HK1232212B - Cycloalkyl-linked diheterocycle derivatives - Google Patents

Description

Cycloalkyl-linked biheterocyclic derivatives

Field of the Invention

The present invention relates to novel cycloalkyl-linked biheterocyclic derivatives that are useful for treating abnormal cell growth, such as cancer, in mammals. The present invention also relates to pharmaceutical compositions containing the compounds and methods of using the compounds and compositions to treat abnormal cell growth in mammals.

Background of the Invention

Tumor cells require nutrients to produce ATP and macromolecules to maintain survival and proliferation. (Ward PS, et al., "Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate", Cancer Cell. 21(3) (2012), pp. 297-308.) Glucose and glutamine are the two main sources of nutrients that tumor cells rely on. Tumor cells preferentially use the glycolytic pathway, even under aerobic conditions, to metabolize glucose to produce lactate and ATP, the so-called Warburg effect. In addition to glucose, many tumor cells rely on glutamine ("Gln") for survival (DeBerardinis RJ, et al., "Q's Next: The Diverse Functions of Glutamine in Metabolism, Cell Biology and Cancer", Oncogene. 29(3) (2010), pp. 313-24; Shanware NP, et al., "Glutamine: Pleiotropic Roles in Tumor Growth and Stress Resistance", J Mol Med (Berl). 89(3) (2011), pp. 229-36.). This amino acid can be metabolized to produce intermediates of the tricarboxylic acid cycle for the production of ATP, as well as building blocks such as lipids and nucleotides to sustain cell proliferation. Gln metabolism is regulated in tumor cells and cross-talks with multiple oncogenic pathways (Gao P, et al., “c-Myc Suppression of miR-23a/b Enhances Mitochondrial GlutaminaseExpression and Glutamine Metabolism”, Nature. 458(7239) (2009), pp. 762-5; Durán RV, et al. “Glutaminolysis Activates Rag-mTORC1 Signaling”, Mol Cell. 47(3) (2012), pp. 349-58; Thangavelu K, et al., “Structural Basis for theAllosteric Inhibitory mechanism of Human Kidney-Type Glutaminase (KGA) and its Regulation by Raf-Mek-Erk Signaling in Cancer Cell Metabolism”, J. Proc Natl Acad Sci USA. 109(20) (2012), pp. 7705-10; Son J, et al., “Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway”, Nature, 496(7443) (2013), pp. 101-5.). Glutamine ligase 1 (GLS1) is an essential enzyme that catalyzes the first step in glutamine metabolism, resulting in the production of glutamate and ammonia. Glutamate is also a key substrate for glutathione synthesis, which plays an important role in redox homeostasis. GLS1 is highly expressed in many tumor types, and myc upregulates GLS1 protein levels through transcriptional repression by miR-23a and miR-23. Inhibition of GLS1 with selective small molecule inhibitors may be valuable for treating different types of cancer (Wise DR, et al., “Glutamine Addiction: a New Therapeutic Target in Cancer”, Trends Biochem Sci. 35(8) 2010, pp.427-33; Shukla K, et al., “Design, Synthesis, and Pharmacological Evaluation of Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) Analogs as Glutaminase Inhibitors”, J Med Chem. 55(23) (2012), pp. 10551-63.). Therefore, compounds that inhibit GLS1 are needed.

SUMMARY OF THE INVENTION

Each of the following embodiments can be combined with any other embodiment described herein without inconsistency between the embodiment described herein and the embodiment with which it is combined. The phrase "or a pharmaceutically acceptable salt thereof" is implicit in the description of all compounds described herein; however, in one aspect of any embodiment herein, the compound is in the form of a free base.

The embodiments described herein relate to compounds of formula (I),

in

A and D are independently 5 or 6-membered heteroaryl optionally substituted with 1 or 2 R ⁷ groups;

L is -(C ₄ -C ₁₀ cycloalkyl)- optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy;

R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -C(O)R ^10a , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups;

R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups;

R ³ , R ⁴ , R ⁵ and R ⁶ are each independently hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₃ -C ₆ cycloalkyl;

each R ⁷ is independently hydrogen, halogen, cyano, C ₁ -C ₂ alkyl, hydroxy, C ₁ -C ₂ alkoxy, or -N(R ¹¹ )(R ¹² ), wherein C ₁ -C ₂ alkyl and C ₁ -C ₂ alkoxy are each independently optionally substituted with halogen or hydroxy;

R ^10a and R ^10b are each independently hydrogen, C ₁ -C ₄ alkyl, –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₁ -C ₄ alkyl, C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2, or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C 10 ₆ alkoxy, –(CH ₂ ) _w –N(R ¹¹ )(R ¹² ), –(CH ₂ ) _w –C(O)N(R ¹¹ )(R ¹² ), –C(O)OR ¹¹ , –N(R ¹¹ )C(O)R ¹² , –S(O) ₂ R ¹¹ or –S(O)N(R ¹¹ )(R ¹² ) group;

each of R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ is independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl or 3-6 membered heterocycloalkyl, wherein C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, cyano, hydroxy and methoxy;

w is 0, 1, 2, or 3;

x is 0 or 1;

y is 0 or 1, provided that at least one of x and y is 0; and

z is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein A and D are independently thiadiazolyl, pyridazinyl optionally substituted with 1 or 2 R ⁷ groups, and 1,2,4-triazinyl optionally substituted with R ⁷ .

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of A and D is

.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein y is 0.

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein D is

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is pyridazinyl optionally substituted with 1 or 2 R ⁷ groups.

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is

.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein x is 0 and y is 0 or 1.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein x is 1 and y is 0.

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein L is

It is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy.

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein L is

It is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy.

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is C ₁ -C ₄ alkyl and R ^10b is C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is hydrogen.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is C ₃ -C ₆ cycloalkyl optionally substituted with 1 or 2 R ¹⁵ groups.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is a 5-6 membered heteroaryl optionally substituted with 1 or 2 R ¹⁵ groups.

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the aryl and heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl and R ^10b is —CH ₂ -pyridinyl, wherein each pyridinyl is optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 wherein the C ₁ -C ₄ alkyl, _4-6 -membered heterocycloalkyl, C ^{6 -C 10} _aryl and 5-10-membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, ² or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C _{1 -C 6} alkoxy, –(CH 2 ) w –N(R _{11 )(R 12 ), –(CH 2 ) w} –C(O)N(R ¹¹ ) ₍ R ¹² ), –C( _O )OR ¹¹ , _–N (R ¹¹ )C(O) ^{R 12 ,} –S(O) ₂ ^{R 11 or} –S(O)N(R ¹¹ )(R ¹² ) group.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is -[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a are each independently optionally substituted with 1 or 2 halogens or C ₁ -C ₄ alkyl, and R ^10b is C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₆ alkoxy.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —(CH ₂ )-(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl and R ^10b is C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₂ alkoxy.

Embodiments described herein relate to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl and R ^10b is —CH ₂ CH ₂ —O—CH ₃ .

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is C ₃ -C ₆ cycloalkyl optionally substituted with 1 or 2 R ¹⁵ groups.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ —(5-6 membered heteroaryl) optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ² is cyclopropyl.

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein L is

x is 0 and y is 0.

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (II),

in

A and D are independently

The condition is that at least one of A and D is

L is -(C ₄ -C ₁₀ cycloalkyl)- optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy;

R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -C(O)R ^10a , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups;

R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups;

R ³ , R ⁴ , R ⁵ and R ⁶ are each independently hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₃ -C ₆ cycloalkyl;

R ⁷ , R ⁸ and R ⁹ are each independently hydrogen, halogen, cyano, C ₁ -C ₂ alkyl, hydroxy, C ₁ -C ₂ alkoxy or —N(R ¹¹ )(R ¹² ), wherein C ₁ -C ₂ alkyl and C ₁ -C ₂ alkoxy are each independently optionally substituted with halogen or hydroxy;

R ^10a and R ^10b are each independently hydrogen, C ₁ -C ₄ alkyl, –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₁ -C ₄ alkyl, C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2, or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C 10 ₆ alkoxy, –(CH ₂ ) _w –N(R ¹¹ )(R ¹² ), –(CH ₂ ) _w –C(O)N(R ¹¹ )(R ¹² ), –C(O)OR ¹¹ , –N(R ¹¹ )C(O)R ¹² , –S(O) ₂ R ¹¹ or –S(O)N(R ¹¹ )(R ¹² ) group;

each of R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ is independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl or 3-6 membered heterocycloalkyl, wherein C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, cyano, hydroxy and methoxy;

w is 0, 1, 2, or 3;

x is 0 or 1;

y is 0 or 1, provided that at least one of x and y is 0; and

z is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein y is 0.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein D is

.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein A is

.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein A is

.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein x is 0 and y is 0 or 1.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein x is 1 and y is 0.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein L is

It is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein L is

It is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (II), or pharmaceutically acceptable salts thereof, wherein R ^10a is C ₁ -C ₄ alkyl and R ^10b is C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (II), or pharmaceutically acceptable salts thereof, wherein at least one of R ¹ and R ² is C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is hydrogen.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is C ₃ -C ₆ cycloalkyl optionally substituted with 1 or 2 R ¹⁵ groups.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is a 5-6 membered heteroaryl group optionally substituted with 1 or 2 R ¹⁵ groups.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the aryl and heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (II), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl and R ^10b is —CH ₂ -pyridinyl, wherein each pyridinyl is optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (II), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 wherein the C ₁ -C ₄ alkyl, _4-6 -membered heterocycloalkyl, C ^{6 -C 10} _aryl and 5-10-membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, ² or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C _{1 -C 6} alkoxy, –(CH 2 ) w –N(R _{11 )(R 12 ), –(CH 2 ) w} –C(O)N(R ¹¹ ) ₍ R ¹² ), –C( _O )OR ¹¹ , _–N (R ¹¹ )C(O) ^{R 12 ,} –S(O) ₂ ^{R 11 or} –S(O)N(R ¹¹ )(R ¹² ) group.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein is -[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a are each independently optionally substituted with 1 or 2 halogens or C ₁ -C ₄ alkyl, and R ^10b is C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₆ alkoxy.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —(CH ₂ )-(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₂ alkoxy groups.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl and R ^10b is —CH ₂ CH ₂ —O—CH ₃ .

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is C ₃ -C ₆ cycloalkyl optionally substituted with 1 or 2 R ¹⁵ groups.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ —(5-6 membered heteroaryl) optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ² is cyclopropyl.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein L is

x is 0 and y is 0.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (II), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (II), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (II), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (II), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (III),

in

A and D are independently

The condition is that at least one of A and D is

L is -(C ₄ -C ₁₀ cycloalkyl)- optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy;

R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -C(O)R ^10a , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups;

R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups;

R ³ and R ⁴ are each independently hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₃ -C ₆ cycloalkyl;

R ⁷ , R ⁸ and R ⁹ are each independently hydrogen, halogen, cyano, C ₁ -C ₂ alkyl, hydroxy, C ₁ -C ₂ alkoxy or —N(R ¹¹ )(R ¹² ), wherein C ₁ -C ₂ alkyl and C ₁ -C ₂ alkoxy are each independently optionally substituted with halogen or hydroxy;

R ^10a and R ^10b are each independently hydrogen, C ₁ -C ₄ alkyl, –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₁ -C ₄ alkyl, C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2, or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C 10 ₆ alkoxy, –(CH ₂ ) _w –N(R ¹¹ )(R ¹² ), –(CH ₂ ) _w –C(O)N(R ¹¹ )(R ¹² ), –C(O)OR ¹¹ , –N(R ¹¹ )C(O)R ¹² , –S(O) ₂ R ¹¹ or –S(O)N(R ¹¹ )(R ¹² ) group;

each of R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ is independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl or 3-6 membered heterocycloalkyl, wherein C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, cyano, hydroxy and methoxy;

w is 0, 1, 2, or 3;

x is 0 or 1; and

z is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein D is

.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein A is

.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein A is

.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein x is 0.

Embodiments described herein relate to compounds of formula (III), or pharmaceutically acceptable salts thereof, wherein x is 1.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein L is

It is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein L is

It is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is C ₁ -C ₄ alkyl and R ^10b is C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is hydrogen.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is C ₃ -C ₆ cycloalkyl optionally substituted with 1 or 2 R ¹⁵ groups.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is a 5-6 membered heteroaryl group optionally substituted with 1 or 2 R ¹⁵ groups.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the aryl and heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl and R ^10b is —CH ₂ -pyridinyl, wherein each pyridinyl is optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (III), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 wherein the C ₁ -C ₄ alkyl, _4-6 -membered heterocycloalkyl, C ^{6 -C 10} _aryl and 5-10-membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, ² or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C _{1 -C 6} alkoxy, –(CH 2 ) w –N(R _{11 )(R 12 ), –(CH 2 ) w} –C(O)N(R ¹¹ ) ₍ R ¹² ), –C( _O )OR ¹¹ , _–N (R ¹¹ )C(O) ^{R 12 ,} –S(O) ₂ ^{R 11 or} –S(O)N(R ¹¹ )(R ¹² ) group.

Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is -[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a are each independently optionally substituted with 1 or 2 halogens or C ₁ -C ₄ alkyl, and R ^10b is C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₆ alkoxy.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (III), or pharmaceutically acceptable salts thereof, wherein R ^10a is —(CH ₂ )-(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₂ alkoxy groups.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl and R ^10b is —CH ₂ CH ₂ —O—CH ₃ .

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is C ₃ -C ₆ cycloalkyl optionally substituted with 1 or 2 R ¹⁵ groups.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ —(5-6 membered heteroaryl) optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ² is cyclopropyl.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein L is

x is 0 and y is 0.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (III), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (III), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (III), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (III), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (IV),

in

A is

L is -(C ₄ -C ₁₀ cycloalkyl)- optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy;

R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -C(O)R ^10a , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups;

R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups;

R ³ and R ⁴ are each independently hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₃ -C ₆ cycloalkyl;

R ⁷ , R ⁸ and R ⁹ are each independently hydrogen, halogen, cyano, C ₁ -C ₂ alkyl, hydroxy, C ₁ -C ₂ alkoxy or —N(R ¹¹ )(R ¹² ), wherein C ₁ -C ₂ alkyl and C ₁ -C ₂ alkoxy are each independently optionally substituted with halogen or hydroxy;

R ^10a and R ^10b are each independently hydrogen, C ₁ -C ₄ alkyl, –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₁ -C ₄ alkyl, C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2, or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C 10 ₆ alkoxy, –(CH ₂ ) _w –N(R ¹¹ )(R ¹² ), –(CH ₂ ) _w –C(O)N(R ¹¹ )(R ¹² ), –C(O)OR ¹¹ , –N(R ¹¹ )C(O)R ¹² , –S(O) ₂ R ¹¹ or –S(O)N(R ¹¹ )(R ¹² ) group;

each of R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ is independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl or 3-6 membered heterocycloalkyl, wherein C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, cyano, hydroxy and methoxy;

w is 0, 1, 2, or 3;

x is 0 or 1; and

z is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

The embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein A is

.

The embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein A is

.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein x is 0.

Embodiments described herein relate to compounds of formula (IV), or pharmaceutically acceptable salts thereof, wherein x is 1.

The embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein L is

It is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy.

The embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein L is

It is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy.

The embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is C ₁ -C ₄ alkyl and R ^10b is C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is hydrogen.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is C ₃ -C ₆ cycloalkyl optionally substituted with 1 or 2 R ¹⁵ groups.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is a 5-6 membered heteroaryl optionally substituted with 1 or 2 R ¹⁵ groups.

The embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the aryl and heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl and R ^10b is —CH ₂ -pyridinyl, wherein each pyridinyl is optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 wherein the C ₁ -C ₄ alkyl, _4-6 -membered heterocycloalkyl, C ^{6 -C 10} _aryl and 5-10-membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, ² or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C _{1 -C 6} alkoxy, –(CH 2 ) w –N(R _{11 )(R 12 ), –(CH 2 ) w} –C(O)N(R ¹¹ ) ₍ R ¹² ), –C( _O )OR ¹¹ , _–N (R ¹¹ )C(O) ^{R 12 ,} –S(O) ₂ ^{R 11 or} –S(O)N(R ¹¹ )(R ¹² ) group.

Embodiments described herein relate to a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is -[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a are each independently optionally substituted with 1 or 2 halogens or C ₁ -C ₄ alkyl, and R ^10b is C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₆ alkoxy.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —(CH ₂ )-(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₂ alkoxy groups.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl and R ^10b is —CH ₂ CH ₂ —O—CH ₃ .

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is C ₃ -C ₆ cycloalkyl optionally substituted with 1 or 2 R ¹⁵ groups.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ —(5-6 membered heteroaryl) optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ² is cyclopropyl.

The embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein L is

x is 0 and y is 0.

The embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (IVa),

in

L is -(C ₄ -C ₁₀ cycloalkyl)- optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy;

R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -C(O)R ^10a , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups;

R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups;

R ³ and R ⁴ are each independently hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₃ -C ₆ cycloalkyl;

R ⁷ and R ⁸ are each independently hydrogen, halogen, cyano, C ₁ -C ₂ alkyl, hydroxy, C ₁ -C ₂ alkoxy, or —N(R ¹¹ )(R ¹² ), wherein C ₁ -C ₂ alkyl and C ₁ -C ₂ alkoxy are each independently optionally substituted with halogen or hydroxy;

R ^10a and R ^10b are each independently hydrogen, C ₁ -C ₄ alkyl, –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₁ -C ₄ alkyl, C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2, or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C 10 ₆ alkoxy, –(CH ₂ ) _w –N(R ¹¹ )(R ¹² ), –(CH ₂ ) _w –C(O)N(R ¹¹ )(R ¹² ), –C(O)OR ¹¹ , –N(R ¹¹ )C(O)R ¹² , –S(O) ₂ R ¹¹ or –S(O)N(R ¹¹ )(R ¹² ) group;

each R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl or 3-6 membered heterocycloalkyl, wherein C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, cyano, hydroxy and methoxy;

w is 0, 1, 2, or 3;

x is 0 or 1; and

z is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein x is 0.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein x is 1.

The embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein L is

It is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy.

The embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein L is

It is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy.

The embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is C ₁ -C ₄ alkyl and R ^10b is C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of Formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is hydrogen.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is C ₃ -C ₆ cycloalkyl optionally substituted with 1 or 2 R ¹⁵ groups.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is a 5-6 membered heteroaryl group optionally substituted with 1 or 2 R ¹⁵ groups.

The embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the aryl and heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl and R ^10b is —CH ₂ -pyridinyl, wherein each pyridinyl is optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IVa), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 wherein the C ₁ -C ₄ alkyl, _4-6 -membered heterocycloalkyl, C ^{6 -C 10} _aryl and 5-10-membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, ² or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C _{1 -C 6} alkoxy, –(CH 2 ) w –N(R _{11 )(R 12 ), –(CH 2 ) w} –C(O)N(R ¹¹ ) ₍ R ¹² ), –C( _O )OR ¹¹ , _–N (R ¹¹ )C(O) ^{R 12 ,} –S(O) ₂ ^{R 11 or} –S(O)N(R ¹¹ )(R ¹² ) group.

Embodiments described herein relate to a compound of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is -[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a are each independently optionally substituted with 1 or 2 halogens or C ₁ -C ₄ alkyl, and R ^10b is C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₆ alkoxy.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —(CH ₂ )-(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl and R ^10b is C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₂ alkoxy.

Embodiments described herein relate to compounds of Formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl and R ^10b is —CH ₂ CH ₂ —O—CH ₃ .

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is C ₃ -C ₆ cycloalkyl optionally substituted with 1 or 2 R ¹⁵ groups.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ —(5-6 membered heteroaryl) optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ² is cyclopropyl.

The embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IVa), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IVa), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein L is

.

The embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IVa), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IVa), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (IVb),

in

L is -(C ₄ -C ₁₀ cycloalkyl)- optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy;

R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -C(O)R ^10a , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups;

R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups;

R ³ and R ⁴ are each independently hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₃ -C ₆ cycloalkyl;

R ^10a and R ^10b are each independently hydrogen, C ₁ -C ₄ alkyl, –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₁ -C ₄ alkyl, C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2, or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C 10 ₆ alkoxy, –(CH ₂ ) _w –N(R ¹¹ )(R ¹² ), –(CH ₂ ) _w –C(O)N(R ¹¹ )(R ¹² ), –C(O)OR ¹¹ , –N(R ¹¹ )C(O)R ¹² , –S(O) ₂ R ¹¹ or –S(O)N(R ¹¹ )(R ¹² ) group;

each of R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ is independently hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl or 3-6 membered heterocycloalkyl, wherein C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, cyano, hydroxy and methoxy;

w is 0, 1, 2, or 3;

x is 0 or 1; and

z is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

Embodiments described herein relate to compounds of formula (IVb), or pharmaceutically acceptable salts thereof, wherein x is 0.

Embodiments described herein relate to compounds of formula (IVb), or pharmaceutically acceptable salts thereof, wherein x is 1.

The embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein L is

It is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy.

The embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein L is

It is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, C ₁ -C ₄ alkyl, hydroxy, and C ₁ -C ₄ alkoxy.

Embodiments described herein relate to compounds of formula (IVb), or pharmaceutically acceptable salts thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is C ₁ -C ₄ alkyl and R ^10b is C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of Formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is hydrogen.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is C ₃ -C ₆ cycloalkyl optionally substituted with 1 or 2 R ¹⁵ groups.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein at least one of R ¹ and R ² is a 5-6 membered heteroaryl group optionally substituted with 1 or 2 R ¹⁵ groups.

The embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein L is

.

Embodiments described herein relate to compounds of formula (IVb), or pharmaceutically acceptable salts thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the aryl and heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl and R ^10b is —CH ₂ -pyridinyl, wherein each pyridinyl is optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IVb), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 wherein the C ₁ -C ₄ alkyl, _4-6 -membered heterocycloalkyl, C ^{6 -C 10} _aryl and 5-10-membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, ² or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C _{1 -C 6} alkoxy, –(CH 2 ) w –N(R _{11 )(R 12 ), –(CH 2 ) w} –C(O)N(R ¹¹ ) ₍ R ¹² ), –C( _O )OR ¹¹ , _–N (R ¹¹ )C(O) ^{R 12 ,} –S(O) ₂ ^{R 11 or} –S(O)N(R ¹¹ )(R ¹² ) group.

Embodiments described herein relate to a compound of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is -[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a are each independently optionally substituted with 1 or 2 halogens or C ₁ -C ₄ alkyl, and R ^10b is C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₆ alkoxy.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —(CH ₂ )-(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl and R ^10b is C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₂ alkoxy.

Embodiments described herein relate to compounds of Formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl and R ^10b is —CH ₂ CH ₂ —O—CH ₃ .

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is C ₃ -C ₆ cycloalkyl optionally substituted with 1 or 2 R ¹⁵ groups.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ —(5-6 membered heteroaryl) optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ² is cyclopropyl.

The embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein L is

.

Embodiments described herein relate to compounds of formula (IVb), or pharmaceutically acceptable salts thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IVb), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyrazolyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein L is

.

Embodiments described herein relate to compounds of formula (IVb), or pharmaceutically acceptable salts thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IVb), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

The embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein L is

.

Embodiments described herein relate to compounds of formula (IVb), or pharmaceutically acceptable salts thereof, wherein

R ¹ is —C(O)R ^10a and R ² is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ² is —C(O)R ^10b and R ¹ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, —C(O)R ^10b , or 5-6 membered heteroaryl, wherein C ₃ -C ₆ cycloalkyl and 5-6 membered heteroaryl are independently optionally substituted with 1 or 2 R ¹⁵ groups; or

R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of Formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹ is —C(O)R ^10a and R ² is —C(O)R ^10b .

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C ₁₀ aryl), or –[C(R ¹³ )(R ¹⁴ )] _z –(5-10 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z –(C ₄ -C ₁₀ cycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(4-6 membered heterocycloalkyl), –[C(R ¹³ )(R ¹⁴ )] _z –(C ₆ -C 10 -C ₁₀ aryl) or -[C(R ¹³ )(R ¹⁴ )] _z -(5-10 membered heteroaryl), wherein the C ₄ -C ₁₀ cycloalkyl, 4-6 membered heterocycloalkyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted by 1, 2 or 3 of the following groups: halogen, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkoxy, -(CH ₂ ) _w -N(R ¹¹ )(R ¹² ), -(CH ₂ ) _w -C(O)N(R ¹¹ )(R ¹² ), -C(O)OR ¹¹ , -N(R ¹¹ )C(O)R ¹² , -S(O) ₂ R ¹¹ or -S(O)N(R ¹¹ )(R ¹² ) groups.

Embodiments described herein relate to a compound of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is –[C(R ¹³ )(R ¹⁴ )] _z -(C ₆ aryl) or –[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the C ₆ aryl and 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 halogen or C ₁ -C ₄ alkyl.

Embodiments described herein relate to a compound of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein R ^10a is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl) and R ^10b is —[C(R ¹³ )(R ¹⁴ )] _z -(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl in R ^10a and R ^10b are each independently optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

Embodiments described herein relate to compounds of formula (IVb), or a pharmaceutically acceptable salt thereof, wherein each R ¹³ and R ¹⁴ is hydrogen and each z is 1.

Embodiments described herein relate to compounds of formula (IVb), or pharmaceutically acceptable salts thereof, wherein R ^10a is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups and R ^10b is —CH ₂ -pyridinyl optionally substituted with 1 or 2 C ₁ -C ₄ alkyl groups.

In some embodiments, the compound is selected from:

(rac)-2-phenyl- N -{6-[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl)methyl]pyridazin-3-yl}acetamide;

2-(pyridin-2-yl)- N -(5-{[(1 R ,3 S )-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;

(rac)-2-(pyridin-2-yl)- N -(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;

2-(pyridin-2-yl)- N -(5-{[(1 S ,3 R )-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;

N -[5-({(1 R ,3 S )-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;

(rac)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;

N -[5-({(1 S ,3 R )-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;

2-phenyl- N -(5-{[(1 R ,3 S )-3-{5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;

(rac)-2-phenyl- N -(5-{[(cis)-3-{5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;

2-phenyl- N -(5-{[(1 S ,3 R )-3-{5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;

(rac)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]benzamide;

(+)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]benzamide;

(-)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]benzamide;

(+)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-phenylacetamide;

(rac) -N- [5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-phenylacetamide;

(-)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-phenylacetamide;

(+)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide;

(-)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide;

(rac) -N- [5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide;

(+)- N -{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4-yl)acetamide;

(-)- N -{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4-yl)acetamide;

2-(pyridin-2-yl)- N -{5-[( cis- 3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide;

2-(pyridin-2-yl)- N -{5-[( trans - 3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide;

(rac) -N- [5-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide;

N , N ′-(spiro[3.3]heptane-2,6-diylbipyridazine-6,3-diyl)bis[2-(pyridin-2-yl)acetamide];

2-(pyridin-2-yl)- N -{5-[(3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}cyclopentyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide;

(rac) -N- (5-{[(cis)-3-{5-[(2,2-dimethylpropionyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-2,2-dimethylpropionamide;

(+)- N -(5-{[(cis)-3-{5-[(2,2-dimethylpropionyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-2,2-dimethylpropionamide;

(-)- N -(5-{[(cis)-3-{5-[(2,2-dimethylpropionyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-2,2-dimethylpropionamide;

(rac)-2-(pyridin-3-yl)- N -(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propionyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)propanamide;

(+)-2-(pyridin-3-yl)- N -(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propionyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)propanamide;

(-)-2-(pyridin-3-yl)- N -(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propionyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)propanamide;

(rac)-5-{[(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol-2-amine;

5-{[(1 R ,3 S )-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol-2-amine;

5-{[(1 S ,3 R )-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol-2-amine;

(rac)- N -(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)acetamide;

(rac) -N- {5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-phenylacetamide;

(+)- N -{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-phenylacetamide;

(-)- N -{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-phenylacetamide;

(rac)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrimidin-2-yl)acetamide;

(rac)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrazin-2-yl)acetamide;

(rac)- N -{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}benzamide;

(rac) -N -[(cis)-5-({3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrimidin-5-yl)acetamide;

(+)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrimidin-5-yl)acetamide;

(-)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrimidin-5-yl)acetamide;

(rac) -N- [5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(6-methylpyridin-3-yl)acetamide;

(+)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(6-methylpyridin-3-yl)acetamide;

(-)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(6-methylpyridin-3-yl)acetamide;

(rac) -N- {5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide;

(+)- N -{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide;

(-)- N -{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide;

(+)- N -{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-5-yl)acetamide;

(-)- N -{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-5-yl)acetamide;

N,N' -{[-1,2,2-trimethylcyclopentane-1,3-diyl]di-1,3,4-thiadiazole-5,2-diyl}diethylamide;

N , N ′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(pyridin-2-yl)acetamide];

N -[5-({ cis- 3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;

N -[5-({trans - 3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;

(+)- N -(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)-2-phenylacetamide;

(-)- N -(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)-2-phenylacetamide;

(rac) -N- [5-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;

(rac)- N -(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)acetamide;

(+)- N -{5-[(cis)-3-{[6-(acetylamino)pyridazin-3-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide;

(-)- N -{5-[(cis)-3-{[6-(acetylamino)pyridazin-3-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide;

(rac)-2-(pyridin-2-yl)- N -{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide;

(+)-2-(pyridin-2-yl)- N -{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide;

(-)-2-(pyridin-2-yl)- N -{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide;

N -{6-[( cis- 3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]pyridazin-3-yl}propionamide;

(+)-2-(pyridin-2-yl)- N -[6-({(cis)-3-[5-(pyridin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)pyridazin-3-yl]acetamide;

(-)-2-(pyridin-2-yl)- N -[6-({(cis)-3-[5-(pyridin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)pyridazin-3-yl]acetamide;

(rac)-2-methyl- N -(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)propanamide;

(+)-2-methyl- N -(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)propanamide;

(-)-2-methyl- N -(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)propanamide;

N -(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)propanamide;

(+)-2-phenyl- N -(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)acetamide;

(-)-2-phenyl- N -(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)acetamide;

(rac)-2-(pyridin-2-yl)- N -[5-({(cis)-3-[5-(pyrimidin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;

2-(pyridin-2-yl)- N -[5-({(cis)-3-[5-(pyrimidin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;

2-(pyridin-2-yl)- N -[5-({3-[5-( trans )(pyridin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;

2-(pyridin-2-yl)- N -[5-({(cis)-3-[5-(pyridin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;

(rac)- N -[5-({(cis)-3-[5-(pyrazin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide;

(rac)- N -(5-{[(cis)-3-{5-[(1-methyl- 1H -pyrazol-3-yl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)acetamide;

N -(5-{[(cis)-3-{5-[(1-methyl- 1H -pyrazol-3-yl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)acetamide;

3-methoxy- N -{5-[(cis)-3-{[6-(propionylamino)pyridazin-3-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}propionamide;

(+)- N -(6-{[(cis)-3-(5-{[(1-methyl- 1H -pyrazol-3-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)propanamide;

(−)- N -(6-{[( cis )-3-(5-{[(1-methyl- 1 H -pyrazol-3-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)propanamide;

N , N ′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)diethylamide;

(rac)- N,N' -(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis(2-methylpropionamide);

( S )- N , N ′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis(2-methylpropionamide);

(rac) -N,N′ -(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(1-methyl-1H-pyrazol-3-yl)acetamide];

( R )- N , N ′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(1-methyl- 1 H -pyrazol-3-yl)acetamide];

( S )- N , N ′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(1-methyl- 1 H -pyrazol-3-yl)acetamide];

N,N′ -(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(pyridin-2-yl)acetamide];

N -[6-({cis - 3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)pyridazin-3-yl]-2-phenylacetamide;

N -[6-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide;

(+)-2-(pyridin-2-yl)- N -{5-[(1-(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)ethyl]-1,3,4-thiadiazol-2-yl}acetamide;

(-)-2-(pyridin-2-yl)- N -{5-[(1-(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)ethyl]-1,3,4-thiadiazol-2-yl}acetamide;

2-methyl- N -{5-[(cis - 3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}propionamide;

N -{5-[ cis- 3-({5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}methyl)cyclobutyl]-1,3,4-thiadiazol-2-yl}propionamide;

N -{5-[trans - 3-({5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}methyl)cyclobutyl]-1,3,4-thiadiazol-2-yl}propionamide;

N -[5-( cis- 3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclobutyl)-1,3,4-thiadiazol-2-yl]-2-(5-methylpyridin-2-yl)acetamide;

2-(5-methylpyridin-2-yl)- N -(5-{[cis- 3- (5-{[(5-methylpyridin-2-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)cyclobutyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;

2-(5-methylpyridin-2-yl)- N -(5-{[trans - 3-(5-{[(5-methylpyridin-2-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)cyclobutyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;

N -[6-({(cis)-3-[5-(cyclopropylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide;

2-(5-methylpyridin-2-yl)- N -{5-[(cis - 3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide;

2-(5-methylpyridin-2-yl)- N -{5-[cis- 3 -({5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}methyl)cyclobutyl]-1,3,4-thiadiazol-2-yl}acetamide;

N -[6-({ trans -3- [5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide;

N -[5-(cis - 3-{[6-(acetylamino)pyridazin-3-yl]methyl}cyclobutyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide;

N -[6-({trans - 3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide;

(+)- N -{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}pyridine-2-carboxamide;

(-)- N -{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}pyridine-2-carboxamide;

2-phenyl- N -{6-[(cis - 3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]pyridazin-3-yl}acetamide;

N -{5-[(1 S ,3 R )-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}propionamide;

2-methyl- N -{5-[(1 S ,3 R )-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}propionamide;

(+)-3-Methoxy- N -{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}propionamide;

(-)-3-Methoxy- N -{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}propionamide;

2-(pyridin-2-yl)- N -{5-[( trans - 3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide;

2-(pyridin-2-yl)- N -{5-[( cis- 3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide;

2-methyl- N -{6-[ cis- 3-({5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}methyl)cyclobutyl]pyridazin-3-yl}propionamide;

(+)-2-(1-methyl- 1H -pyrazol-3-yl)- N -{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide;

(−)-2-(1-methyl-1 H -pyrazol-3-yl)- N -{5-[( cis )-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide;

2-(1-methyl- 1H -imidazol-4-yl)- N -{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide;

(rac)-2-(pyridin-2-yl)- N -(6-{[(cis)-3-(5-{[( 2R )-tetrahydrofuran-2-ylacetyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)acetamide;

(+)-2-(pyridin-2-yl)- N -(6-{[(cis)-3-(5-{[( 2R )-tetrahydrofuran-2-ylacetyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)acetamide;

(-)-2-(pyridin-2-yl)- N -(6-{[(cis)-3-(5-{[( 2R )-tetrahydrofuran-2-ylacetyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)acetamide;

N -[6-({cis - 3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)pyridazin-3-yl]-2-phenylacetamide;

2-(pyridin-2-yl)- N -[5-({(cis)-3-[5-(pyridin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;

( S )- N , N ′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)dipropionamide;

2-methyl- N -[5-(6-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}spiro[3.3]hept-2-yl)-1,3,4-thiadiazol-2-yl]propanamide;

2-methyl- N -{5-[6-(5-{[(1-methyl-1 H -pyrazol-3-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)spiro[3.3]hept-2-yl]-1,3,4-thiadiazol-2-yl}propanamide;

(rac)-1-methyl- N -(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-1H-pyrazole-3-carboxamide;

N,N′ -[cyclopentane-1,3-diyldi-1,3,4-thiadiazole-5,2-diyl]bis[2-(pyridin-2-yl)acetamide];

N,N′ -[cyclohexane-1,3-diyldi-1,3,4-thiadiazole-5,2-diyl]bis[2-(pyridin-2-yl)acetamide];

N,N′ -(cyclohexane-1,4-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(pyridin-2-yl)acetamide];

N,N' -(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)diethylamide;

(rac)-2-( 1H -pyrazol-1-yl)- N -(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;

(rac)-3-( 1H -pyrazol-1-yl)- N -(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)propanamide;

(rac)-2-fluoro- N -(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)benzamide;

(rac)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(1,3-thiazol-4-yl)acetamide;

(rac)-2-fluoro- N -(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)benzamide;

(rac)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(1,3-thiazol-4-yl)acetamide;

(rac)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(1-methyl- 1H -pyrazol-3-yl)acetamide;

(rac)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(1-methyl- 1H -pyrazol-3-yl)acetamide;

(rac)- N -[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-fluorobenzamide;

(rac) -N- [5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(imidazo[1,2- a ]pyridin-2-yl)acetamide; and

(rac)-1-methyl- N- (5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl) -1H -imidazole-4-carboxamide,

or a pharmaceutically acceptable salt thereof.

An embodiment relates to a pharmaceutical composition comprising a compound of any one embodiment of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IVa) or Formula (IVb) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

An embodiment relates to a pharmaceutical composition comprising a compound of any one of the embodiments of Formula (I), (II), (III), (IV), (IVa) or (IVb) or a pharmaceutically acceptable salt thereof and an anticancer agent or radiation therapy for the treatment of cancer.

An embodiment relates to a pharmaceutical composition comprising a compound of any one embodiment of Formula (I), (II), (III), (IV), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, and an anti-tumor agent for use in treating cancer.

Embodiments relate to methods of treating abnormal cell growth in a mammal, comprising administering to the mammal a composition of any embodiment of a compound of Formula (A)-(C), (II), (III), (IV), (IVa)-(IVb), or (IVb)-(IVb) or a pharmaceutically acceptable salt thereof, in an amount effective to treat the abnormal cell growth.

Embodiments relate to methods of treating abnormal cell growth in a mammal, comprising administering to the mammal a compound of any one of the embodiments of Formula (A)-(C), (II), (III), (IV), (IVa)-(IVb), or (IVb)-(IVc), or a pharmaceutically acceptable salt thereof, in an amount effective to treat the abnormal cell growth.

Embodiments are directed to methods of treating abnormal cell growth, wherein the abnormal cell growth is cancer.

Embodiments are directed to methods of treating cancer, wherein the cancer is selected from the group consisting of basal cell cancer, medulloblastoma cancer, liver cancer, rhabdomyosarcoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, renal cell carcinoma, renal pelvis cancer, central nervous system neoplasms, primary central nervous system lymphomas, spinal axis tumors, brainstem gliomas, and pituitary adenomas, or a combination of one or more of the foregoing cancers.

Embodiments are directed to methods of treating lung cancer, wherein the cancer is selected from the group consisting of lung cancer, head and neck cancer, colon cancer, breast cancer, and ovarian cancer, or a combination of one or more of the foregoing cancers.

Detailed Description of the Invention

The following abbreviations may be used herein: Ac (acetyl); AcOH (acetic acid); Ac2O (acetic anhydride); aq. (aqueous); ca. (approximately); DCM (dichloromethane); DEA (diethylamine); DIPEA ( N,N -diisopropylethylamine); DMA (dimethylacetamide); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); Et (ethyl); _Et3N (triethylamine); EtOH (ethanol); EtOAc (ethyl acetate); _Et2O (diethyl ether); Hal (halogen); HATU (2-(7-a-aza- 1H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate); HBTU ( o- (benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate); HPLC (high performance liquid chromatography); hr (one or several hours, as appropriate); IPA (isopropyl alcohol); LCMS (liquid chromatography-mass spectrometry); L-Selectride (lithium tri-sec-butylborohydride); Me (methyl); MeOH (methanol); MeCN (acetonitrile); min (one or several minutes, as appropriate); N (normal); N/D (not determined); NMR (nuclear magnetic resonance); Pd/C (palladium on carbon); Pd ₂ (dba) ₃ (tris(dibenzylideneacetone)dipalladium(0)); Pd(dppf)Cl ₂ ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)); Ph (phenyl); Rt (retention time); sec (one or several seconds, as appropriate); SFC (supercritical fluid chromatography); Si-Thiol (silica 1-propanethiol); T3P (propylphosphonic anhydride); TBME (tert-butyl methyl ether); t -BuOH (2-methyl-2-propanol, tert-butanol, or tert-butyl alcohol); THF (tetrahydrofuran); TLC (thin layer chromatography); TMSCl (trimethylsilyl chloride); tris (tris(hydroxymethyl)aminomethane or 2-amino-2-hydroxymethyl-propane-1,3-diol); U (unit); and v/v (volume/volume).

As used herein, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom, or fluorine, chlorine, bromine, or iodine. Additionally, the term "halogen" refers to F, Cl, Br, or I. For example, the terms fluorine, fluoro, and F are understood to be equivalent herein.

As used herein, the term "alkyl" refers to a saturated monovalent hydrocarbon radical, which, in certain embodiments, contains 1 to 6, 1 to 4, or 1 to 3 carbon atoms, having a straight chain or branched portion. The term " _Ci - _C6 alkyl" refers to an alkyl radical containing 1 to 6 carbon atoms, having a straight chain or branched portion. The term "Ci _{- C6} alkyl" includes within its definition the terms "Ci _{- C2} alkyl,""Ci _{- C3} alkyl," and "Ci- _C4 alkyl." Examples of alkyl radicals include, but are not limited to _, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, and the like.

As used herein, the term "alkoxy" refers to an alkyl group single-bonded to an oxygen atom. The point of attachment of the alkoxy group to the molecule is through the oxygen atom. An alkoxy group can be depicted as alkyl-O-. The term " _C1 - _C6 alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms, with a straight or branched portion. The terms " _C1 - _C2 alkoxy" and " _C1 - _C4 alkoxy" refer to alkoxy groups containing 1 to 2 carbon atoms and 1 to 4 carbon atoms, respectively, with a straight or branched portion. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, and the like.

As used herein, the term "cycloalkyl" refers to a monocyclic, fused or bridged bicyclic or tricyclic carbocyclic group, which, in certain embodiments, contains 3 to 10 carbon atoms. As used herein, a cycloalkyl ring may optionally contain 1 or 2 double bonds. The term "cycloalkyl" also includes spirocycloalkyls, including polycyclic systems linked by a single atom. The terms " _C3 - _C10 cycloalkyl,"" _C3 - _C7 cycloalkyl,"" _C3 - _C4 cycloalkyl,"" _C3 - _C6 cycloalkyl,"" _C4 - _C10 cycloalkyl," and " _C5 - _C7 cycloalkyl" contain 3 to 10, 3 to 7, 3 to 4, 3 to 6, 4 to 10, and 5 to 7 carbon atoms, respectively. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, adamantyl, spiro[3.3]heptyl, and the like.

As used herein, the term "heterocycloalkyl" refers to a non-aromatic, monocyclic, fused or bridged bicyclic or tricyclic, or spirocyclic group, which, in certain embodiments, contains a total of 3 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the sulfur atoms may be optionally oxidized by 1 or 2 oxygen atoms, and the remaining ring atoms are carbon, provided that such ring systems may not contain two adjacent oxygen atoms or two adjacent sulfur atoms. The heterocycloalkyl ring may also be substituted with an oxo (=O) group at any available carbon atom. The ring may also have one or more double bonds. In addition, such groups may be bonded to the remainder of the compound of the embodiments disclosed herein via carbon atoms or heteroatoms (if possible). The terms "3- to 10-membered heterocycloalkyl," "4- to 10-membered heterocycloalkyl," "3- to 7-membered heterocycloalkyl," "3- to 6-membered heterocycloalkyl," and "4- to 6-membered heterocycloalkyl" contain 3 to 10, 4 to 10, 3 to 7, 3 to 6, and 4 to 6 carbon atoms, respectively. Examples of saturated heterocycloalkyl groups include, but are not limited to:

Examples of suitable partially unsaturated heterocycloalkyl groups include, but are not limited to:

As used herein, the term "aryl" refers to a group derived from an aromatic hydrocarbon, which, in certain embodiments, contains 6 to 10 carbon atoms. The term " _C6 - _C10 aryl" contains 5 to 10 carbon atoms. Examples of such groups include, but are not limited to, phenyl and naphthyl. The term "aryl" also includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Examples include, but are not limited to, 1-naphthyl, 2-naphthyl, 1-anthryl, and 2-anthryl. The term "aryl," as used herein, also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as dihydroindanyl, phenanthridinyl, or tetrahydronaphthyl, wherein the linking group or point of attachment is located on the aromatic ring.

As used herein, the term "heteroaryl" refers to an aromatic monocyclic or bicyclic heterocyclic radical having a total of 5 to 12 atoms in the ring and containing 2 to 9 carbon atoms and 1 to 4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, provided that the ring of the radical does not contain two adjacent oxygen atoms or two adjacent sulfur atoms. The terms "5-membered heteroaryl", "6-membered heteroaryl", "5- to 10-membered heteroaryl", "5- to 12-membered heteroaryl", "5- to 6-membered heteroaryl", "4- to 6-membered heteroaryl", and "3- to 5-membered heteroaryl" contain 5, 6, 5 to 10, 5 to 12 ring atoms, 5 to 6, 4 to 6 ring atoms, and 3 to 5 ring atoms, respectively. Heteroaryl includes benzo-fused ring systems. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, furazanyl, thiadiazolyl, thiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, furo[3,2- b ]pyridinyl, benzothiazolyl, benzofurazanyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, phthalazinyl, pyrido[3,4- d ]pyrimidinyl, pteridinyl, and the like.

As used herein, the term "5- to 12-membered heteroaryl" also includes within its scope benzo-fused unsaturated nitrogen heterocycles, which refers to heterocyclic groups in which a heteroatom ring is fused to one or more aromatic rings. Examples include, but are not limited to, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

Unless otherwise indicated, as used herein, the terms "treat" and "treating" mean reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such terms apply, or one or more symptoms of such disorder or condition. Unless otherwise indicated, as used herein, the terms "treatment" and "treating" refer to the act of treating, as "treating" is defined immediately above.

As used herein, an "effective" amount refers to an amount of a substance, agent, compound, or composition, alone or in combination with other agents or substances, that is sufficient to reduce the severity of disease symptoms, increase the frequency and duration of disease-free periods, or prevent damage or disability caused by disease, either as a single dose or according to a multiple dose regimen. One of ordinary skill in the art will be able to determine such an amount based on factors such as the size of the subject, the severity of the subject's symptoms, and the specific composition or route of administration selected. The subject can be a human or non-human mammal (e.g., rabbit, rat, mouse, monkey, or other lower primate).

The embodiments disclosed herein include isotopically labeled compounds that are equivalent to those described in Formula (I), (II), (III), (IV), (IVa), or (IVb), but in which one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the embodiments disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively. Compounds described herein and pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present embodiments. Some isotope-labeled compounds of the embodiments disclosed herein, for example, those incorporating radioisotopes (such as ³ H and ¹⁴ C), can be used in drug and/or substrate tissue distribution assays. Tritiation (i.e. ³ H) and carbon-14 (i.e. ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (i.e. ² H) can obtain certain therapeutic advantages due to greater metabolic stability, such as extended half-life in vivo or reduced dosage requirements, and therefore can be preferred in some cases. The isotope-labeled compounds of the embodiments disclosed herein can generally be prepared by implementing the procedures disclosed in the following schemes and/or Examples and Preparation Examples, by replacing unisotopically labeled reagents with readily available isotope-labeled reagents.

Some embodiments relate to pharmaceutically acceptable salts of the compounds described herein.Pharmaceutically acceptable salts of the compounds described herein include acid addition salts and base addition salts thereof.

Some embodiments also relate to pharmaceutically acceptable acid addition salts of the compounds described herein. Suitable acid addition salts are formed from acids that form non-toxic salts. Non-limiting examples of suitable acid addition salts (i.e., salts containing pharmacologically acceptable anions) include, but are not limited to, acetate, acid citrate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, bitartrate, borate, camphorsulfonate, citrate, cyclamates, edisylate, ethanesulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzoate, hydrochloride/chloride. [0014] The present invention also includes but is not limited to the following salts: benzoate, benzophenone, benzophenone, benzoic acid salt ...

Other embodiments relate to base addition salts of the compounds described herein. Suitable base addition salts are formed from bases that form non-toxic salts. Non-limiting examples of suitable base salts include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

The compounds described herein that are basic in nature are capable of forming a variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds described herein are those that form non-toxic acid addition salts, for example, salts containing pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, malate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts. Compounds described herein that include a basic moiety, such as an amino group, can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above.

Chemical bases useful as reagents for preparing pharmaceutically acceptable base salts of compounds described herein that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts (e.g., N-methylglucamine (meglumine)), and lower alkanolammonium, and other base salts of pharmaceutically acceptable organic amines.

The compounds of the embodiments described herein include all stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the compounds described herein, as well as racemic mixtures, diastereomeric mixtures, and other mixtures of such isomers. Although all stereoisomers are included within the scope of the claims, those skilled in the art will recognize that specific stereoisomers may be preferred.

In some embodiments, the compounds described herein can exist in several tautomeric forms, including enol and imine forms, and keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of this embodiment. Tautomers exist as mixtures of tautomer sets in solution. In solid form, one tautomer is typically predominant. Even if one tautomer can be described, this embodiment includes all tautomers of the compound.

This embodiment also includes atropisomers of the compounds described herein.Atropisomers are compounds that can be separated into isomers with restricted rotation.

Hemisalts of acids and bases can also be formed, for example hemisulphate and hemicalcium salts.

For a review of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

The term "solvate" is used herein to describe a molecular complex comprising a compound described herein and one or more pharmaceutically acceptable solvent molecules (eg, ethanol).

The compounds described herein can also exist in unsolvated and solvated forms. Accordingly, some embodiments relate to hydrates and solvates of the compounds described herein.

Compounds described herein containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. When compounds described herein contain alkenyl or alkenylene, geometric cis/trans (or Z/E) isomers are possible. When structural isomers can be mutually converted via a low energy barrier, tautomerism ("tautomerism") can occur. This can take the form of proton tautomerism in compounds described herein containing, for example, imino, keto or oxime groups, or can take the form of so-called valence tautomerism in compounds containing aromatic moieties. A single compound can exhibit more than one isomeric type.

Included within the scope of this embodiment are all stereoisomers, geometric isomers, and tautomeric forms of the compounds described herein, including compounds exhibiting more than one isomeric type, and mixtures of one or more thereof. Also included are acid addition salts or base salts in which the counterion is optically active, such as d-lactate or l-lysine, or racemic, such as dl-tartrate or dl-arginine.

Cis/trans isomers may be separated by conventional fractionation techniques well known to those skilled in the art, such as chromatography and crystallization.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC) or SFC.

Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound (e.g., an alcohol, or, in the case of compounds described herein containing an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid). The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization, and one or both of the diastereomers converted to the corresponding pure enantiomer by means well known to those skilled in the art.

Unless otherwise indicated, as used herein, "abnormal cell growth" refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the following abnormal growth: (1) tumor cells (tumors) that proliferate by expressing mutant tyrosine kinases or overexpressing receptor tyrosine kinases; (2) benign and malignant cells of other proliferative diseases with abnormal tyrosine kinase activation; (3) any tumor that proliferates through receptor tyrosine kinases; (4) any tumor that proliferates through abnormal serine/threonine kinase activation; (5) benign and malignant cells of other proliferative diseases with abnormal serine/threonine kinase activation; (6) any tumor that proliferates through abnormal signaling, metabolic, epigenetic, and transcriptional mechanisms; and (7) benign and malignant cells of other proliferative diseases with abnormal signaling, metabolic, epigenetic, and transcriptional mechanisms.

Other embodiments are directed to methods of treating abnormal cell growth in a mammal.Other embodiments are directed to methods of treating abnormal cell growth in a mammal comprising administering to the mammal an amount of a compound described herein effective to treat the abnormal cell growth.

In other embodiments, the abnormal cell growth is cancer.

In some embodiments, the cancer is selected from the group consisting of lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, liver cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hematological malignancies, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumor, glioblastoma, brain stem glioma, pituitary adenoma, or a combination of two or more of the foregoing cancers.

Other embodiments relate to methods of treating a solid tumor cancer in a mammal.Some embodiments relate to treating a solid tumor cancer in a mammal comprising administering to the mammal an amount of a compound described herein effective to treat the solid tumor cancer.

In other embodiments, the solid tumor cancer is a breast, lung, colon, brain, prostate, stomach, pancreas, ovary, skin (melanoma), endocrine, uterine, testicular, or bladder solid tumor.

Other embodiments are directed to a method of treating abnormal cell growth in a mammal comprising administering to the mammal an amount of a compound as described herein in combination with an anti-tumor agent selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, anti-hormones, and anti-androgens, in an amount effective to treat the abnormal cell growth.

Further embodiments are directed to pharmaceutical compositions for treating abnormal cell growth in a mammal, comprising an amount of a compound described herein effective to treat the abnormal cell growth and a pharmaceutically acceptable carrier.

Other embodiments relate to methods of treating abnormal cell growth in a mammal, including a human, comprising administering to the mammal an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, effective to treat the abnormal cell growth. In one embodiment of the method, the abnormal cell growth is cancer, including but not limited to lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, or one or more combinations of the foregoing cancers. In one embodiment, the method comprises administering to a mammal an amount of a compound described herein effective to treat the cancer solid tumor. In a preferred embodiment, the solid tumor is breast, lung, colon, brain, prostate, stomach, pancreas, ovary, skin (melanoma), endocrine, uterine, testicular, and bladder cancer.

In another embodiment of the method, the abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy, or restenosis.

Some embodiments relate to a method of treating abnormal cell growth in a mammal comprising administering to the mammal an amount effective to treat the abnormal cell growth of a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with an anti-tumor agent selected from the group consisting of: a mitotic inhibitor, an alkylating agent, an antimetabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an antibody, a cytotoxic agent, an anti-hormone, and an anti-androgen.

Other embodiments relate to pharmaceutical compositions for treating abnormal cell growth in mammals, including humans, comprising an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, effective for treating abnormal cell growth, and a pharmaceutically acceptable carrier. In one embodiment of the composition, the abnormal cell growth is cancer, including but not limited to lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of the pharmaceutical composition, the abnormal cell growth is a benign proliferative disease, including but not limited to psoriasis, benign prostatic hypertrophy, or restenosis.

Other embodiments relate to a method of treating abnormal cell growth in a mammal, comprising administering to the mammal an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, effective to treat the abnormal cell growth, in combination with another anti-tumor agent selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, anti-hormones, and anti-androgens. Some embodiments contemplate a pharmaceutical composition for treating abnormal cell growth, wherein the composition comprises a compound described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, effective to treat the abnormal cell growth, and another anti-tumor agent selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, anti-hormones, and anti-androgens.

Yet further embodiments relate to methods of treating angiogenesis-related disorders in mammals, including humans, comprising administering to the mammal a combination of a compound as defined above, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and one or more of the above-listed anti-tumor agents, in an amount effective to treat the disorder. Such conditions include cancerous tumors, such as melanoma; eye conditions, such as age-related macular degeneration, presumed ocular histoplasmosis syndrome, and retinal neovascularization due to proliferative diabetic retinopathy; rheumatoid arthritis; bone loss conditions, such as osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, hypercalcemia due to tumor metastasis to bone, and glucocorticoid therapy-induced osteoporosis; coronary artery restenosis; and certain microbial infections, including infections associated with microbial pathogens selected from adenoviruses, hantaviruses, Borrelia burgdorferi, Yersinia spp., Bordetella pertussis, and Group A Streptococcus.

Some embodiments relate to methods (and pharmaceutical compositions) for treating abnormal cell growth in a mammal, comprising an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with an amount of one or more agents selected from the group consisting of anti-angiogenic agents, signal transduction inhibitors (e.g., by inhibiting intracellular communication of regulatory molecules that govern fundamental processes of cell growth, differentiation, and survival), and anti-proliferative agents, said amounts together being effective to treat the abnormal cell growth.

Anti-angiogenic agents, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in combination with the compounds described herein in the methods and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX ^™ (celecoxib), Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), and Arcoxia (etoricoxib). Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published on August 6, 1998), WO 98/30566 (published on July 16, 1998), European Patent Publication No. 606,046 (published on July 13, 1994), European Patent Publication No. 931,788 (published on July 28, 1999), WO 90/05719 (published on May 31, 1990), WO 99/52910 (published on October 21, 1999), WO 99/52889 (published on October 21, 1999), WO 99/29667 (published June 17, 1999), PCT International Application No. PCT/IB98/01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), UK Patent Application No. 9912961.1 (filed June 3, 1999), U.S. Provisional Application No. 60/148,464 (filed August 12, 1999), U.S. Patent No. 5,863,949 (issued January 26, 1999), U.S. Patent No. 5,861,510 (issued January 19, 1999), and European Patent Publication No. 780,386 (published June 25, 1997), all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 and/or MMP-9 relative to other matrix metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors that can be used in combination with the compounds described herein are AG-3340, RO 32-3555, RS 13-0830, and the following compounds:

3-[[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionic acid;

3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide;

(2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;

4-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide;

3-[[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionic acid;

4-[4-(4-Chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide;

3-[4-(4-Chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid hydroxyamide;

(2R, 3R) 1-[4-(4-Fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;

3-[[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionic acid;

3-[[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionic acid;

3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide;

3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; and

3-[4-(4-Fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid hydroxyamide;

and pharmaceutically acceptable salts and solvates of said compounds.

VEGF inhibitors, such as sutent and axitinib, can also be combined with the compounds described herein. VEGF inhibitors are described, for example, in WO 99/24440 (published May 20, 1999), PCT International Application No. PCT/IB99/00797 (filed May 3, 1999), WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), U.S. Pat. No. 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), U.S. Pat. No. 5,883,113 (issued March 16, 1999), U.S. Pat. No. 5,886,020 (issued March 23, 1999), U.S. Pat. No. 5,792,783 (issued August 11, 1998), U.S. Pat. 6,653,308 (granted November 25, 2003), WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8, 1999), and WO 98/02437 (published January 22, 1998), all of which are incorporated herein by reference in their entirety. Other examples of some specific VEGF inhibitors are IM862 (Cytran Inc., Kirkland, Washington, USA); Avastin (an anti-VEGF monoclonal antibody from Genentech, Inc., South San Francisco, California); and angiozyme (a synthetic ribonuclease from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California)).

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc), and monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron) can be administered in combination with the compounds described herein. Such erbB2 inhibitors include Herceptin, 2C4, and pertuzumab. Such erbB2 inhibitors include those described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), U.S. Patent No. 5,587,458 (issued December 24, 1996), and U.S. Patent No. 5,877,305 (issued March 2, 1999), each of which is incorporated herein by reference in its entirety. ErbB2 receptor inhibitors useful in the embodiments described herein are also described in U.S. Provisional Application No. 60/117,341 (filed on January 27, 1999) and U.S. Provisional Application No. 60/117,346 (filed on January 27, 1999), both of which are incorporated herein by reference in their entireties. Other erbB2 receptor inhibitors include TAK-165 (Takeda) and GW-572016 (Glaxo-Wellcome).

Various other compounds, such as styrene derivatives, have also been shown to have tyrosine kinase inhibitory properties, and some tyrosine kinase inhibitors have been identified as erbB2 receptor inhibitors. Recently, five European patent publications, namely EP 0 566 226 A1 (published October 20, 1993), EP 0 602 851 A1 (published June 22, 1994), EP 0 635 507 A1 (published January 25, 1995), EP 0 635 498 A1 (published January 25, 1995), and EP 0 520 722 A1 (published December 30, 1992), relate to certain bicyclic derivatives, in particular quinazoline derivatives, which have anticancer properties resulting from their tyrosine kinase inhibitory properties. In addition, World Patent Application WO 92/20642 (published on November 26, 1992) relates to certain bi-monocyclic and bicyclic aryl and heteroaryl compounds that are tyrosine kinase inhibitors useful for inhibiting abnormal cell proliferation. World Patent Applications WO 96/16960 (published on June 6, 1996), WO 96/09294 (published on March 6, 1996), WO 97/30034 (published on August 21, 1997), WO 98/02434 (published on January 22, 1998), WO 98/02437 (published on January 22, 1998), and WO 98/02438 (published on January 22, 1998) also relate to substituted bicyclic heteroaromatic derivatives that are tyrosine kinase inhibitors useful for the same purpose. Other patent applications relating to anticancer compounds are World Patent Application WO 00/44728 (published on August 3, 2000), EP 1029853A1 (published on August 23, 2000) and WO 01/98277 (published on December 12, 2001), all of which are incorporated herein by reference in their entirety.

Epidermal growth factor receptor (EGFR) inhibitors can be administered in combination with the compounds of the present invention. Such EGFR inhibitors include gefitinib, erlotinib, icotinib, afatinib, and dacomitinib. Monoclonal antibody inhibitors of EGFR, such as cetuximab, can also be combined with the compounds of the present invention.

Inhibitors of PI3K, such as PI3Kβ inhibitors, may be administered in combination with the compounds of the present invention.

Mammalian target of rapamycin (mTOR) inhibitors can be administered in combination with the compounds of the present invention. Such mTOR inhibitors include rapamycin analogs and ATP-competitive inhibitors.

c-Met inhibitors can be administered in combination with the compounds of the present invention. Such c-Met inhibitors include crizotinib and ARQ-197. Monoclonal antibody inhibitors of c-Met, such as METMab, can also be combined with the compounds of the present invention.

CDK inhibitors can be administered in combination with the compounds of the present invention. Such CDK inhibitors include palbociclib.

MEK inhibitors can be administered in combination with the compounds of the present invention. Such MEK inhibitors include PD-325901.

PARP inhibitors may be administered in combination with the compounds of the present invention.

JAK inhibitors may be administered in combination with the compounds of the present invention.

Antagonists of programmed death 1 (PD-1) may be administered in combination with the compounds of the present invention.

Other antiproliferative agents that can be used with the compounds described herein include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including compounds disclosed and claimed in the following U.S. patent applications: 09/221,946 (filed December 28, 1998); 09/454,058 (filed December 2, 1999); 09/501,163 (filed February 9, 2000); 09/539,930 (filed March 31, 2000); and 09/202,796 (filed May 22, 1997). ; 09/384339 (filed on August 26, 1999); and 09/383755 (filed on August 26, 1999); and compounds disclosed and claimed in the following U.S. provisional patent applications: 60/168207 (filed on November 30, 1999); 60/170119 (filed on December 10, 1999); 60/177718 (filed on January 21, 2000); 60/168217 (filed on November 30, 1999) and 60/200834 (filed on May 1, 2000). The aforementioned patent applications and provisional patent applications are each incorporated herein by reference in their entirety.

The compounds described herein may also be used with other agents useful for treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing anti-tumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents, such as other farnesyl protein transferase inhibitors, such as those described in the references cited in the "Background" section above. Specific CTLA4 antibodies that can be used in this embodiment include those described in U.S. Provisional Application No. 60/113,647 (filed December 23, 1998), which is incorporated herein by reference in its entirety.

The compounds described herein can be administered as a monotherapy or can be combined with one or more other anti-tumor substances, such as those selected from, for example, mitotic inhibitors, such as vinblastine; alkylating agents, such as cisplatin, oxaliplatin, carboplatin, and cyclophosphamide; antimetabolites, such as 5-fluorouracil, capecitabine, cytosine arabinoside, and hydroxyurea, or one of the preferred antimetabolites disclosed, for example, in European Patent Application No. 239362, such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -N-methylamino]-2-thenoyl)-L-glutamate; growth factor inhibitors; cell cycle inhibitors; intercalating antibiotics, for example, adriamycin and bleomycin; enzymes, for example, interferons; and antihormones, for example, antiestrogens, such as Nolvadex (tamoxifen); or, for example, antiandrogens, such as Casodex (4'-cyano-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide).

The compounds described herein can be used alone or in combination with one or more of a variety of anticancer agents or supportive care agents. For example, the compounds described herein can be used with a cytotoxic agent, such as one or more selected from the group consisting of camptothecin, irinotecan hydrochloride (Camptosar), edotecarin, SU-11248, epirubicin (Ellence), docetaxel (Taxotere), paclitaxel, rituximab (Rituxan), bevacizumab (Avastin), imatinib mesylate (Gleevac), Erbitux, gefitinib (Iressa), and combinations thereof. Some embodiments also encompass the use of the compounds described herein with hormone therapy, such as exemestane (Aromasin), Lupron, anastrozole (Arimidex), tamoxifen citrate (Nolvadex), Trelstar, and combinations thereof. In addition, some embodiments provide for the compounds described herein, alone or in combination with one or more supportive care products, such as a product selected from the group consisting of: filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or a combination thereof. Such combination therapy can be achieved by administering the individual therapeutic components simultaneously, sequentially, or separately.

The compounds described herein can be used with: antineoplastic agents, alkylating agents, antimetabolites, antibiotics, plant-derived antineoplastic agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and/or biological response modifiers. In this regard, the following is a non-limiting list of examples of second agents that can be used with the compounds described herein.

Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, dibromomannitol, carboquinone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum coordination alkylating compounds include, but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin, or satrplatin.

Antimetabolites include, but are not limited to, methotrexate, 6-mercaptopurine nucleoside, mercaptopurine, 5-fluorouracil (5-FU), either alone or in combination with folinic acid, flurbiprofen, UFT, deoxyfluridine, carmofur, cytarabine, cytarabine octadecyl phosphate, enocitabine, S-1, gemcitabine, fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytosine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, noratript, ocfosfate, pemetrexed disodium, premetrexed), pentostatin, pelitrexol, raltitrexed, terepin, trimesate, vidarabine, vincristine, vinorelbine; or one of the preferred antimetabolites disclosed, for example, in European Patent Application No. 239362, such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid.

Antibiotics include, but are not limited to, aclarubicin, actinomycin D, amrubicin, annamycin, bleomycin, daunomycin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neoantigen, peplomycin, pirarubicin, photinib, stimalamer, streptozotocin, valrubicin, or zenastatin.

Hormonal therapies, e.g., exemestane (Aromasin), Lupron, anastrozole (Arimidex), doxercalciferol, fadrozole, formestane; antiestrogens, such as tamoxifen citrate (Nolvadex) and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara), or antiandrogens, such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex® (4'-cyano-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide), and combinations thereof.

Antitumor substances derived from plants include, for example, those selected from mitotic inhibitors such as vinblastine, docetaxel (Taxotere) and paclitaxel.

Cytotoxic topoisomerase inhibitors include one or more agents selected from the group consisting of aclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan hydrochloride (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan, and combinations thereof.

Immunological drugs include interferon and many other immune enhancers. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a or interferon gamma-n1. Other agents include PF3512676, filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, and imiquimod. iquimod), lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab, Provenge.

Biological response modifiers (BRMs) are agents that regulate the defense mechanisms or biological responses of living organisms (such as the survival, growth, or differentiation of tissue cells) to induce them to have anti-tumor activity. Such agents include Coriolus versicolor polysaccharide, Lentinan, Cisoflavone, picibanil, and Ubenimex.

Other anticancer agents include alitretinoin, ampligen, atrasentan bexarotene, bortezomib, bosentan, calcitriol, exisulind, finasteride, fotemustine, ibandronic acid, miltefosine, mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, TLK-286, Velcade, Tarceva, or tretinoin.

Other anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revlimid, squalamine, ukrain, and Vitaxin.

Platinum coordination compounds include, but are not limited to, cisplatin, carboplatin, nedaplatin, or oxaliplatin.

Camptothecin derivatives include, but are not limited to, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, and topotecan.

Tyrosine kinase inhibitors include, for example, Iressa and SU5416.

Antibodies include, for example, Herceptin, Erbitux, Avastin, and Rituximab.

Interferons include, for example, interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, and interferon gamma-n1.

Biological response modifiers include agents that regulate the defense mechanisms or biological responses of living organisms (such as the survival, growth or differentiation of tissue cells) to induce them to have anti-tumor activity. Such agents include, for example, Coriolus versicolor polysaccharide, Lentinan, Cisoflavone, picibanil and Ubenimex.

Other anti-tumor agents include, for example, mitoxantrone, 1-asparaginase, procarbazine, dacarbazine, hydroxyurea, pentostatin, and tretinoin. Additionally, PI3K inhibitors and RAS-targeted cancer therapies can be combined with the compounds described herein.

Some embodiments also relate to pharmaceutical compositions comprising a compound of Formula (I) (I), (II) (III), (IV) (IVa) (IVb) or (IVb) as defined above, or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

Other embodiments relate to pharmaceutical compositions comprising a mixture of a compound of Formula (I) (I), (I), (III), (IV), (IVa) (IVb) or (IVb) as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

For the above therapeutic uses, the dosage administered will of course vary with the compound employed, the mode of administration, the desired treatment and the condition indicated. The daily dose of a compound of Formula (I)-(II)-(III)-(IV)-(IVa)-(IVb) or a pharmaceutically acceptable salt thereof may be in the range of 1 milligram to 1 gram, preferably in the range of 1 mg to 250 mg, more preferably in the range of 10 mg to 100 mg.

This embodiment also encompasses sustained release compositions.

Administration of the compounds described herein (hereinafter referred to as "active compounds") can be achieved by any method capable of delivering the compound to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.

The active compound may be administered as a monotherapy or may be combined with one or more other antitumor substances, for example, those selected from, for example, mitotic inhibitors such as vinblastine; alkylating agents such as cisplatin, oxaliplatin, carboplatin and cyclophosphamide; antimetabolites such as 5-fluorouracil, capecitabine, cytosine arabinoside and hydroxyurea, or one of the preferred antimetabolites disclosed in, for example, European Patent Application No. 239362, such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinoline]-3-yl)-1,2-dihydro-1,2-dihydro-2-methyl ... [00155] In some embodiments, the present invention provides an anti-steroid agent, for example, an anti-steroid agent (e.g., an anti-steroid agent such as Casodex® (4'-cyano-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide). Such combination therapy may be achieved by simultaneous, sequential or separate administration of the individual components of the treatment.

The pharmaceutical composition may be in a form suitable for oral administration (as a tablet, capsule, pill, powder, sustained release formulation, solution or suspension); in a form suitable for parenteral injection (as a sterile solution, suspension or emulsion); in a form suitable for topical administration (as an ointment or cream), or in a form suitable for rectal administration (as a suppository). The pharmaceutical composition may be in a unit dosage form suitable for single administration of a precise dose. The pharmaceutical composition will include conventional pharmaceutical carriers or excipients and the compound described herein as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions, such as aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if necessary.

Suitable pharmaceutical carriers include inert diluents or fillers, water, and various organic solvents. If necessary, the pharmaceutical composition may contain other ingredients, such as flavorings, binders, excipients, etc. Therefore, for oral administration, tablets containing various excipients (such as citric acid) can be used together with various disintegrants (such as starch, alginic acid, and certain complex silicates) and binders (such as sucrose, gelatin, and gum arabic). In addition, lubricants (such as magnesium stearate, sodium lauryl sulfate, and talc) are often used for tableting purposes. Similar types of solid compositions can also be used in soft and hard-filled gelatin capsules. Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycol. When an aqueous suspension or elixir is desired for oral administration, the active compound therein can be combined with various sweeteners or flavorings, coloring matter or dye, and, if necessary, an emulsifier or suspending agent, as well as a diluent (such as water, ethanol, propylene glycol, glycerol, or a combination thereof).

The examples and preparations provided below further illustrate and exemplify the compounds described herein and methods for preparing such compounds. The scope of the embodiments described herein is in no way limited by the following examples and preparations. In the following examples, unless otherwise stated, molecules with a single chiral center exist as a racemic mixture. Unless otherwise stated, those molecules with two or more chiral centers exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers can be obtained by methods known to those skilled in the art.

In the illustrated embodiment, during the chromatographic purification based on HPLC, salt forms are occasionally isolated due to mobile phase additives. In these cases, salts such as formates, trifluoroacetates and acetates are isolated and tested without further processing. It should be recognized that those of ordinary skill in the art can obtain free alkali by standard methods (such as using ion exchange columns, or using gentle aqueous bases to carry out simple alkaline extraction).

In general, the compounds described herein can be prepared by methods known in the art of chemistry, especially in light of the description contained herein. Certain methods for preparing the compounds described herein are provided as additional features of the embodiments and are exemplified in the reaction schemes provided below and in the experimental section.

Unless otherwise indicated, the variables in Schemes A to H have the same meanings as defined herein.

Option A:

As exemplified in Scheme A, monoester monoacid A-1 (which can be obtained from commercial sources or from selective ester hydrolysis or desymmetrization of a symmetrical anhydride under standard literature conditions (see, for example, J. Am. Chem. Soc ., 2000, 122 , 9542 and Helv. Chim. Acta ., 1983, 66 , 2501) undergoes selective reduction of the carboxylic acid moiety using a reducing agent such as borane dimethyl sulfide to provide A-2. The alcohol in A-2 can be halogenated using reagents such as iodine/triphenylphosphine in the presence of a base such as imidazole or carbon tetrabromide to form an alkyl halide such as iodide or bromide to provide A-3. The coupling partner A-5 is obtained by acylation of a commercially available 2-amino-6-halogenated heterocycle A-1 with an acid in the presence of a standard coupling reagent such as HATU or HBTU in the presence of a base such as Hunig's base or triethylamine. 4. The reaction between A-5 and A-3 occurs via a palladium-mediated process such as the Negishi reaction. For example, the halogenated compound A-3 can be activated to an organometallic substance such as an organozincate by treating it with a substance such as zinc powder in the presence of an activator such as 1,2-dibromoethane and TMSCl in a solvent such as DMF, or without activation using diethylzinc for the metalation process. The resulting zincate can be catalyzed by a palladium catalyst such as Pd in the presence of a suitable ligand such as tri(o-tolylphosphine) in a solvent such as DMF. ₂ (dba) ₃ is coupled with a halogenated heterocycle A-5 by a Negishi reaction to obtain A-6. The ester in A-6 is hydrolyzed by an inorganic base such as lithium hydroxide or sodium hydroxide in a solvent such as methanol and water to obtain a carboxylic acid A-7. Condensation of A-7 with thiosemicarbazide in the presence of phosphorus oxychloride as an activator and dehydrating agent provides aminothiadiazole A-8. A-9 is obtained by reaction with an acyl chloride or by acylation of A-8 with a suitable amide coupling agent (such as T3P, HATU or HBTU) and a suitable carboxylic acid in the presence of a base such as pyridine, TEA or Hunig's base in a solvent such as DMF or DMA. Separation of enantiomers can be carried out under standard methods known in the art such as chiral SFC or HPLC to obtain a single enantiomer A-9.

Option B:

As illustrated in Scheme B, diacid B-1 can be obtained from commercial sources, or prepared by the method established in the literature or reported herein. The condensation of B-1 with thiosemicarbazide in the presence of phosphorus oxychloride as an activator and dehydrating agent provides bis-aminothiadiazole B-2. By reacting with acyl chlorides or by using a suitable amide coupling agent (such as T3P, HATU or HBTU) and a suitable carboxylic acid to acylate B-2 in the presence of a base such as pyridine, TEA or Hunig's base in a solvent such as DMF or DMA, symmetrically substituted bis-aminothiadiazole B-3 is obtained. The separation of enantiomers can be implemented under standard methods known in the art such as chiral SFC or HPLC to obtain a single enantiomer of B-3.

Option C:

As exemplified in Scheme C, the monoester monoacid (A-1 in Scheme A) is converted to the mono-thiadiazole under standard conditions known in the art (such as condensation with thiosemicarbazide in the presence of an activating/dehydrating agent such as phosphorus oxychloride) to provide C-1. Acylation of C-1 is carried out under standard conditions (such as condensation with acetyl chloride or acetic anhydride in the presence of a base such as triethylamine in a solvent such as DMF) to give C-2. Ester hydrolysis of C-2 is carried out under basic conditions using a base such as NaOH or LiOH in a solvent such as methanol to give C-3. Condensation of C-3 with hydrazine in the presence of a suitable coupling agent (such as T3P, HBTU or HATU) and a base (such as pyridine, TEA or DIPEA) in a suitable solvent such as DMF gives C-4. Reaction of C-4 with an isothiocyanate in a suitable solvent such as ethyl acetate, THF or dichloromethane gives C-5. Isothiocyanates are commercially available or can be prepared by direct reaction of acyl chlorides with sodium isothiocyanate under conditions well established in the literature. C-5 is cyclized by dehydration under acidic conditions in the presence of a suitable acid such as sulfuric acid to obtain C-8. Alternatively, C-3 is condensed with thiosemicarbazide in the presence of a suitable coupling agent (such as HBTU or HATU) and a base (such as TEA or DIPEA) in a suitable solvent such as DMF to obtain C-6. C-6 is cyclized by dehydration under acidic conditions in the presence of a suitable acid such as sulfuric acid to obtain C-7. C-8 is obtained by reaction with an acyl chloride or by acylation of C-7 with a suitable amide coupling agent (such as T3P, HATU or HBTU) and an appropriate carboxylic acid in the presence of a base such as pyridine, TEA or Hunig's base in a solvent such as DMF or DMA. Separation of enantiomers can be carried out under standard methods known in the art such as chiral SFC or HPLC to obtain a single enantiomer C-8.

Plan D:

As exemplified in Scheme D, the monoester monoacid (A-1 in Scheme A) is converted to the mono-thiadiazole under standard conditions known in the art (such as condensation with thiosemicarbazide in the presence of an activating/dehydrating agent such as phosphorus oxychloride) to provide D-1. D-2 is obtained by reaction with an acyl chloride or by acylation of D-1 using a suitable amide coupling agent (such as T3P, HATU or HBTU) and an appropriate carboxylic acid in the presence of a base such as pyridine, TEA or Hunig's base in a solvent such as DMF or DMA. Ester hydrolysis of D-2 is carried out under basic conditions using a base such as NaOH or LiOH in a solvent such as methanol to give D-3. D-3 is condensed with thiosemicarbazide in the presence of a suitable coupling agent (such as T3P, HBTU or HATU) and a base (such as pyridine, TEA or Hunig's base) in a suitable solvent such as DMF to give D-4. D-4 is cyclized by dehydration under acidic conditions in the presence of a suitable acid such as sulfuric acid to give D-5. Acylation of D-5 is carried out under standard conditions using an acylating agent such as acetic anhydride in a solvent such as acetic acid to give D-6. Separation of enantiomers can be carried out under standard methods known in the art such as chiral SFC or HPLC to give single enantiomer D-6.

Plan E:

As exemplified in Scheme E, cyclic keto-acid E-1 can be obtained from commercial sources or prepared by methods established in the literature or reported herein. Reaction of the ketone functionality with an organophosphorane in a Horner-Wittig-Emmons reaction in the presence of a base such as sodium hydride in a solvent such as THF affords the unsaturated ester E-2. Reduction of the olefin under hydrogen pressure in the presence of a heterogeneous catalyst such as palladium on carbon or platinum oxide in a solvent such as methanol or dichloromethane affords E-3 as a mixture of diastereomers, with reduction from the less hindered face being preferred. Condensation of E-3 with thiosemicarbazide in the presence of phosphorus oxychloride as an activator and dehydrating agent provides the bis-aminothiadiazole E-4. Acylation of E-4 using a suitable amide coupling agent (such as T3P, HATU or HBTU) and an appropriate carboxylic acid in the presence of a base such as pyridine, TEA or Hunig's base in a solvent such as DMF or DMA affords the symmetrically substituted bis-aminothiadiazole E-5. Separation of diastereomers and enantiomers can be carried out by standard methods known in the art such as flash chromatography, chiral SFC or HPLC to give single diastereomer or enantiomer E-5.

Plan F:

As illustrated in Scheme F, monoester monoacid A-1 is condensed with alkyl or aryl substituted thiosemicarbazide F-2 in the presence of phosphorus oxychloride as an activator and dehydrating agent to provide alkyl or aryl substituted aminothiadiazole F-3. Alkyl substituted thiosemicarbazide F-2 is obtained from commercial sources or by the effect of hydrazine on commercial alkyl or aryl isothiocyanate F-1 or by using a well-established alternative method in the literature ( Phosphorus, Sulfur, and Silicon and the Related Elements, 1991, 60 (1-2), 15-19) to obtain. Hydrolysis of ester F-3 using an inorganic base such as lithium hydroxide or sodium hydroxide in a solvent such as methanol and water gives carboxylic acid F-4. Condensation of F-4 with thiosemicarbazide in the presence of phosphorus oxychloride as an activator and dehydrating agent provides bis-aminothiadiazole E-5. Acylation of F-5 with a suitable amide coupling agent (such as T3P, HATU or HBTU) and an appropriate carboxylic acid in the presence of a base such as pyridine, TEA or Hunig's base in a solvent such as DMF or DMA affords the symmetrically substituted bis-aminothiadiazole F-6. Enantiomer separation can be performed under standard methods known in the art such as chiral SFC or HPLC to afford single enantiomers of F-6.

Plan G:

As illustrated in Scheme G, diacid B-1 can be obtained from commercial sources or prepared by methods established in the literature or reported herein. B-1 can be converted to dihalide G-1 via a decarboxylation-halogenation sequence commonly known as the Hunsdiecker reaction, which can occur photochemically in the presence of a suitable halogen source such as diiodohydantoin in a solvent such as 1,2-dichloroethane. Coupling partner A-5 is obtained by acylation of commercially available 2-amino-6-halogenated heterocycle A-4 with an acid in the presence of a standard coupling reagent such as T3P, HATU, or HBTU in the presence of a base such as pyridine, Hunig's base, or TEA. The reaction between A-5 and B-1 occurs via a palladium-mediated process such as the Negishi reaction. For example, di-halogenated compound B-1 can be activated to an organometallic species such as an organozincate by treatment with a species such as zinc powder in the presence of an activating agent such as 1,2-dibromoethane and TMS-Cl in a solvent such as DMF, or without activation using diethylzinc for the metalation process. The obtained zincate can be coupled with a halogenated heterocycle A-5 by a Negishi reaction using a palladium catalyst such as _Pd2 (dba) ₃ in the presence of a suitable ligand such as tri(o-tolylphosphine) in a solvent such as DMF to afford G-2. If necessary, separation of the enantiomers of G-2 can be carried out by standard methods known in the art such as chiral SFC or HPLC to afford a single enantiomer of G-2.

Plan H:

As illustrated in Scheme H, coupling partner A-5 is obtained by acylation of commercially available 2-amino-6-halogenated heterocycle A-4 with an acid in the presence of a standard coupling reagent such as T3P, HATU, or HBTU in the presence of a base such as pyridine, Hunig's base, or TEA. Boronic acid vinyl ester H-1 can be obtained from an established literature procedure involving borylation of the corresponding halogenated α,β-unsaturated cyclic ketone (US 2012/0077814) . The reaction between A-5 and H-1 occurs via a palladium-mediated process such as the Suzuki reaction to provide H-2. For example, A-5 and H-1 can be reacted together at elevated temperature in a mixed solvent system consisting of an organic solvent (e.g., THF, DME, or toluene) and water in the presence of a palladium catalyst such as Pd(dppf) _Cl2 and a suitable base such as _K3PO4 or _CsF . The reduction of the endocyclic olefin of H-2 in the presence of heterogeneous catalysts such as carbon-supported palladium or platinum oxide under hydrogen pressure in solvents such as methanol or dichloromethane gives H-3. H-3 can be finely converted to H-4 by Horner-Wittig-Emmons type olefination, which involves treating with a phosphonate reagent such as diethyl (cyanomethyl)phosphonate in the presence of a strong base such as NaH in a suitable solvent (e.g., THF). The reduction of the exocyclic olefin of H-4 to give H-5 can be achieved by utilizing a hydride-based reagent. For example, lithium tri-sec-butyl borohydride (L-Selectride) can be used as a reducing agent in solvents such as THF at low temperatures to provide H-5 as a mixture of diastereomers. The condensation of H-5 with thiosemicarbazide at high temperatures in the presence of an acid such as TFA provides aminothiadiazole H-6. H-7 is obtained by reaction with an acid chloride or by acylation of H-6 using a suitable amide coupling agent (such as T3P, HATU or HBTU) and an appropriate carboxylic acid in the presence of a base such as pyridine, TEA or Hunig's base in a solvent such as DMF or DMA. Separation of diastereomers and enantiomers can be performed under standard methods known in the art such as chiral SFC or HPLC to obtain a single enantiomer of H-7.

For some steps of the methods for preparing the compounds of the present invention described herein, it is necessary to protect potential reactive functional groups that are not desired to react, and thus to cleave the protecting groups. In such cases, any compatible protecting group may be used. Specifically, protection and deprotection methods such as those described by TW Greene ( Protective Groups in Organic Synthesis , A. Wiley-Interscience Publication, 1981) or PJ Kocienski ( Protecting groups , Georg Thieme Verlag, 1994) may be used.

All of the above reactions and preparations of novel starting materials used in the aforementioned methods are conventional and appropriate reagents and reaction conditions for their performance or preparation, and the procedures for isolating the desired products will be well known to those skilled in the art by reference to literature precedents and the Examples and Preparations thereof.

Example 1 (Scheme A): 2-phenyl- N- (6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3, Preparation of 4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)acetamide

Step 1: Preparation of methyl (cis)-3-(hydroxymethyl)cyclopentanecarboxylate

To a solution of (cis)-3-(methoxycarbonyl)cyclopentanecarboxylic acid (2.7 g, 15.7 mmol) in THF (42 mL) was added borane dimethyl sulfide complex (2.5 mL, 26 mmol) dropwise at -78°C. The reaction mixture was warmed to 0°C and stirred at this temperature for 1 hour. The reaction was stirred at room temperature for 3 hours, cooled back to -20°C and quenched with 1 M KH ₂ PO _4. The resulting reaction mixture was warmed to room temperature, stirred for 20 minutes, and extracted with Et ₂ O (3 x 100 mL). The combined organics were then washed with brine, dried over Na ₂ SO ₄ , and concentrated to give the title compound (2.3 g, 55%) as a clear oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.68 (s, 3 H), 3.59 (dd, J = 6.5, 2.1 Hz, 2H), 2.81 (quin, J = 8.2 Hz, 1 H), 2.13 – 2.26 (m, 1 H), 2.02 – 2.13 (m, 1 H), 1.84 – 1.96 (m, 2 H), 1.72 – 1.84 (m, 1 H), 1.44 – 1.58 (m, 2 H). m/z (APCI+)159.2 (M+H) ⁺ for C ₈ H ₁₄ O ₃ .

Step 2: Preparation of methyl (cis)-3-(iodomethyl)cyclopentanecarboxylate

To a mixture of PPh ₃ (1.0 g, 3.74 mmol) and imidazole (255 mg, 3.74 mmol) in CH ₂ Cl ₂ (14 mL) was added I ₂ (954 mg, 3.74 mmol) in batches at room temperature. The resulting orange suspension was slowly treated with a solution of (cis)-3-(hydroxymethyl)cyclopentanecarboxylic acid methyl ester (538 mg, 3.4 mmol) in CH ₂ Cl ₂ (4 mL) and stirred at room temperature for 14 hours. The reaction mixture was then washed with a Na ₂ S ₂ O ₃ aqueous solution and extracted with CH ₂ Cl _2. The combined organics were dried over Na ₂ SO ₄ and evaporated to obtain the crude title compound. The crude residue was diluted with heptanes and solid filtered to remove triphenylphosphine oxide. The filtrate was evaporated to give a clear oil which was then purified by flash chromatography using a gradient of 0% to 15% CH2Cl2 /heptanes to give methyl (cis)-3-(iodomethyl)cyclopentanecarboxylate ₍ 718 mg, 79 % ₎ as a clear oil. ^1H NMR (400 MHz, CDCl3) δ ppm 3.69 (s, _3H ), 3.23 (d, J = 6.80 Hz, 2H), 2.81-2.92 (m, 1H), 2.16-2.33 (m, 2H), 1.86-2.02 (m, 3H), 1.51-1.55 (m, 1H), 1.38-1.49 (m, 1H).

Step 3: Preparation of N- (6-iodopyridazin-3-yl)-2-phenylacetamide

To a solution of 5-iodopyridazin-3-amine (1.3 g, 5.7 mmol) in DMF (6.7 mL) was added diisopropylethylamine (1.14 mL, 6.83 mmol) dropwise at 0°C, followed by phenylacetyl chloride (0.9 mL, 6.83 mmol). The reaction mixture was then slowly warmed to room temperature overnight. The resulting solution was diluted with water, filtered, and rinsed with water to give the title compound (1.18 g, 61%) as a brown powder. ^1H NMR (400 MHz, CDCl ₃ ) δ ppm 3.84 (s, 2 H), 7.34 – 7.44 (m, 5 H), 7.82 (d, J = 9.32 Hz, 1 H), 8.25 (d, J = 9.32 Hz, 1 H). m/z (APCI+)340.1 (M+H) ⁺ for C ₁₂ H ₁₀ IN ₃ O.

Step 4: (cis)-3-({6-[(phenyl(phenly)acetyl)amino]pyridazin-3-yl}methyl)cyclopentanecarboxylic acid Preparation of esters

To a suspension of Zn powder (226 mg, 3.45 mmol) in dry, degassed DMF (0.5 mL) under N ₂ was added 1,2-dibromoethane (11 μL, 0.12 mmol). The mixture was then heated with a heat gun for approximately 30 seconds until gas evolution was observed from the solution, indicating activation of Zn. The mixture was cooled to room temperature, followed by the addition of TMSCl (16 μL, 0.13 mmol) and stirred at room temperature for 30 minutes. A solution of (cis)-3-(iodomethyl)cyclopentanecarboxylic acid methyl ester (308 mg, 1.15 mmol) in DMF (1 mL) was added to the Zn solution, and the resulting mixture was stirred at room temperature for 1 hour. After Zn is settled, the reaction mixture is filtered through a syringe filter into a mixture of N- (6-iodopyridazine-3-yl)-2-phenylacetamide (195 mg, 0.58 mmol), _Pd2 (dba) ₃ (105 mg, 0.12 mmol) and tri(o-tolyl)phosphine (70 mg, 0.23 mmol) in DMF (2.3 mL). The reaction mixture is purged with _N2 and stirred at 40°C for 50 minutes. Then, Si-Thiol is added to the warm reaction mixture to remove Pd residues. After 20 minutes at 40°C, the mixture is diluted with EtOAc and filtered out to remove _Si -Thiol. The filtrate is washed twice with water, then washed with brine, and dried over _Na2SO4 . Purification via flash chromatography with a gradient of 0% - 55% EtOAc/heptanes afforded (cis)-3-({6-[(phenylacetyl)amino]pyridazin-3-yl}methyl)cyclopentanecarboxylate (69 mg, 34% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.63 (d, J = 9.3 Hz, 1 H), 7.52 (d, J = 9.3 Hz, 1 H), 7.36 –7.45 (m, 5 H), 3.92 (s, 2 H), 3.68 (s, 3 H), 2.99 (d, J = 7.30 Hz, 2 H), 2.74– 2.87 (m, 1 H), 2.31 – 2.44 (m, 1 H), 2.02 – 2.12 (m, 1 H), 1.86 – 1.99 (m,2 H), 1.73 – 1.85 (m, 1 H), 1.49 – 1.60 (m, 1 H), 1.37 – 1.49 (m, 1 H). m/z (APCI+)354.3 (M+H) ⁺ for C ₂₀ H ₂₃ N ₃ O ₃ .

Step 5: Preparation of (cis)-3-({6-[(phenylacetyl)amino]pyridazin-3-yl}methyl)cyclopentanecarboxylic acid

To a solution of (cis)-3-({6-[(phenylacetyl)amino]pyridazin-3-yl}methyl)cyclopentanecarboxylate (205 mg, 0.58 mmol) in a mixture of MeOH (5 mL), water (1.5 mL), and THF (3 mL) was added LiOH (111 mg, 4.64 mmol) at room temperature. After 1 hour, the reaction mixture was evaporated to remove the solvent and washed with _Et2O . The aqueous layer was then acidified to pH 2 with ₁ N _HCl . The resulting solid was filtered, washed with water, and dried under vacuum to give the title compound (96 mg, 49%) as a _white solid. m/z (APCI+) 340.3 (M+H) ⁺ for _C19H21N3O3 .

Step 6: N- [6-({(cis)-3-[(2-thiocarbamoylhydrazine)carbonyl]cyclopentyl}methyl)pyridazine-3-yl Preparation of 2-phenylacetamide

To a mixture of (cis)-3-({6-[(phenylacetyl)amino]pyridazin-3-yl}methyl)cyclopentanecarboxylic acid (96 mg, 0.28 mmol) and HATU (170 mg, 0.42 mmol) in DMF (1.4 mL) was added _Et3N (79 μL, 0.57 mmol) at room temperature. After 10 minutes, the resulting mixture was treated with thiosemicarbazide (39 mg, 0.42 mmol) at room temperature and stirred for 40 minutes. _The reaction mixture was then evaporated under vacuum to remove DMF. The crude compound was used directly in the next step without further purification. m/z ₍ APCI+) 413.3 (M+H) ⁺ _{for C20H24N6O2S} .

Step 7: N- [6-{[(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)- Preparation of 2-phenylacetamide

N- [6-({(cis)-3-[(2-thiocarbamoylhydrazine)carbonyl]cyclopentyl}methyl)pyridazin-3-yl]-2-phenylacetamide (120 mg, 0.29 mmol) was treated with neat sulfuric acid (0.58 mL) at 0°C. After 30 minutes at 0°C, the reaction mixture was added dropwise to ice-cold aqueous _NaHCO₃ . The resulting mixture was extracted four times _{with CH₂Cl₂} and dried _{over Na₂SO₄} . Purification via flash chromatography using a gradient of 0% _to 10% MeOH/ _CH₂Cl₂ afforded N- [6-{[(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)-2-phenylacetamide (44 mg, 38% yield) as a yellow solid. m/z (APCI+) 395.3 (M+H) ⁺ for C ₂₀ H ₂₂ N ₆ OS.

Step 8: 2-phenyl- N- (6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazole-2-yl)- Preparation of 3-[(1-[(1-methyl}cyclopentyl]methyl}pyridazin-3-yl)acetamide

To a mixture of N- [6-{[(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)-2-phenylacetamide (44 mg, 0.11 mmol) and HATU (54 mg, 0.13 mmol) in DMF (2.2 mL) was added _Et3N (63 μL, 0.45 mmol) at room temperature. The resulting mixture was then treated with 2-pyridylacetic acid hydrochloride (22 mg, 0.12 mmol) and stirred at room temperature for 2 hours. The crude product was purified by reverse phase chromatography eluting with MeCN:water (5:95 to 95:5) to give 2- phenyl -N- (6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)acetamide (18 mg, 30%) as a white solid. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.63 (br s, 1 H), 11.22 (s, 1 H), 8.49 (d, J = 4.78 Hz, 1 H), 8.19 (d, J = 9.06 Hz, 1 H), 7.76 (td, J = 7.68, 1.76 Hz, 1 H), 7.56 (d, J = 9.32 Hz, 1 H), 7.19 – 7.43 (m, 7 H), 3.99 (s, 2 H), 3.76 (s, 2 H), 3.44 –3.55 (m, 1 H), 2.94 (d, J = 7.30 Hz, 2 H), 2.03 – 2.28 (m, 3 H), 1.74 – 1.91 (m, 2 H), 1.42 – 1.60 (m, 2 H). m/z (APCI+)514.1 (M+H) ⁺ for C ₂₇ H ₂₇ N ₇ O ₂ S.

Example 2A (Scheme B): 2-(pyridin-2-yl) -N- (5-{[(1 R ,3 S )-3-{5-[(pyridin-2-ylacetyl) Preparation of [amino]-1,3,4-thiadiazol-2-yl]cyclopentyl]methyl]-1,3,4-thiadiazol-2-yl)acetamide

Step 1: 5-(((1 R, 3 S) -3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-yl Preparation of oxazol-2-amine

To a flask containing (1S , 3R )-3-(carboxymethyl)cyclopentanecarboxylic acid (11.4 g, 66.2 mmol) and ground thiosemicarbazide (13.9 g, 152 mmol), _POCl3 was slowly added dropwise until a slurry formed, followed by the remainder of POCl3 (60.8 mL, 652 mmol in total). The mixture was then stirred at 80°C for 30 minutes, with a strong exotherm observed after the initial heating. The reactants were then cooled to room temperature, followed by the dropwise addition of cold ₃ M NaOH (1.32 L). The formed solid was filtered, rinsed with water, and dried under vacuum overnight. Triturated with EtOH, the mixture was then filtered to give 5-(((1R , 3S ) -3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine (12.25 g, 66%) as a brown solid. (400 MHz, DMSO- d ₆ ) δ ppm 6.97 (s, 4 H), 3.27 – 3.34 (m, 1H), 2.85 (d, J = 7.2 Hz, 2 H), 2.13 – 2.38 (m, 2 H), 1.94 – 2.10 (m, 1 H), 1.72 – 1.89 (m, 2H), 1.32 – 1.52 (m, 2H) ppm. m/z (ESI+)283.17 (M+H) ⁺ for C ₁₀ H ₁₄ N ₆ S ₂ .

Step 2: 2-(pyridin-2-yl) -N- (5-{[(1 R ,3 S )-3-{5-[(pyridin-2-ylacetyl)amino]-1,3, Preparation of 4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide

Pyridine (60 mL, 730 mmol) was added to a mixture of 5-(((1 R, 3 S) -3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine (12.25 g, 43.4 mmol) and 2-pyridylacetic acid hydrochloride (18.8 g, 108 mmol). After stirring for 5 minutes, T3P (72.3 mL, 50% in DMF, 121 mmol) was added. Upon addition, a slight exotherm was observed, accompanied by bubbling. The reaction was stirred for 15 minutes and then checked by LCMS. Monoacylated product was still observed, so additional 2-pyridylacetic acid hydrochloride (5 g, 28.7 mmol), T3P (10 mL, 50% in DMF, 16.7 mmol), and pyridine (20 mL, 243 mmol) were added and the reaction stirred overnight. The reaction was concentrated to remove excess pyridine, and the residue was then added dropwise to water with stirring. After the addition was complete, the mixture was adjusted to pH ~7.5 and the solid was filtered and rinsed with water. The solid was triturated with acetone and filtered to yield 2-(pyridin-2-yl) -N- (5-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide (14.6 g, 65%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.65 (br s,2 H), 8.49 (d, J = 4.77 Hz, 2 H), 7.77 (td, J = 7.6, 1.9 Hz, 2 H), 7.39 (d, J = 7.8 Hz, 2 H), 7.28 (ddd, J = 7.6, 4.9, 1.2 Hz, 2 H), 4.00 (s, 4 H), 3.50 (dt, J = 10.3, 7.7 Hz, 1 H), 3.07 (d, J = 7.3 Hz, 2 H), 2.35 – 2.47 (m, 1 H), 2.29 (dt, J = 13.5, 7.1 Hz, 1 H), 2.12 (dtd, J = 15.9, 8.9, 7.7, 3.8 Hz, 1H), 1.76 – 1.96 (m, 2 H), 1.44 – 1.61 (m, 2 H). m/z (ESI+)521.1 (M+H) ⁺ for C ₂₄ H ₂₄ N ₈ O ₂ S ₂ .

Example 2B: 2-(pyridin-2-yl) -N- (5-{[(1 R ,3 S )-3-{5-[(pyridin-2-ylacetyl)amino]-1, Preparation of 3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide dihydrochloride

2-(Pyridin-2-yl) -N- (5-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentylmethyl}-1,3,4-thiadiazol-2-yl)acetamide (10 g, 19.2 mmol) was stirred in MeOH (100 mL) at room temperature, and then HCl (3.47 mL, 42.3 mmol) was added dropwise. The solution was heated to 65°C for 1 hour. The slurry was allowed to cool to room temperature, and the colorless solid was filtered, rinsed with MeOH, and dried to give 2-(pyridin-2-yl) -N- (5-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide (11.25 g, 98%) as the bis-HCl salt, which was shown to be a monohydrate by CHN analysis. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 13.00 (br s, 2 H), 8.70 – 8.80 (m, 2H), 8.21 – 8.30 (m, 2 H), 7.68 – 7.81 (m, 4 H), 4.28 (s, 4 H), 3.43 – 3.52(m, 1 H), 3.11 – 3.43 (m, 2 H), 2.28 – 2.49 (m, 2 H), 2.12 – 2.17 (m, 1 H), 1.81 – 1.90 (m, 2 H), 1.41 – 1.61 (m, 2 H). m/z (ESI+)521.1 (M+H) ⁺ for C ₂₄ H ₂₄ N ₈ O ₂ S ₂ .

The absolute stereochemistry of the final compounds was determined by treating the racemic (cis)-di-acid through the same chemical sequence as described below.

Step 1: 5-(((cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol- Preparation of 2-amine

Combine cis - 3-(carboxymethyl)cyclopentanecarboxylic acid (12.0 g, 63.89 mmol) and thiosemicarbazide (11.64 g, 127.77 mmol) and add _POCl₃ (80 mL). The reaction mixture is heated at 100°C for 3 hours to give a yellow solution, which is then cooled to room temperature. The crude product is quenched in warm water and basified to pH 7 with NaOH 50%. The resulting solid is filtered, washed thoroughly with water, and dried under vacuum at 60°C to give 5-(((cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine (17.0 g, 86%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.00 (s, 4 H), 3.27 – 3.34 (m, 1 H), 2.85 (d, J = 7.2 Hz, 2H), 2.13 – 2.38 (m, 2 H), 1.94 – 2.10 (m, 1 H), 1.72 – 1.89 (m, 2 H), 1.32 –1.52 (m, 2 H) ppm. m/z (ESI+)283.17 (M+H) ⁺ for C ₁₀ H ₁₄ N ₆ S ₂ .

Step 2: 2-(pyridin-2-yl) -N- (5-{[(1 R ,3 S )-3-{5-[(pyridin-2-ylacetyl)amino]-1,3, Preparation of 4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide (Example 2)

5-(((cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine (273 mg, 0.97 mmol) and 2-pyridineacetic acid hydrochloride (369 mg, 2.13 mmol) were slurried in DMF (3 mL) with HATU (882 mg, 2.32 mmol). DIPEA (0.74 mL, 4.2 mmol) was added, and the resulting yellow solution was stirred at room temperature under nitrogen overnight. Once the reaction was confirmed to be complete, water (20 mL) was added, and the reaction was extracted three times with _{CH2Cl2 :} MeOH (20 mL, 90:10). The combined organics were washed with saturated brine and stripped to give an oil. This was first purified by flash chromatography _eluting with _CH2Cl2 :MeOH (97:3 to 90:10) to give 140 mg of an oily solid, which was then purified by reverse phase chromatography eluting with MeCN:water (5:95 to 95:5) containing 0.1% _NH3 to give racemic Example 3 (47 mg, 9%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.68 (s, 2 H), 8.45 – 8.52(m, 2 H), 7.77 (td, J = 7.6, 1.9 Hz, 2 H), 7.39 (d, J = 7.8 Hz, 2 H), 7.28(ddd, J = 7.6, 4.9, 1.2 Hz, 2 H), 4.00 (s, 4 H), 3.50 (dt, J = 10.3, 7.7 Hz, 1 H), 3.07 (d, J = 7.3 Hz, 2 H), 2.35 – 2.47 (m, 1 H), 2.29 (dt, J = 13.5,7.1 Hz, 1H), 2.12 (dtd, J = 15.9, 8.9, 7.7, 3.8 Hz, 1 H), 1.76 – 1.96 (m, 2H), 1.40 – 1.63 (m, 2 H). m/z (ESI+) of C ₂₄ H ₂₄ N ₈ O ₂ S ₂ is 521.1 (M+H) ⁺ .

19 mg was subjected to chiral separation by SFC to obtain two enantiomers. Analytical chiral separation by SFC was performed using a Chiralcel OJ-H column (4.6 mm x 100 mm column, 3 micron particle size) eluted with 30% MeOH (containing 0.1% DEA) in _CO maintained at 120 bar. A flow rate of 4 mL/min gave Rt _{(peak 1)} = 1.60 minutes and Rt _{(peak 2)} = 1.98 minutes.

Example 4 (peak 1): 2 mg, 99% ee (-). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.68(s, 2H), 8.45 – 8.52 (m, 2 H), 7.77 (td, J = 7.6, 1.9 Hz, 2 H), 7.39 (d, J =7.8 Hz, 2 H), 7.28 (ddd, J = 7.6, 4.9, 1.2 Hz, 2 H), 4.00 (s, 4 H), 3.50 (dt, J = 10.3, 7.7 Hz, 1 H), 3.07 (d, J = 7.3 Hz, 2 H), 2.35 – 2.47 (m, 1 H), 2.29(dt, J = 13.5, 7.1 Hz, 1 H), 2.12 (dtd, J = 15.9, 8.9, 7.7, 3.8 Hz, 1 H), 1.76 – 1.96 (m, 2 H), 1.40 – 1.63 (m, 2 H). m/z (ESI+)521.1 (M+H) ⁺ for C ₂₄ H ₂₄ N ₈ O ₂ S ₂ .

Example 2 (peak 2): 2 mg, ~98% ee (+). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm12.68 (s, 2 H), 8.45 – 8.52 (m, 2 H), 7.77 (td, J = 7.6, 1.9 Hz, 2 H), 7.39 (d, J = 7.8 Hz, 2 H), 7.28 (ddd, J = 7.6, 4.9, 1.2 Hz, 2 H), 4.00 (s, 4 H), 3.50 (dt, J = 10.3, 7.7 Hz, 1 H), 3.07 (d, J = 7.3 Hz, 2 H), 2.35 – 2.47 (m,1 H), 2.29 (dt, J = 13.5, 7.1 Hz, 1H), 2.12 (dtd, J = 15.9, 8.9, 7.7, 3.8Hz, 1H), 1.76 – 1.96 (m, 2H), 1.40 – 1.63 (m, 2H). m/z (ESI+)521.1 (M+H) ⁺ for C ₂₄ H ₂₄ N ₈ O ₂ S ₂ .

Crystals of Example 4 were grown by ether vapor diffusion into an 80/20 dichloromethane/methanol solution and subjected to single crystal X-ray diffraction studies to determine the absolute stereochemistry of the cyclopentane ring junction. Example 4 was shown to be 2-(pyridin-2-yl) -N- (5-{[(1S,3R)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide, thus enabling the designation of Example 2 as 2-(pyridin-2-yl) -N- (5-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide. Furthermore, chiral SFC separation of 5-(((cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine and subsequent derivatization to Example 4 and Example 2 enabled the assignment of the stereochemistry of this intermediate for the preparation of enantiopure analogs.

Example 5 (Scheme B): N- [5-({(1 R , 3 S )-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl] Preparation of cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide

To 5-(((cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine (200 mg, 0.708 mmol) suspended in DMA (2 mL) was added dimethylaminopyridine (173 mg, 1.416 mmol) followed by acetyl chloride (151 µL, 2.124 mmol). The reaction was stirred at room temperature for 16 hours to give a suspension, which was then diluted with water (7 mL). The resulting solid was filtered, washed thoroughly with water, and dried under vacuum at 60°C to give 194 mg of a light tan solid. After dissolving in hot DMSO (2 mL), the compound was purified via reverse phase chromatography eluting with 5-100% MeCN/0.1% aqueous formic acid to provide racemic Example 6 (38 mg, 15% yield) as a colorless solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.38 (s, 2 H), 3.57 (m, 1 H), 3.07 (d, J = 7.4 Hz, 2 H), 2.42 (dq, J = 9.8, 7.6 Hz, 1 H), 2.29 (dt, J = 13.4, 7.0Hz, 1H), 2.16 (d, J = 1.2 Hz, 6H), 2.09 – 2.14 (m, 1H), 1.78 – 1.95 (m, 2H), 1.43 – 1.62 (m, 2H). m/z (ESI+)367.12 (M+H) ⁺ for C ₁₄ H ₁₈ N ₆ O ₂ S ₂ .

11 mg was subjected to chiral separation by SFC to obtain two enantiomers. Analytical chiral separation by SFC was performed using a Chiralpak AS-H column (4.6 mm x 250 mm column, 5 micron particle size) eluted with 30% MeOH (containing 0.1% DEA) in _CO maintained at 140 bar. A flow rate of 3 mL/min gave Rt _{(peak 1)} = 3.00 minutes and Rt _{(peak 2)} = 4.62 minutes.

Example 5 (peak 1): 3.89 mg, >98% ee. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.38 (s, 2 H), 3.57 (m, 1 H), 3.07 (d, J = 7.4 Hz, 2 H), 2.42 (dq, J = 9.8, 7.6 Hz, 1 H), 2.29 (dt, J = 13.4, 7.0 Hz, 1 H), 2.16 (d, J = 1.2 Hz, 6 H), 2.09 –2.14 (m, 1 H), 1.78 – 1.95 (m, 2 H), 1.43 – 1.62 (m, 2 H). m/z (ESI+)367.12 (M+H) ⁺ for C ₁₄ H ₁₈ N ₆ O ₂ S ₂ .

Example 7 (peak 2): 3.72 mg, >98% ee. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.38 (s, 2 H), 3.57 (m, 1 H), 3.07 (d, J = 7.4 Hz, 2 H), 2.42 (dq, J = 9.8, 7.6 Hz, 1 H), 2.29 (dt, J = 13.4, 7.0 Hz, 1 H), 2.16 (d, J = 1.2 Hz, 6 H), 2.09 –2.14 (m, 1 H), 1.78 – 1.95 (m, 2 H), 1.43 – 1.62 (m, 2 H). m/z (ESI+)367.12 (M+H) ⁺ for C ₁₄ H ₁₈ N ₆ O ₂ S ₂ .

Example 8 (Scheme B): 2-phenyl- N- (5-{[(1 R , 3 S )-3-{5-[(phenylacetyl)amino]-1,3,4- Preparation of 1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide

To 5-(((cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine (200 mg, 0.708 mmol) suspended in DMA (2 mL) was added dimethylaminopyridine (87 mg, 0.708 mmol) followed by phenylacetyl chloride (281 µL, 2.124 mmol). The reaction was stirred at room temperature for 64 hours to give a clear solution. Water (3 mL) was added, and the mixture was stirred for 30 minutes to give a light tan solid, which was filtered, washed with water, and dried. This solid was dissolved in DMSO (2 mL) and water (4 mL) was added to reprecipitate the product, which was filtered, washed thoroughly with water, and dried under vacuum at 60°C to give racemic Example 9 (225 mg, 55% yield) as a light tan solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.66 (s, 2 H), 6.72 – 7.88 (m, 10 H), 3.78 (d, J = 1.5 Hz, 4 H), 3.49 (dd, J = 10.0, 7.5 Hz, 1 H), 3.05 (d, J = 7.3Hz, 2 H), 2.34 – 2.47 (m, 1 H), 2.26 (dt, J = 13.0, 6.9 Hz, 1 H), 2.03 – 2.17(m, 1 H), 1.76 – 1.93 (m, 2 H), 1.41 – 1.60 (m, 2 H). m/z (ESI+)519.24 (M+H) ⁺ for C ₂₆ H ₂₆ N ₆ O ₂ S ₂ .

190 mg was subjected to chiral separation by SFC to obtain two enantiomers. Analytical chiral separation by SFC was performed using a Chiralpak AS-H column (4.6 mm x 250 mm column, 5 micron particle size) eluted with 40% MeOH (containing 0.1% DEA) in _CO maintained at 140 bar. A flow rate of 3 mL/min gave Rt _{(peak 1)} = 8.51 minutes and Rt _{(peak 2)} = 10.20 minutes.

Example 8 (peak 1): 60.83 mg, >99% ee (+). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm12.66 (s, 2 H), 6.72 – 7.88 (m, 10 H), 3.78 (d, J = 1.5 Hz, 4 H), 3.49 (dd, J = 10.0, 7.5 Hz, 1 H), 3.05 (d, J = 7.3 Hz, 2 H), 2.34 – 2.47 (m, 1 H), 2.26 (dt, J = 13.0, 6.9 Hz, 1 H), 2.03 – 2.17 (m, 1 H), 1.76 – 1.93 (m, 2 H), 1.41– 1.60 (m, 2 H). m/z (ESI+)519.24 (M+H) ⁺ for C ₂₆ H ₂₆ N ₆ O ₂ S ₂ .

Example 10 (peak 2): 61.32 mg, ~ 99% ee (-). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm12.66 (s, 2 H), 6.72 – 7.88 (m, 10 H), 3.78 (d, J = 1.5 Hz, 4 H), 3.49 (dd, J = 10.0, 7.5 Hz, 1 H), 3.05 (d, J = 7.3 Hz, 2 H), 2.34 – 2.47 (m, 1 H), 2.26 (dt, J = 13.0, 6.9 Hz, 1 H), 2.03 – 2.17 (m, 1 H), 1.76 – 1.93 (m, 2 H), 1.41– 1.60 (m, 2 H). m/z (ESI+)519.24 (M+H) ⁺ for C ₂₆ H ₂₆ N ₆ O ₂ S ₂ .

Example 11 (Scheme C): N-{5-[3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentane Preparation of 1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4-yl)acetamide

Step 1: Preparation of methyl [(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]acetate

(cis) -3- (2-methoxy-2-oxoethyl) cyclopentanecarboxylic acid (10 g, 53.7 mmol) and thiosemicarbazide (5.45 g, 59.0 mmol) are suspended in POCl ₃ (50 mL) and heated to reflux for 40 minutes, during which time the suspension becomes a clear yellow solution. The mixture is cooled, evaporated in a vacuum, and then azeotroped three times with toluene to remove the POCl ₃ residue. The gained amber oil is carefully quenched with saturated NaHCO ₃ solution (350 mL) and then extracted into EtOAc (2 x 300 mL). The combined organic extracts are dried over MgSO ₄ and evaporated to obtain a yellow solid (10.3 g). This was purified by flash chromatography (0-10% methanol/ EtOAc elution) to give methyl [(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]acetate (6.3 g, 49% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm7.00 (s, 2 H), 3.58 (s, 3 H), 3.25 – 3.33 (m, 1 H), 2.40 (d, J = 2.3 Hz, 1H), 2.39 (d, J = 1.1 Hz, 1 H), 2.16 – 2.35 (m, 2 H), 1.97 – 2.05 (m, 1 H), 1.81 – 1.91 (m, 1 H), 1.68 – 1.80 (m, 1 H), 1.28 – 1.41 (m, 2 H). m/z (APCI+)242.1 (M+H) ⁺ for C ₁₀ H ₁₅ N ₃ O ₂ S.

Step 2: Preparation of methyl {(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetate

To a solution of methyl [(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]acetate (1.8 g, 7.46 mmol) in CH ₂ Cl ₂ (20 mL) was added Et ₃ N (2.08 mL, 14.9 mmol) followed by acetyl chloride (0.58 mL, 8.20 mmol) at room temperature under nitrogen. The resulting yellow suspension was stirred for 4 hours and then washed with water. The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ , and evaporated to give methyl {(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetate (2.15 g, 100%) as a cream-colored solid. ¹ H NMR (400 MHz, MeOH- d ₄ )δ ppm 3.70 (s, 3 H), 3.47 – 3.63 (m, 1 H), 2.40 – 2.58 (m, 4 H), 2.26 (s, 3H), 1.90 – 2.14 (m, 3 H), 1.48 – 1.63 (m, 2 H). m/z (APCI+)284.1 (M+H) ⁺ for C ₁₂ H ₁₇ N ₃ O ₃ S.

Step 3: Preparation of {(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic acid

To a solution of methyl {(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetate (2.11 g, 7.447 mmol) in MeOH (30 mL) was added 3 M aqueous lithium hydroxide solution (5.0 mL, 14.9 mmol). The solution was stirred at 45°C for 4 hours, then concentrated to remove MeOH and subsequently acidified to pH ~4 with 1 M AcOH. The resulting solution was extracted with EtOAc (3 x 30 mL), and the combined organic _layers were washed with brine. The organics were dried over _Na2SO4 , filtered, and evaporated under vacuum to give {(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic acid (1.7 g, 85%) as a cream-colored solid. m/z (APCI+)270.5 (M+H) ⁺ for C ₁₁ H ₁₅ N ₃ O ₃ S.

Step 4: N- {5-[(cis)-3-(2-hydrazino-2-oxoethyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetyl Preparation of amines

To a solution of {(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic acid (450 mg, 1.67 mmol) in dry DMF (10 mL) was added HBTU (711 mg, 1.84 mmol) and _EtN (0.35 mL, 2.51 mmol). The resulting clear yellow solution was stirred for 1 hour, then hydrazine (0.09 mL, 2.51 mmol) was added and the solution was stirred for an additional 3 hours. The mixture was concentrated to give a cream _- colored solid, which was slurried in CHCl ( _{40 mL) and filtered under vacuum. The solid was washed with more CHCl and dried} under vacuum to give N- {5-[(cis)-3-(2-hydrazino-2-oxoethyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide (447 mg 94%) as a white powder. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.93 (br s, 1 H), 4.17 (br s, 2 H), 3.40 – 3.53 (m, 1 H), 2.20 – 2.38 (m, 2 H), 2.16 (s, 3 H), 2.03 – 2.14 (m, 3 H), 1.74 – 1.90 (m, 2H), 1.31 – 1.50 (m, 2 H). m/z (APCI+)284.1 (M+H) ⁺ for C ₁₁ H ₁₇ N ₅ O ₂ S.

Step 5: N -{[2-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetyl] Preparation of hydrazino]thioformyl}benzamide

To a solution of N- {5-[(cis)-3-(2-hydrazino-2-oxoethyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide (50 mg, 0.18 mmol) in (2 mL) was added benzoyl isothiocyanate (0.028 mL, 0.211 mmol), and the suspension was stirred at 40°C for 3 hours. The mixture was cooled and filtered under vacuum. The solid was washed with EtOAc and then with CH2Cl2 to give N -{ [ ₂ -({(cis ₎ -3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetyl)hydrazino]formothioyl}benzamide (58 mg, 74%) as a cream-colored solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.60 (d, J = 4.40 Hz, 1 H), 12.37 (s, 1 H), 11.67 (s, 1 H), 10.83 (d, J = 4.40 Hz, 1 H), 7.95 (d, J = 7.34 Hz, 2 H), 7.64 (m, J = 7.30Hz, 1 H), 7.52 (t, J = 1.00 Hz, 2 H), 3.44 – 3.58 (m, 1 H), 2.28 – 2.45 (m, 4H), 2.06 – 2.21 (m, 4 H), 1.88 (m, J = 7.30 Hz, 2 H), 1.43 – 1.60 (m, 2H). m/z (APCI+)447.1 (M+H) ⁺ for C ₂₀ H ₂₄ N ₆ O ₃ S ₂ .

Step 6: N- [5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1, Preparation of 3,4-thiadiazol-2-yl]benzamide (Example 11)

N -{[2-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetyl)hydrazinyl]formothioyl}benzamide (58 mg, 0.13 mmol) was stirred in ice-cold sulfuric acid (3 mL) for 3 hours. The clear solution was slowly added to ice-cold water (10 mL) to give an oily suspension. EtOAc (10 mL) was added and the mixture was stirred to give a cream-colored solid. The mixture was filtered under vacuum, and the solid was washed with water, followed by heptanes, to give N- [5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]benzamide (25 mg, 45%, Example 11) as a cream-colored solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm12.89 (br s, 1 H), 12.35 (br s, 1 H), 8.10 (d, J = 7.46 Hz, 2 H), 7.62 – 7.71(m, 1 H), 7.50 – 7.60 (m, 2 H), 3.45 – 3.61 (m, 1 H), 3.12 (d, J = 7.09 Hz, 2H), 2.27 – 2.40 (m, 1 H), 2.07 – 2.24 (m, 4 H), 1.81 – 2.02 (m, 2 H), 1.48 –1.69 (m, 2 H). m/z (APCI+)429.1 (M+H) ⁺ for C ₁₉ H ₂₀ N ₆ O ₂ S ₂ .

16 mg was subjected to chiral separation by SFC to obtain two enantiomers. Analytical chiral separation by SFC was performed using a Chiralpak OJ-H column (4.6 mm x 250 mm column, 5 micron particle size) eluted with 30% MeOH in _CO maintained at 140 bar. A flow rate of 3 mL/min gave Rt _{(peak 1)} = 4.63 minutes and Rt _{(peak 2)} = 5.57 minutes.

Example 12 (peak 1): 5.15 mg, > 99% ee. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm12.89 (br s, 1 H), 12.35 (br s, 1 H), 8.10 (d, J = 7.46 Hz, 2 H), 7.62 – 7.71(m, 1 H), 7.50 – 7.60 (m, 2 H), 3.45 – 3.61 (m, 1 H), 3.12 (d, J = 7.09 Hz, 2H), 2.27 – 2.40 (m, 1 H), 2.07 – 2.24 (m, 4 H), 1.81 – 2.02 (m, 2 H), 1.48 –1.69 (m, 2 H). m/z (APCI+)429.1 (M+H) ⁺ for C ₁₉ H ₂₀ N ₆ O ₂ S ₂ .

Example 13 (peak 2): 5.65 mg, ~99% ee. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm12.89 (br s, 1 H), 12.35 (br s, 1 H), 8.10 (d, J = 7.46 Hz, 2 H), 7.62 – 7.71(m, 1 H), 7.50 – 7.60 (m, 2 H), 3.45 – 3.61 (m, 1 H), 3.12 (d, J = 7.09 Hz, 2H), 2.27 – 2.40 (m, 1 H), 2.07 – 2.24 (m, 4 H), 1.81 – 2.02 (m, 2 H), 1.48 –1.69 (m, 2 H). m/z (APCI+)429.1 (M+H) ⁺ for C ₁₉ H ₂₀ N ₆ O ₂ S ₂ .

Example 14 (Scheme C): N- [5-({(1 R ,3 S )-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl] Preparation of [Cyclopentyl]methyl]-1,3,4-thiadiazol-2-yl]-2-phenylacetamide

Step 1: N -{[2-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetyl] Preparation of hydrazino]thioformyl}-2-phenylacetamide

To a solution of the product of Example 5, Step 4, N- {5-[(cis)-3-(2-hydrazinyl-2-oxoethyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide (100 mg, 0.353 mmol) in EtOAc (2 mL) was added phenylacetyl isothiocyanate (75 mg, 0.424 mmol), and the suspension was stirred at 40 ° C for 3 hours. The mixture was cooled and filtered under vacuum. The solid was washed with EtOAc to give a 50% pure sample of N -{[2-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetyl)hydrazinyl]thiocarbonyl}-2-phenylacetamide as a brown solid (147 mg, 91%). C ₂₀ H ₂₄ N ₆ O ₃ S ₂ has m/z (APCI+)460.9 (M+H) ⁺ , 483 (M+Na) ⁺ .

Step 2: N- [5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)- Preparation of 1,3,4-thiadiazol-2-yl]-2-phenylacetamide (Example 14)

A 50% pure sample of N -{[2-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetyl)hydrazinyl]carbonothioyl}-2-phenylacetamide (147 mg, 0.16 mmol) was stirred in ice-cold sulfuric acid (3 mL) for 3 hours. The clear solution was slowly added to ice-cold water (10 mL) to afford a brown solid, which was filtered under vacuum and washed with water followed by heptane. The brown solid was purified by preparative HPLC to afford racemic N- [5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-phenylacetamide (33 mg, 44%, Example 15) as a cream-colored solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm12.46 (br s, 2 H), 7.16 – 7.42 (m, 5 H), 3.79 (s, 2 H), 3.43 – 3.58 (m, 1 H), 3.06 (d, J = 7.34 Hz, 2 H), 2.36 – 2.47 (m, 1 H), 2.28 (d, J = 12.35 Hz, 1H), 2.16 (s, 4 H), 1.78 – 1.99 (m, 2 H), 1.41 – 1.64 (m, 2 H). m/z (APCI+)443.0 (M+H) ⁺ for C ₂₀ H ₂₂ N ₆ O ₂ S ₂ .

20 mg were subjected to chiral separation by SFC to obtain two enantiomers. Analytical chiral separation by SFC was performed using a Chiralpak OJ-H column (4.6 mm x 250 mm column, 5 micron particle size) eluted with 40% MeOH in _CO maintained at 120 bar. A flow rate of 3 mL/min gave Rt _{(peak 1)} = 4.54 minutes and Rt _{(peak 2)} = 7.67 minutes.

Example 16 (peak 1): 6.89 mg, >99% ee (-). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.46 (br s, 2 H), 7.16 – 7.42 (m, 5 H), 3.79 (s, 2 H), 3.43 – 3.58 (m, 1 H), 3.06 (d, J = 7.34 Hz, 2 H), 2.36 – 2.47 (m, 1 H), 2.28 (d, J = 12.35 Hz, 1 H), 2.16 (s, 4 H), 1.78 – 1.99 (m, 2 H), 1.41 – 1.64 (m, 2 H). m/z (APCI+)443.0 (M+H) ⁺ for C ₂₀ H ₂₂ N ₆ O ₂ S ₂ .

Example 14) (peak 2): 6.98 mg, >99% ee (+). ^1H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.46 (br s, 2 H), 7.16 – 7.42 (m, 5 H), 3.79 (s, 2 H), 3.43 – 3.58 (m, 1 H), 3.06 (d, J = 7.34 Hz, 2 H), 2.36 – 2.47 (m, 1 H), 2.28 (d, J = 12.35 Hz, 1 H), 2.16 (s, 4 H), 1.78 – 1.99 (m, 2 H), 1.41 – 1.64 (m, 2 H). m/z (APCI+)443.0 (M+H) ⁺ for C ₂₀ H ₂₂ N ₆ O ₂ S ₂ .

Example 17 (Scheme C): N- [5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentane Preparation of [1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide

Step 1: N- (5-{(cis)-3-[2-(2-thiocarbamoylhydrazine)-2-oxoethyl]cyclopentyl}-1,3, Preparation of 4-thiadiazol-2-yl)acetamide

To a solution of {(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic acid (700 mg, 2.60 mmol) in dry DMF (10 mL) was added HBTU (1.51 g, 3.90 mmol) and Et ₃ N (0.73 mL, 5.20 mmol). The resulting clear yellow solution was stirred for 1 hour before the addition of thiosemicarbazide (359 mg, 3.90 mmol), which was then stirred overnight. The reaction was concentrated to a yellow slurry, to which was added CH ₂ Cl ₂ (40 mL) to give a cream-colored solid. The solid was filtered under vacuum, washed with CH2Cl2 , and dried to give N- (5-{ ₍ cis ₎ -3-[2-(2-thiocarbamoylhydrazino)-2-oxoethyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)acetamide (671 mg, 75%) as _{a white} powder _. m/z (APCI+) 343.05 (M+H) ⁺ _{for C12H18N6O2S2} .

Step 2: N- (5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)methyl)cyclopentyl Preparation of oxadiazole-2-yl)acetamide

N- (5-{(cis)-3-[2-(2-thiocarbamoylhydrazine)-2-oxoethyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)acetamide (671 mg, 1.96 mmol) was stirred in ice-cold sulfuric acid (3 mL) for 3 hours. The clear solution was slowly added to an ice-cold aqueous solution of _NaHCO₃ to adjust the pH to ~8 (Caution - vigorous gas evolution). The resulting solid was filtered under vacuum and washed thoroughly with water to afford N- (5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)acetamide (449 mg, 71%) as a cream-colored powder. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.96 (s, 2 H), 3.47 – 3.53 (m, 1 H), 2.88 (d, J = 7.30 Hz, 2H), 2.23 – 2.39 (m, 2 H), 2.06 – 2.16 (m, 4 H), 1.79 – 1.94 (m, 2 H), 1.42 –1.58 (m, 2 H). m/z (APCI+)325.05 (M+H) ⁺ for C ₁₂ H ₁₆ N ₆ OS ₂ .

Step 3: N- [5-({(1 R ,3 S )-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methoxy Preparation of [4-(2-(4-thiadiazole-2-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)acetamide (Example 17)]

To a solution of N- (5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)acetamide (95 mg, 0.29 mmol) in dry DMF (2 mL) was added HBTU (136 mg, 0.352 mmol) and _Et3N (0.1 mL, 0.732 mmol) and 2-pyridylacetic acid hydrochloride (61 mg, 0.352 mmol). The resulting clear brown solution was stirred at 50°C for 2 hours. Purification by preparative HPLC gave racemic N- [5-({(1 R ,3 S )-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide as a yellow powder (52 mg, 40%, Example 18). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.50 (br s, 2 H), 8.49 (d, J = 4.03 Hz, 1 H), 7.77 (td, J = 7.70,1.83 Hz, 1 H), 7.39 (d, J = 7.82 Hz, 1 H), 7.28 (dd, J = 7.03, 5.32 Hz, 1 H), 4.00 (s, 2 H) 3.43 – 3.58 (m, 1 H), 3.06 (d, J = 1.00 Hz, 2 H), 2.37 – 2.48 (m, 1 H), 2.25 – 2.35 (m, 1 H), 2.05 – 2.21 (m, 4 H), 1.80 – 1.96 (m, 2 H), 1.44 – 1.62 (m, 2 H). m/z (APCI+)444.1 (M+H) ⁺ for C ₁₉ H ₂₁ N ₇ O ₂ S ₂ .

40 mg was subjected to chiral separation by SFC to obtain two enantiomers. Analytical chiral separation by SFC was performed using a Chiralpak OJ-H column (4.6 mm x 250 mm column, 5 micron particle size) eluted with 30% MeOH in _CO maintained at 120 bar. A flow rate of 3 mL/min gave Rt _{(peak 1)} = 3.47 minutes and Rt _{(peak 2)} = 4.72 minutes.

Example 17 (peak 1): 16.78 mg, > 99% ee (-). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm12.50 (br s, 2 H), 8.49 (d, J = 4.03 Hz, 1 H), 7.77 (td, J = 7.70, 1.83 Hz, 1H), 7.39 (d, J = 7.82 Hz, 1 H), 7.28 (dd, J = 7.03, 5.32 Hz, 1 H), 4.00 (s, 2H) 3.43 – 3.58 (m, 1 H), 3.06 (d, J = 1.00 Hz, 2 H), 2.37 – 2.48 (m, 1 H),2.25 – 2.35 (m, 1 H), 2.05 – 2.21 (m, 4 H), 1.80 – 1.96 (m, 2 H), 1.44 – 1.62 (m, 2 H). m/z (APCI+)444.1 (M+H) ⁺ for C ₁₉ H ₂₁ N ₇ O ₂ S ₂ .

Example 19 (peak 2): 16.86 mg, ~99% ee (+). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm12.50 (br s, 2 H), 8.49 (d, J = 4.03 Hz, 1 H), 7.77 (td, J = 7.70, 1.83 Hz, 1H), 7.39 (d, J = 7.82 Hz, 1 H), 7.28 (dd, J = 7.03, 5.32 Hz, 1 H), 4.00 (s, 2H), 3.43 – 3.58 (m, 1 H), 3.06 (d, J = 1.00 Hz, 2 H), 2.37 – 2.48 (m, 1 H),2.25 – 2.35 (m, 1 H), 2.05 – 2.21 (m, 4 H), 1.80 – 1.96 (m, 2 H), 1.44 – 1.62 (m, 2 H). m/z (APCI+)444.1 (M+H) ⁺ for C ₁₉ H ₂₁ N ₇ O ₂ S ₂ .

Example 20 (Scheme D): N- {5-[(1 R ,3 S )-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl] Preparation of methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4-yl)acetamide

Step 1: 2-((cis)-3-(5-(2-pyrimidin-4-yl)acetylamino)-1,3,4-thiadiazol-2-yl)cyclopentyl)ethyl Preparation of methyl ester

To a mixture of methyl [(cis)-3-(5-amino - 1,3,4-thiadiazol-2-yl)cyclopentyl]acetate (241 mg, 1.0 mmol) and HATU (480 mg, 1.2 mmol) in CH₂Cl₂ (20 mL) was added _Et₃N (0.28 mL, 2.0 mmol ₎ at _room temperature. The resulting mixture was then treated with 2-(pyrimidin-4-yl)acetic _{acid (152 mg, 1.1 mmol) and stirred at room temperature for 2 hours. The resulting orange solution was diluted with water and CH₂Cl₂ .} The organic layer was separated, washed with brine, dried over _Na₂SO₄ , and evaporated to _{afford a yellow solid. Purification via flash chromatography using a gradient of 0% to 30% MeOH/CH₂Cl₂ afforded} the title _compound (185 mg, 51% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm9.16 (s, 1 H), 8.69 (d, J = 5.29 Hz, 1 H), 7.47 (d, J = 5.04 Hz, 1 H), 4.22(s, 2 H), 3.62 (s, 3 H), 3.47 – 3.56 (m, 1 H), 2.34 – 2.48 (m, 4 H), 2.11 – 2.26 (m, 1 H), 1.79 – 2.05 (m, 2 H), 1.38 – 1.58 (m, 2 H). m/z (APCI+)362.2 (M+H) ⁺ for C ₁₆ H ₁₉ N ₅ O ₃ S.

Step 2: 2-((cis)-3-(5-(2-pyrimidin-4-yl)acetylamino)-1,3,4-thiadiazol-2-yl)cyclopentyl)ethyl Acid preparation

Methyl 2-((cis)-3-(5-(2-pyrimidin-4-yl)acetamido)-1,3,4-thiadiazol-2-yl)-cyclopentyl)acetate (1.27 g, 3.52 mmol) was dissolved in a mixture of MeOH (20 mL) and water (10 mL). LiOH (674 mg, 28.2 mmol) was then added to the methyl ester at room temperature and stirred for 2 hours. The reaction mixture was evaporated to remove the MeOH, and the resulting mixture was diluted with water. The crude product was then washed with EtOAc and the aqueous layer was acidified to pH ~3 with 1 N HCl. The resulting solid was filtered, washed with water, and dried under vacuum to give 2-((cis)-3-(5-(2-pyrimidin-4-yl)acetamido)-1,3,4-thiadiazol-2-yl)cyclopentyl)acetic acid (238 mg, 19.5%) as a yellow solid. m/z (APCI+)348.2 (M+H) ⁺ for C ₁₅ H ₁₇ N ₅ O ₃ S.

Step 3: N- (5-((cis)-3-(2-(2-thiocarbamoylhydrazino)-2-oxoethyl)cyclopentyl)-1,3- Preparation of 4-thiadiazol-2-yl)-2-(pyrimidin-4-yl)acetamide

To a mixture of 2-((cis)-3-(5-(2-pyrimidin-4-yl)acetamido)-1,3,4-thiadiazol-2-yl)cyclopentyl)acetic acid (238 mg, 0.69 mmol) and HATU (412 mg, 1.03 mmol) in DMF (3 mL) was added _Et3N (0.19 mL, 1.37 mmol) at room temperature. After 30 minutes, the resulting mixture was treated with thiosemicarbazide (96 mg, 1.03 mmol) at room temperature and stirred _{for 3} hours. The reaction mixture was then evaporated under vacuum to remove DMF. The crude product was _diluted with CH2Cl2 and the resulting solid _was filtered off. The title compound was immediately transferred to the flask used in the dehydration step (step 4). m/z (APCI+ ₎ 421.05 (M+H) ⁺ _{for C16H20N8O2S2} .

Step 4: N- (5-((cis)-3-((5-amino-1,3,4-thiadiazol-2-yl)-methyl)cyclopentyl)-1,3,4-thiadiazol-2-yl Preparation of oxadiazol-2-yl)-2-(pyrimidin-4-yl)acetamide

N-(5-(( cis ) -3-(2-(2-thiocarbamoylhydrazinyl)-2-oxoethyl)cyclopentyl)-1,3,4-thiadiazol-2-yl)-2-(pyrimidin-4-yl)acetamide was treated with neat sulfuric acid at 0°C. After 3 hours at 0°C, the reaction mixture was added dropwise to ice-cold aqueous _NaHCO3 solution. The resulting solid was filtered off, washed with water, and dried under vacuum to give N-(5-(( cis ) -3-((5-amino-1,3,4-thiadiazol-2-yl)methyl)cyclopentyl)-1,3,4-thiadiazol-2-yl)-2-(pyrimidin-4-yl)acetamide (118 mg, 38%) as _{a yellow solid} . m/z (APCI+) 403.2 (M+H) ⁺ _{for Ci6Hi8N8OS2} .

Step 5: N- {5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]- Preparation of 1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4-yl)acetamide (Example 20)

N-(5-(( cis ) -3-((5-amino-1,3,4-thiadiazol-2-yl)methyl)cyclopentyl)-1,3,4-thiadiazol-2-yl)-2-(pyrimidin-4-yl)acetamide (118 mg, 0.293 mmol) was dissolved in AcOH (1 mL) and treated with Ac ₂ O (56 μL, 0.586 mmol) at room temperature. After 30 minutes, the reaction mixture was purified by reverse phase chromatography eluting with MeCN:water (5:95 to 95:5) to give racemic N- {5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4-yl)acetamide (26 mg, 20%) as an orange solid.

26 mg were subjected to chiral separation by SFC to obtain two enantiomers. Analytical chiral separation by SFC was performed using a Chiralpak OJ-H column (4.6 mm x 100 mm column, 5 micron particle size) eluted with 20% MeOH in _CO maintained at 120 bar. A flow rate of 4 mL/min gave Rt _{(peak 1)} = 1.68 minutes and Rt _{(peak 2)} = 1.95 minutes.

Example 21 (peak 1): 7.56 mg, > 99% ee (-). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm9.10 (d, J = 2.9 Hz, 1H), 8.76 (dd, J = 5.3, 2.2 Hz, 1 H), 7.55 (t, J = 3.8Hz, 1 H), 4.03 (d, J = 2.0 Hz, 2 H), 3.50 ( dq . – 1.95 (m, 2 H), 1.43 – 1.60 (m, 2H). m/z (APCI+)445.2 (M+H) ⁺ for C ₁₈ H ₂₀ N ₈ O ₂ S ₂ .

Example 20 (peak 2): 7.96 mg, ~92% ee (+). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm9.10 (d, J = 2.9 Hz, 1 H), 8.76 (dd, J = 5.3, 2.2 Hz, 1 H), 7.55 (t, J = 3.8Hz, 1 H), 4.03 (d, J = 2.0 Hz, 2 H), 3.50 ( dq . – 1.95 (m, 2 H), 1.43 – 1.60 (m, 2H). m/z (APCI+)445.2 (M+H) ⁺ for C ₁₈ H ₂₀ N ₈ O ₂ S ₂ .

Example 22 and Example 23 (Scheme E): 2-(pyridin-2-yl)-N-{5-[(cis)-3-{5-[(pyridin-2-yl)-N-{5-[(cis)-3- acetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide (Example 22) and 2-(pyridin-2-yl)-N-{5-[(trans)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl} Preparation of [4-(4-(4-cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl)acetamide (Example 23)

Step 1: 5-{[3-(5-amino-1,3,4-thiadiazol-2-yl)cyclobutyl]methyl}-1,3,4-thiadiazol-2-amine Preparation

3-(2-tert-Butoxy-2-oxoethyl)cyclobutanecarboxylic acid (prepared as a 4:1 mixture of cis:trans isomers as described in WO2005019221) (2.3 g, 10.74 mmol) and thiosemicarbazide (2.17 g, 23.60 mmol) were suspended in _POCl₃ (10 mL) and heated to reflux for 1 hour, during which time the suspension became a clear yellow solution. The mixture was cooled, evaporated in vacuo, and azeotroped three times with toluene to remove _POCl₃ residues. The resulting amber oil was carefully quenched with saturated _NaHCO₃ solution (100 mL). The resulting suspension was filtered and washed thoroughly with water and heptane to give 5-{[3-(5-amino-1,3,4-thiadiazol-2-yl)cyclobutyl]methyl}-1,3,4-thiadiazol-2-amine (1.34 g, 46%) as a brown powder and a 4:1 mixture of cis:trans isomers. m/z (APCI+) 269.05 (M+H) ⁺ for C ₉ H ₁₂ N ₆ S ₂ .

Step 2: 2-(pyridin-2-yl) -N- {5-[(cis - 3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazole oxazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide (Example 22) and 2-(pyridin-2-yl) -N- {5- [(cis - 3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl Preparation of oxazol-2-yl}acetamide (Example 23)

To a solution of 5-{[3-(5-amino-1,3,4-thiadiazol-2-yl)cyclobutyl]methyl}-1,3,4-thiadiazol-2-amine (200 mg, 7.45 mmol) in dry DMF (2 mL) was added HBTU (865 mg, 2.24 mmol), _Et3N (0.42 mL, 2.98 mmol) and 2-pyridylacetic acid hydrochloride (284 mg, 1.64 mmol). The resulting clear yellow solution was stirred at 50 °C for 2 hours and then purified by preparative HPLC to give cis- and trans - 2-(pyridin-2-yl) -N- {5-[3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide as a brown solid (113 mg, 30%).

Cis and trans isomers were separated by SFC to obtain two diastereomers. Analytical separation by SFC was performed using a Chiralpak OJ-H column (4.6 mm x 150 mm column, 5 micron particle size) eluted with 40% MeOH in _CO maintained at 120 bar. A flow rate of 4 mL/min gave Rt _{(peak 1, cis)} = 1.34 minutes and Rt _{(peak 2, trans)} = 1.72 minutes.

2-(Pyridin-2-yl) -N- {5-[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide ( Example 22 ) >99% de (61.5 mg, 54%) as a cream-colored powder. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.65 (br s, 2 H), 8.49 (d, J =4.28 Hz, 2 H), 7.77 (t, J = 7.52 Hz, 2 H), 7.39 (d, J = 7.70 Hz, 2 H), 7.24 –7.32 (m, 2 H), 4.00 (s, 4 H), 3.74 (s, 1 H), 3.12 (d, J = 7.34 Hz, 2 H), 2.69 (br s, 1 H), 2.52 – 2.61 (m, 2 H), 2.06 (d, J = 10.88 Hz, 2 H). m/ z (APCI+)507.1 (M+H) ⁺ of C ₂₃ H ₂₂ N ₈ O ₂ S ₂

2-(Pyridin-2-yl) -N- {5-[(trans)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide ( Example 23 ) 98% de (12.3 mg, 11%) as a cream-colored powder. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.66 (br s, 2 H), 8.49 (d, J =4.03 Hz, 2 H), 7.76 (t, J = 7.03 Hz, 2 H), 7.39 (d, J = 7.70 Hz, 2 H), 7.20 –7.34 (m, 2 H), 3.87 – 4.08 (m, 5 H), 3.23 (d, J = 7.58 Hz, 2 H), 2.73 – 2.88 (m, 1 H), 2.37 – 2.45 (m, 2 H), 2.21 – 2.34 (m, 2 H). m/z (APCI+)507.1 (M+H) ⁺ of C ₂₃ H ₂₂ N ₈ O ₂ S ₂

Example 24 (Scheme F): N- [5-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentane Preparation of [1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide

Step 1: Preparation of methyl {3-[(cis)-5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetate

3-(2-methoxy-2-oxoethyl)-cyclopentanecarboxylic acid (500 mg, 2.68 mmol) and 4-ethyl-3-thiosemicarbazide (320 mg, 2.68 mmol) are suspended in POCl ₃ (8 mL) in, and are heated to reflux 40 minutes, during which time suspension becomes a clear yellow solution. The mixture is cooled, evaporated in a vacuum, then azeotroped three times with toluene to remove POCl ₃ residue. The gained amber oil is quenched with saturated NaHCO ₃ solution (100 mL) carefully, then extracted into EtOAc (3x 50 mL). The organic extract merged is dried over magnesium sulfate, and evaporated to obtain { 3-[(adapted)-5-(ethylamino)-1,3,4-thiadiazole-2-yl] cyclopentyl } methyl acetate (325 mg, 45%) as a light yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ ppm 3.68 (s, 3 H) 3.29 – 3.47 (m, 3 H) 2.33 – 2.48 (m, 4 H)2.10 – 2.24 (m, 1 H) 1.81 – 2.07 (m, 2 H) 1.40 – 1.56 (m, 2 H) 1.32 (t, J =7.21 Hz, 3 H). m/z (APCI+)270.1 (M+H) ⁺ for C ₁₂ H ₁₉ N ₃ O ₂ S.

Step 2: Preparation of {(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic acid

To a solution of methyl {3-[(cis)-5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetate (325 mg, 1.21 mmol) in MeOH (10 mL) was added 3 M LiOH solution (0.81 mL, 2.41 mmol). The solution was stirred at room temperature overnight, concentrated to remove MeOH, and then acidified to pH ~4 with 1 M AcOH. The resulting solution was extracted with EtOAc _{(3 x 10 mL) followed by CH2Cl2 :} MeOH ( ₉₅ :5, 10 mL). The combined organic layers were dried over _Na2SO4 , filtered, and evaporated under vacuum to afford {(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic acid (289 mg, 94%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.33 – 3.51 (m,3 H), 2.40 – 2.61 (m, 3 H), 2.15 – 2.29 (m, 1 H), 1.98 – 2.11 (m, 1 H), 1.93 (dd, J = 8.74, 4.83 Hz, 1 H), 1.47 – 1.63 (m, 2 H), 1.41 (t, 3 H). m/z (APCI+)256.1 (M+H) ⁺ for C ₁₁ H ₁₇ N ₃ O ₂ S.

Step 3: 5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl} -N -ethyl-1,3,4- Preparation of thiadiazole-2-amine

{(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic acid (289 mg, 1.13 mmol) and thiosemicarbazide (104 mg, 1.13 mmol) were suspended in _POCl₃ (10 mL) and heated to reflux for 1 hour, after which the suspension became a clear yellow solution. The mixture was cooled, evaporated in vacuo, and then azeotroped three times with toluene to remove the _POCl₃ residue. The resulting amber oil was slowly added to ice-cold water ₍ 100 mL) and basified with 0.88 N ammonia. The resulting oil was extracted with EtOAc (3 x 40 mL) and then with CH₂Cl₂ : _MeOH (95:5, 3 x 30 mL). The combined organics were dried over _{Na2SO4 and} concentrated to give 5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl} -N -ethyl-1,3,4-thiadiazol-2-amine (175 mg, 50%) as a cream solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.51 (t, J = 5.07 Hz, 1 H), 6.97 (s, 2 H), 3.34 (m, J = 9.80Hz, 1 H), 3.16 – 3.29 (m, 2 H), 2.81 – 2.93 (m, 2 H), 2.15 – 2.47 (m, 2 H), 2.03 (m, J = 11.90, 7.20 Hz, 1 H), 1.70 – 1.90 (m, 2 H), 1.34 – 1.52 (m, 2H), 1.14 (t, J = 1.00 Hz, 3 H). m/z (APCI+)311.10 (M+H) ⁺ for C ₁₂ H ₁₈ N ₆ S ₂ .

Step 4: N- [5-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3, Preparation of 4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide

To a solution of 5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl} -N -ethyl-1,3,4-thiadiazol-2-amine (88 mg, 0.28 mmol) in dry DMF (2 mL) were added HBTU (164 mg, 0.424 mmol), _Et3N (0.08 mL, 0.566 mmol) and 2-pyridylacetic acid hydrochloride (54 mg, 0.311 mmol). The resulting clear yellow solution was stirred at 50 °C for 2 hours and then purified by preparative HPLC to give a solid that was slurried in heptanes, filtered and dried to give N- [5-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide (36 mg, 30%) as a light yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.65 (br s, 1 H), 8.47 – 8.52 (m, 1 H), 7.77 (td, J = 7.70, 1.83 Hz, 1 H), 7.50 (t, J = 5.20 Hz, 1 H), 7.39 (d, J =7.70 Hz, 1 H), 7.28 (dd, J = 6.60, 5.01 Hz, 1 H), 4.00 (s, 2 H), 3.29 (m, 1H), 3.18 – 3.27 (m, 2 H), 3.05 (d, J = 7.34 Hz, 2 H), 2.31 – 2.45 (m, 1 H),2.15 – 2.27 (m, 1 H), 1.98 – 2.11 (m, 1 H), 1.71 – 1.93 (m, 2 H), 1.39 – 1.53 (m, 2 H), 1.14 (t, J = 7.15 Hz, 3 H). m/z (APCI+)430.10 (M+H) ⁺ for C ₁₉ H ₂₃ N ₇ OS ₂ .

Example 25 (Scheme G): N , N '-(Spiro[3.3]heptane-2,6-diylbipyridazine-6,3-diyl)bis[2-(pyridine Preparation of [(2-pyridin-2-yl)acetamide]

Step 1: Preparation of 2,6-diiodospiro[3.3]heptanes

A solution of spiro[3.3]heptane-2,6-dicarboxylic acid (2.5 g, 11.0 mmol) and diiodohydantoin (11.4 g, 29.9 mmol) in 1,2-dichloroethane (136 mL) was irradiated with _a 500W halogen lamp _for 30 hours under nitrogen. The reaction was poured into saturated _Na₂SO₃ (100 mL) and extracted with _CH₂Cl₂ (2 _x 100 mL). The organic extract was washed with saturated _Na₂SO₃ (100 mL), dried _{over Na₂SO₄} , and concentrated. The residue was purified by column chromatography on silica gel, eluting with 0% - 25% EtOAc/heptanes to provide 2,6-diiodospiro[3.3]heptanes (1.7 g, 36%) as a colorless solid. ¹ H NMR (400MHz, CDCl ₃ ) δ ppm 4.32 (quin, J = 8 Hz, 2 H), 2.81 – 2.88 (m, 4 H), 2.59 –2.70 (m, 4 H).

Step 2: N , N '-(spiro[3.3]heptane-2,6-diylbipyridazine-6,3-diyl)bis[2-(pyridin-2-yl)acetyl Preparation of amine

To a suspension of Zn powder (386 mg, 5.75 mmol) in dry, degassed THF (0.58 mL) under nitrogen was added 1,2-dibromoethane (26 μL, 0.21 mmol). The mixture was then heated with a heat gun for approximately 30 seconds until gas evolution was observed from the solution, indicating activation of the Zn. This process was repeated twice, and the mixture was then cooled to room temperature, followed by the addition of TMSCl (22 μL, 0.17 mmol) and stirred at room temperature for 5 minutes. A solution of 2,6-diiodospiro[3.3]heptanes (500 mg, 1.44 mmol) in THF (1.4 mL) was added to the Zn solution, and the resulting mixture was stirred at 40 ° C for 6 hours. After Zn is settled, the reaction mixture is filtered through a syringe filter into a mixture of N- (6-iodopyridazine-3-yl)-2-(pyridin-2-yl)-acetamide (489 mg, 1.44 mmol), _Pd2 (dba) ₃ (266 mg, 0.29 mmol) and tri(o-tolyl)phosphine (175 mg, 0.58 mmol) in THF (5.2 mL). The reaction mixture is purged with nitrogen and stirred at 40 ° C for 18 hours. The reaction mixture is cooled to room temperature and quenched by adding an _NH4Cl aqueous solution ( _containing 10% _NH4OH ). The mixture is stirred for 1 hour, extracted with _CH2Cl2 , and the organic extract is dried over _Na2SO4 , _filtered and concentrated. Crude LCMS shows that approximately 10% product is formed. This material was purified by reverse phase HPLC to give N '-(spiro[3.3]heptane-2,6-diylbipyridazine-6,3-diyl)bis[2-(pyridin-2-yl)acetamide] (6.8 mg, 1%) as a colorless solid. ¹ H NMR (400 MHz,MeOD- d ₄ ) δ ppm 8.52 (d, J = 4 Hz, 2 H), 8.37 (d, J = 8 Hz, 2 H), 7.81 – 7.84(m, 2 H), 7.61 (d, J = 12 Hz, 2 H), 7.47 (d, J = 8 Hz, 2 H), 7.34 – 7.36 (m, 2 H), 4.04 (s, 4 H), 3.74 (quin, J = 8 Hz, 2 H), 2.45 – 2.72 (m, 2 H), 2.48 –2.54 (m, 2 H), 2.39 – 2.44 (m, 2 H), 2.33 – 2.39 (m, 2H). m/z (APCI+)521.1 (M+H) ⁺ for C ₂₉ H ₂₈ N ₈ O ₂ .

Example 26 (Scheme H): 2-(pyridin-2-yl) -N- {5-[(3-{6-[(pyridin-2-ylacetyl)amino]pyridin- Preparation of [3-oxazin-3-yl}cyclopentyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide

Step 1: Preparation of N- [6-(3-oxocyclopent-1-en-1-yl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide

To a 100 mL pressure flask charged with N- (6-bromopyridazin-3-yl)-2-(pyridin-2-yl)-acetamide (5 g, 17.1 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one (10.7 g, 51.2 mmol), Pd(dppf) _Cl₂ (1.39 g, 1.71 mmol), and CsF (13.0 g, 85.4 mmol) was added THF (142 mL) and water (22.9 mL) under nitrogen. After stirring at room temperature with nitrogen sparging for 5 minutes, the reaction vessel was placed in a preheated 100°C sand bath behind a blast shield. After 18 hours, the mixture was cooled to room temperature, concentrated, diluted with 750 mL _{of CH₂Cl₂} , and allowed to stir for 15 minutes.

The suspension was filtered through a plug of ^Celite® and concentrated. The residue was purified by silica gel chromatography eluting with 0-5% EtOH/EtOAc to provide N- [6-(3-oxocyclopent-1-en-1-yl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide (3.75 g, 75%) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.69 – 8.72 (m, 1 H), 8.56 (d, J = 8 Hz, 2 H), 7.78 – 7.82 (m, 2 H), 7.35 – 7.39 (m, 2 H), 6.76 (s, 1 H), 4.08 (s, 2 H), 3.27 – 3.29 (m, 2 H), 2.62 – 2.65 (m, 2 H). m/z (APCI+)295.1 (M+H) ⁺ for C ₁₆ H ₁₄ N ₄ O ₂ .

Step 2: Preparation of N- [6-(3-oxocyclopentyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide

N- [6-(3-Oxocyclopent-1-en-1-yl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide (1.5 g, 5.1 mmol) was placed in a 500 mL stainless steel Parr explosion-proof bottle and MeOH (255 mL) was added, followed by Pd/C (E101, 10%, wet, 150 mg). The reaction was stirred under 4 bar _H2 pressure for 7 hours. LCMS indicated approximately 50% conversion. Another portion of Pd/C (150 mg) was added, and the reaction was stirred at 50°C under 6 bar _H2 pressure for an additional 18 hours. LCMS indicated complete conversion to the desired product, with approximately 10% overreduction. The reaction was filtered through a ^Celite® plug and concentrated. The residue was purified by silica gel chromatography eluting with 0-5% EtOH/EtOAc to provide N- [6-(3-oxocyclopentyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide as a solid (877 mg, 58%). ¹ H NMR (400 MHz, MeOD- d ₄ ) δ ppm 8.68 – 8.70 (m,1 H), 8.44 (d, J = 8 Hz, 1 H), 7.75 – 7.79 (m, 1 H), 7.27 – 7.39 (m, 3 H), 4.06 (s, 2 H), 3.66 – 3.71 (m, 1 H), 2.66 – 2.76 (m, 2 H), 2.46 – 2.53 (m, 2H), 2.18 – 2.40 (m, 2 H). m/z (APCI+)297.1 (M+H) ⁺ for C ₁₆ H ₁₆ N ₄ O ₂ .

Step 3: N- {6-[( 3E )-3-(cyanomethylene)cyclopentyl]pyridazin-3-yl}-2-(pyridin-2-yl)acetamide Preparation

To a suspension of NaH (65.8 mg, 60% suspension, 1.65 mmol) in THF (4.2 mL) at 0°C was added (cyanomethyl)diethylphosphonate (292 mg, 1.65 mmol) dropwise. After stirring at room temperature for 10 minutes, the solution was diluted with THF (5 mL), and N- [6-(3-oxocyclopentyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide (250 mg, 0.84 mmol) was added in one portion. After 3 hours, the reaction was clean and complete by LCMS _and TLC. The reaction was quenched with saturated aqueous _NH4Cl solution and extracted with _CH2Cl2 . The organic layer was washed with brine, dried _{over Na2SO4} , and concentrated. The residue was purified by silica gel chromatography eluting with 0% - 5% EtOH/EtOAc to provide N- {6-[( 3E )-3-(cyanomethylene)cyclopentyl]pyridazin-3-yl}-2-(pyridin-2-yl)acetamide as a solid (245 mg, 91%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 11.30 (br s, 1 H), 8.48 – 8.50 (m, 1 H), 8.22 – 8.24 (m, 1 H), 7.74 – 7.76 (m, 1 H), 7.63 – 7.76 (m, 1 H), 7.40 – 7.42 (m, 1 H),7.27 – 7.28 (m, 1 H), 5.23 – 5.25 (m, 1 H), 4.00 (s, 2 H), 3.52 – 3.56 (m, 1H), 2.65 – 2.91 (m, 4 H), 2.23 – 2.27 (m, 1 H), 1.92 – 2.01 (m, 1H). m/z (APCI+)320.1 (M+H) ⁺ for C ₁₈ H ₁₇ N ₅ O.

Step 4: Preparation of N- {6-[3-(cyanomethyl)cyclopentyl]pyridazin-3-yl}-2-(pyridin-2-yl)acetamide

To a stirred solution of N- {6-[(3 £ )-3-(cyanomethylene)cyclopentyl]pyridazin-3-yl}-2-(pyridin-2-yl)acetamide (100 mg, 0.31 mmol) in THF (6.26 mL) was added lithium tri-sec-butylborohydride (L-Selectride) (1.56 mL, 1 M in THF, 1.56 mmol) at -78°C, and the reaction was stirred at -78°C for an additional 4 hours _. The reaction was quenched with _saturated aqueous _NH4Cl and allowed to warm to room temperature. The reaction was extracted with _CH2Cl2 , washed with brine, dried over _Na2SO4 , and concentrated. The residue was purified by silica gel chromatography eluting with 0% - 5% EtOH/EtOAc to provide N- {6-[3-(cyanomethyl)cyclopentyl]pyridazin-3-yl}-2-(pyridin-2-yl)acetamide (85 mg, 91%) as a 1:1 mixture of cis and trans diastereomers, which was used directly in the next step without further purification. ¹ H NMR (400MHz, CDCl ₃ ) δ ppm 8.61 – 8.63 (m, 1 H), 8.29 – 8.32 (m, 1 H), 7.55 – 7.65 (m,1 H), 7.13 – 7.24 (m, 3 H), 3.98 (s, 2 H), 3.32 – 3.45 (m, 2 H), 2.20 – 2.41 (m, 4 H), 1.64 – 2.01 (m, 5 H). m/z (APCI+)322.1 (M+H) ⁺ for C ₁₈ H ₁₉ N ₅ O.

Step 5: 2-(pyridin-2-yl) -N- {5-[(3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}cyclopentane Preparation of 1,3,4-thiadiazol-2-yl]-1,3,4-thiadiazole-2-yl}acetamide

To a vial containing N- {6-[3-(cyanomethyl)cyclopentyl]pyridazin-3-yl}-2-(pyridin-2-yl)acetamide (80 mg, 0.25 mmol) and thiosemicarbazide (25 mg, 0.27 mmol) was added trifluoroacetic acid (250 μL). The resulting suspension was placed in a preheated 70°C sand bath, at which point it became homogeneous. After 2 hours, the reaction was approximately 80% complete. The reaction was stirred at 70°C for an additional 2 hours, cooled to room temperature, and concentrated. The residue was quenched with saturated _{aqueous NaHCO₃} and extracted with _CH₂Cl₂ to provide a crude material that was purified by silica gel chromatography eluting with 0%-25% EtOH/EtOAc to provide 27 mg of the intermediate aminothiadiazole and 10 mg of recovered starting material. The aminothiadiazole was dissolved in DMF (70 μL) and 2-pyridylacetic acid hydrochloride (23 mg, 0.13 mmol) and pyridine (32.3 μL, 0.40 mmol) were added. To this mixture was added T3P (86.3 μL, 50% in DMF, 0.15 mmol), and the reaction was stirred at room temperature for 2 hours. LCMS indicated complete consumption of the starting material. The pyridine was removed in vacuo, and the residue was quenched with saturated aqueous _NaHCO3 . The mixture was extracted _{with CH2Cl2} , and the residue was dried _{over Na2SO4} and concentrated. The residue was purified by silica gel chromatography, eluting with 0% – 5% EtOH/EtOAc, to provide 2-(pyridin-2-yl) -N- {5-[(3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}cyclopentyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide (60 mg) as a 1:1 mixture of cis and trans diastereomers. This compound was evaluated by various purification methods, although conditions could not be identified to separate any of the four isomers. Further purification was performed by reverse phase HPLC to afford 2-(pyridin-2-yl) -N- {5-[(3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}cyclopentyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide (3 mg, 2%) as a solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.63 (br s, 1 H), 11.24 (d, J = 4 Hz,1 H), 8.49 (t, J = 8 Hz, 2 H), 8.18 (d, J = 4 Hz, 1 H), 7.76 (t, J = 8 Hz, 2H), 7.57 – 7.61 (m, 1 H), 7.39 (d, J = 8 Hz, 2 H), 7.26 – 7.29 (m, 2 H), 3.99(s, 4 H), 3.46 – 3.50 (m, 1 H), 3.29 – 3.39 (m, 1 H), 3.05 – 3.10 (m, 2 H),1.75 – 2.24 (m, 4 H), 1.51 – 1.59 (m, 1 H), 1.40 – 1.46 (m, 1 H). m/z (APCI+)515.1 (M+H) ⁺ for C ₂₈ H ₂₆ N ₈ O ₂ S.

Preparation Example 1. Preparation of (cis)-3-(methoxycarbonyl)cyclopentanecarboxylic acid

To a suspension of cis - 1,3-cyclopentanedicarboxylic anhydride (3.0 g, 21 mmol) in MeOH (35 mL) was added sodium methoxide (1.2 g, 21 mmol) in portions at room temperature. After 1 hour, the resulting clear solution was evaporated, basified with 1 M NaOH, and washed twice with EtOAc. The aqueous layer was then acidified to pH ~ 2 with 1 N HCl and extracted with CH ₂ Cl ₂ (3 x 25 mL). The combined organics were dried over Na ₂ SO ₄ and evaporated to give (cis)-3-(methoxycarbonyl)cyclopentanecarboxylic acid (2.7 g, 75%) as a clear oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.70 (s, 3 H), 2.76 – 2.94 (m, 2 H), 2.28 (dt, J = 13.3, 8.0 Hz, 1 H), 2.15 (dt, J = 13.3, 9.1 Hz, 1 H), 1.89 – 2.07 (m, 4H). m/z (APCI+)173.2 (M+H) ⁺ for C ₈ H ₁₂ O ₄ .

Preparation Example 2. Preparation of methyl 3-bromopropiolate

To methyl propiolate (60 g, 713.6 mmol) dissolved in acetone (2 L) was added N -bromosuccinimide (147.22 g, 827.13 mmol), followed by silver nitrate (12.12 g, 71.37 mmol). A slight exotherm was observed, and the reaction temperature increased from 21° C. to 32° C., after which the reaction mixture was stirred at room temperature overnight. The resulting grey suspension was evaporated to dryness in vacuo, pentane (100 mL) was added, and filtered through ^Celite® , washing with more pentane. This procedure was repeated twice, and the combined filtrate was then evaporated in vacuo to obtain 113 g of methyl 3-bromopropiolate (98% yield) containing approximately 10% of the starting material. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.78 (s, 3 H).

Preparation Example 3. Preparation of methyl 3-bromobicyclo[2.2.1]hept-2,5-diene-2-carboxylate

Methyl 3-bromopropiolate (113 g, 698 mmol) and freshly cracked cyclopentadiene (92 g, 1.39 mol) were dissolved in toluene (570 mL) and heated to 90°C under nitrogen for 2 hours. The reaction was cooled to room temperature, and the toluene was evaporated in vacuo to give a dark brown oil. This was azeotroped three times with acetonitrile to remove excess dicyclopentadiene, affording the title compound (119 g, 74% yield) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.88– 6.94 (m, 1 H), 6.85 (ddd, J = 5.2, 3.1, 1.0 Hz, 1 H), 4.00 (dqd, J = 2.8,1.7, 0.8 Hz, 1 H), 3.76 (s, 3 H), 3.69 (ddtd, J = 3.2, 2.4, 1.5, 0.7 Hz, 1H), 2.32 (dt, J = 6.7, 1.7 Hz, 1 H), 2.13 (dt, J = 6.7, 1.7 Hz, 1 H).

Preparation Example 4. Preparation of 3,3-dimethoxybicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester

3-Bromobicyclo[2.2.1]hept-2,5-diene-2-carboxylic acid methyl ester (119.0 g, 519.5 mmol) was dissolved in MeOH (1 L) and sodium methoxide (30% solution in 289 mL MeOH) was added, and the reaction mixture was heated under reflux for 45 minutes, followed by addition of saturated NaHCO ₃ aqueous solution (500 mL), followed by addition of water (500 mL) and TBME (1 L). The TBME layer was separated, and the aqueous layer was extracted once more with TBME (1 L). The combined organic extracts were dried over MgSO ₄ and evaporated in vacuo to give 3,3-dimethoxybicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester (75.0 g, 68%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.60 (dd, J = 5.7, 2.8 Hz, 0.5 H), 6.25 (dd, J = 5.6, 3.0 Hz, 0.5 H), 6.13 – 6.18 (m, 0.5 H), 6.07 (dd, J = 5.6, 3.1Hz, 0.5 H), 3.67 (d, J = 18.5 Hz, 3 H), 3.40 (s, 1.5 H), 3.31 (s, 1.5 H), 3.24 (s, 1.5 H), 3.17 (s, 1.5 H), 3.06 (d, J = 3.4 Hz, 0.5 H), 2.92 – 3.04(m, 2 H), 2.50 (d, J = 2.7 Hz, 0.5 H), 2.18 (ddt, J = 9.0, 1.6, 0.9 Hz, 0.5H), 1.67 – 1.73 (m, 0.5 H), 1.63 (dq, J = 9.1, 2.2 Hz, 1 H).

Preparation Example 5. Preparation of methyl 3-oxobicyclo[2.2.1]hept-5-ene-2-carboxylate

3,3-Dimethoxybicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester (75.0 g, 353.37 mmol) was dissolved in THF (400 mL) and 2 M HCl (400 mL) was added. The mixture was stirred at room temperature for 1 hour, then diluted with TBME (1000 mL) and the layers were separated. The aqueous layer was extracted once more with TBME (1000 mL), and the combined organic extracts were dried over _MgSO4 and evaporated in vacuo to give 3-oxobicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester (55.0 g, 93%) as a yellow oil as a mixture of diastereomers. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm6.77 (dd, J = 5.4, 2.7 Hz, 1 H), 6.03 – 6.09 (m, 1 H), 3.72 (d, J = 13.0 Hz, 3 H), 3.34 (dq, J = 2.8, 1.4 Hz, 1 H), 3.18 – 3.23 (m, 1 H), 3.16 (dt, J =3.1, 0.7 Hz, 1 H), 2.14 (dddd, J = 9.6, 2.4, 1.4, 0.6 Hz, 1 H), 1.92 (dtd, J = 9.1, 1.5, 0.8 Hz, 1 H).

Preparation Example 6. Preparation of (cis)-4-(2-methoxy-2-oxoethyl)cyclopent-2-enecarboxylic acid

Methyl 3-oxobicyclo[2.2.1]hept-5-ene-2-carboxylate (55.21 g, 332.24 mmol) was dissolved in dioxane (600 mL) and cooled to 0°C. After adding NaOH (2 M, 149.51 mL, 299.02 mmol) dropwise over 30 minutes, the reaction was stirred for an additional 30 minutes and then quenched with HCl (3 M, 100 mL). The resulting mixture was extracted with EtOAc (2 x 500 mL). After drying the organic layer over MgSO ₄ , the solvent was removed under reduced pressure to give a brown oil, which was purified by flash chromatography, eluting with pure CH ₂ Cl ₂ , followed by 10%/CH ₂ Cl ₂ , and then 15%/CH ₂ Cl ₂ and 20%/CH ₂ Cl ₂ . Evaporation of the appropriate fractions gave (cis)-4-(2-methoxy-2-oxoethyl)cyclopent-2-enecarboxylic acid (40.4 g, 66%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 5.85 (dt, J = 5.7, 2.3 Hz, 1 H), 5.79 (dt, J = 5.6, 2.2 Hz, 1 H), 3.68 (s, 3 H), 3.60 (ddq, J = 9.0, 6.9, 2.4 Hz, 1 H), 3.09 – 3.23 (m, 1 H), 2.36 – 2.55 (m, 3 H), 1.79 (dt, J = 13.3, 6.5 Hz, 1 H).

Preparation Example 7. Preparation of (cis)-3-(2-methoxy-2-oxoethyl)cyclopentanecarboxylic acid

(cis)-3-oxobicyclo[2.2.1]heptane-2-methyl carboxylate (40.4 g, 219.3 mmol) was dissolved in EtOAc (400 mL) and 10% wt. Pd/C (2 g, 5% w/w relative to substrate) was added. The mixture was then stirred at room temperature for 2 hours under a 50 psi hydrogen atmosphere. The catalyst was then removed by filtration through a ^Celite pad and the filtrate was evaporated to give a light yellow oil (41 g). ¹ H NMR showed trace impurities; heptane was added, and the suspension was filtered and evaporated to give (cis)-3-(2-methoxy-2-oxoethyl)cyclopentanecarboxylic acid (31 g, 76% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.67 (s, 3 H), 2.85 (ddd, J = 8.8, 7.5, 1.5 Hz, 1 H), 2.37 –2.43 (m, 2 H), 2.15 – 2.37 (m, 2 H), 1.84 – 2.01 (m, 3 H), 1.49 (dt, J =12.6, 9.4 Hz, 1 H), 1.29 – 1.42 (m, 1 H).

Preparation Example 8. Preparation of (cis)-3-(carboxymethyl)cyclopentanecarboxylic acid

(cis)-3-(2-methoxy-2-oxoethyl)cyclopentanecarboxylic acid (10.6 g, 56.93 mmol) was dissolved in 2 M NaOH (56.9 mL) and stirred at room temperature for 2 hours. The reaction was acidified to pH ~4 with concentrated HCl under ice cooling and stirred at room temperature overnight to allow crystallization. The resulting solid was filtered, washed thoroughly with water, and dried under vacuum at 60°C to yield (cis)-3-(carboxymethyl)cyclopentanecarboxylic acid (6.70 g, 68%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.00 (s, 2 H), 2.61 – 2.78 (m, 1 H), 2.21 – 2.28 (m, 2 H), 2.10 – 2.21 (m, 1 H), 2.02 (dt, J = 12.4, 7.4 Hz, 1 H), 1.70 – 1.84 (m, 3 H), 1.14 – 1.38 (m, 2 H).

Alternative Preparation Example 8. Preparation of (cis)-3-(carboxymethyl)cyclopentanecarboxylic acid

(cis)-3-(2-methoxy-2-oxoethyl)cyclopentanecarboxylic acid (10.6 g, 56.93 mmol) was dissolved in 2 M NaOH (56.9 mL) and stirred at room temperature for 2 hours. The reaction was acidified to approximately pH 4 with concentrated HCl under ice cooling and stirred at room temperature overnight to allow crystallization. The resulting solid was filtered, washed thoroughly with water, and dried under vacuum at 60°C to yield (cis)-3-(carboxymethyl)cyclopentanecarboxylic acid (6.70 g, 68%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.00 (s, 2 H), 2.61 – 2.78 (m, 1 H), 2.21 – 2.28 (m, 2 H), 2.10 – 2.21 (m, 1 H), 2.02 (dt, J = 12.4, 7.4 Hz, 1 H), 1.70 – 1.84 (m, 3 H), 1.14 – 1.38 (m, 2 H).

Preparation Example 9. Preparation of Bicyclo[3.2.1]oct-2-ene

To a stirred solution of norbornene (120 g, 1.27 mol) and triethylbenzylammonium chloride (900 mg, 3.95 mmol) in CHCl ₃ (129 mL) was added 50% aqueous NaOH solution (130 mL). The resulting solution was stirred at room temperature for 3 days. Water (130 mL) was added and the reaction was filtered. The precipitate was washed with CH ₂ Cl ₂ (approximately 500 mL), and the combined organic layers were washed with brine (2 x 300 mL), dried over Na ₂ SO ₄ , and concentrated to give a crude product, which was purified by distillation to give 3,4-dichlorobicyclo[3.2.1]oct-2-ene (123 g, 54%) as a yellow oil.

To a well-stirred solvent of liquid _NH₃ (approximately 500 mL) at approximately -65°C was added Na (24 g, 1.04 mol) in portions over a 40-minute period. After stirring for approximately 20 minutes, a solution of 3,4-dichlorobicyclo[3.2.1]oct-2-ene (20 g, 0.11 mol) in t -BuOH (20 mL) and THF (20 mL) was added dropwise. During the addition, a large amount of precipitate formed. The reaction mixture was stirred at approximately -65°C for approximately another 3 hours. TLC (petroleum ether, detected by _I₂ ) indicated that the reaction was complete. The reaction mixture was warmed to approximately 35°C, solid _NH₄Cl (30 g) was slowly added, and the reaction was stirred for 20 minutes. The resulting mixture was poured into a 5 L beaker, water (300 mL) was slowly added, and the mixture was stirred for 20 minutes. The reaction flask was carefully washed with EtOH to quench any residual sodium. The mixture was extracted with _CH2Cl2 (2 x 500 mL), the organic layer was washed _with water (200 _mL ), dried over _Na2SO4 , and concentrated in vacuo at about 25°C to give bicyclo[3.2.1]oct-2-ene (8 g, ~80% pure, bpt ~138 C, 66%) as a light yellow oil which was used without further purification (for references on the synthesis of the olefin and alternative routes that have been utilized from 4-vinylcyclohex-1-ene, see Tetrahedron Lett ., 2004, 45 , 9447 and Tetrahedron Lett ., 1976, 16 , 1257).

Preparation Example 10. Preparation of (1 S, 3 R )-3-(carboxymethyl)cyclopentanecarboxylic acid

To a well-stirred mixture of bicyclo[3.2.1]oct-2-ene (25 g, 231 mmol) and RuCl ₃ .H ₂ O (1.04 g, 4.62 mmol) in MeCN (250 mL), EtOAc (250 mL) and water (350 mL) was added NaIO ₄ (295 g, 231 mmol) in portions at room temperature over a period of about 60 minutes. The resulting mixture was stirred at room temperature for about 16 hours. TLC (petroleum ether) showed that the reaction was complete. The reaction mixture was filtered, and the filter cake was washed with EtOAc (about 700 mL) and water (300 mL). The organic layer was washed with brine (500 mL), dried over Na ₂ SO ₄ , filtered through Celite ^® and concentrated in vacuo to obtain a gummy residue (30 g). The residue was dissolved in water (about 200 mL) and basified to pH ~10 with a 2M NaOH aqueous solution. The aqueous solution was washed with EtOAc (400 mL), acidified to pH ~4, and then extracted with EtOAc (2 x ₅₀₀ mL). The combined organic layers were dried over _Na2SO4 and concentrated under high vacuum to give racemic (cis)-3-(carboxymethyl)cyclopentanecarboxylic acid (26 g, >90% purity, 65%) as a light brown solid, which was subjected to chiral SFC separation.

A batch of 105 g of the racemic diacid was subjected to chiral separation by SFC using a Chiralcel AD-3 3 μm column (4.6 x 100 mm) eluting with 10 % MeOH at 120 bar with a flow rate of 4 mL/min.

(1R , 3S )-3-(Carboxymethyl)cyclopentanecarboxylic acid (49.2 g) was obtained as Peak 1 ( _Rt = 1.45 min, >99% ee) as a ^white solid; _[ α] ^22D = -7.1° (c = 1.0, MeOH) _.1H NMR (400 MHz, DMSO -d6 ) δ ppm 12.00 (s, 2H), 2.61–2.78 (m, 1H), 2.21–2.28 (m, 2H), 2.10–2.21 (m, 1H), 2.02 (dt, J = 12.4, 7.4 Hz, 1H), 1.70–1.84 (m, 3H), 1.14–1.38 (m, 2H).

(1S , 3R )-3-(Carboxymethyl)cyclopentanecarboxylic acid (49 g) was obtained as Peak 2 ( _Rt = 2.33 min, >99% ee); [α] ^22D = ₊ 7.1° (c = 1.0, MeOH). ^1H NMR (400 MHz, DMSO -d6 ) δ ppm 12.00 (s, _2H ), 2.61–2.78 (m, 1H), 2.21–2.28 (m, 2H), 2.10–2.21 (m, 1H), 2.02 (dt, J = 12.4, 7.4 Hz, 1H), 1.70–1.84 (m, 3H), 1.14–1.38 (m, 2H).

The following examples are performed with noncritical variations or substitutions to the illustrated procedures as will be appreciated by those skilled in the art.

*The compound is a single enantiomer; however, the absolute stereochemistry is unknown. (Stereochemistry is depicted based on the biological activity of compounds for which the absolute stereochemistry is known.)

**Compound is a racemate containing two cis enantiomers.

**Compound is a racemate containing two cis enantiomers.

***Compounds are racemic or mixtures of diastereomers obtained from commercial diacids.

Total L-glutamate determination in cancer cell lysates

Cancer cell lines (BT20, HCT116, SKOV3, HCC70, SUM149, MDA-MB-231, etc.) were plated in 96-well plates and used for total L-glutamate measurement when the monolayer reached approximately 80% confluence. The medium was replaced, and fresh medium containing L-glutamine was added to the 96-well plates. The cells were then immediately incubated with the test compound. The test compound was diluted in 100% DMSO using two- or three-fold serial dilutions. A small volume of the test compound dilution was added to the 96-well plate, resulting in a final DMSO concentration of 0.5% v/v in the cell culture medium. The cells were incubated for 2 hours at 37°C, 5% _CO₂ , and 95% CO₂. After the 2-hour incubation, the cells were washed twice with water. After the final water wash, 100 µL of 50 mM Tris-HCl, pH 7.4, and 0.01% Tween-20 was added to each well, and the plates were frozen at -80°C. The 96-well plate was frozen and thawed a total of three times and then sonicated in a bath sonicator for 5 minutes at 4° C. After sonication, the 96-well plate was centrifuged at 1000 rpm for 5 minutes and 10 μL of the supernatant was transferred to a 384-well assay plate.

Total L-glutamate (L-glutamate) in cell lysate supernatants is detected using glutamate oxidase, horseradish peroxidase, and Amplex Red reagent (10-acetyl-3,7-dihydroxyphenazine, Invitrogen # _A22177 ). In this assay, L-glutamate is oxidized by glutamate oxidase to produce α-ketoglutarate (2-oxopentanedioic acid), _NH₃ , and _H₂O₂ . Horseradish peroxidase (HRP) oxidizes the Amplex Red reagent using _H₂O₂ (hydrogen peroxide) to produce _resorufin , a fluorescent molecule. When resorufin is excited with light of a wavelength of 530-560 nm, it emits light at approximately 585 nm. To detect total L-glutamate in 10 µL of lysate, 15 µL of the enzyme mix is added to each well of a 384-well assay plate. The enzyme mixture is made up of 50 mMTris-HCl pH 7.4, 0.01% Tween-20, 50 μM Amplex Red reagent (ultimate concentration), 0.04U/mL L-glutamate oxidase (ultimate concentration) and 0.125U/mL HRP (ultimate concentration). 384-well assay plates were incubated at room temperature for 5 minutes, then in a fluorometer based on plate such as LJL Analyst or Tecan Infinite plate reader, 530-560 nm excitation wavelength was used to measure the fluorescence intensity in each hole at 585 nm. The dilution of L-glutamic acid standard was used to construct a standard curve for this mensuration. By drawing relative fluorescence units with respect to the log of inhibitor concentration and fitting data to a four-parameter logistic equation to calculate IC ₅₀ .

Reference: Chapman J. and Zhou M. (1999) Microplate-based fluorometricmethods for the enzymatic determination of l-glutamate: application inmeasuring l-glutamate in food samples. Analytica Chim Acta 402:47-52.

The assay results of the tested compounds are listed in Table 2.

.

Claims (19)

1. Compounds of formula (IVa), in L is -( _C4 - _C10 cycloalkyl)-; ^R1 is -C(O) ^R10a ; ^R2 is -C(O) ^R10b ; ^R3 and ^R4 are hydrogen; ^R7 and ^R8 are each independently hydrogen, halogen, cyano, _C1 - _C2 alkyl, hydroxyl, _C1 - _C2 alkoxy or -N( ^R11 )( ^R12 ), wherein the _C1 - _C2 alkyl and C1 _{- C2} alkoxy are each independently optionally substituted with halogen or hydroxyl. ^R10a and ^R10b are each independently _C1 - _C4 alkyl, -[C( ^R13 )( ^R14 )] _z- ( _C6 - _C10 aryl) or -[C( ^R13 )( ^R14 )] _z- (5-10 heteroaryl), wherein the _C1 - _C4 alkyl, _C6 - _C10 aryl and 5-10 heteroaryl are each independently optionally substituted by one, two or three of the following groups: halogen, cyano, _C1 - _C6 alkyl, hydroxyl or _C1 - _C6 alkoxy; ^R11 and ^R12 are hydrogen; ^R13 and ^R14 are hydrogen; x is 1; and z is 0, 1, 2, or 3; Or its pharmaceutically acceptable salt. 2. The compound or salt of claim 1, wherein L is . 3. The compound or salt of claim 2, wherein L is . 4. The compound or salt of claim 3, wherein L is . 5. The compound or salt of claim 2, wherein ^R10a is -[C( ^R13 )( ^R14 )] _z- ( _C6 aryl) or -[C( ^R13 )( ^R14 )] _z- (5-6 heteroaryl) and ^R10b is -[C( ^R13 )( ^R14 )] _z- ( _C6 aryl) or -[C( ^R13 )( ^R14 )] _z- (5-6 heteroaryl), wherein the _C6 aryl and 5-6 heteroaryl in ^R10a and ^R10b are each optionally and independently substituted by one or two halogens or _C1 - _C4 alkyl groups. 6. The compound or salt of claim 2, wherein ^R10a is -[C( ^R13 )( ^R14 )] _z- (5-6 heteroaryl) and ^R10b is -[C( ^R13 )( ^R14 )] _z- (5-6 heteroaryl), wherein the 5-6 heteroaryl groups in ^R10a and ^R10b are each optionally and independently substituted by one or two _C1 - _C4 alkyl groups. 7. The compound or salt of claim 2, wherein ^R10a is _-CH2 -pyridyl and ^R10b is _-CH2 -pyridyl, wherein each pyridyl group is optionally substituted with one or two _C1 - _C4 alkyl groups. 8. The compound of claim 1, wherein it is , Or its pharmaceutically acceptable salt. 9. The compound of claim 1, wherein it is , Or its pharmaceutically acceptable salt. 10. The compound of claim 1, wherein it is , Or its pharmaceutically acceptable salt. 11. The compound of claim 1, wherein it is , Or its pharmaceutically acceptable salt. 12. The compound of claim 1, wherein it is , Or its pharmaceutically acceptable salt. 13. The compound of claim 1, wherein it is , Or its pharmaceutically acceptable salt. 14. The compound of claim 1, wherein it is , Or its pharmaceutically acceptable salt. 15. The compound of claim 1, wherein it is , Or its pharmaceutically acceptable salt. 16. The compound of claim 1, wherein it is , Or its pharmaceutically acceptable salt. 17. The compound of claim 1, wherein it is , Or its pharmaceutically acceptable salt. 18. The compound of claim 1, wherein it is , Or its pharmaceutically acceptable salt. 19. A pharmaceutical composition comprising a compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.