.21 (m, 2 H) 2.60 - 2.72 (m, 2 H) 2.77 - 2.90 (m, 2 H) 2.96 (s, 3 H) 4.32 (q, J=7.14 Hz, 2 H).

[0325] (1-(Methylsulfonyl)cyclobutyl)methanol (I-15C) was prepared from I-15B following a procedure similar to that described for I-2D. I-15C was isolated as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.01 - 2.18 (m, 4 H) 2.51 (br. s., 1 H) 2.63 - 2.74 (m, 2 H) 2.86 (s, 3 H) 4.10 (s, 2 H).

[0326] (1-(methylsulfonyl)cyclobutyl)methyl methanesulfonate (I-15) was prepared from I-15C following a procedure similar to that described for I-2. I-15 was isolated as a tan solid. 1 H NMR (400 MHz, CDCl3) δ ppm 2.05 - 2.24 (m, 4 H) 2.72 - 2.84 (m, 2 H) 2.87 (s, 3 H) 3.11 (s, 3 H) 4.66 (s, 2 H). Intermediate 16 2-(1,1-dioxidetetrahydrothiophen-2-yl)ethyl methanesulfonate [ka]

[0327] 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. To the cooled solution was added nBuLi (10.98 mL, 27.5 mmol) dropwise, followed by benzyl-2-bromoethyl ether (3.99 mL, 25.2 mmol). The resulting solution was allowed to warm slowly to RT. The reaction Upon completion, 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 2M 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 afford I-16B as a colorless oil. LCMS m / z: 255 (M+1).1 H NMR (400 MHz, CDCl3) δ ppm 1.73 - 1.90 (m, 2 H) 2.02 - 2.13 (m, 1 H) 2.14 - 2.39 (m, 3 H) 2.94 - 3.03 (m, 1 H) 3.11 - 3.24 (m, 2 H) 3.59 - 3.71 (m, 2 H) 4.46 - 4.59 (m, 2 H) 7.27 - 7.41 (m, 5 H).

[0328] 2-(2-Hydroxyethyl)tetrahydrothiophene 1,1-dioxide (I-16C). To a solution of I-16B (2.1 g, 8.26 mmol) in EtOH (10 mL) was added Pd / C (0.05 g, 0.047 mmol). The resulting mixture was vigorously stirred overnight under an H atmosphere. The reaction mixture was filtered through a pad of Celite with MeOH. The filtrate was concentrated under reduced pressure to give I-16C as a colorless oil. LCMS m / z: 165 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.74 - 1.92 (m, 3 H) 1.97 - 2.27 (m, 3 H) 2.32 - 2.44 (m, 1 H) 2.93 - 3.05 (m, 1 H) 3.11 - 3.25 (m, 2 H) 3.72 - 3.91 (m, 2 H).

[0329] 2-(1,1-Dioxidetetrahydrothiophen-2-yl)ethyl methanesulfonate) (I-16) was prepared from I-16C following a procedure similar to that described for I-2. The title compound was isolated as a golden oil. LCMS m / z: 243 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 1.80 (dd, J=13.30, 6.26 Hz, 1 H) 2.01 - 2.16 (m, 2 H) 2.22 (d, J=6.26 Hz, 1 H) 2.27 - 2.47 (m, 2 H) 2.96 - 3.03 (m, 1 H) 3.05 (s, 3 H) 3.10 - 3.23 (m, 2 H) 4.36 - 4.41 (m, 2 H). Intermediate 17 N-(4-chlorobenzyl)-1,6-dioxo-1,3,4,6-tetrahydropyrido[2,1-c][1,4]oxazine-7-carboxamide [ka]

[0330] N-(4-chlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (I-17B). 6-Methyl-2-oxo- in DMF (100 mL) To a solution of 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) was added a solution of 4-chlorobenzylamine (5.96 mL, 49.0 mmol) in DMF (50 mL). The resulting solution was stirred at RT. After 72 h, additional 4-chlorobenzylamine (3 mL) was added to drive further conversion. The reaction mixture was cooled to 0 °C, and ice was added directly to the mixture. The cloudy 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 HO and heptane and dried on a frit overnight. I-17B was isolated as a white solid. LCMS m / z: 277 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3 H) 4.50 (d, J=6.26 Hz, 2 H) 6.31 (dd, J=7.43, 0.78 Hz, 1 H) 7.29 - 7.35 (m, 2 H) 7.35 - 7.43 (m, 2H) 8.23 (d, J=7.43 Hz, 1 H) 10.11 (t, J=5.87 Hz, 1 H) 12.48 (br. s., 1 H).

[0331] 5-((4-Chlorobenzyl)carbamoyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (I-17C). To a sealed tube charged with SeO (20 g, 180 mmol) was added I-17B (3 g, 10.84 mmol) and dioxane (120 mL). The resulting mixture was stirred at 120 °C for 72 h, then it was cooled to RT and filtered through a plug of Celite and NaSO. The filtrate was concentrated to give a yellow solid. The solid was dissolved in 150 mL of DMF and treated with oxone (13.33 g, 21.68 mmol). The resulting mixture was stirred at RT overnight, then it was cooled to 0 °C and ice was added directly to the mixture. The contents were diluted with HO and adjusted to pH 1 with 2 M HCl. The resulting precipitate was collected by vacuum filtration. I-17C was isolated as a yellow solid. LCMS m / z: 307 (M+1). 1 H NMR (500 MHz, DMSO-d6) δ ppm 4.49 - 4.57 (m, 2 H) 7.09 (d, J=7.25 Hz, 1 H) 7.35 (d, J=8.51 Hz, 2 H) 7.41 (d, J=8.20 Hz, 2 H) 8.43 (d, J=7.25 Hz, 1 H) 10.18 (br. s., 1 H) 12.40 (br. s., 1 H).

[0332] N-(4-chlorobenzyl)-1,6-dioxo-1,3,4,6-tetrahydropyrido[2,1-c][1,4]oxazine-7-carboxamide (I-17). To a solution of I-17C (1 g, 3.26 mmol) and CsCO (1.594 g, 4.89 mmol) in DMF (50 mL) was added 1,2-dibromoethane (0.309 mL, 3.59 mmol). The resulting mixture was stirred at 60 °C overnight. The reaction mixture was diluted with EtOAc and filtered through a plug of Celite. The filtrate was washed with brine (4x). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. I-17 was isolated as a tan solid. LCMS m / z: 333 (M+1). 1H NMR (500 MHz, CD3OD) δ ppm 4.37 (t, J=4.73 Hz, 2 H) 4.62 (d, J=5.99 Hz, 3 H) 4.69 - 4.74 (m, 2 H) 7.36 (s, 4 H) 7.43 (dd, J=7.57,0.95 Hz, 1 H) 8.55 - 8.58 (m, 1 H) 10.40 (br. s., 1 H). Intermediate 18 2-(2-aminoethyl)isothiazolidine 1,1-dioxide [ka]

[0333] tert-Butyl (2-(3-chloropropylsulfonamido)ethyl)carbamate (I-18B). To a solution of I-18A (1.815 mL, 12.48 mmol) and DIEA (2.398 mL, 13.73 mmol) in THF (100 mL) cooled to 0 °C was added 3-chloropropane-1-sulfonyl chloride (1.670 mL, 13.73 mmol). The reaction was allowed to warm to RT. Upon completion of the reaction, the mixture was diluted with EtOAc and HO. The phases were separated and the organic layer was washed with HO and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. I-18B was isolated as an orange solid. LCMS m / z: 245 (M-55). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.32 - 1.40 (m, 9 H) 2.02 - 2.11 (m, 2 H) 2.94 (t, J=5.67 Hz, 2 H) 2.96 - 3.03 (m, 2 H) 3.05 - 3.13 (m, 2 H)3.70 - 3.75 (m, 2 H) 6.78 - 6.87 (m, 1 H) 7.20 (t, J=5.28 Hz, 1 H).

[0334] tert-Butyl (2-(1,1-dioxidoisothiazolidin-2-yl)ethyl)carbamate (I-18C). To a solution of I-18B (2 g, 6.65 mmol) in DMF (50 mL) cooled to 0 °C was added NaH (60% suspension in mineral oil, 0.293 g, 7.31 mmol). The resulting solution was allowed to warm to RT. After 4 days, the reaction mixture was cooled to 0 °C and diluted with HO and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (4x). The combined organics were washed with brine, dried over sodium sulfate, and concentrated. I-18C was isolated as a light orange oil and used without further purification. LCMS m / z: 265 (M+1). 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.37 (s, 9 H) 2.20 (quin, J=7.09 Hz, 2 H) 3.08 (q, J=6.52 Hz, 2 H) 3.12 - 3.18 (m, 2H) 3.20 (t, J=6.62Hz, 2H) 6.84 (br. s., 1 H).

[0335] 2-(2-aminoethyl)isothiazolidine 1,1-dioxide (I-18). To a solution of I-18C (1.4 g, 5.30 mmol) in dioxane (5.30 mL) was added 4 M HCl in dioxane (3 mL, 12.00 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and triturated with EtO and heptane to give I-18. LCMS m / z: 165 (M+1). Intermediate 19 (1-(methylsulfonyl)azetidin-3-yl)methanamine [ka]

[0336] tert-Butyl ((1-(methylsulfonyl)azetidin-3-yl)methyl)carbamate (I-19B). To a solution of I-19A (0.3 g, 1.611 mmol) and DIEA (0.844 mL, 4.83 mmol) in DCM (10 mL) was added MsCl (0.138 mL, 1.772 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was diluted with DCM and 2 M HCl. The phases were separated, and the organic layer was washed with 2 M HCl (2×). The aqueous extract was extracted with CHCl3 (2×). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford I-19B as a maroon solid. 1 H NMR (400 MHz, CDCl3) δ ppm 1.42 - 1.48 (m, 9 H) 2.78 (dt, J=13.11, 6.75 Hz, 1 H) 2.86 (s, 3 H) 3.36 (t, J=6.46 Hz, 2 H) 3.67 (dd, J=8.02,5.67 Hz, 2 H) 3.99 (t, J=8.22 Hz, 2 H).

[0337] (1-(methylsulfonyl)azetidin-3-yl)methanamine (I-19). To a solution of I-19B (0.417 g, 1.578 mmol) in DCM (5 mL) was added TFA (2 mL, 26.0 mmol). The resulting mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure to afford I-19 as a maroon oil. LCMS m / z: 165 (M+1). Intermediate 20 (1-(methylsulfonyl)azetidin-2-yl)methanamine [ka]

[0338] tert-Butyl ((1-(methylsulfonyl)azetidin-2-yl)methyl)carbamate (I-20B) was prepared from I-20A following a procedure similar to that described for I-19B. 1 H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 8 H) 1.54 - 1.60 (m, 1 H) 1.83 - 1.98 (m, 1 H) 2.17 - 2.30 (m, 1 H) 2.82 - 2.91 (m, 3 H) 3.24 - 3.41 (m,2 H) 3.46 - 3.59 (m, 2 H) 4.26 (br. s., 1 H) 4.69 (br. s., 1 H).

[0339] (1-(methylsulfonyl)azetidin-2-yl)methanamine (I-20) was prepared from I-20B following a procedure similar to that described for I-19C. LCMS m / z: 165 (M+1). Intermediate 21 (1-((1-fluorocyclopropyl)sulfonyl)cyclopropyl)methylmethane sulfonate [ka]

[0340] 2-Thioxopyridin-1(2H)-yl 1-fluorocyclopropanecarboxylate (I-21A) was prepared from 1-fluorocyclopropanecarboxylic acid following a procedure similar to that described for I-7B. I-21A was obtained as a dark residue. MS m / z 214.2 (M+1).

[0341] 2-((1-fluorocyclopropyl)sulfonyl)pyridine (I-21B) was prepared from I-21A following a procedure similar to that described for I-7C. I-21B was isolated as a white solid. MS m / z 202.2 (M+1).

[0342] Sodium 1-fluorocyclopropane-1-sulfinate (I-21C). Ethanethiol (3.97 mL, 53.7 mmol) was added slowly to a stirred suspension of sodium hydride (60% suspension in mineral oil, 1.073 g, 26.8 mmol) in THF (29.8 mL) at 0 °C under argon. After 5 min, a solution of I-21B (1.8 g, 8.95 mmol) in THF (14.9 mL) was added. The mixture was warmed to RT and then to 50 °C. After 2 h, the reaction mixture was diluted with deionized water and adjusted to pH 6 with 2 N HCl and saturated aqueous NaHCO3. The biphasic mixture was concentrated in vacuo. The crude product was suspended in MeOH and filtered through a pad of Celite. The filtrate was concentrated and dried in vacuo to give I-21C as an off-white solid. 1 H NMR (400 MHz, D2O) δ ppm 0.85 - 1.17 (m, 4 H).

[0343] Benzyl 2-((1-fluorocyclopropyl)sulfonyl)acetate (I-21D). Benzyl 2-bromoacetate (1.084 mL, 6.84 mmol) was added to a stirred mixture of I-21C (1.0 g, 6.84 mmol) in DMF (6.84 mL) at RT. After 3 h, the reaction contents were diluted with ion-exchanged water and DCM, and the layers were separated. The aqueous phase was extracted with DCM (2×), and the combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude residue was purified on SiO2 (0–50% EtOAc / heptane) to afford I-21D as a clear oil. 1 H NMR (400 MHz, CDCl3) δ ppm 1.33 - 1.48 (m, 2 H) 1.48 - 1.66 (m, 3 H) 4.24 (d, J=0.64 Hz, 2 H) 5.25 (s, 2 H) 7.27 - 7.50 (m, 5 H). MS m / z 295.1 (M+1).

[0344] Benzyl 1-((1-fluorocyclopropyl)sulfonyl)cyclopropanecarboxylate (I-21E) was prepared from I-21D following a procedure similar to that described for I-2C. The title compound was isolated as a clear oil.1 H NMR (400 MHz, CDCl3) δ ppm 1.19 - 1.45 (m, 2 H) 1.59 - 1.71 (m, 2 H) 1.71 - 1.85 (m, 2 H ) 1.88 - 2.04 (m, 2 H) 5.21 (s, 2 H) 7.31 - 7.55 (m, 5 H). MS m / z 299.1 (M+1).

[0345] (1-((1-fluorocyclopropyl)sulfonyl)cyclopropyl)methanol (I-21F) was prepared from I-21E following a procedure similar to that described for I-2D. I-21F was obtained as a clear oil. MS m / z 195.1 (M+1).

[0346] (1-((1-Fluorocyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-21) was prepared from I-21F following a procedure similar to that described for I-2. I-21 was obtained as a clear oil. MS m / z 273.1 (M+1). Intermediate 22 (1-(cyclobutylsulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0347] Ethyl 2-(cyclobutylthio)acetate (I-22A). A microwave vial was charged with DMF (14.8 mL), ethyl 2-mercaptoacetate (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). The vial was sealed, and the mixture was stirred at 90 °C for 3 days and then 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 give I-22A as an orange oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (td, J=7.13, 2.62 Hz, 2 H) 1.84 - 2.10 (m, 4 H) 2.25 - 2.42 (m, 3 H) 3.16 (d, J=2.59 Hz, 2 H) 3.50 - 3.63 (m, 1 H) 4.15 (qd, J=7.13, 2.57 Hz, 1 H). MS m / z 175.1 (M+1).

[0348] Ethyl 2-(cyclobutylsulfonyl)acetate (I-22B). 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 RT. The mixture was stirred overnight, during which time it changed color 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 give the title compound (I-22B), which contained residual DMF and was used without further purification. MS m / z 207.1 (M+1).

[0349] Ethyl 1-(cyclobutylsulfonyl)cyclopropanecarboxylate (I-22C) was prepared from I-22B following a procedure similar to that described for I-2C. 1 H NMR (400 MHz, CDCl3) δ ppm 1.24 - 1.3 6 (m, 3 H) 1.49 - 1.63 (m, 2 H) 1.70 - 1.80 (m, 2 H) 1.87 - 2.15 (m, 2 H) 2.18 - 2.37 (m, 2 H) 2.48 - 2.71 (m, 2 H) 4.23 (q, J=7.14 Hz, 2 H) 4.39 - 4.59 (m, 1 H). MS m / z 233.2 (M+1).

[0350] (1-(Cyclobutylsulfonyl)cyclopropyl)methanol (I-22D) was prepared from I-22C following a procedure similar to that described for I-2D. MS m / z 191.1 (M+1).

[0351] (1-(Cyclobutylsulfonyl)cyclopropyl)methyl methanesulfonate (I-22) was prepared from I-22D following a procedure similar to that described for I-2. MS m / z 269.2 (M+1). Intermediate 23 tert-Butyl 3-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)sulfonyl)pyrrolidine-1-carboxylate [ka]

[0352] tert-Butyl 3-((2-ethoxy-2-oxoethyl)thio)pyrrolidine-1-carboxylate (I-23A). Two microwave vials were charged with DMF (14.8 mL), ethyl 2-mercaptoacetate (1.763 mL, 15.99 mmol), KCO (0.553 g, 4.00 mmol), and 18-crown-6 (1.057 g, 4.00 mmol), respectively. To one vial was added (S)-tert-butyl 3-bromopyrrolidine-1-carboxylate (1.0 g, 4.00 mmol), and to the other was added (R)-tert-butyl 3-bromopyrrolidine-1-carboxylate (1.0 g, 4.00 mmol). The vials were sealed and stirred in a microwave at 100 °C for 60 minutes. The reaction mixtures were combined, poured into water, and extracted with DCM (3 times). The organic layer was dried over Na2SO4, filtered, and concentrated to give I-23A, which was used without further purification. MS m / z 290.3 (M+1).

[0353] tert-Butyl 3-((2-ethoxy-2-oxoethyl)sulfonyl)pyrrolidine-1-carboxylate (I-23B) was prepared from I-23A following a procedure similar to that described for I-22B. MS m / z 323.3 (M+1).

[0354] tert-Butyl 3-((1-(ethoxycarbonyl)cyclopropyl)sulfonyl)pyrrolidine-1-carboxylate (I-23C) was prepared from I-23B following a procedure similar to that described for I-2C. MS m / z 292.1 (M-tBu+1).

[0355] tert-Butyl 3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)pyridine Roridin-1-carboxylate (I-23D) was prepared from I-23C following a procedure similar to that described for I-2D. MS m / z 250.1 (M-tBu+1).

[0356] tert-Butyl 3-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)sulfonyl)pyrrolidine-1-carboxylate (I-23) was prepared from I-23D following a procedure similar to that described for I-2. MS m / z 384.2 (M+1), 328.1 (M-tBu+1). Intermediate 24 (1-((3,3-difluorocyclobutyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0357] Ethyl 2-((3,3-difluorocyclobutyl)thio)acetate (I-24A). A microwave vial was charged with DMF (14.8 mL), ethyl 2-mercaptoacetate (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). The vial was sealed and stirred in a microwave at 100 °C for 1 h. The reaction mixture was poured into water and extracted with DCM (3 times). The organic layer was dried over Na2SO4, filtered, and concentrated to provide I-24A, which was used without further purification.

[0358] Ethyl 2-((3,3-difluorocyclobutyl)sulfonyl)acetate (I-24B) was prepared from I-24A following a procedure similar to that described for I-22B. 1 H NMR (400 MHz, CDCl3) δ ppm 1.24 - 1.42 (m, 3 H) 2.83 - 3.04 (m, 2 H) 3.04 - 3.22 (m, 2 H) 3.93 (s, 2 H) 3.95 - 4.09 (m, 1 H) 4.17 - 4.39 (m, 3 H). No ionization by LCMS.

[0359] Ethyl 1-((3,3-difluorocyclobutyl)sulfonyl)cyclopropanecarboxylate (I-24C) was prepared from I-24B following a procedure similar to that described for I-2C. 1 H NMR (400 MHz, CDCl3) δ ppm MS m / z 269.1 (M+1).

[0360] (1-((3,3-difluorocyclobutyl)sulfonyl)cyclopropyl)methanol I-24D was prepared from I-24C following a procedure similar to that described for I-2D. MS m / z 227.1 (M+1).

[0361] (1-((3,3-Difluorocyclobutyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-24) was prepared from I-24D following a procedure similar to that described for I-2. MS m / z 305.1 (M+1). Intermediate 25 (1-((3,3-difluoroazetidin-1-yl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0362] Methyl 2-((3,3-difluoroazetidin-1-yl)sulfonyl)acetate (I-25A) was prepared according to the general procedure in Northup, A. et al. J. Med. Chem. 2013, 56, 2294. Hunig's base (4.25 mL, 24.32 mmol) was added to a suspension of 3,3-difluoroazetidin-1-ium chloride (900 mg, 6.95 mmol) in DCM (34.7 mL) under N2 and at 0°C. After 5 min, methyl 2-(chlorosulfonyl)acetate (1799 mg, 10.42 mmol) was added dropwise to the reaction flask. The reaction mixture was gradually warmed to RT and stirred for 4 days. The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM (2x) and the combined organic layers were washed with 1N HCl and brine, dried over Na2SO4, filtered and concentrated to give I-25A, which did not ionize by LCMS.

[0363] Methyl 1-((3,3-difluoroazetidin-1-yl)sulfonyl)cyclopropanecarboxylate (I-25B) was prepared from I-25A following a procedure similar to that described for I-2C. 1 H NMR (400 MHz, CDCl3) δ ppm 1.25 (t, J=7.14 Hz, 2 H) 1.61 - 1.68 (m, 2 H) 1.70 - 1.84 (m, 2 H) 3.78 (s, 3 H) 4.42 (t, J=12.23 Hz, 4 H). MS m / z 256.1 (M+1).

[0364] (1-((3,3-Difluoroazetidin-1-yl)sulfonyl)cyclopropyl)methanol (I-25C) was prepared from I-25B following a procedure similar to that described for I-2D. MS m / z 228.2 (M+1).

[0365] (1-((3,3-Difluoroazetidin-1-yl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-25) was prepared from I-25C following a procedure similar to that described for I-2. MS m / z 306.1 (M+1). Intermediate 26 (1-(azetidin-1-ylsulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0366] Methyl 2-(azetidin-1-ylsulfonyl)acetate (I-26A). To a solution of azetidine (2.343 mL, 34.8 mmol) in DCM (26.1 mL) was added dropwise a solution of methyl 2-(chlorosulfonyl)acetate (3 g, 17.38 mmol) in DCM (8.7 mL) at 0 °C. The reaction mixture was gradually brought to RT. Brine was added and the contents were extracted with DCM (3 times). The combined organic layers were dried over Na SO , filtered, and concentrated in vacuo to afford I-26A as a yellow oil. This material was used without further purification. MS m / z 194.0 (M+1).

[0367] Methyl 1-(azetidin-1-ylsulfonyl)cyclopropanecarboxylate (I-26B) was prepared from I-26A following a procedure similar to that described for I-2C. 1 H NMR (400 MHz, CDCl3) δ ppm 1.49 - 1.64 (m, 2 H) 1.64 - 1.77 (m, 2 H) 2.12 - 2.35 (m, 2 H) 3.76 (s, 3 H) 4.03 - 4.22 (m, 4 H). MS m / z 220.1 (M+1).

[0368] (1-(Azetidin-1-ylsulfonyl)cyclopropyl)methanol (I-26C) was prepared from I-26B following a procedure similar to that described for I-2D. MS m / z 192.1 (M+1).

[0369] (1-(Azetidin-1-ylsulfonyl)cyclopropyl)methyl methanesulfonate (I-26) was prepared from I-26C following a procedure similar to that described for I-2. MS m / z 269.3 (M+1). Intermediate 27 (1-(2-oxooxazolidin-3-yl)cyclopropyl)methyl methanesulfonate [ka]

[0370] Benzyl 1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylate (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 RT. The reaction mixture was stirred at RT for 5 days, after which ion-exchanged water (80 mL) was added. The resulting suspension was stirred at RT for 10 min, and the title compound (I-27A) was collected as a white solid by vacuum filtration. MS m / z 292.3 (M+1).

[0371] Benzyl 1-(((2-bromoethoxy)carbonyl)amino)cyclopropanecarboxylate (I-27B). To a solution of I-27A (800 mg, 2.75 mmol) in DCM (10.3 mL) under N and at 0° C. was added TFA (10.3 mL) over 2 min. The reaction was warmed to RT and stirred for 16 h. The TFA and DCM were removed by rotary evaporation, and the resulting clear oil was concentrated twice from heptane.

[0372] The residue was dissolved in DCM (15 mL) and cooled to 0 °C under N. DMAP (67.1 mg, 0.549 mmol) and NEt (1.148 mL, 8.24 mmol) were added, followed by the dropwise addition of a solution of 2-bromoethyl carbonochloridate (0.295 mL, 2.75 mmol) in DCM (5 mL). After 3 h, the mixture was diluted with DCM and washed with 1 N NaCO. The aqueous layer was extracted with DCM (2 times). The combined organic layers were dried over NaSO, filtered, and concentrated to give I-27B as an off-white solid. MS m / z 344.2 (M+1).

[0373] Benzyl 1-(2-oxooxazolidin-3-yl)cyclopropanecarboxylate (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) under N and at 0 °C. The reaction mixture was warmed to RT and stirred for 16 h, after which it was partitioned between EtOAc and ion-exchanged water. The aqueous layer was extracted with DCM (twice), and the combined organic layers were dried over NaSO, filtered, and concentrated to give I-27C as a cloudy, pale yellow oil. MS m / z 262.2 (M+1).

[0374] 3-(1-(hydroxymethyl)cyclopropyl)oxazolidin-2-one (I-27D) was prepared from I-27C following a procedure similar to that described for I-2D. MS m / z 158.0 (M+1).

[0375] (1-(2-oxooxazolidin-3-yl)cyclopropyl)methylmethanesulfonate The ester (I-27) was prepared from I-27D following a procedure similar to that described for I-2. MS m / z 236.1 (M+1). Intermediate 28 (1-(N,N-dimethylsulfamoyl)cyclopropyl)methyl methanesulfonate [ka]

[0376] Methyl 2-(N,N-dimethylsulfamoyl)acetate (I-28A) was prepared according to Northup, A. et al. J. Med. Chem. 2013, 56, 2294. To a solution of 2 M dimethylamine in THF (19.47 mL, 38.9 mmol) in DCM (10 mL) was added dropwise a solution of methyl 2-(chlorosulfonyl)acetate (3.36 g, 19.47 mmol) in DCM (10 mL) at 0 °C. The reaction mixture was gradually brought to RT. Brine was added, and the contents were extracted with DCM (3 x). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give I-28A as a yellowish-orange oil. 1 H NMR (500 MHz, CDCl3) δ ppm 2.89 - 3.00 (m, 6 H) 3.83 (s, 3 H) 3.95 - 4.02 (m, 2 H). MS m / z 182.2 (M+1).

[0377] Methyl 1-(N,N-dimethylsulfamoyl)cyclopropanecarboxylate (I-28B) was prepared from I-28A following a procedure similar to that described for I-2C. 1 H NMR (500 MHz, CDCl3) δ ppm 1.61 - 1.67 (m, 2 H) 1.72 - 1.83 (m, 2 H) 3.00 (s, 6 H) 3.80 (s, 3 H). MS m / z 208.1 (M+1).

[0378] 1-(Hydroxymethyl)-N,N-dimethylcyclopropane-1-sulfonamide (I-28C) was prepared from I-28B following a procedure similar to that described for I-2D. MS m / z 180.2 (M+1).

[0379] (1-(N,N-dimethylsulfamoyl)cyclopropyl)methyl methanesulfonate (I-28) was prepared from I-28C following a procedure similar to that described for I-2.1 H NMR (500 MHz, CDCl3) δ ppm 1.09 - 1.24 (m, 2 H) 1.50 - 1.68 (m, 2 H) 2.97 (s, 6 H) 3.10 (s, 3 H) 4.46 (s, 2 H). MS m / z 258.2 (M+1). Intermediate 29 (1,1-dioxidetetrahydrothiophen-2-yl)methyl methanesulfonate [ka]

[0380] Tetrahydrothiophene-2-carboxylic acid 1,1-dioxide (I-29A). A 2 M solution of 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) under N and at -78 °C. After 30 min, the yellow suspension was allowed to warm to RT for 10 min and then cooled to -50 °C. The nitrogen inlet was removed, and CO was bubbled through the suspension for 1 h. The reaction mixture became a white suspension, which was gradually warmed to RT and stirred for 3 days. The reaction was quenched with deionized water, and the mixture was partitioned between water and EtOAc. The aqueous layer was washed with EtOAc (2×). The aqueous layer was acidified with 1N and 6N HCl and then extracted with chloroform (3×). NaCl (solid) was added to the aqueous phase, which was re-extracted with chloroform. The combined organic phases were dried over NaSO, filtered, and concentrated in vacuo to afford I-29A as a yellow oil. The crude product also contained unreacted starting material and residual solvent and was used without further purification. MS m / z 165.0 (M+1).

[0381] 2-(Hydroxymethyl)tetrahydrothiophene 1,1-dioxide (I-29B). 1 M Borane tetrahydrofuran 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) under N and at 0° C. The reaction was gradually warmed to RT and stirred overnight. The reaction was quenched by the addition of deionized water and partitioned between DCM and water. The aqueous layer was extracted with chloroform (2×) and 3:1 chloroform:isopropanol (3×). The combined organic layers were washed with 1 N HCl, dried over NaSO, filtered, and concentrated to give I-29B as a clear oil. This material was used without further purification. MS m / z 150.9 (M+1).

[0382] (1,1-Dioxidetetrahydrothiophen-2-yl)methyl methanesulfonate (I-29) was prepared from I-28C following a procedure similar to that described for I-2. The crude product was purified on SiO (0-100% EtOAc / heptane) to afford I-29 as a clear oil. MS m / z 229.1 (M+1). Intermediate 30 1-(aminomethyl)-N-(tert-butyl)cyclopropane-1-sulfonamide [ka]

[0383] N-(tert-butyl)cyclopropanesulfonamide (I-30A) was synthesized by WO200 Prepared according to 8137779. Neat 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) under N and at −20° C. (dry ice / acetone). The resulting orange solution was gradually warmed to RT and stirred for 16 h. The resulting suspension was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was dissolved in DCM and washed with 1 N HCl, water, and brine. The organic phase was dried over NaSO, filtered, and concentrated. The orange solid was recrystallized from 5:1 heptane:EtOAc to give I-30A as white crystals.

[0384] N-(tert-butyl)-1-formylcyclopropane-1-sulfonamide (I-30B) was prepared according to WO2012151195. 1.6 M n-butyllithium in hexanes (28.9 mL, 46.3 mmol) was added dropwise over 10 min to a stirred solution of I-30A (4.0 g, 22.57 mmol) in THF (90 mL) at −78 °C under N. The reaction mixture was stirred at −78 °C for 30 min and then at RT 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 RT and stirred overnight. The reaction was quenched with deionized water and extracted with EtOAc (twice). The aqueous layer was acidified to pH 2 with 1 N HCl, resulting in gas evolution, and extracted with EtOAc (twice). The organic layers were combined and washed with 1N HCl and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give I-30B as a white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 1.35 (s, 9 H) 1.56 - 1.69 (m, 2 H) 1.79 - 1.93 (m, 2 H) 9.53 (s, 1 H). MS m / z 206.3 (M+1).

[0385] N-(tert-butyl)-1-(hydroxymethyl)cyclopropane-1-sulfonamide (I-30C) was prepared according to WO2012151195. 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 evolution. After 10 min, brine was added to the flask, and the contents were extracted with EtOAc (twice) and 3:1 chloroform:isopropanol (once). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give I-30C as a white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 0.94 - 1.07 (m, 2 H) 1.31 - 1.42 (m, 9 H) 1.42 - 1.54 (m, 2 H) 2.62 - 2.84 (m, 1 H) 3.85 (s, 2 H) 4.27 - 4.49 (m, 1 H). MS m / z 208.3 (M+1).

[0386] (1-(N-(tert-butyl)sulfamoyl)cyclopropyl)methyl methanesulfonate (I-30D) was prepared from I-30C following a procedure similar to that described for I-2. 1 H NMR (400 MHz, CDCl3) δ ppm 1.07 - 1.18 (m, 2 H) 1.31 - 1.42 (m, 10 H) 1.54 - 1.63 (m, 2 H) 3.08 (s, 3 H) 4.52 (s, 2 H). MS m / z 286.1 (M+1).

[0387] 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 RT. The flask was immersed in a 60 °C oil bath and stirred under N. After 1 h, the temperature was raised to 90 °C. After 5 h, the reaction mixture was cooled to RT, poured onto crushed ice, and extracted with EtOAc (3 times). The combined organic layers were dried over NaSO, filtered, and concentrated to give I-30E. MS m / z 233.3 (M+1).

[0388] 1-(Aminomethyl)-N-(tert-butyl)cyclopropane-1-sulfonamide (I-30). To a slurry of 10% Pd—C (0.280 g, 0.263 mmol) in THF (3.37 mL) under N was added a solution of I-30E (1.222 g, 5.26 mmol) in MeOH (84 mL). The atmosphere was exchanged by three vacuum / H cycles. The reaction mixture was stirred under 1 atm H for 16 h and then filtered through a pad of Celite. The filtrate was concentrated, and the residue was azeotropically dried twice with toluene to give I-30 as a white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 0.80 - 0.90 (m, 2 H) 1.37 (s, 9 H) 1.40 - 1.47 (m, 3 H) 3.08 (s, 2 H) 4.86 - 5.05 (m, 1 H). MS m / z 207.1 (M+1). Intermediate 31 1-(aminomethyl)-N-(tert-butyl)-N-methylcyclopropane-1-sulfonamide [ka]

[0389] Methyl 2-(N-(tert-butyl)-N-methylsulfamoyl)acetate (I-31A) was prepared from methyl 2-(chlorosulfonyl)acetate and N,2-dimethylpropan-2-amine following a procedure similar to that described for I-26A. 1 H NMR (400 MHz, CDCl3) δ ppm 1.45 (s, 9 H) 2.92 (s, 3 H) 3.79 (s, 3 H) 4.00 (s, 2 H). MS m / z 224.3 (M+1).

[0390] Methyl 1-(N-(tert-butyl)-N-methylsulfamoyl)cyclopropanecarboxylate (I-31B) was prepared from I-31A following a procedure similar to that described for I-2C. 1 H NMR (400 MHz, CDCl3) δ ppm 1.40 (s, 9 H) 1.60 - 1.68 (m, 2 H) 1.73 - 1.88 (m, 2 H) 3.04 (s, 3 H) 3.76 (s, 3 H). MS m / z 250.3 (M+1), 194.2 (M-tBu+1).

[0391] N-(tert-butyl)-1-(hydroxymethyl)-N-methylcyclopropane-1-sulfonamide (I-31C) was prepared from I-31B following a procedure similar to that described for I-2D. MS m / z 222.3 (M+1), 194.2 (M-tBu+1).

[0392] (1-(N-(tert-butyl)-N-methylsulfamoyl)cyclopropyl)methyl methanesulfonate (I-31D) was prepared from I-31C following a procedure similar to that described for I-2. MS m / z 244.1 (M-tBu+1).

[0393] 1-(Azidomethyl)-N-(tert-butyl)-N-methylcyclopropane-1-sulfonamide (I-31E) was prepared from I-31D following a procedure similar to that described for I-30E. MS m / z 191.1 (M-tBu+1).

[0394] 1-(Aminomethyl)-N-(tert-butyl)-N-methylcyclopropane-1-sulfonamide (I-31) was prepared from I-31E following a procedure similar to that described for I-30. MS m / z 221.3 (M+1). Intermediate 32 2-Amino-N,N-dimethylethanesulfonamide [ka]

[0395] 2-(1,3-Dioxoisoindolin-2-yl)-N,N-dimethylethanesulfonamide (I-32A) was prepared according to WO2012115256. To a solution of 2-phthalimidoethanesulfonyl chloride (3.04 g, 11.11 mmol) in THF (40 mL) was added dropwise dimethylamine (40%, aq.) (3.09 mL, 24.44 mmol). The flask was capped, and the reaction was stirred at RT for 30 min. The mixture was concentrated in vacuo, and the resulting white paste was partitioned between saturated aqueous NaHCO3 and 10:1 EtOAc:DCM. The aqueous layer was extracted twice more with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give I-32A as a white solid. MS m / z 283.7 (M+1).

[0396] 2-Amino-N,N-dimethylethanesulfonamide (I-32) was prepared according to WO2012115256. To a stirred suspension of I-32A (1.3 g, 4.60 mmol) in EtOH (46.0 mL) at RT was added hydrazine hydrate, 65% (0.704 mL, 9.44 mmol). The mixture was stirred at RT for 1 h, during which time a white precipitate formed, and then stirred at reflux (80 °C) for 2 h. Upon stirring at reflux, the solution initially became homogeneous, and then a white precipitate separated out. The flask was cooled to RT, and the solid was removed by vacuum filtration. The flask and filter cake were rinsed with additional EtOH. The filtrate was concentrated in vacuo, and the resulting residue was dissolved in DCM. The remaining precipitate was again removed by vacuum filtration, and the filtrate was concentrated to give 2-amino-N,N-dimethylethanesulfonamide I-32 as a pale yellow oil. 1 H NMR (500 MHz, CDCl3) δ ppm 1.56 - 1.97 (m, 2 H) 2.86 - 2.96 (m, 6 H) 3.02 - 3.13 (m, 2 H) 3.24 (t, J=6.15 Hz, 2 H). MS m / z 153.1 (M+1). Intermediate 33 tert-Butyl (2-((2-hydroxypropyl)amino)ethyl)(methyl)carbamate [ka]

[0397] tert-Butyl (2-((2-hydroxypropyl)amino)ethyl)(methyl)carbamate (I-33) was prepared according to the general procedure in PCT International Patent Application No. 2007092435. To a suspension of 10% Pd—C (0.614 g, 0.577 mmol) in EtOAc (2 mL) was added MeOH (80 mL) under nitrogen. To the stirred suspension was added tert-butyl methyl (2-oxoethyl)carbamate (2 g, 11.55 mmol) and 1-aminopropan-2-ol (1.337 mL, 17.32 mmol). The atmosphere was exchanged for H2 by three vacuum / H2 cycles. The reaction mixture was stirred under H2 at RT for 3 days, after which it was filtered through Celite and rinsed with additional methanol. The crude residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed two more times with saturated aqueous NaHCO3, diluted with DCM, dried over Na2SO4, filtered, and concentrated to give I-33 as a clear oil. MS m / z 233.2 (M+1). Intermediate 34 tert-Butyl (2-((1-hydroxypropan-2-yl)amino)ethyl)(methyl)carbamate [ka]

[0398] tert-Butyl (2-((1-hydroxypropan-2-yl)amino)ethyl)(methyl)carbamate (I-34) was prepared from tert-butyl methyl (2-oxoethyl)carbamate and 2-aminopropan-1-ol following a procedure similar to that described for I-33. MS m / z 233.3 (M+1). Intermediate 35 Butyl 9-methyl-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylate [ka]

[0399] Butyl 5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (I-35A). To a suspension of 5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (5 g, 29.9 mmol) in butan-1-ol (120 mL) was added 37% hydrochloric acid (3 mL). The resulting suspension was stirred at 115 °C for 6 days. After cooling the reaction to RT, the unreacted acid was separated from the product by vacuum filtration. The filtrate was concentrated in vacuo using heptane to azeotropically remove butan-1-ol. The resulting residue was suspended in DCM and the contents were filtered again. The orange filtrate was diluted with DCM and saturated The mixture was washed once with aqueous NaHCO. The organic layer was dried over NaSO, filtered, and concentrated to give an orange oil. Heptane was added, and the contents were concentrated again to give the title compound (I-35A) as a yellowish-orange powder. MS m / z 224.2 (M+1).

[0400] 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 at reflux for 5 h, after which it was cooled to RT and filtered through a pad of Celite and NaSO. The filtrate was concentrated in vacuo. The reddish-orange solid was suspended in DCM, and the contents were vacuum filtered through a pad of Celite. The filtrate was washed once with ion-exchanged water, dried over NaSO, filtered, and concentrated in vacuo to give I-35B as a yellowish-orange solid. MS m / z 238.2 (M+1).

[0401] 5-(Butoxycarbonyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (I-35C). 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) was added sodium dihydrogen phosphate (1.449 g, 12.08 mmol) and sodium chlorite (1.365 g, 12.08 mmol) sequentially at 0 °C. The reaction mixture was gradually warmed to RT and stirred overnight. The mixture was acidified to pH 2 with 1 N HCl and extracted with DCM (3 times). The combined organic layers were dried over Na SO , filtered, and concentrated to give I-35C. MS m / z 254.2 (M+1).

[0402] Butyl 6-((2-chloroethyl)carbamoyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (I-35D) was prepared from I-35C following a procedure similar to that described for I-1E. The title compound was obtained as a dark brown solid. MS m / z 315.3 (M+1).

[0403] Butyl 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 at 100 °C in a microwave for 10 min. The reaction mixture was diluted with ion-exchanged 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 give I-35 as a brown solid. 1 H NMR (500 MHz, CDCl3) δ ppm 0.99 (t, J=7.41 Hz, 3 H) 1.41 - 1.53 (m, 2 H) 1.53 - 1.65 (m, 9 H) 1.71 - 1.85 (m, 2 H) 2.52 (s, 3 H) 3.52 - 3.70 (m, 2 H) 4.24 - 4.45 (m, 4 H). MS m / z 279.2 (M+1). Intermediate 36 (1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0404] Butyl 1-methylcyclopropane-1-sulfonate (I-36A). To butyl cyclopropanesulfonate (11.2 g, 62.8 mmol) in THF (200 mL) was added dropwise butyllithium (47.1 mL, 75 mmol) at −78°C. The reaction was stirred at −78°C for 1 h, and then iodomethane (7.82 mL, 126 mmol) was added. The reaction was stirred at −78°C for 1 h and warmed to RT. The reaction 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 (NaSO), and concentrated. Purification on SiO (0–50% EtOAc / heptane) afforded I-36A as a white solid. MS m / z 193.2 (M+1).

[0405] Potassium 1-methylcyclopropane-1-sulfonate (I-36B). To I-36A (10.4 g, 54.1 mmol) in water / DME (150 mL / 150 mL) was added potassium thiocyanate (5.52 g, 56.8 mmol). The reaction was heated to reflux and stirred for 18 hours. The solvent was removed under reduced pressure, and the resulting solid was dried under high vacuum at 50° C. for 5 hours. The crude product (I-36B) was used without further purification.

[0406] Methylcyclopropane-1-sulfonyl chloride (I-36C). To I-36B (9.43 g, 54.1 mmol) in sulfite dichloride (150 mL, 54.1 mmol) was added DMF (1 mL). The reaction was heated to reflux for 16 h. The volatiles were removed under reduced pressure, and the residue was diluted with DCM (200 mL). The organic phase was washed with water (50 mL), dried (MgSO), and concentrated to give the crude product (I-36C), which was used without further purification.

[0407] Sodium 1-methylcyclopropane-1-sulfinate (I-36D) was prepared from I-36C following a procedure similar to that described for I-4E. No ionization was observed by LCMS.

[0408] Benzyl 2-((1-methylcyclopropyl)sulfonyl)acetate (I-36E) was prepared from I-36D following a procedure similar to that described for I-21D. MS m / z 269.2 (M+1).

[0409] Benzyl 1-((1-methylcyclopropyl)sulfonyl)cyclopropanecarboxylate (I-36F) was prepared from I-36E following a procedure similar to that described for I-2C. MS m / z 295.3 (M+1).

[0410] (1-((1-Methylcyclopropyl)sulfonyl)cyclopropyl)methanol (I-36G). To a solution of I-36F (5.7 g, 19.36 mmol) in EtO (100 mL) was added lithium borohydride (0.633 g, 29.0 mmol), followed by the dropwise addition of methanol (1.178 mL, 29.0 mmol). The reaction became milky 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 HCl (4 M, 15 mL) to pH 2. The mixture was concentrated under reduced pressure. The crude product was purified over SiO (0–100% EtOAc / heptane) to afford I-36G as a clear oil. MS m / z 191.2 (M+1).

[0411] (1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-36) was prepared from I-36G following a procedure similar to that described for I-2. I-36 was obtained as a white solid. MS m / z 269.2. Intermediate 37 (1-((1-(difluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0412] Potassium 1-methylcyclopropane-1-sulfonate (I-37B). A solution of oxalyl dichloride (1.305 mL, 14.91 mmol) in DCM (100 mL) was cooled to -78 °C. To the cooled solution was added a solution of DMSO (1.630 mL, 22.94 mmol) in DCM (10 mL). The resulting mixture was stirred at -78 °C for 20 minutes, after which a solution of I-4H (3.40 g, 11.47 mmol) in DCM (10 mL) was added. The resulting mixture was stirred at -78 °C for 1 hour. To the reaction was added NEt (7.99 mL, 57.4 mmol). The reaction was warmed to 0 °C and stirred for 2 hours, after which it was quenched with saturated ammonium chloride. The biphasic mixture was extracted with DCM. The organic extract was washed with ammonium chloride and brine, dried over Na2SO4, and concentrated to give the title product (I-37B) as a yellow oil. MS m / z 295.2 (M+1).

[0413] (((1-((1-(difluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (I-37C). To I-37B (3.38 g, 11.48 mmol) in chloroform (20 mL) was added DAST (4.55 mL, 34.4 mmol). The reaction was stirred at 60 °C for 3 h, after which it was cooled to RT and water (10 mL) was added. The phases were separated and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organics were dried (NaSO) and concentrated. The residue was purified on SiO (0–100% EtOAc / heptane) to give I-37C. MS m / z 317.3 (M+1).

[0414] (1-((1-(difluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (I-37D). I-37C (700 mg, 2.2 mL) in HOAc (10 mL) A flask containing I-37D (100 mg, 1 mmol) and 10% Pd / C (706 mg, 0.66 mmol) was purged with N and charged with H (balloon). The reaction was stirred for 3 h, after which water (15 mL) was added and the mixture was extracted with DCM (2 x 30 mL). The combined organics were dried (NaSO) and concentrated to give I-37D. MS m / z 227.1 (M+1).

[0415] Ethyl 1-(cyclobutylsulfonyl)cyclopropanecarboxylate (I-37). To I-37D (480 mg, 2.122 mmol) and triethylamine (325 μL, 2.334 mmol) in DCM (10 mL) was added methanesulfonyl chloride (174 μL, 2.228 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 h and warmed to RT for 30 min. The mixture was quenched by the addition of cold water. The phases were separated, and the organic layer was dried (MgSO) and concentrated to give I-37 as a white solid. MS m / z 305.1 (M+1). Intermediate 38 (1-(((3-methyloxetan-3-yl)methyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0416] Ethyl 2-(((3-methyloxetan-3-yl)methyl)thio)acetate (I-38A). To a solution of ethyl 2-mercaptoacetate (1.827 ml, 16.66 mmol) in acetone (100 mL) was added K2CO3 (4.19 g, 30.3 mmol) and 3-(bromomethyl)-3-methyloxetane (2.5 g, 15.15 mmol). To the reaction was added NaI (0.454 g, 3.03 mmol). The resulting mixture was stirred at 60 °C for 3 days. The reaction was cooled to RT and filtered to remove insoluble material. The filtrate was concentrated to provide I-38A, which was used without further purification. MS m / z 205.2 (M+1).

[0417] Ethyl 2-(((3-methyloxetan-3-yl)methyl)sulfonyl)acetate (I-38B) was prepared from I-38A following a procedure similar to that described for I-9C. I-38B was isolated as a colorless oil that solidified to a waxy solid. MS m / z 237.1 (M+1).

[0418] Ethyl 1-(((3-methyloxetan-3-yl)methyl)sulfonyl)cyclopropane-1-carboxylate (I-38C) was prepared from I-38B following a procedure similar to that described for I-2C. MS m / z 263.2 (M+1).

[0419] (1-(((3-Methyloxetan-3-yl)methyl)sulfonyl)cyclopropyl)methanol (I-38D) was prepared from I-38C following a procedure similar to that described for I-2D. MS m / z 221.2 (M+1).

[0420] (1-(((3-Methyloxetan-3-yl)methyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-38) was prepared from I-38D following a procedure similar to that described for I-2. MS m / z 299.2 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 4.66 (d, J=6.36 Hz, 2 H) 4.55 (s, 2 H) 4.44 (d, J=6.36 Hz, 2 H) 3.55 (s, 2 H) 3.10 (s, 3 H) 1.68 (s, 3 H) 1.62 - 1.66 (m, 2 H) 1.21 - 1.26 (m, 2 H). Intermediate 39 (1-(((1-(trifluoromethyl)cyclopropyl)methyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0421] (1-(Trifluoromethyl)cyclopropyl)methyl methanesulfonate (I-39A) was prepared from (1-(trifluoromethyl)cyclopropyl)methanol following a procedure similar to that described for I-2. The title compound (I-39A) was isolated as a red oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.31 (s, 2 H) 3.06 (s, 3 H) 1.18 - 1.24 (m, 2 H) 0.93 - 0.99 (m, 2 H).

[0422] Ethyl 2-(((1-(trifluoromethyl)cyclopropyl)methyl)thio)acetate (I-39B). To a solution of ethyl 2-mercaptoacetate (681 μL, 6.21 mmol) in acetone (10 mL) was added KCO (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) sequentially. 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 (400 MHz, CDCl3) δ ppm 4.19 - 4.22 (m, 2 H) 3.23 (s, 2 H) 3.00 (s, 2 H) 1.28 - 1.31 (m, 3 H) 1.04 - 1.11 (m, 2 H) 0.80 - 0.86 (m, 2 H).

[0423] Ethyl 2-(((1-(trifluoromethyl)cyclopropyl)methyl)sulfonyl)acetate (I-39C) was prepared from I-39B following a procedure similar to that described for I-9C. MS m / z 275.2 (M+1). 1 H NMR (400 MHz, CDCl3) δ ppm 4.25 - 4.31 (m, 2 H) 4.02 (s, 2 H) 3.66 (s, 2 H) 1.31 - 1.34 (m, 3 H) 1.24 - 1.28 (m, 2 H) 1.18 - 1.23 (m, 2 H).

[0424] Ethyl 1-(((1-(trifluoromethyl)cyclopropyl)methyl)sulfonyl)cyclopropane-1-carboxylate (I-39D) was prepared from I-39C following a procedure similar to that described for I-2C. 1 H NMR (400 MHz, CDCl3) δ ppm 4.16 - 4.31 (m, 2 H) 3.77 (s, 2 H) 1.79 - 1.85 (m, 2 H) 1.64 - 1.70 (m, 2 H) 1.27 - 1.34 (m, 4 H) 1.24 (s, 4 H).

[0425] (1-(((1-(trifluoromethyl)cyclopropyl)methyl)sulfonyl)cyclopropyl)methanol (I-39E) was prepared from I-39D following a procedure similar to that described for I-2D. MS m / z 259.2 (M+1).

[0426] (1-(((1-(trifluoromethyl)cyclopropyl)methyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-39) was prepared from I-39E following a procedure similar to that described for I-2. MS m / z 337.2 (M+1). Intermediate 40 (1-((tetrahydro-2H-pyran-4-yl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0427] Ethyl 2-((tetrahydro-2H-pyran-4-yl)thio)acetate (I-40A) was prepared from ethyl 2-mercaptoacetate and 4-bromotetrahydro-2H-pyran following a procedure similar to that described for I-24A. The title product (I-40A) was isolated as an orange oil. MS m / z 205.2 (M+1).

[0428] Ethyl 2-((tetrahydro-2H-pyran-4-yl)sulfonyl)acetate (I-40B) was prepared from I-40A following a procedure similar to that described for I-9C. I-40B was isolated as a colorless oily residue. MS m / z 237 (M+1).

[0429] Ethyl 1-((tetrahydro-2H-pyran-4-yl)sulfonyl)cyclopropanecarboxylate (I-40C) was prepared from I-40B following 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).

[0430] (1-((tetrahydro-2H-pyran-4-yl)sulfonyl)cyclopropyl)methanol (I-40D) was prepared from I-40C following a procedure similar to that described for I-2D. I-40D was isolated as a white solid. MS m / z 221 (M+1).

[0431] (1-((tetrahydro-2H-pyran-4-yl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-40) was prepared from I-40D following a procedure similar to that described for I-2. I-40 was isolated as a brown oil. MS m / z 299 (M+1). Intermediate 41 (1-(tert-butylsulfinyl)cyclopropyl)methyl methanesulfonate [ka]

[0432] Benzyl 2-(tert-butylthio)acetate (I-41A). To a solution of 2-methylpropane-2-thiol (5.9 mL, 52.4 mmol) in acetone (50 mL) was added KCO (11.7 g, 85 mmol), NaI (0.39 g, 2.6 mmol), and benzyl 2-bromoacetate (15 g, 65.5 mmol), sequentially. The resulting mixture was stirred at 25 °C for 2 h, after which it 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-41A as a yellow oil. MS m / z 239 (M+1).

[0433] Benzyl 2-(tert-butylsulfinyl)acetate (I-41B). To a solution of I-41A (12.5 g, 52.4 mmol) in methanol (150 mL) and water (15 mL) at 25 °C was added Oxone (17.7 g, 28.8 mmol). The resulting mixture was stirred at 25 °C for 20 min. The suspension was filtered through Celite, and the filtrate was concentrated. The resulting residue was partitioned between ion-exchanged water and DCM. The aqueous phase was extracted with DCM (twice), and the combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified on SiO (0–50% EtOAc / heptane) to give I-41B as a colorless oil. MS m / z 255 (M+1).

[0434] Benzyl 1-(tert-butylsulfinyl)cyclopropanecarboxylate (I-41C). To an ice-cooled solution of I-41B (1.6 g, 6.3 mmol) in DMA (20 mL) was added sodium hydride (60% suspension in mineral oil, 0.45 g, 11.3 mmol). The resulting mixture was stirred at 25 °C for 30 min. To this suspension was added 1,2-dibromoethane (1.4 g, 7.5 mmol), 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 SiO (0–50% EtOAc / heptane) to give I-41C. MS m / z 281 (M+1).

[0435] (1-(tert-Butylsulfinyl)cyclopropyl)methanol (I-41D) was prepared from I-41C following a procedure similar to that described for I-2D. I-41D was obtained as a colorless oil. MS m / z 177 (M+1).

[0436] (1-(tert-butylsulfinyl)cyclopropyl)methyl methanesulfonate (I-41) was prepared from I-41D following a procedure similar to that described for I-2. The title compound I-41 was obtained as a brown solid. MS m / z 255 (M+1). Intermediate 42 (1-((cyclopropylmethyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0437] Ethyl 2-((cyclopropylmethyl)thio)acetate (I-42A) was prepared from ethyl 2-mercaptoacetate and (bromomethyl)cyclopropane following a procedure similar to that described for I-38A. MS m / z 175 (M+1).

[0438] Ethyl 2-((cyclopropylmethyl)sulfonyl)acetate (I-42B) was prepared from I-42A following a procedure similar to that described for I-9C. MS m / z 207 (M+1).

[0439] Ethyl 1-((cyclopropylmethyl)sulfonyl)cyclopropanecarboxylate (I-42C) was prepared from I-42B following a procedure similar to that described for I-2C. The title compound I-42C was isolated as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 4.24 (q, J=7.14 Hz, 2H), 3.37 (d, J=7.29 Hz, 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 / z 233 (M+1).

[0440] (1-((cyclopropylmethyl)sulfonyl)cyclopropyl)methanol (I-42D) was prepared from I-42C following 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).

[0441] (1-((cyclopropylmethyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-42) was prepared from I-42D following a procedure similar to that described for I-2. The title compound I-42 was isolated as a yellow solid. MS m / z 269 (M+1). Intermediate 43 (1-(((1-(cyanomethyl)cyclopropyl)methyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0442] Ethyl 2-(((1-(cyanomethyl)cyclopropyl)methyl)thio)acetate (I-43A) was prepared from ethyl 2-mercaptoacetate and 2-(1-(bromomethyl)cyclopropyl)acetonitrile following a procedure similar to that described for I-38A. MS m / z 214 (M+1).

[0443] Ethyl 2-(((1-(cyanomethyl)cyclopropyl)methyl)sulfonyl)acetate (I-43B) was prepared from I-43A following a procedure similar to that described for I-9C. The title compound I-43B was isolated as a waxy solid. MS m / z 246 (M+1).

[0444] Ethyl 1-(((1-(cyanomethyl)cyclopropyl)methyl)sulfonyl)cyclopropanecarboxylate (I-43C) was prepared from I-43B following a procedure similar to that described for I-2C. MS m / z 272 (M+1).

[0445] 2-(1-(((1-(hydroxymethyl)cyclopropyl)sulfonyl)methyl)cyclopropyl)acetonitrile (I-43D) was prepared from I-43C following 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).

[0446] (1-(((1-(cyanomethyl)cyclopropyl)methyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-43) was prepared from I-42A following a procedure similar to that described for I-9C. The title compound I-43 was isolated as a brown solid. 1 H NMR (500 MHz, CDCl3) δ 4.55 (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). Intermediate 44 (1-(((1-methylcyclopropyl)methyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0447] Ethyl 2-(((1-methylcyclopropyl)methyl)thio)acetate (I-44A). To a solution of ethyl 2-mercaptoacetate (3.39 mL, 30.9 mmol) in DCM (50 mL) was added ZnI (3.29 g, 10.3 mmol) and (1-methylcyclopropyl)methanol (1.0 mL, 10.3 mmol). The resulting mixture was stirred at 20 °C for 8 days. Saturated aqueous NaHCO was slowly added to the reaction, which was stirred vigorously at RT until gas evolution ceased. The organic phase was separated and dried over MgSO. After concentration, crude I-44A was used in the next step without further purification. MS m / z 189.3 (M+1).

[0448] Ethyl 2-(((1-methylcyclopropyl)methyl)sulfonyl)acetate (I-44B) was prepared from I-44A following a procedure similar to that described for I-9C. The title compound I-44B was obtained as a white solid. MS m / z 221.1 (M+1).

[0449] Ethyl 1-(((1-methylcyclopropyl)methyl)sulfonyl)cyclopropane-1-carboxylate (I-44C) was prepared from I-44B following a procedure similar to that described for I-2C. MS m / z 247.2 (M+1).

[0450] (1-(((1-methylcyclopropyl)methyl)sulfonyl)cyclopropyl)methanol (I-44D) was prepared from I-44C following a procedure similar to that described for I-2D. MS m / z 205.1 (M+1).

[0451] (1-(((1-methylcyclopropyl)methyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-44) was prepared from I-44D following a procedure similar to that described for I-2. MS m / z 283.2 (M+1). Intermediate 45 (1-(((1-cyanocyclopropyl)methyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0452] Ethyl 2-(((1-cyanocyclopropyl)methyl)thio)acetate (I-45A) was prepared from ethyl 2-mercaptoacetate and 1-(bromomethyl)cyclopropane-1-carbonitrile following a procedure similar to that described for I-38A. The title compound I-45A was isolated as a brown oil. MS m / z 200.1 (M+1).

[0453] Ethyl 2-(((1-cyanocyclopropyl)methyl)sulfonyl)acetate (I-45B) was prepared from I-45A following a procedure similar to that described for I-9C. MS m / z 232.1 (M+1).

[0454] Ethyl 1-(((1-cyanocyclopropyl)methyl)sulfonyl)cyclopropane-1-carboxylate (I-45C) was prepared from I-45B following a procedure similar to that described for I-2C. MS m / z 258.1 (M+1).

[0455] 1-(((1-(hydroxymethyl)cyclopropyl)sulfonyl)methyl)cyclopropane-1-carbonitrile (I-45D) was prepared from I-45C following a procedure similar to that described for I-2D. MS m / z 216.1 (M+1).

[0456] (1-(((1-cyanocyclopropyl)methyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-45) was prepared from I-45D following a procedure similar to that described for I-2. MS m / z 294.2 (M+1). Intermediate 46 (1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0457] ((1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methoxy)(tert-butyl)dimethylsilane (I-46A). To a solution of I-4H (3 g, 10.12 mmol) and imidazole (2.067 g, 30.4 mmol) in DMF (20 mL) was added TBSCl (2.288 g, 15.18 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was diluted with EtO and washed with saturated citric acid, sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and reduced. Concentrated under reduced pressure. I-46A was isolated as a white solid. LCMS m / z: 411 (M+1). 1 H NMR (500 MHz, DMSO-d6) δ ppm 0.00 - 0.02 (m, 6 H) 0.84 (s, 9 H) 0.98 (td, J=4.73, 2.21 Hz, 2 H) 1.10 (td, J=4.73, 2.52 Hz, 2 H) 1.23 (td, J=4.41, 2.21 Hz, 2 H) 1.30 (td, J=4.73, 2.21 Hz, 2 H) 3.79 (s, 2 H) 3.94 (s, 2 H) 4.49 (s, 2 H) 7.27 - 7.39 (m, 5 H).

[0458] (1-((1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (I-46B). To a solution of I-46A (1.24 g, 3.02 mmol) in EtOH (10 mL) / AcOH (10 mL) was added Pd / C (0.16 g, 0.150 mmol). The atmosphere was exchanged for H. The resulting mixture was stirred at RT. Upon completion of the reaction, the mixture was filtered through a plug of Celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and washed with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. I-46B was isolated as a colorless oil. LCMS m / z: 321 (M+1). 1 H NMR (500 MHz, DMSO-d6) δ ppm 0.04 - 0.07 (m, 6 H) 0.87 (s, 9 H) 1.03 (ttt, J=5.36, 5.36, 3.78, 3.78, 2.52, 2.52 Hz, 4 H) 1.17 (td, J=4.73,2.52 Hz, 2 H) 1.24 (td, J=4.41, 2.52 Hz, 2 H) 3.79 (s, 2 H) 3.95 (s, 2 H).

[0459] (1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-46C) was prepared from I-46B following a procedure similar to that described for I-2. LCMS m / z: 399 (M+1). Intermediate 47 9-Bromo-N-(4-chlorobenzyl)-1,6-dioxo-1,3,4,6-tetrahydropyrido[2,1-c][1,4]oxazine-7-carboxamide [ka]

[0460] 5-Bromo-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (I-47A). NaOH (11.8 g, 295.0 mmol, 3.0 equiv.) was dissolved in water (150 mL) and cooled to 0 °C. Bromine (18.7 g, 118.0 mmol, 1.2 equiv.) was added. 6-Methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (15 g, 98.0 mmol, 1.0 equiv.) was dissolved in NaOH (11.7 g, 292.5 mmol, 2.98 equiv.) in water (45 mL) at 0 °C. NaOBr (prepared above) was added, and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was adjusted to pH 4.0 with 1 N HCl. Acidified to 5. 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 (400 MHz, DMSO-d6) δ 14.45 (s, 1H), 13.72 (s, 1H), 8.58 - 8.13 (m, 1H), 2.48 - 2.42 (m, 3H).

[0461] 5-Bromo-N-(4-chlorobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (I-47B) was prepared from I-47A following a procedure similar to that described for I-17B. LCMS (m / z): 356.0 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.98 (s, 1H), 8.28 (s, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 4.51 (d, J = 6.1 Hz, 2H), 2.38 (s, 3H).

[0462] 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 equiv) was added to a mixture of I-47B (15 g, 42.0 mmol, 1.0 equiv) in 1,4-dioxane (525 mL). The reaction mixture was stirred at 130 °C for 24 h, after which it was filtered through Celite. The filter cake was washed with dichloromethane, and the filtrate was concentrated. The crude residue was purified on SiO (100% dichloromethane) to give I-47C. LCMS (m / z): 369.3 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (d, J = 5.0 Hz, 1H), 9.82 (s, 1H), 8.43 (d, J = 23.7 Hz, 1H), 7.39 (dd, J = 8.5, 2.3 Hz, 2H), 7.34 (d, J = 6.6 Hz, 2H), 4.51 (t, J = 5.9 Hz, 2H).

[0463] 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 equiv) was dissolved in DMF (50 mL). Oxone (10 g, 32.5 mmol, 2.0 equiv) was added and the reaction mixture was stirred at RT for 6 h. The reaction mixture was quenched with water. The precipitated solid was filtered, washed with water and hexane, and triturated with 20% dichloromethane in hexane. The solvent was decanted to give I-47D. LCMS (m / z): 387.0 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 9.85 (s, 1H), 8.32 (d, J = 28.5 Hz, 1H), 8.37 - 6.31 (m, 4H), 4.52 (d, J = 5.9 Hz, 2H).

[0464] 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 following a procedure similar to that described for I-17. LCMS (m / z): 411.0 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (t, J = 6.1 Hz, 1H), 8.43 (s, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 4.77 - 4.63 (m, 2H), 4.55 (t, J = 5.7 Hz, 2H), 4.42 - 4.27 (m, 2H). Intermediate 48 tert-Butyl 2-methyl-2-((1-(((methylsulfonyl)oxy)methyl) Cyclopropyl)sulfonyl)propanoate [ka]

[0465] tert-Butyl 2-((2-methoxy-2-oxoethyl)thio)-2-methylpropanoate (I-48A). Methyl 2-mercaptoacetate (4.6 g, 22.0 mmol, 1.0 equiv) was dissolved in methanol (50 mL) and NaOMe (1.2 g, 22.0 mmol, 1.0 equiv) was added. The reaction mixture was stirred at RT for 2 min, after which tert-butyl 2-bromo-2-methylpropanoate (5 g, 22.0 mmol, 1.0 equiv) was added. The reaction mixture was stirred at RT for 18 h, then quenched with cold water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give the crude residue. The crude residue was purified by silica gel column chromatography (0-10% EtOAc / hexanes) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 3.63 (s, 2H), 1.41 (s, 9H), 1.38 (s, 6H). tert-Butyl 2-((2-methoxy-2-oxoethyl)sulfonyl)-2-methylpropanoate (I-48B) was prepared from I-48A following a procedure similar to that described for I-8C, replacing EtOH with EtOAc. 1 H NMR (400 MHz, DMSO-d6) δ 4.54 - 4.47 (m, 2H), 3.73 (s, 3H), 1.57 - 1.50 (m, 6H), 1.45 (d, J = 6.0 Hz, 9H).

[0466] Methyl 1-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropane-1-carboxylate (I-48C). A solution of I-48B (2.5 g, 8.0 mmol, 1.0 equiv) in DMF (5 mL) was degassed for 10 min. 1,2-Dibromoethane (2.5 g, 13.3 mmol, 1.5 equiv), KCO (3.7 g, 26.0 mmol, 3.0 equiv), and TBAB (0.03 g, 0.08 mmol, 0.01 equiv) 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 give the crude residue. The crude residue was purified by silica gel column chromatography (0–10% EtOAc / hexanes) to give I-48C. 1 H NMR (400 MHz, CDCl3) δ 3.85 - 3.74 (m, 3H), 1.88 - 1.81 (m, 2H), 1.72 - 1.67 (m, 8H), 1.52 (d, J = 6.5 Hz, 9H).

[0467] tert-Butyl 2-((1-(hydroxylmethyl)cyclopropyl)sulfonyl)-2-methylpropanoate (I-48D). I-48C (0.98 g, 3.2 mmol, 1.0 equiv) was dissolved in THF (16 mL) and LiAlH[OC(CH3)3]3 (1 M in THF) (16 mL) was added dropwise. The reaction 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 bed of Celite, which was rinsed with excess EtOAc. The filtrate was concentrated to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 4.05 - 3.98 (m, 1H), 3.81 (s, 2H), 1.58 (d, J = 14.1 Hz, 6H), 1.45 (d, J = 21.7 Hz, 9H), 1.21 (d, J = 11.5 Hz, 4H).

[0468] tert-Butyl 2-methyl-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)sulfonyl)propanoate (I-48). I-48D (0.2 g, 0.72 mmol, 1.0 equiv) was placed in THF (4 mL), TEA (0.22 g, 2.2 mmol, 3.0 equiv) was added, and the reaction mixture was cooled to 0 °C. MeSO2Cl (0.098 g, 0.86 mmol, 1.2 equiv) 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. Intermediate 49 (1-((1-methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methanamine hydrochloride [ka]

[0469] 2-Thioxopyridin-1(2H)-yl 3-methoxy-2,2-dimethylpropanoate (I-49A) was prepared from 3-methoxy-2,2-dimethylpropanoic acid following a procedure similar to that described for I-7B. I-49A was used without purification.

[0470] 2-((1-Methoxy-2-methylpropan-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 give I-49B. The product was used in the next step without further purification.

[0471] 2-((1-Methoxy-2-methylpropan-2-yl)sulfonyl)pyridine (I-49C). I-49B (4 g, 20.3 mmol, 1.0 equiv) was added to water (40 mL) and cooled to 10 °C. Oxone (28.7 g, 46.7 mmol, 2.3 equiv) was added, and the reaction mixture was stirred at RT 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 / hexanes) to give I-49C. LCMS (m / z): 229.8 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (ddd, J = 4.7, 1.7, 0.8 Hz, 1H), 8.15 (td, J = 7.8, 1.7 Hz, 1H), 8.03 (dt, J = 7.9, 1.0 Hz, 1H), 7.76 (ddd, J = 7.6, 4.7, 1.1 Hz, 1H), 3.48 (s, 2H), 3.09 (s, 3H), 1.31 (s, 6H).

[0472] Sodium 1-methoxy-2-methylpropane-2-sulfinate (I-49D). I-49C (1.1 g, 4.9 mmol, 1.0 equiv) was dissolved in THF (12 mL) and cooled to 0 °C. MeSNa (0.85 g, 12.2 mmol, 2.5 equiv) was added, and the reaction mixture was stirred at 0 °C for 2 h and at RT for 24 h. The reaction mixture was concentrated, and the residue was triturated with diethyl ether to remove methylthiopyridine. The crude product was further purified by silica gel column chromatography (20% MeOH / DCM) to give I-49D. 1 H NMR (400 MHz, D2O) δ 3.47 (s, 2H), 3.27 (s, 3H), 1.19 (s, 6H).

[0473] 2-((1-Methoxy-2-methylpropan-2-yl)sulfonyl)acetonitrile (I-49E). To a solution of I-49D (0.5 g, 2.9 mmol, 1.0 equiv) in DMF (5 mL) was added 2-bromoacetonitrile (0.37 g, 3.2 mmol, 1.1 equiv). The reaction mixture was stirred at RT for 24 h. It was 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 the crude residue. The crude residue was purified by silica gel column chromatography (20% EtOAc / hexanes) to give I-49E.

[0474] 1-((1-Methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropane-1-carbonitrile (I-49F). To a solution of I-49E (0.21 g, 1.1 mmol, 1.0 equiv) in DMF (4 mL) was added KCO (0.75 g, 5.5 mmol, 5.0 equiv) and 1,2-dibromoethane (0.62 g, 3.3 mmol, 3.0 equiv). The reaction mixture was stirred at 80 °C for 2 h, after which the reaction was quenched with cold water and extracted with EtOAc. The organic layer was washed with cold water, dried over sodium sulfate, and concentrated to give the crude residue. The crude residue was purified by silica gel column chromatography (15% EtOAc / hexanes) to give I-49F. 1H NMR (400 MHz, CDCl3) δ 4.23 (s, 2H), 3.60 (s, 2H), 3.45 (s, 3H), 1.51 (s, 6H). 1 H NMR (400 MHz, CDCl3) δ 3.62 (s, 2H), 3.43 (d, J = 10.7 Hz, 3H), 1.91 (q, J = 5.2 Hz, 2H), 1.71 (dd, J = 8.7, 5.3 Hz, 2H), 1.56 (s, 6H).

[0475] tert-Butyl ((1-((1-methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)carbamate (I-49G). I-49F (0.15 g, 0.7 mmol, 1.0 equiv) was dissolved in methanol (3 mL) and cooled to 0 °C. NiCl 6H O (0.016 g, 0.07 mmol, 0.1 equiv), (Boc) O (0.3 g, 1.4 mmol, 2.0 equiv), and NaBH (0.18 g, 4.83 mmol, 7.0 equiv) were added, and the reaction mixture was stirred at RT 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 the crude residue. The crude residue was purified by silica gel column chromatography (0–20% EtOAc / hexanes) to give I-49G. 1 H NMR (400 MHz, DMSO-d6) δ 6.87 (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 = 2.1 Hz, 2H).

[0476] (1-((1-methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl (I-49) Methanamine hydrochloride (I-49). To a solution of I-49G (0.08 g, 0.25 mmol, 1.0 equiv) in dichloromethane (2 mL) was added HCl (4 M in 1,4-dioxane) (1 mL). The reaction mixture was stirred at RT for 2 h. 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 (400 MHz, DMSO-d6) δ 7.95 (s, 3H), 3.56 (s, 2H), 3.33 (d, J = 3.6 Hz, 5H), 1.91 (dd, J = 8.9, 5.4 Hz, 1H), 1.75 (dd, J = 8.7, 5.2 Hz, 1H), 1.43 (s, 3H), 1.35 (s, 3H), 1.31 - 1.22 (m, 2H). Intermediate 50 (1-((1-methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0477] Ethyl 2-((1-methoxy-2-methylpropan-2-yl)sulfonyl)acetate (I-50A) was prepared from I-49D following a procedure similar to that described for I-7E. 1 H NMR (400 MHz, DMSO-d6) δ 4.15 (s, 2H), 3.30 (d, J = 4.4 Hz, 2H), 2.89 (d, J = 8.6 Hz, 3H), 2.75 - 2.71 (m, 3H), 1.30 - 1.15 (m, 9H).

[0478] Ethyl 1-((1-methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropane-1-carboxylate (I-50B) was prepared from I-50A following a procedure similar to that described for I-2C. 1H NMR (400 MHz, CDCl3) δ 4.35 - 4.10 (m, 2H), 3.59 - 3.51 (m, 2H), 3.42 - 3.35 (m, 3H), 1.82 - 1.09 (m, 12H).

[0479] 1-((1-Methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methanol (I-50C). I-50B (1 g, 3.7 mmol, 1.0 equiv) 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 equiv) was added dropwise and the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with an aqueous slurry of sodium sulfate, diluted with EtOAc, filtered through a bed of Celite, and concentrated to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 3.78 (s, 1H), 3.56 (s, 1H), 3.18 (s, 1H), 1.42 - 1.03 (m, 4H).

[0480] (1-((1-methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-50) was prepared from I-50C following a procedure similar to that described for I-2. 1 H NMR (400 MHz, CDCl ) δ 4.65 (s, 2H), 3.59 (s, 2H), 3.43 (d, J = 4.5 Hz, 3H), 3.12 (s, 3H), 1.77 - 1.66 (m, 2H), 1.51 - 1.44 (m, 8H). Intermediate 51 2-(Cyclopropylsulfonyl)propyl methanesulfonate [ka]

[0481] Ethyl 2-(cyclopropylsulfonyl)propanoate (I-51A) was prepared from sodium cyclopropanesulfinate and ethyl 2-bromopropanoate following a procedure similar to that described for I-2B. 1 H NMR (400 MHz, CDCl3) δ 4.33 - 4.28 (m, 2H), 2.68 (ddd, J = 9.7, 6.4, 4.0 Hz, 1H), 1.69 (d, J = 7.3 Hz, 3H), 1.44 - 1.28 (m, 3H), 1.28 - 1.20 (m, 2H), 1.14 - 1.06 (m, 2H).

[0482] 2-(Cyclopropylsulfonyl)propan-1-ol (I-51B). Methanol (15 mL) was added dropwise to a flask containing I-51A (3.2 g, 12.9 mmol, 1.0 equiv) and sodium borohydride (1.96 g, 51.9 mmol, 4.0 equiv) at 0 °C. 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 give the title compound. 1 H NMR (400 MHz, 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).

[0483] 2-(Cyclopropylsulfonyl)propyl methanesulfonate (I-51) was prepared from I-51B following a procedure similar to that described for I-2. 1 H NMR (400 MHz, DMSO-d6) δ 4.48 (dd, J = 13.3, 5.4 Hz, 2H), 3.27 (s, 3H), 2.77 - 2.73 (m, 1H), 1.37 (d, J = 7.1 Hz, 3H), 1.14 - 0.86 (m, 4H). Intermediate 52 (1-((1-methoxycyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate [ka]

[0484] Methyl 1-methoxycyclopropane-1-carboxylate (I-52A). 1-Hydroxycyclopropane-1-carboxylic acid (5 g, 49.0 mmol, 1.0 equiv) 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 equiv) and iodomethane (20.9 g, 147.1 mmol, 3.0 equiv) were added, and the reaction mixture was stirred at RT 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 give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 3.66 (s, 2H), 3.30 (s, 2H), 1.19 - 1.13 (m, 3H).

[0485] 1-Methoxycyclopropane-1-carboxylic acid (I-52B). To a solution of I-52A (4.3 g, 33.1 mmol, 1.0 equiv) in THF (40 mL), MeOH (10 mL), and water (10 mL) was added LiOH·HO (2.8 g, 66.2 mmol, 2.0 equiv). The reaction mixture was stirred at RT for 24 h, after which it was 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 give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 3.54 - 2.97 (m, 3H), 2.00 - 1.82 (m, 2H), 1.64 - 0.44 (m, 4H).

[0486] 2-Thioxopyridin-1(2H)-yl 1-methoxycyclopropane-1-carboxylate (I-52C) was prepared from I-52B following a procedure similar to that described for I-7B. 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (dd, J = 7.0, 1.3 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.44 (ddd, J = 7.2, 3.1, 1.4 Hz, 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).

[0487] 2-((1-methoxycyclopropyl)thio)pyridine (I-52D) was prepared from I-52C following a procedure similar to that described for I-49B.

[0488] 2-((1-methoxycyclopropyl)sulfonyl)pyridine (I-52E) was reacted with I- Prepared from I-52D following a procedure similar to that described for 49C. 1 H NMR (400 MHz, DMSO-d6) δ 8.86 - 8.82 (m, 1H), 8.21 - 8.13 (m, 2H), 7.79 (ddd, J = 7.3, 4.7, 1.5 Hz, 1H), 3.43 (s, 3H), 1.58 (dd, J = 8.5, 5.7 Hz, 2H), 1.39 (dd, J = 8.5, 5.8 Hz, 2H).

[0489] Sodium 1-methoxycyclopropane-1-sulfinate (I-52F) was prepared from I-52E following a procedure similar to that described for I-49D. 1 H NMR (400 MHz, DMSO-d6) δ 3.37 (s, 4H), 0.77 (q, J = 4.2 Hz, 3H), 0.42 (q, J = 4.2 Hz, 3H).

[0490] Ethyl 2-((1-methoxycyclopropyl)sulfonyl)acetate (I-52G) was prepared from I-52F following a procedure similar to that described for I-7E. 1 H NMR (400 MHz, DMSO-d6) δ 4.39 (d, J = 8.1 Hz, 2H), 4.18 (dd, J = 9.3, 4.9 Hz, 2H), 3.52 (s, 3H), 1.39 (d, J = 9.5 Hz, 4H), 1.23 (d, J = 7.1 Hz, 3H).

[0491] Ethyl 1-((1-methoxycyclopropyl)sulfonyl)cyclopropane-1-carboxylate (I-52H) was prepared from I-52G following a procedure similar to that described for I-48C. 1 H NMR (400 MHz, DMSO-d6) δ 4.21 - 4.15 (m, 2H), 3.45 (s, 3H), 1.68 (s, 4H), 1.49 (s, 2H), 1.41 (s, 2H), 1.24 (d, J = 7.1 Hz, 3H).

[0492] (1-((1-methoxycyclopropyl)sulfonyl)cyclopropyl)methanol (I-52I) was prepared from I-52H following a procedure similar to that described for I-50C. 1 H NMR (400 MHz, DMSO-d6) δ 5.03 (t, J = 6.3 Hz, 1H), 3.85 (d, J = 6.3 Hz, 2H), 3.48 (s, 3H), 1.38 - 1.26 (m, 4H), 1.23 - 1.14 (m, 2H), 1.14 - 1.03 (m, 2H).

[0493] (1-((1-methoxycyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate (I-52) was prepared from I-52I following a procedure similar to that described for I-2.1 H NMR (400 MHz, DMSO-d6) δ 4.54 (s, 2H), 3.48 (s, 3H), 3.21 (s, 3H), 1.48 (dd, J = 7.5, 5.0 Hz, 2H), 1.42 - 1.34 (m, 4H), 1.19 (t, J = 7.3Hz, 2H). Intermediate 53 tert-Butyl (1-(aminomethyl)cyclopropyl)carbamate [ka]

[0494] Methyl 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylate (I-53A). To a mixture of methyl 1-aminocyclopropane-1-carboxylate hydrochloride (5 g, 43.0 mmol, 1.0 equiv) in dichloromethane (50 mL) was added TEA (18.8 mL, 130.0 mmol, 3.0 equiv) and (Boc)O (14.2 g, 65.0 mmol, 1.5 equiv). The reaction mixture was stirred at RT 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 give I-53A. LCMS (m / z): 216.2 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 3.61 - 3.50 (m, 6H), 1.45 (s, 9H), 1.36 (s, 11H), 1.29 (dd, J = 7.7, 4.5 Hz, 4H), 1.00 (dd, J = 7.7, 4.4 Hz, 4H).

[0495] tert-Butyl (1-(hydroxymethyl)cyclopropyl)carbamate (I-53B) was prepared from I-53A following a procedure similar to that described for I-50C. 1H NMR (400 MHz, DMSO-d6) δ 7.05 (s, 1H), 4.57 (t, J = 5.8 Hz, 1H), 3.37 (d, J = 5.7 Hz, 2H), 0.61 (t, J = 3.1 Hz, 2H), 0.52 (d, J = 2.1 Hz, 2H).

[0496] (1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl methanesulfonate (I-53C) was prepared from I-52B following a procedure similar to that described for I-2. tert-Butyl (1-(azidomethyl)cyclopropyl)carbamate (I-53D). I-53C (1 g, 3.7 mmol, 1.0 equiv) and NaN3 (0.74 g, 11.3 mmol, 3.0 equiv) were added in 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 give the title product. 1 H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 3.34 - 3.08 (m, 3H), 1.38 (s, 9H), 0.67 (s, 4H).

[0497] tert-Butyl (1-(aminomethyl)cyclopropyl)carbamate (I-53). I-53D (0.7 g, 3.3 mmol, 1.0 equiv) was dissolved in methanol (10 mL). Pd / C (10% aqueous) (0.03 g) was added, and the reaction mixture was stirred under an atmosphere of H (gas) at RT for 18 h. The reaction mixture was filtered through a bed of Celite, and the filtrate was concentrated to give the title product. Intermediate 54 (1-((methylsulfonyl)methyl)cyclopropyl) [ka]

[0498] Ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (I-54A). To a solution of diethylcyclopropane-1,1-dicarboxylate (10 g, 42.9 mmol, 1.0 equiv) in THF (220 mL) was added LiAlH[OC(CH3)3]3 (1 M in THF) (100 mL) dropwise. The reaction mixture was stirred at 66 °C for 12 h. The reaction mixture was diluted with 10% aqueous sodium bisulfite and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give the crude residue. The crude residue was purified by silica gel column chromatography (40% EtOAc / hexanes) to give the title product. 1 H NMR (400 MHz, CDCl3) δ 4.17 (q, J = 7.1 Hz, 2H), 3.64 (s, 2H), 2.66 (s, 1H), 1.28 (dt, J = 9.8, 5.8 Hz, 5H), 0.89 (q, J = 4.2 Hz, 2H).

[0499] Ethyl 1-(((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate (I-54B) was prepared from I-54A following a procedure similar to that described for I-2. 1 H NMR (400 MHz, CDCl3) δ 4.18 (q, J = 6.8 Hz, 2H), 3.17 - 3.13 (m, 2H), 3.10 (s, 3H), 1.46 - 1.40 (m, 5H), 1.07 (dd, J = 7.4, 4.5 Hz, 2H).

[0500] Ethyl 1-((methylthio)methyl)cyclopropane-1-carboxylate (I-54C). To a solution of I-54B (7.5 g, 34.0 mmol, 1.0 equiv) in DMF (160 mL) was added CHClSNa (4.7 g, 68.0 mmol, 2.0 equiv). The reaction mixture was stirred at RT for 24 h, after which it was quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give the crude residue. The crude residue was purified by silica gel column chromatography (5% EtOAc / hexanes) to give I-54C. 1 H NMR (400 MHz, CDCl3) δ 4.16 (q, J = 7.1 Hz, 2H), 2.85 (s, 2H), 2.18 (s, 3H), 1.36 - 1.30 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 0.91 (q, J = 4.2Hz, 2H).

[0501] Ethyl 1-((methylsulfonyl)methyl)cyclopropane-1-carboxylate (I-54D) was prepared from I-54C following a procedure similar to that described for I-8C. 1 H NMR (400 MHz, CDCl3) δ 4.18 (q, J = 7.1 Hz, 2H), 3.42 (s, 2H), 2.99 (s, 3H), 1.54 (q, J = 4.6 Hz, 2H), 1.31 - 1.23 (m, 5H).

[0502] (1-((methylsulfonyl)methyl)cyclopropyl)methanol (I-54E). I-54D (3.4 g, 16.5 mmol, 1.0 equiv) was dissolved in THF (34 mL), LiBH4 (2 M in THF) (10 mL, 19.8 mmol, 1.2 equiv) was added dropwise, 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 give the crude residue. The crude residue was purified by silica gel column chromatography (55% EtOAc / hexanes) to give I-54E. LCMS (m / z): 165.2 [M+H]. 1 H NMR (400 MHz, CDCl3) δ 3.63 (s, 2H), 3.19 (s, 2H), 3.03 (s, 3H), 2.68 (s, 1H), 0.80 (t, J = 5.7 Hz, 2H), 0.74 (t, J = 5.7 Hz, 2H).

[0503] (1-((methylsulfonyl)methyl)cyclopropyl)methyl methanesulfonate (I-54F) was prepared from I-54E following a procedure similar to that described for I-2. 1 H NMR (400 MHz, DMSO-d6) δ 4.22 (s, 2H), 3.27 (s, 2H), 3.19 (s, 3H), 3.01 (s, 3H), 0.84 (t, J = 5.6 Hz, 2H), 0.78 (dd, J = 11.3, 4.0 Hz, 2H).

[0504] 1-(azidomethyl)-1-((methylsulfonyl)methyl)cyclopropane (I-54G) was prepared from I-54F following a procedure similar to that described for I-53D. 1 H NMR (400 MHz, DMSO-d6) δ 3.45 (s, 2H), 3.24 (s, 2H), 2.99 (s, 3H), 0.78 - 0.70 (m, 2H), 0.70 - 0.64 (m, 2H).

[0505] (1-((methylsulfonyl)methyl)cyclopropyl)methanamine (I-54) was prepared from I-54G (1.2 g, 6.3 mmol, 1.0 equiv) following a procedure similar to that described for I-53. 1 H NMR (400 MHz, DMSO-d6) δ 3.24 (d, J = 5.2 Hz, 2H), 2.95 (s, 3H), 2.51 (dt, J = 3.5, 1.7 Hz, 2H), 1.78 (d, J = 30.3 Hz, 2H), 0.60 - 0.54 (m, 2H), 0.54 - 0.48 (m, 2H). Intermediate 55 Ethyl 1-(aminomethyl)cyclopropane-1-carboxylate [ka]

[0506] Ethyl 1-(azidomethyl)cyclopropane-1-carboxylate (I-55A) was prepared from I-54B following a procedure similar to that described for I-53D. 1 H NMR (400 MHz, DMSO-d6) δ 4.20 - 4.02 (m, 1H), 3.68 - 3.35 (m, 1H), 1.31 - 1.09 (m, 3H), 1.06 - 0.89 (m, 1H).

[0507] Ethyl 1-(aminomethyl)cyclopropane-1-carboxylate (I-55). To a solution of I-55A (4.5 g, 26.6 mmol, 1.0 equiv) in methanol (45 mL) was added Pd / C (0.45 g) in an autoclave. The reaction mixture was stirred at RT under H (gas) pressure (20 bar) for 24 h. The reaction mixture was filtered through a bed of Celite, and the filtrate was concentrated to give the title product. 1H NMR (400 MHz, DMSO-d6) δ 4.10 - 3.96 (m, 2H), 2.67 (d, J = 19.9 Hz, 2H), 1.19 - 1.11 (m, 3H), 1.02 - 0.94 (m, 2H), 0.86 - 0.78 (m, 2H). Intermediate 56 [ka]

[0508] 2-(1-(methylsulfonyl)cyclopropyl)acetonitrile (I-56A). NaCN (1.9 g, 39.4 mmol, 2.0 equiv) was added to a solution of I-14D (4.5 g, 19.7 mmol, 1.0 equiv) in DMSO (45 mL). The reaction mixture was stirred at 60° C. for 3 h, after which it was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give I-56A. 1 H NMR (400 MHz, DMSO-d6) δ 3.11 (s, 2H), 2.51 (m, 3H), 1.40 - 1.33 (m, 2H), 1.16 - 1.09 (m, 2H).

[0509] Ethyl 2-(1-(methylsulfonyl)cyclopropyl)acetate (I-56B). I-56A (2.5 g, 15.7 mmol, 1.0 equiv) and concentrated HSO (2.5 mL) were added in ethanol (20 mL) in a sealed tube. The reaction mixture was stirred at 120 °C for 12 h. Additional concentrated HSO (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 give I-56B. 1 H NMR (400 MHz, DMSO-d6) δ 4.08 (q, J = 7.1 Hz, 2H), 2.99 (s, 3H), 2.91 (s, 2H), 1.34 (q, J = 4.6 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H), 1.12 - 1.07 (m, 2H).

[0510] 2-(1-(methylsulfonyl)cyclopropyl)ethan-1-ol (I-56C) was prepared from I-56B following a procedure similar to that described for I-51B. 1 H NMR (400 MHz, DMSO-d6) δ 3.59 - 3.50 (m, 2H), 3.00 (d, J = 1.7 Hz, 1H), 2.99 (s, 3H), 2.01 - 1.98 (m, 2H), 1.18 (t, J = 2.9 Hz, 2H), 1.01 (t, J = 3.1 Hz, 2H).

[0511] 2-(1-(methylsulfonyl)cyclopropyl)ethyl methanesulfonate (I-56D) was prepared from I-56C following a procedure similar to that described for I-2. . 1 H NMR (400 MHz, DMSO-d6) δ 4.39 (t, J = 7.0 Hz, 2H), 3.34 (s, 2H), 3.20 (s, 3H), 3.06 (d, J = 3.6 Hz, 3H), 2.28 (t, J = 7.0 Hz, 2H), 1.26 - 1.23 (m, 2H), 1.06 (m, 2H).

[0512] 1-(2-Azidoethyl)-1-(methylsulfonyl)cyclopropane (I-56E) was prepared from I-56D following a procedure similar to that described for I-53D. 1 H NMR (400 MHz, DMSO) δ 3.60 - 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).

[0513] 2-(1-(methylsulfonyl)cyclopropyl)ethan-1-amine (I-56) was prepared from I-56E following a procedure similar to that described for I-53. LCMS (m / z): 164.1 [M+H]. 1 H NMR (400 MHz, DMSO) δ 3.34 (ddd, J = 51.0, 25.2, 8.4 Hz, 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, 1.2 Hz, 2H). Intermediate 57 2-(1-(aminomethyl)cyclopropyl)isothiazolidine 1,1-dioxide [ka]

[0514] Methyl 1-((3-chloropropyl)sulfonamido)cyclopropane-1-carboxylate (I-57A) was prepared from methyl 1-aminocyclopropane-1-carboxylate hydrobromide and 3-chloropropane-1-sulfonyl chloride following a procedure similar to that described for I-18B. LCMS (m / z): 256.3 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 3.75 (dd, J = 6.6, 4.2 Hz, 2H), 3.64 (s, 3H), 3.21 - 3.15 (m, 2H), 2.14 (dt, J = 9.7, 6.7 Hz, 2H), 1.38 (p, J = 5.5 Hz, 2H), 1.27 (dd, J = 7.9, 4.7 Hz, 2H).

[0515] Methyl 1-(1,1-dioxideisothiazolidin-2-yl)cyclopropane-1-carboxylate (I-57B) was prepared from I-57A following a procedure similar to that described for I-18C. LCMS (m / z): 220.2 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 3.65 (d, J = 8.4 Hz, 3H), 3.47 (t, J = 6.7 Hz, 2H), 3.20 (t, J = 7.2 Hz, 2H), 2.31 - 2.22 (m, 2H), 1.38 (s, 2H), 1.32 (d, J = 2.9 Hz, 2H).

[0516] 2-(1-(hydroxymethyl)cyclopropyl)isothiazolidine 1,1-dioxide (I-57C) was prepared from I-57B following a procedure similar to that described for I-2D. LCMS (m / z): 192.3 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 4.72 (t, J = 5.8 Hz, 1H), 3.58 (d, J = 5.8 Hz, 2H), 3.45 (t, J = 6.7 Hz, 2H), 3.15 (t, J = 7.5 Hz, 2H), 2.16 (dt, J = 13.9, 6.9 Hz, 2H), 0.88 (dd, J = 6.7, 4.5 Hz, 2H), 0.71 (dd, J = 6.8, 4.5 Hz, 2H).

[0517] (1-(1,1-Dioxidoisothiazolidin-2-yl)cyclopropyl)methyl methanesulfonate (I-57D) was prepared from I-57C following a procedure similar to that described for I-2. LCMS (m / z): 287.3 [M+18]. 1H NMR (400 MHz, DMSO-d6) δ 3.45 (dt, J = 18.6, 6.7 Hz, 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).

[0518] 2-(1-(azidomethyl)cyclopropyl)isothiazolidine 1,1-dioxide (I-57E) was prepared from I-57D following a procedure similar to that described for I-53D. 1 H NMR (400 MHz, DMSO-d6) δ 3.52 (s, 1H), 3.42 (t, J = 6.7 Hz, 1H), 3.18 (t, J = 7.5 Hz, 1H), 2.19 (dd, J = 14.0, 6.9 Hz, 1H), 1.06 (q, J = 4.9 Hz, 1H), 0.80 (dd, J = 7.0, 5.0 Hz, 1H).

[0519] 2-(1-(aminomethyl)cyclopropyl)isothiazolidine 1,1-dioxide (I-57) was prepared from I-57E following a procedure similar to that described for I-53. LCMS (m / z): 191.2 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 3.37 (dd, J = 13.3, 6.6 Hz, 2H), 3.15 (dd, J = 14.1, 6.8 Hz, 2H), 2.83 - 2.65 (m, 2H), 2.17 (dd, J = 13.8, 6.7 Hz, 2H), 1.68 (s, 2H), 0.86 (d, J = 4.7 Hz, 2H), 0.70 (d, J = 4.4 Hz, 2H). Intermediate 58 1-(Aminomethyl)cyclopropyldimethylcarbamate [ka]

[0520] 1-((dibenzylamino)methyl)cyclopropan-1-ol (I-58A). Tyl dibenzylglycinate (1 g, 3.5 mmol, 1.0 equiv) was dissolved in diethyl ether (10 mL) and cooled to 0 °C. Ti(OiPr) (0.25 g, 0.88 mmol, 0.25 equiv) and EtMgBr (3.0 M in diethyl ether) (4.7 mL, 14.1 mmol, 4.0 equiv) were added, and the reaction mixture was stirred at RT for 24 h. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous ammonium chloride, 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 / hexanes) to give I-58A. LCMS (m / z): 268.3 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 7.0 Hz, 4H), 7.32 (t, J = 7.5 Hz, 4H), 7.23 (t, J = 7.2 Hz, 2H), 5.06 (s, 1H), 3.64 (d, J = 20.7 Hz, 4H), 2.53 (s, 2H), 0.57 - 0.54 (m, 2H), 0.33 (dd, J = 6.7, 4.6 Hz, 2H).

[0521] 1-((Dibenzylamino)methyl)cyclopropyldimethylcarbamate (I-58B). I-58A (5 g, 18.7 mmol, 1.0 equiv) 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 equiv) and dimethylcarbamic chloride (3 g, 28.1 mmol, 1.5 equiv) were added, and the reaction mixture was stirred at RT for 5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give the crude residue. The crude residue was purified by silica gel column chromatography (10% EtOAc / hexanes) to give I-58B. The product was used without further purification. LCMS (m / z): 339.4 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 7.39 - 7.25 (m, 10H), 3.64 (d, J = 15.8 Hz, 4H), 2.83 (d, J = 28.9 Hz, 6H), 2.71 (d, J = 22.3 Hz, 2H), 0.81 - 0.74 (m, 2H), 0.63 (dd, J = 7.6, 5.7 Hz, 2H).

[0522] 1-(Aminomethyl)cyclopropyldimethylcarbamate (I-58). I-58B (0.9 g, 3.78 mmol, 1.0 equiv) was dissolved in methanol (10 mL), Pd(OH) (0.1 g) was added, and the reaction mixture was stirred at RT under H (gas) atmosphere for 24 h. The reaction mixture was filtered through a bed of Celite, and the filtrate was concentrated to give I-58. LCMS (m / z): 159.1 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 2.82 (s, 1H), 2.78 (s, 3H), 0.76 - 0.67 (m, 2H). Intermediate 59 (1-Methoxycyclopropyl)methanamine [ka]

[0523] N,N-Dibenzyl-1-(1-methoxycyclopropyl)methanamine (I-59A). I-58A (2 g, 7.5 mmol, 1.0 equiv.) 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 equiv.) and iodomethane (1.6 g, 11.2 mmol, 1.5 equiv.) were added and the reaction mixture was cooled to 0 °C. The mixture was stirred at RT for 3 h. The reaction mixture was quenched with saturated aqueous ammonium chloride 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 / hexanes) to give the title compound. LCMS (m / z): 282.2 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 7.31 (ddd, J = 37.8, 14.1, 7.0 Hz, 10H), 3.63 (s, 4H), 3.13 (s, 3H), 2.56 (s, 2H), 0.68 (s, 2H), 0.39 (q, J = 5.1Hz, 2H).

[0524] (1-Methoxycyclopropyl)methanamine (I-59) was prepared from I-59A following a procedure similar to that described for I-58. LCMS (m / z): 102.0 [M+H]. 1 H NMR (400 MHz, DMSO) δ 7.56 (s, 2H), 3.21 (s, 3H), 2.97 (s, 2H), 0.79 (dd, J = 7.0, 5.2 Hz, 2H), 0.65 (dd, J = 7.2, 5.1 Hz, 2H). Intermediate 60 N-(2-aminoethyl)-N-methylmethanesulfonamide [ka]

[0525] tert-Butyl (2-(N-methylmethylsulfonamido)ethyl)carbamate (I-60A). To a solution of tert-butyl (2-(methylamino)ethyl)carbamate (0.9 mL, 4.95 mmol) in DCM (25 mL) cooled to 0 °C was added DIEA (2.59 mL, 14.84 mmol), followed by MsCl (0.424 mL, 5.44 mmol). The resulting mixture was warmed to RT and stirred overnight. The reaction mixture was diluted with DCM and washed with 2 M HCl (5 times). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The title compound was isolated as a tan solid. LCMS (m / z): 197.1 [M-tBu+H]. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (s, 9 H) 2.76 (s, 3 H) 2.85 (s, 3 H) 3.08 (d, J=2.35 Hz, 4 H) 6.89 (br. s., 1 H).

[0526] N-(2-aminoethyl)-N-methylmethanesulfonamide (I-60). To a solution of I-60A (1.17 g, 4.64 mmol) in dioxane (4 mL) was added 4 M HCl in dioxane (6 mL, 24.00 mmol). The resulting solution was stirred at RT. Upon completion of the reaction, the mixture was concentrated under reduced pressure. The title compound was isolated as a tan solid. LCMS (m / z): 153.1. 1 H NMR (400 MHz, CD3OD) δ ppm 2.91 (s, 6 H) 3.14 (t, J=5.67 Hz, 2 H) 3.39 - 3.44 (m, 2 H). Intermediate 61 N-(4-cyanobenzyl)-1,6-dioxo-1,3,4,6-tetrahydropyrido[2,1-c][1,4]oxazine-7-carboxamide [ka]

[0527] N-(4-Cyanobenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (I-61A). To a solution of 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (10 g, 65.4 mmol, 1.0 equiv.) in THF (250 mL) was added N-methylmorpholine (19.8 g, 196.1 mmol, 3.0 equiv.), EDC·HCl (15 g, 78.4 mmol, 1.2 equiv.), HOBT (10.6 g, 78.4 mmol, 1.2 equiv.), and 4-(aminomethyl)benzonitrile hydrochloride (16.6 g, 98.0 mmol, 1.5 equiv.). The reaction mixture was stirred at RT for 24 h. The reaction mixture was quenched with water, and the resulting solid was isolated by filtration. The filter cake was washed with water and hexane and dried to give the title compound. LCMS (m / z): 268.5 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.20 (t, J = 6.0 Hz, 1H), 8.24 (d, J = 7.4 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 6.32 (d, J = 7.4 Hz, 1H), 4.60 (d, J = 6.1 Hz, 2H), 2.30 (s, 3H).

[0528] N-(4-cyanobenzyl)-6-formyl-2-oxo-1,2-dihydropyridine-3-carboxamide (I-61B) was prepared from I-61A following a procedure similar to that described for I-47C. LCMS (m / z): 282.1 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.23 (s, 1H), 9.71 (s, 1H), 8.51 (d, J = 7.1 Hz, 1H), 7.84 - 7.80 (m, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 7.1 Hz, 1H), 4.64 (d, J = 6.1 Hz, 2H).

[0529] 5-((4-Cyanobenzyl)carbamoyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (I-61C) was prepared from I-61B following a procedure similar to that described for I-47D. LCMS (m / z): 297.9 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 10.25 (s, 1H), 8.41 (d, J = 7.3 Hz, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 7.2 Hz, 1H), 4.63 (d, J = 6.1 Hz, 2H).

[0530] 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 equiv.) and 1,2-dibromoethane (4.8 g, 25.6 mmol, 2.0 equiv.) were dissolved in DMF (80 mL). TEA (3.9 g , 38.4 mmol, 3.0 equiv) 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 give I-61. LCMS (m / z): 324.4 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (t, J = 6.0 Hz, 1H), 8.46 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 7.5 Hz, 1H), 4.76 - 4.68 (m, 2H), 4.64 (d, J = 6.1 Hz, 2H), 4.36 - 4.25 (m, 2H). Intermediate 62 2-(Cyclopropylsulfonyl)ethan-1-amine hydrochloride [ka]

[0531] Sodium cyclopropanesulfinate (I-62A). Na2SO3 (22.6 g, 178.0 mmol, 1.0 equiv) was added to water (250 mL) and stirred at RT for 10 min. Na2CO3 (37.7 g, 356.0 mmol, 2.0 equiv) was added, and the reaction mixture was stirred at 60 °C for 10 min. Cyclopropanesulfonyl chloride (25 g, 178.0 mmol, 1.0 equiv) was added dropwise, and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated to give the crude residue. The crude residue was dissolved in ethanol (250 mL) and stirred at RT for 20 min. The solid was filtered and washed with ethanol. The filtrate was concentrated to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 1.64 - 1.50 (m, 1H), 0.69 - 0.32 (m, 4H).

[0532] 2-(Cyclopropylsulfonyl)acetonitrile (I-62B) was prepared from I-62A following a procedure similar to that described for I-49E. 1 H NMR (400 MHz, CDCl3) δ 4.11 - 3.92 (m, 2H), 2.73 (tt, J = 7.9, 4.7 Hz, 1H), 1.53 - 1.36 (m, 2H), 1.35 - 1.19 (m, 2H).

[0533] tert-Butyl (2-(cyclopropylsulfonyl)ethyl)carbamate (I-62C). I-62B (5 g, 34.4 mmol, 1.0 equiv) was added to methanol (50 mL) and cooled to 0 °C. NiCl 6H O (0.82 g, 3.44 mmol, 0.1 equiv) was added, and the reaction mixture was stirred at 0 °C for 5 min. NaBH (5.2 g, 138.0 mmol, 4.0 equiv) was added, and the reaction mixture was stirred at RT for 24 h. The reaction mixture was filtered through a bed of Celite, and 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 / hexanes) to give I-62C. 1 H NMR (400 MHz, DMSO-d6) δ 7.04 (t, J = 5.3 Hz, 1H), 3.36 (d, J = 10.1 Hz, 2H), 3.25 (dd, J = 7.9, 5.8 Hz, 2H), 2.75 (dd, J = 7.8, 2.7 Hz, 1H), 1.38 (d, J = 6.2 Hz, 9H), 0.99 (dd, J = 6.0, 1.8 Hz, 4H).

[0534] 2-(Cyclopropylsulfonyl)ethan-1-amine hydrochloride (I-62) was prepared from I-62C following a procedure similar to that described for I-49. LCMS (m / z): 150.1 [M+H, free amine] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 2H), 3.60 - 3.41 (m, 2H), 3.31 - 3.04 (m, 2H), 2.91 (ddd, J = 12.6, 7.8, 4.8 Hz, 1H), 1.18 - 0.90 (m, 4H). Intermediate 63 N-(1-(aminomethyl)cyclopropyl)-N-methylmethanesulfonamide [ka]

[0535] (1-(N-methylmethylsulfonamido)cyclopropyl)methyl methanesulfonate (I-63A) was prepared from N-(1-(hydroxymethyl)cyclopropyl)-N-methylmethanesulfonamide following a procedure similar to that described for I-2. 1 H NMR (400 MHz, DMSO-d6) δ 4.26 (s, 2H), 3.21 (s, 3H), 2.99 (d, J = 12.7 Hz, 3H), 2.88 (d, J = 8.3 Hz, 3H), 1.13 (t, J = 6.2 Hz, 2H), 0.97 (t, J = 6.2 Hz, 2H).

[0536] N-(1-(azidomethyl)cyclopropyl)-N-methylmethanesulfonamide (I-63B) was prepared from I-63A following a procedure similar to that described for I-53D. 1 H NMR (400 MHz, DMSO-d6) δ 3.46 (s, 2H), 2.95 (d, J = 7.6 Hz, 3H), 2.90 - 2.83 (m, 3H), 1.03 (q, J = 5.3 Hz, 2H), 0.86 (q, J = 5.3 Hz, 2H).

[0537] N-(1-(aminomethyl)cyclopropyl)-N-methylmethanesulfonamide (I-63) was prepared from I-63B following a procedure similar to that described for I-53. LCMS (m / z): 179.2 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 3.00 - 2.94 (m, 3H), 2.86 (d, J = 5.5 Hz, 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). Preparation of Compounds of Formula (I) Example 1 N-(4-cyanobenzyl)-2-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[0538] 2-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic acid (Ex-1A). I-1 (5 g, 18.92 mmol) in DMF (140 mL) The solution was cooled to 0 °C. To the cooled solution was added NaH (60% suspension in mineral oil, 1.135 g, 28.4 mmol). The resulting mixture was stirred at 0 °C until effervescence ceased. To the basic mixture was added I-2 (6.26 g, 24.60 mmol) in DMF (40 mL). The resulting mixture was warmed to RT. After 72 h, NaH (60% suspension in mineral oil, 0.378 g, 9.46 mmol) was added. After 2 h, the reaction was diluted with HO. The reaction was stirred at RT for 1 h. The resulting precipitate was isolated by vacuum filtration to give the sodium salt of Ex-1A as a light tan foam. The filtrate was washed with EtOAc. The aqueous layer was adjusted to pH 1 with 2 M HCl. The acidic aqueous layer was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to give a second crop of Ex-1A as a dark tan solid. LCMS m / z: 367 (M+1).

[0539] 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). To a slurry of Ex-1A (2.26 g, 6.17 mmol) in DCM (60 mL) was added oxalyl chloride (0.594 mL, 6.79 mmol), followed by 1 drop of DMF. The reaction immediately evolved gas and became homogeneous. The reaction mixture was stirred at RT for about 1 h, after which it was concentrated under reduced pressure. The residue was dissolved in DCM (60 mL), and 4-(aminomethyl)benzonitrile HCl (1.248 g, 7.40 mmol) was added. To the slurry was added DIEA (2.155 mL, 12.34 mmol). The resulting mixture was stirred at RT for about 1 h. The reaction mixture was diluted with DCM and washed with 2M HCl and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The yellow foam was dissolved in DCM and purified on SiO2 (heptane to acetone) to give the product. The residue was recrystallized by heating in EtOH (890 mL) at reflux in a 2 L Erlenmeyer flask for approximately 30–45 min until the solid dissolved. The solution was allowed to cool slowly to RT over 72 h. The resulting crystalline solid was isolated by vacuum filtration. The filter cake was rinsed with heptane, and the solid was dried under high vacuum overnight. Ex-1 was isolated as slightly yellow needles with a melting point of 186 °C. Figure 1 shows a comparison of the XRPD of the product from this reaction (NX-7) with that of a second polymorph (NX-12) that predominates when the two crystalline forms are slurried together in ethanol. NX-12 appears to be the more stable polymorph.

[0540] The other compounds in the table below were prepared following procedures similar to those described for Ex-1. [Table 1-1] [Table 1-2] Example 4 N-(4-chlorobenzyl)-2-((1-((4-hydroxybutan-2-yl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[0541] 2-((1-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic acid (Ex-4A) was prepared from 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).

[0542] N-(4-chlorobenzyl)-2-((1-((4-hydroxybutan-2-yl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-4). To a solution of Ex-4A (0.2 g, 0.390 mmol) in DCM (3 mL) was added DIEA (0.136 mL, 0.780 mmol) and T3P® (50% in EtOAc, 0.255 mL, 0.429 mmol). The resulting mixture was stirred for about 10 minutes, after which p-chlorobenzylamine (0.057 mL, 0.468 mmol) was added. The reaction mixture was stirred at RT for 1 hour. The mixture was diluted with DCM and washed with 2 M HCl and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in DCM (3 mL) and treated with 4 M HCl in dioxane (1.5 mL, 6.00 mmol). After 30 min, the reaction mixture was diluted with DCM and washed with HO. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified using SFC. Ex-4 was isolated as an off-white solid.

[0543] Compound 5 in the table below was prepared following a procedure similar to that described for Ex-4.

[0544] (R) and (S) N-(4-chlorobenzyl)-2-((1-((4-hydroxybutan-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 subjected to chiral SFC (AD column, 5 mL / min CO2 / EtOH=70 / 30) separation to give the enantiomers of the title compounds.

[0545] (R) and (S) N-(4-cyanobenzyl)-2-((1-((4-hydroxybutan-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 enantiomers of the title compounds.

[0546] The stereochemistry assignments for Ex-6, Ex-7, Ex-8 and Ex-9 are arbitrary. [Table 2-1] [Table 2-2] [Table 2-3] Example 10 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

[0547] 2-((1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic acid (Ex-10A) was prepared from I-1 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).

[0548] 2-((1-((1-(hydroxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-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 at reflux. Upon complete conversion of the acid, the reaction was concentrated under reduced pressure. The residue was dissolved in AcOH and treated with Pd / C (0.06 g, 0.056 mmol). The atmosphere was exchanged with H2 and the reaction mixture was stirred for approximately 2 h. The reaction was filtered through a pad of Celite and the pad was rinsed with EtOH. The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH and treated with 2 M NaOH until the pH was basic. Upon consumption of the ester, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in H2O and washed with EtOAc. The aqueous layer was diluted with 2 M NaOH. The pH was adjusted to 1 with HCl. The acidic aqueous layer was extracted with DCM. The combined DCM extracts were dried over sodium sulfate and concentrated under reduced pressure. Ex-10B was isolated as a yellow solid. LCMS m / z: 397 (M+1).

[0549] 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). 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) was added T3P® (50% in EtOAc, 0.083 mL, 0.277 mmol). The resulting mixture was stirred at RT. Upon 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 over sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (20–60% (0.1% TFA / HO) / (0.1% TFA / MeCN)). The clean fractions were extracted with EtOAc, and the EtOAc extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on SiO (0–100% acetone / heptane) to give Ex-10 as a white solid.

[0550] The other compounds in the table below were prepared following procedures similar to those described for Ex-10. [Table 3]

[0551] The compounds in the table below were prepared from I-1 and either I-5 or I-6 following procedures similar to those described for Ex-10. [Table 4] (Examples 16 / 17)

[0552] 2-((1-((1-(tert-Butoxycarbonyl)azetidin-3-yl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic acid (Ex-16A) was prepared from 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).

[0553] tert-Butyl 3-((1-((7-((4-cyano-3-fluorobenzyl)carbamoyl)-1,6-dioxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)methyl)cyclopropyl)sulfonyl)azetidine-1-carbo The xylate (Ex-16B) was prepared from EX-16A following a procedure similar to that described for Ex-10. Ex-16B was isolated as a yellow oil. MS m / z: 614 (M+1).

[0554] 2-((1-(Azetidin-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). To a solution of Ex-16B (0.163 g, 0.266 mmol) in DCM (5.0 mL) was added TFA (1 mL). The resulting mixture was stirred at RT. 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, CO / MeOH 80 mL / min). Ex-16 was isolated as an off-white solid.

[0555] N-(4-cyano-3-fluorobenzyl)-2-((1-((1-methylazetidin-3-yl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-17). To a solution of Ex-16 (0.068 g, 0.132 mmol) in DCE (1 mL) was added formaldehyde (0.015 mL, 0.199 mmol), followed by sodium triacetoxyborohydride (0.042 g, 0.199 mmol). The resulting mixture was stirred at RT overnight. Additional formaldehyde (0.015 mL, 0.199 mmol) and sodium triacetoxyborohydride (0.042 g, 0.199 mmol) were added until the starting material was completely consumed. The reaction mixture 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 HPLC (SunFire column, HO / ACN 0.1% TFA). Ex-17 was isolated as a white solid.

[0556] The other compounds in the table below were prepared following procedures similar to those described for Ex-16 and Ex-17. [Table 5-1] [Table 5-2]

[0557] The compounds in the table below were prepared from I-1 and I-8 following a procedure similar to that described for Ex-1. [Table 6-1] [Table 6-2]

[0558] The compounds in the table below were prepared from I-1 and I-9 following a procedure similar to that described for Ex-4. [Table 7-1] [Table 7-2]

[0559] The compounds in the table below were prepared from I-1 and I-10 following a procedure similar to that described for Ex-1. [Table 8]

[0560] The compounds in the table below were prepared from I-1 and I-11 following a procedure similar to that described for Ex-10. [Table 9]

[0561] The compounds in the table below were prepared from I-1 and I-12 following a procedure similar to that described for Ex-1. [Table 10-1] [Table 10-2]

[0562] The compounds in the table below were prepared from I-1 and I-13 following a procedure similar to that described for Ex-1. [Table 11-1] [Table 11-2]

[0563] The compounds in the table below were prepared from I-1 and I-14 following a procedure similar to that described for Ex-1. [Table 12-1] [Table 12-2] [Table 12-3]

[0564] The compounds in the table below were prepared from I-1 and I-15 following a procedure similar to that described for Ex-1. [Table 13] (Example 50-1) N-(4-chlorobenzyl)-2-(2-(1,1-dioxidetetrahydrothiophen-2-yl)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[0565] N-(4-chlorobenzyl)-2-(2-(1,1-dioxidotetrahydrothiophen-2-yl)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-50-1) was prepared from I-1 and I-16 following a procedure similar to that described for Ex-1, except that EDC amide coupling was used instead of the acid chloride. To the acid (0.088 g, 0.248 mmol) in DMF (1 mL) was added EDC·HCl (0.057 g, 0.298 mmol) and HOBt (0.046 g, 0.298 mmol). The resulting solution was stirred at RT for approximately 30 min, after which p-chlorobenzylamine (0.091 mL, 0.745 mmol) was added. After about 2 hours, the reaction mixture was diluted with EtOAc, washed with 2M HCl and brine, and dried over sodium sulfate. The dried organic layer was concentrated under reduced pressure. The crude product was purified by HPLC with 0.1% TFA in H2O / ACN to isolate the title compound as an off-white solid. [Table 14] (Example 50-2)

[0566] 2-((1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic acid (Ex-50 -2A). To a solution of I-1 (0.1 g, 0.378 mmol) in DMF (2 mL) was added NaH (60% suspension in mineral oil, 0.023 g, 0.568 mmol). To the basic reaction mixture was added I-46 (0.196 g, 0.492 mmol) in DMF (2 mL). The resulting reaction mixture was stirred at RT. Upon completion of the reaction, it was diluted with EtOAc and HO. The phases were separated and the aqueous layer was extracted with EtOAc (2 times). 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).

[0567] 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). To a solution of Ex-50-2A (0.135 g, 0.264 mmol) in DCM (1 mL) was added DIEA (0.092 mL, 0.529 mmol) and T3P® (50% in EtOAc, 0.205 mL, 0.344 mmol). The resulting mixture was stirred at RT for 10 minutes. To the reaction mixture was added (6-chloropyridin-3-yl)methanamine (0.057 g, 0.397 mmol). Upon complete consumption of the starting material, the reaction mixture was diluted with DCM, washed with 2M HCl, saturated sodium bicarbonate, and dried over 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).

[0568] 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). To a slurry of Ex-50-2B (0.126 g, 0.198 mmol) in DCM was added TFA (1 mL). The reaction mixture was stirred at RT overnight, after which it was 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 on RP HPLC. Ex-50-2 was isolated as a white solid. [Table 15] Example 51 N-(4-chlorobenzyl)-2-(2-(methylsulfonyl)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carbohydrate Voxamide

[0569] N 5 -(4-chlorobenzyl)-1-(2-hydroxyethyl)-N 2 -(2-(methylthio)ethyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (Ex-51A). To a microwave vial containing I-17 (0.225 g, 0.676 mmol) was added ACN (0.5 mL) and 2-(methylthio)ethanamine (0.252 mL, 2.70 mmol). The resulting mixture was heated in a microwave 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 extracted with 2 M Washed with HCl (3 times). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Ex-51A was isolated as a yellow foam. LCMS m / z: 424 (M+1).

[0570] N 5 -(4-chlorobenzyl)-1-(2-chloroethyl)-N 2-(2-(methylthio)ethyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (Ex-51B). To a solution of Ex-51A (0.25 g, 0.590 mmol) in DCM (6 mL) was added NEt (0.247 mL, 1.769 mmol) and MsCl (0.069 mL, 0.885 mmol). Upon complete conversion of the starting material to the alkyl chloride, the reaction mixture was diluted with DCM, washed sequentially with saturated sodium bicarbonate (3 times) and 2 M HCl (2 times), and dried over sodium sulfate. The dried organic layer was concentrated under reduced pressure. The yellow oil was purified on SiO (0–100% EtOAc / heptane) to give Ex-51B as a yellow residue. LCMS m / z: 442 (M+1), 444 (M+3). 1 H NMR (400 MHz, CDCl3) δ ppm 2.14 (s, 3 H) 2.73 - 2.78 (m, 2 H) 3.62 - 3.68 (m, 2 H) 3.88 (t, J=6.26 Hz, 2 H) 4.55 - 4.62 (m, 4 H) 6.57 (d, J=7.43 Hz, 1 H) 7.26 - 7.32 (m, 4 H) 8.53 (d, J=7.43 Hz, 1 H) 9.98 (t, J=5.48 Hz, 1 H).

[0571] N-(4-chlorobenzyl)-2-(2-(methylsulfonyl)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-51). To a solution of Ex-51B (0.153 g, 0.346 mmol) in THF (4 mL) was added NaH (60% suspension in mineral oil, 0.021 g, 0.519 mmol). The resulting mixture was stirred at RT overnight, after which it was diluted 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 over sodium sulfate. The dried organic layer was dissolved in DCM (4 mL) and treated with mCPBA (0.155 g, 0.692 mmol). Upon completion of the reaction, the mixture was diluted with DCM and saturated sodium bicarbonate. The phases were separated, and the organic layer was washed with saturated sodium bicarbonate (5 times). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The yellow residue was purified on SiO (0–100% (5% MeOH / EtOAc) / heptane) to give Ex-51 as a pale yellow solid.

[0572] The other compounds in the table below were prepared following procedures similar to those described for Ex-51. [Table 16-1] [Table 16-2] Example 54 tert-Butyl(2-(7-((4-chlorobenzyl)carbamoyl)-1,6-dioxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)e (methyl)carbamate

[0573] tert-Butyl (2-(5-((4-chlorobenzyl)carbamoyl)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-2-carboxamido)ethyl)(methyl)carbamate (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).

[0574] tert-Butyl (2-(5-((4-chlorobenzyl)carbamoyl)-1-(2-chloroethyl)-6-oxo-1,6-dihydropyridine-2-carboxamido)ethyl)(methyl)carbamate (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).

[0575] tert-Butyl (2-(7-((4-chlorobenzyl)carbamoyl)-1,6-dioxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)ethyl)(methyl)carbamate (Ex-54). To a solution of Ex-54B (0.106 g, 0.202 mmol) in THF (2.5 mL) was added NaH (60% suspension in mineral oil, 0.012 g, 0.303 mmol). The reaction mixture was stirred at RT overnight, after which it was quenched with HO. The aqueous mixture was extracted with CHCl (3×). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on SiO (0–100% (5% MeOH / EtOAc) / heptane) to give Ex-54 as a pale yellow solid.

[0576] The other compounds in the table below were prepared following procedures similar to those described for Ex-54. [Table 17-1] [Table 17-2] Example 58 N-(4-chlorobenzyl)-2-(2-(N-methylmethylsulfonamido)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[0577] N-(4-chlorobenzyl)-2-(2-(methylamino)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-58A): To a flask containing Ex-54 (0.19 g, 0.389 mmol) was added 4 M HCl in dioxane (3 mL, 12.00 mmol). The resulting mixture was stirred at RT overnight, after which it was concentrated under reduced pressure. The residue was co-evaporated with EtOAc / heptane, and the resulting solid was taken to dryness in vacuo. Ex-58A hydrochloride was isolated as a yellow solid. LCMS m / z: 389 (M+1).

[0578] N-(4-chlorobenzyl)-2-(2-(N-methylmethylsulfonamido)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-58): To a solution of Ex-58A (0.035 g, 0.082 mmol) and NEt (0.029 mL, 0.206 mmol) in DCM (1.5 mL) was added MsCl (7.05 μL, 0.091 mmol). The resulting mixture was stirred at RT overnight, after which it was diluted with DCM and 2 M HCl. The phases were separated, and the organic layer was washed with 2 M HCl (3×) and brine and dried over sodium sulfate. The dried organic layer was concentrated under reduced pressure, and the residue was purified by flash chromatography. Ex-58 was isolated as a tan solid.

[0579] The other compounds in the table below were prepared following procedures similar to those described for Ex-58. [Table 18] Example 62 N-(4-chlorobenzyl)-2-(2-(methylsulfonamido)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[0580] tert-Butyl (2-(5-((4-chlorobenzyl)carbamoyl)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-2-carboxamido)ethyl)carbamate (Ex-62A) was prepared from I-17 and N-Boc-ethylenediamine according to a procedure similar to that described for Ex-51A. LCMS m / z: 493 (M+1).

[0581] tert-Butyl (2-(5-((4-chlorobenzyl)carbamoyl)-1-(2-chloroethyl)-6-oxo-1,6-dihydropyridine-2-carboxamido)ethyl)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).

[0582] tert-Butyl (2-(7-((4-chlorobenzyl)carbamoyl)-1,6-dioxo-3,4-dihydro-1H-pyrido[1,2-a]pyrazin-2(6H)-yl)ethyl)carbamate (Ex-62C) was prepared from Ex-62B according to a procedure similar to that described for Ex-54. LCMS m / z: 475 (M+1).

[0583] 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 for Ex-58A. LCMS m / z: 375 (M+1).

[0584] N-(4-chlorobenzyl)-2-(2-(methylsulfonamido)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-62): To a solution of Ex-62D (0.02 g, 0.053 mmol) and NEt (0.019 mL, 0.133 mmol) in DCM (0.5 mL) was added MsCl (4.16 μL, 0.053 mmol). The resulting mixture was stirred at RT. Upon consumption of Ex-62D, the reaction mixture was diluted with DCM and washed with 2 M HCl (twice). The organic layer was purified on SiO (0–100% (5% MeOH / EtOAc) / heptane) to afford Ex-62 as an off-white solid.

[0585] The other compounds in the table below were prepared from I-17 and either N-Boc-N-methylethylenediamine, (S)-2-(aminomethyl)-1-Boc-pyrrolidine or (R)-2-(aminomethyl)-1-Boc-pyrrolidine following procedures similar to those described for Ex-62. [Table 19] Example 64 N-(4-chlorobenzyl)-2-(2-(1,1-dioxidoisothiazolidin-2-yl)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[0586] N 5 -(4-chlorobenzyl)-N 2-(2-(1,1-Dioxidoisothiazolidin-2-yl)ethyl)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (Ex-64E): 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) was added DIEA (0.394 mL, 2.254 mmol). The resulting mixture was stirred at 90 °C. Upon consumption of the starting material, the reaction mixture was cooled to RT, 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. Ex-64E was isolated as a dark orange residue. LCMS m / z: 497 (M+1).

[0587] N 5 -(4-chlorobenzyl)-1-(2-chloroethyl)-N 2 -(2-(1,1- Dioxideisothiazolidin-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 for Ex-51B. LCMS m / z: 515 (M+1), 517 (M+3).

[0588] N-(4-chlorobenzyl)-2-(2-(1,1-dioxidoisothiazolidin-2-yl)ethyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-64): To a solution of Ex-64F (0.081 g, 0.157 mmol) in THF (10 mL) was added NaH (60% suspension in mineral oil, 9.43 mg, 0.236 mmol). The resulting mixture was stirred at RT for 1 h, after which the reaction was quenched with HO. The aqueous layer was extracted with EtOAc. The organic extract was 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 recrystallized from hot EtOH. Ex-64 was collected as yellow needles by vacuum filtration.

[0589] The other compounds in the table below were prepared following procedures similar to those described for Ex-64. [Table 20-1] [Table 20-2] (Example 67-1) N-(4-chlorobenzyl)-2-((1-(methylsulfinyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[0590] N 5 -(4-chlorobenzyl)-1-(2-hydroxyethyl)-N 2 -((1-(methylthio)cyclopropyl)methyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (Ex-67A) was prepared from I-17 and (1-(methylthio)cyclopropyl)methanamine following a procedure similar to that described for Ex-51A. MS m / z 432.3 (M-HO+1).

[0591] N 5 -(4-chlorobenzyl)-1-(2-chloroethyl)-N 2 -((1-(methylthio)cyclopropyl)methyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (Ex-67B). MsCl (0.101 mL, 1.300 mmol) was added to a stirred solution of Ex-67A (531.7 mg, 1.182 mmol) and NEt (0.247 mL, 1.773 mmol) in DCM (11.8 mL) at RT. The mixture was stirred at RT overnight. The reaction mixture was partitioned between ion-exchanged water and DCM, and the aqueous layer was extracted with DCM (2 times). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The crude product was purified on SiO (0–100% EtOAc / heptane) to give Ex-67B. MS m / z 468.3 (M+1).

[0592] N-(4-chlorobenzyl)-2-((1-(methylthio)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-67C) was prepared from Ex-67B according to a procedure similar to that described for Ex-64. The title compound was obtained as an orange solid. MS m / z 432.2 (M+1).

[0593] N-(4-chlorobenzyl)-2-((1-(methylsulfinyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-67-1). Oxone (400 mg, 0.650 mmol) was added to a stirred solution of Ex-67C (511 mg, 1.182 mmol) in methanol (44 mL) and DCM (3.6 mL) at RT. The conversion to the sulfoxide was determined to be complete after 1 h, and the reaction mixture was vacuum filtered through a frit. The filtrate was concentrated, and the resulting solid was partitioned between ion-exchanged water and DCM. The aqueous phase was extracted with DCM (twice), and the combined organic phases were dried over NaSO, filtered, and concentrated to give a yellow foam. The material was purified by SFC to give Ex-67-1 as a pale yellow solid.

[0594] (R) and (S)—N-(4-chlorobenzyl)-2-((1-(methylsulfinyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-67-2, Ex-67-3). Ex-67-1 was subjected to separation by chiral SFC to give the title enantiomeric sulfoxides. Characterization data are in the table below; stereochemical assignments are arbitrary. [Table 21] Example 68 N-(4-cyanobenzyl)-2-((1-(methylsulfinyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[0595] The compounds in the table below were prepared from I-61 and (1-(methylthio)cyclopropyl)methanamine following a procedure similar to that described for Ex-67. [Table 22] Example 69 N-(4-chlorobenzyl)-2-((1-(methoxymethyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide

[0596] N 5 -(4-chlorobenzyl)-1-(2-hydroxyethyl)-N 2 -((1-(methoxymethyl)cyclopropyl)methyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (Ex-69A) was prepared from I-17 and (1-(methoxymethyl)cyclopropyl)methanaminium chloride according to a procedure similar to that described for Ex-64E. Ex-69A was isolated as a dark brown residue. MS m / z 448.3 (M+1).

[0597] N 5 -(4-chlorobenzyl)-1-(2-chloroethyl)-N 2 -((1-(Metoki (Dimethyl)cyclopropyl)methyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (Ex-69B) was prepared from Ex-69A according to a procedure similar to that described for Ex-67B. MS m / z 466.2 (M+1).

[0598] N-(4-chlorobenzyl)-2-((1-(methoxymethyl)cyclopropyl)methyl)-1,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (Ex-69). Sodium hydride (60% suspension in mineral oil, 7.23 mg, 0.181 mmol) was added to a stirred solution of Ex-69B (56.2 mg, 0.121 mmol) in THF (1.5 mL) at RT, resulting in immediate gas evolution. After 1 h, a second portion of sodium hydride (60% suspension in mineral oil, 7.23 mg, 0.181 mmol) was...

Claims

1. A pharmaceutical composition for treating or inhibiting a viral infection, comprising: a) A compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, Cy is phenyl, pyridinyl, pyrimidinyl or 5-8 membered cycloalkyl, Cy is optionally substituted with up to three groups selected from halo, CN, hydroxy, —N(R′) 2 , C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-3 haloalkyl, and C 1-3 alkyl substituted up to three (0-3) times with Z, and when two of said C 1-3 alkyl substituted up to three times with Z are directly bonded to the same carbon atom, they may both be joined together with the carbon to which they are bonded to form a 3-5 membered cycloalkyl ring substituted up to three times with Z; R 1 is selected from H and C 1-3 alkyl; R 2 is selected from H and C 1-3 alkyl; or R 1 and R 2 together with the carbons to which they are attached may form a 3- to 6-membered cycloalkyl ring; R 3 represents up to two (0-2) optional substituents on the ring to which -L-W is directly attached, each of which is independently selected from halo, CN, C 1-3 alkoxy, C 1-3 alkyl, COOR′ and C(O)NR′R′; R 4 is H, halo or C 1-3 alkyl; R 5 is selected from H, halo, CN, C 1-3 alkoxy, —NR′R′, C 1-3 alkyl substituted up to 3 times with Z 5 , C 2-4 alkenyl substituted up to 3 times with Z 5 , C 2-4 alkynyl substituted up to 3 times with Z 5 , and a ring selected from a 3- to 6-membered cycloalkyl ring, a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, and a 5- to 6-membered heteroaryl ring containing up to 4 heteroatoms selected from N, O and S as ring members, wherein said 3- to 6-membered cycloalkyl ring, 4- to 6-membered heterocyclic ring or 5- to 6-membered heteroaryl ring is optionally substituted with 1 to 2 Z 5 ; L is a C 1 -C 4 straight or branched alkylene linker, or when W is an optionally substituted ring, L may be a C 1 -C 4 straight or branched alkylene linker or a bond; W is H, —OH, —OR, —C(O)NR′R′, —COOR′, —NR′R′, —NR′COOR, —NR′C(O)R, —SO 2 R, —SO 2 NR′R′, —NR′SO 2 R, —P(O)(OR′) 2 , or an optionally substituted ring selected from 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocyclyl containing 1 or 2 N, O or S heteroatoms as ring members, and 5 membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, optionally fused to phenyl; Optional substituents on said optionally substituted ring are C 1-3 alkyl, oxo, halo, C 1-3 haloalkyl, -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 -SO 2 NR'-C(O)R, -L 2 -C(O)-NR'-SO 2 R, -L 2 -SOR, -L 2 -S(═O)(═NR')R, -L 2 -NR'SO 2 NR'R', -L 2 -NR'SO 2 R, -L 2 -NR'R', -L 2 -NR'C(O)R', -L 2 -NR'COOR, -L 2 1 to 3 groups selected from -C(O)NR'R' and -L 2 -COOR'; R, at each occurrence, is selected from C 1-4 alkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing up to 4 heteroatoms selected from N, O, and S as ring members, and 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, and S as ring members; each R is C 1-4 alkyl, C 1-2 haloalkyl, oxo, -L 3 -CN, -L 3 -halo, -L 3 -C 1-3 alkoxy, -L 3 -OH, -L 3 -OC(O)-NR'R', -L 3 -SO 2 R', -L 3 -SO 2 NR'R', -L 3 -SO 2 NR'-C(O)R', -L 3 -C(O)-NR'-SO 2 R', -L 3 -SOR', -L 3 -S(═O)(═NR')R', -L 3 -NR'SO 2 NR'R', -L 3 -NR'SO 2 R', -L 3 -NR'R', -L 3 and optionally substituted with one or two groups selected from —NR′C(O)R′, —L 3 —NR′COOR′, —L 3 —C(O)NR′R′ and —L 3 —COOR′, —L 3 — (5- to 6-membered heterocyclyl containing 1 or 2 N, O, or S heteroatoms as ring members), —L 3 —C 3-5 cycloalkyl, and —L 3 — (5- to 6-membered heteroaryl ring having up to 4 heteroatoms, including 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms as ring members), wherein said C 1-4 alkyl, 5- to 6-membered heterocyclyl, C 3-5 cycloalkyl, and 5- to 6-membered heteroaryl ring are halo, C 1-3 alkyl, C 1-3 haloalkyl, —L 4 —OR′, —L 4 —CN, and —L 4 —N(R′), respectively. 2 is optionally further substituted with up to three groups independently selected from R' in each occurrence is independently selected from H; C 1-4 alkyl optionally substituted with halo, -OH, amino, or C 1-2 alkoxy; and C 3-6 cycloalkyl optionally substituted with halo, -OH, amino, or C 1-2 alkoxy; or two R' together with the nitrogen atom to which they are both directly attached may form a 4-6 membered ring optionally containing additional N, O or S as ring members and optionally substituted with 1 to 3 groups selected from C 1-2 alkyl, C 1-2 alkoxy, oxo and hydroxy; each L 2 , L 3 and L 4 is independently a bond or a straight-chain or branched C 1-3 alkylene; Z and Z 5 are independently at each occurrence selected from halo, hydroxy, CN, C 1-3 alkoxy, C 1-3 alkyl and C 3-5 cycloalkyl; two Z groups or two Z 5 groups, both of which together with the carbon atoms to which they are directly attached, may form a 3- to 5-membered cycloalkyl ring or a 4- to 6-membered heterocyclic ring containing O, N, or S as ring members and optionally substituted with up to two groups selected from oxo and C 1-3 alkyl); b) A pharmaceutical composition administered in combination with one or more additional antiviral agents.

2. The pharmaceutical composition described in claim 1, wherein the virus is selected from cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex virus (HSV), herpes simplex virus type 1, herpes simplex virus type 2, herpes virus 6, herpes virus 7, and Kaposi's sarcoma-associated herpes virus.

3. The pharmaceutical composition of claim 1 or claim 2, wherein the one or more additional antiviral agents are selected from one or more of a herpesvirus entry inhibitor, a herpesvirus early transcription event inhibitor, a herpesvirus helicase-primase inhibitor, another herpesvirus DNA polymerase inhibitor, an inhibitor of UL97 kinase, a herpesvirus protease inhibitor, a herpesvirus terminase inhibitor, a herpesvirus maturation inhibitor, an inhibitor of another target in the herpesvirus life cycle, a herpesvirus vaccine, and a herpesvirus biological agent.

4. The pharmaceutical composition of claim 1 or claim 2, wherein the one or more additional antiviral agents are selected from one or more of ganciclovir (Cytovene®), valganciclovir (Valcyte®; Cymeval®), cidofovir (Vistide®), foscarnet (Foscavir®), CMX001, cyclopropavir (MBX-400), valacyclovir (Valtrex®; Zelitrex®), maribavir, AIC246 (Letermovir), artesunate, TransVax, and Cytogam (Cytotect®).

5. A pharmaceutical composition according to any one of claims 1 to 4, wherein each of (a) and (b) is provided together in a fixed combination composition.

6. A pharmaceutical composition described in any one of claims 1 to 4, wherein each of (a) and (b) is provided separately in an individual composition.

7. A pharmaceutical composition described in any one of claims 1 to 6, wherein each of (a) and (b) is provided at a dosage level of between about 10 and 100% of the dosage normally administered in a monotherapy regimen.

8. A pharmaceutical composition described in any one of claims 1 to 7, wherein each of (a) and (b) is provided at a dosage level of between about 10 and 80% of the dosage normally administered in a monotherapy regimen.

9. A pharmaceutical composition for treating or inhibiting a viral infection, comprising: a) a compound, wherein said compound is: 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 and pharmaceutically acceptable salts thereof; b) A pharmaceutical composition administered in combination with one or more additional antiviral agents.

10. The pharmaceutical composition described in claim 9, wherein the virus is selected from cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex virus (HSV), herpes simplex virus type 1, herpes simplex virus type 2, herpes virus 6, herpes virus 7, and Kaposi's sarcoma-associated herpes virus.

11. The pharmaceutical composition of claim 9 or claim 10, wherein the one or more additional antiviral agents are selected from one or more of a herpesvirus entry inhibitor, a herpesvirus early transcription event inhibitor, a herpesvirus helicase-primase inhibitor, another herpesvirus DNA polymerase inhibitor, an inhibitor of UL97 kinase, a herpesvirus protease inhibitor, a herpesvirus terminase inhibitor, a herpesvirus maturation inhibitor, an inhibitor of another target in the herpesvirus life cycle, a herpesvirus vaccine, and a herpesvirus biological agent.

12. The pharmaceutical composition of claim 9 or claim 10, wherein the one or more additional antiviral agents are selected from one or more of ganciclovir (Cytovene®), valganciclovir (Valcyte®; Cymeval®), cidofovir (Vistide®), foscarnet (Foscavir®), CMX001, cyclopropavir (MBX-400), valacyclovir (Valtrex®; Zelitrex®), maribavir, AIC246 (Letermovir), artesunate, TransVax, and Cytogam (Cytotect®).

13. The pharmaceutical composition of any one of claims 9 to 12, wherein each of (a) and (b) is provided together in a fixed combination composition.

14. A pharmaceutical composition according to any one of claims 9 to 12, wherein each of (a) and (b) is provided separately in an individual composition.

15. A pharmaceutical composition described in any one of claims 9 to 14, wherein each of (a) and (b) is provided at a dosage level of between about 10 and 100% of the dosage normally administered in a monotherapy regimen.

16. A pharmaceutical composition described in any one of claims 9 to 15, wherein each of (a) and (b) is provided at a dosage level of between about 10 and 80% of the dosage normally administered in a monotherapy regimen.

17. A combination for treating or inhibiting a viral infection, comprising: a) A compound of formula (I): 【Transformation 69】 or a pharmaceutically acceptable salt thereof, Cy is phenyl, pyridinyl, pyrimidinyl or 5-8 membered cycloalkyl, Cy is optionally substituted with up to three groups selected from halo, CN, hydroxy, —N(R′) 2 , C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-3 haloalkyl, and C 1-3 alkyl substituted up to three (0-3) times with Z, and when two of said C 1-3 alkyl substituted up to three times with Z are directly bonded to the same carbon atom, they may both be joined together with the carbon to which they are bonded to form a 3-5 membered cycloalkyl ring substituted up to three times with Z; R 1 is selected from H and C 1-3 alkyl; R 2 is selected from H and C 1-3 alkyl; or R 1 and R 2 together with the carbons to which they are attached may form a 3- to 6-membered cycloalkyl ring; R 3 represents up to two (0-2) optional substituents on the ring to which -L-W is directly attached, each of which is independently selected from halo, CN, C 1-3 alkoxy, C 1-3 alkyl, COOR′ and C(O)NR′R′; R 4 is H, halo or C 1-3 alkyl; R 5 is selected from H, halo, CN, C 1-3 alkoxy, —NR′R′, C 1-3 alkyl substituted up to 3 times with Z 5 , C 2-4 alkenyl substituted up to 3 times with Z 5 , C 2-4 alkynyl substituted up to 3 times with Z 5 , and a ring selected from a 3- to 6-membered cycloalkyl ring, a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S as ring members, and a 5- to 6-membered heteroaryl ring containing up to 4 heteroatoms selected from N, O and S as ring members, wherein said 3- to 6-membered cycloalkyl ring, 4- to 6-membered heterocyclic ring or 5- to 6-membered heteroaryl ring is optionally substituted with 1 to 2 Z 5 ; L is a C 1 -C 4 straight or branched alkylene linker, or when W is an optionally substituted ring, L may be a C 1 -C 4 straight or branched alkylene linker or a bond; W is H, —OH, —OR, —C(O)NR′R′, —COOR′, —NR′R′, —NR′COOR, —NR′C(O)R, —SO 2 R, —SO 2 NR′R′, —NR′SO 2 R, —P(O)(OR′) 2 , or an optionally substituted ring selected from 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocyclyl containing 1 or 2 N, O or S heteroatoms as ring members, and 5 membered heteroaryl containing up to 4 heteroatoms selected from N, O and S as ring members, optionally fused to phenyl; Optional substituents on said optionally substituted ring are C 1-3 alkyl, oxo, halo, C 1-3 haloalkyl, -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 -SO 2 NR'-C(O)R, -L 2 -C(O)-NR'-SO 2 R, -L 2 -SOR, -L 2 -S(═O)(═NR')R, -L 2 -NR'SO 2 NR'R', -L 2 -NR'SO 2 R, -L 2 -NR'R', -L 2 -NR'C(O)R', -L 2 -NR'COOR, -L 2 1 to 3 groups selected from -C(O)NR'R' and -L 2 -COOR'; R, at each occurrence, is selected from C 1-4 alkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl containing up to 4 heteroatoms selected from N, O, and S as ring members, and 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, and S as ring members; each R is C 1-4 alkyl, C 1-2 haloalkyl, oxo, -L 3 -CN, -L 3 -halo, -L 3 -C 1-3 alkoxy, -L 3 -OH, -L 3 -OC(O)-NR'R', -L 3 -SO 2 R', -L 3 -SO 2 NR'R', -L 3 -SO 2 NR'-C(O)R', -L 3 -C(O)-NR'-SO 2 R', -L 3 -SOR', -L 3 -S(═O)(═NR')R', -L 3 -NR'SO 2 NR'R', -L 3 -NR'SO 2 R', -L 3 -NR'R', -L 3 and optionally substituted with one or two groups selected from —NR′C(O)R′, —L 3 —NR′COOR′, —L 3 —C(O)NR′R′ and —L 3 —COOR′, —L 3 — (5- to 6-membered heterocyclyl containing 1 or 2 N, O, or S heteroatoms as ring members), —L 3 —C 3-5 cycloalkyl, and —L 3 — (5- to 6-membered heteroaryl ring having up to 4 heteroatoms, including 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms as ring members), wherein said C 1-4 alkyl, 5- to 6-membered heterocyclyl, C 3-5 cycloalkyl, and 5- to 6-membered heteroaryl ring are halo, C 1-3 alkyl, C 1-3 haloalkyl, —L 4 —OR′, —L 4 —CN, and —L 4 —N(R′), respectively. 2 is optionally further substituted with up to three groups independently selected from R' in each occurrence is independently selected from H; C 1-4 alkyl optionally substituted with halo, -OH, amino, or C 1-2 alkoxy; and C 3-6 cycloalkyl optionally substituted with halo, -OH, amino, or C 1-2 alkoxy; or two R' together with the nitrogen atom to which they are both directly attached may form a 4-6 membered ring optionally containing additional N, O or S as ring members and optionally substituted with 1 to 3 groups selected from C 1-2 alkyl, C 1-2 alkoxy, oxo and hydroxy; each L 2 , L 3 and L 4 is independently a bond or a straight-chain or branched C 1-3 alkylene; Z and Z 5 are independently at each occurrence selected from halo, hydroxy, CN, C 1-3 alkoxy, C 1-3 alkyl and C 3-5 cycloalkyl; two Z groups or two Z 5 groups, together with the carbon atoms to which they are both directly attached, may form a 3- to 5-membered cycloalkyl ring or a 4- to 6-membered heterocyclic ring containing O, N, or S as ring members and optionally substituted with up to two groups selected from oxo and C 1-3 alkyl); and b) one or more additional antiviral agents A combination comprising:

18. A combination for treating or inhibiting a viral infection, comprising: a) a compound, wherein said compound is: 【Chemistry 72】 【Transformation 73】 【Chemistry 74】 【Chemistry 75】 【Transformation 76】 【Chemical Formula 77】 【Transformation 78】 【Chemistry 79】 【Chemistry 80】 【Chemistry 81】 【Chemistry 82】 【Chemistry 83】 【Chemical 84】 【Chemical 85】 【Chemical 86】 【Transformation 87】 【Chemical 88】 【Chemistry 89】 [Chemical 90] 【Chemistry 91】 【Chemistry 92】 【Chemistry 93】 【Chemical 94】 【Chemical 95】 【Chemistry 96】 【Chemistry 97】 【Chem.98】 【Chem.99】 【Chemistry 100】 【Chemistry 101】 【Chemical Engineering 102】 【Chemistry 103】 【Chemical 104】 【Chemistry 105】 【Chemistry 106】 【Chemistry 107】 【Chemistry 108】 【Chemistry 109】 【Chemical 110】 【Chemistry 111】 【Chemistry 112】 【Chemistry 113】 【Chemistry 114】 【Chemical 115】 【Chemistry 116】 【Chemistry 117】 【Chemistry 118】 【Chemical 119】 【Chemical 120】 【Chemistry 121】 【Chemistry 122】 【Chemical 123】 【Chemistry 124】 【Chemistry 125】 【Chemistry 126】 【Chemistry 127】 【Chemistry 128】 【Chemistry 129】 【Chemistry 130】 【Chemistry 131】 【Chemistry 132】 【Chemistry 133】 【Chemistry 134】 【Chemistry 135】 and pharmaceutically acceptable salts thereof; and b) one or more additional antiviral agents A combination comprising:

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