This application is a continuation application of U.S. patent application Ser. No. 17/694,311, filed Mar. 14, 2022, which claims priority to U.S. Provisional Application No. 63/161,347 filed on Mar. 15, 2021, and U.S. Provisional Application No. 63/266,572, filed Jan. 9, 2022, the contents of which are incorporated herein by reference in their entireties.

›BACKGROUND OF THE INVENTION · 1 of 2

Pathological accumulation of glycogen is a hallmark of several devastating and chronic human diseases. For some of these disorders, the cellular etiology driving this aberrant accumulation has clear genetic underpinnings and for others the mechanistic driving force is more complex. Nonetheless, the consequence of elevated levels of glycogen is altered cellular homeostasis and impaired tissue function over time. The rate limiting enzyme in the glycogen synthesis pathway is the protein Glycogen Synthase (GYS). In humans there are two isoforms GYS1 & GYS2. The former is ubiquitously expressed but highly abundant in muscle cells, while the latter is expressed exclusively in liver. Glycogen synthesis ultimately begins with transport of glucose into cells via the GLUT transporter family of proteins. Conversion of glucose into glycogen follows along a well characterized biochemical conversion pathway to the step where GYS covalently links glucose molecules into long branches via α1,4-glycosidic linkages. The final spherical structure of glycogen results from the action of Glycogen Branching Enzyme (GBE) which introduces α1,6-linkage branch points along the strands. The result of this biochemical chain of events is the generation of an energy dense and highly soluble molecule that can be stored in the cytosol of cells for rapid catabolism into glucose energy when needed. An imbalance in the equilibrium of either glycogen synthesis or glycogenolysis can result in aberrant accumulation of cellular stores of glycogen. It has long been hypothesized that substrate reduction therapy targeted to inhibit glycogen synthase could be an effective treatment for diseases of glycogen storage. Indeed, substrate reduction therapy drugs have been very successful in modulating patient disease course in other storage disorders including Gaucher and Fabry diseases (Platt F M, Butters T D. Substrate Reduction Therapy. Lysosomal Storage Disorders, Springer US chapter 11, pgs 153-168, 2007; Shemesh E, et al. Enzyme replacement and substrate reduction therapy for Gaucher disease. Cochrane Database of Systematic Reviews, Issue 3, 2015). It is the aim of this invention to inhibit glycogen synthase enzyme activity resulting in reduction of tissue glycogen stores with therapeutic benefit to patients suffering the consequences of aberrant cellular glycogen accumulation.

Pompe Disease is a rare genetic disorder caused by the pathological buildup of cellular glycogen due to loss of function (LOF) mutations in the lysosomal enzyme α-glucosidase (GAA). GAA catabolizes lysosomal glycogen and in its absence, glycogen builds up in lysosomes. This triggers a disease cascade beginning with lysosome and autophagosome dysfunction, leading ultimately to cell death and muscle atrophy over time (Raben N, et al. Autophagy and mitochondria in Pompe Disease: nothing is so new as what has long been forgotten. American Journal oMedical Genetics, vol. 160, 2012. van der Ploeg A T and Reuser A J J, Pompe's Disease. Lancet vol. 372, 2008). In humans, the clinical manifestation of the disease results in a spectrum of severity and occurs at a prevalence of one in 40,000 live births (Meena N K, Raben N. Pompe disease: new developments in an old lysosomal storage disorder. Biomolecules, vol. 10, 2020). Infantile onset patients are born with cellular pathology and rapidly develop severe impairments including myopathy, heart defects, organomegaly, and hypotonia which collectively left untreated will take the child's life within a year. The later onset children may develop heart enlargement but are characterized consistently by the progressive loss of motor function, degeneration of skeletal muscle, and ultimate failure of the respiratory system leading to early death. Late onset adult Pompe patients exhibit normal heart function but develop progressive muscle weakness and respiratory decline then failure. The current standard of care for Pompe patients is enzyme replacement therapy (ERT) with recombinant human GAA. ERT treatment has been successful in slowing the rate of disease progression but in the majority of patients there remains incredible unmet need (Schoser B, et al. The humanistic burden of Pompe disease: are there still unmet needs? A systematic review. BMC Neurology, vol. 17, 2017). For over a decade, substrate reduction therapy targeting GYS1 has been hypothesized to be beneficial for the treatment of Pompe disease. In fact, three separate preclinical modalities have demonstrated that GYS1 genetic LOF in Pompe model mice effectively reduces tissue glycogen and improves mouse disease outcomes (Douillard-Guilloux G, et al. Modulation of glycogen synthesis by RNA interference: towards a new therapeutic approach for glycogenosis type I. Human Molecular Genetics, vol. 17, no. 24, 2008; Douillard-Guilloux G, et al. Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease. Human Molecular Genetics, vol. 19, no. 4, 2010; Clayton N P, et al. Antisense oligonucleotide-mediated suppression of muscle glycogen synthase 1 synthesis as an approach for substrate reduction therapy of Pompe Disease. Molecular Therapy—Nucleic Acids, vol. 3, 2014). A small molecule GYS1 inhibitor could be used to address the current unmet needs for Pompe patients either as a single therapy or in combination with standard of care ERT.

Pompe disease is only one of more than a dozen diseases caused by an inborn error of metabolism that result in aberrant build-up of glycogen in various tissues of the body. For some glycogen storage diseases (GSDs), specific dietary regimes effectively manage the disease but for others there are no clinically approved therapeutic interventions to modify disease course. Therefore, inhibition of glycogen synthesis and the concomitant reduction in tissue glycogen levels may be a viable treatment option for these patients. Cori disease, GSD III, is caused by mutations in the glycogen debranching enzyme (GDE) which results in pathological glycogen accumulation in the heart, skeletal muscle, and liver (Kishnani P, et al. Glycogen storage disease type III diagnosis and management guidelines. Genetics in Medicine, vol. 12, no. 7, 2010). While dietary management can be effective in ameliorating aspects of the disease there is currently no treatment to prevent the progressive myopathy in GSD III. Adult polyglucosan body disease (APBD) is an adult-onset disorder caused by loss of activity in the glycogen branching enzyme (GBE1). Deficiency in GBE results in accumulation of long strands of unbranched glycogen which precipitate in the cytosol generating polyglucosan bodies, and ultimately triggering neurological deficits in both the central and peripheral nervous systems. Genetic deletion of GYS1 in the APBD mouse model rescued deleterious accumulation of glycogen, improved life span, and neuromuscular function (Chown E E, et al. GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease. Annals of Clinical and Translational Neurology, vol. 7, no. 11, 2020). Lafora Disease (LD) is a very debilitating juvenile onset epilepsy disorder also characterized by accumulation of polyglucason bodies. Genetic cross of LD mouse models with GYS1 knock out (KO) mice resulted in rescue of disease phenotypes (Pedersen B, et al. Inhibiting glycogen synthesis prevents Lafora disease in a mouse model. Annals of Neurology, vol. 74, no. 2, 2013; Varea O, et al. Suppression of glycogen synthesis as a treatment for Lafora disease: establishing the window of opportunity. Neurobiology of Disease, 2020).

›BACKGROUND OF THE INVENTION · 2 of 2

The reliance on high levels of glycogen by clear cell cancers has recently emerged as a novel therapeutic target. Ewing sarcoma 4(ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma breast cancer (GRCC), acute myeloid leukemia (AML), and nonsmall-cell lung carcinoma (NSCLC) are all examples of cancers histopathologically defined by PAS+ abnormally high levels of cellular glycogen. Elevated transcriptional levels of GYS1 have been significantly correlated with poor disease outcomes in NSCLC (Giatromanolaki A, et al. Expression of enzymes related to glucose metabolism in non-small cell lung cancer and prognosis. Experimental Lung Research, vol. 43, no. 4-5, 2017) and AML (Falantes J F, et al. Overexpression of GYS1, MIF, and MYC is associated with adverse outcome and poor response to azacitidine in myelodysplastic syndromes and acute myeloid leukemia. Clinical Lymphoma, Myeloma & Leukemia, vol. 15, no. 4, 2015). Lentiviral knockdown of GYS1 in cultured myeloid leukemia cells potently inhibited in vitro cancer cell growth and in vivo tumorigenesis (Bhanot H, et al. Pathological glycogenesis through glycogen synthase I and suppression of excessive AMP kinase activity in myeloid leukemia cells. Leukemia, vol. 29, no. 7, 2015). Genetic knock-down of GYS1 in ccRCC cell models both suppresses tumor growth in vivo and increases the synthetic lethality of sunitinub (Chen S, et al. GYS1 induces glycogen accumulation and promotes tumor progression via the NF-kB pathway in clear cell renal carcinoma. Theranostics, vol. 10, no. 20, 2020).

Reduction of GYS1 enzyme activity and reduced cellular stores of glycogen in preclinical models of Pompe disease, APBD, LD, AML, ccRCC, and NSCLC all provide compelling evidence of the potential therapeutic benefit of inhibiting glycogen synthesis. It is the aim of this invention to inhibit glycogen synthase enzyme activity resulting in reduction of tissue glycogen stores with therapeutic benefit to patients suffering the consequences of accumulated cellular glycogen.

›BRIEF SUMMARY OF THE INVENTION · 1 of 5

In one aspect, provided herein is a compound of formula (I′):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

Y 2 and Y 3 are each C, or

one of Y 2 and Y 3 is N and the other of Y 2 and Y 3 is C;

X 1 and X 2 are each independently H, C 1-6 alkyl, or C 1-6 alkoxy;

X 3 and X 4 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl of X 3 and X 4 is optionally substituted with one of more halo;

X 5 is H, C 1-6 alkyl, C 1-6 alkoxy, or C 3-10 cycloalkyl;

either

(1) L 1 is absent; and

Q 1 is selected from (i) to (iv):

(i) phenyl, wherein the phenyl of Q 1 is substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C 3-10 cycloalkyl, or 5-20 membered heteroaryl, wherein

the C 1-6 alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl,

(ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q 1 is optionally substituted with one or more oxo, or C 1-6 alkyl,

(iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein, the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, and

(iv) C 3-10 cycloalkyl;

(2) L 1 is —CH 2 —; and

Q 1 is C 3-10 cycloalkyl;

L 2 is —C(O)— or —S(O) 2 —

R 1 is H or C 1-6 alkyl;

R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl;

R m is H, —OH, or C 1-6 alkyl;

R n is H, C 1-6 alkyl, or C 3-10 cycloalkyl or R n taken together with the carbon atom to which it is attached forms C 3-5 cycloalkyl;

or R k is taken together with either R m or R n , and the atoms to which they are attached, to form cyclopropyl; and

R 2 is selected from (i) to (vii):

(i) C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a , wherein R a is:

(a) —OH, (b) cyano, (c) C 2-6 alkynyl, (d) C 6-20 aryl, wherein the C 6-20 aryl of R a is optionally substituted with one or more halo, cyano, C 1-6 alkoxy, or —NH—C(O)—C 1-6 alkyl, (e) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c , wherein

R c is halo, oxo, C 1-6 alkyl, C 1-6 alkoxy, —C(O)—C 1-6 alkyl, or —C(O)—C 1-6 alkoxy, wherein

the C 1-6 alkyl of R c is optionally substituted with one or more halo or C 2-6 alkynyl, and the —C(O)—C 1-6 alkoxy of R c is optionally substituted with one or more halo,

(f) —N(R c )(R d ), wherein R c and R d of N(Rc)(Rd) are, independently of each other, H, C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, —C(O)—NH 2 , —C(O)—NH(C 1-6 alkyl), —C(O)—N(C 1-6 alkyl) 2 , —C(O)-(3-15 membered heterocyclyl), —CH 2 —C(O)—NH 2 , 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, wherein

the C 1-6 alkyl of R c or R d is optionally substituted with one or more —C(O)—NH 2 , the —C(O)—C 1-6 alkyl of R c or R d is optionally substituted with one or more halo, the 3-15 membered heterocyclyl and the 5-20 membered heteroaryl of R c or R d are independently optionally substituted with one or more C 1-6 alkyl, the —C(O)-(3-15 membered heterocyclyl) of R c or R d is optionally substituted with one or more halo, —C(O)—C 1-6 alkoxy, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl, and the C 1-6 alkyl of the —C(O)—N(C 1-6 alkyl) 2 of R c or R d are, independently of each other, optionally substituted with one or more halo or C 6-20 aryl,

(g) —O—R e , wherein R e is C 1-6 alkyl, C 6-20 aryl, —C(O)-(3-15 membered heterocyclyl), —C(O)—N—(C 1-6 alkyl) 2 , or 5-20 membered heteroaryl, wherein

the C 1-6 alkyl of R e is optionally substituted with one or more C 1-6 alkoxy, wherein the C 1-6 alkoxy is optionally substituted with one or more C 2-6 alkynyl, the C 6-20 aryl of R e is optionally substituted with one or more C 1-6 alkyl, and the —C(O)-(3-15 membered heterocyclyl) of R e is optionally substituted with one or more C 1-6 alkyl, C 1-6 alkoxy, or —C(O)—C 1-6 alkoxy, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl,

(h) —C(O)—R e , wherein R e of —C(O)—R e is —NH 2 , —OH, or 3-15 membered heterocyclyl, or (i) —S(O) 2 —R f , wherein R f is C 1-6 alkyl or 3-15 membered heterocyclyl,

provided that, when R 2 is unsubstituted methyl, then either

(1) Q 1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , C 3-10 cycloalkyl, or —OH, and wherein Q 1 is not unsubstituted pyridyl, or (2) Q 1 is phenyl, wherein the phenyl of Q 1 is substituted with

R s is halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)—C 1-6 alkyl, C 6-20 aryl, C 3-10 cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C 1-6 alkoxy, wherein

In one aspect, provided herein is a compound of formula (I):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl,

›BRIEF SUMMARY OF THE INVENTION · 2 of 5

(ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q 1 is optionally substituted with one or more oxo, and (iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein

the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl;

R 1 is H or C 1-6 alkyl; R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl; R m is H, —OH, or C 1-6 alkyl; R n is H, C 1-6 alkyl, or C 3-10 cycloalkyl; or R k is taken together with either R m or R n , and the atoms to which they are attached, to form cyclopropyl; and R 2 is selected from (i) to (vii): (i) C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a , wherein R a is:

(a) —OH, (b) cyano, (c) C 2-6 alkynyl, (d) C 6-20 aryl, wherein the C 6-20 aryl of R a is optionally substituted with one or more halo, cyano, C 1-6 alkoxy, or —NH—C(O)—C 1-6 alkyl, (e) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b , wherein

R b is halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , C 3-10 cycloalkyl, 3-15 membered heterocyclyl, or —C(O)—C 1-6 alkoxy, wherein

the C 1-6 alkyl of R b is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, and the 3-15-membered heterocyclyl of R b is optionally substituted with one or more halo or —C(O)—C 1-6 alkoxy,

(f) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c , wherein

R c is halo, oxo, C 1-6 alkyl, C 1-6 alkoxy, —C(O)—C 1-6 alkyl, or —C(O)—C 1-6 alkoxy, wherein

the C 1-6 alkyl of R c is optionally substituted with one or more halo or C 2-6 alkynyl, and the —C(O)—C 1-6 alkoxy of R c is optionally substituted with one or more halo,

(g) —N(R c )(R d ), wherein R c and R d are, independently of each other, H, C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, —C(O)—NH 2 , —C(O)—NH(C 1-6 alkyl), —C(O)—N(C 1-6 alkyl) 2 , —C(O)-(3-15 membered heterocyclyl), —CH 2 —C(O)—NH 2 , 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, wherein

the —C(O)—C 1-6 alkyl of R c or R d is optionally substituted with one or more halo, the 3-15 membered heterocyclyl and the 5-20 membered heteroaryl of R c or R d are independently optionally substituted with one or more C 1-6 alkyl, and the —C(O)-(3-15 membered heterocyclyl) of R c or R d is optionally substituted with one or more halo, —C(O)—C 1-6 alkoxy, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl,

(h) —O—R e , wherein R e is C 1-6 alkyl, C 6-20 aryl, —C(O)-(3-15 membered heterocyclyl), —C(O)—N—(C 1-6 alkyl) 2 , or 5-20 membered heteroaryl, wherein

(i) —C(O)—R e , wherein R e is —NH 2 , —OH, or 3-15 membered heterocyclyl, or (j) —S(O) 2 —R f , wherein R f is C 1-6 alkyl or 3-15 membered heterocyclyl,

provided that, when R 2 is unsubstituted methyl, then either

(1) Q 1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q 1 is substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , C 3-10 cycloalkyl, or —OH, or (2) Q 1 is phenyl, wherein the phenyl of Q 1 is substituted with at least one C 3-6 alkyl or at least one C 3-10 cycloalkyl, wherein the at least one C 3-6 alkyl is optionally substituted with one or more halo, and the at least one C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl,

(ii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl of R 2 is optionally substituted with one or more R q , wherein R q is 5-20 membered heteroaryl or C 6-20 aryl, wherein the C 6-20 aryl of R q is optionally substituted with one or more C 1-6 alkoxy, (iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R 2 is optionally substituted with one or more halo, oxo, C 1-6 alkyl, —C(O)—C 1-6 alkyl, or 5-20 membered heteroaryl, (iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R 2 is optionally substituted with one or more R s , wherein R s is C 1-6 alkyl, C 1-6 alkoxy, —NH—C(O)—C 1-6 alkyl, C 6-20 aryl, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl of R s is optionally substituted with one or more C 1-6 alkoxy, (v) —N(R g )(R h ), wherein R g and R h are independently H or C 1-6 alkyl, (vi) —C(O)—R j , wherein R j is C 3-10 cycloalkyl, —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , or —NH (5-20 membered heteroaryl), and (vii) C 6-20 aryl, wherein the C 6-20 aryl of R 2 is optionally substituted with one or more 5-20 membered heteroaryl or —O—R p , wherein R p is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R p is optionally substituted with one or more —C(O)—C 1-6 alkyl.

In one aspect, provided herein is a compound of formula (I-A):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y 1 , R 2 , R k , R x , R y , and R z are as defined elsewhere herein. In another variation, Y 1 , R 2 , R k , R x , R y , and R z of formula (I-A) are as defined for a compound of formula (I′), or formula (I) elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-B):

›BRIEF SUMMARY OF THE INVENTION · 3 of 5

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y 1 , R 2 , R k , R m , R n , R x , and R y are as defined elsewhere herein. In another variation, Y 1 , R 2 , R k , R m , R n , R x , and R y of formula (I-B) are as defined for a compound of formula (I′), or formula (I) elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-C):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 4 , X 5 , R 2 , R k , R u , and R t are as defined elsewhere herein. In another variation, X 4 , X 5 , R 2 , R k , R u , and R t of formula (I-C) are as defined for a compound of formula (I′), or formula (I) elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-D):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 4 , X 5 , R 2 , R k , R u , and R t are as defined elsewhere herein. In another variation, X 4 , X 5 , R 2 , R k , R u , and R t of formula (I-D) are as defined for a compound of formula (I′), or formula (I) elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided is a compound of formula (I′), wherein the compound is a compound of formula (I-D1):

wherein X 4 , X 5 , R 2 , R k , R u , and R z of formula (I-D1) are as defined for a compound of formula (I′) elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided is a compound of formula (I′), wherein the compound is a compound of formula (I-D1):

wherein X 4 , X 5 , R 2 , R k , R t , and R u of formula (I-D2) are as defined for a compound of formula (I′) elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-E):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 , R k , and R m are as defined elsewhere herein. In another variation, R 2 , R k , and R m of formula (I-E) are as defined for a compound of formula (I′), or formula (I) elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I-F):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y 1 , R 2 , R k , R n , R x , and R y are as defined elsewhere herein. In another variation, R 2 , R k , and R m of formula (I-F) are as defined for a compound of formula (I′), or formula (I) elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In one aspect, provided herein is a compound of formula (I′) wherein the compound is of the formula (I-G):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A, L 1 , Y 2 , Y 3 , R 2 , R k , X 1 , X 2 , X 3 , X 4 , and X 5 are as defined elsewhere herein.

In one aspect, provided herein is a compound of formula (I′) wherein the compound is of the formula (I-H):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y 1 , R 2 , R k , R n , R x , and R y are as defined elsewhere herein.

In one aspect, provided herein is a pharmaceutical composition, comprising (i) a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients. In another variation, provided herein is a pharmaceutical composition, comprising (i) a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

In one aspect, provided herein is a method of modulating GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In another variation, provided herein is a method of modulating GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

In one aspect, provided herein is a method of inhibiting GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In another variation, provided herein is a method of inhibiting GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

›BRIEF SUMMARY OF THE INVENTION · 4 of 5

In one aspect, provided herein is a method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of (i) a GYS1 inhibitor, or (ii) a pharmaceutical composition comprising a GYS1 inhibitor and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is a small molecule.

In one aspect, provided herein is a method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In another variation, provided herein is a method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of (i) a composition comprising an effective amount of a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

In one aspect, provided herein is a method of modulating GYS1 in a cell of an an individual in need thereof, comprising administering to the individual an effective amount of (i) a composition comprising an effective amount of a compound of formula (I), or formula (I′) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

In one aspect, provided herein is a method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to glycogen substrate reduction therapy. In some embodiments, the glycogen substrate reduction therapy comprises administration of a GYS1 inhibitor. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

In one aspect, provided herein is a method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In another variation, provided herein is a method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of (i) a composition comprising an effective amount of a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

In one aspect, provided herein is a method of treating a glycogen storage disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to glycogen substrate reduction therapy. In some embodiments, the glycogen substrate reduction therapy comprises administration of a GYS1 inhibitor. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

In one aspect, provided herein is a kit, comprising (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof. In another variation, provided herein is a kit, comprising (i) a composition comprising an effective amount of a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition, comprising a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof.

›BRIEF SUMMARY OF THE INVENTION · 5 of 5

In some aspect, provided herein are methods of preparing a compound of formula (I) or (I′), or any embodiment or variation thereof, such as a compound of formula (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B32), (I-C), (I-D), (I-D1), (I-D32), (I-E), (I-F), (I-G), or (I-H) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

›BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the pathway in which PPP1R3A Loss of Function (LoF) leads to reduction in muscle glycogen.

FIGS. 2 A and 2 B depict the association between PPP1R3A protein truncating variant (PTV) and left ventricular ejection (LVEF) (%) and left ventricle wall thickness (mm) in UK Biobank.

FIGS. 2 C and 2 D depict the association between PPP1R3A protein truncating variant (PTV) and exercise output (watts) and max heart rate (HR) exercise (bpm) in UK Biobank.

FIGS. 2 E and 2 F depict the association between PPP1R3A protein truncating variant (PTV) and PQ interval (ms) and QRS duration (ms) in UK Biobank.

FIGS. 2 G and 2 H depict the association between PPP1R3A protein truncating variant (PTV) and QT interval (ms) and serum glucose (mmol/L) in UK Biobank.

›DETAILED DESCRIPTION OF THE INVENTION · 1 of 32

“Individual” refers to mammals and includes humans and non-human mammals. Examples of individuals include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, individual refers to a human.

As used herein, “about” a parameter or value includes and describes that parameter or value per se. For example, “about X” includes and describes X per se.

As used herein, an “at risk” individual is an individual who is at risk of developing a disease or condition. An individual “at risk” may or may not have a detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s).

“Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results may include one or more of the following: decreasing one or more symptom resulting from the disease or condition; diminishing the extent of the disease or condition; slowing or arresting the development of one or more symptom associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition); and relieving the disease, such as by causing the regression of clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival).

As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.

As used herein, the term “therapeutically effective amount” or “effective amount” intends such amount of a compound of the disclosure or a pharmaceutically salt thereof sufficient to effect treatment when administered to an individual. As is understood in the art, an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.

As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient, or compound, which may be in a pharmaceutically acceptable carrier.

As used herein, by “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects.

The term “alkyl”, as used herein, refers to an unbranched or branched saturated univalent hydrocarbon chain. As used herein, alkyl has 1-20 carbons (i.e., C 1-20 alkyl), 1-16 carbons (i.e., C 1-6 alkyl), 1-12 carbons (i.e., C 1-2 alkyl), 1-10 carbons (i.e., C 1-10 alkyl), 1-8 carbons (i.e., C 1-8 alkyl), 1-6 carbons (i.e., C 1-6 alkyl), 1-4 carbons (i.e., C 1-4 alkyl), or 1-3 carbons (i.e., C 1-3 alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, iso-pentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “butyl” includes n-butyl, sec-butyl, iso-butyl, and tert-butyl; and “propyl” includes n-propyl and iso-propyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkyl” group, may be referred to as an “alkylene”.

The term “alkenyl”, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon double bond. As used herein, alkenyl has 2-20 carbons (i.e., C 2-20 alkenyl), 2-16 carbons (i.e., C 2-16 alkenyl), 2-12 carbons (i.e., C 2-12 alkenyl), 2-10 carbons (i.e., C 2-10 alkenyl), 2-8 carbons (i.e., C 2-8 alkenyl), 2-6 carbons (i.e., C 2-6 alkenyl), 2-4 carbons (i.e., C 2-4 alkenyl), or 2-3 carbons (i.e., C 2-3 alkenyl). Examples of alkenyl include, but are not limited to, ethenyl, prop-1-enyl, prop-2-enyl 1,2-butadienyl, and 1,3-butadienyl. When an alkenyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propenyl” includes prop-1-enyl and prop-2-enyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkenyl” group, may be referred to as an “alkenylene”.

The term “alkynyl”, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon triple bond. As used herein, alkynyl has 2-20 carbons (i.e., C 2-20 alkynyl), 2-16 carbons (i.e., C 2-16 alkynyl), 2-12 carbons (i.e., C 2-12 alkynyl), 2-10 carbons (i.e., C 2-10 alkynyl), 2-8 carbons (i.e., C 2-8 alkynyl), 2-6 carbons (i.e., C 2-6 alkynyl), 2-4 carbons (i.e., C 2-4 alkynyl), or 2-3 carbons (i.e., C 2-3 alkynyl). Examples of alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, and but-3-ynyl. When an alkynyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propynyl” includes prop-1-ynyl and prop-2-ynyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkynyl” group, may be referred to as an “alkynylene”.

›DETAILED DESCRIPTION OF THE INVENTION · 2 of 32

The term “alkoxy”, as used herein, refers to an —O-alkyl moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

The term “aryl”, as used herein, refers to a fully unsaturated carbocyclic ring moiety. The term “aryl” encompasses monocyclic and polycyclic fused-ring moieties. As used herein, aryl encompasses ring moieties comprising, for example, 6 to 20 annular carbon atoms (i.e., C 6-20 aryl), 6 to 16 annular carbon atoms (i.e., C 6-16 aryl), 6 to 12 annular carbon atoms (i.e., C 6-12 aryl), or 6 to 10 annular carbon atoms (i.e., C 6-10 aryl). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.

The term “cycloalkyl”, as used herein, refers to a saturated or partially unsaturated carbocyclic ring moiety. The term “cycloalkyl” encompasses monocyclic and polycyclic ring moieties, wherein the polycyclic moieties may be fused, branched, or spiro. Cycloalkyl includes cycloalkenyl groups, wherein the ring moiety comprises at least one annular double bond. Cycloalkyl includes any polycyclic carbocyclic ring moiety comprising at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, cycloalkyl includes rings comprising, for example, 3 to 20 annular carbon atoms (i.e., a C 3-20 cycloalkyl), 3 to 16 annular carbon atoms (i.e., a C 3-16 cycloalkyl), 3 to 12 annular carbon atoms (i.e., a C 3-12 cycloalkyl), 3 to 10 annular carbon atoms (i.e., a C 3-10 cycloalkyl), 3 to 8 annular carbon atoms (i.e., a C 3-8 cycloalkyl), 3 to 6 annular carbon atoms (i.e., a C 3-6 cycloalkyl), or 3 to 5 annular carbon atoms (i.e., a C 3-5 cycloalkyl). Monocyclic cycloalkyl ring moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbonyl, decalinyl, 7,7-dimethyl-bicyclo [2.2.1]heptanyl, and the like. Still further, cycloalkyl also includes spiro cycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5]undecanyl.

The term “halo”, as used herein, refers to atoms occupying groups VIIA of The Periodic Table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).

The term “heteroaryl”, as used herein, refers to an aromatic (fully unsaturated) ring moiety that comprises one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heteroaryl” includes both monocyclic and polycyclic fused-ring moieties. As used herein, a heteroaryl comprises, for example, 5 to 20 annular atoms (i.e., a 5-20 membered heteroaryl), 5 to 16 annular atoms (i.e., a 5-16 membered heteroaryl), 5 to 12 annular atoms (i.e., a 5-12 membered heteroaryl), 5 to 10 annular atoms (i.e., a 5-10 membered heteroaryl), 5 to 8 annular atoms (i.e., a 5-8 membered heteroaryl), or 5 to 6 annular atoms (i.e., a 5-6 membered heteroaryl). Any monocyclic or polycyclic aromatic ring moiety comprising one or more annular heteroatoms is considered a heteroaryl, regardless of the point of attachment to the remainder of the molecule (i.e., the heteroaryl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heteroaryl moiety). Examples of heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl can be bound via either ring of the fused system.

The term “heterocyclyl”, as used herein, refers to a saturated or partially unsaturated cyclic moiety that encompasses one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes both monocyclic and polycyclic ring moieties, wherein the polycyclic ring moieties may be fused, bridged, or spiro. Any non-aromatic monocyclic or polycyclic ring moiety comprising at least one annular heteroatom is considered a heterocyclyl, regardless of the point of attachment to the remainder of the molecule (i.e., the heterocyclyl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heterocyclyl moiety). Further, the term heterocyclyl is intended to encompass any polycyclic ring moiety comprising at least one annular heteroatom wherein the polycyclic ring moiety comprises at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, a heterocyclyl comprises, for example, 3 to 20 annular atoms (i.e., a 3-20 membered heterocyclyl), 3 to 16 annular atoms (i.e., a 3-16 membered heterocyclyl), 3 to 12 annular atoms (i.e., a 3-12 membered heterocyclyl), 3 to 10 annular atoms (i.e., a 3-10 membered heterocyclyl), 3 to 8 annular atoms (i.e., a 3-8 membered heterocyclyl), 3 to 6 annular atoms (i.e., a 3-6 membered heterocyclyl), 3 to 5 annular atoms (i.e., a 3-5 membered heterocyclyl), 5 to 8 annular atoms (i.e., a 5-8 membered heterocyclyl), or 5 to 6 annular atoms (i.e., a 5-6 membered heterocyclyl). Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Examples of spiro heterocyclyl rings include, but are not limited to, bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

›DETAILED DESCRIPTION OF THE INVENTION · 3 of 32

The term “oxo”, as used herein, refers to a ═O moiety.

The terms “optional” and “optionally”, as used herein, mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not. Accordingly, the term “optionally substituted” infers that any one or more (e.g., 1, 2, 1 to 5, 1 to 3, 1 to 2, etc.) hydrogen atoms on the designated atom or moiety or group may be replaced or not replaced by an atom or moiety or group other than hydrogen. By way of illustration and not limitation, the phrase “methyl optionally substituted with one or more chloro” encompasses —CH 3 , —CH 2 Cl, —CHCl 2 , and —CCl 3 moieties.

It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments.

The term “pharmaceutically acceptable salt”, as used herein, of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use , International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), which is incorporated herein by reference. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, trifluoroacetic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

Isotopically labeled forms of the compounds depicted herein may be prepared. Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively. In some embodiments, a compound of formula (A) is provided wherein one or more hydrogen is replaced by deuterium or tritium.

Some of the compounds provided herein may exist as tautomers. Tautomers are in equilibrium with one another. By way of illustration, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds of this disclosure are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, for example, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, imidic-acid containing compounds are understood to include their amide tautomers.

Also provided herein are prodrugs of the compounds depicted herein, or a pharmaceutically acceptable salt thereof. Prodrugs are compounds that may be administered to an individual and release, in vivo, a compound depicted herein as the parent drug compound. It is understood that prodrugs may be prepared by modifying a functional group on a parent drug compound in such a way that the modification is cleaved in vitro or in vivo to release the parent drug compound. See, e.g., Rautio, J., Kumpulainen, H., Heimbach, T. et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov 7, 255-270 (2008), which is incorporated herein by reference.

The compounds of the present disclosure, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- (or as (D)- or (L)- for amino acids). The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms and mixtures thereof in any ratio. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, for example, chromatography and/or fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC), and chiral supercritical fluid chromatography (SFC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless specified otherwise, it is intended that the present disclosure includes both E and Z geometric isomers. Likewise, cis- and trans- are used in their conventional sense to describe relative spatial relationships.

›DETAILED DESCRIPTION OF THE INVENTION · 4 of 32

A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose structures are non-superimposable mirror images of one another. “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

Where enantiomeric and/or diastereomeric forms exist of a given structure, flat bonds indicate that all stereoisomeric forms of the depicted structure may be present, e.g.,

Where enantiomeric and/or diastereomeric forms exist of a given structure, flat bonds and the presence of a “*” symbol indicate that the composition is made up of at least 90%, by weight, of a single isomer with unknown stereochemistry, e.g.,

Where enantiomeric and/or diastereomeric forms exist of a given structure, wedged or hashed bonds indicate the composition is made up of at least 90%, by weight, of a single enantiomer or diastereomer with known stereochemistry, e.g.,

Where relevant, combinations of the above notation may be used. Exemplified species may contain stereogenic centers with known stereochemistry and stereogenic centers with unknown stereochemistry, stereochemistry, e.g.,

Where relevant, combinations of the above notation may be used. Exemplified species may contain stereogenic centers with known stereochemistry and stereogenic centers bearing a mixture of isomers, e.g.,

Compounds

In one aspect, provided herein is a compound of formula (I′):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

Y 2 and Y 3 are each C, or

one of Y 2 and Y 3 is N and the other of Y 2 and Y 3 is C;

X 1 and X 2 are each independently H, C 1-6 alkyl, or C 1-6 alkoxy;

X 3 and X 4 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl of X 3 and X 4 is optionally substituted with one of more halo;

X 5 is H, C 1-6 alkyl, C 1-6 alkoxy, or C 3-10 cycloalkyl;

either

(1) L 1 is absent; and

Q 1 is selected from (i) to (iv):

(ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q 1 is optionally substituted with one or more oxo, or C 1-6 alkyl,

the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, and

(iv) C 3-10 cycloalkyl;

(2) L 1 is —CH 2 —; and

Q 1 is C 3-10 cycloalkyl;

L 2 is —C(O)— or —S(O) 2 —

R 1 is H or C 1-6 alkyl;

R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl;

R m is H, —OH, or C 1-6 alkyl;

R n is H, C 1-6 alkyl, or C 3-10 cycloalkyl or R n taken together with the carbon atom to which it is attached forms C 3-5 cycloalkyl;

or R k is taken together with either R m or R n , and the atoms to which they are attached, to form cyclopropyl; and

R 2 is selected from (i) to (vii):

(i) C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a , wherein R a is:

R c is halo, oxo, C 1-6 alkyl, C 1-6 alkoxy, —C(O)—C 1-6 alkyl, or —C(O)—C 1-6 alkoxy, wherein

the C 1-6 alkyl of R c is optionally substituted with one or more halo or C 2-6 alkynyl, and the —C(O)—C 1-6 alkoxy of R c is optionally substituted with one or more halo,

(g) —O—R e , wherein R e is C 1-6 alkyl, C 6-20 aryl, —C(O)-(3-15 membered heterocyclyl), —C(O)—N—(C 1-6 alkyl) 2 , or 5-20 membered heteroaryl, wherein

the —C(O)-(3-15 membered heterocyclyl) of R e is optionally substituted with one or more C 1-6 alkyl, C 1-6 alkoxy, or —C(O)—C 1-6 alkoxy, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl,

›DETAILED DESCRIPTION OF THE INVENTION · 5 of 32

(h) —C(O)—R e , wherein R e of —C(O)—R e is —NH 2 , —OH, or 3-15 membered heterocyclyl, or (i) —S(O) 2 —R f , wherein R f is C 1-6 alkyl or 3-15 membered heterocyclyl,

provided that, when R 2 is unsubstituted methyl, then either

In one aspect, provided is a compound of formula (I):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

X 1 and X 2 are each independently H, C 1-6 alkyl, or C 1-6 alkoxy;

X 3 and X 4 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, or 5-20 membered heteroaryl;

X 5 is H, C 1-6 alkyl, C 1-6 alkoxy, or C 3-10 cycloalkyl;

Q 1 is selected from (i) to (iii):

(i) phenyl, wherein the phenyl of Q 1 is substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), or C 3-10 cycloalkyl, wherein

the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl,

(ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q 1 is optionally substituted with one or more oxo, and

the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl;

R 1 is H or C 1-6 alkyl;

R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl;

R m is H, —OH, or C 1-6 alkyl;

R n is H, C 1-6 alkyl, or C 3-10 cycloalkyl;

or R k is taken together with either R m or R n , and the atoms to which they are attached, to form cyclopropyl; and

R 2 is selected from (i) to (vii):

(i) C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a , wherein R a is:

R b is halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , C 3-10 cycloalkyl, 3-15 membered heterocyclyl, or —C(O)—C 1-6 alkoxy, wherein

(f) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c , wherein

R c is halo, oxo, C 1-6 alkyl, C 1-6 alkoxy, —C(O)—C 1-6 alkyl, or —C(O)—C 1-6 alkoxy, wherein

the C 1-6 alkyl of R c is optionally substituted with one or more halo or C 2-6 alkynyl, and the —C(O)—C 1-6 alkoxy of R c is optionally substituted with one or more halo,

(h) —O—R e , wherein R e is C 1-6 alkyl, C 6-20 aryl, —C(O)-(3-15 membered heterocyclyl), —C(O)—N—(C 1-6 alkyl) 2 , or 5-20 membered heteroaryl, wherein

(i) —C(O)—R e , wherein R e is —NH 2 , —OH, or 3-15 membered heterocyclyl, or j) —S(O) 2 —R f , wherein R f is C 1-6 alkyl or 3-15 membered heterocyclyl,

provided that, when R 2 is unsubstituted methyl, then either

(2) Q 1 is phenyl, wherein the phenyl of Q 1 is substituted with at least one C 3-6 alkyl or at least one C 3-10 cycloalkyl, wherein the at least one C 3-6 alkyl is optionally substituted with one or more halo, and the at least one C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl,

(iii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R 2 is optionally substituted with one or more halo, oxo, C 1-6 alkyl, —C(O)—C 1-6 alkyl, or 5-20 membered heteroaryl,

›DETAILED DESCRIPTION OF THE INVENTION · 6 of 32

(iv) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R 2 is optionally substituted with one or more R s , wherein R s is C 1-6 alkyl, C 1-6 alkoxy, —NH—C(O)—C 1-6 alkyl, C 6-20 aryl, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl of R s is optionally substituted with one or more C 1-6 alkoxy,

(v) —N(R g )(R h ), wherein R g and R h are independently H or C 1-6 alkyl,

(vi) —C(O)—R j , wherein R j is C 3-10 cycloalkyl, —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , or —NH (5-20 membered heteroaryl), and

(vii) C 6-20 aryl, wherein the C 6-20 aryl of R 2 is optionally substituted with one or more 5-20 membered heteroaryl or —O—R p , wherein R p is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R p is optionally substituted with one or more —C(O)—C 1-6 alkyl.

Any embodiments provided herein of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, are also, where applicable, embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L 2 is —C(O) or —S(O) 2 —. In some embodiments, L 2 is —C(O)—. In some embodiments, L 2 is —S(O) 2 —.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q 1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo. In some embodiments, Q 1 is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo. In some embodiments, Q 1 is pyridinyl, wherein the pyridinyl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo. In some embodiments, Q 1 is 2-pyridinyl or 3-pyridinyl, wherein the 2-pyridinyl or 3-pyridinyl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo. In some embodiments, Q 1 is 2-pyridinyl, wherein the 2-pyridinyl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo. In some embodiments Q 1 is 2-pyridinyl, wherein the 2-pyridinyl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo. In some embodiments, Q 1 is 2-pyridinyl, wherein the 2-pyridinyl of Q 1 is optionally substituted with one or more fluoro, chloro, methyl, iso-propyl, tert-butyl, cyclopropyl, or cyclobutyl, wherein the cyclopropyl and cyclobutyl are independently optionally substituted with one or more methyl or fluoro.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q 1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo. In some embodiments, Q 1 is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo. In some embodiments, Q 1 is pyridinyl, wherein the pyridinyl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo. In some embodiments, Q 1 is 2-pyridinyl or 3-pyridinyl, wherein the 2-pyridinyl or 3-pyridinyl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo. In some embodiments, Q 1 is 2-pyridinyl, wherein the 2-pyridinyl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo. In some embodiments Q 1 is 2-pyridinyl, wherein the 2-pyridinyl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 1-6 alkoxy, or C 3-10 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo. In some embodiments, Q 1 is 2-pyridinyl, wherein the 2-pyridinyl of Q 1 is optionally substituted with one or more fluoro, chloro, methyl, iso-propyl, tert-butyl, cyclopropyl, cyclobutyl, or methoxy, wherein the methyl is optionally substituted with one or more fluoro and the cyclopropyl and cyclobutyl are independently optionally substituted with one or more methyl or fluoro.

›DETAILED DESCRIPTION OF THE INVENTION · 7 of 32

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q 1 is selected from the group consisting of

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q 1 is selected from

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q 1 is selected from the group consisting of

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q 1 is phenyl, wherein the phenyl of Q 1 is substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), or C 3-10 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, Q 1 is phenyl, wherein the phenyl of Q 1 is substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, or C 3-10 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, Q 1 is phenyl, wherein the phenyl of Q 1 is substituted with one or more fluoro, chloro, methyl, iso-propyl, sec-butyl, tert-butyl, prop-1-en-2-yl, cyclopropyl, or cyclobutyl, wherein the methyl, iso-propyl, sec-butyl, and tert-butyl are independently optionally substituted with one or more halo, and the cyclopropyl and cyclobutyl are independently optionally substituted with one or more fluoro or methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q 1 is phenyl, wherein the phenyl of Q 1 is substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C 3-10 cycloalkyl, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q 1 is selected from the group consisting of

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q 1 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q 1 is optionally substituted with one or more oxo. In some embodiments, Q 1 is

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q, is (i) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q 1 is optionally substituted with one or more oxo, or C 1-6 alkyl, (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein, the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, or (iii) C 3-10 cycloalkyl.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q 1 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q 1 is optionally substituted with one or more oxo, or C 1-6 alkyl. In some embodiments Q 1 is selected from the group consisting of

›DETAILED DESCRIPTION OF THE INVENTION · 8 of 32

In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Q 1 is C 3-10 cycloalkyl. In some embodiments, Q 1 is C 3-6 cycloalkyl. In some embodiments Q 1 is cyclopropyl.

In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L 1 is absent or is —CH 2 —. In some embodiments, L 1 is absent. In some embodiments, L 1 is —CH 2 —. In some embodiments, L 1 is absent and Q 1 is C 3-10 cycloalkyl. In some embodiments, L 1 is absent and Q 1 is C 3-6 cycloalkyl. In some embodiments L 1 is absent and Q 1 is cyclopropyl. In some embodiments, L 1 is —CH 2 — and Q 1 is C 3-10 cycloalkyl. In some embodiments, L 1 is —CH 2 — and Q 1 is C 3-6 cycloalkyl. In some embodiments L 1 is —CH 2 — and Q 1 is cyclopropyl.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 1 , X 2 , X 3 , X 4 , and X 5 are each H. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is H or C 1-6 alkyl. In some embodiments R 1 is H. In some embodiments, R 1 is C 1-3 alkyl. In some embodiments, R 1 is methyl.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl. In some embodiments, R k is H. In some embodiments, R k is halo. In some embodiments, R k is F.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R m is H, —OH, or C 1-6 alkyl. In some embodiments R m is H.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R n is H, C 1-6 alkyl, or C 3-10 cycloalkyl. In some embodiments R n is H.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R m is H, R n is H, and R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl. In some embodiments, R m is H, R n is H, and R k is halo, —OH, or —NH 2 . In some embodiments, R m is H, R n is H, and R k is halo. In some embodiments, R m is H, R n is H, and R k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is taken together with either R m or R n , and the atoms to which they are attached, to form cyclopropyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R n taken together with the carbon atom to which it is attached forms C 3-5 cycloalkyl. In some embodiments, R n taken together with the carbon atom to which it is attached forms cyclopropyl.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a . In some embodiments, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy. In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is 5-20 membered heteroaryl or —(C 1-4 alkyl)(5-20 membered heteroaryl), wherein the C 1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R s . In some embodiments, R 2 is 5-20 membered heteroaryl, wherein the CIA alkyl is optionally substituted with one or more or more —OH, halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R s . In some embodiments, R 2 is (methyl)(5-20 membered heteroaryl), wherein the methyl is optionally substituted with one or more or more —OH, halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R s . In some embodiments, R s is halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)—C 1-6 alkyl, C 6-20 aryl, C 3-10 cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C 1-6 alkoxy. In some embodiments, the C 1-6 alkyl of R s is optionally substituted with one or more halo, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, and the 3-15-membered heterocyclyl of R s is optionally substituted with one or more halo or —C(O)—C 1-6 alkoxy.

›DETAILED DESCRIPTION OF THE INVENTION · 9 of 32

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments, R 2 is

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c .

In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more oxo or C 1-6 alkyl. In some embodiments, R 2 is

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c , wherein R c is oxo, C 1-6 alkyl, or —C(O)—C 1-6 alkoxy, wherein the C 1-6 alkyl of R c is optionally substituted with one or more halo, and the —C(O)—C 1-6 alkoxy of R c is optionally substituted with one or more halo. In some embodiments, R 2 is selected from the group consisting of

In some embodiments of a compound of formula (I′), (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —O—R e , wherein R e is —C(O)-(3-15 membered heterocyclyl) wherein the —C(O)-(3-15 membered heterocyclyl) of R e is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl. In some embodiments, R 2 is selected from the group consisting of

In some embodiments of a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ), wherein one of R c and R d is H, and the other of R c and R d , —C(O)—C 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , or —C(O)-(3-15 membered heterocyclyl). In some embodiments, R 2 is selected from the group consisting of

In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is ethyl, wherein the ethyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ), wherein one of R c and R d is H, and the other of R c and R d , is —C(O)—C 1-6 alkyl. In some embodiments, R 2 is

›DETAILED DESCRIPTION OF THE INVENTION · 10 of 32

In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 1 and X 2 are each independently H, C 1-6 alkyl, or C 1-6 alkoxy. In some embodiments, X 1 and X 2 are each H.

In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 3 and X 4 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl of X 3 and X 4 is optionally substituted with one of more halo.

In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 5 is H, C 1-6 alkyl, C 1-6 alkoxy, or C 3-10 cycloalkyl. In some embodiments, X 5 is H, C 1-4 alkyl, C 1-3 alkoxy, or C 3-6 cycloalkyl. In some embodiments, X 5 is H. In some embodiments, X 5 is isopropyl, n-butyl, iso-butyl or t-butyl.

In some embodiments of a compound of formula (I), X 1 —X 5 are each H, and Q 1 is a 5-20 membered heteroaryl optionally substituted with one or more halo, C 1-6 alkyl, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, X 1 —X 5 are each H, and Q 1 is a 5-6 membered heteroaryl optionally substituted with one or more halo, C 1-6 alkyl, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, X 1 —X 5 are each H, and Q 1 is a pyridinyl optionally substituted with one or more halo, C 1-6 alkyl, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, X 1 —X 5 are each H, and Q 1 is a pyridinyl optionally substituted with one or more halo, C 1-4 alkyl, —NH 2 , or C 3-4 cycloalkyl, wherein the C 3-4 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments of the foregoing, R m is H and R n is H. In some embodiments of the foregoing, R 1 is H. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I), X 1 —X 5 are each H, and Q 1 is phenyl substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), or C 3-10 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, X 1 —X 5 are each H, and Q 1 is phenyl substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-10 membered heterocyclyl), or C 3-10 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, X 1 —X 5 are each H, and Q 1 is phenyl substituted with one or more halo, C 1-4 alkyl, C 2-4 alkenyl, —NH 2 , —NH—C(O)—(C 1-4 alkyl), —NH—C(O)-(3-10 membered heterocyclyl), or C 3-4 cycloalkyl, wherein the C 1-4 alkyl is optionally substituted with one or more halo, and the C 3-4 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of the foregoing, R 1 is H. In some embodiments of the foregoing, R m is H and R n is H. In some embodiments of the foregoing, R k is taken together with either R m or R n , and the atoms to which they are attached, to form cyclopropyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′) or (1), or any embodiment or variation thereof, such as a compound of formula (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-C), (I-D), (I-D1), (I-D2), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented by

with carbon atoms bearing moieties

R k , R m , R n , and R 1 , has a stereochemical configuration of the formula

wherein X 1 , X 2 , X 3 , X 4 , X 5 , Y 2 , Y 3 , R 1 , R k , R m , and R n are as defined elsewhere herein.

In some embodiments of a compound of formula (I′) or (I), or any embodiment or variation thereof, such as a compound of formula (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-C), (I-D), (I-D1), (I-D2), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented by

with carbon atoms bearing moieties

R k , R m , R n , and R 1 , has a stereochemical configuration of the formula

wherein R 1 and R m are both H, and X 1 , X 2 , X 3 , X 4 , X 5 , Y 2 , Y 3 , R k , and R n are as defined elsewhere herein.

with carbon atoms bearing moieties

R k , R m , R m , and R 1 , has a stereochemical configuration of the formula

wherein R 1 , R m , and R n are each H, and X 1 , X 2 , X 3 , X 4 , X 5 , Y 2 , Y 3 , and R k are as defined elsewhere herein.

›DETAILED DESCRIPTION OF THE INVENTION · 11 of 32

with carbon atoms bearing moieties

R k , R m , R n , and R 1 , has a stereochemical configuration of the formula

wherein R 1 , R m , and R n are each H, R k is halo or H, and X 1 , X 2 , X 3 , X 4 , X 5 , Y 2 , and Y 3 are as defined elsewhere herein. In some embodiments, the moiety R k is fluoro.

with carbon atoms bearing moieties

R k , R m , R n , and R 1 , has a stereochemical configuration of the formula

wherein R 1 , R m , and R n are each H, R k is fluoro, and X 1 , X 2 , X 3 , X 4 , X 5 , Y 2 , and Y 3 are as defined elsewhere herein. In some embodiments Y 2 and Y 3 are each C. In some embodiments one Y 2 and Y 3 is C and the other of Y 2 and Y 3 is N.

In some embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-A):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y 1 is CH or N; R x and R z are independently H, halo, C 1-6 alkyl, or —NH 2 , wherein, when Y, is CH, the C 1-6 alkyl of R x or R z may be optionally substituted with one or more halo; and R y is (i) C 1-6 alkyl, (ii), C 2-6 alkenyl, or (iii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some variations, R 2 , R k , R x , R y , and R z of formula (I-A1) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein Y 1 is CR x or N; wherein, when the ring bearing R x , R y and R z is phenyl, R x , R y and R z is H, halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C 3-10 cycloalkyl, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl; and wherein when the ring bearing R x , R y and R z is pyridyl, R x , R y and R z are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein, the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl.

In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R x and R z are independently H, fluoro, chloro, or methyl; and R y is (i) isopropyl, (ii) isopropenyl, or (iii) C 3-4 cycloalkyl, wherein the C 3-4 cycloalkyl is optionally substituted with one or more fluoro or methyl. In some embodiments, R x and R z are independently H, fluoro, chloro, or methyl; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl, wherein the C 3-4 cycloalkyl is optionally substituted with one or more fluoro or methyl. In some embodiments, R x is H, fluoro, chloro, or methyl; R z is H; and R y is (i) isopropyl, or (ii) C 3-4 cycloalkyl, wherein the C 3-4 cycloalkyl is optionally substituted with one or more fluoro or methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R x is fluoro or methyl optionally substituted with one or more fluoro; R y is (i) isopropyl (ii) isopropenyl or (iii) C 3-4 cycloalkyl optionally substituted with one or more halo or C 1-6 alkyl or (iv) butyl; and R z is fluoro or methyl; provided that at least one of R x and R z is halo, CF 2 or CF 3 .

In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or halo. In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or fluoro. In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a . In some embodiments, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy. In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

›DETAILED DESCRIPTION OF THE INVENTION · 12 of 32

In some embodiments of a compound of formula (I′), (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is 5-20 membered heteroaryl or —(C 1-4 alkyl)(5-20 membered heteroaryl), wherein the C 1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R s . In some embodiments, R s is halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)—C 1-6 alkyl, C 6-20 aryl, C 3-10 cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C 1-6 alkoxy. In some embodiments, the C 1-6 alkyl of R s is optionally substituted with one or more halo, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, and the 3-15-membered heterocyclyl of R s is optionally substituted with one or more halo or —C(O)—C 1-6 alkoxy.

In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments, R 2 is

In some embodiments of a compound of formula (I′), (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments, R 2 is

In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more oxo or C 1-6 alkyl. In some embodiments, R 2 is

In some embodiments of a compound of formula (I′), (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c , wherein R c is oxo, C 1-6 alkyl, or —C(O)—C 1-6 alkoxy, wherein the C 1-6 alkyl of R c is optionally substituted with one or more halo, and the —C(O)—C 1-6 alkoxy of R c is optionally substituted with one or more halo. In some embodiments, R 2 is selected from the group consisting of

In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ), wherein one of R c and R d is H, and the other of R c and R d , —C(O)—C 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , or —C(O)-(3-15 membered heterocyclyl). In some embodiments, R 2 is selected from the group consisting of

›DETAILED DESCRIPTION OF THE INVENTION · 13 of 32

In some embodiments of a compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y 1 is CH or N; R x and R z are independently H or halo; R y is C 1-6 alkyl or C 3-10 cycloalkyl; R k is H or halo; and R 2 is selected from (i) to (iii):

(i) C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is

(a) —OH, (b) C 6-20 aryl, wherein the C 6-20 aryl of R a is optionally substituted with one or more halo, cyano, C 1-6 alkoxy, or —NH—C(O)—C 1-6 alkyl, (c) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c , wherein

R c is halo, oxo, C 1-6 alkyl, C 1-6 alkoxy, —C(O)—C 1-6 alkyl, or —C(O)—C 1-6 alkoxy, wherein

the C 1-6 alkyl of R c is optionally substituted with one or more halo or C 2-6 alkynyl, and the —C(O)—C 1-6 alkoxy of R c is optionally substituted with one or more halo,

(d) —N(R c )(R d ), wherein R c and R d of N(Rc)(Rd) are, independently of each other, H, C 1-6 alkyl, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 alkoxy, —C(O)—NH 2 , —C(O)—NH(C 1-6 alkyl), —C(O)—N(C 1-6 alkyl) 2 , —C(O)-(3-15 membered heterocyclyl), —CH 2 —C(O)—NH 2 , 3-15 membered heterocyclyl, or 5-20 membered heteroaryl, wherein

(e) —O—R e , wherein R e is C 1-6 alkyl, C 6-20 aryl, —C(O)-(3-15 membered heterocyclyl), —C(O)—N—(C 1-6 alkyl) 2 , or 5-20 membered heteroaryl, wherein the C 1-6 alkyl of R e is optionally substituted with one or more C 1-6 alkoxy, wherein the C 1-6 alkoxy is optionally substituted with one or more C 2-6 alkynyl, the C 6-20 aryl of R e is optionally substituted with one or more C 1-6 alkyl, and the —C(O)-(3-15 membered heterocyclyl) of R e is optionally substituted with one or more C 1-6 alkyl, C 1-6 alkoxy, or —C(O)—C 1-6 alkoxy, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl, or

(f) —C(O)—R e , wherein R e of —C(O)—R e is —NH 2 , —OH, or 3-15 membered heterocyclyl,

(ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R 2 is optionally substituted with one or more halo, oxo, C 1-6 alkyl, —C(O)—C 1-6 alkyl, or 5-20 membered heteroaryl, (iii) 5-20 membered heteroaryl or —(C 1-4 alkyl)(5-20 membered heteroaryl), wherein the C 1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R s , wherein

the C 1-6 alkyl of R s is optionally substituted with one or more halo, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, and the 3-15-membered heterocyclyl of R s is optionally substituted with one or more halo or —C(O)—C 1-6 alkoxy.

In some embodiments of formula (I-A), Y 1 is CH or N; R x and R z are independently H or halo; R y is C 1-6 alkyl or C 3-10 cycloalkyl; R k is H or halo; R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a ; R a is

(a) —OH, (b) C 6-10 aryl optionally substituted with one or more halo, cyano, C 1-3 alkoxy, or —NH—C(O)—C 1-3 alkyl, or (c) 3-15 membered heterocyclyl optionally substituted with one or more halo, oxo, C 1-6 alkyl, C 1-6 alkoxy, —C(O)—C 1-6 alkyl, or —C(O)—C 1-6 alkoxy.

In some embodiments of formula (I-A), Y 1 is CH or N; R x and R z are independently H or halo; R y is C 1-3 alkyl or C 3-5 cycloalkyl; R k is halo; R 2 is C 1-4 alkyl substituted with one or more R a ; R a is

(a) —OH, (b) C 6-10 aryl optionally substituted with one or more halo, cyano, C 1-3 alkoxy, or —NH—C(O)—C 1-3 alkyl, or (c) C 3-8 heteroaryl optionally substituted with one or more halo, oxo, C 1-6 alkyl, C 1-6 alkoxy, —C(O)—C 1-6 alkyl, or —C(O)—C 1-6 alkoxy.

In some embodiments, provided herein is a compound of formula (I) or formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-A1):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x and R z are independently H, halo, C 1-6 alkyl, or —NH 2 , wherein the C 1-6 alkyl is optionally substituted with one or more halo. In some embodiments, R x is H, halo, or C 1-6 alkyl; R y is (i) C 1-6 alkyl, (ii) C 2-6 alkenyl, or (ii) C 3-10 cycloalkyl; and R z is H, halo or C 1-6 alkyl. In some embodiments, R z is H. In some embodiments, at least one of R x and R z is halo. In some variations, R 2 , R k , R x , R y , and R z of formula (I-A1) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein R x , R y and R z are independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C 3-10 cycloalkyl, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl. In some embodiments, R x is H, halo, or C 1-6 alkyl optionally substituted with one or more halo; R y is (i) C 1-6 alkyl, (ii) C 2-6 alkenyl, (iii) C 3-10 cycloalkyl optionally substituted with one or more halo or C 1-6 alkyl or (iv) butyl; and R z is H, halo or C 1-6 alkyl. In some embodiments, R z is H. In some embodiments, at least one of R x and R z is halo or C 1-6 alkyl optionally substituted with one or more halo.

›DETAILED DESCRIPTION OF THE INVENTION · 14 of 32

In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R x is fluoro or methyl; R y is (i) isopropyl or (ii) C 3-4 cycloalkyl; and R z is fluoro or methyl; provided that at least one of R x and R z is halo. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R x is fluoro or methyl optionally substituted with one or more fluoro; R y is (i) isopropyl (ii) C 3-4 cycloalkyl optionally substituted with one or more halo or C 1-6 alkyl or (iii) butyl; and R z is fluoro or methyl; provided that at least one of R x and R z is halo, CF 2 or CF 3 .

In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or halo. In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or fluoro. In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a . In some embodiments, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy. In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is 5-20 membered heteroaryl or —(C 1-4 alkyl)(5-20 membered heteroaryl), wherein the C 1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R s . In some embodiments, R s is halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)—C 1-6 alkyl, C 6-20 aryl, C 3-10 cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C 1-6 alkoxy. In some embodiments, the C 1-6 alkyl of R s is optionally substituted with one or more halo, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, and the 3-15-membered heterocyclyl of R s is optionally substituted with one or more halo or —C(O)—C 1-6 alkoxy.

In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments, R 2 is

In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments, R 2 is

In some embodiments of a compound of formula (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more oxo or C 1-6 alkyl. In some embodiments, R 2 is

›DETAILED DESCRIPTION OF THE INVENTION · 15 of 32

In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c , wherein R c is oxo, C 1-6 alkyl, or —C(O)—C 1-6 alkoxy, wherein the C 1-6 alkyl of R c is optionally substituted with one or more halo, and the —C(O)—C 1-6 alkoxy of R c is optionally substituted with one or more halo. In some embodiments, R 2 is

In some embodiments of a compound of formula (I′), (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —O—R e , wherein R e is —C(O)-(3-15 membered heterocyclyl) wherein the —C(O)-(3-15 membered heterocyclyl) of R e is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl. In some embodiments, R 2 is

In some embodiments of a compound of formula (I′) (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ), wherein one of R c and R d is H, and the other of R c and R d , —C(O)—C 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , or —C(O)-(3-15 membered heterocyclyl). In some embodiments, R 2 is

In some embodiments of a compound of formula (I′) (I-A1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is ethyl, wherein the ethyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ), wherein one of R c and R d is H, and the other of R c and R d , is —C(O)—C 1-6 alkyl. In some embodiments, R 2 is

In some embodiments, provided is a compound of formula (I) or formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-A2):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x is H, halo, C 1-6 alkyl, or —NH 2 , wherein the C 1-6 alkyl is optionally substituted with one or more halo; and R y is (i) C 1-6 alkyl, (ii), C 2-6 alkenyl, or (iii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, R x is H, halo, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo; and R y is (i), C 1-6 alkyl, (ii) C 2-6 alkenyl, or (iii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, R x is H, halo, or C 1-6 alkyl; and R y is (i) C 1-6 alkyl, (ii) C 2-6 alkenyl, or (iii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some variations, R 2 , R k , R x , and R y of formula (I-A2) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein R x and R y are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C 3-10 cycloalkyl, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl. In some embodiments, R x is H, halo, or C 1-6 alkyl optionally substituted with one or more halo; and R y is (i) C 1-6 alkyl, (ii) C 3-10 cycloalkyl optionally substituted with one or more halo or C 1-6 alkyl or (iii) butyl.

In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R x is H, fluoro, chloro, or methyl, wherein the methyl is optionally substituted with one or more fluoro; and R y is (i) isopropyl, (ii) isopropenyl, (iii) sec-butyl, (iv) tert-butyl, or (v) C 3-4 cycloalkyl, wherein the C 3-4 cycloalkyl is optionally substituted with one or more fluoro or methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 16 of 32

In some embodiments of a compound of formula (I′), (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R x is fluoro or methyl optionally substituted with one or more fluoro; and R y is (i) isopropyl (ii) C 3-4 cycloalkyl optionally substituted with one or more halo or C 1-6 alkyl or (iii) butyl.

In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or halo. In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or fluoro. In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a . In some embodiments, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy. In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

In some embodiments of a compound of formula (I′), (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is —(C 1-4 alkyl)(5-20 membered heteroaryl), wherein the Cia alkyl is optionally substituted with one or more or more —OH, and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R s . In some embodiments, R s is halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)—C 1-6 alkyl, C 6-20 aryl, C 3-10 cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C 1-6 alkoxy. In some embodiments, the C 1-6 alkyl of R s is optionally substituted with one or more halo, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, and the 3-15-membered heterocyclyl of R s is optionally substituted with one or more halo or —C(O)—C 1-6 alkoxy.

In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments, R 2 is

In some embodiments of a compound of formula (I′), (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments, R 2 is

In some embodiments of a compound of formula (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more oxo or C 1-6 alkyl. In some embodiments, R 2 is

In some embodiments of a compound of formula (I′), (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c , wherein R c is oxo, C 1-6 alkyl, or —C(O)—C 1-6 alkoxy, wherein the C 1-6 alkyl of R c is optionally substituted with one or more halo, and the —C(O)—C 1-6 alkoxy of R c is optionally substituted with one or more halo. In some embodiments, R 2 is selected from the group consisting of

›DETAILED DESCRIPTION OF THE INVENTION · 17 of 32

In some embodiments of a compound of formula (I′), (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —O—R e , wherein R e is —C(O)-(3-15 membered heterocyclyl) wherein the —C(O)-(3-15 membered heterocyclyl) of R e is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl. In some embodiments, R 2 is selected from the group consisting of

In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (I′), (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ), wherein one of R c and R d is H, and the other of R c and R d , —C(O)—C 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , or —C(O)-(3-15 membered heterocyclyl). In some embodiments, R 2 is selected from the group consisting of

In some embodiments of a compound of formula (I′) (I-A2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is ethyl, wherein the ethyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ), wherein one of R c and R d is H, and the other of R c and R d , is —C(O)—C 1-6 alkyl. In some embodiments, R 2 is

In some embodiments, provided herein is a compound of formula (I) or formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-A3):

In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R x is H, fluoro, or methyl; and R y is (i) H, (ii) isopropyl, (iii) tert-butyl, or (iv) C 3-4 cycloalkyl, wherein the C 3-4 cycloalkyl is optionally substituted with one or more fluoro or methyl. In some embodiments, R x is H, fluoro, or methyl; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl, wherein the C 3-4 cycloalkyl is optionally substituted with one or more fluoro or methyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or halo. In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or fluoro. In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a . In some embodiments, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy. In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 18 of 32

In some embodiments of a compound of formula (I′), (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is —(C 1-4 alkyl)(5-20 membered heteroaryl), wherein the 5-20 membered heteroaryl is optionally substituted with one or more R s . In some embodiments, R s is halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)—C 1-6 alkyl, C 6-20 aryl, C 3-10 cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C 1-6 alkoxy. In some embodiments, the C 1-6 alkyl of R s is optionally substituted with one or more halo, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, and the 3-15-membered heterocyclyl of R s is optionally substituted with one or more halo or —C(O)—C 1-6 alkoxy.

In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments, R 2 is

In some embodiments of a compound of formula (I′), (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments, R 2 is

In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more oxo or C 1-6 alkyl. In some embodiments, R 2 is

In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I′), (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c , wherein R c is oxo, C 1-6 alkyl, or —C(O)—C 1-6 alkoxy, wherein the C 1-6 alkyl of R c is optionally substituted with one or more halo, and the —C(O)—C 1-6 alkoxy of R c is optionally substituted with one or more halo. In some embodiments, R 2 is

In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof. In some embodiments of a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ). In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ). In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ), wherein one of R c and R d is H, and the other of R c and R d is —C(O)—N(C 1-6 alkyl) 2 . In some embodiments, R 2 is

In some embodiments of a compound of formula (I′), (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ), wherein one of R c and R d is H, and the other of R c and R d , —C(O)—C 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , or —C(O)-(3-15 membered heterocyclyl), wherein the —C(O)-(3-15 membered heterocyclyl) of R c or R d is optionally substituted with one or more halo, —C(O)—C 1-6 alkoxy, or C 1-6 alkyl, and the C 1-6 alkyl of the —C(O)—N(C 1-6 alkyl) 2 of R c or R d are, independently of each other, optionally substituted with one or more halo or C 6-20 aryl. In some embodiments, R 2 is

›DETAILED DESCRIPTION OF THE INVENTION · 19 of 32

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R z is H, halo, C 1-6 alkyl, or —NH 2 and R y is (i) C 1-6 alkyl, (ii), C 2-6 alkenyl, or (iii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, R z is H, halo, or C 1-6 alkyl; and R y is (i) C 1-6 alkyl, (ii), C 2-6 alkenyl, or (iii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, R z is H or C 1-6 alkyl; and R y is (i) C 1-6 alkyl or (ii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R z is H or methyl; and R y is (i) isopropyl, or (ii) C 3-4 cycloalkyl. In some variations, R 2 , R k , R y , and R z of formula (I-A4) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein R y and R z are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein, the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, R z is H, halo, or C 1-6 alkyl, wherein the C 1-6 alkyl of R z is optionally substituted with one or more halo; and R y is (i) C 1-6 alkyl, (ii), or (ii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R z is H or methyl, wherein the methyl of R z is optionally substituted with one or more halo; and R y is (i) isopropyl, or (ii) C 3-4 cycloalkyl.

In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or halo. In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or fluoro. In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a . In some embodiments, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy. In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments, R 2 is

In some embodiments of a compound of formula (I-A4), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more oxo or C 1-6 alkyl. In some embodiments, R 2 is

›DETAILED DESCRIPTION OF THE INVENTION · 20 of 32

In some embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-B):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y 1 is CH or N; R x is H, halo, C 1-6 alkyl, or —NH 2 , wherein, when Y 1 is CH, the C 1-6 alkyl of R x may be optionally substituted with one or more halo; R y is (i) C 1-6 alkyl, (ii), C 2-6 alkenyl, or (iii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl; and Rk is taken together with either Rm or Rn, and the atoms to which they are attached, to form cyclopropyl. In some variations, Y 1 , R 2 , R k , R m , R n , R x , R y , and R z of formula (I-B) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein Y1 is CR x or N; wherein, when the ring bearing R x , and R y is phenyl, R x , and R y are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C 3-10 cycloalkyl, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl; and wherein when the ring bearing R x , and R y is pyridyl, R x , and R y are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein, the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl.

In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y 1 is CH or N; R x is H, halo, C 1-6 alkyl, or NH 2 , wherein, when Y 1 is CH, the C 1-6 alkyl of R x may be optionally substituted with one or more halo; and R y is (i) C 1-6 alkyl, (ii), C 2-6 alkenyl, or (iii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, Y 1 is CH or N; R x is H or halo; R y is C 1-6 alkyl or C 3-10 cycloalkyl; and R k is taken together with either R m or R n , and the atoms to which they are attached, to form cyclopropyl. In some embodiments, Y 1 is CH or N; R x is H or fluoro; R y is (i) isopropyl or (ii) C 3-4 cycloalkyl; and R k is taken together with either R m or R n , and the atoms to which they are attached, to form cyclopropyl. In some embodiments, Y 1 is CH or N; R x is H or fluoro; R y is (i) isopropyl or (ii) C 3-4 cycloalkyl; and R k is taken together with R m and the atoms to which they are attached to form cyclopropyl. In some embodiments, Y 1 is CH or N; R x is H or fluoro; R y is (i) isopropyl or (ii) C 3-4 cycloalkyl; and R k is taken together with R n and the atoms to which they are attached to form cyclopropyl. In some embodiments, Y 1 is CH; R x is H or fluoro; R y is (i) isopropyl or (ii) C 3-4 cycloalkyl; and R k is taken together with R n or R n and the atoms to which they are attached to form cyclopropyl. In some embodiments, Y 1 is N; R x is H or fluoro; R y is (i) isopropyl or (ii) C 3-4 cycloalkyl; and R k is taken together with R n or R n and the atoms to which they are attached to form cyclopropyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a . In some embodiments, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy. In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 21 of 32

In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments, R 2 is

In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more oxo or C 1-6 alkyl. In some embodiments, R 2 is

In some embodiments, provided here is a compound of formula (I) or formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-B1):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y 1 is CH or N; R x is H or halo; and R y is C 1-6 alkyl or C 3-10 cycloalkyl. In some embodiments, Y 1 is CH or N; R x is H or fluoro; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl. In some embodiments, Y 1 is CH; R x is H or fluoro; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl. In some embodiments, Y 1 is N; R x is H or fluoro; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl. In some variations, Y 1 , R 2 , R, and R y of formula (I-B1) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein Y 1 is CR or N; wherein, when the ring bearing R x , and R y is phenyl, R, and R y are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C 3-10 cycloalkyl, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl; and wherein when the ring bearing R x , and R y is pyridyl, R, and R y are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein, the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, Y 1 is CH or N; R x is H or fluoro; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl. In some embodiments, Y 1 is CH; R x is H or fluoro; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl. In some embodiments, Y 1 is N; R x is H or fluoro; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl.

In some embodiments of a compound of formula (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a . In some embodiments, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy. In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 22 of 32

In some embodiments of a compound of formula (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments, R 2 is

In some embodiments of a compound of formula (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more oxo or C 1-6 alkyl. In some embodiments, R 2 is

In some embodiments, provided herein is a compound of formula (I) or formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-B2):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y 1 is CH or N; R x is H or halo; and R y is C 1-6 alkyl or C 3-10 cycloalkyl. In some embodiments, Y 1 is CH or N; R x is H or fluoro; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl. In some embodiments, Y 1 is CH; R x is H or fluoro; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl. In some embodiments, Y 1 is N; R x is H or fluoro; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl. In some variations, Y 1 , R 2 , R, and R y of formula (I-B2) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein Y 1 is CR or N; wherein, when the ring bearing R x , and R y is phenyl, R, and R y are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C 3-10 cycloalkyl, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl; and wherein when the ring bearing R x , and R y is pyridyl, R, and R y are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein, the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments, Y 1 is CH or N; R x is H or fluoro; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl. In some embodiments, Y 1 is CH; R x is H or fluoro; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl. In some embodiments, Y 1 is N; R x is H or fluoro; and R y is (i) isopropyl or (ii) C 3-4 cycloalkyl.

In some embodiments of a compound of formula (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a . In some embodiments, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy. In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 23 of 32

In some embodiments of a compound of formula (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments, R 2 is

In some embodiments of a compound of formula (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more oxo or C 1-6 alkyl. In some embodiments, R 2 is

wherein X 5 is H, C 1-6 alkyl, C 1-6 alkoxy, or C 3-10 cycloalkyl; X 4 is H, halo, C 1-6 alkyl, C 1-6 alkoxy, or 5-20 membered heteroaryl; R v is —NH 2 , —NH—C(O)—(C 1-6 alkyl), or —NH—C(O)-(3-15 membered heterocyclyl); and R w is H, —NH 2 , —NH—C(O)—(C 1-6 alkyl), or —NH—C(O)-(3-15 membered heterocyclyl). In some embodiments, X 5 is H or C 1-6 alkyl; X 4 is H; R v is —NH 2 , —NH—C(O)—(C 1-6 alkyl), or —NH—C(O)-(3-15 membered heterocyclyl); and R w is H, —NH 2 , —NH—C(O)—(C 1-6 alkyl), or —NH—C(O)-(3-15 membered heterocyclyl). In some embodiments, R w is H and R v is —NH—C(O)C 1-6 alkyl. In some embodiments, R w is H and R v is —NH—C(O)CH 3 . In some variations, R 2 , R k , R w , R v , X 4 and X 5 of formula (I-C) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein X 5 is H, C 1-6 alkyl, C 1-6 alkoxy, or C 3-10 cycloalkyl; X 4 is H, halo, C 1-6 alkyl, C 1-6 alkoxy, or 5-20 membered heteroaryl; R v is —NH 2 , —NH—C(O)—(C 1-6 alkyl), or —NH—C(O)-(3-15 membered heterocyclyl); and R w is H, —NH 2 , —NH—C(O)—(C 1-6 alkyl), or —NH—C(O)-(3-15 membered heterocyclyl). In some embodiments, X 5 is H or C 1-6 alkyl; X 4 is H; R v is —NH 2 , —NH—C(O)—(C 1-6 alkyl), or —NH—C(O)-(3-15 membered heterocyclyl); and R w is H, —NH 2 , —NH—C(O)—(C 1-6 alkyl), or —NH—C(O)-(3-15 membered heterocyclyl). In some embodiments, R w is H and R v is —NH—C(O)C 1-6 alkyl. In some embodiments, R w is H and R v is —NH—C(O)CH 3 .

In some embodiments, provided is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-D):

wherein X 5 is H, C 1-6 alkyl, C 1-6 alkoxy, or C 3-10 cycloalkyl; X 4 is H, halo, C 1-6 alkyl, C 1-6 alkoxy, or 5-20 membered heteroaryl; and R t and R u are independently H, C 1-6 alkoxy, or —NH 2 . In some embodiments, X 5 is C 1-6 alkyl; X 4 is H, halo, or C 1-6 alkyl; and R t and R u are independently H or —NH 2 . In some embodiments, at least one of R t and R u is —NH 2 . In some embodiments, R t is H and R u is —NH 2 . In some embodiments, R t is —NH 2 and R u is H. In some variations, R 2 , R k , R t , R u , X 4 and X 5 of formula (I-D) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein X 5 is H, C 1-6 alkyl, C 1-6 alkoxy, or C 3-10 cycloalkyl, X 4 is H, halo, C 1-6 alkyl, C 1-6 alkoxy, or 5-20 membered heteroaryl; and R t and R u are independently H, C 1-6 alkoxy, or —NH 2 . In some embodiments, X 5 is C 1-6 alkyl; X 4 is H, halo, or C 1-6 alkyl; and R t and R u are independently H or —NH 2 . In some embodiments, at least one of R t and R u is —NH 2 . In some embodiments, R t is H and R u is —NH 2 . In some embodiments, R t is —NH 2 and R u is H.

›DETAILED DESCRIPTION OF THE INVENTION · 24 of 32

In some embodiments of a compound of formula (I-C) or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or halo. In some embodiments of a compound of formula (I-C) or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or fluoro. In some embodiments of a compound of formula (I-C) or (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments, provided is a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-D1):

wherein X 5 is H, C 1-6 alkyl, C 1-6 alkoxy, or C 3-10 cycloalkyl; X 4 is H, halo, C 1-6 alkyl, C 1-6 alkoxy, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl of X 4 is optionally substituted with one of more halo; and R t and R u are independently H, C 1-6 alkoxy, or —NH 2 . In some embodiments, X 5 is C 1-6 alkyl; X 4 is H, halo, or C 1-6 alkyl; and R u and R z are independently H, halo or —NH 2 . In some embodiments, at least one of R u and R z is —NH 2 . In some embodiments, R u is H and R z is —NH 2 . In some embodiments, R u is —NH 2 and R z is H. In some embodiments, at least one of R u and R z is halo. In some embodiments, R u is H and R z is fluoro. In some embodiments, R u is fluoro and R z is H.

wherein R k and R m are independently H, OH, —NH 2 , or —NH—C(O)C 1-6 alkyl. In some embodiments, R k is H and R m is H, OH, —NH 2 , or —NH—C(O)C 1-6 alkyl. In some embodiments, R k is H and R m is OH. In some embodiments, R k is H, OH, —NH 2 , or —NH—C(O)C 1-6 alkyl, and R m is H. In some embodiments, R k is OH, —NH 2 , or —NH—C(O)C 1-6 alkyl, and R m is H. In some embodiments, R k is OH, —NH 2 , or —NH—C(O)CH 3 , and R m is H. In some variations, R 2 , R k , and R m of formula (I-E) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein R k and R m are independently H, OH, —NH 2 , or —NH—C(O)C 1-6 alkyl. In some embodiments, R k is H and R m is H, OH, —NH 2 , or —NH—C(O)C 1-6 alkyl. In some embodiments, R k is H and R m is OH. In some embodiments, R k is H, OH, —NH 2 , or —NH—C(O)C 1-6 alkyl, and R m is H. In some embodiments, R k is OH, —NH 2 , or —NH—C(O)C 1-6 alkyl, and R m is H. In some embodiments, R k is OH, —NH 2 , or —NH—C(O)CH 3 , and R m is H.

wherein Y 1 is CH or N; R x is H, halo, C 1-6 alkyl, or —NH 2 , wherein, when Y 1 is CH, the C 1-6 alkyl of R x may be optionally substituted with one or more halo; R y is (i) C 1-6 alkyl, (ii), C 2-6 alkenyl, or (iii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl; R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl; and R x is H, C 1-6 alkyl, or C 3-10 cycloalkyl. In some embodiments, Y 1 is CH or N; R x is H, halo, or C 1-6 alkyl; R y is (i) C 1-6 alkyl, (ii), C 2-6 alkenyl, or (iii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl; R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl; and R x is H, C 1-6 alkyl, or C 3-10 cycloalkyl. In some variations, R 2 , R k , R x , R y , and R z of formula (I-F) are as defined for a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof, wherein Y 1 is CH or N; R x is H, halo, C 1-6 alkyl, or —NH 2 , wherein, when Y 1 is CH, the C 1-6 alkyl of R k may be optionally substituted with one or more halo; R y is (i) C 1-6 alkyl, (ii), C 2-6 alkenyl or (iii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl; R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl; and R n is H, C 1-6 alkyl, or C 3-10 cycloalkyl. In some embodiments, Y 1 is CH or N; R x is H, halo, or C 1-6 alkyl; R y is (i) C 1-6 alkyl, or (ii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl; R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl; and R n is H, C 1-6 alkyl, or C 3-10 cycloalkyl.

In some embodiments of a compound of formula (I-F), Y 1 is CH or N; R x is H, halo, or C 1-6 alkyl; R y is (i) C 1-6 alkyl, (ii), C 2-6 alkenyl, or (iii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl; R k is H or halo; and R n is H, C 1-6 alkyl, or C 3-6 cycloalkyl. In some embodiments, Y 1 is N or CH, R x is H or halo, R y is C 1-6 alkyl or C 3-6 cycloalkyl, R k is H or halo, and R n is C 1-6 alkyl or C 3-6 cycloalkyl. In some embodiments, Y 1 is N or CH, R x is H or fluoro, R y is C 1-6 alkyl or C 3-6 cycloalkyl, R k is H or fluoro, and R n is C 1-6 alkyl or C 3-6 cycloalkyl. In some embodiments, Y 1 is N or CH, R x is H or fluoro, R y is C 1-6 alkyl or C 3-6 cycloalkyl, R k is H or fluoro, and R n is C 1-6 alkyl or C 3-6 cycloalkyl. In some embodiments, Y 1 is N or CH, R x is H or fluoro, R y is C 1-6 alkyl or C 3-6 cycloalkyl, R k is H, and R n is C 1-6 alkyl or C 3-6 cycloalkyl. In some embodiments, Y 1 is N or CH, R x is H or fluoro, R y is C 1-3 alkyl or C 3-6 cycloalkyl, R k is H, and R n is C 1-3 alkyl or C 3-6 cycloalkyl. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 25 of 32

In some embodiments of a compound of formula (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a . In some embodiments, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more R b . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy. In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro. In some variations, the embodiments provided herein also apply to a compound of formula (I′) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any variation or embodiment thereof.

In some embodiments, R 2 is

In some embodiments of a compound of formula (I′), (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is

In some embodiments of a compound of formula (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c . In some embodiments, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more oxo or C 1-6 alkyl. In some embodiments, R 2 is

In some embodiments of a compound of formula (I′) (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c , wherein R c is oxo, C 1-6 alkyl, or —C(O)—C 1-6 alkoxy, wherein the C 1-6 alkyl of R c is optionally substituted with one or more halo, and the —C(O)—C 1-6 alkoxy of R c is optionally substituted with one or more halo. In some embodiments, R 2 is selected from the group consisting of

In some embodiments of a compound of formula (I′), (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —O—R e , wherein R e is —C(O)-(3-15 membered heterocyclyl) wherein the —C(O)-(3-15 membered heterocyclyl) of R e is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, C 1-6 alkoxy, or C 3-10 cycloalkyl. In some embodiments, R 2 is selected from the group consisting of

›DETAILED DESCRIPTION OF THE INVENTION · 26 of 32

In some embodiments of a compound of formula (I′), (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ), wherein one of R c and R d is H, and the other of R c and R d , —C(O)—C 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , or —C(O)-(3-15 membered heterocyclyl). In some embodiments, R 2 is

In some embodiments, provided herein is a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-G):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is (i) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of ring A is optionally substituted with one or more oxo, (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of ring A is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein, the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, or (iii) C 3-10 cycloalkyl.

In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 3 is H, fluoro or methyl optionally substituted with one or more fluoro; X 4 is (i) isopropyl (ii) C 3-4 cycloalkyl optionally substituted with one or more halo or C 1-6 alkyl or (iii) butyl; and R z is fluoro or methyl; provided that at least one of X 3 and X 4 is halo, CF 2 or CF 3 .

In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or halo. In some embodiments of a compound of formula (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is H or fluoro. In some embodiments of a compound of formula (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R k is fluoro.

In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is 5-20 membered heteroaryl or —(C 1-4 alkyl)(5-20 membered heteroaryl), wherein the C 1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R s . In some embodiments, R s is halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)—C 1-6 alkyl, C 6-20 aryl, C 3-10 cycloalkyl, 3-15 membered heterocyclyl, 5-20 membered heteroaryl, or —C(O)—C 1-6 alkoxy. In some embodiments, the C 1-6 alkyl of R s is optionally substituted with one or more halo, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, and the 3-15-membered heterocyclyl of R s is optionally substituted with one or more halo or —C(O)—C 1-6 alkoxy.

In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is selected from the group consisting of

In some embodiments of a compound of formula (I′) (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ), wherein one of R c and R d is H, and the other of R c and R d , —C(O)—C 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , or —C(O)-(3-15 membered heterocyclyl). In some embodiments, R 2 is

In some embodiments of a compound of formula (I′) (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is (i) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of ring A is optionally substituted with one or more oxo, or C 1-6 alkyl, (ii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of ring A is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein, the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, or (iii) C 3-10 cycloalkyl.

In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of ring A is optionally substituted with one or more oxo, or C 1-6 alkyl. In some embodiments ring A is selected from the group consisting of

In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of ring A is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein, the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl. In some embodiments ring A is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of ring A is optionally substituted with one or more C 1-6 alkyl. In some embodiments ring A is selected from the group consisting of

›DETAILED DESCRIPTION OF THE INVENTION · 27 of 32

In some embodiments of a compound of formula (I′), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A is C 3-10 cycloalkyl. In some embodiments, ring A is C 3-6 cycloalkyl. In some embodiments ring A is cyclopropyl.

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y 1 is CR x or N; wherein, when the ring bearing R x , R y and R z is phenyl, R x , R y and R z is H, halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), C 3-10 cycloalkyl, or 5-20 membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH—C(O)—NH(C 1-6 alkyl), —NH—C(O)—C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy, the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, and the 5-20 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl; and wherein when the ring bearing R x , R y and R z is pyridyl, R x , R y and R z are each independently H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein, the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (I), such as a compound of formula (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-C), (I-D), (I-E), or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a . In some embodiments, R 2 is C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl of R 2 is optionally substituted with one or more R q . In other embodiments, R 2 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R 2 is optionally substituted with one or more halo, oxo, C 1-6 alkyl, —C(O)—C 1-6 alkyl, or 5-20 membered heteroaryl. In some embodiments, R 2 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R 2 is optionally substituted with one or more R s . In some embodiments, R 2 is —N(R g )(R h ), wherein R g and R h are independently H or C 1-6 alkyl. In some embodiments, R 2 is —C(O)—R j , wherein R j is C 3-10 cycloalkyl, —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , or —NH (5-20 membered heteroaryl). In some embodiments, R 2 is C 6-20 aryl, wherein the C 6-20 aryl of R 2 is optionally substituted with one or more 5-20 membered heteroaryl or —O(R p ), wherein R p is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R p is optionally substituted with one or more —C(O)—C 1-6 alkyl.

In some embodiments, provided herein is a compound of formula (I′), such as a compound of formula (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-C), (I-D), (I-D1), (I-D2), (I-E), (I-F), (I-G), or (I-H) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a . In some embodiments, R 2 is C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl of R 2 is optionally substituted with one or more R q . In other embodiments, R 2 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R 2 is optionally substituted with one or more halo, oxo, C 1-6 alkyl, —C(O)—C 1-6 alkyl, or 5-20 membered heteroaryl. In some embodiments, R 2 is 5-20 membered heteroaryl, or —(C 1-4 alkyl)(5-20 membered heteroaryl), wherein the C 1-4 alkyl is optionally substituted with one or more or more —OH, halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , and wherein the 5-20 membered heteroaryl is optionally substituted with one or more R s . In some embodiments, R 2 is —N(R g )(R h ), wherein R g and R h are independently H or C 1-6 alkyl. In some embodiments, R 2 is —C(O)—R j , wherein R j is C 3-10 cycloalkyl, —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , or —NH (5-20 membered heteroaryl). In some embodiments, R 2 is C 6-20 aryl, wherein the C 6-20 aryl of R 2 is optionally substituted with one or more 5-20 membered heteroaryl or —O(R p ), wherein R p is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R p is optionally substituted with one or more —C(O)—C 1-6 alkyl.

In some embodiments of a compound of formula (I), or formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Table 1.

Compound Names included in Table 1 and for all intermediates and compounds were generated using ChemDraw® Professional software version 17.1.1.0 or Collaborative Drug Discovery Inc. (CDD) CDD Vault update #3.

A Knime workflow was created to retrieve structures from an internal ChemAxon Compound Registry, generate the canonical smiles using RDKit Canon SMILES node, remove the stereochemistry using ChemAxon/Infocom MolConverter node, and name the structure using ChemAxon/Infocom Naming node. The following denotes the version of the Knime Analytics Platform and extensions utilized in the workflow:

Knime Analytics Platform 4.2.2 RDKit Knime Integration 4.0.1.v202006261025 (this extension includes the RDKit Canon SMILES node) ChemAxon/Infocom Marvin Extensions Feature 4.3.0v202100 (this extension includes the MolConverter node) ChemAxon/Infocom JChem Extensions Feature 4.3.0v202100 (this extension includes the Naming node)

In some embodiments, provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the group consisting of:

›DETAILED DESCRIPTION OF THE INVENTION · 28 of 32

1-cyclopropanecarbonyl-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-acetyl-4-hydroxy-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-acetyl-3-hydroxy-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-acetyl-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-acetyl-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 1-(3-carbamoyl-2-acetamidopropanoyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; tert-butyl N-{2-oxo-2-[2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]ethyl}carbamate; 1-(2-hydroxyacetyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(2-acetamidoacetyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-acetyl-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; 1-(3-carbamoylpropanoyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-acetyl-N-[(5-cyclopropylpyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; 2-acetyl-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-2-azabicyclo[3.1.0]hexane-3-carboxamide; 1-{2-[N-(carbamoylmethyl)acetamido]acetyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-acetyl-5-methyl-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(1,3-oxazol-2-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(4H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-{2-[(3-methyloxetan-3-yl)amino]acetyl}-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-acetamido-5-[4-fluoro-2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-5-oxopentanoic acid; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; 1-(3-acetamidopropanoyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(2-oxopyrrolidin-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1,3-oxazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(4-acetamidobutanoyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 2-acetyl-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-(2-acetamidoacetyl)pyrrolidine-2-carboxamide; 3-acetyl-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-3-azabicyclo[3.1.0]hexane-2-carboxamide; 4-fluoro-1-[2-(2-oxo-1,3-oxazolidin-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(oxetan-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(3-oxomorpholin-4-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-acetyl-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-5-methylpyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1-methyl-1H-pyrazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(3-oxomorpholin-4-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-4H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[3-(1,3-oxazol-2-yl)propanoyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-oxo-1,3-oxazolidin-3-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-pyrazol-5-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3,4-tetrazol-5-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1,2-oxazol-3-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-1-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(2H-1,2,3,4-tetrazol-5-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1,3,4-oxadiazol-2-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-pyrazol-4-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-{2-[(1,3-oxazol-2-yl)amino]acetyl}-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(3-methyl-2-oxoimidazolidin-1-yl)acetyl]pyrrolidine-2-carboxamide; 1-[2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)acetyl]-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-{2-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]acetyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(1H-1,2,4-triazol-1-yl)propanoyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1-methyl-1H-pyrazol-4-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridazin-3-yloxy)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-(1-methyl-5-oxopyrrolidine-2-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(2-chloro-5-fluorophenyl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[4-(pyridin-3-yl)butanoyl]pyrrolidine-2-carboxamide; 4-fluoro-1-(3-oxo-octahydroindolizine-6-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-(2-oxopiperidine-4-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(2-cyano-4-methoxyphenyl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[4-(1H-imidazol-1-yl)butanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyrimidin-5-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-(4-methylpyrimidine-5-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(2-oxo-1,2-dihydropyridin-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[3-(3,5-dimethyl-1,2-oxazol-4-yl)propanoyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(3-fluoro-4-methoxyphenyl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-(1,3-oxazole-5-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[4-(pyridin-4-yl)butanoyl]pyrrolidine-2-carboxamide; 1-[(dimethylcarbamoyl)carbonyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1H-imidazol-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-pyrazol-5-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[2-methyl-3-(1H-1,2,4-triazol-1-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-fluoropyridin-2-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-methyl-1H-indol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(4-acetamidophenyl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1H-imidazol-4-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(pyridin-3-yl)propanoyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(4-methoxyphenyl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(1,5-dimethyl-1H-pyrazol-3-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[3-(2-methylpyridin-3-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyrimidin-2-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(pyrazin-2-yl)propanoyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(2H-1,2,3-triazol-2-yl)acetyl]pyrrolidine-2-carboxamide; 1-[3-(2,6-dimethylpyridin-3-yl)propanoyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(1H-1,2,3-benzotriazol-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridin-3-yloxy)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[3-(1H-imidazol-5-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[3-(5-methyl-1,3,4-thiadiazol-2-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[3-(3,5-dimethyl-1H-pyrazol-1-yl)propanoyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(3-cyanopropanoyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-methyl-1,2,4-oxadiazol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1-methyl-1H-indol-2-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[3-(5-methylpyridin-2-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(2-ethyl-1,3-oxazole-4-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(2-methyl-1,3-thiazol-4-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyrazin-2-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[2-methyl-3-(1H-pyrazol-1-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[3-(1H-indol-3-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-methyl-3-(pyridin-4-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(4-fluoro-1H-indol-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-{4-oxo-4H,5H,6H,7H,8H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl}-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-{2-[5-(propan-2-yl)-1,2,4-oxadiazol-3-yl]acetyl}pyrrolidine-2-carboxamide; 4-fluoro-1-(6-oxopiperidine-3-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyrrolidine-1-sulfonyl)acetyl]pyrrolidine-2-carboxamide; 1-[2-(1,2-benzoxazol-3-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-(2-{[1,2,4]triazolo[1,5-a]pyridin-6-yl}acetyl)pyrrolidine-2-carboxamide; 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-pyrazol-1-yl)propanoyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[3-(3-methoxypyridin-2-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1H-imidazol-1-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(3,5-dimethyl-1,2-oxazol-4-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1-methyl-1H-pyrazol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(1H-1,2,3-triazol-1-yl)propanoyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[3-(1H-imidazol-2-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(2-methylphenoxy)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(3-methyl-1,2-oxazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-(3-methyloxetane-3-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(4-chloro-1H-pyrazol-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(1-ethyl-1H-pyrazole-5-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridin-2-yl)propanoyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(pyrimidin-5-yl)propanoyl]pyrrolidine-2-carboxamide; 4-fluoro-1-(3-methoxy-1-methyl-1H-pyrazole-4-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-methyl-1,3,4-oxadiazol-2-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(1H-pyrazol-4-yl)propanoyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1,3-thiazol-4-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[4-(2-methyl-1H-imidazol-1-yl)butanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-(2-{imidazo[1,2-a]pyridin-3-yl}acetyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(pyridin-2-yl)propanoyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(3-methyl-1,2,4-oxadiazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[3-(6-methylpyridin-3-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-(3-{1H-pyrrolo[2,3-b]pyridin-3-yl}propanoyl)pyrrolidine-2-carboxamide; 4-fluoro-1-(2-oxo-1,3-oxazolidine-5-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(4-methyl-1H-pyrazol-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[3-(1-methyl-1H-pyrazol-4-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,4-triazol-1-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[5-(pyridin-4-yl)-1H-pyrazole-3-carbonyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[3-(2-methylpyridin-4-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-(2-hydroxy-3-methylbutanoyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-(3-{1H-pyrrolo[2,3-b]pyridin-5-yl}propanoyl)pyrrolidine-2-carboxamide; 4-fluoro-1-[4-oxo-4-(pyrrolidin-1-yl)butanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(quinolin-6-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridin-4-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(2,2,2-trifluoroacetamido)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridin-3-yloxy)propanoyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1H-indol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(2-cyclopropyl-2-oxoacetyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-fluoro-2-methoxyphenyl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(6-methoxypyridin-2-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(2-oxo-1,2-dihydropyridin-1-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridin-3-yl)acetyl]pyrrolidine-2-carboxamide; 1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(2,5-dioxoimidazolidin-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(2,5-dimethyl-1,3-thiazol-4-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-methyl-3-(pyridin-2-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(2-oxo-1,2-dihydropyrazin-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(N-methylacetamido)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-methyl-2-(pyridin-2-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(2-oxopiperidin-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(quinolin-5-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[3-(1H-1,2,4-triazol-1-yl)benzoyl]pyrrolidine-2-carboxamide; 4-fluoro-1-{[(2-methylpropyl)carbamoyl]carbonyl}-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,3,4-tetrazol-1-yl)propanoyl]pyrrolidine-2-carboxamide; 4-fluoro-1-(2-oxo-1,2,3,4-tetrahydroquinoline-7-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(2-methyl-1,3-thiazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[3-(6-oxo-1,6-dihydropyridazin-3-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(4-methyl-1H-pyrazol-1-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(pyridin-2-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(3-methyl-1H-pyrazol-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(2-acetamidopyridine-4-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-pyrazol-3-yl)acetyl]pyrrolidine-2-carboxamide; N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-3-[2-(1H-1,2,3-triazol-5-yl)acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1,3,4-oxadiazol-2-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-2-[2-(1H-1,2,3-triazol-5-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide; N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-5-methyl-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-(2-hydroxy-2-methylpropanoyl)pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3,4-tetrazol-5-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-2H-1,2,3,4-tetrazol-2-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-3-[2-(1H-1,2,3-triazol-5-yl)acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-1-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(4-methyl-4H-1,2,4-triazol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1-methyl-1H-1,2,3-triazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1-methyl-1H-1,2,3-triazol-4-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1,2-oxazol-4-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1,2-oxazol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(3-methyl-1H-1,2,4-triazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-pyrazol-5-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-pyrazol-3-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyridin-2-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(5-methyl-1,3,4-oxadiazol-2-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyridin-3-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyrimidin-4-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyrimidin-5-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyrazin-2-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(4-methyl-2,5-dioxopiperazin-1-yl)acetyl]pyrrolidine-2-carboxamide; 1-(2-cyanoacetyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-(2-methanesulfonylacetyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-1-yl)propanoyl]pyrrolidine-2-carboxamide; 1-(4-acetylmorpholine-2-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(4-acetyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(4-acetyl-2-oxopiperazin-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(1-acetylpiperidine-4-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(2,3-dihydroxypropanoyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{8-acetyl-8-azaspiro[4.5]decane-2-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[3-(1H-imidazol-1-yl)-2-methylpropanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{6-acetyl-6-azaspiro[2.5]octane-1-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(1-acetyl-3-methylpyrrolidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(N-methylacetamido)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{2-acetyl-5-oxa-2,6-diazaspiro[3.4]oct-6-ene-7-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[1-acetyl-2-(pyridin-3-yl)pyrrolidine-3-carbonyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[5-(methoxymethyl)-1,2-oxazole-4-carbonyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{6-acetyl-5H,6H,7H,8H-pyrido[3,4-b]pyrazine-7-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(1H-1,2,4-triazol-1-yl)propanoyl]pyrrolidine-2-carboxamide; 1-{5-acetyl-5-azaspiro[2.4]heptane-1-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[3-(1-acetylpyrrolidin-2-yl)propanoyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{4-[(1-acetylazetidin-3-yl)oxy]benzoyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[3-methoxy-2-(N-methylacetamido)butanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(1-acetylpyrrolidin-2-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{7-acetyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{5-acetyl-hexahydro-1H-furo[3,4-c]pyrrole-3a-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(1-acetylpyrrolidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(3-methyl-1H-pyrazol-5-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{5-acetyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(1-acetylpiperidin-4-yl)propanoyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-methyl-2-(1H-1,2,4-triazol-5-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-methyl-2-(1,3,4-oxadiazol-2-yl)propanoyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyridin-4-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-(2-{imidazo[1,2-a]pyridin-3-yl}acetyl)pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-imidazol-1-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1,2-oxazol-5-yl)acetyl]pyrrolidine-2-carboxamide; 1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-[2-(1H-1,2,3-triazol-5-yl)acetyl]-4-azaspiro[2.4]heptane-5-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-(2-{[1,2,4]triazolo[1,5-a]pyridin-6-yl}acetyl)pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(quinolin-6-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-pyrazol-4-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-[2-(piperazin-1-yl)acetyl]pyrrolidine-2-carboxamide; 1-(1-acetyl-3-methylpiperidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(1-acetyl-4-methylazepane-4-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(1-acetylazepane-4-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(1-acetylpiperidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(4-acetylmorpholine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(2-{2-acetyl-2-azaspiro[3.4]octan-5-yl}acetyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{2-acetyl-2-azaspiro[4.4]nonane-6-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{2-acetyl-2-azabicyclo[2.2.2]octane-6-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(1-acetylpiperidin-3-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(4-acetyl-1,4-oxazepane-2-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(1-acetyl-4-methylpiperidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(4-acetyl-2-methylmorpholine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{5-acetyl-hexahydro-2H-furo[2,3-c]pyrrole-3-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{3-acetyl-3-azabicyclo[3.1.0]hexane-1-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{2-acetyl-octahydrocyclopenta[c]pyrrole-4-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{8-acetyl-8-azabicyclo[3.2.1]octane-3-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(1-acetyl-3-methylazetidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{5-acetyl-hexahydro-2H-furo[2,3-c]pyrrole-2-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{3-acetyl-3-azabicyclo[3.2.1]octane-8-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(2-acetyl-octahydro-1H-isoindole-4-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{7-acetyl-7-azabicyclo[2.2.1]heptane-2-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{2-acetyl-5-oxa-2-azaspiro[3.4]octane-7-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(1-acetyl-3-methylazetidin-3-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{2-acetyl-5-oxa-2-azaspiro[3.4]octane-6-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(1-acetyl-2-methylpiperidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-{3-[N-(1-methyl-1H-pyrazol-3-yl)acetamido]propanoyl}-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(1-acetyl-3-fluoroazetidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(1-acetyl-3-methoxyazetidin-3-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{4-acetyl-hexahydro-2H-furo[3,2-b]pyrrole-6-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(1-acetyl-4-ethylpyrrolidine-3-carbonyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{7-acetyl-1-oxo-2,7-diazaspiro[4.4]nonane-4-carbonyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[1-(1,3,4-oxadiazol-2-yl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide; 2-[4-fluoro-2-({[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl N,N-dimethylcarbamate; 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; 2-[4-fluoro-2-({phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl N,N-dimethylcarbamate; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-1,2,3-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide; 1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-[2-(quinolin-5-yl)acetyl]pyrrolidine-2-carboxamide; tert-butyl 4-({2-[4-fluoro-2-({[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)piperazine-1-carboxylate; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide; N-{2-[4-fluoro-2-({[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}piperazine-1-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(quinolin-5-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-[2-(1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; 1-[2-(4-acetylpiperazin-1-yl)acetyl]-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-methyl-2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl)acetyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-[2-(3,5-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; 1-{2-[(dimethylcarbamoyl)(methyl)amino]acetyl}-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-(2-oxo-1,3-oxazolidine-5-carbonyl)pyrrolidine-2-carboxamide; 2-[4-fluoro-2-({[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl piperazine-1-carboxylate; 1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)acetyl]-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 1-tert-butyl 4-{2-[4-fluoro-2-({[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}piperazine-1,4-dicarboxylate; 1-{2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 1-{2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; tert-butyl N-({5-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]-1,3,4-oxadiazol-2-yl}methyl)carbamate; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyridazin-4-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-{2-[5-(trifluoromethyl)-2H-1,2,3,4-tetrazol-2-yl]acetyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-5-methyl-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(pyridazin-3-yl)acetyl]pyrrolidine-2-carboxamide; N-[(5-cyclopropylpyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-oxopiperazin-1-yl)acetyl]pyrrolidine-2-carboxamide; N-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]-4-methylpiperazine-1-carboxamide; N-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]-4-(2,2,2-trifluoroethyl)piperazine-1-carboxamide; N-{2-[4-fluoro-2-({phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-4-(2,2,2-trifluoroethyl)piperazine-1-carboxamide; N-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]-4-(2-methoxyethyl)piperazine-1-carboxamide; 1-{2-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]acetyl}-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(5-methyl-1H-1,2,3-triazol-1-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(4-methyl-1H-1,2,3-triazol-1-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[4-(piperazin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}pyrrolidine-2-carboxamide; N-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]-4-(cyclopropylmethyl)piperazine-1-carboxamide; 4-(cyclopropylmethyl)-N-{2-[4-fluoro-2-({phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}piperazine-1-carboxamide; N-{2-[4-fluoro-2-({phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-4-methylpiperazine-1-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(4-methyl-1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(2-methylquinolin-5-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; tert-butyl N-[(5-{2-[4-fluoro-2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-1,3,4-oxadiazol-2-yl)methyl]carbamate; 1-{2-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{2-[4-(dimethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; tert-butyl 4-(5-{2-[4-fluoro-2-({[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-(2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetyl)pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetyl}pyrrolidine-2-carboxamide; 1-{2-[4-(dimethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide; 1-[2-(3,5-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; 1-{2-[5-(difluoromethyl)-2H-1,2,3,4-tetrazol-2-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 1-{2-[5-(acetamidomethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-{2-[5-(aminomethyl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 1-(2-{5-[(dimethylamino)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[4-(piperazin-1-yl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[4-(morpholin-4-yl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide; 1-(2-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}acetyl)-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-indazol-3-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[5-(trifluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}pyrrolidine-2-carboxamide; 1-[2-(1H-1,2,3-benzotriazol-1-yl)acetyl]-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetyl]pyrrolidine-2-carboxamide; N-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]morpholine-4-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1-methyl-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1-methyl-1H-indol-2-yl)acetyl]pyrrolidine-2-carboxamide; 2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl azetidine-1-carboxylate; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1-methyl-1H-indazol-3-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-methyl-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide; 1-{2-[5-(acetamidomethyl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(4-methyl-1H-imidazol-1-yl)acetyl]pyrrolidine-2-carboxamide; 1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl 4-(cyclopropylmethyl)piperazine-1-carboxylate; 2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl 4-methylpiperazine-1-carboxylate; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-(2-{imidazo[1,2-a]pyridin-3-yl}acetyl)pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-(2-{[1,2,4]triazolo[1,5-a]pyridin-6-yl}acetyl)pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-{2-[(pyrazin-2-yl)amino]acetyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-{2-[4-(piperazin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[(2-ethyl-2H-1,2,3-triazol-4-yl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[(1-ethyl-1H-1,2,3-triazol-4-yl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-methylquinolin-6-yl)acetyl]pyrrolidine-2-carboxamide; 2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl 4-(2-methoxyethyl)piperazine-1-carboxylate; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-{2-[2-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl]acetyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-{2-[methyl(2-methylpyrimidin-4-yl)amino]acetyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(2-methylquinolin-5-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-{2-[(2-methylpyrimidin-4-yl)amino]acetyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-{2-[methyl(pyrazin-2-yl)amino]acetyl}pyrrolidine-2-carboxamide; 4-fluoro-1-(2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetyl)-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[4-(dimethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[4-(dimethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; 1-{2-[4-(dimethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-(2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetyl)pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-(2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetyl)pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(2-methylquinolin-5-yl)acetyl]pyrrolidine-2-carboxamide; tert-butyl 2-[2-(2-{[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]carbamoyl}-4-fluoropyrrolidin-1-yl)-2-oxoethyl]-1H-indole-1-carboxylate; 1-{2-[4-(dimethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-indol-2-yl)acetyl]pyrrolidine-2-carboxamide; 1-[2-(carbamoylamino)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; 1-{2-[4-(dimethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[(2-ethyl-2H-1,2,3-triazol-4-yl)(methyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[(1-ethyl-1H-1,2,3-triazol-4-yl)(methyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[4-(dimethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; 1-{2-[4-(dimethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(dimethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propanoyl]pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-{2-[(methylcarbamoyl)amino]acetyl}-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-{2-[(2-methylpyrimidin-4-yl)amino]acetyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-{2-[(methylcarbamoyl)amino]acetyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetyl]pyrrolidine-2-carboxamide; 1-{2-[(azetidine-1-carbonyl)amino]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 1-{2-[(azetidine-1-carbonyl)amino]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-{2-[(2-methylpyrimidin-4-yl)amino]acetyl}-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; 1-[2-(carbamoylamino)acetyl]-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propanoyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 1-[2-(carbamoylamino)acetyl]-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; 1-{2-[(azetidine-1-carbonyl)amino]acetyl}-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[(methylcarbamoyl)amino]acetyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[(2-methylpyrimidin-4-yl)amino]acetyl}pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetyl]pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; 1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide; 1-{2-[(dimethylcarbamoyl)amino]propanoyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-1-{2-[(3,3-difluoroazetidine-1-carbonyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-(2-{[3-(trifluoromethyl)azetidine-1-carbonyl]amino}acetyl)pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[(dimethylcarbamoyl)amino]propanoyl}-4-fluoropyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-methyl-1,3-oxazol-2-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 1-{2-[(dimethylcarbamoyl)amino]propanoyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-4-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-(3-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}propanoyl)-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 1-{2-[(3,3-difluoroazetidine-1-carbonyl)amino]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-(2-{[3-(trifluoromethyl)azetidine-1-carbonyl]amino}acetyl)pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; 1-{2-[(3,3-difluoroazetidine-1-carbonyl)amino]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[(3,3-difluoroazetidine-1-carbonyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide; N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-3-[2-(1H-1,2,3-triazol-5-yl)acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; 5-methyl-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(4-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-(2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetyl)pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(4-methyl-1,3-oxazol-2-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(4-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}-1-[2-(1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide; 1-{2-[4-(3,3-difluoroazetidin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; 1-{2-[4-(diethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-5-methyl-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; 1-{2-[4-(3,3-difluoroazetidin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[(1,3-oxazol-2-yl)amino]acetyl}pyrrolidine-2-carboxamide; N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-3-[2-(1H-1,2,3-triazol-5-yl)acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[4-(3,3-difluoroazetidin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; 1-{2-[4-(diethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[4-(diethylamino)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-5-methyl-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide; 1-{2-[4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; 1-{2-[4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide; 1-{2-[4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide; 4-fluoro-1-[2-(5-methyl-2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide; N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide; 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methyl-2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide; and N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-3-[2-(1H-1,2,3-triazol-5-yl)acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide 1-{2-[(azetidine-1-carbonyl)amino]acetyl}-N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methy 1}-1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(4-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide 1-{2-[(3,3-difluoroazetidine-1-carbonyl)amino]acetyl}-N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(6-oxo-1,6-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(2-oxo-1,2-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(6-ethoxy-5-methylpyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(4-ethyl-5-oxo-4,5-dihydropyrazin-2-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-{2-[4-(trifluoromethyl)-1,3-oxazol-2-yl]acetyl}pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(3-oxo-3,4-dihydropyrazin-2-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-oxo-4,5-dihydropyrazin-2-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)-6-fluoropyridin-2-yl](phenyl)methyl}-1-[2-(4-ethyl-3-oxo-3,4-dihydropyrazin-2-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide 1-{2-[(azetidine-1-carbonyl)amino]acetyl}-N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide 1-{2-[(3,3-difluoroazetidine-1-carbonyl)amino]acetyl}-N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(4-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide N-{[5-(3,3-difluorocyclobutyl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-{2-[4-(trifluoromethyl)-1,3-oxazol-2-yl]acetyl}pyrrolidine-2-carboxamide 1-{2-[(azetidine-1-carbonyl)amino]acetyl}-N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoropyrrolidine-2-carboxamide N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-{2-[4-(trifluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}pyrrolidine-2-carboxamide N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-[2-(4-methyl-1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide N-{[4-(3,3-difluorocyclobutyl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-{2-[4-(trifluoromethyl)-1,3-oxazol-2-yl]acetyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](pyridin-3-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl azetidine-1-carboxylate 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-indol-2-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(2-oxopiperazin-1-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1-methyl-1H-indazol-3-yl)acetyl]pyrrolidine-2-carboxamide N-{2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}morpholine-4-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(2-methyl-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide 1-[2-(1H-1,3-benzodiazol-1-yl)propanoyl]-4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1H-indazol-3-yl)acetyl]pyrrolidine-2-carboxamide 1-[2-(2,5-dioxopiperazin-1-yl)acetyl]-4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetyl]pyrrolidine-2-carboxamide 1-[2-(1H-1,2,3-benzotriazol-1-yl)acetyl]-4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide 2,2,2-trifluoroethyl 4-{2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-3-oxopiperazine-1-carboxylate 2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl 4-(2-methoxyethyl)piperazine-1-carboxylate 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-{2-[2-oxo-4-(2,2,2-trifluoroethyl)piperazin-1-yl]acetyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}-1-[2-(4H-1,2,4-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide 2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl 4-methylpiperazine-1-carboxylate 2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl 4-(cyclopropylmethyl)piperazine-1-carboxylate 2-[4-fluoro-2-({[3-fluoro-4-(1-methylcyclopropyl)phenyl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate 1-[2-(1H-1,3-benzodiazol-1-yl)propanoyl]-4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-indazol-3-yl)acetyl]pyrrolidine-2-carboxamide N-{2-[4-fluoro-2-({[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}morpholine-4-carboxamide 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(1-methyl-1H-indol-2-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(1-methyl-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(2-methyl-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide 1-[2-(1H-1,2,3-benzotriazol-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-[2-(1H-1,3-benzodiazol-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(1-methyl-1H-indazol-3-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-indol-2-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}-1-[2-(3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)acetyl]pyrrolidine-2-carboxamide tert-butyl 2-{2-[4-fluoro-2-({[6-fluoro-5-(1-methylcyclopropyl)pyridin-2-yl](phenyl)methyl}carbamoyl)pyrrolidin-1-yl]-2-oxoethyl}-1H-indole-1-carboxylate 1-{2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoro-N-{[4-methyl-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-acetyl-N-[(5-cyclobutylpyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide 4-fluoro-N-{[4-methyl-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[4-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-{[4-(difluoromethyl)-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-methyl-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{phenyl[5-(propan-2-yl)-4-(trifluoromethyl)pyridin-2-yl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 1-{2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]acetyl}-4-fluoro-N-{[6-methyl-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide N-[(5-cyclobutylpyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(5-tert-butylpyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-methoxy-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(2-aminopyridin-3-yl)[3-fluoro-4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(4-cyclopropyl-3-fluorophenyl)(1H-pyrazol-5-yl)methyl]-1-(2-acetamidoacetyl)pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](5-fluoropyridin-2-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](5-fluoropyridin-3-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(2-aminopyridin-4-yl)[3-fluoro-4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](3-fluoropyridin-4-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(6-aminopyridin-3-yl)[3-fluoro-4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(6-aminopyridin-2-yl)[3-fluoro-4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(2-aminopyridin-3-yl)[3-methyl-4-(propan-2-yl)phenyl]methyl]-1-{2-[(dimethylcarbamoyl)amino]acetyl}-4-fluoropyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](1H-pyrazol-5-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(2-aminopyridin-3-yl)[3-methyl-4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(2-aminopyridin-3-yl)[3-methyl-4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](2-methoxypyridin-3-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclopropyl)phenyl](2-methylpyridin-3-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl]({imidazo[1,5-a]pyridin-3-yl})methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl]({imidazo[1,5-a]pyridin-1-yl})methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](1H-pyrazol-5-yl)methyl}-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl]({imidazo[1,5-a]pyridin-7-yl})methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](1H-indazol-6-yl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](1H-indazol-6-yl)methyl}pyrrolidine-2-carboxamide 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](1-methyl-1H-indazol-6-yl)methyl}pyrrolidine-2-carboxamide 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](2-methyl-2H-indazol-6-yl)methyl}pyrrolidine-2-carboxamide 1-acetyl-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(1H-indazol-6-yl)methyl]-4-fluoropyrrolidine-2-carboxamide methyl N-({3-[({4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidin-2-yl}formamido)[6-fluoro-5-(propan-2-yl)pyridin-2-yl]methyl]phenyl}methyl)carbamate 1-acetyl-N-[(2-methoxyphenyl)[4-(propan-2-yl)phenyl]methyl]pyrrolidine-2-carboxamide 1-acetyl-N-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]pyrrolidine-2-carboxamide 1-acetyl-N-[(2-methylphenyl)[5-(propan-2-yl)pyridin-2-yl]methyl]pyrrolidine-2-carboxamide N-[(4-cyclopropyl-3-fluorophenyl)(2-oxo-2,3-dihydro-1,3-benzoxazol-7-yl)methyl]-1-(2-acetamidoacetyl)pyrrolidine-2-carboxamide N-[(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)[4-(propan-2-yl)phenyl]methyl]-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](3-fluorophenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](4-fluorophenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(4-cyclopropyl-3-fluorophenyl)(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)methyl]-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(3-acetamidophenyl)[4-(propan-2-yl)phenyl]methyl]-4-fluoro-1-[2-(1-methyl-1H-1,2,3-triazol-4-yl)acetyl]pyrrolidine-2-carboxamide N-[(4-cyclopropyl-3-fluorophenyl)(1-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](3-methoxyphenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-{cyclopropyl[3-fluoro-4-(propan-2-yl)phenyl]methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-{2-cyclopropyl-1-[3-fluoro-4-(propan-2-yl)phenyl]ethyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](3-methoxyphenyl)methyl}pyrrolidine-2-carboxamide N-{[3-(acetamidomethyl)phenyl][6-fluoro-5-(propan-2-yl)pyridin-2-yl]methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](3-{[(methylcarbamoyl)amino]methyl}phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(2-fluorophenyl)methyl]-1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(4-fluorophenyl)methyl]-1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-{[3,5-difluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[(1H-1,2,3-triazol-5-yl)methanesulfonyl]pyrrolidine-2-carboxamide 1-acetyl-N-[(4-cyclobutyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide N-{[3,5-difluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide N-[(4-cyclopropyl-3,5-difluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[2-methyl-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1,3-oxazol-2-yl)acetyl]pyrrolidine-2-carboxamide N-[(3-chloro-4-cyclopropylphenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(4-cyclopropyl-3-methylphenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-{[3,5-difluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-{[3,5-difluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-1-yl)acetyl]pyrrolidine-2-carboxamide N-{[3,5-difluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-methyl-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-{[3-chloro-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(4-cyclobutyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(4-cyclobutyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3,4-tetrazol-1-yl)acetyl]pyrrolidine-2-carboxamide N-{[4-(butan-2-yl)-3-fluorophenyl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-5-methyl-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-{[3-(difluoromethyl)-4-(propan-2-yl)phenyl](phenyl)methyl}-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(1-methylcyclobutyl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(4-cyclopropyl-3-fluoro-5-methylphenyl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-2H-1,2,3,4-tetrazol-2-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{phenyl[4-(propan-2-yl)-3-(trifluoromethyl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(4-tert-butyl-3-fluorophenyl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1H-pyrazol-5-yl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(4H-1,2,4-triazol-3-yl)phenyl]methyl}pyrrolidine-2-carboxamide 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1H-pyrazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide 1-(2-acetamidoacetyl)-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1H-pyrazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1,3-oxazol-5-yl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1,2-oxazol-5-yl)phenyl]methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1-methyl-1H-pyrazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(3-methyl-1H-pyrazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide 1-acetyl-N-{[3-(1,3-dimethyl-1H-pyrazol-5-yl)phenyl][6-fluoro-5-(propan-2-yl)pyridin-2-yl]methyl}-4-fluoropyrrolidine-2-carboxamide 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1,2-oxazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1H-pyrazol-1-yl)phenyl]methyl}pyrrolidine-2-carboxamide 1-acetyl-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide 1-(oct-7-ynoyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide 4-fluoro-1-(1-methyl-1H-indazole-5-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide 4-fluoro-1-[2-(4-methoxyphenyl)cyclopropanecarbonyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide 4-fluoro-1-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-2-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide 4-fluoro-1-[2-(2-methylpropoxy)pyridine-4-carbonyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide 4-fluoro-1-[3-(1H-imidazol-4-yl)propanoyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide 4-fluoro-1-[4-(1H-imidazol-1-yl)pyridine-2-carbonyl]-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}-1-{[(pyridin-3-yl)carbamoyl]carbonyl}pyrrolidine-2-carboxamide 4-fluoro-1-(5-methoxy-1-methyl-1H-pyrazole-3-carbonyl)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}pyrrolidine-2-carboxamide 1-[2-(1,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide 1-{2-[4-(azetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide 4-fluoro-1-[2-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)acetyl]-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide 1-{2-[5-(diethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide 1-{2-[5-(3,3-difluoroazetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide 1-{2-[5-(azetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-(2-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetyl)pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)acetyl]pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(1,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide 1-{2-[4-(azetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[3-(difluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(2-oxo-1,2-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(6-oxo-1,6-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(6-ethoxy-5-methylpyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[4-(trifluoromethyl)-1,3-oxazol-2-yl]acetyl}pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(4-ethyl-5-oxo-4,5-dihydropyrazin-2-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide 1-(2-{[benzyl(trifluoromethyl)carbamoyl]amino}acetyl)-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetyl}pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-[2-(5-oxo-4,5-dihydropyrazin-2-yl)acetyl]pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(diethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-3-methyl-1H-pyrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(4-ethyl-3-oxo-3,4-dihydropyrazin-2-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[4-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[5-(trifluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[4-(difluoromethyl)-1H-1,2,3-triazol-5-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[4-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(3,3-difluoroazetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[3-(difluoromethyl)-4H-1,2,4-triazol-4-yl]acetyl}-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoro-1-{2-[5-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}pyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-[2-(4,5-dimethyl-1,3-oxazol-2-yl)acetyl]-4-fluoropyrrolidine-2-carboxamide 1-{2-[5-(azetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-1-{2-[5-(difluoromethyl)-1H-1,2,3,4-tetrazol-1-yl]acetyl}-4-fluoro-3-hydroxypyrrolidine-2-carboxamide 1-(3-carbamoyl-2-acetamidopropanoyl)-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3,4-tetrazol-1-yl)propanoyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-imidazol-1-yl)propanoyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)propanoyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[(1H-1,2,3-triazol-5-yl)methanesulfonyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}-1-[2-hydroxy-2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 1-{2-[4-(dimethylamino)-1H-1,2,3-triazol-5-yl]acetyl}-4-fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-1,2,3-triazol-5-yl)acetyl]pyrrolidine-2-carboxamide 1-[2-(3,5-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]pyrrolidine-2-carboxamide 1-[2-(1,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-(3-{3-oxo-2H,3H-[1,2,4]triazolo[4,3-a]pyridin-2-yl}propanoyl)pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methyl-1H-pyrazol-1-yl)acetyl]pyrrolidine-2-carboxamide 1-{2-[5-(difluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide 1-[2-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-[2-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-{2-[4-(azetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-{2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}pyrrolidine-2-carboxamide 1-{2-[3-(difluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-{2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(6-oxo-1,6-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide 1-[2-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(2-oxo-1,2-dihydropyridin-3-yl)acetyl]pyrrolidine-2-carboxamide 1-[2-(3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-[2-(1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-[2-(1-ethyl-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-[2-(4-ethyl-5-oxo-4,5-dihydropyrazin-2-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-[2-(6-ethoxy-5-methylpyridin-3-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-[2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-methoxy-1-methyl-1H-1,2,4-triazol-3-yl)acetyl]pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-{2-[4-(trifluoromethyl)-1,3-oxazol-2-yl]acetyl}pyrrolidine-2-carboxamide 4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}-1-[2-(5-oxo-4,5-dihydropyrazin-2-yl)acetyl]pyrrolidine-2-carboxamide 1-{2-[5-(difluoromethyl)-3-methyl-1H-pyrazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-{2-[3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-{2-[5-(diethylamino)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-[2-(4-ethyl-3-oxo-3,4-dihydropyrazin-2-yl)acetyl]-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-{2-[5-(3,3-difluoroazetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-{2-[5-(azetidin-1-yl)-1H-1,2,3-triazol-1-yl]acetyl}-4-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](phenyl)methyl}pyrrolidine-2-carboxamide 1-[2-(1H-1,3-benzodiazol-1-yl)propanoyl]-N-[(4-cyclopropyl-3-fluorophenyl)(phenyl)methyl]-4-fluoropyrrolidine-2-carboxamide

›DETAILED DESCRIPTION OF THE INVENTION · 29 of 32

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

Methods of Treatment

Provided herein is a method of modulating GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a GYS1 inhibitor, or (ii) a pharmaceutical composition, comprising an effective amount of a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

Provided herein is a method of modulating GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

Provided herein is a method of inhibiting GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a GYS1 inhibitor, or (ii) a pharmaceutical composition, comprising an effective amount of a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

Provided herein is a method of inhibiting GYS1 in a cell, comprising exposing the cell to (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

Provided herein is a method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of (i) a GYS1 inhibitor, or (ii) a pharmaceutical composition, comprising a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2. In some embodiments, the individual has a GYS1-mediated disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is cancer. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML). In some embodiments, the GYS1-mediated disease, disorder, or condition is Pompe disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is late-onset Pompe disease (LOPD).

Provided herein is a method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

Provided herein is a method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I′), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

Provided herein is a method of inhibiting glycogen synthesis in an individual in need thereof, comprising administering to the individual an effective amount of (i) a GYS1 inhibitor, or (ii) a pharmaceutical composition, comprising a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients. In certain embodiments the GYS1 inhibitor is a compound of formula (I′), (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is (i) a composition comprising an effective amount of a compound of formula (I′), (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I′), (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the compounds and/or compositions inhibit the hGYS enzyme, and subsequently, the glycogen synthesis in cells.

›DETAILED DESCRIPTION OF THE INVENTION · 30 of 32

Provided herein is a method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to glycogen substrate reduction therapy. In some embodiments, glycogen substrate reduction therapy reduces glycogen stores. In some embodiments, glycogen substrate reduction therapy comprises administering to the individual an effective amount of (i) a GYS1 inhibitor, or (ii) a pharmaceutical composition comprising a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is cancer. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML). In some embodiments, the GYS1-mediated disease, disorder, or condition is Pompe disease.

Provided herein is a method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is cancer. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).

Provided herein is a method of treating a glycogen storage disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to glycogen substrate reduction therapy. In some embodiments, glycogen substrate reduction therapy reduces glycogen stores. In some embodiments, glycogen substrate reduction therapy comprises administering to the individual an effective amount of (i) a GYS1 inhibitor, or (ii) a pharmaceutical composition comprising a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2. In some embodiments, the level of glycogen in the individual is reduced upon treatment. In some embodiments, the level of glycogen in muscle is reduced. In some embodiments, the level of glycogen is skeletal muscle is reduced. In some embodiments, the level of glycogen is reduced at least 10%, at least 20%, at least 30% or at least 50% upon administration of the compound. In some embodiments, the compounds provided herein are effective for treating a lysosomal disorder. In some embodiments, the glycogen storage disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease. In some embodiments, the glycogen storage disease, disorder, or condition is Pompe disease. In some embodiments, the individual has late onset Pompe Disease. In some embodiments, the GYS1 inhibitor comprises a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

Provided herein is a method of treating a glycogen storage disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the level of glycogen in the individual is reduced upon treatment. In some embodiments, the level of glycogen in muscle is reduced. In some embodiments, the level of glycogen is skeletal muscle is reduced. In some embodiments, the level of glycogen is reduced at least 10%, at least 20%, at least 30% or at least 50% upon administration of the compound. In some embodiments, the compounds provided herein are effective for treating a lysosomal disorder. In some embodiments, the glycogen storage disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

›DETAILED DESCRIPTION OF THE INVENTION · 31 of 32

Provided herein is a method of treating Pompe disease in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the individual has infant onset Pompe disease. In some embodiments, the individual has non-classic infant-onset Pompe disease. In some embodiments, the individual has late-onset Pompe disease. In some embodiments, the individual has a deficiency in acid alfa glucosidase (GAA). In some embodiments, the individual has reduced expression of GAA.

In some embodiments, the compounds provided herein reduce and/or eliminate one or more symptoms associated with Pompe disease. In some embodiments, the compounds reduce and/or eliminate weak muscles, poor muscle tone, enlarged liver, failure to grow and gain weight, trouble breathing, feeding problems, infections in the respiratory system, problems with hearing, motor skill delay, heart enlargement, tiredness, lung infection, frequent falling, or irregular heartbeat. In some embodiments, the compounds herein delay progression of Pompe disease.

In some embodiments, the compounds provided herein increase the lifespan of the individual. In some embodiments, the lifespan is increased at least 5, at least 10, or at least 20 years upon treatment.

In some embodiments, the compounds provided herein prevent, reduce, or delay muscle weakness. In some embodiments, muscle weakness is determined by manual muscle testing, sit to stand test, heel-raise test, hand-held dynamometry, or hand grip dynamometry. In some embodiments, strength is graded according to the following scale: 0: No visible muscle contraction; 1: Visible muscle contraction with no or trace movement; 2: Limb movement, but not against gravity; 3: Movement against gravity but not resistance; 4: Movement against at least some resistance supplied by the examiner; 5: Full strength.

Also provided herein is a method of inhibiting a GYS1 enzyme in an individual comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the individual. In some embodiments the GYS1 enzyme is human GYS1 (hGYS1). In some embodiments, the compounds provided herein are inhibit GYS1 at a concentration of less than 10 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein inhibit GYS1 at a concentration of 1-10 μM, 0.01 to 1 μM, or 0.01 to 10 μM.

In some embodiments, the compounds have an IC 50 of less than 10 nM, less than 10 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein have an IC 50 of 1 to 10 nM, 1 to 10 μM, 0.01 to 1 μM, 0.01 to 10 μM, or 0.001 to 0.01 μM.

In some embodiments, glycogen synthesis is inhibited upon administration of a compound provided herein. In some embodiments, glycogen synthesis is reduced at least 10%, at least 20%, at least 40% or at least 50% upon administration.

In some embodiments, the individual receiving treatment is a juvenile human or an infant. In some embodiments, the individual is less than 10 years old, less than 9 years old, less than 8 years old, less than 7 years old, less than 6 years old, less than 5 years old, less than 4 years old, less than 3 years old, less than 2 years old, or less than one year old.

In some embodiments, the methods further comprise enzyme replacement therapy (ERT). Exemplary ERTs include alglucosidase alfa (human recombinant alpha-glucosidase (human GAA)) and those described in Byrne B J et al (2011). Pompe disease: design, methodology, and early findings from the Pompe Registry. Mol Genet Metab 103: 1-11 (herein incorporated by reference in its entirety). In some embodiments, the ERT is selected from the group consisting of Myozyme and Lumizyme. In some embodiments, the ERT is Myozyme. In some embodiments, the ERT is Lumizyme. In some embodiments, the individual has an advanced glycogen storage disease. In some embodiments, the individual has late onset Pompe Disease. Thus, provided herein is a method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to (a) glycogen substrate reduction therapy, such as administering to the individual an effective amount of (i) a GYS1 inhibitor, or (ii) a pharmaceutical composition comprising a GYS1 inhibitor, and one or more pharmaceutically acceptable excipients and (b) enzyme replacement therapy. In some embodiments, the GYS1-mediated disease, disorder, or condition is Pompe disease, such as late-onset Pompe disease. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the individual has a mutation in the GAA gene. In some embodiments, the mutation reduces the level of GAA protein. In some embodiments, the mutation is a loss-of-function mutation. In some embodiments, the mutation is a missense mutation. In some embodiments, the mutation is a deletion. In some embodiments, the mutation is a recessive mutation. In some embodiments, the mutation is a splicing variant.

In some embodiments of the foregoing, the administration is oral administration.

Kits

The present disclosure further provides kits for carrying out the methods of the invention. The kits may comprise a compound or pharmaceutically acceptable salt thereof as described herein and suitable packaging. The kits may comprise one or more containers comprising any compound described herein. In one aspect, a kit includes a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a label and/or instructions for use of the compound in the treatment of a disease or disorder described herein. The kits may comprise a unit dosage form of the compound.

›DETAILED DESCRIPTION OF THE INVENTION · 32 of 32

Provided herein are kits, comprising (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof

Articles of manufacture are also provided, wherein the article of manufacture comprises a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. Also provided herein are articles of manufacture, comprising a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.

›ENUMERATED EMBODIMENTS

The following enumerated embodiments are also contemplated:

›Embodiment 1. A compound of formula (I) · 1 of 5

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

X 1 and X 2 are each independently H, C 1-6 alkyl, or C 1-6 alkoxy; X 3 and X 4 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, or 5-20 membered heteroaryl; X 5 is H, C 1-6 alkyl, C 1-6 alkoxy, or C 3-10 cycloalkyl; Q 1 is selected from (i) to (iii): (i) phenyl, wherein the phenyl of Q 1 is substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), or C 3-10 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl, (ii) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q 1 is optionally substituted with one or more oxo, and (iii) 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl; R 1 is H or C 1-6 alkyl; R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl; R m is H, —OH, or C 1-6 alkyl; R n is H, C 1-6 alkyl, or C 3-10 cycloalkyl; or R k is taken together with either R m or R n , and the atoms to which they are attached, to form cyclopropyl; and R 2 is selected from (i) to (vii): (i) C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a , wherein R a is:

R b is halo, C 1-6 alkyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , C 3-10 cycloalkyl, 3-15 membered heterocyclyl, or —C(O)—C 1-6 alkoxy, wherein

(f) 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c , wherein

R c is halo, oxo, C 1-6 alkyl, C 1-6 alkoxy, —C(O)—C 1-6 alkyl, or —C(O)—C 1-6 alkoxy, wherein

the C 1-6 alkyl of R c is optionally substituted with one or more halo or C 2-6 alkynyl, and the —C(O)—C 1-6 alkoxy of R c is optionally substituted with one or more halo,

(h) —O—R e , wherein R e is C 1-6 alkyl, C 6-20 aryl, —C(O)-(3-15 membered heterocyclyl), —C(O)—N—(C 1-6 alkyl) 2 , or 5-20 membered heteroaryl, wherein

(i) —C(O)—R e , wherein R e is —NH 2 , —OH, or 3-15 membered heterocyclyl, or (j) —S(O) 2 —R f , wherein R f is C 1-6 alkyl or 3-15 membered heterocyclyl,

provided that, when R 2 is unsubstituted methyl, then either

›Embodiment 1. A compound of formula (I) · 2 of 5

Embodiment 2. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo.

Embodiment 3. The compound of embodiment 1 or embodiment 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo.

Embodiment 4. The compound of any one of embodiments 1-3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is pyridinyl, wherein the pyridinyl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo.

Embodiment 5. The compound of any one of embodiments 1-4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is 2-pyridinyl or 3-pyridinyl, wherein the 2-pyridinyl or 3-pyridinyl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo.

Embodiment 6. The compound of any one of embodiments 1-5, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is 2-pyridinyl, wherein the 2-pyridinyl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, —NH 2 , or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo.

Embodiment 7. The compound of any one of embodiments 1-6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is 2-pyridinyl, wherein the 2-pyridinyl of Q 1 is optionally substituted with one or more halo, C 1-6 alkyl, or C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more C 1-6 alkyl or halo.

Embodiment 8. The compound of any one of embodiments 1-7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is 2-pyridinyl, wherein the 2-pyridinyl of Q 1 is optionally substituted with one or more fluoro, chloro, methyl, iso-propyl, tert-butyl, cyclopropyl, or cyclobutyl, wherein the cyclopropyl and cyclobutyl are independently optionally substituted with one or more methyl or fluoro.

Embodiment 9. The compound of any one of embodiments 1-8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is selected from the group consisting of

Embodiment 10. The compound of any one of embodiments 1-9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is selected from the group consisting of

Embodiment 11. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is phenyl, wherein the phenyl of Q 1 is substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, —NH 2 , —NH—C(O)—(C 1-6 alkyl), —NH—C(O)-(3-15 membered heterocyclyl), or C 3-10 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl.

Embodiment 12. The compound of embodiment 1 or embodiment 11, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is phenyl, wherein the phenyl of Q 1 is substituted with one or more halo, C 1-6 alkyl, C 2-6 alkenyl, or C 3-10 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, and the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl.

Embodiment 13. The compound of any one of embodiments 1, 11 and 12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is phenyl, wherein the phenyl of Q 1 is substituted with one or more fluoro, chloro, methyl, iso-propyl, sec-butyl, tert-butyl, prop-1-en-2-yl, cyclopropyl, or cyclobutyl, wherein the methyl, iso-propyl, sec-butyl, and tert-butyl are independently optionally substituted with one or more halo, and the cyclopropyl and cyclobutyl are independently optionally substituted with one or more fluoro or methyl.

Embodiment 14. The compound of any one of embodiments 1 and 11-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is selected from the group consisting of

Embodiment 15. The compound of any one of embodiments 1 and 11-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is selected from the group consisting of

Embodiment 16. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of Q 1 is optionally substituted with one or more oxo.

Embodiment 17. The compound of embodiment 1 or embodiment 16, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is

Embodiment 18. The compound of any one of embodiments 1-17, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 , X 2 , X 3 , X 4 , and X 5 are each H.

›Embodiment 1. A compound of formula (I) · 3 of 5

Embodiment 19. The compound of any one of embodiments 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R m is H, R n is H, and R k is H, halo, —OH, —NH 2 , or —NH—C(O)C 1-6 alkyl.

Embodiment 20. The compound of any one of embodiments 1-19, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R m is H, R n is H, and R k is halo, —OH, or —NH 2 .

Embodiment 21. The compound of any one of embodiments 1-20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R m is H, R n is H, and R k is halo.

Embodiment 22. The compound of any one of embodiments 1-21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R m is H, R n is H, and R k is fluoro.

Embodiment 23. The compound of any one of embodiments 1-18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R k is taken together with either R m or R n , and the atoms to which they are attached, to form cyclopropyl.

Embodiment 24. The compound of any one of embodiments 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is H.

Embodiment 25. The compound of any one of embodiments 1-24, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a .

Embodiment 26. The compound of any one of embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b .

Embodiment 27. The compound of any one of embodiments 1-26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more R b .

Embodiment 28. The compound of any one of embodiments 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy.

Embodiment 29. The compound of any one of embodiments 1-28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

Embodiment 30. The compound of any one of embodiments 1-29, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is selected from the group consisting of

Embodiment 31. The compound of any one of embodiments 1-30, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

Embodiment 32. The compound of any one of embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c .

Embodiment 33. The compound of any one of embodiments 1-25 and 32, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c .

Embodiment 34. The compound of any one of embodiments 1-25, 32, and 33, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c .

Embodiment 35. The compound of any one of embodiments 1-25 and 32-34, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more oxo or C 1-6 alkyl.

Embodiment 36. The compound of any one of embodiments 1-25 and 32-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

Embodiment 37. The compound of any one of embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —O—R e .

Embodiment 38. The compound of any one of embodiments 1-25 and 37, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —O—R e .

›Embodiment 1. A compound of formula (I) · 4 of 5

Embodiment 39. The compound of any one of embodiments 1-25, 37, and 38, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —O—R e , wherein R e is —C(O)-(3-15 membered heterocyclyl).

Embodiment 40. The compound of any one of embodiments 1-25 and 37-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

Embodiment 41. The compound of any one of embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ).

Embodiment 42. The compound of any one of embodiments 1-25 and 41, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ).

Embodiment 43. The compound of any one of embodiments 1-25, 41, and 42, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ), wherein one of R c and R d is H, and the other of R c and R d is —C(O)—N(C 1-6 alkyl) 2 .

Embodiment 44. The compound of any one of embodiments 1-25 and 41-43, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

Embodiment 45. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-A):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein

Y 1 is CH or N; R x and R z are independently H, halo, C 1-6 alkyl, or —NH 2 , wherein, when Y 1 is CH, the C 1-6 alkyl of R x or R z may be optionally substituted with one or more halo; and R y is (i) C 1-6 alkyl, (ii) C 2-6 alkenyl, or (iii) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more halo or C 1-6 alkyl.

Embodiment 46. The compound of embodiment 1 or embodiment 45, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R x is H, fluoro, or methyl, and

R y is (i) isopropyl, or (ii) C 3-4 cycloalkyl, wherein the C 3-4 cycloalkyl is optionally substituted with one or more fluoro or methyl.

Embodiment 47. The compound of any one of embodiments 1, 45, and 46, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R k is H or halo.

Embodiment 48. The compound of any one of embodiments 1-24, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is optionally substituted with one or more R a .

Embodiment 49. The compound of any one of embodiments 1 and 45-48, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of R a is optionally substituted with one or more R b .

Embodiment 50. The compound of any one of embodiments 1 and 45-49, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more R b .

Embodiment 51. The compound of any one of embodiments 1 and 45-50, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH—C(O)C 1-6 alkyl, or —NH—C(O)—C 1-6 alkoxy.

Embodiment 52. The compound of any one of embodiments 1 and 45-51, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —OH or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of R a is optionally substituted with one or more methyl, wherein the methyl is optionally substituted with one or more fluoro.

Embodiment 53. The compound of any one of embodiments 1 and 45-52, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is selected from the group consisting of

Embodiment 54. The compound of any one of embodiments 1 and 45-53, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

Embodiment 55. The compound of any one of embodiments 1 and 45-48, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c .

Embodiment 56. The compound of any one of embodiments 1, 45-48, and 55, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-15 membered heterocyclyl, wherein the 3-15 membered heterocyclyl of R a is optionally substituted with one or more R c .

›Embodiment 1. A compound of formula (I) · 5 of 5

Embodiment 57. The compound of any one of embodiments 1, 45-48, 55, and 56, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more R c .

Embodiment 58. The compound of any one of embodiments 1, 45-48, and 55-57, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl of R a is optionally substituted with one or more oxo or C 1-6 alkyl.

Embodiment 59. The compound of any one of embodiments 1, 45-48, and 55-58, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

Embodiment 60. The compound of any one of embodiments 1 and 45-48, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —O—R e .

Embodiment 61. The compound of any one of embodiments 1, 45-48, and 60, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —O—R e .

Embodiment 62. The compound of any one of embodiments 1, 45-48, 60, and 61, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —O—R e , wherein R e is —C(O)-(3-15 membered heterocyclyl).

Embodiment 63. The compound of any one of embodiments 1, 45-48, and 60-62, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

Embodiment 64. The compound of any one of embodiments 1, 45-48, and 60-63, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1-6 alkyl, wherein the C 1-6 alkyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ).

Embodiment 65. The compound of any one of embodiments 1, 45-48, and 60-64, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ).

Embodiment 66. The compound of any one of embodiments 1, 45-48, and 60-65, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is methyl, wherein the methyl of R 2 is substituted with one or more R a , wherein R a is —N(R c )(R d ), wherein one of R c and R d is H, and the other of R c and R d is —C(O)—N(C 1-6 alkyl) 2 .

Embodiment 67. The compound of any one of embodiments 1, 45-48, and 60-66, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

Embodiment 68. The compound of embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Table 1.

Embodiment 69. A pharmaceutical composition comprising (i) a compound of any one of embodiments 1-68, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

Embodiment 70. A method of modulating GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or embodiments 1-68, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 69.

Embodiment 71. A method of inhibiting GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or embodiments 1-68, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 69.

Embodiment 72. A method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of a compound of any one of embodiments 1-68, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 69.

Embodiment 73. A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of any one of embodiments 1-68, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 69.

Embodiment 74. The method of embodiment 73, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

Embodiment 75. The method of embodiment 73 or embodiment 74, wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

Embodiment 76. The method of any one of embodiments 73-75, wherein the disease, disorder, or condition is Pompe disease.

Embodiment 77. The method of embodiment 73, wherein the disease, disorder, or condition is cancer.

Embodiment 78. The method of embodiment 73 or embodiment 77, wherein the disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).

›Embodiment 79. The method of embodiment 73, wherein the individual has a GAA mutation

Embodiment 80. The method of embodiment 79, wherein the GAA mutation is a loss-of-function mutation.

Embodiment 81. A kit, comprising (i) a compound of any one of embodiments 1-68, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment 69, and (ii) instructions for use in treating an GYS1-mediated disease, disorder, or condition in an individual in need thereof.

Embodiment 82. The kit of embodiment 81, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

Embodiment 83. The kit of embodiment 81 or embodiment 82, wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

Embodiment 84. The kit of any one of embodiments 81-83, wherein the disease, disorder, or condition is Pompe disease.

Embodiment 85. The kit of embodiment 81, wherein the disease, disorder, or condition is cancer.

Embodiment 86. The kit of embodiment 81 or embodiment 85, wherein the disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).

›Embodiment 87. The kit of embodiment 81, wherein the individual has a GAA mutation

Embodiment 88. The kit of embodiment 87, wherein the GAA mutation is a loss-of-function mutation.

Embodiment 89. A method of modulating GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a GYS1 modulator, or a pharmaceutical composition comprising a GYS1 modulator.

Embodiment 90. A method of inhibiting GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a GYS1 inhibitor, or a pharmaceutical composition comprising a GYS1 inhibitor.

Embodiment 91. A method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of a GYS1 inhibitor, or a pharmaceutical composition comprising a GYS1 inhibitor.

Embodiment 92. A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising subjecting the individual to glycogen substrate reduction therapy.

Embodiment 93. The method of embodiment 92, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

Embodiment 94. The method of embodiment 92 or embodiment 93, wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

Embodiment 95. The method of any one of embodiments 92-94, wherein the disease, disorder, or condition is Pompe disease.

Embodiment 96. The method of embodiment 92, wherein the disease, disorder, or condition is cancer.

Embodiment 97. The method of embodiment 92 or embodiment 96, wherein the disease, disorder, or condition is selected from the group consisting of Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen rich clear cell carcinoma (GRCC) breast cancer, non-small-cell lung carcinoma (NSCLC), and acute myeloid leukemia (AML).

›Embodiment 98. The method of embodiment 92, wherein the individual has a GAA mutation

Embodiment 99. The method of embodiment 98, wherein the GAA mutation is a loss-of-function mutation.

Embodiment 100. The method of any one of embodiments 89-91 wherein the GYS1 inhibitor is selective for GYS1 over GYS2.

Embodiment 101. The method of embodiment 100, wherein the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

Embodiment 102. The method of any one of embodiments 92-99 wherein the glycogen substrate reduction therapy comprises administering to the individual a GYS1 inhibitor.

Embodiment 103. The method of embodiment 102, wherein the GYS1 inhibitor is a small molecule.

Embodiment 104. The method of embodiment 103, wherein the GYS1 inhibitor is selective for GYS1 over GYS2.

Embodiment 105. The method of embodiment 104, wherein the GYS1 inhibitor is greater than 500 or 1,000 or 1,500 or 1,700-fold selective for GYS1 over GYS2.

Methods of Preparing

The present disclosure further provides processes for preparing the compounds of present invention. In some aspect, provided herein are processes of preparing a compound of formula (I′) or formula (I), or any embodiment or variation thereof, such as a compound of formula (I-A), (I-B), (I-C), (I-D), (I-D1), (I-D2), (I-E), (I-F), (I-G), (I-H) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, a process for preparing a compound of formula (I′) or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises reacting a compound of formula (I′-1):

or a salt thereof, with a compound of formula R 2 COOH in the presence of a coupling reagent.

In some embodiments, the coupling reagent comprises EDCCl, TCFH, or T3P. In some embodiments, the process further comprises the presence of a base. In some embodiments, the base comprises an amine. In some embodiments, the amine is DMAP, NMM, or a trialkylamine.

In some embodiments, a process for preparing a compound of formula (I′), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises

(a) reacting a compound of formula (I′-2):

or a salt thereof, with a compound of formula (I′-3):

wherein PG is a protecting group, in the presence of a coupling reagent to provide a compound of formula I′-4:

followed by

(b) contacting the compound of formula (I′-4) with an acid to provide a compound of formula (I′).

In some embodiments, the protecting group is an oxycarbonyl group. In some embodiments the protecting group is a tert-butoxycarbonyl.

In some embodiments the acid is HCl or TFA.

›EXAMPLES

The following synthetic reaction schemes, which are detailed in the Schemes and Examples, are merely illustrative of some of the methods by which the compounds of the present disclosure, or an embodiment or aspect thereof, can be synthesized. Various modifications to these synthetic reaction schemes can be made, as will be apparent to those of ordinary skill in the art.

The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure, or any variation or embodiment thereof, may be prepared using appropriate starting materials according to the methods described generally herein and/or by methods available to one of ordinary skill in the art.

›SYNTHETIC EXAMPLES · 1 of 20

As depicted in the Schemes and Examples below, in certain exemplary embodiments, compounds of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are prepared according to the general procedures. The general methods below, and other methods known to synthetic chemists of ordinary skill in the art, can be applied to all formulae, variations, embodiments, and species described herein.

Schemes

Compounds of the formula S1-10 may be prepared according to the general synthetic scheme outlined in Scheme 1.

Condensation of a chiral sulfinamide such as S1-2 with an aldehyde such as S1-1 provides sulfinimine S1-3. Addition of a reagent such as phenylmagnesium bromide at low temperature, followed by warming to ambient temperature provides benzhydryl sulfinamide S1-4. Sulfinamide S1-3 can be converted to the corresponding amine hydrochloride salt upon treatment with HCl in a solvent such as EtOAc. Amide bond formation between S1-5 and a substituted proline analog such as S1-6 may be achieved with a carbodiimide reagent such as EDCI and DMAP as a catalyst. Removal of the N-Boc group of S1-7 via treatment with a protic acid such as trifluoroacetic acid gives rise to amines such as S1-8. Proline amides such as S1-10 may then be generated by coupling with a carboxylic acid such as S1-9 using a coupling agent such as T3P and NMM as a base.

Compounds of the formula S2-12 may be prepared according to the general synthetic scheme outlined in Scheme 2.

Directed ortho-metalation of pyridine S2-1 with an amide base such as LDA in an aprotic solvent such as THF at −78° C. followed by reaction with a ketone such as acetone can generate pyridine S2-2. Treatment of S2-2 with a reducing agent such as triethyl silane and a protic acid such as trifluoroacetic acid generates a mixture of compounds, S2-3 and S2-4. This mixture can be converted to S2-3 by reduction with hydrogen gas and a metal catalyst such as PtO 2 . Metal-halogen exchange can be affected by treatment of S2-3 at −78° C. with n-butyllithium, and the pyridyllithium intermediate may then be reacted with sulfinimine S2-5 to generate S2-6. Treatment with a protic acid such as HCl generates the amine S2-7. Coupling of amine S2-7 with proline derivative S2-8 using TCFH and N-methylimidazole base gives rise to S2-9. Removal of the proline N-Boc group by treatment with a protic acid such as HCl, in an aprotic solvent such as 1,4-dioxane, provides amine S2-10. Amine S2-10 may then be reacted with carboxylic acid S2-11 to generate S2-12, using methods described in Scheme 1.

Compounds of the formulae S3-13 and S3-14 may be prepared according to the general synthetic scheme outlined in Scheme 3.

Condensation of racemic sulfinamide S3-2 with pyridyl aldehyde S3-1 generates sulfinimine S3-3. Reaction with arylmagnesium bromide S3-4 generates S3-5, as a racemate. A Suzuki cross-coupling of S3-5 with a boronic acid such as S3-6 using a palladium catalyst such as Pd(dppf)Cl 2 and an inorganic base such as K 3 PO 4 generates compound S3-7. Treatment of S3-7 with a protic acid such as HCl in an aprotic solvent mixture such as EtOAc/DCM provides amine S3-8. S3-8 may then be coupled with carboxylic acid S3-9 and processed to compounds S3-13 and S3-14 using methods outlined in Scheme 1. If desired, mixtures of stereoisomers may be further purified to provide S3-13 and S3-14 as single isomers, using methods such as reverse-phase HPLC or chiral SFC.

Compounds of the formula S4-17 may be prepared according to the general synthetic scheme outlined in Scheme 4.

Reaction of pyridine S3-1 with an electrophilic brominating agent such as NBS gives pyridine S4-2. Suzuki cross-coupling with cyclopropylboronic acid, using a catalyst such as palladium acetate, a ligand such as tricyclohexyl phosphine, and an inorganic base such K 3 PO 4 in a mixed solvent system such as 1,4-dioxane and water, provides S4-3. Conversion of S4-3 to pyridyl bromide S4-5 can be achieved with a Sandmeyer reaction under the action of isopentyl nitrite and cupric bromide in dibromomethane solvent. Suzuki cross coupling of potassium vinyltrifluoroborate with S4-6 using a palladium catalyst such as Pd(dppf)Cl 2 and an inorganic base such as K 3 PO 4 . Oxidative cleavage of olefin S4-6 with NaIO 4 and K 2 OsO 4 ·2H 2 O in a THF generates aldehyde S4-7. Condensation with sulfinimide S4-8 generates sulfinimine S4-9. Reaction of S4-9 with aryl Grignard reagent S4-10 in a solvent such as DCM at low temperature gives rise to S4-11. Cleavage of sulfinimide S4-11 with a HCl in EtOAc generates amine salt S4-12. S4-12 may then be joined with carboxylic acid S4-13 using a coupling agent such as T3P and a base such as NMM in DMF to produce S4-14. Removal of the N-Boc group with HCl in EtOAc generates amine S4-15, which may then be processed to S4-17 using the procedure described in Scheme 3.

Compounds of the general formula S5-14 can be prepared according to the general scheme outlined in Scheme 5.

Radical bromination of S5-1 with NBS and catalytic AIBN provides S5-2. Oxidation under the action NMMO gives aldehyde S5-3. Condensation of aldehyde with sulfinimide S5-4 using an inorganic base such as cesium carbonate provide sulfinimine S5-5. Addition of an aryl Grignard reagent such as phenylmagnesium bromide at low temperature provides S5-6. Cleavage of the sulfinimide to generate a primary amine salt can be achieved upon treatment with a protic acid such as HCl in a solvent such as EtOAc. Amide bond formation with proline derivative S5-8 proceeds as previously described to give S5-9. Photoredox coupling of triflate S5-10 with S5-9 using an iridium photocatalyst such as (Ir[dF(CF 3 )ppy] 2 (dtbpy))PF 6 , a nickel co-catalyst such as NiCl 2 ·glyme, a ligand such as 4,4-di-tert-butyl-2,2-bipyridyl, sodium carbonate as base, and tris(trimethylsilyl)silane and blue LED gives cyclobutyl adduct S5-11. Removal of the proline Boc protecting group with HCl in EtOAc, followed by amide bond formation under the action of T3P and NMM in DCM gives compounds of formula S5-14.

›SYNTHETIC EXAMPLES · 2 of 20

Compounds of the general formula S6-19 can be prepared according to the general scheme outlined in Scheme 6.

Reduction of carboxylic acid S6-1 with borane-methylsulfide complex gives alcohol S6-2. Conversion of S6-2 to alkyl bromide S6-3 is achieved by treatment with triphenylphosphine and NBS in a solvent such as DCM. Selective displacement of the primary bromide can be achieved upon reaction with TMSCN and TBAF in acetonitrile to provide S6-4. Double alkylation of nitrile S6-4 with a di-triflate such as S6-5 gives rise to cyclobutane S6-6. Hydrolysis of the nitrile on treatment with sulfuric acid at elevated temperature gives acid S6-7. Decarboxylation can be achieved by reaction with KF in DMSO at high temperature to provide S6-8. Suzuki-type cross coupling with potassium vinyltrifluoroborate, a palladium catalyst such as tetrakis triphenylphosphine palladium(0) and a base such as cesium carbonate generates S6-9. Lemieux-Johnson oxidation of S6-9 gives aldehyde S6-10, which may then be condensed with sulfinimide S6-11 under conditions previously described to give S6-12. Addition of an aryl Grignard reagent such as phenylmagnesium bromide to S6-12 gives S6-13. Generation of primary amine salt S6-14 may occur upon treatment with HCl in dioxane. Coupling of S6-14 with proline derivative S6-15 using chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI) gives S6-16. Boc deprotection and proline amide bond formation as described in Scheme 5 gives compounds of formula S6-19.

Compounds of the general formulae S7-12 and S7-13 can be prepared according to the general scheme outlined in Scheme 7.

Condensation of sulfinimide S7-2 with aldehyde S7-1 as previously described, followed by addition of an aryl Grignard reagent such as phenylmagnesium bromide, gives S7-4. Generation of the amine salt and coupling with proline derivative S7-6 may be achieved under conditions previously described. Photoredox coupling of cyclobutyl bromide S7-8 under conditions like those described in Scheme 5 gives S7-9. As previously described, Boc deprotection and amide bond formation generates compounds of formula S7-12. A minor stereoisomer such as S7-13 may also be isolated at this stage.

Compounds of the general formula 3 S8-14 and S8-15 can be prepared according to the general scheme outlined in Scheme 8.

An alternative generation of benzhydryl fragments begins with cross-coupling of S8-1 with isopropenylboronic acid pinacol ester with a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and potassium carbonate as base in a mixed dioxane/water solvent at elevated temperature gives S8-2. Simmons-Smith cyclopropanation gives S8-3. Reduction of ester S8-3 with DIBAL-H, followed by oxidation with MnO 2 gives aldehyde S8-5. Aldehyde S8-5 may then be processed over several steps previously described to give compounds of formula S8-14. Minor diastereomers which could not be separated in previous steps may be isolated at this stage, giving S8-15.

Compounds of the general formula S9-15 can be prepared according to the general scheme outlined in Scheme 9.

An alternative approach to cyclopropane containing analogs begins with directed metalation of S9-1 with LDA and reaction with acetone to generate S9-2. Dehydration under the action of a protic acid such as p-toluene sulfonic acid in toluene at elevated temperature generates olefin S9-3. Cyclopropanation under conditions described in Scheme 8 gives S9-5. Partial reduction of S9-5 to aldehyde S9-6 can be achieved with DIBAL-H in THF at low temperature. Condensation of aldehyde S9-6 with racemic sulfinimide S9-7 gives S9-8. Addition of a Grignard reagent and deprotection under conditions previously described gives amine salt S9-10 as a racemate. Coupling with proline derivative S9-11 under standard conditions and Boc deprotection generates an intermediate which can be further purified by chiral SFC to give amine S9-13 as a single isomer. Conversion to compounds of formula S9-15 occurs under conditions previous described. If the R 2 substituent bears stereogenic atoms that are mixtures, additional purification by chiral SFC may be utilized to generate single isomer analogs.

Compounds of the general formula S10-5 can be prepared according to the general scheme outlined in Scheme 10.

An alternative approach to compounds of formula S10-5 starts with condensation of pyridine S10-1 with sulfinimide S10-2. Addition of an aryllithium reagent such as phenyllithium provides S10-4. Deprotection under standard conditions gives amine salts of formula S10-5, which may be further elaborated as described in the Schemes 1-9 and Schemes 11-15.

Compounds of the general formula S11-12 can be prepared according to the general scheme outlined in Scheme 11.

Yet another alternative approach to amine intermediates such as S11-6 starts with pyridine S11-1. Bis-carbamate formation, followed by treatment copper (II) triflate gives pyridine S11-3. Conversion of S11-3 to the corresponding Grignard reagent with isopropylmagnesium chloride-lithium chloride complex followed by addition to a racemic sulfinimine such as S11-4 gives S11-5. Selective cleavage of the sulfinamide may occur on reaction with iodine at elevated temperature. Coupling with proline derivative S11-7 and further processing to generate compounds of formula S11-12 occurs as previously described. If necessary, mixtures of stereoisomers may be further purified using chiral SFC, to generate compounds as single isomers.

Compounds of the general formula S12-9 can be prepared according to the general scheme outlined in Scheme 12.

An alternative sequence enabling late-stage elaboration of the benzhydryl moieties begins with lithiation of S12-1 and addition of sulfinimine S12-2. Oxidative cleavage with iodine generates S12-4. Coupling with proline derivative S12-5 generates S12-6. Cleavage of the Boc group with TFA generates amine S12-7. Treatment with an acylating agent such as methyl chloroformate and NMI as base gives bis-carbamate S12-8. Selective cleavage of the triazole carbamate moiety can be achieved by reaction with potassium carbonate and methanol at elevated temperature, to generate compounds of formula S12-9.

›SYNTHETIC EXAMPLES · 3 of 20

Compounds of the general formula S13-5 can be prepared according to the general scheme outlined in Scheme 13.

Sulfonamides of formula S13-5 can be generated starting from S13-1. Boc cleavage as previously described gives S13-2. Reaction of S13-2 with sulfonyl chloride S13-3 using a tertiary amine base such as DIPEA gives S13-4. Cleavage of the triazole N-benzyl group occurs under standard hydrogenation conditions to give S13-5.

Compounds of the general formulae S14-6 and S14-7 can be prepared according to the general scheme outlined in Scheme 14.

Bromobenzene analogs bearing heterocycles such as pyrazoles can undergo metalation using an excess of n-BuLi and addition to sulfinimines such as S14-2 to give adducts such as S14-3. Conversion to the amine HCl salt can occur under previously described conditions. Coupling with proline derivative S14-5 under previously described conditions gives compounds of formulae S14-6 and S14-7, which can be isolated as single isomers using methods such as reverse phase prep-HPLC or chiral SFC.

Compounds of the general formula S15-10 and S15-11 can be prepared according to the general scheme outlined in Scheme 15.

An alternative strategy that enables late-stage elaboration to generate compounds of formulae S15-10 and S15-11 begins by selective metal-halogen exchange with S15-1 and addition to sulfinimine S15-2 to generate S15-3. Generation of the amine HCl salt and coupling to proline derivative S15-5 under conditions previously described gives S15-6. S16-6 may then undergo palladium catalyzed borylation to generate boronate ester S15-7. Suzuki-type cross coupling under conditions previously described, using an aryl or heteroaryl bromide such as S15-8 gives S15-9. Cleavage of the trityl protecting from the triazole moiety under protic acid conditions gives compounds of formula S15-10 and S15-11, which can be isolated as single isomers using methods such as flash column chromatography, reverse phase HPLC, or chiral SFC.

Abbreviations used are those conventional in the art and are in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. The following examples are intended to be illustrative only and not limiting in any way.

Intermediate A-1: Synthesis of 2-(1H-1,2,3-triazol-5-yl)acetic acid

Step a: To a mixture of but-3-ynoic acid (7.5 g, 89.2 mmol, 1 eq), Cu(OAc) 2 (1.62 g, 8.92 mmol, 0.1 eq) and sodium ascorbate (3.53 g, 17.8 mmol, 0.2 eq) in H 2 O (75 mL) and t-BuOH (75 mL) at 0° C. was added, in portions, benzyl azide (BnN 3 , 13.9 g, 93.7 mmol, 90% purity, 1.05 eq). The resulting mixture was warmed to 25° C. and stirred for 12 h. The mixture was then filtered and the solids were washed with water (2×20 mL) and dried under reduced pressure to afford 2-(1-benzyl-1H-1,2,3-triazol-4-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 11 N 3 O 2 : 218.1; found 218.1.

Step b: A suspension of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)acetic acid (5 g, 23 mmol, 1 eq) and Pd/C (2.45 g, 10% wt. %) in i-PrOH (300 mL) was stirred under H 2 (50 psi) at 25° C. for 5 h. The reaction mixture was then filtered through a pad of Celite, and the filter cake was washed with CH 2 Cl 2 (3×30 mL). The filtrate was concentrated under reduced pressure to give 2-(1H-1,2,3-triazol-5-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 4 H 5 N 3 O 2 : 128.1; found 128.1.

Intermediate A-2: Synthesis of 2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetic acid

Step a: To a solution of 2,2-difluoroacetic acid (50.0 g, 520 mmol, 1.00 eq) in dry DCM (200 mL) at 0° C. was added a catalytic amount of DMF (4 mL) and oxalyl dichloride (66.1 g, 520 mmol, 45.6 mL, 1.00 eq), sequentially. The resulting mixture was warmed to 20° C. and stirred for 1 h. The reaction mixture was then cooled to 0° C. and a solution of 2-ethoxy-2-oxoethan-1-aminium chloride (80.0 g, 573 mmol, 1.10 eq), TEA (105 g, 1.04 mol, 2.00 eq) and DMAP (7.37 g, 52.1 mmol, 0.10 eq) in DCM (500 mL) was added. The reaction mixture was warmed to 20° C. and stirred for 1 h. The reaction mixture was then quenched with water (100 mL) and extracted with dichloromethane (3×200 mL). The combined organic extracts were washed with brine (500 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give ethyl (2,2-difluoroacetyl)glycinate. This compound was carried forward to the next step without further characterization.

Step b: To a solution of ethyl (2,2-difluoroacetyl)glycinate (25.0 g, 138 mmol, 1.00 eq) in toluene (250 mL) at 25° C. was added 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2λ 5 ,4λ 5 -dithiadiphosphetane (Lawesson's reagent, 67.0 g, 165 mmol, 1.20 eq) under N 2 . The resulting mixture was warmed to 110° C. and stirred for 1 h. The reaction mixture was then cooled to 25° C., and poured into water (300 mL) and NaOCl (˜10% aqueous, 100 mL). The resulting mixture was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (2×200 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give ethyl (2,2-difluoroethanethioyl)glycinate. This compound was carried forward to the next step without further characterization.

Step c: To a mixture of ethyl (2,2-difluoroethanethioyl)glycinate (12.5 g, 63.4 mmol, 1.00 eq) and azido(trimethyl)silane (14.6 g, 127 mmol, 2.00 eq) in DCM (120 mL) at 0° C. under N 2 was added SnCl 4 (41.2 g, 158 mmol, 2.50 eq). The resulting mixture was warmed to 25° C. and stirred for 2 h. The reaction mixture was then cooled to 0° C. and quenched by addition of saturated aqueous NaHCO 3 (200 mL). The resulting biphasic mixture was extracted with DCM (2×100 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography to give ethyl 2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetate. This compound was carried forward to the next step without further characterization.

›SYNTHETIC EXAMPLES · 4 of 20

Step d: Ethyl 2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetate (6.50 g, 31.5 mmol, 1.00 eq) was dissolved in aqueous HCl (6 M, 65 mL) at 20° C. The resulting mixture was warmed to 100° C. and stirred for 20 h. The reaction mixture was then concentrated under reduced pressure to give 2-(5-(difluoromethyl)-1H-tetrazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 4 H 4 F 2 N 4 O 2 : 179.0; FOUND 179.0.

Intermediate A-3: Synthesis of 2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)acetic acid

Step a: To a solution of ethyl 2-azidoacetate (200 mg, 94% purity, 1.5 mmol, 1 eq) in toluene (5 mL) was added ethyl 4,4,4-trifluorobut-2-ynoate (500 mg, 3.0 mmol, 2 eq). The mixture was warmed to 115° C. and stirred for 16 h. The reaction mixture was then cooled to 0° C., quenched with MeOH (10 mL) and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give a mixture of ethyl 1-(2-ethoxy-2-oxoethyl)-4-(trifluoromethyl)-1H-1,2,3-triazole-5-carboxylate and ethyl 1-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate. This compound was carried forward to the next step without further characterization.

Step b: To a mixture of ethyl 1-(2-ethoxy-2-oxoethyl)-4-(trifluoromethyl)-1H-1,2,3-triazole-5-carboxylate and ethyl 1-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate (220.00 mg, 745 μmol, 1 eq) in 1:1 dioxane:H 2 O (4 mL) at 25° C. was added NaOH (60 mg, 1.1 mmol, 1.5 eq). The resulting mixture was stirred at for 16 h. The reaction mixture was then quenched with HCl (6 M, 1 mL) in H 2 O (10 mL) and extracted with DCM (3×20 mL). The aqueous phase was lyophilized to afford a crude solid, which was immediately dissolved in DMSO (3 mL). To the resulting mixture was added Ag 2 CO 3 (140 mg, 508 μmol, 0.5 eq), followed by AcOH (6 mg, 100 μmol, 0.1 eq). The mixture was warmed to 130° C. and stirred for 16 h. The reaction mixture was then quenched with H 2 O (30 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (2×15 ML), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by prep-HPLC to give 2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl) acetic acid. LC-MS (ESI): m/z: [M−H] − calculated for C 5 H 4 F 3 N 3 O 2 : 194.0; found 194.1.

Intermediate A-4: Synthesis of 2-(1H-benzo[d]imidazol-1-yl)acetic acid

Step a: To a solution of 1H-benzo[d]imidazole (10.0 g, 84.6 mmol, 1 eq) in DMF (100 mL) was added Cs 2 CO 3 (33.1 g, 102 mmol, 1.2 eq) and tert-butyl 2-bromoacetate (18.2 g, 93.1 mmol, 1.1 eq). The mixture was stirred at 25° C. for 2 h. The reaction mixture was then filtered and the filtrate was diluted with EtOAc (200 mL). The combined organic extracts were washed with brine (100 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give compound tert-butyl 2-(1H-benzo[d]imidazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 13 H 16 N 2 O 2 : 233.1; found 233.1.

Step b: To a solution of tert-butyl 2-(1H-benzo[d]imidazol-1-yl)acetate (16.8 g, 72.3 mmol, 1 eq) in EtOAc (100 mL) was added HCl/EtOAc (4 M, 200 mL). The mixture was warmed to 60° C. and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure. The resulting crude product was triturated with petroleum ether at 25° C. for 10 min and filtered to give 2-(1H-benzo[d]imidazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 9 H 8 N 2 O 2 : 177.1; found 177.0.

Intermediate A-5: Synthesis of 2-(3-ethyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid

Step a: To a mixture of iodoethane (1.27 g, 8.15 mmol, 3 eq) and 2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (500 mg, 2.72 mmol, 1 eq) in DMF (6 mL) at 20° C. under N 2 was added K 2 CO 3 (1.88 g, 13.5 mmol, 5 eq) in one portion. The resulting mixture was warmed to 70° C. and stirred for 2 h. After this time, the reaction mixture was cooled to 0° C., and the reaction was quenched by addition H 2 O (30 mL). The resulting biphasic mixture was then extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a crude residue that was purified by column chromatography to obtain ethyl 2-(3-ethyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 16 N 2 O 4 : 241.1; found 241.1.

Step b: To a solution of ethyl 2-(3-ethyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate (450 mg, 1.87 mmol, 1 eq) in THF (5 mL) and H 2 O (5 mL) at 20° C. under N 2 was added LiOH (89.7 mg, 3.75 mmol, 2 eq) in one portion. The resulting mixture was stirred at 20° C. for 2 h. After this time, the reaction mixture was diluted with H 2 O (20 mL), and the pH of the solution was adjusted to pH=3 by addition of aqueous HCl (2M). The resulting mixture was then extracted with EtOAc (3×10 mL). The combined organic extracts were then washed with brine (20 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain 2-(3-ethyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 9 H 12 N 2 O 4 : 213.1; found 213.1.

Intermediate A-6: Synthesis of 2-((azetidine-1-carbonyl)oxy)acetic acid

Step a: To a solution of benzyl 2-hydroxyacetate (0.96 g, 5.78 mmol, 821 μL, 1 eq) in THF (10 mL) at 0° C. was added triphosgene (686 mg, 2.31 mmol, 0.4 eq) followed by DIPEA (2.09 g, 16.2 mmol, 2.82 mL, 2.8 eq), and the resulting mixture was stirred at 0° C. for 0.5 h before it was warmed to 25° C. and stirred for 0.5 h. A solution of azetidine (330 mg, 5.78 mmol, 390 μL, 1 eq) in THF (10 mL) and DIPEA (1.05 g, 8.09 mmol, 1.41 mL, 1.4 eq) were then added, and the resulting mixture was stirred at 25° C. for 12 h. The reaction mixture was then diluted with saturated aqueous NaHCO 3 (20 mL), and the resulting biphasic mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-(benzyloxy)-2-oxoethyl azetidine-1-carboxylate. LC-MS (ESI): m/z: [M+H] + calculated for C 13 H 15 NO 4 : 250.1; found 250.2.

›SYNTHETIC EXAMPLES · 5 of 20

Step b: To a mixture of 2-(benzyloxy)-2-oxoethyl azetidine-1-carboxylate (250 mg, 1.00 mmol, 1 eq) in DCE (5 mL) at 25° C. under N 2 was added TEA (20.3 mg, 200 μmol, 27.9 μL, 0.2 eq), Pd(OAc) 2 (56.3 mg, 251 μmol, 0.25 eq) and Et 3 SiH (233 mg, 2.01 mmol, 320 μL, 2 eq). The resulting mixture was stirred at 60° C. for 2 h before it was filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure to give 2-((azetidine-1-carbonyl)oxy)acetic acid. LC-MS (ESI): m/z: [M−H] + calculated for C 6 H 9 NO 4 : 158.0; found 158.1.

The following compounds in Table B-1 were synthesized using procedures similar to Intermediate A-6 using the appropriate starting materials.

Intermediate A-7: Synthesis of 2-(1-benzyl-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-1,2,3-triazol-5-yl)acetic acid

Step a: To a mixture of but-3-ynoic acid (5.00 g, 59.5 mmol, 1.00 eq) in benzyl alcohol (19.3 g, 178 mmol, 18.6 mL, 3.00 eq) at 25° C. was added aqueous HCl (12 M, 297 μL, 37.0% purity, 0.06 eq) in one portion. The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then quenched by addition of H 2 O (30 mL) at 25° C., and the resulting biphasic mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give benzyl but-3-ynoate. This compound was carried forward to the next step without further characterization.

Step b: To a mixture of benzyl azide (3.00 g, 22.5 mmol, 1.00 eq) in THF (45 mL) at 25° C. under N 2 was added LiI (12.1 g, 90.1 mmol, 3.46 mL, 4.00 eq), copper (II) perchlorate hexahydrate (16.7 g, 45.1 mmol, 2.00 eq), and tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA, 1.20 g, 2.25 mmol, 0.100 eq) in one portion. The resulting mixture was stirred at 25° C. for 5 min before TEA (2.28 g, 22.5 mmol, 3.14 mL, 1.00 eq) and benzyl but-3-ynoate (4.32 g, 24.8 mmol, 1.10 eq) were added, and the resulting mixture was stirred at 30° C. for 6 h. The reaction mixture was then quenched by addition H 2 O (30 mL), and the resulting biphasic mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give benzyl 2-(1-benzyl-4-iodo-1H-1,2,3-triazol-5-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 18 H 16 N 3 O 2 : 434.0; found 434.1.

Step c: To a mixture of tert-butyl piperazine-1-carboxylate (645 mg, 3.46 mmol, 5.00 eq) and benzyl 2-(1-benzyl-4-iodo-1H-1,2,3-triazol-5-yl)acetate (300 mg, 693 μmol, 1.00 eq) in toluene (10 mL) at 25° C. under N 2 was added XPhos (83.0 mg, 173 μmol, 0.250 eq), Pd(OAc) 2 (34.0 mg, 152 μmol, 0.220 eq) and Cs 2 CO 3 (677 mg, 2.08 mmol, 3.00 eq) in one portion. The resulting mixture was stirred at 80° C. for 6 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 4-(1-benzyl-5-(2-(benzyloxy)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate. LC-MS (ESI): m/z: [M+H] + calculated for C 27 H 33 N 5 O 4 : 492.2; found 492.3.

Step d: To a mixture of tert-butyl 4-(1-benzyl-5-(2-(benzyloxy)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate (200 mg, 406 μmol, 1.00 eq) in DCE (5 mL) at 25° C. under N 2 were added TEA (8.0 mg, 81.3 μmol, 11.3 μL, 0.2 eq), Et 3 SiH (95.0 mg, 813 μmol, 130 μL, 2.00 eq), Pd(OAc) 2 (23.0 mg, 102 μmol, 0.250 eq) in one portion. The resulting mixture was stirred at 25° C. for 60 min before it was quenched by addition H 2 O (10 mL). The resulting biphasic mixture was then extracted with EtOAc (3×10 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 2-(1-benzyl-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-1,2,3-triazol-5-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 20 H 27 N 5 O 4 : 402.2; found 402.3.

The following compounds in Table B-2 were synthesized using procedures similar to Intermediate A-7 using the appropriate starting materials.

Intermediate A-8: Synthesis of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-hydroxyacetic acid

Step a: To a solution of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)acetic acid (2.00 g, 9.21 mmol, 1 eq) in MeOH (20 mL) at 25° C. was added SOCl 2 (109.54 mg, 920.71 μmol, 66.79 μL, 0.1 eq). The resulting mixture was warmed to 70° C. and stirred for 3 h. The reaction mixture was then quenched with water (20 mL), and the resulting biphasic mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give methyl 2-(1-benzyl-1H-1,2,3-triazol-4-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for Cl 2 H 13 N 3 O 2 : 232.1; found 232.1.

Step b: To a solution of methyl 2-(1-benzyl-1H-1,2,3-triazol-4-yl)acetate (500 mg, 2.16 mmol, 1 eq) and 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (847.45 mg, 3.24 mmol, 1.5 eq) in THF (5 mL) at −65° C. under N 2 was added NaHMDS (1 M in THF, 3.24 mL, 1.5 eq) in THF (5 mL) in a dropwise manner. The resulting mixture was stirred at −65° C. for 2 h. The reaction mixture was adjusted to pH=7 by addition of saturated aqueous NH 4 Cl solution. The resulting biphasic solution was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-hydroxyacetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 11 N 3 O 3 : 234.1; found 234.1.

Intermediate A-9: Synthesis of 2-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetic acid

Step a: To a solution of 3-bromo-2-hydrazineylpyridine (2 g, 10.6 mmol, 1 eq) in THF (20 mL) at 0° C. was added CDI (2.24 g, 13.8 mmol, 1.3 eq). The resulting mixture was warmed to 25° C. and stirred for 2 h. The mixture was then poured into water (20 mL), resulting in the precipitation of a solid. The mixture was then filtered, and the filter cake was washed with water. The washed solid was then dried under reduced pressure to give 8-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. LC-MS (ESI): m/z: [M+H] + calculated for C 6 H 4 BrN 3 O: 214.0; found 213.9.

›SYNTHETIC EXAMPLES · 6 of 20

Step b: To a mixture of 8-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (500 mg, 2.34 mmol, 1 eq) and Pd(t-Bu 3 P) 2 (239 mg, 467 μmol, 0.2 eq) in THF (30 mL) was added (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (1 M in THF, 14.02 mL, 6 eq). The resulting mixture was degassed and purged with N 2 , and then the mixture was warmed to 80° C. and stirred for 2 h under N 2 atmosphere. The mixture was then filtered, and H 2 O (10 mL) was added to the filtrate. The resulting biphasic mixture was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (2×15 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetate. LC-MS (ESI): m/z: [M−H] − calculated for C 12 H 15 N 3 O 3 : 248.1; found 248.1.

Step c: To a solution of tert-butyl 2-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetate (50 mg, 201 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL, 67.3 eq). The resulting mixture was stirred at 25° C. for 15 h. The mixture was then concentrated under reduced pressure to give 2-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetic acid. LC-MS (ESI): m/z: [M-CO 2 H—H] − calculated for C 8 H 7 N 3 O 3 : 148.1; found 148.2.

Intermediate A-10: Synthesis of 2-(2-methylquinolin-5-yl)acetic acid

Step a: To a mixture of methyl 2-(2-chloroquinolin-5-yl)acetate (200 mg, 849 μmol, 1 eq) and dimethylzinc (1 M in toluene, 2.55 mL, 3.00 eq) in dioxane (2 mL) at 25° C. under N 2 was added Pd(dppf)Cl 2 (124 mg, 170 μmol, 0.20 eq) in one portion. The mixture was then degassed and charged with N 2 . The reaction mixture was then warmed to 75° C. and stirred for 1 h. The reaction mixture was then cooled to 25° C. and poured into water (10 mL). The resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 2-(2-methylquinolin-5-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 13 H 13 NO 2 : 216.1; found 216.1.

Step b: Methyl 2-(2-methylquinolin-5-yl)acetate (90 mg, 418 μmol, 1.00 eq) was added to aqueous HCl (6 M, 0.5 mL) in one portion at 25° C. The reaction mixture was then warmed to 100° C. and stirred for 16 h. The reaction mixture was then concentrated under reduced pressure to give 2-(2-methylquinolin-5-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 12 H 11 NO 2 : 202.1; found 202.1.

The following compounds in Table B-3 were synthesized using procedures similar to Intermediate A-10 using the appropriate starting materials.

Intermediate A-11: Synthesis of 2-(5-(difluoromethyl)-2H-tetrazol-2-yl)acetic acid

Step a: A mixture of ethyl 1H-tetrazole-5-carboxylate (25.0 g, 175 mmol, 1.00 eq), tert-butyl 2-bromoacetate (37.7 g, 193 mmol, 28.5 mL, 1.10 eq) and TEA (26.7 g, 263 mmol, 36.7 mL, 1.50 eq) in THF (250 mL) was warmed to 80° C. and stirred for 1 h. The reaction mixture was then cooled and quenched with water (200 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (400 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give ethyl 2-(2-(tert-butoxy)-2-oxoethyl)-2H-tetrazole-5-carboxylate. LC-MS (ESI): m/z: [M+H] + calculated for C 10 H 16 N 4 O 4 : 257.1; found 257.1.

Step b: To a solution of ethyl 2-(2-(tert-butoxy)-2-oxoethyl)-2H-tetrazole-5-carboxylate (35.0 g, 136 mmol, 1.00 eq) in THF (180 mL) at −20° C. under N 2 was added DIBAL-H (1 M in THF, 273 mL, 2.00 eq) in a dropwise manner. The mixture was then warmed to 20° C. and stirred for 1 h. The mixture was then cooled to 0° C. and quenched with water (300 mL) before it was stirred for 10 min. The resulting biphasic mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(5-(hydroxymethyl)-2H-tetrazol-2-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 8 H 14 N 4 O 3 : 215.1; found 215.1.

Step c: To a solution of tert-butyl 2-(5-(hydroxymethyl)-2H-tetrazol-2-yl)acetate (2.00 g, 9.34 mmol, 1.00 eq) in DCM (20 mL) at 20° C. was added PCC (4.02 g, 18.6 mmol, 2.00 eq) and silica gel (4.00 g). The resulting mixture was stirred at 20° C. for 40 h. The reaction mixture was then diluted with water (20 mL), and the resulting biphasic mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(5-formyl-2H-tetrazol-2-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 8 H 12 N 4 O 3 : 213.1; found 213.1.

Step d: To a solution of tert-butyl 2-(5-formyl-2H-tetrazol-2-yl)acetate (400 mg, 1.88 mmol, 1.00 eq) in DCM (4 mL) at 20° C. was added BAST (1.25 g, 5.64 mmol, 1.24 mL, 3.00 eq). The resulting mixture was stirred for 1 h. The mixture was then diluted with water (10 mL), and the resulting biphasic mixture was extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(5-(difluoromethyl)-2H-tetrazol-2-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 8 H 12 F 2 N 4 O 2 : 235.1; found 235.1.

Step e: A solution of tert-butyl 2-(5-(difluoromethyl)-2H-tetrazol-2-yl)acetate (200 mg, 853 μmol, 1.00 eq) in HCl/EtOAc (4 M, 3 mL) was stirred at 20° C. for 16 h. The reaction mixture was then concentrated under reduced pressure to give 2-(5-(difluoromethyl)-2H-tetrazol-2-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 4 H 4 F 2 N 4 O 2 : 179.0; found 179.0.

›SYNTHETIC EXAMPLES · 7 of 20

Intermediate A-12: Synthesis of 2-methyl-2-(1,3,4-oxadiazol-2-yl)propanoic acid

Step a: To a solution of benzyl tert-butyl malonate (4.5 g, 17.9 mmol, 1 eq) in DMF (40 mL) at 20° C. was added Cs 2 CO 3 (14.6 g, 44.9 mmol, 2.5 eq) and iodomethane (10.2 g, 71.9 mmol, 4.48 mL, 4 eq). The resulting mixture was then warmed to 50° C. and stirred for 2 h. The reaction mixture was then cooled to 0° C. and quenched by addition of H 2 O (30 mL). The resulting biphasic mixture was then extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (3×50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 1-benzyl 3-(tert-butyl) 2,2-dimethylmalonate, which was carried forward to the next step without further characterization.

Step b: To a solution of 1-benzyl 3-(tert-butyl) 2,2-dimethylmalonate (4.6 g, 16.5 mmol, 1 eq) in DCM (40 mL) at 25° C. was added TFA (15.0 g, 132 mmol, 9.8 mL, 8.00 eq), and the resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated under reduced pressure to give 3-(benzyloxy)-2,2-dimethyl-3-oxopropanoic acid. LC-MS (ESD): m/z: [M+H] + calculated for C 12 H 14 O 4 : 223.1; found 223.1.

Step c: To a solution of 3-(benzyloxy)-2,2-dimethyl-3-oxopropanoic acid (1 g, 4.50 mmol, 1 eq) and tert-butyl hydrazinecarboxylate (654 mg, 4.95 mmol, 1.1 eq) in DMF (10 mL) at 0° C. was added triethylamine (1.37 g, 13.5 mmol, 1.88 mL, 3 eq) and HATU (1.88 g, 4.95 mmol, 1.1 eq). The resulting mixture was warmed to 25° C. and stirred for 2 h. The reaction mixture was then quenched by addition of H 2 O (30 mL), and the resulting biphasic mixture was then extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(3-(benzyloxy)-2,2-dimethyl-3-oxopropanoyl)hydrazine-1-carboxylate, which was carried forward to the next step without further characterization.

Step d: To a solution of tert-butyl 2-(3-(benzyloxy)-2,2-dimethyl-3-oxopropanoyl)hydrazine-1-carboxylate (1 g, 2.97 mmol, 1 eq) in EtOAc (20 mL) at 25° C. was added HCl in EtOAc (4 M, 17.4 mL, 23.6 eq). The resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated under reduced pressure to give benzyl 3-hydrazineyl-2,2-dimethyl-3-oxopropanoate, which was carried forward to the next step without further characterization.

Step e: To a solution of benzyl 3-hydrazineyl-2,2-dimethyl-3-oxopropanoate (0.7 g, 2.50 mmol, 1 eq) in trimethoxymethane (10 mL) at 25° C. was added 4-methylbenzenesulfonic acid (43.0 mg, 249 μmol, 0.1 eq). The resulting mixture was warmed to 105° C. and stirred for 12 h. The reaction mixture was then cooled and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give benzyl 2-methyl-2-(1,3,4-oxadiazol-2-yl)propanoate, which was carried forward to the next step without further characterization.

Step f: To a solution of benzyl 2-methyl-2-(1,3,4-oxadiazol-2-yl)propanoate (0.4 g, 1.62 mmol, 1 eq), TEA (32.8 mg, 324 μmol, 45.2 μL, 0.2 eq) and tert-butyldimethylsilane (378 mg, 3.25 mmol, 2 eq) in DCE (5 mL) at 25° C. under N 2 was added Pd(OAc) 2 (91.2 mg, 406 μmol, 0.25 eq). The resulting mixture was warmed to 60° C. and stirred for 4 h. The reaction mixture was then filtered through a pad of Celite, and the pad was washed with EtOAc (2×200 mL). The combined filtrates were concentrated under reduced pressure, and the crude residue obtained was purified by prep-HPLC to give 2-methyl-2-(1,3,4-oxadiazol-2-yl)propanoic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 6 H 8 N 2 O 3 : 157.0; found 157.1.

Intermediate A-13: Synthesis of 2-(5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-1,2,3-triazol-1-yl)acetic acid

Step a: To a solution of 5-bromo-1H-1,2,3-triazole (2.0 g, 13.5 mmol, 1 eq) and ethyl 2-bromoacetate (3.39 g, 20.3 mmol, 2.2 mL, 1.5 eq) in DMSO (15 mL) was added DIPEA (5.24 g, 40.6 mmol, 7.06 mL, 3 eq). The resulting mixture was warmed to 50° C. and stirred for 4 h. The reaction mixture was then cooled to 0° C. and quenched by addition of H 2 O (20 mL), and the resulting biphasic mixture was then extracted with EtOAc (2×20 mL). The combined organic extracts were washed with H 2 O (20 mL) and brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(5-bromo-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 6 H 8 BrN 3 O 2 : 234.0; found 234.0.

Step b: To a mixture of ethyl 2-(5-bromo-1H-1,2,3-triazol-1-yl)acetate (250 mg, 1.07 mmol, 1 eq), tert-butyl piperazine-1-carboxylate (1 g, 5.4 mmol, 5 eq), Cs 2 CO 3 (1.1 g, 3.2 mmol, 3 eq), and XPhos (113 mg, 0.12 eq) in toluene (10 mL) was added Pd(OAc) 2 (60 mg, 0.12 eq). The resulting mixture was then degassed and placed under an N 2 atmosphere. The reaction mixture was then warmed to 100° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite, and the filter cake was washed with toluene (2×10 mL). The combined filtrates were then concentrated under reduced pressure, and the crude residue obtained was purified by column chromatography to give tert-butyl 4-(1-(2-ethoxy-2-oxoethyl)-1H-1,2,3-triazol-5-yl)piperazine-1-carboxylate. LC-MS (ESI): m/z: [M+H] + calculated for C 15 H 25 N 5 O 4 : 340.2; found 340.1.

Step c: To a solution of tert-butyl 4-(1-(2-ethoxy-2-oxoethyl)-1H-1,2,3-triazol-5-yl)piperazine-1-carboxylate (95 mg, 280 μmol, 1 eq) in MeOH (4 mL) was added LiOH·H 2 O (23.5 mg, 560 μmol, 2 eq), and the resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue obtained was dissolved in H 2 O (5 mL). The resulting aqueous solution was extracted with EtOAc (2×5 mL), and then the aqueous phase was adjusted to pH 5-6 with aqueous HCl (3 M). The resulting aqueous solution was then extracted with EtOAc (2×6 mL), and the combined organic extracts were washed with brine (5 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 2-(5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-1,2,3-triazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M−t-Bu+H] + calculated for C 13 H 21 N 5 O 4 : 256.1; found 256.0.

›SYNTHETIC EXAMPLES · 8 of 20

The following compounds in Table B-4 were synthesized using procedures similar to Intermediate A-13 using the appropriate starting materials.

Intermediate A-14: Synthesis of 2-(4-(dimethylamino)-1H-1,2,3-triazol-1-yl)acetic acid

Step a: To a mixture of 5-nitro-1H-1,2,3-triazole (11.3 g, 99.1 mmol, 1 eq) and ethyl 2-bromoacetate (24.8 g, 149 mmol, 16.4 mL, 1.5 eq) in DMSO (100 mL) at 25° C. was added DIPEA (38.4 g, 297 mmol, 51.8 mL, 3 eq), and the resulting mixture was stirred at 25° C. for 3 h. The reaction mixture was then cooled to 0° C. and quenched by addition of H 2 O (100 mL), and the resulting biphasic mixture was then extracted with EtOAc (2×70 mL). The combined organic extracts were washed with H 2 O (50 mL) and brine (2×50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(4-nitro-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 6 H 8 N 4 O 4 : 201.0; found 201.0.

Step b: To a solution of ethyl 2-(4-nitro-1H-1,2,3-triazol-1-yl)acetate (11 g, 54.9 mmol, 1 eq) in EtOAc (300 mL) was added Pd/C (1.5 g, 10% purity) under N 2 . The suspension was then degassed under vacuum and placed under an H 2 atmosphere. The resulting mixture was then stirred under H 2 (15 psi) at 25° C. for 8 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to give ethyl 2-(4-amino-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 6 H 10 N 4 O 2 : 171.1; found 171.1.

Step c: A mixture of ethyl 2-(4-amino-1H-1,2,3-triazol-1-yl)acetate (8 g, 47.0 mmol, 1 eq) and paraformaldehyde (14.1 g, 470 mmol, 10 eq) in AcOH (100 mL) was stirred at 25° C. for 60 min. The reaction mixture was then cooled to 0° C. before NaBH 3 CN (8.86 g, 141 mmol, 3 eq) was added in one portion. The resulting mixture was warmed to 25° C. and stirred for 15 h. The reaction mixture was then cooled to 0° C. and quenched by addition H 2 O (100 mL). The pH of the resulting mixture was adjusted to pH=6 using aqueous NaOH (4 M) before it was filtered. The filtrate was then extracted with EtOAc (2×150 mL). The combined organic extracts were washed with brine (2×100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(4-(dimethylamino)-1H-1,2,3-triazol-1-yl)acetate, which was carried forward to the next step without further characterization.

Step d: To a solution of ethyl 2-(4-(dimethylamino)-1H-1,2,3-triazol-1-yl)acetate (7 g, 35.3 mmol, 1 eq) in MeOH (70 mL) and H 2 O (20 mL) at 25° C. was added LiOH·H 2 O (2.96 g, 70.6 mmol, 2 eq). The resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated under reduced pressure. The aqueous solution obtained was then adjusted to pH 5-6 using aqueous HCl (3 M), and the resulting mixture was concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2-(4-(dimethylamino)-1H-1,2,3-triazol-1-yl)acetic acid. LC-MS (ESD): m/z: [M+H] + calculated for C 6 H 10 N 4 O 2 : 171.1; found 171.1.

The following compounds in Table B-5 were synthesized using procedures similar to Intermediate A-14 using the appropriate starting materials.

Intermediate A-15: Synthesis of (2-methylpyrimidin-4-yl)glycine

Step a: To a solution of 4-chloro-2-methylpyrimidine (300 mg, 2.33 mmol, 1 eq) in i-PrOH (3.00 mL) at 25° C. was added TEA (708 mg, 7.00 mmol, 3 eq) and tert-butyl 2-aminoacetate (367 mg, 2.80 mmol, 1.2 eq). The resulting mixture was warmed to 80° C. and stirred for 2 h. The reaction mixture was then quenched by addition H 2 O (10 mL), and the resulting biphasic mixture was then extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (2×10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (2-methylpyrimidin-4-yl)glycinate. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 17 N 3 O 2 : 224.1; found 224.1.

Step b: To a solution of tert-butyl (2-methylpyrimidin-4-yl)glycinate (310 mg, 1.39 mmol, 1 eq) in EtOAc (1.00 mL) was added HCl in EtOAc (4 M, 3 mL, 8.64 eq). The resulting mixture was stirred at 25° C. for 4 h. The reaction mixture was then concentrated under reduced pressure to give (2-methylpyrimidin-4-yl)glycine. LC-MS (ESI): m/z: [M+H] + calculated for C 7 H 9 N 3 O 2 : 168.1; found 168.1.

The following compounds in Table B-6 were synthesized using procedures similar to Intermediate A-15 using the appropriate starting materials.

Intermediate A-16: Synthesis of (3,3-difluoroazetidine-1-carbonyl)glycine

Step a: To a solution of tert-butyl 2-aminoacetate (1.00 g, 7.62 mmol, 1 eq) in THF (10 mL) at 0° C. under N 2 was added CDI (1.36 g, 8.39 mmol, 1.1 eq) and DIPEA (2.96 g, 22.9 mmol, 3 eq). The resulting mixture was stirred at 0° C. for 1 h. 3,3-difluoroazetidine (987 mg, 7.62 mmol, 1 eq, HCl salt) was then added, and the resulting mixture was warmed to 60° C. and stirred for 1 h. The reaction mixture was then diluted with H 2 O (50 mL) and filtered. The filter cake was washed with H 2 O (20 mL), and the washed solid was dried under reduced pressure to give tert-butyl (3,3-difluoroazetidine-1-carbonyl)glycinate. LC-MS (ESI): m/z: [M−t-Bu+H+H] + calculated for C 10 H 16 F 2 N 2 O 3 : 195.0; found 195.0.

Step b: A solution tert-butyl (3,3-difluoroazetidine-1-carbonyl)glycinate (1.3 g, 5.19 mmol, 1 eq) in HCl in dioxane (4 M, 30 mL) was stirred at 20° C. for 1 h. The reaction mixture was then concentrated under reduced pressure, and the crude residue obtained was triturated with MTBE (20 mL) to give (3,3-difluoroazetidine-1-carbonyl)glycine. LC-MS (ESI): m/z: [M+H] + calculated for C 6 H 8 F 2 N 2 O 3 : 195.0; found 195.0.

The following compounds in Table B-7 were synthesized using procedures similar to Intermediate A-16 using the appropriate starting materials.

›SYNTHETIC EXAMPLES · 9 of 20

Intermediate A-17: Synthesis of N-(1-ethyl-1H-1,2,3-triazol-4-yl)-N-methylglycine

Step a: To a solution of 4-nitro-1H-1,2,3-triazole (4.00 g, 35.1 mmol, 1 eq) in DMA (80 mL) at 0° C. was added NaH (1.47 g, 36.8 mmol, 60% purity, 1.05 eq). The resulting mixture was stirred at 0° C. for 0.5 h. EtI (8.20 g, 52.6 mmol, 4.21 mL, 1.5 eq) was then added in one portion, and the resulting mixture was warmed to 20° C. and stirred for 3 h. The reaction mixture was then quenched with H 2 O (150 mL), and the resulting biphasic mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 1-ethyl-4-nitro-1H-1,2,3-triazole. LC-MS (ESI): m/z: [M+H] + calculated for C 4 H 6 N 4 O 2 : 143.0; found 143.1.

Step b: A mixture of 1-ethyl-4-nitro-1H-1,2,3-triazole 1.6 g, 11.3 mmol, 1 eq) and Pd/C (400 mg, 10% purity) in EtOH (20 mL) was degassed with H 2 . The degassed mixture was then warmed to 40° C. and stirred under H 2 (50 psi) for 3 h. The reaction mixture was then cooled and filtered, and the filtrate was concentrated under reduced pressure to give 1-ethyl-1H-1,2,3-triazol-4-amine, which was carried forward to the next step without further purification or characterization.

Step c: A mixture of 1-ethyl-1H-1,2,3-triazol-4-amine (600 mg, 5.35 mmol, 1 eq) and Cs 2 CO 3 (1.74 g, 5.35 mmol, 1 eq) in DMF (3 mL) was stirred at 25° C. for 0.5 h before tert-butyl 2-bromoacetate (1.15 g, 5.89 mmol, 1.1 eq) was added in one portion, and the resulting mixture was warmed to 50° C. and stirred for 12 h. The reaction mixture was then quenched with H 2 O (10 mL) and extracted with EtOAc (2×20 mL). The organic extracts were concentrated under reduced pressure, and the crude residue obtained was purified by column chromatography to give tert-butyl (1-ethyl-1H-1,2,3-triazol-4-yl)glycinate. LC-MS (ESI): m/z: [M−t-Bu+H+H] + calculated for C 10 H 18 N 4 O 2 : 171.1; found 171.1.

Step d: To a solution of tert-butyl (1-ethyl-1H-1,2,3-triazol-4-yl)glycinate (280 mg, 1.24 mmol, 1 eq) in DMA (2 mL) at 0° C. was added NaH (49 mg, 1.24 mmol, 60% purity, 1 eq), and the resulting mixture was stirred at 0° C. for 0.5 h. CH 3 I (175 mg, 1.24 mmol, 1 eq) was then added, and the resulting mixture was warmed to 20° C. and stirred for 3 h. The mixture was then quenched with H 2 O (10 mL), and the biphasic mixture was extracted with EtOAc (2×10 mL). The organic extracts were concentrated under reduced pressure, and the crude residue obtained was purified by prep-TLC to give tert-butyl N-(1-ethyl-1H-1,2,3-triazol-4-yl)-N-methylglycinate. LC-MS (ESI): m/z: [M−t-Bu+H+H] + calculated for C 11 H 20 N 4 O 2 : 185.1; found 185.1.

Step e: A solution of tert-butyl N-(1-ethyl-1H-1,2,3-triazol-4-yl)-N-methylglycinate (130 mg, 541 μmol, 1 eq) in TFA (2.00 g, 17.56 mmol, 32.5 eq) was stirred at 50° C. for 1 h. The reaction mixture was then cooled and concentrated under reduced pressure to give N-(1-ethyl-1H-1,2,3-triazol-4-yl)-N-methylglycine, which was used without any additional purification. LC-MS (ESI): m/z: [M+H] + calculated for C 7 H 12 N 4 O 2 : 185.1; found 185.2.

The following compounds in Table B-8 were synthesized using procedures similar to Intermediate A-17 using the appropriate starting materials.

Intermediate A-18: Synthesis of 2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetic acid

Step a: To a solution of 5-(chloromethyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 678 μmol, 1 eq) in MeCN (2 mL) at 0° C. was added TMSCN (100 mg, 1.02 mmol, 127 μL, 1.5 eq) and TBAF (1 M in THF, 1.02 mL, 1.5 eq). The resulting mixture was warmed to 20° C. and stirred for 3 h. The reaction mixture was then quenched with H 2 O (5 mL) and extracted with EtOAc (2×10 mL). The organic extracts were then concentrated under reduced pressure to give 2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetonitrile. LC-MS (ESI): m/z: [M−H]-calculated for C 5 H 6 N 4 O: 137.0; found 137.2.

Step b: A mixture of 2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetonitrile (30 mg, 217 μmol, 1 eq) in aqueous HCl (12 M, 7.60 mL) was stirred at 60° C. for 1 h. The mixture was then concentrated under reduced pressure to give 2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetic acid. LC-MS (ESI): m/z: [M−H] − calculated for C 5 H 7 N 3 O 3 : 156.0; found 156.2.

The following compounds in Table B-9 were synthesized using procedures similar to Intermediate A-18 using the appropriate starting materials.

Intermediate A-19: Synthesis of 1-trityl-1H-indazole-6-carbaldehyde

Step a: To a solution of 6-bromo-1H-indazole (8 g, 40.6 mmol, 1 eq) in DMF (50 mL) was added trityl chloride (TrtCl, 12.4 g, 44.6 mmol, 1.1 eq) and TEA (7.06 mL, 50.7 mmol, 1.25 eq). The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water, and the resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with MTBE (30 mL) and filtered to give 6-bromo-1-trityl-1H-indazole, which was carried forward to the next step without further purification or characterization.

Step b: To a mixture of 6-bromo-1-trityl-1H-indazole (16.7 g, 38.0 mmol, 1 eq), potassium vinyltrifluoroborate (10.1 g, 76.0 mmol, 2 eq) and TEA (15.8 mL, 14.0 mmol, 3 eq) in i-PrOH (160 mL), was added Pd(dppf)Cl 2 ° CH 2 Cl 2 (1.55 g, 1.90 mmol, 0.05 eq) under N 2 . The resulting mixture was then degassed and placed under an N 2 atmosphere. The reaction mixture was then warmed to 100° C. and stirred for 2 h under N 2 . After cooling, the mixture was filtered, and the filter cake was washed with ethyl acetate (3×100 mL). The combined filtrates were concentrated, and the crude residue obtained was purified by column chromatography to give 1-trityl-6-vinyl-1H-indazole LC-MS (ESI): m/z: [2M+Na] + calculated for C 28 H 22 N 2 : 795.4; found 795.3.

›SYNTHETIC EXAMPLES · 10 of 20

Step c: To a solution of 1-trityl-6-vinyl-1H-indazole (14.2 g, 36.7 mmol, 1 eq) in THF:H 2 O (5:1) (300 mL) at 0° C. was added NaIO 4 (31.4 g, 146 mmol, 4 eq) and K 2 OsO 4 ·2H 2 O (676 mg, 1.84 mmol, 0.05 eq). The resulting mixture was warmed to 50° C. and stirred for 1 h. The reaction mixture was then cooled to 25° C. and quenched with sat. aq. Na 2 S 2 O 3 (100 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL), and the combined extracts were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 1-trityl-1H-indazole-6-carbaldehyde.

Intermediate A-20: Synthesis of 3-(isoxazol-5-yl)benzaldehyde

Step a: To a solution of 1-(3-bromophenyl)ethan-1-one (18.5 g, 92.9 mmol, 1 eq) in toluene (150 mL) was added N,N-dimethylformamide dimethyl acetal (37 mL, 346 mmol, 3.7 eq) at 20° C. The resulting mixture was warmed to 120° C. and stirred for 1 h. The reaction mixture was then cooled to 20° C. and quenched with water (100 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (E)-1-(3-bromophenyl)-3-(dimethylamino)prop-2-en-1-one. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 12 BrNO: 254.1; found 254.1.

Step b: To a solution of (E)-1-(3-bromophenyl)-3-(dimethylamino)prop-2-en-1-one (8 g, 31.4 mmol, 1 eq) in EtOH (50 mL) was added NH 2 OH·HCl (2.63 g, 37.7 mmol, 1.2 eq). The resulting mixture was warmed to 85° C. and stirred for 2 h. The reaction mixture was then cooled to 25° C. and quenched with water (50 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-(3-bromophenyl)isoxazole. LC-MS (ESI): m/z: [M+H] + calculated for C 9 H 6 BrNO: 224.0; found 224.1.

Step c: To a mixture of 5-(3-bromophenyl)isoxazole (8 g, 28.5 mmol, 1 eq), potassium vinyltrifluoroborate (7.65 g, 57.1 mmol, 2 eq) and TEA (11.9 mL, 85.6 mmol, 3 eq) in i-PrOH (50 mL) was added Pd(dppf)Cl 2 ° C. H 2 Cl 2 (1.17 g, 1.43 mmol, 0.05 eq) under N 2 . The resulting mixture was degassed and placed under N 2 , and the reaction mixture was then warmed to 100° C. and stirred for 1 h. The reaction mixture was then cooled, quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-(3-vinylphenyl)isoxazole. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 9 NO: 172.1; found 172.1.

Step d: To a solution of 5-(3-vinylphenyl)isoxazole (1.8 g, 10.5 mmol, 1 eq) in THF (50 mL) and H 2 O (10 mL) was added NaIO 4 (9.00 g, 42.0 mmol, 4 eq) and potassium osmate dihydrate (194 mg, 525 μmol, 0.05 eq). The resulting mixture was warmed to 50° C. and stirred for 1 h. The reaction mixture was then cooled and quenched with water (50 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-(isoxazol-5-yl)benzaldehyde. LC-MS (ESI): m/z: [M+H] + calculated for C 10 H 7 NO 2 : 174.0; found 174.0.

Intermediate A-21: Synthesis of 2-(5-(diethylamino)-1H-1,2,3-triazol-1-yl)acetic acid

Step a: A mixture of ethyl 2-azidoacetate (8 g, 61.9 mmol, 7.08 mL, 1 eq), (iodoethynyl)trimethylsilane (15.2 g, 68.1 mmol, 1.1 eq), copper iodide (1.18 g, 6.20 mmol, 0.1 eq), DIPEA (16.0 g, 123 mmol, 21.5 mL, 2 eq) and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium ditetrafluoroborate (F-TEDA, 32.9 g, 92.9 mmol, 1.5 eq) in H 2 O (80 mL) was degassed and placed under an N 2 atmosphere. The reaction mixture was then stirred for 16 h. The reaction mixture was then diluted with water and extracted with EtOAc (2×200 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(5-iodo-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 6 H 8 IN 3 O 2 : 282.0; found 281.9.

Step b: To a solution of ethyl 2-(5-iodo-1H-1,2,3-triazol-1-yl)acetate (700 mg, 2.49 mmol, 1 eq) in toluene (5 mL) was added N-ethylethanamine (911 mg, 12.4 mmol, 5 eq) and Cs 2 CO 3 (1.62 g, 4.98 mmol, 2 eq). The resulting mixture was degassed and placed under an N 2 atmosphere, and then XPhos (949 mg, 1.99 mmol, 0.8 eq) and Pd(OAc) 2 (112 mg, 498 μmol, 0.2 eq) were added. The resulting mixture was then degassed and placed under an N 2 atmosphere, warmed to 100° C., and stirred for 16 h. After cooling, the reaction mixture was concentrated under reduced pressure. Water (15 mL) was added, and the resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(5-(diethylamino)-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 10 H 18 N 4 O 2 : 227.1; found 227.2.

Step c: To a solution of ethyl 2-(5-(diethylamino)-1H-1,2,3-triazol-1-yl)acetate (200 mg, 883 μmol, 1 eq) in THF (2 mL) at 0° C. was added LiOH (23.3 mg, 972 μmol, 4.85 mL, 1.1 eq) in water (0.5 mL), and the resulting mixture was warmed to 25° C. and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2-(5-(diethylamino)-1H-1,2,3-triazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 8 H 14 N 4 O 2 : 199.1; found 199.2.

›SYNTHETIC EXAMPLES · 11 of 20

Intermediate A-22: Synthesis of 2-(5-(difluoromethyl)-1H-1,2,3-triazol-1-yl)acetic acid

Step a: To a solution of ethynyltriisopropylsilane (15 g, 82.3 mmol, 18.5 mL, 1 eq) in THF (200 mL) at −70° C. was added n-BuLi (2.5 M in hexane, 29.6 mL, 0.9 eq) in a dropwise manner. After 30 min, DMF (10.8 g, 148 mmol, 11.39 mL, 1.8 eq) was added in a dropwise manner, and the resulting mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was then quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-(triisopropylsilyl)propiolaldehyde.

Step b: To a solution of ethyl 2-azidoacetate (2.56 g, 19.8 mmol, 1 eq) in toluene (60 mL) was added 3-(triisopropylsilyl)propiolaldehyde (5 g, 23.8 mmol, 1.2 eq). The resulting mixture was then warmed to 80° C. and stirred for 16 h. After cooling, the reaction mixture was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(5-formyl-4-(triisopropylsilyl)-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 16 H 29 N 3 O 3 Si: 340.2; found 340.3.

Step c: To a solution of ethyl 2-(5-formyl-4-(triisopropylsilyl)-1H-1,2,3-triazol-1-yl)acetate (4.5 g, 13.3 mmol, 1 eq) in DCM (40 mL) at 0° C. was added DAST (5.34 g, 33.1 mmol, 2.5 eq) dropwise in a dropwise manner. The resulting mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was then slowly added into ice-water (50 mL), and the resulting biphasic mixture was extracted with DCM (3×50 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 and filtered, concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(5-(difluoromethyl)-4-(triisopropylsilyl)-1H-1,2,3-triazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 16 H 29 F 2 N 3 O 2 Si: 362.2; found 362.3.

Step d: To a solution of 2-(5-(difluoromethyl)-4-(triisopropylsilyl)-1H-1,2,3-triazol-1-yl)acetate (1 g, 2.77 mmol, 1 eq) in THE (20 mL) was added TBAF (1.45 g, 5.53 mmol, 2 eq). The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then poured into ice-water (20 mL), and the resulting biphasic mixture was extracted with EtOAc (2×20 mL). The water phase was adjusted to pH 3-4 with aqueous HCl (2N) and then extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure to give 2-(5-(difluoromethyl)-1H-1,2,3-triazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 5 H 5 F 2 N 3 O 2 : 178.0; found 178.0.

Intermediate A-23: Synthesis of 2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetic acid

Step a: To a solution of 3-bromo-5-methylpyridin-2(1H)-one (5 g, 26.6 mmol, 1 eq) and K 2 CO 3 (7.35 g, 53.2 mmol, 2 eq) in DMSO (30 mL) was added iodoethane (5.39 g, 34.6 mmol, 1.3 eq). The resulting mixture was warmed to 40° C. and stirred for 4 h. The reaction mixture was then cooled and quenched with H 2 O (30 mL), and the resulting biphasic mixture was then extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-bromo-1-ethyl-5-methylpyridin-2(1H)-one. LC-MS (ESD): m/z: [M+H] + calculated for C 8 H 10 BrNO: 216.0; found 216.1.

Step b: A mixture of 3-bromo-1-ethyl-5-methylpyridin-2(1H)-one (0.1 g, 462 μmol, 1 eq), tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (261 mg, 1.39 mmol, 3 eq), LiF (72.0 mg, 2.78 mmol, 6 eq), and bis(tri-tert-butylphosphine)palladium(0) (23.6 mg, 46.2 μmol, 0.1 eq) in DMF (4 mL) was degassed and placed under an N 2 atmosphere. The reaction mixture was then warmed to 100° C. under in a microwave and stirred for 2 h. The reaction mixture was then cooled and quenched with H 2 O (10 mL), and the resulting biphasic mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetate. LC-MS (ESD): m/z: [M+H] + calculated for C 11 H 15 NO 3 : 210.1; found 210.1.

Step c: To a solution of methyl 2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetate (0.25 g, 1.19 mmol, 1 eq) in EtOH (3 mL) was added a solution of LiOH·H 2 O (100 mg, 2.39 mmol, 2 eq) in H 2 O (1 mL). The resulting mixture was stirred for 2 h and then concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2-(1-ethyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 10 H 13 NO 3 : 196.1; found 196.2.

Intermediate A-24: Synthesis of 2-(5-oxo-4,5-dihydropyrazin-2-yl)acetic acid

Step a: To a solution of 2,5-dibromopyrazine (2 g, 8.41 mmol, 1 eq) in DMF (20 mL) was added K 2 CO 3 (1.51 g, 10.9 mmol, 1.3 eq) and diethyl propanedioate (1.62 g, 10.1 mmol, 1.52 mL, 1.2 eq). The resulting mixture was warmed to 110° C. and stirred for 4 h. The reaction mixture was then cooled and diluted with H 2 O (10 mL). The resulting biphasic mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (2×20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give diethyl 2-(5-bromopyrazin-2-yl)malonate. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 13 BrN 2 O 4 : 317.0; found 317.0.

Step b: Diethyl 2-(5-bromopyrazin-2-yl)malonate (700 mg, 2.21 mmol, 1 eq) was added to aqueous KOH (10 M, 7 mL), and the resulting mixture was warmed to 120° C. and stirred for 16 h. The reaction mixture was then cooled to room temperature, and the pH was adjusted to pH=1 with aqueous HCl (6 N). The reaction mixture was then concentrated under reduced pressure, and the crude residue obtained was purified by prep-HPLC to give 2-(5-oxo-4,5-dihydropyrazin-2-yl)acetic acid. LC-MS (ESI): m/z: [M−H] − calculated for C 6 H 6 N 2 O 3 : 153.0; found 153.1.

›SYNTHETIC EXAMPLES · 12 of 20

Intermediate A-25: Synthesis of 2-(4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl)acetic acid

Step a: A mixture of 1H-1,2,3-triazole (10 g, 144 mmol, 1 eq) and N-iodosuccinimide (81.4 g, 361 mmol, 2.5 eq) in NMP (100 mL) under N 2 atmosphere was warmed to 80° C. and stirred for 1 h. The reaction mixture was then cooled to 0° C. and quenched with saturated aqueous Na 2 SO 3 (15 mL). The resulting precipitate was collected by filtration. The solid was then diluted with H 2 O (50 mL), and the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 4,5-diiodo-1H-1,2,3-triazole. LC-MS (ESI): m/z: [M+H] + calculated for C 2 HI 2 N 3 : 321.8; found 321.8.

Step b: A mixture of 5-diiodo-1H-1,2,3-triazole (4 g, 12.4 mmol, 1 eq) and Na 2 SO 3 (4.71 g, 37.4 mmol, 3 eq) in H 2 O (40 mL) under N 2 atmosphere was warmed to 80° C. and stirred for 2 h. The reaction mixture was then cooled and diluted with H 2 O (20 mL). The resulting biphasic mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 4-iodo-1H-1,2,3-triazole, which was carried forward without further purification. LC-MS (ESI): m/z: [M+H] + calculated for C 2 H 2 IN 3 : 195.9; found 195.9.

Step c: To a mixture of 4-iodo-1H-1,2,3-triazole (2 g, 10.2 mmol, 1 eq) and tert-butyl 2-bromoacetate (5 g, 25.6 mmol, 2.50 eq) in DMSO (20 ML) under N 2 atmosphere was added DIPEA (3.98 g, 30.7 mmol, 3 eq). The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then quenched with H 2 O (30 mL), and the resulting biphasic mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(4-iodo-2H-1,2,3-triazol-2-yl)acetate, which was carried forward to the next step without further characterization.

Step d: To a solution of tert-butyl 2-(4-iodo-2H-1,2,3-triazol-2-yl)acetate (1 g, 3.24 mmol, 1 eq) in dry toluene (25 mL) was added azetidine (923 mg, 16.2 mmol, 5 eq), Cs 2 CO 3 (3.16 g, 9.71 mmol, 3 eq), and XPhos (1.23 g, 2.59 mmol, 0.8 eq) at 25° C., The resulting mixture was then degassed and placed under an N 2 atmosphere before Pd(OAc) 2 (145 mg, 647 μmol, 0.2 eq) was added. The resulting mixture was then degassed, placed under an N 2 atmosphere, warmed to 100° C., and stirred for 16 h. The reaction mixture was then cooled, and water (30 mL) was added. The resulting biphasic mixture was then extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl 2-(4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 18 N 4 O 2 : 239.1; found 239.2.

Step e: A solution of tert-butyl 2-(4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl)acetate (370 mg, 1.55 mmol, 1 eq) in TFA (3 mL, 40.5 mmol) was stirred at 25° C. for 1 h. The mixture was then concentrated under reduced pressure, and the crude residue obtained was triturated with MTBE (3 mL) to give 2-(4-(azetidin-1-yl)-2H-1,2,3-triazol-2-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 7 H 10 N 4 O 2 : 183.1; found 183.2.

The following compounds in Table B-10 were synthesized using procedures similar to Intermediate A-25 using the appropriate starting materials.

Intermediate A-26: Synthesis of 2-(3-(difluoromethyl)-4H-1,2,4-triazol-4-yl)acetic acid

Step a: To a solution of ethyl (2,2-difluoroethanethioyl)glycinate (2 g, 9.29 mmol, 1 eq) and formic hydrazide (669 mg, 11.1 mmol, 1.2 eq) in DCM (100 mL) at 0° C. was added silver benzoate (4.26 g, 18.5 mmol, 2 eq) and AcOH (1.67 g, 27.8 mmol, 3 eq). The resulting mixture was then warmed to 20° C. and stirred for 16 h. The reaction mixture was then filtered, and the filtrate was quenched by addition of ice-water (100 mL). The resulting biphasic mixture was then extracted with DCM (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(3-(difluoromethyl)-5-hydroxy-1,5-dihydro-4H-1,2,4-triazol-4-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 7 H 11 F 2 N 3 O 3 : 224.1; found 224.0.

Step b: A mixture of ethyl 2-(3-(difluoromethyl)-5-hydroxy-1,5-dihydro-4H-1,2,4-triazol-4-yl)acetate (1 g, 4.48 mmol, 1 eq) and 4-methylbenzenesulfonic acid (77.1 mg, 448 μmol, 0.1 eq) in THF (20 mL) was stirred at 20° C. for 16 hours under N 2 . The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(3-(difluoromethyl)-4H-1,2,4-triazol-4-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 7 H 9 F 2 N 3 O 2 : 206.1; found 206.0.

Step c: To a solution of ethyl 2-(3-(difluoromethyl)-4H-1,2,4-triazol-4-yl)acetate (100 mg, 487 μmol, 1 eq) in H 2 O (1 mL) and MeOH (5 mL) was added LiOH·H 2 O (40.9 mg, 974 μmol, 2 eq) at 20° C. The resulting mixture was then stirred at 20° C. for 2 h. The reaction mixture was then concentrated under reduced pressure to remove MeOH. The resulting mixture was then adjusted to pH 3-4 using aqueous HCl (1 M), and the aqueous mixture was then extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (50 mL), dried over with anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 2-(3-(difluoromethyl)-4H-1,2,4-triazol-4-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 5 H 5 F 2 N 3 O 2 : 178.0; found 178.1.

Intermediate A-27: Synthesis of 2-(4-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)acetic acid

›SYNTHETIC EXAMPLES · 13 of 20

Step a: To a solution of POBr 3 (81.8 g, 285 mmol, 29.0 mL, 7 eq) in DMF (40 mL) at 0° C. was added 1-methyl-1H-pyrazol-5-ol (4 g, 40.7 mmol, 1 eq). The resulting mixture was warmed to 50° C. and stirred for 2 h. After cooling, the reaction mixture was quenched by addition saturated aq. Na 2 CO 3 (100 mL) at 0° C. The resulting biphasic mixture was extracted with EtOAc (2×250 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-bromo-1-methyl-1H-pyrazole-4-carbaldehyde. LC-MS (ESI): m/z: [M+H] + calculated for C 5 H 5 BrN 2 O: 189.0; found 188.9.

Step b: To a solution of 5-bromo-1-methyl-pyrazole-4-carbaldehyde (2.5 g, 13.2 mmol, 1 eq) in DCM (20 mL) at 0° C. was added DAST (8.53 g, 52.9 mmol, 4 eq) in a dropwise manner. The resulting mixture was warmed to 20° C. and stirred for 12 h. The reaction mixture was then cooled to 0° C. and quenched by addition H 2 O (30 mL). The resulting biphasic mixture was extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (30 mL), dried over with anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-bromo-4-(difluoromethyl)-1-methyl-1H-pyrazole. LC-MS (ESI): m/z: [M+H] + calculated for C 5 H 5 BrF 2 N 2 : 211.0; found 210.9.

Step c: To a solution of 5-bromo-4-(difluoromethyl)-1-methyl-1H-pyrazole (200 mg, 947 μmol, 1 eq) in DMF (2 mL) was added lithium fluoride (147 mg, 5.69 mmol, 6 eq) and tert-tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (535 mg, 2.84 mmol, 3 eq). The resulting mixture was then degassed and placed under an N 2 atmosphere. Bis(tri-tert-butylphosphine)palladium(0) (48.4 mg, 94.7 μmol, 0.1 eq) was then added, and the resulting mixture was warmed to 100° C. using a microwave and stirred for 1.5 h. After cooling, the reaction mixture was then quenched by addition of H 2 O (15 mL). The resulting biphasic mixture was then filtered and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 2-(4-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 8 H 10 F 2 N 2 O 2 : 205.1; found 205.1.

Step d: To a solution of methyl 2-(4-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)acetate (75 mg, 367 μmol, 1 eq) in EtOH (1 mL) and H 2 O (0.5 mL) was added LiOH·H 2 O (30.8 mg, 734 μmol, 2 eq), and the resulting mixture was stirred at 20° C. for 1 h. The reaction mixture was then quenched by addition of H 2 O (5 mL), and the resulting biphasic mixture was extracted with EtOAc (2×5 mL). The aqueous phase pH was then adjusted to pH 3-4 with aqueous HCl (1M), and the aqueous phase was extracted with EtOAc (2×5 mL). The second set of organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 2-(4-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 7 H 8 F 2 N 2 O 2 : 190.0; found 190.1.

Intermediate A-28: Synthesis of 2-(4-(difluoromethyl)-1H-1,2,3-triazol-5-yl)acetic acid

Step a: A mixture of compound ethyl 4,4-difluoro-3-oxobutanoate (12.0 g, 72.2 mmol, 1 eq), TEA (21.9 g, 217 mmol, 30.1 mL, 3 eq) and azidomethylbenzene (9.62 g, 72.2 mmol, 1 eq) in DMSO (100 mL) was heated and stirred at 70° C. for 16 h. After cooling the mixture was poured into ice-water (100 mL) and extracted with EtOAc (2×200 ML). The combined organic layers were washed with aqueous HCl (0.5 M, 100 mL) and brine (200 mL), dried over anhydrous Na 2 SO 4 filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give ethyl 1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazole-4-carboxylate. LC-MS (ESI): m/z: [M+H] + calculated for Cl 3 H 13 F 2 N 3 O 2 : 282.2; found 282.2.

Step b: To a mixture of ethyl 1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazole-4-carboxylate (3.00 g, 10.7 mmol, 1 eq) in THF (100 mL) was added DIBAL-H (1 M in THF, 64.0 mL, 6 eq) at 0° C. The resulting mixture was warmed to 25° C. and stirred for 1 h. The mixture was quenched by addition of sat. aq. NH 4 Cl (10 mL), and the pH was adjusted to 5 with aqueous HCl (4M) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over with anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography to give (1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methanol LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 11 F 2 N 3 O: 240.1; found 240.1.

Step c: To a solution of compound (1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methanol (2.00 g, 8.36 mmol, 1 eq) and 1,3-dimethylthiourea (DMTU, 392 mg, 3.76 mmol, 0.45 eq) in DCM (20 mL) was added NBS (2.23 g, 12.5 mmol, 1.5 eq) at 0° C. The resulting mixture was warmed to 25° C. and stirred for 2 h. The mixture was quenched with H 2 O (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (80 mL), dried over with anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 1-benzyl-4-(bromomethyl)-5-(difluoromethyl)-1H-1,2,3-triazole. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 10 BrN 3 : 301.9; found 301.9.

Step d: To a solution of compound 1-benzyl-4-(bromomethyl)-5-(difluoromethyl)-1H-1,2,3-triazole (800 mg, 2.65 mmol, 1 eq) and TMSCN (276 mg, 2.78 mmol, 1.05 eq) in MeCN (20 mL) was added TBAF (1 M, 3.97 mL, 1.5 eq) at 0° C. The resulting mixture was warmed to 25° C. and stirred for 30 min. The mixture was quenched by addition of sat. aq. NaHCO 3 (30 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (20 mL), dried over with anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 2-(1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)acetonitrile. LC-MS (ESI): m/z: [M+H] + calculated for C 12 H 10 F 2 N 4 : 249.0; found 249.0.

›SYNTHETIC EXAMPLES · 14 of 20

Step e: A mixture of 2-(1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)acetonitrile (880 mg, 3.55 mmol, 1 eq) in concentrated HCl (20 mL) was stirred at 80° C. for 2 h. After cooling, the mixture was concentrated under reduced pressure. The resulting residue was washed with THF (40 mL) and filtered. The filtrate was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give 2-(1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 12 H 11 F 2 N 3 O 2 : 268.0; found 268.0.

Step f: To a solution of 2-(1-benzyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)acetic acid (300 mg, 1.12 mmol, 1 eq) and concentrated HCl (11.4 mg, 112 μmol, 0.1 eq) in i-PrOH (10 mL) was added Pd/C (100 mg, 10% purity) under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (50 psi) at 25° C. for 16 h. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to give 2-(4-(difluoromethyl)-1H-1,2,3-triazol-5-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 5 H 5 F 2 N 3 O 2 : 178.0; found 178.0.

Intermediate A-29: Synthesis of 2-(5-(trifluoromethyl)-1H-tetrazol-1-yl)acetic acid

Step a: To a solution of ethyl glycinate hydrochloride (10 g, 71.6 mmol, 1 eq) in DCM (100 mL) at 0° C. was added trifluoroacetic anhydride (22.5 g, 107 mmol, 14.9 mL, 1.5 eq) and TEA (36.2 g, 358 mmol, 5 eq). The mixture was then warmed to 20° C. and stirred for 3 h. The reaction mixture was then poured into H 2 O (100 mL), and the resulting biphasic mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over with anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl (2,2,2-trifluoroacetyl)glycinate. LC-MS (ESI): m/z: [M+H] + calculated for C 6 H 8 F 3 NO 3 : 200.0; found 200.0.

Step b: To a solution of ethyl (2,2,2-trifluoroacetyl)glycinate (11 g, 55.2 mmol, 1 eq) in toluene (200 mL) at 20° C. was added Lawesson's reagent (26.8 g, 66.2 mmol, 1.2 eq). The reaction mixture was then warmed to 110° C. and stirred for 1 h. After cooling to 20° C., the reaction mixture was poured into H 2 O (100 mL), and the resulting biphasic mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over with anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl (2,2,2-trifluoroethanethioyl)glycinate. LC-MS (ESI): m/z: [M+H] + calculated for C 6 H 8 F 3 NO 2 S: 216.0; found 215.9.

Step c: To a mixture of ethyl (2,2,2-trifluoroethanethioyl)glycinate (2 g, 9.29 mmol, 1 eq) and TMSN 3 (2.14 g, 18.5 mmol, 2.44 mL, 2 eq) in DCM (40 mL) at 0° C. under a N 2 atmosphere was added SnCl 4 (6.05 g, 23.2 mmol, 2.71 mL, 2.5 eq). The reaction mixture was then warmed to 20° C. and stirred for 16 h. The reaction mixture was then cooled to 0° C. and quenched by slow addition of saturated aq. NaHCO 3 (200 mL). The resulting biphasic mixture was extracted with EtOAc (2×200 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 2-(5-(trifluoromethyl)-1H-tetrazol-1-yl)acetate. LC-MS (ESI): m/z: [M+H] + calculated for C 6 H 7 F 3 N 4 O 2 : 225.0; found 225.0.

Step d: To a solution of ethyl 2-(5-(trifluoromethyl)-1H-tetrazol-1-yl)acetate (500 mg, 2.23 mmol, 1 eq) in MeOH (10 mL) and H 2 O (1 mL) at 20° C. was added LiOH·H 2 O (187 mg, 4.46 mmol, 2 eq). The resulting mixture was stirred at 20° C. for 16 h. The reaction mixture was then adjusted to pH 3-4 with aqueous HCl (1M) and stirred for 5 min. The resulting mixture was then filtered and concentrated under reduced pressure to give 2-(5-(trifluoromethyl)-1H-tetrazol-1-yl)acetic acid which was used without further purification. LC-MS (ESI): m/z: [M+H] + calculated for C 4 H 3 F 3 N 4 O 2 : 197.0; found 196.9.

Intermediate A-30: Synthesis of 2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)acetic acid

Step a: A mixture of ethyl 4,4,4-trifluoro-3-oxobutanoate (1.00 g, 5.43 mmol, 1 eq) and ethyl 2-azidoacetate (701 mg, 5.43 mmol, 1 eq) in toluene (10 mL) was warmed to 120° C. and stirred for 16 h. After cooling, the reaction mixture was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 1-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate. LC-MS (ESI): m/z: [M+H] + calculated for C 10 H 12 F 3 N 3 O 4 : 296.1; found 296.1.

Step b: A mixture of ethyl 1-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate (300 mg, 1.02 mmol, 1 eq) and NaOH (203 mg, 5.08 mmol, 5 eq) in H 2 O (1 mL) and MeOH (10 mL) was stirred at 20° C. for 2 h. The reaction mixture was then acidified to pH=2 with concentrated aq. HCl (12 N). The reaction mixture was concentrated under reduced pressure to give 1-(carboxymethyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 6 H 4 F 3 N 3 O 4 : 240.0; found 240.1.

Step c: A mixture of 1-(carboxymethyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylic acid (250 mg, 1.05 mmol, 1 eq) and Ag 2 CO 3 (28.8 mg, 104 μmol, 0.1 eq) in DMSO (1 mL) and AcOH (6.28 mg, 104 μmol, 0.1 eq) was warmed to 120° C. and stirred for 16 h. After cooling, the reaction mixture was acidified to pH=2 with concentrated aq. HCl (12 N). The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 5 H 4 F 3 N 3 O 2 : 196.0; found 196.1.

Intermediate A-31: Synthesis of (benzyl(trifluoromethyl)carbamoyl)glycine

Step a. To a solution of AgF (1.02 g, 8.04 mmol, 6 eq) in CH 3 CN (10 mL) at 0° C. under an atmosphere of N 2 was added (isothiocyanatomethyl)benzene (0.2 g, 1.34 mmol, 177 μL, 1 eq) in a dropwise manner. Triphosgene (199 mg, 670 μmol, 0.5 eq) was then added. The resulting reaction mixture was warmed to 25° C. and stirred for 16 h. The reaction mixture was then added to MTBE (20 mL) and stirred for 10 min. The precipitate generated was filtered to give benzyl (trifluoromethyl)carbamic fluoride, which was carried forward to the next step without further purification or characterization.

›SYNTHETIC EXAMPLES · 15 of 20

Step b. To as solution of benzyl (trifluoromethyl)carbamic fluoride (0.3 g, 1.36 mmol, 1 eq) in DCM (5 mL) was added benzyl glycinate (448 mg, 2.71 mmol, 2 eq), DIPEA (526 mg, 4.07 mmol, 3 eq), and DMAP (16 mg, 136 μmol, 0.1 eq). The resulting reaction mixture was stirred at 20° C. for 16 h. The reaction was then quenched with water (20 mL), and the resulting biphasic mixture was extracted with DCM (3×20 mL). The combined organic extracts were washed with brine (2×10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give benzyl (benzyl(trifluoromethyl)carbamoyl)glycinate. LC-MS (ESI): m/z: [M+H] + calculated for C 18 H 17 F 3 N 2 O 3 : 367.1; found 367.1.

Step c. To a solution of benzyl (benzyl(trifluoromethyl)carbamoyl)glycinate (150 mg, 409 μmol, 1 eq) in MeOH (3 mL) was added Pd/C (50 mg, 40.9 μmol, 10% purity, 0.1 eq). The resulting mixture was stirred at 25° C. for 16 h under H 2 (15 psi). The reaction mixture was then filtered and concentrated under reduced pressure to give (benzyl(trifluoromethyl)carbamoyl)glycine. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 11 F 3 N 2 O 3 : 277.1; found 277.1.

Intermediate A-32: Synthesis of 2-(5-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid

Step a: To a solution of ethyl aminoglycinate hydrochloride (3 g, 19.4 mmol, 1 eq) in EtOH (30 mL) was added NaOH (776 mg, 19.4 mmol, 1 eq) and ethyl (Z)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (5.13 g, 21.4 mmol, 254 μL, 1.1 eq). The reaction was then stirred at 25° C. for 2 h. The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give ethyl 1-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 13 F 3 N 2 O 4 : 295.1; found 295.2.

Step b: A mixture of ethyl 1-(2-ethoxy-2-oxoethyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (3.5 g, 11.9 mmol, 1 eq) and LiOH·H 2 O (3.49 g, 83.2 mmol, 7 eq) in THF (20 mL) and H 2 O (20 mL) at 25° C. was stirred for 12 h. The reaction mixture was then extracted with EtOAc (50 mL). The combined organic extracts were washed with water (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 1-(carboxymethyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 7 H 5 F 3 N 2 O 4 : 239.0; found 239.1.

Step c: A mixture of 1-(carboxymethyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (400 mg, 1.68 mmol, 1 eq), Cu 2 O (24.0 mg, 168 μmol, 17.2 μL, 0.1 eq) and 1,10-phenantholine (30.3 mg, 168 μmol, 0.1 eq) in NMP (3 mL) were warmed to 150° C. and stirred for 3 h. The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2-(5-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 6 H 5 F 3 N 2 O 2 : 195.0; found 195.0.

Intermediate A-33: Synthesis of (Z)-2-((3-((2-(trimethylsilyl)ethoxy)methyl)oxazol-2(3H)-ylidene)amino)acetic acid

Step a: To a mixture of oxazol-2-amine (640 mg, 7.61 mmol, 1 eq) and NaHCO 3 (639 mg, 7.61 mmol, 296 μL, 1 eq) in MeCN (20 mL) at 0° C. under N 2 was added SEMCl (1.27 g, 7.61 mmol, 1.35 mL, 1 eq). The resulting mixture was warmed to 25° C. and stirred for 16 h. The reaction mixture was then quenched with H 2 O (10 mL), and resulting biphasic mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (20 mL), dried over with anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 3-((2-(trimethylsilyl)ethoxy)methyl)oxazol-2(3H)-imine, which was carried forward to the next step without further purification or characterization.

Step b: A mixture of 3-((2-(trimethylsilyl) ethoxy) methyl) oxazol-2(3H)-imine (1.4 g, 6.53 mmol, 1 eq), K 2 CO 3 (1.81 g, 13 mmol, 2 eq) and ethyl 2-bromoacetate (1.64 g, 9.80 mmol, 1.08 mL, 1.5 eq) in MeCN (50 mL) was warmed to 70° C. and stirred for 3 h. After cooling, the reaction was quenched with H 2 O (20 mL), and the resulting biphasic mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crud residue obtained was purified by column chromatography to give ethyl (Z)-2-((3-((2-(trimethylsilyl)ethoxy)methyl)oxazol-2(3H)-ylidene)amino)acetate, which was carried forward to the next step without further characterization.

Step 3: A mixture of ethyl (Z)-2-((3-((2-(trimethylsilyl)ethoxy)methyl)oxazol-2(3H)-ylidene)amino)acetate (500 mg, 1.66 mmol, 1 eq) and LiOH·H 2 O (210 mg, 4.99 mmol, 3 eq) in MeOH (8 mL) and H 2 O (1 mL) was stirred at 40° C. for 1 h. After cooling, the reaction was diluted with H 2 O (10 mL). The pH of the resulting solution was adjusted to pH=5 using aqueous HCl (4M). The resulting mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (10 mL), dried over with anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give (Z)-2-((3-((2-(trimethylsilyl)ethoxy)methyl)oxazol-2(3H)-ylidene)amino)acetic acid. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 20 N 2 O 4 Si: 273.1; found 273.1.

Intermediate A-34: Synthesis of 3-(difluoromethyl)-4-isopropylbenzaldehyde

Step a: To a solution of methyl 4-bromo-3-formylbenzoate (4.50 g, 18.5 mmol, 1 eq) in DCM (45 mL) at 0° C. was added 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-λ 4 -sulfanamine (BAST, 10.5 mL, 48.1 mmol, 2.6 eq). The mixture was warmed to 25° C. and stirred for 40 min. The mixture was then poured into ice-water (50 mL) and stirred for 5 min. Saturated aqueous NaHCO 3 was then added to adjust the pH to 8. The resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (3×30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 4-bromo-3-(difluoromethyl)benzoate. LC-MS (ESD): m/z: [M+H] + calculated for C 9 H 7 BrF 2 O 2 : 265.0; found 264.9.

›SYNTHETIC EXAMPLES · 16 of 20

Step b: To a mixture of methyl 4-bromo-3-(difluoromethyl)benzoate (4.30 g, 16.2 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.27 g, 19.5 mmol, 1.20 eq), and Cs 2 CO 3 (10.6 g, 32.5 mmol, 2.00 eq) in dioxane (43 mL) and H 2 O (4 mL) at 25° C. under N 2 was added Pd(dppf)Cl 2 CH 2 Cl 2 (1.32 g, 1.62 mmol, 0.10 eq). The resulting mixture was then degassed and then charged with N 2 . The mixture was then warmed to 110° C. and stirred for 30 min. After cooling to room temperature, the mixture was poured into water (20 mL) and stirred for 5 min. The resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduce pressure. The crude residue obtained was purified by column chromatography to give methyl 3-(difluoromethyl)-4-(prop-1-en-2-yl)benzoate. LC-MS (ESD): m/z: [M+H] + calculated for C 12 H 12 F 2 O 2 : 227.1; found 227.1.

Step c: To a solution of methyl 3-(difluoromethyl)-4-(prop-1-en-2-yl)benzoate (2.40 g, 10.6 mmol, 1.00 eq) in MeOH (30 mL) at 25° C. was added Pd/C (1.12 g, 1.06 mmol, 10% purity, 0.1 eq) under N 2 . The suspension was then degassed under vacuum and purged with H 2 . The reaction mixture was then stirred under H 2 (15 psi) at 25° C. for 1 h. The reaction mixture was then filtered and concentrated under reduced pressure to give methyl 3-(difluoromethyl)-4-isopropylbenzoate. LC-MS (ESD): m/z: [M+H] + calculated for C 12 H 14 F 2 O 2 : 229.1; found 229.1.

Step d: To a solution of methyl 3-(difluoromethyl)-4-isopropylbenzoate (2.35 g, 10.3 mmol, 1 eq) in THF (30 mL) at −70° C. under N 2 was added DIBAL-H (1 M in THF, 20.6 mL, 2.00 eq) dropwise. The reaction mixture was then stirred at −70° C. for 2 h under N 2 . The reaction mixture was the warmed to 0° C. and quenched by addition of water (20 mL). The resulting biphasic mixture was then filtered and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine (2×20 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give (3-(difluoromethyl)-4-isopropylphenyl)methanol. LC-MS (ESI): m/z: [M-OH] + calculated for C 11 H 14 F 2 O: 183.1; found 183.1.

Step e: To a mixture of (3-(difluoromethyl)-4-isopropylphenyl)methanol (1.80 g, 8.99 mmol, 1.00 eq) and silica gel (2.91 g) in DCM (20 mL) at 25° C. under N 2 was added PCC (2.91 g, 13.48 mmol, 1.50 eq). The resulting mixture was stirred at 25° C. for 30 min. The reaction mixture was then filtered and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-(difluoromethyl)-4-isopropylbenzaldehyde. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 12 F 2 O: 199.1; found 199.1.

Intermediate A-35: Synthesis of 4-isopropyl-3-methylbenzaldehyde

Step a: To a mixture of 4-bromo-3-methylbenzaldehyde (5 g, 25.1 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (8.44 g, 50.2 mmol, 2 eq), and K 2 CO 3 (10.4 g, 75.4 mmol, 3 eq) in dioxane (60 mL) and H 2 O (6 mL) was added Pd(dppf)Cl 2 (551 mg, 754 μmol, 0.03 eq). The resulting mixture was degassed and purged with N 2 , and then the mixture was warmed to 80° C. and stirred for 16 h under N 2 atmosphere. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-methyl-4-(prop-1-en-2-yl)benzaldehyde (4 g, crude). LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 12 O: 161.1; found 161.1.

Step b: To a solution of 3-methyl-4-(prop-1-en-2-yl)benzaldehyde (4 g, 25.0 mmol, 1 eq) in EtOAc (40 mL) and MeOH (20 mL) was added Rh(PPh 3 )Cl (1.15 g, 1.25 mmol, 0.05 eq) under argon. The resulting suspension was then degassed under vacuum and placed under an H 2 atmosphere. The resulting mixture was then stirred under H 2 (15 psi) at 25° C. for 16 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to give 4-isopropyl-3-methylbenzaldehyde. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 14 O: 163.1; found 163.1.

Intermediate A-36: Synthesis of 4-fluoro-2-iodo-5-isopropylpyridine

Step a: To a mixture of 5-bromo-4-fluoropyridin-2-amine (3 g, 15.7 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.96 g, 23.5 mmol, 1.5 eq), and K 2 CO 3 (6.51 g, 47.1 mmol, 3 eq) in H 2 O (3 mL) and dioxane (30 mL) was added Pd(dppf)Cl 2 (460 mg, 629 μmol, 0.04). The resulting mixture was degassed and purged with N 2 , and then the mixture was warmed to 90° C. and stirred for 16 h under N 2 atmosphere. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-fluoro-5-(prop-1-en-2-yl)pyridin-2-amine. LC-MS (ESI): m/z: [M+H] + calculated for C 8 H 9 FN 2 : 153; found 153.2.

Step b: To a solution of 4-fluoro-5-(prop-1-en-2-yl)pyridin-2-amine (2.2 g, 14.4 mmol, 1 eq) in EtOAc (50 mL) was added Pd/C (1 g, 10% purity) under N 2 . The suspension was then degassed under vacuum and placed under an H 2 atmosphere. The resulting mixture was then stirred under H 2 (20 psi) at 20° C. for 16 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to give 4-fluoro-5-isopropylpyridin-2-amine. LC-MS (ESI): m/z: [M+H] + calculated for C 8 H 11 FN 2 : 155.1; found 155.0.

Step c: To a mixture of 4-fluoro-5-isopropylpyridin-2-amine (2 g, 12.9 mmol, 1 eq) and KI (21.5 g, 129 mmol, 10 eq) in diiodomethane (69.4 g, 259 mmol, 20.9 mL, 20 eq) was added t-BuONO (6.69 g, 64.8 mmol, 5 eq). The resulting mixture was degassed and purged with N 2 , and then the mixture was stirred for 16 h under N 2 atmosphere at 20° C. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography to give 4-fluoro-2-iodo-5-isopropylpyridine. LC-MS (ESI): m/z: [M+H] + calculated for C 8 H 9 FIN: 266.0; found 265.9.

›SYNTHETIC EXAMPLES · 17 of 20

Intermediate A-37: 3-chloro-4-cyclopropylbenzaldehyde

Step a: To a mixture of cyclopropylboronic acid (2.30 g, 26.7 mmol, 1.30 eq), 4-bromo-3-chlorobenzaldehyde (4.5 g, 20.5 mmol, 1.00 eq), and K 3 PO 4 (10.0 g, 47.1 mmol, 2.30 eq) in dioxane (40.0 mL) and H 2 O (4.00 mL) was added Pd(dppf)Cl 2 (750 mg, 1.02 mmol, 0.05 eq). The resulting mixture was degassed and purged with N 2 , and then the mixture was warmed to 90° C. and stirred for 16 h under N 2 atmosphere. The reaction mixture was then dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-chloro-4-cyclopropylbenzaldehyde. LC-MS (ESI): m/z: [M+H] + calculated for C 10 H 9 ClO: 181.0; found 181.1.

Intermediate A-38: 4-cyclopropyl-3,5-difluorobenzaldehyde

Step a: To a solution of 4-bromo-3,5-difluorobenzoic acid (2.7 g, 11.4 mmol, 1 eq), Et 3 N (3.46 g, 34.2 mmol, 4.76 mL, 3 eq) and N,O-dimethylhydroxylammonium chloride (1.33 g, 13.7 mmol, 1.2 eq) in DMF (25 mL) at 0° C. was added HATU (4.55 g, 11.9 mmol, 1.05 eq). The resulting mixture was stirred at 0° C. for 1 h. The reaction was then quenched by addition of H 2 O (80 mL) at 0° C., and the resulting biphasic mixture was then extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (80 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-bromo-3,5-difluoro-N-methoxy-N-methylbenzamide. This compound was carried forward to the next step without further characterization.

Step b: To a mixture of 4-bromo-3,5-difluoro-N-methoxy-N-methylbenzamide (3.15 g, 11.3 mmol, 1 eq), cyclopropylboronic acid (1.45 g, 16.8 mmol, 1.5 eq), K 3 PO 4 (7.16 g, 33.7 mmol, 3 eq), and PCy 3 (315 mg, 1.12 mmol, 0.1 eq) in toluene (60 mL) and H 2 O (6 mL) was added Pd(OAc) 2 (253 mg, 1.12 mmol, 0.1 eq). The resulting mixture was degassed and purged with N 2 , and the resulting mixture was warmed to 90° C. and stirred for 12 h under N 2 atmosphere. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-cyclopropyl-3,5-difluoro-N-methoxy-N-methylbenzamide. This compound was carried forward to the next step without further characterization.

Step c: To a solution of 4-cyclopropyl-3,5-difluoro-N-methoxy-N-methylbenzamide (2.50 g, 10.4 mmol, 1 eq) in THF (20 mL) at −5° C. under N 2 was added DIBAL-H (1 M in THF, 13.47 mL, 1.3 eq). The resulting mixture was then warmed to 0° C. and stirred for 3 h. The reaction mixture was then poured into ice-water (20 mL), adjusted to pH=7 with aq. HCl (4M), and extracted with Et 2 O (3×20 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-cyclopropyl-3,5-difluorobenzaldehyde.

Intermediate A-39: 2-cyclopropyl-1-fluoro-5-iodo-3-methylbenzene

Step a: To a solution of 3-fluoro-5-methylaniline (15.0 g, 120 mmol, 1.00 eq) in DMF (100 mL) at 0° C. was added NBS (21.5 g, 121 mmol, 1.01 eq). The resulting mixture was stirred at 0° C. for 0.5 h. The reaction mixture was then warmed to 25° C. and stirred for 1 h. The reaction mixture was then diluted with water (100 ML) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated aqueous NaHCO 3 , dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-bromo-3-fluoro-5-methylaniline. LC-MS (ESI): m/z: [M+H] + calculated for C 7 H 7 BrFN: 204.0; found 204.0.

Step b: To a solution of 4-bromo-3-fluoro-5-methylaniline (8.0 g, 39.2 mmol, 1.00 eq), tricyclohexylphosphine (2.20 g, 7.84 mmol, 0.20 eq), cyclopropylboronic acid (4.04 g, 47.0 mmol, 1.20 eq), and K 3 PO 4 (25.0 g, 118 mmol, 3.00 eq) in toluene (160 mL) and H 2 O (32 mL) was added Pd(OAc) 2 (880 mg, 3.92 mmol, 0.10 eq). The resulting mixture was degassed and purged with N 2 . The reaction mixture was then warmed to 100° C. and stirred for 16 h under N 2 . After cooling to the room temperature, the reaction mixture was extracted with ethyl acetate (3×80 mL). The combined organic extracts were washed with saturated aqueous NaHCO 3 , dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-cyclopropyl-3-fluoro-5-methylaniline. LC-MS (ESI): m/z: [M+H] + calculated for C 10 H 12 FN: 166.1; found 166.1.

Step c: To a solution of 4-cyclopropyl-3-fluoro-5-methylaniline (4.00 g, 24.21 mmol, 1 eq) in MeCN (40 mL) was added a solution of H 2 SO 4 (18 M, 3.36 mL, 98% purity, 2.50 eq) in H 2 O (40 mL). After stirring 10 min, the reaction mixture was cooled to 0° C., and a solution of NaNO 2 (3.34 g, 48.4 mmol, 2.00 eq) in H 2 O (40 mL) was added over 20 min. A solution of KI (16.1 g, 96.8 mmol, 4.00 eq) in H 2 O (40 mL) was then added to the reaction mixture at 0° C. The reaction mixture was then warmed to 25° C. and stirred under N 2 atmosphere or 0.5 h. The reaction mixture was then extracted with ethyl acetate (3×600 mL). The combined organic extracts were washed with saturated aqueous NaHCO 3 , dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-cyclopropyl-1-fluoro-5-iodo-3-methylbenzene.

Intermediate A-40: 3-fluoro-4-(1-methylcyclopropyl)benzaldehyde

Step a: To a solution of methyltriphenylphosphonium iodide (14.0 g, 34.6 mmol, 1.5 eq) in THF (50.0 mL) was added t-BuOK (3.88 g, 34.6 mmol, 1.5 eq). The resulting mixture was stirred at 25° C. for 30 min. To this mixture was added a solution of 1-(4-bromo-2-fluorophenyl)ethan-1-one (5.00 g, 23.0 mmol, 1 eq) in THF (5.00 mL) at 25° C. The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then cooled to 0° C. and quenched by addition H 2 O (100 mL), and the resulting biphasic mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-bromo-2-fluoro-1-(prop-1-en-2-yl)benzene, which was carried forward to the next step without further characterization.

›SYNTHETIC EXAMPLES · 18 of 20

Step b: To a solution of ZnEt 2 (1 M in hexane, 18.6 mL, 4 eq) in DCM (5.00 mL) at 0° C. under N 2 atmosphere was added TFA (2.12 g, 18.6 mmol, 1.38 mL, 4 eq). The resulting mixture was stirred at 0° C. for 30 min before CH 2 I 2 (4.98 g, 18.6 mmol, 1.50 mL, 4 eq) in DCM (5.00 mL) was added dropwise at 0° C. The resulting mixture was stirred at 0° C. for 30 min before 4-bromo-2-fluoro-1-(prop-1-en-2-yl)benzene (1.00 g, 4.65 mmol, 1 eq) in DCM (5.00 mL) was added dropwise at 0° C. The resulting mixture was then warmed to 25° C. and stirred for 16 h. The reaction mixture was then cooled to 0° C. and quenched by addition of aq. HCl (1N, 50 mL). The resulting biphasic mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (2×50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-bromo-2-fluoro-1-(1-methylcyclopropyl)benzene, which was carried forward to the next step without further characterization.

Step c: To a solution of 4-bromo-2-fluoro-1-(1-methylcyclopropyl)benzene (5 g, 21.8 mmol, 1 eq) in THF (80 mL) at −60° C. under N 2 atmosphere was added n-BuLi (2.5 M in hexane, 8.72 mL, 1 eq). After 30 min, DMF (4.79 g, 65.4 mmol, 3 eq) was added dropwise at −60° C. The resulting mixture was allowed to warm to 25° C. and stirred for 2 h. The reaction mixture was then cooled to 0° C. and quenched by addition saturated aqueous NH 4 Cl (150 mL). The resulting biphasic mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 3-fluoro-4-(1-methylcyclopropyl)benzaldehyde. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 11 FO: 179.1; found 179.1.

Intermediate A-41: 6-fluoro-5-(1-methylcyclopropyl)picolinaldehyde

Step a: To a solution of 2-bromo-6-fluoropyridine (12.5 g, 71.0 mmol, 1.00 eq) in THF (125 mL) at −65° C. under N 2 atmosphere was added LDA (2 M in THF, 35.5 mL, 1.00 eq) in a dropwise manner. The reaction mixture was stirred at −65° C. for 0.5 h before acetone (6.19 g, 106 mmol, 1.50 eq) was added in a dropwise manner at −65° C. The reaction mixture was then stirred at −65° C. for 0.5 h before it was warmed to 0° C., quenched by addition of H 2 O (60 mL), and stirred for 5 min. The resulting biphasic mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-(6-bromo-2-fluoropyridin-3-yl)propan-2-ol. LC-MS (ESD): m/z: [M+H] + calculated for C 8 H 9 BrFNO: 234.0; found 234.0.

Step b: To a solution of 2-(6-bromo-2-fluoropyridin-3-yl)propan-2-ol (13.5 g, 57.7 mmol, 1.00 eq) in toluene (135 mL) was added TsOH (1.99 g, 11.5 mmol, 0.2 eq). The reaction mixture was then warmed to 125° C. and stirred for 16 h. The reaction mixture was then filtered and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 6-bromo-2-fluoro-3-(prop-1-en-2-yl)pyridine. LC-MS (ESD): m/z: [M+H] + calculated for C 8 H 7 BrFN: 216.0; found 215.9.

Step c: To a solution of 6-bromo-2-fluoro-3-(prop-1-en-2-yl)pyridine (6.50 g, 30.1 mmol, 1.00 eq) in MeOH (65 mL) was added TEA (6.09 g, 60.1 mmol, 2.00 eq) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (2.46 g, 3.01 mmol, 0.10 eq). The reaction mixture was then placed under a CO atmosphere (50 psi), warmed to 60° C., and stirred for 1.5 h. The reaction mixture was then concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 6-fluoro-5-(prop-1-en-2-yl)picolinate. LC-MS (ESI): m/z: [M+H] + calculated for C 10 H 10 FNO 2 : 196.1; found 196.1.

Step d: To a solution of ZnEt 2 (1 M in hexane, 102 mL, 5.00 eq) at 0° C. was added TFA (102 mmol, 7.6 mL, 5.00 eq) in DCM (24 mL) in a dropwise manner. The resulting mixture was stirred at 0° C. for 30 min before CH 2 I 2 (27.4 g, 102 mmol, 5.0 eq) in DCM (22 mL) was added in a dropwise manner. The resulting mixture was stirred at 0° C. for 30 min before methyl 6-fluoro-5-(prop-1-en-2-yl)picolinate (4 g, 20 mmol, 1.0 eq) in DCM (12 mL) was added in a dropwise manner at 0° C. The resulting mixture was then warmed to 25° C. and stirred for 15 h. The reaction mixture was then cooled to 0° C. and quenched by addition of saturated aq. NH 4 Cl (100 ml). The resulting biphasic mixture was then extracted with ethyl acetate (3×500 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give methyl 6-fluoro-5-(1-methylcyclopropyl)picolinate. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 12 FNO 2 : 210.1; found 210.1.

Step e: A solution of methyl 6-fluoro-5-(1-methylcyclopropyl)picolinate (1.25 g, 5.97 mmol, 1 eq) in THF (12.5 mL) was degassed and purged with N 2 . The resulting solution was cooled to −65° C., and then DIBAL-H (1 M in THF, 11.95 mL, 2 eq) was added in a dropwise manner. The resulting mixture was stirred at −65° C. for 2 h. The reaction mixture was then warmed to 0° C. and quenched by addition of water (20 mL). The resulting biphasic mixture was then filtered and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine (2×20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 6-fluoro-5-(1-methylcyclopropyl)picolinaldehyde. LC-MS (ESI): m/z: [M+H] + calculated for C 10 H 10 FNO: 180.1; found 180.1.

Intermediate A-42: 4-(tert-butyl)-3-fluorobenzaldehyde

Step a: To a mixture of 3-fluorophenol (10.0 g, 89.20 mmol, 8.20 mL, 1 eq) and AlCl 3 (4.76 g, 35.7 mmol, 1.95 mL, 0.4 eq) in DCM (150 mL) under N 2 was added 2-chloro-2-methyl-propane (12.4 g, 134 mmol, 14.8 mL, 1.5 eq) in a dropwise manner. The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then quenched with water (50 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (3×50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-(tert-butyl)-3-fluorophenol. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 13 FO: 169.1; found 169.1.

›SYNTHETIC EXAMPLES · 19 of 20

Step b: To a solution of 4-(tert-butyl)-3-fluorophenol (3.80 g, 22.6 mmol, 1 eq) and TEA (6.86 g, 67.8 mmol, 9.43 mL, 3 eq) in DCM (15 mL) at 0° C. was added Tf 2 O (3.19 g, 11.3 mmol, 1.86 mL, 0.5 eq) in a dropwise manner. The resulting mixture was warmed to 25° C. and stirred for 2 h. The reaction was then diluted with H 2 O (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-(tert-butyl)-3-fluorophenyl trifluoromethanesulfonate. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 12 F 4 O 3 S: 301.0; found 301.1.

Step c: To a solution of 4-(tert-butyl)-3-fluorophenyl trifluoromethanesulfonate (2.00 g, 6.66 mmol, 1 eq), Et 3 SiH (1.55 g, 13.3 mmol, 2.13 mL, 2 eq), and Na 2 CO 3 (1.41 g, 13.3 mmol, 2 eq) in DMF (15 mL) under N 2 atmosphere was added Pd(dppf)Cl 2 (487 mg, 666 μmol, 0.1 eq). The resulting mixture was placed under CO atmosphere (50 psi), warmed to 75° C., and stirred for 5 h. The reaction mixture was then diluted with H 2 O (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine (3×10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-(tert-butyl)-3-fluorobenzaldehyde. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 13 FO: 181.1; found 181.1.

Intermediate A-43: 3-fluoro-4-(1-methylcyclobutyl)benzaldehyde

Step a: To a solution of 1-bromo-2-fluoro-4-methoxybenzene (23.0 g, 112 mmol, 1 eq) in THF (200 mL) at −78° C. under N 2 atmosphere was added n-BuLi (2.5 M in hexane, 50 mL, 125.0 mmol, 1.1 eq). The resulting mixture was stirred at −78° C. for 1 h before cyclobutanone (7.86 g, 112 mmol, 8.3 mL, 1 eq) was added in a dropwise manner. The resulting mixture was stirred at −78° C. for 2 h. The reaction was then quenched by addition of saturated aqueous NH 4 Cl (200 mL), and the resulting biphasic mixture was extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with water (50 mL) and brine (3×250 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 1-(2-fluoro-4-methoxyphenyl)cyclobutan-1-ol. This compound was carried forward to the next step without further characterization.

Step b: To a solution of 1-(2-fluoro-4-methoxyphenyl)cyclobutan-1-ol (5 g, 25.4 mmol, 1 eq) in DCM (40 mL) at −78° C. was added titanium tetrachloride (9.6 g, 50.9 mmol, 9.67 mL, 2 eq), and the resulting mixture was stirred at −78° C. for 1 h. A solution of dimethylzinc (1 M in heptane, 76.45 mL, 3 eq) was added at −78° C. in a dropwise manner. The resulting mixture was warmed to 25° C. and stirred for 1 h. The reaction mixture was then poured into ice-water (30 mL), and the resulting biphasic mixture was extracted with DCM (50 mL). The organic extracts were then washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-fluoro-4-methoxy-1-(1-methylcyclobutyl)benzene. This compound was carried forward to the next step without further characterization.

Step c: To a solution of 2-fluoro-4-methoxy-1-(1-methylcyclobutyl)benzene (1.5 g, 7.7 mmol, 1 eq) in DCM (2 mL) at −78° C. was added BBr 3 (1 M, 23.17 mL, 3 eq). The resulting mixture was stirred at −78° C. for 0.5 h. The reaction mixture was then warmed to 25° C. and stirred for 1 h. The reaction mixture was then quenched by addition of H 2 O (100 mL), and the resulting biphasic mixture was extracted with DCM (2×50 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-fluoro-4-(1-methylcyclobutyl)phenol. This compound was carried forward to the next step without further characterization.

Step d: To a solution of 3-fluoro-4-(1-methylcyclobutyl)phenol (1.3 g, 7.2 mmol, 1 eq) and TEA (1.4 g, 14.4 mmol, 2.01 mL, 2 eq) in DCM (15 mL) at 0° C. was added Tf 2 O (2.44 g, 8.66 mmol, 1.43 mL, 1.2 eq). The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was then warmed to 20° C. and stirred for 1 h. The reaction mixture was then diluted with DCM (22 ml) and washed with H 2 O (20 mL). The organic solution was then dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-fluoro-4-(1-methylcyclobutyl)phenyl trifluoromethanesulfonate. This compound was carried forward to the next step without further characterization.

Step e: To a solution of 3-fluoro-4-(1-methylcyclobutyl)phenyl trifluoromethanesulfonate (2.2 g, 7.0 mmol, 1 eq), Na 2 CO 3 (1.49 g, 14.09 mmol, 2 eq), and TESH (1.64 g, 14.1 mmol, 2.25 mL, 2 eq) in DMF (40 mL) was added Pd(dppf)Cl 2 (515 mg, 704 μmol, 0.1 eq). The resulting mixture was then placed under CO atmosphere (50 psi), warmed to 70° C., and stirred for 4 h. The reaction mixture was then cooled to 20° C. and diluted with ethyl acetate (50 mL). The organic solution was then washed with H 2 O (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-fluoro-4-(1-methylcyclobutyl)benzaldehyde.

Intermediate A-44: 4-cyclobutyl-3-fluorobenzaldehyde

Step a: To a solution of 4-bromo-3-fluorobenzaldehyde (5 g, 24.63 mmol, 1 eq) and 4-methylbenzenesulfonic acid (848 mg, 4.93 mmol, 0.2 eq) in MeOH (50 mL) was added trimethyl orthoformate (5.23 g, 49.3 mmol, 5.40 mL, 2 eq). The resulting mixture was warmed to 70° C. and stirred for 1 h. The reaction mixture was then poured into ice-water (150 mL) and stirred for 3 min. The resulting biphasic mixture was extracted with ethyl acetate (3×80 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 1-bromo-4-(dimethoxymethyl)-2-fluorobenzene. LC-MS (ESI): m/z: [M-OMe] + calculated for C 9 H 10 BrFO 2 : 217.0; found 217.0.

›SYNTHETIC EXAMPLES · 20 of 20

Step b: To a solution of 1-bromo-4-(dimethoxymethyl)-2-fluorobenzene (1.4 g, 5.62 mmol, 1 eq), cyclobutylboronic acid (5.62 g, 56.2 mmol, 10 eq), and K 2 CO 3 (1.55 g, 11.2 mmol, 2 eq) in toluene (12 mL) and H 2 O (3 mL) under N 2 was added Pd(dppf)Cl 2 ° C. H 2 Cl 2 (918 mg, 1.12 mmol, 0.2 eq). The resulting mixture was warmed to 100° C. and stirred for 1 h. The reaction mixture was then poured into ice-water and stirred for 3 min. The resulting biphasic mixture was extracted with ethyl acetate (3×80 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 1-cyclobutyl-4-(dimethoxymethyl)-2-fluorobenzene, which was carried forward to the next step without further characterization.

Step c: To a solution of 1-cyclobutyl-4-(dimethoxymethyl)-2-fluorobenzene (1 g, 4.46 mmol, 1 eq) in THF (5 mL) at 15° C. was added aq. HCl (1 M, 10.00 mL, 2.24 eq). The resulting mixture was stirred at 15° C. for 1 h. The mixture was poured into ice-water (30 mL) and stirred for 2 min. The resulting biphasic mixture was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 4-cyclobutyl-3-fluorobenzaldehyde, which was used without further purification. LC-MS (ESI): m/z: [M+H] + calculated for C 11 H 11 FO: 179.1; found 179.1.

Intermediate A-45: 4-(sec-butyl)-3-fluorobenzaldehyde

Step a: To a mixture of 4-bromo-3-fluorobenzaldehyde (5.00 g, 24.6 mmol, 1 eq), KOAc (6.04 g, 61.6 mmol, 2.5 eq), and bis(pinacolato)diboron (7.51 g, 29.6 mmol, 1.2 eq) in dioxane (50 mL) was added Pd(dppf)Cl 2 (1.80 g, 2.46 mmol, 0.1 eq). The resulting mixture was degassed and purged with N 2 . The reaction mixture was then warmed to 100° C. and stirred for 3 h. The reaction mixture was then filtered, and the filter cake was washed with 10:1 EtOAc/MeOH (3×200 mL). The combined filtrate and washes were concentrated under reduced pressure. The crude residue obtained was poured into H 2 O (100 mL), adjusted to pH=10 with sat. aqueous Na 2 CO 3 , and extracted with ethyl acetate (3×100 mL). The organic extracts were discarded. The aqueous phase was then adjusted to pH=4 with aq. HCl (4M) and extracted with EtOAc (3×100 ML). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde, which was carried forward to the next step without further characterization.

Step b: To a mixture of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (3.00 g, 12.0 mmol, 1 eq), 2-bromobut-1-ene (1.62 g, 12.0 mmol, 1 eq), and K 2 CO 3 (3.32 g, 24.0 mmol, 2 eq) in dioxane (60 mL) and H 2 O (6 mL) was added Pd(dppf)Cl 2 (439 mg, 600 μmol, 0.05 eq). The reaction was degassed and purged with N 2 . The resulting mixture was then warmed to 90° C. and stirred for 16 h. The reaction mixture was then cooled, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 4-(but-1-en-2-yl)-3-fluorobenzaldehyde, which was carried forward to the next step without further characterization.

Step c: To a solution of 4-(but

›Tables in the description — 15

° C.	degrees Celsius
μL	microliter
[M + XX] +	observed mass
AC 50	half-maximal activity concentration
ACN	acetonitrile
app	apparent (NMR)
BH 3 •THF	borane-tetrahydrofuran complex
BBr 3	boron tribromide
Calc'd	calculated
Cbz-Cl	benzyl chloroformate
CO 2	carbon dioxide
Cs 2 CO 3	cesium carbonate
d	deuterated (NMR solvents)
d	doublet (NMR)
dd	doublet of doublets (NMR)
DCM	dichloromethane
DIAD	diisopropyl azodicarboxylate
DMF	N,N-dimethylformamide
EC 50	half-maximal effective concentration
EDCI	1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
ESI	electrospray ionization
EtOAc	ethyl acetate
EtOH	ethanol
eq	equivalents
g	grams
h	hours
H	hydrogen
HCl	hydrochloric acid
HPLC	high-performance liquid chromatography
IC 50	half-maximal inhibitory concentration
In vacuo	in a vacuum
IUPAC	International Union of Pure and Applied
	Chemistry
MHz	megahertz
J	J-coupling value (NMR)
K 2 CO 3	potassium carbonate
LDA	lithium diisopropylamide
LiHMDS	lithium bis(trimethylsilyl)amide
MeOH	Methanol
MeCN	acetonitrile
m	multiplet (NMR)
mg	milligrams
min	minutes
mL	milliliter
mmol	millimole
mM	millimolar
M	molarity or molar
MS	mass spectrometry
MsCl	methanesulfonyl chloride
MTBE	methyl tert-butyl ether
n/a	not applicable
NBS	N-bromosuccinimide
NH 4	ammonium
NH 4 OH	ammonium hydroxide
NH 4 HCO 3	ammonium bicarbonate
Na 2 SO 4	sodium sulfate
NaBH 3 CN	sodium cyanoborohydride
NMI	N-methylimidazole
NMM	N-methylmorpholine
NMR	nuclear magnetic resonance
NaOH	sodium hydroxide
PCy 3	Tricyclohexylphosphine
PdCl 2 (dppf)	[1,1′-
	Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
pH	potential of hydrogen
PPh 3	triphenyl phosphine
s	singlet (NMR)
SFC	super fluid chromatography
t	triplet (NMR)
T3P	Propanephosphonic acid anhydride
TBAB	tetrabutylammonium bromide
TEA	triethylamine
TFA	trifluoroacetic acid
TFCH	N,N,N′,N′-tetramethylchloroformamidinium
	hexafluorophosphate
THF	tetrahydrofuran
TMSCl	trimethylsilyl chloride
wt. %	weight percent

TABLE B-1 Exact

Intermediate			mass
No.	Structure	IUPAC	(g/mol)	LCMS, Found [M + H] +
B-1-1
2-((4-(tert- butoxycarbonyl)piper- azine-1- carbonyl)oxy)acetic acid	288.1	189.1 [M − Boc + H] +

TABLE B-2 Exact

Intermediate			mass
No.	Structure	IUPAC	(g/mol)	LCMS, Found [M + H] +
B-2-1
2-(1-benzyl-4- morpholino-1H- 1,2,3-triazol-5- yl)acetic acid	302.1	303.2

TABLE B-3 Exact

Intermediate			mass
No.	Structure	IUPAC	(g/mol)	LCMS, Found [M + H] +
B-3-1
2-(2- methylquinolin-6- yl)acetic acid	201.1	202.2

TABLE B-6 Exact

Intermediate			mass
No.	Structure	IUPAC	(g/mol)	LCMS, Found [M + H] +
B-6-1
N-methyl-N-(2- methylpyrimidin-4- yl)glycine	181.1	182.1

TABLE B-7 Exact

Intermediate			mass
No.	Structure	IUPAC	(g/mol)	LCMS, Found [M + H] +
B-7-1
(azetidine-1- carbonyl)glycine	158.1	159.1

TABLE B-9 Exact

Intermediate			mass
No.	Structure	IUPAC	(g/mol)	LCMS, Found [M + H] +
B-9-1
2-(1-methyl-5-oxo- 4,5-dihydro-1H- 1,2,4-triazol-3- yl)acetic acid	157.0	156.1 [M − H] −

TABLE B-10 Exact

Intermediate			mass
No.	Structure	IUPAC	(g/mol)	LCMS, Found [M + H] +
B-10-1
2-(4-(azetidin-1- yl)-1H-1,2,3- triazol-1-yl)acetic acid	182.1	183.2

TABLE B-11 Exact

Intermediate			mass
No.	Structure	IUPAC	(g/mol)	LCMS, Found [M + H] +
B-11-1
(2S,3RS,4RS)-N- ((S)-(5- cyclopropyl-6- fluoropyridin-2- yl)(phenyl)methyl)- 4-fluoro-3- hydroxypyrrolidine- 2-carboxamide	373.2	374.1

TABLE B-12 Exact

Intermediate			mass
No.	Structure	IUPAC	(g/mol)	LCMS, Found [M + H] +
B-12-1
(2S,4R)-1-acetyl-4- fluoropyrrolidine-2- carboxylic acid	175.1	176.0

TABLE 2

Compound	PK/LDH
No.	IC 50 (μM)
1	0.033
2	0.059
3	0.168
4	0.998
5	0.353
6	0.211
7	0.113
8	0.042
9	0.059
10	0.050
11	0.091
12	0.415
13	0.147
14	0.129
15	0.048
16	0.033
17	0.034
18	0.045
19	0.047
20	0.046
21	0.027
22	0.043
23	0.070
24	0.050
25	0.235
26	0.036
27	0.023
28	0.060
29	0.070
30	0.947
31	0.048
32	0.023
33	0.106
34	0.075
35	0.185
36	0.073
37	0.045
38	0.051
39	0.050
40	0.026
41	0.031
42	0.495
43	0.091
44	0.106
45	0.058
46	0.136
47	0.138
48	0.044
49	0.039
50	0.017
51	0.019
52	0.037
53	0.789
54	0.047
55	0.043
56	0.041
57	0.231
58	0.145
59	0.085
60	0.188
61	0.243
62	0.064
63	0.015
64	0.081
65	0.076
66	0.082
67	0.010
68	0.034
69	0.036
70	0.050
71	0.375
72	0.472
73	0.105
74	0.705
75	0.224
76	0.106
77	0.008
78	0.953
79	0.313
80	0.318
81	0.025
82	0.504
83	0.015
84	0.010
85	0.154
86	0.012
87	0.028
88	0.049
89	0.060
90	0.032
91	0.047
92	0.439
93	0.108
94	0.188
95	0.130
96	0.021
97	0.712
98	0.244
99	0.065
100	0.073
101	0.054
102	0.058
103	0.162
104	0.061
105	0.249
106	0.186
107	0.019
108	0.077
109	0.041
110	0.033
111	1.085
112	0.854
113	1.042
114	0.208
115	0.493
116	0.121
117	0.049
118	0.020
119	0.109
120	0.343
121	0.015
122	0.989
123	1.001
124	0.078
125	0.023
126	0.011
127	0.318
128	0.056
129	0.217
130	0.007
131	0.563
132	0.099
133	0.010
134	0.041
135	0.044
136	0.009
137	0.017
138	0.012
139	0.357
140	0.067
141	0.181
142	0.077
143	0.323
144	0.168
145	0.915
146	0.206
147	0.127
148	0.344
149	0.332
150	0.554
151	0.241
152	0.132
153	0.412
154	0.285
155	0.206
156	0.304
157	0.392
158	0.070
159	0.740
160	0.069
161	0.374
162	0.136
163	0.135
164	0.467
165	0.361
166	0.056
167	0.116
168	0.439
169	0.091
170	0.306
171	0.097
172	0.255
173	0.844
174	0.179
175	0.582
176	0.410
177	0.349
178	0.038
179	0.031
180	0.235
181	0.449
182	0.748
183	0.041
184	0.075
185	0.026
186	0.097
187	0.073
188	0.237
189	0.095
190	0.220
191	0.131
192	0.076
193	0.303
194	0.027
195	0.044
196	0.143
197	0.128
198	0.031
199	1.190
200	4.419
201	0.461
202	0.071
203	0.862
204	3.527
205	3.737
206	2.484
207	0.387
208	0.113
209	0.091
210	0.107
211	0.469
212	0.095
213	0.282
214	0.853
215	3.772
216	0.247
217	0.096
218	0.293
219	0.101
220	0.038
221	0.043
222	0.040
223	0.062
224	0.070
225	0.044
226	0.083
227	0.076
228	0.077
229	0.025
230	0.117
231	0.105
232	0.025
233	0.252
234	0.695
235	0.342
236	0.058
237	0.054
238	0.046
239	0.067
240	0.060
241	0.082
242	0.079
243	0.086
244	0.077
245	1.312
246	0.033
247	0.010
248	0.012
249	0.021
250	0.043
251	0.053
252	0.186
253	0.067
254	0.075
255	0.088
256	0.039
257	0.007
258	0.026
259	0.015
260	0.035
261	0.059
262	0.062
263	0.080
264	0.130
265	0.041
266	0.089
267	0.464
268	0.018
269	0.014
270	0.096
271	0.036
272	0.054
273	0.149
274	0.264
275	0.076
276	0.020
277	0.031
278	0.011
279	0.234
280	0.149
281	0.059
282	0.049
283	0.058
284	0.090
285	0.149
286	0.147
287	0.124
288	0.109
289	0.056
290	0.056
291	0.053
292	0.1109
293	0.038
294	0.006
295	0.013
296	0.087
297	0.015
298	0.012
299	0.022
300	0.028
301	0.046
302	0.067
303	0.036
304	0.073
305	0.024
306	0.078
307	0.010
308	0.011
309	0.055
310	0.075
311	0.127
312	0.097
313	0.039
314	0.063
315	0.023
316	0.037
317	0.017
318	0.020
319	0.007
320	0.197
321	0.124
322	0.013
323	0.074
324	0.142
325	0.075
326	0.020
327	0.121
328	0.016
329	0.336
330	0.021
331	0.023
332	0.025
333	0.165
334	0.145
335	0.037
336	0.015
337	0.027
338	0.034
339	0.018
340	0.018
341	0.780
342	0.034
343	0.027
344	0.013
345	0.032
346	0.024
347	0.030
348	0.024
349	0.025
350	0.020
351	0.008
352	0.005
353	0.007
354	0.005
355	0.018
356	0.013
357	0.021
358	0.011
359	0.063
360	0.019
361	0.010
362	0.090
363	0.019
364	0.080
365	0.007
366	0.020
367	0.016
368	0.005
369	0.537
370	0.569
371	0.343
372	0.036
373	0.014
374	0.022
375	0.006
376	0.008
377	0.012
378	0.006
379	0.008
380	0.047
381	0.058
382	0.034
383	0.027
384	0.033
385	0.017
386	0.005
387	0.005
388	0.005
389	0.004
390	0.027
391	0.006
392	0.005
393	0.008
394	0.007
395	0.008
396	0.013
397	0.009
398	0.009
399	0.008
400	0.012
401	0.010
402	0.059
403	0.004
404	0.006
405	0.020
406	0.041
407	0.015
408	0.008
409	0.010
410	0.008
411	0.010
412	0.007
413	0.006
414	0.003
415	0.048
416	0.025
417	0.023
418	0.697
419	2.190
420	3.563
421	0.294
422	0.166
423	0.350
424	0.287
425	0.224
426	0.363
427	0.165
428	0.374
429	0.114
430	0.191
431	0.221
432	0.185
433	0.091
434	0.109
435	0.149
436	0.173
437	0.157
438	0.303
439	0.185
440	0.447
441	0.051
442	0.023
443	0.028
444	0.044
445	0.075
446	0.098
447	0.096
448	0.071
449	0.039
450	0.094
451	0.095
452	0.040
453	0.077
454	0.072
455	0.291
456	0.055
457	0.032
458	0.071
459	0.028
460	0.187
461	0.026
462	0.024
463	0.025
464	0.023
465	0.547
466	0.238
467	0.324
468	0.091
469	0.061
470	0.082
471	0.029
472	0.022
473	0.100
474	0.043
475	0.077
476	0.039
477	0.020
478	0.069
479	0.055
480	0.079
481	0.247
482	0.068
483	0.049
484	0.066
485	0.210
486	0.041
487	0.068
488	0.031
489	0.353
490	0.052
491	0.093
492	0.138
493	0.103
494	0.661
495	0.066
496	0.086
497	0.369
498	>10
499	2.258
500	>100
501	0.003
502	0.01
503	0.008
504	0.003
505	0.02
506	0.004
507	0.022
508	0.021
509	0.008
510	0.009
511	0.012
512	0.015
513	0.014
514	0.007
515	0.004
516	0.008
517	0.008
518	1.498
519	0.008
520	0.557
521	2.606
522	0.005
523	0.005
524	0.006
525	0.004
526	0.011
527	0.007
528	0.015
529	0.016
530	0.012
531	0.008
532	0.065
533	0.043
534	0.057
535	0.012
536	0.024
537	0.011
538	0.048
539	0.068
540	0.047
541	0.055
542	0.011
543	0.049
544	0.011
545	1.68
546	0.027
547	0.016
548	0.328
549	0.006
550	0.042
551	0.007
552	0.082
553	0.008
554	0.034
555	0.097
556	0.027
557	0.424
558	0.136
559	1.58
560	0.144
561	0.036
562	0.685
563	0.063
564	0.056
565	0.048
566	0.046
567	0.642
568	0.089
569	0.066
570	0.082
571	0.075
572	0.205
573	0.178
574	0.022
575	0.119
576	0.085
577	0.478
578	0.613
579	0.059
580	0.249
581	0.269
582	0.319
583	0.105
584	0.104
585	0.202
586	0.010
587	0.109
588	0.036
589	0.101
590	2.553
591	0.032
592	0.01
593	0.019
594	0.05
595	0.025
596	0.02
597	0.064
598	0.153
599	0.04
600	0.036
601	0.034
602	0.092
603	0.602
604	0.176
605	0.168
606	1.125
607	0.333
608	2.856
609	0.225
610	0.107
611	0.547
612	2.182
613	0.130
614	1.149
615	1.578
616	1.324
617	1.644
618	1.515
619	1.157
620	0.142
621	0.555
622	0.443
623	0.111
624	0.408
625	0.139
626	0.805
627	1.618
628	2.778
629	1.483
630	0.092
631	0.176
632	0.013
633	1.598
634	0.043
635	0.082
636	0.071
637	0.453
638	0.399
639	0.921
640	1.445
641	2.95
642	1.333
643	2.185
644	0.273
645	0.1
646	0.048
647	1.643
648	0.616
649	0.483
650	1.436
651	0.077
652	1.203
653	0.262
654	0.252
655	1.008
656	1.301
657	0.127
658	0.099
659	0.331
660	0.309
661	0.043
662	0.227
663	2.022
664	0.115
665	0.099
666	2.273
667	0.023
668	0.025
669	0.04
670	0.071
671	0.849
672	0.082
673	1.74
674	0.096
675	0.101
676	0.554
677	0.051
678	1.065
679	0.577
680	0.015
681	0.03
682	0.116
683	2.362
684	1.332
685	0.204
686	0.013
687	3.82
688	0.106
689	>10.0
690	0.047
691	0.015
692	2.48
693	0.056
694	0.034
695	0.929
696	0.103
697	1.777
698	0.151
699	0.051
700	0.321
701	0.446
702	1.256
703	2.159
704	2.218
705	1.722
707	1.992
708	2.508
709	1.144
710	0.146
711	0.03
712	0.015
713	0.074
714	0.045
715	0.105
716	2.161
717	1.481
718	2.618
719	0.254
720	2.45
721	0.079
722	0.085
723	0.046
724	0.034
725	0.015
726	0.03
727	0.017
728	0.036
729	0.039
730	0.037
731	0.066
732	0.027
733	0.005
734	0.026
735	0.005
736	0.02
737	0.037
738	0.105
739	0.017
740	0.009
741	0.016
742	0.024
743	0.028
744	0.046
745	0.024
746	0.07
747	0.016
748	0.015
749	0.006
750	0.011
751	0.013
752	0.021
753	0.021
754	0.027
755	0.102
756	0.023
757	0.029
758	0.032
759	0.018
760	0.017
761	0.055
762	0.027
763	0.466
764	0.155
765	0.047
766	0.038
767	0.106
768	0.121
769	0.022
770	0.062
771	0.033
772	0.356
773	0.124
774	0.022
775	1.08
776	1.151
777	0.042
778	0.381
779	0.016
780	0.009
781	0.011
782	0.011
783	0.005
784	0.005
785	0.006
786	0.003
787	0.007
788	0.02
789	0.01
790	0.008
791	0.007
792	0.006
793	0.012
794	0.002
795	0.011
796	0.005
797	0.016
798	0.012
799	0.004
800	0.009
801	0.024
802	0.009
803	0.004
804	0.017
805	0.012
806	0.006
807	0.019
808	0.012
809	0.007
810	0.357

TABLE 3

Compound	Avg IC 50
No.	(μM)
1	0.42
2	1.09
17	0.33
21	0.47
49	0.36
77	0.12
126	0.17
136	0.17
138	0.27
145	>10.00
149	>10.00
166	0.78
177	2.09
178	0.41
179	0.4
183	0.93
184	3.03
198	0.39
201	3.7
202	1.86
219	1.41
227	1.31
236	0.81
239	1.56
240	2.09
241	1.14
242	1.14
243	2.25
244	1.8
246	0.62
247	0.18
248	0.2
249	1.15
250	1.27
252	2.48
253	1.09
254	1.23
255	1.01
256	0.99
257	0.24
258	0.74
259	0.28
260	0.53
261	1.8
262	3.63
263	1.95
264	4.29
265	0.83
266	1.22
267	4.3
268	0.83
269	0.24
270	1.4
271	0.87
272	0.71
273	1.79
274	3.23
275	1.05
276	0.4
277	0.65
278	0.23
279	2.31
280	1.53
281	1.56
282	4.18
283	2.4
284	5.19
285	>18.64
286	>30.00
287	11.81
293	0.66
294	0.16
295	0.59
296	4.44
297	0.7
298	0.26
299	0.42
300	0.57
301	0.9
302	1.23
303	1.52
304	2.33
305	0.63
306	0.81
307	0.5
308	0.33
309	0.97
310	1.29
311	2.1
312	0.83
313	0.86
314	1.01
315	0.73
316	0.93
317	0.39
318	0.58
319	0.24
320	1.59
321	1.24
322	0.29
323	0.9
326	0.34
330	0.56
332	0.27
335	0.45
336	0.28
338	0.39
339	0.31
340	0.25
342	0.37
343	0.46
347	0.4
348	0.27
349	0.4
351	0.13
352	0.11
353	0.09
354	0.06
355	0.16
356	0.19
357	0.22
358	0.19
359	0.96
360	0.31
361	0.21
362	1.15
363	0.32
364	0.48
365	1.19
367	0.47
368	0.15
369	>30.00
371	3.88
372	1.1
373	0.21
374	0.36
375	0.57
377	0.14
378	0.17
379	0.19
380	0.45
381	0.44
382	0.52
383	0.41
384	0.7
385	0.39
386	0.08
387	0.03
388	0.12
389	0.05
390	1.03
391	0.15
392	0.1
393	0.12
394	0.15
395	0.24
396	0.33
397	0.4
398	0.28
399	0.15
400	0.17
401	0.29
402	0.85
403	0.14
404	0.07
405	0.49
406	0.76
407	0.42
408	0.35
409	0.29
410	0.13
411	0.22
412	0.12
413	0.16
414	0.06
415	0.71
416	0.47
417	0.45
423	>9.26
425	3.59
427	1.96
431	3.35
433	1.48
442	0.86
445	1.66
446	2.19
447	5.32
448	1.35
449	0.7
450	1.73
451	1.57
452	0.98
453	1.84
454	1.6
455	3.62
456	1.08
457	0.72
458	1.33
459	0.75
460	2.42
461	0.57
462	0.64
463	0.67
464	0.65
465	6.04
466	2.32
467	4.81
468	1.43
469	1.18
470	0.96
471	0.7
472	0.54
473	1.77
474	0.88
475	1.29
476	0.9
477	0.63
478	1.19
479	1.43
480	1.12
481	7.77
482	1.41
483	0.72
484	0.82
485	3.72
486	1.02
487	2.09
488	0.88
490	2.87
491	5.55
492	>30.00
493	15.77
494	12.41
495	1.5
496	1.82
497	>5.67
498	>10.00
501	0.05
502	0.17
503	0.24
504	0.06
505	0.35
506	0.37
507	0.26
508	0.31
509	0.18
510	0.23
511	0.26
512	0.29
513	0.22
514	0.77
515	0.1
516	0.71
517	0.54
518	10.68
519	0.22
520	>30.00
521	>30.00
522	0.45
523	0.08
524	0.19
525	0.05
526	0.13
527	0.25
528	0.33
529	1.04
530	0.91
531	0.06
532	1.18
533	1.21
534	1.28
535	1.22
536	0.35
537	0.16
538	1.22
539	0.96
540	0.59
541	0.65
542	1.48
543	0.61
544	0.26
545	>30.00
546	0.51
547	0.36
548	5.76
549	0.12
550	0.65
551	0.21
552	1.12
553	0.4
554	0.38
555	0.66
556	0.76
557	5.78
558	2.46
559	>22.13
560	1.8
561	0.87
562	7.07
563	0.78
564	0.79
565	1.21
566	0.77
567	11.54
568	0.96
569	0.96
570	1.22
571	0.93
572	3.6
573	1.66
574	0.2
575	2.09
576	1.8
577	3.98
578	6.66
579	1.83
580	4.27
581	3.92
582	8.08
583	1.64
584	4.07
585	3.21
586	0.15
587	2.39
588	0.48
589	1.42
590	23.43
591	0.31
592	0.33
593	0.28
594	0.72
595	0.46
596	0.28
597	1.32
598	2.18
599	0.72
600	0.62
601	0.71
602	0.76
604	1.59
605	2.13
607	3.29
608	>10.00
609	1.65
610	1.01
611	5.32
612	>28.95
622	>10.00
623	4.07
624	5.79
625	1.14
626	>30.00
627	29.51
628	>30.00
629	>23.95
630	2.13
631	13.62
632	0.66
633	>30.00
638	>23.41
650	>10.00
651	1.57
652	21.64
653	3.75
654	3.29
655	>30.00
656	10.85
657	1.5
658	1.66
659	4.35
667	0.29
668	0.32
669	0.47
670	0.66
672	1.22
674	0.71
675	1.13
676	13.99
677	0.99
678	>10.00
679	8.49
680	0.27
681	0.43
682	2.09
683	>30.00
684	13.81
685	2.71
686	0.64
687	>30
690	0.9
691	0.39
692	>30.00
693	1.15
694	1.21
695	>26.28
696	2.71
697	9.2
710	2.34
711	0.63
712	0.33
713	0.86
714	1.39
716	22.26
717	>25.76
718	>30.00
719	2.22
720	>30.00
721	1.09
722	1.45
723	0.72
724	0.63
725	0.31
726	0.54
727	0.91
728	0.79
729	0.71
730	0.76
731	1.62
732	1.37
733	0.15
734	1.73
735	0.27
736	0.78
737	0.55
738	1.21
739	0.34
740	0.32
741	0.71
742	0.63
743	0.48
744	1.52
745	0.51
746	1.62
747	0.42
748	0.53
749	0.25
750	0.26
751	0.47
752	0.64
753	0.32
754	0.42
755	1.06
756	1.7
757	0.4
758	1.16
759	0.59
760	0.37
766	0.35
768	1.23
769	0.29
771	0.54
772	4.53
773	1.2
774	0.19
775	>17.54
776	>9.01
777	0.93
778	7.01
779	0.33
780	0.28
781	0.27
782	0.22
783	0.08
784	0.31
785	0.13
786	0.05
787	0.13
788	0.34
789	0.28
790	0.25
791	0.39
792	0.21
793	0.58
794	0.04
795	0.24
796	0.11
797	0.29
798	0.22
799	0.1
800	0.18
801	0.38
802	0.37
803	0.08
804	0.14
805	0.28
806	0.09
807	0.45
809	0.19
810	5.28

TABLE 4

Compound	Avg_IC50
No.	(μM)
1	>100.0
2	>100.0
3	>100.0
6	>100.0
7	>100.0
8	>100.0
9	>100.0
10	>100.0
11	>100.0
13	>100.0
14	>100.0
15	>100.0
16	>100.0
17	>100.0
18	>100.0
21	>100.0
22	>100.0
23	>100.0
24	>100.0
25	>100.0
26	>100.0
27	>100.0
28	>100.0
29	>100.0
31	>100.0
32	>100.0
33	>100.0
34	>100.0
35	>100.0
36	>100.0
37	>100.0
38	>100.0
40	>100.0
41	>100.0
44	>100.0
46	>100.0
48	>100.0
49	>100.0
50	>100.0
51	>100.0
52	>100.0
55	>100.0
56	>100.0
57	>100.0
58	>100.0
59	>100.0
60	>100.0
61	>100.0
62	>100.0
63	>100.0
64	>100.0
65	>100.0
67	>100.0
68	>100.0
69	>100.0
70	>100.0
73	>100.0
75	>100.0
76	>100.0
77	>100.0
81	>100.0
83	>100.0
84	>100.0
85	>100.0
86	>100.0
87	>100.0
88	>100.0
89	>100.0
90	>100.0
91	>100.0
93	>100.0
94	>100.0
95	>100.0
96	>100.0
98	>100.0
99	>100.0
100	>100.0
101	>100.0
102	>100.0
103	>100.0
104	>100.0
105	>100.0
106	>100.0
107	>100.0
108	>100.0
109	>100.0
110	>100.0
114	>100.0
117	>100.0
118	>100.0
119	>100.0
121	>100.0
125	>100.0
126	>100.0
128	>100.0
129	>100.0
130	>100.0
133	>100.0
134	>100.0
135	>100.0
136	>100.0
137	>100.0
138	>100.0
140	>100.0
141	>100.0
142	>100.0
144	>100.0
146	>100.0
147	>100.0
151	>100.0
154	>100.0
155	>100.0
158	>100.0
160	>100.0
162	>100.0
163	>100.0
166	>100.0
167	>100.0
169	>100.0
171	>100.0
172	>100.0
174	>100.0
178	>100.0
179	>100.0
180	>100.0
183	>100.0
184	>100.0
185	>100.0
187	>100.0
188	>100.0
189	>100.0
190	>100.0
191	>100.0
192	>100.0
193	>100.0
194	>100.0
195	>100.0
196	>100.0
197	>100.0
198	>100.0
202	>100.0
203	>100.0
204	>100.0
205	>100.0
206	>100.0
207	>100.0
208	>100.0
209	>100.0
210	>100.0
213	>100.0
214	>100.0
216	>100.0
217	>100.0
218	>100.0
219	>100.0
220	>100.0
221	>100.0
222	>100.0
223	>100.0
224	>100.0
226	>100.0
227	>100.0
228	>100.0
229	>100.0
231	>100.0
232	>100.0
233	>100.0
236	>100.0
237	>100.0
238	>100.0
239	>100.0
240	>100.0
241	>100.0
242	>100.0
243	>100.0
244	>100.0
245	>100.0
246	>100.0
247	>100.0
248	>100.0
249	>100.0
250	>100.0
251	>100.0
252	>100.0
253	>100.0
254	>100.0
255	>100.0
256	>100.0
257	>100.0
258	>100.0
259	>100.0
260	>100.0
261	>100.0
262	>100.0
263	>100.0
264	>100.0
265	>100.0
266	>100.0
268	>100.0
269	>100.0
270	>100.0
271	>100.0
272	>100.0
273	>100.0
274	>100.0
275	>100.0
276	>100.0
277	>100.0
278	>100.0
279	>100.0
280	>100.0
281	>100.0
282	>100.0
283	>100.0
284	>100.0
287	>100.0
288	>100.0
289	>100.0
290	>100.0
291	>100.0
292	>100.0
293	>100.0
294	>100.0
295	>100.0
296	>100.0
298	>100.0
299	>100.0
300	>100.0
301	>100.0
302	>100.0
303	>100.0
304	>100.0
306	>100.0
307	>100.0
308	>100.0
309	>100.0
310	>100.0
311	>100.0
312	>100.0
313	>100.0
314	>100.0
315	>100.0
316	>100.0
317	>100.0
318	>100.0
319	>100.0
320	>100.0
321	>100.0
322	>100.0
323	>100.0
324	>100.0
325	>100.0
326	>100.0
328	>100.0
330	>100.0
331	>100.0
332	>100.0
333	>100.0
334	>100.0
335	>100.0
336	>100.0
337	>100.0
338	>100.0
339	>100.0
340	>100.0
342	>100.0
343	>100.0
344	>100.0
345	>100.0
346	>100.0
347	>100.0
348	>100.0
349	>100.0
350	>100.0
351	>100.0
352	>100.0
353	>100.0
354	>100.0
355	>100.0
356	>100.0
357	>100.0
358	>100.0
359	>100.0
360	>100.0
361	>100.0
362	>100.0
363	>100.0
364	>100.0
365	>100.0
366	>100.0
367	>100.0
368	>82.29
369	>100.0
371	>100.0
372	>100.0
373	>100.0
374	>100.0
375	>77.43
376	>100.0
377	>100.0
378	>100.0
379	>100.0
380	>100.0
381	>100.0
382	>100.0
383	>100.0
384	>100.0
385	>100.0
386	>100.0
387	36.22
388	>100.0
389	>90.29
390	>100.0
391	89.32
392	>100.0
393	>100.0
394	>100.0
395	>100.0
396	>100.0
398	>100.0
399	>100.0
400	>100.0
401	>100.0
402	>100.0
403	>100.0
404	>100.0
405	>100.0
406	>100.0
407	>100.0
408	>100.0
409	>100.0
410	>100.0
411	>100.0
412	>100.0
413	>100.0
414	78.66
415	>100.0
416	>100.0
417	>100.0
418	>100.0
421	>100.0
422	>100.0
424	>100.0
425	>100.0
426	>100.0
427	>100.0
428	>100.0
430	>100.0
431	>100.0
432	>100.0
433	>100.0
434	>100.0
435	>100.0
436	>100.0
437	>100.0
439	>100.0
441	>100.0
442	>100.0
443	>100.0
444	>100.0
445	>100.0
446	>100.0
447	>100.0
448	>100.0
449	>100.0
450	>100.0
451	>100.0
452	>100.0
453	>100.0
454	>100.0
455	>100.0
456	>100.0
457	>100.0
458	>100.0
459	>100.0
462	>100.0
463	>100.0
464	>100.0
465	>100.0
466	>100.0
467	>100.0
468	>100.0
469	>100.0
470	>100.0
471	>100.0
472	>100.0
474	>100.0
475	>100.0
476	>100.0
477	>100.0
478	68.22
479	>100.0
480	>100.0
481	>100.0
482	>100.0
483	>100.0
484	>100.0
485	>100.0
486	>100.0
487	>100.0
488	>100.0
490	>100.0
491	>100.0
492	>100.0
495	>100.0
496	>100.0
497	>100.0
501	>100.0
502	>100.0
503	>100.0
504	>100.0
505	>100.0
506	>100.0
507	>100.0
508	>100.0
509	>100.0
510	>100.0
511	>100.0
512	>100.0
513	>100.0
514	>100.0
515	>100.0
516	>100.0
517	>100.0
518	>100.0
519	>100.0
520	>100.0
522	>100.0
532	>100.0
533	>100.0
534	>100.0
535	>100.0
536	>100.0
537	>100.0
538	>100.0
539	>100.0
540	>100.0
541	>100.0
542	>100.0
544	>100.0
546	>100.0
547	>100.0
548	>100.0
549	>100.0
550	>100.0
551	>100.0
552	>100.0
553	>100.0
554	>100.0
556	>100.0
558	>100.0
560	>100.0
561	>100.0
562	>100.0
563	>100.0
564	>100.0
565	>100.0
566	>100.0
567	>100.0
568	94.24
569	>100.0
570	>100.0
571	>100.0
572	>100.0
573	>100.0
574	>100.0
575	>100.0
576	>100.0
577	41.18
578	79.27
579	>100.0
580	>100.0
581	>100.0
582	>100.0
583	>100.0
584	>91.76
585	>100.0
586	>100.0
587	>100.0
588	>100.0
589	>100.0
590	>100.0
591	>100.0
592	>100.0
593	>100.0
594	>100.0
595	>100.0
596	>96.68
597	>100.0
599	>100.0
600	>100.0
602	>100.0
603	>100.0
604	>100.0
605	>100.0
607	>100.0
609	>100.0
611	>100.0
613	>100.0
620	>100.0
623	>100.0
625	>100.0
630	>100.0
631	>100.0
632	>100.0
639	>100.0
640	>100.0
642	>100.0
644	>100.0
645	>100.0
646	>100.0
651	>100.0
653	>100.0
659	17.53
660	>100.0
661	>100.0
662	>100.0
664	>100.0
665	>100.0
667	>100.0
668	>100.0
669	>100.0
670	>100.0
671	>100.0
672	>100.0
674	>100.0
675	>100.0
676	>100.0
677	>100.0
679	>100
680	93.0
681	>100.0
682	>100.0
685	>100.0
686	>100.0
690	>100.0
710	>100.0
711	>100.0
719	>100.0
722	>100.0
723	>100.0
724	>100.0
725	>100.0
726	>100.0
727	>100.0
728	>100.0
729	>100.0
731	>100.0
732	>100.0
733	>100.0
734	>100.0
735	>100.0
736	>100.0
765	>100.0
766	>100.0
767	>100.0
768	>100.0
769	>100.0
770	>100.0
771	>100.0
772	>100.0
773	>100.0
774	>100.0
777	>100.0
779	>100.0
780	>100.0
781	>100.0
782	>100.0
783	>100.0
784	>100.0
785	>100.0
786	>100.0
787	>100.0
788	>100.0
789	>100.0
790	>100.0
791	>100.0
792	>100.0
793	>100.0
794	>100.0
795	>100.0
809	>100.0
810	>100.0

TABLE 5

Phenotype	P-value	N
LVEF	0.871	27,716
LV Wall Thickness	0.168	27,579
Exercise Output	0.100	49,616
Max HR Exercise	0.444	49,603
QRS Duration	0.527	29,507
PQ Interval	0.366	16,694
QT Interval	0.222	17,574
Serum Glucose	0.477	294,042

TABLE 6 — Effect

Disease	(SE)	P-value	N Cases
Type 2 Diabetes	−0.094	0.200	18,868
	(0.073)
Liver Cirrhosis	−0.041	0.880	1,325
	(0.273)
Heart Failure	−0.061	0.630	6,117
	(0.127)

description truncated at 500,000 characters

Stored text is truncated at the source; the tail of the description is not held.

Claims as granted

36 claims

Classifications

16 codes

IPC · International Patent Classification

Section C — Chemistry; metallurgy

C07D498/10
C07D491/08
C07D491/048
C07D487/10
C07D487/04
C07D471/04
C07D417/06
C07D413/14
C07D413/06
C07D405/06
C07D403/06
C07D401/14
C07D401/12
C07D401/06
C07D207/16
C07D403/12

Claim changes

Soon

Coming soonHow the claims changed between publication and grant

See which claims were amended, added or cancelled during examination, with every added and removed word marked.

AmendedAddedCancelledUnchanged

The published claims of this application are not paired with the granted ones in what we hold.

File wrapper

⤢ drag to zoom

USPTOApplicanthover for detail · click to open

Pendency

2.4 y

872 days filing → grant

Office actions

none on record

Examiner

Sarah Pihonak

art unit 1627 · TC 1600

Law firm

Law firm · Log in to unlock

Citations: 196 back · 0 forward

See the full prosecution history — every USPTO and applicant action on this file, in order.

Documents

Log in to open the documents of this file: the application as filed, every office action and response, the notice of allowance.

Chain of title

No assignments have been recorded for this application yet.