Compounds and pharmaceutical compositions thereof for the treatment of infectious diseases

Abstract

The present invention discloses compounds according to Formula (I), wherein X, L1, R1 and Cy are as defined herein. Herein are disclosed compounds, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and / or treatment of diseases involving tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM).

Description

NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFECTIOUS DISEASESFIELD

[0001] Herein are provided inter alia, compounds that may be useful in the prophylaxis and / or treatment of tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM). Herein is also provided methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and / or treatment of NTM by administering the compound of the invention.BACKGROUND

[0002] Tuberculosis (TB) is a contagious and deadly disease caused by Mycobacterium tuberculosis (MTB), that has reached pandemic proportions: 8 - 10 million new cases of tuberculosis (TB) are diagnosed each year, leading to death in adults (2-3 million / year) according to the World Health Organization (WHO).

[0003] In addition to TB, recent epidemiological studies have shown the emergence of non-tuberculous mycobacteria (NTM) species in causing lung diseases in humans. Non-tuberculous mycobacteria (NTM) are referred to as atypical mycobacteria and are defined as mycobacteria other than Mycobacterium (M). leprae and M. tuberculosis (MTB) with its close relatives, M. africanum, M. bovis, M. canetti and caprae.

[0004] Although more than 170 NTM species (Gopalaswamy et al. 2020) are present in various environmental niches, only a handful, primarily M avium complex and M abscessus, have been implicated in pulmonary disease causing opportunistic infections in humans with pre-existing conditions, particularly in individuals with suppressed immune systems or underlying structural lung damage such as bronchiectasis, cystic fibrosis (CF), Chronic Obstructive Pulmonary Disease (COPD), or asthma, and patients with other diseases such as HIV and diabetes are at high risk of contracting pulmonary NTM disease. NTM disease is mostly disseminated through aerosols originated from the environment (Gopalaswamy et al. 2020).

[0005] The incidence and number of deaths from NTM disease have steadily increased globally, especially in developed countries (Prevots and Marras 2015). However, early patient diagnosis is challenging due to non-specific symptoms in patients, which may result in underestimation of the overall incidence.

[0006] Although the pathophysiology of TB and NTM diseases share several fundamental cellular and molecular events, the host-susceptibility to MTB and NTM infections are different.

[0007] In general, drug-sensitive TB is treated with a standard multi-drug regimen containing well-defined first- and second-line antibiotics (Gopalaswamy et al. 2020).

[0008] In contrast, the NTM species display significant heterogeneity in their susceptibility to standard anti-TB drugs. Thus, the treatment for NTM diseases usually involves inter alia, the use of macrolides and injectable aminoglycosides. Although well-established international guidelines are available, treatment of NTM disease is mostly empirical, poorly tolerated and is successful in only a proportion of patients. In general, the treatment duration is much longer for NTM diseases (18-24 months), compared to TB, andresection surgery of affected organ(s) is part of treatment for patients with NTM diseases that do not respond to the antibiotic treatment. (Daley et al. 2020; Gopalaswamy et al. 2020).

[0009] In fighting TB and / or NTM, the rifamycins (RIFs) are the most commonly used drugs despite serious drawbacks including: Cyp450 induction, which is particularly problematic for HIV-MTB coinfection, and the existence of resistant mutations that yield RIF-resistant (RIFR ) MTB strains. In addition, certain detoxification pathways are present in some NTM species which render rifamycins inactive.

[0010] Semisynthetic rifamycin derivatives including rifampin, rifalazil (RLZ), rifapentine (RFP), and rifabutin (RFB) appear to show improved antimycobacterial activities. However, all RIFs are ineffective against the most prevalent RIFR MTB mutant (rpoB S450L) (Tuberculosis (2008) 88(2) 148-150), and a major downside to using rifamycins to treat TB is their many drug -drug interactions due to extremely potent activation of the human pregnane X receptor (hPXR) leading to a dramatic induction of CYP2C9, CYP3 A4 and other hepatic metabolizing enzymes and transporters.

[0011] Moreover, chemical modifications of ryfamycins, such as reduction of the C(18)-C(19) double bond resulted in decreased inhibiting power (Dorian et al. 1989).

[0012] The long and toxic treatment, the raise of resistance, the worldwide increasing prevalence and the high hospital costs makes TB and / or NTM infections a high unmet medical need for which new drugs are desperately needed.SUMMARY

[0013] There is a need for new compounds which are not associated with the disadvantages of prior compounds, to provide new treatments and methods of prophylaxis, and / or treatment of TB and / or NTM.

[0014] As such, herein are provided inter alia, compounds that may be useful in the prophylaxis and / or treatment of TB and / or NTM. In particular, the compounds provided herein may show improved potency against TB and / or NTM, reduced toxicity, and / or improved PK / PD profile.

[0015] In some aspects, herein are also provided methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, methods for the prophylaxis and / or treatment of TB and / or NTM by administering the compounds of the invention.

[0016] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula (I):WhereinX is absent, O, or -NR2-;Li is absent, or C1-4 alkylene;R1is phenyl optionally substituted with one or more independently selected R3a,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, Se or S heteroatoms, optionally substituted with one or more independently selected R3b, where the N heteroatoms may optionally be oxidized,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3c,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3d;5-10 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3e;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3f, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3g;Ci -4 alkyl optionally substituted with one or more independently selected R3h;R2is H or C1-4 alkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4agroups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4bgroup,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4c, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more independently selected R4d;Each R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his independently selected from: halo,CN, or- -YA-LA-R5;Each R4a, R4b, R4cand R4dis selected from:halo,- =0,CN, or- -YB-LB-R6;Each YAand YBis independently selected from: absent,Ci-4 alkylene optionally substituted with one or more independently selected halo, or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo;Each LA and LB is independently selected from: absent,- -0-,- -(C=0),- -C(=0)0-,- -C(=NH)NR7a-,- -C(=0)NR7a-,- -C(=O)NR7fS(=O)2-,- -C(=0)NR7f-0-,- -C(=O)-C(=O)NR7f-,- -S(=0)-,- -S(=0)2-,- -OP(=O)(OR7d)O-,- -0C(=0)-,- -0C(=0)-NR7b-,- -S(=O)2NR7b-,- -S(=O)(=NR7b)-,- -NR7bS(=O)2-,- -NR7CC(=0)-,- -NR7CC(=0)0-,- -P(=O)R7d-,- -P(=O)(OR7d)O-,- -NR7e-;Each R5, R6, R7a, R76, R7c, R7d, R7e, and R7fis independently selected from:- H,Ci -4 alkyl optionally substituted with one or more independently selected deuterium, halo, OH, - C(=0)NHCH3, -NHC(=0) CH3, phenyl, cyclopropyl, cyclopropyl substituted with OH, or pyridinyl,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or moreindependently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B, or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, -C(=O)OCH3, -C(=0)0H, -C(=O)-cyclopropyl, - N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, C1.4 alkyl optionally substituted with one or more independently selected halo, or C 1.4 alkoxy optionally substituted with one or more independently selected halo,6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B, or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo, phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkoxy optionally substituted with one or more independently selected halo, where the N heteroatoms of said heteroaryl may optionally be oxidized.

[0017] In an aspect of the invention, the compounds of the invention are provided having a Formula (I):whereinX is absent, O, or -NR2-Li is absent, or C1.4 alkylene;R1is phenyl optionally substituted with one or more independently selected R3a,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3b,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3c,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3d;5-10 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3e;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3f, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R3g;R2is H or Ci-4 alkyl;Cy is:4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4agroups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4bgroup,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4c, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is optionally substituted with one or more independently selected R4d;Each R3a, R3b, R3c, R3d, R3e, R3f, and R3gis independently selected from: halo,CN, or- -YA-LA-R5;Each R4a, R4b, R4cand R4dis selected from: halo,- =0,CN, or- -YB-LB-R6;Each YAand YBis independently selected from: absent,Ci-4 alkylene optionally substituted with one or more independently selected halo,or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo;Each LA and LB is independently selected from: absent,- -O-,- -(C=O),- -C(=O)O-,- -C(=NH)NR7a-,- -C(=O)NR7a-,- -C(=O)NR7fS(=O)2-,- -S(=O)-,- -S(=O)2-,- -OP(=O)(OR7d)O-,- -OC(=O)-- -S(=O)2NR7b-,- -NR7bS(=O)2-,- -NR7CC(=O)-,- -NR7CC(=O)O-,- -P(=O)R7d-,- -NR7e-;Each R5, R6, R7a, R76, R7c, R7d, R7e, and R7fand R7eis independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl or pyridinyl,4-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo, 6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo,phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, - C(=0)NHCH3, CI-4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=O)NH2, -C(=O)NHCH3, CI-4 alkyl optionally substituted with one or more independently selected halo, or Ci-4 alkoxy optionally substituted with one or more independently selected halo.

[0018] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula (I):WhereinX is absent, O, or -NR2-;Li is absent, or C1.4 alkylene;R1is phenyl optionally substituted with one or more independently selected R3a,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3b,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3c,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3d;5-10 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3e;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3f, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R3g;R2is H or Ci-4 alkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4agroups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4bgroup,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4c, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is optionally substituted with one or more independently selected R4d;Each R3a, R3b, R3c, R3d, R3e, R3f, and R3gis independently selected from: halo,CN, or- -YA-LA-R5;Each R4a, R4b, R4cand R4dis selected from: halo,- =0,CN, or- -YB-LB-R6;Each YAand YBis independently selected from: absentCi-4 alkylene optionally substituted with one or more independently selected halo, or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo;Each LA and LB is independently selected from absent,- -O-,- -(C=O),- -C(=O)O-,- -C(=O)NR7a-,- -S(=O)-,- -S(=O)2-,- -S(=O)2NR7b-,- -NR7CC(=O)-,- -P(=O)R7d-,- -NR7e-;Each R5, R6, R7a, R76, R7c, R7d, and R7eis independently selected from:- H,Ci -4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl or pyridinyl,4-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo, phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, - C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo.

[0019] In a particular aspect, the compounds of the invention are provided for use in the prophylaxis and / or treatment of TB and / or NTM.

[0020] Furthermore, it has also been unexpectedly demonstrated that the compounds of the invention exhibit improved DDI profile.

[0021] In a further aspect, herein are also provided pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient, or diluent. In a particular aspect, the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of TB and / or NTM.

[0022] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0023] In a further aspect, this invention provides a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly TB and / or NTM, whichmethod comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.

[0024] The present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine . In a particular aspect, the pharmaceutical composition is for use in the prophylaxis and / or treatment of TB and / or NTM.

[0025] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.

[0026] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.DETAILED DESCRIPTIONDefinitions

[0027] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope.

[0028] When describing inter alia compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0029] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example ‘an analogue’ means one analogue or more than one analogue.

[0030] ‘Alkyl’ means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), n-butyl (- CH2-CH2-CH2-CH3), tert-butyl (-CH2-C(CH3)3), sec-butyl (-CH2-CH(CH3)2), n-pentyl (-CH2-CH2-CH2-CH2-CH3), n-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CHCH3)-C(CH3)H2-CH2-CH3). Particular alkyl groups have between 1 and 4 carbon atoms.

[0031] ‘Alkenyl’ refers to monovalent olefinically (unsaturated) hydrocarbon groups with the number of carbon atoms specified. Particular alkenyl has 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CTUCH2). n-propenyl (-C H2CTUCH2). isopropenyl (-C(CH3)=CH2) and the like.

[0032] ‘Alkylene’ refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can bestraight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH3)- and the like.

[0033] ‘Alkynylene’ refers to divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -C=C-, -CH2- C=C-, and -C(CH3)H-C=CH-.

[0034] ‘Alkoxy’ refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-Ci e alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0035] ‘ Amino’ refers to the radical -NH2.

[0036] ‘Aryl’ refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.

[0037] ‘Cycloalkyl’ refers to non-aromatic fully or partially saturated ring structure, monocyclic, fused polycyclic, spirocyclic or bridged polycyclic, with the number of ring atoms specified. A cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms. When partially saturated, the cycloalkyl may contain one or two double bonds, and more particularly one double bond. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Such polycyclic and / or partially saturated cycloalkyl groups include, by way of example:

[0038] ‘Cyano’ refers to the radical -CN.

[0039] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.

[0040] ‘Hetero’ when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.

[0041] ‘Heteroaryl’ means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. Inparticular, the aromatic ring structure may have from 5 to 9 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0042] “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Partially aromatic heteroaryl bicyclic ring systems can be vicinally fused, i.e., where the rings are linked to each other through two adjacent carbon and / or nitrogen atoms. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-l, 2,3,4- tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 1,3-dihydroisobenzofuran, 2,3-dihydro- benzo[l,4]dioxinyl, benzo[l,3]dioxolyl, 2,2-dioxo-l,3-dihydro-2-benzothienyl, 4, 5,6,7- tetrahydrobenzofuranyl, indolinyl, 1 ,2,3,4-tetrahydro- 1 ,8-naphthyridinyl, l.2.3.4-tctrahydropyrido|2.3- / ? |pyrazinyl and 3.4-dihydro-2 / / -pyrido|3.2- / ? || l,4]oxazinyl.

[0043] Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0044] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0045] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.

[0046] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.

[0047] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0048] Examples of representative heteroaryls include the following:wherein each Y is selected from >C=O, NH, O and S.

[0049] ‘Heterocycloalkyl’ means a non-aromatic fully or partially saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N, P Se, Si, B and S and the number of ring atoms specified. The heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members. Each ring may contain up to four heteroatoms typically selected from nitrogen, phosphorus, sulfur and oxygen. Typically the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. When partially saturated, the heterocycloalkyl may contain one or two double bonds, and more particularly one double bond. Examples of heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (e.g. 1- tetrahydrofuranyl, 2 -tetrahydrofuranyl and 3 -tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1- tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3 -tetrahydrothiophenyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.

[0050] Particular examples of monocyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O-, -Se-, -BH-, B-OH, SifCHs )s and -S-.

[0051] Particular examples of fused bicyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O- -Se-, -BH-, B-OH, Si(CH3)3and - S-.

[0052] Particular examples of bridged bicyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O- -Se-, -BH-, B-OH, Si(CHs)3 and - S- and each Z is selected from N or CH.

[0053] Particular examples of spirocyclic rings are shown in the following illustrative examples:wherein each Y is selected from -CH2-, -NH-, -O— Se-, -BH-, B-OH, Si(CH3)3 and -S-.

[0054] Particular examples of monocyclic partially saturated heterocycloalkyl rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O-, -Se-, -BH-, B-OH, Si(CH3)3 and -S-, and Z is P, N, or CH.

[0055] ‘hydrocarbon chain’ refers to an organic molecule consisting of nothing else but carbon and hydrogen atoms arranged in a chain, which carbon and hydrogen atoms are interconnected to each other by covalent bonding. Each carbon atom in the chain is bonded to one or up to three hydrogen atoms, hydrocarbon chains may be classified as branched, linear, or cyclical. They may also be divided into alkanes, alkenes, alkynes, cycloalkanes, and aryls. A hydrocarbon chain may also be classified as either saturated or unsaturated, or aliphatic or aromatic. A saturated hydrocarbon chain is saturated with hydrogen whereas an unsaturated hydrocarbon chain is one in which hydrogen atom can still be added in the chain by breaking the double -bond (alkene) or triple bond (alkyne) between carbon atoms.

[0056] ‘Hydroxyl’ refers to the radical -OH.

[0057] ‘ Oxo’ refers to the radical =0.

[0058] ‘ Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0059] ‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as -SO3H.

[0060] ‘ Thiol’ refers to the group -SH.

[0061] As used herein, term ‘substituted with one or more’ refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.

[0062] ‘Thioalkoxy’ refers to the group -S-alkyl where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -S-C1-6 alkyl. Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, sec-thiobutoxy, n- thiopentoxy, n-thiohexoxy, and 1,2 -dimethylthiobutoxy. Particular thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0063] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non -aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.

[0064] ‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0065] ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzene sulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-I-carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term ‘pharmaceutically acceptable cation’ refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0066] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0067] ‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0068] ‘ Solvate’ refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0069] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.

[0070] ‘ Effective amount’ means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0071] ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.

[0072] The term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti- malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0073] ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

[0074] As used herein the term tuberculosis (TB) diseases refers to the group of conditions caused by the mycobacterium tuberculosis (MTB), affecting primarily the lungs, but also inter alia, the bones, lymph nodes, bone marrow (miliary TB), liver, heart, genitourinary and gastrointestinal tract, meninges (meningeal tuberculosis) and / or the skin.

[0075] As used herein the term non-tuberculous mycobacteria (NTM) disease, also known as environmental mycobacteria, atypical mycobacteria and mycobacteria other than MTB (MOTT), diseases refers to the group of conditions are mycobacteria which do not cause tuberculosis or leprosy (also known as Hansen's disease). NTM do cause pulmonary diseases that resemble tuberculosis. The most commonclinical manifestation of NTM disease is lung disease, but lymphatic, skin / soft tissue, and disseminated diseases, which can affect nearly all organs are also important.

[0076] ‘Compound(s) of the invention’, and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

[0077] When ranges are referred to herein, for example but without limitation, Ci-s alkyl, the citation of a range should be considered a representation of each member of said range.

[0078] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the Ci-s alkyl, C2-8 alkenyl, Ce-io optionally substituted aryl, and (Ce-io aryl)-(Ci-4 alkyl) esters of the compounds of the invention.

[0079] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature ( referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0080] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (nC), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36C1), chlorine-37 (37C1), fluorine-18 (18F) iodine-123 (123I), iodine-125(125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

[0081] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e.2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such asnC,18F,150 and13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0082] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’.

[0083] Stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.

[0084] ‘ Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of 7i electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.

[0085] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0086] The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.

[0087] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0088] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.EMBODIMENTS

[0089] Herein are provided inter alia, compounds that may be useful in the prophylaxis and / or treatment of NTM. In some aspects, herein are also provided methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, methods for the prophylaxis and / or treatment of NTM by administering the compounds of the invention.

[0090] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula (I):WhereinX is absent, O, or -NR2-Li is absent, or C1.4 alkylene;R1is phenyl optionally substituted with one or more independently selected R3a,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, Se or S heteroatoms, optionally substituted with one or more independently selected R3b, where the N heteroatoms may optionally be oxidized,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3c,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3d;5-10 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3e;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3f, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3g;C1-4 alkyl optionally substituted with one or more independently selected R3h;R2is H or C1.4 alkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4agroups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4bgroup,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4c, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is optionally substituted with one or more independently selected R4d;Each R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his independently selected from: halo,CN, or- -YA-LA-R5;Each R4a, R4b, R4cand R4dis selected from: halo,- =0,CN, or- -YB-LB-R6;Each YAand YBis independently selected from: absent,Ci-4 alkylene optionally substituted with one or more independently selected halo, or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo;Each LA and LB is independently selected from: absent,- -O-,- -(C=O),- -C(=O)O-,- -C(=NH)NR7a-,- -C(=O)NR7a-,- -C(=O)NR7fS(=O)2-,- -C(=O)NR7f-O-,- -C(=O)-C(=O)NR7f-,- -S(=O)-,- -S(=O)2-,- -OP(=O)(OR7d)O-,- -0C(=0)-,- -OC(=O)-NR7b,- -S(=O)2NR7b-,- S(=O)(=NR7b)-,- -NR7bS(=O)2-,- -NR7CC(=O)-,- -NR7CC(=O)O-,- -P(=O)R7d-,- -P(=O)(OR7d)O-,- -NR7e-;Each R5, R6, R7a, R76, R7c, R7d, R7e, and R7fand R7eis independently selected from:- H,Ci -4 alkyl optionally substituted with one or more independently selected deuterium, halo, OH, - C(=0)NHCH3, -NHC(=O) CH3, phenyl, cyclopropyl, cyclopropyl substituted with OH, or pyridinyl,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B, or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, -C(=O)OCH3, -C(=0)0H, -C(=O)-cyclopropyl, - N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0)CH3, -C(=0)NH2, CI_4 alkyl optionally substituted with one or more independently selected halo, or C 1.4 alkoxy optionally substituted with one or more independently selected halo,6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B, or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo, phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo, where the N heteroatoms of said heteroaryl may optionally be oxidized.

[0091] In yet a further aspect, the compounds of the invention are provided having a Formula (I),WhereinX is absent, O, or -NR2-Li is absent, or C1.4 alkylene;R1is phenyl optionally substituted with one or more independently selected R3a,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3b,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3c,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3d;5-10 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3e;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3f, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3g;R2is H or C1-4 alkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4agroups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4bgroup,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4c, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is optionally substituted with one or more independently selected R4d;Each R3a, R3b, R3c, R3d, R3e, R3f, and R3gis independently selected from: halo,CN, or- -YA-LA-R5;Each R4a, R4b, R4cand R4dis selected from:halo,- =0,CN, or- -YB-LB-R6;Each YAand YBis independently selected from: absent,Ci-4 alkylene optionally substituted with one or more independently selected halo, or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo;Each LA and LB is independently selected from: absent,- -0-,- -(C=0),- -C(=0)0-,- -C(=NH)NR7a-,- -C(=0)NR7a-,- -C(=O)NR7fS(=O)2-,- -S(=0)-,- -S(=0)2-,- -OP(=O)(OR7d)O-,- -0C(=0)-- -S(=O)2NR7b-,- -NR7bS(=O)2-,- -NR7CC(=0)-,- -NR7CC(=0)0-,- -P(=O)R7d-,- -NR7e-;Each R5, R6, R7a, R76, R7c, R7d, R7e, and R7fand R7eis independently selected from:- H,Ci -4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl or pyridinyl,4-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, Ci-4 alkyl optionally substituted with one or more independently selected halo, or Ci-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo,6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo, phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1.4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkoxy optionally substituted with one or more independently selected halo.

[0092] In yet a further aspect, the compounds of the invention are provided having a Formula (I), wherein: X is absent, O, or -NR2-;Li is absent, or C1.4 alkylene;R1is phenyl optionally substituted with one or more independently selected R3a,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3b,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3c,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3d,5-10 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3e,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3f, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3g;R2is H or C1.4 alkyl;Cy is:4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4agroups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4bgroup,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4c, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is optionally substituted with one or more independently selected R4d;Each R3a, R3b, R3c, R3d, R3e, R3f, and R3gis independently selected from: halo,CN, or- -YA-LA-R5;Each R4a, R4b, R4cand R4dis selected from: halo,- =0,CN, or- -YB-LB-R6;Each YA and YB is independently selected from: absent,Ci .4 alkylene optionally substituted with one or more independently selected halo, or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo;Each LAand LBis independently selected from: absent,- -O-,- -(C=O),- -C(=O)O-,- -C(=NH)NR7a-,- -C(=O)NR7a-,- -C(=O)NR7fS(=O)2-,- -S(=O)-,- -S(=O)2-,- -S(=O)2NR7b-,- -NR7bS(=O)2-,- -NR7CC(=O)-,- -NR7CC(=O)O-,- -P(=O)R7d-,- -NR7e-;Each R5, R6, R7a, R7h. R7c, R7d, R7e, and R7fis independently selected from:- H,Ci -4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl or pyridinyl,4-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo, phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, - C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo.

[0093] Accordingly, in a second aspect of the invention, the compounds of the invention are provided having a Formula (I) wherein:X is absent, O, or -NR2-Li is absent, or C1.4 alkylene;R1is phenyl optionally substituted with one or more independently selected R3a,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3b,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3c,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3d;5-10 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3e;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3f, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R3g;R2is H or Ci-4 alkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4agroups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4bgroup,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4c, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is optionally substituted with one or more independently selected R4d;Each R3a, R3b, R3c, R3d, R3e, R3f, and R3gis independently selected from: halo,CN, or- -YA-LA-R5;Each R4a, R4b, R4cand R4dis selected from: halo,- =0,CN, or- -YB-LB-R6;Each YA and YB is independently selected from: absent,Ci .4 alkylene optionally substituted with one or more independently selected halo, or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo; Each LA and LB is independently selected from: absent,- -O-,- -(C=O),- -C(=O)O-,- -C(=NH)NR7a-,- -C(=O)NR7a-,- -S(=0)-,- -S(=0)2-,- -S(=O)2NR7b-,- -NR7bS(=O)2-,- -NR7CC(=O)-,- -P(=O)R7d-,- -NR7e-;Each R5, R6, R7a, R76, R7c, R7d, and R7eis independently selected from:- H,Ci -4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl or pyridinyl,4-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, Ci-4 alkyl optionally substituted with one or more independently selected halo, or Ci-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, Ci-4 alkyl optionally substituted with one or more independently selected halo, or Ci-4 alkoxy optionally substituted with one or more independently selected halo,6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo, phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, - C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkoxy optionally substituted with one or more independently selected halo.

[0094] Accordingly, in a second aspect of the invention, the compounds of the invention are provided having a Formula (I) wherein:X is absent, O, or -NR2-;Li is absent, or C1.4 alkylene;R1isphenyl optionally substituted with one or more independently selected R3a,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3b,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3c,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3d,5-10 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3e,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3f, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3g;R2is H or Ci-4 alkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4agroups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4bgroup,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4c, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is optionally substituted with one or more independently selected R4d;Each R3a, R3b, R3c, R3d, R3e, R3f, and R3gis independently selected from: halo,CN, or- -YA-LA-R5;Each R4a, R4b, R4cand R4dis selected from: halo,- =0,CN, or- -YB-LB-R6;Each YA and YB is independently selected from: absent,Ci -4 alkylene optionally substituted with one or more independently selected halo, or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo; Each LAand LBis independently selected from: absent,- -O-,- -(C=O),- -C(=O)O-,- -C(=O)NR7a-,- -S(=O)-,- -S(=O)2-,- -S(=O)2NR7b-,- -NR7CC(=O)-,- -P(=O)R7d-,- -NR7e-;Each R5, R6, R7a, R76, R7c, R7d, and R7eis independently selected from:- H,Ci -4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl or pyridinyl,4-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo, phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, - C(=0)NHCH3, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2,-C(=0)NHCH3, CI-4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkoxy optionally substituted with one or more independently selected halo.

[0095] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4agroups. In a particular embodiment, Cy is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one, two or three independently selected R4agroup. In a more particular embodiment, Cy is pyrrolidinyl, or piperidinyl, each of which is substituted with one, two or three independently selected R4agroup. In a more particular embodiment, Cy is pyrrolidinyl, or piperidinyl, each of which is substituted with one R4agroup.

[0096] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is C3-7 cycloalkyl monocyclic optionally substituted with one or more independently selected R4cgroups. In a particular embodiment, Cy is C3-7 cycloalkyl monocyclic optionally substituted with one, two or three independently selected R4cgroup. In a more particular embodiment, Cy is cyclopentyl or cyclohexyl, each of which is substituted with one, two or three independently selected R4cgroup. In a more particular embodiment, Cy is cyclopentyl or cyclohexyl, each of which is substituted with one R4cgroup.

[0097] In one embodiment, the compound of the invention is according to Formula II:Wherein X, Li, R1and R4aare as described above.

[0098] In one embodiment, the compound of the invention is according to Formula I or II, wherein R4ais -YB-LB-R6, wherein YB, LB, and R6are as previously described. In a particular embodiment, YB is C1-4 alkylene, LB and R6is as previously described. In a more particular embodiment, YB is C1-4 alkylene, LB is absent and R6is as previously described. In a further more particular embodiment, YB is C1-4 alkylene, LB is absent and R6is as previously described. In some embodiments, YB is C1-4 alkylene, LB is absent and R6is C1-4 alkyl optionally substituted with one or more independently selected deuterium, halo, OH, - C(=O)NHCH3, -NHC(=O) CH3, phenyl, cyclopropyl, cyclopropyl substituted with OH, or pyridinyl. In a most particular embodiment, R4ais. -CH2CH2CH3. or -CH2CH(CH3)2.

[0099] In one embodiment, the compound of the invention is according to Formula I or II, wherein R4ais -YB-LB-R6, wherein YB, LB, and R6are as previously described. In a particular embodiment, YB is C1-4 alkylene, LB and R6is as previously described. In a more particular embodiment, YB is C1-4 alkylene, LB isabsent and R6is as previously described. In a further more particular embodiment, YB is C1-4 alkylene, LB is absent and R6is as previously described. In yet a further more particular embodiment, YB is C1-4 alkylene, LB is absent and R6is 4-7 membered monocyclic cycloalkyl. In a most particular embodiment, R4ais. -CH2- Cyclopropyl.

[0100] In one embodiment, the compound of the invention is according to Formula I or II, wherein R4ais -YB-LB-R6, wherein YB, LB, and R6are as previously described. In a particular embodiment, YBis C1.4 alkylene, LBand R6is as previously described. In a more particular embodiment, YBis C1.4 alkylene, LBis absent and R6is as previously described. In a further more particular embodiment, YB is C1-4 alkylene, LB is O, or -C(=O)NR7a, R6and R7aare as previously described. In yet a further more particular embodiment, YB is C1-4 alkylene, LB is O, or -C(=O)NR7a, R6and R7aare H. In a most particular embodiment, R4ais -CH2CH2CH2OH, -CH2CH(CH3)CH2OH, -CH2C(=O)NH2, -CH2CH2CH2C(=O)NH2, -CH2CH(CH3)CH2C(=O)NH2. In some embodiments, R4ais selected from the group comprising - CH2CH2CH3, -CH2CH(CH3)2, -CH2-Cyclopropyl, -CH2CH2CH2OH, -CH2CH(CH3)CH2OH, - CH2C(=O)NH2, -CH2CH2CH2C(=O)NH2, and -CH2CH(CH3)CH2C(=O)NH2.

[0101] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is selected from:wherein * represents the points of attachment.

[0102] In one embodiment, the compound of the invention is according to Formula III:Wherein X, Li, and R1are described previously.

[0103] In one embodiment, the compound of the invention is according to Formula I, II or III, wherein X is absent.

[0104] In one embodiment, the compound of the invention is according to Formula I, II or III, wherein X is -O-.

[0105] In one embodiment, the compound of the invention is according to Formula I, II or III, wherein X is -NR2-, and R2is as previously described. In a particular embodiment, R2is H, or -CH3. In a particular embodiment, R2is H.

[0106] In one embodiment, the compound of the invention is according to Formula I, II or III, wherein Li is absent.

[0107] In one embodiment, the compound of the invention is according to Formula I, II or III, wherein Li is C1.4 alkylene. In a particular embodiment, Li is -CH2-.

[0108] In one embodiment, the compound of the invention is according to Formula IVa, or IVb:wherein R1is described previously.wherein R1and R4aare as described previously.

[0110] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb wherein R1is phenyl optionally substituted with one or more independently selected R3a. In a particular embodiment, R1is phenyl optionally substituted with one, two or three independently selected R3a. In a particular embodiment, R1is phenyl optionally substituted with one or two independently selected R3a. In a particular embodiment, R1is phenyl optionally substituted with one R3a.[OlH] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3b. In a particularembodiment, R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one, two or three independently selected R3b. In a particular embodiment, R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or two independently selected R3b. In a particular embodiment, R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one R3b.

[0112] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb wherein R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3c. In a particular embodiment, R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one, two or three independently selected R3c. In a particular embodiment, R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or two independently selected R3c. In a particular embodiment, R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one R3c.

[0113] In one embodiment, the compound of the invention is according to any one of Formula I-Vb, wherein R1is 3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3d. In a particular embodiment, R1is 3-7 membered monocyclic cycloalkyl optionally substituted with one, two or three groups independently selected from =0 and R3d. In a particular embodiment, R1is 3-7 membered monocyclic cycloalkyl optionally substituted with one or two groups independently selected from =0 and R3d. In a particular embodiment, R1is 3-7 membered monocyclic cycloalkyl optionally substituted with one group independently selected from =0 and R3d.

[0114] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb wherein R1is 5-10 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3e. In a particular embodiment, R1is 5-10 membered bicyclic fused, bridged or spiro cycloalkyl optionally substituted with one, two or three groups independently selected from =0 and R3e. In a particular embodiment, R1is 5-10 membered bicyclic fused, bridged or spiro cycloalkyl optionally substituted with one or two groups independently selected from =0 and R3e. In a particular embodiment, R1is 5-10 membered bicyclic fused, bridged or spiro cycloalkyl optionally substituted with one groups independently selected from =0 and R3e.

[0115] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb wherein R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3f. In a particular embodiment, R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one, two or three independently selected R3f. In a particular embodiment, R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one or two independently selected R3f. In a particular embodiment, R1is 4-7 membered monocyclicheterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one R3f.

[0116] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb wherein R1is 5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3g. In a particular embodiment, R1is 5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one, two or three groups independently selected from =0 and R3g. In a particular embodiment, R1is 5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one or two groups independently selected from =0 and R3g. In a particular embodiment, R1is 5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one groups independently selected from =0 and R3g.

[0117] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis CN. In some embodiments, the compound of the invention is according to any one of Formula I- IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his CN.

[0118] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis halo. In a particular embodiment, one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis selected from F, Cl. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his halo. In a particular embodiment, one or more independently selected R3a, R3b, R3C, R3d, R3e, R3f, R3gand R3his selected from F, Cl.

[0119] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein YA is absent. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein YAis absent.

[0120] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein YA is Ci-4 alkylene optionally substituted with one or more independently selected halo. In one embodiment, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein YAis C1.4 alkylene optionally substituted with one or more independentlyselected halo. In a more particular embodiment, YA is -CH2-, or -CH2CH2-, each of which is optionally substituted with one or more independently selected halo.

[0121] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein YAis 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3C, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein YAis 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo. In a particular embodiment, YA is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is optionally substituted with one or more independently selected halo. In a more particular embodiment, YA is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is optionally substituted with one or more F.

[0122] In some embodiments YAis absent or selected from -CH2-, -CH2CH2-, -CH2- substituted with one or more independently selected halo, -CH2CH2- substituted with one or more independently selected halo, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl substituted with one or more independently selected halo, cyclobutyl substituted with one or more independently selected halo, or cyclopentyl substituted with one or more independently selected halo.

[0123] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein LA is absent. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein LAis absent.

[0124] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein LAis -O-, -C(=O)-, -C(=O)O-, -S(=O)-, or -S(=O)2-. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein LAis -O-, -C(=O)-, -C(=O)O-, -S(=O)-, or -S(=O)2-.

[0125] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein LAis -C(=O)NR7a-, -S(=O)2NR7b-, -NR7cC(=O)-, -P(=O)R7d-, or -NR7e- and each R7a, R76, R7c, R7d, and R7eis as previously described, in a particular embodiment, each R7a, R7h. R7c, R7d, and R7eis independently selected from H, C1-4 alkyl, and 4-7 membered monocyclic cycloalkyl. In a more particular embodiment, each R7a, R7b, R7c, R7d, and R7eis independently selected from H, -CH3, - CH2CH3, and cyclopropyl. In a most particular embodiment, LAis -C(=O)NH-, -S(=O)2NH-, -NHC(=O)-, -P(=O)CH3-, or -NH-.

[0126] In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f,R3gand R3his -YA-LA-R5, wherein LAis absent or is selected from -C(=NH)NR7a-, -C(=O)NR7a-, - C(=O)NR7fS(=O)2-, -C(=O)NR7f-O-, -C(=O)-C(=O)NR7f-, -OP(=O)(OR7d)O-, -OC(=O)-, -OC(=O)-NR7b, -S(=O)2NR7b-, S(=O)(=NR7b)-, -NR7bS(=O)2-, -NR7cC(=O)-, -P(=O)R7d-, -P(=O)(OR7d)O- or -NR7e- and each R7a, R7b, R7c, R7d, R7eand R7fis as previously described. In some embodiments LAis -C(=NH)NR7a-, -C(=O)NR7a-, -C(=O)NR7fS(=O)2-, -C(=O)NR7f-O-, -C(=O)-C(=O)NR7f-, -OP(=O)(OR7d)O-, -OC(=O)-, - OC(=O)-NR7b, -S(=O)2NR7b-, S(=O)(=NR7b)-, -NR7bS(=O)2-, -NR7cC(=O)-, -P(=O)R7d-, -P(=O)(OR7d)O- or -NR7e- and R7a, R7b, R7c, R7d, R7eand R7fis independently selected from H, C1.4 alkyl, and 4-7 membered monocyclic cycloalkyl.

[0127] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein R5is H. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3C, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein R5is H.

[0128] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein R5is C1-4 alkyl. In a particular embodiment, R5is -CH3, or -CH2CH3. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his - YA-LA-R5, wherein R5is C1.4 alkyl.

[0129] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein R5is C1.4 alkyl substituted with one or more independently selected halo, OH, phenyl or pyridinyl. In a particular embodiment, R5is -CH3, or - CH2CH3, each of which is substituted with one or more independently selected halo, OH, phenyl or pyridinyl. In a more particular embodiment, R5is -CF3, -CHF2, -CH2-phenyl, or -CH2-pyridinyl.

[0130] In one embodiment, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein R5is C1-4 alkyl substituted with one or more independently selected deuterium, halo, OH, -C(=O)NHCH3, -NHC(=O)CH3, phenyl, cyclopropyl or pyridinyl. In a particular embodiment, R5is -CH3, or - CH2CH3, each of which is substituted with one or more independently selected deuterium, halo, OH, -C(=O)NHCH3, -NHC(=O)CH3, phenyl, cyclopropyl or pyridinyl. In a more particular embodiment, R5is -CF3, -CHF2, CD3, -CH2-C(=O)NHCH3, -CH2-NHC(=O)CH3, -CH2-phenyl, - CH2-cyclopropyl, or -CH2-pyridinyl.

[0131] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein R5is 4-7 membered monocyclic cycloalkyl. In a particular embodiment, R5is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a particular embodiment, R5is cyclopropyl.

[0132] In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein R5is 3-7 membered monocyclic cycloalkyl.

[0133] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein R5is 4-7 membered monocyclic cycloalkyl substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is cyclopropyl substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, - CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3.

[0134] In one embodiment, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein R5is 3-7 membered monocyclic cycloalkyl substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo.

[0135] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms. In one embodiment, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B or S heteroatoms. In a particular embodiment, R5is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl.

[0136] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In one embodiment, thecompound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P Se, Si, B or S heteroatoms, substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, -C(=O)OCH3, -C(=0)0H, -C(=O)-cyclopropyl, -N(CH3)2, CN, -C(=0)NHCH3, - S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, CI-4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl, each of which is substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl, each of which is substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3. In some embodiments, R5is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl, each of which is substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, -C(=O)OCH3, -C(=0)0H, -C(=O)-cyclopropyl, -N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, -CH3, -CHF2, -CF3, -OCH3, -OCF3, - C(=0)NH2, or -C(=0)NHCH3.

[0137] In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B or S heteroatoms, substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, -C(=0)0CH3, -C(=0)0H, -C(=O)-cyclopropyl, - N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,3,4-selenadiazolyl, 1,4-azasilinanyl or thiomorpholinyl, each of which is substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, -C(=0)0CH3, -C(=0)0H, -C(=O)-cyclopropyl, -N(CH3)2, CN, - C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,3,4-selenadiazolyl, 1,4-azasilinanyl or thiomorpholinyl, each of which is substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, - P(=O)(CH3)2, -C(=0)0CH3, -C(=0)0H, -C(=O)-cyclopropyl, -N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3.

[0138] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein R5is 6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein R5is 6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B or S heteroatoms.

[0139] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein R5is 6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or more independently selected halo, OH, =0, Ci-4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is 6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms substituted with one or more independently selected F, Cl, -OH, =0, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3. In someone embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his - YA-LA-R5, wherein R5is 6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B or S heteroatoms, substituted with one or more independently selected halo, OH, =0, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is 6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, B or S heteroatoms substituted with one or more independently selected F, Cl, -OH, =0, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3.

[0140] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein R5is phenyl. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein R5is phenyl.

[0141] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein R5is phenyl substituted with one or more independently selected halo, OH, -C(=O)NH2, -C(=O)NHCH3, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5,wherein R5is phenyl substituted with one or more independently selected halo, OH, -C(=O)NH2, - C(=O)NHCH3, CI-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is phenyl substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -OCH3, - OCF3, -C(=O)NH2, or -C(=O)NHCH3.

[0142] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein R5is 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms. In a particular embodiment, R5is pyrazolyl, oxazolyl, thiaoxazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, or pyrimidinyl. In one embodiment, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein R5is 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms, where the N heteroatoms of said heteroaryl may optionally be oxidized. In a particular embodiment, R5is pyrazolyl, oxazolyl, thiaoxazolyl, furanyl, thienyl, pyridinyl, pyridinyl-N-oxide, pyrazinyl, or pyrimidinyl.

[0143] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis -YA-LA-R5, wherein R5is 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=O)NH2, -C(=O)NHCH3, CI-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In one embodiment, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his -YA-LA-R5, wherein R5is 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=O)NH2, -C(=O)NHCH3, C1.4 alkyl optionally substituted with one or more independently selected halo, or C 1.4 alkoxy optionally substituted with one or more independently selected halo, where the N heteroatoms of said heteroaryl may optionally be oxidized. In a particular embodiment, R5is pyrazolyl, oxazolyl, thiaoxazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one or more independently selected halo, OH, -C(=O)NH2, -C(=O)NHCH3, CI-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is pyrazolyl, oxazolyl, thiaoxazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, - OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3.

[0144] In some embodiments R5is selected from- H;C1.4 alkyl optionally substituted with one or more independently selected deuterium, halo, OH, - C(=O)NHCH3, -NHC(=O)CH3, phenyl, cyclopropyl or pyridinyl;3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo; preferably said monocyclic cycloalkyl is optionally substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -CH3, -CHF2, -CF3, -0CH3, -OCF3, - C(=0)NH2, or -C(=0)NHCH3;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B or S heteroatoms, optionally substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, -C(=O)OCH3, -C(=0)0H, -C(=O)-cyclopropyl, - N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, -CH3, -CHF2, -CF3, - 0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3;6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, B or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo; preferably said heterocycloalkyl is optionally substituted with one or more independently selected F, Cl, -OH, =0, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or - C(=0)NHCH3; phenyl optionally substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, - CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3;5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, - 0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, where the N heteroatoms of said heteroaryl may optionally be oxidized.

[0145] In some embodiments R5is selected from the group comprising H, -CH3, -CH2CH3, -CF3, -CHF2, CD3, -CH2-C(=O)NHCH3, -CH2-NHC(=O)CH3, -CH2-phenyl, -CH2-cyclopropyl, -CH2-pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or - C(=0)NHCH3cyclobutyl substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, cyclopentyl substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, cyclohexyl substituted with one or more independently selected F, Cl, - OH, =0, phenyl, pyridinyl, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, azetidinyl substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, - P(=O)(CH3)2, -C(=0)0CH3, -C(=0)0H, -C(=O)-cyclopropyl, -N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, oxetanyl substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, -C(=O)OCH3, -C(=O)OH, -C(=O)-cyclopropyl, -N(CH3)2, CN, -C(=O)NHCH3, -S(=O)2CH3, -NHC(=O) CH3, -C(=O)NH2, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3, pyrrolidinyl substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, - C(=O)OCH3, -C(=0)0H, -C(=O)-cyclopropyl, -N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, piperidinyl substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, - C(=O)OCH3, -C(=O)OH, -C(=O)-cyclopropyl, -N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, piperazinyl substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, - C(=O)OCH3, -C(=O)OH, -C(=O)-cyclopropyl, -N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, tetrahydropyranyl substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, - C(=O)OCH3, -C(=O)OH, -C(=O)-cyclopropyl, -N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, morpholinyl substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, - C(=O)OCH3, -C(=O)OH, -C(=O)-cyclopropyl, -N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, 1,3,4-selenadiazolyl substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, - C(=O)OCH3, -C(=O)OH, -C(=O)-cyclopropyl, -N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, 1,4-azasilinanyl substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, - C(=O)OCH3, -C(=O)OH, -C(=O)-cyclopropyl, -N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, thiomorpholinyl substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, - C(=O)OCH3, -C(=O)OH, -C(=O)-cyclopropyl, -N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, 6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, B or S heteroatoms substituted with one or more independently selected F, Cl, -OH, =0, -CH3, -CHF2, - CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, phenyl, phenyl substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3, pyrazolyl, oxazolyl, thiaoxazolyl, furanyl, thienyl, pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyrazolyl optionally substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, - 0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3; oxazolyl optionally substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3; thiaoxazolyl optionally substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3; furanyl optionally substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3; thienyl optionally substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -OCHs. -OCF3, -C(=O)NH2, or -C(=0)NHCH3; pyridinyl optionally substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3; pyridinyl-N-oxide optionally substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3; pyrazinyl optionally substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3and pyrimidinyl optionally substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3.

[0146] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis selected from R5, -CH2-R5, -C(=O)OR5, -C(=O)NHR5, -CH2-C(=O)NHR5, -NHC(=O)R5, - C(=O)R5, -S(=O)2NHR5, -NHS(=O)2R5, -C(=O)NHS(=O)2-R5, -S(=O)2R5, -NHR5, -OR5, -NH-CH2-R5, - NHC(=O)R5or -P(=O)CH3R5.

[0147] In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his selected from R5, -CH2-R5, -C(=O)OR5, -C(=NH)NHR5, -C(=NH)NCH3R5, -C(=O)NHR5, - CH2-C(=O)NHR5, -C(=O)NHS(=O)2R5, -C(=O)NCH3S(=O)2R5, -C(=O)NH-OR5, -C(=O)-C(=O)NHR5, - C(=O)-C(=O)NCH3R5, -OC(=O)-NHR5, -OC(=O)-NCH3R5, -OP(=O)(OH)O-R5, -OP(=O)(OCH3)O-R5, - OC(=O)-R5, -S(=O)(=NH)-R5, -S(=O)(=NCH3)-R5, -OP(=O)(OH)O-R5, -OP(=O)(OCH3)O-R5, - OP(=O)(OCH2CH3)O-R5, -OC(=O)-R5, -NHC(=O)R5, -C(=O)R5, -S(=O)2NHR5, -NHS(=O)2R5, - C(=O)NHS(=O)2-R5, -S(=O)2R5, -NHR5, -OR5, -NH-CH2-R5, -NHC(=O)R5, -P(=O)(OCH3)O-R5, - P(=O)(OCH2CH3)O-R5, or -P(=O)CH3R5.

[0148] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis selected from R5, -CH2-R5, -C(=O)OR5, -C(=O)NHR5, -CH2-C(=O)NHR5, -NHC(=O)R5, - C(=O)R5, -S(=O)2NHR5, -NHS(=O)2R5, -S(=O)2R5, -NHR5, -OR5, -NH-CH2-R5, or -P(=O)CH3R5. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as previously described, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his selected from R5, -CH2-R5, -C(=O)OR5, -C(=O)NHR5, -CH2-C(=O)NHR5, -NHC(=O)R5, -C(=O)R5, - S(=O)2NHR5, -NHS(=O)2R5, -S(=O)2R5, -NHR5, -OR5, -NH-CH2-R5, or -P(=O)CH3R5.

[0149] In one embodiment, R5is H.

[0150] In one embodiment, R5is C1-4 alkyl. In a particular embodiment, R5is -CH3, or -CH2CH3.

[0151] In one embodiment, R5is C1-4 alkyl substituted with one or more independently selected halo, OH, phenyl or pyridinyl. In a particular embodiment, R5is -CH3, or -CH2CH3, each of which is substituted with one or more independently selected halo, OH, phenyl or pyridinyl. In a more particular embodiment, R5is -CF3, -CHF2, -CH2-phenyl, or -CH2-pyridinyl.

[0152] In one embodiment, R5is 4-7 membered monocyclic cycloalkyl. In a particular embodiment, R5is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a particular embodiment, R5is cyclopropyl.

[0153] In one embodiment, R5is 4-7 membered monocyclic cycloalkyl substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, Ci-4 alkyl optionally substituted with one or more independently selected halo, or Ci-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is cyclopropyl substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, - CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3.

[0154] In one embodiment, R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms. In a particular embodiment, R5is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl .

[0155] In one embodiment, R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl, each of which is substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl, each of which is substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3.

[0156] In one embodiment, R5is 6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms.

[0157] In one embodiment, R5is 6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is 6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms substituted with one or more independently selected F, Cl, -OH, =0, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3.

[0158] In one embodiment, R5is phenyl.

[0159] In one embodiment, R5is phenyl substituted with one or more independently selected halo, OH, - C(=O)NH2, -C(=O)NHCH3, CI-4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is phenyl substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3.

[0160] In one embodiment, R5is 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms. In a particular embodiment, R5is pyrazolyl, oxazolyl, thiaoxazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, or pyrimidinyl.

[0161] In one embodiment, R5is 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=O)NH2, -C(=O)NHCH3, CI-4 alkyl optionally substituted with one or more independently selected halo, or Ci-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is pyrazolyl, oxazolyl, thiaoxazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one or more independently selected halo, OH, -C(=O)NH2, -C(=O)NHCH3, Ci-4 alkyl optionally substituted with one or more independently selected halo, or Ci-4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is pyrazolyl, oxazolyl, thiaoxazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, - OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3.

[0162] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis selected from -CH3, -CH2CH3, -CH2CH(CH3)2, -CH2-C(=O)NH2, -CH2-phenyl, and -CH2- pyridinyl. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his selected from -CH3, -CH2CH3, -CH2CH(CH3)2, -CH2-C(=O)NH2, -CH2-phenyl, and - CH2-pyridinyl.

[0163] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0164] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as described for Formula I, and one or more independently selectedR3a, R3b, R3C, R3d, R3e, R3f, R3gand R3his selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0165] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis selected from -OCH3, -OCH2CH3, -OCH2CH(CH3)2, -OCH2-phenyl, -OCH2-pyridinyl. and - O-cyclopropyl. In some embodiment, the compound of the invention is according to any one of Formula I- Vb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his selected from -OCH3, -OCH2CH3, -OCH2CH(CH3)2, -OCH2-phenyl, -OCH2- pyridinyl. and -O-cyclopropyl.

[0166] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, and R3gis selected from -NHCH3, -N(CH3)2, -NH-cyclopropyl, and -NHCH2-phenyl. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his selected from -NHCH3, -N(CH3)2, -NH-cyclopropyl, and -NHCH2-phenyl.

[0167] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his selected from -C(=O)OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -(C=O)NH-pyridinyl, -C(=O)imidazolyl, -C(=O)-pyrazolyl, -C(=O)-pyridinyl, -C(=O)-O, wherein * represents the attachment point.

[0168] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e,wherein * represents the attachment point.

[0169] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d,R3e, R3f, R3gand R3his selected from O , -NH(C=O)pyridinyl, and O , wherein * represents the attachment point.

[0170] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d,R3e, R3f, R3gand R3his selected from -S(=O)2NH2, -S(=O)2NHCH3, andrepresents the attachment point.

[0171] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d,R3e, R3f, R3gand R3his selected from -S(=O)2CH3, -S(=O)2CH2CH3, andwherein * represents the attachment point.

[0172] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his selected from -NHS(=O)2CH3 and -NHS(=O)2CH2CH3.

[0173] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his selected from -C(=NH)NH2,

[0174] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d,

[0175] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his selected from -P(=O)(CH3)2.

[0176] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is as described for Formula I, and one or more independently selected R3a, R3b, R3c, R3d,attachment point.

[0177] In some embodiments each R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his independently selected from F, Cl, CN, -OH, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -OCH2CH3, -OCH2CH(CH3)2, -OCH2-phenyl, -OCH2- pyridinyl. -O-cyclopropyl, -C(=O)NH2, -C(=O)NHCH3, -CH2CH3, -CH2CH(CH3)2, -CH2-C(=O)NH2, - CH2-phenyl, -CH2-pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C(=O)NHCD3, -C(=O)-C(=O)NH2, -C(=O)-C(=O)NHCH3, -OC(=O)-N(CH3)2, - S(=O)(=NH)CH3, -S(=O)(=NCH3)CH3, -P(=O)(OCH2CH3)OCH2CH3, -NHCH3, -N(CH3)2, -NH- cyclopropyl, -NHCH2-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, -C(=O)OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -(C=O)NH-pyridinyl, -C(=O)imidazolyl, -C(=O)-pyrazolyl, -C(=O)-pyridinyl, -C(=O)- cyclopropyl, -NH(C=O)pyridinyl, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2CH3, -S(=O)2CH2CH3, -

[0178] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va,Vb, wherein R1is phenyl.

[0179] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is phenyl substituted with one or more independently selected R3a, wherein one or more R3ais halo. In a particular embodiment, one or more R3ais F or Cl.

[0180] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is phenyl substituted with one or more independently selected R3a, wherein one or more R3ais CN.

[0181] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein phenyl substituted with one or more independently selected R3a, wherein one or more R3ais - YA-LA-R5and each YA, LAand R5is as previously described. In a particular embodiment, YAis absent, LAis -C(=O)NR7a-, and R5is as previously described. In a more particular embodiment, YAis absent, LAis - C(=O)NH-, and R5is as previously described. In a further more particular embodiment, YAis absent, LAis -C(=O)NH-, and R5is 4-7 membered monocyclic cycloalkyl . In a most particular embodiment, YAis absent, LA is -C(=O)NH-, and R5is cyclopropyl, cyclobutyl, or cyclopentyl.

[0182] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is phenyl optionally substituted with one or more independently selected R3a, wherein one or more R3ais -YA-LA-R5and each YA, LA and R5is as previously described. In a particular embodiment, YA is absent, LA is -C(=O)NR7a-, and R5is as previously described. In a more particular embodiment, YA is absent, LA is — C(=O)NH-, and R5is as previously described. In a further more particular embodiment, YA is absent, LA is -C(=O)NH-, and R5is 4-7 membered monocyclic cycloalkyl substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, Ci-4 alkyl optionally substituted with one or more independently selected halo, or Ci-4 alkoxy optionally substituted with one or more independently selected halo. In a most particular embodiment, YA is absent, LA is -C(=O)NH-, and R5is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, Ci-4 alkyl optionally substituted with one or more independently selected halo, or Ci-4 alkoxy optionally substituted with one or more independently selected halo.

[0183] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is phenyl optionally substituted with one or more independently selected R3a, wherein one or more R3ais -YA-LA-R5and each YA, LA and R5is as previously described. In a particular embodiment, YA is absent, LA is -C(=O)NR7a-, and R5is as previously described. In a more particular embodiment, YA is absent, LA is -C(=O)NH-, and R5is as previously described. In a further more particular embodiment, YAis absent, LA is -C(=O)NH-, and R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms. In a most particular embodiment, YA is absent, LA is - C(=O)NH-, and R5is pyrrolidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, piperidinyl, thiomorpholinyl, or azaphosphinanyl.

[0184] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is phenyl optionally substituted with one or more independently selected R3a, wherein one or more R3ais -YA-LA-R5and each YA, LAand R5is as previously described. In a particular embodiment, YA is absent, LA is -C(=O)NR7a-, and R5is as previously described. In a more particular embodiment, YA is absent, LA is -C(=O)NH-, and R5is as previously described. In a further more particular embodiment, YA is absent, LA is -C(=O)NH-, and R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or more independently selected halo, OH, =0, Ci-4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a most particular embodiment, YA is absent, LA is -C(=0)NH-, and R5is pyrrolidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, piperidinyl, thiomorpholinyl, or azaphosphinanyl, each of which is substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo.

[0185] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is phenyl.

[0186] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is phenyl substituted with one or more independently selected R3a. In a particular embodiment, R1is phenyl substituted with one, two or three independently selected R3a. In a more particular embodiment, R1is phenyl substituted with one or two independently selected R3a. In a most particular embodiment, R1is phenyl substituted with one R3a.

[0187] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is phenyl substituted with one or more independently selected R3a, wherein each R3ais independently selected from halo, CN, and -YA-LA-R5, wherein YA, LA, and R5are as previously defined.

[0188] In a particular embodiment, one or more R3ais independently selected from F, Cl, CN, and -YA- LA-R5.

[0189] In a particular embodiment, one or more R3ais independently selected from -YA-LA-R5, wherein YA is absent, LA is selected from -S(=O)2NH-, -C(=O)NH-, and R5is H.

[0190] In another particular embodiment, one or more R3ais independently selected from -YA-LA-R5, wherein YA is absent, LA is selected from -S(=O)2-, -C(=O)NH-, and -O- and R5is C1-4 alkyl. In a particular embodiment, R5is -CH3 or -CH2CH3.

[0191] In a particular embodiment, one or more R3ais independently selected from -YA-LA-R5, wherein YAis absent, LAis selected from -S(=O)2-, NHC(=O)-, and -C(=O)NH-, and R5is 4-7 membered monocyclic cycloalkyl. In a particular embodiment, R5is cyclopropyl.

[0192] In a particular embodiment, one or more R3ais independently selected from -YA-LA-R5, wherein YA is absent, LA is selected from -S(=O)2-, and -C(=O)-, and R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms. In a particular embodiment, R5is azetidinyl, or morpholinyl.

[0193] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is:

[0194] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms. In a particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, or pyrimidinyl. In one embodiment, the compound of the invention is according to any one of Formula I-Vb, wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms where the N heteroatoms may optionally be oxidized. In a particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, where the N heteroatoms may optionally be oxidized.

[0195] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, Se or S heteroatoms, substituted with one or more independently selected R3b. In a particular embodiment, R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, Se or S heteroatoms, substituted with one, two or three independently selected R3b. In a further particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one, two or three independently selected R3b. In a more particular embodiment, R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, Se or S heteroatoms, substituted with one or two independently selected R3b. In a further more particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one or two independently selected R3b. In a most particular embodiment, R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, Se or S heteroatoms, substituted with one R3b. In a further most particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one R3b.

[0196] In one embodiment, the compound of the invention is according to any one of Formula I-Vb, wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, Se or S heteroatoms, substituted with one or more independently selected R3b, where the N heteroatoms may optionally be oxidized. In a particular embodiment, R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, Se or S heteroatoms, substituted with one, two or three independently selected R3b, where the N heteroatoms may optionally be oxidized. In a further particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one, two or three independently selected R3b, where the N heteroatoms may optionally be oxidized. In a more particular embodiment, R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, Se or S heteroatoms, substituted with one or two independently selected R3b, where the N heteroatoms may optionally be oxidized. In a further more particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, thiadiazolyl, selenadiazolyl or pyrimidinyl, each of which is substituted with one or two independently selected R3b, where the N heteroatoms may optionally be oxidized. In a most particular embodiment, R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, Se or S heteroatoms, substituted with one R3b, where the N heteroatoms may optionally be oxidized. In a further most particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, thiadiazolyl, selenadiazolyl or pyrimidinyl, each of which is substituted with one R3b, where the N heteroatoms may optionally be oxidized.

[0197] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, Se or S heteroatoms, substituted with one or more independently selected R3b, wherein each R3bis independently selected from halo, CN, and -YA-LA-R5, wherein YA, LA, and R5are as previously defined. In one embodiment, the compound of the invention is according to any one of Formula I-Vb, wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, Se or S heteroatoms, substituted with one or more independently selected R3b, wherein each R3bis independently selected from halo, CN, and -YA-LA-R5, wherein YA, LA, and R5are as previously defined, where the N heteroatoms may optionally be oxidized.

[0198] In a particular embodiment, one or more R3bis independently selected from F, Cl, CN, and -YA- LA-R5.

[0199] In a particular embodiment, one or more R3bis independently selected from -YA-LA-R5, wherein YAis absent, LAis selected from -C(=O)NH-, -O-, and R5is H.

[0200] In a particular embodiment, one or more R3bis independently selected from -YA-LA-R5, wherein YAis absent, LAis absent, and R5is C1.4 alkyl. In a particular embodiment, R5is -CH3or -CH2CH3.

[0201] In a particular embodiment, one or more R3bis independently selected from -YA-LA-R5, wherein YA is absent, LA is -P(=O)R7d-, each R7dand R5are independently C1-4 alkyl. In a particular embodiment, each R7dand R5are independently -CH3 or -CH2CH3.

[0202] In a particular embodiment, one or more R3bis independently selected from -YA-LA-R5, wherein YAis absent, LAis selected from NHC(=O)-, and R5is 4-7 membered monocyclic cycloalkyl. In a particular embodiment, R5is cyclopropyl.

[0203] In a particular embodiment, one or more R3bis independently selected from -YA-LA-R5, wherein YA is absent, LA is selected from -S(=O)2-, and -C(=O)-, and R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms. In a particular embodiment, R5is azetidinyl, or morpholinyl.

[0204] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb wherein R1is:Vb wherein R1is:wherein * represents the points of attachment.

[0206] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb wherein R1is:wherein * represents the points of attachment.

[0207] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms. In a particular embodiment, R1is indazolyl, benzofuranyl, benzothiazolyl, quinolinyl, or quinazolinyl. In some embodiments, R1is indazolyl, benzofuranyl, benzothiazolyl, quinolinyl, pyrazolo[l,5-a]pyridinyl, benzoxazolyl, naphthyridinyl, triazolopyridinyl, imidazopyridinyl or quinazolinyl.

[0208] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, substituted with one or more independently selected R3c. In a particular embodiment, R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, substituted with one, two or three independently selected R3c. In a further particular embodiment, R1is, indazolyl, benzofuranyl, benzothiazolyl, quinolinyl, or quinazolinyl, each of which is substituted with one, two or three independently selected R3c. In some embodiments, R1is indazolyl, benzofuranyl, benzothiazolyl, quinolinyl, pyrazolo[l,5-a]pyridinyl, benzoxazolyl, naphthyridinyl, triazolopyridinyl, imidazopyridinyl or quinazolinyl, each of which is substituted with one, two or three independently selected R3c. In a more particular embodiment, R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, substituted with one or two independently selected R3c. In a further more particular embodiment, R1is indazolyl, benzofuranyl, benzothiazolyl, quinolinyl, or quinazolinyl, each of which is substituted with one or two independently selected R3c. In some embodiments, R1is, indazolyl, benzofuranyl, benzothiazolyl, quinolinyl, pyrazolo[l,5-a]pyridinyl, benzoxazolyl, naphthyridinyl, triazolopyridinyl, imidazopyridinyl or quinazolinyl, each of which is substituted with one or two independently selected R3c. In a most particular embodiment, R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, substituted with one R3c. In a further most particular embodiment, R1is indazolyl, benzofuranyl, benzothiazolyl, quinolinyl, or quinazolinyl, each of which is substituted with one R3c. In some embodiments, R1is, indazolyl, benzofuranyl, benzothiazolyl, quinolinyl, pyrazolo[l,5-a]pyridinyl, benzoxazolyl, naphthyridinyl, triazolopyridinyl, imidazopyridinyl or quinazolinyl, each of which is substituted with one R3c.

[0209] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is:the points of attachment.

[0210] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is:, wherein * represents the points of attachment.

[0211] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is 3-7 membered monocyclic cycloalkyl. In a particular embodiment, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0212] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is 3-7 membered monocyclic cycloalkyl, substituted with one or more groups independently selected from =0 and R3d. In a particular embodiment, R1is 3-7 membered monocyclic cycloalkyl, substituted with one, two or three groups independently selected from =0 and R3d. In a further particular embodiment, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two or three groups independently selected from =0 and R3d. In a more particular embodiment, R1is 3-7 membered monocyclic cycloalkyl, substituted with one or two groups independently selected from =0 and R3d. In a further more particular embodiment, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or two groups independently selected from =0 and R3d. In a most particular embodiment, R1is 3-7 membered monocyclic cycloalkyl, substituted with one =0 or R3d. In a further most particular embodiment, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one =0 or R3d.

[0213] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is 3-7 membered monocyclic cycloalkyl, substituted with one or more groups independently selected from =0 and R3d, wherein each R3dis independently selected from halo, CN, and - YA-LA-R5, wherein YA, LA, and R5are as previously defined. In a particular embodiment, each R3dF, Cl, CN, and -YA-LA-R5.

[0214] In a particular embodiment, one or more R3dis independently selected from -YA-LA-R5, wherein YA is absent, LA is selected from -C(=0)NH-, and -O-, and R5is H.

[0215] In a particular embodiment, one or more R3dis independently selected from -YA-LA-R5, wherein YA is absent, LA is absent, and R5is Ci-4 alkyl. In a particular embodiment, R5is -CH, or -CH2CH3.

[0216] In a particular embodiment, one or more R3dis independently selected from -YA-LA-R5, wherein YA is absent, LA is -C(=0)NH-, and R5is C1-4 alkyl. In a particular embodiment, R5is -CH3 or -CH2CH3.

[0217] In a particular embodiment, one or more R3dis independently selected from -YA-LA-R5, wherein YA is absent, LA is -C(=0)NH-, and R5is 4-7 membered monocyclic cycloalkyl. In a particular embodiment, R5is cyclopropyl.

[0218] In a particular embodiment, one or more R3dis independently selected from -YA-LA-R5, wherein YAis absent, LAis -C(=O)NHS(=O)2-, and R5is C1.4 alkyl. In a particular embodiment, R5is -CH3or - CH2CH3.

[0219] In a particular embodiment, one or more R3dis independently selected from -YA-LA-R5, wherein YA is absent, LA is -C(=O)NH-, and R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.

[0220] In a particular embodiment, one or more R3dis independently selected from -YA-LA-R5, wherein YA is absent, LA is selected from -S(=O)2-, and -C(=O)-, and R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is azetidinyl, morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, or azaphosphinanyl, each of which is optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is azetidinyl, morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, or azaphosphinanyl.

[0221] In a particular embodiment, one or more R3dis independently selected from -YA-LA-R5, wherein YAis absent, LAis selected from -S(=O)2-, and -C(=O)-, and R5is 6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is oxazabicycloheptanyl, oxazaspiroheptanyl, or oxazaspirononanyl, each of which is optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is oxazabicycloheptanyl, oxazaspiroheptanyl, or oxazaspirononanyl .

[0222] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is:represents the points of attachment.

[0223] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va,Vb, wherein R1is:of attachment.

[0224] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is:

[0225] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is:represents the points of attachment.

[0226] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is:, wherein * represents the points of attachment.

[0227] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is:, wherein * represents the points of attachment.

[0228] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is 5-10 membered bicyclic fused, bridged or spiro cycloalkyl. In a particular embodiment, R1is bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or spiro[3.3]heptanyl. In some embodiments, R1is bicyclo [2. l.l]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, cubanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, or spiro[3.3]heptanyl.

[0229] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is 5-10 membered bicyclic fused, bridged or spiro cycloalkyl, substituted with one or more groups independently selected from =0 and R3e. In a particular embodiment, R1is 5-10 membered bicyclic fused, bridged or spiro cycloalkyl, substituted with one, two or three groups independently selected from =0 and R3e. In a further particular embodiment, R1is bicyclo [2. l. l]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or spiro[3.3]heptanyl, each of which is substituted with one, two or three groups independently selected from =0 and R3e. In some embodiments, R1is bicyclo[2.1.1]hexanyl, bicyclo [2.2. l]heptanyl, bicyclo [2.2.2] octanyl, cubanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, or spiro[3.3]heptanyl, each of which is substituted with one, two or three groups independently selected from =0 and R3e. In a more particular embodiment, R1is 5-10 membered bicyclic fused, bridged or spiro cycloalkyl, substituted with one or two groups independently selected from =0 and R3e. In a further more particular embodiment, R1is bicyclo [2. l.l]hexanyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, or spiro[3.3]heptanyl, each of which is substituted with one or two groups independently selected from =0 and R3e. In some embodiments, R1is bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, cubanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, or spiro[3.3]heptanyl, each of which is substituted with one, or two groups independently selected from =0 and R3e. In a most particular embodiment, R1is 5-10 membered bicyclic fused, bridged or spiro cycloalkyl, substituted with one R3e. In a further most particular embodiment, R1is bicyclo [2. l.l]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or spiro[3.3]heptanyl, each of which is substituted with one R3e. In some embodiments, R1is bicyclo [2. l.l]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, cubanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, or spiro[3.3]heptanyl, each of which is substituted with one R3e.

[0230] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is 5-10 membered bicyclic fused, bridged or spiro cycloalkyl, substituted with one or more groups independently selected from =0 and R3e, wherein each R3eis independently selected from halo, CN, and -YA-LA-R5, wherein YA, LA, and R5are as previously defined. In a particular embodiment, each R3eF, Cl, CN, and -YA-LA-R5.

[0231] In a particular embodiment, one or more R3eis independently selected from -YA-LA-R5, wherein YA is absent, LA is selected from -C(=0)NH-, and -O-, and R5is H.

[0232] In a particular embodiment, one or more R3eis independently selected from -YA-LA-R5, wherein YA is absent, LA is absent, and R5is Ci-4 alkyl. In a particular embodiment, R5is -C H, or -CH2CH3.

[0233] In a particular embodiment, one or more R3eis independently selected from -YA-LA-R5, wherein YA is absent, LA is -C(=O)NH-, and R5is C1-4 alkyl. In a particular embodiment, R5is -CH3 or -CH2CH3.

[0234] In a particular embodiment, one or more R3eis independently selected from -YA-LA-R5, wherein YAis absent, LAis -C(=O)NH-, and R5is 4-7 membered monocyclic cycloalkyl. In a particular embodiment, R5is cyclopropyl.

[0235] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms. In a particular embodiment, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl . In some embodiments, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, oxazepanyl, or azaphosphinanyl.

[0236] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or more groups independently selected from =0 and R3f. In a particular embodiment, R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one, two or three groups independently selected from =0 and R3f. In a further particular embodiment, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl, each of which is substituted with one, two or three groups independently selected from =0 and R3f. In someembodimenst, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, oxazepanyl, or azaphosphinanyl, each of which is substituted with one, two or three groups independently selected from =0 and R3f. In a more particular embodiment, R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or two groups independently selected from =0 and R3f. In a further more particular embodiment, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl, each of which is substituted with one or two groups independently selected from =0 and R3f. In some embodimenst, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, oxazepanyl, or azaphosphinanyl, each of which is substituted with one, or two groups independently selected from =0 and R3f. In a most particular embodiment, R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one =0 or R3f. In a further most particular embodiment, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl, each of which is substituted with one =0 or R3f. In some embodimenst, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, oxazepanyl, or azaphosphinanyl, each of which is substituted with one =0 or R3f.

[0237] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or more groups independently selected from =0 and R3f, wherein each R3fis independently selected from halo, CN, and -YA-LA-R5, wherein YA, LA, and R5are as previously defined. In a particular embodiment, each R3fF, Cl, CN, and -YA-LA-R5.

[0238] In a particular embodiment, one or more R3fis independently selected from -YA-LA-R5, wherein YAis absent, LAis selected from -C(=0)NH-, and -0-, and R5is H.

[0239] In a particular embodiment, one or more R3fis independently selected from -YA-LA-R5, wherein YAis absent, LAis absent, and R5is C1.4 alkyl. In a particular embodiment, R5is -CH3or -CH2CH3.

[0240] In a particular embodiment, one or more R3fis independently selected from -YA-LA-R5, wherein YA is absent, LA is -C(=0)NH-, and R5is C1-4 alkyl. In a particular embodiment, R5is -CH3 or -CH2CH3.

[0241] In a particular embodiment, one or more R3fis independently selected from -YA-LA-R5, wherein YA is absent, LA is -C(=0)NH-, and R5is 4-7 membered monocyclic cycloalkyl. In a particular embodiment, R5is cyclopropyl.

[0242] In a particular embodiment, one or more R3fis independently selected from -YA-LA-R5, wherein YA is absent, LA is absent, -C(=O)-, -C(=0)NH-, -NHC(=0)-, and R5is 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is pyrazolyl, or pyridinyl optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one ormore independently selected halo. In a particular embodiment, R5is pyrazolyl, or pyridinyl optionally substituted with one or more independently selected F, Cl, OH, -C(=0)NH2, -C(=0)NHCH3, -CH3, -CF3, - OCH3, -OCF3.

[0243] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is:* represents the points of attachment.

[0244] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va,wherein * represents the points of attachment.

[0245] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va,Vb, wherein R1is, wherein * represents the points of attachment.

[0246] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is 5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms. In a particular embodiment, R1is 2,5- dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6- azaspiro[3.3]heptanyl, 2-oxa-5 -azabicyclo [2.2. l]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6- azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptane, or oxazepanyl. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is 5-12membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms. In a particular embodiment, R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2-azaspiro[3 ,5]nonanyl, 2-oxa-6-azaspiro[3 ,3]heptanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8- azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptane, 3,8-diazabicyclo[3.2.1]octanyl, 2-oxa-6- azaspiro[3.4]octanyl, 2-oxaspiro[3.5]nonanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptanyl, 2-oxabicyclo[2.1.1]hexanyl, 2-azaspiro[4.5]decane, 7-oxa-4-azaspiro[2.5]octanyl, isoindolinyl or oxazepanyl.

[0247] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is 5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or more groups independently selected from =0 and R3g. In some embodiments, the compound of the invention is according to any one of Formula I-Vb, wherein R1is 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or more groups independently selected from =0 and R3g. In a particular embodiment, R1is 5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one, two or three groups independently selected from =0 and R3g. In a further particular embodiment, R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2- azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-5 -azabicyclo [2.2. l]heptanyl, 4-oxa-7- azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5 -azaspiro [2.4]heptane, or oxazepanyl, each of which is substituted with one, two or three groups independently selected from =0 and R3g. In some embodiments, R1is 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one, two or three groups independently selected from =0 and R3g. In a further particular embodiment, R1is 2,5- dioxaspiro[3 ,5]nonanyl, octahydropyrrolo [3 ,2-b]pyrrolyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6- azaspiro[3 ,3]heptanyl, 2-oxa-5 -azabicyclo [2.2. 1 ]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6- azaspiro [2.5] octanyl, 2,5 -dioxa-8 -azaspiro [3.5 ]nonanyl, 5-azaspiro[2.4]heptane, 3,8- diazabicyclo [3.2. l]octanyl, 2-oxa-6-azaspiro [3 ,4]octanyl, 2-oxaspiro[3.5]nonanyl, 2,5-dioxa-8- azaspiro[3.5]nonanyl, 5 -azaspiro [2.4]heptanyl, 2-oxabicyclo[2.1.1]hexanyl, 2-azaspiro[4.5]decane, 7-oxa- 4-azaspiro[2.5]octanyl, isoindolinyl or oxazepanyl, each of which is substituted with one, two or three groups independently selected from =0 and R3g. In a more particular embodiment, R1is 5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or two groups independently selected from =0 and R3g. In some embodiments, R1is 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or two groups independently selected from =0 and R3g. In a further more particular embodiment, R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2-azaspiro[3 ,5]nonanyl, 2-oxa-6-azaspiro[3 ,3]heptanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptane, or oxazepanyl, each of which is substituted with one or two groups independently selected from =0 and R3g. In some embodiments, R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2-azaspiro[3 ,5]nonanyl, 2-oxa-6-azaspiro[3 ,3]heptanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8- azaspiro[3.5]nonanyl, 5 -azaspiro [2.4]heptane, 3,8-diazabicyclo[3.2.1]octanyl, 2-oxa-6- azaspiro[3.4]octanyl, 2-oxaspiro[3.5]nonanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptanyl, 2-oxabicyclo[2.1.1]hexanyl, 2-azaspiro[4.5]decane, 7-oxa-4-azaspiro[2.5]octanyl, isoindolinyl or oxazepanyl, each of which is substituted with one or two groups independently selected from =0 and R3g. In a most particular embodiment, R1is 5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one R3g. In some embodiments, R1is 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one R3g. In a further most particular embodiment, R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2- azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-5 -azabicyclo [2.2. l]heptanyl, 4-oxa-7- azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5 -azaspiro [2.4]heptane, or oxazepanyl, each of which is substituted with one R3g. In some embodiments, R1is 2,5- dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6- azaspiro[3.3]heptanyl, 2-oxa-5 -azabicyclo [2.2. l]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6- azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptane, 3,8- diazabicyclo[3.2.1]octanyl, 2-oxa-6-azaspiro[3.4]octanyl, 2-oxaspiro[3.5]nonanyl, 2,5-dioxa-8- azaspiro[3.5]nonanyl, 5 -azaspiro [2.4]heptanyl, 2-oxabicyclo[2.1.1]hexanyl, 2-azaspiro[4.5]decane, 7-oxa- 4-azaspiro[2.5]octanyl, isoindolinyl or oxazepanyl, each of which is substituted with one R3g.

[0248] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or more groups independently selected from =0 and R3g, wherein each R3gis independently selected from halo, CN, and -YA-LA-R5, wherein YA, LA, and R5are as previously defined. In a particular embodiment, each R3gF, Cl, CN, and - YA-LA-R5. In some embodiments, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or more groups independently selected from =0 and R3g, wherein each R3gis independently selected from halo, CN, and -YA-LA-R5, wherein YA, LA, and R5are as previously defined. In a particular embodiment, each R3gF, Cl, CN, and - YA-LA-R5.

[0249] In a particular embodiment, one or more R3gis independently selected from -YA-LA-R5, wherein YAis absent, LAis selected from -C(=0)NH-, and -O-, and R5is H.

[0250] In a particular embodiment, one or more R3gis independently selected from -YA-LA-R5, wherein YAis absent, LAis absent, and R5is C1.4 alkyl. In a particular embodiment, R5is -CH3or -CH2CH3.

[0251] In a particular embodiment, one or more R3gis independently selected from -YA-LA-R5, wherein YA is absent, LA is -C(=O)NH-, and R5is C1-4 alkyl. In a particular embodiment, R5is -CH3 or -CH2CH3.

[0252] In a particular embodiment, one or more R3gis independently selected from -YA-LA-R5, wherein YAis absent, LAis -C(=O)NH-, and R5is 4-7 membered monocyclic cycloalkyl. In a particular embodiment, R5is cyclopropyl.

[0253] In a particular embodiment, one or more R3gis independently selected from -YA-LA-R5, wherein YAis absent, LAis absent, -C(=O)-, -C(=O)NH-, -NHC(=O)-, and R5is 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=O)NH2, -C(=O)NHCH3, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is pyrazolyl, or pyridinyl optionally substituted with one or more independently selected halo, OH, -C(=O)NH2, -C(=O)NHCH3, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is pyrazolyl, or pyridinyl optionally substituted with one or more independently selected F, Cl, OH, -C(=O)NH2, -C(=O)NHCH3, -CH3, -CF3, -OCH3, -OCF3.

[0254] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is:represents the points of attachment.

[0255] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va,Vb, wherein R1is:wherein * represents the points of attachment.

[0256] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is:wherein * represents the points of attachment.

[0257] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is:wherein * represents the points of attachment.

[0258] In some embodiments, one or more R3his independently selected from -YA-LA-R5, wherein YA is absent, LA is selected from -C(=O)NR7a- and -C(=O), and R5is H, C1-4 alkyl or optionally substituted 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms.

[0259] In a some embodiments, one or more R3his independently selected from -YA-LA-R5, wherein YA is absent, LA is -C(=O)NH-, -C(=O)NCH3- or -C(=O), and R5is C1.4 alkyl or 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms.

[0260] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, Va, Vb, wherein R1is:wherein * represents the points of attachment.

[0261] In some embodiments R1is selected from phenyl optionally substituted with one or more independently selected from =0 and R3a, preferably said phenyl is optionally substituted with one, two or three independently selected from =0 and R3a; a 5-6 monocyclic heteroaryl selected from pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, thiadiazolyl, or selenadiazolyl, wherein said monocyclic heteroaryl is optionally substituted with one or more independently selected from =0 and R3b; preferably said monocyclic heteroaryl is optionally substituted with one, two or three independently selected from =0 and R3b; where the N heteroatoms may optionally be oxidized; an 8-10 membered fused bicyclic heteroaryl selected from indazolyl, benzofuranyl, benzothiazolyl, quinolinyl, pyrazolo[l,5-a]pyridinyl, benzoxazolyl, naphthyridinyl, triazolopyridinyl, imidazopyridinyl or quinazolinyl, wherein said fused bicyclic heteroaryl is optionally substituted with one or more independently selected from =0 and R3c; preferably said monocyclic heteroaryl is optionally substituted with one, two or three independently selected from =0 and R3c; a 3-7 membered monocyclic cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl wherein said monocyclic cycloalkyl is optionally substituted with one or more independently selected from =0 and R3d; preferably said monocyclic heteroaryl is optionally substituted with one, two or three independently selected from =0 and R3d;a 5-10 membered bicyclic fused, bridged or spiro cycloalkyl selected from bicyclo [2. 1. l]hexanyl, spiro[3.3]heptanyl, cubanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl, wherein said bicyclic fused, bridged or spiro cycloalkyl is optionally substituted with one or more independently selected from =0 and R3e; preferably said monocyclic heteroaryl is optionally substituted with one, two or three independently selected from =0 and R3e; a 4-7 membered monocyclic heterocycloalkyl selected from azetidinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, oxazepanyl, or azaphosphinanyl, wherein said monocyclic heterocycloalkyl is optionally substituted with one or more independently selected from =0 and R3f; preferably said monocyclic heteroaryl is optionally substituted with one, two or three independently selected from =0 and R3f; a 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl selected from 2,5- dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6- azaspiro[3.3]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, 4-oxa- 7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2-oxa-6-azaspiro[3.4]octanyl, 2- oxaspiro[3.5]nonanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptanyl, 2- oxabicyclo[2.1.1]hexanyl, 2-azaspiro[4.5]decane, 7-oxa-4-azaspiro[2.5]octanyl, isoindolinyl or oxazepanyl, wherein said monocyclic heterocycloalkyl is optionally substituted with one or more independently selected from =0 and R3g; preferably said monocyclic heteroaryl is optionally substituted with one, two or three independently selected from =0 and R3g;Ci-4 alkyl optionally substituted with one, two or three independently selected R3h

[0262] In one embodiment, the compound of the invention is selected from the compounds of Table II herein.

[0263] In one embodiment, a compound of the invention are provided in a natural isotopic form.

[0264] In one embodiment, a compound of the invention are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e.2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.

[0265] In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.

[0266] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms couldbe prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the illustrative example as examples.

[0267] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.

[0268] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.

[0269] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

[0270] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound.

[0271] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.

[0272] While specified groups for each embodiment have generally been listed above separately, a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.

[0273] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.

[0274] In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0275] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the Ci to Cs alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.PHARMACEUTICAL COMPOSITIONS

[0276] When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0277] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.

[0278] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term ‘unit dosage forms’ refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefdled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound of the invention according to Formula I is usually a minor component (from about 0. 1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0279] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.

[0280] Injectable compositions are typically based upon injectable sterile saline or phosphate -buffered saline or other injectable carriers known in the art. As before, the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0281] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredientswill typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.

[0282] A compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0283] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17thedition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0284] A compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0285] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.Formulation 1 - Tablets

[0286] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.Formulation 2 - Capsules

[0287] A compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1: 1 weight ratio. The mixture may be fdled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).Formulation 3 - Liquid

[0288] A compound of the invention according to Formula I (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.Formulation 4 - Tablets

[0289] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added asa lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.Formulation 5 - Injection

[0290] A compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg / mL.Formulation 6 - Topical

[0291] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of A compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.METHODS OF TREATMENT

[0292] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine . In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of tuberculosis (TB) and / or non- tuberculous mycobacteria (NTM).

[0293] In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM).

[0294] In additional method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM), which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.

[0295] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM)treatment agent.

[0296] Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 1 g / day for a 40 to 80 kg human patient.

[0297] For the prophylaxis and / or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four (1-4) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regulardose daily are representative regimens. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.

[0298] Using these dosing patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.

[0299] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0300] When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0301] A compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.

[0302] In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient.

[0303] In one embodiment, a compound of the invention is co -administered with the standard of care for Mycobacterium avium complex (MAC) infections, namely azithromycin or clarithromycin, along with ethambutol and rifampin. In a specific embodiment, a compound of the invention could be in the place of rifampin along with azithromycin or clarithromycin, and ethambutol.

[0304] In one embodiment, a compound of the invention is co-administered with the standards of care for Mycobacterium tuberculosis including isoniazid (CAS#54-85-3), pyrazinamide (CAS#98-96-4), and ethambutol (CAS#74-55-5).

[0305] In one embodiment, a compound of the invention is co-administered with one or more compound from one or more compounds from the following classes of compounds;Macrolide antibiotic such as but not limited to azithromycin (CAS#83905-01-5) or clarithromycin(CAS#81103-11-9), aminoglycoside antibiotic such as but not limited to gentamicin (CAS# 1403 -66-3), tobramycin (CAS#32986-56-4), amikacin (CAS#37517-28-5), plazomicin (CAS#1154757-24-0), streptomycin (CAS#57-92-l), neomycin (CAS# 1404-04-2) and paromomycin (CAS# 1263-89-4), carbapenem antibiotics such as but not limited to imipenem (CAS#64221-86-9), meropenem (CAS#119478-56-7),Fluoroquinolones such as but not limited to levofloxacin (CAS#100986-85-4), ciprofloxacin (CAS#85721-33-l), moxifloxacin (CAS# 151096-09-2), ofloxacin (CAS#82419-36-l), gemifloxacin (CAS#175463-14-6) and delafloxacin (CAS#189279-58-l)Oxazolidinones such as but not limited to linezolid (CAS#165800-03-3), posizolid (CAS#252260-02- 9), tedizolid (CAS#856866-72-3) and radezolid (CAS#869884-78-6)Tetracyclines such as but not limited to tetracycline (CAS#60-54-8), doxycycline (CAS#564-25-0), minocycline (CAS#10118-90-8), tigecycline (CAS#220620-09-7)Cephalosporins such as but not limited to cefazolin (CAS#25953-19-9), cephalexin (CAS#25953-19- 9), cefuroxime (CAS#55268-75-2), cefoxitin (CAS#35607-66-0), ceftriaxone (CAS#73384-59-5), ceftazidime (CAS#72558-82-8), cefepime (CAS#88040-23-7), ceftaroline (CAS#229016-73-3) Riminophenazine antimycobacterials such as but not limited to clofazimine (CAS#2030-63-9), and bedaquiline (CAS#843663-66-l)

[0306] In a further embodiment a compound of the invention is used in combination with one or more inhibitor(s) of the mycobacterial enzymes InhA, Dprel, coenzyme A, adenosine triphosphate (ATP) synthase,

[0307] By co-administration is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i. e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times.CHEMICAL SYNTHETIC PROCEDURESGeneral

[0308] The compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0309] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Greene, T W; Wuts, P G M;, 1991).

[0310] The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

[0311] All reagents are of commercial grade and are used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents are used for reactions conducted under inert atmosphere. Reagent grade solvents are used in all other cases, unless otherwise specified.

[0312] Column chromatography was performed using Isolute SPE 20g Flash Si II Column; weak solvent: DCM, strong solvent: 5% methanol in DCM, 30-100% strong solvent over 15 column volumes.

[0313] Silica gel flash column chromatography was performed on:

[0314] Buchi Pure C-810 Flash using Interchim PF-15SIHC-JP / 12G and Interchim PF-15SIHC-JP / 40G columns; weak solvent: DCM, strong solvent: 5% methanol in DCM, 0-100% strong solvent over 25 column volumes, flow 12-25mL / min.

[0315] Interchim puriFlash XS 420 using Interchim PF-15SIHC-JP / 4G column; weak solvent: DCM, strong solvent: 5% methanol in DCM, 0-100% strong solvent over 25 column volumes, flow 12-25mL / min and Interchim PF-15SIHC-JP / 80G column weak solvent: cyclohexane, strong solvent: ethyl acetate, 0- 100% strong solvent over 30 column volumes, flow 24mL / min.

[0316] Silica gel Prep Flash Column Chromatography was performed on Buchi Pure C-850 FlashPrep using XB ridge BEH Cl 8 OBD Prep Column, 130A, 5 pm, 30 mm X 150 mm column, strong solvent: acetonitrile, weak solvent: ammonium bicarbonate water solution buffer pH=9.2, 3%-97%-3% strong solvent over 25 column volumes, flow 17mL / min.LC-MS Methods (analytical):

[0317] Method 1 (LC-MS) 2min low_3 97 BEH

[0318] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLC BEH C18 (50mm x 2.1mm i.d., 1.7pm packing diameter); mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.9 mL / min; 1.5 min 3 % A, 97 % B, flow rate 0.9 mL / min; 1.9 min 3 % A, 97 % B, flow rate 0.9 mL / min; 2.0 min 97 % A, 3 % B, flow rate 0.05 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 100 to 1000 AMU.Method 2 (LC-MS): 2min_high_3_97_BEH

[0319] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLC BEH C18 (50mm x 2.1mm i.d., 1.7pm packing diameter); mobile phase A: 10 mM aqueous solution of ammonium bicarbonate (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.9 mL / min; 1.5 min 3 % A, 97 % B, flow rate 0.9 mL / min; 1.9 min 3 % A, 97 % B, flow rate 0.9 mL / min; 2.0 min 97 % A, 3 % B, flow rate 0.05 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 100 to 1500 AMU.Method 3 (LC-MS): 4minjow _3 97 BEH

[0320] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLC BEH C18 (50mm x 2.1mm i.d., 1.7pm packing diameter); mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.9 mL / min; 3.2 min 97 % A, 3 % B, flow rate 0.9 mL / min; 3.9 min 3 % A, 97 % B, flow rate 0.9 mL / min; 4.0 min 97 % A, 3 % B, flow rate 0.05 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 100 to 1500 AMU.Method 4 (LC-MS): 4minJiigh_3_97_BEH

[0321] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLC BEH C18 (50mm x 2.1mm i.d., 1.7pm packing diameter); mobile phase A: 10 mM aqueous solution of ammonium bicarbonate (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; gradient: 0.0 min 95 % A, 5 % B, flow rate 0.5 mL / min; 3.0 min 95 % A, 5 % B, flow rate 0.5 mL / min; 17.50 min 5 % A, 95 % B, flow rate 0.5 mL / min; 19.00 min 5 % A, 95 % B, flow rate 0.5 mL / min; 19.50 min 95 % A, 5 % B, flow rate 0.5 mL / min; 20.00 min 95 % A, 5 % B, flow rate 0.5 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate -scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 100 to 1500 AMU.Method 5 (LC-MS): 12minJow_3_97_BEH

[0322] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLC BEH C18 (50mm x 2.1mm i.d., 1.7pm packing diameter); mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.9 mL / min; 1.5 min 97 % A, 3 % B, flow rate 0.9 mL / min; 11.5 min 3 % A, 97 % B, flow rate 0.9 mL / min; 12.0 min 97 % A, 3 % B, flow rate 0.05 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 100 to 1500 AMU.Method 6 (LC-MS): 12min_high_3_97_BEH

[0323] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLC BEH C18 (50mm x 2.1mm i.d., 1.7pm packing diameter); mobile phase A: 10 mM aqueous solution of ammonium bicarbonate (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.9 mL / min; 1.5 min 97 % A, 3 % B, flow rate 0.9 mL / min; 11.5 min 3 % A, 97 % B, flow rate 0.9 mL / min; 12.0 min 97 % A, 3 % B, flow rate 0.05 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 100 to 1500 AMU.Method 7 (LC-MS): (8 min lo _pH 3 97 BEH)

[0324] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLC BEH C 18 (100mm x 2.1mm i.d., 1.7pm packing diameter); mobile phase A: Water + 0.1% of Pormic Acid, mobile phase B: Acetonitrile + 0.1% of Formic Acid; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.6 mL / min; 0.5 min 97 % A, 3 % B, flow rate 0.6 mL / min; 7.0 min 3 % A, 97 % B, flow rate 0.6 mL / min; 7.5min 3 % A, 97 % B, flow rate 0.6 mL / min; 7.6 min 97 % A, 3 % B, flow rate 0.6 mL / min; 8.0 min 97 % A, 3 % B, flow rate 0.6 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 400 nm; MS conditions: Ionisation Mode: Electrospray Positive and Negative (ES+ / ES ); Scan Range: 100 to 1500 AMU.Method 8 (LC-MS): (8_min_high _pH 3 97 BEH)

[0325] LC / MS System: Acquity UPLC coupled with SQD mass spectrometer; Column: Acquity UPLC BEH C18 (100mm x 2.1mm i.d., 1.7pm packing diameter); mobile phase A: Water + 0.05% of Ammonia, mobile phase B: Acetonitrile + 0.05% of Ammonia; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.6 mL / min; 0.5 min 97 % A, 3 % B, flow rate 0.6 mL / min; 7.0 min 3 % A, 97 % B, flow rate 0.6 mL / min; 7.5 min 3 % A, 97 % B, flow rate 0.6 mL / min; 7.6 min 97 % A, 3 % B, flow rate 0.6 mL / min; 8.0 min 97 % A, 3 % B, flow rate 0.6 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 400 nm; MS conditions: Ionisation Mode: Electrospray Positive and Negative (ES+ / ES ); Scan Range: 100 to 1500 AMU.Method 9 (Q-TOF) 12 min_high_3-97_BEH

[0326] LC / MS System: Agilent 1260 LC System coupled with SEC and G6540B UHD Accurate-Mass Q- TOF mass spectrometer; Column: Acquity UPLC BEH C18 (2.1 mm x 100 mm, 1.7 pm); mobile phase A: 10 mM aqueous solution of ammonium bicarbonate (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.5 mL / min; 0.5 min 97 % A, 3 % B, flow rate 0.5 mL / min; 8.0 min 0 % A, 100 % B, flow rate 0.5 mL / min; 9.5 min 0 % A, 100 % B, flow rate 0.5 mL / min; 10 min 97 % A, 3 % B, flow rate 0.5 mL / min; 12.0 min 97 % A, 3 % B, flow rate 0.5 mL / min;

[0327] column temperature: 40 °C; UV detection: from 190 nm to 400 nm; makeup composition 0.1% formic acid in acetonitrile; makeup flow 2.5 mL / min; MS conditions: Ion source: dual AJS ESI; Scan Range: 100 to 1000 AMU.Method 10 (Q-TOF) 12 min_low_3-97_BEH

[0328] LC / MS System: Agilent 1260 LC System coupled with SFC and G6540B UHD Accurate-Mass Q- TOF mass spectrometer; Column: Acquity UPLC BEH C18 (2.1 mm x 100 mm, 1.7 pm); mobile phase A: water + 0.1% of formic acid, mobile phase B: acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 0.5 mL / min; 0.0 min 97 % A, 3 % B, flow rate 0.5 mL / min; 8.0 min 0 % A, 100 % B, flow rate 0.5 mL / min; 9.5 min 0 % A, 100 % B, flow rate 0.5 mL / min; 10 min 97 % A, 3 % B, flow rate 0.5 mL / min; 12.0 min 97 % A, 3 % B, flow rate 0.5 mL / min; column temperature: 40 °C; UV detection: from 190 nm to 400 nm; makeup composition 0.1% formic acid in acetonitrile; makeup flow 2.5 mL / min; MS conditions: Ion source: dual AJS ESI; Scan Range: 100 to 1000 AMU.Method 13 (LC-MS): (BEH Neutral 50%)

[0329] LC / MS System: Acquity UPLC H-Class equipped with a Acquity UPLC PDA Detector (range 190-420 nm), a Acquity UPLC ELS Detector and a Acquity TQ Detector (ESI / ESCi); Column: UPLC BEH Premier C18 (50mm x 2.1mm., 1.7pm packing diameter) thermostated at 40°C; mobile phase A: 5 mM aqueous solution of ammonium acetate (adjusted to pH 7 with aq. ammonia) + 5% acetonitrile, mobile phase B: Acetonitrile; Gradient (Time / % of B) 0 / 48, 3.5 / 90, 5 / 90; Flow rate 0.5 mL / min; UV detection:from 190 nm to 420 nm; MS conditions: Ionisation Mode: Positive and Negative Electrospray Ionisation (ESI+ / ESI-); Scan Range: 100 to 1000 m / z, ES+ / -.Method 14 (LC-MS): (BEH Neutral 20%)

[0330] LC / MS System: Acquity UPLC H-Class equipped with a Acquity UPLC PDA Detector (range 190-420 nm), a Acquity UPLC ELS Detector and a Acquity TQ Detector (ESI / ESCi); Column: UPLC BEH Premier C18 (50mm x 2.1mm., 1.7pm packing diameter) thermostated at 40°C; mobile phase A: 5 mM aqueous solution of ammonium acetate (adjusted to pH 7 with aq. ammonia) + 5% acetonitrile, mobile phase B: Acetonitrile; Gradient (Time / % of B) 0 / 16, 3.18 / 58, 4 / 90, 5 / 90; Flow rate 0.5 mL / min; UV detection: from 190 nm to 420 nm; MS conditions: Ionisation Mode: Positive and Negative Electrospray Ionisation (ESI+ / ESI-); Scan Range: 100 to 1000 m / z, ES+ / -.

[0331] LC-MS Methods (preparative):Method 11 (prep-HPLC): C high

[0332] LC / MS System: Waters Mass Directed Auto Purification System with QDa mass

[0333] spectrometer; Column: XBridge C18 OBD (30 x 150mm, 5pm) with XBridge C18 OBD Guard Cartridge (30 x 10mm, 5 pm); mobile phase A: 10 mM aqueous solution of ammonium bicarbonate (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 50 mL / min; 1.0 min 70 % A, 30 % B, flow rate 50 mL / min; 10.0 min 20 % A, 80 % B, flow rate 50 mL / min; 10.5 min 0 % A, 100 % B, flow rate 50 mL / min; 15.0 min 0 % A, 100 % B, flow rate 50 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 50 to 1200 AMU.Method 12 (prep-HPLC): C low

[0334] LC / MS System: Waters Mass Directed Auto Purification System with QDa mass

[0335] spectrometer; Column: XBridge C18 OBD (30 x 150mm, 5pm) with XBridge C18 OBD Guard Cartridge (30 x 10mm, 5 pm); mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 97 % A, 3 % B, flow rate 50 mL / min; 1.0 min 70 % A, 30 % B, flow rate 50 mL / min; 10.0 min 20 % A, 80 % B, flow rate 50 mL / min; 10.5 min 0 % A, 100 % B, flow rate 50 mL / min; 15.0 min 0 % A, 100 % B, flow rate 50 mL / min; column temperature: 40 °C; UV detection: from 210 nm to 350 nm; MS conditions: Ionisation Mode: alternate-scan Positive and Negative Electrospray (ES+ / ES-); Scan Range: 50 to 1200 AMU.Table I. List of abbreviations used in the experimental sectionSYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTIONExample 1. General synthetic routes

[0336] The compounds presented herein may be prepared inter alia, via the general methods presented below.

[0337] The free hydroxyl groups (at C21 and C23) of Rifamycin S are firstly protected, typically as an acetonide. Ester hydrolysis of the acetate at position C25, is followed by activation of this position to install the carbamate at C25. The C18-C19 double bond can be reduced by reaction with hydrazine (or a derivative). After re-oxidation to the naphthoquinone form and removal of the acetonide protecting group, a primary amine (typically ammonia) is introduced at C3, followed by transformation of the ketone at C4 into an imine. The synthetic pathway is finalized by cyclization with a ketone (commercially available or synthesized) to put the spirocycle in place.

[0338] The C18-C19 double bond of Rifabutin can be reduced, e.g. by catalytic hydrogenation using hydrogen gas. The free hydroxyl groups (at C21 and C23) are then protected, typically as an acetonide. Ester hydrolysis of the acetate at position C25, is followed by activation of this position to install the carbamate at C25. The synthetic route is wrapped up by removal of the acetonide protecting group.

[0339] The C18-C19 double bond of Rifabutin can be reduced by catalytic hydrogenation using hydrogen gas. The free hydroxyl groups (at C21 and C23) are then protected, typically as an acetonide, followed by ester hydrolysis of the acetate at position C25. The hydroxy group can then be transformed into a carbamate by two distinct methods: (1) A carboxylic acid derivative of a (het)aryl reacts with DPPA in the presence of base (e.g. DMAP) to give an acyl azide, which thermally undergoes the Curtins rearrangement. The isocyanate thus formed reacts with the free alcohol on C25 to yield the corresponding carbamate. Alternatively, (2) an amine derivative of a (het)aryl reacts with 4-nitrophenyl chloroformate to yield anactivated carbamate species, which is subsequently reacted with the free alcohol on C25 to yield the corresponding carbamate. In both instances, the synthetic route is wrapped up by removal of the acetonide protecting group.

[0340] The C18-C19 double bond of Rifabutin can be reduced, e.g. by catalytic hydrogenation using hydrogen gas. The free hydroxyl groups (at C21 and C23) are then protected, typically as an acetonide, followed by ester hydrolysis of the acetate at position C25. This is followed by protection of the nucleophilic atoms (typically with bis-Alloc protection). The new ester bond at position C25 is then installed via conventional methods, typically coupling with acid anhydride, acyl chloride, or by treating an acid with activating agent, e.g. Shiina reagent (MNBA) in the presence of base to form an activated species. The synthetic pathway is concluded by removal of the protecting groups.1.1. Int i

[0341] To a solution of Rifamycin S (10 g, 14.37 mmol, 1.0 eq.) in anhydrous N,N-dimethylformamide (20 mL) were added 2,2-dimethoxypropane (37.11 mL, 301.8 mmol, 21 eq.) and [(lR,4S)-7,7-dimethyl-2- oxo-norboman-l-yl]methanesulfonic acid (4.007 g, 17.25 mmol, 1.2 eq.), and the reaction mixture was stirred at room temperature for 2h. Then, NaHCOs (4.347 g, 51.74 mmol, 3.6 eq.) was added and the mixture was further stirred for 30 min at room temperature. The reaction mixture was diluted with EtOAc and water was added. After extraction, the combined organic layers were washed with water (3x) and brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford Int 1 (10.43 g, 95% yield).

[0342] LCMS: MW (calcd): 735.3; m / z MW (obsd): 736.4 (M+H)1.2. Int 2

[0343] Int 1 (10.52 g, 14.3 mmol, 1.0 eq.) was added to a solution of KOH (40.11 g, 714.9 mmol, 50 eq.) in anhydrous ethanol (150 mL) cooled to -10 °C, and the reaction mixture was stirred at -10 °C for 5h, and then at 4 °C overnight. The pH of the reaction mixture was then adjusted to ~ 6 with citric acid (10% aqueous solution) while maintaining the temperature below 3 °C. The precipitate formed was fdtered, washed with water, and triturated with cold acetonitrile. The obtained solid was fdtered, washed with cold acetonitrile and dried in vacuo to afford Int 2 (6.01 g, 58% yield).

[0344] LCMS: MW (calcd): 693.3; m / z MW (obsd): 692.4 (M-H)1.3. Int 3

[0345] To a solution of Int 2 (1g, 1.441 mmol, 1.0 eq.) in anhydrous DCM (25 mL), was added CDT (1, l'-carbonyl-di-(l, 2, 4-triazole)) (2366 mg, 14.41 mmol, 10 eq.), and the reaction mixture was stirred for 7 days at 40 °C. Then the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SC>4, fdtered and concentrated under reduced pressure to afford crude Int 3 (1300 mg, 82% purity, 94 % yield).

[0346] LCMS: MW (calcd): 788.3; m / z MW (obsd): 787.3 (M-H)1.4. Int 4

[0347] To a solution of Rifabutin (1.00 g, 1.18 mmol, 1.0 eq.) in EtOH (50 mL) was added PtO2 (27 mg, 0.12 mmol, 0.1 eq.). The resulting mixture was degassed and refilled with hydrogen for three times, and then stirred for 4 hours at room temperature under hydrogen atmosphere (H2balloon, 1 atm). The reaction mixture was filtered, the filter cake was washed with DCM (2 x 100 mL), and the combined filtrates were concentrated under reduced pressure. The crude residue was purified by reversed phase column chromatography (C18 silica gel; ACN / water (with 10 mM NH4HCO3 + 0.1 NH3. water); gradient, 50% to 65% gradient in 30 min; flow rate, 50 mL / min) to afford Int 4 (310 mg, 31% yield).

[0348] LCMS: MW (calcd): 848.5; m / z MW (obsd): 849.5 (M+H)1.5. Int 5

[0349] To a solution of Int 4 (2.05 g, 2.41 mmol, 1.0 eq.) in a mixture of DMF (5 mL) and 2,2- dimethoxypropane (5 mL) was added CSA (0.84 g, 3.62 mmol, 1.5 eq.), and the resulting mixture was stirred at room temperature for 3 hours. Solid NaHCOs (5 eq. vs CSA) was added and the resulting mixture was further stirred at room temperature for 30 minutes. Then the reaction mixture was partitioned between DCM (100 mL) and water (100 mL). The aqueous phase was back-extracted with DCM (3 x 100 mL), the combined organic layers were dried over Na2SO4, fdtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0 - 10% MeOH in DCM) to afford Int 5 (1.87 g, 87% yield).

[0350] LCMS: MW (calcd): 888.5; m / z MW (obsd): 889.5 (M+H)1.6. Int 6

[0351] A mixture of Int 5 (3.97 g, 4.46 mmol, 1.0 eq.) and K2CO3 (3.7 g, 26.79 mmol, 6 eq.) in MeOH (40 mL) was stirred at 50 °C for 2 days. The reaction mixture was cooled to room temperature and partitioned between DCM (100 mL) and brine (100 mL). The organic layer was separated and the aqueous phase was extracted with DCM (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0 - 10% MeOH in DCM) to afford Int 6 (3.10 g, 85% yield).

[0352] LCMS: MW (calcd): 846.5; m / z MW (obsd): 847.5 (M+H)1.7. Int 7

[0353] To a solution of Int 6 (1.00 g, 1.18 mmol, 1.0 eq.) in DCM (12 mL) was added CDT (1.94 g, 11.80 mmol, 10 eq.), and the resulting mixture was stirred at 40 °C for 1 day. The reaction mixture was cooled to room temperature and partitioned between DCM (100 mL) and water (100 mL). The aqueous phase was back-extracted with DCM (2 x 100 mL), and the combined organic layers were dried overNa2SO4 , filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0 - 5% MeOH in DCM) to afford Int 7 (1.02 g, 92% yield).

[0354] LCMS: MW (calcd): 941.5; m / z MW (obsd): 942.5 (M+H)1.8. Int 8

[0355] To a solution of Rifabutin (4.00 g, 4.72 mmol, 1.0 eq.) in EtOH (200 mL) was added PtO2(108 mg, 0.47 mmol, 0.1 eq.). The resulting mixture was degassed and refilled with deuterium three times, and then stirred for 4 hours at room temperature under deuterium atmosphere (D2balloon, 1 atm). The reaction mixture was filtered, the filter cake was washed with DCM (2 x 100 mL), and the combined filtrate fractions were concentrated under reduced pressure. The crude residue was purified by reversed phase column chromatography (C18 silica gel; mobile phase, ACN / water with 10 mM NH4HCO3 + 0.1 NH3. water); gradient, 75% to 95% gradient in 30 min; flowrate, 50 mL / min; detector, UV 254 nm to afford Int 8 (1.09 g, 27% yield).

[0356] LCMS: MW (calcd): 850.5; m / z MW (obsd): 851.5 (M+H)1.9. Int 9

[0357] To a solution of Int 8 (1.09 g, 1.28 mmol, 1.0 eq.) in DML (3 mL) and 2,2-dimethoxypropane (3 mL) was added CSA (0.45 g, 1.92 mmol, 1.5 eq.), and the resulting mixture was stirred at room temperature for 3 hours. Solid NaHC'CL (5 eq. of CSA) was added and the resulting mixture was further stirred at room temperature for 30 minutes. Then the reaction mixture was partitioned between DCM (100 mL) and water (100 mL). The aqueous phase was back-extracted with DCM (3 x 100 mL). The combined organic layers were dried over Na2SC>4, filered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0 - 10% MeOH in DCM) to afford Int 9 (0.81 g, 71% yield).

[0358] LCMS: MW (calcd): 890.5; m / z MW (obsd): 891.5 (M+H)1.10. Int 10

[0359] A mixture of Int 9 (0.81 g, 0.90 mmol, 1.0 eq.) and K2CO3 (0.75 g, 5.40 mmol, 6 eq.) in MeOH (10 mL) was stirred at 50 °C for 2 days. The reaction mixture was cooled to room temperature and partitioned between DCM (100 mL) and brine (100 mL). The organic layer was separated and the aqueous phase was extracted with DCM (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0 - 10% MeOH in DCM) to afford Int 10 (0.52 g, 68% yield).

[0360] LCMS: MW (calcd): 848.5; m / z MW (obsd): 849.5 (M+H)1.11. Int 11

[0361] To a solution of Int 10 (500 mg, 0.58 mmol, 1.0 eq.) in DCM (6 mL) was added 1 -[( 1H-1,2,4- triazol- l-yl)carbonyl]-lH-l, 2, 4-triazole (966 mg, 5.80 mmol, 10 eq.), and the resulting mixture was stirred at 40 °C for 16 hours. The reaction mixture was cooled to room temperature, quenched with water (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over Na2SC>4, fdtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; DCM / MeOH 20: 1) to afford Int 11 (410 mg, 66.37% yield).

[0362] LCMS: MW (calcd): 943.5; m / z MW (obsd): 944.5 (M+H)1.12. Int 12

[0363] To a solution of piperidin-4-one hydrochloride (500 mg, 3.688 mmol, 1.0 eq.) in acetonitrile (20 mL) were added 2-bromoacetamide (508.7 mg, 3.688 mmol, 1.0 eq.) and K2CO3 (1274 mg, 9.219 mmol, 2.5 eq.), and the reaction mixture was stirred at room temperature overnight. The resulting solution was partitioned between ethyl acetate and brine. After extraction, the combined organic fractions were dried (hydrophobic frit) and evaporated under reduced pressure. The crude residue was purified by column chromatography (silica gel; DCM to DCM / MeOH=9: 1) to afford Int 12 (318 mg, 52% yield).1.13. Int 13

[0364] To a stirred solution of tert-butyl N-[(lr,4r)-4-carbamoylcyclohexyl]carbamate (500 mg, 2.063 mmol, 1 eq.) in DCM (5 mL) was added trifluoroacetic acid (5 mL) dropwise at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. Then the mixture was concentrated under reduced pressure to give Int 13 (600 mg, crude) as a white solid, which was used in the next step directly without further purification.

[0365] LCMS: MW (calcd): 142.1; m / z MW (obsd): 143.1 (M+H)1.14. Int 141.14.1. Step i

[0366] To a solution of methyl pyridine -3 -carboxylate (1.00 g, 7.29 mmol, 1.0 eq.) in DCM (10 mL), was added 3-chlorobenzenecarboperoxoic acid (75.0 %, 2013 mg, 8.75 mmol, 1.2 eq.), and the reaction mixture was stirred at room temperature for 18 hours. After complete conversion, the reaction mixture was diluted with DCM and extracted with water. The aqueous layer was extracted 3 times with DCM, and the combined organic extracts were dried over Na2SC>4, filtered, and evaporated under reduced pressure to afford crude 3-(methoxycarbonyl)pyridine 1-oxide (720 mg, 47 % yield).

[0367] LCMS: MW (calcd): 153.0; m / z MW (obsd): 154.0 (M+H)1.14.2. Step ii

[0368] To a solution of 3-(methoxycarbonyl)pyridine 1-oxide (720 mg, 4.70 mmol, 1.0 eq.) in MeOH (6 mL), was added 2M NaOH (2 mL), and the reaction mixture was stirred at room temperature for 6 hours. Then, the reaction mixture was left in the fridge for 30 hours. After complete conversion, the reaction mixture was evaporated under reduced pressure, water was added, and the pH was adjusted to pH=4 with a 3M HC1 solution. After filtration, the filtrate was evaporated under reduced pressure, and triturated with EtOAc to obtain 3 -carboxypyridine 1-oxide (434 mg, 65% yield).

[0369] LCMS: MW (calcd): 139.0; m / z MW (obsd): 140.0 (M+H)1.14.3. Step Hi

[0370] To a solution of 3 -carboxypyridine 1-oxide (150 mg, 1.08 mmol, 1.0 eq.) in DCM (1 mL), were added oxalyl dichloride (144 mg, 1.13 mmol, 1.05 eq.) and DMF (10 pl), and the reaction mixture was stirred at room temperature for 2 hours. The mixture containing crude Int 14 was used as is in the next step.

[0371] To a stirred solution of Int 6 (1.5 g, 1.771 mmol, 1.0 eq.) and DIEA (3.66 g, 28.336 mmol, 16 eq.) in DCM (10 mL) was added chloro(prop-2-en-l-yloxy)methanone (1.71 g, 14.187 mmol, 8.01 eq.) in portions at 0 °C under nitrogen atmosphere, and the mixture was stirred for 2 hours at room temperature. The residue was purified by column chromatography (silica gel; PE / EA 1: 1) to afford Int 15 (1.27 g, 68% yield).

[0372] LCMS: MW (calcd): 1014.5; m / z MW (obsd): 1015.5 (M+H)1.15. Int 161.15.1. Step iTo a solution of (lr,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexane-l-carboxylic acid (1.20 g, 4.93 mmol, 1.0 eq.), methanamine hydrochloride (1.00 g, 14.79 mmol, 3.0 eq.), and HATU (2.81 g, 7.40 mmol, 1.5 eq.) in DMF (50 mL) was added DIEA (2.55 g, 19.73 mmol, 4.0 eq.), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The organic layer was washed with saturated aq.NFLCl (3 x 100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0- 10% MeOH in DCM) to afford tert-butyl N-[(lr,4r)-4- (methylcarbamoyl)cyclohexyl]carbamate (1.1 g, 87% yield).

[0373] LCMS: MW (calcd): 256.2; m / z MW (obsd): 257.2 (M+H)1.15.2. Step ii

[0374] To a solution of tert-butyl N-[(lr,4r)-4-(methylcarbamoyl)cyclohexyl]carbamate (1.1 g, 4.29 mmol, 1.0 eq.) in DCM (9 mL) was added trifluoroacetic acid (3 mL), and the resulting mixture was stirred at roomtemperature for 1 h. Concentrating the mixture afforded Int 16 (1.0 g crude, TFA salt), which was used in the next step without any further purification.

[0375] LCMS: MW (calcd): 156.1; m / z MW (obsd): 157.1 (M+H)1.16. Int 171.16.1. Step iTo a solution of (lr,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexane-l-carboxylic acid (1.20 g, 4.93 mmol, 1.0 eq.), aminocyclopropane (0.84 g, 14.80 mmol, 3.0 eq.), and HATU (2.81 g, 7.40 mmol, 1.5 eq.) in DMF (50 mL) was added DIEA (2.55 g, 19.73 mmol, 4.0 eq.), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (200 mL), and extracted with EtOAc (3 x 200 mL). The organic layer was washed with saturated aq. NH4Q (3 x 100 mL), dried over Na2SC>4, fdtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0- 10% MeOH in DCM) to afford tert-butyl N-[(lr,4r)-4- (cyclopropylcarbamoyl)cyclohexyl]carbamate (850 mg, 55% yield).

[0376] LCMS: MW (calcd): 282.2; m / z MW (obsd): 283.2 (M+H)1.16.2. Step ii

[0377] To a solution of tert-butyl N-[(lr,4r)-4-(cyclopropylcarbamoyl)cyclohexyl]carbamate (850 mg, 3.01 mmol, 1.0 eq.) in DCM (6 mL) was added trifluoroacetic acid (2 mL), and the resulting mixture was stirred at room temperature for Ih. Concentrating the mixture afforded (lr,4r)-4-amino-N-cyclopropylcyclohexane-l- carboxamide (700 mg crude, TFA salt), which was used in the next step directly without any further purification.

[0378] LCMS: MW (calcd): 182.1; m / z MW (obsd): 183.1 (M+H)1.17. Int 181.17.1. Step i(2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1 g, 4.32 mmol, 1.0 eq.) was dissolved in anhydrous DCM (30 mL) and cooled to 0 °C. 2-methylpropyl chloroformate (0.71 g, 5.19 mmol, 1.2 eq.) was added, followed by the addition of NMM (0.52 g, 5.19 mmol, 1.2 eq.). After stirring for 15 min at 0 °C, NH3.H2O (0.91 g, 5.19 mmol, 20% w, 1.2 eq.) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (100 mL), and extracted with DCM (3 x 100 mL). The organic layer was washed with saturated aq. NaHCOs (100 mL), dried over Na2SC>4, filtered, and concentrated under reducedpressure to afford tert-butyl (2R)-2-carbamoylmorpholine-4-carboxylate (1.3 g, 91% yield), which was used in the next step directly without any further purification.

[0379] LCMS: MW (calcd): 230.1; m / z MW (obsd): 231.1 (M+H)1.17.2. Step ii

[0380] To a solution of tert-butyl (2R)-2-carbamoylmorpholine-4-carboxylate (500 mg, 2.17 mmol, 1.0 eq.) in DCM (4 mL) was added trifluoroacetic acid (2 mL), and the resulting mixture was stirred at room temperature for Ih. Concentrated this mixture afforded Int 18 (500 mg crude, TFA salt), which was used in the next step directly without any further purification.

[0381] LCMS: MW (calcd): 130.1; m / z MW (obsd): 131.1 (M+H)1.18. Int 191.18.1. Step iTo a solution of tert-butyl (lR,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.0 g, 4.710 mmol, 1.0 eq.), 3- oxetanone (0.44 g, 6.123 mmol, 1.3 eq.), and NaOAc (0.70 g, 8.478 mmol, 1.8 eq.) in THF (6 mL), was added sodium triacetoxyborohydride (1.50 g, 7.065 mmol, 1.5 eq.), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (200 mL), extracted with EtOAc (3 x 200 mL), and the organic layer was washed with saturated aq. NH4Q (3 x 100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0- 10% MeOH in DCM) to afford tert-butyl (lR,5S)-8-(oxetan-3-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (1.1 g, 87% yield).

[0382] LCMS: MW (calcd): 268.2; m / z MW (obsd): 269.2 (M+H)1.18.2. Step ii

[0383] To a solution of tert-butyl (lR,5S)-8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (500 mg, 1.863 mmol, 1.0 eq.) in DCM (6 mL) was added trifluoroacetic acid (3 mL), and the resulting mixture was stirred at room temperature for 1 h. Concentrating this mixture afforded Int 19 (500 mg crude, TFA salt), which was used in the next step directly without any further purification.

[0384] LCMS: MW (calcd): 168.1; m / z MW (obsd): 169.1 (M+H)1.19. Int 201.19.1. Step i

[0385] To a solution of (lr,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexane-l-carboxylic acid (2 g, 8.22 mmol, 1.0 eq.), dimethylamine (8 mb, 16.0 mmol, 2 M solution in THF, 1.95 eq.), HATU (7.8 g, 20.55 mmol, 2.5 eq.) in DMF (100 mL) was added DIEA (5.3 g, 41.10 mmol, 5.0 eq.), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The organic layer was washed with saturated aq. NH4C1 (3 x 100 mL), dried over Na2SO4, fdtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0-10% MeOH in DCM) to afford tert-butyl N-[(lr,4r)-4- (dimethylcarbamoyl)cyclohexyl]carbamate (1.5 g, 67% yield).

[0386] LCMS: MW (calcd): 270.2; m / z MW (obsd): 271.2 (M+H)1.19.2. Step ii

[0387] To a solution of tert-butyl N-[(lr,4r)-4-(dimethylcarbamoyl)cyclohexyl]carbamate (1.5 g, 5.548 mmol, 1.0 eq.) in DCM (15 mL) was added TFA (5 mL), and the resulting mixture was stirred at room temperature for 1 h. Concentrating the mixture afforded Int 20 (1.5 g, crude, TFA salt), which was used in the next step without any further purification.1.20. Int 211.20.1. Step i

[0388] To a solution of (lr,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexane-l-carboxylic acid (2 g, 8.220 mmol, 1.0 eq.), morpholine (1.4 g, 16.440 mmol, 2.0 eq.), HATU (7.8 g, 20.550 mmol, 2.5 eq.) in DMF (100 mL) was added DIEA (5.3 g, 41.10 mmol, 5.0 eq.), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The organic layer was washed with saturated aq. NH4C1 (3 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0-10% MeOH in DCM) to afford tert-butyl N-[(lr,4r)-4-(morpholine-4- carbonyl)cyclohexyl] carbamate (1.6 g, 62% yield).1.20.2. Step ii

[0389] To a solution of tert-butyl N-[(lr,4r)-4-(morpholine-4-carbonyl)cyclohexyl]carbamate (1.6 g, 5.121 mmol, 1.0 eq.) in DCM (15 mL) was added TFA (5 mL), and the resulting mixture was stirred at room temperature for 1 h. Concentrating the mixture afforded Int 21 (1.6 g, crude, TFA salt), which was used in the next step without any further purification.1.21. Int 221.21.1. Step i

[0390] To a solution of (lr,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexane-l-carboxylic acid (2 g, 8.22 mmol, 1.0 eq.), oxan-4-amine (0.8 g, 8.22 mmol, 1.0 eq.) and HATU (7.8 g, 20.55 mmol, 2.5 eq.) in DMF (41 mL) was added DIEA (5.3 g, 41.10 mmol, 5.0 eq.), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The organic layer was washed with saturated aq. NFLCl (3 x 100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0-10% MeOH in DCM) to afford tert-butyl N-[(lr,4r)-4-[(oxan-4- yl)carbamoyl] cyclohexyl] carbamate (2.2 g, 82% yield).1.21.2. Step ii

[0391] To a solution of tert-butyl N-[(lr,4r)-4-[(oxan-4-yl)carbamoyl]cyclohexyl]carbamate (2.2 g, 6.739 mmol, 1.0 eq.) in DCM (15 mL) was added TFA (5 mb), and the resulting mixture was stirred at room temperature for 1 h. Concentrating the mixture afforded Int 22 (2.3 g crude, TFA salt), which was used in the next step without any further purification.1.22. Int 231.22.1. Step i

[0392] To a solution of (lr,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexane-l-carboxylic acid (2 g, 8.220 mmol, 1.0 eq.), (3R)-oxolan-3-amine (0.9 g, 9.864 mmol, 1.2 eq.) and HATU (7.8 g, 20.55 mmol, 2.5 eq.) in DMF (82 mL) was added DIEA (5.3 g, 41.10 mmol, 5.0 eq.), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The organic layer was washed with saturated aq. NH4CI (3 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0-10% MeOH in DCM) to afford tert-butyl N-[(lr,4r)-4-{[(3R)-oxolan-3- yl] carbamoyl} cyclohexyl] carbamate (1.6 g, 62% yield).1.22.2. Step ii

[0393] To a solution of tert-butyl N-[(lr,4r)-4-{[(3R)-oxolan-3-yl]carbamoyl}cyclohexyl]carbamate (1.6 g, 5.121 mmol, 1.0 eq.) in DCM (15 mL) was added TFA (5 mL), and the resulting mixture was stirred atroom temperature for 1 h. Concentrating the mixture afforded Int 23 (1.5 g crude, TFA salt), which was used in the next step without any further purification.1.23. Int 241.23.1. Step i

[0394] To a solution of (lr,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexane-l-carboxylic acid (2.0 g, 8.22 mmol, 1.0 eq.) and (3S)-oxolan-3-amine (1.43 g, 16.44 mmol, 2.0 eq.) in DMF (15 mL) were added DIEA (3.19 g, 24.66 mmol, 3.0 eq.) and HATU (4.69 g, 12.33 mmol, 1.5 eq.), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0-10% MeOH in DCM) to afford tert-butyl N-[(lr,4r)-4-{[(3S)- oxolan- 3 -yl] carbamoyl} cyclohexyl] carbamate (1.83 g, 71% yield).

[0395] LCMS: MW (calcd): 312.2; m / z MW (obsd): 313.2 (M+H)1.23.2. Step ii

[0396] To a solution oftert-butyl N-[(lr,4r)-4-{[(3S)-oxolan-3-yl]carbamoyl}cyclohexyl]carbamate (1.65 g, 5.282 mmol, 1.0 eq.) in DCM (15 mb) was added trifluoroacetic acid (5 mb), and the resulting mixture was stirred at room temperature for 1 h. Concentrating the mixture afforded Int 24 (1.65 g crude, TFA salt), which was used in the next step without any further purification.

[0397] LCMS: MW (calcd): 212.2; m / z MW (obsd): 213.2 (M+H)1.24. Int 25

[0398] To solution of Int 6 (1.694 g, 2.00 mmol, 1.0 eq.) in DCM (20 mL) was added CDI (3.24 g, 19.98 mmol, 10 eq.), and the resulting mixture was stirred at 40 °C for 1 day. The reaction mixture was cooled to room temperature and partitioned between DCM (100 mL) and water (100 mL). The aqueous phase was back-extracted with DCM (2 x 100 mL), and the combined organic layers were dried overNa2SC>4 , fdtered,and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0 - 5% MeOH in DCM) to afford Int 25 (1.3 g, 69% yield).

[0399] LCMS: MW (calcd): 940.5; m / z MW (obsd): 941.5 (M+H)1.25. Int 26

[0400] To a solution of 5 -amino- l-methylpyrazole-3 -carboxamide (700 mg, 4.995 mmol, 1 eq.) in 1,2- DCE (10 mL) was added pyridine (2.5 mL), and the resulting mixture was stirred at 0 °C for 30 minutes. After addition of 4-nitrophenyl carbonochloridate (1208 mg, 5.994 mmol, 1.2 eq.), the mixture was stirred at rt for 3 hours, and used in the next step without any further work-up.

[0401] LCMS: MW (calcd): 305.1; m / z MW (obsd): 306.1 (M+H)1.26. Int 27

[0402] To a solution of Int 7 (600 mg, 0.637 mmol, 1 eq.) in DCE (6.5 mb) were added 4-nitrophenol (354 mg, 2.55 mmol, 4 eq.) and TEA (0.358 mL, 2.55 mmol, 4 eq.), and the reaction mixture was heated at 60°C overnight. Then, the reaction mixture was diluted with DCM, washed with NH4CI saturated solution (2x) and brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; (DCM / ACN 6: l)in DCM) to afford Int 27 (135 mg, 17% yield).

[0403] LCMS: MW (calcd): 1011.5; m / z MW (obsd): 1012.4 (M+H)1.27. Int 28

[0404] To a solution of 2-amino-l,3,4-thiadiazole (298 mg, 2.95 mmol, 1 eq.) in 1,2-DCE (10 mL) was added pyridine (2.5 mL), and the resulting mixture was stirred at 0 °C for 30 minutes. After addition of 4-nitrophenyl carbonochloridate (714 mg, 3.54 mmol, 1.2 eq.), the mixture was stirred at rt for 3 hours, and used in the next step without any further work-up.

[0405] Example 2. Illustrative compounds2.1. Cpd l

[0406] To a solution of Int 2 (5.430 g, 7.670 mmol, 1.0 eq.) in dry 1,2 -dichloroethane (65 mL), were added nicotinic anhydride (3.50 g, 15.34 mmol, 2 eq.) and DMAP (1.41 g, 11.51 mmol, 1.5 eq.), and the mixture was stirred at rt overnight. The reaction mixture was diluted with DCM, washed with NaHCOs sat. solution, NH4CI sat. solution and brine, and the organic layer was dried over Na2SC>4, fdtered, and evaporated under reduced pressure. The crude residue was purified by column chromatography (silica gel; DCM to DCM / EtOAc / CHsCN 1: 1: 1 as strong solvent) to afford Int Al (1.28g) as well as the corresponding monoester derivative (650 mg).2.1.2.

[0407] To a solution of Int Al (900 mg, 0.996 mmol, 1.0 eq.) in MeOH (30 mb) was added hydrazine hydrate (0.997 g, 19.9 mmol, 2 eq), and the mixture was stirred at 60°C for 18h. Then the reaction mixture was concentrated under reduced pressure to afford Int Bl (0.808 g, 33 % yield).

[0408] LCMS: MW (calcd): 802.4; m / z MW (obsd): 803.3 (M+H)

[0409] To a solution of Int Bl (808 mg, 1.01 mmol, 1.0 eq.) in MeOH (30 ml) was added Manganese(IV) oxide (0.175 g, 2.01 mmol, 2 eq.), and the reaction mixture was stirred at rt for 18h. Then, the reaction mixture was filtered and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography (silica gel; DCM to MeOH) to afford Int Cl (380 mg).

[0410] LCMS: MW (calcd): 800.4; m / z MW (obsd): 801.4 (M+H)2.1.4.

[0411] To a solution of Int Cl (380 mg, 0.474 mmol, 1.0 eq.) in MeOH (1 mb) was added camfor-10- sulphonic acid (0.220 g, 0.949 mol, 2 eq.), and the reaction mixture was stirred at rt for 2 hours. Then, thereaction mixture was partitioned between DCM and sat. aq. sol. NaHCOs, the organic layer was separated and the aqueous phase was extracted with DCM. The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; DCM to MeOH) to afford Int DI (365 mg, 33% yield).

[0412] LCMS: MW (calcd): 760.3; m / z MW (obsd): 761.3 (M+H)2.1.5.

[0413] To a solution of Int DI (365 mg, 0.4797 mmol 1.0 eq.) in N-methylformamide (0.5 mb) was added sodium azide (62.38 mg, 0.9595 mmol, 2 eq.), and the reaction mixture was stirred at 36°C for 17 hours.

[0414] The resulting solution was partitioned between ethyl acetate and brine, the layers were separated, and the water layer was back -extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and evaporated under reduced pressure. The crude residue was purified by column chromatography (silica gel; DCM to 5%MeOH / DCM) to afford Int El (30 mg, 7% yield).

[0415] LCMS: MW (calcd): 775.3; m / z MW (obsd): 776.3 (M+H)2.1.6.

[0416] Through a solution of Int El (30 mg, 0.02861 mmol, 1.0 eq.) in anhydrous tetrahydrofuran (1 mb) was bubbled ammonia gas (generated by dropwise addition of -25% aqueous ammonia solution to sodium hydroxide pellets) at rt. After 2h, the reaction mixture was left to stand at 4°C overnight. Bubbling of ammonia gas was continued for another 7h, the mixture was again left to stand at 4°C overnight, and ammonia gas was once more bubbled through for an additional 5h. The reaction mixture was then evaporated under reduced pressure and dissolved in a minimal volume of dichloromethane. Pentane wasadded and the heterogeneous mixture formed was evaporated under reduced pressure to afford Int Fl (31 mg, quantitative yield).

[0417] LCMS: MW (calcd): 774.4; m / z MW (obsd): 775.7 (M+H)2.1.7. Step vii: Cpd 1

[0418] To a solution of Int Fl (31 mg, 0.02961 mmol, 1.0 eq.) in tetrahydrofuran (0.5 mb) were added 1 - isobutylpiperidin-4-one (11.49 mg, 0.07401 mmol, 2.5 eq.), ammonium acetate (5.705 mg, 0.07401 mmol, 2.5 eq.) and zinc (4.841 mg, 0.07401 mmol, 2.5 eq.), and the reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was evaporated under reduced pressure, the residue was dissolved in dichloromethane and washed with a sat. solution of NH4CI (3x). The organic layer was dried over a hydrophobic frit and evaporated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel; dichlormethane to dichloromethane / methanol 95:5) to afford Cpd 1 (20 mg; 74% yield).

[0419] LCMS: MW (calcd): 911.5; m / z MW (obsd): 912.5 (M+H)

[0420] ’H NMR (CDCh-d, 600 MHz) 5 = 15.03 (s, 1H), 9.16 (dd, 1H), 8.77 (dd, 1H), 8.63 (br s, 1H), 8.59 (s, 1H), 8.26 (dt, 1H), 7.38 (ddd, 1H), 6.25 (d, 1H), 5.71 (ddd, 1H), 4.90 (dd, 1H), 4.61 (d, 1H), 3.60 (br s, 1H), 3.53 (br s, 1H), 3.41 (d, 1H), 3.24 (dd, 1H), 3.02 - 3.15 (m, 2H), 2.97 (br d, 1H), 2.89 (s, 3H), 2.81 - 2.94 (m, 2H), 2.42 - 2.48 (m, 2H), 2.41 (s, 3H), 2.32 - 2.39 (m, 1H), 2.14 - 2.30 (m, 2H), 2.08 - 2.14 (m, 1H), 1.99 - 2.06 (m, 3H), 1.98 (s, 3H), 1.88 - 1.95 (m, 2H), 1.80 - 1.86 (m, 1H), 1.74 (s, 3H), 1.62 - 1.69 (m, 1H), 1.44 - 1.51 (m, 2H), 0.98 (d, 6H), 0.97 (d, 3H), 0.78 (d, 3H), 0.67 (d, 3H), 0.14 (d, 3H).2.2. Cpd 22.2.1. Step i: Int A2

[0421] To Int 3 (1.100 g, 1.394 mmol, 1.0 eq.) in DCM (25 mL) were added morpholine (485.9 mg, 5.578 mmol, 4 eq.) and TEA (564.4 mg, 5.578 mmol, 4 eq.), and the reaction mixture was stirred at room temperature for 18h. Then, the reaction mixture was extracted with water and brine, the organic layer was dried over Na2SC>4, fdtered, and the solvent was evaporated under reduced pressure to afford Int A2 (1130 mg, 72% yield).

[0422] LCMS: MW (calcd): 806.4; m / z MW (obsd): 805.3 (M-H)2.2.2. Step ii: Int B2

[0423] To Int A2 (1.100 g, 1.394 mmol, 1.0 eq.) in MeOH (25.0 mL) was added hydrazine hydrate (1911 mg, 38.17 mmol, 27 eq.), and the reaction mixture was stirred at 60°C for 18h. The reaction mixture was evaporated under reduced pressure and the residue was extracted with DCM and brine. The organic layer was dried over Na2SC>4, fdtered, and the solvent was evaporated under reduced pressure to afford Int B2 (1300 mg, 81% yield).

[0424] LCMS: MW (calcd): 810.4; m / z MW (obsd): 809.3 (M-H)

[0425] To Int B2 (1.300 g, 1.603 mmol, 1.0 eq.) in MeOH (25 mL) was added MnO2(278.7 mg, 3.206 mmol, 2 eq.), and the reaction mixture was stirred at rt for 18h. Then, the reaction mixture was fdtered off and the filtrate was partitioned between dichloromethane and NaHCOs sat. aq. solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel; 5% MeOH / DCM) to afford Int C2 (580 mg, 28% yield).

[0426] LCMS: MW (calcd): 808.4; m / z MW (obsd): 807.2 (M-H)2. .4. Step iv: Int D2

[0427] To a solution of Int C2 (580 mg, 0.7170 mmol, 1.0 eq.) in methanol (5 mL), was added camfor- 10-sulphonic acid (333.1 mg, 1.434 mmol, 2 eq.), and the reaction mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was partitioned between dichloromethane and NaHCOs sat. aq. solution, the organic layer was separated, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel; 5% MeOH / DCM) to afford Int D2 (370 mg, 38% yield).

[0428] LCMS: MW (calcd): 768.4; m / z MW (obsd): 767.5 (M-H)

[0429] To a solution of Int D2 (370 mg, 0.4812 mmol, 1.0 eq.) in N-methylformamide (1 mL), was added sodium azide (62.57 mg, 0.9625 mmol, 2 eq.), and the reaction mixture was stirred at 36°C for 17 hours. Then, the reaction mixture was partitioned between ethyl acetate and NaCl sat. solution, the layers were separated and the aqueous layer was back -extracted with ethyl acetate (2x). The combined organic layers were washed with a NaCl sat. solution (3x), dried over Na2SC>4, fdtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel; 5% MeOH / DCM) to afford Int E2 (100 mg, 20% yield).

[0430] LCMS: MW (calcd): 783.4; m / z MW (obsd): 782.4 (M-H)2.2.6.

[0431] A solution of Int E2 (100 mg, 0. 1276 mmol, 1.0 eq.) in dry THF (5 mL) was bubbled with ammonia gas (generated by dropwise addition of -25% aqueous ammonia solution to sodium hydroxide pellets) at 0-5°C for 7 h, and the reaction mixture was left to stand at 4°C for 18 hours. Then, the reaction mixture was evaporated under reduced pressure to afford Int F2 (95 mg, 66% yield).

[0432] LCMS: MW (calcd): 782.4; m / z MW (obsd): 781.3 (M-H)

[0433] To a solution of Int F2 (45 mg, 0.0397 mmol, 1.0 eq.) in tetrahydrofuran (0.5 mb) were added 1- isobutylpiperidin-4-one (15.39 mg, 0.09915 mmol, 2.5 eq.), ammonium acetate (7.643 mg, 0.09915 mmol, 2.5 eq.) and zinc (6.486 mg, 0.09915 mmol, 2.5 eq.), and the reaction mixture was stirred at room temperature for 2h. Then, the reaction mixture was partitioned between dichloromethane and NH4CI sat. solution, the organic extract was washed again with NH4CI sat. solution, dried over Na2SC>4, fdtered, and evaporated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel; 5% MeOH / DCM) to afford Cpd 2 (21 mg, 56% yield).

[0434] LCMS: MW (calcd): 919.5; m / z MW (obsd): 920.4 (M+H)

[0435] 'H NMR (CDCh-d, 600 MHz) 5 = 14.95 (s, 1H), 8.48 (br s, 1H), 8.46 (s, 1H), 6.17 (d, 1H), 5.58 - 5.62 (m, 1H), 4.77 (dd, 1H), 4.32 (d, 1H), 4.06 (br d, 1H), 3.64 (s, 1H), 3.47 - 3.60 (m, 2H), 3.35 - 3.46 (m, 2H), 3.29 (d, 1H), 3.20 - 3.35 (m, 4H), 3.12 (dd, 1H), 2.96 (s, 3H), 2.87 (br s, 2H), 2.84 (br dd, 1H), 2.58 (s, 1H), 2.51 (br s, 1H), 2.23 - 2.29 (m, 1H), 2.23 (s, 3H), 2.18 - 2.22 (m, 2H), 1.97 - 2.05 (m, 1H), 1.89 - 1.96 (m, 2H), 1.88 (s, 3H), 1.76 - 1.85 (m, 3H), 1.68 - 1.76 (m, 3H), 1.66 (s, 3H), 1.56 (q, 1H), 1.35 (tt, 1H), 1.25 - 1.31 (m, 1H), 0.92 (d, 3H), 0.85 (d, 6H), 0.67 (d, 3H), 0.45 (d, 3H), 0.01 (d, 3H).2.3. Cpd 42.3.1. Step i: Int A4

[0436] To a solution of Int 7 (500 mg, 0.592 mmol, 1.0 eq.) and Int 13 (710.69 mg, 2.960 mmol, 5 eq.) in DMF (10 mL) was added K2CO3 (4.09 g, 29.6 mmol, 50 eq.), and the resulting mixture was stirred at 50 °C for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; DCM / MeOH 20: 1) to afford Int A4 (275 mg, 46% yield).

[0437] LCMS: MW (calcd): 1014.6; m / z MW (obsd): 1015.6 (M+H)2.3.2.

[0438] To a solution of Int A4 (275 mg, 0.271 mmol, 1 eq.) in methanol (5 mL) was added [7,7-dimethyl- 2-oxobicyclo[2.2.1]heptan-l-yl]methanesulfonic acid (106.96 mg, 0.461 mmol, 1.7 eq.), and the resulting mixture was stirred at room temperature for 0.5 hour. Then the reaction mixture was partitioned between DCM (100 mL) and saturated NaHCOs aqueous solution (100 mL). The aqueous phase was back extracted with DCM (2 x 100 mL), and the combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: water(10mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 43% B to73 % B in 10 min; Wave Length: 254nm / 220nm) to afford Cpd 4 (67.9 mg, 25% yield).

[0439] LCMS: MW (calcd): 974.5; m / z MW (obsd): 975.5 (M+H)

[0440] ’H NMR (CDCh-d, 400 MHz) 5 = 15.01 (s, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 6.26 (d, 1H), 5.75 - 5.65 (m, 1H), 5.52 - 5.33 (m, 2H), 4.88 (dd, 1H), 4.64 (d, 1H), 4.38 (d, 1H), 4.17 (d, 1H), 3.75 (s, 1H), 3.43 (dd, 2H), 3.29 (dd, 1H), 3.15 - 2.96 (m, 6H), 2.94 - 2.72 (m, 1H), 2.35 (s, 6H), 2.15 - 1.82 (m, 17H), 1.77(s, 4H), 1.71 - 1.49 (m, 4H), 1.52 - 1.33 (m, 2H), 1.17 - 1.07 (m, 2H), 1.01 (dd, 8H), 0.78 (d, 3H), 0.53 (d, 3H), 0.12 - 0.04 (m, 3H)2.4. Cpd 72.4.1. Step i: Int A 7

[0441] To a solution of Int 6 (2 g, 2.361 mmol, 1.0 eq.) and 3 -carbamoylbenzoic acid (1.95 g, 11.805 mmol, 5 eq.) in DCE (20 mL) were added DMAP (1.44 g, 11.805 mmol, 5 eq.) and DPPA (3.25 g, 11.805 mmol, 5 eq.), and the resulting mixture was further stirred at 50 °C for 16 hours. The reaction mixture was cooled, diluted with DCM (200 mL) and saturated NaHCOs aqueous solution (100 mL) and the mixture was stirred at room temperature for 10 minutes. The organic layers were separated, the aqueous phase was extracted with DCM (2 x 100 mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; DCM / MeOH 10: 1) to afford Int A7 (420 mg, 18% yield).

[0442] LCMS: MW (calcd): 1008.5; m / z MW (obsd): 1009.5 (M+H)

[0443] To a solution of Int A7 (420 mg, 0.416 mmol, 1.0 eq.) in methanol (5 mL) was added [7,7- dimethyl-2-oxobicyclo[2.2.1]heptan-l-yl]methanesulfonic acid (164.34 mg, 0.707 mmol, 1.7 eq.), and the resulting mixture was stirred at room temperature for 0.5 hour. Then, the reaction mixture was partitioned between DCM (100 mL) and saturated NaHCOs aqueous solution (100 mL), the aqueous phase was back- extracted with DCM (2 x 100 mL), the combined organic layers were dried over anhydrous Na2SC>4, fdtered, and the fdtrate was concentrated under reduced pressure. The crude residue was purified by reversed-phased flash chromatography (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: water(10mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 43% B to73 % B in 10 min; Wave Length: 254nm / 220nm) to afford Cpd 7 (145.1 mg, 35% yield).

[0444] LCMS: MW (calcd): 968.5; m / z MW (obsd): 969.5 (M+H)

[0445] 'H NMR (CDCh-d, 400 MHz) 5 = 15.08 (s, 1H), 8.89 - 8.69 (m, 1H), 8.51 (s, 1H), 8.03 - 7.87 (m, 1H), 7.74 - 7.59 (m, 1H), 7.55 (d, 1H), 7.43 (t, 1H), 6.29 (d, 2H), 5.72 (dd, 1H), 4.97 (dd, 1H), 4.37 (d, 1H), 3.92 (d, 1H), 3.66 (s, 1H), 3.44 (d, 1H), 3.33 (dd, 1H), 3.05 (d, 5H), 2.67 (s, 2H), 2.38 (s, 6H), 2.20 - 2.05 (m, 3H), 2.00 (s, 5H), 1.85 (ddd, 3H), 1.77 - 1.64 (m, 8H), 1.54 - 1.41 (m, 2H), 0.99 (dd, 9H), 0.80 (d, 3H), 0.59 (d, 3H), 0.15 (d, 3H)2.5. Cpd 8I l l

[0446] To a stirred solution of Int 15 (600 mg, 0.644 mmol, 1 eq.), DMAP (314.90 mg, 2.578 mmol, 4.0 eq.) and EtsN (326.03 mg, 3.222 mmol, 5.0 eq.) in DCM (5 mL) was added 3 -(carboxy )pyridin-l-ium-l - olate (507.61 mg, 3.222 mmol, 5.0 eq.) dropwise at room temperature under nitrogen atmosphere, and the mixture was stirred for 16 hours at room temperature. The reaction was quenched with saturated NH4CI aqueous solution (50 mL) at room temperature, extracted with CH2Q2 (3 x 80 mL), and the combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford Int A8 (400 mg, crude).

[0447] LCMS: MW (calcd): 1172.5; m / z MW (obsd): 1173.5 (M+H)2.5.2.

[0448] To a stirred solution of Int A8 (370 mg, 0.315 mmol, 1 eq.) in THF (4 mL) was added NaOH (0.25 mg, 0.006 mmol, 0.02 eq.) in portions at room temperature under nitrogen atmosphere, and the mixture was stirred for 16 hours at room temperature. The reaction was quenched with saturated NH4CI aqueous solution (50 mL) at room temperature, the resulting mixture was extracted with EtOAc (3 x 80 mL), and the combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford Int B8 (322 mg, crude).

[0449] LCMS: MW (calcd): 1051.5; m / z MW (obsd): 1052.5 (M+H)2.5.3.

[0450] To a stirred solution of Int B8 (322 mg, 0.306 mmol, 1 eq.) and 1,3 -dimethyl- l,3-diazinane-2, 4,6- trione (215.02 mg, 1.377 mmol, 4.5 eq.) in DCM (4 mL) was added Pd(PPh3)4 (353.63 mg, 0.306 mmol, 1 eq.) in portions at room temperature under nitrogen atmosphere, and the mixture was stirred for 30 minutes at room temperature. The reaction was quenched with saturated NH4CI aqueous solution (50 mL) at room temperature, the resulting mixture was extracted with CH2CI2 (3 x 50 mL), and the combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SC>4. filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; ClLCL / McOH 12: 1) to afford Int C8 (90 mg, 24% yield).

[0451] LCMS: MW (calcd): 967.5; m / z MW (obsd): 968.5 (M+H)2.5.4.

[0452] To a stirred solution of Int C8 (90 mg, 0.093 mmol, 1 eq.) in methanol (1.5 mL) was added [7,7- dimethyl-2-oxobicyclo[2.2.1]heptan-l-yl]methanesulfonic acid (43.19 mg, 0.186 mmol, 2.0 eq.) in portions at room temperature under nitrogen atmosphere, and the mixture was stirred for 30 minutes at room temperature. The resulting mixture was quenched with water (50 mL), extracted with CH2Q2 (3 x 50 mL), and the combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: water (lOmmol / L NH4HCO3),Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 46% B to 76% B in 8min; Wave Length: 254nm / 220nm) to afford Cpd 8 (21.5 mg, 22% yield).

[0453] LCMS: MW (calcd): 927.5; m / z MW (obsd): 926.4 (M-H)

[0454] 'H NMR (CDCh-d, 400 MHz) 5 = 15.01 (s, 1H), 8.68 - 8.95(m, 2H), 8.60 (s, 1H), 8.33 (dt, 1H), 8.01 - 7.71 (m, 1H), 7.41 (dd, 1H), 6.42 - 6.19 (m, 1H), 5.83 - 5.49 (m, 1H), 5.31 - 4.87 (m, 1H), 4.78 - 4.55 (m, 1H), 3.51 (s, 1H), 3.41 (d, 1H), 3.29 - 3.18 (m, 2H), 3.11 - 2.86 (m, 6H), 2.81 - 2.57 (m, 2H), 2.42 (s, 3H), 2.38 - 2.25 (m, 3H), 2.21 - 2.09 (m, 2H), 2.09 - 1.99 (m, 4H), 1.96 - 1.82 (m, 4H), 1.84 - 1.63 (m, 8H), 1.58 - 1.37 (m, 2H), 1.26 (d, 1H), 0.99 (dd, 8H), 0.82 (d, 3H), 0.68 (d, 3H), 0.32 - 0.05 (m, 3H)A solution of 3 -carbamoyl-5 -fluorobenzoic acid (901.97 mg, 4.925 mmol, 5 eq.) in DCM (10 mL) was treated with EtsN (996.77 mg, 9.850 mmol, 10 eq.) and (2-methyl-6-nitrophenyl)carbonyl 2-methyl-6- nitrobenzoate (1.76 mL, 5.122 mmol, 5.2 eq.) at room temperature for 20 minutes. Then, a solution of Int 15 (1 g, 0.985 mmol, 1 eq.) and DMAP (481.36 mg, 3.940 mmol, 4 eq.) in DCM (5 mL) was added dropwise over a period of 15 minutes, and the reaction mixture was stirred at room temperature for 16 hours. Next, the reaction mixture was partitioned between dichloromethane DCM (100 mL) and saturated NaHCCL aqueous solution (50 mL), and the aqueous phase was then back -extracted with DCM (2x 100 mL). Thecombined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford Int All (1.03 g, 89% yield).

[0455] LCMS: MW (calcd): 1095.5; m / z MW (obsd): 1096.5 (M-H)2.6.2.

[0456] To a solution of Int All (900 mg, 0.821 mmol, 1 eq.) in dry DCM (10 mb) were added Pd(PPhs)4 (170.77 mg, 0.148 mmol, 0.18 eq.) and l,3-dimethyl-l,3-diazinane-2, 4, 6-trione (576.84 mb, 3.694 mmol, 4.5 eq.), and the reaction mixture was stirred at room temperature for 30 minutes under nitrogen atmosphere. Then, the reaction mixture was partitioned between dichloromethane (100 mL) and saturated NaHCOs aqueous solution (50 mL), and the aqueous phase was back-extracted with DCM (2x 100 mL). The combined organic layers was were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 5% MeOH in DCM) to afford Int Bll (580 mg, 70% yield).

[0457] LCMS: MW (calcd): 1011.5; m / z MW (obsd): 1012.5 (M+H)2.6.3.

[0458] To a solution of Int Bll (580 mg, 0.573 mmol, 1 eq.) in methanol (5 mL) was added CSA (226.28 mg, 0.974 mmol, 1.7 eq.), and the resulting mixture was stirred at room temperature for half an hour. Then, the reaction mixture was partitioned between DCM (100 mL) and saturated NaHCCL aqueous solution (100 mL), and the aqueous phase was back -extracted with DCM (2x 100 mL). The combined organic layerswere dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase flash chromatography (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: water (lOmM NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 43% B to73 % B in 10 min) to afford Cpd 11 (299.8 mg, 52% yield).

[0459] LCMS: MW (calcd): 971.5; m / z MW (obsd): 972.7 (M+H)’HNMR (CDCh-d, 400 MHz) 5 = 15.06 (s, 1H), 8.70 (d, 1H), 8.59 (s, 1H), 8.19 (t, 1H), 7.84 (m, 2H), 6.28 (d, 2H), 5.78 - 5.65 (m, 2H), 4.92 (dd, 1H), 4.60 (dd, 1H), 3.58 (s, 1H), 3.53 (d, 1H), 3.43 (d, 1H), 3.25 (dd, 1H), 3.04 (s, 3H), 3.00 - 2.96 (m, 3H), 2.75 (s, 2H), 2.43 (s, 3H), 2.40 - 2.28 (m, 3H), 2.15 (m, 2H), 2.12 - 2.04 (m, 5H), 1.89 - 1.76 (m, 5H), 1.71 (s, 4H), 1.53 - 1.48 (m, 2H), 0.99 (d, 9H), 0.80 (d, 3H), 0.69 (d, 3H), 0.17 (d, 3H)2.7. Cpd 12

[0460] To a solution of Int 11 (410 mg, 0.43 mmol, 1.0 eq.) in DCE (8 mL) were added TEA (175 mg, 1.72 mmol, 4.0 eq.) and cis-4-aminocyclohexanol (200 mg, 1.72 mmol, 4.0 eq.), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to room temperature, quenched with water (50 mL), extracted with DCM (3 x 100 mL), and the combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel DCM / MeOH 10: 1) to afford Int A12 (390 mg, 82% yield).

[0461] LCMS: MW (calcd): 989.6; m / z MW (obsd): 990.5 (M-H)

[0462] To a solution of Int A12 (300 mg, 0.30 mmol, 1.0 eq.) in O -methylhydrogenol (3 mL) was added [7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-l-yl]methanesulfonic acid (140 mg, 0.60 mmol, 2.0 eq.), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated NaHCOs aqueous solution (50 mL), extracted with DCM (3 x 100 mL), and the combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by reversed-phase column chromatography (column, 330 g C18 silica gel; mobile phase, 0-70% Acetonitrile in water (10 mM NH4HCO3) in 60 min; flowrate, 40 mL / min; detector, UV 220 nm) to afford crude product, which was re-purified by prep-HPLC (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 57% B to 72% B in 10 min; Wave Length: 254 nm / 220 nm to afford Cpd 12 (88.4 mg, 30% yield), 90.3% d-incorporation assayed by Mass Spectrometry analysis method.

[0463] LCMS: MW (calcd): 949.5; m / z MW (obsd): 950.8 (M+H)

[0464] ’H NMR (CDCh-d, 400 MHz) 5 = 15.01 (s, 1H), 8.64 (s, 1H), 8.49 (m, 1H), 6.25 (d, 1H), 5.73 - 5.66 (m, 1H), 4.89 (m, 1H), 4.77 (d, 1H), 4.47 (m, 1H), 4.20 (m, 1H), 3.94 (s, 1H), 3.76 (s, 1H), 3.55 (m, 1H), 3.41 (d, 1H), 3.31 (d, 1H), 3.10 (s, 3H), 3.07 - 2.94 (m, 3H), 2.69 (s, 2H), 2.34 (s, 3H), 2.31 - 2.24 (m, 3H), 2.05 - 1.95 (m, 5H), 1.93 - 1.80 (m, 4H), 1.77 (s, 3H), 1.73 - 1.60 (m, 13H), 1.45 -1.35 (m, 2H), 1.04 - 0.94 (m, 9H), 0.77 (d, 3H), 0.54 (d, 3H), 0.07 (d, 3H)2.8. Cpd 32

[0465] To a solution of Int 7 (450 mg, 0.478 mmol, 1.0 eq.) in DMF (10 mL) were added K2CO3 (3.30 g, 23.90 mmol, 50 eq.) and Int 17 (696.5 mg, 3.824 mmol, 8.0 eq.), and the resulting mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled, diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (5 x 100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0-10% MeOH in DCM) to afford Int A32 (350 mg, 69% yield).

[0466] LCMS: MW (calcd): 1054.6; m / z MW (obsd): 1055.6 (M+H)

[0467] To a solution of Int A32 (350 mg, 0.332 mmol, 1.0 eq.) in methanol (5 mL) was added CSA (154 mg, 0.664 mmol), and the resulting mixture was stirred at room temperature for 10 min. The reaction mixture was partitioned between DCM (10 mL) and saturated aq. NaHCO3 (10 mL), and the aqueous phase was then back- extracted with DCM (2 x 20 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-achiral SFC (Column: DAICEL DCpak P4VP 3*25 cm, 5pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.3%-7M-NH3-MeOH); Flow rate: 65 mL / min; Gradient (B%): isocratic 22% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; Sample Solvent: MeOH) to afford Cpd 32 (85.8 mg, 27% yield).

[0468] LCMS: MW (calcd): 1014.6; m / z MW (obsd): 1015.4 (M+H)

[0469] 'H NMR (CDCh-d, 400 MHz) 5 = 15.02 (s, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 6.26 (d, 1H), 5.70 (m, 1H), 5.54 (d, 1H), 4.89 (dd, 1H), 4.59 (d, 1H), 4.39 (d, 1H), 4.19 (d, 1H), 3.74 (s, 1H), 3.41 (t, 2H), 3.28 (dd, 1H), 3.09 (s, 3H), 3.03 (dt, 1H), 2.98 (s, 2H), 2.72 (m, 1H), 2.34 (s, 3H), 2.32 (s, 2H), 2.10 - 2.02 (m, 2H), 1.99 (s, 3H), 1.97 (d, 1H), 1.94 (s, 13H), 1.84 (m, 2H), 1.67 (dt, 4H), 1.56 (dd, 1H), 1.48 - 1.33 (m, 2H), 1.18 - 0.99 (m, 5H), 0.96 (d, 6H), 0.78 (t, 5H), 0.60 - 0.44 (m, 5H), 0.08 (d, 3H).2.9. Cpd 402.9.1. Step i: Int A40

[0470] To a solution of Int 7 (450 mg, 0.48 mmol, 1.0 eq.) in DMF (10 mL) were added K2CO3 (3.30 g, 23.90 mmol, 50 eq.) and Int 16 (1.12 g, 7.17 mmol, 15 eq.), and the resulting mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled, diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (5 x 100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0-10% MeOH in DCM) to afford Int A40 (250 mg, 51% yield).

[0471] LCMS: MW (calcd): 1028.6; m / z MW (obsd): 1029.6 (M+H)2.9.2.

[0472] To a solution of Int A40 (250 mg, 0.243 mmol, 1.0 eq.) in methanol (3 mL) was added CSA (113 mg, 0.486 mmol, 2.0 eq.), and the resulting mixture was stirred at room temperature for 10 min. The reaction mixture was partitioned between DCM (10 mL) and saturated aq.NaHCOs (10 mL). The aqueous phase was back- extracted with DCM (2 x 20 mL), and the combined organic layers were dried over Na2SC>4, fdtered, andconcentrated under reduced pressure. The crude residue was purified by prep-achiral SFC (Column: DAICEL DCpak P4VP 3*25 cm, 5pm; Mobile Phase A: CO2, Mobile Phase B: IPA(l%-2M-NH3-MeOH); Flow rate: 65 mL / min; Gradient (B%): isocratic 42% B; Column Temperature: 35 °C; Back Pressure (bar): 100; Wave Length: 220 nm; Sample Solvent: MEOH) to afford Cpd 40 (104.1 mg, 43% yield).

[0473] LCMS: MW (calcd): 988.6; m / z MW (obsd): 989.4 (M+H)

[0474] ’H NMR (CDCh-d, 400 MHz) 5 = 15.02 (s, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 6.24 (d, 1H), 5.74 - 5.66 (m, 1H), 5.48 (q, 1H), 4.89 (dd, 1H), 4.60 (dd, 1H), 4.39 (d, 1H), 4.20 (d, 1H), 3.74 (s, 1H), 3.40 (dd, , 2H), 3.28 (dd, 1H), 3.07 (s, 3H), 3.07 - 3.01 (m, 1H), 3.00 (s, 2H), 2.81 (d, 3H), 2.71 (s, 1H), 2.65 (s, 2H), 2.37 (s, 1H), 2.32 (s, 4H), 2.08 (s, 3H), 2.13 - 2.01 (m, 8H), 1.97 (s, 3H), 1.99 - 1.80 (m, 2H), 1.77 - 1.55 (m, 8H), 1.41 (m, 2H), 1.30 - 1.07 (m, 2H), 0.99 (dd, 9H), 0.76 (d, 3H), 0.51 (d, 3H), 0.07 (d, 3H).2.10. Cpd 602.10.1. Step i: IntA60

[0475] A mixture of Int 7 (400 mg, 0.425 mmol, 1.0 eq.) and methyl 4-aminopiperidine-l -carboxylate (269 mg, 1.700 mmol, 4.0 eq.) in DCE (5 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched with H2O (100 mL), extracted with DCM (2 x 100 mL), and the combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by reversed phase chromatography ( Cis silica gel; mobile phase, ACN / H2O (with 10 mmol / L NH4HCO3); gradient, 70% to 85% gradient in 30 min; flowrate, 40 mL / min; detector, UV 254 nm) to afford Int A60 (200 mg, 46% yield)

[0476] LCMS: MW (calcd): 1030.6; m / z MW (obsd): 1031.5 (M+H)

[0477] To a solution of Int A60 (198 mg, 0.192 mmol, 1.0 eq.) in methanol (3 mL) was added CSA (89 mg, 0.384 mmol), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between DCM (100 mL) and saturated aq. NaHCOs solution (100 mL), and the aqueous phase was then back-extracted with DCM (100 mL). The combined organic layers were dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure. The crude residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 59% B to 89 % B in 10 min; Wave Length: 254nm / 220 nm) to afford Cpd 60 (83.0 mg, 43% yield).

[0478] LCMS: MW (calcd): 990.5; m / z MW (obsd): 991.5 (M+H)

[0479] ’H NMR (CDCh-d, 400 MHz) 5 = 15.04 (s, 1H), 8.65 (s, 1H), 8.50 (s, 1H), 6.26 (d, 1H), 5.70 (m,1H), 4.87 (dd, 1H), 4.70 (d, 1H), 4.31 (d, 1H), 4.19 (d, 1H), 4.09 (s, 3H), 3.71 (d, 4H), 3.68 - 3.56 (m, 1H), 3.40 (d, 1H), 3.28 (dd, 1H), 3.11 - 2.87 (m, 8H), 2.67 (s, 1H), 2.60 (s, 1H), 2.33 (s, 3H), 2.30 (d, 2H), 1.99 (s, 3H), 1.96 (d, OH), 1.84 (m, 1H), 1.77 (s, 3H), 1.67 (q, 1H), 1.28 (t, 2H), 1.01 (d, 3H), 0.95 (d, 6H), 0.77 (d, 3H), 0.53 (d, 3H), 0.08 (d, 3H).2.11. Cpd 642.12. Step i: Int A64

[0480] To a solution of Int 7 (500 mg, 0.53 mmol, 1.0 eq.) in DMF (10 mL) were added K2CO3 (3.6 g, 26.55 mmol, 50 eq.) and Int 18 (483.5 mg, 3.72 mmol, 7.0 eq.), and the resulting mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled, diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (5 x 100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel; 0-10% MeOH in DCM) to afford Int A64 (300 mg, 56% yield).

[0481] LCMS: MW (calcd): 1002.5; m / z MW (obsd): 1003.5 (M+H)

[0482] To a solution of Int A64 (300 mg, 0.299 mmol, 1.0 eq.) in methanol (5 mL) was added CSA (138.9 mg, 0.598 mmol, 2.0 eq.), and the resulting mixture was stirred at room temperature for 10 min. The reaction mixture was partitioned between DCM (10 mL) and saturated aq.NaHCOs (10 mL). The aqueous phase was then back- extracted with DCM (2 x 20 mL), the combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-HPLC (Xbridge Prep OBD Cl 8 Column, 30*150 mm, 5pm; A: Water (lOmmol / L NH4HCO3), B: ACN; 60 mL / min; 36% B to 57 % B in 8 min) to afford Cpd 64 (62.7 mg, 22% yield).

[0483] LCMS: MW (calcd): 962.5; m / z MW (obsd): 963.9 (M+H)

[0484] ’H NMR (CDCh-d, 400 MHz) 5 = 15.03 (s, 1H), 8.57 - 8.52 (m, 1H), 6.47 (s, 1H), 6.26 (d, 1H), 5.71 (dd, 1H), 5.47 (s, 1H), 4.88 (dd, 1H), 4.29 - 4.04 (m, 3H), 3.95 - 3.70 (m, 3H), 3.68 (s, 1H), 3.55 (d, 1H), 3.38 (d, 1H), 3.20 (d, 1H), 3.05 (s, 4H), 2.95 (m, 3H), 2.82 - 2.51 (m, 3H), 2.40 (d, 1H), 2.32 (s, 6H), 2.06 - 2.01 (m, 3H), 1.99 (s, 3H), 1.97 - 1.81 (m, 5H), 1.74 (s, 2H), 1.46 (dt, 1H), 1.39 (q, 1H), 1.00 (dd, 8H), 0.79 (d, 3H), 0.60 (d, 3H), 0.10 (q, 3H).2.13. Cpd 65

[0485] To a solution of Int 7 (500 mg, 0.531 mmol, 1.0 eq.) in DCE (5 mL) were added (lR,5S)-8-(oxetan-3- yl)-3, 8 -diazabicyclo [3.2.1] octane (446 mg, 2.655 mmol, 5.0 eq.) and EtsN (215 mg, 2.124 mmol, 4.0 eq.), and the resulting mixture was stirred at room temperature for 16 horns. The reaction mixture was cooled, diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (5 x 100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-10% MeOH in DCM) to afford Int A65 (400 mg, 72% yield).

[0486] LCMS: MW (calcd): 1040.6; m / z MW (obsd): 1041.6 (M+H)

[0487] To a solution of Int A65 (400 mg, 0.384 mmol, 1.0 eq.) in methanol (5 mL) was added CSA (179 mg, 0.768 mmol, 2.0 eq.), and the resulting mixture was stirred at room temperature for 10 min. The reaction mixture was partitioned between DCM (10 mL) and saturated aq.NaHCOs (10 mL), and the aqueous phase was then back-extracted with DCM (2 x 20 mL). The combined organic layers were dried over Na2SC>4, fdtered, and concentrated under reduced pressure. The crude residue was purified by prep-achiral SFC (Column: GreenSep Naphthyl 30*250mm, 5pm; Mobile Phase A: CO2, Mobile Phase B: ACN: MeOH=4: 1 (0.3%-7M-NH3-MeOH); Flow rate: 75 mL / min; Gradient (B%): isocratic 36% B; Column Temperature (°C): 35; Back Pressure (bar): 100; Wave Length: 220 nm; Sample Solvent: MeOH) to afford Cpd 65 (62 mg, 16% yield).

[0488] LCMS: MW (calcd): 1000.6; m / z MW (obsd): 1001.4 (M+H)

[0489] ’H NMR (CDCh-d, 400 MHz) 5 = 15.00 (d, 1H), 8.65 (s, 1H), 8.48 (d, 1H), 7.26 (s, 1H), 6.24 (dd, 1H), 5.70 (dd, 1H), 4.89 (m, 1H), 4.67 (t, 2H), 4.54 (dt, 3H), 4.20 (d, 1H), 3.87 - 3.68 (m, 2H), 3.60 (qd, 1H), 3.39 (d, 1H), 3.23 (d, 1H), 3.07 (d, 6H), 3.00 (s, 1H), 2.99 - 2.82 (m, 2H), 2.66 (s, 1H), 2.36 (d, 1H), 2.31 (s, 3H), 2.21 - 2.01 (m, 2H), 1.99 (s, 3H), 1.98 - 1.87 (m, 6H), 1.90 - 1.77 (m, 8H), 1.63 (m, 3H), 1.44 (m, 3H), 1.05 - 0.94 (m, 9H), 0.77 (dd, 3H), 0.54 (dd, 3H), 0.08 (dd, 3H).2.14. Cpd 67

[0490] To a solution of Int 25 (941 mg, 1.00 mmol, 1.0 eq.) in DCE (10 mL) was added methyl trifluoromethanesulfonate (155 pL. 1.37 mmol, 1.4 eq.), and the resulting mixture was stirred for 15 min at room temperature. 2-aminobenzamide (654 mg, 4.80 mmol, 4.8 eq.) was added, and the resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was partitioned between DCM (100 mL) and H2O (100 mL), and the aqueous phase was back -extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reversed-phase column chromatography (C18 silica gel; ACN / H2O (with 10 mM NH4HCO3); 70% to 85% gradient in 30 min; flowrate: 40 mL / min) to afford Int A67 (520 mg, 52% yield).

[0491] LCMS: MW (calcd): 1008.5; m / z MW (obsd): 1009.5 (M+H)

[0492] To a solution of Int A67 (200 mg, 0.198 mmol, 1.0 eq.) in methanol (2 mL) was added CSA (92.07 mg, 0.396 mmol, 2.0 eq.), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between DCM (100 mL) and saturated aq.NaHCOs (100 mL), and the aqueous phase was then back-extracted with DCM (100 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-HPLC (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Plow rate: 60 mL / min mL / min; Gradient (B%): 60% B to 90% B in 8min; Wave Length: 254nm / 220nm) to afford Cpd 67 (107 mg, 55%yield).

[0493] LCMS: MW (calcd): 968.5; m / z MW (obsd): 969.5 (M+H)

[0494] ’H NMR (CDCh-d, 400 MHz) 5 = 15.01 (d, 1H), 8.62 (s, 1H), 8.48 (d, 1H), 6.25 (t, 1H), 5.70 (dd, 1H), 4.90 (dd, 1H), 4.66 (d, 1H), 4.63 - 4.51 (m, 3H), 4.44 (t, 1H), 4.23 (dd, 1H), 3.73 (s, 1H), 3.71 - 3.58 (m, 1H), 3.41 (m, 3H), 3.33 - 3.15 (m, 2H), 3.06 (d, 3H), 3.02 - 2.89 (m, 3H), 2.67 (s, 2H), 2.33 (t, 6H), 2.24 - 2.07 (m, 3H), 1.99 (s, 5H), 1.96 - 1.89 (m, 2H), 1.71 - 1.43 (m, 3H), 1.39 (q, 2H), 1.28 (d, 2H), 1.01 (d, 3H), 0.96 (d, 6H), 0.77 (d, 3H), 0.56 (dd, 3H), 0.09 (dd, 3H)2.15. Cpd 87

[0495] To a solution of Int 7 (500 mg, 0.531 mmol, 1.0 eq.) in DMF (10 mL) were added K2CO3 (3.6 g, 26.550 mmol, 50 eq.) and Int 20 (1.5 g, 8.810 mmol, crude, 16.5 eq.), and the resulting mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled, diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (5 x 100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-10% MeOH in DCM) to afford Int A87 (180 mg, 33% yield).

[0496] LCMS: MW (calcd): 1042.6; m / z MW (obsd): 1043.6 (M+H)2.15.2. Step ii: Cpd 87

[0497] To a solution of Int A87 (180 mg, 0.173 mmol, 1.0 eq.) in methanol (3 mL) was added CSA (80.1 mg, 0.346 mmol, 2.0 eq.), and the resulting mixture was stirred at room temperature for 10 min. The reaction mixture was partitioned between DCM (100 mL) and saturated aq.NaHC CL (50 mL), and the aqueous phase was then back -extracted with DCM (2 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-achiral SFC (Column: DAICEL DCpak P4VP 3*25 cm, 5pm; Mobile Phase A: CO2, Mobile Phase B: IPA(1%-2M- NHs-MeOH); Flow rate: 80 mL / min; Gradient (B%): isocratic 36% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; Sample Solvent: MEOH+DCM) to afford Cpd 87 (28 mg, 16% yield).

[0498] LCMS: MW (calcd): 1002.6; m / z MW (obsd): 1003.6 (M+H)

[0499] ’H NMR (CDCh-d, 400 MHz) 5 = 15.01 (s, 1H), 8.64 (s, 1H), 8.47 (s, 1H), 6.25 (d, 1H), 5.75 - 5.66 (m, 1H), 4.89 (dd, 1H), 4.61 (d, 1H), 4.40 (d, 1H), 4.17 (d, 1H), 3.73 (s, 1H), 3.53 - 3.37 (m, 2H), 3.28 (dd, 1H), 3.08 (d, 6H), 2.99 (s, 2H), 2.96 (s, 3H), 2.67 (s, 1H), 2.61 (s, 1H), 2.43 (tt, 1H), 2.35 (s, 3H), 2.32 - 2.29 (m, 4H), 2.15 - 2.00 (m, 4H), 1.97 (d, 1H), 1.89 - 1.79 (m, 5H), 1.77 (s, 3H), 1.76 - 1.62 (m, 8H), 1.42 (m, 2H), 1.28 (s, 1H), 1.21 - 1.05 (m, 2H), 1.03 (d, 3H), 0.94 (d, 6H), 0.76 (d, 3H), 0.52 (d, 3H), 0.08 (d, 3H).2.16. Cpd 922.16.1. Step i: Int A92

[0500] To a solution of Int 7 (500 mg, 0.531 mmol) in DMF (10 mL) were added K2CO3 (3.6 g, 26.550 mmol, 50 eq.) and Int 21 (1600 mg, 7.537 mmol, crude, 14 eq.), and the resulting mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled, diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (5 x 100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-10% MeOH in DCM) to afford Int A92 (200 mg, 34.72% yield).

[0501] LCMS: MW (calcd): 1084.6; m / z MW (obsd): 1085.4 (M+H)2.16.2. Step ii: Cpd 92

[0502] To a solution of Int A92 (200 mg, 0.184 mmol, 1.0 eq.) in methanol (3 mL) was added CSA (86 mg, 0.368 mmol, 2.0 eq.), and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between DCM (100 mL) and saturated aq.NaHCOs (50 mL), and the aqueous phase was then back-extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-achiral SFC (Column: DAICEL DCpak P4VP 3*25 cm, 5pm; Mobile Phase A: CO2, Mobile Phase B: IPA(1%-2M- NHs-MeOH); Flow rate: 80 mL / min; Gradient (B%): isocratic 36% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; Sample Solvent: MEOH+DCM) to afford Cpd 92 (56 mg, 27% yield).

[0503] LCMS: MW (calcd): 1044.6; m / z MW (obsd): 1045.7 (M+H)

[0504] ’H NMR (CDCh-d, 400 MHz) 5 = 15.00 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H), 6.27 (d, 1H), 5.75 - 5.67 (m, 1H), 4.87 (dd, 1H), 4.60 (d, 1H), 4.38 (d, 1H), 4.16 (d, 1H), 3.74 (s, 1H), 3.69 (t, 4H), 3.64 (d,2H), 3.50 (s, 3H), 3.40 (d, 1H), 3.29 (dd, 1H), 3.13 - 3.01 (m, 5H), 2.99 (s, 1H), 2.66 (s, 1H), 2.46 - 2.36 (m, 5H), 2.35 (s, 4H), 2.17 - 2.03 (m, 2H), 1.99 (s, 3H), 1.95 (d, 1H), 1.86 (s, 11H), 1.82 (dq, 1H), 1.69 (td, 3H), 1.45 (q, 1H), 1.39 (t, 1H), 1.21 - 1.05 (m, 2H), 1.07 - 0.95 (m, 9H), 0.78 (d, 3H), 0.53 (d, 3H), 0.09 (d, 3H)2.17. Cpd 1022.17.1. Step i: Int A102

[0505] To a solution of Int 7 (440 mg, 0.467 mmol, 1.0 eq.) in DMF (15 mL) were added K2CO3 (3.2 g, 23.350 mmol, 50 eq.) and Int 22 (2.3 g, 10.163 mmol, 21.7 eq.), and the resulting mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled, diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (5 x 100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-10% MeOH in DCM) to afford Int A102 (250 mg, 48.69% yield).

[0506] LCMS: MW (calcd): 1098.6; m / z MW (obsd): 1099.4 (M+H)

[0507] To a solution of Int A102 (250 mg, 0.227 mmol, 1.0 eq.) in methanol (3 mL) was added CSA (106 mg, 0.454 mmol, 2.0 eq.), and the resulting mixture was stirred at room temperature for 10 min. The reaction mixture was partitioned between DCM (100 mL) and saturated aq.NaHCOs (100 mL), and the aqueous phase was then back -extracted with DCM (2 x 50 mL). The combined organic layers were dried over Na2SC>4, fdtered, and concentrated under reduced pressure. The crude residue was purified by prep-achiral SFC (Column: DAICEL DCpak P4VP 3*25 cm, 5pm; Mobile Phase A: CO2, Mobile Phase B: MeOH(l%- 2M-NH3-MeOH); Flow rate: 80 mL / min; Gradient (B%): isocratic 26% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; Sample Solvent: MeOH) to afford Cpd 102 (80 mg, 33% yield).

[0508] LCMS: MW (calcd): 1058.6; m / z MW (obsd): 1060.2 (M+H)

[0509] ’H NMR (CDCh-d, 400 MHz) 5 = 15.01 (s, 1H), 8.65 (s, 1H), 8.47 (s, 1H), 6.25 (d, 1H), 5.75 - 5.66 (m, 1H), 5.31 (d, 1H), 4.89 (dd, 1H), 4.59 (d, 1H), 4.38 (d, 1H), 4.19 (d, 1H), 4.06 - 3.95 (m, 3H), 3.95 (dd, 1H), 3.73 (s, 1H), 3.54 - 3.37 (m, 4H), 3.29 (dd, 1H), 3.09 (s, 4H), 2.99 (s, 2H), 2.34 (s, 4H), 2.32 (s, 3H), 2.08 (m, 4H), 1.99 (s, 4H), 1.99 - 1.80 (m, 7H), 1.77 (s, 3H), 1.71 - 1.52 (m, 6H), 1.44 (m, 4H), 1.27 (s, 1H), 1.19 - 1.05 (m, 2H), 1.02 (d, 3H), 0.97 (d, 6H), 0.78 (d, 3H), 0.53 (d, 3H), 0.08 (d, 3H)2.18. Cpd 1032.18.1. Step i: Int Al 03

[0510] To a solution of Int 7 (440 mg, 0.467 mmol, 1.0 eq.) in DMF (15 mL) were added K2CO3 (3.2 g, 23.350 mmol, 50 eq.) and Int 23 (1.5 g, 7.06 mmol, 15 eq.), and the resulting mixture was stirred at 50 °C for 3 hours. The reaction mixture was cooled, diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (5 x 100 mL), dried over Na2SC>4, filtered, andconcentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-10% MeOH in DCM) to afford Int A103 (380 mg, 74.97% yield).

[0511] LCMS: MW (calcd): 1084.6; m / z MW (obsd): 1085.4 (M+H)2.18.2. Step ii: Cpd 103

[0512] To a solution of Int A103 (250 mg, 0.227 mmol, 1.0 eq.) in methanol (3 mb) was added CSA (106 mg, 0.454 mmol, 2.0 eq.), and the resulting mixture was stirred at room temperature for 10 min. The reaction mixture was partitioned between DCM (100 mL) and saturated aq.NaHCOs (100 mb), and the aqueous phase was then back -extracted with DCM (2 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-achiral SFC (Column: DAICEL DCpak P4VP 3*25 cm, 5pm; Mobile Phase A: CO2, Mobile Phase B: MeOH(l%- 2M-NH3-MeOH); Flow rate: 80 mL / min; Gradient (B%): isocratic 34% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; Sample Solvent: MEOH) to afford Cpd 103 (80 mg, 33% yield).

[0513] LCMS: MW (calcd): 1044.6; m / z MW (obsd): 1046.0 (M+H)

[0514] 'H NMR (CDCh-d, 400 MHz) 5 = 15.03 (s, 1H), 8.67 (s, 1H), 8.47 (s, 1H), 6.24 (d, 1H), 5.70 (m, 1H), 5.61 (d, 1H), 4.89 (dd, 1H), 4.63 - 4.48 (m, 2H), 4.39 (d, 1H), 4.19 (d, 1H), 3.92 (q, 1H), 3.80 (qd, 2H), 3.74 (s, 1H), 3.66 (dd, 1H), 3.42 (dd, 2H), 3.30 (dd, 1H), 3.09 (s, 3H), 3.07 (d, 1H), 2.97 (m, 3H), 2.65 (s, 1H), 2.58 (s, 1H), 2.41 - 2.22 (m, 7H), 2.14 - 1.73 (m, 23H), 1.72 - 1.52 (m, 2H), 1.42 (m, 1H), 1.19 - 1.04 (m, 2H), 1.02 (d, 3H), 0.95 (d, 6H), 0.78 (d, 3H), 0.53 (d, 3H), 0.07 (d, 3H)2.19. Cpd 1122.19.1. Step i: Int Al 12

[0515] To a solution of Int 7 (500 mg, 0.531 mmol, 1.0 eq.) and Int 24 (824 mg, 2.655 mmol, 5.0 eq.) in DMF (10 mL) was added K2CO3 (3668 mg, 26.55 mmol, 50 eq.), and the resulting mixture was stirred at 50 °C for 3 hours. The reaction mixture was cooled, quenched with H2O (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% MeOH in DCM) to afford Int Al 12 (304 mg, 53% yield).2.19.2. Step ii: Cpd 112

[0516] To a solution of Int A112 (304 mg, 0.28 mmol, 1.0 eq.) in methanol (5 mL) was added CSA (111 mg, 0.476 mmol, 1.7 eq.), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between DCM (100 mL) and saturated aq.NaHCOs (100 mL), and the aqueous phase was then back-extracted with DCM (100 mL). The combined organic layers were dried over Na2SC>4, fdtered, and concentrated under reduced pressure. The crude residue was purified by prep-achiral SFC (Column: DAICEL DCpak P4VP 3*25 cm, 5pm; Mobile Phase A: CO2, Mobile Phase B: MeOH(l%- 2M-NH3-MeOH); Flow rate: 80 mL / min; Gradient (B%): isocratic 32% B; Column Temperature(°C): 35) to afford Cpd 112 (177 mg, 60% yield).

[0517] LCMS: MW (calcd): 1044.6; m / z MW (obsd): 1045.6 (M+H)

[0518] ’H NMR (CDCh-d, 400 MHz) 5 = 15.03 (s, 1H), 8.68 (s, 1H), 8.46 (s, 1H), 6.25 (d, 1H), 5.80 - 5.67 (m, 1H), 5.63 (d, 1H), 4.89 (dd, 1H), 4.59 (d, 1H), 4.53 (m, 1H), 4.44 - 4.25 (m, 1H), 4.19 (d, 1H), 3.94 (q, 1H), 3.80 (m, 2H), 3.73 (s, 1H), 3.65 (dd, 1H), 3.51 - 3.35 (m, 2H), 3.29 (dd, 1H), 3.09 (s, 3H), 3.08 - 3.01 (m, 1H), 3.02 - 2.90 (m, 2H), 2.71 - 2.52 (m, 2H), 2.43 - 2.12 (m, 7H), 2.18 - 1.83 (m, 13H),1.89 - 1.67 (m, 8H), 1.71 - 1.52 (m, 3H), 1.50 - 1.35 (m, 2H), 1.20 - 1.05 (m, 2H), 1.02 (d, 3H), 0.95 (d, 6H), 0.77 (d, 3H), 0.52 (d, 3H), 0.08 (d, 3H)2.20. Cpd 168

[0519] To a solution of Int 27 (150 mg, 0.1482 mmol, 1 eq.) in 1,2-DCE were added methyl (3S)-3- aminopyrrolidine-1 -carboxylate (85.5 mg, 0.5928 mmol, 4 eq.) and TEA (211 pL, 1.186 mmol, 8 eq.), and the reaction mixture was stirred at 60 °C overnight. Additional amounts of methyl (3S)-3-aminopyrrolidine- 1-carboxylate (85.5 mg, 0.5928 mmol, 4 eq.) and TEA (211 pL, 1.186 mmol, 8 eq.) were added, and stirring was continued for another night. The reaction mixture was partitioned between DCM and saturated aq. NaHCOs, and the aqueous phase was then back -extracted with DCM (2x). The combined organic layers were dried over Na2SC>4, fdtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel; DCM to 5% MeOH in DCM), to afford Int A168 (36 mg, 21% yield).

[0520] LCMS: MW (calcd): 1016.5; m / z MW (obsd): 1017.4 (M+H)2.20.2. Step ii: Cpd 168

[0521] To a solution of Int A168 (36 mg, 0.03539 mmol, 1.0 eq.) in ethanol (1 mL) was added CSA (12.33 mg, 0.05309 mmol, 1.5 eq.), and the resulting mixture was stirred at room temperature for 2h. The reaction mixture was partitioned between DCM and saturated aq.NaHCCf. and the aqueous phase was then back- extracted with DCM (2x) and subsequently with a DCM / propan-2-ol 3: 1 mixture. The combined organic layers were dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel; (c-Hex:EtOAc:MeOH 7:2: 1) in DCM), to afford Cpd 168 (19 mg, 51% yield).

[0522] MW (calcd): 976.5; m / z MW (obsd): 977.1 (M+H)

[0523] ’H NMR (CDCls-d, 400 MHz) 5 = 15.01 (s, 1 H), 8.60 (br s, 1 H), 8.49 (s, 1 H), 6.24 (d, 1 H), 5.62 - 5.72 (m, 1 H), 4.84 (br d, 2 H), 4.15 - 4.22 (m, 1 H), 4.12 (br d, 2 H), 3.64 - 3.69 (m, 4 H), 3.52 - 3.61 (m, 1 H), 3.38 - 3.49 (m, 2 H), 3.35 (br d, 1 H), 3.22 (br dd, 2 H), 3.05 (s, 3 H), 2.96 - 3.02 (m, 1 H), 2.93 (br d, 2 H), 2.52 - 2.69 (m, 2 H), 2.31 (s, 4 H), 2.26 (br d, 2 H), 2.04 - 2. 17 (m, 1 H), 1.97 - 2.03 (m, 2 H), 1.95 (s, 3 H), 1.85 - 1.92 (m, 3 H), 1.80 (dt, 5 H), 1.72 (s, 3 H), 1.59 - 1.67 (m, 1 H), 1.38 - 1.46 (m, 1 H), 1.32 (br dd, 1 H), 0.99 (d, 3 H), 0.91 (d, 6 H), 0.74 (d, 3 H), 0.49 (d, 3 H), 0.05 (br d, 3 H)2.21. Cpd 2852.21.1. Step i: Int A285

[0524] To a solution of Int 26 (crude, 4.995 mmol, 4.2 eq.) in 1,2-DCE were added Int 6 (1.0 g, 1.18 mmol), and DMAP (1.40 g, 11.465 mmol), and the resulting mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled to rt, quenched with H2O (100 mL) and extracted with DCM (3x 100 mL). The combined organic layers were washed with brine (3x 50 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase column chromatography (Cl 8 silica gel; 0-70% acetonitrile in water (10 mM NH4HCO3) in 60 min) to afford Int A285 (240 mg, 20% yield)

[0525] LCMS: MW (calcd): 1012.5; m / z MW (obsd): 1013.5 (M+H)

[0526] To a solution of Int A285 (240 mg, 0.237 mmol, 1.0 eq.) in methanol (3 mL) was added CSA (110 mg, 0.474 mmol, 2 eq.), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between DCM (100 mL) and saturated aq.NaHCOs (100 mL), and the aqueous phase was then back-extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase column chromatography (Cl 8 silica gel; 0-90% acetonitrile in water (10 mM NH4HCO3) in 60 min), then repurified by prep-achiral SFC (Column: DAICEL DCpak P4VP 3*25 cm, 5pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.3%-7M-NH3-MeOH); Flow rate: 80 mL / min; Gradient (B%): isocratic 24% B; Column Temperature(°C): 35) to afford Cpd 285 (100 mg, 41% yield).

[0527] LCMS: MW (calcd): 972.5; m / z MW (obsd): 973.5 (M+H)

[0528] ’H NMR (CDCh-d, 400 MHz) 5 = 15.11 (s, 1H), 8.74 (s, 1H), 8.40 (s, 1H), 7.47 (s, 1H), 6.83 (s, 1H), 6.25 (d, 2H), 5.85 - 5.54 (m, 2H), 5.06 - 4.84 (m, 1H), 4.41 (d, 1H), 4.08 (s, 4H), 3.60 (s, 1H), 3.43 (d, 1H), 3.33 (dd, 1H), 3.17 - 2.87 (m, 6H), 2.52 (s, 2H), 2.36 (s, 6H), 2.10 (s, 2H), 2.03 - 1.79 (m, 9H), 1.76 (s, 5H), 1.45 (s, 2H), 0.98 (dd, 9H), 0.78 (d, 3H), 0.58 (d, 3H), 0.11 (d, 3H)2.22. Cpd 325

[0529] To a solution of Int 6 (1.0 g, 1.02 mmol, 1.0 eq.) in DCM (20 mL), cooled to 0°C, were added bromoacetic anhydride (1.32 g, 5.1 mmol, 5 eq.) and DMAP (620 mg, 5.1 mmol, 5 eq.) and the resulting mixture was stirred at 0 °C for lh30. The reaction mixture was washed with a IM aq. HC1 solution (25 mL). The organic layer was then washed with a sat. aq. NaHCO3 solution (25 mL), then with brine (25 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel; (MeOH in DCM, 1% to 4%) to afford 967 mg of IntA325.

[0530] LCMS: MW (calcd): 966.4; m / z MW (obsd): 965.5 (M+H)2.22.2. Step ii: Int B325

[0531] To a solution of N-cyclopropyl-2-oxo-piperidine-4-carboxamide CAS# 1788978-45-9 (540 mg, 1.99 mmol, 3.8 eq.) in dry DMF (20 mL), previously cooled in an ice-bath under Ar, was added NaH (85 mg, 3.6 mmol, 6.8 eq) in three portions over 5 min. The mixture was stirred in the ice-bath for 30 min and then was treated with a solution of Int A325 (640 mg, 0.522 mmol, 1 eq.) in one portion. The mixture was allowed to slowly warm to r.t. and left to stir overnight. The reaction was quenched by addition of a sat. aq. NaHCO3 solution (50 mL), water (30 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine (2x20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel; (MeOH in DCM, 1% to 5%), then by prepTLC purification over silica ((DCM / MeOH / NH4OH : 90 / 5 / 1 system) to afford 193 mg of Int B325, which was used as such in the next step.

[0532] LCMS: MW (calcd): 1068.8; m / z MW (obsd): 1069.7 (M+H)

[0533] To a solution of Int B325 (81 mg, 0.051 mmol, 1.0 eq.) in methanol (2 mL) was added CSA (35 mg, 0.151 mmol, 3 eq.) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by addition of water (10 mL) and DCM (5 mL) and layers were separated. The aqueous layer was further extracted with DCM (5 mL). The combined organic layers were dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel; (MeOH in DCM, 0% to 5%), then repurified by Prep-HPLC (Column: Xbridge BEH C18 OBD column 3* 15 cm, 5pm; Mobile Phase A: 10 mM ammonium bicarbonate andammonium hydroxide in water (pH 9-9.5), Mobile Phase B: acetonitrile; Flow rate: 15 mL / min; Gradient (Time / % of B) 0 / 3, 2.0 / 35, 7.7 / 50, 16.5 / 60, 24.1 / 97, 26.2 / 3) to afford 19 mg of Cpd 325.

[0534] LCMS: MW (calcd): 1028.6; m / z MW (obsd): 1029.8 (M+H)

[0535] 'H NMR (CDCl3-d, 600 MHz) 5 = 14.98 (br s, 1 H), 14.95 (br s, 1 H), 8.73 (br s, 1 H), 8.60 (br s, 1 H), 8.56 (s, 1 H), 8.52 (s, 1 H), 7.02 (br s, 1 H), 6.97 (m, 1 H), 6.27 (d, 1 H), 6.25 (d, 1 H), 5.68 (d, 1 H), 5.67 (d, 1 H), 4.96 (m, 2 H), 4.50 (m, 1 H), 4.45 (m, 1 H), 4.08 (d, 1 H), 4.04 (m, 1 H), 3.72 (d, 1 H), 3.66 (d, 1 H), 3.52-3.45 (m, 1 H), 3.43-3.38 (m, 1 H), 3.37-3.33 (m, 2 H), 3.33-3.25 (m, 2 H), 3.19 (td, 2 H), 3.08 (m, 4 H), 3.06 (s, 3 H), 3.05 (s, 3 H), 2.99 (br d, 2 H), 2.82 (m, 2 H), 2.94-2.76 (m, 4 H), 2.72 (m, 1 H), 2.69 (m, 1 H), 2.64 (dd, 1 H), 2.60 (dd, 1 H), 2.44 (m, 4 H), 2.36 (m, 2 H), 2.30 (s, 3 H), 2.29 (s, 3 H), 2.28 (m, 2 H), 2.25 (m, 4 H), 2.24 (m, 2 H), 2.02 (m, 4 H), 2.00 (m, 2 H), 1.94 (s, 6 H), 1.89 (m, 2 H), 1.86 (m, 1 H), 1.84 (m, 2 H), 1.81 (m, 2 H), 1.76 (m, 3 H), 1.73 (s, 6 H), 1.65-1.61 (m, 2 H), 1.45 (m, 2 H), 1.32 (m, 2 H), 0.99 (d, 6 H), 0.96 (m, 12 H), 0.78-0.72 (m, 10 H), 0.54 (d, 3 H), 0.51 (m, 3 H), 0.51-0.50 (m, 2 H), 0.49-0.46 (m, 2 H), 0.04 (m, 3 H), 0.03 (m, 3 H)2.23. Cpd 334

[0536] To a solution of Int 6 (600 mg, 0.708 mmol, 1.0 eq.) and 2-cyano-2,2-dimethylacetic acid CAS# 22426-30-8 (400 mg, 3.54 mmol, 5 eq.) in DCE (10 mL) were added DMAP (430 mg, 3.54 mmol, 5 eq.) and DPPA (980 mg, 3.54 mmol, 5 eq.) and the resulting mixture was then stirred at 50 °C for 2 hours. The reaction mixture was cooled to room temperature, quenched with water (100 mL) and extracted with DCM (2x100 mL). The combined organic layers were washed with brine (2x50 mL), dried over Na2SC>4,filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluting with a gradient of MeOH in DCM (0% to 5%) to afford 260 mg of Int A334.

[0537] LCMS: MW (calcd): 956.5; m / z MW (obsd): 957.5 (M+H)2.23.2.

[0538] To a solution of Int A334 (260 mg, 0.272 mmol, 1.0 eq.) in EtOH (6 m ) and water (3 m ) was added Hydrido(dimethylphosphinousacid-kP)[hydrogenbis(dimethylphosphinito-kP)]platinum(II) CAS# 173416-05-2 (12 mg, 0.027 mmol, 0. 1 eq.) and the resulting mixture was then stirred at 90 °C for 16 hours under nitrogen. The reaction mixture was then cooled to rt, partitioned between DCM (100 mb) and aq. sat. NaHCOs (100 mb). The aqueous phase was then back extracted with DCM (2 x 100 mb). The organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of MeOH in DCM (0% to 10%) to afford 167 mg of Int B334.

[0539] ECMS: MW (calcd): 974.5; m / z MW (obsd): 975.5 (M+H)

[0540] To a solution of Int B334 (167 mg, 0.179 mmol, 1.0 eq.) in methanol (5 mb) was added CSA (71 mg, 0.304 mmol, 1.7 eq.) and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was portioned between DCM (100 mb) and sat. aq. NaHCOs (100 mb). The aqueous phase was back extracted with DCM (2x50 mb). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by Prep-HPEC (Column: Xbridge BEH Cl 8 OBD column 3* 15 cm, 5pm; Mobile Phase A: 10 mM ammonium bicarbonate in water,Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: isocratic 48% B to 78% B in 8 min) to afford 57 mg of Cpd 334.

[0541] LCMS: MW (calcd): 934.5; m / z MW (obsd): 935.8 (M+H)

[0542] 'H NMR (CDCl3-d, 400 MHz) 5 = 15.00 (s, 1H), 8.57 (s, 2H), 6.30 (d, 2H), 5.25 (d, 2H), 4.89 (t, 1H), 4.17 (d, 1H), 3.83 (d, 1H), 3.63 (s, 2H), 3.40 (d, 1H), 3.35-3.26 (m, 1H), 3.05 (m, 1H), 2.66 (s, 1H), 2.38 (s, 1H), 2.17-2.00 (m, 3H), 1.99 (s, 3H), 1.91 (d, 5H), 1.76 (s, 3H), 1.58 (s, 10H), 1.50 (s, 4H), 1.35 (d, 1H), 1.28 (s, 1H), 1.11-0.91 (m, 8H), 0.79 (d, 3H), 0.56 (d, 3H), 0.10 (d, 3H)Table II. Illustrative compoundsTable III. LCMS and NMR data for illustrative compoundsBIOLOGICAL EXAMPLESExample 3. In vitro assays3.1. Cytochrome P450 Induction in pooled human hepatocytes (mRNA Assessment; CYP3A4 only)3.1.1. Objective

[0543] This assay evaluates the potential of a test compound to induce the cytochrome P450 isoform CYP3A4.

[0544] Cytochrome P450 (CYP) 3A4 induction is an important cause of drug-drug interactions, that can result in undesired therapeutic responses and adverse drug reactions. (Hendriks et al. 2020)3.1.2. Protocol SummaryThis assay assesses the potential of test compounds to induce CYP3 A4 in plated cultures of 5 -donor pooled cryopreserved human hepatocytes at a single concentration of test substance. Induction is assessed by mRNA expression of CYP3A4.3.1.3. Experimental procedure3.1.3.1. Materials

[0545] Test compounds and control compounds (rifampicin as positive control and flumazenil as negative control).

[0546] Cryopreserved pooled human hepatocytes as a 5-donor mixed gender pool obtained from BioIVT.

[0547] TaqMan™ Fast Advanced Cells-to-Ct kit (Life Technologies).

[0548] CellTiter-Fluor™ Cell Viability Assay kit (Promega).

[0549] Matrigel and collagen I-coated 96-well plates (Coming Corporation).

[0550] TaqMan Gene Expression assay probes (Catalog # 4351370) for CYP3A4 (Hs00604506_ml), and the assay probe (Catalog #4448490) for ACTB (HsO 1060665 g 1 ) from Applied Biosystems.3.1.3.2. Methods

[0551] After thawing, hepatocytes are diluted to a seeding density of 0.55 x 106 cells / mL. The suspension (lOOpL) is added to each well of the collagen-coated 96-well plate(s) and incubated for 4-6 hours at 37°C, 5% CO2, and 95% relative humidity. Cell morphology is then assessed, and the medium is replaced with 0.5-0.75 mg / mL of Matrigel diluted in Hepatocyte Incubation Medium (1: 15). After a further 18 h incubation, the cells are ready for study of induction.

[0552] The medium is replaced in each well with the cytotoxicity control, negative control, positive control inducer, or compound solution (125 pL) in duplicate; final compound concentration is 10 pM. The culture medium is replaced with fresh incubation medium containing the test compounds or controls every 24 hours and hepatocytes are exposed to the test article and control inducers for a total of 72 hours.

[0553] After incubation, the medium in the 96-well plates is replaced with 100 pL / well of reagent (CellTiter-Fluor™ Cell Viability Assay components plus glycylphenylalanyl-amino fluoroumarin (GF- AFC) substrate) and incubated for 30 minutes at 37°C. After incubation, to assess cell viability 80 pL / well is transferred from the cell plates to new 96-well black plates. Fluorescence intensity is measured for each well at 400 nm excitation and 505 nm emission with an Infinite 200 PRO microplate reader.

[0554] Extract mRNA from samples using the Cells-to-Ct kit (Life Technologies). After washing, add 50 pL lysis solution (with DNase) to each well and incubate for 8 minutes at room temperature and recover the lysate for the reverse transcription (RT) reaction.3.1.3.3. Data analysis and results

[0555] All calculations are carried out using Microsoft Excel.3.1.3.3.1 Cell Viability

[0556] Percent cell viability was calculated by the equation:

[0557] Percent cell viability (%) — (I(sample)-I(background)) / (I(vehicle)-I(background))x100

[0558] Where I(sampie)is the fluorescence intensity of sample wells, I(vehicie)is the mean fluorescence intensity of the 0.1% DMSO-treated cells, and I(background)is the mean fluorescence intensity of culture medium without cells.3.1.3.4. mRNA Quantification

[0559] The mRNA level in each well was calculated by the equation:

[0560] mRNA = 2ct(ACTB)-Ct(induced)

[0561] Where Ct value is the number of cycles required for the fluorescent signal detected in qPCR to cross a certain threshold. The threshold is generated by the instrument automatically. The Ct(ACTB) is the Ct value of [3-actin and Ct(induced) is the Ct value of CYP isoforms.

[0562] The fold induction for the mRNA level is determined by the equation:

[0563] Fold of induction= mRNA(compound xxx) / mRNA(vehicle).

[0564] Where mRNA(vehicie) is determined by the mean Ct value of the negative control samples treated with DMSO.

[0565] The percent adjusted positive control is determined by the equation:

[0566] % of positive control = (mRNA fold of induction(compound xxx)-l) x 100% / (mRNA fold of induction(positive control)- 1 )

[0567] The amplification efficiency of qPCR is determined by the equation:

[0568] E— 10- l / Slope- 1.

[0569] Where the Slope value is calculated by the standard curve (Ct values to log(cDNA dilutions)).

[0570] The qPCR result was excluded if E < 0.9 or E > 1.1.

[0571] Cell viability is presented as follows:A: %viability > 90B: 70 < %viability < 90 C: %viability < 70Table IV. CYP3A induction values in pooled human hepatocytes of illustrative compounds tested at 10 pMExample 4. Bacterial assays4.1. Susceptibility testing in dose response

[0572] The Minimum Inhibitory Concentration (MIC) against MAB (Mycobacterium abscessus) and MAC (Mycobacterium. Avium) was determined following the broth dilution method (CLSI M24: SUSCEPTIBILITY TESTING 2018). MICs were performed in Middlebrook 7H9 broth (Merck cat n° M0178) supplemented with 10% Middlebrook ADC growth supplement (Merck cat n° M0553), 0.44% glycerol (Sigma cat n° 49781) and 0.05% Tween80 (Sigma cat n° 59924). The inoculum was prepared by picking at least 3 - 5 we 11 -isolated colonies from an agar culture plate and transferred in Dulbecco’s Phosphate Buffered Saline (DPBS) (Gibco catn° 14190-144). Next, the turbidity was adjusted to an optical density (OD) at 600nm of ~0.1 and further diluted 1:200 in bacterial culture medium to achieve a final bacterial density of ~5 x 105Colony Forming Units (CFU / mL). Inocula were plated on Middlebrook 7H11 agar (Merck cat n° M0428) to confirm the bacterial load (CFU / mL).

[0573] Starting from DMSO stock, 2-fold serial ...

Claims

CLAIMS1. A compound, or a pharmaceutically acceptable salt, or solvate, or the salt of a solvate thereof, according to Formula I:WhereinX is absent, O, or -NR2-;Li is absent, or C1-4 alkylene;R1is phenyl optionally substituted with one or more independently selected R3a,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, Se or S heteroatoms, optionally substituted with one or more independently selected R3b, where the N heteroatoms may optionally be oxidized,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3c,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3d;5-10 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3e;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3f, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3g;Ci -4 alkyl optionally substituted with one or more independently selected R3h;R2is H or C1-4 alkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4agroups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4bgroup,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4c, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more independently selected R4d;Each R3a, R3b, R3c, R3d, R3e, R3f, R3gand R3his independently selected from: halo,CN, or- -YA-LA-R5;Each R4a, R4b, R4cand R4dis selected from: halo,- =0,CN, or- -YB-LB-R6;Each YA and YB is independently selected from: absent,Ci-4 alkylene optionally substituted with one or more independently selected halo, or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo;Each LAand LBis independently selected from: absent,- -O-,- -(C=O),- -C(=O)O-,- -C(=NH)NR7a-,- -C(=O)NR7a-,- -C(=O)NR7fS(=O)2-,- -C(=O)NR7f-O-,- -C(=O)-C(=O)NR7f-,- -S(=O)-,- -S(=O)2-,- -OP(=O)(OR7d)O-,- -OC(=O)-,- -OC(=O)-NR7b-,- -S(=O)2NR7b-,- -S(=O)(=NR7b)-,- -NR7bS(=O)2-,- -NR7CC(=O)-,- -NR7CC(=O)O-,- -P(=O)R7d-,- -P(=O)(OR7d)O-,- -NR7e-;Each R5, R6, R7a, R76, R7c, R7d, R7e, and R7fis independently selected from:- H,Ci -4 alkyl optionally substituted with one or more independently selected deuterium, halo, OH, - C(=0)NHCH3, -NHC(=O) CH3, phenyl, cyclopropyl, cyclopropyl substituted with OH, or pyridinyl,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B, or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, -P(=O)(CH3)2, -C(=0)0CH3, -C(=0)0H, -C(=O)-cyclopropyl, - N(CH3)2, CN, -C(=0)NHCH3, -S(=O)2CH3, -NHC(=0) CH3, -C(=0)NH2, C1.4 alkyl optionally substituted with one or more independently selected halo, or C 1.4 alkoxy optionally substituted with one or more independently selected halo,6-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B, or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo, phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, - C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, - C(=0)NHCH3, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo, where the N heteroatoms of said heteroaryl may optionally be oxidized.. A compound or a pharmaceutical acceptable salt according to claim 1, wherein Cy is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one R4agroup.

3. A compound or a pharmaceutical acceptable salt according to claim 2, wherein R4ais . -CH2CH2CH3. -CH2CH(CH3)2, -CH2-Cyclopropyl -CH2CH2CH2OH, -CH2CH(CH3)CH2OH, -CH2C(=O)NH2, - CH2CH2CH2C(=O)NH2, or -CH2CH(CH3)CH2C(=O)NH2.

4. A compound or a pharmaceutical acceptable salt according to claim 1, wherein the compound of the invention is according to Formula III:

5. A compound or a pharmaceutical acceptable salt according to any one of claims 1-4, wherein X is absent, or X is -NR2-, and R2is H.

6. A compound or a pharmaceutical acceptable salt according to any one of claims 1-5, wherein Li is absent.

7. A compound or a pharmaceutical acceptable salt according to any one of claims 1-6, wherein R1is phenyl substituted with one, two or three independently selected R3a.

8. A compound or a pharmaceutical acceptable salt according to any one of claims 1-6, wherein R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, thiadiazolyl, selenadiazolyl or pyrimidinyl, each of which is substituted with one, two or three independently selected R3b, where the N heteroatoms may optionally be oxidized.

9. A compound or a pharmaceutical acceptable salt according to any one of claims 1-6, wherein R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two or three groups independently selected from =0 and R3d.

10. A compound or a pharmaceutical acceptable salt according to any one of claims 1-6, wherein R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, oxazepanyl,or azaphosphinanyl, each of which is substituted with one, two or three groups independently selected from =0 and R3f.

11. A compound or a pharmaceutical acceptable salt according to any one of claims 1 -6, wherein R1iswherein * represents the points of attachment.

12. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-11 and pharmaceutically acceptable excipients.

13. A pharmaceutical composition according to claim 12, comprising a further therapeutical agent.

14. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-11, or a pharmaceutical composition according to claim 12 or 13, for use in medicine.

15. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-11, or a pharmaceutical composition according to claim 12 or 13, for use in the prevention and or treatment of tuberculosis, and / or non-tuberculous mycobacteria diseases.

16. A pharmaceutical composition according to claim 13, wherein the further therapeutical agent is an agent for the prevention and or treatment of tuberculosis, and / or non-tuberculous mycobacteria diseases.

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